Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial i Show more
Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications. Show less
Hepatocellular carcinoma (HCC) is a major malignancy with rising global incidence and mortality. Clinical treatment is limited by molecular heterogeneity and drug resistance. In recent years, endocrin Show more
Hepatocellular carcinoma (HCC) is a major malignancy with rising global incidence and mortality. Clinical treatment is limited by molecular heterogeneity and drug resistance. In recent years, endocrine-disrupting chemicals (EDCs) have attracted attention as emerging risk factors, but systematic pathogenic evidence for their roles in HCC initiation and progression remains insufficient. First, we predicted potential targets of EDCs using SwissTargetPrediction, STITCH, and ChEMBL, and intersected them with differentially expressed genes and key module genes from WGCNA in the GEO database to screen candidate key genes. Second, based on these candidates, we constructed diagnostic models using 14 machine-learning algorithms and evaluated feature importance via the SHAP framework to identify key biomarkers and their functional contributions. Molecular docking and molecular dynamics simulations were used to validate interaction mechanisms between EDCs and key target proteins. We then built a multivariable Cox proportional hazards model in the TCGA-LIHC cohort and performed stratified survival analysis, somatic mutation profiling, and immune evasion characterization. Subsequently, we evaluated the tumor immune microenvironment using CIBERSORT and ssGSEA, and integrated single-cell transcriptomic data to resolve cell-subtype heterogeneity, target expression distributions, and cell-cell communication. Meanwhile, we integrated the GDSC drug-sensitivity database to evaluate associations between risk scores and drug response, and conducted pan-cancer analyses to examine cross-cancer applicability. We identified 18 genes jointly associated with EDCs and HCC, significantly enriched in AMPK, p53, and FoxO signaling pathways and cell cycle-related pathways. Among models built with 14 machine-learning algorithms, CatBoost showed the best discriminative performance and identified CCNB2 and AKR1C3 as core driver genes. Docking and dynamics simulations indicated strong binding affinities and stable binding conformations between EDCs and target proteins including CCNB1 (-8.9 kcal/mol), AKR1C3 (-8.4 kcal/mol), and FADS1 (-8.5 kcal/mol). A multivariable Cox risk model based on nine key genes served as an independent prognostic predictor for HCC (HR = 1.746, 95% CI: 1.477-2.064, P < 0.001). The nomogram achieved AUCs of 0.836, 0.810, and 0.788 at 1, 3, and 5 years, respectively, indicating good predictive performance. The high-risk group was significantly associated with high tumor mutational burden (TMB), TP53 mutations, and low immune evasion scores. Regarding the tumor immune microenvironment, CIBERSORT and ssGSEA analyses showed marked enrichment of Tregs and M0 macrophages, while most effector immune cells and functions were suppressed. Single-cell transcriptomics further showed enrichment of endothelial cells, fibroblasts, hepatocytes, and macrophages in HCC tissues, with notable reductions in T cells, B cells, NK cells, and neutrophils, indicating an immunosuppressive microenvironment with stromal remodeling. Cell-cell communication analysis indicated that the MIF-CD74 receptor axis is central in immune-cell interactions. Drug-sensitivity analysis suggested that the high-risk group was more sensitive to GDC0810, BPD-00008900, and Fulvestrant, indicating potential beneficiary populations. Pan-cancer analysis showed that the risk model also had diagnostic and prognostic value in LUAD, KIRP, KIRC, and KICH, suggesting cross-cancer generalizability. This study systematically reveals that EDCs promote HCC initiation and progression by perturbing cell cycle, metabolic, and immune homeostasis through multi-target, multi-pathway mechanisms. The nine-gene risk model demonstrates superior performance in HCC diagnosis and prognosis and shows potential clinical translational value in drug-sensitivity prediction and pan-cancer analyses. This work provides a new perspective at the intersection of environmental toxicology and precision oncology and informs individualized therapeutic strategies. Show less
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable s Show more
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable strategies for Show less
To explore the associations between accelerometer-measured physical activity patterns and cardiovascular diseases (CVD), CVD-cause mortality, and all-cause mortality in people with osteoarthritis (OA) Show more
