👤 Hong Tang

Sepsis is associated with high morbidity and high mortality and has strongly motivated intense studies into its mechanisms. Antibiotics, aimed to eradicate bacteria, have some impact on the immune system due to anti-inflammatory properties. Tigecycline, an antibiotic of the glycylcycline class, is commonly used for severe infections. This study aimed to investigate tigecycline's mechanism on the inflammatory response of sepsis to find new targets for sepsis treatment. The objective included (i) to observe the changes in inflammatory factors in LPS (lipopolysaccharide) induced septic mice after tigecycline administration, (ii) to detect the effect of tigecycline on macrophages NF-κB (nuclear factor kappa B) signalling. For LPS-induced sepsis in mice and intervention with tigecycline, mice were first injected with tigecycline (6.5 mg/kg) via tail vein followed by LPS (15 mg/kg). Luminex analysis was performed on 16 mediators. NF-κB signalling pathway antibody chip detected the expression of target sites in macrophages of the LPS group and tigecycline + LPS group. Tigecycline has inhibitory effects on LPS-induced inflammatory response in septic mice, decreasing the concentrations of IL (interleukin)-6, IL-27, TNF-α (tumour necrosis factor-α), TNF RII, IFN-γ (interferon-gamma), CCL5/RANTES (CC Motif Chemokine Ligand) while increasing IL-6Rα, IL-10, and TWEAK (TNF-related weak inducer of apoptosis). Tigecycline downregulated phosphorylation levels of key sites JNK (c-Jun N-terminal kinase)1/2/3, p-p65 (s468) and p-p105/p50 (s907) in NF-κB signalling. Tigecycline may inhibit the excessive immune response induced by LPS in sepsis, which may cause a potential protective effect on the host through immune regulation. Show less

In recent years, the discovery of IL-12 family cytokines, which includes IL-12, IL-23, IL-27, IL-35, and IL-39, whose biological functions directly or indirectly affect various autoimmune diseases. In autoimmune diseases, IL-12 family cytokines are aberrantly expressed to varying degrees. These cytokines utilize shared subunits to influence T-cell activation and differentiation, thereby regulating the balance of T-cell subsets, which profoundly impacts the onset and progression of autoimmune diseases. In such conditions, IL-12 family members are aberrantly expressed to varying degrees. By exploring their immunomodulatory functions, researchers have identified varying therapeutic potentials for each member. This review examines the physiological functions of the major IL-12 family members and their interactions, discusses their roles in several autoimmune diseases, and summarizes the progress of clinical studies involving monoclonal antibodies targeting IL-12 and IL-23 subunits currently available for treatment. Show less

Neurodevelopmental disorders (NDDs) exhibit complex genotype-phenotype associations that frequently result in inconclusive variant interpretations, contributing to suboptimal diagnostic yields (~ 40%). Koolen-de Vries syndrome (KdVS), an autosomal dominant NDD caused by KANSL1 haploinsufficiency, exemplifies this diagnostic challenge with its multisystem manifestations and lack of systematic genotype-phenotype associations. To address this gap, we constructed a comprehensive KdVS genotype-phenotype repository by systematically integrating all molecularly confirmed cases from global literature. Comprehensive phenotypic analysis revealed that core KdVS features include developmental delay/intellectual disability, characteristic craniofacial dysmorphism, hypotonia, and multisystem abnormalities. Phenotypic association analysis identified 249 significant correlations, demonstrating that KdVS clinical manifestations are highly interconnected rather than representing isolated features, such as the association between strabismus and hydrocephalus (OR = 14.26). Application of this repository to screen a Chinese rare disease cohort identified 53 KANSL1 variants. Among these, one de novo nonsense variant (NM₀₀₁₁₉₃₄₆₆.2: c.902T > G, p.Leu301Ter) was classified as pathogenic in a Chinese boy with classic KdVS features. The remaining 52 variants were categorized as variants of uncertain significance (VUS), approximately half of which were absent from gnomAD databases. Each VUS was comprehensively annotated with detailed clinical profiles to facilitate phenotype-driven reinterpretation. In conclusion, this study establishes KdVS as a highly interconnected multisystem disorder and demonstrates that deep phenotypic association analysis enhanced genetic diagnosis. This disease-specific repository approach provides a scalable framework for improving molecular diagnostics across rare NDDs. Show less

