Review on dietary supplements as an effective improvement of Alzheimer's disease:focus on structures and mechanisms

Alzheimer’s disease(AD),the major form of neurodegenerative diseases that can severely impede normal cognitive function,makes it one of the most common fatal diseases.There are currently over 50 million AD patients worldwide.The neuropathology of AD is perplexing and there is a scarcity of disease-modifying treatments.Currently,early diagnosis of AD has been made possible with the discovery of biological markers associated with pathology,providing strong support for the improvement of the disease status.The search for inhibitors of AD markers from dietary supplements(DSs)has become a major hot topic.Especially with the widespread use of DSs,DSs containing polyphenols,alkaloids,terpenes,polysaccharides and other bioactive components can prevent AD by reducing Aβdeposition,inhibiting tau protein hyperphosphorylation,reconstructing synaptic dysfunction,weakening cholinesterase activity,regulating mitochondrial oxidative stress,neuronal inflammation and apoptosis.This review summarizes the anti-AD effects of the main DSs and their bioactive constituents,as well as the potential molecular mechanisms covers from 2017 to 2023.Additionally,we discussed the opportunities and challenges faced by DSs in the process of AD prevention and treatment,aiming to further provide new perspectives for functional food development.

Molecular mechanisms underlying the neuroprotection of environmental enrichment in Parkinson’s disease

Parkinson’s disease is the most common movement disorder,affecting about 1%of the population over the age of 60 years.Parkinson’s disease is characterized clinically by resting tremor,bradykinesia,rigidity and postural instability,as a result of the progressive loss of nigrostriatal dopaminergic neurons.In addition to this neuronal cell loss,Parkinson’s disease is characterized by the accumulation of intracellular protein aggregates,Lewy bodies and Lewy neurites,composed primarily of the proteinα-synuclein.Although it was first described almost 200 years ago,there are no disease-modifying drugs to treat patients with Parkinson’s disease.In addition to conventional therapies,non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders.Among such strategies,environmental enrichment,comprising physical exercise,cognitive stimulus,and social interactions,has been assessed in preclinical models of Parkinson’s disease.Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression,enhancing the expression of neurotrophic factors and modulating neurotransmission.In this review article,we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson’s disease,highlighting its influence on the dopaminergic,cholinergic,glutamatergic and GABAergic systems,as well as the involvement of neurotrophic factors.We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson’s disease,highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.

Role of ferroptosis in Parkinson’s disease and intervention mechanism of acupuncture and moxibustion

Parkinson’s disease(PD)is the second neurodegenerative disease in the world.The pathological characteristics of PD are degeneration,loss and death of dopaminergic neurons in the substantia nigra of the midbrain.At present,most scholars believe that the main pathogenesis of PD is α-synuclein aggregation,oxidative stress,mitochondrial dysfunction and neuroinflammatory reaction.More and more studies have demonstrated that ferroptosis plays an important role in the occurrence and development of PD.Ferroptosis is a new type of cell death that is significantly different from traditional apoptosis,scorching and necrosis.Its main feature is iron-dependent lipid peroxidation.Some studies have found that the efficacy of acupuncture and moxibustion in the treatment of PD may be related to the regulation of ferroptosis.Therefore,this study mainly discusses the occurrence and development mechanism of ferroptosis and its role in PD,and the possible mechanism of acupuncture and moxibustion in the treatment of PD dopaminergic neurons,so as to provide theoretical basis for acupuncture and moxibustion in the treatment of PD.

Updates in the pathophysiological mechanisms of Parkinson's disease: Emerging role of bone marrow mesenchymal stem cells

