A review of chemotherapeutic drugs-induced arrhythmia and potential intervention with traditional Chinese medicines.

Significant advances in chemotherapy drugs have reduced mortality in patients with malignant tumors. However, chemotherapy-related cardiotoxicity increases the morbidity and mortality of patients, and has become the second leading cause of death after tumor recurrence, which has received more and more attention in recent years. Arrhythmia is one of the common types of chemotherapy-induced cardiotoxicity, and has become a new risk related to chemotherapy treatment, which seriously affects the therapeutic outcome in patients. Traditional Chinese medicine has experienced thousands of years of clinical practice in China, and has accumulated a wealth of medical theories and treatment formulas, which has unique advantages in the prevention and treatment of malignant diseases. Traditional Chinese medicine may reduce the arrhythmic toxicity caused by chemotherapy without affecting the anti-cancer effect. This paper mainly discussed the types and pathogenesis of secondary chemotherapeutic drug-induced arrhythmia (CDIA), and summarized the studies on Chinese medicine compounds, Chinese medicine Combination Formula and Chinese medicine injection that may be beneficial in intervention with secondary CDIA including atrial fibrillation, ventricular arrhythmia and sinus bradycardia, in order to provide reference for clinical prevention and treatment of chemotherapy-induced arrhythmias.

Residue Effect-Guided Design: Engineering of S. Solfataricus ß-Glycosidase to Enhance Its Thermostability and Bioproduction of Ginsenoside Compound K.

ß-Glycosidase from Sulfolobus solfataricus (SS-BGL) is a highly effective biocatalyst for the synthesis of compound K (CK) from glycosylated protopanaxadiol ginsenosides. In order to improve the thermal stability of SS-BGL, molecular dynamics simulations were used to determine the residue-level binding energetics of ginsenoside Rd in the SS-BGL-Rd docked complex and to identify the top ten critical contributors. Target sites for mutations were determined using dynamic cross-correlation mapping of residues via the Ohm server to identify networks of distal residues that interact with the key binding residues. Target mutations were determined rationally based on site characteristics. Single mutants and then recombination of top hits led to the two most promising variants SS-BGL-Q96E/N97D/N302D and SS-BGL-Q96E/N97D/N128D/N302D with 2.5-fold and 3.3-fold increased half-lives at 95 °C, respectively. The enzyme activities relative to those of wild-type for ginsenoside conversion were 161 and 116%, respectively..

Selenium Donor Inhibited Hepatitis B Virus Associated Hepatotoxicity via the Apoptosis and Ferroptosis Pathways.

Methods: The serum selenium level was determined in 45 patients with HBV-positive HCC (HBV+-HCC group), 45 patients with chronic hepatitis B virus infection (CHB group), and 45 healthy cases (HC group). The sodium selenite (Na2SeO3)-treated HepG2.2.15 cells were used to observe the regulatory role of selenium on HBV replication. D-GalN/erastin-added HL7702 was used to determine the regulatory roles of Na2SeO3 on hepatotoxicity or hepatocyte ferroptosis. The wild-type (WT) C57BL/6 mice and HBx-Tg mice were received lipopolysaccharide (LPS)/D-GalN, together with or without Na2SeO3 administration for indicated period. Following euthanasia, the blood and liver tissue samples were collected, and specific markers were evaluated subsequently. Results: The serum selenium level was downregulated in patients with HBV-positive HCC (HBV+-HCC group) (57.2 ± 22.5 µg/L vs. 91.8 ± 43.9 µg/L, P < 0.001), and its higher level could provide a better prognosis in these patients. The treatment using Na2SeO3, a selenium donor, at high concentration (5 µM), suppressed the HBV replication by about 50% in HepG2.2.15 cells (P < 0.001), through promoting apoptotic cell death and inhibiting cellular inhibitor of apoptosis proteins (cIAPs). In addition, low-dose (500 nM) Na2SeO3 could almost totally reversed the hepatotoxicity induced by hepatitis B virus X protein (HBx) (P < 0.001), which were the main causes of HCC in patients. Studies at the cellular levels showed that low-dose Na2SeO3 inhibited the HBx-related hepatotoxicity by blocking ferroptosis, and glutathione peroxidase 4 (GPX4) mediated this regulatory role. Mice model results confirmed that the treatment with Na2SeO3 could mitigated LPS/D-GalN-induced hepatic injury through ferroptosis pathways. Conclusion: Selenium regulated the dual cell death in different HCC stages via different signaling pathways, which could partly explain the anti-HBV and anti-HCC properties of selenium.

