Effects of Chinese Medicine on Pyroptosis in Coronary Heart Disease.

Pyroptosis, an apoptotic pathway for pro-inflammatory cells, has attracted attention from researchers because of its role in the development of cardiac inflammation reactions. Chinese medicine (CM) has been given more and more attention during the pursuit of a treatment for coronary heart disease (CHD). Evidence suggests that myocardial cell pyroptosis affects the progression of CHD. Pyroptosis pathways include the canonical pyroptosis pathway mediated by the caspase-1 inflammasome and the non-canonical pyroptosis pathway induced by cytoplasmic lipopolysaccharide-activated caspase-4/5/11. The frequently studied compounds that regulate pyroptosis in CHD include astragaloside IV (AS-IV), tanshinone IIA, aucubin, cinnamaldehyde (CD), ginsenoside Rb1, paeoniflorin, apigenin, berberine (BBR), ruscogenin (Rus), and total glucosides of paeonia (TGP). The patent drugs of CM that regulate pyroptosis in CHD include the Qishen granule (QSG), the Simiao Yong'an decoction (SMYAD), the Buyang Huanwu decoction (BYHWD), and the Shexiang Baoxin pill (SBP). Therefore, this paper reviews the pathogenesis of pyroptosis, the role of pyroptosis in CHD, and the potential therapeutic roles of CMs and their active ingredients targeting cell pyroptosis in the development of CHD.

Potential anticancer activities of securinine and its molecular targets.

BACKGROUND: Securinine is an alkaloid identified from the roots and leaves of the shrub Flueggea suffruticosa (Pall.) Baill. The molecular structure of securinine consists of four rings, including three chiral centers. It has been suggested that securinine can be chemically synthesized from tyrosine and lysine. Securinine has long been used to treat central nervous system diseases. In recent years, more and more evidence shows that securinine also has anticancer activity, which has not been systematically discussed and analyzed. PURPOSE: This study aims to propose an overall framework to describe the molecular targets of securinine in different signal pathways, and discuss the current status and prospects of each pathway, so as to provide a theoretical basis for the development securinine as an effective anticancer drug. METHODS: The research databases on the anticancer activity of securinine from PubMed, Scopus, Web of Science and ScienceDirect to 2021 were systematically searched. This paper follows the Preferred Reporting Items and Meta-Analysis guidelines. RESULTS: Securinine has the ability to kill a variety of human cancer cells, including, leukemia as well as prostate, cervical, breast, lung, and colon cancer cells. It can regulate the signal pathways of phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin, Wnt and Janus kinase-signal transducer and activator of transcription, promote cancer cell apoptosis and autophagy, and inhibit cancer cell metastasis. Securinine also has the activity of inducing leukemia cell differentiation. CONCLUSION: Although there has been some experimental evidence indicating the anticancer effect of securinine and its possible pharmacology, in order to design more effective anticancer drugs, it is necessary to study the synergy of intracellular signaling pathways. More in vivo experiments and even clinical studies are needed, and the synergy between securinine and other drugs is also worth studying.

Berberine alleviates NLRP3 inflammasome induced endothelial junction dysfunction through Ca2+ signalling in inflammatory vascular injury.

BACKGROUND: Berberine has received rising attention for its application in cardiovascular disease because of its relationship with inflammation. The endothelial NLRP3 inflammasome triggers inflammatory vascular injury which would lead to cardiovascular disease. Endothelial calcium signalling plays a crucial role in both the activation of NLRP3 inflammasome and endothelial cells dysfunction. However, the efficacy of BBR on the endothelial NLRP3 inflammasome in inflammatory vascular injury remains unknown. PURPOSE: In this study, we focused on the NLRP3 pathway to determine whether BBR regulates endothelial junction function in inflammatory vascular injury. METHODS: The integrity of the junction proteins VE-cadherin (VEC) and zonula occludens-1 (ZO-1) detected by immunofluorescence and immunoblotting was used to determine the therapeutic effect of BBR (50, 100, or 200 mg/kg/day) in LPS (100 µg/kg/day)-induced inflammatory vascular injury in mice and mouse microvascular endothelial cells (MECs) treated with LPS (1 µLPS ) and ATP (5 mM). Endothelial permeability was assessed by FITC-labelled dextran and trans-endothelial electrical resistance (TEER) in vitro. The assembly and activation of NLRP3 inflammasomes were detected by western blotting and immunofluorescence. Pharmacophore-based virtual molecular docking studies and calcium imaging analyses were used to determine the interaction of BBR with the ATP-gated Ca2+ channel P2X7R (purinergic P2X receptor 7) in the context of inflammatory vascular injury. RESULTS: BBR recovered the expression of ZO-1 and VEC and inhibited endothelial NLRP3 inflammasome activation in coronary microvascular endothelium and in MECs. These results suggested a crucial role of the NLRP3 inflammasome in BBR-regulated endothelial integrity. Further analysis demonstrated that BBR treatment suppressed the binding of TXNIP (thioredoxin interacting protein) with NLRP3. Intriguingly, eliminating extracellular Ca2+ showed a similar effect as BBR. Virtual docking analysis indicated that R574 of P2X7R is a potential target for BBR binding. Ca2+ imaging showed that BBR inhibited the Ca2+ influx in response to ATP, supporting the potential interaction of BBR with P2X7R. CONCLUSIONS: These findings suggest that BBR exhibits potential and specific therapeutic value by targeting calcium signals and the endothelial NLRP3 inflammasome in inflammatory vascular injury.