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) is a neuronal system-specific transmembrane protein that is highly expressed in the brains of patients with Alzheimer's disease (AD), and our previous findings showed that LINGO-1 antagonism can improve cognitive function and protect hippocampal GABAergic interneurons in AD model mice. However, the specific mechanism underlying these effects is not clear. In this study, an adeno-associated virus (AAV) was used to directly interfere with hippocampal LINGO-1 in vivo, and LINGO-1 antagonists, cannabinoid type 1 receptor (CB1R) agonists, and CB1R antagonists were used to treat mouse hippocampal neurons (HT22 neurons) in vitro. We found that overexpressing hippocampal LINGO-1 in normal young mice impaired spatial learning and memory and reduced hippocampal CB1R protein levels, whereas silencing hippocampal LINGO-1 in AD model mice had the opposite effect. Additionally, antagonizing LINGO-1 increased CB1R/tyrosine kinase receptor B (TrkB) signalling and rescued CB1R- rich cholecystokinin-GABAergic (CCK-GABAergic) interneurons in HT22 neurons transduced with an APP/PS1-expressing virus. Competitive inhibition of LINGO-1 and CB1R was observed, and antagonizing LINGO-1 reversed the changes in HT22 neurons caused by the inhibition of CB1R, such as the decreases in the protein levels of doublecortin (DCX), TrkB, and phosphorylated TrkB (p-TrkB). These findings provide an important scientific basis for further exploration of the mechanism by which LINGO-1 regulates cognitive function and hippocampal GABAergic interneurons in AD model mice. Show less

Psychological empowerment is a critical factor for employee work well-being, particularly within high-stress professions such as policing. However, experiences of empowerment among individuals are not uniform. This study aims to identify distinct profiles of psychological empowerment among police officers and to examine their associations with perceived coworker support and work well-being. A person-centered approach was adopted. Data were collected from 505 Chinese police officers. Latent Profile Analysis (LPA) was employed to identify subgroups based on their psychological empowerment patterns. The analysis revealed two distinct profiles: a "Globally Disempowered" profile and a "Globally Empowered" profile. Perceived emotional support from coworkers was a significant predictor of profile membership, where higher levels of support increased the likelihood of belonging to the empowered group. Furthermore, officers in the high empowerment profile reported significantly greater work well-being compared to those in the low empowerment profile. The findings underscore the heterogeneity in psychological empowerment experiences within the policing context. They emphasize the pivotal role of fostering emotional peer support as a means to enhance officers' psychological empowerment and, consequently, their work well-being. Practical implications for organizational interventions are discussed. Show less

As university libraries transform into "Learning Commons," peer collaborative learning has become increasingly common. However, the complexity of its effectiveness and its underlying mechanisms remain underexplored. This study systematically investigates the relationship between peer collaborative learning and academic engagement. Integrating both person-centered and variable-centered approaches, the study employs Latent Profile Analysis (LPA) to identify heterogeneous groups of students based on their collaboration patterns and engagement levels, challenging the conventional wisdom that "collaboration is always beneficial." Concurrently, based on Self-Determination Theory (SDT), a mediation model is constructed to test the bridging role of basic psychological needs (competence and relatedness). Using a questionnaire survey, data were collected from 820 university students to measure their quality of peer collaborative learning, basic psychological need satisfaction, and academic engagement. The SPSS PROCESS macro was used for mediation analysis, and Mplus was used for Latent Profile Analysis. (1) LPA identified four heterogeneous profiles: "High-Achieving All-Rounders" (26.1%), "Balanced Developers" (25.5%), "Inefficient Socializers" (27.6%), and "Indifferent and Unengaged" (20.9%). Notably, the largest group, "Inefficient Socializers," exhibited a distinct pattern of "high emotional support, low academic engagement." (2) Basic psychological needs played a significant partial mediating role in the relationship between the quality of peer collaborative learning and academic engagement, with the mediating effect accounting for 52.3% of the total effect. (3) The moderating effect of academic discipline was not significant. The study confirms that while high-quality peer collaboration can promote academic engagement by satisfying students' psychological needs, not all forms of collaboration are beneficial. The discovery of the "Inefficient Socializers"-the largest profile-is the core contribution of this research. It exposes the existence of a "pseudo-collaboration" trap, where social interaction detached from task-oriented goals may actually inhibit academic engagement. This finding offers crucial practical implications for the design of university learning spaces (shifting from "promoting co-presence" to "fostering effective interaction") and for academic advising (enabling the precise identification and intervention for different student types). Show less

Perimenopause is a critical turning point in women's life cycle, and the issue of sleep disturbance during perimenopause not only affects individual health, but also has profound implications for family functioning, socioeconomic status, and public health policies. Therefore, this study aims to explore different potential profiles of sleep quality in perimenopausal women in the community and analyze the influencing factors of different profiles. A cross-sectional study was conducted from July 2024 to December 2024, and a total of 281 perimenopausal women in the community were recruited from 4 communities in Bengbu by convenience sampling. The participants completed the pittsburgh sleep quality index (PSQI), and self-rating anxiety scale (SAS), self-rating depression scale (SDS) and simplified coping style questionnaire (SCSQ). Latent profile analysis(LPA) was employed to identify latent profiles of sleep quality of perimenopausal women in the community. The predictors of sleep quality in different latent profiles were assessed via multinomial logistic regression analysis. One-way ANOVA, chi-square test or Fisher exact test, and the Kruskal-Walis test were used to compare the PSQI scores of perimenopausal women in the community under different latent profile characteristics. The mean age of 281 perimenopausal women was 50.09 ± 5.08 years, and the prevalence of sleep disorders was 31.3%. The sleep quality of perimenopausal women in community could be divided into three different latent profiles: good sleep quality group (68.7%), falling sleep and maintenance difficulty group (24.2%), and poor sleep quality with sleep disorder group (7.1%). Taking the good sleep quality group as the reference group, drinking history (OR = 2.061), chronic disease history (OR = 2.154), spouse's health status (OR = 1.871) and anxiety (OR = 4.390) were the risk factors to predict the difficulty in falling asleep and maintaining sleep in community perimenopausal women (P < 0.05). Spouse's health status (OR = 2.139) and anxiety (OR = 19.029) were the risk factors for poor sleep quality and sleep disorders in community perimenopausal women (P < 0.05). There are three qualitatively different potential profile categories of sleep quality in perimenopausal women in the community, and drinking history, chronic disease, poor spouse health and anxiety have predictive effects on their profile categories. In the future, community nursing staff can take targeted interventions according to different categories of sleep quality in perimenopausal women to improve sleep quality and level of health promotion. Show less

