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Diets rich in taurine can increase the production of taurine-conjugated bile acids, which are known to exert antihypertensive effects. Despite their benefits to the heart, kidney and arteries, their role in the central nervous system during the antihypertensive process remains unclear. Since hypothalamic paraventricular nucleus (PVN) plays a key role in blood pressure regulation, we aimed to investigate the function of bile acids in the PVN. The concentration of bile acids in the PVN of spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKY) fed with normal chow was measured using LC-MS/MS, which identified taurocholic acid (TCA) as the most down-regulated bile acid. To fully understand the mechanism of TCA's functions in the PVN, bi-lateral PVN micro-infusion of TCA was carried out. TCA treatment in the PVN led to a significant reduction in the blood pressure of SHRs, with decreased plasma levels of norepinephrine and improved morphology of cardiomyocytes. It also decreased the number of c-fos+ neurons, reduced the inflammatory response, and suppressed oxidative stress in the PVN of the SHRs. Most importantly, the TGR5 receptors in neurons and microglia were activated. PVN infusion of SBI-115, a TGR5 specific antagonist, was able to counteract with TCA in the blood pressure regulation of SHRs. In conclusion, TCA supplementation in the PVN of SHRs can activate TGR5 in neurons and microglia, reduce the inflammatory response and oxidative stress, suppress activated neurons, and attenuate hypertension.

Background: High blood pressure (BP) is highly prevalent in patients with chronic kidney disease. However, the thresholds to initiate BP-lowering treatment in this population are unclear. We aimed to examine the associations between BP levels and clinical outcomes and provide evidence on potential thresholds to initiate BP-lowering therapy in people with chronic kidney disease., Methods: This nationwide, multicenter, prospective cohort study included 12 523 chronic kidney disease participants without antihypertensive therapy in mainland China. Participants were followed up during 2011 to 2016 for cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, hospitalized or treated heart failure, and cardiovascular death) and renal events (≥20% decline in the estimated glomerular filtration rate, end-stage kidney disease, and renal death)., Results: Overall, 652 cardiovascular events and 1268 renal events occurred during 43 970 person-years of follow-up. We observed a positive and linear relationship between systolic BP and risks of cardiovascular and renal events down to 90 mm Hg, as well as between diastolic BP and risks of renal events down to 50 mm Hg. A J-shaped trend was noted between diastolic BP and risks of cardiovascular events, but a linear relationship was revealed in participants <60 years ( P for interaction <0.001). A significant increase in the risk of cardiovascular and renal outcomes was observed at systolic BP ≥130 mm Hg (versus 90-119 mm Hg) and at diastolic BP ≥90 mm Hg (versus 50-69 mm Hg)., Conclusions: In people with chronic kidney disease, a higher systolic BP/diastolic BP level (≥130/90 mm Hg) is significantly associated with a greater risk of cardiovascular and renal events, indicating potential thresholds to initiate BP-lowering treatment.

Hypertension caused by a high-salt (HS) diet is one of the major causes of cardiovascular diseases. Underlining pathology includes oxidative stress and inflammation in the hypothalamic paraventricular nucleus (PVN). This study investigates genistein's (Gen) role in HS-induced hypertension and the underlying molecular mechanism. We placed male Wistar rats on HS (8% NaCl) or normal salt diet (0.3% NaCl). Then, we injected bilateral PVN in rats with Gen, vehicle, or nicotinamide (NAM) for 4 weeks. Tail cuff was used weekly to assess the systolic pressure, diastolic pressure, and mean arterial pressure (MAP). Cardiac hypertrophy was analyzed by heart weight/body weight ratio and wheat germ agglutinin staining. ELISA kits, Western blot, or dihydroethidium staining determined the levels of inflammatory cytokines and oxidative stress markers. Western blot measured protein levels of Sirt1, Ac-FOXO1, Nrf2, NQO-1, HO-1, and gp91 phox . Our result showed that PVN infusion of Gen significantly reduced the increase of systolic pressure, diastolic pressure, and MAP induced by an HS diet. Additionally, there was a decrease in cardiac hypertrophy and the levels of inflammatory cytokines in PVN and plasma. Meanwhile, PVN infusion of Gen notably inhibited the levels of oxidized glutathione and superoxide dismutase and improved the glutathione level and total antioxidant capacities and superoxide dismutase activities. It also decreased the level of reactive oxygen species and gp91 phox expression in PVN. Furthermore, Gen infusion markedly increases the Sirt1, Nrf2, HO-1, and NQO-1 levels and decreases the Ac-FOXO1 level. However, PVN infusion of NAM could significantly block these changes induced by Gen in HS diet rats. Our results demonstrated that PVN infusion of Gen could inhibit the progression of hypertension induced by an HS diet by activating the Sirt1/Nrf2 pathway., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Many studies demonstrate a J-shaped association between blood pressure and cardiovascular diseases (CVDs), but the findings are plagued by confounding from other traditional cardiovascular risk factors (CVRFs). Our aims were to examine the associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels with CVD in individuals without major CVRFs and whether there were thresholds for the association., Methods: In the 4C study (China Cardiometabolic Disease and Cancer Cohort), 36 042 CVRF-free participants without CVD, diabetes, dyslipidemia, hypertension, or smoking were identified during 2011 to 2012. Among CVRF-free participants, 17 476 CVRF-preferable individuals with better glycemic (fasting glucose, <110 mg/dL; 2-hour post-load glucose, <140 mg/dL) and lipid profile (total cholesterol, <200 mg/dL; LDL [low-density lipoprotein] cholesterol, <130 mg/dL) were selected. The total person-years of follow-up for CVRF-free subjects and CVRF-preferable subjects were 130 147 and 63 573 person-years, respectively. Information on the development of major CVDs was collected during 2014 to 2016. Cox proportional hazard models were performed to estimate the risks for incident CVD by SBP and DBP groups, respectively., Results: We found that both baseline SBP and DBP presented significantly linear associations with CVD risks in CVRF-free and CVRF-preferable participants. There is significant increase in the CVD risk among CVRF-free participants with baseline SBP level of 110 to 119 mm Hg (hazard ratio, 1.79 [95% CI, 1.19-2.71]), 120 to 129 mm Hg (hazard ratio, 2.03 [95% CI, 1.36-3.03]), and 130 to 139 mm Hg (hazard ratio, 2.15 [95% CI, 1.40-3.28]) compared with SBP <110 mm Hg. Significant increases were also observed for DBP level of 80 to 89 mm Hg (hazard ratio, 1.43 [95% CI, 1.03-1.97]) compared with DBP <70 mm Hg. Similar results were observed in CVRF-preferable participants., Conclusions: SBP and DBP with levels currently considered normal were significantly and linearly associated with incident CVD without thresholds above 110/70 mm Hg among Chinese adults without major CVRFs.

