Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional out Show more
Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke . Cis-expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3-6 versus 0-2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome-wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes ( The present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation. Show less
Organophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented. Based on a birth cohort study, we aimed to investigate the association Show more
Organophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented. Based on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth. We measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth. We observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation. Gestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth. Show less
Euphorbia lathyris L. (EL) is a traditional poisonous herbal medicine used to treat dropsy, ascites, amenorrhea, anuria and constipation. Processing to reduce toxicity of EL is essential for its safe Show more
Euphorbia lathyris L. (EL) is a traditional poisonous herbal medicine used to treat dropsy, ascites, amenorrhea, anuria and constipation. Processing to reduce toxicity of EL is essential for its safe and effective application. However, there is little known regarding the molecular mechanism of reducing toxicity after EL processing. This research aimed to screen the differential markers for EL and PEL, explore the differential mechanisms of inflammatory injury induced by EL and processed EL (PEL) to expound the mechanism of alleviating toxicity after EL processing. The results showed that 15 potential biomarkers, mainly belonging to diterpenoids, were screened to distinguish EL from PEL. EL promoted the expressions of TLR4, NLRP3, NF-κB p65, IL-1β and TNF-α, increased lipid rafts abundance and promoted TLR4 positioning to lipid rafts. Meanwhile, EL decreased LXRα and ABCA1 expression, and reduced cholesterol efflux. In contrast to EL, the effects of PEL on these indicators were markedly weakened. In addition, Euphorbia factors L Show less
MicroRNAs are small regulatory molecules that control gene expression. An emerging property of muscle miRNAs is the cooperative regulation of transcriptional and epitranscriptional events controlling Show more
MicroRNAs are small regulatory molecules that control gene expression. An emerging property of muscle miRNAs is the cooperative regulation of transcriptional and epitranscriptional events controlling muscle phenotype. miR-155 has been related to muscular dystrophy and muscle cell atrophy. However, the function of miR-155 and its molecular targets in muscular dystrophies remain poorly understood. Through in silico and in vitro approaches, we identify distinct transcriptional profiles induced by miR-155-5p in muscle cells. The treated myotubes changed the expression of 359 genes (166 upregulated and 193 downregulated). We reanalyzed muscle transcriptomic data from dystrophin-deficient patients and detected overlap with gene expression patterns in miR-155-treated myotubes. Our analysis indicated that miR-155 regulates a set of transcripts, including Show less
Tumor inflammation is one of the hallmarks of tumors and is closely related to tumor occurrence and development, providing individualized prognostic prediction. However, few studies have evaluated the Show more
Tumor inflammation is one of the hallmarks of tumors and is closely related to tumor occurrence and development, providing individualized prognostic prediction. However, few studies have evaluated the relationship between inflammation and the prognosis of bladder urothelial carcinoma (BLCA) patients. Therefore, we constructed a novel inflammation-related prognostic model that included six inflammation-related genes (IRGs) that can precisely predict the survival outcomes of BLCA patients. RNA-seq expression and corresponding clinical data from BLCA patients were downloaded from The Cancer Genome Atlas database. Enrichment analysis was subsequently performed to determine the enrichment of GO terms and KEGG pathways. K‒M analysis was used to compare overall survival (OS). Cox regression and LASSO regression were used to identify prognostic factors and construct the model. Finally, this prognostic model was used to evaluate cell infiltration in the BLCA tumor microenvironment and analyze the effect of immunotherapy in high- and low-risk patients. We established an IRG signature-based prognostic model with 6 IRGs (TNFRSF12A, NR1H3, ITIH4, IL1R1, ELN and CYP26B1), among which TNFRSF12A, IL1R1, ELN and CYP26B1 were unfavorable prognostic factors and NR1H3 and ITIH4 were protective indicators. High-risk score patients in the prognostic model had significantly poorer OS. Additionally, high-risk score patients were associated with an inhibitory immune tumor microenvironment and poor immunotherapy response. We also found a correlation between IRS-related genes and bladder cancer chemotherapy drugs in the drug sensitivity data. The IRG signature-based prognostic model we constructed can predict the prognosis of BLCA patients, providing additional information for individualized prognostic judgment and treatment selection. Show less
Recently, studies on the mechanisms underlying lipid metabolic reprogramming in cancer have increased. However, its significance in cervical cancer remains unclear. In the present study, a prognostic Show more
