👤 Shude Xu

Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctorius exhibit multi-target anti-AS potential, yet their compositional complexity limits clinical translation. This study aimed to systematically identify core anti-AS components from these herbs and enhance their anti-AS efficacy via machine learning-aided screening and nanotechnology-driven codelivery. We initially pioneered a machine learning-aided hybrid strategy integrating network pharmacology and quantitative activity relationship (QSAR) modeling to identify four core anti-AS polyphenols (i.e., salvianic acid A, salvianolic acid B, protocatechuic acid, and hydroxysafflor yellow A). Subsequently, a quaternary metal-phenolic network (SSPH-MPN) was engineered for plaque-targeted codelivery, optimized via the median-effect principle for achieving a synergistic effect based on ROS scavenging efficacy. The optimized SSPH-MPN was characterized by a series of studies, including molecular dynamics simulations, UV, DLS, TEM, FTIR, XPS, and ICP-MS. The anti-AS effect of the optimized SSPH-MPN was evaluated by monitoring oxidative status (ROS levels, antioxidant enzymes SOD, GSH-Px, MDA, T-AOC), inflammatory markers (IL-1β, IL-6, TNF-α), lipid metabolism (DiI-oxLDL uptake, cholesterol efflux, blood lipid levels, lipid accumulation), and plaque areas. The results demonstrated that the optimized SSPH-MPN showed great efficiency in inhibiting lipid uptake and accumulation, and mediating cholesterol efflux in RAW 264.7 cells, and exhibited improved lipid metabolism, attenuated oxidative stress and inflammation, thus acquired diminished plaque area in apoE Show less

Abnormal glymphatic system may play a critical role in amyloid-β (Aβ) accumulation in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients. This study aims to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) and perivascular space volume fraction (PVSVF) to investigate the aberrant glymphatic functions and the association between Aβ deposition and clinical symptoms in AD spectrum. The ALPS index was significantly lower in AD patients compared to MCI and normal controls (NC) groups. Additionally, the AD group showed a significantly higher PVSVF in hippocampus (HP) compared to NC group. No notable variations were observed in the ALPS index or PVSVF across various regions when comparing the MCI group to the NC group. Apolloprotein E (APOE) ε4 + group showed significantly higher PVSVF-HP and PVSVF in basal ganglia compared to APOE ε4 − group. All participants’ HP volume, lower cognitive scores, and higher Our findings demonstrate that glymphatic dysfunction is associated with cognitive decline, underscoring the critical roles of Aβ pathology and the APOE genotype in mediating this relationship. Further exploration of glymphatic function holds significantly promise for advancing research on AD pathogenesis. The online version contains supplementary material available at 10.1186/s13550-025-01339-y. Show less

Core 1 biomarkers, such as amyloid positron emission tomography, capture the earliest biological changes leading to Alzheimer's disease (AD). While APOE is a major genetic factor, the contribution of other variants to Core 1 biomarkers remains unclear. The goal of this study was to determine whether genetic regulators of Core 1 biomarker levels predicted AD pathology better than genetic regulators of clinical AD. Among 955 non-Hispanic White individuals, polygenic scores (PGSs) were built using genome-wide association studies (GWASs) of amyloid PET, plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma p-tau181 and clinical AD GWASs. Baseline and longitudinal associations with plasma biomarkers and cognition were assessed, and replication was conducted in separate cohorts. The Core 1 biomarker PGSs predicted AD pathology and associated cognitive performance better than the AD PGSs in both populations. The Core 1 PGSs show improved predictive value for AD-related plasma biomarkers and early cognitive changes. APOE ε4 explained more variance in plasma p-tau217 than in plasma p-tau181. PGSs based on Core 1 biomarkers outperformed AD PGSs in predicting plasma biomarkers and cognitive decline among asymptomatic individuals in non-Hispanic White and Hispanic individuals. However, the improvement in predictive power was modest and may vary by age. While the variance in p-tau181 and p-tau217 explained by individual Core 1 PGSs remains limited, the distinct genetic signals captured by the best-performing PGSs across different Core 1 biomarkers may provide an opportunity for developing an integrative Core 1 PGS that more effectively predicts plasma p-tau181 and p-tau217 levels than AD-based PGS. Show less