Context: Diabetes, hypertension and dyslipidemia accelerates the incidence of cardiovascular disease (CVD) events. However, data regarding the association between main cardiometabolic morbidities such as diabetes, hypertension, and dyslipidemia and the subsequent risk of CVD events in Chinese adults are still limited., Objective: To investigate the associations between individual and combined cardiometabolic morbidities and incident cardiovascular events in Chinese adults., Methods: Baseline data were obtained from a prospective, nationwide, and population-based cohort study in China during 2011-2012. A total of 133 572 participants aged ≥40 years were included in the study. The main outcome measures were CVD events., Results: Compared with participants without diabetes, hypertension and dyslipidemia, participants with only diabetes (hazard ratio [HR], 1.58; 95% CI, 1.32-1.90) or only hypertension (2.04; 1.82-2.28) exhibited significantly higher risk for CVD events, while participants with only dyslipidemia (0.97; 0.84-1.12) exhibited no significantly higher risk for CVD events. When analyzed collectively, participants with diabetes plus hypertension (HR, 2.67; 95% CI, 2.33-3.06), diabetes plus dyslipidemia (1.57; 1.32-1.87), and hypertension plus dyslipidemia (2.12; 1.88-2.39) exhibited significantly higher risk for CVD. Moreover, participants with the combination of diabetes, hypertension, and dyslipidemia exhibited the highest risk for CVD events (HR, 3.06; 95% CI, 2.71-3.46). Multivariable-adjusted HRs (95% CIs) for CVD associated with diabetes based on fasting glucose ≥7.0 mmol/L, oral glucose tolerance test 2-hour glucose ≥11.1 mmol/L, and hemoglobin A1c ≥6.5% were 1.64 (1.51-1.78), 1.57 (1.45-1.69), and 1.54 (1.42-1.66), respectively; associated with hypertension based on systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg were 1.89 (1.76-2.03) and 1.74 (1.60-1.88), respectively; associated with dyslipidemia based on total cholesterol ≥6.22 mmol/L, low-density lipoprotein cholesterol ≥4.14 mmol/L, high-density lipoprotein cholesterol <1.04 mmol/L, and triglycerides ≥2.26 mmol/L were 1.18 (1.08-1.30), 1.30 (1.17-1.44), 1.00 (0.92-1.09), and 1.10 (1.01-1.20), respectively., Conclusion: Diabetes, hypertension and dyslipidemia showed additive associations with the risk of CVD events in middle-aged and elderly Chinese adults., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Gut dysbiosis and dysregulation of gut-brain communication have been identified in hypertensive patients and animal models. Previous studies have shown that probiotic or prebiotic treatments exert positive effects on the pathophysiology of hypertension. This study aimed to examine the hypothesis that the microbiota-gut-brain axis is involved in the antihypertensive effects of curcumin, a potential prebiotic obtained from Curcuma longa. Male 8- to 10-week-old spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats were divided into four groups: WKY rats and SHRs treated with vehicle and SHRs treated with curcumin in dosage of 100 or 300 mg/kg/day for 12 weeks. Our results show that the elevated blood pressure of SHRs was markedly decreased in both curcumin-treated groups. Curcumin treatment also altered the gut microbial composition and improved intestinal pathology and integrity. These factors were associated with reduced neuroinflammation and oxidative stress in the hypothalamus paraventricular nucleus (PVN). Moreover, curcumin treatment increased butyrate levels in the plasma, which may be the result of increased butyrate-producing gut microorganisms. In addition, curcumin treatment also activated G protein-coupled receptor 43 (GPR 43) in the PVN. These results indicate that curcumin reshapes the composition of the gut microbiota and ameliorates the dysregulation of the gut-brain communication to induce antihypertensive effects., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: National investigations of age-specific modifiable risk profiles for diabetes are crucial to promote personalised strategies for the prevention and control of diabetes, particularly in countries such as China, which is experiencing both a diabetes epidemic and a rapidly ageing population. We aimed to examine the associations of 12 potentially modifiable socioeconomic, lifestyle, and metabolic risk factors with diabetes in a nationwide prospective cohort of Chinese adults across four age groups., Methods: We analysed data from the China Cardiometabolic Disease and Cancer Cohort Study, a nationwide, population-based, cohort study done between Jan 1, 2011, and Dec 31, 2016. Among 93 781 participants without diabetes at baseline and with complete information available about risk factors and diabetes incidence, we examined the hazard ratios (HRs) and population-attributable risk percentages (PAR%s) of incident diabetes associated with 12 potentially modifiable risk factors: two socioeconomic risk factors (less education and intermediate or low grade occupation), five lifestyle risk factors (unhealthy diet, physical inactivity, current alcohol consumption, current smoking, and unhealthy sleep), and five metabolic risk factors (general or central obesity, insulin resistance, prediabetes, hypertension, and dyslipidaemia) across four age groups (40 to <55 years, 55 to <65 years, 65 to <75 years, and ≥75 years)., Findings: With 337 932 person-years' follow-up, 6171 participants developed diabetes. Although diabetes risk attributable to metabolic risk factors decreased slightly with age, metabolic risk factors accounted for most incident diabetes cases across all age groups (from a PAR% of 73·8% in participants aged 40 to <55 years to 65·5% in those aged ≥75 years), with prediabetes (ranging from a PAR% of 56·6% to 47·4%, with increasing age) and hypertension (PAR% of 16·8% to 28·6% with increasing age) being the leading risk factors across all age groups. By contrast, diabetes risk attributable to lifestyle risk factors increased substantially with age (with a PAR% of 9·9% in adults aged 40 to <55 years increasing to 29·7% in adults aged ≥75 years), and was especially evident in participants aged 75 years or older, in whom unhealthy sleep was the largest lifestyle factor, accounting for a PAR% of 17·0%. The impact of socioeconomic risk factors on diabetes was mainly driven by less education, which contributed to a PAR% of 7·1% to 12·4% in participants younger than 75 years but conferred no excess risk in participants aged 75 years or older. The risk of diabetes associated with unhealthy sleep significantly increased with age group (HR 1·04 [95% CI 0·95-1·13] among participants aged 40 to <55 years vs 1·36 [1·01-1·85] among participants aged ≥75 years; p interaction =0·0054), but there was an age-related decrease in the risk of diabetes associated with obesity (1·35 [1·23-1·48] vs 0·99 [0·72-1·36]; p interaction =0·0003), prediabetes (3·00 [2·67-3·37] vs 2·18 [1·41-3·37]; p interaction =0·0014), and dyslipidaemia (1·23 [1·13-1·34] vs 0·90 [0·66-1·21]; p interaction =0·016)., Interpretation: These findings provide novel insights into age-related modifiable risk factor profiles for diabetes in Chinese adults, highlighting the importance of prioritising risk factors according to age groups for effective prevention and management of diabetes., Funding: National Natural Science Foundation of China., Translation: For the Chinese translation of the abstract see Supplementary Materials section., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Long-term maternal salt intake induces the hypertension in offspring. Numerous studies have also indicated that high-salt diet causes the inflammation and an imbalance in neurotransmitters in the paraventricular nucleus (PVN) which increases the blood pressure and sympathetic activity. This study aimed to explore whether maternal salt intake induces hypertension in their male offspring by increasing the inflammation and changing the neurotransmitters balance in the paraventricular nucleus of offspring. This study includes two parts: Part I to explore the effect of high-salt diet on pregnant rats and the changes in inflammation and neurotransmitters in their male offspring PVN; Part II to reveal the influence on their offspring of bilateral PVN infusion of c-Src inhibitor dasatinib (DAS) in pregnant rats fed a high-salt diet. Maternal high-salt diet intake during copulation, pregnancy, and lactation impacted the offspring mean arterial pressure (MAP) and elevated the offspring PVN levels of p-Src, proinflammatory cytokines, and excitatory neurotransmitters. Bilateral PVN infusion of a c-Src inhibitor combined with maternal high-salt diets decreased MAP in the offspring. The infusion was also shown to suppress the Src-induced MAPK/NF-κB signaling pathway (p38 MAPK, JNK, Erk1/2), which attenuates inflammatory reactions. Finally, bilateral PVN infusion of the Src inhibitor in pregnant rat with high-salt diets improved the levels of inhibitory neurotransmitters in offspring PVN, which restored the excitatory-inhibitory neurotransmitter balance in male offspring. High-salt diets increase sympathetic activity and blood pressure in adult offspring, probably by activating the c-Src/MAPKs/NF-κB signaling pathway-induced inflammation. Moreover, NF-κB disrupts the downstream excitatory-inhibitory neurotransmitter balance in the PVN of male offspring., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: N-Methyl-d-aspartate receptor (NMDAR) in the hypothalamic paraventricular nucleus (PVN) plays critical roles in regulating sympathetic outflow. Studies showed that acute application of the antagonists of NMDAR or its subunits would reduce sympathetic nerve discharges. However, little is known about the effect of long-term management of NMDAR in hypertensive animals., Methods: PEAQX, the specific antagonist of NMDAR subunit 2A (GluN2A) was injected into both sides of the PVN of two-kidney, one-clip (2K1C) renal hypertensive rats and control (normotensive rats) for 3 weeks., Results: Three weeks of PEAQX infusion significantly reduced the blood pressure of the 2K1C rats. It managed to resume the balance between excitatory and inhibitory neural transmitters, reduce the level of proinflammatory cytokines and reactive oxygen species in the PVN, and reduce the level of norepinephrine in plasma of the 2K1C rats. PEAQX administration also largely reduced the transcription and translation levels of GluN2A and changed the expression levels of NMDAR subunits 1 and 2B (GluN1 and GluN2B). In addition, NMDAR was known to function through activating the extracellular regulated protein kinases (ERK) or phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways. In our study, we found that in the PVN of 2K1C rats treated with PEAQX, the phosphorylation levels of mitogen-activated protein kinase kinase (MEK), ERK1/2, and cAMP-response element-binding protein (CREB) significantly reduced, while the phosphorylation level of PI3K did not change significantly., Conclusions: Chronic blockade of GluN2A alleviates hypertension through suppression of MEK/ERK/CREB pathway., (© American Journal of Hypertension, Ltd 2021. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Hypertension, as one of the major risk factors for cardiovascular disease, significantly affects human health. Prostaglandin E 2 (PGE 2 ) and the E3-class prostanoid (EP3) receptor have previously been demonstrated to modulate blood pressure and hemodynamics in various animal models of hypertension. The PGE2-evoked pressor and biochemical responses can be blocked with the EP3 receptor antagonist, L-798106 (N-[(5-bromo-2methoxyphenyl)sulfonyl]-3-[2-(2-naphthalenylmethyl) phenyl]-2-propenamide). In the hypothalamic paraventricular nucleus (PVN), sympathetic excitation can be introduced by PGE2, which can activate EP3 receptors located in the PVN. In such a case, the central knockdown of EP3 receptor can be considered as a potential therapeutic modality for hypertension management. The present study examined the efficacy of the PVN infusion of L-798106, by performing experiments on spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). The rats were administered with chronic bilateral PVN infusion of L-798106 (10 μg/day) or the vehicle for 28 days. The results indicated that the SHRs had a higher mean arterial pressure (MAP), an increased Fra-like (Fra-LI) activity in the PVN, as well as a higher expression of gp 91phox , mitogen-activated protein kinase (MAPK), and proinflammatory cytokines in the PVN compared with the WKYs. Additionally, the expression of Cu/Zn-SOD in the PVN of the SHRs was reduced compared with the WKYs. The bilateral PVN infusion of L-798106 significantly reduced MAP, as well as plasma norepinephrine (NE) levels in the SHRs. It also inhibited Fra-LI activity and reduced the expression of gp 91phox , proinflammatory cytokines, and MAPK, whereas it increased the expression of Cu/Zn-SOD in the PVN of SHRs. In addition, L-798106 restored the balance of the neurotransmitters in the PVN. On the whole, the findings of the present study demonstrate that the PVN blockade of EP3 receptor can ameliorate hypertension and cardiac hypertrophy partially by attenuating ROS and proinflammatory cytokines, and modulating neurotransmitters in the PVN.

