👤 Mengdi Yu

Kidney renal clear cell carcinoma (KIRC), the predominant subtype of renal cell carcinoma, poses significant health risks. The rapid progression and resistance to targeted therapies highlight the need for new tumor markers and therapeutic targets. FADS1, part of the fatty acid desaturase family, regulates fatty acid synthesis and participates in lipid metabolism. However, its role in KIRC is not well-studied. The study utilized bioinformatics analysis through the TCGA database and other platforms to identify FADS1 expression levels in KIRC. Twenty pairs of KIRC clinical tissue samples were used for qPCR verification. Meanwhile, eight pairs of KIRC clinical tissue samples were used for Western blot verification. Conduct statistical evaluation, including Wilcoxon rank sum test and Kaplan-Meier analysis, to explore the correlation between FADS1 expression and clinical pathological features and immune infiltration. In addition, in vitro experiments were conducted to confirm the biological function of FADS1. The findings indicated that FADS1 is highly expressed in KIRC and contributes to tumor development. FADS1's role in lipid metabolism leads to lipid accumulation within tumor cells, which may influence the occurrence and progression of KIRC. TIMER analysis revealed a correlation between FADS1 expression and the infiltration levels of various immune cells, indicating its potential role in modulating immune characteristics. FADS1 could serve as a prognostic biomarker associated with immunity in KIRC, highlighting its potential as a diagnostic and therapeutic target. The study underscores the importance of further research into FADS1's role in lipid metabolism and immune infiltration to develop effective therapeutic strategies. Show less

Preclinical data have shown that low levels of metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolites and long-term ASCVD risk is not known. We characterised the plasma metabolomic profile (1228 metabolites) of 1852 participants (58.1 ± 7.5 years old, 69.6% female, 43.6% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Logistic regression was used to assess the impact of metabolite levels on ASCVD risk (nonfatal MI, revascularisation, and cardiac mortality). We additionally explored the effect of genetic variants neighbouring ASCVD-related genes on the levels of metabolites predictive of ASCVD events. The Atherosclerosis Risk in Communities (ARIC) study (n = 4790; 75.5 ± 5.1 years old, 57.4% female, 19.5% self-identified as Black) was used as an independent validation cohort. In fully adjusted models, alpha-ketobutyrate [AKB] (OR 0.62 [95% CI, 0.49-0.80]; p < 0.001), and 1-palmitoyl-2-linoleoyl-GPI [OR, 0.62, 95% CI, 0.47-0.83; p < 0.001], two metabolites in amino acid and phosphatidylinositol lipid pathways, respectively, showed a significant protective association with incident ASCVD risk in both Heart SCORE and ARIC cohorts. Three plasmalogens and a bilirubin derivative, whose levels were regulated by genetic variants neighbouring FADS1 and UGT1A1, respectively, exhibited a significant protective association with ASCVD risk in the Heart SCORE only. Higher mid-life levels of AKB and 1-palmitoyl-2-linoleoyl-GPI metabolites may be associated with lower risk late-life ASCVD events. Further research can determine the causality and therapeutic potential of these metabolites in ASCVD. This study was funded by the Pennsylvania Department of Health (ME-02-384). The department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Additional funding was provided by National Institutes of Health (NIH) grant R01HL089292 and UL1 TR001857 (Steven Reis). Further, NIH funded R01HL141824 and R01HL168683 were used for the ARIC study validation (Bing Yu). Show less

