Introduction: Atherosclerosis (AS), the main pathological basis of cardiovascular and cerebrovascular diseases, is associated with lipid disorders, inflammation, oxidative stress, and vascular smooth muscle cell (VSMC) dysfunction. DNA methylation is a key epigenetic mechanism that plays a pivotal role in regulating the pathological processes of AS. Traditional Chinese medicine (TCM), which has multi-component and multi-target actions, has shown considerable advantages in treating AS through DNA methylation pathways. Natural Chinese herbal medicines with low toxicity and high efficiency can reduce blood pressure, protect vascular endothelial cells, stabilize arterial plaques, and participate in AS prevention and treatment via epigenetic modification, anti-inflammatory, and lipid metabolism-regulating effects. Methods: A comprehensive literature review was conducted on PubMed, Web of Science, Google Scholar, and CNKI, focusing on TCM active ingredients and their role in DNA methylation in AS. Results: Our article summarizes the latest research on how TCM and its active components intervene in AS by regulating DNA methylation. Specifically, TCM modulates site-specific DNA methylation to regulate lipid metabolism and foam cell formation, inhibit inflammation, alleviate oxidative stress, and balance phenotypic switching as well as the proliferation and apoptosis of VSMCs. These mechanisms provide novel epigenetic targets for AS treatment beyond conventional lipid-lowering therapies. Discussion: Integrating advanced technologies with TCM research and developing DNA methylation-targeting agents can improve AS therapy. This cross-disciplinary approach not only enriches the epigenetic regulatory theory of TCM but also paves the way for translating these findings into clinical practice. Our findings offer personalized therapeutic options for AS that do not depend solely on lipid-lowering mechanisms.

Aging is closely associated with epigenetic alterations, including changes in DNA methylation, acetylation, and shifts in histone modification patterns, which drive cellular decline and increase susceptibility to diseases. This review examines the connection between aging-related diseases and epigenetic mechanisms and explores how dietary interventions can influence this process. We discuss the Mediterranean diet (MD), caloric restriction (CR), and the ketogenic diet (KD) as key nutritional strategies. These interventions supply essential substrates and regulate enzymes central to epigenetic remodeling, thereby affecting gene expression networks involved in inflammation, metabolism, and cellular stress responses. By correcting age related epigenetic dysregulation, such dietary patterns can slow attenuate cellular senescence and reduce the risk of chronic diseases. Current evidence supports the association between diet quality and decelerated epigenetic aging. Future research is needed to establish causality and to develop personalized nutritional approaches for promoting longevity and healthspan.

Diet is a key regulatory factor for the gut microbiota, profoundly influencing its composition and metabolic activities, and is of great significance to the occurrence and development of atherosclerosis. Dysregulation of the gut microbiota can alter the production of key microbial metabolites. These metabolites play a crucial role in regulating host lipid metabolism, inflammatory responses, and endothelial integrity, and these factors are closely related to the pathogenesis of atherosclerotic plaques. In this review, we identify several key findings. Short-chain fatty acids, particularly butyrate and propionate, exert anti-atherosclerotic effects by promoting regulatory T cell differentiation, inhibiting histone deacetylases, and improving endothelial function. Bile acids modulate atherosclerosis via farnesoid X receptor and TGR5 signaling, with microbiota-mediated secondary bile acid composition playing a critical but species-dependent role. Tryptophan metabolites derived from both host and microbial metabolism exhibit dual roles in vascular inflammation, with indole-3-propionic acid and indole-3-carboxaldehyde showing consistent atheroprotective effects in preclinical models. Trimethylamine N-oxide is consistently associated with increased cardiovascular risk in observational studies, yet causal evidence in humans remains inconclusive. A high-fiber and plant-based diet can promote the growth of beneficial microbiota and the production of short-chain fatty acids, while a Western and high-protein diet can increase proteolytic bacteria and raise the level of trimethylamine N-oxide. In addition, food and medicine homologous compounds (including saponins, flavonoids, polysaccharides, and alkaloids) can regulate the composition of the gut microbiota and the activity of microbial enzymes, which represents a promising but unvalidated therapeutic strategy. This review consolidates the evidence regarding the intricate interplay between dietary habits, gut microbiota, and metabolite dynamics, highlighting their collective influence on atherosclerotic cardiovascular disease.

