👤 Yi-Ping Fu

Atherosclerosis is a primary contributor to worldwide morbidity and mortality. Failure to timely clear apoptotic cells can trigger a cascade reaction, where the necrotic core expands until the fibrous cap is ruptured, and atherosclerotic plaques become vulnerable. Efferocytosis is an important method for recognizing and eliminating apoptotic cells. Nevertheless, the specific effect of efferocytosis on atherosclerosis remains uncertain. This study aimed to identify and verify the relevant characteristics of efferocytosis for detecting atherosclerosis. The data of gene expression patterns of atherosclerosis were sourced from the Gene Expression Omnibus (GEO) database, and the differential expression analyses of efferocytosis-related genes (EFRGs) were performed between the atherosclerosis samples and the control samples. Subsequently, protein-protein interaction (PPI), correlation analysis, and functional enrichment analysis were performed to reveal the interaction between molecules as well as their pathways. Machine learning (ML) was employed to determine hub genes to construct a clinical prediction model. At the same time, immune infiltration, single-cell transcriptome analysis, and cell experiments were conducted in both atherosclerosis and control samples to provide a reference for the immune cell landscape and the cell heterogeneity under this condition. The study revealed that 14 genes were closely related to efferocytosis in atherosclerosis. Among them, an ML model was used to screen 5 potential diagnostic biomarkers, including tumor necrosis factor (TNF), apolipoprotein E (ApoE), neutrophil cytosolic factor 1 (NCF1), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase-3 like-protein-1 (CHI3L1). Subsequent external validation indicated that, except for TNF, the other 4 genes were all upregulated. From the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) analysis, those 5 genes were all significantly associated with various immune cells. Further single-cell RNA sequencing (scRNA-seq) analysis demonstrated that those 5 genes were selectively upregulated in the macrophages of atherosclerosis lesions, which was supported by mRNA levels in cell experiments. This study clarified the association between atherosclerosis and efferocytosis, and established an effective diagnostic model. Moreover, potential treatment targets for atherosclerosis were identified, offering new insights into the potential mechanism of atherosclerosis. Show less

Aging populations face increasing incidence of neurological disorders, including Alzheimer's disease (AD) and late-onset epilepsy (LOE), which demonstrate a bidirectional relationship where AD is a risk factor for LOE and LOE is a risk factor for AD. While the APOE gene is a known shared risk factor, comprehensive genetic studies for LOE remain limited. This study employed a multi-task learning framework using Elastic Net modeling to systematically identify shared genetic risk factors between AD and LOE. We analyzed electronic health records from UCLA Health System (N = 416,212; genetic subset N = 16,500) and validated findings in the All of Us dataset (N = 52,493). Longitudinal analyses confirmed strong bidirectional associations between AD and LOE. The multi-task learning approach identified eight shared-risk single nucleotide polymorphisms mapping to key genes including the APOE-TOMM40-APOC1 cluster, BIN1, CLU, PVRL2, and TRAPPC6A. These shared-risk genes were enriched in pathways related to lipid metabolism, amyloid catabolic processes, and tau protein binding. A shared genetic risk score effectively stratified patients into distinct AD-LOE risk groups. This study represents an initial systematic identification of potential shared genetic factors between AD and LOE using multi-task learning. While our findings suggest possible shared genetic contributions, particularly in the APOE region, and highlight tau-mediated mechanisms as potential therapeutic targets, further validation is needed to establish the extent of genetic overlap between these conditions. Show less

Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE Show less

Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatments such as statin drugs and stent implantation are associated with significant side effects or limited efficacy, highlighting the urgent need for new therapeutic strategies. Pulsed electromagnetic fields (PEMFs), due to their noninvasive nature and anti-inflammatory properties, show potential in the treatment of atherosclerosis. This study utilized ApoE-/- mice, ApoE-/-NLRP3-/- knockout mice, human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), and human plasma samples for experiments, revealing significant endothelial cell (EC) inflammation and pyroptosis during the progression of atherosclerosis. PEMFs were found to effectively inhibit the activation of the NLRP3 inflammasome, reduce plaque formation, and delay the progression of atherosclerosis. Proteomic analysis of plasma from atherosclerosis patients further indicated elevated expression levels of proteins related to inflammation and pyroptosis, with particularly notable changes in membrane proteins. Mechanistic studies demonstrated that PEMFs improve mitochondrial dysfunction in ECs by regulating membrane tension and the mechanosensitive tension-mediated transient receptor potential vanilloid 4 (TRPV4) channels, thereby reducing pyroptosis. This discovery not only reveals a novel mechanobiological pathway but also provides a solid theoretical foundation for the development of PEMF-based therapies for atherosclerosis. Schematic diagram of the mechanism by which PEMFs treat atherosclerosis (created in BioRender). Wei, B. (2025) https://BioRender.com/undefined ). Show less