Recently, studies on the mechanisms underlying lipid metabolic reprogramming in cancer have increased. However, its significance in cervical cancer remains unclear. In the present study, a prognostic signature was constructed for patients with cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) using the expression profiles of lipid metabolism-related genes (LMRGs). Furthermore, using various bioinformatics methods, a prognostic gene signature was developed for progression-free survival (PFS). This signature was externally validated using a cervical cancer dataset (GSE44001). The characteristics of the molecular subgroups of LMRGs were analyzed, and target LMRGs were identified via differential gene analysis of the expression profiles and weighted gene correlation network analysis. Thereafter, the identified target genes were used to develop the prognostic gene signature using univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses. The performance of the LMRG signature was evaluated using Kaplan-Meier curves, time-dependent receiver operating characteristic curves, decision curve analysis, mutation landscapes, gene set enrichment analysis, and immune score calculation. As a result, a novel eight-LMRG signature comprising ALDH3B2, CERS3, FA2H, GLTP, NR1H3, PLIN3, SLC44A3, and SQLE was constructed. Using this gene signature, patients with CESC and significantly distinguished PFS were divided. This eight-LMRG signature exhibited independent prognostic potential and superior predictive performance compared with a previously developed 12-gene signature. Our findings suggest that our novel eight-LMRG signature contributes to the implementation of precision medicine strategies for managing patients with cervical cancer by facilitating CESC prognosis. Show less
Retinal neovascularization poses heightened risks of vision loss and blindness. Despite its clinical significance, the molecular mechanisms underlying the pathogenesis of retinal neovascularization re Show more
Retinal neovascularization poses heightened risks of vision loss and blindness. Despite its clinical significance, the molecular mechanisms underlying the pathogenesis of retinal neovascularization remain elusive. This study utilized single-cell multiomics profiling in an oxygen-induced retinopathy (OIR) model to comprehensively investigate the intricate molecular landscape of retinal neovascularization. Mice were exposed to hyperoxia to induce the OIR model, and retinas were isolated for nucleus isolation. The cellular landscape of the single-nucleus suspensions was extensively characterized through single-cell multiomics sequencing. Single-cell data were integrated with genome-wide association study (GWAS) data to identify correlations between ocular cell types and diabetic retinopathy. Cell communication analysis among cells was conducted to unravel crucial ligand-receptor signals. Trajectory analysis and dynamic characterization of Müller cells were performed, followed by integration with human retinal data for pathway analysis. The multiomics dataset revealed six major ocular cell classes, with Müller cells/astrocytes showing significant associations with proliferative diabetic retinopathy (PDR). Cell communication analysis highlighted pathways that are associated with vascular proliferation and neurodevelopment, such as Vegfa-Vegfr2, Igf1-Igf1r, Nrxn3-Nlgn1, and Efna5-Epha4. Trajectory analysis identified a subset of Müller cells expressing genes linked to photoreceptor degeneration. Multiomics data integration further unveiled positively regulated genes in OIR Müller cells/astrocytes associated with axon development and neurotransmitter transmission. This study significantly advances our understanding of the intricate cellular and molecular mechanisms underlying retinal neovascularization, emphasizing the pivotal role of Müller cells. The identified pathways provide valuable insights into potential therapeutic targets for PDR, offering promising directions for further research and clinical interventions. Show less
The application of rituximab has significantly enhanced the overall survival rates in patients with diffuse large B-cell lymphoma (DLBCL). Regrettably, a significant number of patients still progress Show more
The application of rituximab has significantly enhanced the overall survival rates in patients with diffuse large B-cell lymphoma (DLBCL). Regrettably, a significant number of patients still progress to relapse/refractory DLBCL (rrDLBCL). Herein, we employed targeted sequencing of 55 genes to investigate if gene mutations could predict the progression to rrDLBCL. Additionally, we compared the mutation profiles at the time of DLBCL diagnosis with those found in rrDLBCL cases. Our findings highlighted significantly elevated mutation frequencies of Collectively, this study elucidates some of the genetic mechanisms contributing to the progression of rrDLBCL and suggests that the presence of Show less
This study aimed to identify and validate a 9-gene signature for predicting overall survival (OS) in glioma patients. Analysis of multiple gene expression datasets led to the identification of 135 can Show more
This study aimed to identify and validate a 9-gene signature for predicting overall survival (OS) in glioma patients. Analysis of multiple gene expression datasets led to the identification of 135 candidate genes associated with OS in glioma patients. Further analysis revealed that IGFBP2, PBK, NRXN3, TGIF1, DNAJA4, and LGALS3BP were identified as risk factors for OS, while ENAH, PPP2R2C, and SPHKAP were found to be protective factors. Multifaceted validation using different databases confirmed their differential expression patterns in glioma tissues compared to normal brain tissue. By utilizing LASSO regression and multivariate Cox regression analysis, a risk score was developed based on the expression levels of the 9 crucial genes. The risk score showed a significant correlation with OS in both training and validation cohorts and yielded superior predictive accuracy compared to individual gene expression. Moreover, a predictive nomogram incorporating the risk score, WHO grade, age, IDH mutation, and 1p/19q co-deletion was constructed and validated, which exhibited high predictive capabilities for survival rates at different time points. Enrichment analysis revealed the involvement of extracellular matrix-related pathways and immune system signaling in glioma prognosis. Furthermore, the risk score showed a strong correlation with immune cell infiltration and immune checkpoint expression, suggesting its potential role in the tumor immune microenvironment. In conclusion, our study provides a robust 9-gene signature and a predictive nomogram for evaluating the prognosis of glioma patients, offering valuable insights into personalized treatment strategies. Show less