To explore the associations between accelerometer-measured physical activity patterns and cardiovascular diseases (CVD), CVD-cause mortality, and all-cause mortality in people with osteoarthritis (OA). OA participants from the UK biobank with ≥36 h of accelerometer data, collected over one-week, were analyzed. Moderate to vigorous physical activity (MVPA) patterns were classified as: 'weekend warriors' (≥150 min/week, >50% on 1-2 days), active regular (>150 min/week), or inactive (<150 min/week). Mean min per week of light physical activity (LPA) were categorized into quartiles based on the distribution in the analytical sample. Among 10 210 study participants (mean age 58.1 ± 7.1 years; 64.5% female) followed for a median of 6.9 years, there were 1,538 incident cases of CVD, and 358 deaths, including 90 from CVD. Compared with inactive MVPA, both weekend warrior (adjusted hazard ratio, aHR (95% CIs); 0.73 (0.64-0.82)) and active regular MVPA (0.75 (0.65-0.87)) significantly lowered the risks of incident CVD. Notably, only the weekend warrior group showed significant reductions in CVD-cause mortality (0.55, 0.33-0.92), and all-cause mortality (0.75 (0.59-0.96)). Higher levels of LPA may link to lower CVD, CVD-cause mortality, and all-cause mortality risks in a dose-response manner. Subgroup analysis indicated that more prominent associations were found in individuals with a body mass index >30 or those aged over 60. Engaging in a weekend warrior pattern may confer unique survival benefits for OA patients, especially among older adults and those with obesity. LPA may have dose-dependent protective effects for CVD and mortality risk in OA patients. Show less
Xi-Yu Zhao, Zhen-Qi Wu, Tian-Yu Zhang+4 more · 2026 · Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica · added 2026-04-24
Attention deficit hyperactivity disorder(ADHD), a common neurodevelopmental disorder in children, is characterized by inattention, hyperactivity, and impulsivity. Epidemiological surveys show that the Show more
Attention deficit hyperactivity disorder(ADHD), a common neurodevelopmental disorder in children, is characterized by inattention, hyperactivity, and impulsivity. Epidemiological surveys show that the prevalence of ADHD in children is gradually increasing worldwide, and it is the most common childhood mental disorder in China. Because of the complex clinical symptoms, multiple co-morbidities, and unknown etiology, ADHD has far-reaching negative impacts on individuals, families, and the society. Behavioral interventions, as a pillar in the management of ADHD, play a targeted role in improving children's social functioning, with significant benefits supported by evidence. However, they are constrained by uneven resources, poor compliance, and insufficient continuity, Western medicine has multiple adverse effects and unclear long-term effects in the treatment of ADHD despite the definite efficacy. Accordingly, there is an urgent need to find safe and effective therapies suitable for children. With a holistic view and treatment based on syndrome differentiation, traditional Chinese medicine(TCM) has significant advantages in treating ADHD via multiple targets, which involves dopamine(DA), norepinephrine(NE), 5-hydroxytryptamine(5-HT), cyclic adenosine monophosphate(cAMP), brain-derived neurotrophic factor(BDNF) and other signaling pathways. Through these pathways, TCM can treat ADHD through the regulation of neurotransmitters, enhancement of prefrontal and striatal functions, enhancement of neuronal protection, attenuation of neuroinflammation, and reduction of neuronal apoptosis. However, a systematic study remains to be conducted. This paper summarizes the signaling pathways related to the treatment of ADHD by TCM in the past two decades, aiming to provide reference for delving into the mechanism and exploring effective TCM prescriptions for ADHD in children and to give full play to the advantages of the efficacy and characteristics of TCM. Show less
This study aims to evaluate the association between multiple lipid indices and coronary collateral circulation (CCC) in patients diagnosed with acute ST-segment elevation myocardial infarction (STEMI) Show more
