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Injectable hydrogel implants represent a promising therapeutic approach for ischemic heart failure; but their efficacy is often limited by low bioactivity, poor durability, and inadequate injection techniques. Herein, a unique hydrogel incorporating extracellular matrix from fish swim bladder (FSB-ECM), which has distinct advantages over mammalian derived ECM, such as low antigenicity, bioactivity, and source safety, is developed. It consists of collagen, glycoproteins, and proteoglycans, including 13 proteins common in the myocardial matrix and three specific proteins: HSPG, Col12a1, and vWF. This hydrogel enhances cardiac cell adhesion and stretching while promoting angiogenesis and M2 macrophage polarization. In addition, its storage modulus (G') increases over time, reaching about 1000 Pa after 5 min, which facilitates transcatheter delivery and in situ gelling. Furthermore, this hydrogel provides sustained support for cardiac contractions, exhibiting superior longevity. In a rat model of ischemic heart failure, the ejection fraction significantly improves with FSB-ECM treatment, accompanied by increased angiogenesis, reduced inflammation, and decreased infarct size. Finally, RNA sequencing combined with in vitro assays identifies ANGPTL4 as a key protein involved in mediating the effects of FSB-ECM treatment. Overall, this new injectable hydrogel based on FSB-ECM is suitable for transcatheter delivery and possesses remarkable reparative capabilities for treating heart failure. Show less

Tea polyphenols are a class of natural plant compounds with potent antioxidant properties, and their critical role in regulating lipid metabolism has been demonstrated in numerous studies. However, systematic research on the effects of tea polyphenols on lipid metabolism in lion-head geese remains limited. In this study, we examined the impact of tea polyphenols on lipid metabolism in geese through an integrative analysis of transcriptomics and metabolomics. A total of 240 healthy male lion-head geese with similar body weights at 1 day of age were randomly allocated into two treatment groups (6 replicates per group, with 20 geese per replicate). The control group received a basal diet, while the experimental group was supplemented with 1000 mg/kg of tea polyphenols (50.4 % catechin purity) in the basal diet for 18 weeks. The results indicated that serum total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) activities were significantly increased (P < 0.05), while malondialdehyde (MDA) levels were significantly decreased (P < 0.05) in the tea polyphenol group compared to the control group. Additionally, serum triglycerides (TG), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) activities were significantly lower (P < 0.05) in the tea polyphenol group than in the control group. Hepatic transcriptomic analysis further revealed that tea polyphenols significantly modulated the expression of several genes involved in lipid metabolism, including angiopoietin-like 4 (ANGPTL4), which plays a role in regulating lipid homeostasis, as well as glycerophosphodiester phosphodiesterase domain containing 2 (GDPD2), immunoglobulin heavy chain (IGH), proto-oncogene protein c-fos (FOS), and matrix metallopeptidase 1 (MMP1), etc. Serum metabolomic analysis also demonstrated significant alterations in lipid metabolites induced by tea polyphenols, including the downregulation of fatty acyl metabolites such as L-Palmitoylcarnitine and Hexadecanal. Moreover, the combined analysis revealed a strong positive correlation between ANGPTL4 and the organic compounds of steroidal saponins, such as Glucoconvallasaponin B, and negative correlations with glycerophospholipid metabolites, such as LysoPC (P-16:0). The comprehensive analysis suggests that the inclusion of tea polyphenols in the diet enhances the antioxidant capacity of lion-head geese, improves hepatic lipid profiles, and regulates lipid metabolism via modulating lipid metabolism-related genes and metabolites. Show less

