Background Pathological ventricular remodeling following myocardial infarction (MI) severely impacts long term prognosis of patients, yet effective interventions to halt its progression remain limited. Hongqi Shenmai Yin (HSY) has been used in clinical practice for many years, can improve cardiac function in MI patients. However, its underlying therapeutic mechanisms remain unclear. Purpose This study aimed to determine whether HSY alleviates adverse cardiac remodeling following MI by inhibiting stimulator of interferon genes (STING)-dependent PANoptosis. Methods The MI model was established by ligating the left anterior descending coronary artery (LAD) in rats. Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) identified bioactive compounds in HSY. Cardiac function, hypertrophy, and fibrosis were assessed via echocardiography and histological staining. ELISA measured cardiac injury biomarkers, inflammatory cytokines, and oxidative stress markers. Transcriptomic analyses identified potential HSY targets in post-MI remodeling. Molecular docking and surface plasmon resonance (SPR) assessed binding interactions between HSY’s key active components and STING. Mechanistic rescue experiments determined whether HSY regulates PANoptosis via STING inhibition. Functional studies were further conducted by transfecting H9c2 cardiomyocytes with lentivirus vectors encoding STING-overexpression. Results HSY attenuated inflammation, oxidative stress, and adverse remodeling while improving cardiac function post-MI. UPLC-MS identified 107 major HSY constituents. Transcriptomics linked HSY’s cardioprotective effects to STING signaling and PANoptosis modulation. Molecular docking and SPR confirmed strong binding affinity between HSY’s primary active compounds and STING. Both in vivo and in vitro experiments revealed that HSY suppressed STING-induced ZBP1-PANoptosome assembly, downregulating PANoptosis-associated proteins (p-MLKL, p-RIPK1, p-RIPK3, GSDMD-NT, GSDME-NT, Cle-CASP1, Cle-CASP3, Cle-CASP8) in post-MI remodeling. Conclusion HSY attenuated adverse cardiac remodeling following MI by inhibiting STING-mediated ZBP1-PANoptosome assembly and subsequent PANoptosis. These findings supported HSY’s clinical potential in treating post-MI cardiac remodeling.

BACKGROUND:Post-myocardial infarction heart failure (post-MI HF) is driven by adverse ventricular remodeling and mitochondrial dysfunction. Cardiolipin is essential for mitochondrial integrity, but its upstream regulation in failing myocardium remains unclear. Whether Hongqi Shenmai Decoction (HQSMD) preserves cardiolipin homeostasis through epidermal growth factor receptor (EGFR)/Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling has not been defined. PURPOSE:To determine whether HQSMD alleviates post-MI HF by preserving cardiolipin-related metabolic homeostasis through modulation of the EGFR/JAK2-STAT3 pathway. STUDY DESIGN:An in vivo post-MI HF mouse model and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R)-injured AC16 cardiomyocyte model were integrated with chemical profiling, multi-omics analysis, target validation, and epidermal growth factor (EGF)-mediated rescue experiments. METHODS:Cardiac function, infarct injury, fibrosis, oxidative stress, mitochondrial ultrastructure, and mitochondrial function were assessed. Ultra-performance liquid chromatography-mass spectrometry, transcriptomics, untargeted metabolomics, molecular docking, surface plasmon resonance, western blotting, immunofluorescence, and cardiolipin-related functional assays were performed. RESULTS:HQSMD improved cardiac function and attenuated infarction, remodeling, oxidative stress, and mitochondrial injury in post-MI HF mice. Multi-omics analyses implicated EGFR/JAK-STAT signaling and cardiolipin-related glycerophospholipid disturbances. HQSMD suppressed MI- or OGD/R-induced phosphorylation of EGFR, JAK2, and STAT3 Tyr705 while preserving mitochondrial STAT3/Ser727 signaling. In cardiomyocytes, HQSMD reduced apoptosis and restored mitochondrial dynamics, biogenesis, redox balance, membrane potential, mPTP function, cardiolipin-associated fluorescence, and cardiolipin-related enzyme expression. EGF partially reversed these effects. CONCLUSION:HQSMD protects against post-MI HF mainly by attenuating pathological EGFR/JAK2-dependent STAT3 Tyr705 activation, thereby preserving cardiolipin-related metabolic homeostasis and mitochondrial integrity.