This study aims to evaluate the association between multiple lipid indices and coronary collateral circulation (CCC) in patients diagnosed with acute ST-segment elevation myocardial infarction (STEMI). This was a cross-sectional retrospective study involving 421 patients with STEMI who underwent coronary angiography between January 2022 and December 2024. Participants were categorized into a poor CCC group (Rentrop grade 0-1) and a good CCC group (Rentrop grade 2-3) according to Rentrop grading criteria. The following lipid parameters were evaluated as both continuous and categorical variables: total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) [Lp(a)], apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), non-HDL-C/HDL-C, ApoB/ApoA-I, atherogenic index of plasma (AIP), and lipoprotein composite index (LCI). The associations between these lipid indices and CCC status were assessed using multivariate logistic regression and receiver operating characteristic (ROC) curve analysis. Multivariate logistic regression analysis revealed that higher HDL-C quartiles were significantly associated with reduced odds of poor CCC (odds ratio [OR]: 0.544, 95% confidence interval [CI]: 0.351-0.771, P < 0.05), whereas elevated LDL-C (OR: 29.299, 95% CI: 3.562-240.976, P < 0.05), non-HDL-C (OR: 50.140, 95% CI: 5.408-464.834, P < 0.01), and non-HDL-C/HDL-C (OR: 4.510, 95% CI: 1.186-25.368, P < 0.05) quartiles were significantly associated with increased odds of poor CCC. Receiver operating characteristic (ROC) curve analysis demonstrated that LDL-C (cutoff: 3.265, AUC: 0.647, 95% CI: 0.573-0.721, P < 0.001), non-HDL-C (cutoff: 2.735, AUC: 0.752, 95% CI: 0.688-0.816, P < 0.001), and non-HDL-C/HDL-C (cutoff: 2.393, AUC: 0.686, 95% CI: 0.611-0.761, P < 0.001) exhibited favorable predictive performance for poor CCC. Stratification analysis showed that the highest prevalence of poor CCC was observed in patients with concurrently elevated levels of LDL-C, non-HDL-C, and non-HDL-C/HDL-C. Several lipid indices-including LDL-C, non-HDL-C, and the non-HDL-C/HDL-C ratio-are significantly associated with impaired CCC in patients with STEMI. Notably, non-HDL-C exhibits the strongest association with CCC dyscrasia and therefore warrants early clinical attention. Show less
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the ef Show more
Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the effects of Orientin on oxidized low-density lipoprotein and high glucose (ox-LDL/HG)-triggered endothelial cell injury and diabetes-accelerated atherosclerosis remain unclear. ApoE Show less
Validate the clinical utility of exosome cargo (miRNAs/proteins) and NLRP3/BDNF as key regulatory molecules for acupuncture-mediated spinal cord injury (SCI) recovery. From the establishment of the da Show more
Validate the clinical utility of exosome cargo (miRNAs/proteins) and NLRP3/BDNF as key regulatory molecules for acupuncture-mediated spinal cord injury (SCI) recovery. From the establishment of the database to May 2025, a literature search was conducted on PubMed, and Embase, using keywords ["exosome cargo" or "exosome"], ["acupuncture" or "acupuncture and moxibustion" or "electroacupuncture" or "EA"], ["spinal cord injury" or "SCI"], ["immune regulation"], ["inflammatory reaction"], ["neuroregeneration" or "nerve"]. Including peer-reviewed studies on human/animal models, articles that do not meet the requirements are excluded. Preclinically, MSC-exosomal miR-145-5p suppressed TLR4/NF-κB signaling, reducing spinal IL-1β by 47% in SD rats. Schwann cell-exosomal MFG-E8 activated SOCS3/STAT3, increasing M2 macrophage CD206 by 63% and raising rat BBB scores by 3.8 points; Treg-exosomal miR-2861 upregulated tight junction proteins (occludin/ZO-1) to repair the blood-spinal cord barrier. Acupuncture (EA at GV14/GV4) upregulated spinal BDNF by 72% and NGF by 58% via Wnt/β-catenin, while EA at GV6/GV9 downregulated NLRP3 by 42-58% and TNF-α by 35-47%. Clinically, EA at EX-B2 increased ASIA scores by 3.2±1.1 points (Guo et al). Besides, 5x/week EA improved ASIA vs 3x/week (+6.4 points). EA+exercise reduced MAS by 1.6-2.9 points, with outcomes correlated to peripheral NLRP3 reduction, BDNF elevation, and MBI/WISCIII increases. Exosome cargo (miR-145-5p/MFG-E8) and NLRP3/BDNF are key regulatory molecules underlying acupuncture-mediated SCI recovery. However, limitations (small RCT samples, heterogeneous acupuncture protocols, unstandardized exosome isolation) hinder translation. Future work should focus on standardized biomarker detection, exosome engineering, and large-scale clinical trials. Show less
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed de Show more