Exercise (Ex) has long been recognized to produce beneficial effects on hypertension (HTN). This coupled with evidence of gut dysbiosis and an impaired gut-brain axis led us to hypothesize that reshaping of gut microbiota and improvement in impaired gut-brain axis would, in part, be associated with beneficial influence of exercise. Male spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were randomized into sedentary, trained, and detrained groups. Trained rats underwent moderate-intensity exercise for 12 weeks, whereas, detrained groups underwent 8 weeks of moderate-intensity exercise followed by 4 weeks of detraining. Fecal microbiota, gut pathology, intestinal inflammation, and permeability, brain microglia and neuroinflammation were analyzed. We observed that exercise training resulted in a persistent decrease in systolic blood pressure in the SHR. This was associated with increase in microbial α diversity, altered β diversity, and enrichment of beneficial bacterial genera. Furthermore, decrease in the number of activated microglia, neuroinflammation in the hypothalamic paraventricular nucleus, improved gut pathology, inflammation, and permeability were also observed in the SHR following exercise. Interestingly, short-term detraining did not abolish these exercise-mediated improvements. Finally, fecal microbiota transplantation from exercised SHR into sedentary SHR resulted in attenuated SBP and an improved gut-brain axis. These observations support our concept that an impaired gut-brain axis is linked to HTN and exercise ameliorates this impairment to induce antihypertensive effects.

