The kidding traits of goats are an important index of production. However, the molecular regulatory mechanisms of kidding traits in goats have not been fully elucidated. This study aimed to investigat Show more
The kidding traits of goats are an important index of production. However, the molecular regulatory mechanisms of kidding traits in goats have not been fully elucidated. This study aimed to investigate the molecular regulatory network of kidding traits in goats. Multi-omics revealed the enrichment of 10 signaling pathways, with fatty acid biosynthesis, biosynthesis of unsaturated fatty acids, and steroid hormone biosynthesis pathways being closely related to reproduction. Interestingly, the key rate-limiting enzymes, fatty acid synthase (FASN), stearoyl-CoA desaturase 5 (SCD5), fatty acid desaturase 1 (FADS1), 3β-hydroxysteroid dehydrogenase/isomerase (3BHSD), and steroidogenic acute regulatory protein (STAR) enriched in these pathways regulate changes in reproduction-related metabolites. In interference experiments, it was observed that suppressing these key rate-limiting enzymes inhibited the expression of CYP19A1, ESR2, and FSHR. Furthermore, interference inhibited granulosa cell proliferation, caused cell cycle arrest, and promoted apoptosis. Thus, these results suggest that the specific markers of nanny goats with multiple kids are the key rate-limiting enzymes FASN, SCD5, FADS1, 3BHSD, and STAR. These findings may greatly enhance the understanding of regulatory mechanisms that govern goat parturition. Show less
Anorectal malformations (ARMs) are congenital diseases that lead to postoperative fecal incontinence, constipation, and soiling, despite improvements in surgery; however, their pathological mechanisms Show more
Anorectal malformations (ARMs) are congenital diseases that lead to postoperative fecal incontinence, constipation, and soiling, despite improvements in surgery; however, their pathological mechanisms remain unclear. Here, we report the role of microRNA-141-3p in maintaining homeostasis between apoptosis and autophagy in the lumbosacral defecation center of fetal rats with ARMs. Elevated microRNA-141-3p expression inhibited YIN-YANG-1 expression by binding its 3' UTR, and repressed autophagy and triggered apoptosis simultaneously. Then, adenylate cyclase 3 was screened to be the downstream target gene of YIN-YANG-1 by chromatin immunoprecipitation sequencing experiments, and Yin Yang 1 could positively activate the transcription of adenylate cyclase 3 by directly interacting with the motif GAGATGG and ATGG in its promoter. Intraamniotic microinjection of adeno-rno-microRNA-141-3p-sponge-GFP in fetal rats with ARMs on embryonic day 15 restored apoptosis-autophagy homeostasis. These findings reveal that microRNA-141-3p upregulation impaired homeostasis between apoptosis and autophagy by inhibiting the YIN-YANG-1/adenylate cyclase 3 axis, and that intraamniotic injection of anti-microRNA-141-3p helped maintain homeostasis in the lumbosacral defecation center of ARMs during embryogenesis. Show less
Short-chain chlorinated paraffins (SCCPs), a class of persistent organic pollutants, have been found to cause diverse organ and systemic toxicity. However, little is known about their neurotoxic effec Show more
Short-chain chlorinated paraffins (SCCPs), a class of persistent organic pollutants, have been found to cause diverse organ and systemic toxicity. However, little is known about their neurotoxic effects. In this study, we exposed BV2, a mouse microglia cell line, to environmentally relevant concentration of SCCPs (1 μg/L, 10 μg/L, 100 μg/L) for 24 h to investigate their impacts on the nervous system. Our observations revealed that SCCPs induced the activation of BV2 microglia, as indicated by altered morphology, stimulated cell proliferation, enhanced phagocytic and migratory capabilities. Analysis at the mRNA level confirmed the activation status, with the downregulation of TMEM119 and Tgfbr1, and upregulation of Iba1 and CD11b. The upregulated expression of genes such as cenpe, mki67, Axl, APOE and LPL also validated alterations in cell functions. Moreover, BV2 microglia presented an M2 alternative phenotype upon SCCPs exposure, substantiated by the reduction of NF-κB, TNF-α, IL-1β, and the elevation of TGF-β. Additionally, SCCPs caused lipid metabolic changes in BV2 microglia, characterized by the upregulations of long-chain fatty acids and acylcarnitines, reflecting an enhancement of β-oxidation. This aligns with our findings of increased ATP production upon SCCPs exposure. Intriguingly, cell activation coincided with elevated levels of omega-3 polyunsaturated fatty acids. Furthermore, activated microglial medium remarkably altered the proliferation and differentiation of mouse neural stem cells. Collectively, exposure to environmentally relevant concentrations of SCCPs resulted in activation and lipid metabolic alterations in BV2 microglia, potentially impacting neurogenesis. These findings provide valuable insights for further research on the neurotoxic effect of SCCPs. Show less