Hepatic ischemia‒reperfusion injury (HIRI) is a common pathological phenomenon after hepatectomy and liver transplantation. Here, we aim to explore the role of Axin formation inhibitor 1 (Axin1) in HIRI. In this work, we find that the expression of Axin1 is upregulated after HIRI. Cellular experiments confirme that Axin1 knockdown alleviated hypoxia/reoxygenation (H/R)-induced inflammation and apoptosis. Subsequently, we construct a HIRI model based on transgenic hepatocellular-specific Axin1 knockout and overexpression male mice and find that Axin1 deletion alleviated inflammation and apoptosis. Transcriptome sequencing reveal that the genes whose expression differed after Axin1 overexpression are significantly enriched in the PPAR signaling pathway. Furthermore, we demonstrate that Axin1 negatively regulates the expression of PPARβ, thereby activating the NF-κB pathway. Mechanistically, Axin1 binds to PPARβ to enhance the ubiquitination-mediated degradation of PPARβ by the E3 ubiquitin ligase RBBP6. Notably, adenovirus-mediated Axin1 knockdown block I/R damage in mice. Our study results demonstrate that Axin1 exacerbates HIRI by promoting the ubiquitination and degradation of PPARβ, which in turn activates the NF-κB signaling pathway. These results suggest that Axin1 may be a potential therapeutic target for HIRI. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear pathogenesis and no effective treatment methods. HY-021068 (HY), a novel class I drug, exhibits significant neuroprotective properties in ischemic brain injury. Recent studies suggest that neuronal ferroptosis may be a critical contributor to the onset and progression of AD. However, it is still unclear whether HY treatment has protective effects on AD by inhibiting ferroptosis. In this study, APP/PS1 double transgenic mice were used to investigate the effect and mechanism of HY in AD. In vitro, HT22 cells were stimulated with Amyloid β Show less

Amyloid-β (Aβ) deposition was an important pathomechanisms of Alzheimer's disease (AD). Aβ generation was highly regulated by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which is a prime drug target for AD therapy. The silence of BACE1 function to slow down Aβ production was accepted as an effective strategy for combating AD. Herein, BACE1 interfering RNA, metallothionein (MT) and ruthenium complexes ([Ru(bpy) Show less

Aβ is believed to play a significant role in synaptic degeneration observed in Alzheimer's disease and is primarily investigated as a secreted peptide. However, the contribution of intracellular Aβ or other cleavage products of its precursor protein (APP) to synaptic loss remains uncertain. In this study, we conducted a systematic examination of their cell-autonomous impact using a sparse expression system in rat hippocampal slice culture. Here, these proteins/peptides were overexpressed in a single neuron, surrounded by thousands of untransfected neurons. Surprisingly, we found that APP induced dendritic spine loss only when co-expressed with BACE1. This effect was mediated by β-CTF, a β-cleavage product of APP, through an endosome-related pathway independent of Aβ. Neuronal expression of β-CTF in mouse brains resulted in defective synaptic transmission and cognitive impairments, even in the absence of amyloid plaques. These findings unveil a β-CTF-initiated mechanism driving synaptic toxicity irrespective of amyloid plaque formation and suggest a potential intervention by inhibiting the endosomal GTPase Rab5. Show less

Branched-chain amino acids (BCAAs), including valine, leucine and isoleucine, are essential nutrient signals that influence mammalian animal metabolism. Many enzymes are involved in the metabolism of BCAAs, such as branched-chain amino acid transaminases (BCATs), branched-chain α-keto acid dehydrogenase (BCKDH), and BCKDH kinase (BCKDK). The aberrant expression of enzymes involved in BCAA metabolism and an imbalance in BCAA amino acid intake can lead to disordered metabolism. Aberrant BCAA metabolism can lead to several diseases, such as human ovarian disease, including ovarian cancer (OC), polycystic ovary syndrome (PCOS), and premature ovarian failure (POF), which are common gynaecological diseases. The overexpression of BCATs is found in OC, which promotes BCAA catalysis to provide a large amount of energy for tumorigenesis. However, BCKDK is overexpressed in epithelial ovarian cancer (EOC), which promotes proliferation and migration via MEK-ERK. In addition, several studies have reported that high levels of BCAAs are increased in the plasma of PCOS and POF patients. This review focuses on the role of BCAA metabolism and potential management methods for OC, PCOS and POF. Show less

