Long-term antigen-specific data in PMN among Chinese populations remain limited. This study evaluated six target antigens and their clinical significance during extended follow-up. We retrospectively Show more
Long-term antigen-specific data in PMN among Chinese populations remain limited. This study evaluated six target antigens and their clinical significance during extended follow-up. We retrospectively analyzed 132 treatment-naïve PMN patients diagnosed by biopsy (2010-2018) and followed for a median of 62.9 months. Renal tissue expression of PLA2R, THSD7A, NELL-1, PCDH7, EXT1, and EXT2 was assessed by immunohistochemistry, and serum anti-PLA2R antibodies were measured by ELISA. Associations between antigen profiles and 5-year outcomes (remission, renal survival, malignancy) were evaluated. PLA2R was the predominant antigen (84.1%), followed by THSD7A (5.3%) and NELL-1 (0.76%); no PCDH7, EXT1, or EXT2 positivity was detected. PLA2R-negative patients were more often female (71.4% vs. 36.0%, This >5-year Chinese PMN cohort provides the first comprehensive analysis of six target antigens. PLA2R remains predominant, while PLA2R-negative patients distinct immunopathologic features yet favorable long-term outcomes. A population-specific anti-PLA2R cutoff showed good diagnostic performance for predicting tissue antigen deposition. Rare antigens were infrequent and their malignancy associations require cautious interpretation. These findings provide long-term antigen-specific data supporting antigen-guided, population-adapted precision management of PMN. 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
Caloric restriction (CR) improves metabolic health and reduces the risk of aging-related vascular diseases. However, the systematic metabolic reprogramming associated with CR remains unclear. To addre Show more
Caloric restriction (CR) improves metabolic health and reduces the risk of aging-related vascular diseases. However, the systematic metabolic reprogramming associated with CR remains unclear. To address this, we performed multi-tissue metabolomic profiling (liver, heart, and serum) in apolipoprotein E-deficient (ApoE-/-) mice subjected to CR. Metabolomic analyses of the multiple tissues revealed that glycerophospholipid metabolism pathway was consistently modulated by CR. To explore its relevance in vascular diseases, we performed serum metabolomic profiling in an abdominal aortic aneurysm (AAA) model induced by angiotensin Ⅱ (AngⅡ) infusion in ApoE-/- mice. The level of lysophosphatidylethanolamine (LPE) (16:0/0:0), a metabolite in the glycerophospholipid metabolism pathway, was elevated during AAA progression and significantly reduced by CR intervention, suggesting its potential as a vascular disease risk factor. Notably, glycerophospholipid metabolism and LPE (16:0) were significantly associated with vascular diseases and aging-related indicators in human multi-omics data, including public transcriptomic and lipidomic, and our serum multi-omics profiling of 76 healthy aged individuals. Collectively, our findings establish glycerophospholipid metabolism and LPE (16:0) as systemic signatures of CR with diagnostic potential. They highlight a crucial link between systemic metabolism and vascular remodeling and remodeling-associated vascular diseases, while also functioning as indicators of systemic aging. Show less
Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies Show more
Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies substantially improve circulating lipid profiles, strategies that provide more durable, safe, and efficient control of lipid metabolism are still needed. Epigenome editing offers a promising approach for long-lasting repression of disease-modifying genes without altering the underlying DNA sequence. Here, we develop CRISPRoff platforms delivered by adeno-associated virus or lipid nanoparticle to epigenetically silence hepatic Hmgcr or Pcsk9 in vivo. In both C57BL/6J wild-type and ApoE Show less
The bioactive peptide setmelanotide is a validated MC4R agonist, yet its clinical utility is constrained by poor aqueous solubility and dose-limiting, off-target hyperpigmentation. To overcome these d Show more
The bioactive peptide setmelanotide is a validated MC4R agonist, yet its clinical utility is constrained by poor aqueous solubility and dose-limiting, off-target hyperpigmentation. To overcome these dual liabilities, we executed a synergistic optimization strategy guided by detailed SAR investigation. This approach unveiled two critical design principles: a C-terminal "cationic imperative", where lysine uniquely conferred a > 20-fold solubility enhancement while retaining potency, and rational manipulation of the core pharmacophore, which imparted >100-fold selectivity over MC1R/MC3R. This synergy yielded the lead compound SC19, which integrates these features into a balanced profile of sub-nanomolar potency (EC₅₀ = 0.12 nM; pEC₅₀ = 9.93), exceptional selectivity, and high aqueous solubility. In a diet-induced obesity model, SC19 demonstrated robust efficacy comparable to setmelanotide in reducing weight gain and improving lipid profiles, affirming its therapeutic potential. This work not only presents a promising lead compound but also validates a synergistic optimization blueprint for concurrently enhancing the pharmacological and drug-like properties of therapeutic peptides. Show less
Post-stroke seizures are a common and debilitating complication with limited therapeutic options, underscoring the need to identify novel molecular targets. Disruption of chloride homeostasis via impa Show more