Previously characterized as an oncogenic player in breast cancer, the function of circular RNA NINL (circNINL) in lung cancer (LC) remained elusive. This study aimed to delineate the biological role o Show more
Previously characterized as an oncogenic player in breast cancer, the function of circular RNA NINL (circNINL) in lung cancer (LC) remained elusive. This study aimed to delineate the biological role of circNINL in LC and to unveil its potential molecular mechanisms. We discovered elevated expression levels of circNINL and Fibroblast Growth Factor Receptor 1 (FGFR1) concomitant with diminished expression of microRNA-3918 (miR-3918) in LC specimens. Knockdown of circNINL led to a marked decrease in cell proliferation, migration, invasion, and aerobic glycolysis, alongside an upsurge in apoptosis in LC cells. Either downregulation of miR-3918 or overexpression of FGFR1 mitigated the suppressive impact of circNINL knockdown on LC pathogenesis. Mechanistic studies validated that circNINL served as a competitive endogenous RNA for miR-3918, thus influencing FGFR1 expression. Further, in vivo experiments using nude mouse xenograft models underscored that silencing circNINL substantially curtailed tumor growth in LC. Collectively, these findings illuminate that circNINL exacerbates LC malignancy via the miR-3918/FGFR1 axis, a process integrally linked with the activation of aerobic glycolysis. Show less
Most coronary artery disease (CAD) risk loci identified by genome-wide association studies (GWAS) are located in non-coding regions, hampering the interpretation of how they confer CAD risk. It is ess Show more
Most coronary artery disease (CAD) risk loci identified by genome-wide association studies (GWAS) are located in non-coding regions, hampering the interpretation of how they confer CAD risk. It is essential to integrate GWAS with molecular traits data to further explore the genetic basis of CAD. We used the probabilistic Mendelian randomization (PMR) method to identify potential proteins involved in CAD by integrating CAD GWAS data (∼76,014 cases and ∼264,785 controls) and human plasma proteomes (N = 35,559). Then, Bayesian co-localization analysis, confirmatory PMR analysis using independent plasma proteome data (N = 7752), and gene expression data (N1 = 213, N2 = 670) were performed to validate candidate proteins. We further investigated the associations between candidate proteins and CAD-related traits and explored the rationality and biological functions of candidate proteins through disease enrichment, cell type-specific, GO, and KEGG enrichment analysis. This study inferred that the abundance of 30 proteins in the plasma was causally associated with CAD ( Our integration analysis has identified 30 candidate proteins for CAD, which may provide important leads to design future functional studies and potential drug targets for CAD. Show less
Ovarian cancer (OC) is the malignant tumor with the highest mortality among gynecological cancers. Chemotherapy resistance is a major obstacle to OC therapy. Circular RNAs (circRNAs) play crucial role Show more
Ovarian cancer (OC) is the malignant tumor with the highest mortality among gynecological cancers. Chemotherapy resistance is a major obstacle to OC therapy. Circular RNAs (circRNAs) play crucial roles in cancer development and chemoresistance. However, the role and potential mechanism of has-circ-001567 (circ-VPS13C) in chemoresistance of OC remain unknown. The levels of circ-VPS13C, miR-106b-5p and 14-3-3 zeta (YWHAZ) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell Counting Kit-8 (CCK-8) assay was used to assess cell viability and calculate the half inhibition concentration (IC Circ-VPS13C and YWHAZ were up-regulated, while miR-106b-5p was down-regulated in DDP-resistant OC tissues and cells. Knockdown of circ-VPS13C enhanced DDP sensitivity by repressing autophagy in DDP-resistant cells. Circ-VPS13C increased DDP resistance via sponging miR-106b-5p. Moreover, miR-106b-5p directly targeted YWHAZ. Up-regulation of YWHAZ alleviated the decrease in DDP resistance caused by circ-VPS13C depletion. In addition, circ-VPS13C silencing decreased DDP resistance Circ-VPS13C knockdown enhanced DDP sensitivity of OC through modulation of autophagy via the miR-106b-5p/YWHAZ axis, providing a new biomarker for improving the efficacy of OC chemotherapy. Show less
Previous studies have revealed that Propane-2-sulfonic acid octadec-9-enyl-amide(N15) exerts a protective role in the inflammatory response after ischemic stroke and in neuronal damage. However, littl Show more
Previous studies have revealed that Propane-2-sulfonic acid octadec-9-enyl-amide(N15) exerts a protective role in the inflammatory response after ischemic stroke and in neuronal damage. However, little is known about N15 in Alzheimer's disease (AD). The aim of this study was to investigate the effects of N15 on AD and explore the underlying molecular mechanism. AD mice model was established by lateral ventricular injection with Aβ N15 treatment significantly reduced neurocognitive dysfunction, which also significantly activated the expression of PPARα/γ at an optimal dose of 200 mg/kg. Administration of N15 alleviated the formation of Aβ amyloid in the hippocampus of AD mice, enhanced the BDNF mRNA expression, decreased the mRNA and protein levels of PS1 and BACE1, upregulated ADAM10 mRNA and protein levels. N15 exerts its neuroprotective effects through the activation of PPARα/γ and may be a potential drug for the treatment of AD. Show less
