Chemical Compositions of Scutellaria baicalensis Georgi. (Huangqin) Extracts and Their Effects on ACE2 Binding of SARS-CoV-2 Spike Protein, ACE2 Activity, and Free Radicals.

The water and ethanol extracts of huangqin, the roots of Scutellaria baicalensis Georgi. with potential antiviral properties and antioxidant activities, were investigated for their chemical profiles and their abilities to interfere with the interaction between SARS-CoV-2 spike protein and ACE2, inhibiting ACE2 activity and scavenging free radicals. A total of 76 compounds were tentatively identified from the extracts. The water extract showed a greater inhibition on the interaction between SARS-CoV-2 spike protein and ACE2, but less inhibition on ACE2 activity than that of the ethanol extract on a per botanical weight concentration basis. The total phenolic content was 65.27 mg gallic acid equivalent (GAE)/g dry botanical and the scavenging capacities against HO●, DPPH●, and ABTS●+ were 1369.39, 334.37, and 533.66 µmol trolox equivalent (TE)/g dry botanical for the water extract, respectively. These values were greater than those of the ethanol extract, with a TPC of 20.34 mg GAE/g, and 217.17, 10.93, and 50.21 µmol TE/g against HO●, DPPH●, and ABTS●+, respectively. The results suggested the potential use of huangqin as a functional food ingredient in preventing COVID-19.

YouTube online videos as a source for patient education of cervical spondylosis-a reliability and quality analysis.

BACKGROUND: Given a prolonged course of Cervical spondylosis (CS) could cause irreversible neurological deficits, it is crucial to disseminate CS-related health information to the public to promote early diagnosis and treatment. YouTube has been widely used to search for medical information. However, the reliability and quality of videos on YouTube vary greatly. Thus, this study aimed to assess the reliability and educational quality of YouTube videos concerning CS and further explore strategies for optimization of patient education. METHODS: We searched YouTube online library for the keywords "cervical spondylosis", "cervical radiculopathy" and "cervical myelopathy" on January 15, 2023. Ranked by "relevance", the first 50 videos of each string were recorded. After exclusions, a total of 108 videos were included. All videos were extracted for characteristics and classified based on different sources or contents. Two raters independently evaluated the videos using Journal of American Medical Association (JAMA) benchmark criteria, Modified DISCERN (mDISCERN) tool, Global Quality Scale (GQS) and Cervical-Spondylosis-Specific Scale (CSSS), followed by statistical analyses. All continuous data were described as median (interquartile range). RESULTS: All videos had median values for JAMA, mDISCERN, GQS and CSSS scores of were 3.00 (1.00), 3.00 (2.00), 2.00 (1.00) and 7.00 (8.88), respectively. There were significant differences in VPI (P = 0.009) and JAMA (P = 0.001), mDISCERN (P < 0.001), GQS (P < 0.001) and CSSS (P < 0.001) scores among different sources. Videos from academic source had advantages in reliability and quality scores than other sources. VPI (P < 0.001), mDISCERN (P = 0.001), GQS (P < 0.001) and CSSS (P = 0.001) scores also significantly differed among videos of various contents. Spearman correlation analysis indicated VPI was not correlated with either reliability or quality. Multiple linear regression analysis showed a longer duration and an academic source were independent predictors of higher reliability and quality, while a clinical source also led to the higher video quality. CONCLUSIONS: The reliability and educational quality of current CS-related videos on YouTube are unsatisfactory. Users face a high risk of encountering inaccurate and misleading information when searching for CS on YouTube. Longer duration, source of academic or clinician were closely correlated to higher video reliability and quality. Improving the holistic reliability and quality of online information requires the concerted effort from multiple parties, including uploaders, the platform and viewers.

New Evidence for Artemisia absinthium as an Alternative to Classical Antibiotics: Chemical Analysis of Phenolic Compounds, Screening for Antimicrobial Activity.