The variants of nucleoporins are extremely rare in hereditary steroid-resistant nephrotic syndrome (SRNS). Most of the patients carrying such variants progress to end stage kidney disease (ESKD) in th Show more
The variants of nucleoporins are extremely rare in hereditary steroid-resistant nephrotic syndrome (SRNS). Most of the patients carrying such variants progress to end stage kidney disease (ESKD) in their childhood. More clinical and genetic data from these patients are needed to characterize their genotype-phenotype relationships and elucidate the role of nucleoporins in SRNS. Four patients of SRNS carrying biallelic variants in the NUP93, NUP107 and NUP160 genes were presented. The clinical and molecular genetic characteristics of these patients were summarized, and relevant literature was reviewed. All four patients in this study were female and initially presented with SRNS. The median age at the onset of the disease was 5.08 years, ranging from 1 to 10.5 years. Among the four patients, three progressed to ESKD at a median age of 7 years, ranging from 1.5 to 10.5 years, while one patient reached stage 3 chronic kidney disease (CKD3). Kidney biopsies revealed focal segmental glomerulosclerosis in three patients. Biallelic variants were detected in NUP93 in one patient, NUP107 in two patients, as well as NUP160 in one patient respectively. Among these variants, five yielded single amino acid substitutions, one led to nonsense mutation causing premature termination of NUP107 translation, one caused a single nucleotide deletion resulting in frameshift and truncation of NUP107. Furthermore, one splicing donor mutation was observed in NUP160. None of these variants had been reported previously. This report indicates that biallelic variants in NUP93, NUP107 and NUP160 can cause severe early-onset SRNS, which rapidly progresses to ESKD. Moreover, these findings expand the spectrum of phenotypes and genotypes and highlight the importance of next-generation sequencing in elucidating the molecular basis of SRNS and allowing rational treatment for affected individuals. Show less
Blood always shows coagulation changes after spinal cord injury (SCI), and identifying these blood changes may be helpful for diagnosis and treatment of SCI. Nevertheless, studies to date on blood coa Show more
Blood always shows coagulation changes after spinal cord injury (SCI), and identifying these blood changes may be helpful for diagnosis and treatment of SCI. Nevertheless, studies to date on blood coagulation changes after SCI in humans are not comprehensive. Therefore, this study aims to identify blood coagulation diagnostic biomarkers and immune changes related to SCI and its severity levels. Human blood sequencing datasets were obtained from public databases. Differentially expressed coagulation-related genes were analyzed (DECRGs). Enrichment analysis and assessment of immune changes were conducted. Weighted gene co-expression network analysis, least absolute shrinkage and selection operator logistic regression were used to identify biomarkers. Validation for these biomarkers was performed. The correlation between biomarkers and immune cells was evaluated. Transcription factors, miRNA, lncRNA, and drugs that can regulate biomarkers were analyzed. DECRGs associated with SCI and its different grades were identified, showing enrichment in altered coagulation and immune-related signaling pathways. ADAM9, CD55, and STAT4 were identified as coagulation diagnostic biomarkers for SCI. IRF4 and PABPC4 were identified as coagulation diagnostic biomarkers for American Spinal Injury Association Impairment Scale (AIS) A grade of SCI. GP9 was designated as a diagnostic biomarker for AIS D grade of SCI. Immune changes in blood of SCI and its different grades were observed. Correlation between diagnostic biomarkers and immune cells were identified. Transcription factors, miRNA, lncRNA, and drugs that can regulate diagnostic biomarker expression were discovered. Therefore, detecting the expression of these putative diagnostic biomarkers and related immune changes may be helpful for predicting the severity of SCI. Uncovering potential regulatory mechanisms for biomarkers may be beneficial for further research. Show less
Alternative polyadenylation (APA) plays a vital regulatory role in various diseases. It is widely accepted that APA is regulated by APA regulatory factors. Whether APA regulatory factors affect the pr Show more
Alternative polyadenylation (APA) plays a vital regulatory role in various diseases. It is widely accepted that APA is regulated by APA regulatory factors. Whether APA regulatory factors affect the prognosis of renal cell carcinoma remains unclear, and this is the main topic of this study. We downloaded the transcriptome and clinical data from The Cancer Genome Atlas (TCGA) database. We used the Lasso regression system to construct an APA model for analyzing the relationship between common APA regulatory factors and renal cell carcinoma. We also validated our APA model using independent GEO datasets (GSE29609, GSE76207). It was found that the expression levels of 5 APA regulatory factors (CPSF1, CPSF2, CSTF2, PABPC1, and PABPC4) were significantly associated with tumor gene mutation burden (TMB) score in renal clear cell carcinoma, and the risk score constructed using the expression level of 5 key APA regulatory factors could be used to predict the outcome of renal clear cell carcinoma. The TMB score is associated with the remodeling of the immune microenvironment. By identifying key APA regulatory factors in renal cell carcinoma and constructing risk scores for key APA regulatory factors, we showed that key APA regulators affect prognosis of renal clear cell carcinoma patients. In addition, the risk score level is associated with TMB, indicating that APA may affect the efficacy of immunotherapy through immune microenvironment-related genes. This helps us better understand the mRNA processing mechanism of renal clear cell carcinoma. Show less
