Endometrial cancer (EC) is the most common gynecologic malignancy, yet effective therapies for advanced and recurrent disease remain limited. Sodium butyrate (NaB), a gut microbiota-derived short-chain fatty acid (SCFA) with known anticancer activity, remains poorly understood in EC. In this study, we investigated the anticancer effects of NaB in two EC cell lines, HEC1A and AN3CA. NaB dose-dependently inhibited cell viability, colony formation, and migration in both cell lines, with HEC1A cells exhibiting greater sensitivity. NaB differentially modulated epithelial-mesenchymal transition (EMT)-related markers between the two cell lines. NaB markedly induced apoptosis in HEC1A cells, whereas AN3CA cells showed resistance to apoptotic cell death, despite mitochondrial membrane depolarization occurring in both cell lines. Cell cycle analysis revealed subG1-accumulation in HEC1A cells and G1 phase arrest in AN3CA cells. Notably, NaB potently suppressed thymidylate synthase (TS) at both mRNA and protein levels in both cell lines, representing the first demonstration of TS suppression by NaB in EC. NaB also broadly reprogrammed pyrimidine metabolism by downregulating de novo synthesis enzymes while upregulating salvage pathway components. Taken together, these findings suggest that TS suppression and pyrimidine metabolic reprogramming are important components of the in vitro response of EC cells to NaB. These results provide mechanistic insight into the metabolic effects of NaB in EC and support further investigation of this pathway in pharmacologically relevant and locally applicable therapeutic contexts.
Osteosarcoma typically arises during adolescence, posing a significant challenge. Despite comprehensive treatment strategies encompassing surgery, radiation therapy, and chemotherapy, which can notably enhance long-term survival rates among osteosarcoma patients, the 5-year survival rate for metastatic cases remains discouragingly low. Consequently, early diagnosis and prompt intervention are paramount in improving the prognosis of patients afflicted with this condition. Metabolic reprogramming holds paramount significance in the initiation and progression of tumors. In this meticulous investigation, we devised a risk prediction model that encompasses seven pivotal nucleotide metabolism-related genes: MYC, MUC1, IMPDH1, SAMHD1, NUDT13, UCK2, and NUDT16. This model was formulated leveraging six advanced machine learning algorithms. The results demonstrated that the risk prediction model exhibited robust prognostic predictive capability. Notably, patients identified with a high-risk phenotype exhibited a significantly lower long-term survival rate, coupled with elevated expression of immunosuppressive genes, highlighting the importance of metabolic reprogramming in influencing both survival outcomes and immune status. The multivariate Cox regression analysis confirmed that our model serves as an independent prognostic indicator, significantly impacting the long-term prognosis of osteosarcoma patients. Subsequently, we developed and validated a nomogram, which accurately predicts 1-, 3-, and 5-year survival rates for these patients. Furthermore, we compared chemosensitivity between high- and low-risk groups, gaining valuable insights into potential therapeutic differences. In conclusion, this model demonstrates superior prognostic predictive capability and holds promise in guiding chemotherapy treatment strategies for osteosarcoma patients, thereby enhancing treatment outcomes.
Retinal ischemia-reperfusion (IR) elicits microglia-driven neuroinflammation and mitochondrial failure that led to retinal ganglion cell (RGCs) loss, yet effective disease-modifying therapies remain limited. Acarbose (ACA), an α-glucosidase inhibitor widely used for diabetes, has recently been recognized for its dual regulatory potential on immune metabolism and aging-associated neurodegeneration. Here, we demonstrate that intravitreal ACA administration attenuates retinal inflammation and improves RGCs survival following IR injury. Single-cell RNA sequencing revealed extensive inflammatory activation and metabolic reprogramming across the retina, characterized by enhanced nicotinamide adenine dinucleotide (NAD) catabolism, particularly in microglia. ACA treatment was associated with reversal of these alterations, replenished NAD levels, and restored mitochondrial integrity. Integrative proteomic and biochemical analyses identified pyruvate kinase, muscle-type 2 (Pkm2) as a candidate regulatory node affected by ACA. Intravitreal delivery of siPkm2 partially protected against IR injury, and co-administration with ACA produced an additive trend in neuroprotection. Mechanistically, ACA upregulated sirtuin 1 (Sirt1) and reduced Pkm2 acetylation at lysine 270 (K270), which was linked to pro-inflammatory microglial activation. Structure-based virtual screening further identified HY-113082, a small molecule targeting Pkm2-K270, which synergized with ACA to suppress inflammation and enhance retinal protection. Moreover, Pkm2fl/flCx3cr1-Cre mice conferred partial resistance to IR injury, but blunted the additional benefit of HY-113082 when combined with ACA, consistent with on-target engagement. Our findings support that ACA exerts retinal protection through the Sirt1-Pkm2-NAD axis, suggesting a metabolic checkpoint that integrates immune and mitochondrial regulation. This study provides mechanistic insight into ACA's dual immunometabolic and neuroprotective actions, holding promise for therapeutic insights into neuroinflammation.
