Qianyang yuyin granule ameliorates mitochondrial dysfunction of hypertensive myocardial remodeling.

ETHNOPHARMACOLOGICAL RELEVANCE: Clinical studies have found that Qianyang Yuyin granule (QYYYG), a kind of oral Chinese patent medicine, had definite clinical effect for hypertensive myocardial remodeling. However, the potential mechanism is not entirely clear. AIM OF THE STUDY: The purpose of this research was to explore the underlying mechanism QYYYG on the treatment of hypertensive myocardial remodeling. MATERIALS AND METHODS: Analysis the transcriptome data from the NCBI public platform GEO database and our study to explore the key pathological change of myocardial tissues in hypertensive mice and the main pathway of QYYYG in treating hypertensive myocardial remodeling. Network pharmacological analysis was used to predict the potential target of QYYYG. The molecular docking and molecular dynamics simulation was used for molecular binding analysis of specific compounds and target proteins. In the experiment in vivo, the effect of QYYYG on hypertensive myocardial remodeling and myocardial mitochondrial dysfunction in hypertensive mice caused by Ang Ⅱ was estimated. In the experiment in vitro, the Ang Ⅱ-induced myocardial remodeling model in H9c2 cells was constructed, and the effect of QYYYG on ameliorating myocardial remodeling and mitochondrial dysfunction was evaluated. RESULTS: Transcriptome analysis suggested that mitochondrial dysfunction was a key pathological change of myocardial tissues in hypertensive mice, and QYYYG could improve hypertensive myocardial remodeling through enhancing mitochondrial biogenesis to repair myocardial mitochondrial dysfunction. Network pharmacological analysis predicted that SIRT1 was an important potential target of QYYYG in treating hypertensive myocardial remodeling, and basically all the active components, especially quercetin, had a great binding affinity with SIRT1. Experiments in vivo proved that QYYYG had great efficacy hypertensive myocardial remodeling in Ang Ⅱ-treated mice. It was found that QYYYG improved the quality and quantity of mitochondria, and increased SIRT1 levels in myocardial tissue of Ang Ⅱ-treated mice. In Ang Ⅱ-treated H9c2 cells, with intervention of QYYYG, myocardial remodeling and myocardial mitochondrial dysfunction was ameliorated. In addition, QYYYG up-regulated SIRT1 expression and enhanced mitochondrial biogenesis in Ang Ⅱ-treated H9c2 cells. CONCLUSION: This study suggested that mitochondrial dysfunction was an important pathological change of myocardial tissues in hypertensive mice. QYYYG might ameliorate the mitochondrial dysfunction of hypertensive myocardial remodeling through up-regulating SIRT1 expression to enhance the mitochondrial biogenesis.

Association between immune-inflammation-based prognostic index and depression: An exploratory cross-sectional analysis of NHANES data.

BACKGROUND: Immune-inflammatory mediators influence numerous immune and inflammatory pathways, elevating the likelihood of depression. The systemic immune-inflammation index (SII) emerges as an innovative prognostic indicator, integrating various peripheral blood immune cell subpopulations, specifically neutrophils, platelets, and lymphocytes. This exploratory study aims to examine the correlation between SII and depression. METHODS: Data from the 2005-2020 National Health and Nutrition Examination Survey (NHANES) were utilized. Depression was diagnosed with a Patient Health Questionnaire score of 10 or higher. The relationship between log2-SII and depression incidence was analyzed using a restricted cubic spline (RCS). Logistic regression was employed to calculate the odds ratio of depression concerning log2-SII. In cases of non-linearity, piecewise linear models with change points were applied to assess the associations in both the overall population and specific subgroups. Additionally, subgroup analyses were conducted to determine the applicability of the findings to particular populations. RESULTS: A total of 42,133 participants were included in the study, comprising 49.32 % men and 50.68 % women, with an average age of 47.02 ± 17.45 years. RCS analysis demonstrated a J-shaped non-linear relationship between log2-SII and depression incidence. When log2-SII was ≥8.50, SII showed a positive association with depression incidence, even after adjusting for covariates. Additionally, each unit increase in log2-SII corresponded to an 18 % rise in depression incidence (OR = 1.18, 95 % CI: 1.10-1.27). Subgroup analysis further revealed that the association between SII and depression incidence varied across different populations. LIMITATIONS: Due to the cross-sectional nature of NHANES, causality or long-term implications cannot be inferred. Further research is needed to ascertain if a longitudinal relationship exists between SII and depression. CONCLUSION: Our findings suggest a significant and complex non-linear association between SII and depression. However, further basic and prospective studies are necessary to explore SII's impact on depression and clarify its underlying mechanisms. Additionally, these studies will provide a foundation for personalized interventions targeting the immune-inflammatory processes in patients with depression and elevated SII.

