Language：English  

DOI： 10.1038/s41440-024-02035-5

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-024-01927-w

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-024-01950-x

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-024-02026-6

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-024-01891-5

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-024-01811-7

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-024-01836-y

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-024-01750-3

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-024-01794-5

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-024-01746-z

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-024-01740-5

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-024-01744-1

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Given the significance of the intrauterine lipid environment in glucose metabolic homeostasis in offspring, the present study was undertaken to investigate the feasibility and efficacy of pemafibrate, a triglyceride-lowering peroxisome proliferator-activated agent, for maternal high-fat diet (HFD) intake-induced glucose metabolic dysfunction in offspring. A mouse model of HFD-induced gestational obesity was employed, and pemafibrate was orally administered from day 10 of gestation until delivery. The influences of maternal pemafibrate treatment on biological processes and toxicity were evaluated in both newborns and 12-week-old offspring. The findings of a dose-dependent decrease of β cell islet mass and of impairment of glucose tolerance and insulin sensitivity in offspring suggest that maternal pemafibrate intervention can prevent maternal HFD-intake-induced diabetes in offspring. Of particular interest in the prevention of future glucose metabolic dysfunction in offspring, low-dose maternal pemafibrate treatment (0.02 mg/kg/day) had sufficient efficacy and appeared to be safe in offspring. Therefore, pemafibrate may be a potential agent for the prevention of maternal high-fat exposure-induced diabetes in offspring. Abbreviations: CD, control diet; DEG, differentially expressed genes; GTT, glucose tolerance test; HFD, high-fat diet; ITT, insulin tolerance test; MC, 0.5w/v% methyl cellulose 400 solution; PPAR, triglyceride-lowering peroxisome proliferator-activated receptor; RNA-seq, RNA sequencing; TC, total cholesterol; TG, triglycerides.

DOI： 10.1016/j.bcp.2024.116454

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-024-01680-0

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-024-01646-2

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-024-01625-7

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background This research investigates the incidence, suspected causes, and diagnostic procedures for perioperative anaphylaxis (POA), a potentially severe complication, in secondary care hospitals across Japan. Methodology We surveyed Saiseikai hospitals and gathered data on surgical procedures, POA occurrences, potential triggers, and diagnostic methods. Results Among 70,523 surgeries, seven were associated with POA, resulting in an approximate incidence rate of 0.01%. Rocuronium was the most commonly suspected trigger, followed by sugammadex, latex, and angiography contrast agents. Despite the importance of skin tests as the most basic and crucial diagnostic method, they were conducted in only three instances. No in vitro tests for drug identification were conducted, and in four cases, the cause was determined merely based on the timing of drug administration, indicating significant diagnostic limitations. Conclusions The study underscores the critical situation in Japan regarding insufficient diagnostic practices and difficulties in identifying triggering drugs rather than the consistent prevalence of POA in secondary care facilities. The findings emphasize the need for improved diagnostic proficiency and more rigorous drug identification practices to ensure prompt and accurate POA diagnosis. It is essential to conduct further research and interventions to increase patient safety during the perioperative period in secondary care settings.

DOI： 10.7759/cureus.57555

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Background

The ATP2B1 gene encodes for a calcium pump, which plays a role in removing Ca2+ from cells and maintaining intracellular Ca2+ homeostasis. Reduction of the intracellular Ca2+ concentration in CD4+ T cells is thought to reduce the severity of colitis, while elevation of Ca2+ in CD4+ T cells induces T cell hyperactivity. Our aim was to clarify the role of ATP2B1 in CD4+ T cells and in inflammatory bowel disease development.

Methods

A murine CD4+ T cell–specific knockout (KO) of ATP2B1 was created using a Cre-loxP system. CD4+ T cells were isolated from thymus, spleen, and blood using fluorescence-activated cell sorting. To quantify messenger RNA levels, quantitative real-time polymerase chain reaction was performed.

Results

Although the percentages of CD4+ T cells in both KO mouse spleen and blood decreased compared with those of the control samples, both T-bet (a T helper 1 [Th1] activity marker) and GATA3 (a Th2 activity marker) expression levels were further increased in KO mouse blood CD4+ T cells (vs control blood). Diarrhea and colonic wall thickening (with mucosal changes, including crypt distortion) were seen in KO mice but not in control mice. Prior to diarrhea onset, the KO mouse colon length was already noted to be shorter, and the KO mouse stool water and lipid content were higher than that of the control mice. Tumor necrosis factor α and gp91 expressions were increased in KO mouse colon.

Conclusions

Lack of ATP2B1 in CD4+ T cells leads to Th1 and Th2 activation, which contributes to colitis via elevation of tumor necrosis factor α and oxidative stress.

DOI： 10.1093/ibd/izae045

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Hypertension, a disease whose prevalence increases with age, induces pathological conditions of ischemic vascular disorders such as cerebral infarction and myocardial infarction due to accelerated arteriosclerosis and circulatory insufficiency of small arteries and sometimes causes hemorrhagic conditions such as cerebral hemorrhage and ruptured aortic aneurysm. On the other hand, as it is said that aging starts with the blood vessels, impaired blood flow associated with vascular aging is the basis for the development of many pathological conditions, and ischemic changes in target organs associated with vascular disorders result in tissue dysfunction and degeneration, inducing organ hypofunction and dysfunction. Therefore, we hypothesized that hypertension is associated with all age-related vascular diseases, and attempted to review the relationship between hypertension and diseases for which a relationship has not been previously well reported. Following our review, we hope that a collaborative effort to unravel age-related diseases from the perspective of hypertension will be undertaken together with experts in various specialties regarding the relationship of hypertension to all pathological conditions.

DOI： 10.1038/s41440-024-01642-6

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Thirty-year % increase of adults with hypertension in the European/ Americas and South-East Asia/ Western Pacific (WHO region). Create using the data from: World Health Organization. Global report on hypertension: the race against a silent killer. Geneva, Switzerland: 2023.

DOI： 10.1038/s41440-024-01622-w

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01578-3

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Aim: Given its excellent capability of escaping from unavoidable harm and death, Turritopsis sp. (T. sp.) has captured the attention and fascination of scientists as a less conventional tool for aging research. The current study introduces a method for establishment of a research model and comprehensive transcriptomic analysis to reveal the structural and functional diversity of T. sp. Methods: T. sp. medusae collected from the Pacific Ocean near Japan were reared using a common laboratory setting. Tissues of the gastrovascular cavity part (GP) and nerve ring part (NP) were collected, and total RNA was extracted. Bulk RNA-seq was performed to compare the different transcriptome landscapes between GP and NP. Results: The GP fragment could be utilized for studies related to stress response and systemic senescence, while the NP fragment could be used to explore system rejuvenation, self-repair and regeneration. Conclusions: As a less conventional system for aging research, by employing the most recently developed tools and techniques in the genomic revolution, comprehensive elucidation of the composition, development, and functions of T. sp. enabled us to explore the underlying mechanisms of the response to environmental stress and rejuvenation.

DOI： 10.1016/j.bbrep.2023.101613

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01532-3

Scopus

PubMed

researchmap

Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01548-9

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Introduction: With the aim of optimizing the balance of maintaining a safe oxygen saturation and reducing the risk of retinopathy of prematurity in human neonates with fetal growth restriction (FGR), the present study investigated the distinct effects of oxygen supplementation on the retinal neovasculature using a murine premature neonatal oxygen-induced retinopathy (OIR) model with or without fetal growth restriction. Methods: For comparison with normal birth-weight neonates, maternal low-protein diet-induced FGR neonates were subjected to fluctuating oxygen levels to generate oxygen-induced retinopathy. The retinal neovasculature was histologically evaluated, and comprehensive transcriptome analysis was conducted. Results: Compared to OIR neonates with normal birth weight, significant amelioration of the neovasculature, as indicated by decreases in the number of branch junctions, vascular distribution, maximal vascular radius and microaneurysm-like tufts, was observed in OIR mice with FGR. The results of retinal RNA-sequencing revealed downregulation of angiogenic factors that trigger pathological retinal neovascularization, such as the mitogen-activated protein kinase pathway and corresponding upstream signaling pathways in OIR mice with FGR. Conclusion: Our findings demonstrated that FGR neonates have a higher capacity for retinal oxygen stress, and the risk of OIR development is attenuated compared to that in mature neonates with normal birth weight.

DOI： 10.3389/fcell.2024.1288212

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The diagnosis of vasculitis in rheumatoid arthritis (RV) is associated with considerable mortality; therefore, understanding the basic mechanisms underlying the pathogenesis of vasculitis is very important. Animal models of vasculitis have contributed to elucidating such mechanisms. We here introduce a Candida albicans water-soluble glycoprotein (CAWS)-induced vasculitis model and the methodological approach to evaluate inflammatory vascular change.

DOI： 10.1007/978-1-0716-3682-4_28

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

To protect subjects who participate in human research, Institutional Review Boards (IRBs) play an important role in reviewing research and determining the validity of a study by comprehensively examining it for ethical issues, including invasiveness and management of personal information. They conduct regular and independent reviews to protect the health, rights, and welfare of research subjects. When we as researchers conduct clinical research, we must obtain IRB approval and submit our research for investigation of ethical issues before we begin.

DOI： 10.1007/978-1-0716-3682-4_31

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

[Figure not available: see fulltext.]

DOI： 10.1038/s41440-023-01471-z

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Aims: The activity and interactions of cellular subpopulations in the adipose tissue microenvironment are critical for the coordination of local and systemic adaptation during pregnancy. With a particular interest in parametrial adipose tissue (PmAT), single-cell RNA-sequencing (scRNA-seq) was utilized to unveil the gestative cellular composition and functional shift. Materials and methods: To identify cell-type-enriched transcriptome profiles, a total of 18,074 cells in adipose tissue were studied. The cell populations were cataloged, and signaling crosstalk between adipocytes and other composition factions via soluble and membrane-bound factors were evaluated. Key findings: A marked decline of pregnancy adipocytes and relative elevation of non-adipocyte fractions were observed. A subpopulation of adipocytes, Adipo_5, with unique properties in the response to estrogen and the embryonic processes involved in pregnancy, was defined. Interactome analysis revealed the potential contribution of PmAT to the establishment of maternal-fetal immune tolerance. During gestation, adipocytes shut down outgoing signaling, resulting in deterioration of the resistin-related incoming signaling network in B cells, which would therefore benefit tissue-specific maternal-fetal tolerance. Furthermore, a subpopulation of adipocytes, Aipo_2, was also considered to take part in a paradigm shift in the process of pregnancy-induced chemical stiffness-triggered vesicular remodeling via the THBS signaling pathway network. Significance: These data-derived findings will encourage investigation into the role of pregnant PmTA in pregnancy-related immunological, hypertensive and metabolic disorders, with the ultimate goal of establishing preventive strategies to mitigate these pregnancy-related health challenges. This translational aspect of our work holds significant promise for improving maternal and fetal well-being.

DOI： 10.1016/j.lfs.2023.122214

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01411-x

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

With the aim of offsetting immune dysfunction preceded by sarcopenia, the feasibility and efficiency of nutritional leucine supplementation were evaluated using a murine denervation-induced sarcopenia model. Sciatic nerve axotomy caused significant loss of skeletal muscle of the hind limbs and accelerated mitochondrial stress along with suppressed ATP production in spleen-derived T cells. Dietary leucine intake not only ameliorated muscle mass anabolism in a sarcopenic state, but also restored mitochondrial respiratory function, as indicated by elevated levels of basal respiration, maximal respiration, spare respiratory capacity, and ATP production, in T cells, which in turn led to downregulated expression of mTOR and downstream signals, as indicated by the findings of comprehensive transcriptome analysis. Consequentially, this finally resulted in amelioration of the sarcopenia-induced relative Th1/Th17-dominant proinflammatory microenvironment. These results highlight the importance of leucine-promoted metabolic cues in directing T cell fate in a sarcopenic microenvironment. The present study provides insights that particularly help rationalize the design and optimization of leucine supplementation for chronic sarcopenic patients with autoimmune diseases.

DOI： 10.1016/j.jnutbio.2023.109508

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01376-x

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01378-9

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Total 276 manuscripts were published in Hypertension Research in 2022. Here our editorial members picked up the excellent papers, summarized the current topics from the published papers and discussed future perspectives in the sixteen fields. We hope you enjoy our special feature, 2023 update and perspectives in Hypertension Research.

DOI： 10.1038/s41440-023-01398-5

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01356-1

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Tight junction disruption and dysfunction are involved in the progression of blood-brain barrier (BBB) breakdown. Recent investigations have revealed BBB disruption in patients with vascular cognitive decline. Our previous studies showed that miR-501-3p negatively regulates cerebral endothelial tight junction protein-1, resulting in the disruption of the BBB, and playing an important role in the development of vascular cognitive impairment. BBB breakdown in white matter lesions is often seen in the patients with vascular mild cognitive impairment (MCI). We therefore hypothesize that most early-phase MCI patients may demonstrate elevated expression of miR-501-3p and sought to investigate whether serum exosome miR-501-3p levels could be a clinical indicator for detecting mild cognitive impairment. One hundred and seventy-eight subjects (aged 73 [68-75] years, 53% male) were recruited for this study. The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was used for detecting MCI. Serum exosome miR-501-3p expression levels were measured by qPCR methods. Patients were divided into two groups depending on whether their miR-501-3p ∆Ct values were above ("High"; n = 74) or below ("Low"; n = 104) cutoff levels determined by ROC curve. MCI was detected significantly more often in the miR-501-3p-High group (vs. -Low group, 63.5% vs. 47.1%, respectively; p < 0.05). Multivariate logistic regression analysis showed a significant association between MCI status and High miR-501-3p (odds ratio 2.662; p < 0.01), improved vs. known risk factors. In non-diabetic patients, High miR-501-3p was positively associated with MCI status (odds ratio 3.633; p < 0.01) and also positively associated with MCI status in those with atherosclerosis (odds ratio 3.219; p < 0.01). The present study demonstrates that elevated expression of blood exosomal miR-501-3p can indicate the presence of MCI in human patients. Early detection of vascular injuries may allow a reduction in progressive dementia through the management of vascular risk factors.

DOI： 10.1111/jnc.15911

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01339-2

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01337-4

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01319-6

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01285-z

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01296-w

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01256-4

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Angiotensin converting enzyme 2 (ACE2) functions as an enzyme that produces angiotensin 1-7 (A1-7) from angiotensin II (AII) in the renin-angiotensin system (RAS). We evaluated aging phenotypes, especially skeletal muscle aging, in ACE2 systemically deficient (ACE2 KO) mice and found that ACE2 has an antiaging function. The characteristic aging phenotype observed in ACE2 KO mice was not reproduced in mice deficient in the A1-7 receptor Mas or in Tsukuba hypertensive mice, a model of chronic AII overproduction, suggesting that ACE2 has a RAS-independent antiaging function. In this review, the results we have obtained and related studies on the aging regulatory mechanism mediated by RAS components will be presented and summarized. We evaluated the aging phenotype of ACE2 systemically deficient (ACE2 KO) mice, particularly skeletal muscle aging, and found that ACE2 has an antiaging function. The characteristic aging phenotype observed in ACE2 KO mice was not reproduced in Mas KO mice, angiotensin 1-7 receptor-deficient mice or in Tsukuba hypertensive mice, a model of chronic angiotensin II overproduction, suggesting that the antiaging functions of ACE2 are independent of the renin-angiotensin system (RAS).

DOI： 10.1038/s41440-023-01189-y

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-023-01264-4

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-023-01235-9

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-023-01295-x

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01280-4

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01213-1

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Frailty attracts research as it represents a significant target for intervention to extend the healthy life span. An unanswered question in this field is the time point during the life-course at which an individual becomes predisposed to frailty. Here, we propose that frailty has a fetal origin and should be regarded as part of the spectrum of the developmental origins of health and disease. The developmental origins of health and disease theory originated from findings linking the fetal environment to lifestyle-related disorders such as hypertension and diabetes. Coincidentally, a recent trend in frailty research also centers on vascular dysfunction and metabolic alterations as the causality of lifestyle-related disorders such as sarcopenia and dementia. Here, we explore the relationship between fetal programming, frailty-related disorders (sarcopenia and dementia), and other age-related diseases mainly based on reports on intrauterine growth restriction. We propose a "total" life-course approach to combat frailty. With this viewpoint, not only physicians and gerontologists but also obstetricians and pediatricians should team up to overcome age-related diseases in the elderly. Geriatr Gerontol Int 2023; 23: 263-269.

DOI： 10.1111/ggi.14565

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-023-01172-7

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-022-01153-2

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-023-01174-5

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Molecular hydrogen is not only expected to be used as an energy-generating resource, but also to have preventive effects on a variety of clinical manifestations related to oxidative stress through scavenging radicals or regulating gene expression. In the current study, we investigated the influence of intermittent environmental exposure to hydrogen gas at a safe concentration (1.3%) on photoaging using an ultraviolet A (UVA)-irradiated murine model. METHODS: To mimic the expected human daily activity cycle, UVA exposure in the daytime and hydrogen exposure in the night-time, an original design, UVA-transmission, hydrogen-exposure system was established. Mice were bred under experimental conditions of UVA irradiation and normal air for 8 h (outdoor time 09.00-17.00 hours), and UVA non-irradiation and inhalation of hydrogen gas for 16 h (indoor time 17.00-09.00 hours), and the daily cycle was continued for up to 6 weeks. The progression of photoaging, including morphological changes, collagen degradation and UVA-related DNA damage, was evaluated. RESULTS: Intermittent administration of hydrogen gas by our system prevented UVA-induced epidermal signs, such as hyperplasia, melanogenesis and appearance of senescence cells, and UVA-induced dermal signs, such as collagen degradation. In addition, we detected attenuation of DNA damage in the hydrogen exposure group as indirect evidence that intermittent exposure to hydrogen gas reduced oxidative stress. CONCLUSIONS: Our findings support the notion that long-term, intermittent environmental exposure to hydrogen gas in daily life has a beneficial effect on UVA-induced photoaging. Geriatr Gerontol Int 2023; ••: ••-••.