Transposable elements (TEs) are significant drivers of genome evolution, influencing the genome dynamics of clonal fungal pathogens such as those in the Fusarium oxysporum species complex (FOSC) that cause Fusarium wilt in over 100 plant hosts. Among these, Tropical Race 4 (TR4), a clonal lineage within the FOSC, poses a severe threat to global banana production. However, the contribution of TEs to genome variation and functional traits in TR4 remains poorly understood. Here, we investigated Helitron-associated structural variations in a TR4 strain from Mozambique (M1). This revealed two large deletions in core chromosomes associated with an active FoHeli1 Helitron transposon. One of these (464 kb) disrupted 151 genes, including the entire fusaric acid (FA) biosynthetic gene cluster, consequently abolishing FA production, altering secondary metabolite profiles, and increasing sensitivity to exogenous FA. Despite these metabolic changes, infection assays using wild-type, mutant, knock-out, and complemented strains demonstrated that FA production is dispensable for TR4 virulence in banana. Our study highlights the role of FoHeli1 in modulating the genetic and metabolic landscape of TR4, underscoring the broader impact of TEs on fungal genome evolution and functional diversification, especially in clonal lineages.
Starch serves as a vital energy reserve in plants. During its biosynthesis, malto-oligosaccharides (MOS) are essential primers. One of the key pathways for MOS production involves plastidial α-glucan phosphorylase (PHS1/Pho1) and disproportionating enzyme (DPE1). However, the functional relationship between these enzymes is unclear. Here, we demonstrate that rice PHS1 and DPE1 assemble into a multimeric complex. Cryo-EM structures of the PHS1-DPE1 complex reveal an assembly mechanism and suggest a potential substrate tunnel. Biochemical assays show the complex dramatically enhances catalytic efficiency over individual enzymes. Single-molecule fluorescence resonance energy transfer (smFRET) visualizes conformational dynamics, enabling rapid substrate transfer between the enzymes. We further identify the unique L80 loop in PHS1 as a potential regulator. Its deletion reduces catalytic efficiency and prolongs conformational state lifetimes during substrate transfer, thereby reducing the production of longer MOSs. Our findings establish that the PHS1-DPE1 complex facilitates efficient MOS primer synthesis through efficient substrate transfer or diffusion between the two enzymes, providing mechanistic insight into a critical step of starch biosynthesis with agronomic implications.
Considering the devastating effect of salt stress on crops the present study investigates the regulatory role of exogenous silymarin in enhancing antioxidant defense system and morpho-physiology of Brassica napus under salt stress. Twenty-three-day-old rapeseed (Brassica napus cv. BARI Sarisha-18) plants were supplemented with a foliar spray of 250 ppm silymarin followed by two doses of NaCl, viz. 75 and 150 mM. This growing condition was maintained for the following 30 days. Salinity resulted in reduced biomass production, growth attributes, and relative water content of rapeseed plants with increased levels of Na+ ions, hydrogen peroxide (H2O2), lipid peroxidation, electrolyte leakage (EL), and proline (Pro) content. This led to oxidative damage by suppressing the activities of antioxidant enzymes. Silymarin reduced lipid peroxidation, H2O2, EL, and Pro content by 23, 15, 9, and 17%, respectively in 150 mM NaCl-stressed plants compared to their corresponding controls. The activities of glyoxalase, as well as antioxidant enzymes such as ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, glutathione reductase, catalase, glutathione peroxidase, glutathione S-transferase, peroxidase, lipoxygenase, and superoxide dismutase were also upregulated due to silymarin application. Findings from the current study suggest that salt-induced rapeseed plants exhibited reduced growth attributes alongside elevated oxidative stress markers, including both enzymatic and non-enzymatic antioxidants. Furthermore, it highlights the potential of silymarin as a potential growth regulator and antioxidant that can enhance salt tolerance in rapeseed plants by reducing the harmful effects of reactive oxygen species.