Post-stroke seizures are a common and debilitating complication with limited therapeutic options, underscoring the need to identify novel molecular targets. Disruption of chloride homeostasis via impaired potassium chloride cotransporter 2 (KCC2) activity is a key driver of neuronal hyperexcitability. While microglia are a predominant source of brain-derived neurotrophic factor (BDNF) in the acute phase after brain injury, the role of microglial BDNF and its signaling in KCC2 dysregulation and early post-stroke seizure susceptibility remain poorly defined. Using a middle cerebral artery occlusion-reperfusion (MCAO-R) mouse model and oxygen-glucose deprivation/reoxygenation (OGD/R) in hippocampal neurons, we assessed KCC2 function, neuronal excitability, and seizure susceptibility. Pharmacological tools, including the microglial inhibitor minocycline, the TrkB antagonist K252a, the loop diuretic furosemide (FUR), repurposed here as a KCC2-stabilizing agent, and the KCC2 activator CLP290, were employed. Techniques included immunofluorescence, Western blotting, patch-clamp electrophysiology, electroencephalography (EEG), and behavioral seizure assessment. MCAO-R and OGD/R significantly reduced membrane KCC2 expression, leading to a depolarizing shift in the GABA equilibrium potentials (E Our findings identify microglia-derived BDNF/TrkB signaling as a critical upstream pathway mediating KCC2 dysfunction in early post-stroke seizure. Targeting this axis by inhibiting microglial activation, blocking TrkB, or directly enhancing KCC2 function with activators like CLP290 represents a promising therapeutic strategy for stroke-related epilepsy. Show less
Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoin Show more
Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoints that can be therapeutically targeted to restore M2 bias remain poorly defined. Here, we aimed to determine whether the RNA-binding protein TAF15 acts as a post-transcriptional stabilizer of the M2-promoting CEBPB/APOE/PTX3 axis, thereby accelerating DFU healing. First, we confirmed that APOE positively regulates PTX3, which supports M2 polarization and the proliferation and migration of HDF. CEBPB transcriptionally activated APOE and promoted M2 macrophage polarization. TAF15 stabilized CEBPB mRNA and affected HDF cell proliferation and migration by promoting M2 macrophage polarization. Additionally, TAF15 overexpression partially counteracted the disruption of M2 macrophage polarization caused by APOE silencing and facilitated DFU wound healing. Collectively, our findings establish TAF15-driven stabilization of CEBPB mRNA as a target point that sequentially activates APOE/PTX3 signaling to enforce M2 polarization and accelerate DFU closure. This study provides a preclinical rationale for the development of TAF15-targeted oligonucleotides or small-molecule strategies to reprogram wound macrophages and improve DFU outcomes in patients with diabetes. Show less
The integrated stress response (ISR) has been implicated in cognitive decline associated with ageing and neurodegenerative diseases. Pharmacological inhibition of the ISR using the small-molecule ISRI Show more
The integrated stress response (ISR) has been implicated in cognitive decline associated with ageing and neurodegenerative diseases. Pharmacological inhibition of the ISR using the small-molecule ISRIB has demonstrated promising neuroprotective effects in several preclinical models. However, its potential therapeutic value in vascular cognitive impairment (VCI) remains largely unexplored. Here, we established a modified permanent bilateral carotid occlusion (2-VO) rat model of VCI and investigated the therapeutic potential of the ISRIB via microinjection in hippocampal dentate gyrus (DG). VCI rats exhibited elevated expression of vascular endothelial growth factor (VEGF), cluster of differentiation 34 (CD34), ionized calcium-binding adapter molecule 1 (Iba1), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), indicating successful establishment of the model. Behavioral assessments revealed that VCI rats exhibited impaired spatial, working, and recognition memory. Bioinformatic analysis highlighted ISR pathway activation in VCI. Furthermore, elevated phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) and activating transcription factor 4 (ATF4) protein levels in the DG confirmed ISR activation in the DG of VCI rats. VCI also reduced neuronal integrity, as evidenced by decreased Nissl body density. ISRIB treatment significantly improved cognitive performance, suppressed ATF4 expression, enhanced puromycin-labeled protein synthesis, and restored phosphorylated cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) signaling. Notably, ISRIB increased c-fos activation and upregulated synaptophysin and postsynaptic density protein 95 (PSD95) expression in the DG of VCI rats, indicating enhanced neuronal activity and synaptic function. Our results indicate that ISR activation contributes to hippocampal-dependent memory impairment in VCI. ISRIB effectively restores synaptic function and cognition, underscoring its therapeutic value and translational potential in treating VCI. Show less
Alzheimer' s disease (AD) is a progressive neurodegenerative disorder characterized by a spectrum of cognitive impairments, ranging from mild memory loss to severe cognitive decline and, ultimately, d Show more