DOI： 10.1111/ggi.14562

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-01122-9

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-01090-0

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-01108-7

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-022-01109-6

Scopus

PubMed

researchmap

Publishing type：Part of collection (book)   Publisher：Springer International Publishing  

DOI： 10.1007/16833_2022_108

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

The coronavirus disease 2019 (COVID-19) affects infected patients even after the acute phase and impairs their health and quality of life by causing a wide variety of symptoms, referred to as long COVID. Although the evidence is still insufficient, hypertension is suspected to be a potential risk factor for long COVID, and the occurrence of cardiovascular diseases seems to be a key facet of multiple conditions observed in long COVID. Nonetheless, there are few reports that comprehensively review the impacts of long COVID on hypertension and related disorders. As a sequel to our previous report in 2020 which reviewed the association of COVID-19 and hypertension, we summarize the possible influences of long COVID on hypertension-related organs, including the cardiovascular system, kidney, and endocrine system, as well as the pathophysiological mechanisms associated with the disorders in this review. Given that the clinical course of COVID-19 is highly affected by age and sex, we also review the impacts of these factors on long COVID. Lastly, we discuss areas of uncertainty and future directions, which may lead to better understanding and improved prognosis of clinical problems associated with COVID-19. [Figure not available: see fulltext.]

DOI： 10.1038/s41440-022-01145-2

Scopus

PubMed

researchmap

Other Link： https://www.nature.com/articles/s41440-022-01145-2

Language：English   Publisher：Springer Science and Business Media LLC  

The coronavirus disease 2019 (COVID-19) affects infected patients even after the acute phase and impairs their health and quality of life by causing a wide variety of symptoms, referred to as long COVID. Although the evidence is still insufficient, hypertension is suspected to be a potential risk factor for long COVID, and the occurrence of cardiovascular diseases seems to be a key facet of multiple conditions observed in long COVID. Nonetheless, there are few reports that comprehensively review the impacts of long COVID on hypertension and related disorders. As a sequel to our previous report in 2020 which reviewed the association of COVID-19 and hypertension, we summarize the possible influences of long COVID on hypertension-related organs, including the cardiovascular system, kidney, and endocrine system, as well as the pathophysiological mechanisms associated with the disorders in this review. Given that the clinical course of COVID-19 is highly affected by age and sex, we also review the impacts of these factors on long COVID. Lastly, we discuss areas of uncertainty and future directions, which may lead to better understanding and improved prognosis of clinical problems associated with COVID-19.

DOI： 10.1038/s41440-022-01134-5

Scopus

PubMed

researchmap

Other Link： https://www.nature.com/articles/s41440-022-01134-5

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-01072-2

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.immuno.2022.100018

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-01050-8

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-022-01021-z

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-01026-8

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Aiming at complete excision of cholesteatoma during trympanomastoidectomy and therefore reducing the risk of recurrence, intraoperative imaging techniques are required to assist the visualization of cholesteatoma residue. Galectin-7 has been demonstrated to be a biomarker for cholesteatoma matrix and used for intraoperatively identifying the excision margins. METHODS: A galectin-7-targeted DNA-aptamer library was generated for labeling the cholesteatoma matrix using cell-systematic evolution of ligands by an exponential enrichment technique. The binding characteristics of the identified aptamers were analyzed, and structure optimization of the identified aptamers was carried out both in silico and in vitro. FINDINGS: A fluorophore-labeled structure-optimized DNA fragment was commercially synthesized as a non-invasive aptamer-based probe for intraoperative lesion detection. Using galectin-7-aptamer-guided molecular imaging, the excision margins of cholesteatoma matrix and surrounding normal tissue were successfully achieved within 15-20 min. CONCLUSIONS: Galectin-7-targeted aptamers could benefit molecular imaging-guided surgical treatment, which would enable clinicians to not only intraoperatively detect the locations of cholesteatoma matrix in the middle ear, but also assess the postoperative response of the expression profile to therapy. It is highly expected that further efforts for rational design and development should be directed towards the development of clinically translatable aptamer-based imaging agents.

DOI： 10.1016/j.jphs.2022.08.002

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-00998-x

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

[Image: see text]

DOI： 10.1038/s41440-022-00997-y

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The pulmonary pathological findings associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result from the release of multiple proinflammatory cytokines, which causes the subsequential damage of the lungs. The current study was undertaken to investigate the responses of mast cells to viral inoculation and their contribution to host defenses from the point of view of viral entry. Pseudovirions, in which the spike glycoprotein of SARS-CoV-2 was incorporated, triggered activation of mast cells, and a mast cell-derived chymase, MCP2, formed a complex with spike protein, which promoted protease-dependent viral entry. According to the quantification results of viral entry, 10 μM quercetin, a mast cell stabilizer, potentially potently inhibited 41.3% of viral entry, while 100 μM chymostatin, which served as a chymase inhibitor, suppressed 52.1% of viral entry, compared to non-treated cells. Study using mast cell-deficient mice showed that the absence of mast cells may influence early viral loading in the upper respiratory tract, which consequently increases the risk of viral invasion into the lower respiratory system. Furthermore, mast cell-deficient mice exhibited ongoing infection in the late phase post-viral inoculation, while clearance of virus-positive cells was observed in wild-type mice. In conclusion, mast cells act as a multifaceted immune modulator that is equipped with both protective effects and pathogenic influences on viral entry of SARS-CoV-2. The utility of mast cell stabilizers and chymase inhibitors in the treatment of SARS-CoV-2-induced acute respiratory syndrome should be optimized regarding the infection stage and the risk of cytokine storm.

DOI： 10.1016/j.ejphar.2022.175169

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-00974-5

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-00964-7

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

In 2021, 217 excellent manuscripts were published in Hypertension Research. Editorial teams greatly appreciate the authors' contribution to hypertension research progress. Here, our editorial members have summarized twelve topics from published work and discussed current topics in depth. We hope you enjoy our special feature, "Update on Hypertension Research in 2021".

DOI： 10.1038/s41440-022-00967-4

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-00941-0

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

BACKGROUNDS: Many factors are involved in cellular aging, and senescence induction requires complex regulation of various signaling networks and processes. Specifically, in the area of aging-related vascular cognitive impairment, laboratory-based findings have not yet yielded agents of practical use for clinical settings. One possible reason is that the physiologic elements of aging have been insufficiently considered. We sought to establish techniques to better model cellular aging using modulation of microRNAs, aiming to identify key microRNAs capable of fine-tuning aging-associated genes, and thereby regulating the senescence of vascular endothelial cells. METHODS: We utilized expression microRNA arrays to evaluate control and senescent vascular endothelial cells in order to identify testable candidates. Bioinformatic analysis was used to select key microRNAs. These candidates were then modulated in vitro using microRNA mimics and inhibitors in endothelial cells, and senescence-associated gene expression patterns were evaluated by qPCR. RESULTS: Seventeen microRNAs were found to be significantly increased more than 2-fold in senescent cells. Of those, bioinformatic analysis concluded that miR-181a-5p, miR-30a-5p, miR-30a-3p, miR-100-5p, miR-21-5p, and miR-382-5p were likely associated with regulation of cellular senescence. We evaluated the potential targets of these six microRNAs by comparing them with cell-cycling and apoptosis-related genes from published mRNA transcriptional array data from aged tissues, and found that miR-181a-5p, miR-30a-5p and miR-30a-3p were enriched in overlapping targets compared with the other candidates. Modulation of these microRNAs in vascular endothelial cells revealed that over-expression of miR-30a-5p, and inhibition of both miR-30a-3p and miR-181a-5p, induced senescence. CONCLUSION: miR-181a-5p, miR-30a-5p and miR-30a-3p likely contribute to aging-associated vascular endothelial cell senescence.

DOI： 10.1016/j.bbrep.2022.101281

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-00915-2

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The long-term effect of changes in maternal dietary composition during pregnancy on the offspring's metabolic homeostasis is uncertain. We aimed to investigate the long-term effects of maternal balanced low-fat interventions on metabolic homeostasis of the offspring using a mouse model of gestational obesity induced by a high-fat diet (HFD). Male newborns in the balanced low-fat intervention group had significantly lower serum insulin and higher serum adiponectin levels than those in the HFD group. Changes in maternal dietary composition improved glucose tolerance in pups at 3 and 12 weeks of age. We also performed transcriptomic analysis of the liver in neonatal and 3-week-old pups. Genes in the peroxisome proliferator-activated receptor signaling pathway were significantly down-regulated in neonates in the balanced low-fat intervention group compared with the HFD group. A maternal balanced low-fat diet fully compensated for the detrimental effects of a maternal HFD on glucose metabolism, insulin tolerance, circulating insulin, dyslipidemia, and body weight gain in male offspring by changing the gene expression profile. These data suggest that maternal balanced low-fat intervention is critical for improving the metabolic health of future generations.

DOI： 10.1016/j.jnutbio.2022.108971

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Diabetes confers a high risk of developing poor health in later life in women. Based on the Developmental Origins of Health and Disease theory, the present study was undertaken to investigate the efficacy of perinatal fat restriction in maternal high-fat-exposed female offspring to maintain glucose homeostasis in later life between adulthood and aging. METHODS: Low-fat dietary intervention during either gestation or lactation was performed using a high-fat diet-induced maternal obesity mouse model (HFD mice). Physiological metabolic parameters, including body weight and serum levels of total cholesterol and triglycerides, were monitored. Glucose tolerance test and insulin sensitivity test were performed in 12- and 70-week-old offspring. Insulin-positive islet cells were also observed using immunohistochemical staining. RESULTS: HFD significantly induced abnormal weight gain, hyperlipidemia and impairment of both glucose tolerance and insulin sensitivity in offspring. Standard diet intake after weaning improved weight gain, serum total cholesterol level and glucose tolerance, but not insulin sensitivity, in 70-week-old offspring. Only perinatal fat restriction during both gestation and lactation, followed by standard food intake for the rest of their life, provided adequate efficacy to restore insulin sensitivity in aging female progeny. CONCLUSIONS: Perinatal low-fat intervention may prevent deterioration of glucose metabolism. To improve the health status over a female's lifespan, appropriate nutritional intervention during the early developmental stage may reset the disease trajectory and prevent the onset and development of diabetes. Geriatr Gerontol Int 2022; 22: 441-448.

DOI： 10.1111/ggi.14378

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-022-00878-4

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-00894-4

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Aldosterone (Aldo) breakthrough is a well-known phenomenon that occurs in patients with long-term renin-angiotensin aldosterone system (RAAS) blockade using inhibitors of renin or angiotensin converting enzyme or angiotensin II type 1 receptor blockers. The blockade of the mineralocorticoid receptor (MR), an Aldo binding receptor, is effective in managing patients with resistant hypertension, defined as uncontrollable blood pressure despite the concurrent use of three antihypertensive drugs. In other words, MR inhibitors are not used as first-line antihypertensive drugs in most guidelines for hypertension management. Aldo breakthrough puts hypertensive patients at higher risk of cardiovascular disease and worsens future outcomes. This review discusses Aldo secretion and the mechanism of Aldo breakthrough, dependent or independent of the RAAS, with consideration of the pharmacological aspects of this phenomenon, as well as hypothetical views.

DOI： 10.1038/s41440-022-00913-4

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-00871-x

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-022-00869-5

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Despite the challenges associated with the coronavirus pandemic, the last 2 years have been active periods for hypertension research and initiatives in Asia. There are new hypertension guidelines from the World Health Organization that can be interpreted and applied locally. This is also the case for data from the latest Blood Pressure Lowering Treatment Trialists' Collaboration meta-analysis, which showed that greater reductions in systolic blood pressure (BP) are associated with lower risks of cardiovascular events. The randomized controlled Strategy of Blood Pressure Intervention in the Elderly Hypertensive study and the Salt Substitute and Stroke Study provide local data to inform practice. Other initiatives to help reduce high salt intake in Asia are also underway. Both drug-resistant and nocturnal hypertension are appropriate areas of focus in Asia, and there are an increasing number of pharmacological and non-pharmacological treatment options for these conditions. Digital therapeutics to promote uptake and implementation of lifestyle interventions are showing promise, and other digital-based strategies such as telemedicine, wearable BP monitors to detect beat-by-beat BP and artificial intelligence will no doubt become integral parts of future strategies to reduce the burden of hypertension and hypertension-related disease. A number of initiatives from the Hypertension Cardiovascular Outcome Prevention and Evidence in Asia Network and Japanese Society of hypertension are underway, and there is good reason for optimism regarding the ongoing and future management of hypertension in Asia based on these and the active research activities in the region.

DOI： 10.1038/s41440-022-00874-8

Scopus

PubMed

researchmap

Language：English   Publisher：(一社)日本内分泌学会  

researchmap

Language：English  

DOI： 10.1038/s41440-021-00830-y

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-021-00813-z

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-021-00789-w

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-021-00790-3

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

In 2020, 199 papers were published in Hypertension Research. Many excellent papers have contributed to progress in research on hypertension. Here, our editorial members have summarized eleven topics from published work and discussed current topics in depth. We hope you enjoy our special feature, Annual Reports on Hypertension Research.

DOI： 10.1038/s41440-021-00766-3

Scopus

PubMed

researchmap

Language：Japanese   Publisher：Japanese Pharmacological Society  

Aiming at complete excision of cholesteatoma during trympanomastoidectomy and therefore reducing the risk of recurrence, the current study was undertaken to develop a seed DNA-aptamer-based fluorophore-probe, which targets human galectin-7, as an intraoperative lesion-identifying indicator for the surgical treatment of cholesteatoma. A galectin-7-targeted DNA-aptamer library was generated for labeling the cholesteatoma matrix using cell-based systematic evolution of ligands by an exponential enrichment technique. The binding characteristics of the identified aptamers were analyzed, and structure optimization of the identified aptamers was carried out both in silico and in vitro. Using galectin-7-aptamer guided molecular imaging, the excision margins of cholesteatoma matrix and surrounding normal tissue were successfully observed in a xenografted cholesteatoma model. It is highly expected that specific galectin-7-aptamers could progress to future clinical trials for both imaging and therapeutic applications and therefore benefit cholesteatoma patients.

DOI： 10.1254/jpssuppl.96.0_2-b-p-169

CiNii Research

researchmap

Language：English  

DOI： 10.1038/s41440-021-00721-2

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin-(1-7), respectively, is the primary process that counteracts activation of the canonical renin-angiotensin system (RAS). Although inhibition of canonical RAS could delay the progression of physiological aging, we recently reported that deletion of Mas had no impact on the aging process in mice. Here, we used male mice with a deletion of only AT2 or a double deletion of AT2 and Mas to clarify whether these receptors contribute to the aging process in a complementary manner, primarily by focusing on aging-related muscle weakness. Methods and Results Serial changes in grip strength of these mice up to 24 months of age showed that AT2/Mas knockout mice, but not AT2 knockout mice, had significantly weaker grip strength than wild-type mice from the age of 18 months. AT2/Mas knockout mice exhibited larger sizes, but smaller numbers and increased frequency of central nucleation (a marker of aged muscle) of single skeletal muscle fibers than AT2 knockout mice. Canonical RAS-associated genes, inflammation-associated genes, and senescence-associated genes were highly expressed in skeletal muscles of AT2/Mas knockout mice. Muscle angiotensin II content increased in AT2/Mas knockout mice. Conclusions Double deletion of AT2 and Mas in mice exaggerated aging-associated muscle weakness, accompanied by signatures of activated RAS, inflammation, and aging in skeletal muscles. Because aging-associated phenotypes were absent in single deletions of the receptors, AT2 and Mas could complement each other in preventing local activation of RAS during aging.

DOI： 10.1161/JAHA.120.021030

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-021-00676-4

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1016/j.bja.2021.04.009

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Dietary palmitic acid (PA) promotes liver fibrosis in patients with nonalcoholic steatohepatitis (NASH). Herein, we clarified the intestinal absorption kinetics of dietary PA and effect of trans-portal PA on the activation of hepatic stellate cells (HSCs) involved in liver fibrosis in NASH. Blood PA levels after meals were significantly increased in patients with NASH compared to those in the control. Expression of genes associated with fat absorption and chylomicron formation, such as CD36 and MTP, was significantly increased in the intestine of NASH model rats compared with that in the controls. Plasma levels of glucagon-like peptide-2, involved in the upregulation of CD36 expression, were elevated in NASH rats compared with those in the controls. Furthermore, portal PA levels after meals in NASH rats were significantly higher than those in control and nonalcoholic fatty liver rats. Moreover, PA injection into the portal vein to the liver in control rats increased the mRNA levels associated with the activation of HSCs. Increased intestinal absorption of diet-derived PA was observed in NASH. Thus, the rapid increase in PA levels via the portal vein to the liver may activate HSCs and affect the development of liver fibrosis in NASH.

DOI： 10.1038/s41598-021-92790-z

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

We compared the toxicokinetics of methylmercury (MeHg) in KK-Ay type 2 diabetic mice and C57BL/6J mice to evaluate how metabolic changes associated with diabetes affect MeHg toxicokinetics. A single dose of MeHg (0.2, 1, or 5 mg mercury/kg) was administered orally to 12-week-old KK-Ay and C57BL/6J male mice. Total mercury concentrations in plasma, blood cells, whole blood, and tissues (brain, kidneys, liver, and pancreas) were measured after 4, 7, 11, and 14 days. The volume of distribution/bioavailability and the elimination rate constant per day were higher in KK-Ay mice, while the terminal elimination half-life was lower in almost all samples of KK-Ay mice. The area under the curve was lower in all blood and almost all tissue samples from KK-Ay mice. Total clearance/bioavailability was lower in all blood and tissue samples of KK-Ay mice at all MeHg doses. These results indicate that MeHg is more rapidly absorbed by, and eliminated from, the blood cells, brain, liver, kidney, and pancreas of KK-Ay mice under the experimental conditions. Different patterns of tissue-to-plasma and tissue-to-whole blood partition coefficients suggest that notable differences in MeHg transfer between plasma and blood cells affect its distribution in tissues of the two mouse strains. These findings are useful to understand the selective distribution of MeHg to target organs and the sensitivity to MeHg in pathological states.