The protein branched-chain ketoacid dehydrogenase kinase (BCKDK), which regulates the metabolism of branched-chain amino acids, has recently been implicated in tumor progression. However, the role of BCKDK in lung cancer remains largely unexplored. In this study, we explored the mechanisms by which BCKDK influences lung cancer progression and contributes to drug resistance. By integrating single-cell RNA and bulk RNA sequencing data from lung cancer patients, we identified BCKDK as a novel gene related to malignant epithelial cells, involved in tumor initiation and associated with poor patient prognosis. Subsequently, through a series of molecular biology experiments, we demonstrated that BCKDK promotes aerobic glycolysis, Trametinib resistance, and tumor progression in lung cancer by upregulating MYC transcription. Mechanistically, BCKDK interacts with BCLAF1 to promote its phosphorylation at the serine 285 site. This modification facilitates BCLAF1 binding to the MYC promoter, thereby enhancing MYC transcription. Subsequently, elevated MYC levels upregulate hexokinase 2, promoting aerobic glycolysis and lung cancer progression. In addition, the elevated glycolysis product, lactate, promotes Trametinib resistance by upregulating the ABC transporters. Taken together, our data identify BCKDK as a novel regulator of aerobic glycolysis that promotes lung cancer progression and Trametinib resistance through the BCKDK/BCLAF1/MYC/HK2 axis. Targeting BCKDK in combination with Trametinib may offer a promising treatment for lung cancer. Graphical representation of the BCKDK/BCLAF1/MYC/HK2 axis and its role in Trametinib resistance and lung cancer progression. Created with BioRender.com. Show less

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer. Previous studies have highlighted the critical roles of complement and coagulation cascades in tumor development, maintenance, and therapeutic response. However, the overall impact of complement and coagulation cascade-related (CCCR) genes on LUAD progression and their role in the tumor microenvironment (TME) remain insufficiently explored. Therefore, we screened CCCR genes with important roles in LUAD using RNA sequencing data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Subsequently, a prognostic model, based on 8 hub genes (IGFBP1, TUBB, PLEK2, CNTNAP2, CPS1, EREG, CENPE, HBEGF) identified using the Lasso-Cox algorithm, was developed to stratify LUAD patients into high- and low-risk groups. This model demonstrated strong predictive capability and calibration, with an AUC of 0.816 in the external validation cohort. Multiomics clustering revealed that 2 cancer subtypes (CSs) are associated with prognosis, with CS2 demonstrating the most favorable prognostic outcome and validating the validity of the prognostic model. Additionally, we analyzed the immune infiltration, tumor mutation burden (TMB) and immunophenoscore (IPS) of the riskscore in the models. Through this analysis, we have identified for the first time CCCR genes are highly associated with clinical characteristics, immune cell infiltration patterns, and immune therapeutic responses of LUAD. This prognostic model constructed based on CCCR genes represents a valid tool for the prognosis of LUAD patients. Our findings provide valuable insights into the prognostic and immunological relevance of CCCR genes in LUAD, offering a robust foundation for personalized treatment strategies and future research. Show less

In recent years, polysaccharides from Codonopsis pilosula (CPs) have received increasing attention for their excellent behaviors in immune-regulation. However, the relationship between the structure and immunomodulatory activity has rarely been reported. In this work, four fractions purified from crude CPs (CPW, CPS0.2, CPS0.5, CPS1) by chromatographic column separation were explored with both structure and immunomodulatory effects by THP-1 cells. The results showed that the monosaccharide composition, chain conformation, molecular weight (M Show less

DHX36 is an ATP-dependent DNA/RNA helicase that unwinds the guanine-quadruplexes (G4s) of DNA or RNA and regulates their metabolism for key biological functions. Breast cancer is a malignant tumor and effective targeted therapy drugs are limited, even though chemotherapy is generally used. In this study, we found that overexpression of DHX36 promotes breast cancer cell growth, migration, and invasion in vitro, while knocking down or knocking out reversed in vitro and in vivo. Moreover, DHX36 was highly expressed in most clinical breast tumor tissues compared with the matched healthy tissues. Accordingly, higher DHX36 expression correlated with poor recurrence-free survival (RFS) in the patients of breast cancer. These results substantiate that DHX36 might be a diagnostic and prognostic biomarker and is a proto-oncogene that promotes the growth and metastasis of breast cancer. Thus, targeting DHX36-associated G4s in genes, particularly in proto-oncogenes, might be a novel anticancer strategy. Show less