To assess the association between the single nucleotide polymorphisms (SNP) rs174575 and rs2845574 of the fatty acid desaturase 2 (FADS2) gene and gestational diabetes mellitus (GDM). A total of 1 514 pregnant women who visited West China Second University Hospital of Sichuan University between January 1, 2013 and December 31, 2021 were enrolled in this study. Among them, 583 were diagnosed with gestational diabetes mellitus (GDM group), and 931 had normal pregnancies (control group). The SNPs rs174575 and rs2845574 of the FADS2 gene were analyzed using Sanger DNA sequencing. Plasma levels of insulin (INS), apolipoprotein A1 (apoA1) and apolipoprotein B (apoB) were measured using enzymatic methods, chemiluminescence and immunoturbidimetry. This study was approved by the Medical Ethics Committee of the West China Second University Hospital of Sichuan University (Ethics No.: 2020-036). The main genotype at the rs174575 C/G and rs2845574 C/T loci were CC in both GDM and control groups. No significant difference was found between the GDM and control groups regarding the genotypic or allelic frequencies of rs174575 and rs2845574 sites (P > 0.05). Among the GDM group, individuals with the GG genotype at the rs174575 site had lower plasma HDL-C levels compared to those with the CC genotype (P < 0.05), and had higher atherogenic indices (AI) compared with the CC and CG genotype (P < 0.05; P < 0.05). Individuals with the TT genotype at the rs2845574 site had higher AI compared with the CT genotype (P < 0.05). Among the control group, individuals with the GG genotype had lower diastolic blood pressure (DBP) compared to those with the CC genotype (P < 0.05). Additional subgroup analysis demonstrated that the rs174575 polymorphism was associated with AI levels in obesity subgroup of GDM, TG levels in non-obese subgroup of control and DBP levels in the obese subgroup of control (P < 0.05; P < 0.05; P < 0.05). The FADS2 rs174575 and rs2845574 polymorphisms in GDM patients are associated wit HDL-C and AI levels, and the FADS2 rs174575 polymorphisms was also associated with DBP levels in normal pregnant women. The AI and DBP levels have a BMI-dependent effect. Show less

Gut microbiota-derived compounds are pivotal in modulating host immunity by regulating the functions of various key innate and adaptive immune cells. Epstein-Barr virus-induced gene 3 (EBI3) serves as the beta subunit shared by the heterodimeric cytokines interleukin (IL)-27 and IL-35. Both these cytokines have been documented to inhibit the development of T helper 2 (Th2) and T helper 17 (Th17) cells, while enhancing the function of regulatory T cells (Tregs). EBI3, itself, has also been shown to regulate cell-mediated immune responses. Despite their critical roles in maintaining immune homeostasis, there is a significant lack of robust, high-throughput-compatible assays to evaluate the secretion of IL-27, IL-35, or EBI3. In this study, we detail the development of a novel amplified luminescent proximity homogeneous assay (AlphaLISA™) to quantify EBI3 secretion by tolerogenic dendritic cells. We utilized this assay to screen a library of 9739 small proteins derived from the human gut microbiota to identify compounds that could stimulate EBI3 secretion. Our findings revealed the immunoregulatory potential of VAC18, an unknown protein from Fusicatenibacter saccharivorans (Clostridiumcluster XIVa) which significantly induces the secretion of both EBI3 and IL-27. This is the first study to demonstrate the effect of gut microbiota derived peptides on the balanced secretion of EBI3 and IL-27. Show less

The "cold" tumor microenvironment of oral squamous cell carcinoma (OSCC), where tumor-associated lymphatic vessels play a critical role in the transport of immune cells, is associated with a poor prognosis. However, the effect of tumor-induced lymphangiogenesis on CD8+ T cell infiltration and its role in the formation of the tumor immune microenvironment remain unclear. We analyzed the prognostic significance of several lymphangiogenesis factors in OSCC with The Cancer Genome Atlas dataset, and confirmed the impact of fibroblast growth factor-2 (FGF-2) on prognosis in tissue specimens. Subsequently, we investigated the effects of FGF-2 on the proliferation, migration, and tube formation capacities of lymphatic endothelial cells, and CD8+ T cell infiltration through in vivo and in vitro experiments. Survival analysis was performed by Kaplan-Meier analysis and log-rank tests. The hazard ratio was calculated by Cox proportional hazards model. Patients with high FGF-2 levels and increased numbers of peritumoral lymphatic vessels were associated with a worse prognosis. Furthermore, we demonstrated that tumor cell-derived FGF-2 promoted lymphangiogenesis by regulating the FGFR1/PTEN/AKT axis and increased the secretion of CXCL9 to recruit and egress CD8+ T cells via neo-lymphatic vessels. PD-166866, an inhibitor of FGFR1, suppressed lymphangiogenesis and the secretion of CXCL9 to increase CD8+ T cell infiltration and inhibit tumor progression. Our data suggest that FGF-2 is a significant prognostic factor that induces lymphangiogenesis and affects intratumoral CD8+ T cells, contributing to the formation of a "cold" tumor microenvironment in OSCC. FGF-2/FGFR1 could serve as an effective target for improving the prognosis of OSCC. Show less