This study aimed to investigate the correlation between changes in intestinal toxicity and compositional alterations of Euphorbiae Ebracteolatae Radix(commonly known as Langdu) before and after milk processing, and to explore the detoxification mechanism of milk processing. Mice were intragastrically administered the 95% ethanol extract of raw Euphorbiae Ebracteolatae Radix, milk-decocted(milk-processed), and water-decocted(water-processed) Euphorbiae Ebracteolatae Radix. Fecal morphology, fecal water content, and the release levels of inflammatory cytokines tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) in different intestinal segments were used as indicators to evaluate the effects of different processing methods on the cathartic effect and intestinal inflammatory toxicity of Euphorbiae Ebracteolatae Radix. LC-MS/MS was employed to analyze the small-molecule components in the raw product, the 95% ethanol extract of the milk-processed product, and the milky waste(precipitate) formed during milk processing, to assess the impact of milk processing on the chemical composition of Euphorbiae Ebracteolatae Radix. The results showed that compared with the blank group, both the raw and water-processed Euphorbiae Ebracteolatae Radix significantly increased the fecal morphology score, fecal water content, and the release levels of TNF-α and IL-1β in various intestinal segments(P<0.05). Compared with the raw group, all indicators in the milk-processed group significantly decreased(P<0.05), while no significant differences were observed in the water-processed group, indicating that milk, as an adjuvant in processing, plays a key role in reducing the intestinal toxicity of Euphorbiae Ebracteolatae Radix. Mass spectrometry results revealed that 29 components were identified in the raw product, including 28 terpenoids and 1 acetophenone. The content of these components decreased to varying extents after milk processing. A total of 28 components derived from Euphorbiae Ebracteolatae Radix were identified in the milky precipitate, of which 27 were terpenoids, suggesting that milk processing promotes the transfer of toxic components from Euphorbiae Ebracteolatae Radix into milk. To further investigate the effect of milk adjuvant processing on the toxic terpenoid components of Euphorbiae Ebracteolatae Radix, transmission electron microscopy(TEM) was used to observe the morphology of self-assembled casein micelles(the main protein in milk) in the milky precipitate. The micelles formed in casein-terpenoid solutions were characterized using particle size analysis, fluorescence spectroscopy, ultraviolet spectroscopy, and Fourier-transform infrared(FTIR) spectroscopy. TEM observations confirmed the presence of casein micelles in the milky precipitate. Characterization results showed that with increasing concentrations of toxic terpenoids, the average particle size of casein micelles increased, fluorescence intensity of the solution decreased, the maximum absorption wavelength in the UV spectrum shifted, and significant changes occurred in the infrared spectrum, indicating that interactions occurred between casein micelles and toxic terpenoid components. These findings indicate that the cathartic effect of Euphorbiae Ebracteolatae Radix becomes milder and its intestinal inflammatory toxicity is reduced after milk processing. The detoxification mechanism is that terpenoid components in Euphorbiae Ebracteolatae Radix reassemble with casein in milk to form micelles, promoting the transfer of some terpenoids into the milky precipitate.