Glioblastoma is the most aggressive form of primary brain tumor, characterized with poor prognosis and resistance to conventional therapies. Increasing evidence points to oxidative stress and redox dysregulation as important contributors to glioblastoma progression. Previously, chloride intracellular channel protein 4 (CLIC4), a redox-sensitive protein, has been implicated in cancer biology. However, its roles in glioblastoma remain poorly understood. Here, we found that CLIC4 expression is upregulated in glioblastoma tissues and cell lines, and is positively correlated with tumor malignancy and poor survival outcomes in patients with glioblastoma. Gene silencing of CLIC4 significantly reduces glioblastoma cell viability, migration, and proliferation in vitro and suppress tumor growth in vivo. Mechanistically, CLIC4 appears to maintain redox homeostasis by regulating mitochondrial functions, including membrane potential, mass, ROS production, and the activity of complexes III and IV. Moreover, a G-quadruplex (G4) structure located in CLIC4 promoter region is related to CLIC4 upregulation by oxidative stress in glioblastoma. This G4 structure can be readily oxidized to a parallel conformation, thereby enhancing its binding with DHX36 protein to promote gene transcription. Collectively, these findings position CLIC4 as a pivotal modulator of oxidative stress in glioblastoma and a potential target for developing therapeutic approaches for the treatment of glioblastoma. Show less

Reproductive and growth traits are key economic traits in sheep. This study aims to identify key single nucleotide polymorphisms (SNPs) and candidate genes associated with reproductive and growth traits in Tianmu polytocous sheep through a genome-wide association study (GWAS). The findings are expected to provide both a theoretical foundation for molecular breeding in this breed and novel insights into the genetic basis of ovine reproductive and growth performance. This study took 483 adult Tianmu polytocous ewes as the research subjects, collected their lambing records, measured their phenotypic values of growth traits (3 weight and 11 body size traits), and collected their blood samples for whole-genome resequencing to identify SNPs in the Tianmu polytocous sheep genome. The results identified a total of 9,499,019 (3× coverage) and 27,413,216 (30× coverage) high-quality SNPs in the Tianmu polytocous sheep genome. Subsequently, the association analysis between SNPs and reproductive and growth traits was conducted using a mixed linear model. A total of 92, 66, 18, 28, 6, 42, 3, 3, 6, 1, 12, 3, 22, 8, 6, and 3 SNPs were found associated with litter size at first parity, litter size at second parity, litter size at third parity, litter size at fourth parity, birth weight, weaning weight, body height, withers height, body length, head length, head width, cannon bone circumference, forelimb height, chest girth, chest depth, and withers width, respectively. Further, based on SNP annotation, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, candidate genes associated with the reproductive and growth traits were identified. Among these genes, 11 Show less

Based on the Caco-2 cell heat stress model, the study explored the heat stress preventive regulatory mechanisms of key polyphenol fractions in mung bean by metabolomics and transcriptomics association analysis. Results Mung bean polyphenol intervention before heat stress significantly reduced the elevated expression level of heat shock protein 70 (HSP70) caused by 39 °C temperature. At the metabolic level, mung bean polyphenols could play a role in heat stress regulation by alleviating oxidative stress damage. At the gene level, mung bean polyphenols showed regulation of cell proliferation, differentiation, and DNA damage, with DUSP6 and NEURL3 as key regulatory genes. The correlation analysis showed that nucleotide metabolism, and oxidative phosphorylation metabolism were the key pathways in the regulation of mung bean polyphenols by heat stress. Then mung bean polyphenols can exert heat stress preventive activity through the regulation of cellular oxidative damage and energy metabolism. This study provides a good idea for the research and development of dietary intervention products for heat stress. Show less

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disease. Genetic linkage analyses have identified that mutations in the exostosin glycosyltransferase (EXT)1 and EXT2 genes are linked to HME pathogenesis, with EXT1 mutation being the most frequent. The aim of this study was to generate a mice model with Ext1 gene editing to simulate human EXT1 mutation and investigate the genetic pathogenicity of Ext1 through phenotypic analyses. We designed a pair of dual sgRNAs targeting exon 1 of the mice Ext1 gene for precise deletion of a 46 bp DNA fragment, resulting in frameshift mutation of the Ext1 gene. The designed dual sgRNAs and Cas9 proteins were injected into mice zygotes cytoplasm. A total of 14 mice were obtained via embryo transfer, among which two genotypic chimera mice had a deletion of the 46 bp DNA fragment in exon 1 of the Ext1 gene. By hybridization and breeding, we successfully generated heterozygous mice with edited Ext1 gene (Ext Show less