To determine whether lipoprotein(a) [Lp(a)] and cumulative Lp(a) (CumLp(a)) are associated with adverse outcomes in patients with acute myocardial infarction (AMI). This cohort study included 2,634 hospitalized patients diagnosed with AMI who underwent coronary angiography at Zhongda Hospital, Southeast University, from July 2013, to December 2021. The main outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as cardiovascular (CV) death, non-fatal myocardial infarction, non-fatal stroke, or unplanned revascularization—occurring singly or in combination. We used Cox proportional hazards models, with subgroup and sensitivity analyses, restricted cubic spline (RCS) modeling, and threshold-effect assessment to evaluate the relationships between Lp(a), CumLp(a), and prognosis. Across a median 55.2-month follow-up, 907 participants (34.40%) experienced a MACCE, 342 (13.00%) patients had CV death, 177 (6.70%) patients had non-fatal MI, 202 (7.70%) patients had non-fatal stroke, 399 (15.10%) patients underwent unplanned revascularization, and all-cause death occurred in 547 (20.80%) patients. Multivariable Cox regression models demonstrated a significantly increased risk of MACCE, CV death, non-fatal MI, and non-fatal stroke in both the higher Lp(a) and higher CumLp(a) groups compared with the lower groups (HRs for Lp(a): 1.652, 2.157, 3.455, and 1.930; HRs for CumLp(a): 1.697, 1.675, 3.759, and 2.032), and every one-unit rise in CumLp(a), the risk of MACCE, CV death, non-fatal MI and non-fatal stroke increased by 1.3%, 1.4%, 1.9% and 1.2%, respectively. The majority of subgroup and sensitivity checks consistently supported a stable link between Lp(a)/CumLp(a) and the risks of MACCE, CV death, non-fatal MI, and stroke. Analyses using RCS and threshold models revealed that Log Higher levels of Lp(a) and CumLp(a) are linked to a greater risk of poor outcomes among patients with AMI as the index event, highlighting their potential value for risk stratification and guiding clinical decision-making. The online version contains supplementary material available at 10.1186/s12944-025-02800-6. Show less

Low physical activity (LPA) is associated with cardiovascular and cerebrovascular pathologies. This study aimed to assess the prevalence of several noncommunicable diseases relating to LPA. Using the 2021 Global Burden of Disease data set, we modelled LPA-related disease burdens across 204 countries and territories, quantifying mortality counts, age-standardised mortality rates, and disability-adjusted life years (DALYs) for five noncommunicable diseases. We conducted multivariable stratification analyses to assess variations by gender, age, and sociodemographic index (SDI) quintiles. We used age-period-cohort modelling to project burden trajectories, while applying counterfactual decomposition frameworks to delineate synergistic interactions between LPA and risk factors. We found that LPA accounted for 555 101 related deaths globally in 2021 across the five studied pathologies, mostly among individuals aged 60-94 years. Association between LPA-related disease burden and SDI followed a U-shaped distribution across regions and diseases. Among individuals aged 60-89 years, LPA-related deaths were significantly higher in women than in men, indicating a disproportionate burden on elderly females. Ischaemic heart disease (IHD) trends stabilised in low- and middle-SDI regions but declined significantly in high-SDI regions, underscoring global health disparities. From 2007 to 2011, LPA DALYs and mortality risk ratios for IHD, stroke, and lower extremity peripheral arterial disease declined from >1 to <1, whereas diabetes mellitus exhibited an opposite trend, highlighting LPA's persistent and significant impact on diabetes-related morbidity. Demographic shifts and epidemiological transitions were primary drivers of LPA-related disease burden across five pathologies. In high-SDI regions, epidemiological changes predominated, whereas population growth was a key factor in low- and middle-SDI regions. Synergistic interaction of these factors with LPA is projected to substantially amplify future disease burden. Physical activity should be increased among elderly women to address health risks associated with LPA. Likewise, urgent public health interventions are needed for LPA-related diabetes. As IHD burden rises in low- and middle-SDI regions, vascular disease care strategies require optimisation. Moreover, high-SDI regions should strengthen nationwide physical activity promotion, while low- and middle-SDI areas must enhance healthcare infrastructure and manage population growth to reduce LPA-related disease burdens. Show less