Artemisia absinthium, an important herb of the Artemisia genus, was evaluated in this study for its potential as an alternative to classical antibiotics. The antimicrobial activity of methanol extracts of A. absinthium (MEAA) was evaluated using the broth microdilution method, revealing that A. absinthium exhibited broad-spectrum antibacterial and antifungal activity. Ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF-MS) was used to analyze the chemical profile of the MEAA, with a focus on flavonoids, quinic acids, and glucaric acids. A total of 90 compounds were identified, 69 of which were described for the first time in A. absinthium. Additionally, a new class of caffeoyl methyl glucaric acids was identified. The main active compounds were quantified and screened for antimicrobial activity. A. absinthium was found to be rich in quinic acids and flavonoids. The screening for antimicrobial activity also revealed that salicylic acid, caffeic acid, casticin, and 3,4-dicaffeoylquinic acid had varying degrees of antimicrobial activity. The acute toxicity of MEAA was examined following OECD guidelines. The administration of 5000 mg/kg bw of MEAA did not result in mortality in male and female mice. Furthermore, there were no observed effects on the visceral organs or general behavior of the mice, demonstrating the good safety of MEAA. This study provides new evidence for the use of A. absinthium as an alternative to classical antibiotics in addressing the problem of bacterial resistance.

Exploring the possible mechanism(s) underlying the nephroprotective effect of Zhenwu Decoction in diabetic kidney disease: An integrated analysis.

BACKGROUND: Diabetic kidney disease (DKD) is one of the major chronic microvascular complications of diabetes and the main cause of end-stage renal failure. Zhenwu Decoction (ZWD), an ancient classic herbal formula in Chinese medicine, has been clinically used for the treatment of kidney disease in China for many years. However, there is currently limited research investigating the application of ZWD in the treatment of DKD and the underlying chemical and biochemical mechanisms involved. Therefore, in the present study, we aimed to identify active components in ZWD and unravel the possible mechanism(s) of action for ZWD in treating DKD. METHODS: The protective effect of ZWD against DKD was evaluated utilizing an in vitro model of diabetic renal proximal tubulopathy. The major chemical components from ZWD were identified by LC-MS/MS. Drug targets were predicted by submitting the SMILES (Simplified Molecular Input Line Entry System) of the compounds to SEA (Similarity Ensemble Approach) search server and SwissTargetPrediction. The differentially expressed genes (DEGs) of the disease were collected and integrated from GeneCards. The constructions of "Compounds-potential targets interaction" (CTI) network and Protein-Protein Interaction (PPI) network, as well as topology analysis were conducted by Cytoscape. Gene Ontology (GO) enrichment and Metacore pathway enrichment analysis were also performed. Lastly, molecular docking and experimental studies were adopted to validate the core target and identify an active component(s) of ZWD. RESULTS: We demonstrated that the ZWD extract could significantly rescue the palmitic acid (PA) and high glucose-induced apoptotic cell death in HK-2 cells, and the cytoprotection was accompanied by decreases in the extent of reactive oxygen species (ROS) production, mitochondrial membrane depolarization and ATP depletion. Fifty-seven compounds in the aqueous extract of ZWD were identified by LC-MS. The results of PPI analysis showed that top hub genes involved epidermal growth factor receptor (EGFR), Signal Transducer and Activator of Transcription 3 (STAT3), Serine/Threonine Kinase 1 (AKT1), Vascular Endothelial Growth Factor A (VEGFA) and Fibroblast Growth Factor 2 (FGF2). Pathway enrichment analysis revealed the involvement of S1P1 receptor signaling and EGFR pathways. The results of molecular docking analysis showed that albiflorin has a high binding affinity to EGFR. Albiflorin could also exert protective effects in an HK-2 cell model of DKD, which may be related to the inhibition of the high glucose/high lipid-induced EGFR and Akt phosphorylation. CONCLUSION: ZWD has been shown to be effective in ameliorating cell death in an experimental model of DKD. The beneficial effect of ZWD against DKD was associated with the interactions between the active ingredients and the hub genes, such as EGFR, STAT3, AKT1, and VEGF-A. Albiflorin may be one of the active components responsible for the nephroprotective effect in ZWD.

Efficacy and Optimal Dose of Coenzyme Q10 Supplementation on Inflammation-Related Biomarkers: A GRADE-Assessed Systematic Review and Updated Meta-Analysis of Randomized Controlled Trials.