Thyroid cancer, the most common endocrine malignancy, is characterized by a unique and complex tumor microenvironment (TME). To unravel the high tumor heterogeneity and molecular mechanisms driving cancer progression, we performed single-cell RNA sequencing (scRNA-seq) analysis, enabling a comprehensive exploration of cellular diversity and molecular dynamics at single-cell resolution. We employed Principal Component Analysis (PCA) and Uniform Manifold Approximation and Projection (UMAP) for dimensionality reduction and subsequent identification of cellular clusters. Differential gene expression analysis across subclusters was conducted using the FindAllMarkers function, while the DoHeatmap function was utilized to visualize the distribution of differentially expressed genes. The AUCell algorithm was applied to evaluate pathway enrichment within specific cell subtypes. To decipher cellular communication networks, we integrated the CellChat and NicheNet algorithms, which revealed intricate intercellular signaling interactions. Finally, multiplex immunohistochemistry (mIHC) was performed to validate key cellular interactions identified in silico. By analyzing 405,077 single cells from 50 thyroid cancer samples (including papillary, anaplastic, and metastatic tumors) and 14 normal thyroid tissues, we identified four major cellular subpopulations through unbiased clustering based on gene expression patterns and representative cellular markers. The TME was found to encompass diverse immune, endothelial, and mesenchymal cell subtypes, including novel populations such as CD4 + HSPA1A + T cells. Functional pathway enrichment analysis highlighted the roles of abundant cell types in tumor progression. Cell-cell communication analysis uncovered potential immunotherapeutic targets and revealed critical crosstalk among hub niche cells, including APOE+ macrophages, EMT-like cancer-associated fibroblasts (CAFs), and RBP7+ endothelial cells. These findings were further validated by multiplex immunohistochemistry, confirming the spatial organization and interactions of these cell populations within the TME. Our study provides a comprehensive single-cell transcriptomic atlas of thyroid cancer, offering profound insights into tumor heterogeneity, the functional roles of key niche cells, and potential biomarkers for anticancer therapy. These findings not only enhance our understanding of thyroid cancer biology but also pave the way for the development of novel therapeutic strategies targeting the TME. Show less

Atherosclerosis (AS) is a chronic inflammatory disorder characterized by foam cell formation and persistent inflammation as central pathological drivers. Although colchicine (Col) exhibits potent anti-inflammatory activities, its clinical application is limited by a narrow therapeutic window. In the present study, we developed phosphatidylserine-exposing nanovesicles (Col@PSVs) that leverage the innate phagocytic capacity of macrophage-derived foam cells by presenting surface "eat-me" signals, thereby enabling targeted immune modulation. The synergistic collaboration between Col and PSVs allows low-dose Col to retain robust anti-inflammatory efficacy while mitigating dose-dependent toxicity. Mechanistically, Col@PSVs potently suppress CCR7-mediated NF-κB signaling activation in foam cells, leading to a marked downregulation of pro-inflammatory cytokine and disruption of inflammatory cascades. In ApoE Show less

