Apolipoproteins and cortical morphology are closely associated with memory complaints, and both may contribute to the development of Alzheimer's disease. To examine whether apolipoprotein B (ApoB), ap Show more
Apolipoproteins and cortical morphology are closely associated with memory complaints, and both may contribute to the development of Alzheimer's disease. To examine whether apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA1), and their ratio (ApoB/ApoA1) are associated with cortical morphology in patients with memory complaints. Ninety-seven patients underwent neuropsychological testing, measurements of ApoB, ApoA1, ApoB/ApoA1, plasma Alzheimer's biomarker, apolipoprotein E (ApoE) genotyping, and 3T structural magnetic resonance imaging (sMRI) scans. Based on sMRI scanning locations, patients were categorized into the University of Electronic Science and Technology (UESTC) and the Fourth People's Hospital of Chengdu (FPHC). The Computational Anatomy Toolbox within Statistical Parametric Mapping was used to calculate each patient's cortical morphology index based on sMRI data. The cortical morphology index and apolipoproteins were also analyzed. Significant positive correlations were found between ApoB and sulcal depth in the lateral occipital cortex among the UESTC, the FPHC, and the total sample groups, and negative correlations were observed between sulcal depth in the lateral occipital cortex and the scores of the Shape Trails Test Part A and B. In the FPHC group, the scores of the Montreal Cognitive Assessment Basic, delayed recall of the Auditory Verbal Learning Test, Animal Fluency Test and Boston Naming Test were positively correlated with the sulcal depth. ApoB is associated with the sulcal depth in the lateral occipital cortex, potentially relating to speed/executive function in individuals with memory complaints. Show less
Yunjia Chen, Ender Karaca, Nathaniel H Robin+6 more · 2024 · Genetics in medicine : official journal of the American College of Medical Genetics · Elsevier · added 2026-04-24
Multiple studies suggest an association between DLG2 and neurodevelopmental disorders and indicate the haploinsufficiency of this gene; however, few cases have been thoroughly described. We performed Show more
Multiple studies suggest an association between DLG2 and neurodevelopmental disorders and indicate the haploinsufficiency of this gene; however, few cases have been thoroughly described. We performed additional studies to confirm this clinical association and DLG2 haploinsufficiency. Chromosomal microarray analysis was performed on 11,107 patients at the Cytogenetics Laboratory at the University of Alabama at Birmingham. The Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database were selected for the association analysis. Fifty-nine patients from the literature and DECIPHER, all having DLG2 intragenic deletions, were included for comprehensive analysis of the distribution of these deletions. A total of 13 patients with DLG2 intragenic deletions, from 10 families in our cohort, were identified. Nine of 10 probands presented with clinical features of neurodevelopmental disorders. Congenital anomalies and dysmorphism were common in our cohort of patients. Association analysis showed that the frequency of DLG2 deletions in our cohort is significantly higher than those in the Database of Genomic Variants-Gold Standard Variants and the Genome Aggregation Database. Most of DLG2 intragenic deletions identified in 69 unrelated patients from our cohort, the literature, and DECIPHER map to the 5' region of the gene, with a hotspot centered around HPin7, exon 8, and HPin8. Our findings reinforce the link between DLG2 intragenic deletions and neurodevelopmental disorders, strongly support the haploinsufficiency of this gene, and indicate that these deletions might also have an association with congenital anomalies and dysmorphism. Show less
Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD Show more
Long-term exposure to lead (Pb) can result in chronic damage to the body through accumulation in the central nervous system (CNS) leading to neurodegenerative diseases, such as Alzheimer's disease (AD). This study delves into the intricate role of miR-671/CDR1as regulation in the etiology of AD-like lesions triggered by chronic Pb exposure in adult mice. To emulate the chronic effects of Pb, we established a rodent model spanning 10 months of controlled Pb administration, dividing 52 C57BL/6J mice into groups receiving varying concentrations of Pb (1, 2, or 4 g/L) alongside an unexposed control. Blood Pb levels were monitored using serum samples to ensure accurate dosing and to correlate with observed toxicological outcomes. Utilizing the Morris water maze, a robust behavioral assay for assessing cognitive functions, we documented a dose-dependent decline in learning and memory capabilities among