👤 Zhiqin Zeng

Impaired nuclear translocation of glucocorticoid receptor (GR) has been implicated in hippocampal vulnerability in Alzheimer's disease (AD), yet the molecular basis of this defect remains poorly understood. This study identified Huntingtin-associated protein 1 (Hap1) as a critical regulator of GR nuclear translocation in the hippocampus. Specifically, Hap1 expression progressively declined in the hippocampus of APP/PS1 mice with advancing age and pathological burden. Hippocampal Hap1 knockdown induced pronounced cognitive deficits and synaptic deterioration, as indicated by reduced dendritic arborization, decreased spine density, impaired long-term potentiation, and exacerbated amyloid-β deposition. Mechanistic analyses showed that Hap1 deficiency increased GR ubiquitination and proteasomal degradation and, more importantly, disrupted ligand-dependent GR translocation to the nucleus, thereby attenuating GR-dependent brain-derived neurotrophic factor transcription. In parallel, Hap1 knockdown elevated corticosterone concentration and induced depression-like behavior, consistent with hypothalamic-pituitary-adrenal axis dysregulation. Collectively, these findings establish defective GR nuclear trafficking driven by loss of Hap1 function as a key pathomechanism linking intracellular transport failure to synaptic dysfunction in AD and highlight Hap1 as a potential therapeutic target. Show less

The mechanisms underlying individual variability in acupuncture analgesia among patients with chronic pain remain unclear. This randomized controlled trial investigated the core mechanisms of differential responses to acupuncture from genetic, neuroimaging, and transcriptomic perspectives in patients with chronic pain due to knee osteoarthritis (KOA). A total of 180 KOA chronic knee pain patients were randomly assigned to verum acupuncture (VA), sham acupuncture (SA), celecoxib (SC), placebo (PB), or waiting list (WL) groups (36 each). Over 2 weeks, VA/SA received 10 sessions, SC/PB oral medication for 14 days, and WL no intervention. Baseline 3.0T MRI 3D-T1 scans and genotyping (GABRB3 rs4906902, OPRM1 rs1799971, COMT rs4680, BDNF rs6265) were performed. Efficacy was assessed via VAS and WOMAC; responders/non-responders were defined by minimally clinically important difference. Chi-square test, logistic regression, voxel-based morphometry (VBM), and Allen Human Brain Atlas-based partial least squares regression were used. No significant difference in primary outcomes was observed between VA and SA, so they were combined as the acupuncture group (AG) to enhance statistical power. Only AG had a significant association between GABRB3 rs4906902 AG/GG genotype and acupuncture response (p < 0.05); other loci showed no correlation. AG/GG carriers in AG had lower gray matter volume in caudate head, putamen, and ventral striatum, with higher GABRB3 expression in these regions. Genetic polymorphisms at GABRB3 rs4906902 could influence the analgesic effect of acupuncture treatment in patients with KOA chronic knee pain, with AG/GG genotype carriers exhibiting superior analgesic effects. This finding may be associated with pain-modulating brain regions' gray matter volume reduction and upregulation of GABRB3 gene expression. Show less

Dietary diversity plays a crucial role in maintaining physical function. This study explored the association and potential mechanisms between dietary diversity and gait characteristics measured by wearable devices in older adults. This cross-sectional study included 861 older adults aged 60 years or above. Dietary diversity score (DDS) was assessed using a standard food frequency questionnaire. A multi-sensor gait system was used to measure periodic, kinetic, and spatiotemporal gait parameters during a 12-meter walking test. The coefficient of variation (CV) was calculated for each parameter to assess gait stability. Multivariable linear regression models were conducted to examine the relationship between DDS and gait parameters, adjusting for demographics, lifestyle factors, cognitive function, and comorbidities. Participants had a mean age of 70.25 ± 6.19 years, with 58.30% being female. After adjusting for all covariates, each 1-SD increase in DDS was positively associated with Z-scores of landing control force (β = 0.072, SE = 0.033, P = 0.033), foot-off angle (β = 0.076, SE = 0.033, P = 0.021), gait speed (β = 0.086, SE = 0.033, P = 0.008), step length (β = 0.068, SE = 0.031, P = 0.032), and stride length (β = 0.078, SE = 0.033, P = 0.013). Furthermore, higher DDS was negatively associated with the CVs of initial limb support time, step time, stride time, ground reaction force, landing control force, foot-off angle, gait speed, and step length (all P < 0.05). We also identified biomarkers simultaneously related to both DDS and gait characteristics, including albumin, leptin, myostatin, brain-derived neurotrophic factor, insulin-like growth factor-1, high-sensitivity C-reactive protein, interleukin-6, and glutathione reductase. Higher DDS is associated with superior kinetic and spatiotemporal gait vigor performance and enhanced gait stability. Pathways involving nutritional status, energy metabolism, inflammatory regulation, antioxidant defense, and neural function may underpin this association. Show less

Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA during chronic intermittent ethanol exposure: initial sensitization was followed by a phase of attenuated and dysregulated response upon the first high-concentration exposure, culminating in stable hyper-responsiveness. Chronic ethanol exposure impaired long-term potentiation of GABAergic synapses (LTP Show less

Early vascular regeneration is important for the speedy recovery of neurological function following ischemic stroke. M2-like microglia polarization decreases and vascular regeneration weakens with aging. The function of mitochondrial respiratory chain is dependent on M2-like polarization in microglia. A murine model of middle cerebral artery occlusion (MCAO) was used to perform animal behavioral assessments, immunoblotting, tube formation and chick embryo chorioallantoic membrane assays. A D-galactose-induced cellular senescence model was established in BV2 cells. Aging significantly exacerbates acute brain injury 24 hours post-cerebral ischemia-reperfusion, with increased expression of M1-like microglial markers and a concomitant decrease in M2-like microglial markers. Additionally, aging can inhibit DARS2 protein expression, adversely affect angiogenesis and reduce brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGFA) expression. In vitro, oxygen-glucose deprivation/reoxygenation and re-glucose (OGD/R) demonstrated that This study suggests that aging impedes M2-like microglial polarization by downregulating DARS2 expression in microglia, thereby impairing emergency angiogenesis during acute ischemic stroke and exacerbating neuronal damage. Show less

Transcriptomics provides mechanistic insights into chemical toxicity and serves as a hypothesis-generating tool for prioritizing potential adverse outcomes. Here, we introduced a transcriptomics-guided outcome prediction (T-GOP) framework, a hypothesis-informed approach that uses transcriptomic enrichment to prioritize end points for targeted experimental validation. As a case study, the ecotoxicological effects of the PFOS alternative, sodium Show less

Lithium deficiency may contribute to Alzheimer disease pathogenesis. No randomized clinical trial has examined lithium's effects on cognition, neuroimaging, and plasma biomarkers in mild cognitive impairment (MCI). To examine the feasibility, safety, and preliminary efficacy of lithium carbonate for delaying cognitive decline in older adults with MCI. This single-site, randomized, double-blind, placebo-controlled pilot feasibility clinical trial was conducted at the University of Pittsburgh School of Medicine from February 2018 to August 2024, with 2-year follow-up. Analyses used linear mixed-effects models in the intention-to-treat population. Adults aged 60 years or older with MCI who were free of major psychiatric or neurologic illness and contraindications to lithium were included. Of 170 individuals assessed, 83 were randomized (41 lithium vs 42 placebo), with 80 starting treatment (41 lithium vs 39 placebo). Data were analyzed from August 2024 to December 2025. Daily low-dose lithium carbonate or placebo for 2 years. Six prespecified coprimary outcomes included cognitive performance (California Verbal Learning Test-II [CVLT-II] delayed recall, Brief Visuospatial Memory Test-Revised, preclinical Alzheimer cognitive composite), hippocampal volume, cortical gray matter volume, and brain-derived neurotrophic factor. Among 80 participants (mean [SD] age, lithium: 72.93 [8.77] years; placebo: 71.22 [6.47] years; 56% female), none of the 6 coprimary outcomes met the prespecified significance threshold. Mean (SD) CVLT-II baseline scores were 7.95 (3.4) for lithium and 7.90 (3.9) for placebo; scores declined 1.42 points annually in the placebo group vs 0.73 points in the lithium group (difference, 0.69 points per year; 95% CI, 0.01-1.37; P = .05). Hippocampal and cortical volumes showed a decline over time in both groups, but no significant treatment × time interactions. Serious adverse events occurred in 12 of 41 (29%) receiving lithium vs 9 of 39 (23%) receiving placebo; none were definitely treatment related. One death occurred in the placebo group. Common adverse events included increased creatinine levels (12 of 41 [29%] with lithium vs 12 of 39 [31%] with placebo), diarrhea (12 of 41 [29%] vs 6 of 39 [15%]), tiredness (12 of 41 [29%] vs 6 of 39 [15%]), and tremor occurrence (10 of 41 [24%] vs 6 of 39 [15%]). This pilot randomized clinical trial established feasibility, confirmed safety and tolerability, and generated effect size estimates for future trials of low-dose lithium in MCI. None of the coprimary outcomes met the prespecified significance threshold. ClinicalTrials.gov Identifier: NCT03185208. 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 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