The Association of Systemic Inflammatory Response Index and Neutrophil-to-High-Density Lipoprotein Ratio Mediated by Fasting Blood Glucose with 90-Day Prognosis in Acute Ischemic Stroke Patients.

INTRODUCTION: The contribution of individual and combined inflammatory markers for the prognosis of acute ischemic stroke (AIS) remains elusive. This study investigated the effect of systemic inflammatory response index (SIRI), and neutrophil to high-density lipoprotein ratio (NHR), which is mediated by fasting blood glucose (FBG), on 90-day prognosis of patients with AIS. METHODS: In this pre-specified substudy of an observational cohort study, 2,828 patients with AIS were enrolled from the Nanjing Stroke Registry between January 2017 and July 2021. Peripheral venous blood was collected from patients fasting for at least 8 h within 24 h of admission to gather information on the following parameters: neutrophil count, lymphocyte count, monocyte count, HDL level, and fasting blood glucose level. Then, the SIRI and NHR values were calculated. Following this, the correlation among SIRI, NHR, and modified Rankin Scale (mRS) scores 90 days after onset was examined via univariate and multivariate logistic analyses. Lastly, mediation analysis was performed to examine the relationship between systematic inflammatory response and study outcomes mediated by FBG. RESULTS: SIRI and NHR were both negatively correlated with clinical outcomes (p < 0.05). Logistic regression analysis revealed that SIRI and NHR were independently associated with poor outcomes after adjusting for potential confounders. Subgroup analyses further validated these correlations. Meanwhile, mediation analysis corroborated that FBG partially mediated the associations between SIRI and a poor prognosis at 90 days (indirect effect estimate = 0.0038, bootstrap 95% CI 0.001-0.008; direct effect estimate = 0.1719, bootstrap 95% CI 0.1258-0.2179). Besides, FBG also played a mediating role between NHR and poor outcomes (indirect effect estimate = 0.0066, bootstrap 95% CI 0.002-0.120; direct effect estimate = 0.1308, bootstrap 95% CI 0.0934-0.1681). CONCLUSION: Our study demonstrated that SIRI and NHR are positively associated with poor clinical and mortality outcomes at 90 days in AIS patients, which was partially mediated by FBG.

Relationship of Day-by-Day Blood Pressure Variability and Admission Stroke Severity in Acute Ischemic Stroke.

OBJECTIVES: Research on the association between stroke severity and day-by-day blood pressure variability (BPV) in acute ischemic stroke (AIS) is rare as the majority focus on the blood pressure (BP) or the short-term BPV. Our study aims to explore the exact roles of daily BPV through the 7-day commencement on stroke severity in AIS. METHODS: The study included 633 patients with AIS, defining AIS as the time from the beginning of symptom up to 7 days with recording BP twice a day as well as calculating the daily BPV, and then matching them to the stroke severity. The logistic regression models were used to evaluate associations between stroke severity and day-by-day BPV. We used the smooth curve fitting to identify whether there was a nonlinear association. In addition, the subgroup analyses were performed using the logistic regression. RESULTS: According to the modified National Institutes of Health Stroke Scale score, 301 (47.5%) patients were allocated to the mild stroke group and 332 (52.5%) to the moderate-to-severe stroke group. In terms of stroke categories, we found no significant difference between BP at admission or mean BP. However, the moderate-to-severe stroke group exhibited higher daily BPV. The multiple logistic regression analysis indicated that day-by-day BPV was positively correlated to stroke severity [odds ratio (OR)=1.05, 95% CI:1.01-1.1, P=0.03 for SBP-SD; OR=1.08, 95% CI:1.01-1.15, P=0.03 for SBP-CV; OR=1.04, 95% CI:1.01-1.07, P=0.015 for SBP-SV). CONCLUSIONS: High day-by-day BPV in AIS was associated with more severe stroke independent of BP levels.

Comprehensive effects of traditional Chinese medicine treatment on heart failure and changes in B-type natriuretic peptide levels: A meta-analysis.