Huibin Huang, Juan Li, Tianhua Chen+5 more · 2024 · Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology · Taylor & Francis · added 2026-04-24
To analyse changes in lipid levels during the development of intrahepatic cholestasis of pregnancy (ICP) and identify new biomarkers for predicting ICP. A retrospective case-control study was conducte Show more
To analyse changes in lipid levels during the development of intrahepatic cholestasis of pregnancy (ICP) and identify new biomarkers for predicting ICP. A retrospective case-control study was conducted to analyse 473 pregnant women who underwent regular prenatal examinations and delivered at the Women and Children's Hospital, School of Medicine, Xiamen University, between June 2020 and June 2023, including 269 normal pregnancy controls and 204 pregnant women with cholestasis. Patients with ICP with gestational diabetes mellitus (GDM) have lower high-density lipoprotein (HDL) levels than in those without GDM. Total bile acid (TBA) levels were significantly higher in pregnant women with GDM than those without. The apolipoprotein A (APOA) level was lower in patients with ICP and hypothyroidism than those without hypothyroidism. TBA levels were significantly higher in pregnant women with hypothyroidism than those without. Triglyceride (TG) levels were significantly higher in patients with preeclampsia (PE) than those without. HDL and APOA levels were lower in women with ICP complicated by preterm delivery than those with normal delivery. The AUC (area under the curve) of the differential diagnosis of cholestasis of pregnancy for the APOA/APOB (apolipoprotein B) ratio was 0.727, with a sensitivity of 85.9% and specificity of 47.5%. The results suggested that dyslipidaemia is associated with an increased risk of ICP and its complications. The timely detection of blood lipid and bile acid levels can assist in the diagnosis of ICP and effectively prevent ICP and other complications. Show less
Osimertinib, a promising and approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a standard strategy for EGFR-mutant non-small cell lung cancer (NSCLC Show more
Osimertinib, a promising and approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a standard strategy for EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, developed resistance is unavoidable, which reduces its long-term effectiveness. In this study, RNA sequencing was performed to analyze differentially expressed genes (DEGs). The PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to identify the key genes for clinical prognosis and gene correlation respectively. Protein expression was determined by western blot analysis. Cell viability assay and Ki67 staining were used to evaluate the effect of osimertinib on tumor cells. Finally, we screened out two hub genes, myelocytomatosis oncogene (Myc) and axis inhibition protein 1 (Axin1), upregulated in three osimertinib-resistant cell lines through RNA sequencing and bioinformatics analysis. Next, cell experiment confirmed that expression of C-MYC and AXIN1 were elevated in different EGFR mutant NSCLC cell lines with acquired resistance to osimertinib, compared with their corresponding parental cell lines. Furthermore, we demonstrated that AXIN1 upregulated the expression of C-MYC and mediated the acquired resistance of EGFR mutant NSCLC cells to osimertinib in vitro. In conclusion, AXIN1 affected the sensitivity of EGFR mutant NSCLC to osimertinib via regulating C-MYC expression in vitro. Targeting AXIN1/MYC signaling may be a potential new strategy for overcoming acquired resistance to osimertinib. Show less
Diabetic retinopathy (DR) is a severe microangiopathy of diabetes. Müller cells play an important role in the development of DR. Acteoside (ACT) has been reported to be effective in the treatment of D Show more
Diabetic retinopathy (DR) is a severe microangiopathy of diabetes. Müller cells play an important role in the development of DR. Acteoside (ACT) has been reported to be effective in the treatment of DR. In this study, we explored the molecular mechanism of ACT in the treatment of DR from the perspective of the reactive proliferation of Müller cells. The effect of ACT on DR was investigated via high-glucose (HG) treatment of Müller RMC-1 cells and an injection of streptozotocin (STZ) in constructed DR cells and animal models. The results showed that after ACT treatment, damage to the retinal structure in DR rats was alleviated, the number of hemangiomas was reduced, and the penetration of blood vessels was weakened. In addition, ACT treatment improved the hypertrophy and gliogenesis