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed death ligand-1 signaling induce tumor regression in some patients with NSCLC, but most patients with NSCLC exhibit resistance to ICIs therapy. NSCLC shapes the potent tumor immunosuppressive microenvironment (TIME) that underlies tumor immune tolerance and acquired resistance. Therefore, elucidating the cellular and molecular mechanisms by which NSCLC establishes and sustains the TIME is essential for developing novel strategies to overcome immune resistance and enhance the clinical benefit of ICIs. The correlation between sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) expression and ICIs was analyzed via immunohistochemistry. Cell migration assay was performed to assess the effect of SAMHD1 on macrophage recruitment. Multicolor flow cytometry was performed to analyze the effect of SAMHD1 knockdown on the tumor microenvironment. SAMHD1 regulation of the dual specificity phosphatase 6-extracellular regulated protein kinases 1/2 (DUSP6-ERK1/2) pathway was verified by RNA sequencing and western blotting. Here, we identify the SAMHD1 as a potential therapeutic target and a major determinant of poor response to ICIs in patients with NSCLC. Tumors with high SAMHD1 expression show resistance to anti-PD-1 antibody (αPD-1) treatment, whereas tumors with low SAMHD1 expression are highly sensitive. SAMHD1-dependent resistance to αPD-1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, SAMHD1 regulates the expression of macrophage-associated chemokines by influencing the activation of the DUSP6-ERK1/2 pathway, which contributes to TAMs aggregation within NSCLC tumors to shape an immunosuppressive microenvironment. The HIV accessory protein viral protein-x (VPX) specifically degrades SAMHD1 to promote HIV replication. Similarly, the vpx-engineered oncolytic adenovirus (oAd-vpx) targets SAMDH1 degradation to enhance oncolytic adenovirus replication and weaken the hostile immune microenvironment shaped by TAMs, thereby triggering a CD8+T-cell-dependent antitumor immune response. The combination of oAd-vpx and αPD-1 inhibits tumor growth and enhances sensitivity to ICIs in both mouse and human NSCLC. This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC. Show less
In vitro maturation (IVM) is highly susceptible to influences of the culture environment, which can lead to increased intracellular reactive oxygen species (ROS) levels and thereby induce a stress res Show more
In vitro maturation (IVM) is highly susceptible to influences of the culture environment, which can lead to increased intracellular reactive oxygen species (ROS) levels and thereby induce a stress response in oocytes, ultimately reducing the developmental potential of early embryos. Brain-derived neurotrophic factor (BDNF) is an ovarian endocrine factor that can enhance the function of follicular granulosa cells and promote oocyte maturation, but the specific pathways remain unclear. We supplemented IVM cultures of sheep oocytes with BDNF and examined aspects of oocyte nuclear and cytoplasmic maturation. The addition of 50 ng/mL BDNF promoted the expansion of cumulus cells and increased the rates of first polar body extrusion, cleavage, and blastocyst formation. Compared with untreated controls, BDNF-treated oocytes had improved Ca Show less
Facial nerve injury (FNI) is a common peripheral neuropathy that severely impairs facial function and quality of life. Qianzheng Powder (QZP) is a traditional Chinese herbal formula used to treat faci Show more
Facial nerve injury (FNI) is a common peripheral neuropathy that severely impairs facial function and quality of life. Qianzheng Powder (QZP) is a traditional Chinese herbal formula used to treat facial paralysis clinically, yet its neuroprotective mechanisms remain unclear. This study aims to evaluate the therapeutic effects of QZP on FNI and potential underlying mechanisms. A FNI model was established in male C57BL/6 mice by performing facial nerve crush surgery. QZP (3.51 g/kg) was administered orally once daily for 14 days post-surgery. Facial function was assessed behaviorally. Tissue samples were collected on day 21 for histological evaluation, qPCR and Western blotting. Liver and kidney safety were also assessed via H&E staining and serum biochemical markers. QZP significantly improved facial motor function from day 7 post-injury. Additionally, QZP treatment mitigated neuronal loss in the facial motor nucleus, attenuated buccinator muscle atrophy, and enhanced myelin regeneration, as evidenced by increased MPZ and MBP expression. These were consistent with the increace of the BDNF, TrkB, and QZP promotes structural and functional recovery of facial nerve following injury, likely through activation of the BDNF/TrkB/CREB axis, and demonstrates a favorable safety profile. These findings support its potential as a therapeutic adjunct in peripheral nerve repair. Show less
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a Show more
Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a key mediator of fibroblast phenotypic remodeling via monocarboxylate transporter 1 (MCT1)-mediated histone H3 lysine 23 lactylation (H3K23la) in HS. Elevated lactate levels and MCT1 expression were observed in HS tissues, with macrophages in stiff mechanical microenvironments identified as the primary lactate source. Lactate influx through MCT1 upregulated H3K23la, thereby promoting transcriptional activation of profibrotic genes HEY2 and COL11A1. Mechanistically, HEY2 activated YAP1/SMAD2 signaling, while COL11A1 stabilized MCT1 to enhance lactate transport, forming a positive loop that amplified fibrosis. Fibroblast-specific Mct1 deletion or pharmacological inhibition of Mct1 in male mice reduced collagen deposition, accelerated wound healing, and attenuated scar formation. Our findings redefine the macrophage-fibroblast crosstalk in HS and establish the MCT1-H3K23la-HEY2/COL11A1 axis, particularly its self-reinforcing loop, as a novel therapeutic target. Show less
Cerebral palsy (CP), the most prevalent pediatric motor disorder with significant cognitive comorbidity (> 50%), lacks therapies addressing both impairments in moderate-to-severe cases. This study dem Show more
Cerebral palsy (CP), the most prevalent pediatric motor disorder with significant cognitive comorbidity (> 50%), lacks therapies addressing both impairments in moderate-to-severe cases. This study demonstrates that human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-Exos) exert profound therapeutic effects in a rat model of moderate-to-severe CP established via bilateral carotid artery occlusion with hypoxia. Intravenously administered hUCMSC-Exos displayed sustained brain retention and significantly restored motor coordination and cognitive function. The recovery was primarily mediated through enhanced remyelination driven by promoted oligodendrocyte maturation and differentiation (elevated oligodendrocyte lineage transcription factor 2 and myelin basic protein). Concurrently, the treatment attenuated key pathological processes involving sustained neuroinflammatory responses (reduced ionized calcium-binding adapter molecule 1, tumor necrosis factor-α, and interleukin-6) while elevating brain-derived neurotrophic factor. Our findings establish hUCMSC-Exos as a promising dual-modality therapy for moderate-to-severe CP, mechanistically linked to robust remyelination and coordinated modulation of core disease mechanisms. Show less
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating Show more
Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing apolipoprotein E (ApoE), which was correlated with poor survival in patients with RCC. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC. NRF1 drives formation of ApoEhigh cancer-associated fibroblasts that secrete NRG1 to stimulate stemness of renal cell carcinoma, revealing a stromal-mediated mechanism that can be inhibited to improve treatment of advanced kidney cancer. Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-est Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen-cholinergic-NGF axis: E Show less
Current in vitro enzyme inhibition assays often involve subjective data analysis based on the researcher's experience. In this study, we developed a multi-dimensional quantitative integration platform Show more
Current in vitro enzyme inhibition assays often involve subjective data analysis based on the researcher's experience. In this study, we developed a multi-dimensional quantitative integration platform (MDQIP) that uses a model to objectively calculate and rank compound activities, addressing the limitations of traditional "experience-driven" evaluations, accelerates the screening and evaluation of potential AChE inhibitors from Red Gastrodia elata, offering a more efficient approach to drug discovery. Ultrafiltration-LC screening identified parishin A as having the most stable binding, with binding degree and recovery rates of 98.85% and 99.39%, respectively. Molecular docking revealed that parishins A and C were the strongest AChE inhibitors, exhibiting stable binding through hydrogen bonds, π-alkyl, and π-π interactions. Molecular dynamics simulations confirmed the stability of these compounds, with binding energies of -82.65 ± 4.24 and - 80.69 ± 4.19 kcal/mol. Enzyme kinetics showed that parishins A and C are mixed-type inhibitors, with IC Show less
This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. C Show more
This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status. Show less
Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by whi Show more