ETHNOPHARMACOLOGICAL RELEVANCE:Myocardial ischemia-reperfusion (I/R) injury stands as a significant contributor to cardiovascular disease. Shengmai-Yin (SMY), a traditional Chinese medicine, is widely used in myocardial infarct treatment. However, the specific mechanism of SMY in treating myocardial I/R injury is currently limited. AIM OF STUDY:The study aimed to investigate the therapeutic efficacy of SMY in addressing myocardial I/R injury and elucidate its specific mechanisms. MATERIALS AND METHODS:The active components of SMY were quantified using Ultra-high performance liquid chromatography-MS/MS (UPLC-MS/MS). Sprague-Dawley (SD) rats were treated with SMY post-I/R model establishment. Cardiac injury was assessed by heart weight to body weight ratio. Left ventricular function and infarct volume were evaluated using ultrasound cardiography and TTC staining. Tissue lesions were examined via hematoxylin-eosin (HE) and Sirius Red staining. Co-Immunoprecipitation (Co-IP) technology explored absent in melanoma 2 (AIM2) and K27 Ubiquitination Modification (K27-Ub) interactions. Immunofluorescence staining detected Apoptosis-associated Speck-like Protein containing a CARD (ASC) and AIM2 co-localization. Adeno-associated Virus (AAV) was used to upregulate AIM2 levels, while Shikonin was used to downregulate AIM2, to explore its roles in SMY's therapeutic effects on I/R injury. RESULTS:SMY can reduce infarct size and enhance cardiac function. Furthermore, SMY can inhibit tissue fibrosis. Fibrosis markers and proinflammatory factors were reduced after SMY treatment. Serum levels of Lactate Dehydrogenase (LDH) and Creatine Kinase -MB (CK-MB) were also decreased. Mechanistically, SMY inhibits the activation of the AIM2 inflammasome by downregulating the K27 ubiquitination of AIM2. Overexpression of AIM2 reversed the anti-I/R effect of SMY, suggesting that AIM2 plays a crucial role in I/R injury. The AIM2 inhibitor counteracts the therapeutic effect of SMY. CONCLUSION:SMY inhibits the K27 ubiquitination modification of AIM2 and inhibits the activation of AIM2 inflammasomes after myocardial I/R injury.