We aimed to explore the treatment effect and therapeutic mechanisms of baicalin in Alzheimer's disease (AD). The AD rat model was established by intracerebroventricular injection of Aβ1-40, with rats in the baicalin group receiving baicalin intraventricular injections. Morris Water Maze and Hematoxylin-eosin (H&E) Staining were employed to detect the successful model construction and baicalin treatment effect. The proteins extracted from the hippocampus were subjected to proteomics analysis. Bioinformatics technology was employed for differential protein screening, functional classification, and enrichment. Western Blot was employed to validate the expressions of differentially expressed proteins (DEPs) and the protein modification alternations. Water maze test confirmed the successful AD model construction and baicalin can improve learning and memory abilities. A total of 26 DEPs associated with 28 Gene Ontology (GO) functions were identified in the model and 32 DEPs were obtained between the baicalin group and the model. Bioinformatics analysis demonstrated that AD occurrence resulted in neuronal dysfunction and was associated with immune responses. The baicalin therapeutic effect on AD may be associated with metabolic processes, vitamin response, angiogenesis regulation, and fatty acid response. Immunoglobulin heavy constant mu (Ighm) and Immunoglobulin G2a (IgG2a) exhibited significant increases in AD and baicalin attenuated their expressions, while Fatty acid desaturase 1 (Fads1) exhibited a significantly diminished expression and baicalin could reverse the trend. Succinylation detection exhibited the differentially expressed at 35 kD between the model and baicalin group. Baicalin intervention may ameliorate cognitive impairment in AD rats by modulating the expressions of proteins and the succinylation modifications. Show less

Gut microbiota dysbiosis has been linked to the progression of age-related macular degeneration, though the underlying molecular mechanisms remain unclear. This study is the first to systematically link gutMGene-derived genes to AMD pathogenesis using a multi-algorithm machine learning approach. Using the gutMGene database, we identified gut microbiota-related genes and analyzed the GSE29801 dataset for differential expression. Our enrichment analysis revealed unique insights into the involvement of gut microbiota-related genes in inflammatory, immune response, and metabolic pathways in age-related macular degeneration. Machine learning algorithms (LASSO, Random Forest, XGBoost) identified five consistent biomarker genes: CXCL10, FADS3, GHRL, APOE, and VEGFA. A nomogram was developed to predict AMD risk, showing moderate-to-high predictive accuracy with area under the curve of 0.719 (GSE29801) and 0.933 (GSE99248). Gene set variation analysis indicated upregulation of inflammatory and immune pathways and downregulation of lipid metabolism pathways in age-related macular degeneration. Single-gene set enrichment analysis further underscored the roles of diagnostic genes in immune response and metabolic regulation. This study contributes novel evidence that gut microbiota dysbiosis influences AMD progression through systemic inflammatory and metabolic pathways, and highlights potential therapeutic targets. Show less

Podocyte injury is central to diabetic kidney disease (DKD) pathogenesis, however, the mechanisms underlying podocyte loss remain unclear. Emerging evidence underscores the involvement of fibroblast growth factors (FGFs) in renal pathophysiology. Here we reveal a previously unappreciated role of podocyte-secreted FGF4 in safeguarding renal function. FGF4 expression is downregulated in renal tissues from DKD patients and animal models, correlating with disease severity. Podocyte-specific deletion of Fgf4 exacerbated podocyte loss and accelerated DKD progression in mice. Conversely, treatment with recombinant FGF4 (rFGF4) improved glomerular filtration and reduced renal injury and fibrosis in diabetic male mice. These effects are primary mediated by activating the FGFR1-AMPK-FOXO1 signaling cascade in podocytes, which mitigates oxidative stress, suppresses apoptosis, and fosters podocyte survival. Notably, rFGF4 also restores the morphology and function of human podocytes exposed to high glucose. Our findings establish FGF4 as a critical regulator of podocyte homeostasis and a potential therapeutic target for DKD. Show less