Dual GIP/GLP-1 receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive. To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism. To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic sequencing analyses of adipose tissues. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice. Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications. Show less
The presence of a blood-brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous Show more
The presence of a blood-brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous neurodegenerative diseases, particularly Alzheimer's disease. Delivering small interfering RNA (siRNA) via nanoparticles represents a highly promising approach for treating Alzheimer's disease. Nevertheless, developing a safe and efficient siRNA delivery system remains challenging. To enhance brain targeting and therapeutic efficacy, we developed an siRNA nanocarrier system based on PAH-AM-PEG-ApoE (PAPA) nanoparticles (PAPA/siRNA NPs), which facilitates BBB penetration. In this study, an siRNA nanocarrier delivery system modified with ApoE peptide (PAPA/siRNA NPs) developed by our research team was employed to simultaneously encapsulate BACE1-siRNA and GSK3β-siRNA. The PAPA/siRNA NPs were prepared through self-assembly and electrostatic binding. The particle size distribution profile and zeta potential of the PAPA/siRNA NPs were analysed with dynamic light scattering, while its morphology was examined with transmission electron microscopy. For in vitro assessments, flow cytometry, confocal laser scanning microscopy, PCR, and Western blotting were employed to evaluate the cellular uptake, gene silencing capacity, and endosomal escape. The biodistribution was investigated by in vivo imaging technology, and the therapeutic effect on AD was verified in AD model mice. The prepared PAPA/siRNA NPs exhibited a regular spherical appearance with a uniform particle size distribution profile. In in vitro cell experiments, the PAPA/siRNA NPs demonstrated excellent cellular uptake ability and efficient endosomal escape. Meanwhile, the dual-loaded siRNA nanocarrier delivery system effectively inhibited the expression of GSK3β and BACE1 genes. In vivo experimental results showed that the siRNA could successfully cross the BBB and deliver to the brain. It not only significantly prolonged the half-life of siRNA but also greatly reduced the generation of pathological β-amyloid and phosphorylated microtubule-associated protein tau, showing excellent therapeutic effects in the treatment of AD. In this study, we successfully constructed a brain-targeted siRNA nanocarrier delivery system for double-gene knockdown. This system can efficiently overcome the obstacle of the BBB, markedly alleviating cognitive and memory deficits in AD mice. It paves the way for novel strategies in the clinical treatment of AD and is expected to bring new breakthroughs and changes to the conquest of this disease. Show less
Alzheimer's disease (AD) is characterized by amyloid plaques that form complex microenvironments in the brain. However, the molecular composition of these plaques and their temporal regulation are not Show more
Alzheimer's disease (AD) is characterized by amyloid plaques that form complex microenvironments in the brain. However, the molecular composition of these plaques and their temporal regulation are not well defined. Here, we developed a sensitive workflow for quantitative proteomic profiling of single plaques using refined laser capture microdissection and data-independent acquisition mass spectrometry (LCM-DIA-MS). From >200 plaques and control regions in AD mouse models (5xFAD and APP-KI) and human brains, we quantified >7,000 proteins, revealing stage-dependent, cell-type-related remodeling of the amyloid proteome (amyloidome). Temporal profiling uncovered early immune and lysosomal activation followed by engagement of RNA processing and synaptic pathways. Cross-model and cross-species analyses determined a conserved amyloidome including APOE, MDK, PTN, and HTRA1, validated by co-localization in imaging analysis. Network analysis highlighted modules in lipid transport, vesicle organization, and autophagy. These findings establish amyloid plaques as conserved, dynamic multicellular hubs that link amyloid accumulation to downstream cellular events. Show less