The hypothalamic paraventricular nucleus (PVN) plays crucial roles in central cardiovascular regulation. Increasing evidence in humans and rodents shows that vitamin D intake is important for achieving optimal cardiovascular function. The purpose of this study was to investigate whether calcitriol, an active form of vitamin D, improves autonomic and cardiovascular function in hypertensive rats and whether PVN oxidative stress and inflammation are involved in these beneficial effects. Male spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were treated with either calcitriol (40 ng/day) or vehicle (0.11 μL/h) through chronic PVN infusion for 4 weeks. Blood pressure and heart rate were recorded continuously by radiotelemetry. PVN tissue, heart and plasma were collected for molecular and histological analysis. Compared to WKY rats, SHR exhibited increased systolic blood pressure, sympathetic drive, and cardiac hypertrophy and remodeling. These were associated with higher mRNA and protein expression levels of high mobility box 1 (HMGB1), receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), proinflammatory cytokines, NADPH oxidase subunit in the PVN. In addition, increased norepinephrine in plasma, elevated reactive oxygen species levels and activation of microglia in the PVN were also observed in SHR. Chronic calcitriol treatment ameliorated these changes but not in WKY rats. Our results demonstrate that chronic infusion of calcitriol in the PVN ameliorates hypertensive responses, sympathoexcitation and retains cardiovascular function in SHR. Reduced inflammation and oxidative stress within the PVN are involved in these calcitriol-induced effects., Competing Interests: Declaration of Competing Interest All authors confirm that they are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Toll-like receptor 4 (TLR4) and cellular Src (c-Src) are closely associated with inflammatory cytokines and oxidative stress in hypertension, so we designed this study to explore the exact role of c-Src in the mechanism of action of the TLR4 signaling pathway in salt-induced hypertension. Salt-sensitive rats were given a high salt diet for 10 weeks to induce hypertension. This resulted in higher levels of TLR4, activated c-Src, pro-inflammatory cytokines, oxidative stress, and arterial pressure. Infusion of a TLR4 blocker into the hypothalamic paraventricular nucleus (PVN) decreased the activated c-Src, while microinjection of a c-Src inhibitor attenuated the PVN levels of nuclear factor-kappa B, pro-inflammatory cytokines, and oxidative stress. Our findings suggest that a long-term high-salt diet increases TLR4 expression in the PVN and this promotes the activation of c-Src, which upregulates the expression of pro-inflammatory cytokines and results in the overproduction of reactive oxygen species. Therefore, inhibiting central c-Src activity may be a new target for treating hypertension.

Metformin (MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension. This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus (PVN). Salt-sensitive rats received a high-salt (HS) diet to induce hypertension, or a normal-salt (NS) diet as control. At the same time, they received intracerebroventricular (ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure (MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity, reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in salt-sensitive hypertension via attenuating oxidative stress, inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN.

Angiotensin (Ang)-(1-7) is an important biologically-active peptide of the renin-angiotensin system. This study was designed to determine whether inhibition of Ang-(1-7) in the hypothalamic paraventricular nucleus (PVN) attenuates sympathetic activity and elevates blood pressure by modulating pro-inflammatory cytokines (PICs) and oxidative stress in the PVN in salt-induced hypertension. Rats were fed either a high-salt (8% NaCl) or a normal salt diet (0.3% NaCl) for 10 weeks, followed by bilateral microinjections of the Ang-(1-7) antagonist A-779 or vehicle into the PVN. We found that the mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma norepinephrine (NE) were significantly increased in salt-induced hypertensive rats. The high-salt diet also resulted in higher levels of the PICs interleukin-6, interleukin-1beta, tumor necrosis factor alpha, and monocyte chemotactic protein-1, as well as higher gp91 phox expression and superoxide production in the PVN. Microinjection of A-779 (3 nmol/50 nL) into the bilateral PVN of hypertensive rats not only attenuated MAP, RSNA, and NE, but also decreased the PICs and oxidative stress in the PVN. These results suggest that the increased MAP and sympathetic activity in salt-induced hypertension can be suppressed by blockade of endogenous Ang-(1-7) in the PVN, through modulation of PICs and oxidative stress.

Background: Inflammation has been implicated in the development of cardiovascular disease. We determined whether nod-like receptor with pyrin domain containing 3 (NLRP3) involved in the process of prehypertension, central blockade of NLRP3 decreased inflammation reaction, regulated neurohormonal excitation, and delayed the progression of prehypertension., Methods: Prehypertensive rats were induced by 8% salt diet. The rats on high-salt diet for 1 month were administered a specific NLRP3 blocker in the hypothalamic paraventricular nucleus (PVN) for 4 weeks. ELISA, western blotting, immunohistochemistry, and flow cytometry were used to measure NLRP3 cascade proteins, pro-inflammation cytokines (PICs), chemokine ligand 2 (CCL2), C-X-C chemokine receptor type 3 (CXCR3), vascular cell adhesion molecule 1 (VCAM-1), neurotransmitters, and leukocytes count detection, respectively., Results: NLRP3 expression in PVN was increased significantly in prehypertensive rats, accompanied by increased number of microglia, CD4 + , CD8 + T cell, and CD8 + microglia. Expressions of PICs, CCL2, CXCR3, and VCAM-1 significantly increased. The balance between 67-kDa isoform of glutamate decarboxylase (GAD67) and tyrosine hydroxylase (TH) was damaged. Plasma norepinephrine (NE) in prehypertensive rats was increased and gamma-aminobutyric acid (GABA) was reduced. NLRP3 blockade significantly decreased blood pressure, reduced PICs, CCL2, VCAM-1 expression in PVN, and restored neurotransmitters. Blood pressure and inflammatory markers were upregulated after termination of central blockage NLRP3., Conclusions: Salt-induced prehypertension is partly due to the role of NLRP3 in PVN. Blockade of brain NLRP3 attenuates prehypertensive response, possibly via downregulating the cascade reaction triggered by inflammation and restoring the balance of neurotransmitters.

