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.

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.

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.

Catalpol provides a protective effect on fibrillary Aß1-42 -induced barrier disruption in an in vitro model of the blood-brain barrier.

Excessive amyloid beta (Aß) deposition in brain is mainly responsible for cell damage and blood-brain barrier (BBB) disruption in Alzheimer's disease (AD). Catalpol, an iridoid glucoside extracted from the root of Rehmannia glutinosa Libosch, has neuroprotective effect against AD. It is unclear whether catalpol has a protective effect on Aß-induced BBB leakage. We employed an immortalized endothelial cell line (bEnd.3) and astrocytes co-culture to mimic a BBB model in vitro and investigated the effect of catalpol on BBB. We found that treatment with catalpol decreased BBB hyperpermeability induced by fibrillar Aß1-42 . Data from western blotting showed that catalpol prevented fibrillar Aß1-42 -induced bEnd.3 cell apoptosis through mitochondria-dependent and death receptor pathways; decreased the levels of matrix metalloproteinases (MMPs), MMP-2, MMP-9, and the receptor for advanced glycation end products; and increased the levels of tight junction proteins (ZO-1, occludin, and claudin-5), low-density lipoprotein receptor-related protein 1, and P-glycoprotein in fibrillar Aß1-42 -treated bEnd.3 cells. Moreover, catalpol also enhanced soluble Aß efflux across the fibrillar Aß1-42 -treated bEnd.3 cells BBB monolayer model. Altogether, our results suggest that catalpol alleviate fibrillar Aß1-42 -induced BBB disruption, enhance soluble Aß clearance, and offer a feasible therapeutic application in AD treatment.

[Huangqi Danshen decoction attenuates isoproterenol-induced myocardial remodeling via STIM1, TRPC1, CaN and NFATc3 pathways in rats].

To investigate the inhibitory effect of Huangqi Danshen decoction (HDD) on isoproterenol (ISO)-induced myocardial remodeling and explore its effect on STIM1, TRPC1, CaN and NFATc3 expressions. ISO (2.5 mg•kg⁻¹â€¢d⁻¹×14 d) was given by subcutaneous injection to establish myocardial remodeling models in rats, and then were randomly divided into control group, ISO model group, HDD5 group (HDD 5 g•kg⁻¹â€¢d⁻¹+ISO), and HDD10 group (HDD 10 g•kg⁻¹â€¢d⁻¹+ISO). After intervention for 4 weeks, the heart mass index (HW/BW) and the left ventricular mass index (LVW/BW) were calculated; the structure of myocardium was observed by echocardiography; the pathological changes of myocardium were observed by HE staining; levels of BNP, CaN and CaM kinases II in serum were detected by ELISA, and the protein expression levels of STIM1, TRPC1, p-CaN, p-NFATc3, and NFATc3 in left ventricular tissues were detected by Western blot. The results showed that the HW/BW and LVW/BW in ISO group were greater than those in HDD5 group and HDD10 group (P<0.05); Echocardiography showed that HDD inhibited ISO-induced increase in LVEDD and LVESD; ELISA results showed that HDD could significantly inhibit the increase of BNP, CaN and CaM kinases II levels in serum of rats with ISO-induced myocardial remodeling (P<0.01). Western blot results showed that STIM1, TRPC1, p-CaN, p-NFATc3 and NFATc3 expression levels were increased in the myocardial tissues of ISO group rats, and after HDD administration, the above expression levels were decreased in group ISO, HDD for myocardial tissue after administration of STIM1, TRPC1, p-CaN, p-NFATc3 and NFATc3 expression decreased (P<0.05). Our findings indicated that HDD can attenuate the myocardial remodeling induced by ISO, and its mechanism may be related to down-regulating the expression levels of STIM1, TRPC1, CaM kinases II, p-CaN/CaN and p-NFATc3/NFATc3.

[Safety and Tolerance of Healthy People to Injection of Astragalosides-a New Drug for Coronary Heart Disease].

