Phytomedicine最新文献

Objective: This study was to investigate the mechanism of Ling-Gui-Zhu-Gan decoction (LGZGD) in regulating lipid metabolism and thus inhibiting ferroptosis.

Methods: UPLC for the determination of the main chemical composition of LGZGD. A HF-induced rat model of metabolic cardiomyopathy was established. Echocardiography was used to detect cardiac function. Serum lipid levels, myocardial injury markers, and lipid peroxidation levels were detected. Pathological changes were detected. Lipid deposition was assessed by oil red O, and the mitochondrial ultrastructure was observed by electron microscopy. Mechanistically, PLIN5, CD36, ATGL, GPX4, ACSL4, FPN1, DRP1, MFF, FIS1, and OPA1 expressions were examined. After PA-induced H9c2 cells established, apoptosis, myocardial injury markers, and lipid peroxidation levels were detected and lipid deposition levels were assessed. The expressions of PLIN5, CD36, ATGL, GPX4, ACSL4 and FPN1 were detected. H9c2 cardiomyocytes with transient knockdown of PLIN5 and overexpression of PLIN5 were constructed and treated with drug administration and modeling, and the apoptosis level was detected by flow cytometry, the levels of lipid peroxidation and ROS were detected by fluorescence, and the protein and gene expressions of ACSL4 and GPX4 were detected. Results The main active components of LGZGD were liquiritin, isoliquiritin, cinnamic acid, cinnamaldehyde, glycyrrhizic acid, and atractylenolide III. LGZGD significantly improved cardiac dysfunction, lowered lipid level and lipid deposition, reduced CK, NT-proBNP and MDA levels, restored SOD levels, and improved inflammatory cell infiltration as well as collagen fiber deposition. LGZGD decreased the expression of PLIN5, CD36, ACSL4, and increased the expression of ATGL, GPX4, and FPN1. LGZGD also decreased the gene expression of DRP1, MFF, FIS1, and increased OPA1 expression. LGZGD significantly ameliorated PA-induced apoptosis, decreased lipid deposition, lowered lipid peroxidation levels and CK level, decreased PLIN5, CD36, and ACSL4 expressions, and increased ATGL, GPX4, and FPN1 expressions. LGZGD reversed cardiomyocyte injury aggravated by transient knockdown of PLIN5, decreased apoptosis levels, lipid peroxidation levels, ROS levels, and ACSL4 expressions, and increased GPX4 expression. LGZGD enhanced cardiomyocyte protection after overexpression of PLIN5, reduced apoptosis levels, lipid peroxidation level and ROS level, decreased ACSL4 expression, and increased GPX4 expression.

Conclusion: PLIN5 interferes with lipid peroxidation, regulates mitochondrial function, and inhibits HF-induced ferroptosis in cardiomyocytes. LGZGD ameliorates impairment of cardiac structural function in model rats through PLIN5-mediated ferroptosis pathway, and has the effect of preventing metabolic cardiomyopathy.

Background: Autophagy has been recently emerged as a prominent factor in the pathogenesis of ischemic stroke (IS) and is increasingly being considered as a potential therapeutic target for IS. Gnetum parvifolium has been identified as a potential therapeutic agent for inflammatory diseases such as rheumatism and traumatic injuries. However, the pharmacological effects of Gnetupindin A (GA), a stilbene compound isolated from Gnetum parvifolium, have not been fully elucidated until now.

Objective: Here we identified the therapeutic potential of GA for IS, deeply exploring the possible mechanisms related to its regulation of autophagy.

Methods: The mouse model of middle cerebral artery occlusion-reperfusion (MCAO/R) and the oxygen-glucose deprivation reperfusion (OGD/R)-exposed cells served as models to study the protection of GA against IS. The adeno-associated virus (AAV) encoding shAtg5, in conjunction with autophagy inhibitor 3-Methyladenine (3-MA) were utilized to explore the role of GA in regulating autophagy following IS. Molecular docking, CETSA, and DARTS were used to identify the specific therapeutic target of GA. PI3K inhibitor LY294002 was employed to test the participation of PI3K in GA-mediated autophagy and neuroprotective effects following IS.

Results: Our findings revealed that treatment with GA significantly alleviated the brain infract volume, edema, improved neurological deficits and attenuated apoptosis. Mechanistically, we found that GA promoted autophagic flow both in vivo and in vitro after IS. Notably, neural-targeted knockdown of Atg5 abolished the neuroprotective effects mediated by GA. Inhibition of autophagy using 3-MA blocked the attenuation on apoptosis induced by GA. Moreover, molecular docking, CETSA, and DARTS analysis demonstrated that GA specifically targeted PI3K and further inhibited the activation of PI3K/AKT/mTOR signaling pathway. LY294002, which inhibits PI3K, reversed GA-induced autophagy and neuroprotective effects on OGD/R-treated cells.