the Pb-exposed mice. Histopathological examination of the hippocampal tissue revealed tell-tale signs of AD-like neurodegeneration, characterized by the accumulation of amyloid plaques and neurofibrillary tangles. At the molecular level, a significant upregulation of AD-associated genes, namely amyloid precursor protein (APP), β-secretase 1 (BACE1), and tau, was observed in the hippocampal tissue of Pb-exposed mice. This was accompanied by a corresponding surge in the protein levels of APP, BACE1, amyloid-β (Aβ), and phosphorylated tau (p-tau), further implicating Pb in the dysregulation of these key AD markers. The expression of CDR1as, a long non-coding RNA implicated in AD pathogenesis, was found to be suppressed in Pb-exposed mice. This observation suggests a potential mechanistic link between Pb-induced neurotoxicity and the dysregulation of the CDR1as/miR-671 axis, which warrants further investigation. Moreover, our study identified a dose-dependent alteration in the intracellular and extracellular levels of the transcription factor nuclear factor-kappa B (NF-κB). This finding implicates Pb in the modulation of NF-κB signaling, a pathway that plays a pivotal role in neuroinflammation and neurodegeneration. In conclusion, our findings underscored the deleterious effects of Pb exposure on the CNS, leading to the development of AD-like pathology. The observed modulation of NF-κB signaling and miR-671/CDR1as regulation provides a plausible mechanistic framework for understanding the neurotoxic effects of Pb and its potential contribution to AD pathogenesis. Show less
Prenatal exposure to perfluorooctane sulfonate (PFOS) is associated with adverse health effects, including congenital heart disease, yet the underlying mechanisms remain elusive. Herein, we aimed to e Show more
Prenatal exposure to perfluorooctane sulfonate (PFOS) is associated with adverse health effects, including congenital heart disease, yet the underlying mechanisms remain elusive. Herein, we aimed to evaluate the embryotoxicity of PFOS using C57BL/6 J mice to characterize fetal heart defects after PFOS exposure, with the induction of human embryonic stem cells (hESC) into cardiomyocytes (CMs) as a model of early-stage heart development. We also performed DNA methylation analysis to clarify potential underlying mechanisms and identify targets of PFOS. Our results revealed that PFOS caused septal defects and excessive ventricular trabeculation cardiomyopathy at 5 mg/kg/day in embryonic mice and inhibited the proliferation and pluripotency of ESCs at concentrations >20 μM. Moreover, it decreased the beating rate and the population of CMs during cardiac differentiation. Decreases were observed in the abundances of NPPA+ trabecular and HEY2+ compact CMs. Additionally, DNA methyl transferases and ten-eleven translocation (TET) dioxygenases were regulated dynamically by PFOS, with TETs inhibitor treatment inducing significant decreases similar as PFOS. 850 K DNA methylation analysis combined with expression analysis revealed several potential targets of PFOS, including SORBS2, FHOD1, SLIT2, SLIT3, ADCY9, and HDAC9. In conclusion, PFOS may reprogram DNA methylation, especially demethylation, to induce cardiac toxicity, causing ventricular defects in vivo and abnormal cardiac differentiation in vitro. Show less
Clinical observations indicate that blood lipids may be risk factors for lateral epicondylitis (LE) of the humerus, and lipid-lowering drugs are also used for the prevention and treatment of tendon di Show more
Clinical observations indicate that blood lipids may be risk factors for lateral epicondylitis (LE) of the humerus, and lipid-lowering drugs are also used for the prevention and treatment of tendon diseases, but these lack high-quality clinical trial evidence and remain inconclusive. Mendelian randomization (MR) analyses can overcome biases in traditional observational studies and offer more accurate inference of causal relationships. Therefore, we employed this approach to investigate whether blood lipids are risk factors for LE and if lipid-lowering drugs can prevent it. Genetic variations associated with lipid traits, including low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), were obtained from the UK Biobank and the Global Lipids Genetics Consortium (GLGC). Data on genetic variation in LE were sourced from FinnGen, including 24,061 patients and 275,212 controls. Subsequently, MR analyses were conducted to assess the potential correlation between lipid traits and LE. Additionally, drug-target Mendelian randomization analyses were performed on 10 drug targets relevant to LE. For those drug targets that yielded significant results, further analysis was conducted using colocalization techniques. No correlation was found between three blood lipid traits and LE. Lipoprotein lipase (LPL) enhancement is significantly associated with a decreased risk of LE (OR = 0.76, [95% CI, 0.65-0.90], The three lipid traits are not risk factors for lateral epicondylitis. LPL is a potential drug target for the prevention and treatment of LE. Show less
Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken t Show more
Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs. Show less
Obesity is an important cause for the precocious or early puberty. However, the association between obesity-related loci and the risk of precocious puberty as well as the effect of gene-environment in Show more
Obesity is an important cause for the precocious or early puberty. However, the association between obesity-related loci and the risk of precocious puberty as well as the effect of gene-environment interaction are unclear, especially in the Chinese children population. This was a case-control study using baseline data from two cohorts and hospital cases in China. 15 SNPs loci and several environmental factors were included in the analysis of 1201 participants. Chi-square test and logistic regression were used to analyze the association between SNPs and precocious puberty. Additionally, exploratory factor analysis was conducted on 13 environmental variables, and then to explore their interaction with genes on precocious puberty. The effect allele C of rs571312, and G of rs12970134 MC4R were associated with precocious puberty in girls with obesity. Regarding the gene-environment interaction, we found that when girls were in the high socioeconomic status, the rs571312 (OR: 3.996; 95% CI: 1.694-9.423) and rs12970134 (OR: 3.529; 95% CI: 1.452-8.573) risk genotypes had a greater effect on precocious puberty. The obesity risk gene polymorphisms MC4R rs571312 and rs12970134 were associated with precocious puberty in Chinese girls with obesity, and girls with risk genotypes and high socioeconomic status should be given extra attention. This is the first study that identified the association between rs571312 and rs12970134 of MC4R gene and precocious puberty in Chinese children. We found that when girls were in the high socioeconomic status, the risk genotypes of rs571312 and rs12970134 had a greater effect on precocious puberty. The results of this study have great public health implications. It is recommended that girls who are in high socioeconomic status and have a high genetic risk for early sexual maturity should closely monitor their pubertal development and consider early intervention strategies. Show less
Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making Show more
Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery. Show less
Frailty is an emerging global burden of disease, characterized as an age-related clinical syndrome. Recent studies have suggested a potential link of circulating protein levels with the onset of frail Show more
Frailty is an emerging global burden of disease, characterized as an age-related clinical syndrome. Recent studies have suggested a potential link of circulating protein levels with the onset of frailty. This study aims to analyze the potential causal relationships of plasma proteins with frailty using a Mendelian Randomization (MR) study design. Associations of plasma proteins with frailty were assessed using inverse variance weighted (IVW), MR-Egger regression, weighted median, maximum-likelihood method, and MR-PRESSO test. Protein-protein interaction network construction and gene ontology functional enrichment analysis were conducted based on MR-identified target proteins. After false discovery rate (FDR) correction, MR analysis identified five plasma proteins, including BIRC2 [OR = 0.978, 95%CI (0.967-0.990)] and PSME1 [OR = 0.936, 95%CI (0.909-0.965)], as protective factors against frailty, and 49 proteins, including APOB [OR = 1.053, 95%CI (1.037-1.069)] and CYP3A4 [OR = 1.098, 95%CI (1.068-1.128)], as risk factors. Network analysis suggested BIRC2, PSME1, APOE, and CTNNB1 as key intervention targets. This study employed MR design to investigate the association of circulating plasma proteins with frailty, identified five proteins negatively associated with frailty risk and 49 proteins positively associated with frailty. Show less
Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid-beta (Aβ) plaques is a distinctive pathological feature of AD patients. The aims of this Show more
Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid-beta (Aβ) plaques is a distinctive pathological feature of AD patients. The aims of this study were to evaluate the therapeutic effect of chicoric acid (CA) on AD models and to explore its underlying mechanisms. APPswe/Ind SH-SY5Y cells and 5xFAD mice were treated with CA. Soluble Aβ1-42 and Aβ plaque levels were analyzed by ELISA and immunohistochemistry, respectively. Transcriptome sequencing was used to compare the changes in hippocampal gene expression profiles among the 5xFAD mouse groups. The specific gene expression levels were quantified by qRT-PCR and Western blot analysis. It was found that CA treatment reduced the Aβ1-42 levels in the APPswe/Ind cells and 5xFAD mice. It also reduced the Aβ plaque levels as well as the APP and BACE1 levels. Transcriptome analysis showed that CA affected the synaptic-plasticity-related genes in the 5xFAD mice. The levels of L1CAM, PSD-95 and synaptophysin were increased in the APPswe/Ind SH-SY5Y cells and 5xFAD mice treated with CA, which could be inhibited by administering siRNA-L1CAM to the CA-treated APPswe/Ind SH-SY5Y cells. In summary, CA reduced Aβ levels and increased the expression levels of synaptic-function-related markers via L1CAM in AD models. Show less
Inflammatory bowel disease (IBD) can be identified as an inflammatory disorder in the intestine, being characterized by maladjusted immune responses and chronic inflammation of the intestinal tract. H Show more
Inflammatory bowel disease (IBD) can be identified as an inflammatory disorder in the intestine, being characterized by maladjusted immune responses and chronic inflammation of the intestinal tract. However, as the etiology and pathogenesis are still unclear, more effective therapeutic approaches are needed. Recent studies have discovered a new cytokine, interleukin-27 (IL-27), which belongs to the superfamily of IL-6 and IL-12, demonstrating multiple functions in many infectious diseases, autoimmune diseases, and cancers. Interleukin-27 is mainly produced by antigen presentation cells (APCs) such as dendritic cells and mononuclear macrophages, playing a dual regulatory role in immunological response. Therefore, this updated review aims to summarize the new progress of the regulatory role of IL-27 in IBD and focus more on the interaction between IL-27 and immune cells, hoping to provide more evidence for the potential IBD treatment mediated by IL-27. Show less
Accumulating evidence has illustrated that the E3 ubiquitin ligases critically participate in the development and progression of cardiovascular diseases. Dysregulation of E3 ubiquitin ligases exacerba Show more
Accumulating evidence has illustrated that the E3 ubiquitin ligases critically participate in the development and progression of cardiovascular diseases. Dysregulation of E3 ubiquitin ligases exacerbates cardiovascular diseases. Blockade or activation of E3 ubiquitin ligases mitigates cardiovascular performance. Therefore, in this review, we mainly introduced the critical role and underlying molecular mechanisms of E3 ubiquitin ligase NEDD4 family in governing the initiation and progression of cardiovascular diseases, including ITCH, WWP1, WWP2, Smurf1, Smurf2, Nedd4-1 and Nedd4-2. Moreover, the functions and molecular insights of other E3 ubiquitin ligases, such as F-box proteins, in cardiovascular disease development and malignant progression are described. Furthermore, we illustrate several compounds that alter the expression of E3 ubiquitin ligases to alleviate cardiovascular diseases. Therefore, modulation of E3 ubiquitin ligases could be a novel and promising strategy for improvement of therapeutic efficacy of deteriorative cardiovascular diseases. Show less
The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritab Show more
The increased prevalence of opioid use disorder (OUD) makes it imperative to disentangle the biological mechanisms contributing to individual differences in OUD vulnerability. OUD shows strong heritability, however genetic variants contributing toward vulnerability remain poorly defined. We performed a genome-wide association study using over 850 male and female heterogeneous stock (HS) rats to identify genes underlying behaviors associated with OUD such as nociception, as well as heroin-taking, extinction and seeking behaviors. By using an animal model of OUD, we were able to identify genetic variants associated with distinct OUD behaviors while maintaining a uniform environment, an experimental design not easily achieved in humans. Furthermore, we used a novel non-linear network-based clustering approach to characterize rats based on OUD vulnerability to assess genetic variants associated with OUD susceptibility. Our findings confirm the heritability of several OUD-like behaviors, including OUD susceptibility. Additionally, several genetic variants associated with nociceptive threshold prior to heroin experience, heroin consumption, escalation of intake, and motivation to obtain heroin were identified. Tom1, a microglial component, was implicated for nociception. Several genes involved in dopaminergic signaling, neuroplasticity and substance use disorders, including Brwd1, Pcp4, Phb1l2 and Mmp15 were implicated for the heroin traits. Additionally, an OUD vulnerable phenotype was associated with genetic variants for consumption and break point, suggesting a specific genetic contribution for OUD-like traits contributing to vulnerability. Together, these findings identify novel genetic markers related to the susceptibility to OUD-relevant behaviors in HS rats. Show less