Background/aims: Exercise training (ExT) was associated with cardiovascular diseases including hypertension. The rostral ventrolateral medulla (RVLM) is a key region for central control of blood pressure and sympathetic nerve activity. Therefore, this study aimed to investigate the mechanisms within RVLM that can influence exercise training induced effects in salt-induced hypertension., Methods: Male Wistar rats were fed with a normal salt (0.3%) (NS) or a high salt (8%) (HS) diet for 12 weeks to induce hypertension. Then these rats were given moderate-intensity ExT for a period of 12 weeks. RVLM was used to determine glutamate and gamma-aminobutyric acid (HPLC), phosphorylated IKKβ, Fra-LI, 67-kDa isoform of glutamate decarboxylase (GAD67), proinflammatory cytokines (PIC) and NADPH-oxidase (NOX) subunits expression (Immunohistochemistry and Immunofluorescence, Western blotting). PIC and NF-κB p65 activity in the plasma were evaluated by ELISA studies. Renal sympathetic nerve activity (RSNA) was recorded and analyzed using the PowerLab system., Results: High salt diet resulted in increased mean arterial pressure and cardiac hypertrophy. These high salt diet rats had higher RVLM levels of glutamate, PIC, phosphorylated IKKβ, NF-κB p65 activity, Fra-LI, superoxide, NOX-2 (gp91phox) and 4, and lower RVLM levels of gamma-aminobutyric acid and GAD67, and higher plasma levels of PIC, norepinephrine, and higher RSNA. ExT attenuated these changes in salt-induced hypertensive rats., Conclusions: These findings suggest that high salt diet increases the activity of NF-κB and the levels of PIC and oxidative stress, and induces an imbalance between excitatory and inhibitory neurotransmitters in the RVLM. ExT attenuates hypertension and cardiac hypertrophy partially mediated by attenuating oxidative stress and modulating neurotransmitters in the RVLM., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Brain renin-angiotensin system (RAS) could regulate oxidative stress in the paraventricular nucleus (PVN) in the development of hypertension. This study was designed to explore the precise mechanisms of RAS acting on reactive oxygen species (ROS) in salt-induced hypertension. Male Wistar rats were administered with a high-salt diet (HS, 8.0% NaCl) for 8 weeks to induced hypertension. Those rats were received PVN infusion of AT1R antagonist losartan (LOS, 10 μg/h) or microinjection of small interfering RNAs for protein kinase C γ (PKCγ siRNA) once a day for 2 weeks. High salt intake resulted in higher levels of AT1R, PKCγ, Rac1 activity, superoxide and malondialdehyde (MDA) activity, but lower levels of copper/zinc superoxide dismutase (Cu/Zn-SOD), superoxide dismutase (SOD) and glutathione (GSH) in PVN than control animals. PVN infusion of LOS not only attenuated the PVN levels of AT1R, PKCγ, Rac1 activity, superoxide and decreased the arterial pressure, but also increased the PVN antioxidant capacity in hypertension. PVN microinjection of PKCγ siRNA had the same effect on LOS above responses to hypertension but no effect on PVN level of AT1R. These results, for the first time, identified that the precise signaling pathway of RAS regulating ROS in PVN is via AT1R/PKCγ/Rac1 in salt-induced hypertension.

Previous findings from our laboratory and others indicate that the main therapeutic effect of angiotensin II type 1 receptor (AT1-R) antagonists is to decrease blood pressure and exert anti-inflammatory effects in the cardiovascular system. In this study, we determined whether AT1-R antagonist telmisartan within the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and hypothalamic inflammation via both the TLR4/MyD88/NF-κB signaling pathway and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the PVN in hypertensive rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated for 4weeks through bilateral PVN infusion with the AT1-R antagonist telmisartan (TEL, 10μg/h), or losartan (LOS, 20μg/h), or the PPAR-γ antagonist GW9662 (GW, 100μg/h), or vehicle via osmotic minipump. Mean arterial pressure (MAP) was recorded by a tail-cuff occlusion method. PVN tissue and blood were collected for the measurement of AT1-R, PPAR-γ, pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6), inducible nitric oxide synthase (iNOS), TLR4, MyD88, nuclear factor-kappa B (NF-κB) activity and plasma norepinephrine (NE), respectively. Hypertensive rats exhibited significantly higher level of AT1-R and lower level of PPAR-γ in the PVN. PVN treatment with TEL attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, IL-6, iNOS levels, and plasma NE in SHR but not in WKY rats. These results were associated with reduced TLR4, MyD88 and NF-κB levels and increased PPAR-γ level in the PVN of hypertensive rats. Our findings suggest that TLR4/MyD88/NF-κB signaling and PPAR-γ within the PVN are involved in the beneficial effects of telmisartan in hypertension., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Salusin β is a newly identified bioactive peptide, which shows peripheral hypotensive, mitogenic and proatherosclerotic effects. The present study was undertaken to investigate the role of salusin β within the nucleus tractus solitarii (NTS) and the underlying mechanism in regulating blood pressure and heart rate (HR) in spontaneously hypertensive rats (SHR). Our results showed that bilateral or unilateral microinjection of salusin β (0.4-40 pmol) into the NTS in SHR decreased mean arterial pressure and HR in a dose-dependent manner. Bilateral microinjection of salusin β (4 pmol) within NTS improved baroreflex sensitivity functions in SHR. Pretreatment with glutamate receptors antagonist kynurenic acid (5 nmol) into the NTS in SHR did not alter the salusin β (4 pmol) induced hypotension and bradycardia. Likewise, bilateral vagotomy also did not alter the salusin β (4 pmol) induced hypotension and bradycardia. However, pretreatment with GABAA receptors agonist muscimol (100 pmol) within the rostral ventrolateral medulla (RVLM) in SHR almost completely abolished the hypotension and bradycardia evoked by intra-NTS salusin β (4 pmol). Our findings suggested that microinjection of salusin β into the NTS produced hypotension and bradycardia, as well as improved baroreflex sensitivity functions, via inhibiting the activities of presympathetic neurons in the RVLM in SHR.