AIM: To explore the approaches exerted by mesenchymal stem cells (MSCs) to improve Parkinson’s disease (PD) pathophysiology.METHODS: MSCs were harvested from bone marrow of femoral bones of male rats, grown and propagated in culture. Twenty four ovariectomized animals were classified into 3 groups: Group (1) was control, Groups (2) and (3) were subcutaneously administered with rotenone for 14 d after one month of ovariectomy for induction of PD. Then, Group (2) was left untreated, while Group (3) was treated with single intravenous dose of bone marrow derived MSCs (BM-MSCs). SRY gene was assessed by PCR in brain tissue of the female rats. Serum transforming growth factor beta-1 (TGF-β1), monocyte chemoattractant protein-1 (MCP-1) and brain derived neurotrophic factor (BDNF) levels were assayed by ELISA. Brain dopamine DA level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) and nestin gene expression were detected by semi-quantitative real time PCR. Brain survivin expression was determined by immunohistochemical procedure. Histopathological investigation of brain tissues was also done.RESULTS: BM-MSCs were able to home at the injured brains and elicited significant decrease in serum TGF-β1 (489.7 ± 13.0 vs 691.2 ± 8.0, P < 0.05) and MCP-1 (89.6 ± 2.0 vs 112.1 ± 1.9, P < 0.05) levels associated with significant increase in serum BDNF (3663 ± 17.8 vs 2905 ± 72.9, P < 0.05) and brain DA (874 ± 15.0 vs 599 ± 9.8, P < 0.05) levels as well as brain TH (1.18 ± 0.004 vs 0.54 ± 0.009, P < 0.05) and nestin (1.29 ± 0.005 vs 0.67 ± 0.006, P < 0.05) genes expression levels. In addition to, producing insignificant increase in the number of positive cells for survivin (293.2 ± 15.9 vs 271.5 ± 15.9, P > 0.05) expression. Finally, the brain sections showed intact histological structure of the striatum as a result of treatment with BM-MSCs.CONCLUSION: The current study sheds light on the therapeutic potential of BM-MSCs against PD pathophysiology via multi-mechanistic actions.

Research progress in mechanism of curcumin in treatment of Parkinson disease

Curcumin(Cur)is an important bioactive component of polyphenols in the rhizomes of Curcuma longa L.,Tulipa gesneriana L.and other Curcuma plants.It has a wide range of pharmacological effects such as anti-tumor,anti-atherosclerosis,anti-inflammatory,and neuroprotection.Parkinson disease(PD)is a neurodegenerative disease that often occurs in the elderly.Its main pathological characteristics are the characteristic loss of substantia nigra dopaminergic neurons,the decrease of dopamine content in the striatum,and the formation of Lewy bodies.At present,the main methods of clinical treatment of PD include drug therapy and surgical operation,but due to its complicated pathogenesis,they can only play a role in relieving,but cannot be completely cured.Modern pharmacological studies have shown that Cur has certain effects in the treatment of PD.①Anti-oxidative stress:oxidative stress is closely related to the degeneration of dopaminergic neurons.Studies have found that Cur can increase the activity of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px),reduce malondialdehyde(MDA)content,thereby reducing oxidative stress damage and protecting dopaminergic neuron.②Reduce inflammation in brain tissue:neuroinflammation plays an important role in the development of PD.Reducing the level of inflammatory factors can have a certain therapeutic effect on PD.Studies have shown that high-dose Cur can reduce the levels of interleukin-6(IL-6),IL^(-1)β,and tumor necrosis factor-α(TNF-α)in brain tissue,reduce inflammation,inhibit further neuronal damage,improve learning and memory,and exert neuroprotective effects.③Activation of autophagy:the abnormal accumulation ofα-Synuclein(α-Syn)in Lewy bodies is closely related to PD,and autophagy dysfunction leads toα-Syn clearance obstacles and an important factor of abnormal aggregation.Cur can increase the expression of microtubule-associated protein 1 light chain 3(LC3-Ⅱ)and lysosome-associated membrane protein 2A(LAMP2A),and reduce the protein and mRNA expression ofα-Syn.It can be seen that Cur promotes the elimination ofα-Syn and protects neurons from damage by activating autophagy.④Inhibition of mitochondrial dysfunction:mitochondria plays a central regulatory role in the process of cell apoptosis,and mitochondrial dysfunction is related to reactive oxygen species,energy and mitochondrial membrane potential,which may cause substantia nigra striatal neuropathy.Experiments have shown that Cur can reduce the active oxygen content in PC12 cells induced by MPP+,maintain the normal membrane potential of mitochondria,thereby stabilizing mitochondrial function and inhibiting PC12 cell apoptosis.This study summarized the action mechanism of Cur in the treatment of PD,and clarified the basis of its pharmacodynamics, providing a reference for the clinical research and new drug develop ment research of Cur in the treatment of PD.