Musk secreted by the musk glands in male forest musk deer (FMD; Moschus berezovskii) is highly valued for its pharmaceutical and perfumery applications. However, the regulatory mechanisms underlying m Show more
Musk secreted by the musk glands in male forest musk deer (FMD; Moschus berezovskii) is highly valued for its pharmaceutical and perfumery applications. However, the regulatory mechanisms underlying musk secretion are not well understood. This study aimed to investigate the genes and transcription factors involved in musk secretion across different periods and ages. We analyzed the musk glands of adult male FMD during the non-secretory and secretory periods, as well as juvenile and adult male FMD during the secretory period, using single-cell multiome ATAC+gene expression technique. Our analysis identified 13 cell types, including acinar cells of Types 1 and 2. Chromatin accessibility analysis and gene expression data confirmed that the genes Map3k2, Hsd17b12, and Jun are critical for musk secretion. Additionally, EHF, NR4A2, and FOXO1 proteins play crucial regulatory roles. Weighted gene co-expression network analysis (WGCNA) highlighted the importance of GnRH signaling pathway in musk secretion. Gene set enrichment analysis (GSEA) showed that the steroid hormone biosynthesis pathway is notably enriched in acinar cells. Furthermore, intercellular communication appears to influence both the initiation and maintenance of musk secretion. These findings provide valuable insights into the molecular pathways of musk secretion in FMD, offering potential avenues for increasing musk production and developing treatment for inflammation and tumors. Show less
Non-obstructive azoospermia (NOA) is a major contributor of male infertility. Herein, we used existing datasets to identify novel biomarkers for the diagnosis and prognosis of NOA, which could have gr Show more
Non-obstructive azoospermia (NOA) is a major contributor of male infertility. Herein, we used existing datasets to identify novel biomarkers for the diagnosis and prognosis of NOA, which could have great significance in the field of male infertility. NOA datasets were obtained from the Gene Expression Omnibus (GEO) database. CIBERSORT was utilized to analyze the distributions of 22 immune cell populations. Hub genes were identified by applying weighted gene co-expression network analysis (WGCNA), machine learning methods, and protein-protein interaction (PPI) network analysis. The expression of hub genes was verified in external datasets and was assessed by receiver operating characteristic (ROC) curve analysis. Gene set enrichment analysis (GSEA) was applied to explore the important functions and pathways of hub genes. The mRNA-microRNA (miRNA)-transcription factors (TFs) regulatory network and potential drugs were predicted based on hub genes. Single-cell RNA sequencing data from the testes of patients with NOA were applied for analyzing the distribution of hub genes in single-cell clusters. Furthermore, testis tissue samples were obtained from patients with NOA and obstructive azoospermia (OA) who underwent testicular biopsy. RT-PCR and Western blot were used to validate hub gene expression. Two immune-related oxidative stress hub genes ( It appears that Show less
Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD Show more
Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD), in which two hallmarks are well-established as cerebral β-amyloid protein (Aβ) deposition and Tau-centered neurofibrillary tangles. We found that STAU1 protein level was significantly increased in cells that stably express full-length APP and the brain of APP/PS1 mice, an animal model of AD. STAU1 knockdown, as opposed to overexpression, significantly decreased the protein levels of β-amyloid converting enzyme 1 (BACE1) and Aβ. We further found that STAU1 extended the half-life of the BACE1 mRNA through binding to the 3' untranslated region (3'UTR). Transcriptome analysis revealed that STAU1 enhanced the expression of growth arrest and DNA damage 45 β (GADD45B) upstream of P38 MAPK signaling, which contributed to STAU1-induced regulation of Tau phosphorylation at Ser396 and Thr181. Together, STAU1 promoted amyloidogenesis by inhibiting BACE1 mRNA decay, and augmented Tau phosphorylation through activating GADD45B in relation to P38 MAPK. Targeting STAU1 that acts on both amyloidogenesis and tauopathy may serve as an optimistic approach for AD treatment. Show less
Papillary thyroid carcinoma (PTC) is the most prevalent type of thyroid cancer and its incidence is rising globally. The molecular mechanisms of PTC progression remain unclear, hindering the developme Show more