OBJECTIVES: To assess the safety and tolerance of healthy volunteers to as tragalosides injection (AGI), and to determine a safe dose range for phase II clinical trial. METHODS: A total of 62 healthy volunteers participated in this study, with 26 being given a single AGI of 100 mL, 200 mL, 300 mL, 400 mL, 500 mL, or 600 mL and 36 subjects being given 500 mL, 400 mL, 200 mL or 300 mL of AGI once a day for 7 d. Discomfortsymptoms, vital signs and safety problems were recorded 3 d and 7 d after the administration of AGI. The results were analyzed. RESULTS: Of the 62 participants, 40 adverse events (AEs) were reported by 31 participants, which included 23 mild adverse reactions (ADRs) and 4 moderate ADRs. Nine AEs were reported by 9 participants with single AGI, including 7 ADRs. Fourteen AEs were reported by 10 participants with 500 mL and 400 mL multiple AGI, including 12 ADRs occurred in 9 participants.Seventeen AEs were reported by 12 participants with 300 mL and 300 mL multiple AGI, including 3 mild ADRs. The main ADRs included abnormal liver function [slightly elevated glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST),and serum total bilirubin (TBil)], low blood potassium, increased urine red blood cell count, rash, and phlebitis. CONCLUSIONS: The maximum tolerance is 600 mL for single-dose treatment, and 400 mL for multiple-dose (7 d). The dose guidance given in this study should be examined its effects and safety in patients with coronary heart disease in phase II clinical trial.

Qian Yang Yu Yin Granule-containing serum inhibits angiotensin II-induced proliferation, reactive oxygen species production, and inflammation in human mesangial cells via an NADPH oxidase 4-dependent pathway.

BACKGROUND: Qian Yang Yu Yin Granule (QYYYG), a traditional Chinese herbal medicine, has been indicated for renal damage in hypertension for decades in China, but little remains known regarding its underlying molecular mechanism. Therefore, we performed the current study in order to investigate the underlying molecular mechanism of QYYYG in the treatment of hypertensive renal damage. METHODS: We hypothesize that QYYYG relieves hypertensive renal injury through an angiotensin II (Ang II)-nicotinamide adenine dinucleotide phosphate (NAPDH)-oxidase (NOX)-reactive oxygen species (ROS) pathway. In this study, we investigated the effects of QYYYG-containing serum (QYGS) in human mesangial cells (HMCs) against Ang II-induced cell proliferation, ROS production, and inflammation through the seropharmacological method. RESULTS: We found that QYGS could inhibit cell proliferation in Ang II-treated HMCs. In addition, QYGS considerably suppressed production of ROS, decreased mRNA and protein expression of NAPDH-oxidase 4 (NOX4), p22 (phox) , and activated Ras-related C3 botulinum toxin substrate 1 (GTP-Rac1); as well as counteracted the up-regulation of inflammatory markers including tumor necrosis factor-α (TNF-α), nuclear factor-κB (NF-κB) p65, and interleukin 6 (IL-6). These effects were further confirmed in HMCs transfected with specific small interfering RNA (siRNA) targeting NOX4. CONCLUSIONS: Taken together, these results suggest that a NOX4-dependent pathway plays an important role in regulating the inhibitory effect of QYGS. Our findings provide new insights into the molecular mechanisms of QYYYG and their role in the treatment of hypertensive nephropathy.

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.

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.

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.

[Effects of ApoE gene polymorphism on anti-inflammatory action of xuezhikang capsule].

