Tanshinone IIA inhibits cardiomyocyte pyroptosis through TLR4/NF-κB p65 pathway after acute myocardial infarction.

Background: Tanshinone IIA, derived from Radix Salviae Miltiorrhizae (Salvia miltiorrhiza Bunge), constitutes a significant component of this traditional Chinese medicine. Numerous studies have reported positive outcomes regarding its influence on cardiac function. However, a comprehensive comprehension of the intricate mechanisms responsible for its cardioprotective effects is still lacking. Methods: A rat model of heart failure (HF) induced by acute myocardial infarction (AMI) was established via ligation of the left anterior descending coronary artery. Rats received oral administration of tanshinone IIA (1.5 mg/kg) and captopril (10 mg/kg) for 8 weeks. Cardiac function was assessed through various evaluations. Histological changes in myocardial tissue were observed using staining techniques, including Hematoxylin and Eosin (HE), Masson, and transmission electron microscopy. Tunel staining was used to detect cell apoptosis. Serum levels of NT-pro-BNP, IL-1ß, and IL-18 were quantified using enzyme-linked immunosorbent assay (ELISA). Expression levels of TLR4, NF-κB p65, and pyroptosis-related proteins were determined via western blotting (WB). H9C2 cardiomyocytes underwent hypoxia-reoxygenation (H/R) to simulate ischemia-reperfusion (I/R) injury, and cell viability and apoptosis were assessed post treatment with different tanshinone IIA concentrations (0.05 µg/ml, 0.1 µg/ml). ELISA measured IL-1ß, IL-18, and LDH expression in the cell supernatant, while WB analysis evaluated TLR4, NF-κB p65, and pyroptosis-related protein levels. NF-κB p65 protein nuclear translocation was observed using laser confocal microscopy. Results: Tanshinone IIA treatment exhibited enhanced cardiac function, mitigated histological cardiac tissue damage, lowered serum levels of NT-pro-BNP, IL-1ß, and IL-18, and suppressed myocardial cell apoptosis. Moreover, tanshinone IIA downregulated the expression of TLR4, NF-κB p65, IL-1ß, pro-IL-1ß, NLRP3, Caspase-1, and GSDMD-N pyroptosis-related proteins in myocardial tissue. Additionally, it bolstered H/R H9C2 cardiomyocyte viability, curbed cardiomyocyte apoptosis, and reduced the levels of TLR4, NF-κB p65, IL-1ß, pro-IL-1ß, NLRP3, Caspase-1, and GSDMD-N pyroptosis-related proteins in H/R H9C2 cells. Furthermore, it hindered NF-κB p65 protein nuclear translocation. Conclusion: These findings indicate that tanshinone IIA enhances cardiac function and alleviates myocardial injury in HF rats following AMI. Moreover, tanshinone IIA demonstrates potential suppression of cardiomyocyte pyroptosis. These effects likely arise from the inhibition of the TLR4/NF-κB p65 signaling pathway, presenting a promising therapeutic target.

Blood urea nitrogen to creatinine ratio and long-term survival in patients with chronic heart failure.

OBJECTIVES: To explore the correlation between Blood urea nitrogen to creatinine ratio (BUN/Scr ratio) and prognosis of patients with chronic heart failure complicated with renal injury. METHODS: A retrospective analysis of 504 patients hospitalized in Guang 'anmen Hospital, Chinese Academy of Traditional Chinese Medicine from March 2006 to June 2014 was conducted. The baseline data were analyzed, and the cutoff value was obtained by receiver operator characteristic curve (ROC) analysis, according to the cutoff value, all the participants were divided into two groups, BUN/Scr < 19.37 group (280 cases) and BUN/Scr ≥ 19.37 group (224 cases). The main end point was defined as all-cause death. The long-term mortality of the two groups was evaluated, and Kaplan-Meier survival curve was drawn. Univariate analysis was performed on all the variables affecting the patient's prognosis, and the variables with P < 0.05 were put into Cox regression model, and subgroup analysis was performed on the variables that might affect the patient's prognosis. RESULTS: The baseline data of 504 patients were analyzed and found that the median follow up was 683. Through ROC analysis of 504 subjects, the cutoff value of BUN/Scr was 19.37. The results of Kaplan-Meier survival curve showed that the mortality rate of patients with ratio ≥ 19.37 was higher than that of patients with ratio < 19.37. After multivariate analysis, COX regression model showed that the mortality of patients with BUN/Scr ≥ 19.37 was 1.885 times that of patients with BUN/Scr < 19.37 [HR = 1.885 (1.298-2.737), P = 0.001]. Subgroup analysis showed that the relationship between BUN/Scr and the prognosis of CHF was influenced by NYHA and eGRF (P < 0.05). CONCLUSIONS: BUN/Scr ratio is related to the poor prognosis of patients with CHF, and is an independent predictor of all-cause death.