BACKGROUND: Heart failure (HF), a common cardiovascular condition, is characterized by significant morbidity and mortality. While traditional Chinese medicine (TCM) is often used as a complementary approach in HF management, systematic evaluations of its impact on clinical outcomes, TCM syndrome scores, and B-type natriuretic peptide (BNP) levels are lacking. This study fills this gap through a comprehensive analysis of randomized controlled trials (RCTs) focusing on TCM for HF treatment. It encompasses an assessment of methodological quality, a meta-analysis, and an evaluation of evidence quality based on established standards. The results offer crucial insights into the potential advantages and constraints of TCM in HF management. AIM: To systematically analyze the effects of TCM on the clinical comprehensive outcomes, TCM syndrome scores, and BNP levels in patients with HF and evaluated the quality of evidence for these trials. METHODS: RCTs on TCM for HF treatment published since the establishment of the database were searched in four Chinese and English databases, including China National Knowledge Infrastructure, Wanfang, VIP Information Chinese Science and Technology Journal, and PubMed. Methodological quality was assessed for the included studies with the Cochrane risk-of-bias assessment tool, and the meta-analysis and publication bias assessment was performed with the RevMan5.3 software. Finally, the quality of evidence was rated according to the GRADE criteria. RESULTS: A total of 1098 RCTs were initially retrieved. After screening, 16 RCTs were finally included in our study, which were published between 2020 and 2023. These RCTs involved 1660 HF patients, including 832 in the TCM group [TCM combined with conventional Western medicine (CMW) treatment] and 828 in the CWM group (CWM treatment). The course of treatments varied from 1 wk to 3 months. TCM syndrome differentiation was analyzed in 11 of the included RCTs. In all included RCTs, outcome indicators included comprehensive clinical outcomes, TCM syndrome scores, and BNP levels. The meta-analysis results showed significant differences between the TCM and CWM groups in terms of comprehensive clinical outcomes [risk ratio = -0.54; 95% confidence interval (CI) = -0.61, -0.47; P < 0.00001], TCM syndrome scores [weighted mean difference (WMD) = -142.07; 95%CI = -147.56, -136.57; P < 0.00001], and BNP levels (WMD = -142.07; 95%CI = -147.56, -136.57; P < 0.00001). According to the GRADE criteria, RCTs where "TCM improves clinical comprehensive outcomes" were rated as low-quality evidence, and RCTs where "TCM reduces TCM syndrome scores" or "TCM decreases BNP levels" were rated as medium-quality evidence. CONCLUSION: TCM combined with CWM treatment effectively improves comprehensive clinical outcomes and diminishes TCM syndrome scores and BNP levels in HF patients. Given the low and medium quality of the included RCTs, the application of these results should be cautious.

Sex- and reproductive status-specific relationships between body composition and non-alcoholic fatty liver disease.

BACKGROUND: Sex and reproductive status differences exist in both non-alcoholic fatty liver disease (NAFLD) and body composition. Our purpose was to investigate the relationship between body composition and the severity of liver steatosis and fibrosis in NAFLD in different sex and reproductive status populations. METHODS: This cross-sectional study included 880 patients (355 men, 417 pre-menopausal women, 108 post-menopausal women). Liver steatosis and fibrosis and body composition data were measured using FibroScan and a bioelectrical impedance body composition analyzer (BIA), respectively, and the following parameters were obtained: liver stiffness measurement (LSM), controlled attenuation parameter (CAP), waist circumference (WC), body mass index (BMI), percent body fat (PBF), visceral fat area (VFA), appendicular skeletal muscle mass (ASM), appendicular skeletal muscle mass index (ASMI), fat mass (FM), fat free mass (FFM), and FFM to FM ratio (FFM/FM). Multiple ordinal logistic regression (MOLR) was used to analyze the independent correlation between body composition indicators and liver steatosis grade and fibrosis stage in different sex and menopausal status populations. RESULTS: Men had higher WC, ASM, ASMI, FFM, and FFM/FM than pre- or post-menopausal women, while pre-menopausal women had higher PBF, VFA, and FM than the other two groups (p < 0.001). Besides, men had greater CAP and LSM values (p < 0.001). For MOLR, after adjusting for confounding factors, WC (OR, 1.07; 95% CI, 1.02-1.12; P = 0.011) and FFM/FM (OR, 0.52; 95% CI, 0.31-0.89; P = 0.017) in men and visceral obesity (OR, 4.16; 95% CI, 1.09-15.90; P = 0.037) in post-menopausal women were independently associated with liver steatosis grade. WC and visceral obesity were independently associated with liver fibrosis stage in men (OR, 1.05; 95% CI, 1.01-1.09, P = 0.013; OR, 3.92; 95% CI, 1.97-7.81; P < 0.001, respectively). CONCLUSIONS: Increased WC and low FFM/FM in men and visceral obesity in post-menopausal women were independent correlates of more severe liver steatosis. In addition, increased WC and visceral obesity were independent correlates of worse liver fibrosis in men. These data support the sex- and reproductive status-specific management of NAFLD.

An integrated approach of high-performance liquid chromatography-mass spectrometry-based chemical profiling, network pharmacology, and molecular docking to reveal the potential mechanisms of Qishen Gubiao granules for treating coronavirus disease 2019.