Alzheimer’s disease (AD) is a leading cause of dementia, imposing a substantial burden on individuals and society. While existing therapies can reduce the symptoms of AD, they do not offer genuine therapeutic effectiveness. Adiponectin Receptor Agonist (ADN-R Ag) has been proposed as a novel therapeutic agent for AD. This study aims to evaluate its efficacy in treating AD model mice. A systematic search of PubMed, Scopus, Cochrane Library, and Web of Science was conducted up to May 3, 2025. Research investigating the impact of ADN-R Ag on cognitive performance and associated molecular pathways in Alzheimer’s disease models, specifically APP/PS1, P301S, and 5XFAD mice, was incorporated. The Alzheimer’s disease models in the study were male and ranged in age from 5.5 to 8 months. Studies evaluating the effect of ADN-R Ag on AD model mice through cognitive function tests and related molecular mechanisms were included. Methodological quality assessment was performed using the CAMARADES tool for animal studies. The meta-analysis was performed following Cochrane guidelines. Six articles were included for the review. ADN-R Ag significantly improved cognitive function in the meta-analysis. The weighted mean difference of ADN-R Ag was 21.75 (95% CI: 16.61–26.88; Based on the current study, ADN-R Ag has therapeutic effects on AD. However, considering the complex underlying molecular mechanisms and limited prior studies, further research is needed. The online version contains supplementary material available at 10.1186/s12883-025-04356-5. Show less

Hepatocellular carcinoma (HCC) represents a particularly aggressive form of cancer, characterized by its rapid progression and a complex interplay with the surrounding immune cellular environment. The primary objective of this study was to comprehensively investigate the role of ANGPTL4 in the context of HCC, utilizing RNA sequencing (RNA-seq) techniques to explore its impact on the M2 polarization of tumor-associated macrophages (TAM) and to uncover potential mechanisms driving HCC progression. To achieve this, we performed a transcriptome analysis of HCC cell lines, alongside cells obtained after co-culturing these lines with macrophages. By comparing gene expression profiles between the experimental groups exposed to ANGPTL4 and control groups, we aimed to identify specific molecular pathways associated with ANGPTL4's function. In addition to gene expression analysis, we employed flow cytometry to assess the polarization status of TAM. Furthermore, we utilized immunohistochemistry to evaluate the distribution of macrophages within HCC tissues and to quantify the expression levels of M2 macrophage markers. The results derived from RNA-seq analysis were particularly revealing; treatment with ANGPTL4 led to a significant upregulation of genes linked to M2 polarization, notably including CD206 and Arg1. In subsequent experimental observations, it became evident that ANGPTL4 not only facilitated the M2 polarization of macrophages but also enhanced the proliferation and migratory capacity of HCC cells through the upregulation of these same cytokines. Show less

Wernicke encephalopathy (WE) is a life-threatening neuropsychiatric disorder caused by thiamine deficiency (TD). One cause of TD is restrictive food intake. We present a girl with severe, treatment-resistant obesity from infancy due to hyperphagia caused by melanocortin 4 receptor (MC4R) deficiency. When aged 16 years, she presented at the emergency department with diplopia, headache, confusion, and ataxia. She had lost 25 kg in the previous 2 months because of anxiety-induced avoidant and restrictive food intake, despite persistent hyperphagia. Her anxiety had been triggered by a period of nausea and fear of vomiting. Neurological examination revealed horizontal and vertical nystagmus and bilateral abducens nerve palsy. Brain MRI showed typical lesions for WE, such as T2/fluid-attenuated inversion recovery hyperintensities in the medial thalamus, leading to a prompt diagnosis, which was later confirmed by a low thiamine value. Daily intravenous thiamine treatment resulted in significant neurological improvement within days. Her eating behavior gradually normalized with psychological support. This case is notable for the coexistence of hyperphagia and restrictive eating in a patient with MC4R deficiency, demonstrating that limited and restrictive food intake can occur even in the presence of monogenic obesity. This suggests complex interactions between hunger and fear pathways, warranting further research to better understand the pathophysiology of hyperphagia and identify new therapeutic targets for MC4R deficiency. Clinicians should consider WE, even in patients with (severe) obesity. Important signs are restrictive eating and neurological symptoms. Prompt thiamine therapy should be initiated when suspected. Show less

