👤 Y Zhai

Substance Use Disorders (SUD) have escalated into a global public health crisis, with their core pathology encompassing not only physiological dependence and a heightened risk of relapse, but also profound social cognitive impairments caused by chronic substance abuse. These impairments constitute a major barrier to rehabilitation yet remain largely overlooked in current treatment frameworks. This review develops and substantiates an innovative theoretical framework centered on the "Exercise-Irisin-Social Brain" axis. We propose a core pathway hypothesis: regular exercise can induce the release of the myokine irisin from skeletal muscle, which then enters the bloodstream and crosses the blood-brain barrier to act on the prefrontal cortex, which is the central hub of social cognition and executive function. Through potential mechanisms including the upregulation of brain-derived neurotrophic factor and the suppression of neuroinflammation, irisin may contribute to the repair of the executive function network that underlies higher-order social cognition, thereby improving social cognitive abilities and ultimately providing a supportive foundation for the reconstruction of social functioning in individuals with SUD. This new paradigm not only provides a testable biological pathway for understanding how exercise may repair the addicted brain, but also transcends the limitations of traditional models that focus primarily on withdrawal and relapse, by elevating rehabilitation goals to emphasize the restoration of social functioning. Show less

This study aimed to elucidate the sedative-hypnotic effects of a stem-derived bioactive fraction from Syringa oblata Lindl. (ZDX) and to reveal its underlying mechanisms, thereby providing a theoretical and practical basis for the development of new sleep aid drugs. ZDX was prepared by optimizing the extraction and purification procedures. Using UPLC-Q-TOF-MS, the prototype compounds absorbed into the brain of insomnia mice were analyzed, and 15 bioactive compounds were identified or predicted, including Dihydrocubebin, (-)-Cubebin, Isoguamarol, and others. Its efficacy and mechanisms were investigated using network pharmacology, transcriptomics, metabolomics, and molecular docking, complemented by in vivo pharmacodynamic and molecular analyses. In an insomnia mouse model, ZDX significantly increased body weight, reduced sleep latency, and prolonged total sleep duration, while alleviating anxiety and depression-like behaviors and improving histopathological damage in the hippocampus and hypothalamus, showing significant sedative-hypnotic effects. Mechanistically, ZDX modulated key genes and proteins involved in the cAMP signaling pathway, enhanced superoxide dismutase activity, reduced malondialdehyde levels, decreased inflammatory cytokines (IL-6, IL-1β, and TNF-α), and restored neurotransmitter homeostasis in the brain. Collectively, ZDX exerts sedative-hypnotic effects, at least in part, by activating the cAMP/PKA-CREB-BDNF axis and coordinately regulating neurotransmission, oxidative stress, and inflammation. Show less

Traumatic spinal cord injury (SCI) induces neuronal apoptosis and neuroinflammation, which exacerbate secondary damage and hinder functional recovery. Efficient clearance of apoptotic cells and modulation of the inflammatory microenvironment of spinal cord are essential for promoting tissue repair. This study aimed to investigate whether Midkine (MDK), a heparin-binding growth factor, facilitates functional recovery after SCI and explores the underlying mechanisms. A rat model of moderate SCI was established using Allen's impact method. Lentiviral vectors were used to overexpress MDK in the spinal cord. Behavioral assessments, including BBB score and gait analysis, were performed to evaluate motor function recovery. Motor evoked potentials (MEPs) serve as a neurophysiological tool for evaluating the functional integrity of the corticospinal tract. In vivo and in vitro experiments were conducted to assess microglial efferocytosis and elucidate the underlying molecular mechanisms. Transcriptomic bioinformatic analysis suggests that SCI is characterized by pronounced accumulation of apoptotic cells and robust neuroinflammatory responses, whereas single-cell analysis implicates MDK as a key contributor to neurorepair after SCI. MDK expression is dynamically regulated following SCI, with an early upregulation followed by a gradual decline over time, its location predominantly observed around microglial cells. Functionally, MDK overexpression significantly enhances motor recovery after SCI, accompanied by reduced neuroinflammation, decreased neuronal apoptosis, and improved neuroprotection. Mechanistically, MDK promotes microglial efferocytosis both in vivo and in vitro, activates the AKT/mTOR signaling pathway, upregulates BDNF and LRP-1 expression, and facilitates microglial polarization toward an anti-inflammatory M2 phenotype. Notably, inhibition of LRP-1 with receptor-associated protein (RAP) abolished the efferocytic and neuroprotective effects of recombinant MDK, highlighting LRP-1 as a key mediator of MDK's actions in microglia. Our study unveils the MDK/LRP-1/efferocytosis axis as a previously unrecognized therapeutic target for SCI. By orchestrating apoptotic cell clearance, dampening neuroinflammation, and fostering neuroprotection, this axis critically shapes the post-injury microenvironment to facilitate recovery. These findings suggest that MDK-centered therapy may represent a strategy for spinal cord repair, with LRP-1 modulation offering precise control over microglial responses. Show less

