Sex differences and related estrogenic effects in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is an essential subtype of heart failure accounting for 40% of the total. However, the related pathological mechanism and drug therapy research have been stagnant for a long time. The direct cause of this dilemma is the heterogeneity of HFpEF. And some researchers believe that there is no common pathway to reach the origin of HFpEF; others argue that there is an unidentified unified pathophysiological process hidden beneath the ice surface. Aside from the debate, a series of clinical studies have shown that hypertension and obesity play a fundamental role in the pathogenesis of HFpEF. These results imply that there may be two parallel pathological processes interweaved in one disease, manifested as multiple coexistent pathological phenomena, like a shadow. Meanwhile, the prevalence of HFpEF in women is higher than in men in any given age group, especially prominent in elderly patients. These pathological processes and epidemiological data reflect gender differences, reminding us to shift our attention to estrogen. This article will review the parallel pathogenesis of HFpEF, and also introduce sex differences and the potential effect of estrogen in this condition below.

SUMO1 regulates post-infarct cardiac repair based on cellular heterogeneity / 药物分析学报

Small ubiquitin-related modifier(SUMOylation)is a dynamic post-translational modification that maintains cardiac function and can protect against a hypertrophic response to cardiac pressure overload.However,the function of SUMOylation after myocardial infarction(MI)and the molecular details of heart cell responses to SUMO1 deficiency have not been determined.In this study,we demonstrated that SUMO1 protein was inconsistently abundant in different cell types and heart regions after MI.However,SUMO1 knockout significantly exacerbated systolic dysfunction and infarct size after myocardial injury.Single-nucleus RNA sequencing revealed the differential role of SUMO1 in regulating heart cells.Among cardiomyocytes,SUMO1 deletion increased the Nppa+Nppb+Ankrd1+cardiomyocyte subcluster pro-portion after MI.In addition,the conversion of fibroblasts to myofibroblasts subclusters was inhibited in SUMO1 knockout mice.Importantly,SUMO1 loss promoted proliferation of endothelial cell subsets with the ability to reconstitute neovascularization and expressed angiogenesis-related genes.Computational analysis of ligand/receptor interactions suggested putative pathways that mediate cardiomyocytes to endothelial cell communication in the myocardium.Mice preinjected with cardiomyocyte-specific AAV-SUMO1,but not the endothelial cell-specific form,and exhibited ameliorated cardiac remodeling following MI.Collectively,our results identified the role of SUMO1 in cardiomyocytes,fibroblasts,and endothelial cells after Ml.These findings provide new insights into SUMO1 involvement in the patho-genesis of MI and reveal novel therapeutic targets.

Research progress in sodium calcium exchanger and heart failure with preserved ejection fraction / 中国临床药理学与治疗学

Sodium calcium exchanger (NCX) is encoded by the SCL8 family genes and belongs to the cation/Ca

Traditional Chinese medicine in COVID-19

COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread across the globe, posing an enormous threat to public health and safety. Traditional Chinese medicine (TCM), in combination with Western medicine (WM), has made important and lasting contributions in the battle against COVID-19. In this review, updated clinical effects and potential mechanisms of TCM, presented in newly recognized three distinct phases of the disease, are summarized and discussed. By integrating the available clinical and preclinical evidence, the efficacies and underlying mechanisms of TCM on COVID-19, including the highly recommended three Chinese patent medicines and three Chinese medicine formulas, are described in a panorama. We hope that this comprehensive review not only provides a reference for health care professionals and the public to recognize the significant contributions of TCM for COVID-19, but also serves as an evidence-based in-depth summary and analysis to facilitate understanding the true scientific value of TCM.

SERCA2a: a key protein in the Ca2+ cycle of the heart failure.

Calcium ion (Ca2+) cycle plays a crucial role in the contraction and relaxation of cardiomyocytes. The sarcoplasmic reticulum (SR) acts as an organelle for storing Ca2+, which mediated the release and re-uptake of Ca2+ during contraction and relaxation. Disorders of SR function lead to the dysfunction of Ca2+ cycle and myocardial cell function. The sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) acts as a subtype of SERCA expressed in the heart, which mediates the contraction of cardiomyocytes and Ca2+ in the cytoplasm to re-enter into the SR. The rate of uptake of Ca2+ by the SR determines the rate of myocardial relaxation. The regulation of SERCA2a activity controls the contractility and relaxation of the heart, affecting cardiac function. The expression and activity of SERCA2a are reduced in failing hearts. Gene therapy by increasing the expression of SERCA2a in the heart has been proven effective. In addition, SERCA2a is regulated by a variety of factors, including transmembrane micropeptides, protein kinases, and post-translational modifications (PTMs). In this review, we discuss the regulatory factors of SERCA2a and provide new insights into future treatments and the direction of heart failure research. In addition, gene therapy for SERCA2a has recently emerged as therapeutic option and hence will be discussed in this review.