To determine whether low-density lipoprotein cholesterol (LDL-C) levels, set by the balance of clearance and production, causally contribute to septic shock 28-day mortality. We measured LDL-C levels and genotypes in patients with septic shock. Using Genotyping and Genome-Wide Association Study summary statistics from over 150,000 Japanese participants, we genetically predicted pre-infection LDL-C levels. Two-sample Mendelian randomization was used to assess the causal relationship between predicted pre-infection LDL-C levels and 28-day mortality. We analyzed PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) genotypes to determine if LDL-C clearance or production was the underlying mechanism. Multicenter ICUs in Japan. Genotyped septic shock patients ( n = 614). None. Predicted pre-infection LDL-C levels were much higher than directly measured LDL-C levels at the onset of septic shock (141 mg/dL vs. 40 mg/dL, p < 0.001). Two-sample Mendelian randomization revealed that high predicted pre-infection LDL-C levels were causally associated with increased septic shock 28-day mortality (hazard ratio, 2.78; p = 0.039). PCSK9 genetic variants that increase LDL-C clearance via the LDL receptor (genetically proxied PCSK9 inhibitor treatment) were associated with decreased mortality ( p = 0.003) while HMGCR genetic variants that decrease LDL-C production (genetically proxied statin treatment) were not associated with decreased septic shock mortality (indeed the opposite effect was observed, p = 0.039). The two main genetic variants driving the association between high predicted pre-infection LDL-C levels and increased mortality were in apolipoprotein genes ( ApoB100 -rs13306206 and ApoE -rs7412), apolipoproteins involved in LDL-C binding to the LDL receptor. Low LDL-C clearance explains the causal association between high genetically predicted pre-infection LDL-C levels and increased septic shock mortality. PCSK9 , ApoB , and ApoE variants were identified as causal, all related to the LDL receptor or its interaction with LDL-C. Enhancing LDL receptor-mediated clearance of pathogen lipid toxins may improve septic shock outcomes. Show less

Aberrant activation of fibroblast growth factor receptors (FGFRs) plays a critical role in tumorigenesis across multiple cancer types, driving the development of various FGFR inhibitors. Despite clinical advances, therapeutic efficacy remains limited by the emergence of drug resistance, primarily mediated by gatekeeper mutations in FGFRs. To overcome this challenge, we designed and synthesized a novel series of 7-(1-methyl-1 Show less

While a growing body of literature exists on initial word-to-meaning mapping and retrieval of fully lexicalized words, our understanding on the consolidation that occurs between these two stages remains limited. The current study investigated the neural correlates of retrieving newly learned word using oscillatory brain dynamics. Participants learned to associate new words with unknown objects and performed overt and covert naming tasks during the first and last days of a five-day training period. Behavioral results showed improved overt naming on Day 5 compared to Day 1. Selecting only words that were successfully produced in the overt naming task, we examined oscillatory activity associated with word retrieval while participants produced new words covertly, both pre- (Day 1) and post (Day 5) learning. The results showed a robust alpha (8-12 Hz) and lower beta (13-25 Hz) power decrease during covert naming after learning. We hypothesize that this alpha-beta power decrease indexes successful word retrieval following consolidation. Show less

Pharmacological modulation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) through dual GIP/GLP-1 receptor agonists, commonly used for diabetes and obesity, shows promise in reducing alcohol consumption. We applied drug-target Mendelian randomization (MR) using genetic variation at these loci to assess their long-term effects on problematic alcohol use (PAU), binge drinking, alcohol misuse classifications, liver health, and other substance use behaviors. Genetic proxies for lowered BMI, modeling the appetite-suppressing and weight-reducing effects of variants in both the GIPR and GLP1R loci ("GIPR/GLP1R"), were linked with reduced binge drinking in the primary (β = -0.44, 95% CI [-0.72, -0.15], P = 2.42 × 10 Show less