Natural products as the calcium channel blockers for the treatment of arrhythmia: Advance and prospect.

Arrhythmia is one of the commonly heart diseases with observed abnormal heart-beat rhythm that caused by the obstacles of cardiac activity and conduction. The arrhythmic pathogenesis is complex and capricious and related with other cardiovascular diseases that may lead to heart failure and sudden death. In particular, calcium overload is recognized as the main reason causing arrhythmia through inducing apoptosis in cardiomyocytes. Moreover, calcium channel blockers have been widely used as the routine drugs for the treatment of arrhythmia, but the different arrhythmic complications and adverse effects limit their further applications and demand new drug discovery. Natural products have always been the rich minerals for the development of new drugs that could be employed as the versatile player for the discovery of safe and effective anti-arrhythmia drugs with new mechanisms. In this review, we summarized natural products with the activity against calcium signaling and the relevant mechanism of actions. We are expected to provide an inspiration for the pharmaceutical chemists to develop more potent calcium channel blockers for the treatment of arrhythmia.

Effects of traditional Chinese exercises on the rehabilitation of patients with chronic heart failure: A meta-analysis.

Background: With the development of rehabilitation medicine, exercise therapy has gradually become one of the methods to prevent and treat cardiovascular diseases. It is widely used in clinic because it can further reduce the mortality rate, improve clinical symptoms, restore the activity ability of the body, improve the quality of life of patients and reduce the hospitalization rate. Traditional Chinese exercises have developed rapidly in recent years, which mainly include Baduanjin, Tai Ji, etc. However, meta-analyses of all types of exercises are not well characterized. Objectives: To evaluate the effect of traditional Chinese exercises (TCEs) on the rehabilitation of patients with chronic heart failure (CHF) using a meta-analysis. Methods: A systematic search of randomized controlled trials (RCTs) on TCEs for patients with CHF in 13 databases (PubMed, China National Knowledge Infrastructure, etc.). Meta-analysis was performed using Review Manager software (version 5.3) after two investigators independently screened the studies, assessed the quality of the studies, and extracted the data. Results: Meta-analysis of 21 randomized controlled trials which involved 1,665 patients with chronic heart failure showed that practicing TCEs was effective in improving patients' physiological outcomes such as VO2max [MD = 2.14, 95% CI (1.02, 3.26), P < 0.001], AT [MD = 1.61, 95% CI (1.06, 2.16), P < 0.001], and left ventricular ejection fraction [MD = 2.60, 95% CI (1.17, 4.02), P < 0.001]. Non-physiological outcomes benefited from the application of TCEs: 6-min walking distance [MD = 38.55, 95% CI (36.67, 40.42), P < 0.001], quality of life [MD = 5.52, 95% CI (3.17, 7.88), P < 0.001], and single-item TCM symptom scores in CHF patients: tiredness and fatigue [MD = 0.78, 95% CI (0.03, 1.53), P = 0.04], shortness of breath [MD = 0.44,95% CI (0.26, 0.62), P < 0.0001], facial puffiness and limb swelling [MD = 0.44,95% CI (0.12, 0.76), P = 0.007], palpitations [MD = 0.68,95% CI (0.14, 1.21), P = 0.01] were improved. Conclusions: TCEs improved several recovery indicators, heart failure-related clinical symptoms, quality of life, and physiological indicators in patients with CHF. It is worthwhile to expand the participants for practical application in clinical practice, but the existing evidence is insufficient and the heterogeneity of outcome is large. Therefore, more high-quality clinical trials are needed to support these results. Systematic review registration: PROSPERO, identifier [CRD42022383246].