OBJECTIVE: To study the effects of ApoE gene polymorphism on anti-inflammatory action of Xuezhikang Capsule. METHODS: One hundred and two patients with hyperlipidemia (as the treated group) and one hundred healthy volunteers (as the control group) were enrolled in the case-control study. Total DNA of the peripheral blood was extracted and ApoE genotypes were determined by PCR sequence analysis. The serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and high sensitivity C reactive protein (hs-CRP)were measured in all subjects. The changes of TNF-alpha, IL-6, and hs-CRP were detected before and after 6-week Xuezhikang Capsule treatment, thus analyzing the correlation between ApoE gene polymorphism and changes of each inflammatory factor. RESULTS: The frequency of E3/3 genotype was 86% (86/100 cases)in the control group, significantly higher than that of the treated group (62.7%, 64/102 cases). The frequency of E3/4 genotype was 6% (6/100 cases) in the control group, significantly lower than that of the treated group (21.6%, 22/102 cases; both P < 0.05). Compared with the control group, the serum levels of TNF-alpha, IL-6, and hs-CPR were higher in the treated group before treatment (P < 0.05). In hyperlipidemia patients with E3/4 + E4/4 genotype, the serum level of TNF-alpha was higher than that of E3/3 genotype (P < 0.05); the serum level of IL-6 was higher than that of E2/E2 + E2/E3 genotype (P < 0.05); the serum level of hs-CRP was higher than that of E2/E2 + E2/E3 and E3/E3 genotype (P < 0.05). But there was no statistical difference in the serum levels of TNF-alpha, IL-6, or hs-CPR between E3/3 and E2/E2 + E2/E3 genotype. After 6-week intervention of Xuezhikang Capsule, the serum levels of TNF-alpha, IL-6, and hs-CRP were lower in the treated group (P < 0.05), but the serum levels of TNF-alpha and IL-6 were still higher than those of the control group (P < 0.05). But there was no statistical difference in the decrement of TNF-alpha, IL-6, or hsCRP among E2/E2 + E2/E3, E3/E3, or E3/4 + E4/4 genotypes (P > 0.05). CONCLUSIONS: The distribution of ApoE gene polymorphism is different between the hyperlipidemia patients and the healthy people. Chronic inflammatory reactions exist in hyperlipidemia patients, especially in those with e4 allele. Xuezhikang Capsule showed anti-inflammatory effects, but ApoE gene polymorphism did not affect its effects.

[Effect of Jiangzhi Kangyanghua mixture on high-sensitivity C-reactive protein and vascular endothelial functions of hypertension patients].

To observe the effect of Jiangzhikangyanghua Mixture on high-sensitivity CRP (hs-CRP) and vascular endothelial functions of essential hypertension (EH) patients. In this study, 72 cases of out-patients with EH were selected from department of cardiology of Wujin hospital of traditional Chinese Medicine, and randomly divided into the control group (n= 36, amlodipine 5 mg qd + valsartan 80 mg qd) and the test group (n =36 amlodipine 5 mg qd + valsartan 80 mg qd + Jiangzhikangyanghua mixture 20 mL tid). The contents of hs-CRP, ET-1 and NO were measured before and after treatment for two months. The result showed that the contents of hs-CRP, ET-1 in both groups reduced (P <0. 05) , while the test group show a more significant reduction than the control group (P <0. 05). After the treatment, the content of NO raised in both group, while the test group show a more significant increase than that of the control group (P <0. 05). This study indicated that Jiangzhi Kangyanghua mixture could reduce the contents of hs-CRP and ET-1 and raise NO of EH patients.

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.

Sortilin-related VPS10 domain containing receptor 1 and Alzheimer's disease-associated allelic variations preferentially exist in female or type 2 diabetes mellitus patients in southern Han Chinese.