Colon cancer is reported as third most prevalent malignancy worldwide, while sericin being an antioxidant, is now used in biomedical applications due to its biochemical characteristics and has shown potential efficacy to treat colon cancer. Sericin was isolated by the degumming process followed by the characterization by using FTIR, UV, XRD, and SEM techniques to confirm the successful synthesis of SAgNPs and SChiAgNPs. The male Balb C mice were then divided into 13 groups. Group 1: Control, Group 2: DMH (20 mg/kg) (injected (IP) thrice a week for 14 weeks). Groups 3,4,5: Sericin (S) (100 mg/kg), Sericin silver nanoparticles (SAgNPs) (100 mg/kg), and Sericin Chitosan silver nanoparticles (SChiAgNPs) (100 mg/kg) were given orally for 14 weeks respectively. Groups 6,7,8,9 were considered as preventive groups and were given DMH (IP) + 5-FU (IP), DMH(IP) + S (orally), DMH (IP) + SAgNPs (orally), DMH (IP) + SChiAgNPs (orally) respectively for the period of 14 weeks Groups 10,11,12,13 were considered as treatment groups and were given 5-FU (5 mg/kg) (IP), (S) (100 mg/kg) (orally), (SAgNPs) (100 mg/kg) (orally), (SChiAgNPs) (100 mg/kg) (orally) for a period of first 7 weeks after 7 weeks of DMH administration (IP). After 14 weeks period study, blood samples and colon tissue were used for the analysis of biochemical markers i.e., CEA, CA19-9, TIMP-1, and IL-6, IL-8, IL-27, SOD, CAT, GR, GSH, GST, MDA and MMP-7 via ELISA and histopathological analysis. The UV absorption peaks obtained at 435 and 463 nm indicated the formation of SAgNPs and SChiAgNPs formation respectively. FTIR spectra peaks obtained, indicate NH stretching of primary and secondary amine group), (NH stretching of amine salt) (N=C=S stretching of thiocyanate compound), (CC stretching of alkene), (NO stretching of nitro compound), (SO stretching of sulfonyl chloride), (CN stretching of amine) and (C-O-O stretching) for sericin, SAgNPs, and SChiAgNPs, confirming, the presence of theses functional groups. The XRD pattern revealed that SAgNPs and SChiAgNPs had structure crystalline structures. EDX characterization peaks for SAgNPs indicated the presence of silver along with other elements including; calcium, oxygen carbon, while EDX characterization peaks for SChiAgNPs indicated the presence of silver along with other elements including; oxygen, carbon, sodium, phosphorus, Sulphur and chlorine. SEM analysis showed that SAgNPs are of spherical shape, while the SChiAgNPs displayed the rectangular shape. The results for biomarker analysis indicated significantly elevated levels of CEA, CA19-9, TIMP-1, IL-6, IL-8, IL-27, MDA, and MMP-7 in DMH treated group (p ≤ 0.001) which were decreased significantly in SChiAg(T) (p ≤ 0.001). In contrast, levels of SOD, GR, GSH, CAT and GST were reduced significantly in DMH treated group, which were increased significantly in SChiAg(T) (p ≤ 0.001). The histopathological analysis of proximal and distal parts of colon tissue of the DMH-treated group showed low-grade dysplasia (LGD), and high-grade dysplasia (HGD) while SChiAgNPs improved the histopathological changes induced by DMH. The findings suggest that Sericin Chitosan conjugated silver nanoparticles showed their efficacy against DMH-induced colon cancer, making a potential future in the anticancer research field. Show less

Molecular research for genetic variants underlying body weight (BW) provides crucial information for this important selected trait when developing productive poultry breeds, lines and crosses. We searched for molecular markers-single nucleotide polymorphisms (SNPs)-and candidate genes associated with this trait in 240 F Show less

Coronary artery disease (CAD) is showing a trend toward earlier onset. Premature CAD (PCAD) is clinically defined as CAD with onset before the age of 55 in males and 65 in females. Notably, many young patients subsequently hospitalized with acute cardiovascular events had undergone annual physical examinations before hospitalization, yet were not identified as high-risk by current risk stratification guidelines or traditional risk assessment tools. This study aims to investigate the diagnostic capacity of novel inflammatory biomarkers (including the monocyte-to-high-density lipoprotein cholesterol ratio (MHR), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), apolipoprotein B to apolipoprotein A-1 ratio (apoB/apoA-1), and low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (LDL-c/HDL-c)) for PCAD, thereby providing the evidence-based foundation for PCAD screening. A total of 1,012 young subjects (male<55 years, female<65 years) undergoing diagnostic coronary angiography (CAG) at the Third Affiliated Hospital of Zunyi Medical University (from January 2022 to February 2023) were retrospectively analyzed. We stratified 1,012 eligible participants into two groups: 521 angiographically confirmed PCAD cases and 491 controls with normal coronary arteries. Comprehensive baseline characteristics, including cardiovascular risk profiles and core laboratory-measured inflammatory markers, were recorded. The Mann-Whitney U test and binary logistic regression analysis were employed to assess the associations between inflammatory biomarkers and PCAD. The areas under the receiver operating characteristic (ROC) curves (AUCs) were calculated to evaluate their diagnostic performance for PCAD. The odds ratio (OR) values for MHR, NLR, LDL-c/HDL-c, and apoB/apoA-1 were 5.592 (95% CI: 2.886-7.836), 1.671 (95% CI: 1.500-1.861), 1.663 (95% CI: 1.419-1.950), and 6.268 (95% CI: 2.765-8.213), respectively (all The apoB/apoA-1 outperformed MHR, NLR, and LDL-c/HDL-c as an inflammatory biomarker in PCAD. Its diagnostic capacity was notably enhanced in ACS subgroups. A comprehensive model combining apoB/apoA-1 with traditional risk factors demonstrated exceptional accuracy. Incorporating this biomarker into routine screening protocols could significantly strengthen preventive strategies. Show less