Medicago varia Martyn. exhibited enhanced cold tolerance that was correlated with coordinated adjustments in root xylem structure, modulation of cell wall components, and reprogramming of secondary metabolism, suggesting an integrated adaptive mechanism linking structure, composition, and metabolism. Alfalfa, as one of the most valuable perennial forage crops, is cultivated worldwide. However, its productivity is being threatened by extreme cold events. This study tried to understand the mechanisms of Medicago varia Martyn. (MvM) and Medicago sativa L. (MS) to combat cold climate through chemical, anatomical, spectral, and metabolic analysis. The results showed that MvM had higher content of neutral detergent soluble (74.60%) and soluble proteins (0.15 mg/g), yet lower content of cellulose (10.45%) as compared to MS. Additionally, fourier transform infrared spectroscopy analysis also confirmed differences in functional groups associated with cellulose, hemicellulose, and lignin between MS and MvM. The smaller diameter and higher density of vessel in MvM were consistent with anatomical traits predicted to enhance hydraulic safety under freeze-thaw stress. Metabolomic profiling identified 831 and 604 differentially accumulated metabolites in MvM roots at flowering and senescence stages, with significant enrichment in pathways related to isoflavonoid biosynthesis, arginine/proline metabolism, and tryptophan metabolism. Key metabolites, such as Calceolarioside B, hydroxytyrosol, and Medicarpin, were markedly up-regulated in MvM. Hierarchical clustering highlighted species-specific accumulation of phenylpropanoids and alkaloids in MvM. These findings suggested that the enhanced cold tolerance of MvM might involve in coordinated structural adjustments in root xylem, modulation of cell wall composition, and reprogramming of secondary metabolism. This study provided new insights into the integrative mechanisms of cold adaptation in alfalfa and supported the development of cold-resistant varieties for cultivation in high-latitude regions.
Off-site fattening of Tibetan sheep is a key strategy to mitigate the effects of high-altitude grassland degradation and winter forage scarcity, promoting sustainable development in plateau animal husbandry. However, transport stress (TS) presents a significant challenge to realizing its benefits. The mechanism by which TS affects the health of Tibetan sheep by regulating rumen microbial and serum metabolite rhythmic changes remains unclear. This study selected six healthy male Tibetan sheep, aged seven months and of comparable body weight, for the transport experiment. Blood and rumen fluid samples were collected at four-hour intervals during 24-hour periods pre-transport (CON) and post-transport (TS) for serum indicators, serum metabolome, and rumen microbiome analyses. The results showed that TS significantly increased serum concentrations of cortisol (COR), melatonin (MT), lipopolysaccharide-binding protein (LBP), serum amyloid A (SAA), and non-esterified fatty acid (NEFA), while significantly decreasing glucose (GLU), total antioxidant capacity (T-AOC), and glutathione peroxidase (GPx) (P < 0.05). Furthermore, the circadian rhythms of COR, MT, LBP, SAA, NEFA, and GPx were significantly disrupted (ADJ.P < 0.05). TS reduced the proportion of rumen microbial circadian rhythms from 3.46% to 1.99%, with Prevotella, Butyrivibrio, and Ruminococcus losing their circadian rhythmicity in the TS phase (ADJ.P < 0.05). Additionally, TS decreased the proportion of circadian rhythm-regulated serum metabolites from 51.74% to 29.51%. In the TS phase, rhythmically regulated metabolites, including 3',5'-cyclic AMP, fumarate, dopamine, glutathione, and angiotensin (1-7), were enriched in pathways such as oxidative phosphorylation, retinol metabolism, and tryptophan metabolism. Multi-omics analyses demonstrated significant correlations between Ruminococcus and energy metabolites (malic acid, 3',5'-cyclic AMP, fumarate, NEFA), and between Butyrivibrio, Anaeroplasma, and inflammatory/antioxidant markers (glutathione, SAA, LBP). In conclusion, this study reveals that TS induces a homeostatic imbalance in Tibetan sheep by disrupting the circadian rhythms of both the rumen microbiota and host metabolism. These findings provide a theoretical basis and molecular targets for developing interventions to alleviate TS in livestock.