Danqi soft caspule prevents atrial fibrillation by ameliorating left atrial remodeling through inhibiting cardiac fibroblasts differentiation and function.

BACKGROUND: Danqi soft capsule (DQ) is a Chinese herb medicine with a remarkable protective effect on cardio-cerebrovascular diseases. PURPOSE: The study aimed to investigate the role and mechanism of DQ on left atrial (LA) remodeling and atrial fibrillation (AF) occurrence in rats with post-myocardial infarction (MI) induced heart failure (HF). METHODS: MI in rats was established by ligation of the left anterior descending coronary artery. DQ was administered to the post-MI induced HF rats over a 4-week period. AF inducibility was detected using the transesophageal programmed electrical stimulation technology. Echocardiogram, histology, and western blot analysis were performed. Meanwhile, cardiac fibroblasts (CFs) were performed to determine the effects of DQ on CFs function by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT), flow cytometry, transwell assay and ELISA. RESULTS: The DQ-treated rats showed lower rates of AF inducibility and shorter AF durations than the MI rats. Moreover, DQ inhibited fibrosis and increased the expression of Cx43 in the left atrium; it also inhibited the myofibroblasts differentiation by reducing the expression of cytokines TNF-α, IL-6, and TGF-ß1 via the TGF-ß1/Smad 3 pathway. In addition, DQ inhibited the proliferation, migration, and collagen secretion of CFs in vitro. CONCLUSIONS: DQ reduces the risk of AF in post-MI HF rats by ameliorating LA arrhythmogenic substrate via inhibiting the function of proliferation, migration, collagen secretion, and myofibroblasts differentiation of CFs. Together, these results indicate the therapeutic potential of DQ in AF by delaying the progression of LA remodeling in post-MI-induced HF. Targeting CFs may be a novel prospective therapeutic avenue for AF after MI.

Hsa_circ_0001879 promotes the progression of atherosclerosis by regulating the proliferation and migration of oxidation of low density lipoprotein (ox-LDL)-induced vascular endothelial cells via the miR-6873-5p-HDAC9 axis.

Atherosclerosis (AS) is a typical vascular disease. Emerging evidence has shown that circRNAs play key roles in the progression of AS, but the potential function and underlying mechanism of hsa_circ_0001879 remains unknown. We detected the expression level of hsa_circ_0001879 was determined by qRT-PCR, and the proliferation rate and migration ability of HUVECs were measured by CCK-8 assay and Transwell assay, respectively. Proliferative markers and epithelium mesenchymal transition (EMT) markers were measured through immunoblotting. A dual luciferase activity assay was performed to detect the interaction between circRNAs, miRNAs, and mRNAs. Hsa_circ_0001879 was upregulated in AS patients. Hsa_circ_0001879 inhibited the proliferation and migration ability of Human umbilical vein endothelial cells (HUVECs). Hsa_circ_0001879 directly bound to miR-6873-5p and acted as a sponge. miR-6873-5p-induced HDAC9 mRNA degradation was inhibited by hsa_circ_0001879. Hsa_circ_0001879 decreased the proliferation and migration of HUVECs by inhibiting miR-6873-5p-induced HDAC9 degradation.

Left atrial fibrosis in atrial fibrillation: Mechanisms, clinical evaluation and management.

