👤 Riping Wu

Pediatric arterial ischemic stroke (AIS) is the leading cause of stroke in children and approximately two-thirds of affected patients experience permanent neurological sequelae. Although basic fibroblast growth factor (bFGF) has positive effects on neural development, axon regeneration, and synaptic reconstruction, its effects in AIS remain unclear. Here, we examined the role of bFGF in post-ischemic cognitive function in juvenile rats. Behavioral assessments using the Morris water maze and the three-chamber test revealed that bFGF knockdown impairs spatial learning, memory, and social interactions. Golgi staining and electron microscopy demonstrated that bFGF knockdown disrupts neuronal axon morphology and synaptic ultrastructure. In the hippocampus of AIS rats, bFGF deficiency significantly reduced PSD95 and synapsin I protein levels. Moreover, bFGF knockdown decreased autophagy and apoptosis markers while increasing necrosis indicators. Mechanistically, loss of bFGF inhibited phosphorylation of mammalian target of rapamycin (mTOR), a process regulated by fibroblast growth factor receptor 1 (FGFR1). We further show that bFGF interacts with FGFR1 and caveolin-1 (Cav1), a membrane scaffold protein; knockdown of Cav1 in the hippocampus similarly attenuated mTOR signaling. Collectively, our results suggest that bFGF deficiency suppresses Cav1, thereby inhibiting mTOR signaling and exacerbating cognitive deficits after AIS in juvenile rats. These findings provide insight into the molecular mechanisms underlying pediatric AIS. Show less

Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the global population and poses a remarkably serious threat to human health. The effect and potential molecular mechanisms of combined cold exposure and exercise intervention on NAFLD remain unclear. A high-fat diet-induced NAFLD mouse model was used. Twenty-four NAFLD mice were divided into three groups and subjected to cold exposure (5°C), regular-temperature exercise (22°C), or combined cold exposure and exercise (5°C) for 8 wk, 5 d·wk -1 , once daily for 1 h each session. Intervention effects were evaluated through bodyweight, liver mass, liver/bodyweight ratio, blood lipid profile, circulating fibroblast growth factor 21 (FGF21) levels, and liver histopathology. Immunoblotting and quantitative PCR were used to assess the protein and gene expression of liver FGF21, β-klotho, and FGFR1 to preliminarily elucidate the molecular mechanisms underlying NAFLD improvement by combined cold exposure and exercise. Compared with cold exposure or regular-temperature exercise alone, combined cold exposure and exercise significantly reduced the bodyweight, liver weight, and liver/bodyweight ratio in the NAFLD mice. The levels of blood lipids, circulating FGF21, and liver glycogen also significantly decreased. Furthermore, the combined intervention significantly reduced liver fat deposition and fibrosis and significantly increased the expression of FGFR1 and β-klotho proteins, suggesting the activation of the FGF21-β-klotho/FGFR1 signaling pathway. This preclinical study demonstrates that combined cold exposure and exercise synergistically alleviates NAFLD progression in animal models, primarily by activating the FGF21-β-klotho/FGFR1 pathway to enhance lipid metabolism and reduce liver injury. These findings highlight the translational potential of dual environmental and behavioral interventions, providing a mechanistic foundation for developing nonpharmacological therapies targeting metabolic pathways in humans, particularly for NAFLD patients resistant to conventional lifestyle modifications or pharmacotherapy. Show less

Lipolysis in white adipose tissue (WAT) provides fatty acids as energy substrates for thermogenesis to increase energy expenditure. Syndecan-4 (Sdc4) is a transmembrane proteoglycan bearing heparan sulfate chains. Although single nucleotide polymorphisms (SNPs) of the Sdc4 gene have been identified linking to metabolic syndromes, its specific function in adipose tissue remains obscure. Here, we show that Sdc4 serves as a regulator of lipid metabolism and adaptive thermogenesis. Sdc4 expression and shedding are elevated in the white adipose tissue (WAT) of diet-induced obese mice. Adipocyte-specific deletion of Sdc4 promotes lipolysis and WAT browning, thereby raising whole-body energy expenditure to protect against diet-induced obesity. Mechanistically, fibroblast growth factor 2 (FGF2) is a paracrine factor that maintains energy homeostasis. Elevated shed Sdc4 concentrates and delivers FGF2 to fibroblast growth factor receptor 1 (FGFR1) on adipocytes, which in turn suppresses lipolysis by reducing hormone-sensitive lipase (HSL) activity, thus exaggerating adipose tissue dysfunction upon high-fat diet induction. Sdc4-deficient adipocytes show higher lipolytic and thermogenic capacity by enhancing HSL phosphorylation and UCP1 expression. Overall, our study reveals that adipocyte-derived shed Sdc4 is a novel suppressor of lipolysis, contributing to decreased energy expenditure, thus exaggerating obesity. Targeting shed Sdc4 is a potential therapeutic strategy for obesity. Show less