Acquired renal cysts (ARC) are associated with kidney function decline, necessitating novel dietary pattern (DP) analyses in large cohorts. This UK Biobank prospective cohort study (2006-2010) included participants with ≥2 dietary records, excluding those with severe kidney damage. The constructed comprehensive dietary pattern integration (CDPI) utilized reduced rank regression (RRR) and latent profile analysis (LPA). ARC cases (ICD-10: N28.1) were assessed via Cox regression for risk and dose-response, with NMR metabolites examined as mediators. Among 119,709 participants (median follow-up: 10.57 years), 850 ARC cases were identified. Lipid-rich and hyperglycemic diets increased ARC risk [e.g., HRs for G1.DP1: 1.080 (1.024, 1.139); G1.DP2: 1.144 (1.048, 1.249)], while micronutrient-rich diets showed weak protective effects [G4.DP1: 0.943 (0.892, 0.998)]. LPA confirmed RRR findings, and 7/251 NMR metabolites had significant mediating effects. Diets high in fat (cheese, butter, pizza) and sugar (chocolate, sugary drinks) elevated ARC risk, whereas micronutrient- and fiber-rich diets (vegetables, fruit, lean poultry, nuts, eggs) were protective. Key mediators included branched-chain amino acids, IGF-1, and RBC distribution width. Show less

Evidence has linked self-reported sedentary behaviors with dementia and cognitive impairment; however, the underlying mechanisms remain poorly understood. We investigated the associations of accelerometer-measured sedentary behavior patterns with gray matter atrophy patterns in rural-dwelling older adults, while taking into account the manner in which sedentary time is accrued (in short or long bouts). This community-based study involved 911 dementia-free older adults (age ≥ 60 years, 59% women) who participated in both ActiGraph and brain MRI substudies within MIND-China (2018-2020). Sedentary behavior parameters (total sedentary time, mean sedentary bout duration, and sedentary breaks) were recorded with accelerometers. Regional gray matter volumes (GMV) were measured using voxel-based morphometry (VBM) methods. Data were analyzed using the general linear regression models, restricted cubic spline curves, and VBM analysis. There was an inverted U-shaped association between daily sedentary time and GMV in temporal, cingulate, and medial temporal cortex, while longer mean sedentary bout duration was linearly related to decreased GMV in total, frontal, temporal, insula, cingulate, and medial temporal cortex. Greater daily time spent in light or moderate-to-vigorous physical activity (LPA and MVPA) was correlated with larger insula GMV. The VBM analysis suggested that prolonged daily total sedentary time and mean sedentary bout duration were significantly associated with smaller GMV in extensive brain regions, especially in thalamus and insula. In conclusion, gray matter atrophy associated with sedentary behavior in older adults is characterized by reduced GMV in global, frontal, temporal, medial temporal, and cingulate cortex, especially in the insula and thalamus regions. Show less

Third-generation EGFR tyrosine kinase inhibitors (TKI) have revolutionized the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). However, acquired resistance remains a significant challenge. This study investigates the metabolic mechanisms driving third-generation EGFR-TKI resistance. We conducted plasma metabolomics analysis on 216 longitudinal samples from 186 patients with NSCLC enrolled in the clinical trial of rezivertinib (NCT03386955). Additionally, multiomics profiling of rezivertinib-resistant cell lines, functional in vitro experiments, and single-cell RNA sequencing analyses of 215 patients with NSCLC were integrated to reveal underlying mechanisms. Nonresponder patients exhibited elevated glycerophospholipids and dysregulated lysophospholipid (LPL) metabolism. Unsupervised clustering identified two patient subgroups, with cluster 1 (characterized by high LPL levels) associated with poorer survival (P = 0.022). A metabolite-based predictive model achieved robust performance [AUC: 0.7762 (training) and 0.7485 (test)]. Longitudinal analyses demonstrated LPLs and lysophosphatidic acid (LPA) accumulation during the resistance process. Integrated multiomics analyses highlighted epithelial-mesenchymal transition and glycerophospholipid reprogramming in rezivertinib-resistant cells. Functional assays confirmed that LPA promoted cell migration and invasion and attenuated the efficacy of third-generation EGFR-TKI, whereas disruption of the LPA-LPA receptor signaling axis reversed LPA-mediated resistance. Single-cell RNA sequencing identified an LPA-secreting malignant subset (cluster c4), characterized by enhanced epithelial-mesenchymal transition activation and extensive microenvironmental cross-talk through Wnt, TGF-β, and extracellular matrix signals. Our study highlights the pivotal role of LPA-mediated signaling and metabolic reprogramming in third-generation EGFR-TKI resistance. Targeting LPA production or its downstream pathways may offer novel therapeutic strategies to overcome resistance. This study provides critical metabolic insights for managing EGFR-mutant NSCLC. Show less