Background Atherosclerosis, a leading cause of cardiovascular morbidity and mortality, is driven by endothelial dysfunction. While metabolic reprogramming toward glycolysis in endothelial cells exacerbates disease progression, the role of lactate-derived lactylation in atherogenesis remains poorly understood. Methods We performed RNA-seq on aortic tissues from atherosclerotic mice to identify differentially expressed genes, along with Seahorse XF metabolic flux analysis. Endothelium-specific solute carrier family 22 member 6 (Slc22a6) knockout and AAV-delivered acyl-CoA synthetase short-chain family member 1 (Acss1) knockdown mice were established on an ApoEKO background. Integrated multi-omics (RNA-seq, CUT&Tag, metabolomics) elucidated downstream regulatory networks, and in vivo pharmacological inhibition validated key pathways. Results Our study reveals a marked elevation of histone H3 Lysine 9 Lactylation (H3K9la) relative to acetylation in atherosclerotic aortic tissue, potentially via SLC22A6-mediated glycolytic enhancement and lactate uptake. Additionally, endothelial-specific knockout of Slc22a6 attenuates H3K9la-driven endothelial dysfunction and atherosclerosis. Integrated RNA-seq and CUT&Tag analyses identify that upregulated ACSS1 and E1A binding protein p300 (EP300) drive H3K9la, which transcriptionally activates stearoyl-CoA desaturase 1 (SCD1), thereby exacerbating endothelial dysfunction. Pharmacological inhibition of H3K9la or SCD1 alleviates endothelial dysfunction and atherosclerosis in vitro and in vivo. We further establish the clinical relevance of lactate, SLC22A6, and ACSS1 in atherosclerosis. Conclusions Our findings unveil a metabolism-epigenetics-transcription regulatory axis in endothelial pathophysiology, thus providing novel therapeutic strategies for atherosclerosis by targeting the SLC22A6-dependent ACSS1-H3K9la-SCD1 pathway.

BACKGROUND:Trimethylamine N-oxide (TMAO), a product of the gut microbiota, is essential to the pathophysiology of atherosclerotic cardiovascular disease (ASCVD). Although Liuwei Dihuang Formula (LWDH) can ameliorate perimenopausal atherosclerosis (AS) and modulate gut microbes, it is unknown how it regulates the trimethylamine (TMA)-TMAO pathway. PURPOSE:This study aimed to examine whether LWDH could attenuates perimenopausal AS by modulating the gut microbiota-TMA-TMAO axis and to clarify the associated mechanisms, with an emphasis on its possible synergistic interaction with the probiotic Bifidobacterium animalis subsp. Lactis (B.lactis). METHODS:In ApoE knockout (ApoE-/-) mice, a perimenopausal AS model was established via bilateral ovariectomy combined with a high-fat diet (HFD), followed by LWDH intervention. The TMAO and TMA levels in plasma and the liver were measured using targeted metabolomics. Microbial communities were analyzed using 16S rRNA sequencing. In vitro microbial culture experiments were carried out to validate the LWDH effect on the key bacterial populations and metabolic pathways. A combined intervention with LWDH and B.lactis was also performed to evaluate the potential synergistic effects. RESULTS:LWDH significantly reduced aortic plaque burden and decreased plasma and hepatic TMAO levels in perimenopausal AS mice. Mechanistic analyses revealed that LWDH remodeled the gut microbiota, suppressed TMA-producing bacteria, and enhanced TMA degradation, thereby reducing systemic TMAO accumulation. Notably, 16S rRNA sequencing revealed a close link between decreased Bifidobacterium abundance and elevated TMAO levels. In vitro assays confirmed that LWDH enhanced the TMA-degrading activity of B. lactis and downregulated the cutC gene in Escherichia coli, resulting in reduced TMA synthesis. Combined LWDH and B.lactis intervention led to greater reductions in plasma TMAO compared to B. lactis alone, accompanied by improved lipid metabolism and attenuation of systemic inflammation. CONCLUSION:These findings are the first to show that LWDH mitigated perimenopausal AS progression by modulating the gut microbiota-dependent TMA-TMAO axis. The dual mechanisms of enhancing TMA degradation and inhibiting TMA production, together with the synergistic effects of LWDH and B. lactis, highlight a novel therapeutic strategy that integrates traditional Chinese medicine and probiotics for AS management.