Congenital hypogonadotropic hypogonadism (CHH) is a rare condition characterized by incomplete pubertal development, infertility, and gonadotropin-releasing hormone deficiency, associated with mutations in more than 50 genes. We aimed to conduct an etiological analysis of a CHH Chinese family and summarize the clinical presentations and genetic changes of reported similar cases. Whole-exome sequencing (WES) was performed to identify the molecular cause in the proband. In silico tools were employed to analyze the pathogenicity of the variants. Reported cases with similar clinical features and associated genes were summarized by searching through PubMed/MEDLINE using keywords 'FGFR1,' 'CHH,' and 'Kallmann syndrome (KS).' Genetic analysis revealed a novel likely pathogenic deletion mutation in the FGFR1 gene (NM₀₂₃₁₁₀.3: c.263₂₆₄del (Val88Alafs*22)) in a Chinese family exhibiting micropenis and underdeveloped testes. A total of 38 cases with CHH or KS have been previously reported. This study identified a novel FGFR1 deletion variant responsible for CHH, expanding the known mutational spectrum of FGFR1. Typical manifestations include delayed puberty and diverse presentations. The genotype-phenotype correlation in CHH remains unclear and may involve oligogenic effects and epigenetic regulation. Show less

Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS. Show less

Knee osteoarthritis (KOA) is a chronic inflammatory joint disorder marked by cartilage degradation and immune microenvironment dysregulation. While transcriptomic studies have identified key pathways in KOA, the interplay between ferroptosis (an iron-dependent cell death mechanism) and immune dysfunction at single-cell resolution remains unexplored. This study integrates single-cell and bulk transcriptomics to dissect ferroptosis-driven immune remodeling and identify diagnostic biomarkers in KOA. We analyzed scRNA-seq data (GSE255460, Twelve chondrocyte clusters were identified, including ferroptosis-active homeostasis chondrocytes (HomC) ( This study establishes ferroptosis as one of the key drivers immune-metabolic dysfunction in KOA, with HomC acting as a hub for FGF-mediated synovitis and ECM remodeling. The diagnostic model and regulon network ( Show less

Multiple cancers are driven by aberrant fibroblast growth factor receptor (FGFR) signaling and vascular endothelial growth factor receptor (VEGFR)-linked angiogenesis. Several therapeutic agents targeting FGFR and VEGFR have been developed and approved for use in solid cancers; however, there is still a high unmet medical need for new agents that have a more powerful antitumor activity and a broader antitumor spectrum. Here, we report the discovery of FH-2001, a novel and potent FGFR/VEGFR dual inhibitor, with additional activity of modulating programmed cell death ligand 1 (PD-L1) gene expression. In biochemical assays, FH-2001 showed potent inhibition of FGFR1, 2, 3, and 4, with half-maximal inhibitory concentration (IC 50 ) of 0.2, 0.2, 0.4, and 2.0 nM, respectively, and VEGFR1, 2, and 3, with IC 50 values of 2.0, 0.3, and 0.5 nM, respectively. FH-2001 significantly suppressed the cell growth of FGFR- or VEGFR-driven cancer cell lines. In representative cell line- and patient-derived tumor xenografts with aberrant FGFR or VEGFR signaling, FH-2001 substantially inhibited tumor growth. Furthermore, FH-2001 demonstrated marked antitumor activities when treated alone or combined with PD-L1 or PD-1 antibody in syngeneic mouse models. Flow cytometric analysis revealed that FH-2001 alone or in combination with anti-PD-L1 increased T and natural killer cells and decreased myeloid cells in the tumor microenvironment. Mechanistically, FH-2001 treatment dramatically reduced c-Myc and PD-L1 mRNA and protein levels in a dose-dependent manner in vitro . Taken together, FH-2001 is a promising dual-target inhibitor of FGFR and VEGFR and also modulates cancer immunity, while its robust antitumor activity positions it as a potentially class-leading anticancer agent. Show less