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease worldwide and is closely associated with obesity, diabetes, and other metabolic disorders. Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease worldwide and is closely associated with obesity, diabetes, and other metabolic disorders. Because MASLD progression poses serious health risks, elucidating the underlying mechanisms is essential to guide early intervention and therapeutic strategies. Proteomic analysis was used to identity high-fat diet (HFD)-induced proteins in mouse liver. Galectin-1 (GAL1) expression was assessed via immunohistochemistry in human liver tissues. Liver-specific GAL1-deficient mice were generated using adeno-associated virus. Mice were fed either a chow diet or an HFD. Functional studies were performed in cell lines using western blotting, RT-qPCR, immunofluorescence, co-immunoprecipitation, mass spectrometry, and molecular docking analysis. GAL1 expression was elevated in liver tissues from patients with MASLD and in mouse models. Liver-specific GAL1 knockdown alleviated hepatic steatosis and enhanced fatty acid oxidation (FAO). Mechanistically, GAL1 competitively bound to the BRCT domain of poly (ADP-ribose) polymerase 1 (PARP1), thereby interfering with its interaction with the WW domain -containing E3 ubiquitin protein ligase 2 (WWP2). Hepatic GAL1 knockdown promoted the PARP1 -WWP2 interaction and subsequently facilitated ubiquitin-dependent degradation of PARP1. This degradation led to increased NAD Hepatic deficiency of GAL1 alleviates hepatic steatosis by enhancing FAO through promotion of ubiquitin-dependent PARP1 degradation, thereby restoring NAD Show less
Post-cardiac surgery anxiety or depression (PCPAD) is a common neuropsychiatric complication following cardiovascular interventional procedures, which significantly increases the risk of adverse cardi Show more
Post-cardiac surgery anxiety or depression (PCPAD) is a common neuropsychiatric complication following cardiovascular interventional procedures, which significantly increases the risk of adverse cardiovascular events and long-term mortality. Existing treatment strategies have limitations, and clinical needs remain unmet. The gut-brain axis (GBA) serves as a core network regulating neuroimmune and endocrine responses, and its imbalance involves key links such as intestinal flora dysbiosis and neuroimmune crosstalk disorders. It is closely related to the pathogenesis of this complication, providing a novel perspective for targeted interventions. This review aims to systematically clarify the mechanism of GBA in PCPAD, comprehensively explore therapeutic strategies targeting this axis, and focus on the intervention value and application potential of natural products. The study was designed and conducted in strict accordance with the PRISMA 2020 guidelines. Relevant literatures were searched from PubMed, Web of Science Core Collection, ScienceDirect, Embase, Cochrane Library, and CNKI databases from their inception to December 2025. Literatures focusing on GBA-related mechanisms of PCPAD or investigating the mechanisms and clinical applications of natural products targeting GBA for PCPAD treatment were included. Conference abstracts, case reports, duplicate publications, and other ineligible literatures were excluded. Through quality control strategies including double independent screening and verification, priority inclusion of high-credibility evidence, and data cross-validation, 168 eligible literatures were finally included. The composition and functions of GBA, its imbalance mechanisms, and the basic and clinical evidence of natural product-based interventions were systematically analyzed. Studies have shown that GBA imbalance is the core pathogenesis of PCPAD, among which the inflammatory cascade initiated by intestinal flora dysbiosis, abnormal activation of the neuroendocrine axis, disorder of immune-nerve crosstalk, and abnormal gene and epigenetic regulation are key pathological links. In summary, GBA imbalance, especially gut microbiota dysbiosis and neuroimmune interactions, plays a critical role in the pathogenesis of PCPAD. Natural products (including traditional Chinese medicine (TCM) monomers, TCM compound prescriptions, patented TCM drugs, and natural products from other plant sources worldwide) can exert therapeutic effects by synergistically regulating GBA homeostasis through multiple targets. Specifically, they include increasing the abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus, promoting the production of anti-inflammatory metabolites such as short-chain fatty acids, repairing intestinal barrier function, inhibiting pro-inflammatory pathways such as NF-κB and NLRP3 inflammasome, and regulating the levels of neurotransmitters and neurotrophic factors such as 5-HT and BDNF. Basic and clinical studies have confirmed that these natural products have high biocompatibility and low toxic side effects, and are compatible with the safe medication needs of patients during