The existence of a definite direct causal relationship between vitiligo and diverse autoimmune disorders remains unknown due to the influence of confounding factors and potential reverse causality. Mendelian randomization (MR) is a technique employed to explore causal connections between two phenotypes. In our research, bidirectional two-sample MR analyses were utilized to evaluate the causal connections between vitiligo and multiple autoimmune diseases (systemic lupus erythematosus, Graves' disease, inflammatory bowel disease, alopecia areata [AA], type 1 diabetes mellitus [T1MD], and rheumatoid arthritis [RA]). Furthermore, we utilized summary-based Mendelian randomization (SMR) analysis to search for common susceptibility loci between two diseases that reciprocally elevate each other's risk. Finally, colocalization analyses were used to validate the robustness of the selected genes. There was an indication of potential causation between RA and vitiligo (IVW OR = 1.19; 95% CI = 1.05-1.13; p = 0.008). Furthermore, evident causal connections exist between vitiligo and AA (IVW OR = 1.14; 95% CI = 1.04-1.26; p = 0.008), T1MD (IVW OR = 1.14; 95% CI = 1.06-1.23; p < 0.001), and RA (IVW OR = 1.08; 95% CI = 1.03-1.13; p < 0.001). In SMR analyses and colocalization analyses, we identified three shared genes associated with both vitiligo and RA, including: FCRL3, FADS1, and FADS2. Our findings demonstrated that vitiligo and RA mutually act as risk factors for each other. Additionally, vitiligo had significant causal relationships with AA and type 1 diabetes. Show less

Cadherin-11 (CDH11), a specialized cell-cell adhesion protein, plays an essential role in tissue injury, inflammation and repair. This study aimed to investigate the role of CDH11 in severe asthma. Bronchial biopsy specimens were obtained from healthy subjects and patients with severe asthma. Two murine models of severe asthma were established using either TDI (toluene diisocyanate) or OVA (ovalbumin)/CFA (complete Freund's adjuvants). A selective CDH11 antagonist SD133 (100 mg/kg) was given to allergen-exposed mice after airway challenge. The effects of recombinant CDH11 were also tested in vivo, and FGFR1 inhibition was used to explore a possible mechanism for CDH11-induced inflammatory responses in the lung. We detected upregulated expression of CDH11 in the airway mucosa of severe asthma patients when compared with the healthy control. In the OVA/CFA-induced model, though CDH11 expression in the lung remained unchanged, pharmacological antagonism of CDH11 with SD133 dramatically decreased airway neutrophil accumulation, as well as IL-6 production, but had no effect on eosinophilic infiltration, type 2 inflammation (IL-4 and IL-5) nor airway hyperresponsiveness. In the TDI model, pulmonary CDH11 expression was upregulated. Treatment with SD133 inhibited TDI-induced airway hyperresponsiveness and neutrophilic inflammation, decreased IL-6 and TNF-α production, with no effect on airway eosinophil counts and type 2 inflammatory cytokines. In addition, intratracheal instillation of recombinant CDH11 led to neutrophil recruitment in the lungs of mice, which could be attenuated by inhibition of FGFR1 signaling. CDH11 contributes to airway neutrophilic inflammation in severe asthma through the FGFR1 pathway. Show less

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by deficient secretion or action of gonadotropin-releasing hormone. While its characteristics are well-documented in adults, data from prepubertal patients remain limited. To investigate the clinical, hormonal, and genetic characteristics of CHH in male patients aged < 18 years and assess age-related changes in testicular function. Retrospective analysis of data from patients with CHH. Tertiary pediatric endocrine referral center. Overall, 121 male patients with CHH, aged 0-18 years, were included. Hormonal profiles, genetic variants, and testicular function indicators across different age groups. All patients had micropenis, and 41.3% had cryptorchidism. The > 14-year group had fewer combined cases of both conditions but more isolated micropenis (p = 0.001). Inhibin B, luteinizing hormone, follicle-stimulating hormone, and post-human chorionic gonadotropin testosterone levels were significantly higher in the ≤ 3-year group (p < 0.05). Leydig and Sertoli cell function declined with age. Inhibin B < 33.895 pg/mL and anti-Müllerian hormone (AMH) < 17.545 ng/mL predicted Leydig cell dysfunction with sensitivities of 78.5% and 85.7% and specificities of 82.3% and 73.8%, respectively. Pathogenic variants were identified in 84.6% of cases, with fibroblast growth factor receptor 1, chromodomain helicase DNA-binding protein 7, and prokineticin receptor 2 being the most frequently impacted. CHH should be suspected in boys with micropenis and cryptorchidism. AMH and inhibin B are key markers for early detection of Leydig cell dysfunction, with genetic testing being essential for diagnosis. Show less