Qi-Po-Sheng-Mai granule ameliorates Ach-CaCl2 -induced atrial fibrillation by regulating calcium homeostasis in cardiomyocytes.

BACKGROUND: Atrial fibrillation (AF) is one of the most common arrhythmias encountered in clinical settings. Currently, the pathophysiology of AF remains unclear, which severely limits the effectiveness and safety of medical therapies. The Chinese herbal formula Qi-Po-Sheng-Mai Granule (QPSM) has been widely used in China to treat AF. However, its pharmacological and molecular mechanisms remain unknown. PURPOSE: The purpose of this study was to investigate the molecular mechanisms and potential targets of QPSM for AF. STUDY DESIGN AND METHODS: The AF model was induced by Ach (66 µg/ml) and CaCl2 (10 mg/kg), and the dose of 0.1 ml/100 g was injected into the tail vein for 5 weeks. QPSM was administered daily at doses of 4.42 and 8.84 g/kg, and amiodarone (0.18 g/kg) was used as the positive control. The effect of QPSM on AF was assessed by electrocardiogram, echocardiography, and histopathological analysis. Then, we employed network pharmacology with single nucleus RNA sequencing (snRNA-Seq) to investigate the molecular mechanisms and potential targets of QPSM for AF. Furthermore, high performance liquid chromatography (HPLC) method was used for component analysis of QPSM, and molecular docking was used to verify the potential targets. Using the IonOptix single cell contraction and ion synchronization test equipment, single myocyte length and calcium ion variations were observed in real time. The expression levels of calcium Transporter-related proteins were detected by western blot and immunohistochemistry. RESULTS: Based on an Ach-CaCl2-induced AF model, we found that QPSM treatment significantly reduced atrial electrical remodeling-related markers, such as AF inducibility and duration, and attenuated atrial dilation and fibrosis. Network pharmacology identified 52 active ingredients and 119 potential targets for QPSM in the treatment of AF, and 45 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched, among which calcium pathway had the greatest impact. Using single nucleus sequencing (snRNA-seq), we identified cardiomyocytes as the most differentially expressed in response to drug treatment, with nine differentially expressed genes enriched in calcium signaling pathways. High performance liquid chromatography and molecular docking confirmed that the core components of QPSM strongly bind to the key factors in the calcium signaling pathway. Additional experiments have shown that QPSM increases calcium transients (CaT) and contractility in the individual cardiomyocyte. This was accomplished by increasing the expression of CACNA1C and SERCA2a and decreasing the expression of CAMK2B and NCX1. CONCLUSION: The present study has systematically elucidated the role of QPSM in maintaining calcium homeostasis in cardiomyocytes through the regulation of calcium transporters, which could lead to new drug development ideas for AF.

Effects of garlic supplementation on components of metabolic syndrome: a systematic review, meta-analysis, and meta-regression of randomized controlled trials.

BACKGROUND: Garlic (Allium sativum), the underground bulb of the Allium genus, has been consumed on Earth for thousands of years. Many clinical trials of garlic supplementation on components of metabolic syndrome (MetS) have emerged in recent years, but there is no consensus on the effect. This meta-analysis aimed at systematically evaluating the effect of garlic supplementation on components of MetS. METHODS: In this meta-analysis, we searched Pubmed, Embase, Cochrane, Medline, Web of Science databases, and clinical trials online sites from inception to November 1, 2022, with language restrictions to English. We engaged participants > 18 years and eligible for the clinical diagnosis of MetS or those with metabolic disorders and garlic was the only intervention. Outcomes included waist circumference, and body mass index, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure, and fasting blood glucose. Meta-regression and subgroup analyses were conducted based on six covariates (total sample size, the mean age, the mean dose, the duration of intervention, the oral form of garlic, and the dietary intervention). RESULTS: Results from 19 RCTs were included engaging 999 participants. Compared to placebo, garlic significantly reduced TG [SMD (95%CI) = -0.66 (-1.23, -0.09)], TC [SMD (95%CI) = -0.43 (-0.86, -0.01)], LDL [SMD (95%CI) = -0.44(-0.88, -0.01)], DBP [SMD (95%CI) = -1.33 (-2.14, -0.53)], BMI [SMD (95%CI) = -1.10(-1.90, -0.20)], and WC [SMD (95%CI) = -0.78(-1.09, -0.47)]. Meta-regression showed age and sample size are potential effect modifiers. CONCLUSION: According to the results of meta-analysis, the modulatory effect of garlic on some MetS components is evident. More high-quality, large-scale RCTs are needed to confirm iat based on the high heterogeneity and potential publication bias of the current data. TRIAL REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=373228 , ID: CRD42022373228.