DOI： 10.1002/jat.4078

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Amyloid-β (Aβ) induces cerebrovascular damage and is reported to stimulate endothelial cell senescence. We previously demonstrated that angiotensin II (Ang II)-promoted vascular senescence. We examined the possible cross-talk between Ang II and Aβ in regulating brain vascular smooth muscle cell (BVSMC) senescence. METHODS: BVSMCs were prepared from adult male mice and stimulated with Ang II (0, 0.1, 1, 10, and 100 nmol/l) and/or Aβ 1-40 (0, 0.1, 0.3, 0.5, 1, 3, and 5 µmol/l) for the indicated times. Cellular senescence was evaluated by senescence-associated β-galactosidase staining. RESULTS: Treatment with Ang II (100 nmol/l) or Aβ (1 µmol/l) at a higher dose increased senescent cells compared with control at 6 days. Treatment with Ang II (10 nmol/l) or Aβ (0.5 µmol/l) at a lower dose had no effect on senescence whereas a combined treatment with lower doses of Ang II and Aβ significantly enhanced senescent cells. This senescence enhanced by lower dose combination was markedly blocked by valsartan (Ang II type 1 receptor inhibitor) or TAK-242 (Aβ receptor TLR4 inhibitor) treatment. Moreover, lower dose combination caused increases in superoxide anion levels and p-ERK expression for 2 days, NF-κB activity, p-IκB, p-IKKα/β, p16 and p53 expression for 4 days, and an obvious decrease in pRb expression. These changes by lower dose combination, except in p-IκB expression and NF-κB activity, were significantly inhibited by pretreatment with U0126 (ERK inhibitor). CONCLUSIONS: Ang II and Aβ synergistically promoted BVSMC senescence at least due to enhancement of the p-ERK-p16-pRb signaling pathway, oxidative stress, and NF-κB/IκB activity.

DOI： 10.1093/ajh/hpaa218

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本耳鼻咽喉科頭頸部外科学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background: Tight junction (TJ) disruption and dysfunction are involved in the progression of arteriosclerosis. miR-501-3p regulates endothelial TJ protein-1, resulting in TJ disruption. Because exosomal microRNAs can travel to distant tissues and influence cell behavior, patients with elevated miR-501-3p may experience accelerated vascular disease progression secondary to miR-501-3p-induced reductions in TJ. This study investigated whether plasma exosome miR-501-3p levels are associated with vascular stiffness, an indicator for arteriosclerotic changes. Methods and Results: Fifty-one subjects (mean [±SD] age 70±8 years, 37% male) enrolled in a medical checkup program were recruited to the study. Brachial-ankle arterial pulse wave velocity (baPWV) and plasma exosome miR-501-3p expression were measured. Patients were divided into 2 groups depending on whether their miR-501-3p ∆Ct values were above ("High"; n=24) or below ("Low"; n=27) the cut-off levels determined by receiver operating characteristic (ROC) curve analysis. Median (interquartile range) baPWV levels were significantly higher in the miR-501-3p High than Low group (1,664 [1,496-1,859] vs. 1,450 [1,353-1,686] cm/s, respectively; P<0.05). Multivariate logistic regression analysis showed a significant association between increased baPWV and High miR-501-3p expression (odds ratio 4.66). At follow-up visits (mean 62 months later), baPWV remained significantly higher in the miR-501-3p High than Low group (1,830 [1,624-2,056] vs. 1,620 [1,377-1,816] cm/s, respectively; P<0.05). Conclusions: High expression levels of exosome miR-501-3p contribute to arteriosclerotic changes.

DOI： 10.1253/circrep.CR-20-0135

PubMed

researchmap

Publishing type：Part of collection (book)  

Allergic diseases, including allergic rhinitis and asthma, reduce the quality of life when severe. Allergic disease is conventionally characterized by an increase in serum immunoglobulin E and activation of type 2 helper T cells and eosinophils. There is accumulated evidence that Enterococcus faecalis, a kind of lactobacillus preparation, has a significant effect on various allergic diseases through regulation of the systemic immune response. Since E. faecalis is a gram-positive, facultative anaerobic organism and causes infectious diseases such as bacteremia, E. faecalis preparations have been investigated and developed as a tyndallized probiotic. In addition, tyndallized treatment with E. faecalis FK-23 augments the effect on health promotion. It has been reported that lysed E. faecalis FK-23 (LFK) as a tyndallized probiotic has health-promoting effects by activation of Treg cells. We also reported that oral administration of LFK provides therapeutic benefit in ovalbumin-induced asthma model mice through regulation of the Treg/Th17 balance. Many of the studies were conducted by a group at Nichinichi Pharmaceutical Co., Ltd. The effects of LFK preparation on allergic diseases are introduced in this article.

DOI： 10.1016/B978-0-12-819815-5.00032-X

Scopus

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japanese Pharmacological Society  

With the spread of new coronavirus infections (COVID-19), universities/colleges have transformed their educational format from conventional group education to distance learning. In order to share information on the new educational format among the members of the society, the Physiological Society of Japan and the Japanese Pharmacological Society (JPS) jointly conducted the "Emergency Joint Survey on Responses of Universities to COVID-19 and Its Impact on Physiology and Pharmacology Education". The JPS surveyed pharmacology departments/divisions at schools of pharmacy, medicine, dentistry, and veterinary medicine in 202 universities (response rate 89%) from August to September 2020. 85% of the universities changed the lecture method, and 70% changed the practical training. 30%, 30%, and 40% of the lectures were live, on-demand, and mixed (combination of live and on-demand) lectures, respectively. 25% of the practical training was live or a combination of live and on-demand lectures, and 45% was on-demand delivery. There are many problems to do online methods such as stable network environment, lack of the reality for students and difficulty of the check of their understanding. On the other hand, there are unexpected benefits in online methods such as anytime learning, an increase in questions from students and repeatable learning. More than 60% considered employing the newly introduced educational styles even after the pandemic. Students' mental health problems and disruption of daily rhythms, quality assurance of online education, and copyright issues were also concerned. Pharmacology education faces a significant turning point in introducing and improving distance learning with or post the COVID-19 pandemic.

DOI： 10.1254/fpj.21025

Scopus

PubMed

CiNii Books

CiNii Research

researchmap

Other Link： https://www.jstage.jst.go.jp/article/fpj/156/6/156_21025/_pdf

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Japan Geriatrics Society  

DOI： 10.3143/geriatrics.58.167

PubMed

CiNii Books

CiNii Research

researchmap

Other Link： https://www.jstage.jst.go.jp/article/geriatrics/58/1/58_58.167/_pdf

Language：English   Publishing type：Research paper (scientific journal)  

Mast cell (MC) exocytosis is organized by prenylated protein, including Rab families. Among Rab proteins, Rab3a, Rab27a, and Rab11 are responsible for exocytosis arrangement. Rab3a and Rab27a are contributed to exocytosis by interacting with other exocytosis proteins. Zoledronate administration disrupted the Rab prenylation process that affected its interaction with other proteins, and finally, its function. The present study has investigated the effect of zoledronate on the histamine release (HR) from RBL-2H3 cells. The main focus is to answer the question of whether zoledronate affects Rab27a/Doc2a interaction. Histamine release on RBL-2H3 cells after zoledronate or clodronate administration was measured using HPLC-fluorometry. Dinitrophenylated bovine serum albumin (DNP-BSA) (20 ng/mL) or ionomycin (1 µM) are used as secretagogues. Calcium (Ca2+) influx observation was performed using Fura-2A/M. In situ proximity ligation assay (PLA) is used to investigate Rab27a/Doc2a interaction after bisphosphonates (BPs) treatment. Histamine concentration measurement with HPLC-fluorometry showed that zoledronate (30, 100 µM) inhibited HR from antigen-activated RBL-2H3 cells. Zoledronate showed less inhibition in cells activated with ionomycin. Intracellular Ca2+ concentration and Ca2+ flux rate from the extracellular compartment was not changed by zoledronate administration. No changes in Rab27a/Doc2a interaction after zoledronate treatment. Histamine release inhibition by zoledronate in DNP-BSA-activated RBL-2H3 cells is not related to the disruption of Rab27a/Doc2a interaction and is not involve the change in Ca2+ influx.

DOI： 10.1248/bpb.b21-00717

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1016/j.bja.2020.05.046

Scopus

PubMed

researchmap

Language：English  

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than seven million people worldwide, contributing to 0.4 million deaths as of June 2020. The fact that the virus uses angiotensin-converting enzyme (ACE)-2 as the cell entry receptor and that hypertension as well as cardiovascular disorders frequently coexist with COVID-19 have generated considerable discussion on the management of patients with hypertension. In addition, the COVID-19 pandemic necessitates the development of and adaptation to a "New Normal" lifestyle, which will have a profound impact not only on communicable diseases but also on noncommunicable diseases, including hypertension. Summarizing what is known and what requires further investigation in this field may help to address the challenges we face. In the present review, we critically evaluate the existing evidence for the epidemiological association between COVID-19 and hypertension. We also summarize the current knowledge regarding the pathophysiology of SARS-CoV-2 infection with an emphasis on ACE2, the cardiovascular system, and the kidney. Finally, we review evidence on the use of antihypertensive medication, namely, ACE inhibitors and angiotensin receptor blockers, in patients with COVID-19.

DOI： 10.1038/s41440-020-0515-0

Scopus

PubMed

researchmap

Language：English  

DOI： 10.1111/ggi.14018

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本抗加齢医学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

OBJECTIVE: Identification of undefined risk factors will be crucial for the development of therapeutic strategies in hearing impairment. Platelets are likely to affect the development of sudden sensorineural hearing loss, which is a primary risk factor for permanent hearing impairment. This implies that abnormal platelets might contribute to long-term hearing loss. This study investigated the role of platelets in the development of hearing impairment over a 5-year period. METHODS: This study was a retrospective cohort study and consisted of a population-based survey, which was performed for 1,897 participants in 2014 to 2019. To evaluate the effect of platelet level on hearing ability, the subjects were divided into two groups: a high-normal platelet group (25 ∼ 40 × 104 cells/μL) and a low-normal platelet group (15 ∼ 25 × 104 cells/μL). Subjects were defined as having hearing impairment when pure tone audiometry was over 25 dB HL in either ear (tested in 2017 and 2019). Incidence of hearing impairment was analyzed. RESULTS: Incidence of hearing impairment at low frequencies was significantly higher in the low-normal platelet group than in the high-normal group year over year. Low-normal platelet count associated with low-frequency hearing impairment (LFHI) incidence (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.15-4.76). In the low-normal platelet group, subjects whose counts declined from baseline developed more LFHI than those whose counts increased over time. Further, decreasing platelets appeared to be an independent risk factor contributing to the incidence of LFHI (OR, 2.10; 95%CI, 1.09-4.06) in the low-normal platelet group. CONCLUSION: Both a low-normal platelet and a declining platelet count were independently associated with the incidence of LFHI. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E1287-E1295, 2021.

DOI： 10.1002/lary.28970

Scopus

PubMed

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/lary.28970

Language：English   Publishing type：Research paper (scientific journal)  

Anaphylaxis during general anaesthesia is a significant clinical challenge for anaesthesiologists. Approximately 50% of perioperative anaphylaxis cases lack the presence of specific IgE antibodies. Mas-related G-protein coupled receptor X2 (MRGPRX2) in humans and its mouse orthologue Mas-related G-protein coupled receptor B2 (Mrgprb2) are crucial receptors in non-IgE-dependent histamine release. Anaesthetics such as rocuronium and atracurium cause perioperative anaphylaxis by activating histamine release via the Mrgprb2 pathway. We hypothesized that antagonistic DNA aptamers that target MRGPRX2 can prevent perioperative anaphylaxis. Selection of a DNA aptamer that specifically binds MRGPRX2 was achieved by using our modified Systematic Evolution of Ligands by Exponential enrichment (SELEX) approach. Our SELEX process used MRGPRX2-proteoliposomes synthesised by a wheat germ cell-free system as templates. The activity of the selected aptamer to inhibit histamine release from MRGPRX2-activated mast cells and in an anaphylaxis rat model transplanted with this cell line was examined. Our selection process identified aptamer-X35 with the sequence 5'-ATGACCATGACCCTCCACACTGTAGGCACCACGGGTCCCTGGCAGTTAAAAGTACGTTTGTCAGACTGTGGCAGGGAAACA-3'. In silico 2D modelling of aptamer-X35 revealed a structure with a small loop and a long stem. Aptamer-X35 inhibited histamine release from mast cells by 70%. Subcutaneous injection of 30 nmol of aptamer-X35 inhibited the anaphylactic reaction in the rat anaphylaxis model. This study demonstrated that aptamer-X35 selected by the modified SELEX approach reduced histamine release by inhibiting the MRGPRX2 pathway. Overall, our findings establish aptamer-X35 as a potential therapeutic candidate against perioperative anaphylaxis.

DOI： 10.1016/j.ejphar.2020.173104

Scopus

PubMed

researchmap

Language：English  

The renin-angiotensin system (RAS) plays crucial roles in the control of blood pressure and sodium homeostasis. Moreover, RAS also acts as a key player in cell and organ senescence, mainly by activation of the classical axis of angiotensin (Ang) converting enzyme (ACE)/Ang II/Ang II type 1 receptor via overproduction of reactive oxygen species. Overactivation of the classical RAS axis induces organ dysfunction in the vasculature, brain, kidney and skeletal muscle, resulting in atherosclerosis, stroke, chronic kidney disease and sarcopenia. Moreover, RAS has been shown to regulate lifespan, using gene-modification models. Recently, mice lacking the Ang II type 1 receptor were shown to exhibit an increase in lifespan compared with control mice. Here, the effect of RAS on age-related tissue dysfunction in several organs is reviewed, including not only the classical axis but also protective functions of RAS such as the ACE2/Ang (1-7)/Mas axis. Geriatr Gerontol Int 2020; ••: ••-••.

DOI： 10.1111/ggi.13927

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The neuroinflammation in the ischemic brain could occur as sterile inflammation in response to damage-associated molecular patterns (DAMPs). However, its long-term dynamic transcriptional changes remain poorly understood. It is also unknown whether this neuroinflammation contributes to the recovery or just deteriorates the outcome. The purpose of this study is to characterize the temporal transcriptional changes in the post-stroke brain focusing on DAMPs-related genes by RNA-sequencing during the period of 28 days. We conducted the RNA-sequencing on day 1, 3, 7, 14, 28 post-stroke in the mouse photothrombosis model. The gross morphological observation showed the ischemic lesion on the ipsilateral cortex turned into a scar with the clearance of cellular debris by day 28. The transcriptome analyses indicated that post-stroke period of 28 days was classified into four categories (I Baseline, II Acute, III Sub-acute-#1, IV Sub-acute-#2 phase). During this period, the well-known genes for DAMPs, receptors, downstream cascades, pro-inflammatory cytokines, and phagocytosis were transcriptionally increased. The gene ontology (GO) analysis of biological process indicated that differentially expressed genes (DEGs) are genetically programmed to achieve immune and inflammatory pathways. Interestingly, we found the biphasic induction of various genes, including DAMPs and pro-inflammatory factors, peaking at acute and sub-acute phases. At the sub-acute phase, we also observed the induction of genes for phagocytosis as well as regulatory and growth factors. Further, we found the activation of CREB (cAMP-response element binding protein), one of the key players for neuronal plasticity, in peri-ischemic neurons by immunohistochemistry at this phase. Taken together, these findings raise the possibility the recurrent inflammation occurs at the sub-acute phase in the post-stroke brain, which could be involved in the debris clearance as well as neural reorganization.

DOI： 10.1186/s13041-020-00598-1

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: To promote understanding of the pathogenesis of cognitive impairment or dementia, we explored the potential interaction between transient cerebral ischemia and amyloid-β (Aβ) infusion in mediating cognitive decline and examined the possible ameliorative effect of angiotensin II type 2 (AT2) receptor activation in vascular smooth muscle cells (VSMC) on this cognitive deficit. METHODS: Adult male wild-type mice (WT) and mice with VSMC-specific AT2 receptor overexpression (smAT2) were subjected to intracerebroventricular (ICV) injection of Aβ1-40. Transient cerebral ischemia was induced by 15 min of bilateral common carotid artery occlusion (BCCAO) 24 h after Aβ injection. RESULTS: Aβ injection in WT induced a cognitive decline, whereas BCCAO did not cause a significant cognitive deficit. In contrast, WT with BCCAO following Aβ injection exhibited more marked cognitive decline compared to Aβ injection alone, in concert with increases in superoxide anion production, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and expression of p22phox, p40phox, monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-1β in the hippocampus, and upregulation of RAGE (receptor for advanced glycation end product), an Aβ transporter. BCCAO following Aβ injection further enhanced neuronal pyknosis in the hippocampus, compared with BCCAO or Aβ injection alone. In contrast, smAT2 did not show a cognitive decline, increase in oxidative stress, inflammation, and RAGE level or neuronal pyknosis, which were induced by BCCAO with/without Aβ injection in WT. CONCLUSIONS: Transient cerebral ischemia might worsen Aβ infusion-mediated cognitive decline and vice versa, with possible involvement of amplified oxidative stress and inflammation and impairment of the RAGE-mediated Aβ clearance system, contributing to exaggerated neuronal degeneration. AT2 receptor activation in VSMC could play an inhibitory role in this cognitive deficit.

DOI： 10.1186/s12974-020-01775-8

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Molecular hydrogen is thought to have an inhibitory effect on oxidative stress, thereby attenuating the onset and progression of various diseases including cardiovascular disease; however, few reports have assessed the preventive effect of constitutive inhalation of hydrogen gas on of vascular remodeling. Here, we investigated the effect of constitutive inhalation of hydrogen gas on vascular neointima formation using a cuff-induced vascular injury mouse model. After constitutive inhalation of compressed hydrogen gas (O2 21%, N2 77.7%, hydrogen 1.3%) or compressed air only (O2 21%, N2 79%) by C57BL/6 mice for 2 weeks from 8 weeks of age in a closed chamber, inflammatory cuff injury was induced by polyethylene cuff placement around the femoral artery under anesthesia, and hydrogen gas administration was continued until sampling of the femoral artery. Neointima formation, accompanied by an increase in cell proliferation, was significantly attenuated in the hydrogen group compared with the control group. NADPH oxidase NOX1 downregulation in response to cuff injury was shown in the hydrogen group, but the expression levels of NADPH oxidase subunits, p40phox and p47phox, did not differ significantly between the hydrogen and control groups. Although the increase in superoxide anion production did not significantly differ between the hydrogen and control groups, DNA damage was decreased as a result of reduction of reactive oxygen species such as hydroxyl radical (⋅OH) and peroxynitrite (ONOO-) in the hydrogen group. These results demonstrate that constitutive inhalation of hydrogen gas attenuates vascular remodeling partly via reduction of oxidative stress, suggesting that constitutive inhalation of hydrogen gas at a safe concentration in the living environment could be an effective strategy for prevention of vascular diseases such as atherosclerosis.