The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles in biological processes. This study aims to explore the impact and mechanisms of circRNA505 on antler chondrocytes. Functional experiments demonstrated that m5C-modified circRNA505 inhibits antler chondrocyte proliferation, enhances osteogenic differentiation, and facilitates cellular glycolysis. Mechanistically, dual luciferase and AGO2-RIP assays revealed a direct binding relationship between circRNA505, miR-127, and p53. Rescue assays further showed that circRNA505 affects cell proliferation and differentiation through the miR-127/p53 axis. Meanwhile, RNA Antisense Purification (RAP) screening and analysis of related proteins binding to circRNA505 demonstrated that circRNA505 binds to LDHA and increases the level of LDHA phosphorylation through FGFR1 to promote cellular glycolysis by FISH-IF, RIP, and Western blot experiments. Additionally, Me-RIP assays confirmed the m5C methylation modification of circRNA505. NSUN2 mediates the m5C modification of circRNA505, affecting its stability, while the m5C reader ALYREF promotes the nuclear export of circRNA505 in an ALYREF-dependent manner. This study provides new insights into the regulatory mechanisms underlying rapid antler development. Show less

Cardiac ischemia/reperfusion (I/R) induces systemic oxidative stress, which in turn gives rise to the development of multiple organ abnormalities, including brain injury. The paraventricular nucleus (PVN) of the hypothalamus is a cardiovascular regulatory center. Aerobic exercise is an effective intervention to protect the heart against I/R injury. However, the effect of aerobic exercise on cardiac I/R-induced neuronal injury in the PVN has not been fully elucidated. The aim of this study is to investigate whether aerobic exercise can up-regulate fibroblast growth factor 21 (FGF21) and alleviate neuronal oxidative stress and ferroptosis in the PVN caused by cardiac I/R. In vivo, after six weeks of aerobic exercise, the cardiac I/R model was established by ligating the left anterior descending (LAD) coronary artery for 30 min, followed by 2 h of reperfusion. Cardiac function and heart rate variability (HRV) were measured. Morphological changes, oxidative stress, expression of FGF21 and its downstream signaling molecules, as well as ferroptosis-related indicators in the PVN, were evaluated. In vitro, HT22 cells were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) and treated with recombinant human FGF21 (rhFGF21) and compound C to elucidate the potential mechanism. Cardiac I/R induced iron deposition, elevated expression of lipid peroxidation drivers, and impaired antioxidant capacity in the PVN, which collectively contributed to neuronal ferroptosis. Aerobic exercise up-regulated the expression of FGF21, FGFR1, and PGC-1α, maintained the phosphorylation of AMPKα, enhanced antioxidant capacity, reduced ROS and lipid peroxidation, regulated iron homeostasis, and effectively attenuated neuronal ferroptosis induced by cardiac I/R. In addition, rhFGF21 protected HT22 cells against OGD/R-induced oxidative stress and ferroptosis, which was blocked by AMPK inhibition. FGF21 plays a pivotal role in regulating neuronal oxidative stress and ferroptosis. Aerobic exercise could increase the expression of FGF21, FGFR1, and PGC-1α, maintain the phosphorylation of AMPKα, and alleviate cardiac I/R-induced neuronal oxidative stress and ferroptosis. These results confirm the protective effect of aerobic exercise against cardiac I/R-induced brain injury and provide an experimental basis for studying the relationship between exercise and the "heart-brain axis." Show less