Aberrant microglial activation and impaired adult hippocampal neurogenesis play critical roles in the pathogenesis of depression. Although electroacupuncture (EA) has demonstrated clinical antidepressant efficacy, the underlying mechanisms by which it modulates microglial activity and promotes neurogenesis remain unclear. Male C57BL/6 J mice were subjected to chronic unpredictable mild stress (CUMS) for three weeks. Following this period, the mice were divided into groups receiving either EA at the Yintang (GV29) and Baihui (GV20) acupoints, imipramine (IMI) as a positive control, or no treatment (vehicle control) for an additional 3 weeks. To evaluate depressive-like behaviors, we conducted the sucrose preference test, forced swimming test, and tail suspension test. Anxiety-like behaviors were assessed using the open field test and elevated plus maze. We employed immunofluorescence, Golgi staining, Western blotting, and real-time quantitative PCR (qRT-PCR) to elucidate the effects of EA on microglia-driven hippocampal neurogenesis and BDNF signaling. Notably, loss-of-function experiments utilizing PLX5622 for microglial ablation and ANA-12 for TrkB blockade demonstrated the necessity of both microglia and BDNF signaling for the therapeutic efficacy of EA. EA treatment significantly alleviated CUMS-induced anxiodepressive behaviors. This behavioral recovery was associated with a phenotypic shift in microglia towards a pro-neurogenic state in the hippocampus. Importantly, microglia were essential for the therapeutic effects of EA, as evidenced by their ablation with PLX5622. Furthermore, EA enhanced neurogenesis by orchestrating a multi-step augmentation of BDNF signaling, which involved PKA activation, subsequent release from MeCP2-mediated transcriptional repression, and ultimately increased maturation of BDNF. Our findings demonstrate that EA exerts antidepressant effects by promoting a pro-neurogenic transformation of microglia. Mechanistically, these microglia enhance BDNF function via the PKA/MeCP2/BDNF pathway, thereby facilitating hippocampal neurogenesis and restoring synaptic plasticity, which collectively alleviate depressive symptoms. Show less

Alzheimer's disease is characterized by intertwined pathologies including neuroinflammation, driven by microglial dysfunction, and metabolic disturbances such as lipid dyshomeostasis. Mesenchymal stem cell-derived exosomes (MSC-Exos) hold therapeutic promise, Still, it is unknown whether they can simultaneously address these co-occurring impairments via specific molecular cargos, such as long non-coding RNAs (lncRNAs). Transcriptome sequencing of exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) revealed high expression of the long noncoding RNA ENST00000629969 (hereinafter referred to as lncRNA-9969). We isolated exosomes from hUC-MSCs (WT-Exo) and established human umbilical cord blood mesenchymal stem cells stably knocked down for lncRNA-9969 via siRNA, from which corresponding exosomes (KD-Exo) were isolated. Cross-species analysis identified the mouse homolog of lncRNA-9969 as ENSMUST00000200021 (hereinafter referred to as lncRNA-0021). Cellular experiments employed an Aβ₂₅₋₃₅-induced SH-SY5Y cell model to evaluate the protective effects of exosomes. In animal experiments, 6-month-old APP/PS1 mice received biweekly tail vein injections of WT-Exo or KD-Exo for 4 weeks. Phenotypic and mechanistic analyses were subsequently conducted using the Morris water maze, Western blot, immunofluorescence, qPCR, and transmission electron microscopy. In Aβ-injured SH-SY5Y cells, WT-Exo significantly attenuated cellular damage and promoted Aβ clearance, whereas the protective effect of KD-Exo was markedly reduced. In APP/PS1 mice, WT-Exo treatment significantly improved spatial memory deficits and upregulated hippocampal expression of synaptic proteins synaptophysin (Syn) and brain-derived neurotrophic factor (BDNF). Molecular mechanism studies demonstrated that lncRNA-0021 directly binds mmu-miR-6361. Through this ceRNA mechanism, exosome-delivered lncRNA activated the mTOR/p70S6K autophagy pathway, regulated lipid metabolism-related genes, promoted microglial polarization toward the protective M2 phenotype, and suppressed pyroptosis. These beneficial changes were not observed in the KD-Exo-treated group. hUC-MSC-derived exosomes exert neuroprotective effects by delivering functional lncRNA-9969. Its highly conserved homolog in mice, lncRNA-0021, achieves coordinated multi-target regulation of neuroinflammation, pyroptosis, and metabolic disturbances by sequestering miR-6361 and activating downstream signaling pathways. This study elucidates the central role of exosomal lncRNAs in AD pathology and provides new insights for developing RNA-based multi-target therapeutic strategies. Show less