Radiation-induced brain injury (RIBI) is a significant complication following radiotherapy for brain tumors, leading to neurocognitive deficits and other neurological impairments. This study aims to identify potential biomarkers and therapeutic targets for RIBI by utilizing advanced proteomic techniques to explore the molecular mechanisms underlying RIBI. A rat model of RIBI was established and subjected to whole-brain irradiation (30 Gy). Tandem mass tagging (TMT)-based quantitative proteomics, combined with high-resolution mass spectrometry, was used to identify differentially expressed proteins (DEPs) in the brain tissues of irradiated rats. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to identify the biological processes and pathways involved. Protein-protein interaction (PPI) networks were constructed to identify key hub proteins. A total of 35 DEPs were identified, including PHLDA3, APOE and CPE. GO enrichment analysis revealed that the DEPs were mainly involved in lipid transport, cell adhesion, and metabolic processes. KEGG analysis highlighted the enrichment of pathways related to metabolism, tight junctions, and PPAR signaling. APOE was identified as a key hub protein through PPI network analysis, indicating its potential role in RIBI pathophysiology. Immunohistochemistry further validated the increased expression of PHLDA3, APOE, and CPE in the brain tissue of irradiated rats. This study provides valuable insights into the molecular mechanisms of RIBI by identifying key proteins and their associated pathways. The findings suggest that these proteins, particularly APOE and PHLDA3, could serve as potential biomarkers and therapeutic targets for clinical intervention in RIBI. These results not only enhance our understanding of RIBI's molecular pathology but also open new avenues for the development of targeted therapies to mitigate radiation-induced neurotoxicity. Show less

This paper aims to investigate m6A modification during DKD progression. We evaluated m6A regulators expression in peripheral blood mononuclear cells, whole kidney tissue, glomerular, and tubulointerstitial samples. CIBERSORT and single-sample gene set enrichment analysis analyzed glomerular immune characteristics. Logistic-LASSO regression were used to develop the m6A regulators model that can identify early DKD. Consensus clustering algorithms were used to classify DKD in glomerular samples into m6A modified subtypes based on the expression of m6A regulators. Gene set variation analysis algorithm was used to evaluate the functional pathway enrichment of m6A modified subtypes. Weighted gene co-expression network analysis and protein-protein interaction networks identified m6A modified subtype marker genes. The Nephroseq V5 tool was used to evaluate the correlation between m6A modified subtypes marker genes and renal function. DKD patients' m6A regulators expression differed from the control group in various tissue types. DKD stages have various immune characteristics. The m6A regulators model with YTHDC1, METTL3, and ALKBH5 better identified early DKD. DKD was divided into two subtypes based on the expression of 26 m6A regulators. Subtype 1 was enriched in myogenesis, collagen components, and cytokine receptor interaction, while subtype 2 was enriched in protein secretion, proliferation, apoptosis, and various signaling pathways (e.g., TGFβ signaling pathway, PI3K/AKT/mTOR pathway, and etc.). Finally, AXIN1 and GOLGA4 were identified as possible biomarkers associated with glomerular filtration rate. From the viewpoint of m6A modification, the immune characteristics and molecular mechanisms of DKD at various stages are different, and targeted treatment would improve efficacy. Show less

Idiopathic pulmonary fibrosis is a progressive and lethal interstitial lung disease with an unclear etiology and limited treatment options. Fatty acid synthase (FASN) plays various roles in metabolic-related diseases. This study demonstrates that FASN expression is increased in fibroblasts from the lung tissues of patients with idiopathic pulmonary fibrosis and in bleomycin-treated mice. In MRC-5 cells, the inhibition of FASN using shRNA or the pharmacological inhibitor C75 resulted in the increased mRNA and protein expression of glycogen synthase kinase 3β and Axin1, both negative regulators of the Wnt/β-catenin signaling pathway, and promoted autophagy. This outcome led to a decrease in β-catenin protein and mRNA levels, effectively inhibiting the proliferation, migration, and differentiation of lung fibroblasts into myofibroblasts, while inducing the differentiation of fibroblasts into adipofibroblasts. In vivo experiments showed that C75 alleviated bleomycin-induced lung fibrosis in mice by inhibiting β-catenin. In conclusion, these findings suggest that inhibiting FASN in fibroblasts may diminish the activity of the Wnt/β-catenin signaling pathway, providing a potential therapeutic avenue for pulmonary fibrosis. Show less