SCOPE: Coenzyme Q10 (CoQ10) has become a popular nutritional supplement due to its wide range of beneficial biological effects. Previous meta-analyses show that the attenuation of CoQ10 on inflammatory biomarkers remains controversial. This meta-analysis aims to assess the efficacy and optimal dose of CoQ10 supplementation on inflammatory indicators in the general population. METHODS AND RESULTS: Databases are searched up to December 2022 resulting in 6713 articles, of which 31 are retrieved for full-text assessment and included 1517 subjects. Double-blind randomized controlled trials (RCTs) of CoQ10 supplementation are eligible if they contain C reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). CoQ10 supplementation can significantly reduce the levels of circulating CRP (SMD: -0.40, 95% CI: [-0.67 to -0.13], p = 0.003), IL-6 (SMD: -0.67, 95% CI: [-1.01 to -0.33], p < 0.001), and TNF-α (SMD: -1.06, 95% CI: [-1.59 to -0.52], p < 0.001) and increase the concentration of circulating CoQ10. CONCLUSION: This meta-analysis provides evidence for CoQ10 supplementation to reduce the level of inflammatory mediators in the general population and proposes that daily supplementation of 300-400 mg CoQ10 show superior inhibition of inflammatory factors.

Bioactive Compositions of Cinnamon (Cinnamomum verum J. Presl) Extracts and Their Capacities in Suppressing SARS-CoV-2 Spike Protein Binding to ACE2, Inhibiting ACE2, and Scavenging Free Radicals.

Cinnamon (Cinnamomum verum J. Presl) bark and its extracts are popular ingredients added to food and supplement products. It has various health effects, including potentially reducing the risk of coronavirus disease-2019 (COVID-19). In our study, the bioactives in cinnamon water and ethanol extracts were chemically identified, and their potential in suppressing SARS-CoV-2 spike protein-angiotensin-converting enzyme 2 (ACE2) binding, reducing ACE2 availability, and scavenging free radicals was investigated. Twenty-seven and twenty-three compounds were tentatively identified in cinnamon water and ethanol extracts, respectively. Seven compounds, including saccharumoside C, two emodin-glucuronide isomers, two physcion-glucuronide isomers, and two type-A proanthocyanidin hexamers, were first reported in cinnamon. Cinnamon water and ethanol extracts suppressed the binding of SARS-CoV-2 spike protein to ACE2 and inhibited ACE2 activity in a dose-dependent manner. Cinnamon ethanol extract had total phenolic content of 36.67 mg gallic acid equivalents (GAE)/g and free radical scavenging activities against HO• and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS•+) of 1688.85 and 882.88 µmol Trolox equivalents (TE)/g, which were significantly higher than those of the water extract at 24.12 mg GAE/g and 583.12 and 210.36 µmol TE/g. The free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) of cinnamon ethanol extract was lower than that of the water extract. The present study provides new evidence that cinnamon reduces the risk of SARS-CoV-2 infection and COVID-19 development.

Oxypalmatine regulates proliferation and apoptosis of breast cancer cells by inhibiting PI3K/AKT signaling and its efficacy against breast cancer organoids.

BACKGROUND: Breast cancer (BC) is known as the most common cancer in women. Discovering novel and effective drugs is a priority for the treatment of BC. Oxypalmatine (OPT) is a natural protoberberine-type alkaloid isolated from Phellodendron amurense Rupr. (Rutaceae) with potential anti-cancer activity. PURPOSE: This investigation aimed to elucidate the biological role and potential mechanisms of OPT in BC cells, and intended to assess the therapeutic potential of OPT in BC patient-derived organoid models. METHODS: CCK-8 and EdU assays, and flow cytometry were used to test the activity of OPT against BC cells. In addition, patient-derived organoid models were constructed to assess the therapeutic efficiency of OPT in BC. Besides, network pharmacological analysis and RNA sequencing analysis were performed to predict the underlying anti-BC mechanism of OPT. Moreover, Western blot analysis was applied to test the expression of genes modulated by OPT. RESULTS: OPT attenuated the proliferation and DNA replication, and induced apoptosis in multiple BC cells. Interestingly, OPT also exerted a cytotoxic effect on BC organoids characterized as luminal A, HER2-overexpressing, and triple-negative subtypes, indicating that OPT was a potential broad-spectrum anticancer drug. Network pharmacological analysis suggested that OPT might affect signals contributing to BC progression, including PI3K/AKT, MAPK, and VEGFA-VEGFR2 signaling pathways. Moreover, bioinformatics analysis of data from our RNA sequencing suggested that PI3K/AKT was a downstream pathway of OPT in BC. Finally, OPT was shown to inactivate PI3K/AKT signaling pathway in BC cells by Western blot analysis. CONCLUSIONS: Collectively, our study demonstrated that OPT suppressed proliferation and induced apoptosis through mitigating the PI3K/AKT signaling pathway in BC cells. Moreover, our work first adopted BC organoid models to confirm OPT as an effective and promising drug, laying a foundation for the potential use of OPT in BC treatment.