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, with a range of manifestations, such as hepatic steatosis. Our previous study showed that Kaili Sour Soup (KSS) significantly attenuated hepatic steatosis in rats. This study explored the main components of KSS and the mechanisms by which it exerts its protective effects against NAFLD. Twenty-four 6-week-old male Sprague-Dowley (SD) rats were randomly assigned to three treatments: feeding a normal standard diet, a high-fat diet, or a high-fat diet plus gavage KSS. The effects of KSS treatment on hepatic lipid accumulation were assessed using biochemical, histological, and molecular experiments. The amounts of KSS ingredients were measured using biochemical assays. Network pharmacology analyses were performed to identify the hub genes of KSS targets and enriched pathways. CCK-8 assay was used to determine the effect of free fatty acids (FFA), lycopene, and estrogen on HepG2 viability. Quantitative Real-Time polymerase chain reaction (qRT-PCR) and Western blot assays were performed to determine the effect of KSS or lycopene on estrogen signaling and expression of lipid metabolism-related molecules. Statistical analyses were performed using GraphPad Prism and SPSS. KSS alleviated fat deposition in rat liver tissue and affected the expression of hepatic lipid synthesis, catabolism, and oxidative molecules. Lycopene was identified as the ingredient with the highest amount in KSS. Network pharmacology analyses showed that the hub genes were enriched in the estrogen signaling pathway. Cellular experiments showed that lycopene increased the expression of Estrogen Receptor α (ERα), Carnitine palmitoyltransferase 1 A ( KSS ameliorated abnormal lipid metabolism in patients with NAFLD. Lycopene was the major component of KSS, and it affected estrogen signaling and the expression of lipid metabolism molecules. In short, both KSS and LYC could change lipid metabolism by lowering lipid accumulation and raising lipolysis. Show less

Long-persistent luminescence (LPL) materials have applications from safety signage to bioimaging; however, existing organic LPL (OLPL) systems do not align with human scotopic vision, which is sensitive to blue light. We present a strategy to blueshift the emissions in binary OLPL systems by upconverting the charge-transfer (CT) to a locally excited (LE) singlet state. Through rigorous steady-state and time-resolved photoluminescence spectroscopy and wavelength-resolved thermoluminescence measurements, we provide the direct experimental evidence for this upconversion in OLPL systems featuring small energy offsets between the lowest-energy CT and LE singlet states. These systems exhibited strong room temperature LPL, particularly when extrinsic electron traps are added. Importantly, the developed OLPL system achieved Class A (ISO 17398) LPL, matching well with human scotopic vision. The findings not only elucidate the role of small energy offsets in modulating LPL but also provide potential avenues for enhancing the efficiency and applicability of OLPL materials. Show less

The effects of starvation and re-feeding on Jian carp (Cyprinus carpio var. Jian) remain incompletely understood. This study investigated changes in growth performance, liver antioxidant capacity, intestinal morphology, fatty acid profile, and expression of genes related to lipid metabolism. Juvenile C. carpio var. Jian, with initial body weight of 29.50 ± 2.00 g, were reared in 15 cylindrical culture barrels (200L) at a stocking density of 10 fish per barrel. These fish were subjected to five feeding regimes: a continuous feeding group (control group, treatment A), complete fasting (treatment B), 1, 2, and 3 days starvation within one week, followed by re-feeding 6 days (treatment C), 5 days (treatment D), and 4 days (treatment E). The results indicated significantly lower growth performance in C. carpio var. Jian in treatments B and E compared to the control and treatment C (P < 0.05). Intestinal length (only 627 ± 13.14 μm in treatment B) was significantly reduced, and an increase in vacuoles was observed in C. carpio var. Jian with the prolonged starvation. Antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were significantly (P < 0.05) improved in treatment C when compared with treatments B, D and E.. In contrast, malondialdehyde (MDA) value was lowest (12.62 ± 0.60 nmol/mL) in treatment B. Furthermore, continuous starvation significantly decreased the total lipid and fatty acids contents in the muscle (P < 0.05). Compared with the control group, the reduction of total lipid and fatty acids contents was 31.53 % and 4.57 %, respectively, particularly affecting n3PUFA and n6PUFA. However, after one-day re-feeding, these contents resumed. Lipid metabolism is closely related to fish health, while in the current study, the genes related to lipid metabolism including lipoprotein lipase (LPL), 6-phosphogluconate dehydrogenase (G6PD), and peroxisome proliferator-activated receptor alpha (PPARα) did not differ significantly in treatment C compared to the control group (P > 0.05). In contrast, expressions in treatments B, D, and E were significantly reduced (P < 0.05). Taken together, prolonged starvation (>one day per week) not only affected the growth, which may further disrupt the intestinal structure, weaken antioxidant capacity, but also attenuate lipid deposition. Show less

To establish an The 6-8-week-old C57BL/6N female mice and BALB/c female mice were used as the donor and recipient mice of the aGVHD model, respectively. Bone marrow transplantation (BMT) mouse model ( An The adipogenic differentiation capacity of MSCs is inhibited by aGVHD mouse serum. Show less