Long-noncoding RNAs as epigenetic regulators in neurodegenerative diseases

The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation.Editing the epigenome and epitranscriptome directs the fate of the transcript influencing the functional outcome of each mRNA.In this context,non-coding RNAs play a decisive role in addressing the expression regulation at the gene and chromosomal levels.Long-noncoding RNAs,consisting of more than 200 nucleotides,have been shown to act as epigenetic regulators in several key molecular processes involving neurodegenerative disorders,such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis and Huntington’s disease.Long-noncoding RNAs are abundantly expressed in the central nervous system,suggesting that their deregulation could trigger neuronal degeneration through RNA modifications.The evaluation of their diagnostic significance and therapeutic potential could lead to new treatments for these diseases for which there is no cure.

Repositioning of clinically approved drug Bazi Bushen capsule for treatment of Alzheimer′s disease using network pharma⁃cology approach and in vitro experimental validation

OBJECTIVE To explore the new indications and key mechanism of Bazi Bushen capsule(BZBS)by network pharmacology and in vitro experiment.METHODS The potential tar⁃get profiles of the components of BZBS were pre⁃dicted.Subsequently,new indications for BZBS were predicted by disease ontology(DO)enrich⁃ment analysis and initially validated by GO and KEGG pathway enrichment analysis.Further⁃more,the therapeutic target of BZBS acting on AD signaling pathway were identified by intersec⁃tion analysis.Two Alzheimer′s disease(AD)cell models,BV-2 and SH-SY5Y,were used to pre⁃liminarily verify the anti-AD efficacy and mecha⁃nism of BZBS in vitro.RESULTS In total,1499 non-repeated ingredients were obtained from 16 herbs in BZBS formula,and 1320 BZBS targets with high confidence were predicted.Disease enrichment results strongly suggested that BZBS formula has the potential to be used in the treat⁃ment of AD.In vitro experiments showed that BZ⁃BS could significantly reduce the release of TNF-αand IL-6 and the expression of COX-2 and PSEN1 in Aβ25-35-induced BV-2 cells.BZBS reduced the apoptosis rate of Aβ25-35 induced SH-SY5Y cells,significantly increased mitochon⁃drial membrane potential,reduced the expres⁃sion of Caspase3 active fragment and PSEN1,and increased the expression of IDE.CONCLU⁃SIONS BZBS formula has a potential use in the treatment of AD,which is achieved through regu⁃lation of ERK1/2,NF-κB signaling pathways,and GSK-3β/β-catenin signaling pathway.Further⁃more,the network pharmacology technology is a feasible drug repurposing strategy to reposition new clinical use of approved TCM and explore the mechanism of action.The study lays a foun⁃dation for the subsequent in-depth study of BZBS in the treatment of AD and provides a basis for its application in the clinical treatment of AD.

Attention-Based Deep Learning Model for Early Detection of Parkinson’s Disease

Parkinson’s disease(PD),classified under the category of a neurological syndrome,affects the brain of a person which leads to the motor and non-motor symptoms.Among motor symptoms,one of the major disabling symptom is Freezing of Gait(FoG)that affects the daily standard of living of PD patients.Available treatments target to improve the symptoms of PD.Detection of PD at the early stages is an arduous task due to being indistinguishable from a healthy individual.This work proposed a novel attention-basedmodel for the detection of FoG events and PD,andmeasuring the intensity of PD on the United Parkinson’s Disease Rating Scale.Two separate datasets,that is,UCF Daphnet dataset for detection of Freezing of Gait Events and PhysioNet Gait in PD Dataset were used for training and validating on their respective problems.The results show a definite rise in the various performance metrics when compared to landmark models on these problems using these datasets.These results strongly suggest that the proposed state of the art attention-based deep learning model provide a consistent as well as an efficient solution to the selected problem.High valueswere obtained for various performance metrics like accuracy of 98.74%for detection FoG,98.72%for detection of PD and 98.05%for measuring the intensity of PD on UPDRS.The model was also analyzed for robustness against noisy samples,where also model exhibited consistent performance.These results strongly suggest that the proposed model provides a better classification method for selected problem.