Qishen Gubiao granules, a traditional Chinese medicine preparation composed of nine herbs, have been widely used to prevent and treat coronavirus disease 2019 with good clinical efficacy. In the present study, an integrated strategy based on chemical profiling followed by network pharmacology and molecular docking was employed, to explore the active components and potential molecular mechanisms of Qishen Gubiao granules in the therapy of coronavirus disease 2019. Using the ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry technique, a total of 186 ingredients corresponding to eight structure types in Qishen Gubiao preparation were identified or structurally annotated with the elucidation of the fragmentation pathways in the typical compounds. The network pharmacology analysis screened 28 key compounds including quercetin, apigenin, scutellarein, luteolin and naringenin acting on 31 key targets, which possibly modulated signal pathways associated with immune and inflammatory responses in the treatment of coronavirus disease 2019. The molecular docking results observed that the top 5 core compounds had a high affinity for angiotensin-converting enzyme 2 and 3-chymotrypsin-like protease. This study proposed a reliable and feasible approach for elucidating the multi-components, multi-targets, and multi-pathways intervention mechanism of Qishen Gubiao granules against coronavirus disease 2019, providing a scientific basis for its further quality evaluation and clinical application.

Qian Yang Yu Yin granule improves hypertensive renal damage: A potential role for TRPC6-CaMKKß-AMPK-mTOR-mediated autophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Qian Yang Yu Yin granules (QYYYG) have a long history in the treatment of hypertensive renal damage (HRD) in China. Clinical studies have found that QYYYG stabilizes blood pressure and prevents early renal damage. However, the exact mechanism is not entirely clear. AIM OF THE STUDY: To evaluate the therapeutic effect and further explore the therapeutic mechanism of QYYYG against HRD. MATERIALS AND METHODS: The efficacy of QYYYG in treating HRD was assessed in spontaneous hypertension rats (SHR). Renal autophagy and the TRPC6-CaMKKß-AMPK pathway in rats were evaluated. The regulatory role of QYYYG in angiotensin II (Ang II) induced abnormal autophagy in rat podocytes was determined by detecting autophagy-related proteins, intracellular Ca2+ content, and the TRPC6-CaMKKß-AMPK-mTOR pathway expressions. Finally, we established a stable rat podocyte cell line overexpressing TRPC6 and used the cells to verify the regulatory effects of QYYYG. RESULTS: QYYYG alleviated HRD and reversed the abnormal expression of autophagy-related genes in the SHR. In vitro, QYYYG protected against Ang II-induced podocyte damage. Furthermore, treatment of podocytes with QYYYG reversed Ang II-induced autophagy and inhibited Ang II-stimulated TRPC6 activation, Ca2+ influx and activation CaMKKß-AMPK pathway. Overexpression of TRPC6 resulted in pronounced activation of CaMKKß, AMPK, and autophagy induction in rat podocytes, which were significantly attenuated by QYYYG. CONCLUSIONS: The present study suggested that QYYYG may exert its HRD protective effects in part by regulating the abnormal autophagy of podocytes through the TRPC6-CaMKKß-AMPK-mTOR pathway.

QishenYiqi dripping pill protects against myocardial ischemia/reperfusion injury via suppressing excessive autophagy and NLRP3 inflammasome based on network pharmacology and experimental pharmacology.

Background: Myocardial ischemia/reperfusion (I/R) injury is associated with multiple serious clinical manifestations. Autophagy is upregulated in a short period of ischemia and further enhanced during reperfusion phase, which was considered as a "double-edged sword" in the pathological process of myocardial I/R injury. In addition, NLRP3 inflammasome triggers myocardial inflammatory response, which leads to cardiomyocyte death via pyroptosis and promotes subsequent myocardial remodelling. Qishen Yiqi Dripping Pill (QSYQ) has been recognized as a potential protective agent of cardiovascular diseases. Objective: We predicted the bioactive compounds, targets and pathways of OSYQ intervening on myocardial I/R injury by network pharmacology. Furthermore, we investigated the effect of QSYQ on myocardial I/R injury and explored its underlying mechanism via autophagy and NLRP3 Inflammasome. Methods: Bioactive compounds, targets of QSYQ and relevant targets of myocardial I/R injury were collected from public databases. The protein-protein interaction network, Gene ontology and KEGG pathway enrichment analysis were carried out to screen the key compounds, target genes, functional annotation and pivotal pathways. Molecular docking was used to validate the binding association between target genes and key bioactive ingredients. Furthermore, sixty SD rats were randomized into four groups: 1) sham, 2) model, 3) captopril and 4) QSYQ pretreatment (14 days before and after surgery). Each arm was subjected to ischemia/reperfusion surgery except sham arm (30 min coronary ligation, then reperfusion). Left ventricular (LV) function were evaluated and the hearts were used to evaluate size of myocardial infarction, cardiomyocyte fibrosis, and myocardial autophagosomes. Results: The network pharmacology revealed the mechanism of QSYQ intervening on myocardial I/R injury might be related to NOD-like receptor signaling pathway, PI3K-Akt signaling pathway, autophagy-animal, etc., Molecular-docking suggested the core target proteins had good binding association with bioactive compounds of QSYQ. The experiment confirmed that QSYQ attenuated myocardial infarct size, decreased inflammatory infiltration and collagen fiber deposition and alleviated the autophagosome and myocardium ultrastructure injury, leading to LV systolic function improvement. The possible mechanism of cardioprotection was due to regulating autophagy-related proteins, activating PI3K/Akt-mTOR signaling pathway, and inhibiting activation and assembly of NLRP3 inflammasome. Conclusion: QSYQ ameliorated myocardial I/R injury via suppressing excessive autophagy and NLRP3 Inflammasome.