Papillary thyroid carcinoma (PTC) is the most prevalent type of thyroid cancer and its incidence is rising globally. The molecular mechanisms of PTC progression remain unclear, hindering the development of effective treatments. This study focuses on hsa_circ₀₀₀₈₀₁₆ (circFGFR1), a circular RNA significantly up-regulated in PTC cells. Silencing circFGFR1 inhibited PTC cell proliferation and increased cell apoptosis, suggesting its role in PTC progression. The RNA-binding protein FUS was identified as a promoter of circFGFR1 formation. While circFGFR1 does not influence FGFR1 mRNA translation, it inhibits ubiquitination and degradation of FGFR1 protein, prolonging its half-life. CircFGFR1 also interacts with protein CBL, inhibiting CBL-mediated ubiquitination of FGFR1 proteins. Rescue assays confirmed circFGFR1 promotes PTC cell growth through mediating FGFR1. This study highlights the potential of circFGFR1 as a therapeutic target, offering insights into PTC's molecular mechanisms, and paving the way for novel treatment strategies. Show less
Coronary artery disease (CAD) remains the primary cause of death worldwide, and familial hypercholesterolemia (FH) is a common disease that leads to CAD. This study aimed to explore the difference in Show more
Coronary artery disease (CAD) remains the primary cause of death worldwide, and familial hypercholesterolemia (FH) is a common disease that leads to CAD. This study aimed to explore the difference in CAD risk between FH and non-FH patients with high low-density lipoprotein cholesterol (LDL-C) levels. Individuals (≥18 years) who underwent coronary angiography (CAG) from June 2016 to September 2020 were consecutively enrolled. Participants with LDL-C levels ≥4.0 mmol/L were ultimately included in this study. For all participants, next-generation sequencing was performed with expanded gene panels including 11 genes (LDLR, APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, LIPA, LPA, APOBR, LRPAP1, and STAP1). A total of 223 individuals were included in this study. According to the CAG findings, 199 CAD patients and 24 non-CAD patients were included. The proportions of FH genes, regardless of whether 3 major genes or all 11 genes were sequenced, were not significantly different between the CAD and non-CAD groups ( FH mutation did not increase the rate of CAD in individuals with an MLDL-C level ≥4.0 mmol/L. However, among CAD patients (MLDL-C level ≥4.0 mmol/L) with almost normal renal function (≥87.4 ml/min/1.73 m Show less
Lipid metabolism disorders appear to play an important role in the ageing process, thus understanding the cellular and molecular mechanisms underlying the association of ageing with elevated vulnerabi Show more
Lipid metabolism disorders appear to play an important role in the ageing process, thus understanding the cellular and molecular mechanisms underlying the association of ageing with elevated vulnerability to lipid metabolism related diseases is crucial towards promoting quality of life in old age. MicroRNAs (miRNAs) have emerged as crucial regulators of lipid metabolism, and some miRNAs have key roles in ageing. In this study, we investigated changes in liver lipid metabolism of ageing mice and the mechanisms of the altered expression of miRNAs in the ageing liver which contributes to the age-dependent increase in lipid synthesis. Here we found that miR-743b-3p was higher expressed in the liver tissues of ageing mice through the small RNA sequencing and bioinformatics analysis, and its target PPM1K was predicted and confirmed the target relationship of miR-743b-3p with PPM1K in the aged mouse liver tissues and the cultured senescent hepatocytes in vitro. Moreover, using the transfected miR-743b-3p mimics/inhibitors into the senescent hepatocyte AML12. We found that miR-743b-3p inhibition reversed the hepatocyte senescence, and finally decreased the expression of genes involved in lipid synthesis(Chrebp, Fabp4, Acly and Pparγ) through increasing the target gene expression of PPM1K which regulated the expression of branched-chain amino acids (BCAA) metabolism-related genes (Bckdhα, Bckdk, Bcat2, Dbt). These results identify that age-induced expression of miR-743b-3p inhibits its target PPM1K which induces BCAA metabolic disorder and regulates hepatocyte lipid accumulation during ageing. Show less
Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remain Show more