BACKGROUND AND PURPOSE:Euphorbia pekinensis (EP) is known to cause significant intestinal toxicity, primarily manifesting as severe diarrhoea, yet the precise molecular mechanisms and the active components responsible have remained elusive. This study aimed to identify the diarrheal constituents of EP and elucidate the molecular pathway through which they induce gut toxicity. EXPERIMENTAL APPROACH:The laxative effects of EP components were assessed in vivo using mouse models and diarrhoea-related indicators, with histological analysis of intestinal tissue. Ex vivo rabbit intestinal tract assays were employed to study smooth muscle contraction. The underlying mechanism was investigated using intestinal organoid fluorescence co-localization and analysis of tryptophan metabolites in mice to determine the role of enterochromaffin (EC) cells and serotonin (5-HT). KEY RESULTS:We identified specific glycosphingolipids (GSLs), including a novel hexosylceramide (HexCer), as the primary toxic agents in EP. These GSLs act as direct agonists of the TRPA1 ion channel on intestinal EC cells. This activation triggers a TRPA1-mediated influx of Ca2+ into EC cells, leading to excessive 5-HT release. The resulting localized overstimulation of 5-HT receptors causes aberrant intestinal smooth muscle contraction and epithelial hypersecretion, culminating in severe diarrhoea. CONCLUSION AND IMPLICATIONS:This research reveals that the gut toxicity of EP is driven by a previously unrecognized GSL-TRPA1-5-HT signalling pathway in the intestinal epithelium. These findings provide a clear mechanistic basis for EP-induced diarrhoea and highlight a potential new target for managing gut toxicity.

Hypercholesterolemia poses a significant cardiovascular risk, particularly in postmenopausal women. The anti-hypercholesterolemic properties of Lactiplantibacillus plantarum ATCC8014 (LP) are well recognized; however, its improving symptoms on postmenopausal hypercholesterolemia and the possible mechanisms have yet to be elucidated. Here, we utilized female ApoE-deficient (ApoE-/-) mice undergoing bilateral ovariectomy, fed a high-fat diet, and administered 109 colony-forming units (CFU) of LP for 13 consecutive weeks. LP intervention reduces total cholesterol (TC) and triglyceride (TG) accumulation in the serum and liver and accelerates their fecal excretion, which is mainly accomplished by increasing the excretion of fecal secondary bile acids (BAs), thereby facilitating cholesterol conversion. Correlation analysis revealed that lithocholic acid (LCA) is an important regulator of postmenopausal lipid abnormalities. LP can reduce LCA accumulation in the liver and serum while enhancing its fecal excretion, accomplished by elevating the relative abundances of Allobaculum and Olsenella in the ileum. Our findings demonstrate that postmenopausal lipid dysfunction is accompanied by abnormalities in BA metabolism and dysbiosis of the intestinal microbiota. LP holds therapeutic potential for postmenopausal hypercholesterolemia. Its effectiveness in ameliorating lipid dysregulation is primarily achieved through reshaping the diversity and abundance of the intestinal microbiota to correct BA abnormalities.

Pinellia ternata, a widely used traditional Chinese medicine, contains a strong mucosal irritant that is connected with Pinellia ternata lectin (PTL) in its tubers. The purpose of this study was to explore the mechanisms by which PTL induces inflammation. We found that in RAW264.7 cells, PTL activated the PI3K/Akt/mTOR and NF-κB pathways, which resulted in the release of proinflammatory cytokines. Flow cytometry and laser confocal microscopy analysis showed that FITC-labeled PTL bound to the macrophages’ surface. Based on kinetic analyses and protein-protein docking simulations, PTL was shown to bind toll-like receptor 4 (TLR4).it was demonstrated that PTL binds highly to Toll-like receptor 4 (TLR4). TLR4 knock-down or knockout resulted in a decrease in both cytokine release and PI3K/Akt/mTOR and NF-κB pathway activation in PTL-stimulated macrophages or mice. RNA-seq analysis showed that genes involved in the PI3K/Akt/mTOR signaling pathway were strongly upregulated in response to PTL stimulation, confirming that the PI3K/Akt/mTOR pathway is linked to the inflammatory effect of PTL in RAW264.7 cells. These findings reveal that PTL can mediate inflammation through TLR4 and activating the PI3K/Akt/mTOR to regulate NF-κB signaling pathways.