Effects of Coenzyme Q10 Supplementation on Lipid Profiles in Adults: A Meta-analysis of Randomized Controlled Trials.

CONTEXT: Previous meta-analyses have suggested that the effects of coenzyme Q10 (CoQ10) on lipid profiles remain debatable. Additionally, no meta-analysis has explored the optimal intake of CoQ10 for attenuating lipid profiles in adults. OBJECTIVE: This study conducted a meta-analysis to determine the effects of CoQ10 on lipid profiles and assess their dose-response relationships in adults. METHODS: Databases (Web of Science, PubMed/Medline, Embase, and the Cochrane Library) were systematically searched until August 10, 2022. The random effects model was used to calculate the mean differences (MDs) and 95% CI for changes in circulating lipid profiles. The novel single-stage restricted cubic spline regression model was applied to explore nonlinear dose-response relationships. RESULTS: Fifty randomized controlled trials with a total of 2794 participants were included in the qualitative synthesis. The pooled analysis revealed that CoQ10 supplementation significantly reduced total cholesterol (TC) (MD -5.53 mg/dL; 95% CI -8.40, -2.66; I2 = 70%), low-density lipoprotein cholesterol (LDL-C) (MD -3.03 mg/dL; 95% CI -5.25, -0.81; I2 = 54%), and triglycerides (TGs) (MD -9.06 mg/dL; 95% CI -14.04, -4.08; I2 = 65%) and increased high-density lipoprotein cholesterol (HDL-C) (MD 0.83 mg/dL; 95% CI 0.01, 1.65; I2 = 82%). The dose-response analysis showed an inverse J-shaped nonlinear pattern between CoQ10 supplementation and TC in which 400-500 mg/day CoQ10 largely reduced TC (χ2 = 48.54, P < .01). CONCLUSION: CoQ10 supplementation decreased the TC, LDL-C, and TG levels, and increased HDL-C levels in adults, and the dosage of 400 to 500 mg/day achieved the greatest effect on TC.

Dose-Response Effect of Coenzyme Q10 Supplementation on Blood Pressure among Patients with Cardiometabolic Disorders: A Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-Assessed Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Previous studies have shown beneficial effects of coenzyme Q10 (CoQ10) supplementation on blood pressure (BP). However, the optimal intake of CoQ10 for BP regulation in patients with cardiometabolic disorders is unknown, and its effect on circulating CoQ10 is also unclear. We aimed to assess the dose-response relation between CoQ10 and BP, and quantify the effect of CoQ10 supplementation on the concentration of circulating CoQ10 by synthesizing available evidence from randomized controlled trials (RCTs). A comprehensive literature search was performed in 3 databases (PubMed/MEDLINE, Embase, and Cochrane Library) to 21 March, 2022. A novel 1-stage restricted cubic spline regression model was used to evaluate the nonlinear dose-response relation between CoQ10 and BP. Twenty-six studies comprising 1831 subjects were included in our meta-analysis. CoQ10 supplementation significantly reduced systolic blood pressure (SBP) (-4.77 mmHg, 95% CI: -6.57, -2.97) in patients with cardiometabolic diseases; this reduction was accompanied by a 1.62 (95% CI: 1.26, 1.97) µg/mL elevation of circulating CoQ10 compared with the control group. Subgroup analyses revealed that the effects of reducing SBP were more pronounced in patients with diabetes and dyslipidemia and in studies with longer durations (>12 wk). Importantly, a U-shaped dose-response relation was observed between CoQ10 supplementation and SBP level, with an approximate dose of 100-200 mg/d largely reducing SBP (χ2 = 10.84, Pnonlinearity = 0.004). The quality of evidence was rated as moderate, low, and very low for SBP, diastolic blood pressure (DBP), and circulating CoQ10 according to the Grading of Recommendations, Assessment, Development, and Evaluation approach (GRADE), respectively. The current finding demonstrated that the clinically beneficial effects of CoQ10 supplementation may be attributed to the reduction in SBP, and 100-200 mg/d of CoQ10 supplementation may achieve the greatest benefit on SBP in patients with cardiometabolic diseases. This study was registered on PROSPERO as CRD42021252933.