Biocatalytic strategies for the production of ginsenosides using glycosidase: current state and perspectives.

Panax ginseng is a traditional Chinese medicine with significant pharmaceutical effects and broad application. Rare ginsenosides with high antitumor activities can be generated via oriented modification of their glycosyl moiety. For this purpose, suitable microorganisms and their enzymatic systems can be used. In this review, we address several issues associated with these systems. Under aerobic conditions, fungus biotransformation provides an efficient and inexpensive biotransformation process that can be easily scaled up. Considering the profound use of probiotics, wild strains generally recognized as safe have shown a potential through classical fermentation in food manufacturers of deglycosylated ginsenosides. Commonly applied recombinant enzymes from E. coli, especially recombinant hyperthermophilic enzymes, showed efficient conversion in biomedical or pharmaceutical industries. In this review, key genes dedicated to the production of ginsenosides (especially in Saccharomyces cerevisiae) are highlighted in relation to the large-scale production of ginsenosides. We also evaluate biocatalytic strategies that are aimed to improve product specificity and biocatalytic efficiency with industrial applications. Perspectives of protein engineering and solvent engineering in the development and large-scale preparation of ginsenosides in anticancer drugs, food and health care products are explored. KEY POINTS : • Modification of ginsenosides with food/engineered microorganisms is summarized. • Optimization of cell factories by protein engineering remains challenging. • Solvent engineering offers an attractive potential alternative.

[Biocatalytic strategies in producing ginsenoside by glycosidase-a review].

Panax ginseng is a traditional Chinese medicine with significant pharmaceutical effects and wide application. Through orientational modification and transformation of ginsenoside glycosyl, rare ginsenosides with high antitumor activities can be generated. Traditional chemical methods cannot be applied in clinic. because of extremely complex preparation technologies and very high cost Transformations using microorganisms and their enzymatic systems provide the most feasible methods for solving the main problems. At present, the key problems in enzymatic synthesis of ginsenosides include low specific enzyme activities, identity of enzymes involved in the enzymatic synthesis, and their catalytic mechanisms, as well as nonsystematic studies on structural bioinformatics; specificity of enzymatic hydrolysis for saponin glycosyl has been rarely studied. Many reviews have been reported on glycosidase molecular recognition, immobilization, and biotransformation in ionic liquids (ILs), whereas ginsenoside transformation and application have not been systematically studied. To evaluate theoretical and applied studies on ginsenoside-oriented biotransformation, by reviewing the latest developments in related fields and evaluating the widely applied biocatalytic strategy, this review aims to evaluate the ginsenoside-oriented transformation method with improved product specificity, increased biocatalytic efficiency, and industrial application prospect based on the designed transformations of enzyme and solvent engineering of ILs. Therefore, useful theoretical and experimental evidence can be obtained for the development of ginsenoside anticancer drugs, large-scale preparation, and clinical applications in cancer therapy.

Therapeutic Effect of Ilex hainanensis Merr. Extract on Essential Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