One-step cell biomanufacturing platform:porous gelatin microcarrier beads promote human embryonic stem cell-derived midbrain dopaminergic progenitor cell differentiation in vitro and survival after transplantation in vivo

Numerous studies have shown that cell replacement therapy can replenish lost cells and rebuild neural circuitry in animal models of Parkinson’s disease.Transplantation of midbrain dopaminergic progenitor cells is a promising treatment for Parkinson’s disease.However,transplanted cells can be injured by mechanical damage during handling and by changes in the transplantation niche.Here,we developed a one-step biomanufacturing platform that uses small-aperture gelatin microcarriers to produce beads carrying midbrain dopaminergic progenitor cells.These beads allow midbrain dopaminergic progenitor cell differentiation and cryopreservation without digestion,effectively maintaining axonal integrity in vitro.Importantly,midbrain dopaminergic progenitor cell bead grafts showed increased survival and only mild immunoreactivity in vivo compared with suspended midbrain dopaminergic progenitor cell grafts.Overall,our findings show that these midbrain dopaminergic progenitor cell beads enhance the effectiveness of neuronal cell transplantation.

Links between COVID-19 and Parkinson’s disease/Alzheimer’s disease:reciprocal impacts,medical care strategies and underlying mechanisms

The impact of coronavirus disease 2019(COVID-19)pandemic on patients with neurodegenerative diseases and the specific neurological manifestations of COVID-19 have aroused great interest.However,there are still many issues of concern to be clarified.Therefore,we review the current literature on the complex relationship between COVID-19 and neurodegenerative diseases with an emphasis on Parkinson’s disease(PD)and Alzheimer’s disease(AD).We summarize the impact of COVID-19 infection on symptom severity,disease progression,and mortality rate of PD and AD,and discuss whether COVID-19 infection could trigger PD and AD.In addition,the susceptibility to and the prognosis of COVID-19 in PD patients and AD patients are also included.In order to achieve better management of PD and AD patients,modifications of care strategies,specific drug therapies,and vaccines during the pandemic are also listed.At last,mechanisms underlying the link of COVID-19 with PD and AD are reviewed.

Compound heterozygous p.L483P and p.S310G mutations in GBA1 cause type 1 adult Gaucher disease:A case report

BACKGROUND Gaucher disease(GD)is caused by a GBA1 gene mutation that leads to decreased acidβ-glucosidase activity[glucocerebrosidase(GCase)].This study aimed to identify and characterise compound heterozygous mutations in GBA1 in a patient with type 1 GD.CASE SUMMARY Here,we report a rare adult-onset type 1 GD in a 46-year-old female patient with clinical manifestations of giant spleen,thrombocytopenia,and bone pain,diagnosed by enzymatic and genetic testing.Enzymology and whole exome sequencing revealed heterozygous missense mutations in exon 10 c.1448T>C(p.L483P)and exon 7 c.928A>G(p.S310G)of GBA1.The latter was first reported in patients with GD.Structural modelling showed that p.S310G and p.L483P were distant from the GCase active site.The p.S310G mutation in domain 1 may decrease stability between theα2 andα3 helices of GBA1.The p.L483P mutation in domain 2 reduced the van der Waals force of the side chain and disrupted the C-terminalβ-sheet.The patient was treated with imiglucerase replacement therapy,and her condition was stable.CONCLUSION The p.L483P/p.S310G novel compound heterozygous mutation underlies type 1 GD and likely affects GCase protein function.This is the first description of p.S310G being associated with mild type 1 GD in the context of a coinherited p.L483P mutation.