of Müller cells during DR, promoted the expression of Kir4.1 and activated the PI3K/Akt signaling pathway. ACT treatment inhibited the proliferation and migration of RMC-1 cells and promoted the expression of Kir4.1. TXNIP overexpression effectively reversed the inhibitory effect of ACT on the proliferation and migration of Müller cells and its induction of Kir4.1 expression. In addition, TXNIP knockdown effectively reversed the inhibitory effect of HG on the expression of p-PI3K and p-Akt, whereas TXNIP overexpression had the opposite effect, and treatment with the PI3K/AKT pathway inhibitor LY294002 effectively reversed the effect of TXNIP knockdown. Animal experiments also confirmed that the therapeutic effect of ACT on DR rats could be reversed by the overexpression of TXNIP or LY294002. In conclusion, ACT inhibits Müller cell reactive proliferation and alleviates diabetic retinopathy by regulating TXNIP and mediating the expression of Kir4.1 channels in a PI3K/Akt-dependent manner. Show less
The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is Show more
The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role. Show less
Excessive fluoride exposure induces skeletal fluorosis, but the specific mechanism responsible is still unclear. Therefore, this study aimed to identify the pathogenesis of fluoride-induced bone injur Show more
Excessive fluoride exposure induces skeletal fluorosis, but the specific mechanism responsible is still unclear. Therefore, this study aimed to identify the pathogenesis of fluoride-induced bone injuries. We systematically searched fluoride-induced bone injury-related genes from five databases. Then, these genes were subjected to enrichment analyses. A TF (transcription factor)-mRNA-miRNA network and protein-protein interaction (PPI) network were constructed using Cytoscape, and the Human Protein Atlas (HPA) database was used to screen the expression of key proteins. The candidate pharmacological targets were predicted using the Drug Signature Database. A total of 85 studies were included in this study, and 112 osteoblast-, 35 osteoclast-, and 41 chondrocyte-related differential expression genes (DEGs) were identified. Functional enrichment analyses showed that the Atf4, Bcl2, Col1a1, Fgf21, Fgfr1 and Il6 genes were significantly enriched in the PI3K-Akt signaling pathway of osteoblasts, Mmp9 and Mmp13 genes were enriched in the IL-17 signaling pathway of osteoclasts, and Bmp2 and Bmp7 genes were enriched in the TGF-beta signaling pathway of chondrocytes. With the use of the TF-mRNA-miRNA network, the Col1a1, Bcl2, Fgfr1, Mmp9, Mmp13, Bmp2, and Bmp7 genes were identified as the key regulatory factors. Selenium methyl cysteine, CGS-27023A, and calcium phosphate were predicted to be the potential drugs for skeletal fluorosis. These results suggested that the PI3K-Akt signaling pathway being involved in the apoptosis of osteoblasts, with the IL-17 and the TGF-beta signaling pathways being involved in the inflammation of osteoclasts and chondrocytes in fluoride-induced bone injuries. Show less
Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Show more
Obstructive sleep apnea (OSA) is considered to be an important contributor of dyslipidemia. However, there lacks observational studies focusing on the potential effect of lipid management on OSA risk. Thus, we aimed to investigate the genetic association of lipid-modifying therapy with risk of OSA. A drug-target mendelian randomization (MR) study using both cis-variants and cis-expression quantitative trait loci (eQTLs) of lipid-modifying drug targets was performed. The MR analyses used summary-level data of genome wide association studies (GWAS). Primary MR analysis was conducted using inverse-variance-weighted (IVW) method. Sensitivity analysis was performed using weighted median (WM) and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Genetically proxied low-density lipoprotein cholesterol (LDL-C)-lowering effect of cholesteryl ester transfer protein (CETP) was associated with reduced risk of OSA (odds ratio [OR] =0.75, 95% confidence interval [CI]: 0.60-0.94, false discovery rate [FDR] q value = 0.046). A significant MR association with risk of OSA was observed for CETP expression in subcutaneous adipose tissue (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049), lung (OR = 0.94, 95%CI: 0.89-1.00, FDR q value = 0.049) and small intestine (OR = 0.96, 95%CI: 0.93-1.00, FDR q value = 0.049). No significant effects of high-density lipoprotein cholesterol (HDL-C)-raising effect of CETP inhibition, LDL-C-lowering and triglycerides-lowering effect of other drug targets on OSA risk were observed. The present study presented genetic evidence supporting the association of LDL-C-lowering therapy by CETP inhibition with reduced risk of OSA. These findings provided novel insights into the role of lipid management in patients with OSA and encouraged further clinical validations and mechanistic investigations. Show less