Peritoneal metastasis (PM) in gastric cancer (GC) remains a formidable clinical challenge. Although exosomes are critical mediators of tumor-microenvironment communication, their mechanistic role in linking mesothelial-mesenchymal transition (MMT) to peritoneal dissemination remains poorly understood. This study elucidates a GC-derived exosomal microRNA (miRNA)-driven pathway that orchestrates peritoneal metastasis. Integrated exosomal miRNA sequencing and The Cancer Genome Atlas (TCGA) analysis identified miR-196a-5p as highly enriched in GC-derived exosomes. Functional assays, including in vitro co-culture experiments, and in vivo PM models, demonstrated that GC-derived exosomal miR-196a-5p directly induces MMT in peritoneal mesothelial cells (HMrSV5) and contributed to the formation of metastatic tumors. Mechanistically, miR-196a-5p binds the 3'-untranslated region (UTR) of F-box protein 45 (FBXO45), an E3 ubiquitin ligase, suppressing its expression and thereby stabilizing snail family transcriptional repressor 1 (Snai1)-a key transcription factor in epithelial-mesenchymal transition (EMT). RNA immunoprecipitation sequencing (RIP seq), dual-luciferase reporter assays, co-immunoprecipitation (CO-IP), and rescue experiments validated the miR-196a-5p/FBXO45/Snai1 axis. Notably, miR-196a-5p disrupts FBXO45-mediated Snai1 ubiquitination and degradation, promoting MMT-driven peritoneal niche remodeling and metastatic progression. These findings reveal a novel exosome-mediated mechanism underlying GC dissemination and highlight miR-196a-5p and FBXO45 as promising therapeutic targets for PM. Show less

Tropicoporus linteus (formerly Phellinus linteus) is a medicinal fungus used in China, Korea and Japan for its therapeutic properties. This study assessed the antioxidant capabilities of cold-water extract (xSHTM) from a T. linteus cultivar (SH02), and its terpenoid content. The potential of bioactive compounds in T. linteus as treatment against Alzheimer's disease (AD) was also explored with pharmacokinetic prediction via SwissADME and molecular docking. xSHTM is found to have high superoxide anion scavenging capability (expressed as trolox equivalents (35.10 ± 2.58) mmol/g), and its terpenoid content is expressed as 490.12 ± 31.51 mg LE/g of extract. SwissADME was used to screen all 68 of the compounds contained in T. linteus according to PubChem to identify their pharmacokinetic properties. Nine bioactive compounds are selected based on their gastrointestinal absorption, lipophilicity, water solubility, violation of Lipinski's rule, and the ability to cross the blood-brain barrier (BBB) to proceed with molecular docking against common AD treatment targets, acetylcholinesterase (AChE) and β-secretase (BACE1), which revealed 4 compounds with high binding affinity (expressed as Kcal/mol). Phellilin B and phellilane L showed binding affinities of -8.8 and -8.0, respectively, when docked against AChE, while phellinulin L, phellinulin K and phellilin B showed binding affinities of -7.4, -7.3 and -7.1 respectively when docked against BACE1. Show less