DOI： 10.1371/journal.pone.0227582

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Inhibition of the renin-angiotensin system (RAS) has been shown to alleviate muscle atrophy both under pathological conditions and during physiological aging. We recently reported that the deletion of angiotensin converting enzyme 2 (ACE2), which converts Angiotensin II to Angiotensin-(1-7) in mice, leads to the early manifestation of aging-associated muscle weakness along with the increased expression of p16INK4a, a senescence-associated gene, and increased central nuclei in the tibialis anterior (TA) muscle in middle age. As ACE2 is multifunctional and functions beyond its role in the RAS, we investigated whether activation of the RAS primarily contributes to muscle weakness in ACE2 knockout (KO) mice by comparing these mice to Tsukuba hypertensive (TH) mice that overproduce human angiotensin II. The grip strength of young (6 months) and middle-aged (15 months) TH mice was consistently lower than that of wild-type mice at the same ages. Middle-aged TH mice were continuously lean with extremely reduced adiposity. Central nuclei in the gastrocnemius (GM) muscle were increased in ACE2KO mice, while no apparent morphological change was observed in the GM muscles of TH mice. Increased expression of p16INK4a along with alterations in the expression of several sarcopenia-associated genes were observed in the GM muscles of ACE2KO mice but not TH mice. These findings suggest that chronic overactivation of the RAS does not primarily contribute to the early aging phenotypes of skeletal muscle in ACE2KO mice.

DOI： 10.1038/s41440-019-0375-7

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Mice and rats are important animal models for mast cell (MC) study. However, rat Mas-related-GPCR-B3 receptor (MRGPRB3) has been less studied than its mouse counterpart. Therefore, we aimed to characterize rat MRGPRB3. METHODS: Mrgprb3 mRNA expression was assessed in peritoneal cells (RPCs) and peritoneal MCs (RPMCs) of wild-type rats, RPCs of MC-deficient rats, and RBL-2H3 cells by reverse-transcriptase polymerase chain reaction (RT-PCR). RPMCs, MRGPRX2-transfected and non-transfected RBL-2H3 cells were activated by 15-30 min incubation with DNP-BSA, substance-P (SP), or compound-48/80. L732138 or CP96344 was used as a tachykinin/neurokinin-1-receptor antagonist. Histamine release from MCs was measured by HPLC fluorometry. RESULTS: Mrgprb3 mRNA expression was found in all cells, with the highest level in wild-type RPCs. All cells responded to DNP-BSA, but only MRGPRX2-transfected-RBL-2H3 cells and RPMCs responded to all activators. L732138 (0.1-10 μM) and CP96344 (1-100 μM) suppressed SP (10 μM)-induced RPMC activation. L732138 inhibition was dose independent, whereas CP96344 inhibition occurred in a dose-dependent manner. Additionally, only CP96344 suppressed SP (100 μM)- and compound-48/80 (10 μg/mL)-induced RPMC activation. CONCLUSIONS: RPMCs expressing functional MRGPRB3 response upon MRGPRX2 ligands to regulated MC-mediated activities. It`s provide novel insights for future pseudo-allergic studies in rodents.

DOI： 10.1007/s00011-020-01319-z

Scopus

PubMed

researchmap

Publishing type：Research paper (scientific journal)  

Scopus

researchmap

Language：Japanese   Publisher：Japanese Pharmacological Society  

In present study, we aimed to investigate the feasibility of machine-learning-based classification using clinical features of patients for risk predication of anesthesia-related anaphylaxis.

After data pre-processing, the performance of four classification methods, which were integrated with four feature selection methods, were evaluated using two-layer cross-validation. Linear Discriminate Analysis in conjunction with Recursive Feature Elimination presented the best performance, with accuracy of 0.867 and Matthews correlation coefficient of 0.558 with 25 features used in the classification.

This study presents initial proof of the capability of a machine-learning-based strategy for forecasting low-prevalence anesthesia-related anaphylaxis. In future, we plan to utilize an extended database including preoperative information and vital-sign streams to define personalized risk status for anaphylaxis.

DOI： 10.1254/jpssuppl.93.0_3-p-385

CiNii Research

researchmap

Publishing type：Research paper (scientific journal)  

Four publications in Nature and Cell followed by WHO advise on “life-course approach” on preconception and perinatal factors; these factors appear to be essential for achieving the population health goals of the UNO in 2030. The interaction of the genes and the internal and external environment can influence fetal development, the health of mothers and offspring. The role of pre-conception and perinatal behavioral factors of parents on genetic/epigenetic inheritance of cardio-metabolic diseases (CMDs) risk in the off-spring in humans is not least known. The role of epigenetic inheritance, the passing of phenotypic change to subsequent generations in ways that are outside the genetic code of DNA, are not well known. It is unclear whether a complex set of factors, including nutritional factors, come into play during epigenetic inheritance from father and mother to offspring. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring inducing obesity and insulin resistance not yet known in humans [1]. Pregnant women require more energy, protein, iron, iodine, vitamin A, folate, and other nutrients because nutrient deficiencies are associated with maternal complications and death, fetal and newborn death, birth defects, and decreased physical and mental potential of the child. Deficiency of omega-3 fatty acid and flavonoids during pregnancy can increase oxidative stress and systemic inflammation, which may predispose to impaired beta-cell function, and smooth muscle dysfunction leading to increased risk of CMDs. There is an unmet need to find out that adequate energy intake and a diversified diet that includes fruit, vegetables, and animal products throughout the life cycle helps ensure that women enter pregnancy and lactation without deficiencies and obtain adequate nutrients during periods of heightened demand. Since CMDs may develop due to transgenerational inheritance, our strategy is to find out the effects of Indo-Mediterranean diets vs control diet, among father and mother, on complications of pregnancy, fetal development and cardio-metabolic risk factors in the offspring. The outcome of this study may indicate beneficial effects on the mother's health, fetal development, insulin sensitivity, in infancy, mediated by epigenetic and genetic alterations.

Scopus

researchmap

Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Practice conducted in the Department of Pharmacology in medical schools plays an important role in learning the effect and risk of drugs through animal experiments as not only pharmacological but also ethical education. However, due to the budget reduction in the practice and cost cut for the instructors, performing practice with enough quality is so difficult in almost all medical schools. Thus, we have started a consortium of practice and education together with five pharmacology departments in the Chugoku and Shikoku regions to share practice tools and equipment, to develop human resource of instructors and to collaborate with each other. Here, we demonstrate our approach.</p>

DOI： 10.1254/jpssuppl.93.0_1-S16-4

CiNii Research

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Mesenchymal stem cell (MSC)-based articular regeneration might be beneficial for both protecting and rebuilding cartilaginous tissues in the management of rheumatoid arthritis. However, it is unclear how current immunosuppressive strategies influence the multipotency of MSCs. The present study was undertaken to profile the direct effectiveness of major antirheumatic drugs including methotrexate, prednisolone, adalimumab, and tocilizumab on the multipotency of MSCs, with a special focus on chondrogenesis. The inhibitory effects of methotrexate on adipogenesis, osteogenesis, and chondrogenesis were observed to occur in a dose-dependent manner in an in vitro differentiation system. Prednisolone enhanced adipogenesis, but reduced alkaline phosphatase activity in osteoprogenitors and suppressed the formation of chondrospheroids. Adalimumab suppressed alkaline phosphatase activity, while tocilizumab diminished osteogenesis and chondrogenesis of MSCs in vitro. Chondrogenesis of antirheumatic drug-treated MSCs was also evaluated in vivo using a scaffolded spheroid-engrafted murine model. The biologics examined appeared to be relatively safe for cartilaginous formation, but methotrexate and prednisolone exhibited opposing influences on chondrogenesis. Taken together, these results reveal the direct efficacy of major antirheumatic agents on the multipotency of MSCs. Therefore, our findings suggest that optimization of medication protocols is further required for therapeutic approaches involving cartilaginous tissue engineering.

DOI： 10.3389/fphar.2020.01004

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The angiotensin-converting enzyme 2 (ACE2)-angiotensin 1-7 (A1-7)-A1-7 receptor (Mas) axis plays a protective role in the renin-angiotensin system (RAS). We recently found that ACE2 knockout (ACE2KO) mice exhibit earlier aging-associated muscle weakness, and that A1-7 alleviates muscle weakness in aging mice. In the present study, we investigated the role of the A1-7-Mas pathway in the effect of ACE2 on physiological aging. Male wild-type, ACE2KO, and Mas knockout (MasKO) mice were subjected to periodical grip strength measurement, followed by administration of A1-7 or vehicle for 4 weeks at 24 months of age. ACE2KO mice exhibited decreased grip strength after 6 months of age, while grip strength of MasKO mice was similar to that of wild-type mice. A1-7 improved grip strength in ACE2KO and wild-type mice, but not in MasKO mice. Muscle fibre size was smaller in ACE2KO mice than that in wild-type and MasKO mice, and increased with A1-7 in ACE2KO and WT mice, but not in MasKO mice. Centrally nucleated fibres (CNFs) and expression of the senescence-associated gene p16INK4a in skeletal muscles were enhanced only in ACE2KO mice and were not altered by A1-7. ACE2KO mice, but not MasKO mice, exhibited thinning of peripheral fat along with increased adipose expression of p16INK4a A1-7 significantly increased bone volume in wild-type and ACE2KO mice, but not in MasKO mice. Our findings suggest that the impact of ACE2 on physiological aging does not depend on the endogenous production of A1-7 by ACE2, while overactivation of the A1-7-Mas pathway could alleviate sarcopenia and osteoporosis in aged mice.

DOI： 10.1042/CS20190573

Scopus

PubMed

researchmap

Language：English  

Dementia is one of the greatest public health concerns for the modern aging world. Over the last decade, most researchers developing new therapeutic strategies for dementia have focused on amyloid-β. In contrast, numerous recent studies have indicated that vascular risk factors are associated with various forms of dementia, and that in fact most forms of dementia can be considered an extension of vascular disease. Accordingly, it is sensible to pursue treatment approaches that focus on the blood vessels. Blood-brain barrier (BBB) disruptions in the white matter of patients with vascular cognitive impairment (VCI) have been observed using imaging analysis, and might be potential targets for novel VCI treatment. Tight junctions between cerebral endothelial cells play an important role in the function of the BBB, and recent studies have demonstrated the essential role of microRNAs in regulating tight junctions. Further elucidation of the mechanisms of tight junction-disruption in dementia are likely to lead to promising novel treatments. In this article, we summarize current knowledge regarding microRNAs and vascular cognitive impairment and the possibility of utilizing microRNAs as biomarkers for BBB dysfunction, and seek to envision future therapeutic strategies.

DOI： 10.1016/j.phrs.2019.104266

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

We investigated the effects of variations in anesthesia exposure time prior to conducting anxiety response behavioral testing in sham controls from an experimental murine model. The staying time in the center area of the Open Field test in the "long exposure" group was significantly decreased compared to that of the "short exposure" group. Significant correlation was found between anesthesia time and the duration of staying time in the center area. We conclude that anesthesia time may have a significant impact on behavioral anxiety testing in this context, and advise careful control of this parameter in protocol optimization in related surgical animal models.

DOI： 10.1016/j.jphs.2019.03.007

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The resources of released histamine from activated mast cells, as initial effectors of allergic disease, include not only endogenous prepackaged histamine and newly synthesized histamine, but also histamine that is obtained through the de novo reuptake pathway. To investigate the de novo histamine production pathway, a mast cell line, RBL-2H3 Sc98 in which endogenous histamine production is lacking and only the de novo histamine release pathway via transporters is maintained, was used to dissect histamine reuptake in the present study. Histamine content measurements indicated that RBL-2H3 Sc98 cells took up extracellular histamine for storage in granules and subsequent release after stimulation by an antigen. Profiling and inhibition analysis of possible transporters suggested that the plasma membrane monoamine transporter and organic cation transporter 1 may be candidate transporters for histamine uptake from extracellular spaces, and that vesicular monoamine transporter 2 was responsible for intracellular vesicle uptake. These results may provide the foundation to understand the contribution of exogenous histamine to outward histamine release that is mediated by mechanisms other than conventional exocytosis.

DOI： 10.1016/j.ejphar.2019.01.050

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Chèdiak-Higashi syndrome is a rare autosomal recessive disease that causes hypopigmentation, recurrent infections, mild coagulation defects and neurological problems. Beige mice carry a mutation in the lysosome trafficking regulator (LYST) gene and display some of the key characteristics of human Chèdiak-Higashi syndrome, in particular, a high susceptibility to infection due to aberrant natural killer (NK) cell and polymorphonuclear leucocyte function. Morphological analysis of beige mice reveals the presence of enlarged lysosomes in a variety of cell types, including leucocytes, hepatocytes, fibroblasts and renal tubule cells. To examine the process of granule maturation and degranulation in beige mice mast cells, morphological studies have been conducted using a combination of electrophysiological techniques; however, few functional studies have been conducted with mast cells, such as mediator release. The aim of the present study was to determine the morphological and functional characteristics of skin and peritoneal mast cells and bone marrow-derived mast cells of homozygous (bg/bg) and heterozygous (bg/+) beige mice and wild-type (+/+) mice. The histamine concentration was lower in the peritoneal and bone marrow-derived mast cells of bg/bg mice compared with those of bg/+ and +/+ mice, but the histamine release response was potentiated. In vivo studies of passive cutaneous anaphylaxis showed no differences between bg/bg mice and either bg/+ or +/+ mice. Although bg/bg mast cells with enlarged granules display specific exocytotic processes in vitro, the consequences of mast cell activation in beige mice were similar to those of wild-type mice in vivo.

DOI： 10.1016/j.intimp.2019.01.053

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.18632/aging.101868

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Vascular calcification is a common finding in atherosclerosis and in patients with chronic kidney disease. The renin-angiotensin system plays a role in the pathogenesis of cardiovascular remodeling. Here, we examined the hypothesis that angiotensin II type 2 receptor (AT2) stimulation has inhibitory effects on phosphate-induced vascular calcification. In vivo, calcification of the thoracic aorta induced by an adenine and high-phosphate diet was markedly attenuated in smooth muscle cell-specific AT2-overexpressing mice (smAT2-Tg) compared with wild-type and AT2-knockout mice (AT2KO). Similarly, mRNA levels of relevant osteogenic and vascular smooth muscle cell marker genes were unchanged in smAT2-Tg mice, while their expression was significantly altered in wild-type mice in response to high dietary phosphate. Ex vivo, sections of thoracic aorta were cultured in media supplemented with inorganic phosphate. Aortic rings from smAT2-Tg mice showed less vascular calcification compared with those from wild-type mice. In vitro, calcium deposition induced by high-phosphate media was markedly attenuated in primary vascular smooth muscle cells derived from smAT2-Tg mice compared with the two other mouse groups. To assess the underlying mechanism, we investigated the effect of PPAR-γ, which we previously reported as one of the possible downstream effectors of AT2 stimulation. Treatment with a PPAR-γ antagonist attenuated the inhibitory effects on vascular calcification observed in smAT2-Tg mice fed an adenine and high-phosphate diet. Our results suggest that AT2 activation represents an endogenous protective pathway against vascular calcification. Its stimulation may efficiently reduce adverse cardiovascular events in patients with chronic kidney disease.

DOI： 10.1016/j.kint.2018.07.028

Scopus

PubMed

researchmap

Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>Recently, we reported that drinking of <i>Citrus unshiu</i> juice (CU) or <i>Citrus iyo</i> juice (CI) drinking attenuated vascular remodeling in vascular injury mouse model. This effect was more marked with CI. Therefore, we focused on flavanone, hesperidin, which is more abundantly contained in CI compared with CU, and investigated the effect of hesperidin in vascular injury in mice. Eight-week-old male C57BL/6 mice were administrated 100 mg/kg/day hesperidin orally by gavage. Two weeks after administration, vascular injury was induced by polyethylene cuff placement on the femoral artery. Neointima formation was determined 14 days after cuff placement by evaluating intima/media ratio. One week after cuff placement, mRNA levels were measured by quantitative real-time RT-PCR. Treatment with hesperidin did not change systolic blood pressure and body weight compared with that in control mice. Neointima formation in the injured artery was significantly increased 2 weeks after cuff placement. Treatment with hesperidin significantly decreased neointimal formation. Expression of mRNA of tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 were increased by cuff placement. These increases tended to decrease in treatment with hesperidin. These results suggest that the intake of hesperidin in citrus fruits juice should prevent vascular injury.</p>

DOI： 10.1254/jpssuppl.92.0_1-P-071

researchmap

Publishing type：Research paper (scientific journal)  

Prediabetes, diabetes, hypertension, and coronary artery diseases are important components of metabolic syndrome which is a risk factor of CMDs. Eating slowly is a crucial concept in behavioral nutrition which is recommended for management of obesity. However, in subjects with diabetes and metabolic syndrome, eating slowly is believed to have an important effect on satiety control leading to weight loss. While fast eating without mastication is associated with metabolic syndrome and cardio-metabolic diseases (CMDs), slow eating with mastication may be protective against these diseases. Regular mastication may also inhibit memory dysfunction and dementia. Regular active mastication improves the performance of sustained cognitive tasks by increasing the activation of the hippocampus and the prefrontal cortex, the brain regions that are essential for cognitive processing. Abnormal mastication caused by experimental occlusal disharmony in animals produces chronic stress, which in turn suppresses spatial learning ability leading to decline in memory function. Mastication measurement device may be used to assess dose response in relation to health and diseases.

Scopus

researchmap

Language：English  

BACKGROUND: Hypertension is one of the most relevant risk factors in vascular aging, stroke and vascular dementia (VD). In the elderly, the prevalence of mixed dementia, which consists of Alzheimer's disease (AD) and VD, is increased. Moreover, disorders of blood vessels are reported to be involved in the onset and progression of AD. Thus, hypertension generally plays an important role in dementia overall. MAIN TEXT: Mid-life hypertension is reported to be related to the incidence of dementia, but it is reported that antihypertensive treatment in aged people cannot prevent the onset and progression of dementia. The renin-angiotensin system (RAS) is deeply involved in not only hypertension but also lifestyle-related diseases, and may contribute to the pathological mechanism in dementia; thus, RAS regulation is expected to prevent dementia. Small vessel structural changes in lifestyle-related diseases may play a role in dementia in the elderly. CONCLUSION: Here, we discuss the role of blood pressure elevation in dementia and the therapeutic possibility of antihypertensive treatment against dementia.