Atrial fibrillation (AF), the commonest arrhythmia, shows associations with various disease conditions. Mounting evidence indicates that atrial fibrosis is an important part of the arrhythmogenic substrate, with an essential function in the generation of conduction abnormalities that underlie the transition from paroxysmal to persistent AF, which in turn contributes to AF perpetuation. Left atrial (LA) fibrosis is considered a possible major factor and predictor in AF treatment. The present review provides insights into LA fibrosis' association with AF. The information is focused on clinical aspects and mechanisms, clinical evaluating methods that evaluate fibrosis changes and examining possible options for the prevention of atrial fibrosis.

Prevention of platelet aggregation and arterial thrombosis using a modified Shenzhu Guanxin Formula.

OBJECTIVE: Modified Shenzhu Guanxin Formula (mSGF) has beneficial effects in coronary artery disease. Previously, we found that mSGF inhibited platelet aggregation in rats. In the present study we further investigated the antiplatelet and antithrombotic activities of mSGF in rats. METHODS: Rats were orally administered mSGF (4.2, 8.4, or 16.8 g crude drug/kg), the adenosine 5'-diphosphate (ADP) receptor antagonist clopidogrel (7.875 mg/kg), or saline once a day for 7 days. The effects of mSGF on platelet aggregation were measured. Levels of cyclic adenosine monophosphate (cAMP) and phosphoinositide 3-kinase (PI3K) signaling were analyzed by ELISA and western blotting, respectively. The antithrombotic effect of mSGF was investigated using a FeCl3-induced carotid arterial thrombosis model and effects on bleeding time were assessed in a rat tail transection model. RESULTS: mSGF significantly inhibited ADP-induced platelet aggregation in a dose-dependent manner, elevated cAMP levels and inhibited phosphorylation of extracellular signal-regulated kinase (ERK) and PI3K/protein kinase B (Akt). Moreover, mSGF dose-dependently inhibited thrombosis in a FeCl3-induced carotid arterial thrombus model and had a significantly smaller effect on bleeding time compared with clopidogrel. CONCLUSIONS: mSGF represents a potent and safe antithrombotic agent whose antiplatelet activity is probably mediated through blockade of PI3K/Akt signaling and increased cAMP generation.

Isoproterenol Increases Left Atrial Fibrosis and Susceptibility to Atrial Fibrillation by Inducing Atrial Ischemic Infarction in Rats.

Left atrial (LA) fibrosis is a major arrhythmogenic substrate for atrial fibrillation (AF). The purpose of this study was to assess whether isoproterenol (ISO) induces LA fibrosis and increases susceptibility to AF, exploring the underlying mechanisms. Male Sprague-Dawley rats were subcutaneously injected ISO once per day for 2 days. Five weeks after injection, the ISO group had higher susceptibility AF and prolonged AF duration compared with the control group. ISO decreased LA conduction velocity (CV) and increased LA conduction heterogeneity. ISO increased fibrosise areas and the protein levels of collagen types I and III in the left atrium. Antifibrosis drug pirfenidone decreased AF occurrence and reduced LA fibrosis in ISO treated rats. ISO injection induced atrial ischemia infarction by increasing heart rate and decreasing diastolic and systolic blood pressures. These findings demonstrated that ISO increases susceptibility to AF by increasing LA fibrosis and LA conduction abnormalities 5 weeks after injection. ISO injection induces atrial ischemic injury is the main cause of fibrosis. Rats with ISO-induced LA fibrosis may be used in further AF research.

Salvianolic acid B protects against myocardial ischaemia-reperfusion injury in rats via inhibiting high mobility group box 1 protein expression through the PI3K/Akt signalling pathway.

Salvianolic acid B (Sal B) has a significant protective effect on myocardial ischaemia-reperfusion (I/R) injury. Therefore, the aims of this study were to determine the effects of Sal B on myocardial ischaemic-reperfusion (I/R) injury in rats and to explore whether its underlying mechanism of cardioprotection occurs through activating the expression of the phosphoinositide 3-kinase/protein, kinase B (PI3K/Akt) and inhibiting the expression of high mobility group protein 1 (HMGB1). Ninety Sprague-Dawley rats were randomized into five groups: group 1 (sham-operated), group 2 (myocardial I/R), group 3 (low dose of Sal B+I/R), group 4 (high dose of Sal B+I/R), and group 5 (high dose of Sal B+I/R+LY294002, which is a specific PI3k inhibitor). All I/R rats received 30 min myocardial ischaemia followed by 24-h reperfusion. Cardiac function, infarct size, myocardial injury marker levels, inflammatory response and cardiomyocyte apoptosis as well as Bcl-2, Bax, P-Akt, HMGB1 and TLR4 expression were measured. In the current study, Sal B significantly ameliorated myocardial I/R injury in a dose-dependent manner, ameliorated cardiac function, reduced myocardial infarction size, decreased myocardial injury marker expression, decreased inflammatory responses, reduced apoptosis, activated PI3K/Akt expression and inhibited HMGB1 expression. However, all effects of Sal B were significantly reversed by LY294002. Overall, the present study indicated that Sal B attenuated myocardial I/R injury by activating PI3K/Akt and inhibiting the release of HMGB1 in rats.