BACKGROUND: Both in vitro and in vivo, overexpression of the sortilin-related VPS10 domain containing receptor 1 (SORCS1) protein lowers amyloid-ß generation. Recent studies have shown that SORCS1 variations in intron 1 are associated with sporadic Alzheimer's disease (SAD), but the results remain inconsistent. METHODS: In order to clarify the role of the SORCS1 gene in southern Han Chinese, we genotyped eight single nucleotide polymorphisms (SNP) of SORCS1 in 128 SAD patients and 92 healthy controls. RESULTS: By dividing patients and controls according to apolipoprotein status, sex and whether they had type 2 diabetes mellitus, we found that rs7907690 C allele frequencies were significantly higher in the Alzheimer's disease (AD) patients with type 2 diabetes mellitus than in the controls (P=0.041). Also, the rs600879 GG genotype and G allele worked as protective factors of SAD in women (GG genotype, P=0.007; G allele, P=0.009). In multilocus analysis, the frequency of an eight-single nucleotide polymorphism rs601883/rs7907690/rs600879/rs17277986/rs2900717/rs10884399/rs11193170/rs4918280 CCGGACGG haplotype was significantly higher in AD patients (6.3%), especially in female AD patients (9.5%), than in the controls (0.5%) (P=0.003; P=0.0002). However, the CTGGACGG haplotype was significantly lower in AD patients (9.3%) than in controls (20.3%) (P=0.001). The association remained significant even after Bonferroni correction for the number of haplotypes. CONCLUSION: This study provides evidence that variations in the SORCS1 gene influence susceptibility to SAD in southern Han Chinese. The genetic link between AD and SORCS1 gene variations are influenced by ethnic background, sex and whether an individual has type 2 diabetes mellitus.

[Treadmill exercise test in patients with coronary artery myocardial bridging].

OBJECTIVE: To observe treadmill exercise test (TET) characteristics in patients with myocardial bridging (MB). METHODS: TET results from January 2003 to December 2010 were retrospectively analyzed in 156 patients with confirmed MB diagnosis. MB patients were divided into smoking group (68 cases) and non-smoking group (88 cases). Coronary angiography results were used to analyze the relations between MB length, myocardial ischemia and exercising duration. RESULTS: (1) MB was documented on two coronary arteries in 2 patients (1%), MB was detected in single artery in 154 patients (99%), of whom 146 cases were located at left anterior descending artery, 8 cases were located at right coronary artery. The degree of narrowing of MB was graded 1 (less than 50%) in 16 patients (10%), grade 2 (50% to 75%) in 108 patients (69%) and grade 3 (greater than 75%) in 32 patients (21%). The length of MB ranged between 4 to 40 mm, MB length was less than 10 mm in 40 patients (26%), between 11 to 20 mm in 48 patients (31%), between 21 to 30 mm in 44 patients (28%), greater than 31 mm in 24 patients (15%). (2) TET positive rate was 41% (64/156) and the TET positive rate was significantly higher in smoking group than in non-smoking group [57% (39/68) vs. 28% (25/88, P < 0.01)]. (3) The length of MB was positively related to the ST-segment depression (r = 0.723, P < 0.01) and negatively related to exercising duration (r = -0.828, P < 0.01). Heart rate was positively related to the ST-segment depression (r = 0.368, P < 0.01). CONCLUSIONS: TET may serve as a good test to assess myocardial ischemia in patients with MB. The length of MB is positively related with myocardial ischemia and negatively related with exercising duration. Smoking might increase myocardial ischemic incidence in MB patients, MB patients should be advised to stop smoking.

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.

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.

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.

[Distribution of Apo E gene sequencing in patients with coronary heart disease of phlegm-stasis syndrome].

OBJECTIVE: To study the correlation between Apo E gene polymorphism and patients with coronary heart disease (CHD) of phlegm-stasis syndrome (PSS). METHODS: 78 CHD patients were assigned to PSS (49 cases) and non-phlegm-stasis syndrome (NPSS). Polymorphisms of Apo E gene in 78 CHD patients and 100 healthy subjects were detected by complete DNA sequencing. RESULTS: Five gene types as E3/3, E4/4, E2/ 3, E2/4, and E3/4 were detected in the two groups. The frequencies of genotype E3/3 and epsilon 3 allele were significantly lower in CHD patients than in the healthy subjects (P<0.01). But the frequencies of genotype E3/4 and epsilon 4 allele were significantly higher in CHD patients than in the healthy subjects (P<0.01). In CHD patients, the frequencies of genotype E2/4 + E3/4 + E4/4 and epsilon 4 allele were higher in PSS than in NPSS. CONCLUSIONS: Apo E epsilon 4 allele was a susceptible allele to CHD, which was closely correlated to CHD PSS. It was inferred that it might be one of main susceptible alleles for CHD PSS.