Alzheimer' s disease (AD) is a progressive neurodegenerative disorder characterized by a spectrum of cognitive impairments, ranging from mild memory loss to severe cognitive decline and, ultimately, death. The global incidence of AD is projected to increase significantly, with late-onset AD being predominantly sporadic in nature. Over the past three decades, the Apolipoprotein E (APOE) gene has been recognized as the most important single genetic determinant of sporadic AD risk. The APOE4 allele is a major risk factor for AD and is known to exacerbate the pathological process for AD. Identifying protective variants that may reduce the risk or delay the onset of AD is of great significance for the development of effective treatments. This review comprehensively examines the protective effects of APOE and its related protective mutations. It also explores the impact of these unique protective variants at the cellular level during the pathological progression of AD. Furthermore, the review compiles new insights for AD treatment offered by these protective mutations, exploring the potential applications of APOE and its related protective variants in advanced therapeutic strategies, including gene editing, RNA editing, and stem cell therapy. Show less
CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mu Show more
CTNNB1-mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mutated tumors has not been examined. In addition, there are ongoing questions on the ability of AXIN1 mutations to activate the Wnt pathway in hepatocellular carcinoma. AXIN1 mutated tumors (N=18) were studied, along with control groups: CTNNB1 (N=17), APC (6), or "Other" genes in the Wnt pathway (5). Wnt pathway activation was studied by immunostains for beta-catenin and glutamine synthetase. Findings were supplemented by gene expression analysis using TCGA data. On histologic examination, the classic morphology associated with beta-catenin mutations was found in all 4 groups: 8/18 AXIN1 (44%), 10/17 CTNNB1 (59%), 4/6 APC (67%), and 1/5 Other (20%). By immunohistochemistry, Wnt pathway activation was found in 11/18 AXIN1 (61%), 15/17 CTTNB1 (88%), 6/6 APC (100%), and 5/5 (100%) of Other. In AXIN1-mutated tumors, the Wnt pathway was weakly activated. Glutamine synthetase stains also highlighted a new "progressed pattern" associated with distinct subnodules of staining. Tertiary lymphoid structures were uncommon except for cases with CTTNNB1 mutations plus additional mutations in the Wnt pathway. In summary, the classic morphology associated with CTNNB1 mutations is found in hepatocellular carcinomas with mutations in AXIN1, APC, and other Wnt genes. AXIN1 mutated tumors have Wnt activation that is detectable but at lower levels than CTNNB1 mutated tumors. As tumors progress, their level of Wnt activation can change. Show less
Neuropathic pain (NP) is a debilitating condition with limited treatment options. The ethanolic extract of Bauhinia brachycarpa Benth (EEBb) has demonstrated antinociceptive effects in NP, but its act Show more
Neuropathic pain (NP) is a debilitating condition with limited treatment options. The ethanolic extract of Bauhinia brachycarpa Benth (EEBb) has demonstrated antinociceptive effects in NP, but its active components and underlying mechanisms of action remain largely unexplored. Bauhinia brachycarpa Benth (BBB), an ethnic medicine in China, has antinociceptive effect on neuropathic pain (NP). In this study, an effective portion from BBB was screened and its antinociceptive mechanism was investigated. After the preparation of ethanolic extract from BBB (EEBb) and different soluble portion from EEBb (peEEBb, eaEEBb, nbEEBb), the total content of flavonoids and phenolic acids were measured. A partial sciatic nerve ligation (PSNL) model in vivo was applied to evaluate the antinociceptive effect and the influence on microglia function of these samples. The possible acting target of BBB was predicted by network pharmacology. And the mechanism of nbEEBb, the most effective antinociceptive portion, were studied by PSNL model in vivo and ATP-induced activation of BV2 model in vitro. nbEEBb had the strongest ability of alleviating NP as well as the obvious effect on microglia polarization. The action of nbEEBb was positively correlated to the total content of flavonoids or phenolic acids. nbEEBb inhibited the protein and gene expressions of most key components in P2X4-BDNF-TrkB signaling pathway. nbEEBb is the most effective portion from BBB on NP, and its mechanism refers to the inhibition of P2X4-BDNF-TrkB signaling pathway, which involved in neuron-microglia interaction. Show less
Xin Huang, Yan-Yun Sun, Yi-Ren Qin+15 more · 2026 · Journal of controlled release : official journal of the Controlled Release Society · Elsevier · added 2026-04-24
Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activa Show more
Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD. Show less
Atherosclerosis is a chronic and progressive inflammatory disease that can lead to adverse cardiovascular and cerebrovascular events. Phenotypic switching of vascular smooth muscle cells (VSMCs) plays Show more
Atherosclerosis is a chronic and progressive inflammatory disease that can lead to adverse cardiovascular and cerebrovascular events. Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a pivotal role in its development and progression, but the upstream regulatory mechanisms remain incompletely defined. Here, we identify ubiquitin-fold modifier 1 (UFM1), a ubiquitin-like protein, as a critical regulator of VSMCs plasticity and atherogenesis. In VSMCs stimulated with oxidized low-density lipoprotein (ox-LDL), UFM1 overexpression markedly attenuated phenotypic switching, restoring contractile features and suppressing synthetic activation, accompanied by reduced proliferation and migration. In contrast, UFM1 knockdown further exacerbated these phenotypic alterations. In ApoE Show less