The Ebola virus (EBOV) has emerged as a significant global health concern, notably during the 2013-2016 outbreak in West Africa. Despite the clinical approval of two EBOV antibody drugs, there is an u Show more
The Ebola virus (EBOV) has emerged as a significant global health concern, notably during the 2013-2016 outbreak in West Africa. Despite the clinical approval of two EBOV antibody drugs, there is an urgent need for more diverse and effective antiviral drugs, along with comprehensive understanding of viral-host interactions. In this study, we harnessed a biologically contained EBOVΔVP30-EGFP cell culture model which could recapitulate the entire viral life cycle, to conduct a genome-wide CRISPR/Cas9 screen. Through this, we identified PIK3C3 (phosphatidylinositide 3-kinase) and SLC39A9 (zinc transporter) as crucial host factors for EBOV infection. Genetic depletion of SLC39A9 and PIK3C3 lead to reduction of EBOV entry, but not impact viral genome replication, suggesting that SLC39A9 and PIK3C3 act as entry factors, facilitating viral entry into host cells. Moreover, PIK3C3 kinase activity is indispensable for the internalization of EBOV virions, presumably through the regulation of endocytic and autophagic membrane traffic, which has been previously recognized as essential for EBOV internalization. Notably, our study demonstrated that PIK3C3 kinase inhibitor could effectively block EBOV infection, underscoring PIK3C3 as a promising drug target. Furthermore, biochemical analysis showed that recombinant SLC39A9 protein could directly bind viral GP protein, which further promotes the interaction of viral GP protein with cellular receptor NPC1. These findings suggests that SLC39A9 plays dual roles in EBOV entry. Initially, it serves as an attachment factor during the early entry phase by engaging with the viral GP protein. Subsequently, SLC39A9 functions an adaptor protein, facilitating the interaction between virions and the NPC1 receptor during the late entry phase, prior to cathepsin cleavage on the viral GP. In summary, this study offers novel insights into virus-host interactions, contributing valuable information for the development of new therapies against EBOV infection. Show less
The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maint Show more
The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maintaining Treg cell homeostasis and function by regulating cellular metabolic activities. Disruption of Vps34 in Treg cells leads to spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number of Treg cells, particularly eTreg cells with highly immunosuppressive activity. Mechanistically, the poor survival of Vps34-deficient Treg cells is attributed to impaired endocytosis, intracellular vesicular trafficking and autophagosome formation, which further results in enhanced mitochondrial respiration and excessive ROS production. Removal of excessive ROS can effectively rescue the death of Vps34-deficient Treg cells. Functionally, acute deletion of Vps34 within established Treg cells enhances anti-tumor immunity in a malignant melanoma model by boosting T-cell-mediated anti-tumor activity. Overall, our results underscore the pivotal role played by Vps34 in orchestrating Treg cell homeostasis and function towards establishing immune homeostasis and tolerance. Show less
Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on se Show more
Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in Show less
Neuroinflammation serves as a critical local defense mechanism against secondary brain injury following intracerebral hemorrhage (ICH), and astrocytes play a prominent role in this process. In this st Show more
Neuroinflammation serves as a critical local defense mechanism against secondary brain injury following intracerebral hemorrhage (ICH), and astrocytes play a prominent role in this process. In this study, we investigated astrocytic changes during the inflammatory state after ICH to identify new targets for improving the inflammatory response. We stimulated mouse astrocytes with lipopolysaccharide (LPS) RNA sequencing revealed that 2,717 genes were differentially expressed in the LPS group compared to those in the saline group, with notable enrichment of the autophagic pathway. By intersecting the 2,717 differentially expressed genes (DEGs) with autophagy-related genes, we identified 36 autophagy-related DEGs and seven hub genes. Previous studies and quantitative reverse transcription-polymerase chain reaction results confirmed the increased expression of phosphatidylinositol 3-kinase catalytic subunit type 3 (Pik3c3), AKT serine/threonine kinase 1 (Akt1), and unc-51 like autophagy activating kinase 2 (Ulk2) in astrocytes after ICH. Transcription factors and target miRNAs were identified for the final three DEGs, and 3-methyladenine and leupeptin were identified as potential therapeutic agents for ICH. Our findings suggest that astrocyte autophagy plays a critical role in ICH complexity, and that Pik3c3, Akt1, and Ulk2 may be potential therapeutic targets. Show less