Circadian rhythm in cardiovascular diseases: a bibliometric analysis of the past, present, and future.

BACKGROUND: One of the most prominent features of living organisms is their circadian rhythm, which governs a wide range of physiological processes and plays a critical role in maintaining optimal health and function in response to daily environmental changes. This work applied bibliometric analysis to explore quantitative and qualitative trends in circadian rhythm in cardiovascular diseases (CVD). It also aims to identify research hotspots and provide fresh suggestions for future research. METHODS: The Web of Science Core Collection was used to search the data on circadian rhythm in CVD. HistCite, CiteSpace, and VOSviewer were used for bibliometric analysis and visualization. The analysis included the overall distribution of yearly outputs, top nations, active institutions and authors, core journals, co-cited references, and keywords. To assess the quality and efficacy of publications, the total global citation score (TGCS) and total local citation score (TLCS) were calculated. RESULTS: There were 2102 papers found to be associated with the circadian rhythm in CVD, with the overall number of publications increasing year after year. The United States had the most research citations and was the most prolific country. Hermida RC, Young ME, and Ayala DE were the top three writers. The three most notable journals on the subject were Chronobiology International, Hypertension Research, and Hypertension. In the early years, the major emphasis of circadian rhythm in CVD was hormones. Inflammation, atherosclerosis, and myocardial infarction were the top developing research hotspots. CONCLUSION: Circadian rhythm in CVD has recently received a lot of interest from the medical field. These topics, namely inflammation, atherosclerosis, and myocardial infarction, are critical areas of investigation for understanding the role of circadian rhythm in CVD. Although they may not be future research priorities, they remain of significant importance. In addition, how to implement these chronotherapy theories in clinical practice will depend on additional clinical trials to get sufficient trustworthy clinical evidence.

Role of puerarin in pathological cardiac remodeling: A review.

Pathological cardiac remodeling normally involves changes in structure, function, and energy metabolism of the heart induced by cardiac injury or load, terminally leading to heart failure. Cardiac remodeling plays an essential role in the progression of cardiovascular disease, thus increasingly identified as an important therapeutic target for heart failure of all pathogenesis. Puerarin, as a natural isoflavone mainly from Pueraria lobata （Willd.）Ohwi, has been developed as injections, eye drops, microemulsions, etc., and is widely used in the clinical treatment of cardiovascular diseases in eastern Asia countries. In recent years, a growing number of studies have shown that puerarin significantly inhibits myocardial hypertrophic growth, myocyte death, fetal gene expression, fibroblast proliferation and activation, improves energy metabolism, promotes post-infarction angiogenesis, and suppresses inflammation and oxidative stress, consequently attenuating or preventing cardiac remodeling in response to multiple stimuli ( e.g., pressure overload, MIRI, MI, Iso, and Ang II stimulation). This review summarized the roles and underlying molecular mechanisms of puerarin in cardiac remodeling induced by diverse etiologies, aiming to help develop novel therapeutic strategies to prevent or reverse pathological ventricular remodeling.

Acupuncture as Adjuvant Therapy for Treating Stable Angina Pectoris with Moderate Coronary Artery Lesions and the Mechanism of Heart-Brain Interactions: A Randomized Controlled Trial Protocol.

