Background:The DNA damage repair mechanism plays a crucial role in the occurrence and development of hepatocellular carcinoma(HCC),and RAD51-associated protein 1(RAD51AP1)has received increasing attention as an import...Background:The DNA damage repair mechanism plays a crucial role in the occurrence and development of hepatocellular carcinoma(HCC),and RAD51-associated protein 1(RAD51AP1)has received increasing attention as an important protein in the homologous recombination repair pathway.However,the role of RAD51AP1 and its molecular regulatory mechanism in HCC still need further investigation.Methods:We first analysed RAD51AP1 expression,functional enrichment and prognostic value in HCC.Then,the miRWalk,miRDB,and Encyclopedia of RNA Interactomes databases were used to predict the corresponding microRNAs and long noncoding RNAs of RAD51AP1,and their expression levels and prognostic value were analysed.Results:RAD51AP1 was upregulated in the majority of cancers include HCC.The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that RAD51AP1 was mainly involved in pathways related to the cell cycle and repair in HCC.Moreover,the expression level of RAD51AP1 was significantly correlated with T stage,pathologic stage,histologic grade and the level of alpha-fetoprotein.In addition,RAD51AP1 was an independent risk factor significantly and had a high predictive value in HCC.Based on ceRNA network,RAD51AP1 may be regulated by upstream MSC-AS1 and hsa-miR-23c to affect the HCC occurrence and development.Conclusions:High expression of RAD51AP1 plays an important biological role in the cell cycle and repair pathways,and has important diagnostic and prognostic value in HCC.Based on the regulatory mechanism of ceRNA network,we speculate that lncRNA MSC-AS1 acts on hsa-miR-23c and regulates DNA damage repair of HCC through RAD51AP1.It provides a new perspective for further study of DNA damage repair mechanism and potential related treatment of HCC.展开更多
Human T-cell lymphotropic virus type 1(HTLV-1)is associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis(HAM/TSP).It has been reported that the HTLV-1 proteins(specifically TAX and...Human T-cell lymphotropic virus type 1(HTLV-1)is associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis(HAM/TSP).It has been reported that the HTLV-1 proteins(specifically TAX and HBZ)can modulate FOXp3,resulting in an immune imbalance that can favor the progression of HAM/TSP.This review aims to summarize the literature in order to clarify the relationship between the expression of HTLV-1 m RNAs and/or viral proteins(TAX and HBZ)with the expression of mRNA and/or protein FOXp3 and their correlation with HAM/TSP development.This systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis.The search strategy was performed on the Medical Literature Analysis and Retrieval System Online and Latin American and Caribbean Literature in Health Sciences Platform using subject descriptors.After screening,six articles were included in this review.The studies suggested that TAX and HBZ have a directly proportional correlation with FOXp3 in individuals with HAM/TSP,which also presented an increased expression of FOXp3 compared to asymptomatic controls and/or healthy donors.This systematic review indicates that TAX and HBZ can interact with FOXp3 and that interaction may influence HAM/TSP development.展开更多
Human T-cell lymphotropic virus type 1(HTLV-1)-associated myelopathy/tropical spastic paraparesis(HAM/TSP) is a slowly progressive neurodegenerative disorder in which lesions of the central nervous system cause progre...Human T-cell lymphotropic virus type 1(HTLV-1)-associated myelopathy/tropical spastic paraparesis(HAM/TSP) is a slowly progressive neurodegenerative disorder in which lesions of the central nervous system cause progressive weakness, stiffness, and a lower limb spastic paraparesis. In some cases, polymyositis, inclusion bodymyositis, or amyotrophic lateral sclerosis-like syndromes are associated with HTLV-1. TSP was first described in Jamaica in 1888 and known as Jamaican peripheral neuritis before TSP was related to HTLV-1 virus, the first retrovirus being identified, and the disease is since named HAM/TSP. There is no established treatment program for HAM/TSP. Prevention is difficult in lowincome patients(i.e., HTLV-1 infected breast feeding mothers in rural areas, sex workers). Thus, there is a need for new therapeutic avenues. Therapeutic approaches must be based on a better understanding, not only of clinical and clinicopathological data, but also of the pathophysiology of the affection. Consequently, a better understanding of existing or newly developed animal models of HAM/TSP is a prerequisite step in the development of new treatments.展开更多