Intervertebral disc degeneration (IVDD) is the leading cause of lower back pain (LBP). β-arrestin 1 (ARRB1) is a multifunctional protein that regulates numerous pathological processes. The aim of this Show more
Intervertebral disc degeneration (IVDD) is the leading cause of lower back pain (LBP). β-arrestin 1 (ARRB1) is a multifunctional protein that regulates numerous pathological processes. The aim of this study was to investigate the role of ARRB1 in IVDD. The expression of ARRB1 in nucleus pulposus (NP) of rats with IVDD was assayed. Next, rat nucleus pulposus cells (NPCs) were infected with lentiviruses containing shArrb1 (LV-shArrb1) and overexpressing Arrb1 (LV-oeArrb1). The roles of Arrb1 in serum-deprived NPCs were investigated by measuring apoptosis, extracellular matrix degradation, and autophagic flux. For experiments in vivo, LV-oeArrb1 lentivirus was injected into the NP tissues of IVDD rats to evaluate the effects of Arrb1 overexpression on NP. In the NP tissues of IVDD rats, ARRB1 and cleaved caspase-3 expression increased, and the ratio of LC3II/LC3I protein expression was upregulated. Arrb1 knockdown aggravated extracellular matrix degradation, cellular apoptosis, and impairment of autophagic flux in rat NPCs under serum-deprived conditions, whereas Arrb1 overexpression significantly reversed these effects. ARRB1 interacted with Beclin 1, and Arrb1 knockdown suppressed the formation of the Beclin1-PIK3C3 core complex. The autophagy inhibitor 3-methyladenine (3-MA) offset the protective effects of Arrb1 overexpression in serum-deprived NPCs. Furthermore, Arrb1 overexpression inhibited apoptosis and extracellular matrix degradation, promoted autophagy in NP, and delayed the development of IVDD in rats. ARRB1 prevents extracellular matrix degradation and apoptosis of NPCs by upregulating autophagy and ameliorating IVDD progression, presenting an innovative strategy for the treatment of IVDD. Show less
AMP-activated protein kinase (AMPK) is a widely distributed and evolutionarily conserved serine/threonine protein kinase present in eukaryotic cells. In regulating cellular energy metabolism, AMPK pla Show more
AMP-activated protein kinase (AMPK) is a widely distributed and evolutionarily conserved serine/threonine protein kinase present in eukaryotic cells. In regulating cellular energy metabolism, AMPK plays an extremely important role as an energy metabolic kinase. When the body is in a low energy state, AMPK is activated in response to changes in intracellular adenine nucleotide levels and is bound to adenosine monophosphate (AMP) or adenosine diphosphate (ADP). Activated AMPK regulates various metabolic processes, including lipid and glucose metabolism and cellular autophagy. AMPK directly promotes autophagy by phosphorylating autophagy-related proteins in the mammalian target of rapamycin complex 1 (mTORC1), serine/threonine protein kinase-dysregulated 51-like kinase 1 (ULK1) and type III phosphatidylinositol 3-kinase-vacuolar protein-sorting 34 (PIK3C3-VPS34) complexes. AMPK also indirectly promotes autophagy by regulating the expression of downstream autophagy-related genes of transcription factors such as forkhead box O3 (FOXO3), lysosomal function transcription factor EB (TFEB) and bromodomain protein 4 (BRD4). AMPK also regulates mitochondrial autophagy, induces the division of damaged mitochondria and promotes the transfer of the autophagic response to damaged mitochondria. Another function of AMPK is to regulate mitochondrial health by stimulating mitochondrial biogenesis and participating in various aspects of mitochondrial homeostasis regulation. This review discusses the specific regulation of mitochondrial biology and internal environmental homeostasis by AMPK signaling channels as central to the cellular response to energy stress and regulation of mitochondria, highlighting the key role of AMPK in regulating cellular autophagy and mitochondrial autophagy, as well as advances in research on the regulation of mitochondrial homeostasis. Show less
Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, whic Show more
Macroautophagy/autophagy is essential for the degradation and recycling of cytoplasmic materials. The initiation of this process is determined by phosphatidylinositol-3-kinase (PtdIns3K) complex, which is regulated by factor BECN1 (beclin 1). UFMylation is a novel ubiquitin-like modification that has been demonstrated to modulate several cellular activities. However, the role of UFMylation in regulating autophagy has not been fully elucidated. Here, we found that VCP/p97 is UFMylated on K109 by the E3 UFL1 (UFM1 specific ligase 1) and this modification promotes BECN1 stabilization and assembly of the PtdIns3K complex, suggesting a role for VCP/p97 UFMylation in autophagy initiation. Mechanistically, VCP/p97 UFMylation stabilizes BECN1 through ATXN3 (ataxin 3)-mediated deubiquitination. As a key component of the PtdIns3K complex, stabilized BECN1 facilitates assembly of this complex. Re-expression of VCP/p97, but not the UFMylation-defective mutant, rescued the VCP/p97 depletion-induced increase in MAP1LC3B/LC3B protein expression. We also showed that several pathogenic VCP/p97 mutations identified in a variety of neurological disorders and cancers were associated with reduced UFMylation, thus implicating VCP/p97 UFMylation as a potential therapeutic target for these diseases. Show less
The endoplasmic reticulum (ER) serves as a hub for various cellular processes, and maintaining ER homeostasis is essential for cell function. Reticulophagy is a selective process that removes impaired Show more