Mechanisms of motor symptom improvement by long-term Tai Chi training in Parkinson’s disease patients

Background:Tai Chi has been shown to improve motor symptoms in Parkinson’s disease(PD),but its long-term effects and the related mechanisms remain to be elucidated.In this study,we investigated the effects of long-term Tai Chi training on motor symptoms in PD and the underlying mechanisms.Methods:Ninety-five early-stage PD patients were enrolled and randomly divided into Tai Chi(n=32),brisk walk-ing(n=31)and no-exercise(n=32)groups.At baseline,6 months and 12 months during one-year intervention,all participants underwent motor symptom evaluation by Berg balance scale(BBS),Unified PD rating-scale(UPDRS),Timed Up and Go test(TUG)and 3D gait analysis,functional magnetic resonance imaging(fMRI),plasma cytokine and metabolomics analysis,and blood Huntingtin interaction protein 2(HIP2)mRNA level analysis.Longitudinal self-changes were calculated using repeated measures ANOVA.GEE(generalized estimating equations)was used to assess factors associated with the longitudinal data of rating scales.Switch rates were used for fMRI analysis.False discovery rate correction was used for multiple correction.Results:Participants in the Tai Chi group had better performance in BBS,UPDRS,TUG and step width.Besides,Tai Chi was advantageous over brisk walking in improving BBS and step width.The improved BBS was correlated with enhanced visual network function and downregulation of interleukin-1β.The improvements in UPDRS were asso-ciated with enhanced default mode network function,decreased L-malic acid and 3-phosphoglyceric acid,and increased adenosine and HIP2 mRNA levels.In addition,arginine biosynthesis,urea cycle,tricarboxylic acid cycle and beta oxidation of very-long-chain fatty acids were also improved by Tai Chi training.Conclusions:Long-term Tai Chi training improves motor function,especially gait and balance,in PD.The underlying mechanisms may include enhanced brain network function,reduced inflammation,improved amino acid metabolism,energy metabolism and neurotransmitter metabolism,and decreased vulnerability to dopaminergic degeneration.Trial registration This study has been registered at Chinese Clinical Trial Registry(Registration number:ChiCTR2000036036;Registration date:August 22,2020).

基于脑肠轴理论的中药及干细胞诊疗帕金森病研究进展

帕金森病(Parkinson's disease, PD)发病机制复杂,目前尚无治愈方法。脑肠轴是帕金森病的诊疗方向之一。中药与干细胞对帕金森病脑肠轴途径均有明确疗效,中药还可进一步调控干细胞增殖与分化。对于帕金森病脑肠轴方向的诊疗进行综述,探讨中药及干细胞疗法,并对中药调控干细胞通过脑肠轴治疗帕金森病的潜力进行探讨。

肾素-血管紧张素系统与中枢神经系统疾病的关联及中医药的干预调控作用

肾素-血管紧张素系统(RAS)在水、电解质和血压动态调控中发挥重要作用。RAS组分也广泛分布在脑组织,参与多种中枢神经系统疾病的病理过程。从血管紧张素转化酶(ACE)-血管紧张素Ⅱ(AngⅡ)-血管紧张素1型受体(AT1R)、ACE2-Ang-(1-7)-Mas受体(MasR)双轴,探讨RAS与中枢神经系统疾病(阿尔茨海默病、帕金森病、抑郁症、缺血性脑卒中等)的病理机制关联,并总结分析中药及中医非药物疗法基于RAS的靶向干预途径及防治中枢神经系统疾病的效应与作用机制,为中西医结合防治中枢神经系统疾病、中药新药研发提供参考。

基于网络药理学和分子对接研究蒙药额尔敦-乌日勒对帕金森病的作用机制

目的:基于网络药理学方法挖掘蒙药额尔敦-乌日勒治疗帕金森病的主要活性成分和药物靶点,揭示其潜在的可能作用机制,并运用分子对接研究药物与靶点蛋白结合能力。方法:依据中药系统药理学分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSCP)挖掘额尔敦-乌日勒的活性成分及对应靶点,以药动参数生物利用度(oral bioavailability,OB)≥30%、类药性(drug-likeness,DL)≥0.18:为条件进行筛选,运用GeneCards、OMIM和TTD数据库筛选出额尔敦-乌日勒活性成分治疗帕金森病的可能靶点,运用Cytoscape 3.9.1绘制Venn图,借助STRING数据库绘制蛋白互作(protein-protein interaction,PPI)网络图;应用微生信在线软件及Metascape数据库查找蒙药额尔敦-乌日勒潜在的活性成分及治疗帕金森病的潜在作用靶点,并将靶点进行基因本体(gene ontology,GO)及京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析,并将药物小分子和靶点蛋白进行分子对接。结果:蒙药额尔敦-乌日勒中筛选出DL及OB值好的活性成分118种,预测治疗帕金森病的靶点207个,GO功能富集分析及KEGG富集分析显示,蒙药额尔敦-乌日勒治疗帕金森病的机制主要涉及RNA聚合酶启动子转录的正调控、正调控DNA模板转录和调控基因表达等生物过程,其涉及的通路包括AKT1、TP53、TNF、VEGFA、CASP3等。结论:蒙药额尔敦-乌日勒治疗帕金森病是多成分、多靶点、多通路的作用结果,为蒙药额尔敦-乌日勒治疗帕金森病的进一步研究提供了理论依据。

