Accumulation of damaged mitochondria is a well-established hallmark of age-related neurodegenerative disorders, including Alzheimer's disease (AD). Increasing evidence suggests that mitophagy, a selective autophagic degradation of damaged mitochondria, plays an important role in AD progression. The interaction between mitophagy deficits and amyloid-β (Aβ) or Tau pathology may establish a vicious cycle that ultimately results in neuronal damage and death. Mitochondrial dysfunction exacerbates AD pathogenesis by activating the NLRP3 inflammasome, whereas modulation of mitophagy may confer neuroprotection by attenuating inflammation in neurons and microglia. Pathological ferroptosis has emerged as a potential key driver of AD, with mitophagy intriguingly demonstrating a dual role in this process. In this review, we elucidate the molecular mechanisms underlying mitophagy and its involvement in AD, thereby providing insights into AD pathogenesis. We further highlight the therapeutic potential of targeting mitophagy as a promising strategy for AD intervention.

目的:观察利胆化痰活血方对高脂高糖高盐饮食诱导的代谢综合征大鼠肥胖相关指标的影响.方法:将42只SD大鼠随机分为普通饲料喂养的空白组(Control组,9只)和高脂高糖高盐饮食喂养的造模组(Model组,33只),喂养12周建立代谢综合征大鼠模型.成模后将模型组分为代谢综合征组(MS组,8只)、利胆化痰活血方低剂量组(LHH-L组,8只)、利胆化痰活血方中剂量组(LHH-M组,8只)、利胆化痰活血方高剂量组(LHH-H组,9只),药物组分别予相应药物,Control组和MS组予生理盐水,灌胃6周.各组分别测量大鼠体质量、腹围、体长,取材后称量肝湿质量、内脏脂肪质量,计算肝体比和Lee's肥胖指数.结果:干预6周后,与MS组比较,LHH-H组体质量、肝湿质量、肝体比、Lee's肥胖指数均降低(P＜0.05),内脏脂肪质量、脂肪系数显著降低(P＜0.01);肝脏脂肪变程度明显减轻.结论:利胆化痰活血方能够改善MS大鼠肥胖指标.

目的 观察利胆化痰活血方(LHH)对代谢综合征SD大鼠胆汁酸代谢的影响.方法 将24只雄性SD大鼠随机分为空白组(Control组,n=8)和模型组(Model组,n=16),Control组大鼠予普通饲料,Model组大鼠予高脂高糖高盐饲料喂养12周造模,成模后,将Model组按随机原则分代谢综合征组(MS组)与利胆化痰活血方组(LHH组),每组8只.LHH组灌胃6周后,对大鼠肝脏、粪便和血清取材进行胆汁酸检测.结果 LHH干预6周,与MS组比较,LHH组大鼠粪便石胆酸(LCA)含量显著降低(P<0.05),肝组织牛磺石胆酸(TLCA)含量显著升高(P<0.05),血清样本中胆酸(CA)、鹅去氧胆酸(CDCA)含量显著升高(P<0.05).结论 LHH能够改善MS大鼠胆汁酸代谢.

Objective. To explore the potential active components and corresponding target herb pairs of Radix Ginseng (Renshen) and Radix Bupleuri (Chaihu) in the treatment of nonalcoholic fatty liver disease (NAFLD) through network pharmacology and in vitro experiments. Methods. The active components and potential targets of the herb pair of Renshen and Chaihu were screened through a network database system, and Venn analysis was performed with the obtained NAFLD targets. The intersecting targets were analysed for gene ontology (GO) functions and Kyoto Encyclopedia of Genes and Genome (KEGG) pathways, and a protein-protein interaction (PPI) network was generated. Cytoscape software was used to construct active component-target networks of the Renshen and Chaihu herb pair. Free fatty acids were added to the HepG2 cell line to create high-fat models that were treated with different concentrations of stigmasterol. The effect of stigmasterol on the lipid metabolism in HepG2 cells and PPARγ-knockdown cells was determined by oil red O staining, Nile red staining, and TG level. PPARγ and UCP-1 mRNA, and protein expression levels were detected by qRT-PCR and Western blot analyses, respectively. Results. Twenty active components obtained from the Renshen and Chaihu herb pair were identified. The herb pair active component-target network showed that both Renshen and Chaihu contained stigmasterol and kaempferol as active components. The PPI network comprised 63 protein nodes. GO enrichment analysis and KEGG pathway enrichment analysis showed that the targets were mainly involved in lipid metabolism. Eight core targets were identified: AKT1, PPARG, MAPK3, TNF, TP53, SIRT1, STAT3, and PPARA. In vitro experiments demonstrated that stigmasterol reduced lipid accumulation and TG levels in HepG2 cells, and the mechanism may have been related to the activation of the PPARγ-UCP-1 signalling pathway. Conclusion. This study preliminarily illustrated the potential components and corresponding core targets of the Renshen and Chaihu herb pair in treating NAFLD. The effect of stigmasterol on the PPARγ-UCP-1 signalling pathway in enhancing lipid metabolism may represent one of the mechanisms of the Renshen and Chaihu herb pair in the treatment of NAFLD. The results provide new evidence and research insights to reveal the roles of Renshen and Chaihu in the management of NAFLD.