Ethanol extracts of Danlou tablet attenuate atherosclerosis via inhibiting inflammation and promoting lipid effluent.

As a chronic inflammatory disease, atherosclerosis is characterized by accumulation of lipid-rich macrophages on the inner walls of arteries. Deposited macrophages promote atherosclerotic lesion progression; therefore they are viewed as the main targets in order to alleviate atherosclerosis. Danlou tablet, a patented Chinese Medicine, has long been used to treat cardiovascular diseases. In the present study, we used Apolipoprotein E-deficient (ApoE-/-) mice model and in vitro cell line of RAW264.7 to explore the mechanisms of ethanol extracts of Danlou tablet (EEDT) in treating atherosclerosis. The potential targets that EEDT works to treat atherosclerosis were predicted by "Network pharmacology analysis", based on which we designed mRNA array of 93 genes. Then mRNA array and oil red O staining were performed in aortic extracted from the cohorts of Control (C57BL/6 mice, chow fed), Model (ApoE-/- C57BL/6 mice, 20 weeks of high-fat diet) and EEDT intervening (ApoE-/- mice, 20 weeks of high-fat diet with 12 weeks of EEDT treatment) group. Furthermore, mRNA array, inflammation cytokines and lipid content were examined in RAW264.7 cell line. It was showed that EEDT decreased the expressions of inflammation cytokines by down regulating NF-κB singling pathway and accelerated cholesterol effluent through activating PPARα/ABCA1 signaling pathway. On the other hand, activation of NF-κB pathway or suppression of PPARα/ABCA1 signaling pathway both abolished the therapeutic effect of EEDT. In conclusion, EEDT played a key role in anti-inflammation and preventing lipid deposition in macrophages of atherosclerosis via suppressing NF-κB signaling and triggering PPARα/ABCA1 signaling pathway.

Biomarkers in heart failure: the past, current and future.

Despite the enhanced knowledge of the pathophysiology of heart failure (HF), it still remains a serious syndrome with substantial morbidity, mortality, and frequent hospitalizations. These are due to the current improvements in other cardiovascular diseases (like myocardial infarction), the aging population, and growing prevalence of comorbidities. Biomarker-guided management has brought a new dimension in prognostication, diagnosis, and therapy options. Following the recommendation of natriuretic peptides (B-type natriuretic peptide and N-terminal-proBNP), many other biomarkers have been thoroughly studied to reflect different pathophysiological processes (such as fibrosis, inflammation, myocardial injury, and remodeling) in HF and some of them (like cardiac troponins, soluble suppression of tumorigenesis-2, and galectin 3) have subsequently been recommended to aid in the diagnosis and prognostication in HF. Consequently, multi-marker approach has also been approved owing to the varied nature of HF syndrome. In this review, we discussed the guidelines available for HF biomarkers, procedures for evaluating novel markers, and the utilities of both emerging and established biomarkers for risk stratification, diagnosis, and management of HF in the clinics. We later looked at how the rapidly emerging field-OMICs, can help transform HF biomarkers discoveries and establishment.

Study on the Effects of Danhong Injection on Gene Expression Profile of Acute Myocardial Infarction Model Rats by Gene Chip Technique / 中国药房

OBJECTIVE： To investigate the effects of Danhong injection （DHI） on gene expression profile of acute myocardial infarction （AMI） model rats. METHODS： Male SD rats were randomly divided into sham operation group， model group and DHI group （0.76 mL/kg）， with 10 rats in each group. AMI model was established by ligation of left anterior descending coronary artery in model group and DHI group. After modeling， sham operation group and model group were given constant volume of normal saline intramuscularly， and DHI group was given relevant medicine intramuscularly， once a day， for consecutive 14 days. After last administration， myocardial tissue in the marginal zone of infarction was separated. The change of gene expression profile was detected by gene chip technique. Using fold-change of relative expression as index， differentially expressed microRNA （miRNA） were screened. On the basis of retrieving their corresponding genes， gene ontology （GO） and KEGG pathway enrichment analysis were carried out by using DAVID bioinformatics resource database and KEGG pathway database， respectively. TargetScan database was used to predict the target gene messenger RNA （mRNA） corresponding to differentially expressed miRNA. Cytoscape 3.6.1 software was used to construct and analyze the miRNA-mRNA network. Agilent GeneSpring GX v11.5 software was used to screen target genes and miRNA related to inflammation in the above networks. RESULTS： Compared with sham operation group， there were 22 differentially expressed miRNAs in model group， 5 up-regulated and 17 down-regulated. Compared with model group， there were 26 differentially expressed miRNAs in DHI group， and all of them were up-regulated. The differentially expressed miRNAs related to DHI therapy for AMI included rno-let-7a-5p， rno-let-7d-5p， rno-let-7f-5p， rno-miR-26b-5p， rno-miR-29b-3p， cel-miR-39-3p， cel-miR-39-5p， rno-miR-142-5p， rno-miR-191a-5p， rno-miR-409a-3p. Results of GO analysis and KEGG pathway enrichment analysis showed that differentially expressed miRNAs were mainly concentrated in membrane-bound organelles， cytoplasm， endometrial system and other cell components. The molecular functions such as protein binding and ion binding were exerted through biological processes such as anatomical structure development， multicellular tissue development and development process，which were mainly enriched in calcium signaling pathway， PPAR signaling pathway， VEGF signaling pathway， cell apoptosis， glycosylphosphatidylinositol anchored biosynthesis， valine， leucine and isoleucine degradation， etc. miRNA-mRNA network analysis showed that there were 25 target gene mRNAs corresponding to differentially expressed miRNA and 24 miRNAs related to it. There were 6 inflammation-related target genes （IL6， IL1b， TNF， TLR4， CRP， CXCL12） in this network， involving 19 differentially expressed miRNAs. CONCLUSIONS： The therapeutic effect of DHI on AMI may be related to regulating the expression of related miRNA， affecting signal transduction of calcium ion， PPAR and VEGF pathways， and regulating the secretion of inflammatory markers such as interleukin， chemokine and C-reactive protein.