DOI： 10.1186/s40885-019-0135-7

Scopus

PubMed

researchmap

Publishing type：Research paper (scientific journal)  

Adaptations may be defined as any alterations, molecular and clinical, that provide better capability to an organism to face the adverse effects of environmental factors. Adaptations could be clinical or biological, and could be subdivided into genetic, epigenetic, immunological (increase in PG1), and anti-oxidative. Exercise enhances the synthesis of CoQ10 antioxidant and high-density lipoprotein cholesterol, as well as vascular endothelial, neuronal and myocardial growth factors, whereas yoga stretching enhances resolvin, which are protective mechanisms of adaptations. Mediterranean-style diets decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines, thus increasing the molecular capability of adaptation by counteracting the adverse effects of environmental risk factors. DNA is a reasonably conserved molecule but epigenetic and genetic alterations can occur due to environmental factors such as Western-style diets, pollutants and radiations resulting in to DNA methylation. Some of these changes occur to counteract the adverse effects of these environmental factors which may be called adaptations. The surface of the genes can be altered through manipulations via mRNA, siRNA, histone modification causing epigenetic modulation. Regulating telomere-associated genes we can induce molecular adaptation by Mediterranean-style diet and moderate physical activity. We can also enhance adaptation through beneficial mutations or using allele from the standing genetic variations. Whether it is DNA, RNA, protein, receptor, enzyme, all of these will contribute to molecular adaptability. Functional food such as curcumin, fenugreek and Mediterranean-style foods can alter transcription, thus bring about adaptation. Molecular adaptation may include biophysical changes which may terminate in clinical manifestations such as central obesity which is an adaptation against increased intake of Western-style diets and sedentary behavior. More studies are needed to establish the role of adaptation in cardiovascular and cardiomyocyte dysfunction that leads to chronic heart failure.

Scopus

researchmap

Language：Japanese   Publisher：Japanese Pharmacological Society  

<p>We previously observed that vascular remodeling in response to vascular injury is exaggerated in fetal growth restriction (FGR) mice. We reported that angiotensin II type 2 receptor (AT₂R) stimulation prevented cerebral ischemic damage. The AT₂R is highly expressed in fetal mice. However, the effects of AT₂R on ischemic brain damage in FGR mice is unclear. Therefore, we investigated the roles of AT₂R in brain damage in FGR mice using transgenic mice with overexpressed AT₂R in vascular smooth muscle cell (smAT₂-Tg) mice. Dams (wild-type and smAT₂-Tg mice) were fed an isocaloric diet containing 20% protein (NP) or 8% protein (LP) until delivery. On the day of delivery, all dams were returned to the NP diet. After weaning, offspring were fed the NP diet. When male offspring were 10 weeks of age, cerebral ischemic injury was induced by transient middle cerebral artery occlusion (MCAO). Systolic blood pressure did not differ among all groups at 10 week of age. Ischemic area 48 hours after MCAO in NP mice was smaller in smAT₂-Tg mice. Stroke size in WT-LP mice was significantly larger compared with WT-NP mice. This aggravation of stroke size by LP was weaker in smAT₂-Tg-LP mice. Cerebral blood flow in the whole brain in smAT₂-Tg mice was attenuated compared with that in WT mice at 48 hours after MCAO. These results suggested that AT₂R could enhance the cerebral protective effects in FGR at least in part due to the increase of CBF after ischemia.</p>

DOI： 10.1254/jpssuppl.92.0_2-P-041

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Calcium is a ubiquitous intracellular messenger that has a crucial role in determining the proliferation, differentiation, and functions of multipotent mesenchymal stem cells (MSCs). Our study is aimed at elucidating the influence of genetically manipulating Ca2+ release-activated Ca2+ (CRAC) channel-mediated intercellular Ca2+ signaling on the multipotency of MSCs. The abilities of genetically engineered MSCs, including CRAC-overexpressing and CRAC-knockout MSCs, to differentiate into multiple mesenchymal lineages, including adipogenic, osteogenic, and chondrogenic lineages, were evaluated. CRAC channel-mediated Ca2+ influx into these cells was regulated, and the differentiation fate of MSCs was modified. Upregulation of intracellular Ca2+ signals attenuated the adipogenic differentiation ability and slightly increased the osteogenic differentiation potency of MSCs, whereas downregulation of CRACM1 expression promoted chondrogenic differentiation potency. The findings demonstrated the effects of genetically manipulating MSCs by targeting CRACM1. CRAC-modified MSCs had distinct differentiation fates to adipocytes, osteoblasts, and chondrocytes. To aid in the clinical implementation of tissue engineering strategies for joint regeneration, these data may allow us to identify prospective factors for effective treatments and could maximize the therapeutic potential of MSC-based transplantation.

DOI： 10.1155/2019/7510214

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The brain renin-angiotensin system plays a crucial role in ischemic stroke. It is known that stimulation of the angiotensin II type 2 (AT2) receptor protects against ischemic brain injury. We recently demonstrated that AT2 receptor stimulation by compound 21 (C21), a direct AT2 receptor agonist, inhibited vascular intimal proliferation with activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ). However, whether direct AT2 receptor stimulation protects against ischemic brain injury via PPAR-γ activation is still unknown. 8-week-old male C57BL/6 J mice were subjected to middle cerebral artery (MCA) occlusion. 2 weeks before MCA occlusion, they were administered C21 with or without GW9662, a PPAR-γ antagonist. Neurologic deficit, ischemic size, superoxide anion, superoxide dismutase (SOD) activity, expression of NADPH subunits and blood brain barrier (BBB) stabilization were assessed 24 h after MCA occlusion. Cerebral blood flow (CBF) was measured in the core and periphery of the MCA territory before, immediately after, 1 h and 24 h after MCA occlusion. Treatment with C21 markedly decreased the neurologic deficit and ischemic size with an increase in CBF, SOD activity and BBB stabilization genes compared with the non-treated group. Co-administration of GW9662 partially attenuated this protective effect of C21 on neurologic deficit and ischemic size via an increase in superoxide anion production and a decrease of SOD activity and BBB stabilization genes, while GW9662 treatment alone had no significant effect on neurologic deficit and ischemic size. These results suggest that direct AT2 receptor stimulation has a preventive effect on stroke-induced brain injury partly due to activation of PPAR-γ.

DOI： 10.1038/s41440-018-0082-9

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Interferon-regulatory factor (IRF)-1-dependent genes in neurons play a role in ischemic neuronal death; however, the roles of IRF-1 in dementia are not well investigated. Therefore, we assessed the effect of IRF-1 on cognitive function using a vascular cognitive impairment mouse model created by chronic cerebral hypoperfusion. Male 10-week-old C57BL/6 (wild-type; WT) and IRF-1-knockout (IRF-1KO) mice were used in this study. A chronic cerebral hypoperfusion mouse model was generated by bilateral common carotid artery stenosis (BCAS) treatment. After 6 weeks of BCAS, the mice were subjected to the Morris water maze test five times a day for 5 days. In the Morris water maze task, escape latency was significantly prolonged in sham-operated IRF-1KO mice compared with sham-operated WT mice. However, BCAS treatment cancelled such difference in spatial learning between WT and IRF-1KO mice. BCAS treatment decreased CBF, but no significant difference was observed between the two strains after BCAS. Sham-operated IRF-1KO mice showed a decrease in mRNA expression of caspase-1 and an increase in IRF-2 expression in the hippocampus. Expression of angiotensin II type 2 (AT2) receptor, which induces better cognitive function, is regulated by IRF-1; however, no obvious difference in AT2 receptor expression was observed between the two strains even after BCAS. These results suggest that IRF-1 has a protective effect on cognitive decline in a normal condition; however, there was no obvious effect on cognition after chronic cerebral hypoperfusion treatment.

DOI： 10.1038/s41440-018-0080-y

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Methylmercury (MeHg) is known to cause neurobehavioral impairment in human and experimental animals. We previously reported that MeHg (5 mg Hg/kg) induced severe neurobehavioral dysfunction in 4-week-old KK-Ay mice, although it is difficult to evaluate quantitatively the neurobehavioral impairment in MeHg-treated KK-Ay mice because of their obesity. The aim of this study was to evaluate MeHg-induced neurobehavioral dysfunction in KK-Ay mice using the dynamic weight-bearing test, which analyzes the animal's weight distribution between the four limbs. Male 12-week-old KK-Ay mice were treated with MeHg (5 mg Hg/kg) three times per week for 5 weeks. Body weight loss began after approximately 2 weeks of MeHg treatment, and decreased significantly at 4 weeks. Seven of the nine MeHg-treated mice exhibited overt neurological symptoms such as ataxia and gait disturbance. The weight-bearing load was lower for the forelimb than for the hindlimb at baseline and until 1 week after MeHg treatment was initiated. In weeks 2-4, the dynamic weight-bearing loads on the forelimb and hindlimb were similar. The load on the forelimb exceeded the load on the hindlimb after 5 weeks of treatment. This finding indicates that the dynamic weight-bearing test is useful for semi-quantitative evaluation of neurobehavioral impairment in MeHg-treated rodents, and is less stressful for the animals. Infiltration of CD204-positive macrophages was observed in the sciatic nerve of MeHg-treated mice, suggesting that CD204 can serve as a useful marker of tissue injury in peripheral nerves and a possible target in regenerating peripheral nerves and controlling neuropathies.

DOI： 10.1002/jat.3710

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science  

Mast cells, in addition to endocrine cells and neurons, are typical secretory cells. Their function in allergic inflammation is to secrete inflammatory mediators from secretory vesicles. Intracellular synthesized inflammatory mediators are transported by vesicular monoamine transporters (VMATs) to vesicles where they are stored. After stimulation, the contents of the secretory vesicles are released via exocytosis. This study established a high throughput imaging screening system to monitor the functions of secretory vesicles in mast cells, including molecular uptake via VMAT2 and the exocytotic process, by using a novel fluorescent probe, FFN206, which was developed as a VMAT2 substrate. After loading with FFN206, the rapid uptake of FFN206 was observed and secretory vesicles in mouse bone marrow derived mast cells and a cultured mast cell line were clearly visualized. FFN206 uptake by secretory vesicles was time-dependent and was blocked by reserpine. Furthermore, exocytotic trafficking was monitored dynamically by real-time high-throughput fluorescence quantitation. In the present study, we verified the application of FFN206 for the monitoring of functional vesicles. This high-throughput screening system may benefit instinctive drug evaluation.

DOI： 10.1371/journal.pone.0198785

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

Our previous report indicated that sarcopenia is associated with arterial stiffness and cardiovascular death. The renin-angiotensin system (RAS) plays an important role in cardiovascular disease and its activation may be correlated with sarcopenia according to basic research. However, few clinical studies have assessed the correlation between skeletal muscle loss and RAS component concentrations in healthy subjects. The purpose of this study was to investigate the relationships between the excretion of angiotensinogen (AGT) and aldosterone (Ald) in 24-h urine samples and clinical and sarcopenic indices. A total of 344 people participated in a voluntary medical check-up program, "Anti-Aging Doc", and underwent measurement of their sarcopenia-related indices. Urine samples were collected for 24-h within 8 weeks after a medical check-up using a partition cup and a proportional sampling method. Urine AGT and Ald levels were evaluated by enzyme-linked immunosorbent assay (ELISA). After compensating for possible confounding parameters, including baPWV, the 24-h urinary excretion of AGT was independently and negatively associated with the thigh muscle cross-sectional area. On the other hand, urinary Ald excretion was not associated with sarcopenia-related indices after compensation, even though it showed a modest but significantly positive association with sarcopenic indices in single regression analysis. Urinary AGT was related to sarcopenic indices and may be involved in the pathogenesis of sarcopenia. On the other hand, urinary Ald was not related to sarcopenic indices when considering other risk factors.

DOI： 10.1038/s41440-018-0021-9

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Inc.  

Nitrogen-containing bisphosphonates (NBPs) have been widely used as bone anti-resorptive drugs for the treatment of osteoclast-dependent bone disorders. Zoledronate is currently the most potent NBP, and has potential as an inhibitor of farnesyl pyrophosphate synthase. The present study was undertaken to elucidate the possible effects of zoledronate on FcεRI-dependent mast cell activity in vitro, which is essential for in maintaining homeostasis of the gastrointestinal mucosa. Treatment with zoledronate significantly diminished exocytosis of mast cells, which was reflected by a decrease of FcεRI-dependent histamine release compared to that in vehicle-treated mast cells. Our single-vesicle monitoring and biochemical results suggested that zoledronate modulates intracellular formation of the myosinVa/Rab3a complex and syntaxin4/VAMP7 complex, which are critical in vesicle motility, and therefore disturbs exocytosis via suppression of the velocity of intracellular vesicles and inhibition of membrane fusion. Our findings imply that oral administration of zoledronate could modulate mucosal immune function by blocking mast cell function, and this risk should be of concern in the clinical usage of NBPs.

DOI： 10.1016/j.bcp.2018.02.013

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science  

The Morris water maze test (MWM) is a useful tool to evaluate rodents’ spatial learning and memory, but the outcome is susceptible to various experimental conditions. Thigmotaxis is a commonly observed behavioral pattern which is thought to be related to anxiety or fear. This behavior is associated with prolonged escape latency, but the impact of its frequency in the early stage on the final outcome is not clearly understood. We analyzed swim path trajectories in male C57BL/6 mice with or without bilateral common carotid artery stenosis (BCAS) treatment. There was no significant difference in the frequencies of particular types of trajectories according to ischemic brain surgery. The mouse groups with thigmotaxis showed significantly prolonged escape latency and lower cognitive score on day 5 compared to those without thigmotaxis. As the next step, we made a convolutional neural network (CNN) model to recognize the swim path trajectories. Our model could distinguish thigmotaxis from other trajectories with 96% accuracy and specificity as high as 0.98. These results suggest that thigmotaxis in the early training stage is a predictive factor for impaired performance in MWM, and machine learning can detect such behavior easily and automatically.

DOI： 10.1371/journal.pone.0197003

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本腎臓学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media S.A.  

G-protein-coupled receptors (GPCRs) are membrane proteins distributed on the cell surface, and they may be potential drug targets. However, synthesizing GPCRs in vitro can be challenging. Recently, some cell-free protein synthesis systems have been shown to produce a large amount of membrane protein combined with chemical chaperones that include liposomes and glycerol. Liposomes containing high concentrations of glycerol are known as glycerosomes, which are used in new drug delivery systems. Glycerosomes have greater morphological stability than liposomes. Proteoglycerosomes are defined as glycerosomes that contain membrane proteins. Human histamine H1 receptor (HRH1) is one of the most studied GPCRs. In this study, we synthesized wild-type HRH1 (WT-HRH1) proteoglycerosomes and D107A-HRH1, (in which Asp107 was replaced by Ala) in a wheat germ cell-free protein synthesis system combined with asolectin glycerosomes. The mutant HRH1 has been reported to have low affinity for the H1 antagonist. In this study, the amount of synthesized WT-HRH1 in one synthesis reaction was 434 ± 66.6 μg (7.75 ± 1.19 × 103pmol). The specific binding of [3H]pyrilamine to the WT-HRH1 proteoglycerosomes became saturated as the concentration of the radioligand increased. The dissociation constant (Kd) and maximum density (Bmax) of the synthesized WT-HRH1 were 9.76 ± 1.25 nM and 21.4 ± 0.936 pmol/mg protein, respectively. However, specific binding to D107A-HRH1 was reduced compared with WT-HRH1 and the binding did not become saturated. The findings of this study highlight that HRH1 synthesized using a wheat germ cell-free protein synthesis system combined with glycerosomes has the ability to bind to H1 antagonists.

DOI： 10.3389/fphar.2018.00038

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Heart Association Inc.  

Background--The classical renin-angiotensin system is known as the angiotensin (Ang)-converting enzyme/Ang II/Ang type 1 receptor axis, which induces various organ damage including cognitive decline. The angiotensin-converting enzyme 2/Ang-(1-7)/ Mas axis is known to exert antagonistic actions against the classical renin-angiotensin system axis in the cardiovascular system. However, its roles in the brain remain unclear. We examined possible roles of the angiotensin-converting enzyme 2/Ang-(1-7)/Mas axis in cognitive function, employing vascular cognitive impairment model mice. Methods and Results--Male 10-week-old C57BL6 (wild-type mice, Mas1 knockout mice, Ang II type 2 receptor knockout mice, and Ang II type 2 receptor/Mas1 double knockout mice were subjected to bilateral carotid artery stenosis (BCAS) surgery. Six weeks after treatment, they were subjected to cognitive tasks. Brain samples were used for histopathological analysis. Cognitive function was significantly impaired in wild-type and double knockout mice after BCAS. On the other hand, the cognitive function of Mas1 knockout mice was maintained in spite of the reduction of cerebral blood flow with BCAS. Total cell number in the dentate gyrus region was significantly reduced after BCAS in wild-type but not in Mas1 knockout mice. The number of doublecortin-positive cells in the subgranular zone was not significantly different between wild-type and Mas1 knockout mice. Ang-(1-7) administration did not improve cognitive function in all mice after BCAS surgery. Conclusions--Lack of the Mas receptor may have a protective effect against chronic brain ischemia when the Ang II type 2 receptor exists.

DOI： 10.1161/JAHA.117.008121

Scopus

PubMed

researchmap

Publishing type：Part of collection (book)  

The diagnosis of vasculitis in rheumatoid arthritis (RV) is associated with considerable mortality; therefore, understanding the basic mechanisms underlying the pathogenesis of vasculitis is very important. Animal models of vasculitis have contributed to elucidating such mechanisms. We here introduce a Candida albicans water-soluble (CAWS) glycoprotein-induced vasculitis model and the methodological approach to evaluate inflammatory vascular change.