the organ function recovery period after cardiac surgery. Several natural products have been proven to modulate GBA dysfunction, with potential for clinical therapeutic application. This review systematically elucidates a new paradigm of precise intervention for PCPAD via natural products that regulate GBA through multiple targets, addressing the limitation of traditional single-target therapies and providing a low-cost, easily promotable solution for clinical translation. Additionally, natural product-based interventions offer a novel approach for treating post-cardiac surgery complications. In the future, it is necessary to further conduct large-sample, multicenter clinical trials to clarify their mechanisms of action and standardized dosage regimens, strengthen toxicological research, facilitate the translation from basic research to clinical practice, and provide more precise therapeutic strategies for patients. Show less
Alzheimer's disease (AD) is a common dementia in the elderly population, typically manifested through symptoms of cognitive impairment (CI) and memory loss. Pathologically, it is characterized by abno Show more
Alzheimer's disease (AD) is a common dementia in the elderly population, typically manifested through symptoms of cognitive impairment (CI) and memory loss. Pathologically, it is characterized by abnormally elevated levels of amyloid-β (Aβ) deposition and tau phosphorylation. Given the rapid rate of population aging, many scientists are investigating AD, focusing on its pathogenic mechanisms and potential treatments. Unfortunately, to date, no highly effective therapeutic strategies have emerged. Intriguingly, multiple studies have revealed alterations in the gut microbiome of individuals with AD, suggesting it may serve as a novel avenue for investigating AD pathogenesis. Show less
Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain Show more
Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain, offering novel therapeutic strategies for neuropsychiatric disorders. Recent findings reveal that beyond their transient psychotropic effects, these compounds activate serotonin 5-HT Show less
Daiyue Li, Yu Zhang, Ruonan Wang+6 more · 2026 · Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · Elsevier · added 2026-04-24
Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key dr Show more
Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways. Show less
Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. T Show more
Evidence proved that electroacupuncture (EA) combined with antidepressants can improve the antidepressant effectiveness for depressed patients. However, the clinical mechanisms of EA remain unclear. This study aimed to observe the mechanism of EA as an adjunct therapy to escitalopram oxalate (EO) on depressed patients. This study was designed as a single-blinded, double-dummy randomized controlled trial. 61 participants were diagnosed with mild-to-moderate depression according to the International Classification of Diseases 10th Edition (ICD-10, F32) were randomly allocated to receive EA + EO placebo, EO + sham EA, or EA + EO for six weeks treatment. The clinical assessment including depression severity, quality of life (QOL) and clinical safety. Biological indicators of immune-inflammation, the brain-derived neurotrophic factor and glucocorticoid inducible genes in peripheral blood of participants were measured by using enzyme linked immunosorbent assay and real-time polymerase chain reaction respectively before and after treatment. Three interventions improved the depression severity and QOL (P < 0.05), and no inter-group difference was found in the 6th week (P > 0.05). Anxiety psychic and somatic general symptoms in the EA + EO group were improved significantly than those of the other two groups (P < 0.05). After six-week treatment of EA + EO, blood SGK1 mRNA, GILZ mRNA, and BDNF levels were increased significantly ( Show less
Ren Zhang · 2026 · Trends in molecular medicine · Elsevier · added 2026-04-24
The angiopoietin-like protein (ANGPTL)3/8 complex regulates triglyceride partitioning, and its selective blockade lowers triglycerides while raising HDL-cholesterol (HDL-C). Clinical and genetic evide Show more
The angiopoietin-like protein (ANGPTL)3/8 complex regulates triglyceride partitioning, and its selective blockade lowers triglycerides while raising HDL-cholesterol (HDL-C). Clinical and genetic evidence support ANGPTL3/8 antagonism as a precision therapy for mixed dyslipidemia, monogenic hypertriglyceridemia (CREBH or APOA5 deficiency), and diabetic dyslipidemia by correcting a fundamental disturbance in lipid partitioning. Show less