Diabetic retinopathy (DR) is the leading manifestation of diabetic microangiopathy. However, effective biomarkers and therapies are lacking. Circular RNAs (circRNAs) have been implicated in various diseases including DR. However, the role of circRNAs in DR remains elusive. In the present study, circNXN was upregulated in high glucose (HG)-treated human retinal microvascular endothelial cells (hRMECs). circNXN knockdown inhibited the proliferation, migration, and angiogenesis of hRMECs and promoted apoptosis. In addition, circNXN acted as a sponge for miR-338-3p to facilitate the FGFR1 (fibroblast growth factor receptor 1) expression. Furthermore, rescue assays revealed that the reduced promoting effect on hRMECs induced by the knockdown of circNXN could be reversed by a miR-338-3p inhibitor in HG-treated hRMECs. Additionally, in a DR rat model, circNXN downregulation ameliorated retinal vasculature changes. Our findings reveal a new therapeutic strategy for DR that may provide a new approach to clinical DR therapy. Show less

While fibroblast growth factor receptor 2 (FGFR2) emerges as an appealing cancer therapeutic target, so far there is no selective FGFR2 inhibitor on the market. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors with compound BW710 being the representative. Compound BW710 potently inhibited the proliferation of BaF3-FGFR2 cells with an IC Show less

Synthetic vascular grafts are promising conduits for small caliber arteries. However, due to restenosis caused by intimal hyperplasia, they cannot keep long patency in vivo. In this work, through single cell RNA sequencing, we found that thrombospondin-1 (THBS1) was highly expressed in the regenerated smooth muscle cells (SMCs) in electrospun polycaprolactone (PCL) vascular grafts. The expression of THBS1 by injured SMCs was confirmed in a balloon-induced vascular injury model. Downregulation of Thbs1 expression maintained contractile phenotypes of SMCs and reduced neointimal hyperplasia after vascular injury via inhibition of FGFR1/EGR1 signaling by decreasing THBS1 expression. THBS1 small interfering RNA (THBS1-siRNA) was then loaded into macrophage membrane (MM) hybrid lipid nanoparticles (Lipid NP@MM), which were used to modify PCL vascular grafts via polydopamine (PDA) coatings. Lipid NP@MM not only protected THBS1-siRNA from degradation but also improved its internalization by SMCs to decrease the level of THBS1 expression. PCL vascular grafts modified with PDA coatings and Thbs1-siRNA-loaded Lipid NP@MM showed significantly reduced intimal hyperplasia. Thus, the downregulation of THBS1 expression in regenerated SMCs in vascular grafts is a promising strategy to inhibit intimal hyperplasia during vascular graft regeneration in vivo. Show less

Pheochromocytomas and paragangliomas (PPGLs) exhibit the highest degree of heritability among all human tumors, yet the genetics of urinary bladder paragangliomas (UBPGLs) remains poorly understood. The present study aims to examine the characteristics of a cohort of Chinese patients with UBPGLs, focusing particularly on genetics. The study included 70 Chinese patients with UBPGLs from 15 centers in China, 240 patients with non-head and neck PGLs (non-HNPGLs) outside the urine bladder, and 16 Caucasian patients with UBPGLs. Tumor DNA samples were sequenced by next generation sequencing. All identified pathogenic variants (PVs) were confirmed by Sanger sequencing. Among the 70 Chinese patients, PVs were identified in 38 cases: 23 in cluster 1 A (13 SDHB, 1 SDHD, 1 SDHA, 4 IDH1, 2 SLC25A11, and 2 FH), 4 in cluster 1B (3 EPAS1 and 1 EGLN1), and 11 in cluster 2 genes (7 HRAS, 1 FGFR1, 2 NF1, and 1 H3F3A). Compared with other non-HNPGLs, UBPGLs had more PVs in cluster 1 A genes (32.9% vs. 14.2%, p < 0.001), but fewer in cluster 1B (5.7% vs. 19.2%, p = 0.002) and cluster 2 genes (15.7% vs. 42.5%, p < 0.001). PVs in SDHB (18.6%) was the most common in Chinese patients with UBPGLs, followed by HRAS (10.0%). No PVs was found in 45.7% of all UBPGLs. PVs in HRAS, SLC25A11, EPAS1, and FH were also identified in Caucasians with UBPGLs. Chinese patients with UBPGLs have a diverse genetic profile. PVs in cluster 1 A genes underlie nearly 1/3 of patients, highlighting the importance of genetic testing. Diverse germline and somatic PVs are also present in Caucasian patients with UBPGLs. Show less

Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous subtype of breast cancer. miRNAs play an essential role in TNBC pathogenesis and prognosis. Obesity is linked with an increased risk for several cancers, including breast cancer. Obesity is also related to the dysregulation of miRNA expression in adipose tissues. However, there is limited knowledge about race- and obesity-specific differential miRNA expression in TNBC. We performed miRNA sequencing of 48 samples (24 tumor and 24 adjacent non-tumor tissues) and RNA sequencing of 24 tumors samples from Black (AA) and White (EA) TNBC patients with or without obesity. We identified 55 miRNAs exclusively associated with tumors in obese EA patients and 33 miRNAs in obese AA patients, each capable of distinguishing tumor tissues from obese from lean individuals within their respective racial groups. In EA, we detected 41 significant miRNA-mRNA correlations. Notably, miR-181b-5p and miR-877-5p acted as negative regulators of tumor-suppressor genes (e.g., Show less

Cardiac hypertrophy (CH), a pathological response to stress, is intricately regulated by the dynamic control of gene expression. This study explored the role of super-enhancers (SEs) and the transcription factor Mef2c in CH regulation. Using a transverse aortic constriction (TAC) mouse model, we demonstrated that inhibition of SEs with JQ-1, a BET inhibitor, significantly attenuated hypertrophic responses, as evidenced by reduced heart weight indices, enhanced cardiac function, and decreased expression of hypertrophic marker proteins BNP and β-MHC. Further analysis revealed that Mef2c, a key transcription factor, is driven by SEs in CH. In vivo and in vitro overexpression of Mef2c promotes CH, while deletion of the Mef2c SE region alleviates this condition. Mechanistically, we identified Hey2 as a downstream target of Mef2c and demonstrated that Mef2c regulates CH through the Hey2/Notch/p38 signaling pathway. Our findings provide novel insights into the molecular mechanisms underlying CH and suggest potential therapeutic targets for its treatment. Show less

Tetralogy of Fallot (TOF) is the most common cyanotic heart defect in neonates. While there is compelling evidence of genetic contribution to the etiology of TOF, the contribution of noncoding variants to the development of the defect remains unexplored. Potentially damaging noncoding de novo variants (NC DNVs) were detected from 141 Chinese nonsyndromic TOF trios (CHN-TOF) and compared with those detected in the Pediatric Cardiac Genomics Consortium (PCGC). Bioinformatic analyses on noncoding and previously detected coding DNVs were performed to identify developmental pathways affected in TOF. Chinese but not PCGC-TOF patients showed a notably increased burden of putative damaging NC DNVs (n = 249). In Chinese, NC and coding DNVs were predominantly associated with cardiomyocyte differentiation and with chamber/valve/aorta development, respectively, producing a combined enrichment in NOTCH signaling (p = 1.1 × 10 Show less

Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function. Show less

Single nucleotide polymorphisms (SNPs) located in the genes participating in the steroid hormone metabolism pathway may influence the outcomes of androgen deprivation therapy (ADT) in prostate cancer (PCa) patients, but findings on the Chinese population remain limited. A multicentric cohort of 301 Chinese PCa patients receiving first-line ADT was enrolled. Germline SNPs located in 62 steroid hormone metabolism-related genes were analyzed for associations with time to ADT failure using multivariate Cox regression. Important expression quantitative trait loci (eQTLs) were discovered. Four SNPs were significantly associated with time to ADT failure: rs36119043 in AKR1D1 (hazard ratio, HR = 2.02, 95% confidence interval, 95% CI: 1.44-2.85, p = 5.72 × 10 SNPs in the steroid hormone metabolism pathway can predict time to ADT failure in Chinese PCa patients, supporting their potential role for drug response and pharmacogenomic stratification. Show less