The present investigation set out to examine potential categories regarding depressive symptoms in frail senior individuals in China and to identify the contributing variables associated with each category, with the goal of informing more targeted mental health interventions. Data were drawn from the 2018 China Health and Retirement Longitudinal Survey, commonly called CHARLS, which comprised an overall cohort of 1083 qualifying respondents. A latent profile analysis (LPA) revealed the following four distinct depression profiles: a Low Depression-High Loneliness Group (38.4%), a Moderately Low Depression-High Suicidal Ideation Group (7.5%), a Moderately High Depression-High Negative Emotion Group (33.4%), and a High Depression-High Suicidal Ideation Group (20.7%). Ordered multi-categorical logistic regression and restricted cubic spline analyses revealed that age, gender, body pain, pension insurance, sleep duration, and frailty index were significant predictors of depression classification. These findings suggest that depressive symptoms among frail older individuals in China are markedly heterogeneous, highlighting the need to develop differentiated intervention strategies for distinct depression risk groups to promote their mental health. Show less

Hypothalamic pro-opiomelanocortin (POMC) neurons are classically viewed as mediators of satiety, acting in response to metabolic and hormonal cues and in opposition to Agouti-related protein (AgRP) neurons to maintain energy balance. This model, centered on the appetite-suppressant effects of the POMC-derived neuropeptide α-melanocyte-stimulating hormone (α-MSH) through its activation of melanocortin-4 receptors (MC4R), has shaped our understanding of feeding and body weight regulation for decades. However, recent discoveries have challenged and expanded this traditional view, revealing that POMC neurons are not a uniform population dedicated solely to satiety control. Single-cell transcriptomic analyses have revealed striking molecular heterogeneity, reflected in distinct anatomical distributions, receptor expression profiles, electrophysiological properties, and projection patterns - all supporting the idea of functional specialization within this neuronal population. In this review, we propose a conceptual framework that integrates POMC neuronal heterogeneity with the regulation of appetite, metabolic physiology, and behavior beyond feeding. We highlight emerging evidence showing that discrete POMC neuronal subpopulations respond to specific combinations of interoceptive and environmental cues to orchestrate diverse adaptive responses. This perspective underscores the developmental plasticity and functional versatility of POMC neurons, offering new insights into the mechanisms of obesity and potentially paving the way for novel targeted therapeutic strategies. Show less

AD is a neurodegenerative disorder and is associated with the presence of amyloid-β plaques and neurofibrillary tangles leading to net loss of neurons, which demonstrates an urgent unmet need to develop new human health therapies based on the fundamental mechanisms of oxidative stress and neuroinflammation. This work is a computational assessment of the potential use of neolupenol, a triterpenoid produced in Pluchea lanceolata, as a pharmacologically active compound that exerted its beneficial effect through the modulation of the Keap1-Nrf2 axis, one of the central regulators of the antioxidant response. Using an integrated approach that combined network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we identified neolupenol as a high-affinity Keap1-binding molecule capable of activating the Nrf2-mediated neuroprotective pathway. Virtual screening of 25 phytochemicals from Pluchea lanceolata (retrieved from the PubChem database) with customized filters revealed neolupenol as the top candidate, showing strong binding affinity (- 8.22 kcal/mol; Ki = 1.45 µM) toward the Keap1 Kelch domain (PDB ID: 2FLU). The docked complex demonstrated hydrogen bonds with VAL463 (2.17 Å), THR560, and ILE559, along with hydrophobic interactions involving CYS513, ALA366, and VAL514, which collectively stabilized the ligand at the Neh2-binding interface. Network pharmacology yielded 30 of such common targets of AD-neolupenol (e.g., GSK3B, CASP3, TNF, and BACE1), enriched in pathways such as amyloid processing, tau phosphorylation, oxidative stress response, and lipid metabolism (FDR-adjusted p < 0.0001). Complex stability was verified by MD simulations (100 ns): RMSD of the backbone 2.34-3.84 = 2.34 Å, unchanged radius of gyration (17.8-18.0 Å), and stable inter-hydrogen bonding. Residues VAL561, PHE577, and SER602 were found to have an interaction occupancy of > 70%, providing a basis of dynamic stability. The triterpenoid cavity appeared in neolupenol contributing to pleasant PK, the ability to herald the blood-brain barrier, and suboptimal toxicity. These results position neolupenol as a potent, multi-target neuroprotective agent that disrupts Keap1-Nrf2 interaction, promoting Nrf2 nuclear translocation and antioxidant gene activation. Future work warrants in vivo validation of its efficacy in mitigating AD pathology and clinical translation. Show less