Binge drinking causes a range of problems especially damage to the nervous system, and the specific neural mechanism of brain loss and behavioral abnormalities caused by which is still unclear. Extrac Show more
Binge drinking causes a range of problems especially damage to the nervous system, and the specific neural mechanism of brain loss and behavioral abnormalities caused by which is still unclear. Extracellular regulated protein kinases (ERK) maintain neuronal survival, growth, and regulation of synaptic plasticity by phosphorylating specific transcription factors to regulate expression of brain-derived neurotrophic factor (BDNF). Dual-specific phosphatase 1 (DUSP1) and DUSP6 dephosphorylate tyrosine and serine/threonine residues in ERK1/2 to inactivate them. To investigate the molecular mechanism by which alcohol affects memory and emotion, a chronic intermittent alcohol exposure (CIAE) model was established. The results demonstrated that mice in the CIAE group developed short-term recognition memory impairment and anxiety-like behavior; meanwhile, the expression of DUSP1 and DUSP66 in the mPFC was increased, while the levels of p-ERK and BDNF were decreased. Micro-injection of DUSP1/6 inhibitor BCI into the medial prefrontal cortex (mPFC) restored the dendritic morphology by reversing the activity of ERK-BDNF and ultimately improved cognitive and emotional impairment caused by CIAE. These findings indicate that CIAE inhibits ERK-BDNF by increasing DUSP1/6 in the mPFC that may be associated with cognitive and emotional deficits. Consequently, DUSP1 and DUSP6 appear to be potential targets for the treatment of alcoholic brain disorders. Show less
Zhonglin Li, Jinfang Zhao, Ya Wu+9 more · 2024 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
According to recent research, metabolic-associated fatty liver disease (MAFLD) has emerged as an important underlying etiology of hepatocellular carcinoma (HCC). However, the molecular mechanism of MA Show more
According to recent research, metabolic-associated fatty liver disease (MAFLD) has emerged as an important underlying etiology of hepatocellular carcinoma (HCC). However, the molecular mechanism of MAFLD-HCC is still unclear. Tumor necrosis factor receptor-associated factor 2 (TRAF2) is the key molecule to mediate the signal of inflammatory NF-κB pathway. This study aims to investigate the potential dysregulation of TRAF2 and its biological function in MAFLD-HCC. Huh7 TRAF2 Show less
Altered expression and activity of solute carrier family 4 member 4 (SLC4A4) could affect the growth, survival and metastasis of tumor cells. Currently, the role of SLC4A4 in lung adenocarcinoma (LUAD Show more
Altered expression and activity of solute carrier family 4 member 4 (SLC4A4) could affect the growth, survival and metastasis of tumor cells. Currently, the role of SLC4A4 in lung adenocarcinoma (LUAD) immunotherapy and prognosis was not entirely clear. We analyzed SLC4A4 expression in LUAD tissues and cell lines using quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of SLC4A4 overexpression on angiogenesis, cell migration, invasion, and epithelial-mesenchymal transition were examined. Public databases helped construct a risk model evaluating SLC4A4's expression on LUAD prognosis and immunotherapy response. Additionally, a xenograft model, flow cytometry, and enzyme-linked immunosorbent assay further explored SLC4A4's role in tumor immune microenvironment infiltration. Upregulation of SLC4A4 promoted apoptosis in the LUAD cell line and significantly inhibited the migration and invasive ability of cancer cells (P<0.01). A total of 10 key genes (including SIGLEC6, RHOV, PIR, MOB3B, MIR3135B, LPAR6, KRT8, ITGA2, CPS1, and C6) were screened according to SLC4A4 expression, immune score and stromal score, and a prognostic model with good outcome was constructed (AUC values of which in the training cohort at 1,3, and 5 years reached 0.73, 0.73, and 0.72, respectively). Importantly, we demonstrated that high expression of SLC4A4 was able to increase the proliferation level and cytokine secretion of CD8+ T cells for the purpose of promoting the immune system response to LUAD. Our study revealed that SLC4A4 can serve as a prognostic indicator for LUAD, providing new insights into the treatment and diagnosis of LUAD. Show less
The trophoblast epithelial-to-mesenchymal transition (EMT) is a procedure related to embryo implantation, spiral artery establishment and fetal-maternal communication, which is a key event for success Show more
The trophoblast epithelial-to-mesenchymal transition (EMT) is a procedure related to embryo implantation, spiral artery establishment and fetal-maternal communication, which is a key event for successful pregnancy. Inadequate EMT is one of the pathological mechanisms of recurrent miscarriage (RM). Whole-exome sequencing revealed that the mutation of bromodomain PHD-finger transcription factor (BPTF) was strongly associated with RM. In the present study, the effects of BPTF on EMT and the underlying mechanism were investigated. We found that the expression of BPTF in the villi of RM patients was significantly downregulated. Gene Ontology (GO) analysis revealed that BPTF participated in cell adhesion. The knockdown of BPTF prevented EMT and attenuated trophoblast invasion in vitro. BPTF activated Slug transcription by binding directly to the promoter region of the Slug gene. Interestingly, the protein levels of both Slug and BPTF were decreased in the villous cytotrophoblasts (VCTs) of RM villi. In conclusion, BPTF participates in the regulation of trophoblast EMT by activating Slug expression, suggesting that BPTF defects are an important factor in RM pathogenesis. Show less