Acetylcholinesterase (AChE) inhibitors are crucial for the symptomatic management of Alzheimer's disease (AD), with natural products-particularly botanical sources like Yellow Gastrodia elata (YGE)-serving as promising reservoirs of such inhibitors. Nevertheless, comprehensive screening and mechanistic characterization of their inhibitory potential remain limited. This study sought to identify potent AChE inhibitors from YGE, investigate their mechanisms of action, and assess their therapeutic prospects for AD. Methodologically, an integrated approach was employed, combining ultrafiltration-liquid chromatography (UF-LC) for rapid inhibitor screening, molecular docking and dynamics simulations for mechanistic insight, two-stage high-speed countercurrent chromatography for compound isolation, enzyme kinetics to delineate inhibition modalities, and network pharmacology to uncover relevant AD-related targets. The findings identified seven active constituents with notable AChE inhibition, among which parishins A and G were obtained at high purity (98.26% and 97.26%, respectively) and exhibited mixed-type inhibition with low IC Show less

Bushen Huoxue Acupuncture shows potential in treating neurodegenerative diseases, but its mechanisms remain incompletely understood. Using the senescence-accelerated mouse-prone 8 (SAMP8) mouse model, we assessed cognitive function via the Morris water maze test, hippocampal neuronal apoptosis with terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and microglial activation through immunohistochemistry. Serum levels of inflammatory cytokines [tumor necrosis factor-alpha, interleukin (IL)-1β, and IL-6] were quantified by enzyme-linked immunosorbent assay. The expression of SIRT2 pathway-related proteins, along with Aβ deposition, was analyzed using Western blotting, immunohistochemistry, and immunofluorescence. The results demonstrated that Bushen Huoxue Acupuncture improved cognitive function in SAMP8 mice, reducing hippocampal neuronal apoptosis and decreasing serum levels of pro-inflammatory cytokines. Additionally, it reduced the levels of Aβ42, a more aggregation-prone and toxic Aβ subtype, in both hippocampal tissues and serum, as well as the number of CD68-positive cells in hippocampal tissues, suggesting the inhibition of amyloid pathology and neuroinflammatory. The treatment also downregulated SIRT2, BACE1, and APP-CTF while increasing RTN4B expression. Notably, Bushen Huoxue Acupuncture outperformed non-acupoint acupuncture in enhancing cognitive function and reducing inflammation. Our findings indicate that Bushen Huoxue Acupuncture alleviates cognitive deficits and neuroinflammation by suppressing the SIRT2-mediated RTN4B/BACE1 pathway, highlighting acupuncture as a promising therapy for neurodegenerative diseases. Show less

Synaptic dysfunction and synapse loss occur in Alzheimer's disease (AD). The current study aimed to identify synaptic-related genes with diagnostic potential for AD. Differentially expressed genes (DEGs) were overlapped with phenotype-associated module selected through weighted gene co-expression network analysis (WGCNA), and synaptic-related genes. The overlapped hub genes were further processed using machine learning algorithms, intersected with module gene from protein-protein interaction (PPI) network constructed with DEGs, to yield co-hub genes. The diagnostic potentials of the co-hub genes were examined by receiver operating characteristic (ROC) analysis. Correlation between co-hub genes with clinical features and immune cell infiltration was analyzed. Finally, the expression of co-hub genes was analyzed in several datasets and validated in AD transgenic mice. A total of three co-hub genes were identified, including MAP1B, L1CAM, and GABBR2. GABBR2 showed area under the curve (AUC) values of 0.98, 0.81, and 0.88 in the training and two external validation datasets. GABBR2 was negatively correlate with beta- and gamma-secretase activities, and infiltration of natural killer T cells and effector memory CD8 T cells. Finally, GABBR2 was validated to be downregulated in AD transgenic mice, aligning with bioinformatic findings. GABBR2 overexpression in N2a/APP cells increased ADAM10 while decreased of BACE1, leading to upregulation of sAPPα while downregulation of sAPPβ. In conclusion, GABBR2 acts as a novel biomarker for the diagnosis of AD and negatively correlated with Aβ in AD. Show less

Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including APP, RARRES2, FAM3A, HAMP, CAMP, GNLY, and PI3. Senescent RPE cells expressed lower levels of APP and RARRES2 mRNA, accompanied by increased intracellular retention of E. coli in a bactericidal assay. Silencing APP, not RARRES2, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (BACE1) and γ-secretase (PS1), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration. Show less

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by pathogenesis involving numerous factors. Recent research has highlighted the significant role of autoimmunity in the initiation and progression of AD, with autoantibodies emerging as a pivotal area of investigation. Nevertheless, the influence of autoantibodies in AD is marked by substantial heterogeneity, they may either mitigate disease progression by clearing pathogenic protein aggregates or exacerbate the pathological process through mechanisms such as the activation of inflammatory responses or the induction of neuronal damage.ObjectiveThis review aims to synthesize the various roles of autoantibodies in AD, examine the factors that influence their functions, and assess their potential application in precision immunotherapy.MethodsPubMed and Web of Science databases were searched for English-language papers (2015-2025). Peer-reviewed human, animal and cell studies, systematic reviews and meta-analyses were screened independently by two reviewers.ResultsA total of 87 studies were selected for inclusion, spanning human, animal, and cellular research. The findings indicated that certain autoantibodies, such as those targeting amyloid-β, tau, or 4-hydroxynonenal, may confer neuroprotective effects. Conversely, other autoantibodies, including those against BACE1, aquaporin-4, or HuD, may exacerbate AD pathology. Importantly, some autoantibodies were found to exhibit dual roles, contingent upon their specific modifications or the context of the disease.ConclusionsAutoantibodies constitute a double-edged immune axis in AD. Their impact hinges on antigen class, disease stage, isotype affinity and glycosylation. Precision strategies-like CAAR-T cell therapy, glycosylation modulation, and affinity optimization-offer therapeutic promise but require further validation. Show less

β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme for amyloid-β (Aβ) generation and is considered promising drug target for Alzheimer's disease (AD). The co-chaperone BAG3 (Bcl-2-associated athanogene 3) plays an important role in maintaining intracellular protein homeostasis by regulating heat shock protein 70 (HSP70). Here, we reported that BAG3 expression was significantly elevated in AD. It interacted with and stabilized BACE1 by delaying its degradation through ubiquitin-proteasome and autophagy-lysosomal pathways. BAG3 Show less

The Gastrointestinal (GI) microbiome and gut-brain axis are associated with the progression and pathology of Alzheimer's disease (AD). Amyloid deposition is thought to be a driver of AD, causing synaptic dysfunction and neuronal death in the brain. Chronic constipation is a common gastrointestinal (GI) dysmotility in AD patients, which impacts patient outcomes and quality of life. It is unknown if enteric amyloidosis disrupts myenteric neuron function and causes GI dysmotility. Untreated male and female APP/PS1 (a transgenic murine model of brain amyloidosis) and sex-matched control mice were followed until 12 months of age. A separate cohort of mice was treated with a vehicle or the beta-secretase (BACE1) inhibitor, lanabecestat, starting at 5 months of age until 7 months. GI motility was assessed in all mice by measuring whole GI transit in vivo. Propulsive colonic motility and GI smooth muscle contractions were measured ex vivo. At 7 or 12 months old, amyloidosis in the brain and myenteric plexus was determined by immunohistochemistry or ELISA; the myenteric neural density, including the cholinergic and nitrergic neurons, was evaluated by immune staining and RT-PCR; expression of pro-inflammatory factors in the GI wall was assessed by RT-PCR. By 7 months of age, male and female APP/PS1 mice developed abundant amyloid plaques in the brain. Aged untreated male APP/PS1 mice also demonstrated Aβ deposition in the colonic myenteric ganglia, which was associated with increased fecal output and faster whole GI transit starting at 4-7 months old, but vehicle- and lanabecestat-treated male APP/PS1 mice had similar GI motility to their non-genetic controls until 7 months old. None of the female APP/PS1 mice showed GI dysmotility or myenteric amyloidosis. Two months of lanabecestat treatment effectively reduced amyloid plaque burden in the brains of female APP/PS1 mice but not in male APP/PS1 mice. Treatment with lanabecestat did not affect myenteric Aβ intensity or GI motility in all APP/PS1 mice. All APP/PS1 mice did not show myenteric neuronal degeneration or inflammation until 12 months old. APP/PS1 mice do not recapitulate myenteric amyloidosis persistently and lack the phenotype of constipation observed in human AD patients; these mice should not be considered an adequate murine model for studying the role of myenteric amyloidosis in GI dysmotility. An adequate animal model with myenteric amyloidosis is required for further study. Show less