Daily blood pressure variability in relation to neurological functional outcomes after acute ischemic stroke.

Background: Prior research has shown inconclusive findings regarding the relationship between blood pressure variability (BPV) in acute ischemic stroke (AIS) and functional outcomes. Most research has examined the connection between short-term BPV during the early 24-72 h after the occurrence of ischemic stroke and functional prognosis. We sought to determine the relationship between daily BPV at 7 days of commencement and functional outcomes during the 3 months following AIS. Methods: Altogether, 633 patients with AIS admitted within 72 h of commencement were enrolled. AIS was defined as the time from the onset of symptoms to 7 days. Throughout this period, blood pressure (BP) was recorded twice daily (casual BP cuffs). The daily BPV, with standard deviation (SD) and coefficient of variation (CV), was calculated and matched to the functional results. The adverse outcome was characterized as a modified Rankin scale (mRS)≥3, which comprised the recurrence of stroke, clinical intracranial bleeding, and death. Results: In total, 633 participants were included, and the incidence of adverse outcomes was 14.06% (89/633). There was a significant positive correlation between daily BPV and adverse outcomes but not between mean BP and risk. Smooth curve fitting revealed a U-shaped connection between the mean BP and adverse clinical outcomes. Multivariable logistic regression analysis showed an independent correlation between daily BPV and an adverse outcome in the top vs. bottom quartile of systolic BPV (odds ratio [OR] = 2.4, 95% confidence interval [CI]: 1.17-4.96, P = 0.018 for SD; OR = 2.4, 95% CI: 1.17-4.93, P = 0.017 for CV) during a 3-month follow-up period. Identical results have been reported for diastolic BPV. Conclusion: Irrespective of BP level, elevated daily systolic BPV and diastolic BPV in AIS were associated with an increased risk of adverse outcomes within 3 months. We also discovered a U-shaped association between the mean BP and adverse clinical outcomes. These findings suggested that BPV should be a risk factor for adverse outcomes after ischemic stroke, which provided new insight into BP management strategy.

Efficacy and safety of naotaifang capsules for hypertensive cerebral small vessel disease: Study protocol for a multicenter, randomized, double-blind, placebo-controlled clinical trial.

Background: Hypertensive cerebral small vessel disease (HT-CSVD) is a cerebrovascular clinical, imaging and pathological syndrome caused by hypertension (HT). The condition manifests with lesions in various vessels including intracranial small/arterioles, capillaries, and small/venules. Hypertensive cerebral small vessel disease has complex and diverse clinical manifestations. For instance, it can present as an acute stroke which progresses to cause cognitive decline, affective disorder, unstable gait, dysphagia, or abnormal urination. Moreover, hypertensive cerebral small vessel disease causes 25-30% of all cases of ischemic strokes and more than 50% of all cases of single or mixed dementias. The 1-year recurrence rate of stroke in cerebral small vessel disease patients with hypertension is 14%. In the early stage of development, the symptoms of hypertensive cerebral small vessel disease are concealed and often ignored by patients and even clinicians. Patients with an advanced hypertensive cerebral small vessel disease manifest with severe physical and mental dysfunction. Therefore, this condition has a substantial economic burden on affected families and society. Naotaifang (NTF) is potentially effective in improving microcirculation and neurofunction in patients with ischemic stroke. In this regard, this multicenter randomized controlled trial (RCT) aims to furtherly evaluate the efficacy and safety of naotaifang capsules on hypertensive cerebral small vessel disease. Methods: This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 388 eligible subjects were recruited from the First Hospital of Hunan University of Chinese Medicine, Hunan Academy of Chinese Medicine Affiliated Hospital, the First Hospital of Shaoyang University, the First Traditional Chinese Medicine Hospital of Changde, and Jiangmen Wuyi Hospital of Traditional Chinese Medicine from July 2020 to April 2022. After a 4-week run-in period, all participants were divided into the intervention group (represented by Y-T, N-T) and control group (represented by Y-C, N-C); using a stratified block randomized method based on the presence or absence of brain damage symptoms in hypertensive cerebral small vessel disease (represented by Y and N). The Y-T and N-T groups were administered different doses of naotaifang capsules, whereas Y-C and N-C groups received placebo treatment. These four groups received the treatments for 6 months. The primary outcome included Fazekas scores and dilated Virchow-robin spaces (dVRS) grades on magnetic resonance imaging (MRI). The secondary outcomes included the number of lacunar infarctions (LI) and cerebral microbleeds (CMB) on magnetic resonance imaging, clinical blood pressure (BP) level, traditional Chinese medicine (TCM) syndrome scores, mini-mental state examination (MMSE) scale, and safety outcomes. Fazekas scores, dilated Virchow-robin spaces grades, and the number of lacunar infarctions and cerebral microbleeds on magnetic resonance imaging were tested before enrollment and after 6 months of treatment. The clinical blood pressure level, traditional Chinese medicine syndrome scores, mini-mental state examination scale and safety outcomes were tested before enrollment, after 3-month, 6-month treatment and 12th-month follow-up respectively. Conclusion: The protocol will comfirm whether naotaifang capsules reduce Fazekas scores, dilated Virchow-robin spaces grades, and the number of lacunar infarctions and cerebral microbleeds, clinical blood pressure, increase mini-mental state examination scores, traditional Chinese medicine syndrome scores of Qi deficiency and blood stasis (QDBS), and improve the quality of life of subjects. The consolidated evidence from this study will shed light on the benefits of Chinese herbs for hypertensive cerebral small vessel disease, such as nourishing qi, promoting blood circulation and removing blood stasis, and dredging collaterals. However, additional clinical trials with large samples and long intervention periods will be required for in-depth research. Clinical Trial registration: www.chictr.org.cn, identifier ChiCTR1900024524.

