Antihypertensive treatment during pregnancy induces long-term changes in gut microbiota and the behaviors of the attention deficit hyperactivity disorder offspring.

The pathogenesis of attention-deficit/hyperactivity disorder (ADHD) has not been fully elucidated. Gestational hypertension could double the probability of ADHD in the offspring, while the initial bacterial communication between the mother and offspring has been associated with psychiatric disorders. Thus, we hypothesize that antihypertensive treatment during pregnancy may abate the impairments in neurodevelopment of the offspring. To test this hypothesis, we chose Captopril and Labetalol, to apply to pregnant spontaneously hypertensive rat (SHR) dams and examined the outcomes in the male offspring. Our data demonstrated that maternal treatment with Captopril and Labetalol had long-lasting changes in gut microbiota and behavioral alterations, including decreased hyperactivity and increased curiosity, spatial learning and memory in the male offspring. Increased diversity and composition were identified, and some ADHD related bacteria were found to have the same change in the gut microbiota of both the dam and offspring after the treatments. LC-MS/MS and immunohistochemistry assays suggested elevated expression of brain derived neurotrophic factor (BDNF) and dopamine in the prefrontal cortex and striatum of offspring exposed to Captopril/ Labetalol, which may account for the improvement of the offspring's psychiatric functions. Therefore, our results support the beneficial long-term effects of the intervention of gestational hypertension in the prevention of ADHD.

Faecalibacterium prausnitzii Attenuates CKD via Butyrate-Renal GPR43 Axis.

BACKGROUND: Despite available clinical management strategies, chronic kidney disease (CKD) is associated with severe morbidity and mortality worldwide, which beckons new solutions. Host-microbial interactions with a depletion of Faecalibacterium prausnitzii in CKD are reported. However, the mechanisms about if and how F prausnitzii can be used as a probiotic to treat CKD remains unknown. METHODS: We evaluated the microbial compositions in 2 independent CKD populations for any potential probiotic. Next, we investigated if supplementation of such probiotic in a mouse CKD model can restore gut-renal homeostasis as monitored by its effects on suppression on renal inflammation, improvement in gut permeability and renal function. Last, we investigated the molecular mechanisms underlying the probiotic-induced beneficial outcomes. RESULTS: We observed significant depletion of Faecalibacterium in the patients with CKD in both Western (n=283) and Eastern populations (n=75). Supplementation of F prausnitzii to CKD mice reduced renal dysfunction, renal inflammation, and lowered the serum levels of various uremic toxins. These are coupled with improved gut microbial ecology and intestinal integrity. Moreover, we demonstrated that the beneficial effects in kidney induced by F prausnitzii-derived butyrate were through the GPR (G protein-coupled receptor)-43. CONCLUSIONS: Using a mouse CKD model, we uncovered a novel beneficial role of F prausnitzii in the restoration of renal function in CKD, which is, at least in part, attributed to the butyrate-mediated GPR-43 signaling in the kidney. Our study provides the necessary foundation to harness the therapeutic potential of F prausnitzii for ameliorating CKD.

Curcumin ameliorates hypertension via gut-brain communication in spontaneously hypertensive rat.

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.

Calcitriol ameliorated autonomic dysfunction and hypertension by down-regulating inflammation and oxidative stress in the paraventricular nucleus of SHR.

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.

Irisin lowers blood pressure by activating the Nrf2 signaling pathway in the hypothalamic paraventricular nucleus of spontaneously hypertensive rats.

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.

Inhibition of Hypothalamic Inhibitor κB Kinase ß/Nuclear Transcription Factor κB Pathway Attenuates Metabolism and Cardiac Dysfunction in Type 2 Diabetic Rats.