Aims: High salt-induced oxidative stress plays an important role in the development of hypertension. Alpha lipoic acid (ALA) is extensively recognized as having a powerful superoxide inhibitory property. In this study, we determined whether ALA supplementation attenuates oxidative stress in hypothalamic paraventricular nucleus (PVN), decreases the sympathetic activity and arterial pressure in high salt-induced hypertension by cross-talking with renin-angiotensin system (RAS) and pro-inflammatory cytokines (PICs)., Methods: Male Wistar rats were administered a normal-salt diet (NS, 0.3% NaCl) or a high-salt diet (HS, 8.0% NaCl) for 8 weeks. These rats received ALA (60mg/kg) dissolved in vehicle (0.9% saline) or an equal voleme of vehicle, by gastric perfusion for 9 weeks., Results: High salt intake resulted in higher renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP). These rats also had higher levels of superoxide, gp91(phox), gp47(phox) (subunits of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), angiotensin II type1 receptor (AT1-R), interleukin-1beta (IL-1β), interleukin-6 (IL-6), and lower levels of interleukin-10 (IL-10) and copper/zinc superoxide dismutase (Cu/Zn-SOD) than control animals. Treatment with ALA significantly attenuated the levels of superoxide, gp91(phox), gp47(phox), ACE, AT1-R, IL-1β and IL-6, increased the levels of IL-10 and Cu/Zn-SOD, and decreased MAP and RSNA compared with high-salt induced hypertensive rats. The mRNA expression of gp47(phox) and gp91(phox) are in accordance with their protein expression., Conclusion: These findings suggest that supplementation of ALA obviously decreases the sympathetic activity and arterial pressure in high salt-induced hypertension by improving the superoxide inhibitory property, suppressing the activation of RAS and restoring the balance between pro- and anti-inflammatory cytokines in the PVN., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Salusin-β, a multifunctional bioactive peptide, is considered as a promising candidate biomarker for predicting cardiovascular diseases. This study was designed to determine whether inhibition of salusin-β in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by restoring neurotransmitters and cytokines. Male Sprague Dawley rats were fed with a normal salt diet (NS, 0.3%) or a high salt diet (HS, 8%) for 8 weeks to induce hypertension. Then, these rats received bilateral PVN infusion of a specific salusin-β blocker, antisalusin-β IgG (SIgG), or control IgG (CIgG) for 2 weeks. HS rats exhibited higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/bodyweight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and messenger RNA levels of cardiac atrial natriuretic peptide (ANP), and β-myosin heavy chain. Compared with NS rats, HS rats had higher levels of glutamate, norepinephrine, tyrosine hydroxylase, proinflammatory cytokines, and lower levels of gamma-aminobutyric acid, interleukin 10, and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN, and higher plasma levels of proinflammatory cytokines. Chronic PVN infusion of SIgG attenuated all these changes in HS rats. Our findings suggest that HS rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between proinflammatory and anti-inflammatory cytokines in the PVN; and chronic inhibition of salusin-β in the PVN restores neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive responses and cardiac hypertrophy.

Salusin β is a multifunctional bioactive peptide and is considered as a promising candidate biomarker for predicting atherosclerotic cardiovascular diseases. The present study was designed to investigate the roles and mechanisms of salusin β in the paraventricular nucleus (PVN) in attenuating hypertension and hypothalamic inflammation and whether central salusin β blockade has protective effects in essential hypertension. Normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were used in this study. The rats were chronic PVN infusion either specific salusin β blocker, antisalusin β IgG (SIgG), or control IgG (CIgG) for 2 weeks. Hypertensive rats had significantly increased salusin β expression compared with normotensive rats. Central blockade of salusin β attenuated hypertension, reduced circulating norepinephrine (NE) levels, and improved cardiac hypertrophy and function in hypertensive rats. Salusin β blockade significantly reduced proinflammatory cytokines (PICs), nuclear factor-kappa B (NF-κB) activity, reactive oxygen species (ROS) levels, and altered renin-angiotensin system (RAS) components in the PVN of hypertensive rats. These findings suggest that the beneficial effects of salusin β blockade in essential hypertension are possibly due to down-regulate of inflammatory molecules and ROS in the PVN.

Reactive oxygen species (ROS) in the brain plays an important role in the progression of hypertension and hydrogen peroxide (H2O2) is a major component of ROS. The aim of this study is to explore whether endogenous H2O2 changed by polyethylene glycol-catalase (PEG-CAT) and aminotriazole (ATZ) in the hypothalamic paraventricular nucleus (PVN) regulates neurotransmitters, renin-angiotensin system (RAS), and cytokines, and whether subsequently affects the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in high salt-induced hypertension. Male Sprague-Dawley rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 10 weeks. Then rats were treated with bilateral PVN microinjection of PEG-CAT (0.2 i.u./50nl), an analog of endogenous catalase, the catalase inhibitor ATZ (10nmol/50nl) or vehicle. High salt-fed rats had significantly increased MAP, RSNA, plasma norepinephrine (NE) and pro-inflammatory cytokines (PICs). In addition, rats with high-salt diet had higher levels of NOX-2, NOX-4 (subunits of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), interleukin-1beta (IL-1β), glutamate and NE, and lower levels of gamma-aminobutyric acid (GABA) and interleukin-10 (IL-10) in the PVN than normal diet rats. Bilateral PVN microinjection of PEG-CAT attenuated the levels of RAS and restored the balance of neurotransmitters and cytokines, while microinjection of ATZ into the PVN augmented those changes occurring in hypertensive rats. Our findings demonstrate that ROS component H2O2 in the PVN regulating MAP and RSNA are partly due to modulate neurotransmitters, renin-angiotensin system, and cytokines within the PVN in salt-induced hypertension., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To conduct a meta-analysis summarizing the risk of cardiovascular disease (CVD) and all-cause mortality (ACM) in relation to alcohol consumption in patients with hypertension, focusing on clarifying dose-response associations., Patients and Methods: PubMed and EMBASE were searched for eligible prospective cohort studies from December 3, 1949, through January 18, 2014. The semi-parameter method and dose-response analysis were used., Results: Nine studies (11 cohorts) were included in the meta-analysis. Compared with the lowest alcohol level (abstainers/occasional drinkers), the pooled relative risk (RR) was 0.72 (95% CI, 0.68-0.77) for the third highest category (median, 10 g/d), 0.81 (95% CI, 0.71-0.93) for the second highest category (median, 20 g/d), and 0.60 (95% CI, 0.54-0.67) for the highest category (median, 30 g/d). A J-shaped relationship between alcohol use and ACM was observed, and the nadir (RR, 0.82; 95% CI, 0.76-0.88) was found to be at a dose of 8 to 10 g of alcohol consumption per day., Conclusion: Findings of this meta-analysis suggest that low-to-moderate alcohol consumption was inversely significantly associated with the risk of CVD and ACM in patients with hypertension., (Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin-angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension., Methods and Results: Male Sprague-Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91(phox) (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1 beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91(phox), ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats., Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The renin-angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5μg/h) or vehicle for 4weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Hypothyroidism and subclinical hypothyroidism may be associated with hypertension and metabolic syndrome. The aim of this study was to investigate the relationship between thyroid-stimulating hormone (TSH) and blood pressure, as well as the relationship between thyroid function and insulin resistance in middle-aged and elderly Chinese., Methods: This was a cross-sectional, community-based study. Serum TSH, fasting glucose and insulin were measured in 2,988 subjects aged 35-80 years. Logistic regression analysis was used to identify the risk factors for hypertension. Analysis of variance and multiple linear regression analysis were performed to characterise the relationship among TSH, insulin resistance and blood pressure., Results: Higher serum TSH concentration was found to be an independent risk factor for hypertension in females (odds ratio 1.4, 95% confidence interval 1.02-1.93; p-value = 0.039). The female group with subclinical hypothyroidism and high normal TSH (2.5-4.8 mIU/L) were more susceptible to high blood pressure than those with low normal TSH (0.3-2.5 mIU/L) (p-value < 0.05). After adjustment for waist-hip ratio and body mass index, neither the correlation between blood pressure and homeostasis model assessment of insulin resistance (HOMA-IR) nor the correlation between TSH and HOMA-IR were found to be significant in this study., Conclusion: This study provides evidence that both subclinical hypothyroidism and high normal TSH are independent risk factors for hypertension in middle-aged and elderly Chinese women.