This study aims to establish a standardized mouse model of Alzheimer's disease(AD) with spleen-kidney deficiency and stagnant phlegm syndrome(AD-SKDSP) based on TCM theory, so as to provide a disease-syndrome combined model that aligns with the TCM diagnosis and treatment paradigm of "disease-syndrome-formula-efficacy" for modern research on AD prevention and treatment. Four-month-old male double-transgenic APP/PS1 mice were used as AD model animals. A standardized animal model of AD-SKDSP was constructed by high-sugar and high-fat diet feeding combined with ice-water bath and tail-clamping stimulation. The mice were randomly divided into an AD model group, an AD-SKDSP group, an AD Zhinao Capsule group, and a normal control group consisting of same-litter and age-matched male C57BL/6J mice. Corresponding drug treatments were administered at designated time points. During the eight-week modeling period, the following parameters were measured: physical sign scores, grip strength, body weight, 24-hour food intake, 24-hour fecal water content, female mouse fertility, Morris water maze performance, nose-tongue-collateral-foot color, hippocampus detected by hematoxylin-eosin(HE) staining, Aβ₍₁₋₄₂₎ and brain-derived neurotrophic factor(BDNF) detected by immunohistochemistry, whole blood and plasma viscosity, 2-hour D-xylose, testosterone(T), estradiol(E₂₎, calcium(Ca), phosphorus(P), bone Gla protein(BGP), hippocampal synapsin(SYN) and postsynaptic density protein 95(PSD-95) mRNAs, and SYN, PSD-95, and BDNF proteins. The results showed that by the end of the 4th week, compared with the normal control group, the AD model group, AD-SKDSP group, and AD Zhinao Capsule group exhibited progressively increased physical sign scores and 24-hour fecal water content, and progressively decreased grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). Compared with the AD model group, the AD-SKDSP group and AD Zhinao Capsule group showed significantly increased physical sign scores and 24-hour fecal water content, along with significantly reduced grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). From the 5th week onward, compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant reductions in physical sign scores and 24-hour fecal water content, as well as significant increases in grip strength, body weight, and 24-hour food intake with prolonged intragastric administration of Zhinao Capsule(P<0.05, P<0.01). By the end of the 8th week, compared with the normal control group, the AD model group and AD-SKDSP group exhibited significantly decreased female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E₂, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression. Meanwhile, platform latency, hippocampal Aβ₍₁₋₄₂₎ expression, and whole blood and plasma viscosity(low, medium, and high shear rates) were significantly increased, while platform crossings and target quadrant swimming time were markedly reduced(P<0.05, P<0.01). Hippocampal CA1 neurons in these groups displayed partial loss of normal morphology, with pyknotic or swollen nuclei, deep blue staining, disorganized distribution, and a thickness of "3-5" layers. Compared with the AD model group, the AD-SKDSP group showed significant reductions in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E₂, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant increases in platform latency, hippocampal Aβ₍₁₋₄₂₎ expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant decreases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neurons exhibited irregular shapes, increased nuclear pyknosis, intensified deep blue staining, a thickness of "1-3" layers, and chaotic distribution. Compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant increases in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E₂, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant decreases in platform latency, hippocampal Aβ₍₁₋₄₂₎ expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant increases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neuronal pathology was markedly alleviated. In summary, guided by the holistic concept and syndrome differentiation theory of TCM and on the basis of characteristics of "spleen deficiency", "kidney deficiency", and "intermingled phlegm and blood stasis", this study successfully established a standardized AD-SKDSP animal model by combining a high-sugar and high-fat diet with ice-water bath and tail-clamping stimulation for eight weeks. This modeling method exhibits strong controllability, minimal physicochemical stimulation, reproducibility, and verifiability, providing a stable and standardized disease-syndrome combined animal model for future research on the "disease-syndrome-formula-efficacy" paradigm in AD-SKDSP. Show less