Depression is a major global health burden, and current treatments are limited by delayed onset and incomplete efficacy, highlighting the need for novel, mechanism-based therapies. Chronic restraint stress (CRS) induces behavioral, hormonal, and synaptic changes relevant to depression, but the role of adiponectin signaling remains unclear. Here, we examined whether the adiponectin receptor agonist AdipoRon exerts antidepressant-like effects via brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in mice subjected to 14 days of CRS. CRS produced anxiety- and depression-like behaviors, elevated plasma corticosterone, reduced circulating adiponectin, and selectively decreased hippocampal adiponectin and adiponectin receptor 2 (AdipoR2), accompanied by reduced PSD-95 and GluA1 in CA3 and the dentate gyrus (DG). AdipoRon treatment (20 mg/kg, days 8-14) prevented behavioral deficits, normalized corticosterone and adiponectin levels, and restored hippocampal AdipoR2, PSD-95, and GluA1 expression in CA3 and DG. AdipoRon also reversed CRS-induced decreases in hippocampal phosphorylated AMPK (p-AMPK), PPARα, BDNF, and phosphorylated TrkB (p-TrkB), with p-AMPK/AMPK and PPARα levels positively correlating with BDNF. Immunofluorescence confirmed BDNF recovery in CA3 and DG. Importantly, pretreatment with the TrkB antagonist ANA-12 abolished the behavioral, hormonal, and molecular effects of AdipoRon, indicating that its actions require BDNF-TrkB activation. These findings suggest that AdipoRon mitigates CRS-induced deficits via hippocampal AdipoR2-AMPK-PPARα-BDNF-TrkB signaling and highlight AdipoR2 as a promising target for depression therapy under chronic stress. Show less

With the rapid progression of global population aging, the incidence of cognitive dysfunction-related disorders is steadily increasing. In recent years, growing attention has been directed toward the interaction between the gut microbiota and the central nervous system (CNS). The gut-brain axis (GBA), as a bidirectional communication pathway, plays an increasingly recognized role in regulating cognitive functions. Ganoderma lucidum polysaccharides (GLP), a traditional medicinal and edible substance, can regulate gut microbiota homeostasis and short-chain fatty acid (SCFAs) levels through the GBA. GLP reduces the Firmicutes/Bacteroidetes ratio, significantly increases the abundance of Lactobacillus, and further suppresses oxidative stress and inflammatory responses by controlling microglial overactivation and neuroinflammation, thereby enhancing the expression of synapse-associated proteins and brain-derived neurotrophic factor (BDNF). Consequently, GLP shows potential for improving cognitive dysfunction. This review systematically summarizes the bioactivities of GLP, explores the neurodegenerative mechanisms of aging, and proposes the possibility that GLP mitigates aging-induced inflammation and improves cognitive function via modulation of the gut microbiota. Show less

Pine nut oil (PNO) is a candidate alternative to corn oil (CO) owing to comparable unsaturated fatty-acid profiles and enrichment in pinolenic acid (Δ5-18:3) and lipid-soluble micronutrients. We systematically compared extraction routes (solvent, supercritical CO₂, pressing), established solvent extraction as the optimal balance of yield and bioactive retention, and then characterized solvent-extracted oils from eight provenances using a weighted composite score to nominate Pinus tabuliformis for in vivo testing. In diet-induced obese mice (12-week Western diet, then 12-week intervention, n = 10 per group), replacing CO with PNO lowered body-mass gain and liver weight and improved serum lipids (triglycerides ↓ ∼ 28 %, total cholesterol ↓ ∼ 15 %, LDL-C ↓ ∼ 20 %) without affecting HDL-C or glucose; ALT and AST fell by ∼30 %, indicating hepatoprotection. Hepatic multi-omics revealed coherent remodeling toward PUFA-rich phospholipid species, activation of PPAR-centered peroxisomal/mitochondrial fatty-acid degradation and circadian pathways, and integrative correlations implicating Cyp4a10/14, Ehhadh, Slc27a2, Fgf21, Angptl4, and Plin5. Collectively, PNO reoriented hepatic lipid flux toward oxidation and membrane remodeling, supporting its development as a nutritionally advantaged culinary oil. Show less