Conclusion: We demonstrated, for the first time, that GA protects against IS through promoting the PI3K/AKT/mTOR-dependent autophagy pathway. Our findings provide a novel mechanistic insight into the anti-IS effect of GA in regulating autophagy.

Background: Liver fibrosis is a dynamic process marked by the accumulation of extracellular matrix due to hepatic stellate cells (HSCs) activation. Ginsenoside compound K (CK), a rare derivative of its parent ginsenosides, is known to significantly ameliorate metabolic disorders.

Purpose: The aim of this study was to elucidate the protective effects of CK against liver fibrosis with a focus on metabolic regulation.

Methods: We established liver fibrosis models in mice using carbon tetrachloride (CCl₄) challenge, bile duct ligation, or a methionine-choline deficient diet, with continuous oral administration of CK at specified doses and intervals. Simultaneously, we examined the impact of CK on metabolic regulation in cultured HSCs and investigated the associated mechanisms.

Results: CK was found to alleviate liver injury and curb fibrotic responses in mouse models, as well as decrease elevated levels of liver enzyme. Metabolomic analysis in vitro highlighted the crucial roles of pyruvate and glutamine metabolism in metabolic remodeling. Immunohistochemical staining indicated significantly elevated expressions of lactate dehydrogenase A (LDHA) (p = 0.014) and glutaminase 1 (GLS1) (p = 0.024) in liver cirrhosis patients. Comparable alterations were noted in the liver of model mice and in cultured HSCs. Molecular docking and bio-layer interferometry demonstrated that CK interacts with and inhibits the activities of LDHA and GLS1. As expected, CK attenuated glycolysis and glutaminolysis, reducing HSC growth dependently on lactate and α-ketoglutarate (α-KG). Upon HSC activation, metabolism is reprogrammed with Myc as a key regulator, transcriptionally controlling LDHA, GLS1, and glutamine transporters SLC1A5 and SLC38A5. CK inhibited Myc induction, integrating glycolysis and glutaminolysis regulation to counteract the fibrotic response.

Conclusion: CK inhibited LDHA and GLS1 activities, thereby inhibiting hepatic fibrosis. These findings offer new insights into the role of ginsenosides in liver protection, especially regarding metabolic disorders.

Background: Bone marrow mesenchymal stem cells (BMSCs) derived exosomes have demonstrated potential therapeutic efficacy on myocardial ischemia/reperfusion injury (MI/RI). This study has explored the underlying mechanisms of Danshen decoction (DSD) pretreated BMSCs-exosomes to treat MI/RI in vivo and in vitro.

Methods: Extracellular vesicles extracted from BMSCs were identified, miRNA sequencing was performed to screen the effects of DSD, and verified to target TXNIP in vivo. After MI/RI modeling, rats were treated with BMSCs-exosomes pretreated with DSD or miRNA inhibitor. BMSCs-exosomes, DSD-pretreated BMSCs-exosomes, and miRNA inhibitor/anti-miRNA-pretreated BMSCs-exosomes were used to treat H9c2 cells or MI/RI rats. CCK-8, Tunnel staining, and flow cytometry were performed to measure cell viability. LDH, CK, CK-MB were detected to evaluate cell injury. MDA, SOD, and ROS were used to confirm oxidative stress. Furthermore, IL-1β, IL-18, cleaved-caspase-1, pro-caspase-1, NLRP3, TXNIP, and GSDMD were quantified for the TXNIP/NLRP3/Caspase-1 signaling activation. In addition, echocardiography was used to observe the heart function, and H&E stain was performed to detect pathological injury.

Results: Following DSD pretreatment, there was a marked elevation in the expression levels of miR-93-5p, miR-16-5p, and miR-15b-5p, with miR-93-5p exhibiting the highest baseMean value. The administration of a miR-93-5p inhibitor yielded effects counteractive to those observed with DSD treatment, leading to reduced cell proliferation, heightened oxidative stress (as indicated by increased levels of SOD and ROS, alongside a decrease in MDA), and enhanced cell apoptosis. Furthermore, DSD effectively mitigated the miR-93-5p-induced upregulation of key inflammatory and apoptotic markers, including IL-1β, IL-18, caspase-1, NLRP3, TXNIP, and GSDMD. Notably, exosomes derived from DSD-pretreated BMSCs demonstrated a capacity to alleviate cardiac damage.