BACKGROUND: Inflammation and oxidative stress play important roles in energy imbalance and its complications. Recent research indicates that hypothalamic inflammation may contribute to the pathogenesis of metabolic syndrome and cardiac dysfunction, but the mechanisms remain unclear. We hypothesized that suppression of the proinflammatory IKKß/NF-κB pathway in the hypothalamus can improve energy balance and cardiac function in type 2 diabetic (T2D) rats. METHODS: Normal and T2D rats received bilateral hypothalamic arcuate nucleus (ARC) infusions of the IKKß inhibitor SC-514 or vehicle via osmotic minipump. Metabolic phenotyping, immunohistochemical analyses, and biochemical analyses were used to investigate the outcomes of inhibition of the hypothalamic IKKß. Echocardiography and glucometer were used for measuring cardiac function and blood glucose, respectively. Blood samples were collected for the evaluation of circulating proinflammatory cytokines. Heart was harvested for cardiac morphology evaluations. The ARC was harvested and analyzed for IKKß, NF-κB, proinflammatory cytokines, reactive oxygen species (ROS), and NAD(P)H (gp91phox, p47phox) oxidase activity levels and neuropeptides. RESULTS: Compared with normal rats, T2D rats were characterized by hyperglycemia, hyperinsulinemia, glucose intolerance, cardiac dysfunction, as well as higher ARC levels of IKKß, NF-κB, proinflammatory cytokines, ROS, gp91phox, and p47phox. ARC infusion of the IKKß inhibitor SC-514 attenuated all these changes in T2D rats, but not in normal rats. CONCLUSIONS: Our results indicate that the hypothalamic IKKß/NF-κB pathway plays a key role in modulating energy imbalance and cardiac dysfunction, suggesting its potential therapeutic role during type 2 diabetes mellitus.

Validation of Single Centre Pre-Mobile Atrial Fibrillation Apps for Continuous Monitoring of Atrial Fibrillation in a Real-World Setting: Pilot Cohort Study.

BACKGROUND: Atrial fibrillation is the most common recurrent arrhythmia in clinical practice, with most clinical events occurring outside the hospital. Low detection and nonadherence to guidelines are the primary obstacles to atrial fibrillation management. Photoplethysmography is a novel technology developed for atrial fibrillation screening. However, there has been limited validation of photoplethysmography-based smart devices for the detection of atrial fibrillation and its underlying clinical factors impacting detection. OBJECTIVE: This study aimed to explore the feasibility of photoplethysmography-based smart devices for the detection of atrial fibrillation in real-world settings. METHODS: Subjects aged ≥18 years (n=361) were recruited from September 14 to October 16, 2018, for screening of atrial fibrillation with active measurement, initiated by the users, using photoplethysmography-based smart wearable devices (ie, a smart band or smart watches). Of these, 200 subjects were also automatically and periodically monitored for 14 days with a smart band. The baseline diagnosis of "suspected" atrial fibrillation was confirmed by electrocardiogram and physical examination. The sensitivity and accuracy of photoplethysmography-based smart devices for monitoring atrial fibrillation were evaluated. RESULTS: A total of 2353 active measurement signals and 23,864 periodic measurement signals were recorded. Eleven subjects were confirmed to have persistent atrial fibrillation, and 20 were confirmed to have paroxysmal atrial fibrillation. Smart devices demonstrated >91% predictive ability for atrial fibrillation. The sensitivity and specificity of devices in detecting atrial fibrillation among active recording of the 361 subjects were 100% and about 99%, respectively. For subjects with persistent atrial fibrillation, 127 (97.0%) active measurements and 2240 (99.2%) periodic measurements were identified as atrial fibrillation by the algorithm. For subjects with paroxysmal atrial fibrillation, 36 (17%) active measurements and 717 (19.8%) periodic measurements were identified as atrial fibrillation by the algorithm. All persistent atrial fibrillation cases could be detected as "atrial fibrillation episodes" by the photoplethysmography algorithm on the first monitoring day, while 14 (70%) patients with paroxysmal atrial fibrillation demonstrated "atrial fibrillation episodes" within the first 6 days. The average time to detect paroxysmal atrial fibrillation was 2 days (interquartile range: 1.25-5.75) by active measurement and 1 day (interquartile range: 1.00-2.00) by periodic measurement (P=.10). The first detection time of atrial fibrillation burden of <50% per 24 hours was 4 days by active measurement and 2 days by periodic measurementThe first detection time of atrial fibrillation burden of >50% per 24 hours was 1 day for both active and periodic measurements (active measurement: P=.02, periodic measurement: P=.03). CONCLUSIONS: Photoplethysmography-based smart devices demonstrated good atrial fibrillation predictive ability in both active and periodic measurements. However, atrial fibrillation type could impact detection, resulting in increased monitoring time. TRIAL REGISTRATION: Chinese Clinical Trial Registry of the International Clinical Trials Registry Platform of the World Health Organization ChiCTR-OOC-17014138; http://www.chictr.org.cn/showprojen.aspx?proj=24191.

Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats.

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 IKKß, 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 IKKß, 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.

Central blockade of NLRP3 reduces blood pressure via regulating inflammation microenvironment and neurohormonal excitation in salt-induced prehypertensive rats.

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.

Central administration of tert-butylhydroquinone attenuates hypertension via regulating Nrf2 signaling in the hypothalamic paraventricular nucleus of hypertensive rats.

Reactive oxygen species (ROS) in the paraventricular nucleus (PVN) play a pivotal role in the pathogenesis of hypertension. Nuclear factor E2-related factor-2 (Nrf2) is an important transcription factor that modulates cell antioxidant defense response against oxidative stress. The present study aimed to explore the efficacy of PVN administration of tert-butylhydroquinone (tBHQ), a selective Nrf2 activator, in hypertensive rats. 16-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were used in this study. These rats were chronic bilateral PVN infusion of tBHQ (0.8µg/day), or oxygen free radical scavenger tempol (20µg/h), or vehicle for 2weeks. SHR rats had higher mean arterial pressure (MAP), plasma norepinephrine (NE) levels, and sympathetic nerve activity (RSNA) and lower PVN levels of Nrf2, hemeoxygenase-1 (HO-1), superoxide dismutase-1 (SOD1) and catalase (CAT) as compared with those in the WKY group. Bilateral PVN infusion of tBHQ or tempol significantly reduced MAP, RSNA, plasma NE levels in SHR rats. In addition, tBHQ treatment enhanced the nuclear accumulation of Nrf2 and increased the expression of HO-1, CAT and SOD1 in SHR rats. Furthermore, tBHQ attenuated PVN levels of ROS, the expression of proinflammatory cytokines and restored the imbalance of neurotransmitters in PVN. Knockdown of Nrf2 in the PVN by adeno-associated virus mediated small interfering RNA abrogated the protective effects of tBHQ on hypertension. These findings suggest that PVN administration of tBHQ can attenuate hypertension by activation of the Nrf2-mediated signaling pathway.

TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in 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)-1ß, 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-1ß, 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.

Blockade of Salusin-ß in Hypothalamic Paraventricular Nucleus Attenuates Hypertension and Cardiac Hypertrophy in Salt-induced Hypertensive Rats.

Salusin-ß, 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-ß 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-ß blocker, antisalusin-ß 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 ß-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-ß in the PVN restores neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive responses and cardiac hypertrophy.

Chronic infusion of lisinopril into hypothalamic paraventricular nucleus modulates cytokines and attenuates oxidative stress in rostral ventrolateral medulla in hypertension.

