The rising global incidence of cardiovascular diseases (CVDs) poses a serious challenge to public health systems, and there is an urgent need to alleviate this disease burden through innovative treatment strategies. Cardiomyocyte energy metabolism is highly dependent on fatty acid β-oxidation (FAO), which is a process that releases energy in the form of ATP. Impaired FAO not only reduces ATP generation but also induces pathological lipid deposition in cardiomyocytes, leading to cardiac dysfunction. As a selective autophagic process responsible for intracellular lipid droplet degradation, lipophagy serves as a critical regulator of myocardial energetic homeostasis through its coordination of the dynamic balance between lipolytic metabolism and fatty acid oxidation. Although lipophagy serves as a key regulatory node for fatty acid metabolism and maintains core functions in cardiovascular homeostasis, its precise pathological mechanisms in cardiovascular diseases remain incompletely clarified. The bidirectional regulatory mode of lipophagy, together with the causal regulation between fatty acid metabolic flux and lipotoxicity accumulation, is critical for dissecting molecular pathogenesis of cardiovascular lesions. This review systematically integrates and analyzes the bidirectional regulatory networks of various lipophagy subtypes, and summarizes cutting-edge research progress in cardiovascular diseases such as atherosclerosis, myocardial ischemia-reperfusion injury and diabetic cardiomyopathy. It provides theoretical basis for developing novel cardiovascular disease treatment strategies targeting lipophagy pathways.

BACKGROUND:Chemotherapy-induced peripheral neuropathy (CIPN) is a serious clinical problem with no widely applicable solutions. Modified Wen Luo Tong (mWLT) was designed specifically for paclitaxel-related CIPN, yet its efficacy and mechanisms remain unclear. This study aimed to investigate its therapeutic effects and potential mechanisms via network pharmacology and animal experimental validation. METHODS:Paclitaxel-induced CIPN rat models were treated with mWLT pediluvium. The effect of mWLT was estimated by behavior test. The components and targets of 5 herbs in mWLT were screened from TCMSP and TCMIP databases. CIPN-related targets were retrieved from Genecards and DisGeNET. Networks of gene ontology and pathway associations related to intersection targets were constructed and visualized. A pharmacological network encompassing the intersecting genes and active components was mapped out. A protein-protein interaction network was established for these intersecting targets and visualized using Cytoscape software. Finally, the findings derived from network pharmacology were validated through a series of in vivo experiments, including ELISA, Western Blot, immunohistochemistry and RT-qPCR. Molecular docking was used to predict binding sites between small molecules of mWLT and CX3CR1. RESULTS:mWLT ameliorates mechanical withdrawal threshold of CIPN model rats. Three hundred and three targets of mWLT against CIPN were identified through intersection analysis, and 8 hub targets such as IL6, TNF and STAT3 were pinpointed. Enrichment analysis of intersection targets highlighted cellular response to cytokine stimulus, JAK-STAT3 pathway and NF-κB pathway. Thus, we speculated that mWLT may exert its effects by acting on IL6 and TNF, subsequently regulating IL6-JAK-STAT3 and TNFα-NF-κB signaling pathway, ultimately mitigating CIPN. Experimental validation demonstrated that mWLT significantly decreased the levels of IL-6, IL-1β and TNF-α in both spinal cord and plasma. Additionally, mWLT downregulated the phosphorylation of JAK, STAT3 and NF-κB in spinal cord. Further analyses using Immunohistochemistry, Western Blot and ELISA confirmed that mWLT reduced the protein expression of CX3CL1. RT-qPCR results revealed downregulation of Cx3cl1 and Cx3cr1 mRNA level in spinal cord and dorsal root ganglia. Molecular docking predicts 4 potential of compounds derived from mWLT to treat CIPN targeting CX3CR1. CONCLUSION:mWLT exerts therapeutic effects in the treatment of CIPN by inhibiting CX3CL1/CX3CR1 axis and modulating JAK-STAT3 and NF-κB pathway.