MicroRNA-155: a Novel Armamentarium Against Inflammatory Diseases.

An increasing number of diseases are being newly closely associated with inflammation, where microRNAs seem to play a critical role in the whole disease process from initiation to development. MicroRNAs are small non-coding RNAs that govern gene expression and modulation by means of mRNA degradation or translational repression. After several profound research studies, new correlations between microRNA-155 and inflammation-related diseases are strongly emerging. Hence, we review in this paper the possible molecular mechanisms of microRNA-155 in inflammatory disorders. Furthermore, we also consider the feasibility of targeting it as a bright alternative to improve the early diagnose statistics and treatments in those diseases. MicroRNA-155 features a novel breakthrough in fine-tuning inflammatory responses and, thereby, in treating a wide spectrum of diseases with inflammation as a common denominator.

Effect of Shenfu Injection on the Expression Profile of Myocardial miRNA in Rats with Chronic Conges-tive Heart Failure / 中国药房

OBJECTIVE:To study the effect of Shenfu injection(SFI)on the expression profile of myocardial miRNA in rats with chronic congestive heart failure (referring to heart failure). METHODS:40 rats were randomly divided into sham operation group (normal saline,ip),model group (normal saline,ip),valsartan group (positive control,10 mg/kg,ig) and SFI group (0.75 mL/kg,im),10 in each group. Except for sham operation group,another groups were reduced heart failure. After modeling, rats in other groups received related medicines,once a day. Affymetrix miRNA V4.0 chip technology was conducted to analyze the miRNA expression in myocardial tissue of rats with heart failure after administration for 28 d,and screen the miRNA on common differential expression in myocardial tissue of rats in each group. The miRNA associated with heart failure was analyzed by thresh-old of differential gene expression multiple value greater than or equal to 1.1. Gene Ontology (GO) analysis was used to analyze functional classification and biological signaling pathway of differentially expressed genes. RESULTS:There were totally 29 miR-Nas on common differential expression and 7 miRNAs associated with heart failure (rno-miR-30c-1-3p, rno-miR-125b-5p, rno-miR-133a-5p,rno-miR-199a-5p,rno-miR-221-3p,rno-miR-146a-5p and rno-miR-1-3p). SFI can significantly downregulate the expressions of rno-miR-125b-5p,rno-miR-133a-5p,rno-miR-221-3p,rno-miR-1-3p in myocardial tissue of rats (P<0.05 or P<0.01). Results of GO analysis showed,miRNAs on differential expression were mainly related to signal transduction,cytoplasm and nucleotide binding. CONCLUSIONS:SFI plays the role of anti-heart failure by participating in the downregulation of miRNAs associated with heart failure process and then affecting related signal pathways transduction after the combination of cyto-plasm and nucleotide.

Recognition of Pathogenesis of Climacteric Syndrome / 世界科学技术-中医药现代化

At present,most of the scholars of traditional Chinese medicine (TCM) considered that climacteric syndrome was caused by yin-deficiency,as the therapy of nourishing yin and clearing heat was the most common treatment,neglecting the pathologic role of yang-deficiency in climacteric syndrome.This paper redefined the pathogensis of climacteric syndrome and its syndromes based on differentiation in Gynecology of Traditional Chinese Medicine of various versions and in accordance with previous syndrome epidemiological results over it.The emerge of hot flushes and sweating,forgetful and hyposexuality was prevalent.The inaccurate description of hot flash and sweating in climacteric syndrome was rectified.The therapeutic effects of nourishing yin therapy on vasomotion were discussed based on the understanding of etiology,pathology and treatment of climacteric syndrome in ancient Chinese medical books.The phytoestrogens action of warming kidney-yang drugs was summarized from the aspect of modern pharmacology for exploring the significance of the role of yang-deficiency in climacteric syndrome.The treatment against yang-deficiency would be an innovative clinical pathway of climacteric syndrome.