Interleukin-33 (IL-33), an emerging cytokine within the IL-1 family, assumes a pivotal function in the control of obesity. However, the specific mechanism of its regulation of obesity formation remains unclear. In this study, we found that the expression level of IL-33 increased in visceral adipose tissue in mice fed with a high-fat diet (HFD) compared with that in mice fed with a normal diet (ND). In vitro, we also found the expression level of IL-33 was upregulated during the adipogenesis of 3T3-L1 cells. Functional test results showed that knockdown of IL-33 in 3T3-L1 cells differentiation could promote the accumulation of lipid droplets, the content of triglyceride and the expression of adipogenic-related genes (i.e. PPAR-γ, C/EBPα, FABP4, LPL, Adipoq and CD36). In contrast, overexpression of IL-33 inhibits adipogenic differentiation. Meanwhile, the above tests were repeated after over-differentiation of 3T3-L1 cells induced by oleic acid, and the results showed that IL-33 played a more significant role in the regulation of adipogenesis. To explore the mechanism, transcriptome sequencing was performed and results showed that IL-33 regulated the PPAR signaling pathway in 3T3-L1 cells. Further, Western blot and confocal microscopy showed that the inhibition of IL-33 could promote PPAR-γ expression by inhibiting the Wnt/β-catenin signal in 3T3-L1 cells. This study demonstrated that IL-33 was an important regulator of preadipocyte differentiation and inhibited adipogenesis by regulating the Wnt/β-catenin/PPAR-γ signaling pathway, which provided a new insight for further research on IL-33 as a new intervention target for metabolic disorders. Show less
Psoriasis is an inflammatory skin disease, there is no radical cure. Traditional Chinese medicine has accumulated a lot of clinical experience in the treatment of psoriasis and developed a variety of Show more
Psoriasis is an inflammatory skin disease, there is no radical cure. Traditional Chinese medicine has accumulated a lot of clinical experience in the treatment of psoriasis and developed a variety of treatment methods, among which Yinxieling optimization formula (PSORI-CM01) have a definite clinical effect in the treatment of psoriasis, but their mechanism of action is still unclear. To investigate the molecular mechanism of the PSORI-CM01 in the treatment of psoriasis. Firstly, potential active compounds and key signaling pathways of PSORI-CM01 were explored by the systems pharmacology method. Then MTT assay was used to screen the potentially active compounds of PSORI-CM01, and explore the combined effects of potentially active compounds. The regulation of potentially active compounds on inflammatory factors were evaluated by a Human Th17 Magnetic Bead Panel. The regulation of PSORI-CM01 on key targets in the key signaling pathways were explored by qRT-PCR method. Finally, the molecular mechanism of PSORI-CM01 in the treatment of psoriasis was explained by the systems pharmacology method. The potentially active compounds of PSORI-CM01 included gallic acid, liquiritigenin, rosmarinic acid, syringic acid, isoliquiritin apioside, caffeic acid, naringenin, cryptochlorogenic acid, (+)-taxifolin, p-coumaric acid, chlorogenic acid, fraxin, 5-hydroxymethylfurfural, lithospermic acid, isoliquiritigenin, salviandic acid B, octahydrocurcumin, catechin, syringaldehyde, methyl rosmarinate, paeonol, protocatechuic acid, astilbin, isoastilbin, isofraxidin and zederone. Both antagonistic and synergistic effects were determined in the combinations of active compounds. Most of the active compounds up-regulated IL-2, IL-6, IL-9 and TNF-α, and down-regulated IFN-γ, IL-1β, IL-2, IL-9, IL-10, IL-13, IL-15, IL-17F, IL-21, IL-22 and IL-27. The PI3K-Akt signaling pathway would be the key signaling pathway of PSORI-CM01. The qRT-PCR results showed that its compounds can effectively regulate the expression of key targets in this pathway. The molecular mechanism of PSORI-CM01 for treating psoriasis would be mediated by regulating the network of inflammatory factors through the PI3K-Akt signaling pathway. Show less
Parkinson's disease (PD) is a progressive neurodegenerative disease whose etiology is attributed to development of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra (SN). Cu Show more
Parkinson's disease (PD) is a progressive neurodegenerative disease whose etiology is attributed to development of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra (SN). Currently, there are no definitive diagnostic indicators for PD. In this study, we aimed to identify potential diagnostic biomarkers for PD and analyzed the impact of immune cell infiltrations on disease pathogenesis. The PD expression profile data for human SN tissue, GSE7621, GSE20141, GSE20159, GSE20163 and GSE20164 were downloaded from the Gene Expression Omnibus (GEO) database for use in the training model. After normalization and merging, we identified differentially expressed genes (DEGs) using the Robust rank aggregation (RRA) analysis. Simultaneously, DEGs after batch correction were identified. Gene interactions were determined through venn Diagram analysis. Functional analyses and protein-protein interaction (PPI) networks were used to the identify hub genes, which were visualized through Cytoscape. A Lasso Cox regression model was employed to identify the potential diagnostic genes. The