Bone angiogenesis is important for bone formation and regeneration after bone injury. Endothelial-derived angiogenic factors are key signal transducers in the bone microenvironment and maintain vascul Show more
Bone angiogenesis is important for bone formation and regeneration after bone injury. Endothelial-derived angiogenic factors are key signal transducers in the bone microenvironment and maintain vascular-osteogenic coupling during bone regeneration. CGRP, a bone sensory neuron-derived peptide, contributes to bone formation, but the potential mechanism by which it improves bone regeneration via angiogenesis is unclear. Here, we demonstrate that CGRP may contribute to bone repair in the elderly, as human CGRP levels are inversely proportional to age and proportional to bone mass in clinical data and bulk transcriptome data. Based on single-cell RNA sequencing data and experimental analyses, CGRP is found to promote the angiogenesis of human microvascular endothelial cell line-1 in vitro through the FAK-AKT-VEGF pathway. CGRP gene deletion in mice reduced bone vascular density and bone mass, and delayed angiogenesis and bone regeneration at the bone defect site. Recombinant CGRP restored bone repair after defect introduction. It also promoted Angptl4 secretion by bone vascular endothelial cells, thereby driving osteogenic differentiation of bone marrow mesenchymal stem cells and enhancing bone regeneration after bone injury. Treatment with recombinant Angptl4 enhanced bone healing in a mouse bone defect model. These integrated analysis reveal the important role and mechanism of CGRP in vascular-mediated osteogenesis, suggesting a novel therapeutic strategy for promoting bone regeneration. Show less
Hemodialysis, as one of the main alternative treatment methods for end-stage renal disease, has received much attention in recent years. Due to the particularity of hemodialysis treatment, patients ha Show more
Hemodialysis, as one of the main alternative treatment methods for end-stage renal disease, has received much attention in recent years. Due to the particularity of hemodialysis treatment, patients have a relatively high risk of infection during the treatment process. Hemodialysis nurses, who are the main executors of the treatment operations and have the most contact with patients, have a close relationship with the infection risk of patients. The level of their hospital infection prevention and control literacy is closely related to the infection risk of patients. To explore the current level of knowledge, attitudes, and practices (KAP) of hospital infection prevention and control among haemodialysis nurses in the Sichuan Province, China, and identified their potential categories. This provided evidence-based recommendations for improving infection control management in hemodialysis departments. A cross-sectional study was conducted From July 15 to August 15, 2025 using a convenience sampling method to survey 470 hemodialysis nurses from 78 hospitals in Sichuan Province. Participants were licensed nurses with over 3 months of hemodialysis experience. Data were collected using the A total of 460 valid questionnaires were collected, with an effective response rate of 97.87%. The average scores for knowledge, attitudes, and practices related to hospital infection prevention and control among haemodialysis nurses were 4.67 ± 0.43, 4.59 ± 0.43, and 4.74 ± 0.34, respectively. Three latent profile models were constructed, with the two-class model identified as the optimal solution, which were defined as the "Low KAP Group" (25.9%) and "High KAP Group" (74.1%). Logistic regression analysis revealed that sex, responsibility for infection control, hospital level, annual number of infection control training sessions, organizational support, and work engagement were significant influencing factors ( The KAP level of haemodialysis nurses in hospital infection prevention and control was relatively high. Hospital managers should tailor supportive work environments on the basis of the individual characteristics and work engagement of haemodialysis nurses to improve the KAP level of nosocomial infection prevention and control among haemodialysis nurses. Show less
The brain-derived neurotrophic factor ( A total of 43 first-episode mania patients (FEM), 110 multiple-episode mania patients (MEM) and 80 healthy controls were enrolled in our study. We investigated Show more
The brain-derived neurotrophic factor ( A total of 43 first-episode mania patients (FEM), 110 multiple-episode mania patients (MEM) and 80 healthy controls were enrolled in our study. We investigated the impact of We found a significant interaction between This is the first study to demonstrate that The online version contains supplementary material available at 10.1186/s12888-026-07949-7. Show less
Fusion genes are pivotal drivers of tumorigenesis, often generating oncogenic chimeric RNAs and fusion circular RNAs. However, the mechanisms by which these transcripts synergistically contribute to c Show more