Paroxysmal nocturnal haemoglobinuria (PNH) is a disorder resulting from erythrocyte membrane deficiencies caused by PIG-A gene mutations. While current treatments alleviate symptoms, they fail to addr Show more
Paroxysmal nocturnal haemoglobinuria (PNH) is a disorder resulting from erythrocyte membrane deficiencies caused by PIG-A gene mutations. While current treatments alleviate symptoms, they fail to address the underlying cause of the disease-the pathogenic PNH clones. In this study, we found that the expression of carbamoyl phosphate synthetase 1 (CPS1) was downregulated in PNH clones, and the level of CPS1 was negatively correlated with the proportion of PNH clones. Using PIG-A knockout K562 (K562 KO) cells, we demonstrated that CPS1 knockdown increased cell proliferation and altered cell metabolism, suggesting that CPS1 participates in PNH clonal proliferation through metabolic reprogramming. Furthermore, we observed an increase in the expression levels of the histone demethylase JMJD1C in PNH clones, and JMJD1C expression was negatively correlated with CPS1 expression. Knocking down JMJD1C in K562 KO cells upregulated CPS1 and H3K36me3 expression, decreased cell proliferation and increased cell apoptosis. Chromatin immunoprecipitation analysis further demonstrated that H3K36me3 regulated CPS1 expression. Finally, we demonstrated that histone demethylase inhibitor JIB-04 can suppressed K562 KO cell proliferation and reduced the proportion of PNH clones in PNH mice. In conclusion, aberrant regulation of the JMJD1C-H3K36me3-CPS1 axis contributes to PNH clonal proliferation. Targeting JMJD1C with a specific inhibitor unveils a potential strategy for treating PNH patients. Show less
Total ginsenosides (TG), the major active constituents of ginseng, have been proven to be beneficial in treatment of Alzheimer's disease (AD). However, the underlying mechanism of TG remains unclear. Show more
Total ginsenosides (TG), the major active constituents of ginseng, have been proven to be beneficial in treatment of Alzheimer's disease (AD). However, the underlying mechanism of TG remains unclear. APP/PS1 mice and N2a/APP695 cells were used as in vivo and in vitro model, respectively. Morris water maze (MWM) was used to investigate behavioral changes of mice; neuronal pathological changes were assessed by hematoxylin and eosin (H&E) and nissl staining; immunofluorescence staining was used to examine amyloid beta (Aβ) deposition; Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to examine the expression of relative amyloidogenic genes and proteins. Moreover, the antagonist of PPARγ, GW9662, was used to determine whether the effects of TG on Aβ production were associated with PPARγ activity. TG treatment increased the spatial learning and memory abilities of APP/PS1 mice while decreasing the Aβ accumulation in the cortex and hippocampus. In N2a/APP695 cells, TG treatment attenuated the secretion of Aβ1-40 and Aβ1-42 acting as an PPARγ agonist by inhibiting the translocation of NF-κB p65. Additionally, TG treatment also decreased the expression of amyloidogenic pathway related gene BACE1, PS1 and PS2. TG treatment reduced the production of Aβ both in vivo and in vitro. Activating PPARγ might be a potential therapeutic target of TG in facilitating Aβ clearance and ameliorating cognitive deficiency in APP/PS1 mice. Show less
This study leverages the most up-to-date lipidomic data to provide fresh perspectives on the treatment and prevention of atopic dermatitis. The analysis utilized genome-wide association study (GWAS) d Show more
This study leverages the most up-to-date lipidomic data to provide fresh perspectives on the treatment and prevention of atopic dermatitis. The analysis utilized genome-wide association study (GWAS) data on 179 circulating plasma lipids and AD GWAS data. The primary analysis method employed was the inverse variance weighting (IVW) method, and several sensitivity analyses were conducted to ensure the reliability of the results. Additionally, summary-data-based MR (SMR) and colocalization analysis were utilized to investigate the underlying biological pathways of AD. After rigorous analyses, the IVW method utilized in TSMR analysis pinpointed six plasma lipids with potentially reduced AD risk when elevated. Subsequently, MVMR analysis revealed that there is no independent causal effect of different lipids within the same subtype on AD. Bidirectional MR analysis did not indicate reverse causality, and SMR analysis suggested FADS1 and FADS2 as potential drug targets for AD treatment. This MR study demonstrated a causal relationship between specific plasma lipid levels and AD risk at the genetic level, which can be used for clinical screening of AD plasma lipid biomarkers and provides a novel perspective on potential therapeutic strategies. Show less