Soluble Free, Soluble Conjugated, and Insoluble Bound Phenolics in Tomato Seeds and Their Radical Scavenging and Antiproliferative Activities.

The soluble free, soluble conjugated, and insoluble bound phenolic compounds in tomato seeds were extracted and analyzed using ultra-high-performance liquid chromatography-high-resolution mass spectrometry. Total phenolic content (TPC) and free radical scavenging activities along with the antiproliferative effects against the human colorectal cancer cell line (HCT-116) were also examined for the soluble free, soluble conjugated, and insoluble bound phenolic fractions. 13, 7, and 10 compounds were tentatively identified in the soluble free, soluble conjugated, and insoluble bound phenolic fractions, respectively, including indole-3-acetic acid derivatives, flavonoids, phenolic acid, and tyramine-derived hydroxycinnamic acid amines. The insoluble bound phenolic fraction was observed to have a greater TPC value and stronger free radical scavenging activities against ABTS•+, DPPH•, and peroxyl radicals and a stronger inhibitory effect against HCT-116 cells compared with the soluble free and the soluble conjugated fractions. Soluble free and insoluble bound fractions significantly inhibited the proliferation of the HCT-116 cell line, and no antiproliferative effects were observed with the soluble conjugated fraction under the experimental conditions. The results may provide a foundation for future application of tomato seeds as nutraceuticals in dietary supplements and functional foods.

Fire needle for recurrent aphthous stomatitis: A protocol for systematic review and network meta-analysis.

BACKGROUND: Recurrent aphthous stomatitis (RAS), are common inflammatory lesions of the oral mucous, usually round or ovoid, circumscribed by erythematous haloes with a yellow-grey floor and mostly painful. The purpose of this study was to evaluate the efficacy and safety of fire needle in the treatment of RAS. METHODS: PubMed, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chinese VIP Information, Wanfang Database, and Chinese Biomedical Literature Database were searched by 2 reviewers from the inception until December 2021. The original study that randomized control trials of fire needle for RAS will be selected and is not limited by country or language. In addition, researches in progress, the reference lists and the citation lists of identified publications will be retrieved similarly. Study selection, data extraction, and assessment of the quality will be performed independently by 2 reviewers who have been trained prior to data extraction. A meta-analysis will be conducted if the quantity and quality of the original studies included are satisfactory; otherwise, a descriptive analysis will be conducted. Review Manager V5.4 software will be using for data synthesis and assessment of the risk of bias according to Cochrane Handbook. RESULTS: This study will provide a comprehensive review of current evidence for the treatment of fire needle on RAS. CONCLUSION: The conclusion of this study will provide a judging basis that whether the treatment of RAS with fire needle is effective. INPLASY REGISTRATION NUMBER: INPLASY2021120118.

Comparison of Phytochemical Profiles of Wild and Cultivated American Ginseng Using Metabolomics by Ultra-High Performance Liquid Chromatography-High-Resolution Mass Spectrometry.

American ginseng (Panax quinquefolius L.) has been recognized as a valuable herb medicine, and ginsenosides are the most important components responsible for the health-beneficial effects. This study investigated the secondary metabolites responsible for the differentiation of wild and cultivated American ginsengs with ultrahigh-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS)-based metabolomic approach. An in-house ginsenoside library was developed to facilitate data processing and metabolite identification. Data visualization methods, such as heatmaps and volcano plots, were utilized to extract discriminated ion features. The results suggested that the ginsenoside profiles of wild and cultivated ginsengs were significantly different. The octillol (OT)-type ginsenosides were present in greater abundance and diversity in wild American ginsengs; however, a wider distribution of the protopanaxadiol (PPD)-and oleanolic acid (OA)-type ginsenosides were found in cultivated American ginseng. Based on the tentative identification and semi-quantification, the amounts of five ginsenosides (i.e., notoginsenoside H, glucoginsenoside Rf, notoginsenoside R1, pseudoginsenoside RT2, and ginsenoside Rc) were 2.3-54.5 fold greater in wild ginseng in comparison to those in their cultivated counterparts, and the content of six ginsenosides (chicusetsusaponin IVa, malonylginsenoside Rd, pseudoginsenoside Rc1, malonylfloralginsenoside Rd6, Ginsenoside Rd, and malonylginsenoside Rb1) was 2.6-14.4 fold greater in cultivated ginseng compared to wild ginseng. The results suggested that the in-house metabolite library can significantly reduce the complexity of the data processing for ginseng samples, and UHPLC-HRMS is effective and robust for identifying characteristic components (marker compounds) for distinguishing wild and cultivated American ginseng.