Conclusion: DSD may target miR-93-5p within BMSC-derived exosomes to confer protection against cardiac damage by inhibiting the activation of the TXNIP/NLRP3/Caspase-1 signaling pathway, thereby mitigating cardiomyocyte pyroptosis. This study provides a theoretical foundation for the application of DSD in the treatment of MI/RI.

Background: Optimizing medication to improve exercise tolerance in patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI) is limited. Yangxinshi tablets, an herbal-based oral medicine, relieve symptoms of angina might be that they can improve energy metabolism of the ischemic myocardium. We conducted a randomized trial to assess the efficacy and safety of Yangxinshi vs. trimetazidine in improving exercise tolerance in patients with CHD after PCI.

Methods: This prospective, randomized, double-blind, double-dummy, multicenter, non-inferiority study enrolled patients aged 18-75 years with CHD who underwent their first PCI within 2 months of diagnosis. Patients were randomized to Yangxinshi plus trimetazidine-placebo or trimetazidine plus Yangxinshi-placebo for 24 weeks. The primary endpoint was the change in metabolic equivalents (METs) assessed by cardiopulmonary exercise test (CPET) between 0 and 24 weeks. Secondary endpoints were comprehensive variables of the CPET, health status and adverse events. This study has been registered at ClinicalTrials. gov (NCT03809273).

Results: Between August 1, 2019, and March 31, 2022, a total of 681 patients were randomized to Yangxinshi (n = 341) or trimetazidine (n = 340). After 24 weeks, the exercise tolerance of patients increased by 0.77±1.25 METs in the Yangxinshi group and 0.76±1.00 METs in the trimetazidine group (difference, 0.01; 95 % confidence interval [CI], -0.17 to 0.19), meeting the predefined non-inferiority threshold. Better outcomes were observed in the Yangxinshi group compared with the trimetazidine group for patient-reported depression (PHQ-9; -1.88±3.32 vs. -0.93±3.68; p < 0.001) and anxiety (GAD-7; -1.70±3.26 vs. -0.39±3.29; p < 0.001). Adverse events were similar in both groups.

Conclusions: In patients with CHD after PCI, Yangxinshi was non-inferior to trimetazidine in improving exercise tolerance during the 24-week treatment period. Notably, patients in the Yangxinshi group showed a better mental health profile compared with trimetazidine recipients.

Background: Although our previous work confirmed 20(R)-ginsenoside Rg3 (R-Rg3), which is an active ingredient in the Panax Ginseng C.A. Meyer, to have good anti-diabetic activity, its beneficial effect on diabetic retinal injury was found to be limited.

Purpose: This study aims to investigate the protective effects of R-Rg3 on diabetes-induced retinal injury and the associated molecular mechanisms of action.

Methods: Diabetic retinal injury was induced in mice using a combination of a high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). R-Rg3 (10 and 20 mg/kg) was subsequently administered for 6 weeks. The human retinal endothelial cells (HRECs) were subjected to high glucose (HG)-induced injury for the in vitro analysis and treated with R-Rg3 (4, 8, 16 μM), antioxidant N-Acetylcysteine (NAC, 1 mM) and Nrf2 inhibitor ML385 (5 μM). The mice retinas then underwent functional and histopathological analysis. Expression levels of proteins related to the Nrf2/HO-1 axis, tight junction proteins, endoplasmic reticulum (ER) stress and the apoptosis in retinal tissue and HRECs were determined by western blot. Expressions of ZO-1 and Nrf2 in the retina and HRECs were assessed by immunofluorescence. Additional evaluations included measuring body weights, fasting blood glucose (FBG), lipid levels and oxidative markers.

Results: The results showed 6 weeks of R-Rg3 treatment significantly restored the functional changes and redox system imbalance that was induced by HFD/STZ in mice. R-Rg3 was also found to significantly reduce retinal barrier damage and thickness changes resulting from hyperglycaemia exposure. At the same time, R-Rg3 also protected HRECs from HG-induced damage. R-Rg3 could also activate Nrf2/HO-1 axis and inhibit endoplasmic reticulum stress as a means of alleviating retinal endothelial cells apoptosis. The molecular docking results also demonstrated that R-Rg3 had a good binding ability with Nrf2.

Conclusion: Our study suggested Nrf2/HO-1 axis might be crucial for the ability of R-Rg3 to prevent diabetic retinal injury.