Rheumatoid arthritis (RA) frequently leads to osteoporosis (OP) and increased fracture risk. The protein Klotho plays a recognized role in bone metabolism, yet its specific function in RA-associated osteoporosis (RA-OP) remains incompletely understood. This study investigated the molecular mechanisms by which Klotho maintains bone homeostasis in RA-OP patients. We quantified Klotho levels in RA-OP patients and healthy controls and then conducted in vitro experiments using mouse embryonic osteoblast precursor cell line (MC3T3-E1) preosteoblastic cells to examine Klotho's effects on osteogenic differentiation and ferroptosis. We assessed osteogenic differentiation through runt-related transcription factor 2 (Runx2), collagen type i alpha 1 chain (Col1a1), and osteocalcin (Ocn) expression, while ferroptosis regulation was evaluated via glutathione peroxidase 4 (Gpx4) and Acyl-CoA synthetase long-chain family member 4 (Acsl4) expression. The interaction between fibroblast growth factor 23 (Fgf23) and fibroblast growth factor receptor 1 (Fgfr1) was analyzed using coimmunoprecipitation assays, with Fgf23's role examined through knockdown and overexpression experiments. Results showed RA-OP patients had significantly reduced Klotho levels compared to controls. Klotho overexpression in MC3T3-E1 cells enhanced osteogenic differentiation and protected against ferroptosis by upregulating Gpx4. Mechanistically, Klotho facilitated Fgf23-Fgfr1 interaction and repressed nuclear factor κ (NF-κB) signaling. Our findings demonstrate that Klotho mediates osteogenic action through the Fgf23/Fgfr1-NF-κB pathway while simultaneously protecting osteoblasts from ferroptosis, advancing our understanding of RA-OP pathophysiology and identifying Klotho as a promising therapeutic target for preventing RA-related bone loss. Show less

Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its antibacterial properties remain unknown. Here, we demonstrated that DZB displays broad-spectrum activity against Show less

SANET-ep (NCT02588170) and SANET-p (NCT02589821) demonstrated the efficacy and safety of surufatinib versus placebo in patients with advanced extra-pancreatic and pancreatic neuroendocrine tumours (NETs). Here, we present a pooled analysis of final overall survival (OS) from two randomised phase 3 studies. The SANET studies were randomised, placebo-controlled, double-blind, phase 3 studies in China, comparing the efficacy and safety of oral 300-mg surufatinib (n = 265) versus placebo (n = 133) in patients with unresectable/metastatic, well-differentiated NETs (grade 1/2). After progression of disease or study unblinding, patients receiving placebo crossed over/switched to open-label surufatinib. By pooling the data from the two studies, OS analysis was completed using Kaplan-Meier methodology and a Cox proportional hazards model in the intention-to-treat population. Exploratory analyses were performed using different models to correct the confounding effect introduced by crossover. Long-term safety was assessed. At study termination, 69 % of the placebo group had crossed over/switched to surufatinib. Median OS was 50.1 versus 46.8 months for patients initially on surufatinib versus those initially on placebo (stratified hazard ratio [HR] 0.935, 95 % confidence interval [CI] 0.684-1.278; p = 0.6727). After correcting the confounding effect introduced by crossover/switching, the HR ranged from 0.558 to 0.825. Commonly (≥10 %) reported treatment-related adverse events (grade 3/4) included hypertension and proteinuria. OS of patients initially on surufatinib was not significantly longer versus patients initially on placebo, likely due to the high amount of crossover from placebo to surufatinib. No new safety signals were observed. SANET-ep (NCT02588170) and SANET-p (NCT02589821). Show less

The current study aims to investigate whether exosomal miRNAs are involved in lipid reduction by selenium (Se) in the liver of grass carp, through miRNA sequencing, transfection of miRNA mimic (miR-22m) or inhibitor (miR-22i), isolation of hepatocyte-derived exosomes and treatment, and detection of lipid metabolism-related genes and proteins. The miRNAs sequencing and bioinformatics revealed that miR-22 was most abundantly expressed in the differentially expressed miRNAs after selenium treatment, and was enriched in lipid metabolism-related pathways. Moreover, Se significantly up-regulated the miR-22 levels and reduced the lipid content in liver or hepatocytes of grass carp. Furthermore, the miR-22m significantly increased levels of miR-22 and reduced lipid content in grass carp hepatocytes, which were consistent with the Se-treatment. However, the miR-22i reversed these trends. Besides, the miR-22 suppressed the FGFR1-PI3K-AKT-mTOR signaling pathway and its downstream genes related to lipid synthesis. More importantly, the Se-treated hepatocyte-exosomes which were enriched in the miR-22 significantly reduced the triglycerides content in the oleic acid-treated hepatocytes. In summary, Se alleviated high fat-induced lipid accumulation in grass carp liver by up-regulating the expression of miR-22 which negatively regulates FGFR1 and its downstream regulatory genes. Moreover, exosomes participate in the lipid reduction by Se, which may be through carrying miR-22. Show less