AbstractThis study aimed to develop an efficient one-pot synthesis for high-yield, high-purity neocryptotanshinone (compound 3), characterize its oral acute toxicity in compliance with regulatory guidelines, and evaluate its cardioprotective potential against doxorubicin-induced cardiotoxicity. The compound was synthesized, purified and verified by nuclear magnetic resonance spectroscopy, high-resolution mass spectrometry, and high-performance liquid chromatography, with a yield of more than 80% and a purity of more than 99.0%. The acute toxicity test conducted according to the OECD 420/423 guidelines showed that the median lethal dose of compound 3 was 1000 - 1500 mg/kg, with toxic signs reversible within 48 hours. No marked organ toxicity was observed at 1000 mg/kg, while only male mice displayed hippocampal neuron atrophy above 1500 mg/kg. In vitro, compound 3 exhibited lower cytotoxicity and comparable cardiomyocyte protection relative to commercial references. In vivo, it ameliorated cardiac dysfunction, mitigated myocardial damage, decreased oxidative stress and inhibited apoptosis in doxorubicin-treated mice. This work provides toxicologically sound data supporting the scalable preparation and safety profile of neocryptotanshinone, furnishing scientific evidence relevant to regulatory risk assessment and supporting its further development for human health applications.

ObjectiveTherapeutic angiogenesis has become a promising approach for treating ischemic heart disease (IHD). The present study aims to investigate the effects of Qishen Granule (QSG) on angiogenesis in myocardial ischemia (MI) and the potential mechanism.MethodsIn vivo study was conducted on rat model of myocardial infarction. QSG was performed daily at a dose of 2.352 g/kg for four weeks. Cardiac function was assessed by echocardiogram and pro-angiogenic effects were evaluated by Laser Doppler and CD31 expression. Oxygen-glucose deprivation (OGD) was applied in cultured human umbilical vein endothelial cells (HUVECs). Cell viability, wound healing and tube formation assay were used to test functions of HUVECs. ELISA and Western blots were used to assess protein expressions of bone morphogenetic protein 2-delta-like 4-notch homolog 1 (BMP2-Dll4-Notch1) signaling pathway.ResultsThe results showed that QSG improved heart function, cardiac blood flow and microvessel density in myocardial ischemic rats. In vitro, QSG protected HUVECs by promoting the cell viability and tube formation. QSG upregulated bone morphogenetic protein-2 (BMP2) and downregulated delta-like 4 (Dll4) and notch homolog 1 (Notch1) expressions both in rats and HUVECs.ConclusionQSG protected against MI by promoting angiogenesis through BMP2-Dll4-Notch1 pathway. BMP2 might be a promising therapeutic target for IHD.

Chemotherapy-induced cardiovascular disease has become one of the main causes of death in cancer survivors. Several international authoritative societies have developed a number of guidelines to standardize clinical practice for the emerging discipline of cardio-oncology, aiming to allow patients to receive cancer treatment while reducing the risk of cardiovascular events. Anthracyclines, as the earliest first-line chemotherapy drugs, have attracted much attention from researchers due to their severe cardiotoxicity. Although targeted therapy and immunotherapy strategies improve anticancer efficacy, they also increase the risk of cardiotoxicity. Therefore, anthracyclines are still indispensable in cancer treatment, and in-depth understanding of the mechanism of cardiotoxicity will help to develop effective therapeutic strategies. This review aims to summarize the new mechanisms of cardiotoxicity caused by anthracyclines and current emerging therapeutic strategies.