Allogeneic hematopoietic stem cell transplantation is an established curative therapy for many hematological diseases, but graft-versus-host disease remains a major cause of morbidity and mortality. Tacrolimus, a calcineurin inhibitor, is widely used for prophylaxis because it suppresses T-cell activation. However, its clinical use is complicated by a narrow therapeutic window and marked pharmacokinetic variability. Therapeutic drug monitoring based on trough whole-blood concentrations is routinely used to guide dosing, but this approach has limitations, particularly in transplantation recipients who experience rapid physiological and hematological changes. This review summarizes recent insights into determinants of tacrolimus pharmacology in hematopoietic stem cell transplantation and discusses emerging perspectives for individualized dosing. Tacrolimus exerts its immunosuppressive effects by forming a complex with FK506-binding proteins that inhibits calcineurin and suppresses activation of nuclear factor of activated T cells. Beyond this canonical mechanism, interactions with FK506-binding proteins influence the distribution of tacrolimus within blood cells. Because tacrolimus strongly divides into erythrocytes and leukocytes, whole-blood concentrations reflect systemic exposure and drug binding within circulating blood components. In recipients of hematopoietic stem cell transplantation, marked fluctuations in blood cell counts during conditioning therapy and hematopoietic recovery can alter this distribution, potentially causing changes in concentrations without corresponding changes in pharmacologically active exposure. Genetic variation in drug-metabolizing enzymes further contributes to variability in tacrolimus pharmacokinetics. In particular, polymorphisms in the gene encoding cytochrome P450 3A5 influence tacrolimus metabolism and may affect early dose requirements during the post-transplant period. Additionally, temporal fluctuations in tacrolimus exposure within individual patients are increasingly recognized as clinically relevant. Measures that capture the proportion of time during which concentrations remain within the therapeutic range provide a useful indicator of exposure stability. Tacrolimus therapy after hematopoietic stem cell transplantation is influenced by molecular pharmacology, blood cell-dependent distribution, genetic determinants of metabolism, and temporal variability in drug exposure. Integrating these factors may improve understanding of therapeutic drug monitoring and promote more individualized strategies to maintain stable immunosuppression and improve transplant outcomes.
Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.
Climate-driven heat stress disrupts metabolic homeostasis in livestock, yet the molecular mechanisms underlying adaptive responses remain poorly understood. Here, we integrated newly generated plasma metabolomic data from 111 heat-stressed cows with previously published whole-genome sequencing datasets from the same animals, identifying 30 metabolic markers and 27 copy number variations (CNVs) associated with 25 candidate genes involved in the regulation of these metabolites. Notably, a CNV hotspot encompassing CIITA emerged as a key pleiotropic locus strongly associated with acylcarnitine levels, body weight, and rectal temperature. Heat exposure suppressed CIITA expression in skeletal muscle, correlating with impaired myogenic development. We demonstrate that CIITA overexpression in vitro induces coordinated remodeling of cell cycle-related gene expression and partially alleviates heat-induced inhibition of myoblast proliferation. Moreover, CIITA overexpression markedly suppresses long-chain fatty acid β-oxidation and mitochondrial electron transport activity, accompanied by reduced adenosine triphosphate production, suggesting that CIITA may limit metabolic heat generation by constraining mitochondrial metabolic flux. Overall, these findings position CIITA as a central integrative regulator linking immune function, energy metabolism, and cell proliferation during bovine adaptation to heat stress, and highlight a potential genetic target for improving thermotolerance in livestock.
High-altitude pulmonary hypertension (HAPH), classified as Group 3 pulmonary hypertension, is a significant threat to the health of high-altitude populations. The scarcity of studies in diverse populations has become a research bottleneck, limiting diagnostic and therapeutic advances. In this first proteomic study focusing on the eastern Pamir Plateau (Kizilsu Kyrgyz Autonomous Prefecture, Xinjiang), plasma samples were analyzed using data-independent acquisition (DIA) mass spectrometry. Differential expression analysis in parallel with weighted gene co-expression network analysis was performed to identify core pathways and hub proteins, and gene set enrichment analysis was used for quality assessment. Integrative analysis of the two methods was used to select candidates for validation by enzyme-linked immunosorbent assay (ELISA) in an independent cohort. Among > 1400 detected proteins, 123 were differentially expressed and 45 were identified as hub proteins significantly associated with HAPH. Extracellular matrix (ECM) remodeling- and angiogenesis-related proteins were upregulated, whereas proteins related to enzyme activity, iron metabolism, and inflammatory responses were downregulated. Integrative analysis identified 23 core proteins, with ECM-receptor interaction and TGF-β/Smad signaling identified as key pathways. ELISA confirmed that plasma levels of THBS2, LOXL1, and POSTN were significantly elevated in patients with HAPH (P < 0.05). Among these, THBS2 and LOXL1 levels were positively correlated with mPAP (THBS2: r = 0.389, 95% CI: 0.034-0.657, P = 0.033; LOXL1: r = 0.457, 95% CI: 0.115-0.701, P = 0.011). ECM remodeling is closely associated with HAPH in this indigenous high-altitude population. THBS2, LOXL1, and POSTN show potential as biomarkers and therapeutic targets.