With a rapidly aging population, the prevalence of hypertension in adults continues to rise, placing a substantial and escalating social and economic burden. Ilex hainanensis Merr. is commonly used as a folk remedy for treating hypertension, dyslipidemia, and inflammation in China. This systematic review aims to evaluate current evidence for the therapeutic effect of Ilex hainanensis Merr. extract (EIH) on essential hypertension. Six electronic databases (Pubmed, MEDLINE, The Cochrane Central Register of Controlled Trials, Chinese Scientific Journals Database, Wanfang and CNKI) were searched to identify eligible randomized controlled trials (RCTs) relevant to EIH on essential hypertension up to Jan 2018. Six RCTs including 772 participants met eligibility criteria. Methodological quality of the trials was generally low. Meta-analysis showed that EIH demonstrated a beneficial effect for lowering systolic and diastolic blood pressure (SBP/DBP), left ventricular mass (LVM) in participants with essential hypertension. There was no significant difference between EIH and antihypertensive drugs in SBP (WMD: -0.44 [-2.30, 1.43]; P = 0.65), DBP (WMD: WMD: -0.02 [-1.13, 1.09]; P = 0.98) and LVM (WMD: -1.36 [-4.99, 2.26]; P = 0.46). Moreover, one trial showed that EIH combined with antihypertensive drugs was more effective in lowering blood pressure than those antihypertensive drugs used alone. However, the findings were limited by the small sample sizes, duration and low methodological quality of the trials. This is the first systematic review of EIH on essential hypertension. More rigorous RCTs with high quality are still needed to prove the effectiveness and safety of EIH and its preparations for essential hypertension.

Anticancer effects of ginsenoside Rk3 on non-small cell lung cancer cells: in vitro and in vivo.

Ginsenoside Rk3 (Rk3) is present in the roots of processed Panax notoginseng herbs and it exerts anti-platelet aggregation, pro-immunogenic and cardioprotective effects. However, little is known regarding the anticancer activities of this compound, especially in lung cancer. This study was designed to investigate the anticancer effects of Rk3 on non-small cell lung cancer (NSCLC) cells and in an H460 xenograft tumor model. Our results showed that Rk3 reduced cell viability, inhibited both cell proliferation and colony formation, and induced G1 phase cell cycle arrest by downregulating the expression of cyclin D1 and CDK4 and upregulating the expression of P21. Rk3 also induced apoptosis in a concentration-dependent manner in H460 and A549 cells by Annexin V/PI staining, TUNEL assay and JC-1 staining, resulting in a change in the nuclear morphology. Moreover, Rk3 induced the activation of caspase-8, -9, and -3, promoted changes in mitochondrial membrane potential, decreased the expression of Bcl-2, increased the expression of Bax, and caused the release of cytochrome c, which indicated that the apoptosis-inducing effects of Rk3 were triggered via death receptor-mediated mitochondria-dependent pathways. Furthermore, Rk3 significantly inhibited the growth of H460 xenograft tumors without an obvious effect on the body weight of the treated mice. Histological analysis indicated that Rk3 inhibited tumor growth by altering the proliferation and morphology of tumor cells. In addition, we confirmed that Rk3 inhibited angiogenesis via CD34 staining and chick embryo chorioallantoic membrane (CAM) assay in vivo. Taken together, our findings revealed not only the anticancer effect of Rk3 on NSCLC cells but also a new promising therapeutic agent for human NSCLC.

DDR2-CYR61-MMP1 Signaling Pathway Promotes Bone Erosion in Rheumatoid Arthritis Through Regulating Migration and Invasion of Fibroblast-Like Synoviocytes.

Regulation of matrix metalloproteinases (MMPs) by collagen in the fibroblast-like synoviocytes (FLSs) plays a critical role in joint destruction in rheumatoid arthritis (RA). Our previous study indicated that discoidin receptor 2 (DDR2) mediated collagen upregulation of MMPs. However, the precise underlying mechanism remains unclear. We report here that CYR61, a secreted, extracellular matrix-associated signaling protein which is capable of regulating a broad range of cellular activities, including cell adhesion, migration, proliferation, and apoptosis, is significantly upregulated in collagen II-stimulated RA FLS. Further studies found that collagen II-activated phosphorylated-DDR2 induces CYR61 through activation of transcription factor activator protein 1 (AP-1). The elevated CYR61, in turn, accelerates MMP1 production via ETS1 (ETS proto-oncogene 1). In addition, CYR61 significantly promotes FLS invasion and migration. Blockade of CYR61 by an adenovirus expressing CYR61 shRNA (Ad-shCYR61) in vivo remarkably ameliorated the severity of arthritis, reduced inflammatory cytokine secretion, and attenuated bone erosion as detected by micro-computed tomography (µCT), in collagen-induced arthritis (CIA) rats. Taken together, we uncovered the Collagen II-DDR2-AP-1-CYR61-ETS1-MMP1 loop in RA FLS. In which, CYR61 acts as a hinge to promote cartilage damage through regulating FLS invasion, migration, and MMP1 production and the inflammatory cascade in RA. Thus, CYR61 may be a promising diagnostic and therapeutic target for RA treatment. © 2016 American Society for Bone and Mineral Research.