Association of endothelial nitric oxide synthase intron 4a/b gene polymorphisms and hypertension: a systematic review and meta-analysis.

OBJECTIVE: We conducted meta-analysis of relevant case-control trials to determine the association between endothelial nitric oxide synthase (eNOS) intron 4a/b gene polymorphisms and hypertension susceptibility. METHODS: We searched the PubMed, Cochrane, and Embase databases using relevant keywords and reviewed pertinent literature sources. All articles published up to July 2019 were considered for inclusion. Based on the qualified studies, we performed a meta-analysis of the associations between eNOS intron 4a/b polymorphisms and the risk of hypertension. RESULTS: Fourteen studies were included in this meta-analysis, including 3344 cases and 3377 controls. The eNOS intron 4a/b locus was significantly associated with increased susceptibility to hypertension (including essential hypertension) in the overall population, according to dominant, allelic, homozygote, heterozygote, and regressive models, in the mixed population according to the regressive model, and in Caucasians according to the dominant, allelic, heterozygote, and regressive models. The eNOS intron 4a/b locus was also significantly associated with increased susceptibility to essential hypertension in the mixed population according to the heterozygote model. CONCLUSION: eNOS intron 4a/b gene polymorphisms increase susceptibility to hypertension, including essential hypertension.

Anterograde regulation of mitochondrial genes and FGF21 signaling by hepatic LSD1.

Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here, we show that histone demethylase LSD1 KO from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in the nucleus. Lsd1 KO reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPß and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in the liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.

Qian Yang Yu Yin Granule Improves Renal Injury of Hypertension by Regulating Metabolic Reprogramming Mediated by HIF-1α/PKM2 Positive Feedback Loop.

Protection against hypoxia injury is an important therapeutic strategy for treating hypertensive nephropathy. In this study, the effects of Qian Yang Yu Yin granule (QYYY) on spontaneously hypertensive rats fed with high salt diet and HEK293T cells exposed to hypoxia were investigated. After eight weeks' treatment of QYYY, blood pressure, serum creatinine, serum cystatin C, blood urea nitrogen, urinary ß2-microglobulin, urinary N-acetyl-ß-glucosaminidase, and urinary microalbumin were assessed. The changes of hypoxia-inducible factor-1α (HIF-1α), pyruvate kinase M2 (PKM2), glucose transport 1 (GLUT1), lactate dehydrogenase A (LDH-A), connective tissue growth factor (CTGF), transforming growth factor-ß1 (TGF-ß1), ATP, lactate, pyruvate, and pathology were also assessed in vivo. HEK293T cells pre-treated with QYYY and/or HIF-1α over expressing cells were cultured in a three gas hypoxic incubator chamber (5% CO2, 1% O2, 94% N2) for 12 h and then the expressions of HIF-1α, PKM2, GLUT1, LDH-A, CTGF, TGF-ß1, ATP, lactate, and pyruvate were detected. Our results showed that QYYY promoted the indicators of renal inflammation and fibrosis mediated by HIF-1α/PKM2 positive feedback loop in vivo and vitro. Our findings indicated that QYYY treated hypertensive nephropathy by regulating metabolic reprogramming mediated by HIF-1α/PKM2 positive feedback loop.