The human lipidome comprises numerous complex lipids, dysregulation of which can contribute to the pathogenesis of a wide range of diseases. Despite the high heritability of parts of the lipidome, the genetic architecture of many circulating lipid species and their structure remains mostly unknown. Thus, we perform genome-wide association studies on 970 lipid species and 267 fatty acid composite measures using samples from the population-based Rhineland Study (n = 6096). We validate our findings using corresponding data from two other independent cohorts, including FinnGen (n = 7266) and EPIC-Potsdam (n = 1188). Out of 217 lead genomic loci, we find 136 to be novel, such as FDFT1. Using mendelian randomization and individual-level gene expression data, we identify 43 possible causal associations between candidate genes and corresponding lipid species, including FDFT1 - diacylglycerol (16:0/18:0). Our findings provide new insights into the intricate genetic underpinnings of lipid metabolism, which may facilitate risk stratification and discovery of new therapeutic targets.
Myasthenia Gravis (MG) is divided into ocular (OMG) and generalized (GMG) subtypes. While clinical diagnosis is well-established, understanding the underlying biochemical mechanisms and metabolic shifts during disease progression remains challenging; untargeted metabolomics offers a novel perspective to explore these systemic alterations. To characterize the serum metabolic landscape of MG patients and identify potential metabolic signatures associated with disease subtypes (OMG and GMG) via untargeted metabolomics. 91 participants (41 GMG, 22 OMG, 28 healthy controls [HC]) were enrolled. Fasting serum samples were analyzed by LC-MS/MS. Multivariate analyses (PCA, PLS-DA/OPLS-DA), differential metabolite screening (VIP > 1.0, p < 0.05), and KEGG pathway enrichment were performed. HC and MG groups showed distinct metabolic profiles. MG had 515 (175 up, 340 down) and 368 (146 up, 222 down) differential metabolites in positive/negative ion modes, respectively. Key perturbed pathways included glycerophospholipid, sphingolipid metabolism, and unsaturated fatty acid biosynthesis. Ten representative metabolites (e.g., ubiquinone, cortisol) differed significantly among groups; clustering analysis revealed distinct metabolite abundance trajectories across HC, OMG, and GMG. MG is associated with notable systemic metabolic dysregulation, particularly in lipid-related pathways. Rather than serving as immediate diagnostic tools, these integrative metabolic signatures provide a crucial biochemical framework for understanding disease pathogenesis and offer valuable clues for future hypothesis-driven research and prospective validation.
The gut microbiome supports digestion, immunity, and metabolism; its imbalance (dysbiosis) drives inflammation and metabolic dysfunction, contributing to chronic diseases such as diabetes, cardiovascular disease, inflammatory bowel disease, and autoimmune disorders. Medicinal plants provide a wide range of phytochemicals (such as polyphenols, flavonoids, alkaloids, saponins), which reach the colon and undergo two-sided interactions with microbes in the gut, acting as potential microbiome modulators and substrates of biotransformation into bioactive metabolites. This structured narrative review synthesises evidence from peer-reviewed studies indexed in PubMed, Scopus, and Web of Science over the last 10 years on the role of medicinal plants in microbiome-mediated chronic disease modulation. This literature is organised into three mechanistic axes: (i) perturbations, defined here as measurable shifts in microbial diversity or taxonomic composition relative to a baseline or healthy reference state, together with beneficial taxa enrichment; (ii) alterations in microbial metabolite output, especially short-chain fatty acids (SCFAs) and other immunometabolic mediators; and (iii) downstream host metabolic and immune signalling. Rather than broad descriptive summaries, the literature is organised using an axis-based mechanistic framework, highlighting key translational constraints such as botanical heterogeneity, dose/formulation variability, and inconsistent microbiome endpoint standardisation, that must be addressed to strengthen human evidence and clinical relevance. Illustrative microbiome-mediated processes involve botanicals such as turmeric (curcumin), ginseng (ginsenosides), and green tea (catechins), though evidence strength varies by study design. Future progress requires standardised phytochemical characterisation, microbiome-stratified trials, and integration of multi-omics with artificial intelligence analytics to enhance mechanistic insight, identify responders, and enable personalised plant-based microbiome therapies.