A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis.

The main etiopathogenesis of rheumatoid arthritis (RA) is overexpressed inflammatory cytokines and tissue injury mediated by persistent NF-κB activation. MicroRNAs widely participate in the regulation of target gene expression and play important roles in various diseases. Here, we explored the mechanisms of microRNAs in RA. We found that microRNA (miR)-10a was downregulated in the fibroblast-like synoviocytes (FLSs) of RA patients compared with osteoarthritis (OA) controls, and this downregulation could be triggered by TNF-α and IL-1ß in an NF-κB-dependent manner through promoting the expression of the YingYang 1 (YY1) transcription factor. Downregulated miR-10a could accelerate IκB degradation and NF-κB activation by targeting IRAK4, TAK1 and BTRC. This miR-10a-mediated NF-κB activation then significantly promoted the production of various inflammatory cytokines, including TNF-α, IL-1ß, IL-6, IL-8, and MCP-1, and matrix metalloproteinase (MMP)-1 and MMP-13. In addition, transfection of a miR-10a inhibitor accelerated the proliferation and migration of FLSs. Collectively, our data demonstrates the existence of a novel NF-κB/YY1/miR-10a/NF-κB regulatory circuit that promotes the excessive secretion of NF-κB-mediated inflammatory cytokines and the proliferation and migration of RA FLSs. Thus, miR-10a acts as a switch to control this regulatory circuit and may serve as a diagnostic and therapeutic target for RA treatment.

Effect of ferrous ion on ε-poly-L-lysine biosynthesis by Streptomyces diastatochromogenes CGMCC3145.

ε-Poly-L-lysine (ε-PL) is known as an amino acid homopolymer occurring in nature. It is mainly produced by bacteria belonging to the family of Streptomycetaceae. In this study, the effect of ferrous ion on the metabolic pathway such as key enzyme activities and substrate consumptions relating to ε-PL production were investigated. When 0.1 mM Fe(2+) was supplemented into the culture medium of Streptomyces diastatochromogenes CGMCC3145 for 72 h of cultivation, the yield of ε-PL and biomass were enhanced by 29.2 and 41.9%, respectively, compared with those of the control. Synchronously, consumptions of glucose, ammoniac nitrogen, and phosphorus were increased by 50, 67.6, and 35.7%, respectively. The enzyme activity measurements showed that the specific activities of proteinase, phosphatase, glutamate dehydrogenase, and aspartate aminotransferase activities were improved for 2.32, 3.68, 1.72, and 1.50 folds, respectively, however, aspartokinase and ε-PL synthetase were hardly affected by ferrous ion. These results manifested that Fe(2+) can improve the yield of ε-PL by promoting aspartate production, and the aspartate was further catalyzed to produce much more L-lysine, precursor for ε-PL biosynthesis.

[Study on preparation of the inclusion compound of curcumin with beta-cyclodextrin].

OBJECTIVE: The inclusion compound of curcumin with, beta-CD was preparated to increase the solubility and bioavaliability of curcumin. METHODS: Prepare inclusion compound was studied with orthogonal design. The inclusion compound was verified with fluorometry, TLC, and phase solubility. RESULT: The best way to prepare inclusion compound are as follows: the molar ratio between curcumin and, beta-CD is 1:1, temperture is 40 degrees C, reaction time is 2 h. CONCLUSION: Solubility of inclusion compound is 10 times than curcumin.