Ethnopharmacological relevance Shenling Baizhu San (SLBZS) is a Traditional Chinese Medicine (TCM) formula composed of 10 medicinal herbs, historically used to strengthen the spleen, replenish qi, and alleviate fatigue-related symptoms. SLBZS originates from the 'Taiping Huimin Heji Ju Fang' of the Song Dynasty. Central fatigue (CF), a subtype of fatigue, is considered in TCM to be closely associated with spleen deficiency. However, there is currently a lack of research on SLBZS's therapeutic effects on CF and the pharmacological mechanisms underlying its potential benefits. Aim of the study This study aims to assess the effects of SLBZS on CF in rats induced by the Modified Multiple Platform Method (MMPM) and to elucidate the underlying mechanisms, focusing on mitochondrial biogenesis and SIRT1/PGC-1α pathway regulation. Materials and methods CF was induced in male Wistar rats using MMPM, involving intermittent sleep deprivation over 21 days. SLBZS was administered at low(LSLBZS), medium(MSLBZS), and high doses(HSLBZS). Chemical components of SLBZS were identified and quantified using Liquid Chromatography-Tandem Mass Spectrometry(LC-MS/MS). Behavioral tests evaluated physical performance, emotional state, and cognitive function, while serum biochemical markers, mitochondrial morphology, and the protein and gene expression levels of the SIRT1/PGC-1α pathway were analyzed to explore underlying mechanisms. Results A total of 141 main compounds in SLBZS were identified, comprising various components such as flavonoids, phenylpropanoids, terpenoids, among others. SLBZS significantly improved physical performance, alleviated negative emotions, and enhanced cognitive function in CF rats. Biochemically, SLBZS increased serum ATP levels and reduced fatigue-related markers. Mitochondrial analysis demonstrated that SLBZS reversed mitochondrial degeneration, increased mitochondrial number, and increased mtDNA copy number in the hippocampus. Furthermore, SLBZS upregulated SIRT1 /PGC-1α pathway expression at both the protein and gene levels in the hippocampus. Notably, the HSLBZS group demonstrated particularly pronounced effects. Conclusion SLBZS significantly alleviates CF symptoms enhances mitochondrial function via upregulating the SIRT1/PGC-1α pathway, positioning it as a promising alternative for CF management by addressing both its physiological and symptomatic aspects.

OBJECTIVE:To study the effect of Shexiang Tongxin Dropping Pill (STDP) on angiogenesis in diabetic cardiomyopathy mice with coronary microcirculation dysfunction (CMD). METHODS:According to a random number table, 6 of 36 SPF male C57BL/6 mice were randomly selected as the control group, and the remaining 30 mice were injected with streptozotocin intraperitoneally to replicate the type 1 diabetes model. Mice successfully copied the diabetes model were randomly divided into the model group, STDP low-dose group [15 mg/(kg·d)], medium-dose group [30 mg/(kg·d)], high-dose group [60 mg/(kg·d)], and nicorandil group [15 mg/(kg·d)], 6 in each group. The drug was given by continuous gavage for 12 weeks. The cardiac function of mice in each group was detected at the end of the experiment, and coronary flow reserve (CFR) was detected by chest Doppler technique. Pathological changes of myocardium were observed by hematoxylin-eosin staining, collagen fiber deposition was detected by masson staining, the number of myocardial capillaries was detected by platelet endothelial cell adhesion molecule-1 staining, and the degree of myocardial hypertrophy was detected by wheat germ agglutinin staining. The expression of the vascular endothlial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) signaling pathway-related proteins in myocardial tissue was detected by Western blot. RESULTS:Compared with the model group, medium- and high-dose STDP significantly increased the left ventricular ejection fraction and left ventricular fraction shortening (P<0.01), obviously repaired the disordered cardiac muscle structure, reduced myocardial fibrosis, reduced myocardial cell area, increased capillary density, and increased CFR level (all P<0.01). Western blot showed that high-dose STDP could significantly increase the expression of VEGF and promote the phosphorylation of vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase, protein kinase B, and eNOS (P<0.05 or P<0.01). CONCLUSION:STDP has a definite therapeutic effect on diabetic CMD, and its mechanism may be related to promoting angiogenesis through the VEGF/eNOS signaling pathway.

Myocardial infarction-induced heart failure(HF)is the leading cause of mortality and disability worldwide[1].Studies have established that HF is characterized by impaired mitochondrial energy production[2].Hence,pharmacological targeting of energy production pathways has emerged as a promising strategy against HF[3].Retinoid X receptor α(RXRα)is a ligand-activated tran-scription factor.It can form homodimers or heterodimers to acti-vate the transcription of genes involved in substrate utilization and oxidative phosphorylation[4].Of these,RXRα homodimers have been shown to regulate mitochondrial complex I in a ligand activation-dependent manner and subsequently control the rate of substrate utilization and ATP production[5].Therefore,RXRαhomodimers are an ideal target for regulating energy metabolism in mitochondria,and their activation is a promising strategy for HF treatment[6].However,agonists with high affinity and specific activation of RXRα homodimers are currently lacking.The develop-ment of selective agonists of RXRα homodimers for use as cardio-protective agents is thus urgently needed.