DOI： 10.1007/978-1-4939-8802-0_23

Scopus

PubMed

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

Increase in milk and dairy intake reduces the development of all-cause dementia, especially Alzheimer's disease(AD)in elderly Japanese population from the Hisayama study. Recent meta-analysis also indicates that beneficial effect of milk and dairy intake on cognitive disorders is significantly observed in Asian population. We have reported that oral administration of milk peptide, CH-3 to AD model mice not only improved cognitive function but also suppressed the expression of inflammatory cytokines and production of oxidative stress. Moreover, administration of other milk proteins improves cognitive function or outcome in AD patients. These findings indicate that milk and dairy intake have possible anti-dementia effects. Further analysis should be necessary to overcome the explosion of dementia worldwide with lifestyle modification.

PubMed

researchmap

DOI： 10.1097/01.hjh.0000500987.39434.12

PubMed

researchmap

DOI： 10.1097/01.hjh.0000500554.97597.16

PubMed

researchmap

Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/hr.2016.3

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Angiotensin II type 2 (AT(2)) receptor stimulation could exert beneficial effects on vascular remodeling. Previously, we reported that AT(2) receptor stimulation ameliorated insulin resistance in diabetic mice accompanied by PPAR gamma activation which also plays a variety of crucial roles in the vasculature. Therefore, this study aimed to investigate the vascular protective effect of the AT(2) receptor with activation of PPAR gamma involving AT(2) receptor-interacting protein (ATIP).
Vascular injury was induced by polyethylene-cuff placement around the femoral artery in C57BL/6J mice. Treatment with compound 21 (C21), an AT(2) receptor agonist, decreased neointimal formation, cell proliferation, and the mRNA levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-alpha, and interleukin-1 beta, and phosphorylation of nuclear factor-kappa B, and increased PPAR gamma DNA-binding activity in the injured artery, whereas these inhibitory effects of C21 were attenuated by co-treatment with a PPAR gamma antagonist, GW9662. Treatment of vascular smooth muscle cells (VSMC) with C21 prepared from smAT(2) transgenic mice, which highly express the AT(2) receptor in VSMC, increased both PPAR gamma activity and its DNA-binding activity determined by dual-luciferase assay and electrophoresis mobility shift assay (EMSA), respectively. We observed that ATIP was involved in PPAR gamma complex formation, and that transfection of siRNA of ATIP1 attenuated the AT(2) receptor-mediated increase in PPAR gamma activity in VSMC. In response to AT(2) receptor stimulation, ATIP was translocated from the plasma membrane to the nucleus.
Our results suggest a new mechanism by which AT(2) receptor stimulation activates PPAR gamma, thereby resulting in amelioration of vascular intimal proliferation, and that ATIP plays an important role in AT(2) receptor-mediated PPAR gamma activation.

DOI： 10.1093/ajh/hpv168

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

BACKGROUND
We investigated the effects of fetal growth restriction (FGR) induced by maternal protein restriction on inflammatory vascular remodeling using a cuff-induced vascular injury mouse model.
METHODS
Dams (C57BL/6J strain mice) were fed an isocaloric diet containing 20% protein (normal protein; NP) or 8% protein (low protein; LP) from 10 weeks of age until delivery. On the day of delivery, all dams were returned to the NP diet. After weaning, offspring were fed the NP diet. When offspring were 10 weeks of age, vascular injury was induced by polyethylene cuff placement around the femoral artery.
RESULTS
Birth weight in offspring from dams fed LP until delivery (LPO) was significantly lower, but body weight was the same at 2 weeks after birth compared with that in NP offspring (NPO). Arterial blood pressure at 12 weeks of age did not differ between LPO and NPO. Neointima formation was exaggerated in LPO compared with NPO and associated with an increase in cell proliferation assessed by proliferating cell nuclear antigen (PCNA) staining index. Moreover, LPO showed enhanced expression of monocyte chemotactic protein-1, interleukin (IL)-6, IL-1 beta, tumor necrosis factor-a, and production of superoxide anion in the injured artery. Moreover, mRNA expression of isoforms of NAD(P)H oxidase subunits such as p22phox, p40phox, p47phox, p67phox, gp91phpx, and Rac1 in the injured arteries were enhanced in LPO. Furthermore, HIF-1 alpha expression was increased in LPO compared with that in NPO.
CONCLUSIONS
These results suggest that maternal low-protein diet-induced FGR increases susceptibility of the vasculature to postnatal injury.

DOI： 10.1093/ajh/hpv072

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Aims/hypothesis Recent clinical studies have shown that renal sympathetic denervation (RDX) improves glucose metabolism in patients with resistant hypertension. We aimed to elucidate the potential contribution of the renal sympathetic nervous system to glucose metabolism during the development of type 2 diabetes.
Methods Uninephrectomised diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats underwent RDX at 25 weeks of age and were followed up to 46 weeks of age.
Results RDX decreased plasma and renal tissue noradrenaline (norepinephrine) levels and BP. RDX also improved glucose metabolism and insulin sensitivity, which was associated with increased in vivo glucose uptake by peripheral tissues. Furthermore, RDX suppressed overexpression of sodium-glucose cotransporter 2 (Sglt2 [also known as Slc5a2]) in renal tissues, which was followed by an augmentation of glycosuria in type 2 diabetic OLETF rats. Similar improvements in glucose metabolism after RDX were observed in young OLETF rats at the prediabetic stage (21 weeks of age) without changing BP.
Conclusions/interpretation Here, we propose the new concept of a connection between renal glucose metabolism and the renal sympathetic nervous system during the development of type 2 diabetes. Our data demonstrate that RDX exerts beneficial effects on glucose metabolism by an increase in tissue glucose uptake and glycosuria induced by Sglt2 suppression. These data have provided a new insight not only into the treatment of hypertensive type 2 diabetic patients, but also the pathophysiology of insulin resistance manifested by sympathetic hyperactivity.

DOI： 10.1007/s00125-015-3771-9

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Introduction: Binge eating disorder (BED) is associated with dopaminergic activation as food reward, resulting in metabolism-related disorders. Stimulation of angiotensin type 2 (AT(2)) receptor is reported to inhibit dopamine synthesis. We investigated the possible roles of AT(2) receptor-mediated dopamine regulation in the pathogenesis of BED.
Materials and methods: Male C57BL/6 mice, type 2 diabetic (KKAy) mice and AT(2) receptor-null (AT(2)KO) mice at eight weeks old were treated with AT(2) receptor agonist, compound 21 (C21) or saline for two weeks. Mice were subjected to fasting for two days followed by re-feeding for seven days.
Results: Treatment with C21 attenuated the rebound proportion of body weight, food intake and water intake in KKAy mice, but not in C57BL/6 and AT(2)KO mice. Dopamine concentration in the striatum was further increased by fasting in KKAy and AT(2)KO mice. Administration of C21 significantly attenuated this fasting-induced increase in dopamine level only in KKAy mice. Dopamine receptor D1, D2 expression in the substantia nigra were markedly lower in KKAy mice compared with C57BL/6 mice, while administration of C21 increased their expression in KKAy mice.
Conclusions: Our study suggests that AT(2) receptor stimulation may be a new therapeutic approach to improve eating disorder associated with dopamine resistance.

DOI： 10.1177/1470320315573680

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The purpose of this study was to investigate the behavior of platelets (rolling and adhesion) in cerebral microvessels of angiotensin II type-2 receptor-knockout (AT2RKO) mice after transient bilateral carotid artery occlusion using intravital fluorescence microscopy. Twenty AT2RKO mice, consisting of 11 mice in the sham group and 9 mice in the ischemia reperfusion group (reperfusion after 15 min of bilateral, total carotid artery occlusion) were used in this study. The hole traversed the bone and dura mater, but arachnoid, pia mater, and cerebral parenchyma were preserved. Platelets were harvested from donor mice and stained using carboxyfluorescein diacetate succinimidyl ester. The number of platelets showing rolling and adhesion to pial vessels in AT2 deficient mice at 3 and 6 h after cerebral ischemia reperfusion was significantly higher than that in the sham group (P &lt; 0.05). In addition, AT2 receptor has an inhibitory role in platelet rolling and adhesion after cerebral ischemia reperfusion.

DOI： 10.1007/s11239-015-1254-y

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/hr.2015.87

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Angiotensin II receptor blockers (ARBs) are known to prevent ischemic brain damage after stroke. Natriuretic peptides, which are increased by a neprilysin inhibitor, are also reported to protect against brain damage. Therefore, we investigated the possible protective effect of valsartan (VAL) compared with LCZ696 (VAL+ neprilysin inhibitor; 1:1) after middle cerebral artery (MCA) occlusion. Eight-week-old male C57BL/6J mice were treated with VAL (3 mg/kg per day) or LCZ696 (6 mg/kg per day) for 2 weeks before MCA occlusion. Blood pressure and heart rate were measured by telemetry. Cerebral blood flow (CBF) was determined by laser-Doppler flowmetry, Ischemic area was evaluated by tripherlytetrasodium chloride staining, and oxidative stress was determined by dihydroethidium staining. Blood pressure and heart rate were not significantly different before and after treatment. Pre-treatment with LCZ696 or VAL reduced the ischemic area, and this effect of LCZ696 was more marked than that of VAL pre-treatment. The decrease in CBF in the peripheral region of the ischemic area was significantly attenuated by pretreatment with LCZ696 or VAL, without any significant effect on CBF in the core region. VAL or LCZ696 pre-treatment significantly decreased the increase of superoxide anion production in the cortex on the ischemic side. However, no significant difference in CBE. and superoxide anion production was observed between VAL and LCZ696 pre-treatment. The preventive effect of LCZ696 on ischemic brain damage after stroke was more marked than that of VAL. LCZ696 could be used as a new approach to prevent brain damage after stroke. (246 words) (C) 2015 Elsevier B.V. All rights reserved,

DOI： 10.1016/j.ejphar.2015.05.059

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Angiotensin II type 2 (AT(2)) receptor activation has been reported to play a role in cognitive function, although its detailed mechanisms and pathologic significance are not fully understood. We examined the possibility that direct AT(2) receptor stimulation by compound 21 (C2I) could prevent cognitive decline associated with hypoperfusion in the brain. We employed a bilateral common carotid artery stenosis (BCAS) model in mice as a model of vascular dementia. The Morris water maze task was performed 6 weeks after BCAS operation. Azilsartan (0.1 mg/kg/day) or C2I (10 Ag/kg/day) was administered from I week before BCAS. Cerebral blood flow (CBF) and inflammatory cytokine levels were also determined. Wild type (WT) mice showed significant prolongation of escape latency after BCAS, and this cognitive impairment was attenuated by pretreatment with azilsartan. Cognitive impairment was more marked in AT(2) receptor knockout (AT(2)KO) mice, and the preventive effect of azilsartan on cognitive decline was weaker in AT(2)KO mice than in WT mice, suggesting that the improvement of cognitive decline by azilsartan may involve stimulation of the AT(2) receptor. The significant impairment of spatial learning after BCAS in WT mice was attenuated by C2I treatment. The decrease in CBF in the BCAS treated group was blunted by C2I treatment, and the increase in TNF-alpha and MCP-1 mRNA expression after BCAS was attenuated by C2I treatment. These findings indicate that direct AT(2) receptor stimulation attenuates ischemic vascular dementia induced by hypoperfusion at least in part through an increase in CBF, and a reduction of inflammation. (C) 2015 American Society of Hypertension. All rights reserved.

DOI： 10.1016/j.jash.2015.01.010

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Citrus fruits are thought to have inhibitory effects on oxidative stress, thereby attenuating the onset and progression of cancer and cardiovascular disease; however, there are few reports assessing their effect on vascular remodeling. Here, we investigated the effect of drinking the juice of two different citrus fruits on vascular neointima formation using a cuff-induced vascular injury mouse model. Male C57BL6 mice were divided into five groups as follows: 1) Control (water) (C), 2) 10% Citrus unshiu (CU) juice (CU10), 3) 40% CU juice (CU40), 4) 10% Citrus iyo (CI) juice (CI10), and 5) 40% CI juice (CI40). After drinking them for 2 weeks from 8 weeks of age, cuff injury was induced by polyethylene cuff placement around the femoral artery. Neointima formation was significantly attenuated in CU40, CI10 and CI40 compared with C; however, no remarkable preventive effect was observed in CU10. The increases in levels of various inflammatory markers including cytokines such as monocyte chemotactic protein-1, interleukin-6 (IL-6), IL-1 beta, and tumor necrosis factor-alpha in response to vascular injury did not differ significantly between C, CU10 and CI10. The increases in cell proliferation and superoxide anion production were markedly attenuated in CI10, but not in CU10 compared with C. The increase in phosphorylated ERK expression was markedly attenuated both in CU10 and CI10 without significant difference between CU10 and CI10. Accumulation of immune cells did not differ between CU10 and CI10. These results indicate that drinking citrus fruit juice attenuates vascular remodeling partly via a reduction of oxidative stress. Interestingly, the preventive efficacy on neointima formation was stronger in CI than in CU at least in part due to more prominent inhibitory effects on oxidative stress by CI.

DOI： 10.1371/journal.pone.0117616

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

AimThe renin-angiotensin system (RAS) is involved in the pathogenesis of ischemic brain damage, and is suggested to have therapeutic potential in stroke by large clinical trials. However, the changes of serum RAS components in patients with acute stroke are totally unknown. We assessed the serum levels of RAS components in acute stroke patients, and investigated the relationship between RAS and stroke subtype.
MethodsLevels of angiotensin-converting enzyme (ACE), ACE2 and angiotensinII in serum from patients with acute stroke (n=117; male 75, female 42, age 6913years) were measured by an established enzyme-linked immunosorbent assay method. Diagnosis of subtypes of ischemic stroke was based on the Trial of Org10172 in Acute Stroke Treatment classification. The Kruskal-Wallis test with post-hoc Mann-Whitney U-test with Bonferroni correction was carried out for statistical analysis.
ResultsClassification of stroke was as follows: large-artery atherosclerosis (n=44), cardioembolism (n=33), small-vessel occlusion (n=31), stroke of other determined etiology (n=9). Levels of angiotensinII and ACE did not show significant differences among each group. However, serum ACE2 level was significantly higher in the cardioembolism group than in the small-vessel occlusion group (cardioembolism 13 +/- 9.3ng/mL, large-artery atherosclerosis 10.2 +/- 6.8ng/mL, small-vessel occlusion 7.2 +/- 3.7ng/mL, stroke of other determined etiology 10.2 +/- 7.3ng/mL). ACE2 level showed a positive correlation with serum brain natriuretic peptide level (P=0.031). In contrast, angiotensinII concentration showed a negative correlation with National Institute of Health Stroke Scale score on admission (P=0.023).
ConclusionsThese findings suggest that changes of serum RAS components could reflect stroke subtypes and predict stroke severity. Geriatr Gerontol Int 2014; 14: 793-798.

DOI： 10.1111/ggi.12167

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Background
Stroke is a leading cause of death and disability; however, meta-analysis of randomized controlled trials of blood pressure-lowering drugs in acute stroke has shown no definite evidence of a beneficial effect on functional outcome. Accumulating evidence suggests that angiotensin II type 1 receptor blockade with angiotensin II type 2 (AT(2)) receptor stimulation could contribute to protection against ischemic brain damage. We examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) initiated even after stroke can prevent ischemic brain damage.
Methods
Stroke was induced by middle cerebral artery (MCA) occlusion, and the area of cerebral infarction was measured by magnetic resonant imaging. C21 (10 mu g/kg/day) treatment was initiated immediately after MCA occlusion by intraperitoneal injection followed by treatment with C21 once daily.
Results
We observed that ischemic area was enlarged in a time dependent fashion and decreased on day 5 after MCA occlusion. Treatment with C21 initiated after MCA occlusion significantly reduced the ischemic area, with improvement of neurological deficit in a time-dependent manner without affecting blood pressure. The decrease of cerebral blood flow after MCA occlusion was also ameliorated by C21 treatment. Moreover, treatment with C21 significantly attenuated superoxide anion production and expression of proinflammatory cytokines, monocyte chemoattractant protein 1, and tumor necrosis factor a. Interestingly, C21 administration significantly decreased blood-brain barrier permeability and cerebral edema on the ischemic side.
Conclusions
These results provide new evidence that direct AT2 receptor stimulation with C21 is a novel therapeutic approach to prevent ischemic brain damage after acute stroke.

DOI： 10.1093/ajh/hpu015

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/Mas axis against the ACE/Ang II/Ang II type 1 (AT(1)) receptor axis in blood pressure control has been previously described. We examined the possibility that this pathway might be involved in the anti-hypertensive effect of a newly developed AT(1) receptor blocker (ARB), azilsartan, and compared azilsartan's effects with those of another ARB, olmesartan. Transgenic mice carrying the human renin and angiotensinogen genes (hRN/hANG-Tg) were given azilsartan or olmesartan. Systolic and diastolic blood pressure, as determined by radiotelemetry, were significantly higher in hRN/hANG-Tg mice than in wild-type (WT) mice. Treatment with azilsartan or olmesartan (1 or 5 mg kg(-1) per day) significantly decreased systolic and diastolic blood pressure, and the blood pressure-lowering effect of azilsartan was more marked than that of olmesartan. The urinary Na concentration decreased in an age-dependent manner in hRN/hANG-Tg mice. Administration of azilsartan or olmesartan increased urinary Na concentration, and this effect was weaker with olmesartan than with azilsartan. Azilsartan decreased ENaC-alpha mRNA expression in the kidney and decreased the ratio of heart to body weight. Olmesartan had a similar but less-marked effect. ACE2 mRNA expression was lower in the kidneys and hearts of hRN/hANG-Tg mice than in WT mice. This decrease in ACE2 mRNA expression was attenuated by azilsartan, but not by olmesartan. These results suggest that the hypotensive and anti-hypertrophic effects of azilsartan may involve activation of the ACE2/Ang-(1-7)/Mas axis with AT(1) receptor blockade.