ETHNOPHARMACOLOGICAL RELEVANCE:Myocardial fibrosis is one of the pathological characteristics of advanced diabetic cardiomyopathy (DCM) and serves as the strong evidence of poor prognosis. Among them, the transdifferentiation of cardiac fibroblasts (CFs) may play a crucial role in the development of myocardial fibrosis in DCM. Tinglu Yixin granule (TLYXG) has been clinically used for many years and can significantly improve cardiac function of patients with DCM. However, the effect of TLYXG on myocardial fibrosis in DCM remains unknown, and the underlying mechanisms of its efficacy have yet to be fully understood. AIM OF THE STUDY:This study aimed to investigate the impact and underlying mechanism of TLYXG on myocardial fibrosis in diabetes mice. MATERIALS AND METHODS:The bioactive compounds in TLYXG were identified using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The potential mechanism of TLYXG in treating DCM was predicted using network pharmacology combined with molecular docking and protein-protein docking. The mice model of type 2 diabetes were established by intraperitoneal injection of streptozotocin (STZ) and the high-fat diet (HFD). Indicators of pancreatic islet function, lipids, oxidative stress, and inflammatory factors were tested using kits. Cardiac function was assessed in diabetic mice using echocardiography. Histologic staining was performed to evaluate myocardial hypertrophy and fibrosis. Mechanistically, the hypothesis was tested through rescue experiments. The expression levels of transient receptor potential channel 6 (TRPC6), transforming growth factor-β1 (TGF-β1), collagen I (COL-I) and alpha-smooth muscle actin (α-SMA), along with the mRNA and phosphorylation levels of SMAD family member 3 (Smad3) and protein 38 mitogen-activated protein kinase (p38 MAPK), were assessed using quantitative RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence. Neonatal lactating mice were used to extract primary CFs for vitro experiments. Scratch and transwell assays were conducted to assess CFs migration and invasion abilities. Western blot and immunofluorescence were used to evaluate the expression levels of CFs transdifferentiation markers COL-I and α-SMA. RESULTS:A total of 168 active ingredients were detected in TLYXG based on UPLC-MS and databases. Network pharmacology indicated that TLYXG could improve DCM through inflammatory mediator regulation of TRP channels, TGF-beta signaling pathway, and MAPK signaling pathway. ELISA results showed that TLYXG could ameliorate metabolic levels, inflammation, and oxidative stress in diabetic mice. Echocardiography suggested that TLYXG improved cardiac systolic and diastolic dysfunction in diabetic mice. Histological analysis revealed that TLYXG alleviated myocardial fibrosis in diabetes mice. Additionally, molecular docking analysis indicated strong binding activity between the main active ingredients of TLYXG and TRPC6 of the TRP family. At the molecular level, TLYXG reduced the mRNA and protein expression levels of TRPC6 and TGF-β1 and inhibited the mRNA and phosphorylation levels of Smad3 and p38 MAPK. Furthermore, TLYXG inhibited CFs migration and invasion, and reduced the expression levels of the CFs transdifferentiation markers COL-I and α-SMA. CONCLUSION:TLYXG inhibited the proliferation, migration, invasion and transdifferentiation of CFs by suppressing TGF-β1/Smad3/p38 MAPK signaling through down-regulation of TRPC6, thereby ameliorating myocardial fibrosis in diabetes mice.

Background:Ischemic heart disease (IHD) places a heavy burden on individual and public health. Nevertheless, comprehensive assessments of the burden of IHD in the elderly are absent. It is imperative to update the burden of IHD in older adults and predict the trends. Methods:The absolute numbers and age-standardized rates (ASRs) of prevalence, mortality, and disability-adjusted life-years (DALYs) for IHD among people aged 60-89 years from 1990 to 2019 were analyzed based on the Global Burden of Disease Study 2019 (GBD 2019). Joinpoint regression analysis was utilized to evaluate the epidemiologic trend of IHD in the elderly from 1990 to 2019. Bayesian age-period-cohort model was used to predict the burden of IHD among the elderly from 2020 to 2034. Results:Age-standardized prevalence rate (ASPR), age-standardized incidence rate (ASIR), age-standardized DALY rate (ASDR), and age-standardized mortality rate (ASMR) of IHD in older adults have declined slightly over the past 30 years. In 2019, the ASPR, ASIR, ASDR, and ASMR among the elderly with IHD were 14,280.53 (95% UI, 12,301.34-16,610.6), 1,445.21 (1,142-1,793.58), 11,225.74 (10,342.09-11,960.64), and 675.24 (614.21-721.75) per 100,000. The burden of IHD was significantly higher in older men than in women during the study period. In terms of socio-demographic index (SDI), countries and territories with lower SDI bore a more severe burden of IHD. The burden of IHD in the elderly varied considerably across countries. Uzbekistan had the largest increase in rates of prevalence, incidence, DALY, and mortality. The projections show a downward trend in DALY and mortality rates for IHD in older adults from 2020 to 2034, but incidence and prevalence will increase. Conclusion:From 1990 to 2019, the worldwide burden of IHD among the elderly witnessed a decline. The IHD burden varied significantly across countries and territories. Policymakers should rationalize the allocation of health resources and implement effective prevention and treatment strategies to reduce the burden of IHD among the elderly in economically less developed countries and regions.