BackgroundDoxorubicin (DOX) is widely used for the treatment of a variety of cancers. However, its clinical application is limited by dose-dependent cardiotoxicity. Recent findings demonstrated that autophagy inhibition and apoptosis of cardiomyocytes induced by oxidative stress dominate the pathophysiology of DOX-induced cardiotoxicity (DIC), however, there are no potential molecules targeting on these.PurposeThis study aimed to explore whether aucubin (AU) acting on inimitable crosstalk between NRF2 and HIPK2 mediated the autophagy, oxidative stress, and apoptosis in DIC, and provide a new and alternative strategy for the treatment of DIC.Methods and ResultsWe first demonstrated the protection of AU on cardiac structure and function in DIC mice manifested by increased EF and FS values, decreased serum CK-MB and LDH contents and well-aligned cardiac tissue in HE staining. Furthermore, AU alleviated DOX-induced myocardial oxidative stress, mitochondrial damage, apoptosis, and autophagy flux dysregulation in mice, as measured by decreased ROS, 8-OHdG, and TUNEL-positive cells in myocardial tissue, increased SOD and decreased MDA in serum, aligned mitochondria with reduced vacuoles, and increased autophagosomes. In vitro, AU alleviated DOX-induced oxidative stress, autophagy inhibition, and apoptosis by promoting NRF2 and HIPK2 expression. We also identified crosstalk between NRF2 and HIPK2 in DIC as documented by overexpression of NRF2 or HIPK2 reversed cellular oxidative stress, autophagy blocking, and apoptosis aggravated by HIPK2 or NRF2 siRNA, respectively. Simultaneously, AU promoted the expression and nuclear localization of NRF2 protein, which was reversed by HIPK2 siRNA, and AU raised the expression of HIPK2 protein as well, which was reversed by NRF2 siRNA. Crucially, AU did not affect the antitumor activity of DOX against MCF-7 and HepG2 cells, which made up for the shortcomings of previous anti-DIC drugs.ConclusionThese collective results innovatively documented that AU regulated the unique crosstalk between NRF2 and HIPK2 to coordinate oxidative stress, autophagy, and apoptosis against DIC without compromising the anti-tumor effect of DOX in vitro.

Objective To study the protective effect of Qishen Granules and modified formulas on cardiac hypertrophy induced by pressure overload.Methods The cardiac hypertrophy model was constructed by minimally transverse aortic constriction in C57BL/6J mice.After the operation, model mice were randomly divided into a model group, a Qishen Granules group, a qi-benefiting group, and a yang-warming, blood-activating, and toxin-removing group.A sham operation group was set up for control.Corresponding drugs or solvents were administered by gavage every day.After four weeks of treatment, the mice were evaluated by echocardiography for left ventricular posterior wall thickness at end-diastole（LVPWd）,left ventricular posterior wall thickness at end-systole（LVPWs）,left ventricular internal dimension at end-diastole（LVIDd）,left ventricular internal dimension at end-systole（LVIDs）,and systolic function[ejection fraction（EF）and fractional shortening（FS）]in the physiological state.Body weifht（BW）,heart weight（HW）,lung weight（LW）,and tibial length（TL）were measured and organ coefficients were calculated.Morphological changes of the heart, cardiomyocytes, and cardiac fibrosis were assessed by observing macroscopic specimens, WGA staining, and Masson staining.Results Compared with the sham operation group, the model group showed increased LVPWd, LVPWs, LVIDd, and LVIDs, decreased EF and FS,increased HW/BW and HW/TL,enlarged heart and cross-sectional area of cardiomyocytes, and severe cardiac fibrosis（P＜0.01）.The above abnormal changes in the Qishen Granules group and modified formulas group were improved to different degrees as compared with the conditions in the model group（P＜0.05,P＜0.01）,and the Qishen Granules group showed the optimal effect.The efficacy of the yang-warming, blood-activating, and toxin-removing group was similar to that in the Qishen Granules group, while the qi-benefiting group showed an improving trend with significant differences in some indicators.Conclusion Qishen Granules and modified formulas can ameliorate cardiac hypertrophy, fibrosis and dysfunction.There is a synergistic effect of qi-benefiting drugs and yang-warming, blood-activating, and toxin-removing drugs, and the whole prescription can play the optimal curative effect.