The incidence of obesity has significantly increased worldwide. However, it is still unclear about the genetic susceptibility of obesity. Here we performed the largest European meta-analysis of genome-wide association study, including 98,421 obesity cases and 2,108,019 healthy controls. We identified 322 novel genome-wide significant obesity-associated loci and 23 of 32 known loci. SNP-based heritability analyses revealed that common variants explain 17.19 ± 0.59% of genetic risk for obesity, whereas MiXeR predicted an estimated 1.6 million effective sample sizes explaining 90% of obesity-associated phenotypic variance. Across 345 obesity-associated loci, 2000 likely causal genes are indicated, and 410 causal genes are prioritized. Tissue specificity enrichment analyses demonstrated that obesity-related causal genes mainly expressed in brain putamen basal ganglia, hippocampus, amygdala, substantia nigra, and caudate basal ganglia. The genetic correlation and gene-set analyses showed that apart from obesity-related diseases, some brain diseases and mood (e.g., broad depression, neuroticism, mood swings), inflammatory and allergic diseases diseases (e.g., asthma, spondyloarthritis, Hashimoto thyroiditis), cardiovascular diseases (e.g., hypertension, myocardial infarction, coronary artery disease), and lung disease (e.g., interstitial lung disease, chronic obstructive pulmonary disease, lung cancer) have the positive correlations with obesity. Gene-drug interaction analysis suggested that obesity-associated genes overlapped with targets of current medications for obesity. Finally, we used this meta-analysis to explore some potential targets (e.g., GLP1R, SIGMAR1, MC4R) and drug repurposing (e.g., iloprost, flunarizine, edrophonium chloride) for obesity. We identified 345 genome-wide significant loci, including 322 novel loci for obesity. Based on 345 loci, we provided new biological insights to the etiology of obesity. Of clinical interest, we provided some potential targets and drug repurposing for obesity. Show less

With global climate warming increasingly threatening aquatic ecosystems, prolonged exposure to high temperatures has become a major environmental stressor for both wild and cultured fish. However, the long-term effects of chronic heat stress on blood physiology and hematopoietic processes remain poorly understood. To assess the long-term impacts of chronic heat stress on hematopoiesis in largemouth bass (Micropterus salmoides), we conducted a 180-day acclimation experiment at 34 °C. Hematological analyses showed significant reductions in red blood cell counts and hemoglobin concentrations, indicating impaired oxygen transport capacity. Blood cell morphology was altered, with erythrocytes exhibiting a lower major-to-minor axis ratio and leukocytes (lymphocytes and granulocytes) showing increased volumes. Histological and ultrastructural observations of the head kidney revealed tissue loosening, hemosiderin deposition, mitochondrial damage, and elevated apoptosis. Furthermore, transcriptomic analysis combined with GO and KEGG enrichment revealed that pathways involved in vascular development, stress response, and fatty acid metabolism were significantly activated under heat stress. Notably, key genes associated with angiogenesis, lipid metabolism, stimuli response, apoptosis and immunity, including mmp9, angptl4, abca1 and stab2, were markedly upregulated, suggesting their crucial roles in vascular remodeling and thermotolerance. Together, these results provide the first integrative cellular and molecular characterization of hematopoietic responses to prolonged high temperature in M. salmoides. The findings enhance understanding of fish physiological plasticity under environmental stress and have implications for aquaculture management and the development of heat-resilient strains. Show less