ETHNOPHARMACOLOGICAL RELEVANCE:Diabetic cardiac autonomic neuropathy (DCAN) is one of the serious complications of diabetes and greatly increased the risk of cardiovascular disease mortality. Huangqi Guizhi Wuwu Decoction (HGWD) has been proven effective for DCAN, while the underlying mechanism remains unclarified. AIM OF THE STUDY:To observe the clinical efficacy of HGWD on DCAN and elucidate its potential mechanisms with the animal model. MATERIALS AND METHODS:In this study, a total of 202 patients who met the inclusion criteria were recruited for the clinical trial and were randomly divided into two groups. Betaloc® Zok was used as the positive drug. The effect of HGWD on heart rate variability in DCAN patients was observed. To further clarify its underlying mechanism, the contents of the 7 major components of HGWD were determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The potential mechanism of HGWD in treating DCAN was predicted using network pharmacology combined with molecular docking and protein-protein docking. The diabetic rat model was induced using the high-fat diet (HFD) and streptozotocin (STZ) injection. After successful modeling, rats were pretreated with adeno-associated viral vectors containing transient receptor potential melastatin type 7 (TRPM7) recombinant plasmids (pAAV-TRPM7) for 4 weeks. RESULTS:Clinical research showed that HGWD could reduce the number of ventricular premature beats, improve heart rate variability, and correct the imbalance of cardiac autonomic nerves in DCAN patients. In vivo experiments demonstrated that HGWD reduced susceptibility to arrhythmia, ameliorated diabetes-induced myocardial fibrosis, inhibited cardiac autonomic remodeling, and promoted repair of cardiac sympathetic nerves in diabetic rats. Mechanistically, HGWD had an ameliorative effect on DCAN by up-regulating the AMPK/TrkA (adenosine 5'-monophosphate-activated protein kinase/tyrosine kinase receptor A) pathway, thereby inhibiting the TRPM7 channel. CONCLUSIONS:HGWD inhibited cardiac autonomic nervous system remodeling, reduced susceptibility to ventricular arrhythmias, and improved DCAN through the regulation of the AMPK/TrkA/TRPM7 pathway, which provided the strong support for its clinical application.

Due to the complex regulatory mechanisms of cholesterol absorption, synthesis, and metabolism in patients with hyperlipidemia, doubling the dosage of statins reduced the serum low-density lipoprotein cholesterol (LDL-C) level by only 6%. The clinical research found that gypenosides (Gyps), as a natural PCSK9 inhibitor, can further reduce lipid levels in hyperlipidemia patients on top of atorvastatin, breaking through the "6% rule of statins". Results demonstrated that Gyps significantly reduced hepatic lipid content, decreased lipid droplet (LDs) accumulation in liver tissue, alleviated the degree of hepatic steatosis, and activated the autophagy in high-fat diet (HFD)-fed golden Syrian hamsters. Gyps reduced lipid deposition in free fatty acid (FFA)-stimulated HepG2 cells and promoted clearance of LDL-C from the blood by activating lipophagy through the regulation of the AMPK/mTOR/ULK1 signaling pathway. This lipophagy activation led to the intracellular metabolism of lipids, achieving the goal of lipid reduction. Gyps-induced lipophagy effectively decreased lipid levels without hepatotoxicity.

Introduction:Perilipin 5 (PLIN5) is a key protein attached to lipid droplets that plays a critical role in cellular lipid metabolism. However, its involvement in cardiomyocyte ferroptosis has not been fully elucidated. This study explored the impact of PLIN5 on ferroptosis in H9c2 cells and a rat model of myocardial infarction (MI). Methods:H9c2 cells were treated with H2O2 and Erastin, while the rat model of MI was established by ligating the left anterior descending coronary artery. Results:We found that after MI, cardiac subcellular iron levels increased and the expression of PLIN5 decreased. Overexpression of PLIN5 reduced lipid peroxidation, enhanced ferroptosis resistance, decreased iron accumulation, and lowered TfR expression. Additionally, there was an interaction between PLIN5 and ubiquitin-specific peptidase 10 (USP10). PLIN5 increased the ubiquitination of p53. USP10 and MG-132 blocked the regulatory effect of PLIN5 on TfR expression. Overexpression of USP10 weakened the inhibitory effect of PLIN5 on ferroptosis. In vivo experiments showed that overexpression of PLIN5 significantly reduced ferroptosis in the infarcted myocardium. Discussion:Perilipin 5 may exert cardioprotective effects by regulating the USP10 and p53-TfR axis.