Sesamin Protects against and Ameliorates Rat Intestinal Ischemia/Reperfusion Injury with Involvement of Activating Nrf2/HO-1/NQO1 Signaling Pathway.

Intestinal ischemia-reperfusion (I/R) may induce cell/tissue injuries, leading to multiple organ failure. Based on our preexperiments, we proposed that sesamin could protect against and ameliorate intestinal I/R injuries and related disorders with involvement of activating Nrf2 signaling pathway. This proposal was evaluated using SD intestinal I/R injury rats in vivo and hypoxia/reoxygenation- (H/R-) injured rat small intestinal crypt epithelial cell line (IEC-6 cells) in vitro. Sesamin significantly alleviated I/R-induced intestinal histopathological injuries and significantly reduced serum biochemical indicators ALT and AST, alleviating I/R-induced intestinal injury in rats. Sesamin also significantly reversed I/R-increased TNF-α, IL-6, IL-1ß, and MPO activity in serum and MDA in tissues and I/R-decreased GSH in tissues and SOD in both tissues and IEC-6 cells, indicating its anti-inflammatory and antioxidative stress effects. Further, sesamin significantly decreased TUNEL-positive cells, downregulated the increased Bax and caspase-3 protein expression, upregulated the decreased protein expression of Bcl-2 in I/R-injured intestinal tissues, and significantly reversed H/R-reduced IEC-6 cell viability as well as reduced the number of apoptotic cells among H/R-injured IEC-6 cell, showing antiapoptotic effects. Activation of Nrf2 is known to ameliorate tissue/cell injuries. Consistent with sesamin-induced ameliorations of both intestinal I/R injuries and H/R injuries, transfection of Nrf2 cDNA significantly upregulated the expression of Nrf2, HO-1, and NQO1, respectively. On the contrary, either Nrf2 inhibitor (ML385) or Nrf2 siRNA transfection significantly decreased the expression of these proteins. Our results suggest that activation of the Nrf2/HO-1/NQO1 signaling pathway is involved in sesamin-induced anti-inflammatory, antioxidative, and antiapoptotic effects in protection against and amelioration of intestinal I/R injuries.

Rg3 promotes the SUMOylation of SERCA2a and corrects cardiac dysfunction in heart failure.

SUMOylation of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) has been shown to play a critical role in the abnormal Ca2+ cycle of heart failure. Ginsenoside Rg3 (Rg3), the main active constituent of Panax ginseng, exerts a wide range of pharmacological effects in cardiovascular diseases. However, the effect of Rg3 on abnormal Ca2+ homeostasis in heart failure has not been reported. In this study, we showed a novel role of Rg3 in the abnormal Ca2+ cycle in cardiomyocytes of mice with heart failure. Among mice undergoing transverse aortic constriction, animals that received Rg3 showed improvements in cardiac function and Ca2+ homeostasis, accompanied by increases in the SUMOylation level and SERCA2a activity. In an isoproterenol (ISO)-induced cell hypertrophy model, Rg3 reduced the ISO-induced Ca2+ overload in HL-1 cells. Gene knockout of SUMO1 in mice inhibited the cardioprotective effect of Rg3, and SUMO1 knockout mice that received Rg3 did not exhibit improved Ca2+ homeostasis in cardiomyocytes. Additionally, mutation of the SUMOylation sites of SERCA2a blocked the positive effect of Rg3 on the ISO-induced abnormal Ca2+ cycle in HL-1 cells, and was accompanied by an abnormal endoplasmic reticulum stress response and generation of ROS. Our data demonstrated that Rg3 has a positive effect on the abnormal Ca2+ cycle in the cardiomyocytes of mice with heart failure. SUMO1 is an important factor that mediates the protective effect of Rg3. Our findings suggest that drug intervention by regulating the SUMOylation of SERCA2a can provide a novel therapeutic strategy for the treatment of heart failure.