Pharamacological action in Toddalia asiatica Lam.:research advances / 国际药学研究杂志

Radix Toddaliae asiaticae which belongs to Toddalia genus of Rutaceae family is a folk medicine in China. Modern pharmacological studies have shown its anti-inflammatory,analgesic,antioxidative,antibacterial,antifungal,cardiovascular protec?tive,antitumor activities and so on. The review systematically summarizes pharmacological effects,which can provide references for reasonable utilization.

Interaction of anti-thrombotic and anti-inflammatory activities of commonly used traditional Chinese medicine for promoting blood circulation and removing blood stasis revealed by network pharmacology analysis / 药学学报

Chinese traditional patent medicine for promoting blood circulation and removing blood stasis(PBCRBS) originated from traditional Chinese medicine theory and had approved efficacy and safety standards. However, its compatibility regularity and anti-thrombotic mechanism is not clear. To analyze the compatibility regularity and anti-thrombotic mechanism of Chinese traditional patent medicine for PBCRBS, a statistical and bioinformatics analysis was carried out using traditional Chinese medicine inheritance support system (TICMISS, V2.0) and ingenuity pathway analysis (IPA). The compatibility regularity analysis shows that the most commonly used herb combinations are Danshen (Salvia miltiorrhiza Bge.), Chuanxiong (Ligusticum chuanxiong Hort.) and Honghua (Carthamustinctorius L.). The anti-thrombotic mechanism analysis reveals that 25 ingredients have an effect on 29 thrombosis related molecules which 23 molecules are related to inflammation response. Furthermore, there are 5 inflammation molecules (NOS2, PTGS2, IL6, TNF, IL1β) served as major targets. At the same time, Danshen, Chuangxiong and Honghua mainly used as sovereign herb or minister herb in the application of cardiovascular and cerebrovascular diseases. Therefore, Chinese traditional patent medicine for PBCRBS probably has an effect on anti-thrombotic activity through inhibiting the inflammatory response. In summary, the most commonly used herb combinations of Chinese traditional patent medicine for PBCRBS are Danshen, Chuanxiong and Honghua. Inhibiting inflammatory response, especially inflammation related molecules (NOS2, PTGS2, IL6, TNF and IL1β), is probably a new starting point to clarify the anti-thrombotic mechanism of Chinese patent medicine for PBCRBS.

Advance of research on toxic attenuation by compatibility of traditional Chinese medicine prescriptions / 中国中药杂志

The Chinese herbs have been used for thousands years, their effects were certified in clinic. The compatibility of Chinese medicine prescriptions is the basis principle in clinical application. In order to enhance efficacy and reduce toxicity, reasonable compatibility of the Chinese herbs is the main method for the safety and effective use. However, it is not clear about its mechanism. So it is necessary to study their mechanisms by using the modern pharmacological technology. At present, there are some studies on the mechanisms of the compatibility relating with toxicity or adverse effect attenuation, for instance, reducing the dose of toxic Chinese herbs, changing their pharmacokinetic parameter and resisting the damage to human body system. In this paper, we planed to review the attenuation mechanism of the prescription compatibility from relevant studies.

Effects of Yangxue Qingnao Granules on Blood Pressure and Plasma Levels of Endothelin, Calcitonin Gene Related Peptide and NO in Rats with Renal Hypertension / 中药新药与临床药理

Objective To evaluate the effects of Yangxue Qingnao Granules (YQG) in decreasing blood pressure in rats with renal hypertension and to investigate its mechanism.Methods Modified Goldblatt renal hypertension rat models were used.The rats were randomized into 6 groups: model group,YQG groups (treated with high-,moderate-and low-dose respectively),Captopril Tablets group and Niuhuang Jiangya Pills group, 10 rats in each group. The model group was given with distilled water and the other groups with corresponding drugs by gavage, once time a day. Blood pressure was detected in 1st, 2nd and 4th week after treatment. Four weeks after treatment plasma levels of endothelin (ET),calcitonin gene related peptide(CGRP) and nitric oxide(NO) were examined by radioimmunoassay.Results Plasma level of ET was increased and those of NO and CGRP were decreased in rats with renal hypertension. YQG could decrease ET level and increase the levels of NO and CGRP, high-dose YQG in particular (P