Neuroblastoma is the most common extracranial solid tumor in children and has complex genetic underpinnings. Previous genome-wide association studies (GWASs) have identified many loci associated with neuroblastoma susceptibility; however, their application in risk prediction for Chinese children has not been systematically explored. This study seeks to enhance neuroblastoma risk prediction by validating these loci and evaluating their performance in polygenic risk models. We validated 35 GWAS-identified neuroblastoma susceptibility loci in a cohort of Chinese children, consisting of 402 neuroblastoma patients and 473 healthy controls. Genotyping these polymorphisms was conducted via the TaqMan method. Univariable and multivariable logistic regression analyses revealed the genetic loci significantly associated with neuroblastoma risk. We constructed polygenic risk models by combining these loci and assessed their predictive performance via area under the curve (AUC) analysis. We also established a polygenic risk scoring (PRS) model for risk prediction by adopting the PLINK method. Fourteen loci, including ten protective polymorphisms from Our findings validate multiple loci as neuroblastoma risk factors in Chinese children and demonstrate the utility of polygenic risk models, particularly the PRS, in improving risk prediction. These results suggest that integrating multiple genetic variants into a PRS can enhance neuroblastoma risk stratification and potentially improve early diagnosis by guiding targeted screening programs for high-risk children. Show less

This study aims to investigate how Bifidobacterium breve BBr60 improves obesity-related metabolic disorders by modulating the gut microbiota-SCFAs axis, thereby affecting inflammatory factors and metabolic hormones. A randomized, double-blind, placebo-controlled trial was conducted. A total of 75 individuals with obesity subjects (BMI ≥ 28) were enrolled and randomly assigned to either the BBr60 intervention group (10 billion CFU daily) and the placebo group. After the 12-week intervention, 65 participants (BBr60: n = 33; placebo: n = 32) completed the study and were included in the primary analysis. All participants received standardized nutritional counseling aimed at a moderate energy intake (~ 1800 kcal/day, including a daily intake of 25 g of dietary fiber.). Every week, we call participants at a fixed time to inquire about their weekly diet and weight changes, and provide dietary suggestions for the following week based on the inquiry results. Participants were instructed to maintain their usual physical activity levels throughout the study. The composition of the gut microbiota was analyzed by 16 S sequencing, fecal SCFAs were detected by GC-MS, and serum levels of IL-27, IL-1β, and metabolic hormones were measured using ELISA technology. Metabolic indicators such as body weight, body fat percentage, and HOMA-IR were also assessed. The BBr60 intervention significantly increased fecal butyrate levels (p < 0.001), accompanied by a decrease in IL-1β levels (p < 0.05) and an upregulation of IL-27 (p < 0.01). In terms of metabolic hormones, leptin (LEP), adiponectin (ADPN), connecting peptide (C-P), pancreatic polypeptide (PP), peptide YY (PYY), Glucose-dependent insulinotropic polypeptide (GIP), and Glucagon-Like Peptide-1 (GLP-1) were all significantly elevated (p < 0.05), while Homeostasis Model Assessment for Insulin Resistance(HOMA-IR) was significantly reduced in the BBr60 group (p < 0.05). In the control group, C-P, PP, and GIP were significantly increased (p < 0.05), whereas LEP, ADPN, PYY, GLP-1, and HOMA-IR showed no difference before and after the 12-week period. Correlation analysis indicated that butyrate levels were significantly positively correlated with GLP-1 and IL-27, and negatively correlated with IL-1β. Bifidobacterium breve BBr60, by remodeling the gut microbiota-SCFAs axis, inhibits the pro-inflammatory factor IL-1β, activates the anti-inflammatory signal IL-27, and synergistically regulates the metabolic hormone network (such as GLP-1, ADPN), significantly improving obesity-related metabolic disorders. This study provides a theoretical basis and intervention targets for the clinical application of probiotics targeting the "microbiota-SCFAs-inflammation/hormone axis," and future research can explore precise probiotic treatment regimens based on individual microbiota characteristics. Show less

Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in innate immunity, play pivotal regulatory roles in sepsis pathogenesis. While Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, is traditionally believed to exert immunosuppressive effects through membrane anchoring, its involvement in macrophage polarization during sepsis remains unclear. This study investigated the spatial distribution of PD-L1 in macrophages and its regulatory effects on inflammatory responses during sepsis. This study investigated PD-L1’s regulatory role in macrophage polarization through RNA sequencing, Immunoprecipitation-mass spectrometry, molecular docking, and site-directed mutagenesis, with preliminary validation in C57BL/6 mice. Using GEO database analysis combined with qRT-PCR and Western blotting, we confirmed elevated PD-L1 expression in sepsis and M1-polarized macrophages. Laser scanning confocal microscopy demonstrated dual localization of PD-L1, appearing both on the plasma membrane and intracellularly within M1 macrophages. RNA sequencing revealed PD-L1’s promotion of M1 polarization through enhanced AIM2 expression in the NOD-like receptor pathway. Integrated analyses employing mass spectrometry, molecular docking, site-directed mutagenesis, and Western blotting demonstrated PD-L1 binding to AIM2, which augmented expression of downstream effector molecules (IL-18 and IFN-γ) and potentiated STAT1 activation. Silencing AIM2 by siRNA or IL-18 antagonism reversed PD-L1-induced M1 markers (IL-27, IL-6, iNOS/NO). PD-L1 was further shown to exacerbate pathological progression in septic mouse models. Our study demonstrated that sepsis-induced PD-L1 overexpression in macrophages exacerbates pathological progression by upregulating AIM2 expression, binding to AIM2 to enhance IL-18 production, which activates STAT1 to drive M1 polarization. The online version contains supplementary material available at 10.1186/s12964-025-02578-1. Show less

Sow colostrum is rich in lactoferrin (LF), which can be orally administered to protect piglets from porcine epidemic diarrhea virus (PEDV) infection, thereby reducing piglet mortality. Previous study has shown that sows fed with recombinant B. subtilis expressing 4,4-diaponeurosporene (B.S-Dia) have significantly higher LF levels in their colostrum compared to sows fed with B. subtilis. This suggests that 4,4-diaponeurosporene (DNP) produced by B.S-Dia may influence LF content in sow colostrum. In this study, we first extracted DNP expressed by the recombinant probiotic using acetone-hexane extraction. Flow cytometry, RT-qPCR, and ELISA analyses demonstrated that DNP promoted dendritic cell (DCs) maturation and increased the expression of IL-1β and IL-27. We then established a method for isolating neutrophils from sow colostrum and set up a co-culture system of neutrophils and DCs to investigate factors regulating LF secretion. The results indicated that DCs secretions enhanced LF expression in neutrophils. Finally, the application of IL-27 inhibitors confirmed that IL-27 produced by DCs upregulates LF secretion in neutrophils. These findings elucidate the mechanism by which DNP promotes LF production in colostrum and provide a theoretical foundation for using B.S-Dia to prevent and control PEDV infection in piglets. Show less

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide. Despite its high mortality rate, the development of effective targeted therapies remains challenging due to an incomplete understanding of their underlying molecular mechanisms. Here, we highlight a pivotal role for IL27/IL27RA signalling in driving HCC progression. Our findings reveal that IL27RA is significantly upregulated in HCC. Both in vitro and in vivo experiments demonstrated that IL27RA knockdown markedly inhibited the proliferation and metastasis of HCC cells. Mechanistic investigations show that IL27RA promotes HCC progression through activation of the STAT3/TGF-β signalling pathway. Specifically, STAT3 enhances TGFβR1 protein stability by increasing the transcription of USP15. Notably, IL27RA regulates the proliferation and metastatic potential of liver cancer cells in a TGFβR1-dependent manner. In summary, these results underscore the critical role of IL27RA in HCC progression, identifying it as a promising therapeutic target for HCC treatment. Show less

B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27-IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 interaction-mediated self-targeting, these cells promoted B cell PD-L1 expression and immune evasion. Mechanistically, Show less

Obesity is turning into a more critical problem for public health. Vitamin D The study aims to examine the influence of VD Firstly, a small sample population study was conducted to compare the disparities in serum 25(OH)D A correlation was identified between serum 25(OH)D The study shows that VD Show less

This study aimed to investigate the expression and clinical significance of interleukin-27 (IL-27) and forkhead box P3 (Foxp3) in oral squamous cell carcinoma (OSCC) tissues, analyze their co-expression correlations, and explore their potential as prognostic biomarkers and therapeutic targets for OSCC. Immunohistochemistry (IHC) was used to detect the expression of the two subunits of IL-27, IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), and Foxp3 in OSCC tissues and normal tissues. Chi-square test was used to analyze the correlation between the expression of the three in OSCC tissues and the clinical pathological parameters of patients. The IHC results showed that the expressions of IL-27p28, EBI3 and Foxp3 proteins in OSCC tissues were all higher than those in normal control tissues( The expression levels of IL-27p28, EBI3 and Foxp3 in OSCC tissues are significantly upregulated, indicating that the three play important roles in the occurrence and development of OSCC tumors. Furthermore, its high expression is associated with various clinicopathological characteristics of OSCC patients and can be used as a potential indicator for evaluating the prognosis of OSCC patients. Show less