The hypothalamic paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) play a critical role in the generation and maintenance of sympathetic nerve activity. The renin-angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. This study was designed to determine whether inhibition of the angiotensin-converting enzyme (ACE) in the PVN modulates cytokines and attenuates oxidative stress (ROS) in the RVLM, and decreases the blood pressure and sympathetic activity in renovascular hypertensive rats. Renovascular hypertension was induced in male Sprague-Dawley rats by the two-kidney one-clip (2K1C) method. Renovascular hypertensive rats received bilateral PVN infusion with ACE inhibitor lisinopril (LSP, 10µg/h) or vehicle via osmotic minipump for 4weeks. Mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), and plasma proinflammatory cytokines (PICs) were significantly increased in renovascular hypertensive rats. The renovascular hypertensive rats also had higher levels of ACE in the PVN, and lower level of interleukin-10 (IL-10) in the RVLM. In addition, the levels of PICs, the chemokine MCP-1, the subunit of NAD(P)H oxidase (gp91(phox)) and ROS in the RVLM were increased in hypertensive rats. PVN treatment with LSP attenuated those changes occurring in renovascular hypertensive rats. Our findings suggest that the beneficial effects of ACE inhibition in the PVN in renovascular hypertension are partly due to modulation cytokines and attenuation oxidative stress in the RVLM.

Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension.

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-1ß) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91(phox), ACE and IL-1ß 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.

Testis specific protein, Y-encoded-like 2 activates JAK2/STAT3 pathway in hypothalamic paraventricular nucleus to sustain hypertension.

BACKGROUND: In the hypothalamic paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHRs), the expression of Testis specific protein, Y-encoded-like 2 (TSPYL2) and the phosphorylation level of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) are higher comparing with the normotensive Wistar-Kyoto rats (WKY). But how they are involved in hypertension remains unclear. TSPYL2 may interact with JAK2/STAT3 in PVN to sustain the high blood pressure during hypertension. METHODS: Knockdown of TSPYL2 via adeno-associated virus (AAV) carrying shRNA was conducted through bilateral micro-injection into the PVN of SHR and WKY rats. JAK2/STAT3 inhibition was achieved by intraperitoneally or PVN injection of AG490 into the SHRs. Blood pressure (BP), plasma norepinephrine (NE), PVN inflammatory response, and PVN oxidative stress were measured. RESULTS: TSPYL2 knock-down in the PVN of SHRs but not WKYs led to reduced BP and plasma NE, and deactivation of JAK2/STAT3, decreased expression of pro-inflammatory cytokine IL-1ß, and increased expression of anti-inflammatory cytokine IL-10 in the PVN. Meanwhile, AG490 administrated in both ways reduced the blood pressure in the SHRs and deactivated JAK2/STAT3 but failed to change the expression of TSPYL2 in PVN. AG490 also downregulated expression of IL-1ß and upregulated expression of IL-10. Both knockdown of TSPYL2 and inhibition of JAK2/STAT3 can reduce the oxidative stress in the PVN of SHRs. CONCLUSION: JAK2/STAT3 is regulated by TSPYL2 in the PVN of SHRs, and PVN TSPYL2/JAK2/STAT3 is essential for maintaining high blood pressure in the hypertensive rats, making it a potential therapeutic target for hypertension.

Taurocholic acid ameliorates hypertension through the activation of TGR5 in the hypothalamic paraventricular nucleus.

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.

Efficacy of moxibustion in diarrhea-predominant irritable bowel syndrome model rats: a systematic review and meta-analysis.