DOI： 10.1038/hr.2014.49

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Cross talk between the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis and the ACE2/Ang-(1-7)/Mas axis plays a role in the pathogenesis of cardiovascular remodeling. Furthermore, possible stimulation of the Ang II type 2 (AT2) receptor by Ang-(1-7) has been highlighted as a new pathway. Therefore, we examined the possibility of whether the ACE2/Ang-(1-7)/Mas axis and Ang-(1-7)/AT2 receptor axis are involved in the inhibitory effects of AT1 receptor blockers on vascular remodeling. Wild-type, Mas-knockout, and AT2 receptor knockout mice were used in this study. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. Some mice were treated with azilsartan, an AT1 receptor blocker, or Ang-(1-7). Neointimal formation 2 weeks after cuff placement was more marked in Mas-knockout mice compared with wild-type mice. Treatment with azilsartan or Ang-(1-7) attenuated neointimal area, vascular smooth muscle cell proliferation, increases in the mRNA levels of monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1β, and superoxide anion production in the injured artery; however, these inhibitory effects of azilsartan and Ang-(1-7) were less marked in Mas-knockout mice. Administration of azilsartan or Ang-(1-7) attenuated the decrease in ACE2 mRNA and increased AT2 receptor mRNA but did not affect AT1 receptor mRNA or the decrease in Mas mRNA. The inhibitory effect of Ang-(1-7) on neointimal formation was less marked in AT2 receptor knockout mice compared with wild-type mice. These results suggest that blockade of the AT1 receptor by azilsartan could enhance the activities of the ACE2/Ang-(1-7)/Mas axis and ACE2/Ang-(1-7)/AT2 receptor axis, thereby inhibiting neointimal formation.

DOI： 10.1161/HYPERTENSIONAHA.113.02426

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Type 2 diabetes mellitus (T2DM) is known to be associated with increased risk of cognitive impairment including Alzheimer disease. Recent studies have suggested an interaction between angiotensin II and N-methyl-D-aspartic acid (NMDA) glutamate receptors. We previously reported that stimulation of the angiotensin II type 2 (AT(2)) receptor exerts brain protective effects. A newly developed AT(2) receptor agonist, compound 21 (C21), has enabled examination of the direct effect of AT(2) receptor stimulation in vivo. Accordingly, we examined the possible synergistic effect of C21 and memantine on cognitive impairment in T2DM mice, KKAy. KKAy were divided into four groups; (1) control, (2) treatment with C21 (10 mu g/kg/day), (3) treatment with memantine (20 mg/kg/day), and (4) treatment with both for 4 weeks, and subjected to Morris water maze tasks. Treatment with C21 or memantine alone at these doses tended to shorten escape latency compared to that in the control group. C21 treatment increased cerebral blood flow (CBF), but memantine did not influence CBE Treatment with C21 or C21 plus memantine increased hippocampal field-excitatory postsynaptic potential (f-ERSP). Moreover, treatment with memantine or C21 increased acetylcholine level, which was lower in KKAy than in wild-type mice, and C21 plus memantine treatment enhanced memantine or C21-induced acetylcholine secretion. This study provides an insight into new approaches to understand the interaction of angiotensin II and neurotransmitters. We can anticipate a new therapeutic approach against cognitive decline using C21 and memantine. (C) 2013 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejphar.2013.12.015

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：English   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：English   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：English   Publisher：ELSEVIER IRELAND LTD  

The renin-angiotensin-aldosterone system (RAAS) is known to be closely linked to the pathogenesis of insulin resistance. The angiotensin (Ang) II type 1 (AT(1)) receptor mediates the major effects of Ang II in adipose tissue, and blockade of the AT(1) receptor improves insulin sensitivity, with enhanced adipocyte differentiation. In contrast, the role of angiotensin type 2 (AT(2)) receptor activation in insulin sensitivity is still controversial, although AT(2) receptor functions are thought to be mutually antagonistic against those of the AT(1) receptor in the cardiovascular system. Aldosterone exerts its biological roles via the mineral-corticoid receptor (MR), and inhibition of MR signaling in adipose tissue ameliorates inflammation, with upregulation of insulin-mediated glucose transport and adipocyte differentiation. Clinical studies indicate that blockade of RAAS prevents the new onset of type 2 diabetes and improves the metabolic syndrome in diabetic patients. We here review the recent concepts of the roles of RAAS in adipose tissue. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2012.03.005

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本抗加齢医学会  

researchmap

Language：Japanese   Publisher：(一社)日本老年医学会  

researchmap

Language：Japanese   Publisher：(一社)日本老年医学会  

researchmap

Language：Japanese   Publisher：(一社)日本老年医学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

We demonstrated that angiotensin II type 2 (AT(2)) receptor-interacting protein (ATIP) 1 ameliorates inflammation-mediated vascular remodeling independent of the AT(2) receptor, leading us to explore the possibility of whether ATIP1 could exert anti-inflammatory effects and play a role in other pathophysiological conditions. We examined the possible anti-inflammatory effects of ATIP1 in adipose tissue associated with amelioration of insulin resistance. In mice fed a high-cholesterol diet, adipose tissue macrophage (ATM) infiltration and M1-to-M2 ratio were decreased in ATIP1 transgenic mice (ATIP1-Tg) compared with wild-type mice (WT), with decreased expression of inflammatory cytokines such as tumor necrosis factor-alpha and monocyte chemoattractant protein-1 in white adipose tissue (WAT), but an increase in interleukin-10, an anti-inflammatory cytokine. Moreover, 2-[H-3]deoxy-d-glucose (2-[H-3]DG) uptake was significantly increased in ATIP1-Tg compared with WT. Next, we examined the roles of ATIP1 in BM-derived hematopoietic cells, employing chimeric mice produced by BM transplantation into irradiated type 2 diabetic mice with obesity, KKAy, as recipients. ATM infiltration and M1-to-M2 ratio were decreased in ATIP1 chimera (ATIP1-tg as BM donor), with improvement of insulin-mediated 2-[H-3] DG uptake and amelioration of inflammation in WAT. Moreover, serum adiponectin concentration in ATIP1 chimera was significantly higher than that in WT chimera (WT as BM donor) and KKAy chimera (KKAy as BM donor). These results indicate that ATIP1 could exert anti-inflammatory effects in adipose tissue via macrophage polarization associated with improvement of insulin resistance, and ATIP1 in hematopoietic cells may contribute to these beneficial effects on adipose tissue functions in type 2 diabetes.

DOI： 10.1371/journal.pone.0060067

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：WILEY  

Here, we briefly review the role of the renin-angiotensin system (RAS) in cognitive impairment and neurodegenerative disease, mainly discussing our experimental studies on the angiotensin II type 2 (AT(2)) receptor. Ischemic brain damage is enhanced in mice with overexpression of angiotensin II, with reduced cerebral blood flow in the penumbra and an increase in oxidative stress in the ischemic area. Angiotensin II binds two types of receptors, type 1 (AT(1)) and type 2 (AT(2)). Our previous experiments showed that AT(1) receptor signaling has a harmful effect, and AT(2) receptor signaling has a protective effect on the brain after stroke. AT(2) receptor signaling in bone marrow stromal cells or hematopoietic cells was shown to prevent ischemic brain damage after middle cerebral artery occlusion. In contrast, AT(2) receptor signaling also affects cognitive function. We showed that direct stimulation of the AT(2) receptor by a newly generated direct AT(2) receptor agonist, Compound 21 (C21), enhanced cognitive function in wild-type (C57BL6) mice and an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid beta (1-40). Finally, we carried out clinical research by investigating the levels of RAS components in patients with neurodegenerative diseases. We observed a reduction of angiotensin II and angiotensin converting enzyme (ACE) 2 levels, and an increase in ACE level in cerebrospinal fluid from patients with multiple sclerosis. These results suggest that RAS is also involved in neurodegenerative disease. Therefore, regulation of RAS might be a new therapeutic target to protect neurons from neural diseases. Geriatr Gerontol Int 2013; 13: 13-18.

DOI： 10.1111/j.1447-0594.2012.00900.x

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The renin-angiotensin system (RAS) has been postulated to regulate not only systemic hemodynamic and hydromineral homeostasis but also individualorgan function in the normal condition. On the other hand, its systemic and localactivationleads to hypertension and diabetes mellitus,resulting intarget end organ damage.RAS in the brain is also well known to be involved in the pathogenesis and progression of neuronal disease, as well as regulating blood pressure, sympathetic activity, vasopressin secretion, thirst and sodium appetite.There is increasing evidence that RAS may contribute to neuroinflammation associated with many neuronal diseases in several animal models. Moreover, recent clinical evidence indicates that RAS blockade, including that byangiotensin converting enzyme inhibitors and angiotensin II receptor blockers, has beneficial effects in treating stroke, cognitive dysfunction, Alzheimer disease and other neuronal diseases, suggesting the potential of RAS as a new therapeutic target in neuronal diseases. This article reviews the recent findings ofbrain RAS involvement and thetherapeutic potential of regulating RAS in neuronal disease. © 2013 Bentham Science Publishers.

DOI： 10.2174/15734021113099990004

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2174/15734021113099990001

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Additional beneficial effects of angiotensin II type 1 (AT(1)) receptor blockers beyond AT(1) receptor blockade have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2). We examined the possible synergistic effects of the combination of irbesartan with rosuvastatin on preventing vascular remodeling focusing on the MCP-1/CCR2 pathway. We observed that administration of irbesartan and CCR2 antagonist, propagermanium, at noneffective doses, decreased the neointima with a decrease in PCNA labeling index in the injured mouse femoral artery induced by cuff placement. We also observed that administration of a noneffective dose of rosuvastatin with propagermanium decreased the neointima area, suggesting that the inhibitory effect of rosuvastatin on neointima formation is at least partly attributable to blockade of the MCP-1/CCR2 pathway. Moreover, we demonstrated that the combination of irbesartan with rosuvastatin decreased neointima formation. MCP-1 mRNA level was significantly increased in injured femoral arteries, and administration of irbesartan with rosuvastatin decreased the mRNA levels of MCP-1, TNF alpha, and IL-1 beta, and increased PPAR gamma mRNA expression. These results suggest that the synergistic inhibitory effects of irbesartan with rosuvastatin on neointima formation may involve attenuation of MCP-1/CCR2 signaling. J Am Soc Hypertens 2012;6(6):375-384. (C) 2012 American Society of Hypertension. All rights reserved.

DOI： 10.1016/j.jash.2012.10.002

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Objectives: The role of angiotensin II type 2 (AT(2)) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type 2 diabetes (T2DM) with PPAR gamma activation, mainly focusing on adipose tissue.
Methods: T2DM mice, KK-Ay, were subjected to intraperitoneal injection of C21 and/or a PPAR gamma antagonist, GW9662 in drinking water for 2 weeks. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[H-3] deoxy-D-glucose in white adipose tissue. Morphological changes of adipose tissues as well as adipocyte differentiation and inflammatory response were examined.
Results: Treatment with C21 ameliorated insulin resistance in KK-Ay mice without influencing blood pressure, at least partially through effects on the PPAR gamma pathway. C21 treatment increased serum adiponectin concentration and decreased TNF-alpha concentration; however, these effects were attenuated by PPAR gamma blockade by co-treatment with GW9662. Moreover, we observed that administration of C21 enhanced adipocyte differentiation and PPAR gamma DNA-binding activity, with a decrease in inflammation in white adipose tissue, whereas these effects of C21 were attenuated by co-treatment with GW9662. We also observed that administration of C21 restored beta cell damage in diabetic pancreatic tissue.
Conclusion: The present study demonstrated that direct AT(2) receptor stimulation by C21 accompanied with PPAR gamma activation ameliorated insulin resistance in T2DM mice, at least partially due to improvement of adipocyte dysfunction and protection of pancreatic beta cells.

DOI： 10.1371/journal.pone.0048387

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese  

Angiotensin receptor blockers(ARBs) are used as the first-choice anti-hypertensives for prevention of multiple organ damage. Recently, the next-generation ARBs have been expected to have more preventive effect for cardiovascular diseases. For example, metabosartans which have a partial agonistic effect of peroxisome proliferator-activated receptor gamma induce an improvement of metabolism compared with ordinary ARBs. Moreover, LCZ696, ARB with a neprilysin inhibitor which increases natriuretic peptides has a significant reduction in blood pressure compared with ARB. Furthermore, ARBs with nitric oxide donor or endothelin receptor blocker have been reported to have a benefit beyond ordinary ARBs. Dual action in the next multi-functional ARBs may be a strong therapeutic contributor for patients with multiple organ dysfunction.

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

An adverse relationship between suboptimal fetal environments and the development of adult diseases, such as hypertension, type II diabetes, and cardiovascular disease, has been reported in numerous studies. The purpose of this study was to investigate the strain difference of offspring's response to maternal malnutrition during pregnancy and the involvement of the renin-angiotensin system (RAS) in the development of adult hypertension using C57BL/6J (C57) mice and angiotensin II (Ang II) type 1 receptor-associated protein-transgenic (ATRAP-Tg) mice. Pregnant dams were fed an isocaloric diet containing either 20% (normal protein; NP) or 8% (low protein; LP) protein. Birth weight was significantly reduced in C57-LP offspring, but not in ATRAP-Tg-LP offspring. Arterial blood pressure was higher in C57-LP offspring than in the other groups. In contrast, ATRAP-Tg-LP offspring did not show an increase in blood pressure compared with NP offspring. Renal angiotensin II type 1 (AT(1)) receptor expression was not altered by maternal malnutrition, whereas angiotensin II type 2 receptor expression was significantly decreased in C57-LP offspring. In conclusion, these findings suggest that a suboptimal intrauterine environment induces adult hypertension because of an alteration of expression of RAS components, which was partly suppressed by sustained ATRAP overexpression via attenuation of the AT(1) receptor-mediated pathological response. J Am Soc Hypertens 2012;6(5):324-330. (C) 2012 American Society of Hypertension. All rights reserved.

DOI： 10.1016/j.jash.2012.07.001

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：English   Publisher：PORTLAND PRESS LTD  

The RAS (renin-angiotensin system) plays a role not only in the cardiovascular system, including blood pressure regulation, but also in the central nervous system. AngII (angiotensin II) binds two major receptors: the AT(1) receptor (AngII type 1 receptor) and AT(2) receptor (AngII type 2 receptor). It has been recognized that AT(2) receptor activation not only opposes AT(1) receptor actions, but also has unique effects beyond inhibitory cross-talk with AT(1) receptor signalling. Novel pathways beyond the classical actions of RAS, the ACE (angiotensin-converting enzyme)/AngII/AT(1) receptor axis, have been highlighted: the ACE2/Ang-(1-7) [angiotensin-(1-7)]/Mas receptor axis as a new opposing axis against the ACE/AngII/AT(1) receptor axis, novel AngII-receptor-interacting proteins and various AngII-receptor-activation mechanisms including dimer formation. ATRAP (AT(1)-receptor-associated protein) and ATIP (AT(2)-receptor-interacting protein) are well-characterized AngII-receptor-associated proteins. These proteins could regulate the functions of AngII receptors and thereby influence various pathophysiological states. Moreover, the possible cross-talk between PPAR (peroxisome-proliferator-activated receptor)-gamma and AngII receptor subtypes is an intriguing issue to be addressed in order to understand the roles of RAS in the metabolic syndrome, and interestingly some ARBs (AT(1)-receptor blockers) have been reported to have an AT(1)-receptor-blocking action with a partial PPAR-gamma agonistic effect. These emerging concepts concerning the regulation of AngII receptors are discussed in the present review.

DOI： 10.1042/CS20110677

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Angiotensin II type 2 (AT(2)) receptor-interacting protein (ATIP), which interacts with the C-terminal tail of the AT(2) receptor, regulates the functions of the AT(2) receptor. We have reported that AT(2) receptor stimulation attenuated vascular senescence. Therefore, we examined the possible negative role of ATIP in regulating vascular senescence. We generated ATIP-transgenic (Tg) mice, and cultured vascular smooth muscle cells (VSMCs). Persistent angiotensin II stimulation induced increases in SA-beta-gal-positive cells and the level of a DNA damage marker, 8-OHdG in VSMC, whereas these effects of angiotensin II were attenuated in VSMC prepared from ATIP-Tg mice. Angiotensin II treatment also upregulated the expression of methyl methanesulfonate-sensitive 2 (MMS2), a DNA repair factor, and Src homology 2 domain-containing protein-tyrosine phosphatase I (SHP-1) activity, whereas these effects of angiotensin II were further enhanced in ATIP-Tg VSMC. In vivo, x-ray irradiation to mice caused increases in SA-beta-gal-positive area and 8-OHdG level in the thoracic aorta; however, these effects were reduced in ATIP-Tg mice, with a significant increase in MMS2 expression. These results suggest that ATIP could inhibit VSMC senescence, involving MMS2 expression and SHP-1 activity. ATIP might be a new therapeutic molecule to treat vascular aging and age-related vascular diseases. J Am Soc Hypertens 2012;6(3):179-184. (C) 2012 American Society of Hypertension. All rights reserved.

DOI： 10.1016/j.jash.2012.01.006

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

We reported previously that an angiotensin II type 1 receptor blocker, telmisartan, improved cognitive decline with peroxisome proliferator-activated receptor-gamma activation; however, the detailed mechanisms are unclear. Enhanced blood-brain barrier (BBB) permeability with alteration of tight junctions is suggested to be related to diabetes mellitus. Therefore, we examined the possibility that telmisartan could attenuate BBB impairment with peroxisome proliferator-activated receptor-gamma activation to improve diabetes mellitus-induced cognitive decline. Type 2 diabetic mice KKA(y) exhibited impairment of cognitive function, and telmisartan treatment attenuated this. Cotreatment with GW9662, a peroxisome proliferator-activated receptor-gamma antagonist, interfered with these protective effects of telmisartan against cognitive function. BBB permeability was increased in both the cortex and hippocampus in KKAy mice. Administration of telmisartan attenuated this increased BBB permeability. Coadministration of GW9662 reduced this effect of telmisartan. Significant decreases in expression of tight junction proteins and increases in matrix metalloproteinase expression, oxidative stress, and proinflammatory cytokine production were observed in the brain, and treatment with telmisartan restored these changes. Swollen astroglial end-feet in BBB were observed in KKAy mice, and this change in BBB ultrastructure was decreased in telmisartan. These effects of telmisartan were weakened by cotreatment with GW9662. In contrast, administration of another angiotensin II type 1 receptor blocker, losartan, was less effective compared with telmisartan in terms of preventing BBB permeability and astroglial end-foot swelling, and coadministration of GW9662 did not affect the effects of losartan. These findings are consistent with the possibility that, in type 2 diabetic mice, angiotensin II type 1 receptor blockade with peroxisome proliferator-activated receptor-gamma activation by telmisartan may help with protection against cognitive decline by preserving the integrity of the BBB.