Background Myocardial ischemia/reperfusion (MI/R) injury is the main cause of death worldwide and poses a significant threat to cardiac health. Ginsenoside Rg1 has been shown to have inhibitory effects on inflammatory activation, oxidative stress, and cardiac injury, suggesting that Rg1 may have therapeutic effects on MI/R injury. However, the mechanism remains to be further studied. Materials and Methods Left anterior descending coronary artery ligation was performed in Sprague-Dawley rats to construct an MI/R model in vivo. Organ index, electrocardiogram, infarct size, histopathological changes, and detection of cardiac injury and inflammatory factors in the rats were used to evaluate myocarditis, macrophage polarization, and fibrosis. We also used rat bone marrow-derived macrophages (BMDMs) to further investigate the effects of Rg1 on absent in melanoma 2 (AIM2) activation and macrophage polarization in vitro. Results Administration of Rg1 exhibited dose-dependent cardioprotective effects and effectively reduced MI/R injury. Rg1 significantly attenuated myocardial inflammation and inhibited M1 macrophage polarization during MI/R injury. Furthermore, Rg1 significantly reduced cardiac fibrosis in response to MI/R injury. This anti-fibrotic effect may contribute to the preservation of cardiac structure and function following an ischemic insult. Meanwhile, Rg1 effectively inhibited the activation of the AIM2 inflammasome in vitro, highlighting its potential as a key regulator of inflammatory pathways. Conclusion Our findings elucidate the multifaceted mechanisms underlying Rg1's cardioprotective effects, including its ability to mitigate inflammation, modulate macrophage polarization, and inhibit fibrosis.

Background Nutritional deficiencies (ND) continue to threaten the lives of millions of people around the world, with children being the worst hit. Nevertheless, no systematic study of the epidemiological features of child ND has been conducted so far. Therefore, we aimed to comprehensively assess the burden of pediatric ND. Methods We analyzed data on pediatric ND between 1990 and 2019 from the Global Burden of Disease study (GBD) 2019 at the global, regional, and national levels. In addition, joinpoint regression models were used to assess temporal trends. Results In 2019, the number of prevalent cases of childhood malnutrition increased to 435,071,628 globally. The global age-standardized incidence, prevalence, and DALY rates showed an increasing trend between 1990 and 2019. Meanwhile, the burden of child malnutrition was negatively correlated with sociodemographic index (SDI). Asia and Africa still carried the heaviest burden. The burden and trends of child malnutrition varied considerably across countries and regions. At the age level, we found that malnutrition was significantly more prevalent among children < 5 years of age. Conclusion Pediatric ND remains a major public health challenge, especially in areas with low SDI. Therefore, primary healthcare services in developing countries should be improved, and effective measures, such as enhanced pre-school education, strengthened nutritional support, and early and aggressive treatment, need to be developed.