Ginsenosides for cardiovascular diseases; update on pre-clinical and clinical evidence, pharmacological effects and the mechanisms of action.

Cardiovascular disease (CVD) remains the major cause of death worldwide, accounting for almost 31% of the global mortality annually. Several preclinical studies have indicated that ginseng and the major bioactive ingredient (ginsenosides) can modulate several CVDs through diverse mechanisms. However, there is paucity in the translation of such experiments into clinical arena for cardiovascular ailments due to lack of conclusive specific pathways through which these activities are initiated and lack of larger, long-term well-structured clinical trials. Therefore, this review elaborates on current pharmacological effects of ginseng and ginsenosides in the cardiovascular system and provides some insights into the safety, toxicity, and synergistic effects in human trials. The review concludes that before ginseng, ginsenosides and their preparations could be utilized in the clinical treatment of CVDs, there should be more preclinical studies in larger animals (like the guinea pig, rabbit, dog, and monkey) to find the specific dosages, address the toxicity, safety and synergistic effects with other conventional drugs. This could lead to the initiation of large-scale, long-term well-structured randomized, and placebo-controlled clinical trials to test whether treatment is effective for a longer period and test the efficacy against other conventional therapies.

Pharmacological Activity and Mechanism of Tanshinone IIA in Related Diseases.

Salvia miltiorrhiza: (Danshen) is a significant (traditional Chinese medication) natural remedy, enhancing blood circulation and clear blood stasis. In this view, it is widely used against several heart diseases, eg, cardiomyopathy, arrhythmia, and congenital heart defects. Tanshinone IIA (tan-IIA) is the main fat-soluble component of Salvia miltiorrhiza. Modern pharmacological study shows that tan-IIA has anti-inflammatory and anti-oxidant activities. Tan-IIA induces remarkable cardioprotective effects via enhancing angiogenesis which may serve as an effective treatment against cardiovascular diseases (CVD). There is also evidence that tan-IIA has extensive immunomodulatory effects and plays a significant role in the development and function of immune cells. Tan-IIA reduces the production of inflammatory mediators and restores abnormal signaling pathways via regulating the function and activation of immune cells. It can also regulate signal transduction pathways, ie, TLR/NF-κB pathway and MAPKs/NF-κB pathway, thereby tan-IIA has an anti-inflammatory, anticoagulant, antithrombotic and neuroprotective role. It plays a protective role in the pathogenesis of cardiovascular disorders (ie, atherosclerosis, hypertension) and Alzheimer's disease. It has also been revealed that tan-IIA has an anti-tumor role by killing various tumor cells, inducing differentiation and apoptosis, and has potential activity against carcinoma progression. In the review of this fact, the tan-IIA role in different diseases and its mechanism have been summarized while its clinical applications are also explored to provide a new perspective of Salvia miltiorrhiza. An extensive study on the mechanism of action of tan-IIA is of great significance for the effective use of Chinese herbal medicine and the promotion of its status and influence on the world.

13-Methylberberine improves endothelial dysfunction by inhibiting NLRP3 inflammasome activation via autophagy induction in human umbilical vein endothelial cells.

BACKGROUND: Atherosclerosis, the underlying cause of the majority of cardiovascular diseases, is a lipid-driven, inflammatory disease of the large arteries. Atherosclerotic cardiovascular disease (ASCVD) threatens human lives due to high morbidity and mortality. Many studies have demonstrated that atherosclerosis is accelerated via activation of the NLRP3 inflammasome. The NLRP3 inflammasome plays a critical role in the development of vascular inflammation and atherosclerosis. In atherosclerotic plaques, excessive generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome. 13-Methylberberine (13-MB) is a newly synthesized compound used in traditional Chinese medicine that has outstanding antibacterial, antitumor, and antiobesity activities, especially anti-inflammatory activity. However, the role of 13-MB in atherosclerosis needs to be explored. METHODS: CCK-8 assays and flow cytometry were conducted to determine the cell viability and apoptotic profiles of human umbilical vein endothelial cells (HUVECs) treated with 13-MB. Carboxy-DCFH-DA and JC-10 assays were used to measure ROS and determine mitochondrial membrane potential. Western blot analysis was performed to investigate proteins that are associated with the NLRP3 inflammasome and autophagy. ELISA was used to detect and quantify inflammatory cytokines related to the NLRP3 inflammasome. Transfection and confocal microscopy were conducted to observe autophagy. RESULTS: Pretreatment with 13-MB markedly reduced cytotoxicity and apoptosis, as well as intracellular ROS production, in H2O2-induced HUVECs. Moreover, 13-MB showed a protective effect in maintaining mitochondrial membrane potential. 13-MB also suppressed NLRP3 inflammasome activation and promoted autophagy induction in HUVECs. CONCLUSION: 13-MB exerts cytoprotective effects in an H2O2-induced cell injury model by inhibiting NLRP3 inflammasome activation via autophagy induction in HUVECs. These anti-inflammatory and autophagy induction activities may provide valuable evidence for further investigating the potential role of 13-MB in atherosclerosis.