手诊纹路诊断法是观察手部纹路进行疾病诊断的方法,是手诊法中的重要组成部分,是临床疾病诊断的重要辅助手段,但学界对此尚缺乏系统、充分的研究.本文对具代表性的手纹诊断法望小儿指纹法、手诊九宫八卦诊法、星丘学说诊法、皮肤纹理学等进行学术流派溯源与诊断特点探讨,并阐述各学说对手纹诊断法的理论影响,以期推动手诊法的继承与发展,为研究者提供便利.

目的 基于HSP27-TLR4/NF-κB通路探讨芪参颗粒对大鼠心肌梗死后炎症反应的影响及潜在机制.方法 48只雄性SD大鼠分别进行左冠状动脉前降支结扎术造模或假手术,将假手术大鼠分为对照组、芪参颗粒对照组,造模大鼠分为模型组和芪参颗粒组.术后24 h予芪参颗粒(2.352 g/kg)或蒸馏水灌胃,每日1次,连续1周.超声检测大鼠心功能,免疫荧光、HE和Masson染色评估心肌结构、炎症及纤维化改变,ELISA检测血浆热休克蛋白27(HSP27)含量,Western blot检测心肌组织Toll样受体(TLR)4 和核因子-κB(NF-κB)蛋白表达.结果 与对照组比较,模型组大鼠左室舒张末期前壁厚度、左室收缩末期前壁厚度(LVAWs)、左室舒张末期后壁厚度(LVPWd)、左心室收缩末期后壁厚度、射血分数(EF)和短轴缩短率(FS)显著降低(P<0.01),左室舒张末期内径、左室收缩末期内径(LVIDs)、左室舒张末期容积、左室收缩末期容积(LVESV)显著升高(P<0.05,P<0.01);心肌细胞大量坏死,梗死边缘区心肌细胞代偿性肥大且排列紊乱,血管旁和心肌间质内大量炎性细胞浸润和胶原纤维沉积;血浆HSP27含量显著增加(P<0.01),心肌组织TLR4、NF-κB p65蛋白表达显著升高(P<0.05).与模型组比较,芪参颗粒组大鼠LVAWs、LVPWd、EF和FS显著升高,LVIDs、LVESV显著降低(P<0.05,P<0.01);心肌组织炎性细胞浸润、心肌细胞存活情况和间质纤维化情况显著改善;血浆HSP27含量显著减少(P<0.01),心肌组织TLR4、NF-κB p65蛋白表达显著降低(P<0.05).结论 芪参颗粒可能通过降低血浆HSP27含量抑制TLR4/NF-κB通路,从而减轻炎症反应,改善心肌梗死后心室重构和心功能下降.