BACKGROUND:Huangqi-Danshen decoction (HDD) is a classic traditional Chinese medicine for treating heart failure. Pericardial adipose tissue (PAT) has recently gained increasing attention in cardiovascular diseases. PURPOSE:This study aimed to investigate the effect of pericardial adipose tissue-derived extracellular vesicles on heart failure, the protective effect of HDD on myocardial remodel in heart failure rats, and identify the potential molecular mechanisms involved. METHODS:UPLC-MS/MS identified active components of HDD. Extracellular vesicles (EVs) from pericardial adipose tissue of sham-operated and HF rats were identified through transmission electron microscopy, nanoparticle tracking analysis and western blot. EVs were co-cultured with H9c2 cardiomyocytes in order to examine their uptake and effects. MicroRNA sequencing, dual-luciferase reporter assay and PCR were conducted for exploring specific mechanisms of EVs on hypertrophic cardiomyocytes. In vivo, heart failure was modeled in rats via transverse aortic constriction (TAC). In vitro, the hypertrophic cardiomyocyte model were established using Ang II-induced H9c2 cardiomyocytes. RESULTS:UPLC-MS/MS identified 11 active components in serum of HDD administrated rats. Echocardiography showed HDD improved cardiac function in TAC model rats. HE and Masson staining indicated HDD ameliorated myocardial hypertrophy and fibrosis. MicroRNA sequencing found that HDD treatment resulted in 37 differentially expressed miRNAs (DMEs) (p < 0.05 and |log2FC| ≥ 1). KEGG analysis revealed that DEMs were enriched in the AMPK signaling pathway. PCR identified miR-27a-3p with the greatest difference in AMPK-related DMEs. Dual-luciferase reporter assay and Targetscan website were utilized to identify the target relationship between miR-27a-3p and PRKAA2 (AMPKα2). The miR-27a-3p negatively regulated AMPKα2 to inhibit mitophagy mediated by PINK1/Parkin pathway. HDD inhibited miR-27a-3p secretion from failing heart pericardial adipose tissue-derived extracellular vesicles, thereby improving inflammation, cardiac function, and myocardial remodeling through above pathways. CONCLUSION:HDD inhibited the PAT-derived extracellular vesicular miR-27a-3p in failing hearts to activate AMPK/PINK1/Parkin signaling-mediated mitophagy, which improved cardiomyocyte energy metabolism, myocardial remodeling and heart failure.

BackgroundAstragalus mongholicus (AM) and Salvia miltiorrhiza (SM) are commonly used in traditional Chinese medicine to treat heart failure (HF). Ferroptosis has been studied as a key factor in the occurrence of HF. It remains unclear whether the combined use of AM and SM can effectively improve HF and the underlying mechanisms.ObjectiveThis study aims to explore whether the combined use of AM and SM can improve HF by inhibiting ferroptosis. It also examines the roles and interactions of the pathways associated with GPX4, FSP1, and DHODH.MethodsIn vitro experiments used angiotensin II-induced (4 μM for 48 h) hypertrophic H9c2 cells, while in vivo studies employed a rat model of transverse aortic constriction-induced (to 1 mm for 8 weeks) HF. Interventions included decoctions of AM and SM (for animal experiments) and medicated serum (for cell experiments), along with specific pathway inhibitors such as erastin, FSP1 inhibitor and brequinar. Subsequently, various molecular biology methods were used to measure the protein levels of GPX4, FSP1, and DHODH, as well as each sample group’s ferroptosis-related and HF-related indicators, to elucidate the underlying mechanisms.ResultsThe combined use of AM and SM can effectively restore the levels of GPX4, FSP1, and DHODH that are reduced after HF, as well as improve indicators related to ferroptosis and HF. When GPX4, FSP1, or DHODH is inhibited, the ferroptosis-inhibiting effect and the ability of AM and SM to improve HF are both weakened. When two of the three proteins are inhibited, the protective effect of HDC is strongest when GPX4 is retained, followed by FSP1, and weakest when DHODH is retained.ConclusionThis study confirms that the combined use of AM and SM inhibits ferroptosis and alleviates HF by increasing GPX4, FSP1, and DHODH levels. It shows that the protective effect is strongest through GPX4, followed by FSP1, and weakest through DHODH. These findings provide new insights into the therapeutic mechanisms of this combination of botanical drugs.