Fusion genes are pivotal drivers of tumorigenesis, often generating oncogenic chimeric RNAs and fusion circular RNAs. However, the mechanisms by which these transcripts synergistically contribute to cancer progression remain poorly understood. Here, we identified a lung cancer-specific chimeric RNA KANSL1-ARL17A (chKANSARL) and its circular variant fusion circular RNA KANSL1-ARL17 A (F-circKA), both derived from the fusion gene KANSARL. Functional assays revealed that overexpression of either chKANSARL or F-circKA significantly enhanced lung cancer cell proliferation, migration, and invasion, while their knockdown suppressed these malignant phenotypes. In vivo experiments demonstrated that chKANSARL overexpression accelerated tumor growth in immunodeficient mice. Notably, coexpression experiments uncovered a synergistic regulatory interaction between F-circKA and chKANSARL, amplifying oncogenic effects. Mechanistically, miRNA sequencing and dual-luciferase assays revealed that F-circKA acts as a molecular sponge for miR-6860, thereby derepressing chKANSARL expression. Rescue experiments further validated this regulatory axis, wherein miR-6860 inhibition reversed the tumor-suppressive effects of F-circKA knockdown. Collectively, our study identifies and characterizes a novel F-circKA/miR-6860/chKANSARL regulatory axis, revealing how dual transcriptional outputs from the KANSARL fusion gene can synergistically drive lung cancer progression. These findings highlight a previously unrecognized layer of cooperative regulation between linear and circular fusion RNAs in oncogenesis and provide a new framework for understanding fusion gene-mediated tumorigenesis. Show less
Hepatocellular carcinoma (HCC) exhibits high recurrence rates and limited therapeutic options. Endothelial cell-specific molecule 1 (ESM1) and angiopoietin-like 4 (ANGPTL4) are implicated in tumor pro Show more
Hepatocellular carcinoma (HCC) exhibits high recurrence rates and limited therapeutic options. Endothelial cell-specific molecule 1 (ESM1) and angiopoietin-like 4 (ANGPTL4) are implicated in tumor progression, yet their synergistic role in HCC lipid metabolism and angiogenesis remains unexplored. We integrated multi-omics approaches, including RNA sequencing, metabolomics, and immunoprecipitation-mass spectrometry, in HCC cell lines and patient-derived xenograft models. Key experiments involved Co-IP, Western blotting, tube formation assays, and clinical tissue microarray analysis to validate the ESM1-ANGPTL4-FASN-trioleate axis. ESM1 and ANGPTL4 formed a positive feedback loop, stabilizing fatty acid synthase (FASN) to promote trioleate synthesis. Trioleate activated the NF-κB/IL-17 pathway in HCC cells and upregulated CD99 in endothelial cells, driving angiogenesis. In vivo, ESM1/ANGPTL4 knockdown suppressed tumor growth, which was rescued by trioleate supplementation. Clinical data revealed elevated ESM1/ANGPTL4 expression in bevacizumab-resistant HCC, correlating with poor prognosis. The ESM1-ANGPTL4-FASN-trioleate axis orchestrates metabolic reprogramming and endothelial activation, representing a promising therapeutic target. Future studies should explore combination therapies targeting this axis and overcoming bevacizumab resistance in HCC. Show less
Given the heterogeneous nature of Alzheimer's disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain. This s Show more
Given the heterogeneous nature of Alzheimer's disease (AD) and its higher prevalence in females, it is crucial to understand sex-related differences in AD presentation and changes in the brain. This systematic review investigates sex differences in AD and summarizes key findings from neuroimaging studies over the past two decades to examine how genetics, hormones, and lifestyle factors influence neuroimaging biomarkers and their correlation with cognitive decline and AD progression. A comprehensive literature search was conducted across several databases for human studies from 2004 to 2024 related to AD, biological sex differences, and neuroimaging. After a 3-step review process, the final extraction included 120 peer-reviewed studies using various neuroimaging modalities, such as MRI, amyloid-beta PET, tau-PET, and fluorodeoxyglucose (FDG) PET, to investigate sex as a biological predictor variable in adults with or at risk for AD. Over 90% of the reviewed studies identified clear sex-specific patterns of imaging biomarkers related to cognitive reserve, hormonal changes, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle factors. Machine learning studies increasingly incorporate sex as a key variable, revealing sex-specific biomarkers and improving model performance in predicting disease status and progression. Considering biological sex in AD research is essential for improving diagnostic accuracy, tailoring interventions, and health outcomes. This systematic review identifies sex-specific patterns in neuroimaging biomarkers of AD, influenced by cognitive reserve, hormones, APOE-ɛ4 genotype, inflammation, vascular health, and lifestyle. Recognizing these differences is crucial for understanding, diagnosis, and treatment efficacy. Show less
To characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohn's disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. Prospective coho Show more
To characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohn's disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. Prospective cohort study. Two large multi-center cohorts (UK Biobank [UKB] and Whitehall II [WHII] study) across the UK and an Eastern multi-center cohort ONE-IBD Study from China. UK Biobank discovery cohort (n=10,229) for signature derivation, internal validation cohort (n=91,306), external validation cohort Whitehall-II (n=7,893), and three additional cohorts (two Western and ONE-IBD) for validation of key metabolic drivers. Primary outcomes were UPF-related circulating metabolic signatures and their associations with CD risk; secondary outcomes included evidence supporting causal roles of candidate metabolites and genetic pathways assessed by Mendelian randomization, colocalization, and gene-environment analysis. A UPF metabolic signature of 73 metabolites was constructed and validated across cohorts (Spearman ρ: 0.20-0.25). More pronounced UPF metabolic signature was associated with increased CD risk (HR The adverse effects of UPF on CD risk may be driven by a relative deficiency of protective metabolites such as DHA, apart from additive harm to metabolic depletion. This reframes UPF-related risk and highlighting potential targets for precision nutrition in CD prevention. Show less