More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. Show more
More than 60 monogenic genes mutated in steroid-resistant nephrotic syndrome (SRNS) have been identified. Our previous study found that mutations in nucleoporin 160 kD (NUP160) are implicated in SRNS. The NUP160 gene encodes a component of the nuclear pore complex. Recently, two siblings with homozygous NUP160 mutations presented with SRNS and a nervous system disorder. However, replication of nephrotic syndrome (NS)-associated phenotypes in a mammalian model following loss of Nup160 is needed to prove that NUP160 mutations cause SRNS. Here, we generated a podocyte-specific Nup160 knockout (Nup160podKO) mouse model using CRISPR/Cas9 and Cre/loxP technologies. We investigated NS-associated phenotypes in these Nup160podKO mice. We verified efficient abrogation of Nup160 in Nup160podKO mice at both the DNA and protein levels. We showed that Nup160podKO mice develop typical signs of NS. Nup160podKO mice exhibited progression of proteinuria to average albumin/creatinine ratio (ACR) levels of 15.06 ± 2.71 mg/mg at 26 weeks, and had lower serum albumin levels of 13.13 ± 1.34 g/l at 30 weeks. Littermate control mice had urinary ACR mean values of 0.03 mg/mg and serum albumin values of 22.89 ± 0.34 g/l at the corresponding ages. Further, Nup160podKO mice exhibited glomerulosclerosis compared with littermate control mice. Podocyte-specific Nup160 knockout in mice led to NS and glomerulosclerosis. Thus, our findings strongly support that mutations in NUP160 cause SRNS. The newly generated Nup160podKO mice are a reliable mammalian model for future study of the pathogenesis of NUP160-associated SRNS. Show less
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors originating from the digestive system. Tertiary lymphoid structures (TLS), non-lymphoid tissues outside of the lymphoid organs Show more
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors originating from the digestive system. Tertiary lymphoid structures (TLS), non-lymphoid tissues outside of the lymphoid organs, are closely connected to chronic inflammation and tumorigenesis. However, the detailed relationship between TLS and HCC prognosis remained unclear. In this study, we aimed to construct a TLS-related gene signature for predicting the prognosis of HCC patients. The Cancer Genome Atlas (TCGA) clinical data from 369 HCC tissues and 50 normal liver tissues were utilized to examine the differential expression of TLS-related genes. Based on least absolute shrinkage and selection operator (LASSO) Cox regression analysis, the prognostic model was constructed using the TCGA cohort and validated in the GSE14520 cohort and International Cancer Genome Consortium (ICGC) cohort. The Kaplan-Meier (KM) and receiver operating characteristic (ROC) curves were employed to validate the predictive ability of the prognostic model. Furthermore, Cox regression analysis was applied to identify whether the TLS score could be employed as an independent prognosis factor. A nomogram was developed to predict the survival probability of HCC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed for TLS-related genes. Genetic mutation analysis, the CIBERSORT algorithm, and single-sample gene set enrichment analysis (ssGSEA) were used to assess the tumor mutation landscape and immune infiltration. Finally, the role of the TLS score in HCC therapy was investigated. Six genes were included in the construction of our prognostic model (CETP, DNASE1L3, PLAC8, SKAP1, C7, and VNN2), and we validated its accuracy. Survival analysis showed that patients in the high-TLS score group had a significantly better overall survival than those in the low-TLS score group. Univariate, multivariate Cox regression analysis and the establishment of a nomogram indicated that the TLS score could independently function as a potential prognostic marker. A significant association between TLS score and immunity was revealed by an analysis of gene alterations and immune cell infiltration. In addition, two subtypes of the TLS score could accurately predict the effectiveness of sorafenib, transcatheter arterial chemoembolization (TACE), and immunotherapy in HCC patients. In this research, we conducted and validated a prognostic model associated with TLS that may be helpful for predicting clinical outcomes and treatment responsiveness for HCC patients. Show less
Lung squamous cell carcinoma (LUSC), a subset of non-small cell lung cancer (NSCLC), accounts for about 30% of all lung cancers (LC) and exhibits a dismal response to current therapeutic protocols. Ex Show more