BACKGROUND:Aggrephagy is a critical compensatory mechanism for the elimination of misfolded proteins resulting from stress and depends on the autolysosome degradation of protein aggregates. However, there have been few mechanism research related to aggrephagy in myocardial ischemia/reperfusion (I/R) injury. Neocryptotanshinone (NCTS) is a fat-soluble active compound extracted from Salvia miltiorrhiza, and may be cardioprotective against I/R. However, the efficacy and specific mechanism of NCTS on I/R have not been studied.PURPOSE:The current study aimed to investigate the molecular mechanism of NCTS involved in the therapeutic effect on I/R, with a special emphasis on the up-regulation of the ERK1/2-Nrf2-LAMP2 pathway to increase autolysosomal degradation during aggrephagy.METHODS:A rat model of myocardial I/R injury was constructed by left anterior descending (LAD) ligation-reperfusion. To verify cardiac protection, autolysosome clearance of protein aggregates, and their intracellular biological mechanism, an oxygen-glucose deprivation/recovery (OGD/R)-induced H9c2 cardiomyocyte model was created.RESULTS:NCTS was found to have a significant cardioprotective effect in I/R rats as evidenced by remarkably improved pathological anatomy, decreased myocardial damage indicators, and substantially enhanced cardiac performance. Mechanistically, NCTS might boost the levels of LAMP2 mRNA and protein, total and Ser40 phosphorylated Nrf2, and Thr202/Tyr204p-ERK1/2 protein. Simultaneously, the cytoplasmic Nrf2 level was reduced after NCTS administration, which was contrary to the total Nrf2 content. However, these beneficial changes were reversed by the co-administration with ERK1/2 inhibitor, PD98059. NCTS therapy up-regulated Rab7 protein content, Cathepsin B activity, and lysosomal acidity, while down-regulating autophagosome numbers, Ubiquitin (Ub), and autophagosome marker protein accumulations through the above signaling pathway. This might indicate that NCTS enhanced lysosomal fusion and hydrolytic capacity. It was also found that NCTS intervention limited oxidative stress and cellular apoptosis both in vivo and in vitro.CONCLUSIONS:We reported for the first time that NCTS promoted the autolysosome removal of protein aggregation both in vivo and in vitro, to exert the therapeutic advantages of myocardial I/R injury. This was reliant on the up-regulation of the ERK1/2-Nrf2-LAMP2 signaling pathway.

BACKGROUND:Although the development of therapies for heart failure (HF) continues apace, clinical outcomes are often far from ideal. Unc51-like-kinase 1 (ULK1)-mediated mitophagy prevents pathological cardiac remodeling and heart failure (HF). Molecularly ULK1-targeted agent to enhance mitophagy is scanty.HYPOTHESIS/PURPOSE:This study aimed to investigate whether Ginsenoside Rg3 (Rg3) can activate ULK1 to trigger FUNDC1-mediated mitophagy for protecting heart failure.METHODS:Molecular docking and surface plasmon resonance were used to detect the ULK1 binding behavior of Rg3. Established HF model in rats and transcriptome sequencing were used to evaluate the therapeutic effect and regulatory mechanism of Rg3. Loss-of-function approaches in vivo and in vitro were performed to determine the role of ULK1 in Rg3-elicited myocardial protection against HF. FUNDC1 recombinant plasmid of site mutation was applied to elucidate more in-depth mechanisms.RESULTS:Structurally, a good binding mode was unveiled between ULK1 and Rg3. In vivo, Rg3 improved cardiac dysfunction, adverse remodeling, and mitochondrial damage in HF rats. Furthermore, Rg3 promoted Ulk1-triggered mitophagy both in vivo and in vitro, manifested by the impetus of downstream Fundc1-Lc3 interaction. Of note, the protective effects conferred by Rg3 against mitophagy defects, pathological remodeling, and cardiac dysfunction were compromised by Ulk1 gene silencing both in vivo and in vitro. Mechanistically, Rg3 activated mitophagy by inducing ULK1-mediated phosphorylation of FUNDC1 at the Ser17 site, not the Ser13 site.CONCLUSION:Together these observations demonstrated that Rg3 acts as a ULK1 activator for the precise treatment of HF, which binds to ULK1 to activate FUNDC1-mediated mitophagy.

目的 通过观测阿霉素诱导的心脏毒性(doxorubicin-induced cardiactoxicity,DIC)小鼠模型的宏观体征和微观指标,建立稳定的DIC病证结合动物模型,探讨DIC小鼠模型中医证候变化规律.方法 将20只SPF级C57 BL/6野生型小鼠随意分为模型组和正常组,每组10只,模型组小鼠行尾静脉注射阿霉素5 mg/kg,正常组小鼠尾静脉注射生理盐水,1次/周,共注射4周.每次尾静脉注射第2天,观察小鼠一般状况,统计小鼠舌色三原色(RGB)比值、负重力竭游泳时间.采用超声心动检测及病理苏木精-伊红(HE)染色、Masson染色、TUNEL染色进行模型评价.生化法检测小鼠血清乳酸脱氢酶(LDH)、肌酸激酶同工酶(CK-MB)、丙二醛(MDA)、血清超氧化物歧化酶(SOD)、一氧化氮(NO)及小鼠组织三磷酸腺苷(ATP)含量.结果 造模第1周,与正常组比较,模型组小鼠精神萎靡,活动喘息加重、活动减少、体质量下降(P<0.05)、力竭游泳时间缩短(P<0.05);第2周起,小鼠舌质暗红出现瘀斑,舌质r值降低(P<0.01),g、b值升高(P<0.05).与正常组比较,模型组小鼠LDH、CK-MB和MDA含量增加(P<0.01),SOD、NO及ATP含量降低(P<0.01).结论 DIC小鼠模型,宏观体征、证候随时间延长和疾病进展,综合微观血生化及宏观指征结果,DIC小鼠模型1周出现气虚证,2～4周逐渐演变为气虚血瘀证.