慢性疲劳综合征( chronic fatigue syndrome, CFS)是一组持续或反复发作半年以上,且排除其他疾病或药物导致的不明原因的疲劳为主要特征的全身性症候群,并常伴低热(或自觉发热)、头痛、咽痛、无红肿的关节疼痛、肌肉酸痛等躯体症状,以及短期内的记忆力减退、注意力不易集中、睡眠障碍、焦虑抑郁等精神心理症状.

BackgroundMetabolic syndrome (MS) is a group of complex medical conditions that can lead to serious cardiovascular and cerebrovascular diseases. According to the theory of traditional Chinese medicine (TCM), MS can be divided into two main subtypes termed 'phlegm-dampness syndrome' (TSZE) and 'qi-yin deficiency syndrome' (QYLX). At present, the research into intestinal microbiota of different TCM syndromes of MS and its association with clinical manifestation is lacking. Materials and methodsUsing 16S rRNA sequencing, we performed a cross-sectional analysis of human gut microbiota between two different TCM syndromes (QYLX and TSZE, n=60) of MS, and their differences with healthy participants (n=30). ResultsWe found that the QYLX and TSZE groups differ from the healthy control group in the overall gut microbiota composition, and some specific microbial taxa and functional pathways. Moreover, significantly differentially abundant taxa and distinct BMI-correlated taxa were observed between QYLX and TSZE groups, suggesting the potential contribution of gut microbiota to the distinction between the two TCM syndromes. The predicted functional profiles also showed considerable differences, especially pathways related to amino acid metabolism and lipopolysaccharide synthesis. ConclusionOur study highlights the gut microbiota's contribution to the differentiation between two TCM syndromes of MS and may provide the rationale for adopting different microbiota-directed treatment strategies for different TCM syndromes of MS in the future.

目的 利用网络药理学和分子对接技术探讨利胆化痰活血方治疗代谢综合征的药效活性成分及作用机制.方法 通过TCMSP数据库(http://tcmspw.com/tcmsp.php)和SwissTargetPrediction(http://www.swisstargetprediction.ch)筛选利胆化痰活血方的有效成分及靶点,从DisGeNET数据库(https://www.disgenet.org)中获取代谢综合征疾病靶点,与利胆化痰活血方有效成分靶点进行韦恩分析.针对利胆化痰活血方有效成分和代谢综合征相关靶点进行GO功能分析与KEGG通路富集分析,并建立交集靶点的PPI网络和有效成分-核心靶点关联网络.利用分子对接技术预测有效成分与靶点的潜在结合活性.结果 网络药理学分析得出38个活性成分和14个靶点组成的129个有效成分与靶点组合可能是其潜在起效组合.其作用通路与内分泌抵抗,EGFR酪氨酸激酶抑制剂耐药,HIF-1信号通路,FoxO信号通路,Rap1信号通路,MAPK信号通路,ErbB信号通路,鞘脂信号通路,Ras信号通路,趋化因子信号通路相关.分子对接将其聚焦到AKT1,PPARG及MMP9三个靶点中,动物实验显示,代谢综合征大鼠肝脏中AKT1,PPARG的mRNA水平显著降低(P<0.05,P<0.01),经过利胆化痰活血方治疗后显著升高(P<0.05,P<0.01).结论 本研究发现利胆化痰活血方可能作用于肝脏中AKT1和PPARG治疗代谢综合征,对进一步揭示利胆化痰活血方对代谢综合征的治疗作用提供新的证据和研究思路.