Cognitive dysfunction increases as menopause progresses. We previously found that estrogen receptors (ERs) contribute to dyslipidemia, but the specific relationship between ERs, dyslipidemia and cognitive dysfunction remains poorly understood. In the present study, we analyzed sequencing data from female hippocampus and normal breast aspirate samples from normal and Alzheimer’s disease (AD) women, and the results suggest that abnormal ERs signaling is associated with dyslipidemia and cognitive dysfunction. We replicated a mouse model of dyslipidemia and postmenopausal status in LDLR−/− mice and treated them with β-estradiol or simvastatin, and found that ovariectomy in LDLR−/− mice led to an exacerbation of dyslipidemia and increased hippocampal apoptosis and cognitive impairment, which were associated with reduced estradiol levels and ERα, ERβ and GPER expression. In vitro, a lipid overload model of SH-SY-5Y cells was established and treated with inhibitors of ERs. β-estradiol or simvastatin effectively attenuated dyslipidemia-induced neuronal apoptosis via upregulation of ERs, whereas ERα, ERβ and GPER inhibitors together abolished the protective effect of simvastatin on lipid-induced neuronal apoptosis. We conclude that decreased estrogen and its receptor function in the postmenopausal stage promote neuronal damage and cognitive impairment by exacerbating dyslipidemia, and that estrogen supplementation or lipid lowering is an effective way to ameliorate hippocampal damage and cognitive dysfunction via upregulation of ERs.

BACKGROUND:Myocardial ischemia (MI) can cause angina, myocardial infarction, and even death. Angiogenesis is beneficial for ensuring oxygen and blood supply to ischemic tissue, promoting tissue repair, and reducing cell damage. In this study, we evaluated the effects of Salvianolic acid B (Sal B) against myocardial ischemia and explored its underlying mechanism on autophagy.METHODS:The anti-apoptosis effect of Sal B was conducted by staining Annexin V-FITC/PI and Hoechst as well as evaluating apoptosis bio-markers at protein level in H9c2 cells at glucose deprivation condition. HUVECs were co-cultured with H9c2, and the tube formation assay was used to monitor Sal B's impact on angiogenesis. The MI model of mice was induced by intraperitoneal injection of isoproterenol (ISO). The effect of Sal B on MI mice was evaluated by HE, Masson, immunohistochemistry, WB and kits. In addition, Atg5 siRNA was applied to verify whether the protective effect of Sal B was regulated to autophagy.RESULTS:In H9c2, Sal B reduced the levels of lactate dehydrogenase (LDH), malondialdehyde (MDA) and reactive oxygen species (ROS), improved the levels of superoxide dismutase (SOD) and mitochondrial membrane potential, downregulated the expressions of Bax and cleaved-Caspase3, upregulated the expression of Bcl-2. Therefore, Sal B could significantly inhibit the damage of H9c2 caused by glucose deprivation. In the co-culture system of H9c2 and HUVECs, vascular endothelial growth factor (VEGF) level in the supernatant was dramatically raised by Sal B. Sal B upregulated the expressions of VEGF, platelet derived growth factor (PDGF) and endothelial marker CD31. It implied that Sal B exerted a significant pro-angiogenic effect. Moreover, Sal B increased the expression of LC3, Atg5, and Beclin1, while reducing the level of P62. When the expression of Atg5 was inhibited, the protective effects of Sal B on apoptosis and angiogenesis was reversed.CONCLUSIONS:Sal B inhibited cardiomyocyte apoptosis and promoted angiogenesis by regulating autophagy, thereby improving MI.

Acute cardiovascular events increase significantly in postmenopausal women. The relationship between estrogen receptor (ER) and plaque stability in the postmenopausal stage remains to be elucidated. We aimed to explore whether ERα activation improves plaque instability in the postmenopausal stage. Here, we report that postmenopausal women showed increased macrophage activation and plaque instability with increased MCP-1, MMP9, TLR4, MYD88 and NF-κB p65 and decreased ERα and TIMP1 expression in the vascular endothelium. Moreover, ovariectomy in LDLR-/- mice resulted in a significant increase in plaque area and necrotic core area, as well as a significant decrease in collagen content and an increase in macrophage accumulation in the artery. Ovariectomy also reduced serum estrogen levels and ERα expression and upregulated TLR4 and MMP9 expression in arteries in LDLR-/- mice. Estrogen or phytoestrogen therapy upregulated the expression level of ERα in ovariectomized mice and increased plaque stability by inhibiting macrophage accumulation and TLR4 signaling. In vitro, LPS incubation of RAW264.7 cells resulted in a significant decrease in ERα and TIMP1 expression and an increase in TLR4 activation, and estrogen or phytoestrogen treatment increased ERα and TIMP1 expression and inhibited TLR4 activation and MMP9 expression in LPS-treated RAW264.7 cells. Compared to control siRNA transfected RAW264.7 cells, TLR4 siRNA promoted TIMP1 expression in RAW264.7 cells with LPS incubation, but did not affect ERα expression in RAW264.7 cells with or without LPS treatment. The ERα inhibitor MPP abolished the regulatory effect of estrogen or phytoestrogen on LPS-induced RAW264.7 cells. In conclusion, the present study demonstrates that decreased ERα expression promotes macrophage infiltration and plaque instability in the postmenopausal stage, and activation of ERα in the postmenopausal stage alleviates atherosclerotic plaque instability by inhibiting TLR4 signaling and macrophage-related inflammation.