Cognitive impairments in major depressive disorder (MDD) affect patients' social functioning, with underlying mechanisms involving gut microbiota and inflammatory factors remaining unclear. The study analyzed cognitive function, gut microbiota changes, and inflammatory factor levels in 39 unmedicated MDD patients and 41 healthy controls, employing correlation and moderation effect analysis. MDD patients scored lower than controls in cognitive functions like information processing speed, attention/vigilance, verbal learning, visual learning and social cognition. They showed reduced gut microbiota diversity and increased levels of inflammatory markers (TNF-α, IL-1, IL-6, IL-17, IL-27, IL-33). Sellimonas abundance correlated negatively with attention/vigilance, moderated by TNF-α, IL-27, and IL-33. This relationship was stronger at lower inflammation levels. MDD patients exhibit multi-domain cognitive dysfunction alongside pro-inflammatory states and disrupted gut microbiota. The abundance of Sellimonas significantly predicts attention/vigilance deficits. Inflammatory factors modulate the impact of gut microbiota on cognitive function, suggesting chronic low-grade inflammation as a key risk factor for cognitive impairment in MDD. Show less

The newly generated CD4 single-positive (SP) T lymphocytes are featured by enhanced IL-4 but repressed IFN-γ production. The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4 Show less

Diabetic foot ulcer (DFU), a serious complication of diabetes, is a life-threatening disease that often leads to lower limb amputation and a shortened lifespan. Interleukin-27 (IL-27) is a member of the IL-12 family and has the potential to exert dual effects on the immune response. The role of IL-27 in diabetic skin wound healing is unknown. The aim of this study was to investigate whether there is abnormal expression of IL-27 in diabetic skin and whether supplementation with IL-27 can promote diabetic wound healing by modulating macrophage polarization. We established a streptozotocin (STZ)-induced diabetic mouse model and constructed diabetic wounds. We assessed protein expression by western blotting (WB) and immunohistochemical (IHC) staining. We also performed hematoxylin-eosin (H&E) staining and Masson's trichrome staining. In the presence of lipopolysaccharide (LPS) and high glucose (HG), we treated the mononuclear macrophage line RAW264.7 and bone marrow-derived macrophages (BMDMs) with IL-27. To assess macrophage polarization, we examined the expression of inducible nitric oxide synthase (iNOS), IL-1β and arginase-1 (Arg-1). To understand the underlying mechanisms, we used macrophage IL-27ra knockout mice to knockout macrophage IL-27 receptors. Our in vivo experiments revealed that the expression of IL-27 in the skin of diabetic mice was significantly decreased and that supplementation with IL-27 promoted diabetic wound healing. In vitro, compared with the LPS group, supplementation with IL-27 alleviated the suppression of multiple cellular functions, such as iNOS and IL-1β expression, cell migration, and phagocytosis, in macrophages after HG exposure. Mechanistically, we found that IL-27 expression was decreased and that the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation was inhibited in diabetic skin, leading to an inability of wound macrophages to polarize to an M1 phenotype effectively, which in turn blocked M1-to-M2 polarization of wound macrophages and ultimately delayed wound healing. The present study revealed that supplementation with IL-27 promoted M1-to-M2 polarization of wound macrophages and diabetic wound healing through the IL-27-IL-27Rα-p-STAT3 axis. These findings suggest that IL-27 may be a potential therapeutic target for DFU. Show less

Obesity arises from an imbalance between adipogenesis and adipocyte thermogenesis. Interleukin-27 (IL-27), a heterodimer cytokine, is known to promote thermogenesis in brown adipose tissue. However, its role in adipogenesis remains unclear. This study aims to investigate the effects of IL-27 on adipogenesis both in vitro and in vivo, and to elucidate the underlying mechanisms. In vitro, an adipogenic differentiation model of adipose-derived mesenchymal stem cells (ADSCs) demonstrate that IL-27 is non-cytotoxic to ADSCs and inhibits ADSCs adipogenic differentiation. In vivo, using a high-fat diet (HFD)-induced obese mouse model and a targeted adipose tissue-specific IL-27 overexpression adeno-associated viral (AAV) vector, we confirm that IL-27 suppresses adipogenesis, prevents weight gain, and improves glucose and lipid metabolic homeostasis in obese mice. Additionally, the inhibition of adipogenesis by IL-27 is mediated through HDAC6 activation of the TGFβ/Smad3 signaling pathway. Our study suggests that IL-27 is a potential therapeutic target for obesity and metabolic disorders. Show less