Anxiety disorder is a highly prevalent psychological illness, and research has shown that obesity is a significant risk factor for its development. This study explored the ameliorative effects and mechanisms of saponins from Panax japonicus(SPJ) on anxiety disorder in mice fed a high-fat diet(HFD). Fifty C57BL/6J mice were randomly divided into normal control diet(NCD) group, HFD group, and low-and high-dose SPJ groups. At week 12, six mice from the HFD group were further divided into a control group(treated with DMSO) and an exogenous fibroblast growth factor 21(FGF21) group(administered rFGF21). The anxiety-like behavior of the mice was assessed using the open field test and elevated plus maze test. Hematoxylin-eosin(HE) staining and oil red O staining were performed to observe pathological changes in the liver and adipose tissue. Glucose metabolism was evaluated through the glucose tolerance test(GTT) and insulin tolerance test(ITT). Western blot analysis was performed to detect the expression of FGF21 and its downstream-related proteins in the liver and cortex, along with the expression of brain-derived neurotrophic factor(BDNF), disks large homolog 4(DLG4), and synaptophysin(SYP) in the cortex. Real-time quantitative fluorescent PCR(qPCR) was used to detect the expression of FGF21 and its receptor genes in the liver and cortex. Immunofluorescence staining was employed to examine the expression of neuronal activator c-Fos, FGF21, and the FGF21 co-receptor β-klotho in the cerebral cortex. The results showed that SPJ significantly improved the frequency of activity in the open arms of the elevated plus maze and the central area of the open field in HFD mice, up-regulated the expression of BDNF, DLG4, and SYP, and effectively alleviated anxiety-like behaviors in HFD mice. Compared with the NCD group, HFD mice exhibited up-regulated expression of FGF21 in the liver and cerebral cortex, while the expression of fibroblast growth factor receptor 1(FGFR1) and β-klotho was significantly down-regulated, suggesting that HFD mice exhibited FGF21 resistance. SPJ markedly up-regulated the β-klotho levels in HFD mice, reversing FGF21 resistance. Further comparison with exogenously administered FGF21 revealed that SPJ activates brain cortical regions in a consistent manner, and additionally, SPJ promotes the number and colocalization of c-Fos and β-klotho positive cells in the brain cortex. In summary, SPJ effectively alleviates anxiety-like behaviors in HFD mice. Its mechanism is associated with up-regulation of β-klotho expression in the brain, reversal of FGF21 resistance, and subsequent activation of neurons in the cerebral cortex and amygdala. Show less

Patients with cancer undergoing cisplatin chemotherapy frequently experience cardiotoxic side effects that significantly affect their prognosis and survival rates. Our study found that Panax ginseng root extract exerted a significant protective effect against cisplatin-induced myocardial cell injury. The present study aims to elucidate the underlying mechanisms by which the bioactive components of Panax ginseng mitigate cisplatin-induced cardiotoxicity (CIC). In vitro, the candidate active components were screened by network pharmacological prediction and in neonatal rat ventricular myocytes (NRVMs), and their mechanisms of action were verified by transcriptome sequencing, western blotting, gene overexpression, immunoprecipitation, immunofluorescence, and cellular thermal shift assays. A C57BL/6 CIC mouse model was established to verify the protective effects of the candidate components and the in vivo mechanism of the candidate components. Through network pharmacology prediction and cellular activity screening of ginseng root compounds, ginsenoside Rh2(S) (Rh2) was identified as a significant active component. Transcriptomic, in vitro, and in vivo experiments demonstrated that Rh2 can activate the Pak1/Limk1/cofilin phosphorylation pathway, thereby inactivating the actin-severing protein cofilin and protecting cardiomyocytes from cisplatin-induced actin depolymerization. Additionally, Rh2 suppressed the ROS/caspase-3/GSDME pathway to inhibit cisplatin-induced pyroptosis. Furthermore, co-immunoprecipitation and overexpression experiments confirmed that Rh2 activated the FGFR1/HRAS axis, thereby simultaneously regulating the two aforementioned pathways to combat CIC. This study demonstrated for the first time that Rh2 is the main active component in Panax ginseng that maintains cytoskeletal homeostasis and inhibits pyroptosis by regulating the FGFR1/HRAS pathway to resist CIC. This study aimed to provide a theoretical basis for expanding the targets and pathways of CIC treatment, and for the development of related drugs. Show less