DOI： 10.1161/HYPERTENSIONAHA.112.192401

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS LTD  

Patients with type 2 diabetes mellitus (T2DM) exhibit more severe cognitive decline in females compared with males; however, the preventive approach to this gender-specific cognitive decline is still an enigma. Spironolactone is a potassium-sparing diuretic that also acts as an androgen receptor antagonist. Here, we investigated whether spironolactone attenuates cognitive impairment observed in female T2DM mice. Adult wild-type (WT) mice and an obese T2DM model, KKAy mice, were employed in this study. Cognitive function was evaluated by the shuttle avoidance test and Morris water maze test. Administration of spironolactone (50 mg/kg per day in chow) had no significant effect on blood pressure, glucose tolerance or insulin resistance. In WT mice, no significant sex difference in cognitive function was observed; however, treatment with spironolactone improved spatial memory in the water maze, especially in female WT mice. Administration of spironolactone markedly improved the cognitive decline in female KKAy mice up to the level in male KKAy mice. Spironolactone treatment also improved cognitive function in ovariectomized-KKAy mice, but failed to improve it in those with administration of estradiol (200 A mu g/kg per day). In diabetic mice, spironolactone improved impaired cognitive function observed in female mice, suggesting that spironolactone may prevent cognitive impairment associated with diabetes in females clinically.

DOI： 10.1177/1470320311412810

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

We examined the possibility that direct stimulation of the angiotensin II type 2 (AT(2)) receptor by a newly generated direct AT(2) receptor agonist, Compound 21 (C21), enhances cognitive function. Treatment with C21 intraperitoneal injection for 2 weeks significantly enhanced cognitive function evaluated by the Morris water maze test in C57BL6 mice, but this effect was not observed in AT(2) receptor-deficient mice. However, C21-induced cognitive enhancement in C57BL6 mice was attenuated by coadministration of icatibant, a bradykinin B-2 receptor antagonist. Administration of C21 dose dependently increased cerebral blood flow assessed by laser speckle flowmetry and hippocampal field-excitatory postsynaptic potential (f-EPSP) determined by electrophysiological techniques in C57BL6 mice. Furthermore, activation of the AT(2) receptor by C21 promoted neurite outgrowth of cultured hippocampal neurons prepared from fetal transgenic mice expressing green fluorescent protein. Finally, we investigated the pathologic relevance of C21 for spatial learning using an Alzheimer's disease mouse model with intracerebroventricular injection of amyloid-beta (1 to 40). We observed that treatment with C21 prevented cognitive decline in this model. These results suggest that a direct AT(2) receptor agonist, C21, enhances cognitive function at least owing to an increase in CBF, enhancement of f-EPSP, and neurite outgrowth in hippocampal neurons. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 248-255; doi:10.1038/jcbfm.2011.133; published online 5 October 2011

DOI： 10.1038/jcbfm.2011.133

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Interleukin 17 (IL-17) is known to contribute to the pathogenesis of hypertension, atherosclerosis, and adipocyte differentiation; however, the roles of IL-17 in glucose metabolism remain to be elucidated. Angiotensin II type 1 receptor blockers improve insulin resistance at least in part because of the amelioration of inflammation. Therefore, we examined the possible roles of IL-17 in the pathogenesis of insulin resistance in type 2 diabetes mellitus using a mouse model, KK-Ay, and angiotensin II type 1 receptor-mediated insulin resistance. KK-Ay mice were administered control-IgG(2A) or anti-IL-17 antibody 5 times at a dose of 100 mu g every second day by IP injection. KK-Ay mice were administered telmisartan for 2 weeks. C57BL/6J mice treated with angiotensin II infusion for 2 weeks were administered telmisartan or hydralazine. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[H-3]deoxy-D-glucose in peripheral tissues. Serum IL-17 concentration in KK-Ay mice was significantly higher than that in C57BL/6J mice. Treatment of KK-Ay mice with anti-IL-17 antibody significantly increased 2-[H-3]deoxy-D-glucose uptake in skeletal muscle but not in white adipose tissue and attenuated the increase in blood glucose level after a glucose load. Blockade of IL-17 enhanced the expression of adipocyte differentiation markers and adiponectin. Treatment with telmisartan decreased serum IL-17 concentration in KK-Ay and ameliorated angiotensin II-induced insulin resistance with a decrease in serum IL-17 level in C57BL/6J. In conclusion, IL-17 could play an important role in the pathogenesis of angiotensin II type 1 receptor-induced insulin resistance. (Hypertension. 2012;59[part 2]:493-499.). Online Data Supplement

DOI： 10.1161/HYPERTENSIONAHA.111.183178

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1155/2012/596796

Scopus

PubMed

researchmap

Language：English  

Vascular inflammation plays a crucial role in atherosclerosis, and its regulation is important to prevent cerebrovascular and coronary artery disease. The inflammatory process in atherogenesis involves a variety of immune cells including monocytes/macrophages, lymphocytes, dendritic cells, and neutrophils, which all express peroxisome proliferator-activated receptor-γ (PPAR-γ). PPAR-γ is a nuclear receptor and transcription factor in the steroid superfamily and is known to be a key regulator of adipocyte differentiation. Increasing evidence from mainly experimental studies has demonstrated that PPAR-γ activation by endogenous and synthetic ligands is involved in lipid metabolism and anti-inflammatory activity. In addition, recent clinical studies have shown a beneficial effect of thiazolidinediones, synthetic PPAR-γ ligands, on cardiovascular disease beyond glycemic control. These results suggest that PPAR-γ activation is an important regulator in vascular inflammation and is expected to be a therapeutic target in the treatment of atherosclerotic complications. This paper reviews the recent findings of PPAR-γ involvement in vascular inflammation and the therapeutic potential of regulating the immune system in atherosclerosis. © 2012 Kousei Ohshima et al.

DOI： 10.1155/2012/508416

Scopus

PubMed

researchmap

Language：English  

The brain renin-angiotensin system (RAS) has been highlighted as having a pathological role in stroke, dementia, and neurodegenerative disease. Particularly, in dementia, epidemiological studies indicate a preventive effect of RAS blockade on cognitive impairment in Alzheimer disease (AD). Moreover, basic experiments suggest a role of brain angiotensin II in neural injury, neuroinflammation, and cognitive function and that RAS blockade attenuates cognitive impairment in rodent dementia models of AD. Therefore, RAS regulation is expected to have therapeutic potential for AD. Here, we discuss the role of angiotensin II in cognitive impairment and AD. Angiotensin II binds to the type 2 receptor (AT and works mainly by binding with the type 1 receptor (AT. ATreceptor signaling plays a role in protection against multiple-organ damage. A direct ATreceptor agonist is now available and is expected to reduce inflammation and oxidative stress and enhance cell differentiation. We and other groups reported that ATreceptor activation enhances neuronal differentiation and neurite outgrowth in the brain. Here, we also review the effect of the ATreceptor on cognitive function. RAS modulation may be a new therapeutic option for dementia including AD in the future. © 2012 Masaki Mogi et al.

DOI： 10.1155/2012/169649

Scopus

PubMed

researchmap

Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/hr.2011.148

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：English   Publisher：(株)メディカルレビュー社  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective Angiotensin-converting enzyme 2 (ACE2) generates angiotensin-(1-7) [Ang-(1-7)], a peptide highlighted as exerting a pivotal role in cardiovascular remodeling. Moreover, the ACE2/Ang-(1-7)/Mas axis directly activates endothelial nitric oxide (NO) synthase and NO generation in the heart. However, the role of ACE2 in cardiovascular remodeling induced by persistent inhibition of NO under chronic activation of the renin-angiotensin system (RAS) remains poorly understood.
Methods and results Chimeric hypertensive mice that exhibit activation of the human RAS were produced by mating human renin (hRN) and human angiotensinogen (hANG) transgenic mice. Persistent NO inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) was started at 8 weeks of age for 4 weeks. After administration of L-NAME, blood pressure (BP) markedly increased in the chimeric mice (hRN/hANG-Tg), whereas wild-type mice (C57BL/6J) showed little increase in BP. Cardiovascular remodeling with enhanced oxidative stress in hRN/hANG-Tg was markedly accelerated by NO inhibition compared with that in wild-type mice. Moreover, ACE2 mRNA expression and activity in cardiac tissue were markedly reduced in L-NAME-treated hRN/hANG-Tg. Co-administration of an angiotensin II type 1 (AT(1)) receptor blocker (ARB), olmesartan, inhibited L-NAME-induced cardiovascular remodeling and improved the reduction in cardiac ACE2. The preventive effect of olmesartan on cardiac hypertrophy was blunted by co-administration of a selective Ang-(1-7) antagonist, [D-Ala(7)]-Ang-(1-7).
Conclusion Our findings demonstrate that cardiovascular remodeling induced by persistent NO inhibition was enhanced in hRN/hANG-Tg. An ARB, olmesartan, blunted cardiac remodeling induced by NO inhibition with RAS activation partially through the ACE2/Ang-(1-7)/Mas axis in addition to directly through its classical ACE/Ang II/AT(1) receptor axis-blocking action. J Hypertens 29: 2236-2245 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

DOI： 10.1097/HJH.0b013e32834bbb4d

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：Japanese   Publisher：(NPO)日本高血圧学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The angiotensin II type 2 (AT(2)) receptor is expressed in bone marrow cells and may affect cell differentiation. We previously reported a beneficial role of the AT(2) receptor in ischemic brain damage. Here, we investigated the effect of AT(2) receptor stimulation in hematopoietic cells on ischemic brain injury using chimeric mice. Chimeric mice were generated by bone marrow transplantation into wild-type mice after irradiation. Bone marrow cells were prepared from wild-type (Agtr2(+)) or AT(2) receptor-deficient mice (Agtr2(-)). Six weeks after bone marrow transplantation, these chimeric mice were subjected to ischemia/reperfusion injury. Both Agtr2(+) and Agtr2(-) chimeric mice did not show a significant change in systolic and diastolic blood pressures, whereas body weight decreased in Agtr2(-) chimera. Twenty-four hours after ischemia/reperfusion injury, ischemic brain damage in Agtr2(-) chimera was exaggerated compared with that in Agtr2(+) chimera. Moreover, cerebral blood flow in the peripheral region before and after ischemia/reperfusion injury was decreased in Agtr2(-) chimera. The inflammatory response in the ipsilateral hemisphere was not significantly different, whereas tumor necrosis factor-alpha and monocyte chemoattractant protein 1 expressions tended to increase in the Agtr2 chimeric brain. Expression of methylmethane sulfonate 2, which has a neuroprotective effect, was lower in the brain of Agtr2(-) chimera. These results indicate that deletion of AT(2) receptor in blood cells has a harmful effect on ischemic brain injury. (Hypertension. 2011;58:404-409.)

DOI： 10.1161/HYPERTENSIONAHA.111.177873

Web of Science

Scopus

PubMed

researchmap

Language：English   Publisher：WILEY-BLACKWELL  

Recent clinical studies have demonstrated that angiotensin II type 1 (AT(1)) receptor blockers (ARBs) reduce the onset of stroke, stroke severity and the incidence and progression of Alzheimer's disease and dementia. We can expect that ARBs exert these effects by both AT(1) receptor blockade and angiotensin II type 2 (AT(2)) receptor stimulation. Moreover, recent experimental results support the notion that AT(2) receptor stimulation with AT(1) receptor blockade could contribute to protection against ischaemic brain damage at least partly due to an increase in cerebral blood flow and decrease in oxidative stress, and prevent cognitive decline. Cellular therapy has been focused on as a new therapeutic approach to restore injured neurons. In this context, it has been reported that AT(2) receptor stimulation enhances neurite outgrowth and decreases neural damage, thereby enhancing neurogenesis. Moreover, additional beneficial effects of ARBs with an AT(1) receptor blocking action with a partial peroxisome proliferator-activated receptor (PPAR)-gamma agonistic effect have been reported, and interaction of AT(2) receptor activation and PPAR-gamma might be involved in these ARBs' effects. This article reviews the effects of regulation of activation of angiotensin II receptor subtypes on ischaemic brain damage and cognitive function, focusing on the effects of AT(2) receptor stimulation.

DOI： 10.1111/j.1476-5381.2010.01167.x

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are known to prevent the onset of stroke and to attenuate neural damage. Additional beneficial effects of ARBs, independent of AT(1) receptor blockade, have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2), due to its molecular structure. We examined the possible synergistic effects of co-administration of irbesartan with propagermanium, a CCR2 antagonist, on ischemic brain damage. Administration of propagermanium decreased ischemic brain area after middle cerebral artery occlusion (MCAO). To study the possible synergistic effects of propagermanium with ARBs, we employed non-effective lower doses of irbesartan and losartan. Administration of irbesartan with propagermanium decreased the ischemic brain area more markedly compared with propagermanium alone, but co-administration of losartan did not. MCP-1 mRNA level was significantly increased on the ipsilateral side after MCAO, and administration of irbesartan with propagermanium decreased the MCP-1 level, whereas co-administration of losartan did not. Similar results were obtained for MCP-1 protein level. CCR2 mRNA expression was significantly elevated on the ipsilateral side: however, no significant difference was observed between each group. mRNA levels of other inflammatory cytokines such as TNF-alpha and IL-1 beta also significantly increased on the ipsilateral side, but the expression levels were not changed by each drug treatment. Taking these findings together, irbesartan exerts more beneficial effects on ischemic brain damage with an MCP-1 receptor blocker, at least due to its inhibitory effects on MCP-1/CCR2 signaling beyond AT(1) receptor blockade. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2011.04.142

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The contribution of the renin-angiotensin-aldosterone system (RAAS) to central nervous system (CNS) disorders is not yet fully understood. RAAS has been shown to be involved in the proliferation of astrocytes, which have a role in neuronal damage contributing to neurodegenerative diseases. However, the direct relationship between RAAS and neuronal damage is still unclear. We therefore examined the effect of angiotensin (Ang) II and aldosterone (Aldo) on damage to spinal ganglion neurons (SGNs) by regulating astrocytes. Ang II stimulation significantly increased DNA damage in SGNs in a time-dependent manner. This increase in DNA damage was further enhanced when SGNs were co-cultured with astrocytes. On the other hand, no significant increase was observed in SGNs co-cultured with astrocytes without Ang II stimulation. Moreover, the addition of conditioned medium from Ang II-treated astrocytes exacerbated SGN DNA damage. An Ang II type 1 receptor blocker, valsartan, inhibited Ang II-stimulated DNA damage but not DNA damage induced by conditioned medium prepared from astrocyte cultures. In contrast, an Aldo antagonist, eplerenone, significantly inhibited DNA damage induced by the culture medium from Ang II-treated astrocytes. Ang II-stimulated Aldo secretion in the conditioned medium from astrocytes. Furthermore, the administration of Aldo alone also enhanced DNA damage in SGNs. Finally, flow cytometric analysis showed that Ang II or Aldo treatment markedly increased the percentage of dead SGNs. In conclusion, Ang II- and Aldo-induced neuronal damage in SGNs through astrocytes regulation. Blocking Ang II and Aldo to target astrocytes might be useful for the treatment of CNS disorders. Hypertension Research (2011) 34, 773-778; doi:10.1038/hr.2011.38; published online 7 April 2011

DOI： 10.1038/hr.2011.38

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

BACKGROUND
The present study examined the inhibitory action of temporary treatment with an angiotensin type 1 (AT(1)) receptor blocker (ARB) on vascular remodeling using hypertensive mice with overexpression of the human renin (hRN) and angiotensinogen (hANG) genes.
METHODS
hRN/hANG transgenic mice (hRN/hANG-Tg) were treated with an ARB, valsartan, from 4 weeks of age. In some mice, valsartan treatment was stopped at 8 weeks of age (temporary treatment). Inflammatory vascular injury was induced by polyethylene-cuff placement around the femoral artery at the age of 10 weeks.
RESULTS
Compared with wild-type (WT) mice, hRN/hANG-Tg showed higher blood pressure (BP) and enhancement of oxidative stress and medial thickening even before cuff placement. Inflammatory vascular remodeling and oxidative stress after cuff placement were further enhanced in hRN/hANG-Tg.Temporary treatment with valsartan continuously lowered BP even after cessation of administration, and inhibited these changes. In contrast, administration of hydralazine lowered BP to a similar level to that with valsartan, but did not inhibit medial thickening and inflammatory vascular remodeling. In contrast to the valsartan treatment, BP immediately increased to the untreated level after cessation of hydralazine.
CONCLUSIONS
These results indicate that temporary ARB treatment leads to prolonged effect of BP lowering and prevents vascular remodeling in hypertensive mice induced by activation of the human reninangiotensin system.The inhibitory action of valsartan is not due to the BP lowering but is at least in part due to a decrease in oxidative stress and inflammation.

DOI： 10.1038/ajh.2011.6

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本透析医学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

Although it is feared that diabetes-induced cognitive decline will become a major clinical problem worldwide in the future, the detailed pathological mechanism is not well known. Because patients with diabetes have various complications of vascular disease, with not only macrovascular but also microvascular disorders, vascular disorders in the brain are considered to be one of the mechanisms in diabetes-induced cognitive impairment. Indeed, disruption of the blood-brain barrier (BBB) has been observed in some diabetic patients and experimental diabetes models. Moreover, white matter lesions, part of the evidence of BBB dysfunction, are reported to be observed more frequently in patients with diabetes. Animal studies demonstrate that diabetes enhances BBB permeability through a decrease in the level of tight junction proteins and an increase in matrix metalloproteinase activity. However, there are several reports indicating that BBB disruption does not occur with diabetes. Therefore, the association of BBB breakdown with diabetes-induced cognitive impairment is not conclusive. Recently, neuronal diseases involving dementia have been induced experimentally through dysfunction of neurovascular coupling, which involves blood vessels, astrocytes and neutrons. Diabetes-induced cognitive decline may be induced via disruption of neurovascular coupling, with not only vascular disorder but also impairment of astrocytic trafficking. Here, the relation between vascular disorder and cognitive impairment in diabetes is discussed. (Circ J 2011; 75: 1042 1048)

DOI： 10.1253/circj.CJ-11-0121

Web of Science

Scopus

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本抗加齢医学会  

researchmap