Objective: To investigate the relationship of four single nucleotide polymorphism (SNP) haplotypes in the angiotensinogen (AGT) gene to the primary hypertension with or without cerebral infarction in the Li nationality of Hainan, China., Methods: Total 300 subjects were allocated into three different groups: Group 1, 100 patients who have primary hypertension; Group 2, 100 patients who have primary hypertension with cerebral infarction; and control group, 100 healthy individuals. The genotypes of all subjects were determined by PCR-sequencing to analyze the four polymorphisms at position -152 (G-A), -20 (A-C), -18 (C-T), and -6 (A-G) in the promoter region of AGT., Results: The frequencies of CT genotype of AGT-18 and T allele in Group 1 (P = 0.003, P = 0.004) and Group 2 (P = 0.002, P = 0.002) were both significantly higher than in healthy controls. The frequency of G allele of AGT-6 was significantly higher in Group 2 than in the control group (P = 0.016), while there is no significant difference between Group 1 and the control. Haplotype analysis revealed that H6 haplotype frequency which included -20C and -6G was significantly increased in Group 2 (P = 0.003) compared with the control group, while H5 haplotype frequency which included -20C and -18T was significantly increased in Group 1 (P = 0.006) versus the control., Conclusion: The -20 (A-C) and -18 (C-T) of the AGT may play an important role in pathogenesis of primary hypertension; and -20 (A-C), -18 (C-T), and -6 (A-G) may be the genetic risk factors for the onset of primary hypertension with cerebral infarction in the Li nationality of Hainan, China.

ObjectivesTo assess antibody responses to an inactivated SARS-CoV-2 vaccine in individuals aged 50 and older.MethodsWe conducted a post-market cross-sectional seroepidemiology study. We recruited 4,632 vaccinated individuals aged 50 and older, measured their total serum SARS-CoV-2-specific antibody (TA), and collected correlates. The primary outcome was the geometric mean titer (GMT) of TA, and the secondary outcome was the decline of TA with age. Univariate, bivariate, and multivariate analyses were used to examine the associations of the TA GMT with age, and trend analyses were used to test whether their associations were significant.ResultsAll participants had a detectable TA, which was generally at a low level across all age groups. The TA GMT (95% CI) in AU/mL was 3.05 (2.93, 3.18); the corresponding arithmetic mean (95% CI) was 17.77 (16.13, 19.42) in all participants and 4.33 (3.88, 4.84), 3.86 (3.49, 4.28), 3.24 (2.92, 3.59), 2.77 (2.60, 2.96), and 2.65 (2.48, 2.83) in the age groups of 50-54, 55-59, 60-64, 65-74, and 75 years or older, respectively. The TA GMT decreased with age with a Ptrend < 0.001. The TA GMT was significantly lower in those with hypertension or diabetes compared to those with neither.ConclusionThe inactivated SARS-CoV-2 vaccine is effective in individuals aged 50 and older. This is the first study that has found an inverse dose-response relationship between ages and the low-level TAs. Older people, especially those with chronic diseases, should get the SARS-CoV-2 vaccine, and their vaccination frequency, dose, and method may need to be different from those of younger people.