Breast cancer is the most frequently diagnosed cancer, with metastasis accounting for the majority of cancer-related deaths. The mechanisms of early-stage breast cancer metastasis to regional immune sites like lymph nodes remain elusive. Here, we performed an in-depth proteomic and phosphoproteomic analysis of a substantial series of breast cancer samples, alongside genomic and transcriptomic evaluations. This cohort encompasses 195 specimens: 65 primary breast tumors, their corresponding normal tissues, and metastatic axillary lymph nodes. We offer an overview of the molecular alterations at the transcriptomic, proteomic, and phosphoproteomic levels during lymph node metastasis. Notably, the findings indicate that regional lymph node metastasis is primarily influenced by proteomic and phosphoproteomic alterations, rather than genomic or transcriptomic changes. We found the ANGPTL4 and HMGB1 could serve as the biomarker of lymph node metastasis. Data analysis and cell experiments involving silencing of the alternative splicing factor HNRNPU demonstrated that alternative splicing plays a significant role in modulating protein expression, phosphorylation profiles and cell proliferation. The key phosphorylation sites, including MARCKSL1-S104 and FKBP15-S320, as well as the upstream kinase PRKCB, were identified as playing crucial roles in breast cancer lymph node metastasis. Targeted intervention of the kinase PRKCB resulted in effectively suppressing the proliferation and metastasis of breast cancer tumor cells. Immune profiling analysis and experimental validation of breast cancer cell cocultured with CD8+ T cell reveals correlations between phosphorylation of MARCKSL1-S104 and FKBP15-S320 with immune checkpoint PD-L1 expression, and their impact on tumor cell apoptosis, suggesting a potential mechanism of immune evasion in metastasis. This study systematically characterizes the molecular landscape and features of primary breast tumors and their matched metastatic lymph nodes. These insights enhance our understanding of early-stage breast cancer metastasis and may pave the way for improved diagnostic tools and targeted therapeutic strategies. Show less

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

Vascular calcification (VC) is prevalent in patients with chronic renal failure (CRF), and it is closely related to the morbidity and mortality of cardiovascular diseases; however, no medical treatments are available for this condition. Recent clinical studies have shown that plasma apolipoprotein C3 (ApoC3) levels are positively correlated with VC. However, whether ApoC3 is involved in VC remains unclear. Sections of calcified renal arteries from CRF patients were immunostained to measure calcium deposition and ApoC3 expression. VC was induced in ApoC3 transgenic (Tg) and knockout (KO) mice by both 5/6 nephrectomy and vitamin D ApoC3 expression levels were increased in calcified arteries from mice and patients with CRF. ApoC3 overexpression exacerbated calcium deposition in the calcified aortas from Tg mice in vivo, and in calcified aortic rings of Tg mice ex vivo and VSMCs infected by adenovirus of ApoC3 in vitro. Consistently with these findings, ApoC3 deficiency alleviated these effects. Furthermore, ApoC3 overexpression increased ferroptosis in calcified aortas and VSMCs, whereas ApoC3 deficiency suppressed ferroptosis. Further investigation revealed that ApoC3 inhibited the AMPK/NRF2 signaling pathway through toll-like receptor 2 (TLR2) in calcified VSMCs, downregulated the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), subsequently increased lipid peroxidation and promoted ferroptosis, ultimately exacerbating calcification in the VSMCs. Furthermore, we found that knockdown of ApoC3 by siRNA remarkably attenuated calcification of renal arterial rings in humans. We demonstrated that ApoC3 exacerbated VC and increased the osteogenic transdifferentiation in VSMCs by increasing ferroptosis. ApoC3 might be a potential target for VC treatment. Show less

What is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency? This study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency. Congenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD). The study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing. Genetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated. Cleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). N/A. Non-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken. This study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency. This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B₂₀₁₂₇₅ to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests. Show less

Intervertebral disc degeneration (IVDD), a major cause of low back pain, is primarily characterized by compromised regeneration ability of nucleus pulposus-derived stem cells (NPSCs) owing to their senescence. The role of NPSCs as major regenerative cells in IVDD is garnering attention. However, the drivers and mechanisms of NPSCs reactivation and regeneration are poorly understood, limiting the development of targeted therapies. The fibroblast growth factor (FGF) family has shown increasing promise in tissue regeneration; however, the key factors involved in IVDD remain unclear. To elucidate the regenerative driver of NPSCs and the underlying anti-senescence mechanism to provide a potential therapeutic strategy. Single cell RNA sequencing (scRNA-seq) and bulk RNA sequencing were performed to identify the key NPSCs clusters and regenerative drivers in IVDD. Clinical IVDD samples were collected to determine the alterations in the NPSCs subset proportion and the expression of regeneration factors. Further, NPSCs senescence and in vivo models were utilized to investigate the specific mechanisms and therapeutic effects. Thy-1 membrane glycoprotein (THY1) Our findings elucidate the pivotal roles of THY1 Show less

Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) function. A subset of individuals with CHH also present with developmental anomalies, including midline defects such as cleft lip and/or palate (CLP). This study investigates the genetic overlap between CHH and CLP. A total of 336 individuals diagnosed with CHH were clinically assessed for associated phenotypes, including CLP. High-throughput sequencing was performed using a targeted gene panel encompassing known CHH- and CLP-related genes. Variants were analyzed and classified according to the American College of Medical Genetics and Genomics (ACMG) criteria for pathogenicity. CLP was present in 21 patients with CHH (6%). Pathogenic or likely pathogenic variants in genes associated with both CHH and CLP-such as FGFR1 and CHD7-were identified in eight individuals. Furthermore, 17% of the patients with CHH without CLP harbored deleterious variants in genes implicated in clefting, including DVL3, PLCB4, NIPBL, and EDNRA. Evidence of digenic inheritance involving both CHH- and CLP-related genes was observed in multiple cases. FGFR1 variants were the most frequently detected and were commonly associated with anosmia and additional developmental anomalies. These findings highlight a genetic and phenotypic continuum between CHH and CLP, underscoring the involvement of shared developmental pathways. The high prevalence of FGFR1 variants in patients with CHH and CLP supports its role as a pleiotropic gene. Understanding the overlapping genetic mechanisms may enhance diagnostic precision and inform personalized management strategies for affected individuals. Show less

The aim of this study was to investigate the impact of interleukin-27 (IL- 27) gene polymorphism and additional interactions with environmental factors on non-small cell lung cancer (NSCLC) risk based on a Chinese population. SNPStats online software ( http://bioinfo.iconcologia.net/SNPstats ) was used for Hardy-Weinberg equilibrium (HWE) testing. Stratified analysis was performed by logistic regression model to examine the impact of IL- 27 gene SNPs and environmental factors, and additional gene-environment interaction on NSCLC risk. Logistic regression analysis showed a significant association between rs153109, rs181206 and increased NSCLC risk. However, no significant relationship was found between NSCLC risk and rs17855750 or rs40837 genotype with minor allele. Logistic regression also indicated a significant association between smoking status or alcohol consumption and NSCLC risk in this study. We performed crossover analysis to investigate the interaction between two SNPs (rs153109 and rs181206) and two environmental factors (smoking status and alcohol consumption) using logistic regression. We found that ever or current smokers with rs153109- AG or GG genotype have the highest NSCLC risk, compared with never smokers with the AA genotype after covariate adjustment, OR (95%CI) = 3.02 (1.97-5.12), p = 0.012. However, no significant interaction effect was found between rs153109 and alcohol consumption, rs181206 and smoking, rs181206 and alcohol consumption. Our results support an important association of the IL- 27 gene rs153109, rs181206, smoking and alcohol consumption with increased NSCLC risk. We also found a significant impact of an interaction between rs153109 minor allele and ever or current smoking on NSCLC risk. Show less

Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder during pregnancy associated with adverse maternal and fetal outcomes, highlighting the urgent need for novel, genetically supported drug targets due to suboptimal glycemic control and safety concerns with existing therapies. This study integrated cis-expression quantitative trait loci (cis-eQTL) of druggable genes with genome-wide association data to identify putative causal genes for GDM through two-sample Mendelian randomization (MR), with significant associations further validated using multi-tissue summary data-based Mendelian randomization (SMR), colocalization analysis, cis-protein quantitative trait loci (cis-pQTL) MR, and single-cell RNA sequencing (scRNA-seq) to confirm tissue- and cell type specific expression. MR analysis identified 15 genes significantly associated with GDM risk after Bonferroni correction, with SMR and colocalization analyses confirming robust associations for five key genes: higher expression of NRBP1, LPL, and BTN3A2 was causally linked to reduced GDM risk, while elevated GSTM1 and GRINA levels were associated with increased risk. ScRNA-seq revealed distinct expression patterns in placental cell types, with NRBP1 and GRINA highly expressed in trophoblasts and certain immune cell populations. Phenome-wide association studies revealed no significant pleiotropic effects, and pharmacological drug-target databases identified several compounds with potential regulatory interactions. This multi-omics study successfully identifies several genetically supported, druggable targets for GDM, providing a robust foundation for developing mechanism-based therapeutics and precision prevention strategies in pregnancy metabolism. Show less