This study examined how different photoperiods affect net energy partitioning and explored the mechanisms via blood biochemistry, gut microbiota, and fecal metabolites. Twelve healthy crossbred pigs (47.7 ± 7.5 kg) were randomly allocated to two groups and subjected to a self-controlled crossover design. Following an 8-day baseline under a normal photoperiod (12L:12D, 12 h light:12 h dark), pigs were assigned to two photoperiod treatment groups: prolonged photoperiod (18L:6D, 18 h light:6 h dark; P group) and shortened photoperiod (6L:18D, 6 h light:18 h dark; S group). Measurements during the baseline (12L:12D) and treatment phases are designated as N1/P (for the P group) and N2/S (for the S group), respectively. The treatment periods were interspersed with the baseline 12L:12D photoperiod and repeated six times. It was observed that, compared to N2, shortened photoperiod (S) had significantly higher net energy deposition, net energy for protein deposition, and net energy for fat deposition ( Show less

Coronary heart disease (CHD) burden is increasing, and traditional obesity measures inadequately capture fat distribution and associated CHD risk. A body shape index (ABSI) is an emerging anthropometric metric of fat distribution, but evidence linking ABSI to CHD is limited, particularly in the Chinese population. This case-control study in southern China investigated the association of ABSI and related factors with CHD risk, aiming to facilitate early identification of high-risk individuals. We retrospectively studied 996 patients who underwent coronary angiography in a southern Chinese hospital. After strict screening and propensity score matching (PSM), 125 patients with CHD (>50% coronary stenosis) and 125 controls (<50% stenosis) were selected. Key CHD risk predictors were identified using feature-selection techniques (LASSO regression, recursive feature elimination, random forest importance). Univariate and multivariate logistic regression models were constructed for CHD prediction. Model performance was evaluated by receiver operating characteristic (ROC) analysis and compared to individual predictors using the DeLong test. A nomogram was developed for individualized risk estimation. Baseline characteristics were well matched between CHD and control groups after PSM. Across feature-selection methods, the most influential predictors for CHD included ABSI, prealbumin (PA), direct-to-total bilirubin ratio (DB/TB), apolipoprotein B (ApoB), globulin (GLO), apolipoprotein A-I (ApoA-I), and essential hypertension (EH). Each of these factors showed a significant univariate association with CHD ( This study identifies ABSI as a potential predictor of CHD risk among southern Chinese populations. Integrating ABSI with other candidate predictors improves the model's predictive performance. A multifactorial approach may better characterize CHD risk in this population and could inform prevention strategies. Show less

This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and genotype and allele frequencies were compared between groups. Multivariate logistic regression analyzed the link between ApoE polymorphisms and CAD risk in populations at middle and high altitudes. The data revealed significant differences in These findings validated that the Show less

Staphylococcus aureus is a significant pathogen that poses a threat to both human and animal health. Its pathogenicity in humans has been extensively studied, however, the signaling pathways and key genes in Koi Carp responding to S. aureus from human rhinitis remain unclear. In this study, we established an intraperitoneal infection model in koi carp (Cyprinus carpio) using an S. aureus isolate from patients with rhinitis and integrated RNA-seq, qPCR, and ELISA to dissect the host response. Our findings reveal a dual-module immune evasion strategy employed by S. aureus in koi carp. Module I: The pathogen down-regulated the entire complement coagulation cascade (C3, C9, CFH, F7/9/10) and apolipoprotein-mediated opsonins (APOA1, APOB, APOC1/2), thereby crippling innate clearance. Module II: The host mounted a restricted but potent counter-response, characterized by type I IFN signalling (gvin1, MHC-I), NK/T-cell co-stimulation (CD244, SLAMF5), and the selective induction of IL-8 and IL-1β, while IL-6, IL-10, and TNF-α remained unchanged. Functionally, serum superoxide dismutase (SOD), catalase (CAT), and lysozyme (LZM) activities surged, confirming an oxidative burst, whereas splenic CD22R protein decreased, indicating B-cell disinhibition. These results establish a molecular basis for understanding the interaction between human-derived S. aureus and the immune system of aquatic organisms. Show less

Lanthanum (La), the second most produced rare earth element, is detected in various environmental and human samples. Epidemiological studies have reported a strong association between La exposure and liver injury. However, the effects of early La exposure on liver development and underlying mechanisms remain limited. Here, we evaluate the hepatotoxicity of LaCl Show less