Idiopathic hypogonadotropic hypogonadism (IHH) is a set of rare diseases characterized by abnormal sexual development with clinical heterogeneity and genotypic complexity. This study aims to investigate the phenotypic and genotypic characteristics of male IHH in southern China, and evaluate the therapeutic effects of current treatments. Fifty-one male IHH patients from southern China were enrolled in this study. Their clinical, imaging, hormonal and genetic findings were analyzed retrospectively. In this study, the most common causative gene of IHH was FGFR1 (45.10%), followed by ANOS1 (21.57%) and CHD7 (17.65%). Forty-five different variants, including 22 known and 23 novel variants, were found. The mean age at diagnosis was 7.84 ± 5.89 years, the most common clinical phenotype was micropenis (98.04%), the most frequent imaging feature was abnormal ultrasound of sexual glands (86.84%), and the most representative biochemical manifestations were low basal luteinizing hormone (LH) and testosterone (98.04% and 100.00%, respectively). Age-phenotype and genotype-phenotype correlations were observed in this cohort. The penile length, testicular volume, basal testosterone, and the proportion of patients with low basal inhibin B were associated with age. Most patients with ANOS1 variant had a family history, impaired olfactory function, and much lower basal anti-mullerian hormone (AMH), whereas patients with CHD7 variant were younger, presented CHARGE phenotypes, and had higher basal follicle-stimulating hormone (FSH) and LH. Moreover, 34 patients were treated with different strategies for 2.75 ± 1.82 years. After treatment, the penile length, and the levels of FSH, LH and testosterone increased significantly. Our study adds 51 southern Chinese male patients, and expands the mutational spectrum for IHH. Our cohort suggests that a combination of clinical, biochemical and genetic criteria will facilitate early diagnosis. Our work also highlights the differentially diagnostic values of family history, impaired olfactory function, CHARGE features, and basal AMH, FSH and LH in distinguishing different molecular bases of IHH. Show less

Sciatica, often resulting from lumbar disc herniation or nerve compression, disrupts electrical signal transmission, leading to muscle atrophy, mitochondrial dysfunction, and impaired energy metabolism. This study explored the therapeutic effects of Fu's subcutaneous needling (FSN) in a chronic constriction injury (CCI) rat model, assessing its impact on neuropathic pain, muscle mass, and structural integrity. Histological and ultrastructural analyses demonstrated that FSN alleviated hypersensitivity, reduced muscle atrophy, preserved mitochondrial density, and maintained glycogen storage. Gene expression and pathway enrichment analyses revealed FSN's involvement in PI3K-Akt, MAPK signaling, oxidative phosphorylation, and mitophagy, suggesting its role in modulating energy metabolism and cellular repair. FSN also normalized energy-related proteins FGFR1, FGFR3 and phosphorylated FOXO3, highlighting their significance in muscle repair and regeneration. These findings provide novel insights into FSN's potential for counteracting neuropathy-induced muscle damage and improving mitochondrial function, supporting its clinical application. Additionally, FSN's role in muscle repair suggests a connection between growth factor signaling and nerve regeneration, offering a foundation for future research on muscle-neural recovery mechanisms. Show less

The high mortality rate of severe heat stroke is mainly related to multiple organ dysfunction syndrome (MODS), and respiratory failure caused by acute lung injury (ALI) is a significant factor in the development of MODS during the course of severe heat stroke. Previous research has demonstrated that severe heat stroke-induced acute lung injury (sHS-ALI) is associated with an increase in reactive oxygen species (ROS) in vascular endothelial cells (VECs), but the specific initiating factors and intermediate mechanisms involved are unclear. In this study, the mRNA profiles of mouse lung tissues were analysed using high-throughput sequencing. Genome-wide knockout was performed using CRISPR-Cas9 technology to identify a cohort of differentially expressed genes that promote human umbilical vein endothelial cells survival after heat stress. The expression of key proteins [fibroblast growth factor 23 (FGF23), phosphorylated fibroblast growth factor receptor-1 (p-FGFR-1), FGFR-1, phosphorylated phospholipase C-γ2 (p-PLC-γ2), PLC-γ2, p-p47 In this study, we first screened sHS-ALI target genes by cross-comparison This study confirmed that FGF23/FGFR1 signalling, as an upstream priming factor, mediated NOX2-ROS activation in VECs after heat stress, thus participating in the sHS-ALI process. FGFR-1 Y766 phosphorylation is essential for FGF23/FGFR-1 signalling activation in VECs, which is involved in sHS-ALI. These findings further clarify the mechanism underlying sHS-ALI and contribute to reducing the mortality and morbidity of severe heat stroke. Show less