Abstract Background The long-term excessive intake of exogenous cholesterol can lead to abnormally elevated blood lipid levels and induce cardiovascular and cerebrovascular diseases. However, the influence and relevance of exogenous cholesterol on plasma cholesterol components were still unclear, and the influence on intestinal lipid metabolism targets needs to be further explored. Methods In vivo, the C57BL/6 + NF group and ApoE−/− + NF group mice were fed a normal specific pathogen-free (SPF) diet; the ApoE−/− + HF group mice were fed a high-cholesterol SPF diet. The plasma and jejunum tissue homogenate were obtained for non-targeted lipid metabolomics. The lipid droplets in tissues were observed by transmission electron microscope and oil red O staining. Jejunum tissue morphology was observed by HE staining. The kits were used to detect lipid content in plasma, tissues, intestinal contents, and cells. Western blot, RT-PCR, immunohistochemistry (IHC), and immunofluorescence (IF) were used to observe the key target of lipid metabolism. In vitro, the final concentration of cholesterol was 100 μmol/L in Caco-cells. Oil red O staining, western blot, RT-PCR and immunofluorescence (IF) were used to observe the changes of lipid metabolism. Finally, the influence of liver X receptor alpha (LXRα) on intestinal cholesterol metabolism was clarified by applying the LXRα inhibitor GSK2033 and siRNA targeting LXRα. Results The aortic arch and intestinal villi of the two groups of ApoE−/− mice showed apparent lesions and lipid accumulation, and there were significant changes in a variety of lipids in the plasma and jejunum. Additionally, jejunum LXRα was markedly activated. High cholesterol can significantly activate LXRα in Caco-2 cells. After LXRα was inhibited, the protein level of ATP-binding cassette transporter A1/G5/G8 (ABCA1/G5/G8) decreased, and the quantity and volume of intracellular lipids soared. Conclusion In a high-cholesterol environment, the intestine promotes the excretion of cholesterol from the cell through the LXRα-ABCA1/G5/G8 pathway, reduces the intestinal intake of a variety of exogenous cholesterol, and reduces the risk of AS. Graphical Abstract

目的 初步探讨绝经后脂质代谢紊乱是否参与抑郁症状的形成.方法 24只LDLR-/-和16只WT C57BL/6J雌鼠,分为5组(n=8),分别为:WT+普通饮食组(WT)、WT+高脂饮食组(WT-H)、LDLR-/-去卵巢+普通饮食组(LDLR-/-)、LDLR-/-去卵巢+高脂饮食组(LDLR-/--H)、LDLR-/-去卵巢+高脂饮食+辛伐他汀组(XF),连续喂养3个月.LDLR-/-雌鼠双侧卵巢摘除联合高脂饮食建立绝经后脂质代谢紊乱模型.检测小鼠体重、脑总胆固醇(TC)及海马ERα、ERβ水平、抑郁行为、脑内5-HT水平;对脑TC水平和抑郁相关指标进行相关性分析.结果 (1)LDLR-/--H组可复制绝经后脂质代谢紊乱特征,表现为小鼠体重显著增加、脑TC水平显著升高、海马ERβ表达明显下降;(2)LDLR-/--H组小鼠水平和垂直运动均显著降低,TST静止时间显著增加,脑5-HT水平显著降低;(3)XF组小鼠脑TC水平显著下降、抑郁行为明显改善、5-HT水平明显提高;(4)小鼠脑TC水平与5-HT水平及抑郁样行为显著相关.结论 绝经后脂质代谢紊乱能诱导抑郁症状发生,通过调节脂质代谢可以显著改善抑郁症状.