Objective: To systematically evaluate the efficacy of moxibustion in diarrhea-predominant irritable bowel syndrome (IBS-D) model rats. Methods: A comprehensive search was conducted in the China National Knowledge Infrastructure, WanFang Data, VIP, PubMed, Embase, and Web of Science databases from their inception to June 30, 2023. Relevant animal experiments investigating moxibustion for treating IBS-D in model rats were included. Two independent researchers screened the literature, extracted data, and evaluated the risk of bias in the selected studies. The meta-analysis was performed using RevMan 5.3 software. Results: In total, 21 animal studies comprising 680 model rats were included. The meta-analysis results demonstrated that moxibustion enhanced the threshold capacity of the abdominal withdrawal reflex (AWR) [standardized mean difference (SMD) = 1.84; 95% confidence interval (CI): 1.09, 2.60; p < 0.00001], ameliorated the rate of loose stool (SMD = -4.03; 95% CI: -5.76, -2.30; p < 0.00001), and decreased the colon 5-hydroxytryptamine (SMD = -3.67; 95% CI: -5.33, -2.01; p < 0.00001), serum interleukin-1ß (SMD = -3.24, 95% CI: -4.06, -2.41; p < 0.00001), serum tumor necrosis factor-α (SMD = -2.35, 95% CI: -4.12, -0.58; p < 0.00001), and serum substance P (SMD = -5.14, 95% CI: -8.45, -1.83; p = 0.002) concentrations. Moxibustion did not affect the blood calcitonin gene-related peptide level compared to the blank model group (p = 0.15). Conclusion: Moxibustion modulated the brain-gut interaction, reduced visceral hypersensitivity, inhibited intestinal inflammation, and regulated the immune balance, improving the rate of loose stool and increasing the AWR threshold capacity in IBS-D model rats, achieving good analgesic and antidiarrheal effects. However, these conclusions require further validation due to limitations in the quantity and quality of the included studies.

Phase Interface Regulating on Amorphous/Crystalline Bismuth Catalyst for Boosted Electrocatalytic CO2 Reduction to Formate.

Electroreduction of carbon dioxide into readily collectable and high-value carbon-based fuels is greatly significant to overcome the energy and environmental crises yet challenging in the development of robust and highly efficient electrocatalysts. Herein, a bismuth (Bi) heterophase electrode with enriched amorphous/crystalline interfaces was fabricated via cathodically in situ transformation of Bi-based metal-phenolic complexes (Bi-tannic acid, Bi-TA). Compared with amorphous or crystalline Bi catalyst, the amorphous/crystalline structure Bi leads to significantly enhanced performance for CO2 electroreduction. In a liquid-phase H-type cell, the Faraday efficiency (FE) of formate formation is over 90% in a wide potential range from -0.8 to -1.3 V, demonstrating a high selectivity toward formate. Moreover, in a flow cell, a large current density reaching 600 mA cm-2 can further be rendered for formate production. Theoretical calculations indicate that the amorphous/crystalline Bi heterophase interface exhibits a favorable adsorption of CO2 and lower energy barriers for the rate-determining step compared with the crystalline Bi counterparts, thus accelerating the reaction process. This work paves the way for the rational design of advanced heterointerface catalysts for CO2 reduction.

Na+/K+-ATPase Alpha 2 Isoform Elicits Rac1-Dependent Oxidative Stress and TLR4-Induced Inflammation in the Hypothalamic Paraventricular Nucleus in High Salt-Induced Hypertension.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Diosgenin exerts an antihypertensive effect in spontaneously hypertensive rats via gut-brain communication.

Gut microbiota is well-established to regulate host blood pressure. Diosgenin is a natural steroid sapogenin with documented anti-inflammatory, antioxidant and antihypertensive properties. We aimed to investigate whether the antihypertensive effects of diosgenin are mediated by the microbiota-gut-brain axis in spontaneously hypertensive rats (SHR). 15-Week-old male Wistar Kyoto rats (WKY) and age-matched SHR were randomly distributed into three groups: WKY, SHR treated with a vehicle, and SHR treated with diosgenin (100 mg kg-1). Our results showed that diosgenin prevented elevated systolic blood pressure (SBP) and ameliorated cardiac hypertrophy in SHR. Moreover, the gut microbiota composition and intestinal integrity were improved. Furthermore, increased butyrate-producing bacteria and plasma butyrate and decreased plasma lipopolysaccharides were observed in SHR treated with diosgenin. These findings were associated with reduced microglial activation and neuroinflammation in the paraventricular nucleus. Our findings suggest that diosgenin attenuates hypertension by reshaping the gut microbiota and improving the gut-brain axis.