Salvianolic acid B (Sal B), the main water-soluble polyphenolic constituent of Danshen, is noted for its anti-inflammatory, antioxidant, and antiapoptotic properties, particularly in cardiovascular protection. However, the mechanisms by which Sal B affects myocardial fibrosis require further investigation. In vivo, we established a diabetic mouse model using a high-fat diet and intraperitoneal streptozotocin (STZ) administration. Mice were then treated with Sal B, the transient receptor potential channel 6 (TRPC6) inducers, or their combination. Upregulation of TRPC6 worsened myocardial pathology, leading to cardiac hypertrophy and collagen fiber deposition. In vitro, transforming growth factor (TGF)-beta 1 induced transdifferentiation of cardiac fibroblasts into myofibroblasts, creating a myofibroblast cell model. Sal B, TRPC6 inducers, or their combination were administered. TRPC6 upregulation increased procollagen type I C-terminal propeptide (PICP) and procollagen type III N-terminal propeptide (PIIINP) secretion, promoting myofibroblast proliferation and migration. Our study indicates that TRPC6 expression is upregulated in myocardial fibrosis, enhancing TGF-beta/Smad3 signaling and promoting collagen I (COL-1) synthesis. Sal B inhibited abnormal TRPC6 expression and TGF-beta/Smad3 activation, mitigating these effects. Thus, Sal B alleviates myocardial fibrosis in diabetes by modulating TRPC6 expression and TGF-beta/Smad3 signaling pathway.

Myocardial infarction (MI) is a potentially fatal disease that causes a significant number of deaths worldwide. The strategy of increasing fatty acid oxidation in myocytes is considered a therapeutic avenue to accelerate metabolism to meet energy demands. We conducted the study aiming to investigate the effect of KN-93, which induces histone deacetylase (HDAC)4 shuttling to the nucleus, on fatty acid oxidation and the expression of related genes.A mouse model of myocardial infarction was induced by isoprenaline administration. Heart damage was assessed by the detection of cardiac injury markers. The level of fatty acid oxidation level was evaluated by testing the expression of related genes. Both immunofluorescence and immunoblotting in the cytosol or nucleus were utilized to observe the distribution of HDAC4. The interaction between HDAC4 and specificity protein (SP)1 was confirmed by co-immunoprecipitation. The acetylation level of SP1 was tested after KN-93 treatment and HDAC4 inhibitor. Oxygen consumption rate and immunoblotting experiments were used to determine whether the effect of KN-93 on increasing fatty acid oxidation is through HDAC4 and SP1.Administration of KN-93 significantly reduced cardiac injury in myocardial infarction and promoted fatty acid oxidation both in vitro and in vivo. KN-93 was shown to mediate nuclear translocation of HDAC4. HDAC4 was found to interact with SP1 and reduce SP1 acetylation. HDAC4 or SP1 inhibitors attenuated the effect of KN-93 on fatty acid oxidationIn conclusion, KN-93 promotes HDAC4 translocation to the nucleus, thereby potentially enhancing fatty acid oxidation by SP1