目的:考察六味地黄丸对肾阴虚型绝经后女性冠心病经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)术后临床症状及雌激素、血脂、炎症水平的影响.方法:选择2019年1月至2020年12月于南京中医药大学附属中西医结合医院行PCI术后肾阴虚型绝经后女性患者80例,随机分为对照组和治疗组,2组患者术后均给予标准治疗,治疗组加用六味地黄丸.观察2组治疗前后中医证候积分与中医临床疗效及不良反应,血脂水平及血脂达标率,雌激素水平及炎症指标变化.结果:经治疗后,2组各项中医证候积分均明显下降,其中治疗组腰膝酸软、烦热和盗汗中医症候积分显著低于对照组(P＜0.05);治疗组中医临床疗效显著高于对照组(P＜0.05);治疗组较对照组TC及LDL-C水平显著下降(P＜0.05),同时治疗组LDL-C达标率较对照组显著提升(P＜0.05);治疗组雌二醇水平较对照组显著提高(P＜0.05),治疗组hs-CRP水平较对照组显著降低(P＜0.05);2组均未发生严重不良反应,不良反应发生率差异无统计学意义(P＞0.05).结论:六味地黄丸显著降低绝经后女性LDL-C和hs-CRP水平且未增加不良反应发生率,可能是通过雌激素-脂质代谢-炎症反应轴提高绝经后女性体内雌激素水平实现抗动脉粥样硬化,减少冠心病事件的发生.

Background: Postmenopausal women have a high incidence of atherosclerosis. Phytosterols have been shown to have cholesterol-lowering properties. Alisa B 23-acetate (AB23A) is a biologically active plant sterol isolated from Chinese herbal medicine Alisma. However, the atherosclerosis effect of AB23A after menopause and its possible mechanism have not been reported yet. Purpose: To explore whether AB23A can prevent atherosclerosis by regulating farnesoid X receptor and subsequently increasing fecal bile acid and cholesterol excretion to reduce plasma cholesterol levels. Methods: Aortic samples from premenopausal and postmenopausal women with ascending aortic arteriosclerosis were analyzed, and bilateral ovariectomized (OVX) female LDLR(-/-)mice and free fatty acid (FFA)-treated L02 cells were used to analyze the effect of AB23A supplementation therapy. Results: AB23A increased fecal cholesterol and bile acids (BAs) excretion dependent on activation of hepatic farnesoid X receptor (FXR) in ovariectomized mice. AB23A inhibited hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) and sterol 12 alpha-hydroxylase (CYP8B1) via inducing small heterodimer partner (SHP) expression. On the other hand, AB23A increased the level of hepatic chenodeoxycholic acid (CDCA), and activated the hepatic BSEP signaling. The activation of hepatic FXR-BSEP signaling by AB23A in ovariectomized mice was accompanied by the reduction of liver cholesterol, hepatic lipolysis, and bile acids efflux, and reduced the damage of atherosclerosis. In vitro, AB23A fixed abnormal lipid metabolism in L02 cells and increased the expression of FXR, BSEP and SHP. Moreover, the inhibition and silencing of FXR canceled the regulation of BSEP by AB23A in L02 cells. Conclusion: Our results shed light into the mechanisms behind the cholesterol-lowering of AB23A, and increasing FXR-BSEP signaling by AB23A may be a potential postmenopausal atherosclerosis therapy.