The endoplasmic reticulum (ER) serves as a hub for various cellular processes, and maintaining ER homeostasis is essential for cell function. Reticulophagy is a selective process that removes impaired ER subdomains through autophagy-mediatedlysosomal degradation. While the involvement of ubiquitination in autophagy regulation is well-established, its role in reticulophagy remains unclear. In this study, we screened deubiquitinating enzymes (DUBs) involved in reticulophagy and identified USP20 (ubiquitin specific peptidase 20) as a key regulator of reticulophagy under starvation conditions. USP20 specifically cleaves K48- and K63-linked ubiquitin chains on the reticulophagy receptor RETREG1/FAM134B (reticulophagy regulator 1), thereby stabilizing the substrate and promoting reticulophagy. Remarkably, despite lacking a transmembrane domain, USP20 is recruited to the ER through its interaction with VAPs (VAMP associated proteins). VAPs facilitate the recruitment of early autophagy proteins, including WIPI2 (WD repeat domain, phosphoinositide interacting 2), to specific ER subdomains, where USP20 and RETREG1 are enriched. The recruitment of WIPI2 and other proteins in this process plays a crucial role in facilitating RETREG1-mediated reticulophagy in response to nutrient deprivation. These findings highlight the critical role of USP20 in maintaining ER homeostasis by deubiquitinating and stabilizing RETREG1 at distinct ER subdomains, where USP20 further recruits VAPs and promotes efficient reticulophagy. Show less
Anodized titania nanotubes have been considered as an effective coating for bone implants due to their ability to induce osteogenesis, whereas the osteogenic mechanism is not fully understood. Our pre Show more
Anodized titania nanotubes have been considered as an effective coating for bone implants due to their ability to induce osteogenesis, whereas the osteogenic mechanism is not fully understood. Our previous study has revealed the potential role of autophagy in osteogenic regulation of nanotubular surface, whereas how the autophagy is activated remains unknown. In this study, we focused on the cell membrane curvature-sensing protein Bif-1 and its effect on the regulation of autophagy. Both autophagosomes formation and autophagic flux were enhanced on the nanotubular surface, as indicated by LC3-II accumulation and p62 degradation. In the meanwhile, the Bif-1 was significantly upregulated, which contributed to autophagy activation and osteogenic differentiation through Beclin-1/PIK3C3 signaling pathway. In conclusion, these findings have bridged the gap between extracellular physical nanotopography and intracellular autophagy activation, which may provide a deeper insight into the signaling transition from mechanical to biological across the cell membrane. Show less
Hyperparathyroidism (HPT) manifests as a complex condition with a substantial disease burden. While advances have been made in surgical interventions and non-surgical pharmacotherapy for the managemen Show more
Hyperparathyroidism (HPT) manifests as a complex condition with a substantial disease burden. While advances have been made in surgical interventions and non-surgical pharmacotherapy for the management of hyperparathyroidism, radical options to halt underlying disease progression remain lacking. Identifying putative genetic drivers and exploring novel drug targets that can impede HPT progression remain critical unmet needs. A Mendelian randomization (MR) analysis was performed to uncover putative therapeutic targets implicated in hyperparathyroidism pathology. Cis-expression quantitative trait loci (cis-eQTL) data serving as genetic instrumental variables were obtained from the eQTLGen Consortium and Genotype-Tissue Expression (GTEx) portal. Hyperparathyroidism summary statistics for single nucleotide polymorphism (SNP) associations were sourced from the FinnGen study (5590 cases; 361,988 controls). Colocalization analysis was performed to determine the probability of shared causal variants underlying SNP-hyperparathyroidism and SNP-eQTL links. Five drug targets (CMKLR1, FSTL1, IGSF11, PIK3C3 and SLC40A1) showed significant causation with hyperparathyroidism in both eQTLGen and GTEx cohorts by MR analysis. Specifically, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and solute carrier family 40 member 1 (SLC40A1) showed strong evidence of colocalization with HPT. Multivariable MR and Phenome-Wide Association Study analyses indicated these two targets were not associated with other traits. Additionally, drug prediction analysis implies the potential of these two targets for future clinical applications. This study identifies PIK3C3 and SLC40A1 as potential genetically proxied druggable genes and promising therapeutic targets for hyperparathyroidism. Targeting PIK3C3 and SLC40A1 may offer effective novel pharmacotherapies for impeding hyperparathyroidism progression and reducing disease risk. These findings provide preliminary genetic insight into underlying drivers amenable to therapeutic manipulation, though further investigation is imperative to validate translational potential from preclinical models through clinical applications. Show less
We aimed to investigate the cardiomyocyte-protective effects of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on ischemia/reperfusion (I/R)-injured rats and to explore the mechanisms. Ca Show more