人参、石菖蒲及其药对防治阿尔茨海默症的药理作用研究进展

阿尔茨海默病(Alzheimer′s disease,AD)病因复杂,发病机制尚未完全阐明,现有药物仅能缓解其症状,亟待研发有效的治疗药物。作为补虚药及开窍药的代表药物,人参及石菖蒲均有提高记忆力、改善学习能力及减轻认知障碍的药理作用,是中医治疗痴呆症的常用药物。人参-石菖蒲药对联用可促进活性成分入脑发挥药效,并通过抗炎、抗氧化应激、调节神经元-突触可塑性等多途径延缓AD进程,具有多层次、多系统和多靶点的作用特点。该文尝试总结现有研究成果,为进一步探讨人参、石菖蒲的联用,实现协同增效的作用机制以及配伍的量效关系奠定基础,为研制防治AD的中药创新药物提供科学依据。

基于网络药理学研究珍珠通络丸对帕金森病的作用机制

目的:通过网络药理学和分子对接技术预测蒙药珍珠通络丸治疗帕金森病(PD)的机制。方法:利用TCMSP数据库筛选珍珠通络丸主要活性成分及其可能的作用靶点。利用OMIM、GeneCards、TTD网站获得PD的疾病靶点。利用Venny 2.1.0网站绘制Venny图,并通过STRING网站获得蛋白互作(PPI)网络图。利用微生信网站进行基因本体(GO)及京都基因与基因组百科全书(KEGG)富集分析。结果:按照筛选标准,珍珠通络丸的主要活性成分有112种,可能用于治疗PD的靶点有199个;KEGG富集通路发现珍珠通络丸治疗PD主要通过脂质和动脉粥样硬化、肿瘤坏死因子、IL-17、PI3K-AKT、细胞凋亡等信号通路;分子对接结果显示槲皮素、山柰酚、木樨草素、β-谷甾醇、黄芩素等有效化合物都能与AKT1、JUN、TNF、PRKACA等核心蛋白良好的结合。结论:珍珠通络丸改善PD的作用机制可能是与调控AKT1、JUN、TNF、PRKACA等靶蛋白的活性有关,为研究珍珠通络丸治疗PD的活性成分和分子机制提供依据。

针刺治疗帕金森病相关发病机制研究进展

帕金森病(parkinson’s disease,PD)是一种常见的中枢神经系统神经退行性疾病,其主要病理特点是黑质区域多巴胺(DA)神经元的大量变性丢失,其主要症状体现为运动迟缓、在静态状态会发生震颤、情绪异常和身体姿势不稳等。目前可知,帕金森病并非仅由单一因素引发,而是多种因素共同作用结果。西药效果虽然明显,但都不能根治且有明显的不良反应。其中大量研究数据显示,针刺在改善帕金森病方面,具有明显的疗效。文章借助最新的国内外有关研究论文,从神经传导递质、氧化应激反应、免疫炎性反应、蛋白质降解系统的障碍、线粒体功能失调、肠-脑轴等多个视角全方位解读了针刺治疗帕金森综合征的相关作用机制,为针刺治疗帕金森提供新思路。