Alzheimer's disease (AD) is a multifactorial neuropathology characterized by the accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs) and cholinergic system dysfunction. At present, there is no effective treatment strategy for AD. Our previous research showed that ZJQ-3F acts as an inhibitor of AChE/BACE1/GSK3β, and showed good blood-brain barrier permeability, appropriate bioavailability and oral safety. In order to further study, the protective effect of ZJQ-3F on APP/PS1/Tau transgenic mice was determined. APP/PS1/Tau transgenic mice model of AD was treated with ZJQ-3F from the age of 8 to 12 months, and then behavioral tests was conducted. Western blot, immunohistochemistry and immunofluorescence staining were used to evaluate the level of tau protein, Aβ plaques and synaptic function. Our results revealed that administration of ZJQ-3F could improve the cognitive function of APP/PS1/Tau transgenic mice. In addition, compared with APP/PS1/Tau mice, the protein expression levels of tau protein phosphorylation site at Ser396, Thr212 and Thr181 in the cortex and hippocampus of ZJQ-3F treated mice was significantly decreased. Moreover, the results showed that ZJQ-3F significantly reduced the deposition of Aβ in the cortex and hippocampus. Furthermore, the results indicated that the protein expression levels of PSD95, SYP and SYT in the cortex and hippocampus were increased markedly after ZJQ-3F was given. Our studies suggest that the chronic administration of ZJQ-3F can improve learning and memory ability, reduce tau protein phosphorylation, reduce Aβ deposition and improve synaptic dysfunction in APP/PS1/Tau transgenic model of AD, indicating that ZJQ-3F can be used as a multi-target inhibitor to slow down the progress of AD. Show less

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD. Show less

People with mild cognitive impairment (MCI) carry a considerable risk of developing dementia. Studies have shown that female sex hormones have long-lasting neuroprotective and anti-aging properties, and the increased risk of MCI and AD is associated with the lack of estrogen during menopause. Previous studies have shown that Tiao Geng Decoction (TGD) may have antioxidant and anti apoptotic properties, which may prevent neurodegenerative diseases. However, whether TGD is effective in improving mild cognitive impairment due to postmenopausal estrogen deficiency and its potential pharmacological mechanisms remain unclear. The aim of this study was to investigate the possible pharmacological mechanisms of TGD in preventing postmenopausal MCI. We utilized RNA-seq technology to screen for differentially expressed genes (DEGs) and enrichment pathways in the hippocampal tissue of different groups of mice. Additionally, we adopted single-cell sequencing technology to study the cell types of Alzheimer's disease (AD) group and Normal Control (NC) group, the differential marker genes of each cell subgroup, and the GO enrichment analysis of each cell type. Both RNA sequencing and single-cell sequencing results showed a significant correlation between TGD and NF-κb pathway in improving mild cognitive impairment in postmenopausal women. The experimental verification results showed that the spatial learning and memory abilities of APP/PS1 model mice were weakened after ovariectomy, and the reproductive cycle on vaginal smears was in the interphase of diestrus. The levels of serum E2, and P-tau181 in mice were significantly down regulated, while the levels of brain tissue homogenate A β 42, IL-1 β, and IL-18 were significantly up-regulated, indicating successful modeling. Combining Western blotting, RT-qPCR, and transmission electron microscopy analyses, it was found that the low estrogen environment induced by oophorectomy can activate the NF-κb signaling pathway, activate the expression of NLRP3 inflammasome and A β secretase BACE1, and induce neuroinflammatory damage in hippocampal astrocytes. These results conform to the modeling characteristics of MCI. After TGD intervention, the spatial learning and memory abilities of MCI mice were significantly improved. The pharmacological validation results indicated that high concentration doses of TGD had a more significant effect on MCI. Subsequently, we used high concentration TGD (0.32 g/ml) as the traditional Chinese medicine group for further validation, protein blotting and RT-qPCR results indicated that TGD can effectively stimulate the secretion of ER α and ER β, inhibit the NF-κb pathway, downregulate BACE1, and inhibit the expression of NLRP3 inflammasome related proteins. In addition, the immunofluorescence results of hippocampal astrocytes showed that TGD can effectively facilitate the expression of AQP1 and significantly lower the sedimentation of A β compared with the model group. Our research suggests that there is a high correlation between a low estrogen environment and the occurrence and development of MCI. TGD may regulate the ERs/NF - κ b/AQP1 signaling pathway, promote estrogen secretion, activate AQP1, reduce A β deposition, reverse MCI neuroinflammatory injury, improve mild cognitive impairment, and prevent the occurrence of AD. This study revealed for the first time that TGD may be a potential new alternative drug for preventing and improving menopausal MCI. Show less