Cancer-targeted therapies are progressively pivotal in oncological care. Observational studies underscore the emergence of cancer therapy-related cardiovascular toxicity (CTR-CVT), impacting patient outcomes. We aimed to investigate the causal relationship between different types of cancer-targeted therapies and cardiovascular disease (CVD) outcomes through a two-sample Mendelian randomization (MR) study. This genome-wide association study was conducted using a two-sample Mendelian randomization framework. Genetic instruments for drug target gene expression were extracted from the eQTLGen consortium (31684 individuals, 37 cohorts). Genome-wide association study (GWAS) summary statistics for 19 cardiovascular diseases were derived from the FinnGen database. Primary analysis was carried out using the summary-data-based MR (SMR) method, with sensitivity analysis for validation. Colocalization analysis identifies shared causal variants between exposure eQTLs and CVD-associated single-nucleotide polymorphisms (SNPs). Among the 39 drug target genes, 8 were identified with detectable cis-eQTLs and were subsequently validated through positive control analysis for further investigation. In the SMR and sensitivity analyses, genetically proxied VEGFA inhibition showed significantly strong association with stroke (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.09-1.26, p = 1.33 × 10 This genetic association study revealed evidence supporting the genetic association between the use of VEGFA inhibitors and increased stroke risk, highlighting the need for enhanced pharmacovigilance. These findings underscore the delicate balance between cardiovascular toxicity risk and the benefits of cancer-targeted therapy. Show less

Sepsis is characterized by a life-threatening syndrome caused by an unbalanced host response to infection. Fibroblast growth factor 8 (FGF8) has been newly identified to play important roles in inflammation and innate immunity, but its role in host response to sepsis is undefined. A cecal ligation and puncture (CLP)-induced mouse sepsis model was established to evaluate the immunomodulatory function of FGF8 during sepsis. The underlying molecular mechanisms were elucidated by cell models using relevant molecular biology experiments. The clinical value of FGF8 in the adjuvant diagnosis of sepsis was evaluated using clinical samples. FGF8 protein concentrations were elevated in CLP-induced septic mice compared to controls. In vivo, FGF8 blockade using anti-FGF8 antibody significantly increased mortality and bacterial burden and was paralleled by significantly aggravated tissue injury after CLP. Therapeutic administration of recombinant FGF8 (rFGF8) improved the bacterial clearance and mortality of septic mice in a FGFR1-dependent manner. In vitro, FGF8 directly enhanced bacterial phagocytosis and killing of macrophages by enhancing the phosphorylation of the ERK1/2 signaling pathway, which could be abrogated with the ERK1/2 pathway inhibitor U0126. Clinically, serum FGF8 levels in both adult and pediatric patients with sepsis in an intensive care unit were significantly higher than those in healthy controls. These results present a previously unrecognized role of FGF8 in improving survival of sepsis by enhancing host immune defense. Therefore, targeting FGF8 may provide new strategies for the diagnosis and immunotherapy of sepsis. Show less