目的 通过数据库预测和分子对接技术探究小儿广朴止泻口服液治疗腹泻的活性成分和作用机制,并在大鼠小肠上皮IEC-6细胞上进行初步实验验证.方法 通过中药系统药理学平台(TCMSP)数据库和文献检索获取小儿广朴止泻口服液的化学成分;采用GeneCards和DisGeNET数据库获得腹泻相关基因,构建蛋白质-蛋白质相互作用(protein-protein interaction network,PPI)网络获得小儿广朴止泻口服液治疗腹泻的重要靶点,并进行基因本体(gene ontology,GO)功能及京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)通路富集分析;使用Autodock Vina软件进行分子对接验证.采用脂多糖(lipopolysaccharide,LPS)诱导IEC-6细胞损伤模型,采用MTT、ELISA法检测小儿广朴止泻口服液对细胞凋亡及炎症的影响,并通过Western blotting法验证其可能的作用机制.结果 小儿广朴止泻口服液的主要活性成分有63个,预测获得重要靶点86个,核心靶点28个;GO功能和KEGG通路富集分析显示小儿广朴止泻口服液主要调控了机体炎症反应、细胞增殖、细胞凋亡等生物过程,涉及肿瘤坏死因子(tumor necrosis factor,TNF)、Toll样受体(Toll-like receptor,TLR)、缺氧诱导因子-1(hypoxia inducible factor-1,HIF-1)以及磷酸肌醇-3-激酶(phosphatidylinositol-3-kinase,PI3K)-蛋白激酶B(proteinkinaseB,Akt)等信号通路.体外结果表明小儿广朴止泻口服液能显著升高LPS诱导的IEC-6细胞存活率(P＜0.01),显著抑制炎症因子白细胞介素-6(interleukin-6,IL-6)、IL-1β和TNF-α的分泌(P＜0.01),显著下调剪切型半胱氨酸天冬氨酸蛋白酶-3(cleavedcystein-asparateprotease-3,cleavedCaspase-3)、Caspase-8、核因子-κB p65(nuclearfactor-κBp65,NF-κBp65)蛋白表达(P＜0.01),上调 β-catenin 蛋白表达(P＜0.01).结论 小儿广朴止泻口服液可能通过抑制炎症反应和细胞凋亡治疗腹泻.

目的 基于雌激素受体α(ERα)研究丹皮酚对巨噬细胞表型转换的影响.方法 利用100μg·L-1脂多糖(LPS)和20μg·L-1γ-干扰素(IFN-γ)联用复制巨噬细胞M1极化模型.ELISA实验观察丹皮酚对白介素-10(IL-10)、肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)、丙二醛(MDA)、超氧化物歧化酶(SOD)的影响.进一步用Western blot检测巨噬细胞M1表型标志物一氧化氮合酶iNOS、CD86和M2表型标志物精氨酸酶-1(Arg-1)、CD163的表达,并利用阻断剂和shRNA干扰的方法验证丹皮酚的效应是否通过ERα实现.结果 ELISA结果表明丹皮酚可降低模型组TNF-α、IL-1β和MDA的含量,升高IL-10和SOD的含量.Western blot结果显示,丹皮酚可降低模型组iNOS、CD86的蛋白表达,升高Arg-1、CD163的蛋白表达.ERα选择性阻断剂MPP和ERαshRNA均能降低丹皮酚的药效,ERβ选择性阻断剂PHTPP对丹皮酚的效应没有明显改变.结论 丹皮酚可通过ERα诱导巨噬细胞向M2型转化,改善动脉粥样硬化.

Inflammatory response-mediated excessive apoptosis is the main pathological alteration in the development of diabetic cardiomyopathy (DCM). The role of astragaloside IV (AS-IV) in the treatment of DCM is still unclear. In vivo model was established by high-fat diet plus 1% STZ, and in vitro model was established by 30 mmol/L glucose. AS-IV reduced fasting blood glucose, improved cardiac function and cardiac pathology, and decreased the excessive deposition of myocardial interstitial collagen. In addition, AS-IV inhibited the protein levels of TLR4, MYD88, NF-κB p65, Caspase-3, TGF-β and Colleagn I, and TNF-α and IL-1β activities. Moreover, AS-IV also inhibited the overactivation of TLR4/MyD88/NF-κB signaling pathway and apoptosis of cardiomyocytes induced by high-glucose in H9c2 cells and myocardial fibroblasts. In conclusion, AS-IV can inhibit the over-activation of TLR4/MyD88/NF-κB signaling pathway, inhibit the inflammatory response, anti-apoptosis, which has a significant prevention and treatment effect on DCM.