To investigate the effects and underlying mechanism of ionizing radiation on the adipogenic of mesenchymal stem cells (MSCs). Mouse MSCs were cultured in vitro and treated with 2 Gy and 6 Gy radiation with Bulk RNA-seq suggested that ionizing radiation promotes adipogenic differentiation of MSCs and up-regulation of oxidative stress-related genes and pathways. The results of Oil Red O staining and qPCR showed that ionizing radiation promoted the adipogenesis of MSCs, with high expression of Ionizing radiation promotes adipogenesis of MSCs in mice, and oxidative stress pathway participates in this effect, blocking Show less

In acute lymphoblastic leukaemia (ALL), cytoplasmic CD3 (cCD3) is a defining marker for T-lineage, and CD19 plus additional B-cell marker(s) for B-lineage. We identified 23 ALL cases in which the lymphoblasts expressed both cCD3 and CD19, making lineage assignment challenging. These cases represented approximately 10% of cCD3+ ALL and expressed a median of two additional B-cell markers other than CD19, including CD79a (76%), CD22 (22%), PAX5 (57%) and CD10 (44%). Two cases were mixed for T/B-lineage ALL, both positive for BCR::ABL1 rearrangement. In the remaining 21 cases, IgH and/or IgK/L rearrangement were detected in 1 of 19 cases and TRG/TRB in 13 of 21 (62%) cases. Other T-ALL characteristic genetic abnormalities included NOTCH1 mutations (7/21, 33%), PHF6 (6/21, 29%), JAK3 (4/21, 19%), PICALM::MLLT10, TLX3::BCL11B, TRB::HOXA13, SPTAN1::NUP214 and deletion of CDKN2A/CDKN2B. In the 16 cases that demonstrated a T-ALL genetic profile, CD22 (2/16, 13%) was found to be a more specific additional B-lineage marker than CD79a (11/15, 73%), PAX5 (8/14, 57%) or CD10 (7/16, 44%). Our data suggest that mixed T/B-ALL is extremely rare, with most cases associated with BCR::ABL1 and blast crisis of myeloproliferative neoplasms. The majority of cases represent early T-precursor lymphoblastic leukaemia expressing aberrant B-cell markers. We also showed persistent CD19 expression in relapsed/residual disease (16/17, 94%), suggesting its potential role as a therapeutic target and as a marker for detection of residual/relapse disease in these ALL cases. Show less

To determine whether insulin controls hepatic de novo lipogenesis (DNL) through an HCF-1-dependent modulation of ChREBP that is distinct from the canonical SREBP1c pathway. AML-12 mouse hepatocytes were subjected to 10 μg/mL insulin and 25 mM glucose for 6 h. IRβ or HCF-1 was knocked down with lentiviral shRNA (≈80 % efficiency). Lipid droplets were quantified by Nile-Red staining; mRNA and protein levels were measured by RT-qPCR, Western blot, immunofluorescence and RNA-seq. Co-immunoprecipitation was used to test complex formation. Insulin reduced lipid accumulation and suppressed ChREBP protein and its nuclear localization in AML-12 hepatocytes without altering SREBP1c. Knock-down of IRβ or HCF-1 abolished insulin-mediated ChREBP suppression, increased lipid droplets and up-regulated lipogenic genes. HCF-1 co-immunoprecipitated with IRβ, indicating formation of an insulin-responsive IRβ/HCF-1 complex that restrains ChREBP-driven lipogenesis. We identify an IRβ/HCF-1/ChREBP regulatory node in hepatocytes that can repress lipogenic genes independently of SREBP1c. The axis constitutes a testable target for understanding selective insulin action on hepatic lipid metabolism and for future in-vivo studies of fatty-liver disease. Show less

Polygonum multiflorum Thunb., a plant rich in diverse bioactive constituents, has been widely used in East Asia in functional foods and medicine to ameliorate inflammatory disorders through its multi-component activity. The effectiveness of these botanical extracts is thought to involve complex interactions among diverse constituents; however, the molecular basis of such interactions remains insufficiently understood. In this study, we explored the anti-inflammatory properties of the ethanol extract of Polygonum multiflorum (PME) through a combination of chemical profiling and computational analysis. PME was found to reduce the production of nitric oxide, inducible nitric oxide synthase, and interleukin-6 in LPS-stimulated RAW 264.7 macrophages. Using HS-SPME-GC-MS in conjunction with network pharmacology, we identified 32 volatile constituents, among which five core compounds were predicted to be associated with three inflammation-related targets: ESR1, FASN, and NR1H3. Dual-ligand molecular docking and molecular dynamics simulations suggested that the sequence of ligand binding may influence the stability and interaction patterns of protein-ligand complexes, offering insights into possible mechanisms of synergy and antagonism mediated by key residues such as ARG394 in ESR1. Overall, these findings contribute to a better understanding of how binding order and structural context may shape constituent-target interactions, providing a basis for the further development of multi-component natural product strategies against inflammation. This study underscores the relevance of incorporating multi-ligand dynamics into natural product research and presents an integrated experimental-computational framework to investigate the cooperative or competitive behaviors of functional food constituents, thereby supporting the rational design of optimized multi-target formulations. Show less