中枢疲劳属于疲劳的亚型之一,是由于中枢神经系统功能失常,从而导致躯体、神经、心理等系列的疲劳样反应.近年来,中枢疲劳发生率逐年升高,已成为困扰人们健康的主要问题之一.本文结合现代医学概念及特征阐述中枢疲劳的中医理论内涵及辨证思路,从病因、病机、症状等方面进行探析论述,认为中枢疲劳的中医药内涵为"神劳""神疲",其病位在"脾",病性属"湿",从脾虚湿盛论治中枢疲劳更符合现代人的疲劳状态.

Aim: Inflammation and fibrosis have been shown to be critical factors in heart failure (HF) progression. Calycosin (Cal) is the major active component of Astragalus mongholicus Bunge and has been reported to have therapeutic effects on the cardiac dysfunction after myocardial infarction. However, whether Cal could ameliorate myocardial infarction (MI)-induced inflammation and fibrosis and precise mechanisms remain uncertain. The aim of this study is to explore the role of Cal in HF and to clarify the underlying mechanisms.Methods: For in vivo experiments, rats underwent left anterior descending artery ligation for heart failure model, and the cardioprotective effects of Cal were measured by echocardiographic assessment and histological examination. RNA-seq approach was applied to explore potential differential genes and pathways. For further mechanistic study, proinflammatory-conditioned media (conditioned media)-induced H9C2 cell injury model and TGFβ-stimulated cardiac fibroblast model were applied to determine the regulatory mechanisms of Cal.Results: In the in vivo experiments, echocardiography results showed that Cal significantly improved heart function. GO and reactome enrichment revealed that inflammation and fibrosis pathways are involved in the Cal-treated group. KEGG enrichment indicated that the PI3K–AKT pathway is enriched in the Cal-treated group. Further experiments proved that Cal alleviated cardiomyocyte inflammatory responses evidenced by downregulating the expressions of phosphorylated IκB kinase α/β (p-IKKα/β), phosphorylated nuclear factor kapa B (p-NFκB), and tumor necrosis factor α (TNFα). Besides, Cal effectively attenuated cardiac fibrosis through the inhibitions of expressions and depositions of collagen I and collagen III. In the in vitro experiments, the phosphatidylinositol three kinase (PI3K) inhibitor LY294002 could abrogate the anti-inflammation and antifibrosis therapeutic effects of Cal, demonstrating that the cardioprotective effects of Cal were mediated through upregulations of PI3K and serine/threonine kinase (AKT).Conclusion: Cal inhibited inflammation and fibrosis via activation of the PI3K–AKT pathway in H9C2 cells, fibroblasts, and heart failure in postacute myocardial infarction rats.