针刺调节BDNF/TrkB信号通路改善中枢神经系统疾病的研究进展

BDNF/TrkB信号通路作为神经元生长、发育和突触可塑性的关键调节器,广泛参与中枢神经系统疾病的发生发展,如缺血性脑卒中、阿尔茨海默病、帕金森病和脊髓损伤等。研究表明针刺能调节BDNF/TrkB信号通路的活性,对以上疾病具有显著的治疗潜力,其作用机制与参与突触结构重塑,抑制神经细胞凋亡,促进神经发生和突触再生等有关。本文综述了BDNF/TrkB相关信号通路在中枢神经系统疾病中的作用以及针刺对该通路的调控机制,以期为临床治疗提供新思路。未来研究应深入探究针刺对BDNF/TrkB信号通路的精准调控,以开发更高效安全的治疗策略。

基于网络药理学和分子对接探究牛膝-肉苁蓉-山茱萸治疗帕金森病的作用机制

目的:基于网络药理学和分子对接技术对牛膝-肉苁蓉-山茱萸治疗帕金森病的作用机制进行分析探究。方法:利用中药系统药理数据库与分析平台(TCMSP)查询牛膝、肉苁蓉、山茱萸的有效成分和靶点。使用TCMSP查询药物成分及成分2D结构,并导入PubChem数据库中查询成分对应Canonical SMILES,导入SwissTargetPrediction获取成分对应靶点;将成分2D结构导入PharmMapper数据库获取成分靶点。将药物、成分、靶点导入CytoScape 3.10.0软件中,构建药物-成分-靶点网络。使用GeneCards、PharmGKB、DrugBank、Therapeutic Target Database数据库预测帕金森相关的疾病靶点。将牛膝-肉苁蓉-山茱萸成分作用靶点与帕金森病的疾病靶点分别导入Venny 2.1获取药物-疾病交集靶点。将交集靶点导入STRING数据库,构建蛋白质-蛋白质相互作用网络图,使用CytoNCA APP及R语言获取核心靶点,并获取核心靶点网络图。将上述交集靶点通过MetaScape数据库中进行基因本体论(GO)富集分析及京都基因与基因组百科全书(KEGG)通路富集分析。使用AutoDock Vina 1.1.2将牛膝、肉苁蓉、山茱萸的度值最高核心成分与核心靶点进行分子对接。结果:获得药物核心成分8个,主要为槲皮素、汉黄芩素、β-谷甾醇、山柰酚、豆甾醇、巴马汀、花生四烯酸、5-烯-3β-乙二醇。核心靶点12个,主要为RAC-α丝氨酸/苏氨酸蛋白激酶(RAC-alpha serine/Threonine-protein Kinase,AKT1)、雌激素受体1(Estrogen Receptor,ESR1)、过氧化物酶体增殖激活受体γ(Peroxisome Proliferator-activated Receptorγ,PPARG)、半胱氨酸蛋白酶-3(Caspase-3,CASP3)、白蛋白(Albumin,ALB)、表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)和热休克蛋白90α家族A类成员1(Heat Shock Protein HSP 90-alpha,HSP90AA1)等。GO富集结果显示主要是分子功能的负调控、活性氧代谢过程的调控、化学突触传递的调节、水解酶活性的调节、脂质代谢过程的正调控、核被膜、电压门控钙通道复合体、轴膜、细胞顶端、谷氨酸能突触、酰胺结合、信号受体调节活性、天冬氨酸型内肽酶活性、抗氧化活性、磷脂酶激活剂活性等。KEGG富集包括20个信号通路(P<0.01),主要包括脂质-动脉粥样硬化通路、癌症路径信号通路、糖尿病性心肌病信号通路、甲状旁腺激素的合成、分泌和作用信号通路、补体与凝血级联信号通路、癌症转录失调信号通路、卵母细胞减数分裂信号通路、坏死性凋亡信号通路、甲状腺激素合成信号通路、钙信号通路等。结论:牛膝-肉苁蓉-山茱萸治疗帕金森主要是槲皮素、花生四烯酸酯、β-谷甾醇、5-烯-3β-乙二醇等多种有效成分作用于AKT1、ESR1、PPARG等靶点,通过对细胞荷尔蒙、细菌、激素水平的调节以及磷代谢的正向调节等,调控脂质-动脉粥样硬化通路、癌症路径信号通路、糖尿病性心肌病信号通路等信号通路,协同发挥治疗帕金森病的作用。