Patients on dialysis often suffer from carnitine deficiency due to reduced intake, reduced synthesis in the kidneys, and clearing through dialysis. Carnitine deficiency may lead to anemia, cardiomyopathy, hypotension, and so on. Several studies have shown that supplementing with L-carnitine can diminish the above symptoms in adult dialysis patients, but whether children can benefit from L-carnitine remains unclear. This study was performed to investigate the effect of L-carnitine in children with kidney failure undergoing dialysis. PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), WanFang Data, and VIP database were electronically searched from database inception to December 2023.  STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs), cohort studies, case-control studies, cross-section studies, and case series studies that evaluated the impact of L-carnitine on children. Patients aged less than 18 years with kidney failure undergoing dialysis.  STUDY APPRAISAL AND SYNTHESIS METHODS: We assessed the quality of studies using the RoB2 tool recommended by the Cochrane Handbook, the Newcastle-Ottawa Quality Assessment Scale (NOS), the checklist recommended by Agency for Healthcare Research and Quality (AHRQ), and the quality evaluation tool recommended by the National Institutes of Health (NIH). We conducted only descriptive analyses and did not perform meta-analysis due to significant differences in study types and limited data. A total of 194 patients were included in 9 studies, of which 3 were RCT studies; 2 were cohort studies, and 4 were case series studies. Due to limited data, we only conducted descriptive analysis rather than meta-analysis. For children undergoing hemodialysis, cohort study of high-quality showed that L-carnitine significantly improved hemoglobin (Hb) and reduced the required erythropoiesis-stimulating agent (ESA) dose; RCT study of moderate-quality indicated that L-carnitine did not influence serum lipid profiles except for reducing apolipoprotein B (ApoB). Cohort study of moderate-quality showed that L-carnitine improved cardiac function; RCT study of moderate-quality indicated that L-carnitine did not influence albumin, C-reactive protein (CRP), interleukin-6 (IL-6), and quality of life. For children undergoing peritoneal dialysis, only serum lipid profiles were analyzed. RCT and case series studies of moderate-quality indicated that L-carnitine did not influence serum lipid profiles except for reducing ApoB. The number of studies enrolled was limited, and their quality was not high. Our study found that children with kidney failure requiring dialysis could partially benefit from L-carnitine, including increased Hb, decreased ESA requirement, reduced ApoB, and improved cardiac function. Further RCTs of high quality are still needed to clarify this issue. This study provided more comprehensive and credible evidence for clinical use of L-carnitine in children. PROSPERO registration number CRD420250649553. Show less

Diabetic foot ulcers (DFU) are a major complication of diabetes, and its pathogenesis remains incompletely elucidated. Converging evidence indicates that oxidative stress and dysregulated mitochondrial polarization participate in DFU progression, nominating these processes as therapeutically actionable targets. This study integrates bulk and single-cell transcriptomic data with machine learning to reconstruct cross-scale, cell type-resolved molecular atlases and regulatory networks. Macrophages and fibroblasts emerged as communication hubs, dominating pathway enrichment and ligand-receptor programs such as macrophage migration inhibitory factor signaling pathway (MIF), ANNEXIN signaling pathway, and COMPLEMENT signaling pathway. Peptidylprolyl isomerase F (PPIF), which encodes cyclophilin D (CypD) and apolipoprotein E (APOE) were further prioritized as putative drivers within macrophages and fibroblasts, and a five-gene classifier was derived with robust performance (internal/external AUC = 0.833/0.933). Within DFU lesions, under the control of non-coding RNA circuitry, SOX5 may shape the inflammatory microenvironment, APOE may participate in lipid-metabolic remodeling, and PPIF (CypD) likely links reactive oxygen species (ROS) accumulation to a p53-dependent mitochondrial death pathway (necroptosis/apoptosis). Orthogonal validation showed significantly increased CypD in diabetic foot ulcer skin (DFUS) and diabetic foot ulcer tendon (DFUT) relative to diabetic foot skin (DFS) and DFT (Diabetic foot tendon), with up-regulated p53 and Cytc and down-regulated ApoE in DFUS; in primary foot-skin fibroblasts, a high-glucose plus tert-butyl hydroperoxide (HG+TBHP) model reproduced elevated ROS, loss of mitochondrial Δψm (mitochondrial membrane potential), growth restriction, and apoptosis, supporting a ROS-CypD/mPTP (mitochondrial permeability transition pore)-Δψm depolarization-p53/Cytc apoptosis axis. The delineated PPIF-centered regulatory network includes upstream transcription factors CEBPB/REL/SPI1 and a downstream ceRNA axis comprising miR-128-3p/miR-23a-3p-long non-coding RNA OIP5-AS1. Additionally, the significant role of polarization-specific reprogramming in regulating macrophage function highlights therapeutic strategies focused on metabolic reprogramming and inhibition of the PPIF/mPTP pathway. Collectively, a cell type-resolved molecular map of DFU is provided, healing-relevant cell populations and regulatory circuits are prioritized, and a translational, testable intervention framework is proposed. Show less