Excessive inflammation in sepsis causes microvascular dysfunction associated with organ dysfunction and high mortality. The present studies aimed to examine the therapeutic potential of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor in a clinically relevant polymicrobial sepsis model in mice. Sepsis was induced by cecal ligation and puncture (CLP). Mice were grouped into: Sham control+vehicle; Group 2: CLP+vehicle; Group 3: CLP+dexamethasone (10 mg/kg, s.c.) given 6 h after CLP; Group 4: CLP+linagliptin (1 mg/kg, s.c.) given 6 h after CLP. The experiment was terminated 24 hours after CLP in two experimental sets. Seven-day survival following CLP was determined in a third experimental set. Treatment with linagliptin inhibited DPP-4 activity, increased the levels of active forms of endogenous gastric inhibitory polypeptide and glucagon-like peptide-1, without affecting the blood glucose levels in CLP mice. Compared to vehicle treatment, administration of linagliptin reduced sepsis-induced tissue hyper permeability as evidenced by a reduction in vascular Evans blue leakage, prevented edema formation in the lung, heart, liver and kidney. Furthermore, linagliptin or dexamethasone reduced sepsis-induced proinflammatory cytokine and chemokine production, such as IL-1β, IL-2, IL-10, IL-23, IL-27, VCAM-1, eotaxin, MDC, MCSF1, GCP-2, and NGAL. Importantly, administration of linagliptin improved the 7-day survival rate following CLP in mice. RNA sequencing in lung and heart revealed that linagliptin attenuated key inflammatory pathways including TNF alpha (via NFκB) and IL6/JAK/STAT3 signaling and activated interferon signaling in the heart. Linagliptin treatment can attenuate the inflammatory response, protect against severe sepsis-induced vascular hyperpermeability, reduce multiorgan injury, and most importantly, improve the survival. Show less

Disrupting liver immune homeostasis drives inflammation. Recent evidence shifts immunoregulatory focus to hepatocytes, though the mechanisms remain poorly defined. Forkhead box O1 (FoxO1) is a critical homeostasis regulator, but its function in liver immune homeostasis is unknown. We aimed to clarify the role of hepatocyte FoxO1 in liver immune homeostasis and inflammation. Human liver FoxO1 expression and its association with inflammation were analyzed in patients with various inflammation-related liver diseases. Hepatocyte-specific Foxo1 knockout (FoxO1 △hepa ) mice were established. Hepatocyte-specific gene interference was employed in alcoholic hepatitis and hepatic schistosomiasis murine models. Transcriptomic, single-cell RNA sequencing, and CUT&Tag analyses were performed to elucidate the underlying mechanisms. Hepatocyte FoxO1 levels in human inflammatory livers declined prevalently and were inversely correlated with inflammation and fibrosis. Around 15-18 weeks after birth, FoxO1 △hepa mice exhibited mild spontaneous hepatic inflammation with natural killer T (NKT) cell and neutrophil accumulation. NKT cell depletion in FoxO1 △hepa mice with alcoholic hepatitis or hepatic schistosomiasis (HS) significantly reduced neutrophil accumulation and protected against liver inflammation and damage. Mechanistically, FoxO1 promoted retinoic acid synthesis to induce hepatocyte CD1d expression, which is necessary for regulating NKT cell apoptosis. Innovatively, decreased JMJD1C expression in hepatocytes caused histone H3 lysine 9 (H3K9) dimethylation at the Foxo1 promoter, repressing its transcription and disrupting local immune homeostasis. Our findings uncover a hitherto unrecognized mechanism for hepatocyte-based control of liver inflammation, in which hepatocyte FoxO1 maintained by JMJD1C restrains local NKT cells and neutrophils via CD1d induction, providing promising targets for inflammatory liver diseases. Show less