TkMYC2 mediates jasmonate-induced drought resistance and rubber biosynthesis simultaneously in Taraxacum kok-saghyz. Taraxacum kok-saghyz (T. kok-saghyz) is an important natural rubber-producing plant, yet its cultivation is often limited by drought stress, and the regulatory mechanisms underlying rubber biosynthesis and laticifer development remain incompletely understood. This study focused on TkMYC2, a core transcription factor in the jasmonate (JA) signaling pathway. Through homologous and heterologous genetic transformation, we systematically elucidated its dual functions in conferring drought tolerance and driving rubber biosynthesis. TkMYC2 expression was induced by both drought and methyl jasmonate (MeJA). Overexpression of TkMYC2 significantly enhanced the tolerance of transgenic plants to osmotic and drought stress by activating the antioxidant system (SOD, POD, CAT), maintaining ROS homeostasis, and reducing membrane lipid peroxidation. Using yeast two-hybrid and bimolecular fluorescence complementation assays, we demonstrated a direct physical interaction between TkMYC2 and TkJAZ11, a key repressor in the JA pathway. Phenotypic analyses showed that TkMYC2 overexpression promoted root thickening, laticifer development, and natural rubber accumulation, functionally supporting the hypothesis that rubber biosynthesis drives laticifer development. In summary, TkMYC2 acts as a critical molecular hub concurrently regulating drought stress response and rubber biosynthesis, providing new insights into jasmonate-mediated coordination of stress resilience and secondary metabolism, and offering a genetic resource for molecular breeding of T. kok-saghyz with enhanced yield and stress tolerance.
Regular exercise promotes health through multiple mechanisms, with DNA methylation serving as a key epigenetic modification involved in the molecular regulation induced by exercise. Peripheral blood, as an accessible tissue, is commonly used to study exercise-induced DNA methylation changes. This systematic review aims to synthesize evidence from human exercise intervention studies on the effects of exercise on peripheral blood DNA methylation and related epigenetic markers, and to evaluate their potential as biomarkers of exercise efficacy. The study protocol was registered in PROSPERO (CRD420251069398). A systematic search was conducted in Pubmed, Web of Science, Cochrane Library, Embase and Scopus databases from database inception through 29 May 2025 for all English-language studies. Eligible studies were included. Risk of bias of randomized controlled trials were assessed using the Cochrane collaboration's tool (version 5.1.0) and quasi-experimental studies were assessed using the JBI Critical Appraisal Checklists for Quasi-Experimental Studies. The results were summarized using narrative synthesis. Twenty-nine studies were included, covering both acute and long-term exercise interventions. Acute exercise induced minor and mostly statistically nonsignificant changes in peripheral blood DNA methylation, whereas long-term exercise elicited significant methylation remodeling in genes related to metabolism, inflammation, and immune function. Exercise dose (frequency, intensity, and duration) and population characteristics influenced the magnitude and scope of methylation responses. Peripheral blood DNA methylation provides robust evidence for exercise-mediated systemic epigenetic regulation and shows promise as a biomarker for exercise adaptation and intervention effects. Future research should optimize intervention designs and methodological standards to deepen understanding of exercise epigenetic mechanisms.
