Alzheimer’s disease (AD) is the leading cause of dementia among the elderly, yet effective treatments remain elusive. Total saikosaponins (TSS), the primary bioactive components in Bupleurum chinense, have shown promising therapeutic effects against AD in previous studies. Methods: To delve deeper into the mechanisms underlying the therapeutic role of TSS in AD, we investigated its neuroprotective effects and associated molecular mechanisms in APP/PS1 mice. Further, we employed metabolomic and proteomic analyses, with a focus on the potential protein-level changes induced by TSS, particularly those related to metabolite accumulation in the brain. Results: Our results showed that lysophosphatidylcholine, adenosine, and sphingomyelin in plasma might serve as potential biomarkers. Compared to the control group, AD mice exhibited significantly increased expression of proteins related to neuroinflammatory pathways, whereas proteins involved in cAMP signaling, cGMP-PKG signaling, and synaptic plasticity pathways were significantly downregulated. Notably, these signaling pathways were partially reversed in APP/PS1 mice following TSS administration. Behavioral tests demonstrated that TSS effectively improved the learning and memory functions of mice. Conclusions: Our findings suggest that TSS ameliorate cognitive decline through regulating neuroinflammatory pathways, cAMP and cGMP signaling, and synaptic plasticity pathways, providing insights into its therapeutic potential in AD.

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly. Contemporary treatments can only relieve symptoms but fail to delay disease progression. Curcumin is a naturally derived compound that has demonstrated significant therapeutic effects in AD treatment. Recently, molecular hybridization has been utilized to combine the pharmacophoric groups present in curcumin with those of other AD drugs, resulting in a series of novel compounds that enhance the therapeutic efficacy through multiple mechanisms. In this review, we firstly provide a concise summary of various pathogenetic hypotheses of AD and the mechanism of action of curcumin in AD, as well as the concept of molecular hybridization. Subsequently, we focus on the recent development of hybrid molecules derived from curcumin, summarizing their structures and pharmacological activities, including cholinesterase inhibitory activity, Aβ aggregation inhibitory activity, antioxidant activity, and other activities. The structure-activity relationships were further discussed.

Background: Alcohol abuse triggers neuroinflammation, leading to neuronal damage and further memory and cognitive impairment. Few satisfactory advances have been made in the management of alcoholic central ner-vous impairment. Therefore, novel and more practical treatment options are urgently needed. Butyrate, a crucial metabolite of short-chain fatty acids (SCFAs), has been increasingly demonstrated to protect against numerous metabolic diseases. However, the impact of butyrate on chronic alcohol consumption-induced central nervous system (CNS) lesions remains unknown. Methods: In this study, we assessed the possible effects and underlying mechanisms of butyrate on the attenuation of alcohol-induced CNS injury in mice. Firstly, sixty female C57BL/6 J mice were randomly divided into 4 groups: pair-fed (PF) group (PF/CON), alcohol-fed (AF) group (AF/CON), PF with sodium butyrate (NaB) group (PF/NaB) and AF with NaB group (AF/NaB). Each group was fed a modified Lieber-DeCarli liquid diet with or without alcohol. After six weeks of feeding, the mice were euthanized and the associated indicators were investigated.Results: As indicated by the behavioral tests and brain morphology, dietary NaB administration significantly ameliorated aberrant behaviors, including locomotor hypoactivity, anxiety disorder, depressive behavior, impaired learning, spatial recognition memory, and effectively reduced chronic alcoholic central nervous system damage. To further understand the underlying mechanisms, microglia-mediated inflammation and the associated M1/M2 polarization were measured separately. Firstly, pro-inflammatory TNF-alpha, IL-1 beta, and IL-6 in brain and peripheral blood circulation were decreased, but IL-10 were increased in the AF/NaB group compared with the AF/CON group. Consistently, the abnormal proportions of activated and resting microglial cells in the hippo -campus and cortex regions after excessive alcohol consumption were significantly reduced with NaB treatment. Moreover, the rectification of microglia polarization (M1/M2) imbalance was found after NaB administration via binding GPR109A, up-regulating the expression of PPAR-gamma and down-regulating TLR4/NF-Kappa B activation. In addition to the direct suppression of neuroinflammation, intriguingly, dietary NaB intervention remarkably increased the levels of intestinal tight junction protein occludin and gut morphological barrier, attenuated thelevels of serum lipopolysaccharide (LPS) and dysbiosis of gut microbiota, suggesting that NaB supplementation effectively improved the integrity and permeability of gut microecology. Finally, the neurotransmitters including differential Tryptophan (Trp) and Kynurenine (Kyn) were found with dietary NaB administration, which showed significantly altered and closely correlated with the gut microbiota composition, demonstrating the complex interactions in the microbiome-gut-brain axis involved in the efficacy of dietary NaB therapy for alcoholic CNS lesions.Conclusion: Dietary microbial metabolite butyrate supplementation ameliorates chronic alcoholic central nervous damage and improves related memory and cognitive functions through suppressing microglia-mediated neuro-inflammation by GPR109A/PPAR-gamma/TLR4-NF-Kappa B signaling pathway and modulating microbiota-gut-brain axis.