Yangonin protects against non-alcoholic fatty liver disease through farnesoid X receptor.

BACKGROUD: Non-alcoholic fatty liver disease (NAFLD) is currently evolving as the most common liver disease worldwide. Dyslipidemia, pathoglycemia and insulin resistance are the major risk factors for the development of NAFLD. To date, no effective drug therapies for this condition have been approved. PURPOSE: The present study was to investigate the protective effects of yangonin, a kavalactone isolated from Kava, against NAFLD and further elucidate the mechanisms in vivo and in vitro. STUDY DESIGN: A high-fat diet (HFD) induced mouse NAFLD model was used with or without yangonin treatment. METHODS: The body weight, relative liver weight and serum biochemical indicators were measured. H&E and Oil Red O staining were used to identify the amelioration of the liver histopathological changes. Serum and hepatic triglyceride, free fatty acids and total cholesterol were analyzed. siRNA, quantitative real-time PCR and Western blot assay were used to clarify the mechanisms underlying yangonin protection. RESULTS: Yangonin had obvious protective effects against NAFLD via farnesoid X receptor (FXR) activation. Through FXR activation, yangonin attenuated lipid accumulation in the liver via inhibition of hepatic lipogenesis-related protein including sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthetase (FAS), acetyl-CoA carboxylase 1 (ACC1) and stearoyl-CoA desaturase 1 (SCD1). Besides, yangonin promoted lipid metabolism through an induction in genes required for lipoprotein lipolysis and fatty acid ß-oxidation. Furthermore, yangonin modulated blood glucose homeostasis through regulation of gluconeogenesis-related gene phosphoenol pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), and glycogen synthesis-related gene glycogen synthase kinase 3ß (GSK3ß) and pyruvate dehydrogenase (PDase). Also, yangonin increased insulin sensitivity through upregulating phosphorylation of insulin responsive substrate 1, 2 (IRS-1 and IRS-2). Then, in vivo and in vitro evidence further demonstrated the involvement of FXR activation in yangonin hepatoprotection. CONCLUSIONS: Yangonin protects against NAFLD due to its activation of FXR signalling to inhibit hepatic lipogenesis and gluconeogenesis, and to promote lipid metabolism and glycogen synthesis, as well as insulin sensitivity.

YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect.

Polo-like kinase 4 (PLK4) is indispensable for precise control of centriole duplication. Abnormal expression of PLK4 has been reported in many human cancers, and inhibition of PLK4 activity results in their mitotic arrest and apoptosis. Therefore, PLK4 may be a valid therapeutic target for antitumor therapy. However, clinically available small-molecule inhibitors targeting PLK4 are deficient and their underlying mechanisms still remain not fully clear. Herein, the effects of YLT-11 on breast cancer cells and the associated mechanism were investigated. In vitro, YLT-11 exhibited significant antiproliferation activities against breast cancer cells. Meanwhile, cells treated with YLT-11 exhibited effects consistent with PLK4 kinase inhibition, including dysregulated centriole duplication and mitotic defects, sequentially making tumor cells more vulnerable to chemotherapy. Furthermore, YLT-11 could strongly regulate downstream factors of PLK4, which was involved in cell cycle regulation, ultimately inducing apoptosis of breast cancer cell. In vivo, oral administration of YLT-11 significantly suppressed the tumor growth in human breast cancer xenograft models at doses that are well tolerated. In summary, the preclinical data show that YLT-11 could be a promising candidate drug for breast tumor therapy.