Background. Stable angina pectoris with moderate coronary artery lesions is a syndrome caused by coronary artery stenosis, which endangers the quality of life. Previous acupuncture studies have shown effectiveness as a complementary therapy for ischaemic heart disease. However, more clinical evidence is needed for verification, and the mechanism should be investigated, especially involving the functional interactions between the heart and brain. Therefore, we designed a clinical trial to provide more evidence for acupuncture efficacy and its mechanism in ischaemic heart disease. Methods/Design. A total of 80 participants will be randomized to the electroacupuncture group and sham-electroacupuncture group at a ratio of 1 : 1. This trial will be conducted over 8 weeks, including a 2-week screening, 2-week treatment, and 4-week follow-up. All participants will continue to receive similar basic disease treatment procedures before the trial (including lifestyle changes and treatment for standard supportive medications, hypertension, and hyperlipidaemia, such as aspirin, metoprolol succinate, atorvastatin, and sodium fosinopril). Additionally, 12 sessions of acupuncture will be administered during the treatment period. The main outcome is Seattle Angina Questionnaire scores. The other observation indices are the heart rate variability and self-rating anxiety scale and self-rating depression scale scores. To explore mechanisms based on the hypothesis of a correlation between heart and brain function, fMRI scans will be used to detect functional brain changes in 15 patients from each group at baseline and at the end of treatment. Finally, the efficacy of acupuncture will be evaluated, and the HRV and imaging data will be correlated with clinical data to investigate the possible relationships between the brain and heart activity. Discussion. This trial will provide evidence for acupuncture as adjuvant therapy for the treatment of stable angina pectoris with moderate coronary artery lesions. The results will shed light on potential mechanisms of heart-brain interactions underlying acupuncture as an adjuvant therapy for treating ischaemic heart disease. Trials registration: Clinical Trial, https://clinicaltrials.gov/ct2/show/ChiCTR1900024937. Registered 4 August 2019, http://www.chictr.org.cn/.

Efficacy and safety of Linggui Zhugan decoction in the treatment of chronic heart failure with Yang deficiency: A protocol for systematic review and meta-analysis.

BACKGROUND: Chronic heart failure (CHF) is an advanced stage of various heart diseases and has become a major global health problem. In 2018, the Chinese guideline for the diagnosis and treatment of HF suggested adding traditional Chinese medicine (TCM) as an adjunct to the treatment of CHF, but also pointed out the need for more convincing clinical evidences. Linggui Zhugan decoction (LGZGD) is one of the widely used TCM for CHF treatment, especially for patients with Yang deficiency. Given that treatment based on syndrome differentiation is an important principle in TCM, we provide a protocol to systematically evaluate efficacy and safety of LGZGD for CHF with Yang deficiency. METHODS: We will search the following electronic databases from inception to April 30, 2021, including PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure, VIP Information Database, Chinese Biomedical Literature Database (CBM), and Wanfang Database. Randomized controlled trials (RCT) examining the LGZGD on CHF patients with Yang deficiency will be included. Study selection, data extraction and quality assessment will be conducted by 2 researchers, respectively. The primary outcome measures will be n-terminal brain natriuretic peptide and left ventricular ejection fraction. The risk of bias will be evaluated by the Cochrane Collaboration tool. We will use the fixed-effects model or random-effects model of RevMan V.5.3 based on the results of heterogeneity assessment. The evidence quality of results will be assessed by Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: It will provide the results about efficacy and safety of LGZGD in the treatment of CHF with Yang deficiency by various comprehensive assessments. CONCLUSIONS: This study will provide reliable evidences about the efficacy and safety of LGZGD in the treatment of CHF with Yang deficiency. ETHICS AND DISSEMINATION: Ethical approval is not necessary for this study because the data extracted does not involve any individual privacy. We plan to presented the results of this review in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD 42019140797.

[Relationship between Chinese medicine syndrome and peripheral blood stem cells in patients with ischemic heart failure].

OBJECTIVE: To explore the relationship of Chinese medicine syndromes with heart function and peripheral blood stem cells (PBSCs) count in patients with ischemic heart failure (IHF). METHODS: Clinical materials of 208 inpatients with IHF were collected and the characteristics of their Chinese medicine syndromes were summarized, the number of PBSC was counted with flow cytometer, and the differences of left ventricular ejection fraction (LVEF), N-terminal brain natriuretic peptide (NT-proBNP) and PBSC count related to various syndrome factors and syndrome types were compared using One-way ANOVA. RESULTS: LVEF >50% was found in patients with syndromes of qi-deficiency, yin-deficiency, turbid-phlegm and blood-stasis, while <50% in those of yang-deficiency and fluid-retention, showing significant differences between the former four syndromes and the latter two syndromes. Compared them with syndromes of qi-deficiency, yin-deficiency, turbid-phlegm and blood-stasis, NT-proBNP in the yang deficiency group and water retention group was higher (P<0.01); the PBSC count in patients with yang-deficiency syndrome factor was the least, which was significantly different to that in patients with the former four syndromes (P<0.01, P<0.05), but it was insignificantly different to that with water-retention; LVEF >50% in syndrome types of Xin-Fei qi-deficiency, deficiency of qi and yin, qi-deficiency with blood-stasis and phlegm accumulation in Fei, but <50% in syndrome types of Xin-Shen yang-deficiency and yang-deficiency with water-retention. Compared them with syndrome types of Xin-Fei qi-deficiency, deficiency of qi and yin, qi-deficiency with blood-stasis and phlegm accumulation in Fei, the difference was statistically significant (P<0.05, P<0.01); The highest level of NT-proBNP was shown in syndrome type of yang-deficiency with water-retention, the secondary was in Xin-Shen yang-deficiency, and all showed significant differences as compared with that in other syndrome types (P<0.05); while difference of PBSC count in patients with various syndrome types showed insignificance (P>0.05). CONCLUSION: Chinese medicine syndrome is correlated with heart function and PBSC count in patients with IHF, and the PBSC count in patients with characteristics of yang-deficiency syndrome is lower.