Abstract Introduction: Oligodendrocyte precursor cells (OPCs) differentiation dysfunction is closely related to demyelinating diseases and cognitive dysfunction. P75 neurotrophin receptor (P75NTR) is a prototypical co-receptor that induces Schwann cell death via γ-secretase-dependent regulated intramembrane proteolysis. This study hypothesizes that P75NTR may also assists in inhibiting OPCs differentiation.Methods Male C57BL/6 mice were fed 0.2% cuprizone (CPZ) continuously for 6 weeks to establish the acute demyelinating model (CPZ mice). Morris Water Maze and Elevated Plus Maze tests were used to assess the behavioral changes of these mice. Immunohistochemistry and Western blot were used to detect the OPCs and oligodendrocytes (OLs) protein markers. Furthermore, γ-secretase inhibitor DAPT (GSI-IX) was injected into the hippocampus at the fifth week of establishing the demyelinating model to investigate the effects of DAPT on OPCs differentiation and the mice’s behavioral changes.Results CPZ mice performed abnormal behavioral changes, and the protein expression of the OLs marker 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) decreased. However, the OPCs marker neural/glial antigen 2 (NG2) protein expression increased. After DAPT treatment, the abnormal behavior improved, CNPase increased, and NG2 decreased.Conclusions P75 cleavage plays an inhibitory role during the OPCs differentiation resulting in inefficient OPCs differentiation and recurrent demyelinating diseases.

Abstract Introduction: Oligodendrocyte precursor cells (OPCs) differentiation dysfunction is closely related to demyelinating diseases and cognitive dysfunction. P75 neurotrophin receptor (P75NTR) is a prototypical co-receptor that induces Schwann cell death via γ-secretase-dependent regulated intramembrane proteolysis. This study hypothesizes that P75NTR may also assists in inhibiting OPCs differentiation. Methods Male C57BL/6 mice were fed 0.2% cuprizone (CPZ) continuously for 6 weeks to establish the acute demyelinating model (CPZ mice). Morris Water Maze and Elevated Plus Maze tests were used to assess the behavioral changes of these mice. Immunohistochemistry and Western blot were used to detect the OPCs and oligodendrocytes (OLs) protein markers. Furthermore, γ-secretase inhibitor DAPT (GSI-IX) was injected into the hippocampus at the fifth week of establishing the demyelinating model to investigate the effects of DAPT on OPCs differentiation and the mice’s behavioral changes. Results CPZ mice performed abnormal behavioral changes, and the protein expression of the OLs marker 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) decreased. However, the OPCs marker neural/glial antigen 2 (NG2) protein expression increased. After DAPT treatment, the abnormal behavior improved, CNPase increased, and NG2 decreased. Conclusions P75 cleavage plays an inhibitory role during the OPCs differentiation resulting in inefficient OPCs differentiation and recurrent demyelinating diseases.

Abstract Background Alcohol can cause neuroinflammation, leading to neuron damage and further memory and cognitive impairment. Recent animal studies have shown that the exposure to chronic alcohol consumption induces robust inflammatory microglial activation in the brain. However, as a novel anti-inflammation approach, the impact of sodium butyrate on chronic alcohol-induced neuroinflammation still remains unclear. Methods Sixty female C57BL/6J mice were randomly divided into 4 groups: pair-fed (PF) group (PF/CON), alcohol-fed (AF) group (AF/CON), PF with sodium butyrate (NaB) group (PF/NaB) and AF with NaB group (AF/NaB). Each group was fed a modified Lieber-DeCarli liquid diet with or without alcohol. Mice were subjected to different behavioral tests to assess aberrant behaviours (deficits in cognitive functions, depression and anxiety). Pathological changes were further investigated by Hematoxylin and eosin staining (HE) and Nissl staining. The microglial activation and microglial polarization were observed by immunohistochemistry (IHC), immunofluorescence (IF) and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of inflammatory factors. G-protein coupled receptor 109A (GPR109A), peroxisome proliferator-activated receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) mRNA and protein levels were evaluated by reverse transcription‑quantitative (RT‑q) PCR and western blot (WB). Results As indicated by the behavioural tests, inflammatory indicators, microglial activation (M1/M2 microglia polarization) and brain morphology, sodium butyrate administration ameliorated aberrant behaviours (locomotor hypoactivity, anxiety disorders and depressive behaviours, impaired learning and spatial recognition memory), effectively reduced neuroinflammation and neuronal damage. The effectiveness of sodium butyrate may attribute to the GPR109A receptor in microglia by up-regulating the expression of PPAR-γ and inhibiting the activation of NF-κB. Conclusion Sodium butyrate ameliorates neuroinflammation induced by chronic alcohol exposure and improves memory and cognitive functions in mice via modulating microglia-mediated GPR109A / PPAR-γ / NF-κB signaling pathway.

目的:探讨环指蛋白146 (RNF146)在Aβ诱导C6细胞的凋亡过程中的作用.方法:大鼠神经胶质瘤细胞株C6细胞分为对照组(control)和Aβ处理组(Aβ).Annexin V-EGFP/PI染色法检测细胞凋亡,Western Blot方法检测C6细胞中RNF146的表达和凋亡诱导因子(AIF)蛋白的表达和分布.结果:与对照组比较,Aβ处理能够促进细胞凋亡,同时减少细胞中RNF146的表达,并促进AIF核转位.结论:Aβ可导致C6细胞凋亡,其机制与RNF146表达下调并激活AIF核转位有关.