To investigate the role of apelin in regulating proliferation, migration and angiogenesis of bladder cancer cells and the possible regulatory mechanism. GEO database was used to screen the differentially expressed genes in bladder cancer tissues and cells. Bladder cancer and paired adjacent tissues were collected from 60 patients for analysis of apelin expressions in relation to clinicopathological parameters. In cultured bladder cancer J82 cells and human umbilical vein endothelial cells (HUVECs), the effects of transfection with an apelin-overexpressing plasmid or specific siRNAs targeting apelin, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) on proliferation and migration of J82 cells and tube formation in HUVECs were examined using plate cloning assay, Transwell assay, and angiogenesis assay; the changes in FGF2 expression and FGFR1 phosphorylation were detected using Western blotting. The expression level of apelin was significantly higher in bladder cancer tissues than adjacent tissues, and bladder cancer cell lines (T24 and J82) also expressed higher mRNA and protein levels of apelin than SV-HUC-1 cells. Apelin expression level in bladder cancer tissues was correlated with tumor invasion, distant metastasis and advanced TNM stages. Apelin knockdown significantly suppressed proliferation and migration of J82 cells and decreased the total angiogenic length of HUVECs. In contrast, apelin overexpression significantly promoted proliferation and migration and enhanced FGFR1 phosphorylation in J82 cells, and increased the total angiogenesis length in HUVECs, but this effects were effectively mitigated by transfection of the cells with FGF2 siRNA or FGFR1 siRNA. High expression of apelin promotes J82 cell proliferation and migration and HUVEC angiogenesis by promoting activation of the FGF2/FGFR1 pathway. Show less

Fibroblast growth factor receptors (FGFRs) represent promising therapeutic targets in various malignancies, yet the clinical application of FGFR covalent inhibitors has been impeded by several significant challenges, including unquantifiable target engagement, undefined off-target effects, and the emergence of drug resistance. In this study, we designed and synthesized a series of FGFR activity-based probes (ABPs) derived from FIIN-2, a pioneering selective, next-generation irreversible covalent FGFR inhibitor with demonstrated efficacy against gatekeeper mutations. Among them, FP1 exhibited comparable inhibitory potency to FIIN-2. FP1 could facilitate precise in vitro and in situ labeling and visualization of both FGFR1-4 and their mutants. Utilizing FP1, we successfully mapped the target spectrum of FIIN-2 in MDA-MB-453 cells through activity-based protein profiling (ABPP), and established a robust framework for employing our probe as a generalizable tool to systematically evaluate the on- and off-target activities of prospective FGFR covalent inhibitors. Overall, the FGFR ABP offers a promising strategy for elucidating the engagement of FGFR, profiling the target specificity and mechanisms of covalent FGFR inhibitors, and offering potential avenues for overcoming drug resistance. Show less

The treatment of functional tricuspid regurgitation (TR) is still controversial. Characterizing the cellular composition of the tricuspid valve and identifying the molecular alterations of each cell type in valves with TR will advance our understanding of the mechanisms of TR and guide improvements in treatment. The authors aimed to investigate the changes in cellular composition and gene expression patterns of cells in regurgitant tricuspid valves and shed light on the mechanisms of functional TR. To improve our understanding of the pathogenesis of functional TR, we performed single-cell RNA sequencing of tricuspid valve from 10 patients, including 5 patients with moderate-to-severe functional TR and 5 nondiseased control subjects. Multiplexed fluorescence was used to detect the spatial distributions of valvular cell states and validated the cell-cell interaction. We assessed the transcriptional profiles of 84,102 cells and identified 6 major cell clusters, along with 25 cell subtypes, in the specimens. Valve interstitial cells (VICs) were the largest population. VICs and lymphoid cells exhibited more heterogeneity in TR patients. VICs exhibited higher transcriptional activity toward matrifibrocyte-like cells and myofibroblast-like cell differentiation, myeloid cells activated immune response, and lymphoid cells promoted fibrosis. In TR, the alternation of COMP-CD47 and FGF2-FGFR1 interaction may occur in TR specimens, which may serve as promising therapeutic targets for TR. Our single-cell atlas highlights the transcriptomic heterogeneity underlying the cell functions and interactions in human tricuspid valves and defines molecular and cellular perturbations in functional TR. We identified VIC clusters with fibrosis activation accumulated in TR valves. 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

Understudied orphan GPCRs lack identified natural ligands, yet understanding their function is critical for therapeutic development. GPRC5B is a brain-enriched, retinoic acid (RA)-induced orphan GPCR. While RA is used to treat severe acne, chronic exposure is associated with depression, likely due to its inhibition of adult hippocampal neurogenesis. Here, we tested whether GPRC5B plays a role in the molecular and cellular mechanisms underlying RA-induced depressive-like behaviors in mice by suppressing adult hippocampal neurogenesis. We found that Gprc5b knockout (KO) mice were resilient to RA-induced behavioral effects and that RA increased GPRC5B expression in the hippocampal neurogenic subgranular zone. This correlated with RA-mediated inhibition of adult hippocampal neurogenesis, an effect absent in Gprc5b KO mice, which also exhibited a larger pool of proliferative neuronal stem cells. Collectively, these findings suggest that GPRC5B mediates RA-induced anti-neurogenic effects and depressive-like behaviors. Show less