Peripheral nerve injury (PNI) can transform primary somatosensory neurons to a regenerative state. However, the details of the transcriptomic changes associated with the nerve regeneration of somatosensory neurons remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) is conducted on mouse dorsal root ganglion (DRG) cells after the early stage of nerve injury on day 3 after chronic constriction injury (CCI). We observe that a novel CCI-induced neuronal population (CIP) emerge and express high levels of activating transcription factor ( Show less

The role of FGF is the least understood of the morphogens driving mammalian gastrulation. Here we investigated the function of FGF in a stem cell model for human gastrulation known as a 2D gastruloid. We found a ring of FGF-dependent ERK activity that closely follows the emergence of primitive streak (PS)-like cells but expands further inward. We showed that this ERK activity pattern is required for PS-like differentiation and that loss of PS-like cells upon FGF receptor inhibition can be rescued by directly activating ERK. We further demonstrated that the ERK-ring depends on localized activation of basolaterally positioned FGF receptors (FGFR) by endogenous FGF gradients. We confirmed and extended previous studies in analyzing expression of FGF pathway components, showing FGFR1 is the main receptor, FGF2 is highly expressed across several cell types, and FGF4/17 are the main FGF ligands expressed in the PS-like cells, similar to the human and monkey embryo but different from the mouse. We found that knockdown of FGF4 greatly reduced PS-like differentiation while FGF17 knockdown primarily affected subsequent mesoderm differentiation. FGF8 expression was spatially displaced from PS-markers and FGF4 expression and peaked earlier, while knockdown led to an expansion in PS-like cells, suggesting FGF8 may counteract FGF4 to limit PS-like differentiation. Thus, we have identified a previously unknown role for FGF-dependent ERK signaling in 2D gastruloids and possibly the human embryo, driven by a mechanism where FGF4 and FGF17 signal through basally localized FGFR1 to induce PS-like cells and their derivatives, potentially restricted by FGF8. Show less

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), has been implicated in promoting renal fibrogenesis. Nevertheless, its precise role and underlying mechanisms remain incompletely defined. To investigate the role of EZH2 in partial epithelial-mesenchymal transition (pEMT) and renal fibrosis, we utilized a mouse model with renal tubular cell-specific EZH2 deletion and administered gambogic acid (GA), a selective EZH2 degrader, following unilateral ureteral obstruction (UUO). In vitro, mouse renal epithelial cells were stimulated with TGF-β1 and treated with either EZH2-specific siRNA or GA to assess the effects on EMT and Notch1/3 signaling. In addition, chromatin immunoprecipitation (ChIP) assays were conducted to evaluate the binding of EZH2 and H3K27me3 to the promoters of Notch1 and Notch3. Compared with wild-type controls, mice with tubular cell-specific EZH2 deletion exhibited significantly reduced renal fibrosis, characterized by decreased expression of fibronectin, collagen III, vimentin, and Snail, while preserving E-cadherin levels in injured kidneys. Pharmacological degradation of EZH2 with GA produced comparable antifibrotic effects. UUO injury markedly upregulated Notch1, Notch3, the Notch intracellular domain, Hes1, Hey2, and Jagged-1; these increases were significantly suppressed by either EZH2 deletion or GA treatment. Similarly, in vitro, GA or EZH2-specific siRNA inhibited the expression of Notch signaling molecules in TGF-β1-treated renal epithelial cells. Chromatin immunoprecipitation analyses revealed direct binding of EZH2 and H3K27me3 to the Notch1 and Notch3 promoters. UUO injury enhanced EZH2 binding while reducing H3K27me3 enrichment at these sites, effects reversed by GA treatment. These findings demonstrate that epithelial EZH2 contributes to pEMT in renal tubular cells and promotes renal fibrosis, at least in part through activation of Notch signaling. Targeting EZH2 may hold potential as a therapeutic approach for chronic kidney disease. Show less