MYBPC3 mutations are the leading cause of hypertrophic cardiomyopathy. Here, to study the pathogenesis of hypertrophic cardiomyopathy, we created a MYBPC3 knockout (KO) model using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). MYBPC3-deleted hiPSC-CMs revealed the characteristics of heart failure, which exhibited increased contractility at 30 days but decreased at 40 days. Furthermore, at 40 days, it also shows abnormal calcium handling, increased ROS levels, and mitochondrial damage. Further RNA sequencing revealed that the oxidative stress pathway was aberrant, in addition to alterations linked to hypertrophic cardiomyopathy. Moreover, after adding melatonin to hiPSC-CMs at 30 days, MYBPC3-deleted hiPSC-CMs showed restored calcium handling capacity, decreased ROS levels, and improved myocardial contractility. In summary, reducing ROS can improve the phenotype of hypertrophic cardiomyopathy. Show less

Some individuals are more susceptible to developing or suffering from pain states than others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, we defined pain susceptibility by recapitulating inter-individual differences in pain responses in mice exposed to a paradigm of socially transferred allodynia (STA), and with a combination of chemogenetic, molecular, pharmacological and electrophysiological approaches, we identified GABA-ergic neurons in the dorsal raphe nucleus (DRN) as a cellular target for the development and maintenance of STA susceptibility. We showed that DRN GABA-ergic neurons were selectively activated in STA-susceptible mice when compared with the unsusceptible (resilient) or control mice. Chemogenetic activation of DRN GABA-ergic neurons promoted STA susceptibility; whereas inhibiting these neurons prevented the development of STA susceptibility and reversed established STA. In in vitro slice electrophysiological analysis, we demonstrated that melanocortin 4 receptor (MC4R) enriched in DRN GABA-ergic neurons was a molecular target for regulating pain susceptibility, possibly by affecting DRN GABA-ergic neuronal activity. These results establish the DRN GABA-ergic neurons as an essential target for controlling pain susceptibility, thus providing important information for developing conceptually innovative and more accurate analgesic strategies. Show less

The clinical significance and contribution of the lipid profile in atherosclerosis are well established. However, further investigation is needed in stroke patients, particularly regarding apolipoprotein B100 (ApoB100), a novel non-traditional lipid component in the lipid profile. To explore lipid parameters and their impact on stroke outcomes in patients with and without thrombolysis. We prospectively enrolled patients with acute ischemic stroke (AIS) at a single center, including those who did and did not receive thrombolysis. Participants were stratified into improvement (favorable outcome at 2 weeks) and non-improvement groups. Demographic, laboratory, imaging, and clinical scale data were compared between groups. Random forest analyses were used to evaluate the predictive value and importance of individual lipid measures: triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), ApoB100, and lipoprotein(a), which better describe the internal characteristics of the profile. Complete data were available for 262 AIS patients, 165 of whom received thrombolysis. Plasma ApoB100 levels were significantly lower in the thrombolysis group (p < 0.001) and decreased ApoB100 levels were independently associated with 2-week stroke improvement (p = 0.009, OR = 0.89, 95% CI: 0.84-0.93). Random-forest feature-importance plots revealed that HDL and ApoB100 (each contributing > 15%) were the strongest lipid predictors of a favorable outcome, outperforming the other lipid variables. We found that thrombolysis is associated with ApoB100 decrease and a decrease in ApoB100 can predict the 2-week functional improvement in stroke. HDL and ApoB100 emerge as more important determinants of favorable AIS outcomes in this machine-learning analysis. These findings warrant external validation in multi-center trials. ChiCTR1800018315, 11/09/2018. Show less

Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC. We found that activating expression of the Alzheimer's disease-associated beta-secretase 1 (BACE1) led to a substantial increase in brain metastases. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified that BACE1 acts through epidermal growth factor receptor to drive this metastatic phenotype. Together, our data highlight the power of in vivo CRISPR activation screening to unveil molecular drivers and potential therapeutic targets of NSCLC brain metastasis. Show less