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Background: An association between hemoglobin and metabolic syndrome (MetS) has been reported. However, the relationships between hemoglobin and individual MetS components remain unclear. Therefore, we investigated these associations at baseline and at the 3-year follow-up. Methods: We enrolled 9960 middle-aged and elderly subjects (6726 women and 3234 men) and performed a 3-year follow-up cohort study. All subjects completed a questionnaire and underwent anthropometric measurements and laboratory tests. Logistic regression models were developed to assess the association between hemoglobin and MetS and its components. Results: MetS was present in 45.1% of women and 41.4% of men at baseline. The hemoglobin concentration was positively correlated with SBP, DBP, TGs, WC, FPG, insulin, HOMA-IR, BMI and uric acid (p < 0.05). The mean hemoglobin concentration was higher in subjects with hypertension, high TGs, abdominal obesity or elevated FPG (p < 0.01). At follow-up, elevated hemoglobin correlated with an increased incidence and ORs for MetS, high TGs, low HDL-c, hyperuricemia and NAFLD but not abdominal obesity, BP or FPG in women. Increased hemoglobin corresponded with an increased incidence and ORs for MetS, abdominal obesity, low HDL-c, hyperuricemia and NAFLD but not BP, high TGs or FPG in men. Conclusions: Hemoglobin may play a role in predicting new-onset MetS in both women and men. Hemoglobin was notably correlated with future risk of high TGs, low HDL-c, hyperuricemia, and NAFLD among women and abdominal obesity, low HDL-c, hyperuricemia, and NAFLD among men. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to identify the prevalence and gender differences of metabolic syndrome in young new-onset ketosis-prone type 2 diabetic (KPT2D) individuals. Patients and Methods: A retrospective study was conducted in Shanghai Xin Hua Hospital from 2007 to 2019. A total of 304 patients from 12 to 40 years of age with newly diagnosed diabetes presenting with ketosis were analyzed. The clinical features and laboratory results of KPT2D and type 1 diabetic (T1D) individuals were compared. Prevalence and gender differences of metabolic syndrome in the KPT2D subjects were analyzed. Results: The prevalence of metabolic syndrome (P < 0.0001) was significantly higher in young KPT2D than T1D subjects. The prevalence of high blood pressure (P < 0.0001), central obesity (P < 0.0001), low plasma HDL-C concentration (P = 0.045), and hypertriglyceridemia (P < 0.0001) was elevated in the KPT2D subjects compared with T1D. Male predominance (89%) was presented in the KPT2D subjects. The prevalence of metabolic syndrome (P = 0.0002) was significantly higher in young male than female KPT2D subjects. The presence of central obesity (P < 0.0001) and high blood pressure (P =0.03) was higher in male KPT2D subjects than female. The presence of serum triglyceride concentrations ≥ 2.3mmol/L was significantly higher (P = 0.011) in male KPT2D subjects than female. Conclusion: Significantly higher prevalence of metabolic syndrome in young KPT2D patients compared with T1D patients could be an important reference for diabetic differential diagnosis. KPT2D presented a higher predominance in young males, who had higher prevalence of metabolic syndrome than young females. [ABSTRACT FROM AUTHOR]

BACKGROUND Toll-like receptor 4 (TLR4) has been implicated in the progression of cardiovascular disease, including hypertension. However, the role of TLR4 in the development of prehypertension is uncertain. METHODS Prehypertensive rats were treated with 8% salt for 12 weeks to induce prehypertension. These rats were then given either TAK-242 selective TLR4 blocker, or vehicle by bilateral micro-injection to the paraventricular nucleus (PVN). Blood pressure (BP) and renal sympathetic nerve activity were recorded. PVN expression of TLR4, myeloid differentiation factor 88 (Myd88), nuclear factor-kappa B (NF-κB) p65, proinflammation cytokines (PICs), interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha (TNF-α), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), NADPH oxidase 4 (NOX4), Cu/Zn superoxide dismutase (SOD) level, tyrosine hydroxylase, and 67 kDa isoform of glutamate decarboxylase (GAD67) were tested to determine the influence of TLR4 blockade. RESULTS TLR4 expression increased significantly in the PVN of high-salt groups with a corresponding increase in reactive oxygen species (ROS) and PICs. TLR4 blockade significantly reduced the signaling molecules downstream TLR4 and the expression of TNF-α, IL-6, IL-1β, decreased ROS, NOX2, NOX4 level, increased Cu/Zn-SOD, re-balanced neurotransmitters, and regulated sympathetic nerve activity in the PVN of prehypertensive rats. CONCLUSIONS Salt-induced prehypertension is partly due to the upregulation of TLR4 in PVN. Blockade of TLR4 in the brain reduced salt-induced prehypertension response, possibly through downregulation of ROS and PICs expression, and the restorage of neurotransmitter balance in the PVN. [ABSTRACT FROM AUTHOR]

Numerous studies have indicated that a high salt diet inhibits brain Na+/K+-ATPase (NKA) activity, and affects oxidative stress and inflammation in the paraventricular nucleus (PVN). Furthermore, Na+/K+-ATPase alpha 2-isoform (NKA α2) may be a target in the brain, taking part in the development of salt-dependent hypertension. Therefore, we hypothesized that NKA α2 regulates oxidative stress and inflammation in the PVN in the context of salt-induced hypertension. Part I: We assessed NKA subunits (NKA α1, NKA α2, and NKA α3), Na+/K+-ATPase activity, oxidative stress, and inflammation in a high salt group (8% NaCl) and normal salt group (0.3% NaCl). Part II: NKA α2 short hairpin RNA (shRNA) was bilaterally microinjected into the PVN of salt-induced hypertensive rats to knockdown NKA α2, and we explored whether NKA α2 regulates downstream signaling pathways related to protein kinase C γ (PKC γ)-dependent oxidative stress and toll-like receptor 4 (TLR4)-induced inflammation in the PVN to promote the development of hypertension. High salt diet increased NKA α1 and NKA α2 protein expression in the PVN but had no effect on NKA α3 compared to the normal salt diet. Na+/K+-ATPase activity and ADP/ATP ratio was lower, but NAD(P)H activity and NF-κB activity in the PVN were higher after a high salt diet. Bilateral PVN microinjection of NKA α2 shRNA not only improved Na+/K+-ATPase activity and ADP/ATP ratio but also suppressed PKC γ-dependent oxidative stress and TLR4-dependent inflammation in the PVN, thus decreasing sympathetic activity in rats with salt-induced hypertension. NKA α2 in the PVN elicits PKC γ/Rac1/NAD (P)H-dependent oxidative stress and TLR4/MyD88/NF-κB-induced inflammation in the PVN, thus increasing MAP and sympathetic activity during the development of salt-induced hypertension. [ABSTRACT FROM AUTHOR]

The original version of this article unfortunately contained a mistake in the name of one co-author. The correct name of the co-author "Juan Ba" should be "Juan Bai". [ABSTRACT FROM AUTHOR]

Exercise training is one of the major non-pharmacological treatments for hypertension. However, the central mechanism by which exercise training attenuates the hypertensive responses remains unclear. Irisin is a muscle-secreted cytokine derived from fibronectin type III domain containing 5 (FNDC5) that will be released into the circulation during exercise. We hypothesized that irisin may play a role in the blood pressure regulation by exercise. To examine the hypothesis, our study investigated the effect of irisin on hypertension and its central mechanism. The study was performed in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats. We found that intravenous injection of irisin effectively reduced blood pressure, plasma norepinephrine, paraventricular nucleus (PVN) levels of neuronal activation, oxidative stress and inflammation in SHRs. Moreover, irisin activated nuclear factor E2-related factor-2 (Nrf2) and restored the imbalance of neurotransmitters in the PVN. Our study also found PVN knockdown of Nrf2 abolished the protective effects of irisin on hypertension. These findings demonstrate irisin can improve hypertension via Nrf2-mediated antioxidant in the PVN. [ABSTRACT FROM AUTHOR]