Yin-xing-tong-mai decoction attenuates atherosclerosis via activating PPARγ-LXRα-ABCA1/ABCG1 pathway.

Atherosclerosis is now the major cause of mortality and morbidity worldwide. Formation of macrophage-derived foam cells is a hallmark of atherosclerosis, which is regulated by cholesterol uptake, intracellular metabolism, and efflux. PPARγ-LXRα-ABCA1/ABCG1 pathway plays an important part in regulating cholesterol efflux and this pathway could be a promising target for treating atherosclerosis. However, due to undesirable systemic effects, PPARγ agonist therapy for atherosclerosis remains challenging. Many traditional Chinese medicine has been well accepted and applied in atherosclerosis treatment. Yin-xing-tong-mai decoction (YXTMD) has been applied for treating atherosclerosis for decades. However, the mechanism remains to be explored. Here, we showed that YXTMD effectively attenuated atherosclerosis in ApoE-/- mice. YXTMD increased cholesterol efflux of foam cell by upregulation of ABCA1 and ABCG1 in vivo and in vitro. Through bioinformatic analysis and experimental validation, we found that PPARγ was an important downstream effector of YXTMD in macrophages. Reduction of PPARγ significantly decreased LXRα, ABCA1, and ABCG1 expression in macrophages, with reduced cholesterol efflux. In conclusion, these findings confirmed that YXTMD attenuated atherosclerosis by activating the PPARγ-LXRα- ABCA1/ABCG1 pathway to enhance cholesterol efflux.

Effects of Shenfu Qiangxin Drink on H2O2-induced oxidative stress, inflammation and apoptosis in neonatal rat cardiomyocytes and possible underlying mechanisms.

The aim of the present study was to investigate the effects of Shenfu Qiangxin Drink (SFQXD) on acute myocardial infarction (AMI) and identify the possible underlying mechanisms. Levels of reactive oxygen species (ROS) and inflammatory factors, including interleukin (IL)-6, IL-1ß and tumor necrosis factor-α (TNF-α) in the blood samples of patients with AMI were measured using commercially available kits by visible spectrophotometry after SFQXD administration. The contents of phosphorylated (p-) forkhead box O3a (FOXO3a) was examined using an ELISA kit. In addition, a hydrogen peroxide (H2O2)-induced myocardial injury model was established in vitro using neonatal rat cardiomyocytes. Following treatment with SFQXD, the levels of intracellular ROS, cell apoptosis, oxidative stress- and inflammation-related markers were measured using commercially available kits by visible spectrophotometry. Additionally, western blot analysis was used to measure the expression of sirtuin-4 (SIRT4), p-FOXO3a, acetylated FOXO3a (ace-FOXO3a) and apoptosis-related genes (Bcl-2, Bax, BIM and cleaved caspase-3). Subsequently, to investigate the possible underlying regulatory mechanisms, SIRT4 expression was silenced by transfection with small hairpin RNA against SIRT4, following which changes in the extent of oxidative stress, inflammation and apoptosis were assessed. The levels of ROS and interleukin (IL)-1ß were found to be significantly reduced, whilst FOXO3a phosphorylation was markedly increased following administration with SFQXD. In vitro, SFQXD dose-dependently inhibited H2O2-induced oxidative stress, inflammation and apoptosis in neonatal rat cardiomyocytes. In addition, FOXO3a phosphorylation was markedly upregulated whilst FOXO3a acetylation was downregulated following treatment of H2O2-induced primary neonatal cardiomyocytes with SFQXD. SIRT4 knockdown also markedly reversed the effects of SFQXD on oxidative stress, inflammation and apoptosis in neonatal rat cardiomyocytes. In conclusion, these findings demonstrated that SFQXD may alleviate oxidative stress-induced myocardial injury by potentially regulating SIRT4/FOXO3a signaling, suggesting that SFQXD may be of clinical value for the treatment of AMI.

Association of urine albumin-to-creatinine ratio with subclinical systolic dysfunction in hypertensive patients but not normotensive subjects: Danyang study.