Decline in pulmonary function (PF) and respiratory muscle strength (RMS) is influenced by environmental and genetic factors and is inconsistently linked to cognitive outcomes. This study explores the associations between PF, RMS, and cognitive function among community-dwelling older adults in China, analyzing interactions with APOE Ɛ4 and the mediating effect of serum total bilirubin. About 1,081 Hubei Memory and Aging Cohort (HMACS) participants underwent PF (PEF, FEV1 and FVC), RMS (MIP and MEP) assessment, cognitive tests, APOE genotyping, and bilirubin measurement. Multivariate logistic regression and general linear regression were used to analyze associations. Among 1,081 participants (mean age 70.52 ± 5.55 years), 26.1% had cognitive impairment. Lower PF and RMS scores were associated with cognitive impairment. Higher comprehensive PF (c-PF) and RMS indices protected against cognitive impairment (eg, c-PF: OR = 0.482-0.609, PF (especially PEF) and RMS (especially MEP) indices are significantly associated with cognitive function and impairment in older adults, independent of APOE Ɛ4 status. These findings provide biomarkers for assessing cognitive health risk and a basis for interventions targeting PF and RMS to preserve cognitive function. Show less

To investigate the controversial association between exogenous hormone use (EHU) and dementia, with a focus on subtype-specific risks. This prospective cohort study followed 273,069 women in the UK Biobank over 3,802,608 person-years, identifying 4,710 dementia cases. Cox models assessed use of oral contraceptive (OC) and hormone replacement therapy (HRT) in relation to all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD) across treatment durations. Subgroup analyses were stratified by age, ethnicity, APOE status, education, income, and reproductive factors. A systematic review was conducted to synthesize existing evidence. In the cohort study, OC use was associated with reduced risks of all-cause dementia (HR 0.90, 95%CI 0.84-0.95), AD (HR 0.87, 95%CI 0.79-0.95), and VaD (HR 0.81, 95%CI 0.70-0.93), particularly after 4-14 years of use. HRT showed no significant association with increased dementia risk. Synthesized results largely corroborated these findings: OC use was associated with reduced risks of dementia (HR 0.90, 95%CI 0.89-0.92); and although four European studies reported a moderately increased AD risk after post-menopausal HRT use, neither cohort-based studies (HR 0.98, 95%CI 0.90-1.06) nor traditional case-control studies (OR 1.00, 95%CI 0.90-1.11) found an association between HRT and dementia. Our combined evidence does not support an increased risk of dementia associated with OC use; similarly, no clear association was observed between HRT and increased dementia risk. Clinical decisions on EHU should be individualized, balancing overall benefits against potential risks. Show less

Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Alzheimer's disease patients (mild cognitive impairment to moderate dementia) received biweekly lecanemab (10 mg/kg). A matched Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort served as comparator. Cognitive tests, plasma biomarkers, and optional amyloid/tau positron emission tomography (PET) were assessed over 6 months. Lecanemab significantly attenuated cognitive decline versus ADNI. Plasma Aβ42, Aβ40, phosphorylated tau 217 (p‑tau217), glial fibrillary acidic protein (GFAP), and ratios showed robust changes; a p‑tau217 reduction correlated with amyloid PET clearance (mean -22.1 Centiloid; 29.2% turned amyloid-negative). Apolipoprotein E (APOE) ε4 non-carriers showed greater improvements. Infusion reactions occurred in 11.1% and amyloid-related imaging abnormalities in 9.2% (1.6% symptomatic), with no stage-related safety differences. Lecanemab was effective and well tolerated in real-world Chinese patients. Plasma p‑tau217 may serve as a sensitive, minimally invasive treatment-response biomarker. Show less

Atherosclerotic macrophages predominantly exhibit a pro-inflammatory phenotype, driving chronic inflammatory and accelerating atherosclerotic progression. Interferon regulatory factor 5 (IRF5) is highly expressed in lesional macrophages within advanced atherosclerotic plaques, where it promotes the secretion of pro-inflammatory cytokines. However, current approaches lack an effective therapeutic strategy to specifically silence this gene in lesional macrophages for atherosclerosis treatment. This study aims to develop and evaluate a dual-targeted, siRNA-based nanotherapeutic platform that selectively acts on atherosclerosis-promoting genes in plaque macrophages, offering a potential strategy for treating atherosclerosis by reprogramming lesional macrophages. Here we designed and developed dual-targeted liposome-based nano-immunotherapeutics encapsulating small interfering RNA (siRNA) against IRF5 (siIRF5) to reprogram macrophage phenotypes within advanced plaques. In high-fat diet-fed Show less