We aimed to investigate the cardiomyocyte-protective effects of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on ischemia/reperfusion (I/R)-injured rats and to explore the mechanisms. Cardiomyocytes were divided into control group, ischemia/reperfusion group (I/R group), ischemia/reperfusion+exosome group (I/R+Exo group) or ischemia/reperfusion+exosomes transfected with miR-101a-3p inhibitor group (I/R+Exo inhibitor group). MiR-101a-3p levels were lower in I/R and I/R+Exo inhibitor groups than in control and I/R+Exo groups. Apoptosis rate and cleaved caspase 3 expression were higher in I/R and I/R+Exo inhibitor groups. The levels of superoxide dismutase (SOD) in cardiomyocytes of I/R group and I/R+Exo inhibitor group were lower than those of control group and I/R+Exo group, and the levels of malondialdehyde (MDA) and the relative production of oxygen species clusters (ROS) in cardiomyocytes of I/R group and I/R+Exo inhibitor group were higher than those of control group and I/R+Exo group. The levels of interleukin-10 (IL-10), interleukin-6 (IL-6), tumour necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) were higher in the I/R group and the I/R +Exo inhibitor group than in the control group and the I/R+Exo group. Bioinformatics analysis suggested that Pik3c3 is the most promising gene involved in miR-101a-3p-mediated apoptosis in cardiomyocytes, and in vitro experiments confirmed that low expression of miR-101a-3p significantly up-regulated the mRNA and protein expression levels of Pik3c3. BMSCs-derived exosomes have a protective effect on cardiomyocytes from I/R-injured rats, and the mechanism may be related to the inhibition of oxidative stress and inflammatory responses in cardiomyocytes by exosome-delivered miR-101a-3p. Show less
LC3-associated phagocytosis (LAP) is an instrumental machinery for the clearance of extracellular particles including apoptotic cells for the alleviation of inflammation. While pharmacological approac Show more
LC3-associated phagocytosis (LAP) is an instrumental machinery for the clearance of extracellular particles including apoptotic cells for the alleviation of inflammation. While pharmacological approaches to modulate LAP for inflammation regulation have been poorly explored, in our study we identified a novel compound, columbamine (COL), which can trigger LAP and enhance efferocytosis in an animal model of colitis to attenuate inflammation. We found that COL directly binds to and biasedly activates FPR2 (formyl peptide receptor 2) to promote efferocytosis and alleviate colitis. Biochemically, COL induces an interaction between RAC1 and the PIK3C3/VPS34-RUBCN/RUBICON complex, stimulating LC3-associated efferocytosis. These findings provide a novel interpretation of the potential roles of LAP in regulating inflammatory bowel disease (IBD), reveal the relationship between G protein-coupled receptors (GPCRs) and LAP, and highlight the role of RAC1 in regulating the PIK3C3/VPS34-RUBCN complex in LAP. Show less
The excessive activation of immune responses will trigger autoimmune diseases or inflammatory injury. The endosomal sorting complexes required for transport (ESCRT) system can capture and mediate ubiq Show more
The excessive activation of immune responses will trigger autoimmune diseases or inflammatory injury. The endosomal sorting complexes required for transport (ESCRT) system can capture and mediate ubiquitinated protein degradation, which timely terminates signaling pathway hyperactivation. However, whether the ESCRT system participates in regulating RIGI-like receptor (RLR)-mediated antiviral responses remains unknown. In this study, we show that LTN1/listerin, a major component of RQC, can recruit E3 ubiquitin ligase TRIM27 to trigger K63-linked polyubiquitination of RIGI and IFIH1/MDA5. This K63-linked polyubiquitination facilitates the sorting and degradation of RIGI and IFIH1 proteins through the ESCRT-dependent pathway. Concordantly, LTN1 deficiency enhances the innate antiviral response to infection with RNA viruses. Thus, our work uncovers a new mechanism for RIGI and IFIH1 degradation and identifies the role of LTN1 in negatively regulating RLR-mediated antiviral innate immunity, which may provide new targets for the intervention of viral infection. Show less
ENDOG, a mitochondrial intermembrane space located endonuclease, participates in DNA fragmentation and apoptosis by translocating to the nucleus. ENDOG can also relocate to the mitochondrial matrix, w Show more
ENDOG, a mitochondrial intermembrane space located endonuclease, participates in DNA fragmentation and apoptosis by translocating to the nucleus. ENDOG can also relocate to the mitochondrial matrix, where it regulates mitochondrial genome cleavage. However, the biological function of cytoplasm-translocated ENDOG remains unclear. Our previous study reported that starvation induces the release of ENDOG from mitochondria to the cytoplasm, promoting macroautophagy/autophagy in a process conserved across species. We demonstrate that ENDOG can be phosphorylated by GSK3B, which enhances ENDOG binding to YWHAG/14-3-3γ, and leads to the release of TSC2 and PIK3C3/VPS34 from YWHAG/14-3-3γ, followed by MTORC1 pathway suppression and autophagy initiation. Additionally, we recently reported that ENDOG can also activate the MTORC2-AKT-ACLY signaling axis by promoting the release of RICTOR and TSC2 from YWHAG/14-3-3γ, resulting in acetyl-CoA production. Furthermore, cytoplasmic ENDOG can translocate to the endoplasmic reticulum, where it binds with HSPA5/BIP to release ERN1/IRE1a-EIF2AK3/PERK to activate the endoplasmic reticulum stress response, eventually promoting lipid synthesis. Collectively, ENDOG will be released from the mitochondrial intermembrane space, and translocated to the mitochondrial matrix, cytoplasm, and nucleus during different stress stimulation, where it digests DNA or interacts with crucial proteins to regulate different biological functions, including apoptosis, autophagy, mitophagy, and lipid synthesis. Show less
Zhuo Chen, Shengnan Liu, Junsheng Wang+1 more · 2024 · Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer · added 2026-04-24
Acute pancreatitis (AP) is a common digestive emergency, needs early prediction and recognition. The study examined the clinical value of long non-coding RNA SNHG1 in AP, and explored its related mech Show more