The association of albuminuria, as measured by urine albumin-to-creatinine ratio (UACR) concentration, with subclinical cardiac dysfunction in hypertensive patients is unclear. Our study aimed to examine its relationship in hypertensive patients compared with that in normotensive patients. The study participants were recruited from Danyang, a city of Jiangsu Province from 2017 to 2019. Categorical and continuous analyses were performed with sex-specific UACR tertiles and natural logarithmically transformed UACR, respectively. Comprehensive echocardiography including conventional imaging, tissue Doppler imaging, and 2D speckle tracking was performed using Philips CX50 device. The 2857 participants (mean age = 52.7 ± 11.8 years) included 1673 (58.6%) women, 1125 (39.4%) hypertensive patients, 546 (19.1%) patients with microalbuminuria, and 38 (1.3%) patients with macroalbuminuria. Comorbidities were increasingly prevalent across the tertiles of UACR. Increased left ventricular (LV) mass index, decreased global longitudinal strain (GLS) and LV ejection fraction, lower E/A ratio and e' velocity, and higher E/e' ratio were significantly associated with higher UACR on unadjusted analyses (p ≤ .01). After adjustment for covariates, UACR was only independently associated with lower GLS (tertile 3 = 20.7% vs. tertile 1 = 20.9%; p = .04). The results of hypertensive patients (p ≤ .04) but not normotensive patients (p ≥ .16) were similar to those of the total cohort. Subgroup analyses revealed similar results in patients without coronary artery disease, or without LV hypertrophy, or without diabetes. In conclusion, increased UACR is associated with worse subclinical systolic function in Chinese hypertensive patients but not in normotensive participants.

Association Between ALDH-2 rs671 and Essential Hypertension Risk or Blood Pressure Levels: A Systematic Review and Meta-Analysis.

Background: The association between Aldehyde dehydrogenase II (ALDH-2) rs671 polymorphism and essential hypertension (EH) risk or blood pressure (BP) levels remains unclear. Objective: To systematically review the influence of the aldehyde dehydrogenase II rs671 polymorphism on essential hypertension risk and blood pressure levels. Methods: The PubMed, EMbase, Web of Science, Cochrane Library, CNKI and CBM databases were electronically searched to identify case-control or cohort studies published prior to July 2019 that examined the association between the rs671 polymorphism and the risk of essential hypertension or blood pressure levels. A meta-analysis was conducted with Stata 15.1 software. Results: Twenty-two articles were included. Among these articles, 20 incorporated 30 individual studies evaluating the association between the rs671 polymorphism and EH (11,051 hypertensive patients and 15,926 normotensive controls), and 8 incorporated 12 individual studies evaluating the association between the rs671 polymorphism and BP (20,512 subjects). The results of the meta-analysis showed that the mutation of the rs671 polymorphism was associated with a significantly decreased risk of EH in all models: allelic model (OR = 0.80, 95% CI: 0.73-0.87), homozygous model (OR = 0.71, 95% CI: 0.63-0.80), heterozygous model (OR = 0.79, 95% CI: 0.72-0.87), dominant model (OR = 0.79, 95% CI: 0.71-0.87), and recessive model (OR = 0.76, 95% CI: 0.68-0.85). In the stratified analyses, significant associations were found for males, drinkers and population-based studies. Simultaneously, the A carriers had lower SBP (WMD = -1.78, 95% CI: -3.02 to -0.53) and DBP (WMD = -1.09, 95% CI: -1.58 to -0.61) levels than individuals with the GG homozygote. Conclusion: The collective findings of this meta-analysis suggested that the ALDH-2 rs671 polymorphism represented an important genetic marker in the development of hypertension. Considering the overall quality of evidence and the relatively small pooled sample size, more well-conducted high-quality studies are required to verify the above conclusion. Systematic Review Registration Number: PROSPERO (CRD42019129746).

Danhong Injection for the Treatment of Hypertensive Nephropathy: A Systematic Review and Meta-Analysis.

OBJECTIVE: Danhong Injection (DHI) has been widely used to treat various diseases in China for many years. The objective of this systematic review was to evaluate the efficacy of DHI combined with antihypertensive drugs for treatment of hypertensive nephropathy. METHODS: Seven databases were searched from inception to September 21st, 2019. Randomized controlled trials comparing DHI combined with antihypertensive drugs versus antihypertensive drugs alone were extracted. The primary outcome was microalbuminuria (mALB). Secondary outcomes included systolic blood pressure (SBP), diastolic blood pressure (DBP), and serum creatinine (SCr). RESULTS: Fifteen studies were included in the meta-analysis, which indicated that DHI combined with antihypertensive drugs has advantages compared with antihypertensive drugs alone for reducing mALB [weighted mean difference (WMD) = -12.86, 95% confidence interval (CI) (-14.72, -11.0), P < 0.01], lowering SBP [WMD = -2.84, 95% CI (-4.56, -1.12), P = 0.001] and DBP [WMD = -2.38, 95% CI (-4.34, -0.43), P = 0.017], and decreasing SCr [WMD = -40.45, 95% CI (-55.69, -25.21), P < 0.01]. CONCLUSION: The combination of DHI with antihypertensive drugs appears to be more effective than antihypertensive drugs alone for treatment of hypertensive nephropathy. A moderate duration (≤4 weeks) of DHI administration is reasonable, and longer treatment with DHI should be avoided, according to the results of subgroup analysis.