[Research progress of traditional Chinese medicine for stem cell therapy of ischemic heart disease].

Regeneration myocardium by stem cell transplantartion has become a focus in research areas of cardial vascular disease. This review deals the role of traditional Chinese medicine in stem cell threapy of ischemic heart disease, such as mobilizing bone marrow stem cells, promoting stem cell proliferation, survival, induced them to differentiate into cardiomyocytes, and so on, showing good application prospects.

Serum proteomes of hypertension patients with abundant phlegm-dampness.

OBJECTIVE: To study the serum proteomes of essential hypertension (EH) patients with abundant phlegm-dampness, and try to find special proteins associated with abundant phlegm-dampness syndrome. METHODS: Fifty-nine hypertension patients were included, and the patients were divided into abundant phlegm-dampness syndrome group (39 cases) and non-phlegm-dampness syndrome group (20 cases). To find the special proteins associated with abundant phlegm-dampness, the EH patients with non-phlegm-dampness and another 30 healthy persons were regarded as control. Weak cation nano-magnetic beads were used to capture proteins in serum, and proteomic fingerprint was made by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). All the proteomic fingerprints were analyzed by Biomarker Wizard 3.1 Software. Then Biomarker Patterns Software (BPS) 5.0 was used to identify the differentiated proteins, which could induce phlegm-dampness. RESULTS: There were 102 differentiated protein peaks between abundant phlegm-dampness and the control group. The best markers of abundant phlegm-dampness were protein peaks with the mass to charge ratio (m/z) of 9,334.958 m/z (the expression increased), 9,280.191 m/z (the expression decreased), 8,030.794 m/z (the expression increased), and 2,941.551 m/z (the expression increased). These four protein peaks found by BPS could induce abundant phlegm-dampness. They could be used to separate the abundant phlegm-dampness syndrome from the healthy persons and the hypertension patients with non-phlegm-dampness. The sensitivity of the model was 93.103% (27/29), specificity was 92% (23/25), false positive rate was 8% (2/25), false negative rate was 6.897% (2/29) and Youden's index was 85.103%. Blind test data indicated a sensitivity of 90% (9/10) and a specificity of 88% (22/25), and the false positive rate was 12% (3/25), false negative rate was 10% (1/10), and Youden's index was 78%. CONCLUSION: The differentiated proteins between the abundant phlegm-dampness group and the control group are the material foundation of abundant phlegm-dampness. The selected differentiated proteins can be used to distinguish the EH patients with abundant phlegm-dampness from the healthy persons and the EH patients with non-phlegm-dampness. The molecular biology diagnosis model can offer an objective and accurate way for TCM syndrome differentiation.

[Influence of shenfu injection on heart function and bone marrow stem cell mobilization in patients with chronic heart failure of coronary heart disease].

OBJECTIVE: To explore the influence of Shenfu Injection (SFI) on heart function and bone marrow stem cell mobilization in patients with chronic heart failure. METHODS: Sixty-three patients of coronary heart disease (CHD) with chronic heart failure were randomly assigned to the control group (32 cases) and the treatment group (31 cases). Western medical conventional treatment was given to all patients, but SFI was given once a day to patients in the treatment group additionally at the dose of 40 mL by dripping after dilution. After one week of treatment, the cardiac function indexes, including left ventricular ejection fraction (LVEF), stroke volume (SV) and cardiac output (CO), as well as the number of CD34+ stem cells in the peripheral blood were detected and compared. RESULTS: After treatment, all the three cardiac function indexes were improved obviously in both groups (P < 0.01), but the improvement in the treatment group was more significant than that in the control group (P < 0.05). CD34+ stem cells were insignificantly changed in the control group after treatment, while it significantly increased in the treatment group (P < 0.01), showing significant difference between groups. CONCLUSION: SFI can significantly enhance the systolic function of heart, increase the number of CD34+ stem cells in the peripheral blood, and promote the mobilization of bone marrow stem cells, which is possibly one of its acting mechanisms for improving the cardiac function.