Shensong Yangxin capsule reduces atrial fibrillation susceptibility by inhibiting atrial fibrosis in rats with post-myocardial infarction heart failure.

PURPOSE: Shensong Yangxin (SSYX) capsule is a traditional Chinese medicine that has been used widely to treat cardiac arrhythmia. This study aimed to assess whether SSYX prevents atrial fibrillation (AF) after chronic myocardial infarction (MI)-induced heart failure and to determine the underlying mechanisms. MATERIALS AND METHODS: The study included 45 male Sprague Dawley rats. The rats underwent MI induction or sham surgery. One week after MI induction surgery, we performed serial echocardiography and administered SSYX capsule to some rats that experienced MI. After 4 weeks of treatment, AF inducibility was assessed with transesophageal programmed electrical stimulation technology. Additionally, multielectrode array assessment, histological analysis, and Western blot analysis were performed. RESULTS: AF inducibility was significantly lower in SSYX rats than in MI rats (33.3% vs 73.3%, P<0.05). Additionally, conduction velocities in the left atrium were greater in SSYX rats than in MI rats. Moreover, SSYX decreased left atrial fibrosis, downregulated TGF-ß1, MMP-9, TIMP-I, and type I and III collagen expressions, and inhibited the differentiation of cardiac fibroblasts to myofibroblasts. CONCLUSION: SSYX reduces AF inducibility after MI by improving left atrial conduction function via the inhibition of left atrial fibrosis. It prevents the development of an MI-induced vulnerable substrate for AF.

A multicentre randomized clinical trial on efficacy and safety of huxin formula in patients undergoing percutaneous coronary intervention.

Percutaneous coronary intervention (PCI) is widely used in clinical treatment of coronary artery disease. However, the effects of PCI on preventing restenosis after revascularization and improving the quality of life were not satisfying. Huxin Formula is formulated by modifying an experienced Chinese medicine formula and has been widely used in clinical practice due to its marked effects on coronary heart disease. A multicentre double-blind randomized controlled clinical trial was designed to evaluate the effects and safety of Huxin Formula in patients undergoing PCI. Our results showed that there was no significant difference between the two groups in main outcomes. For patients with ejection fraction (EF) >50%, score of the quality of life scale was higher in treatment group compared with control group. For patients with unstable angina, score of the quality of life scale in 360 days was significantly higher in treatment group compared with control group (P < 0.05). No obvious adverse reaction was found in the use of Huxin Formula. In conclusion, Huxin Formula, believed to be a safe treatment for patients after PCI, has benefits in improving the quality of life in patients with unstable angina though it failed to show superiority in primary and secondary outcomes.

Activated nuclear factor-kappaB and increased tumor necrosis factor-alpha in atrial tissue of atrial fibrillation.

OBJECTIVES: To depict the interaction between atrial fibrillation (AF) and inflammatory reaction, studies were taken to measure the activity of NF-kappaB in myocardium, the concentration of regional inflammatory factors and the pathological process of the right atrium in patients with AF. DESIGN: Patients with valvular disease with AF or sinus rhythm (SR) were recruited and compared. Before the extracorporal circulation, about 250 mg tissue of right atrium was collected for pathological examination. The activity of NF-kappaB in myocardium was measured by electrophoretic mobility shift assay (EMSA), and the concentration of cardiac tissue interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha) was determined by radioimmuoassay. RESULTS: Patients with valvular disease with AF exhibited higher NF-kappaB activity, higher concentration of TNF-alpha and IL-6, severe lymphomonocyte infiltration, and more fibrosis than those patients with valvular disease with SR. There were significant positive correlations among NF-kappaB activity and levels of TNF-alpha and IL-6 and collagen volume fraction. CONCLUSIONS: This study proved the presence of inflammation in atrial myocardium by triggering inflammatory reaction.