Wild isolates of Toxoplasma gondii may exhibit different virulence characteristics and host adaptability compared with those of laboratory strains. In this study, we isolated a novel rodent-derived T. gondii strain, denoted TgRodGz1, and evaluated its pathogenic features. TgRodGz1 was isolated from T. gondii-positive wild rodents in Guangdong Province and compared with the RH and Me49 strains in C57BL/6 mice. Virulence and intestinal injury were evaluated by survival analysis, brain cyst quantification, histopathology, tight junction assessment and qPCR. Gut microbiota and metabolic alterations were analyzed by metagenomic sequencing and LC-MS/MS-based metabolomics. Compared with theT. gondii laboratory strains RH and Me49, TgRodGz1 was associated with more pronounced intestinal injury, including villus atrophy, barrier disruption and downregulation of tight junction proteins and increased gut permeability and inflammation. Metagenomic analysis revealed significant intestinal flora dysbiosis, with a marked reduction in beneficial bacteria and expansion of pathogenic bacteria. Metabolomic analysis revealed suppression of arachidonic acid (ARA) metabolism during TgRodGz1 infection. Supplementation with ARA did not directly inhibit parasite growth but significantly alleviated intestinal lesions, reduced brain cyst burden and attenuated inflammatory responses, including microglial activation. These findings suggest that TgRodGz1 represents a distinct T. gondii genotype associated with pronounced intestinal pathology and suggest that ARA supplementation may alleviate intestinal and neuroinflammatory changes associated with T. gondii infection.
The China-ASEAN regional medical procurement platform was launched in early 2025. However, the scope and operational mechanisms of the platform remain unclear. This study aims to assess medicine prices and affordability in China and ASEAN countries, explore potential implementation challenges of the platform, provide policy suggestions. We selected commonly used medicines from four ATC categories (alimentary tract and metabolism, cardiovascular system, anti-infective for systemic use, nervous system). Prices were standardized to WHO defined-daily-dose (DDD) prices and converted into median price ratio (MPR) using Management Sciences for Health (MSH) international reference prices (IRP). All prices data were collected from official public sources and converted to US dollars using the official 2024 annual average exchange rate. Affordability was estimated the number of days' statutory gross daily minimum wages required to purchase one DDD, with wage data obtained from the International Labor Organization (ILO). Descriptive statistics were performed. A total of 68 medicines were included, with 68, 68, 60, and 59 available in China, Thailand, Indonesia, and the Philippines, respectively. Median MPRs were 0.88 (IQR:0.46-3.49), 0.97 (IQR:0.50-2.20), 1.69 (IQR:0.77-3.16), 1.86(IQR:0.72-5.03), respectively, and 45.6%, 45.6%, 61.7%, and 67.8% of medicines were priced above the IRPs. Prices varied widely across and within countries. For cardiovascular medicines, median MPRs exceeded the IRPs in China 1.72(IQR:0.53-6.30), Indonesia 1.79(IQR:0.78-2.80), the Philippines 2.85(IQR:1.31-6.43), while Thailand achieved a lower price of 0.78(IQR:0.31-1.37). The overall affordability was higher in China, Indonesia and Thailand, where one DDD of medicine required less than 6% of a day's wage, with median values of 4.8% (IQR:2.5%-19.3%), 5.1% (IQR:2.3%-9.6%), and 3.6% (IQR:1.8%-8.1%), respectively, compared with 14.0% (IQR:5.4%-37.7%) in the Philippines. Sensitivity analysis excluding extreme affordability values yielded similar results. Our findings suggest that understanding cross-country disparities in medicine prices and affordability may help inform the design of future regional purchasing strategies. Realizing the benefits of such joint procurement will require strong political commitment to establish a legal framework, enhance price transparency, harmonize regulations, and strengthen supply chains to ensure the platform's effectiveness and sustainability.
Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism presenting with acute liver failure, cirrhosis, or neurologic involvement. Liver transplantation (LT) is the definitive treatment; however, data remain limited, particularly from regions reliant on living donor LT (LDLT). We retrospectively analyzed a prospectively collected transplant database, identifying all patients (≥ 14 years) who underwent LT for WD between January 2001 and December 2023. Data on demographics, LT indications, disease characteristics, pre-transplant therapy, complications, and outcomes were collected. Survival was assessed using Kaplan-Meier methods, and neurologic outcomes from clinical documentation. Forty-one patients underwent LT for WD (median age: 23 years; 51.2% female). Ascites was present in 68.4%, encephalopathy in 32.4%, and hepatocellular carcinoma in 5.1%. Acute liver failure was the initial presentation in 17.9%. LDLT comprised 53.7%. Acute cellular rejection occurred in 29.7% but was manageable; no patient required re-transplantation. Neurologic involvement was present in 17.1%, with 71% improving post-LT. One-, five-, and ten-year survival rates were 94%, 94%, and 82%. LT for WD yields excellent long-term survival. Neurologic improvement occurred in most Neuro-Wilson patients, supporting LT even in neurologically affected cases. LDLT plays a crucial role in regions with limited deceased donors.