GSE20292 dataset was used for validation. The proportion of infiltrating immune cells in the samples were determined via the CIBERSORT method. Sixty-two DEGs were screened in this study. They were found to be enriched in nerve conduction, dopamine (DA) metabolism, and DA biosynthesis Gene Ontology (GO) terms. The PPI network and Lasso Cox regression analysis revealed seven potential diagnostic genes, namely SLC18A2, TAC1, PCDH8, KIAA0319, PDE6H, AXIN1, and AGTR1, were subsequently validated in peripheral blood samples obtained from healthy control (HC) and PD patients, as well as in the GSE20292 dataset. The results revealed the exceptional sensitivity and specificity of these genes in PD diagnosis and monitoring. Moreover, PD patients exhibited a higher number of plasma cells, compared to HC individuals. The SLC18A2, TAC1, PCDH8, KIAA0319, PDE6H, AXIN1, and AGTR1 are potential diagnostic biomarkers for PD. Our findings also reveal the essential roles of immune cell infiltration in both disease onset and trajectory. Show less
Aurora kinase A (AURKA) is a serine/threonine-protein kinase that regulates microtubule organization during neuron migration and neurite formation. Decreased activity of AURKA was found in Alzheimer's Show more
Aurora kinase A (AURKA) is a serine/threonine-protein kinase that regulates microtubule organization during neuron migration and neurite formation. Decreased activity of AURKA was found in Alzheimer's disease (AD) brain samples, but little is known about the role of AURKA in AD pathogenesis. Here, we demonstrate that AURKA is expressed in primary cultured rat neurons, neurons from adult mouse brains, and neurons in postmortem human AD brains. AURKA phosphorylation, which positively correlates with its activity, is reduced in human AD brains. In SH-SY5Y cells, pharmacological activation of AURKA increased AURKA phosphorylation, acidified endolysosomes, decreased the activity of amyloid beta protein (Aβ) generating enzyme β-site amyloid precursor protein cleaving enzyme (BACE-1), increased the activity of the Aβ degrading enzyme cathepsin D, and decreased the intracellular and secreted levels of Aβ. Conversely, pharmacological inhibition of AURKA decreased AURKA phosphorylation, de-acidified endolysosomes, decreased the activity of cathepsin D, and increased intracellular and secreted levels of Aβ. Thus, reduced AURKA activity in AD may contribute to the development of intraneuronal accumulations of Aβ and extracellular amyloid plaque formation. Show less
Mutational signature analysis gained significant attention for providing critical insights into the underlying mutational processes for various DNA single base substitution (SBS) signatures and their Show more
Mutational signature analysis gained significant attention for providing critical insights into the underlying mutational processes for various DNA single base substitution (SBS) signatures and their associations with different cancer types. Recently, RNA single base substitution (RNA-SBS) signatures were defined and described by decomposing RNA variants found in non-small cell lung cancer. Through statistical association, they attributed Apolipoprotein B mRNA Editing Enzyme, Catalytic Polypeptide 3A (APOBEC3A) mutagenesis to the RNA-SBS2 signature. Here, we provide the first validation of an RNA-SBS mutational signature by decomposing novel exogenous and endogenous APOBEC3A RNA editing signatures into COSMICv3.4 RNA-SBS reference signatures. Additionally, we have identified novel RNA-SBS signatures for APOBEC1, APOBEC3B, and APOBEC3G. Show less
Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FD Show more
Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC Show less
Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alve Show more
Although recent studies provide mechanistic understanding to the pathogenesis of radiation induced lung injury (RILI), rare therapeutics show definitive promise for treating this disease. Type II alveolar epithelial cells (AECII) injury in various manner results in an inflammation response to initiate RILI. Here, we reported that radiation (IR) up-regulated the TNKS1BP1, causing progressive accumulation of the cellular senescence by up-regulating EEF2 in AECII and lung tissue of RILI mice. Senescent AECII induced Senescence-Associated Secretory Phenotype (SASP), consequently activating fibroblasts and macrophages to promote RILI development. In response to IR, elevated TNKS1BP1 interacted with and decreased CNOT4 to suppress EEF2 degradation. Ectopic expression of EEF2 accelerated AECII senescence. Using a model system of TNKS1BP1 knockout (KO) mice, we demonstrated that TNKS1BP1 KO prevents IR-induced lung tissue senescence and RILI. Notably, this study suggested that a regulatory mechanism of the TNKS1BP1/CNOT4/EEF2 axis in AECII senescence may be a potential strategy for RILI. Show less