Cardiovascular-Kidney-Metabolic (CKM) syndrome is characterized by the interrelatedness of chronic kidney disease, cardiovascular disease, and metabolic disorders. Although physical activity is widely acknowledged as an effective intervention for improving the prognosis of chronic diseases, its impact on all-cause mortality among patients with CKM syndrome remains unclear. To investigate the impact of physical activity on all-cause mortality among patients with CKM syndrome. Data from the 2011 wave of the China Health and Retirement Longitudinal Study were used as the baseline, with follow-up conducted until 2013. According to the International Physical Activity Questionnaire criteria, weekly physical activity levels were divided into three categories: light-volume physical activity (LPA), moderate-volume physical activity (MPA), and vigorous-volume physical activity (VPA). Cox proportional hazards regression models were employed to assess the impact of varying levels of physical activity on all-cause mortality. Restricted cubic spline analysis was used to explore possible nonlinear relationships. A total of 3343 patients with CKM syndrome were enrolled in this study. During the 2-year follow-up period, 44 deaths were recorded. After adjusting for potential confounders, VPA was associated with a 54% lower risk of all-cause mortality (adjusted hazard ratios, 0.46; 95% confidence interval: 0.24-0.89). Dose-response relationships demonstrated that all-cause mortality decreased as physical activity increased, with a 5.8% reduction in all-cause mortality risk for every 1000 MET-min/week increment in physical activity levels. VPA was significantly associated with reduced all-cause mortality in patients with CKM syndrome. Encouraging patients with CKM syndrome to engage in increased physical activity may improve clinical outcomes. Key messages What is already known on this topic: Cardiovascular-Kidney-Metabolic (CKM) syndrome involves a complex interplay between cardiovascular disease, metabolic disorders, and chronic kidney disease. While prior studies have established that physical activity can decrease mortality risk in the general population as well as in patients with cardiovascular and metabolic syndromes, the evidence regarding its impact on individuals with CKM syndrome remains limited. Additionally, there is a lack of detailed dose-response analyses of physical activity specifically targeting this high-risk population. What this study adds: This study provides novel evidence indicating that vigorous-volume physical activity (>3000 MET-minutes/week) significantly decreases all-cause mortality by 54% among patients with CKM syndrome, whereas moderate-volume, and light-volume physical activities show no significant effects. Notably, a linear dose-response relationship was established, demonstrating that each 1000-MET increment corresponds to a 5.8% reduction in mortality risk. These findings address a critical knowledge gap by quantifying both the threshold and incremental benefits of physical activity specifically for individuals with CKM syndrome, a population characterized by unique multisystem pathophysiology. How this study might affect research, practice, or policy: The findings of this study have the potential to substantially impact clinical practice by offering evidence-based thresholds for physical activity recommendations in the management of CKM syndrome. The benefits associated with vigorous-volume physical activity (>3000 MET-minutes/week) may encourage guideline committees to formulate more precise exercise prescriptions tailored to this high-risk population. Additionally, these results can be incorporated into a multidisciplinary care framework designed for managing complex chronic conditions. Show less

Integrated multi-omics analysis has revolutionized the investigation of plant-derived compounds for type 2 diabetes mellitus (T2DM). Solanesol, a bioactive constituent from Solanaceae plants, exhibits high oral bioavailability and translational potential for multi-target therapeutics. This study aimed to elucidate the multi-target mechanisms and multi-organ protective effects of solanesol in T2DM management through integrated multi-omics approaches, to bridge the gap between phytochemical discovery and clinical translation. In Lepr Solanesol improved glucose tolerance, insulin sensitivity, and reduced serum lipids, hepatic gluconeogenesis, uric acid, white adipose mass, pancreatic/hepatic inflammation, and renal fibrosis. Mechanistically, solanesol: 1) enriched beneficial gut microbiota (Alistipes, Anaerotruncus, and Parasutterella) and increased levels of long-chain unsaturated fatty acids; 2) rebalanced the dysfunctional mitochondrial oxidative phosphorylation​​ microenvironment by modulating the expression and the activities of respiratory chain Complexes I-V; 3) modulated hepatic lipid metabolism by ​inhibiting​​ de novo ​​lipogenesis​​ via the Acly-Acaca-Fasn pathway, promoting cholesterol efflux and fatty acid oxidation​​ through Abca1/Fabp5, and attenuating inflammation​​ via Lpl-PPARδ downregulation. Solanesol demonstrates multi-organ protective effects through gut microbiota-metabolite crosstalk and hepatic lipid/redox homeostasis regulation. Its multi-target efficacy and oral bioavailability position it as a novel, clinically translatable candidate for T2DM management. Show less