ETHNOPHARMACOLOGICAL RELEVANCE:QiXian Granule (QXG) is an integrated traditional Chinese medicine formula used to treat postmenopausal atherosclerotic (AS) cardiovascular diseases. The previous studies have found that QXG inhibited isoproterenol (ISO)-induced myocardial remodeling. And its active ingredient, Icraiin, can inhibit ferroptosis by promoting oxidized low-density lipoprotein (xo-LDL)-induced vascular endothelial cell injury and autophagy in atherosclerotic mice. Another active ingredient, Salvianolic Acid B, can suppress ferroptosis and apoptosis during myocardial ischemia/reperfusion injury by reducing ubiquitin-proteasome degradation of Glutathione Peroxidase 4 (GPX4) and down-regulating the reactive oxygen species (ROS)- c-Jun N-terminal kinases (JNK)/mitogen-activated protein kinase (MAPK) pathway.AIM OF THE STUDY:The objective of this research was to assess the possible impact of QXG on atherosclerosis in postmenopausal individuals and investigate its underlying mechanisms.MATERIALS AND METHODS:Female ApoE-/- mice underwent ovariectomy and were subjected to a high-fat diet (HFD) to establish a postmenopausal atherosclerosis model. The therapeutic effects of QXG were observed in vivo and in vitro through intraperitoneal injection of erastin, G-protein Coupled Estrogen Receptor (GPER) inhibitor (G15), and silent Mucolipin Transient Receptor Potential Channel 1 (TRPML1) adenovirus injection via tail vein. UPLC-MS and molecular docking techniques identified and evaluated major QXG components, contributing to the investigation of QXG's anti-postmenopausal atherosclerotic effects.RESULTS:QXG increased serum Estradiol levels, decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, which indicated QXG had estrogen-like effects in Ovx/ApoE-/- mice. Furthermore, QXG demonstrated the potential to impede the progression of AS in Ovx/ApoE-/- mice, as evidenced by reductions in serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C) levels. Additionally, QXG inhibited ferroptosis in Ovx/ApoE-/- mice. Notably, UPLC-MS analysis identified a total of 106 active components in QXG. The results of molecular docking analysis demonstrated that Epmedin B, Astragaloside II, and Orientin exhibit strong binding affinity towards TRPML1. QXG alleviates the progression of atherosclerosis by activating TRPML1 through the GPER pathway or directly activating TRPML1, thereby inhibiting GPX4 and ferritin heavy chain (FTH1)-mediated iron pendant disease. In vitro, QXG-treated serum suppressed proliferation, migration, and ox-LDL-induced MMP and ROS elevation in HAECs.CONCLUSION:QXG inhibited GPX4 and FTH1-mediated ferroptosis in vascular endothelial cells through up-regulating GPER/TRPML1 signaling, providing a potential therapeutic option for postmenopausal females seeking a safe and effective medication to prevent atherosclerosis. The study highlights QXG's estrogenic properties and its promising role in combating postmenopausal atherosclerosis.

水饮和水饮乘肺是高血压兼变证心衰发病的关键病邪证素和基本病机.针对水饮其性趋下如何上凌心肺在心衰发病中的认知难点,提出"饮邪稽伏,风邪引动,水饮上乘"病机论.认为肝肾阴虚,肺脾肾气虚为高血压心衰病的发病基础.肺脾气虚,营卫失调而外风易袭;肝肾阴虚,阴不敛阳而内风易动,肺脾肾虚、输布失职而水饮稽伏.风邪引动,水饮上乘,凌心射肺,发为喘、闷、悸、肿、汗、痞等心衰诸证.提出以"治风为要,调枢为基,防生为重"的治则,以及"调营卫御外风,滋阴津息内风,调肝脾利枢机,泻肺水助肺宣,补心气畅血脉,温肾阳助气化"的治法.

Myocardial ischemia/reperfusion injury (MIRI) is related to ferroptosis and apoptosis elicited by reactive oxygen species (ROS). In this research, we investigated the protective effect of salvianolic acid B (SAB) as a natural antioxidant on ferroptosis and apoptosis in the MIRI process, and discussed the protective mechanism inhibiting ubiquitin-proteasome degradation of glutathione peroxidase 4 (GPX4) and the c-Jun N-terminal kinases (JNK) apoptosis signal pathway. We observed that ferroptosis and apoptosis occurred in the MIRI rat model in vivo and the H9c2 cardiomyocyte hypoxia/reoxygenation (H/R) damage model in vitro. SAB can alleviate tissue damage related to ROS, ferroptosis and apoptosis. Ubiquitin-proteasome degradation of GPX4 occurred in H/R models, and SAB reduced the ubiquitin-proteasome degradation of GPX4. SAB downregulates JNK phosphorylation and the expression of BCL2-Associated X (Bax)/B-cell lymphoma-2 (Bcl-2) and Caspase-3 to inhibit apoptosis. The role of GPX4 in the cardioprotection of SAB was further verified by the elimination effect of the GPX4 inhibitor RAS-selective lethal 3 (RSL3). This research shows that SAB may be used as a myocardial protective agent against oxidative stress, ferroptosis and apoptosis, and has potential clinical application prospects.