Accelerometer-derived physical activity is associated with reduced stroke risk. The biological pathways underpinning this relationship, however, are not yet understood. Herein, we aim to identify meta Show more
Accelerometer-derived physical activity is associated with reduced stroke risk. The biological pathways underpinning this relationship, however, are not yet understood. Herein, we aim to identify metabolic signatures associated with accelerometer-measured PA and investigate their relationships with reduced stroke incidence. Utilizing UK Biobank accelerometer data, we derived physical activity into total physical activity (TPA), moderate-to-vigorous physical activity (MVPA), and light physical activity (LPA) and linked them to 249 NMR-quantified plasma metabolites. The metabolomic signatures (TPA-/MVPA-/LPA-metabolomic signatures) were developed through internal validation followed by elastic-net regression modeling. Cox proportional hazards models evaluated activity-stroke associations (adjusted for sociodemographic/genetic factors), followed by mediation analysis to quantify metabolomic signature effects. Through UK Biobank study (N = 29445; 14.1-year follow-up with 513 stroke events), we identified 195 TPA, 173 MVPA, and 164 LPA metabolite associations (FDR < 0.05), with 107, 92, and 15 validated, respectively. Elastic net-derived physical activity-metabolomic signatures (TPA-/MVPA-metabolomic signatures) correlated with physical activity intensities (r = 0.20-0.30, P < 0.001) and were associated with reduced stroke risk: TPA-metabolomic signatures (HR = 0.61, 95% CI: 0.44-0.87); MVPA-metabolomic signatures (HR = 0.50, 95%CI: 0.29-0.88). Mediation analyses showed TPA-metabolomic signatures and MVPA-metabolomic signatures explained 12.2% and 8.5% of physical activity-stroke associations (P < 0.001), implicating specific lipoprotein subclasses and lipids as key mediators. TPA-metabolomic signatures and MVPA-metabolomic signatures, particularly the 11 key metabolites included, significantly mediate the association between accelerometer-derived physical activity and stroke risk. Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbili Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSC@Exo) represent promising nanoscale carriers for targeted drug delivery. In this study, Baicalein (Bac), a potent antioxidant and anti-inflammatory flavonoid, was encapsulated into hUC-MSC-derived exosomes (Exo@Bac) to enhance its therapeutic efficacy. The neuroprotective potential of Exo@Bac was evaluated in a rat model of Aβ1-42-induced AD. Rats received intraperitoneal injections of Bac, hUC-MSC@Exo, or Exo@Bac, and cognitive performance was assessed using the passive avoidance test and Morris water maze. Exo@Bac treatment significantly improved memory deficits and elevated brain-derived neurotrophic factor (BDNF) expression compared to controls. Histopathological analyses revealed reduced neuronal damage and apoptosis, alongside decreased Aβ1-42 deposition in Exo@Bac-treated rats. Furthermore, Exo@Bac enhanced antioxidant defense (increased SOD), attenuated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lowered lipid peroxidation (MDA). Mechanistically, Exo@Bac promoted AMPK phosphorylation while suppressing NF-κB p65 signaling, indicating modulation of both oxidative stress and neuroinflammatory pathways. These findings demonstrate that Exo@Bac acts as a nanotherapeutic agent capable of mitigating AD pathology, highlighting its potential as a novel strategy for Alzheimer's disease therapy. 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
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally prevalent disease, yet its genetic architecture remains incompletely characterized. We integrated genome-wide association Show more
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally prevalent disease, yet its genetic architecture remains incompletely characterized. We integrated genome-wide association study data from multiple cohorts totaling nearly 3 million individuals of European ancestry and applied cross-trait genomic modeling of hepatic fat and seven cardiometabolic traits to construct an MASLD-specific polygenic architecture. We identified 128 risk variants across 100 loci and prioritized 55 effector genes, including established (e.g., Show less
Gary Chen, Adrienne Sexton · 2026 · Patient education and counseling · Elsevier · added 2026-04-24
This scoping review aims to map the experiences and outcomes of patients and their families undergoing genetic testing and counseling regarding dementia to inform future research directions and clinic Show more