Alzheimer's disease (AD) disproportionately affects women and carriers of the apolipoprotein E ε4 allele (APOE4), yet little is known about how sex and APOE interact to influence white matter (WM) integrity during disease progression. We integrated diffusion MRI and matched blood transcriptomic data to investigate these interactions and their underlying biological mechanisms. WM microstructure was quantified using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), and regional vulnerability was assessed with a composite vulnerability score (CVS) derived from associations between diffusion features and AD severity across clinical traits in each of the four sex-APOE groups (female or male, with or without APOE4). Brain parcellation with the Eve atlas revealed regions consistently affected across sex-APOE groups (e.g., parahippocampal and superior temporal gyri) and regions specific to individual groups (e.g., the cingulum in females with APOE4 and the middle frontal gyrus in males without APOE4). Gene co-expression network analysis of the matched blood expression data identified gene subnetworks linked to group-specific regional vulnerability, including a muscle tissue morphogenesis module regulated by NEURL1B and HIST1H2BN associated with middle frontal gyrus vulnerability. These findings demonstrate that sex and APOE genotype jointly shape region-specific WM vulnerability and its molecular signatures in AD. Understanding these interactions provides novel mechanistic insights and may inform precision approaches to drug development, biomarker discovery, and clinical trial design for AD. Show less

Abdominal aortic aneurysm (AAA) is a cardiovascular condition characterized by the abnormal dilation of the abdominal aorta. A circular RNA (circRNA) microarray was utilized to identify differentially expressed circRNAs in angiotensin II (Ang II)-stimulated AAA mice. Male apolipoprotein E-deficient (apoE-/-) mice were randomly assigned to 2 groups and subjected to 28 days of infusion with either Ang II or saline. At the end of the experiment, the mice were euthanized via exsanguination under anesthesia. The periadventitial tissues were carefully removed from the aortic wall to measure the maximal external diameter of the suprarenal aorta, and then stored for further analysis. Samples from both the control and AAA groups were used for circRNA expression profiling. The R package Bioconductor was employed to perform Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Arraystar's proprietary miRNA target prediction software, integrating miRanda and TargetScan, was used to predict the circRNA/miRNA interactions. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to confirm the reliability of the microarray results. A total of 13,103 circRNAs were detected. Compared to the control group, 90 circRNAs were upregulated and 234 were downregulated in the Ang II-induced AAA group. Gene Ontology analysis indicated that the target genes associated with the differentially expressed circRNAs were involved in a variety of biological processes. The KEGG pathway analysis revealed that the differentially expressed circRNAs influenced several critical pathways, including the MAPK signaling pathway, insulin signaling pathway, Ras signaling pathway, and autophagy. The results of RT-qPCR showed that the expression levels of circRNA₃₀₃₉₅, circRNA₃₀₃₉₈ and circRNA₀₁₂₅₉₄ were significantly increased in AAA, while circRNA₀₀₆₀₉₇ and circRNA₀₀₉₉₃₂ were notably decreased. The top 5 miRNAs related to each validated circRNA were identified through bioinformatic analysis. Among these differentially expressed circRNAs, miR-136-5p was predicted to be the target gene of circRNA₃₀₃₉₈ with high probability. The differential expression of various circRNAs identified in AAA suggests that the circRNA-miRNA-mRNA axis may serve as a potential molecular regulatory mechanism for AAA. Show less

Atherosclerosis (AS), a chronic inflammatory process driven largely by macrophage-mediated plaque formation, remains poorly understood in mitochondrial-macrophage crosstalk. While CYBA polymorphisms correlate with cardiovascular risk, the functional role of CYBA in connecting mitochondrial dysfunction to macrophage phenotypic alteration and functional modulation remains largely unknown. In this study, we integrated multi-omics profiling of AS immune microenvironments with mitochondrial-associated gene sets. Machine learning and single-cell RNA sequencing identified CYBA as a key oxidative stress regulator. CYBA expression was significantly upregulated both in oxidized low-density lipoprotein (ox-LDL)-stimulated THP-1 macrophages and in atherosclerotic lesions, with immunofluorescence confirming macrophage enrichment. Show less