Encephalocraniocutaneous lipomatosis (ECCL) is a rare somatic disorder caused by mutations in various genes of the RAS-MAPK pathway. Distinctive features of ECCL include nevus psiloliparus, scalp alopecia, ocular choristomas, and intracranial lipomas. ECCL is most commonly associated with FGFR1 and KRAS mutations. An NRAS variant causing ECCL has only been reported in the literature once. We present the case of a female infant with ECCL, harboring an NRAS somatic mutation, variant c.37G>C (p.Gly13Arg). This is the second reported case of an NRAS variant in ECCL and the first to document an associated intracranial lipoma. The report highlights the genotypic, clinical, and neuroradiological presentation of ECCL, its overlap and distinctions with other mosaic RASopathies, and reviews the recommended diagnostic approach when ECCL is suspected. Show less

As resident immune surveillance cells within the central nervous system (CNS), microglia exert pivotal biological functions in maintaining CNS homeostasis through dynamic modulation of their proliferative capacity, chemotactic motility, efferocytosis activity, and biphasic secretory mechanisms involving both neuromodulatory factors and pro-inflammatory mediators. These specialized macrophages not only serve as the first line of defense in innate immunity but also orchestrate the regulation of adaptive immune responses; whose functional status directly governs both the physiological integrity of neural circuits and the progression of pathological outcomes. Notably, in neurodegenerative disease models, microglial functional states exhibit pronounced heterogeneity and are tightly regulated by microenvironmental cues. Upon encountering sustained hyperactivation or functional impairment, these cells precipitate a cascade of deleterious events within the neurovascular unit. Building upon these pathophysiological mechanisms, targeted modulation of microglial polarization equilibrium has emerged as a pivotal research focus in developing innovative neuroprotective therapeutic strategies. This review systematically integrates empirical evidence derived from cutting-edge methodologies-including molecular imaging, single-cell multi-omics profiling, and conditional genetic ablation-to mechanistically dissect the dual regulatory roles of microglia in orchestrating neural homeostatic maintenance and driving pathological progression in neurological disorders. Show less

The role of mesenchymal stromal/stem cells (MSCs) in tumour development and progression remains a subject of debate. Previous studies have reported contradictory outcomes, possibly due to variations in experimental design and the use of xenograft models. Xenograft models limit interpretation and translation due to cross-species variability. To address these limitations, we employed an isogenic mouse model of spontaneous breast cancer (BC) to investigate the impact of murine MSCs on BC development and progression. MSCs isolated from FVB/N mouse adipose tissue (mASCs) were administered to female mice with palpable mammary tumours. Tumour volume and mass were assessed, and analysis of histopathological necrosis and gene expression was conducted on mammary (MT) and lung metastatic tumours (LT). No change in MT mass and volume was observed between mASC-treated and control mice. However, mASC treatment led to increased necrosis in LT but not in MT. Immunohistochemistry revealed that mASC-treated mice had fewer CD163+ anti-inflammatory macrophages in the LT but not in the MT. Tgf-β3, vegfr1, and cd105 were observed and downregulated in both MT and LT in mASC-treated mice. The downregulation of cd36 and tgf-β3 contributes to pro-tumourigenic activities, whereas the downregulation of vegfr1 and cd105 is associated with an anti-tumour effect. In the mASC treatment group, all cytokines tested for, except IL-27, were elevated. This study suggests that mASCs are anti-tumourigenic in pulmonary metastatic BC. Our findings emphasize the importance of considering the tumour microenvironment and employing relevant animal models when investigating the impact of MSCs on tumour progression. Show less

In this study, to achieve more effective blood sugar lowering and weight-loss effects, eight glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic peptide (GIP)/glucagon (GCG) triple receptor agonists were designed and synthesized. Their sixteen related conjugates were obtained through Cys alkylation and Lys esterification modifications with two fatty acid side chains, respectively. After chemical structure confirmation using high-resolution mass spectrometry and peptide mapping, in vitro and in vivo biological effects of TRA01-24 were assessed. The structure-activity relationship (SAR) data on the amino acids, fatty acids, linkers and biological effects in vitro and in vivo of TRA01-24 have been summarized. Furthermore, peptide-protein molecular docking elucidated the structural basis for the biased agonist activity of TRA22 at GLP-1R, characterized by strong GLP-1R activation but weak GCGR and GIPR activation. In conclusion, a lead compound with excellent efficacy in vitro and in vivo, TRA24, was screened, which had better in vivo efficacy than tirzepatide in both normal and db/db mice. Show less