Systemic lupus erythematosus (SLE) is a complex and incurable autoimmune disease, so several drug remission for SLE symptoms have been developed and used at present. However, treatment varies by patient and disease activity, and existing medications for SLE were far from satisfactory. Novel drug targets to be found for SLE therapy are still needed. Mendelian randomization (MR), an observational study way, was performed to explore potential drug targets for SLE using protein quantitative trait loci (pQTL) from recently published genome-wide association studies (GWAS) of cerebrospinal fluid (CSF) and plasma proteins, which obtained genetic instruments for 154 CSF proteins of 971 participants, and 734 plasma proteins of 23591 participants. Bidirectional Mendelian randomization analysis, colocalization analysis, and phenotype scanning were performed to find key proteins for SLE. In addition, external data verification was implemented to further consolidate the Mendelian randomization findings. Candidate proteins as targets to find drugs and discuss the druggability. Finally, Network pharmacology and molecular docking methods were used to verify the effects of Voclosporin and Cyclosporine on SLE targets. Protein-protein interaction (PPI) and core target analysis of candidate drugs and SLE overlapping targets were performed to identify potential hub targets and interactions. The affinity between drug targets and SLE targets was confirmed by molecular docking. In the preliminary analysis, we identified four key proteins as possible drug targets in CSF and plasma proteins, included ICAM-1(P = 4.62E-05, OR = 0.90(0.86, 0.95)), sICAM-1(P = 4.62E-05, OR = 0.49(0.35, 0.69)), FCG2B (P = 7.63E-11, OR = 0.57(0.48, 0.67)), PPP3CA; PPP3R1 (P = 5.47E-07, OR = 0.66(0.57, 0.78)). Among them, ICAM1 was detected in both CSF and plasma proteins. By excluding reverse causality, confounding factors, and linkage disequilibrium (LD), we identified PPP3CA; PPP3R1 as novel drug targets for SLE, including Voclosporin and Cyclosporine. Finally, the Drugbank database shows that novel drugs contain 33 targets for treating SLE. PPI suggested that SIRT1, ACE, PTGS2, and BACE1 were pivotal targets for SLE treatment. In addition, the molecular docking showed that the bioactive molecules of Voclosporin and Cyclosporine had a good affinity with the target of SLE. Our integrative analysis suggested that levels of circulating PPP3CA; PPP3R1 had causal effects on SLE risk and served as potential treatment targets. Moreover, this study provides new evidence for Voclosporin as an SLE treatment through Mendelian randomization and Network pharmacology, and warrants further clinical investigation. Show less

Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans. Show less

Pericytes regulate cerebral blood flow (CBF) and excess amyloid in the brain. Pericyte dysfunction may contribute to the pathology of Alzheimer's disease (AD). Acorus tatarinowii (AT), a Chinese medicine commonly used to treat AD, protects the central nervous system. However, whether AT can regulate pericyte function and ameliorate cognitive dysfunction remains unclear. We employed a novel target recognition assay, quantitative measurement of CBF, hematoxylin and eosin staining, immunofluorescence staining, and Western blot to investigate the role of AT in improving cognitive function in patients with AD. Additionally, we investigated the therapeutic potential of β-Asarone, the primary active compound in AT, for treating AD by modulating pericyte function using transmission electron microscopy, silver staining, electrical impedance, and other methodologies. The results revealed that administration of AT effectively alleviated the cognitive impairments induced by D-galactose in mice, as evidenced by enhanced CBF, improved histological characteristics of damaged brain tissue cells, increased expression of platelet-derived growth factor-β (PDGF-β), decreased Aβ accumulation via enhanced lipoprotein receptor-related protein 1 (LRP1), and reduced beta-site APP-cleaving enzyme 1 (BACE1). β-Asarone treatment mitigated ROS release and BACE1 expression while elevating the cell index in Aβ1-40 injured mouse brain vascular pericytes (MBVP). These findings suggest that AT has the potential to enhance CBF and mitigate pericellular dysfunction, thereby ameliorating Aβ deposition in the brain and improving cognitive impairment in patients with AD. Show less

Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1β, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD. Show less

Advanced renal cell carcinoma (RCC) primarily relies on targeted and immune-based therapies, yet these treatments often face limitations due to inefficacy and drug resistance. Branched-chain α-keto-acid dehydrogenase kinase (BCKDK) has been implicated in promoting RCC metastasis, but its specific substrates and the mechanisms underlying its regulation of RCC progression remain poorly understood. This study uncovers a novel mechanism whereby BCKDK-mediated AKT phosphorylation drives RCC tumorigenesis and drug resistance. Elevated BCKDK expression correlates with poor prognosis in RCC clinical samples. BCKDK deficiency inhibits RCC cell proliferation and tumorigenesis both in vitro and in vivo. Mechanistic investigations reveal that BCKDK directly binds to and regulates the phosphorylation of AKT. BCKDK-mediated phosphorylation of AKT decreases ubiquitin-mediated AKT protein degradation, and promotes tumorigenesis via activation of the AKT/mTOR signaling pathway. RNA sequencing identifies BCKDK's involvement in the drug metabolism network and apoptotic signaling pathways. The BCKDK/AKT/ABCB1 axis mediates doxorubicin resistance. Targeting BCKDK/AKT inhibits the growth of RCC patient-derived organoids (PDOs), enhances doxorubicin-induced apoptosis in RCC cells, and suppresses tumor growth in vivo. These findings identify a previously unrecognized phosphorylation substrate of BCKDK and highlight the critical role of the BCKDK/AKT signaling axis in RCC progression, offering a promising target for therapeutic intervention. Show less

Cancer is one of the major diseases threatening human health in the world. According to the latest global cancer statistics from the International Agency for Research on Cancer (IARC), there were approximately 20 million new cancer cases and 10 million cancer deaths worldwide. Amidst this global health concern, branched chain amino acids have emerged as key players, playing an important role in the occurrence and development of cancer. In certain malignancies like colorectal cancer, the average level of BCAA in tumor tissues is twice that in normal tissues. BCAA metabolism is intricately associated with the progression of multiple tumors and is modulated by diverse enzymes, including BCAT, BCKDH, and BCKDK. The metabolism of BCAA involves multiple enzymes and biochemical processes via signaling pathways such as PI3K/AKT/mTOR and AMPK/mTOR, etc. In addition, mTOR inhibitors show potential value in cancer treatment by regulating the metabolism and signaling pathways of tumor cells, which provides a new direction for anticancer efforts. Simultaneously, BCAAs are closely associated with tumor immunity, including NK cells, CD4 Show less