Diabetes has been regarded as an independent risk factor for Alzheimer's disease (AD). Liraglutide could improve cognition in AD mouse models, but its precise mechanism remains unclear. In this study, we used STZ-induced diabetic rats and HT-22 cells to investigate the effects of liraglutide. The MWM test, MTT assay, ELISA, western blot, and immunofluorescence were used in this research. Diabetic rats induced by STZ displayed a longer escape latency and entered the target zone less frequently (p < 0.05) in the MWM test. Intraperitoneal injection of liraglutide improved the cognition of diabetic rats (p < 0.05) and reduced Aβ42 expression in the hippocampus (p < 0.05). In vivo experiments showed that HT-22 cell viability decreased in the HG group, but liraglutide (100 nmol/L and 1 μmol/L) enhanced HT-22 cell viability (p < 0.05). Oxidative stress markers were upregulated in HT-22 cells in the HG group, while liraglutide treatment significantly reduced these markers (p < 0.05). Western blot and immunofluorescence analyses demonstrated increased levels of Aβ, BACE1, and γ-secretase in HT-22 cells in the HG group (p < 0.05), whereas these levels were reduced in the liraglutide treatment group (p < 0.05). These effects were reversed by the nuclear factor kappa B (NF-κB) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitors (p < 0.05). These findings suggest that liraglutide improved the cognition of diabetic rats and might exert its protective effects by reducing oxidative stress, downregulating BACE1 and γ-secretase expression, and decreasing Aβ deposition via the NF-κB and ERK1/2 pathways. Show less

Dysregulation of hepatic lipid homeostasis constitutes a core pathogenic mechanism in metabolic dysfunction-associated fatty liver disease (MAFLD); however, the regulatory role of circular RNAs (circRNAs) in this process remains unclear. In this study, hepatic circRNAs transcriptomic profiling of MAFLD patients identified circSETD2-generated from exons 16-18 of the SETD2 gene-as a stably expressed and significantly upregulated novel circRNA with a closed circular structure localized in the cytoplasm of MAFLD patient liver tissues. Silencing circSETD2 attenuated free fatty acid - induced lipid accumulation in vitro by reducing lipogenesis and enhancing fatty acid β-oxidation. In high fat diet - fed mice, hepatic circSETD2 silencing mitigated steatosis, improved liver function, and reversed dyslipidemia. Mechanistically, RNA pull-down coupled with LC-MS/MS identified carbamoyl phosphate synthetase 1 (CPS1) as a circSETD2-interacting protein, which was subsequently validated by RNA immunoprecipitation and fluorescence in situ hybridization. Pharmacological modulation of CPS1 enzymatic activity in circSETD2-silenced cells established its mediator role. Specifically, circSETD2 directly bound to CPS1, reducing its enzymatic activity and thereby exacerbating lipid metabolic disturbances and disease progression in MAFLD. In summary, circSETD2 drives MAFLD pathogenesis by impairing CPS1-mediated regulation of lipid homeostasis, positioning it as a promising prognostic biomarker and therapeutic target. Show less

Long noncoding RNAs (lncRNAs), non-protein-coding transcripts exceeding 200 nucleotides, are critical regulators of gene expression through chromatin remodeling, transcriptional modulation, and post-transcriptional modifications. While ionizing radiation (IR) induces cellular damage through direct DNA breaks, reactive oxygen species (ROS)-mediated oxidative stress, and bystander effects, the functional involvement of lncRNAs in the radiation response remains incompletely characterized. Here, through genome-wide CRISPR activation (CRISPRa) screening in non-small cell lung cancer (NSCLC) cells, we identified LOC401312 as a novel radiosensitizing lncRNA, the stable overexpression of which significantly enhanced IR sensitivity. Transcriptomic profiling revealed that LOC401312 transcriptionally upregulates carbamoyl-phosphate synthase 1 (CPS1), a mitochondrial enzyme involved in pyrimidine biosynthesis. Notably, CPS1 overexpression recapitulated the radiosensitization phenotype observed with LOC401312 activation. Mechanistic investigations revealed that CPS1 suppresses the phosphorylation of ATM kinase (Ser1981) protein, which is a key mediator of DNA damage checkpoint activation. This study established the LOC401312-CPS1-ATM axis as a previously unrecognized regulatory network governing radiation sensitivity, highlighting the potential of lncRNA-directed metabolic rewiring to impair DNA repair fidelity. Our findings not only expand the functional landscape of lncRNAs in DNA damage response but also provide a therapeutic rationale for targeting the LOC401312-CPS1 axis to improve radiotherapy efficacy in NSCLC. Show less

Primary membranous nephropathy (pMN) often progresses to end-stage renal disease (ESRD) in the absence of immunosuppressive therapy. The immunological mechanisms driving pMN progression remain insufficiently understood. We developed a single-cell transcriptomic profile of peripheral blood mononuclear cells (PBMCs) from 11 newly-diagnosed pMN patients and 5 healthy donors. Through correlation analysis, we identified potential biomarkers for disease stratification and poor prognosis. Expression levels of several proinflammatory factors were significantly increased in patients compared to healthy donors, such as interleukins ( Our study provides insight into the immunological mechanism of pMN and identifies numerous biomarkers and signaling pathways as potential therapeutic targets for managing the progression of high-risk pMN. Show less

Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. However, its underlying pathogenesis and mechanisms driving metastasis remain poorly understood. Here, we identified a novel super-enhancer-associated long noncoding RNA (SE-lncRNA), Zinc Finger MIZ-Type Containing 1 Antisense RNA 1 (ZMIZ1-AS1), which is highly expressed in osteosarcoma and promoted tumor cell proliferation, migration, and invasion. Mechanistically, the m⁶A demethylase ALKBH5 post-transcriptionally stabilized ZMIZ1-AS1 through m⁶A demethylation. Furthermore, ZMIZ1-AS1 directly bound to the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1), facilitating the translocation of PTBP1 from the nucleus to the cytoplasm. The relocalized PTBP1 then bound to and stabilized fibroblast growth factor receptor 1 (FGFR1) mRNA. In nude mouse models, ZMIZ1-AS1 overexpression promoted tumor growth and lung metastasis. Notably, combined inhibition of ALKBH5 (using ALKBH5-IN-5) and FGFR1 (using BGJ398/infigratinib) synergistically suppressed ZMIZ1-AS1-driven oncogenesis in vivo. Our study establishes the ALKBH5/ZMIZ1-AS1/PTBP1/FGFR1 signaling axis as a key driver of osteosarcoma progression and a promising target for therapeutic intervention. Show less

Recent researches highlight the interdependence of lipoprotein(a) [Lp(a)] and Lp(a)-associated cardiovascular risk with the background inflammatory burden. This study aimed to investigate whether systemic inflammation modulates Lp(a)-associated coronary stenosis in chronic coronary syndromes (CCS). A total of 1513 participants undergoing angiography at a tertiary cardiology center in China were included in our retrospective, cross-sectional study. Participants were categorized into normal, mild, and severe groups based on the Gensini Scores, which quantitatively assess stenosis severity. Multinomial logistic models were calculated according to accompanying systemic inflammation concentration. Participants with elevated Lp(a) levels had a high coronary stenosis risk: fully adjusted model odds ratios (ORs) [95% confidence intervals (CIs)] for the mild vs. normal and severe vs. normal groups were 1.47 (1.11-1.96) and 1.68 (1.21-2.33). Notably, the strongest Lp(a)-coronary stenosis associations after multi-variable adjustment persisted only in low inflammation concentration [systemic inflammation response index (SIRI) < 0.64)] [mild vs. normal, OR 2.03, 95% CI 1.17-3.54, Elevated Lp(a) correlates with coronary stenosis only in low inflammation concentration. Considering systemic inflammation in personalized Lp(a)-lowering therapies is more conducive for CCS managements. Show less

Pulmonary fibrosis (PF) is a progressive and fatal disease, and recent studies have revealed its key role in the autotaxin (ATX)-lysophosphatidic acid (LPA) signaling pathway, revealing the therapeutic potential of targeting ATX. Herein, starting from PAT-409, a series of novel ATX inhibitors containing the 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one core were designed to improve the pharmacological activity and physicochemical properties. The most promising compound 19 exhibited potent ATX inhibition (IC 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

Anoikis is a new mode of cell death that has been shown to correlate significantly with tumors. However, the clinical prognostic significance of anoikis in lung squamous cell carcinoma (LUSC) remains poorly studied. The differentially expressed ARGs and candidate genes were selected by the differential analysis to construct a predictive model. Independent prognostic gene was determined by Cox and LASSO analysis and we used the HCC95 and NCI H520 cell line to verify the gene function. We used the data from TCGA, GEO, GeneCards, and Harmonizome databases to analyze the immune microenvironment, functional enrichment, and drug sensitivity analysis. We identified 717 differentially expressed and selected 3 ARGs (FADD, SNAI1, and BAG4) to construct a predictive model. We found that SNAI1 is an independent prognostic gene and confirmed that knocking out the SNAI1 inhibited the HCC95 We used ARGs to construct a prognosis model for LUSC that can accurately predict the prognosis of LUSC patients. ARGs, especially SNAI1, play an essential role in developing LUSC. These findings could provide individualized treatment plans and new research ideas for LUSC patients. Show less