This scoping review aims to map the experiences and outcomes of patients and their families undergoing genetic testing and counseling regarding dementia to inform future research directions and clinical practice. Rigorous scoping review methodology was followed. Ovid Medline, Embase, PsycINFO, and CINAHL were searched with keywords and MeSH terms related to "genetic testing", "genetic counseling", "dementia", "decision making", and "patient outcomes" for peer-reviewed studies with adult participants published over the last ten years. Thirty-six articles met inclusion criteria. Narrative synthesis organized findings into temporal categories including motivations for genetic testing, experiences during the testing/counseling process, and outcomes after testing. Common motivators included reducing uncertainty, reproductive planning, life planning, and the prospect of a treatment becoming available in the future. A lack of current treatments and fear that knowledge of genetic risk would be difficult to cope with were common barriers to testing. Patient-centered communication improved satisfaction. Genetic testing was generally psychologically well tolerated, and a wide range of practical responses were reported including changes to lifestyle, diet, advanced care and financial planning, and engaging in clinical trials. This review maps the experiences and outcomes of genetic testing or counseling for people with or at potentially increased genetic risk of dementia. Genetic testing and counseling for directly causal dementia genes and APOE genotype appears well tolerated but long-term outcome data is lacking. Motivations, concerns and perceived benefits of knowing genetic results vary depending on personal, familial and cultural viewpoints. Genetic counseling can help patients and families prepare, reduce decisional regret, and adapt to results. Motivations varied, and a patient-centered approach addressing both information and psychological aspects improves satisfaction. Future longitudinal research should ascertain ways to support individuals from a wide range of demographics with understanding and adjusting to genetic risk information regarding dementia. Show less
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with systemic manifestations, including cognitive impairment linked to gut‒brain axis dysregulation. While probiotic therapies show prom Show more
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with systemic manifestations, including cognitive impairment linked to gut‒brain axis dysregulation. While probiotic therapies show promise, their mechanisms in mitigating neuropsychiatric comorbidities remain unclear. Here, we investigated the therapeutic potential of Show less
Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein that has been established as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic Show more
Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein that has been established as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Structurally composed of a low-density lipoprotein (LDL)-like particle covalently linked to apolipoprotein(a) [apo(a)], Lp(a) exhibits unique atherogenic, thrombogenic, and inflammatory properties, largely due to its role as a carrier of oxidized phospholipids (OxPL). Plasma Lp(a) concentrations are predominantly determined by the number of kringle IV type 2 (KIV-2) repeats in the LPA gene, with minimal influence from lifestyle or environmental factors. Despite substantial evidence linking elevated Lp(a) to cardiovascular risk, clinical testing remains underutilized, especially in East Asian countries. In Taiwan, although population-level Lp(a) concentrations are comparatively low, a significant subset exceeds risk thresholds, with local studies confirming its prognostic value in coronary artery disease and ischemic stroke. Barriers, including limited physician awareness, implementation barriers, and therapeutic nihilism, contribute to its under-recognition. This review highlights the molecular features of Lp(a), its pathogenesis of cardiovascular disorders, epidemiology, and current barriers and future advances in diagnostic testing, with a particular focus on implications for cardiovascular risk management in Taiwan. Show less
The clinical interpretation of Alzheimer's disease (AD) is frequently complicated by the prevalence of missense variants designated as being of uncertain significance within associated genes. Conventi Show more
The clinical interpretation of Alzheimer's disease (AD) is frequently complicated by the prevalence of missense variants designated as being of uncertain significance within associated genes. Conventional computational prediction tools often overlook disease-specific pathophysiological contexts and lack pertinence and interpretability. Therefore, the present study aimed to develop a novel, interpretable framework for predicting the pathogenicity of AD missense variants by integrating transcriptomic and proteomic data enrichment patterns with machine learning methods. A cross-sectional variant-level analysis was performed using publicly available databases. Missense variants in APOE, APP, PSEN1, PSEN2, SORL1, and TREM2 reported in AD patients were retrieved from Alzforum and compared with missense variants from individuals without neurological diseases, as cataloged in the gnomAD v2.1.1 non-neuro subset. Variants were annotated with tissue-specific expression, secondary structure, relative solvent accessibility, and other functional features using tools like AlphaFold. Enrichment of specific features was assessed with Fisher's exact tests with Bonferroni correction for multiple comparisons. Given that PSEN1 showed the strongest enrichment signals, six machine-learning algorithms were trained on PSEN1 variants to distinguish AD-associated variants from gnomAD variants, using a 10 × 5 nested cross-validation scheme. External validation was conducted using PSEN1 missense variants from ClinVar annotated as pathogenic/likely pathogenic or benign/likely benign. Model performance was compared with SIFT and PolyPhen-2, and interpretability was evaluated by feature ablation and SHapley Additive exPlanations analyses. AD-associated variants exhibited statistically