目的 探索不同配伍比例柴胡人参药对对非酒精性脂肪性肝病(NAFLD)大鼠糖脂代谢的影响.方法 将48只Wistar大鼠随机分为正常组(C组)8只和造模组40只.C组给予普通饲料及0.9％NaCl溶液灌胃,造模组给予高脂高糖饲料及0.9％NaCl溶液灌胃,造模成功后将造模组大鼠随机分成模型组(M组)、柴胡人参1∶1组(CR 1∶1组)、柴胡人参1∶2.5组(CR 1∶2.5组)、柴胡人参2.5∶1组(CR2.5∶1组)、奥贝胆酸组(OB组),每组8只.各用药组给予高脂高糖饲料及相应药物灌胃.各组干预结束后称量大鼠体质量、肝湿重,观察病理染色,检测肝功能、血脂、空腹血糖(FBG)、胰岛素敏感指数(ISI)和胰岛素抵抗指数(HOMA-IR).结果 与正常组比较,M组大鼠丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、总胆固醇(TC)、三酰甘油(TG)、FBG、胰岛素含量(FINS)、胰岛素抵抗指数(HOMA-IR)水平升高,胰岛素敏感指数(ISI)水平下降,肝脏脂肪变性及炎症程度加重.与M组比较,各用药组的糖代谢、脂代谢有一定程度的改善.具体而言,各用药组之间比较,CR 2.5∶1组的体质量、肝湿重,以及TC、ALT、AST、FBG、FINS、HOMA-IR、脂肪变性及炎症评分下降较其余两组显著,ISI水平升高也最显著,故柴胡人参配伍2.5∶1时的药效作用最佳;与OB组比较,CR 2.5∶1组体质量水平下降更为显著,而肝湿重、TC、AST、FBG、ISI及炎症评分的改善不如OB组显著.结论 柴胡人参药对可以改善NAFLD大鼠的糖脂代谢,其最佳配伍比例为柴胡与人参2.5∶1.

代谢综合征是心脑血管疾病相关的多种危险因素在体内集结的状态,少阳枢机不利被认为是代谢综合征的使动因素.和解少阳法能够调节人体气血津液,使人体气机通畅,气血运行无阻,津液输布正常,而达到五脏协调,六腑通畅,人体代谢平衡的状态.小柴胡汤是和解少阳的第一方,研究发现小柴胡汤对于代谢综合征组分疾病,即:肥胖、高血压、高血脂、糖尿病等均有良好疗效,笔者基于小柴胡汤和解少阳枢机不利对代谢综合征组分疾病的相关研究展开论述,以期为临床上代谢综合征患者的治疗起到指导作用.

目的:观察利胆化痰活血方对高脂高糖高盐饮食诱导的代谢综合征大鼠糖脂代谢及血压的影响.方法:42只SD大鼠随机分为空白组,模型组,利胆化痰活血方低、中、高剂量(6.25 g· kg-1、12.5 g·kg-、25 g· kg-1)组.采用喂养12周的高脂高糖高盐饮食建立代谢综合征(metabolic syndrome,MS)大鼠模型,空白组大鼠喂养普通饲料.各组大鼠分别予相应药物,空白组和模型组予同体积的生理盐水,连续6周.各组分别测量大鼠尾动脉收缩压,并取腹主动脉血检测血清总胆固醇(total cholesterol,TC)、三酰甘油(triglyceride,TG)、高密度脂蛋白胆固醇(high density lipid protein cholesterol,HDL-C)、低密度脂蛋白胆固醇(low density lipid protein cholesterol,LDL-C)、空腹血糖(fasting blood glucose,FBG)、空腹胰岛素(fasting serum lisulin,FINS)水平,计算胰岛素抵抗指数(insulin resistant index,IRI);选取空白组,模型组和利胆化痰活血方高剂量组,取肝脏,行HE染色,观察光镜下脂肪变程度;评估利胆化痰活血方的疗效.结果:利胆化痰活血方干预6周后,与模型组比较,利胆化痰活血方高剂量组大鼠血清TC、TG、FINS、IRI均明显降低(P＜0.05),显著降低LDL-C、FBG和收缩压水平(P＜0.01);肝脏脂肪变程度明显减轻.结论:利胆化痰活血方能够改善MS大鼠糖脂代谢,并降低血压.