Cholesterol-loaded macrophage foam cells are a key feature of atherosclerotic plaques. Oxysterol-binding protein-related protein 2 (ORP2) facilitates the transport of cholesterol from lysosomes to the plasma membrane in cultured cell lines. However, the role of ORP2 in macrophages and its involvement in atherosclerosis remain unclear. In this study, we found ORP2 expression was reduced in atherosclerotic vessels and in macrophages exposed to oxidized LDL (ox-LDL). Myeloid-specific human ORP2 overexpression (hORP2 Show less

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms, with a particular focus on mitochondrial function and apoptosis. Differential expression analyses were performed across three datasets-The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma (LIHC), GSE36076, and GSE95698-to identify overlapping differentially expressed genes (DEGs). A prognostic risk model was then constructed. Cysteine/serine-rich nuclear protein 1 ( A six-gene prognostic model was established, comprising downregulated genes ( Show less

Osteosarcoma (OS) is highly malignant and easily prone to lung metastasis. The mechanisms of lung metastasis in OS remain unclear. The single-cell RNA sequencing (scRNA-seq) samples in this study included six primary osteosarcoma samples (published in-house data), two lung metastasis samples (GSE152048), and four normal bone tissue samples (GSE169396). To identify potential targets for metastasis, bulk RNA sequencing data from four primary tumors and four lung metastases (in-house data) were also analyzed. scRNA-seq identified five tumor cell subpopulations. CytoTRACE and lung metastasis scores indicated that the C1 subpopulation was most closely associated with lung metastasis. By intersecting lung metastasis-related genes identified via hdWGCNA analysis with differentially expressed genes from bulk RNA sequencing, Show less

Biliary atresia (BA) is a severe pediatric liver disease in which progressive liver fibrosis (LF) significantly affects the prognosis. Epithelial-mesenchymal transition (EMT) is considered a key factor in the development and progression of LF. This study aimed to investigate the role and mechanism of PEAK1-related kinase activating pseudokinase 1 (PRAG1) in the EMT-related LF process in BA. We found that the expression of PRAG1 was significantly elevated in both patients with BA and the bile duct ligation (BDL) model, and predominantly localized on biliary epithelial cells. Also, the expression of PRAG1 positively correlated with the cholangiocyte marker KRT19 and the mesenchymal marker ACTA2, and increased with the severity of fibrosis. In human intrahepatic biliary epithelial cells (HIBECs), PRAG1 promoted the expression of mesenchymal markers (VIM and ACTA2) and fibrosis markers (COL1A1 and FN1), inhibited the expression of the epithelial marker CDH1, and enhanced cell proliferation. The key factor of EMT-SNAIL1 presented increased expression and delayed degradation after overexpression of PRAG1. Moreover, we identified PRAG1 could bind with F-box protein 11 (FBXO11) and subsequently reversed FBXO11-mediated inhibition of SNAIL1 protein expression, cell proliferation, and the EMT phenotype. This study provides the potential role of PRAG1 in the mechanisms underlying the LF progression of BA. Show less

Previous researches have indicated the oncogenic effect of circCOL1A2 in several cancers, such as tongue squamous cell carcinoma, gastric cancer, and colorectal cancer. Regrettably, the functions and mechanisms of circCOL1A2 in lung cancer, a disease with the highest global incidence and mortality rates and with 85 % of cases classified as non-small cell lung cancer (NSCLC), remain largely unexplored. Hsa_circ₀₀₈₁₁₁₁ (circCOL1A2) was identified from GSE236879 dataset of Gene Expression Omnibus (GEO) database. Its expression was validated in 37 paired samples of cancerous and adjacent normal tissues from NSCLC patients, as well as in cell lines. The function of hsa_circ₀₀₈₁₁₁₁ was analyzed using CCK-8, Matrigel transwell, Western blot, and immunofluorescence assays in vitro, and by conducting subcutaneous xenograft experiments in mouse. The underlying mechanisms were explored using bioinformatics analysis, RNA pull-down experiments, and RNA immunoprecipitation. High expression of hsa_circ₀₀₈₁₁₁₁ was observed in NSCLC tissues and cell lines. This was positively correlated with the TNM stage and lymph node metastasis of NSCLC patients. Hsa_circ₀₀₈₁₁₁₁ overexpression promoted the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of NSCLC cells. Conversely, its downregulation showed the opposite effects. In vivo studies revealed that silencing hsa_circ₀₀₈₁₁₁₁ inhibited tumor growth, EMT, and MMP9 expression in tumor tissues. Mechanically, hsa_circ₀₀₈₁₁₁₁ enhanced Slug mRNA stability by interacting with the RNA-binding protein IGF2BP2. Taken together, hsa_circ₀₀₈₁₁₁₁ is an oncogenic circRNA that promotes NSCLC malignancy by regulating IGF2BP2-mediated Slug mRNA stability. Hsa_circ₀₀₈₁₁₁₁ has the potential to be a diagnostic and therapeutic target for NSCLC. Show less

Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells (HSCs) into CAFs in liver metastasis of gastric adenocarcinoma (GAC). POU6F2 expression was examined by real-time PCR, Western blot and immunohistochemical staining. The functional roles of POU6F2 in GAC liver metastasis were investigated both cellular experiments in vitro and in vivo using a mouse model of subcutaneous splenic injection. ChIP and ELISA assays were used to explore the underlying molecular mechanism of POU6F2 in liver metastasis of GAC. Here we reported that POU6F2 was upregulated in GAC tissue with liver metastasis, which predicted poor early liver metastasis. Upregulating POU6F2 promoted EMT, invasion and migration of GAC cells in vitro, and the liver metastasis of GAC cells in vivo. Mechanic investigation further revealed that upregulating POU6F2 promoted the invasion and metastasis of GAC by transcriptional upregulation of EMT-inducer SNAI1, and promoting the conversion of HSCs into CAFs dependent on transcriptional upregulation of IGF2-induced activation of PI3K/AKT signaling. Our findings uncover a novel dual mechanism by which POU6F2 promotes liver metastasis of GAC. Show less

The functional and pharmacological significance of dopamine receptor D4 (DRD4) in psychiatric and neurological disorders is well elucidated. However, the roles of DRD4 in colorectal cancer (CRC) remain unclear. This study observes a significant upregulation of DRD4 expression in clinical samples, which is negatively correlated with patient prognosis. In vitro, overexpression of DRD4 causes a constitutive activation of β-Arrestin2/PP2A/AKT independent of dopamine. Interestingly, this classical signaling pathway is not associated with the phenotype of DRD4-promoted migration and invasion in CRC cells. Instead, DRD4 interacts with transforming growth factor beta receptors (TGFBR1 and TGFBR2) to activate Smad2 phosphorylation and promote Smad2/Smad4 complex nucleus translocation. Then, SNAI1 and JAG1 are transcriptionally activated to induce epithelial-mesenchymal transition and enhance the metastatic potential of CRC. Notably, the COOH-terminal domain is identified as the key intracellular region for the pro-metastatic roles of DRD4. Furthermore, treatment with a TGFBR1 inhibitor combined with a BMP inhibitor effectively counteracts the pro-metastatic effects induced by DRD4 both in vitro and in vivo. In conclusion, these findings uncover an unconventional role for DRD4 beyond its classic function as a neurotransmitter receptor. The intracellular signaling of DRD4 interacting with TGFBR1 can be targeted pharmacologically for CRC therapy. Show less

Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could serve as a rapid and cost-effective biomarker for assessing the risk of cisplatin-induced acute kidney injury. The functional conservation from human to mouse and widespread signals of positive natural selection suggest that both SVs likely influence local adaptation, phenotypic diversity, and disease susceptibility across diverse human populations. Show less

Autoantibodies hold promise for diagnosing lung cancer. However, their effectiveness in early-stage detection needs improvement. In this study, we investigated novel IgG and IgM autoantibodies for detecting early-stage lung adenocarcinoma (Early-LUAD) by employing a multi-step approach, including Human Proteome Microarray (HuProtTM) discovery, focused microarray verification, and ELISA validation, on 1246 individuals consisting of 634 patients with Early-LUAD (stage 0-I), 280 patients with benign lung disease (BLD), and 332 normal healthy controls (NHCs). HuProtTM selected 417 IgG/IgM candidates, and focused microarray further verified 55 significantly elevated IgG/IgM autoantibodies targeting 32 tumor-associated antigens in Early-LUAD compared to BLD/NHC/BLD+NHC. A novel panel of 10 autoantibodies (ELAVL4-IgM, GDA-IgM, GIMAP4-IgM, GIMAP4-IgG, MGMT-IgM, UCHL1-IgM, DCTPP1-IgM, KCMF1-IgM, UCHL1-IgG, and WWP2-IgM) demonstrated a sensitivity of 70.5% and a specificity of 77.0% or 80.0% for distinguishing Early-LUAD from BLD or NHC in ELISA validation. Positive predictive values for distinguishing Early-LUAD from BLD with nodules ≤ 8 mm, 9-20 mm, and > 20 mm significantly increased from 47.27%, 52.00%, and 62.90% [low-dose computed tomography (LDCT) alone] to 79.17%, 71.13%, and 87.88% (10-autoantibody panel combined with LDCT), respectively. The combined risk score (CRS), based on the 10-autoantibody panel, sex, and imaging maximum diameter, effectively stratified the risk for Early-LUAD. Individuals with 10 ≤ CRS ≤ 25 and CRS > 25 indicated a higher risk of Early-LUAD compared to the reference (CRS < 10), with adjusted odds ratios of 5.28 [95% confidence interval (CI): 3.18-8.76] and 9.05 (95% CI: 5.40-15.15), respectively. This novel panel of IgG and IgM autoantibodies offers a complementary approach to LDCT in distinguishing Early-LUAD from benign nodules. Show less