Notch2 activation promotes kidney cyst growth. Silencing Notch2 ameliorated cyst growth in mice with autosomal dominant polycystic kidney disease. Notch signaling, a conserved mechanism of cell-to-cell communication, plays a crucial role in regulating cellular processes, such as proliferation and differentiation, in a context-dependent manner. However, the specific contribution of Notch signaling to the progression of polycystic kidney disease (PKD) remains unclear. We investigated the changes in Notch signaling activity (Notch1–4) in the kidneys of patients with autosomal dominant PKD (ADPKD) and two ADPKD mouse models (early and late onset). Multiple genetic and pharmacologic approaches were used to explore Notch2 signaling during kidney cyst formation in PKD. Notch2 expression was significantly increased in the kidney tissues of patients with ADPKD and ADPKD mice. Targeted expression of Notch2 intracellular domain in renal epithelial cells resulted in cyst formation and kidney failure in neonatal and adult mice. Mechanistically, Notch2/Hey2 signaling promoted renal epithelial cell proliferation by driving the expression of the E26 transformation–specific homologous factor (Ehf). Depletion of Ehf delayed Notch2 intracellular domain overexpression–induced cyst formation and kidney failure in mice. A gain-of-function mutation in exon 34 of Notch2 signaling promoted kidney cyst growth, partially by upregulating Ehf expression. Show less

17β-hydroxysteroid dehydrogenase type 3 deficiency is a 46,XY difference of sex development (DSD) that may present in childhood with inguinal testes or at puberty following virilization. We present four individuals, assigned female at birth, to highlight complexities and considerations surrounding orchiectomy. We reviewed the literature and created a "FACT sheet" to guide shared decision-making for patients, parents, and providers. "Ruth" presented at 16 months with inguinal herniae and underwent orchiectomy, based on parental preference. "Erica" presented at 13 years with voice deepening; she and her parents chose pubertal suppression and eventual orchiectomy. "Riley" presented at 18 months with inguinal herniae; after pubertal suppression and estrogen replacement, orchiectomy at age 13 years revealed germ cell neoplasia Show less

Coronary artery disease (CAD) is an immune-mediated disorder driven by dysregulated T cell responses. Interleukin-27 (IL-27) has immunoregulatory properties, but its role in CAD remains unclear. This study is the first to investigate the effects of IL-27 on CD4⁺LAP⁺ T cells in CAD and to explore its interaction with interleukin-2 (IL-2) in modulating immune imbalance. CAD severity was quantified by the Gensini score. Plasma IL-27 and oxidized low-density lipoprotein (ox-LDL) were measured by ELISA. Flow cytometry assessed CD4⁺ T cell subsets, while qRT-PCR and Western blot evaluated lineage-specific transcription factors. IL-27 levels were elevated in acute coronary syndrome and correlated with ox-LDL and Gensini scores. Patients with severe CAD showed a Th1/Th17-dominant profile and reductions in Th2, CD4⁺LAP⁺, and Tregs. In vitro, IL-27 promoted Th1 differentiation via T-bet/IFN-γ upregulation and suppressed Th2, Th17, and regulatory subsets, counteracting IL-2-induced expansion of Tregs and CD4⁺LAP⁺ cells. These effects were dose dependent and favored pro-inflammatory responses. IL-27 drives immune imbalance in CAD by reinforcing Th1 polarization and antagonizing IL-2-mediated regulation. Beyond mechanistic insights, these findings identify IL-27 as a potential biomarker for disease severity and a candidate therapeutic target in CAD. Show less

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

Hyperactivation of cutaneous macrophages promotes the development of chronic pain. Stimulation of nociceptive regions promotes neuroplasticity, which affects pain perception and related physiological responses. However, the specific mechanisms by which cutaneous macrophages sense and elicit nociceptive responses are unknown. Here, we exacerbated the reduction of systemic pain threshold after chronic heart failure (CHF) by silencing follistatin-like 1 (FSTL1), especially the abnormal cutaneous nociceptive sensation at PC6 acupoint, the site associated with cardiac involvement pain. The upregulation of P2Y6 and interleukin-27 expression is intimately linked to the activation of skin macrophages. Hyperactivation of P2Y6 receptor (P2Y6R) may be associated with MHC II M1 Show less