目的 探究丹七片(DQP)基于神经酰胺通路抗心肌脂毒性的药效及机制研究.方法 利用冠状动脉左前降支结扎术制备心肌梗死后心力衰竭动物模型,分为假手术组、模型组、丹七片组、辛伐他汀组.利用超声、血生化、病理切片染色、蛋白免疫印迹法(Western Blot)和酶联免疫吸附(ELISA)法等技术进行相应指标的检测.结果 与模型组比较,丹七片组左心室射血分数(LVEF)和左心室短轴缩短率(LVFS)升高(P<0.01或P<0.001),而左室收缩末期内径(LVESD)和左室舒张末期内径(LVEDD)降低(P<0.05或P<0.01).苏木精-伊红(HE)和Masson染色显示,丹七片能够减轻小鼠心肌损伤的程度,改善病理结构变化.血清检测结果提示丹七片可以有效降低心肌损伤标志物肌酸激酶同工酶(P<0.05)、肌钙蛋白I(P<0.001)的表达,进而减轻心脏损伤程度.此外,丹七片干预后可明显下调单链丝氨酸棕榈酰转移酶长链1(SPTLC1)及SPT长链2(SPTLC2)蛋白的表达(P<0.05或P<0.01),并明显降低心肌组织内神经酰胺含量(P<0.001).结论 丹七片可能通过调控从头合成途径关键限速酶单链丝氨酸棕榈酰转移酶来降低心力衰竭小鼠心肌神经酰胺水平,从而改善小鼠心功能,减轻心肌损伤.

BackgroundMitophagy can regulate mitochondrial homeostasis, preserve energy metabolism and cardiomyocytes survival effectively to restrain the development of heart failure (HF). Danqi Pill (DQP), composed of the dry roots of Salvia miltiorrhiza Bunge and Panax notoginseng, is included in the 2015 national pharmacopeia and effective in the clinical treatment of coronary heart diseases. Our previous studies have approved that DQP exerted remarkable cardioprotective effects on HF. However, the effect and mechanism of DQP on mitophagy have not been proved yet.Hypothesis/PurposeWe aim to explore whether DQP regulates mitophagy to protect against HF and to elucidate the in-depth mechanism.Study DesignThe HF rat model for evaluating DQP's efficacy was established with left anterior descending coronary artery ligation. The oxygen-glucose deprivation-reperfusion-induced cardiomyocyte model was conducted to clarify the potential mechanism of DQP.MethodsThe mitochondria-targeted fluorescent protein Keima (mt-Keima) was applied for detecting mitophagy flux. Co-immunofluorescence and co-immunoprecipitation were performed to detect protein co-localization. Flow cytometry for JC-1 and Annexin-FITC/PI staining was utilized for assessing mitochondrial activity and function.ResultsIn vivo, medium dose of DQP (1.5 g/kg) notably improved cardiac function and inhibited cardiac apoptosis in HF rats. Co-immunofluorescent staining of LC3B and TOM20 showed that DQP restored mitophagy. Further co-immunoprecipitation demonstrated that DQP increased the co-localization of FUNDC1 with either ULK1 or PGAM5. In vitro, DQP markedly protected mitochondrial membrane potential damage, reduced cardiomyocytes apoptosis, decreased the level of mitochondrial ROS, and increased the ATP level. Parallel with the in vitro results, DQP increased the interaction of FUNDC1 and LC3B, while knockdown of FUNDC1 diminished the interaction. Besides, Mt-Keima signaling detection further confirmed that DQP significantly promoted mitophagy. Intriguingly, knockdown of ULK1 or PGAM5 separately weakened rather than eliminated these effects of DQP on FUNDC1-mediated mitophagy, mitochondrial homeostasis and energy metabolism.ConclusionOur results demonstrated that DQP protected against HF by improving FUNDC1-mediated mitophagy to perverse energy metabolism through the coordinated regulation of ULK1 and PGAM5.

Doxorubicin (DOX) is an anthracycline chemotherapy drug, which is indispensable in antitumor therapy. However, its subsequent induction of cardiovascular disease (CVD) has become the primary cause of mortality in cancer survivors. Accumulating evidence has demonstrated that cardiac mitochondrial bioenergetics changes have become a significant marker for doxorubicin-induced cardiotoxicity (DIC). Here, we mainly summarize the related mechanisms of DOX-induced cardiac mitochondrial bioenergetics disorders reported in recent years, including mitochondrial substrate metabolism, the mitochondrial respiratory chain, myocardial ATP storage and utilization, and other mechanisms affecting mitochondrial bioenergetics. In addition, intervention for DOX-induced cardiac mitochondrial bioenergetics disorders using chemical drugs and traditional herbal medicine is also summarized, which will provide a comprehensive process to study and develop more appropriate therapeutic strategies for DIC.