significant enrichment within some transcriptomic or proteomic features, with PSEN1 contributing significantly to the enrichment observed across these features. Random forest and gradient boosting models achieved high performance in the internal training dataset and maintained high recall in the external validation dataset, outperforming SIFT and approaching the performance of PolyPhen-2. Relative solvent accessibility was the most discriminative individual feature, while regional and topological features provided complementary discriminative power. This integrative, multi-omics framework links disease-specific enrichment patterns with interpretable gene-level machine learning for AD missense variants. The results highlight the importance of expression level, structural context, etc. for PSEN1 variant pathogenicity and may help prioritize variants for functional studies. Further validation in additional genes and independent cohorts is warranted prior to any clinical application. Show less
This study investigated longitudinal plasma serotonin dynamics across the Alzheimer's disease (AD) continuum (cognitively normal [CN], mild cognitive impairment [MCI], and AD) to determine whether bas Show more
This study investigated longitudinal plasma serotonin dynamics across the Alzheimer's disease (AD) continuum (cognitively normal [CN], mild cognitive impairment [MCI], and AD) to determine whether baseline serotonin and its 24-month change are associated with CSF amyloid-β (Aβ42), tau biomarkers, amyloid PET burden, structural brain integrity, and cognitive decline. Data from 959 ADNI participants (CN = 306, MCI = 421, AD = 232) with baseline and 24-month follow-up were analyzed. Measures included plasma serotonin, CSF biomarkers (Aβ42, total tau, p-tau181), florbetapir PET, MRI (hippocampal volume, cortical thickness), and cognitive tests (MMSE, ADAS-Cog 11, CDR-SB). Group differences were tested using ANOVA or Kruskal-Wallis, and associations were examined via partial correlations and mixed-effects models adjusted for age, sex, education, and APOE ε4, with FDR correction. The results revealed that baseline plasma serotonin levels showed a stepwise decline across the clinical continuum (CN > MCI > AD; p ≤ 0.05), consistent with progressive serotonergic dysregulation. In AD participants, higher baseline serotonin was significantly associated with less amyloid pathology and preserved brain structure, including higher CSF Aβ42 (β = 0.28, FDR p = 0.01), lower florbetapir PET SUVR (β = -0.31, FDR p = 0.02), and larger hippocampal volume (β = 0.33, FDR p = 0.02). Higher serotonin was also linked to better cognitive performance (MMSE: β = 0.22, FDR p = 0.02; ADAS-Cog 11: β = -0.24, FDR p = 0.02). Longitudinally, decreases in serotonin over 24 months in AD were associated with worsening amyloid burden (ΔPET SUVR: β = -0.29, FDR p = 0.02) and accelerated hippocampal atrophy (β = 0.32, FDR p = 0.01). Baseline serotonin predicted smaller 24-month declines in CSF Aβ42 (β = 0.28, FDR p = 0.01) and reduced hippocampal volume loss (β = 0.31, FDR p = 0.01). In CN and MCI groups, associations between serotonin and AD biomarkers or cognitive outcomes were not significant after FDR correction. On the whole, lower plasma serotonin levels are linked to amyloid pathology, hippocampal neurodegeneration, and cognitive decline in AD, supporting serotonin's potential as a stage-specific biomarker and mechanistic contributor to disease progression. Integrative longitudinal studies are needed to clarify causality and evaluate serotonergic pathways as therapeutic targets. Show less
The polyphenols in grains are highly active, but some polyphenols in highland barley are in a bound form and have extremely low bioavailability. Fermentation by lactic acid bacteria (LAB) is capable o Show more
The polyphenols in grains are highly active, but some polyphenols in highland barley are in a bound form and have extremely low bioavailability. Fermentation by lactic acid bacteria (LAB) is capable of altering the functionality of foods. This research investigated the effects of fermentation with different LAB, such as Lactobacillus acidophilus (LAC), Lactobacillus casei (LCA), Lactobacillus rhamnosus (LRH), Lactobacillus plantarum (LPL), and Lactobacillus bulgaricus (LBU), on the hypoglycemic activity and mechanism of polyphenols in highland barley. The hypoglycemic activity of the fermentation products was measured by in vitro antioxidant, enzyme activity, and glucose consumption experiments. Untargeted metabolomic analysis used UHPLC-Q Exactive HF-X/MS to reveal distinct metabolic profiles among the fermented groups. Molecular docking and western blot experiments were conducted to elucidate the mechanism underlying the hypoglycemic effect of fermentation products. Polyphenolic antioxidant activity in highland barley and its inhibitory activities against α-glucosidase and α-amylase were increased after LAC fermentation. Furthermore, the fermented extracts improved glucose consumption in HepG2 cells. The content determination and metabolomic analysis showed that fermented highland barley polyphenols were increased, and 113 differential phenolic metabolites were identified and annotated, among which 44 exhibited a significant upregulation compared with raw highland barley polyphenols. At the molecular level, the polyphenol extract upregulated PI3K and phosphorylated Akt expression in HepG2 cells. Overall, the results indicate that fermentation by LAC biotransformed highland barley polyphenols into smaller molecules with improved hypoglycemic activities, thereby enhancing their bioavailability. Show less