Lung squamous cell carcinoma (LUSC), a subset of non-small cell lung cancer (NSCLC), accounts for about 30% of all lung cancers (LC) and exhibits a dismal response to current therapeutic protocols. Existed studies have indicated that aberrations in fibroblast growth factor receptors (FGFRs) play a pivotal role in the progression of LUSC, rendering them as attractive targets for therapeutic intervention in this cancer type. This study found that Erdafitinib (Erda), a novel pan-FGF receptor tyrosine kinase inhibitor (TKI), exerted a cytotoxic effect on LUSC cells. However, STAT3, the downstream target of FGFRs, remained still activated despite Erdafitinib treatment. Then, a STAT3 inhibitor, Stattic (Sta), was concurrently used with Erdafitinib, and the combined treatment demonstrated a synergistic efficacy in both Show less
Unexplained recurrent pregnancy loss (URPL) is a clinical dilemma in reproductive fields. Its diagnosis is mainly exclusionary after extensive clinical examination, and some of the patients may still Show more
Unexplained recurrent pregnancy loss (URPL) is a clinical dilemma in reproductive fields. Its diagnosis is mainly exclusionary after extensive clinical examination, and some of the patients may still face the risk of miscarriage. We analyzed follicular fluid (FF) from Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the DEPs are involved in the biological processes (BP) of complement and coagulation cascades. Apolipoproteins (APOs) are key proteins in the PPI network. ELISA confirmed that APOB was low-expressed in both the FF and peripheral blood of URPL patients. Dysregulation of the immune network intersecting coagulation and inflammatory response is an essential feature of URPL, and this disequilibrium exists as early as the oogenesis stage. Therefore, earlier intervention is necessary to prevent the development of URPL. Moreover, aberrant lipoprotein regulation appears to be a key factor contributing to URPL. The mechanism by which these factors are involved in the complement and coagulation cascade pathways remains to be further investigated, which also provides new candidate targets for URPL treatment. Show less
Rev-erbɑ (NR1D1) is a nuclear receptor superfamily member that plays a vital role in mammalian molecular clocks and metabolism. Rev-erbɑ can regulate the metabolism of drugs and the body's glucose met Show more
Rev-erbɑ (NR1D1) is a nuclear receptor superfamily member that plays a vital role in mammalian molecular clocks and metabolism. Rev-erbɑ can regulate the metabolism of drugs and the body's glucose metabolism, lipid metabolism, and adipogenesis. It is even one of the important regulatory factors regulating the occurrence of metabolic diseases (e.g., diabetes, fatty liver). Metabolic enzymes mediate most drug metabolic reactions in the body. Rev-erbɑ has been recognized to regulate drug metabolic enzymes (such as Cyp2b10 and Ugt1a9). Therefore, this paper mainly reviewed that Rev-erbɑ regulates I and II metabolic enzymes in the liver to affect drug pharmacokinetics. The expression of these drug metabolic enzymes (up-regulated or down-regulated) is related to drug exposure and effects/ toxicity. In addition, our discussion extends to Rev-erbɑ regulating some transporters (such as P-gp, Mrp2, and Bcrp), as they also play an essential role in drug metabolism. Finally, we briefly describe the role and mechanism of nuclear receptor Rev-erbɑ in lipid and glucose homeostasis, obesity, and metabolic disorders syndrome. In conclusion, this paper aims to understand better the role and mechanism of Rev-erbɑ in regulating drug metabolism, lipid, glucose homeostasis, obesity, and metabolic disorders syndrome, which explores how to target Rev-erbɑ to guide the design and development of new drugs and provide scientific reference for the molecular mechanism of new drug development, rational drug use, and drug interaction. Show less
Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly u Show more
Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly understood. To gain insight into the role of pregnancy in modulating immune responses at baseline and upon SARS-CoV-2 infection, we collected peripheral blood mononuclear cells and plasma from 226 women, including 152 pregnant individuals and 74 non-pregnant women. We find that SARS-CoV-2 infection is associated with altered T cell responses in pregnant women, including a clonal expansion of CD4-expressing CD8 Show less
Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma Show more
Atherosclerosis is the most common cause of cardiovascular diseases. Clinical studies indicate that loss-of-function ASGR1 (asialoglycoprotein receptor 1) is significantly associated with lower plasma cholesterol levels and reduces cardiovascular disease risk. However, the effect of ASGR1 on atherosclerosis remains incompletely understood; whether inhibition of ASGR1 causes liver injury remains controversial. Here, we comprehensively investigated the effects and the underlying molecular mechanisms of ASGR1 deficiency and overexpression on atherosclerosis and liver injury in mice. We engineered After being fed a Western diet for 12 weeks, Inhibition of ASGR1 inhibits atherosclerosis in Western diet-fed Show less