Neuroinflammation-related amyloid-beta peptide (Aβ) accumulation after cerebral ischemia/reperfusion (I/R) accounts for cerebral I/R injuries and poststroke dementia. Recently, pyroptosis, a proinflammatory cell death, has been identified as a crucial pathological link of cerebral I/R injuries. However, whether pyroptosis acts as a trigger of Aβ accumulation after cerebral I/R has not yet been demonstrated. Blood-brain barrier (BBB) and glymphatic system mediated by aquaporin-4 (AQP-4) on astrocytic endfeet are important pathways for the clearance of Aβ in the brain, and pyroptosis especially occurring in astrocytes after cerebral I/R potentially damages BBB integrity and glymphatic function and thus influences Aβ clearance and brain homeostasis. In present study, the method of middle cerebral artery occlusion/reperfusion (MCAO/R) was used for building models of focal cerebral I/R injuries in rats. Then, we used lipopolysaccharide and glycine as the agonist and inhibitor of pyroptosis, respectively, Western blotting for detections of pyroptosis, AQP-4, and Aβ1-42 oligomers, laser confocal microscopy for observations of pyroptosis and Aβ locations, and immunohistochemical stainings of SMI 71 (a specific marker for BBB integrity)/AQP-4 and Nissl staining for evaluating, respectively, BBB-glymphatic system and neuronal damage. The results showed that pyroptosis obviously promoted the loss of BBB integrity and AQP-4 polarization, brain edema, Aβ accumulation, and the formation of Aβ1-42 oligomers and thus increased neuronal damage after cerebral I/R. However, glycine could inhibit cerebral I/R-induced pyroptosis by alleviating cytomembrane damage and downregulating expression levels of cleaved caspase-11/1, N-terminal gasdermin D, NLRP3 (nucleotide-binding domain, leucine-rich repeat containing protein 3), interleukin-6 (IL-6) and IL-1β and markedly abate above pathological changes. Our study revealed that pyroptosis is a considerable factor causing toxic Aβ accumulation, dysfunctional BBB-glymphatic system, and neurological deficits after cerebral I/R, suggesting that targeting pyroptosis is a potential strategy for the prevention of ischemic stroke sequelae including dementia.

目的 探究利胆化痰活血方对代谢综合征伴缺血性脑血管病患者肥胖和糖脂代谢的影响.方法 选择2016年7月1日—2019年6月30日在上海交通大学附属第六人民医院治疗的代谢综合征伴缺血性脑血管病患者180例,采用随机方法将患者分成2组,西医组给予健康生活行为干预及常规西药治疗,联合组在西医组治疗基础上给予利胆化痰活血方治疗,2组均治疗6个月.观察2组患者治疗前后体重、体质指数(BMI)、腰围、空腹血糖(FPG)、空腹胰岛素(FINS)、胰岛素敏感指数(IRI)以及血脂情况,记录2组不良反应发生情况.结果 治疗后,联合组体重、BMI、腰围、FPG、FINS、IRI、三酰甘油(TG)水平均明显低于治疗前及西医组(P均<0.05),高密度脂蛋白胆固醇(HDL-C)水平均明显高于治疗前及西医组(P均<0.05);西医组仅体重、FPG、FINS、IRI、TG水平明显降低(P均<0.05).2组均未发生严重药物不良反应.结论 利胆化痰活血方可显著减轻代谢综合征伴缺血性脑血管病患者肥胖,改善糖脂代谢紊乱.

Amyloid-β peptide (Aβ) accumulation is a detrimental factor in cerebral ischemia/reperfusion (I/R) injuries accounting for dementia induced by ischemic stroke. In addition to blood brain barrier (BBB), the glymphatic system mediated by aquaporin-4 (AQP-4) on astrocytic endfeet functions as an important pathway for the clearance of Aβ in the brain. Cerebral I/R induced astrocytic pyroptosis potentially causes the AQP-4 polarization loss and dysfunctional BBB-glymphatic system exacerbating the accumulation of Aβ. Furthermore, Aβ toxicity has been identified as a trigger of pyroptosis and BBB damage, suggesting an amplified effect of Aβ accumulation after cerebral I/R. Therefore, based on our previous work, this study was designed to explore the intervention effects of Tongxinluo (TXL) on astrocytic pyroptosis and Aβ accumulation after cerebral I/R in rats. The results showed that TXL intervention obviously alleviated the degree of pyroptosis by downregulating expression levels of cleaved caspase-11/1, N-terminal gasdermin D, nucleotide-binding oligomerization domain-like receptors pyrin domain containing 3 (NLRP3), interleukin-6 (IL-6), and cleaved IL-1β and abated astrocytic pyroptosis after cerebral I/R. Moreover, TXL intervention facilitated to restore AQP-4 polarization and accordingly relieve Aβ accumulation around astrocytes in ischemic cortex and hippocampus as well as the formation of toxic Aβ (Aβ1–42 oligomer). Our study indicated that TXL intervention could exert protective effects on ischemic brain tissues against pyroptotic cell death, inhibit astrocytic pyroptosis, and reduce toxic Aβ accumulation around astrocytes in cerebral I/R injuries. Furthermore, our study provides biological evidence for the potential possibility of preventing and treating poststroke dementia with TXL in clinical practice.