Acute pancreatitis (AP) is a common digestive emergency, needs early prediction and recognition. The study examined the clinical value of long non-coding RNA SNHG1 in AP, and explored its related mechanism for AP. A total of 288 AP cases and 150 healthy persons were recruited, the AP patients were grouped based on AP severity. AR42J cells were treated with 100nM caerulein to stimulate AP in vitro. qRT-PCR was performed for mRNA detection. Receiver operating characteristic (ROC) curve was drawn for diagnostic significance evaluation. The relationship of SNHG1 and miR-140-3p was verified via luciferase reporter and RNA immunoprecipitation (RIP) assay. AP cases had high expression of SNHG1, and it can differentiate AP cases from healthy people with the area under the curve (AUC) of 0.899. Severe AP cases had high values of SNHG1, which was independently related to AP severity. SNHG1 knockdown relieved caerulein-induced AR42J cell apoptosis and inflammatory response. miR-140-3p interacted with SNHG1, and reversed the role of SNHG1 in caerulein-induced AR42J cell injury. RAB21 was a candidate target of miR-140-3p, and was at high expression in AP cell models. SNHG1 may be a promising biomarker for the detection of AP, and serves as a potential biological marker for further risk stratification in the management of AP. SNHG1 knockdown can relieve inflammatory responses and pancreatic cell apoptosis by absorbing miR-140-3p. Show less
no PDFDOI: 10.1615/JEnvironPatholToxicolOncol.2024053229
Tumor metastasis is a spatial and temporal process that starts with remodeling to generate a proper premetastatic niche in a distant tissue. Infiltration of immunosuppressive macrophages is one of the Show more
Tumor metastasis is a spatial and temporal process that starts with remodeling to generate a proper premetastatic niche in a distant tissue. Infiltration of immunosuppressive macrophages is one of the notable characteristics in the premetastatic niche, which is a fundamental requirement for primary tumor metastasis. Here, we demonstrated that small extracellular vesicles (sEV) carrying RAB21 homed to lung macrophages and interacted with integrin-β1 on macrophages. ABHD12 expression was high in lung metastatic tumors and was mostly expressed by macrophages. Head and neck squamous cell carcinoma (HNSCC)-derived sEVs carrying ABHD12-polarized macrophages toward an immunosuppressive phenotype, driving premetastatic niche formation, which facilitated lung metastasis. ABHD12 additionally upregulated S1PR1 by activating the AKT-FoxO1 pathway in macrophages, and significantly enhanced antitumor responses were observed in tumor models treated with agents targeting both S1PR1 and PD-1. Collectively, our study suggests that RAB21+ABHD12+ sEVs derived from HNSCC cells contribute to the formation of the immunosuppressive microenvironment in the premetastatic niche and are a potential therapeutic target for enhancing the antitumor efficacy of anti-PD-1 therapy. Show less
Platycodon grandiflorum (PG) has been widely applied as a conductant drug by ancient and modern traditional Chinese medicine practitioners during long-term clinical practice. However, determining how Show more
Platycodon grandiflorum (PG) has been widely applied as a conductant drug by ancient and modern traditional Chinese medicine practitioners during long-term clinical practice. However, determining how to guide other medicines to the targeted lungs in traditional Chinese medicine (TCM) prescription remains unclear. An ethanol soluble fraction (Fr. B) was obtained by macroporous resin and 75 % ethanol precipitate. The components were unambiguously determined as fructooligosaccharides and small molecule weight (M Show less
Asthma is a global chronic respiratory disease with complex pathogenesis. While current therapies offer some relief, they often fall short in effectively managing symptoms and preventing exacerbations Show more
Asthma is a global chronic respiratory disease with complex pathogenesis. While current therapies offer some relief, they often fall short in effectively managing symptoms and preventing exacerbations for numerous patients. Thus, understanding its mechanisms and discovering new drug targets remains a pressing need for better treatment. Using the GEO dataset, we screened differentially expressed genes (DEGs) in asthma patients' blood. Employing Summary Data-based Mendelian Randomization (SMR) and Two-Sample Mendelian Randomization (TSMR), we pinpointed asthma causal genes, causal DNA methylation sites, and methylation sites affecting gene expression, cross validated with at least 2 large-scale GWAS from each source. We utilized colocalization for genetic associations, meta-analysis for data integration, two-step MR for methylation-gene-asthma mediation mechanism. Druggability was evaluated using Open Target, virtual screening, and docking. Among the 954 DEGs found in asthma patients' blood, increased expression of CEP95 (discovery, OR_SMR = 0.94, 95% CI: 0.91-0.97), RBM6 (discovery, OR_SMR = 0.97, 95% CI: 0.95-0.99), and ITPKB (discovery, OR_SMR = 0.82, 95% CI: 0.74-0.92) in the blood decreased the risk of asthma, higher levels of HOXB-AS1 (discovery, OR_SMR = 1.05, 95% CI: 1.03-1.07), ETS1 (discovery, OR_SMR = 1.62, 95% CI: 1.29-2.04), and JAK2 (discovery, OR_SMR = 1.13, 95% CI: 1.06-1.21) in the blood increased the risk of asthma. Additionally, a total of 8 methylation sites on ITPKB, ETS1, and JAK2 were identified to influence asthma. An increase in methylation at site cg16265553 raised the risk of asthma partially by suppressing ITPKB expression. Similarly, increased methylation at cg13661497 reduced the asthma risk totally by suppressing JAK2 expression. The impact of CEP95, HOXB-AS1, and RBM6 expressions on asthma was further confirmed in lung tissues. Except for HOXB-AS1, all the other genes were potential druggable targets. Our study highlighted that specific gene expressions and methylation sites significantly influence asthma risk and revealed a potential methylation-to-gene-to-asthma mechanism. This provided pivotal evidence for future targeted functional studies and the development of preventive and treatment strategies. Show less