BACKGROUND Melanotic Xp11-associated tumors are rare mesenchymal-derived tumors. So far,most primary melanotic Xp11-associated tumors have been reported in the kidney, and reports of this tumor in the gastrointestinal...BACKGROUND Melanotic Xp11-associated tumors are rare mesenchymal-derived tumors. So far,most primary melanotic Xp11-associated tumors have been reported in the kidney, and reports of this tumor in the gastrointestinal tract are rare.CASE SUMMARY Here we describe the case of a 25-year-old woman who presented with a melanotic Xp11-associated tumor in the sigmoid colon. Colonoscopy revealed a large mucosal bulge in the sigmoid colon, approximately 32 cm inside the anus.The surface was rough with local erosion. The tumor was brittle on biopsy and bled easily. Computed tomography revealed thickening of the rectal wall with edema. Postoperative pathology indicated the likelihood of a perivascular epithelioid cell tumor. Histologically, the tumor comprised plump epithelioid cells with abundant clear to lightly eosinophilic cytoplasm and round nuclei arranged in an alveolar or trabecular pattern. The tumor cells were strongly positive for HMB-45, Melan-A, Cathepsin K, and TFE3 but negative for vimentin,smooth muscle actin, S100 protein, CD10, CK20, and desmin. The tumor cells had a low Ki-67 labeling index(approximately 2%). Fluorescence in situ hybridization revealed TFE3 fracture. Based on these histologic and immunohistochemical features, a diagnosis of melanotic Xp11-associated tumor of the sigmoid colon was made.CONCLUSION In summary, we report the clinicopathological features of a primary tumor that is extremely rare in the sigmoid colon and review the clinicopathological characteristics of melanotic Xp11-associated tumors, compatible with the very rare tumor termed "melanotic Xp11 translocation renal cancer" in all aspects.展开更多
Neurofibromatosis type 1(NF-1) is commonly associated with benign or malignant tumors in both the central and peripheral nervous systems. However, rare cases of NF-1-associated multiplerectal neuroendocrine tumors hav...Neurofibromatosis type 1(NF-1) is commonly associated with benign or malignant tumors in both the central and peripheral nervous systems. However, rare cases of NF-1-associated multiplerectal neuroendocrine tumors have been reported. This report describes a case of a 39 year old female with NF-1 and intermittent hematochezia as a primary symptom. Physical examination showed multiple subcutaneous nodules and café au lait spots with obvious scoliosis of the back. Imaging examinations and colonoscopy found malformation of the left external iliac vein and multiple gray-yellow nodules with varying sizes and shapes in the rectal submucosal layer. Histological and immunohistochemical results suggested multiple rectal neuroendocrine tumors, a rare disease with few appreciable symptoms and a particularly poor prognosis. The patient with NF-1 presented here had not only multiple rectal neuroendocrine neoplasms but also vascular malformations, scoliosis and other multiple system lesions. This case therefore contributes to improving clinical understanding, diagnosis and treatment of related complications for patients with NF-1 who present with associated medical conditions.展开更多
Pancreatic neuroendocrine tumors(PNTs) are relatively uncommon although these neoplasms have been noted to grow in occurrence in recent decades.Surgical removal of locally advanced PNTs involving major vessels and adj...Pancreatic neuroendocrine tumors(PNTs) are relatively uncommon although these neoplasms have been noted to grow in occurrence in recent decades.Surgical removal of locally advanced PNTs involving major vessels and adjacent organs is warranted by reason of an appreciably more favorable prognosis as compared to exocrine pancreas cancer.We are reporting a case of successful multi-organ resection combined with a wide excision of the superior mesenteric,common,proper,left and right hepatic arteries(in the presence of the hepatomesenteric trunk variant of aberrant arterial anatomy) for multifocal PNTs in the setting of multiple neuroendocrine neoplasia type 1 syndrome.The procedure resulted in pain abolition,a significant improvement in the patient's life quality and allowed her to return to work.Follow-up computed tomography at 15 mo post-surgery showed no evidence of disease recurrence.展开更多
Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE^(-/-)mice.However,little is known about the role of lnc_000048 in classica...Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE^(-/-)mice.However,little is known about the role of lnc_000048 in classically activated macrophage(M1)polarization.In this study,we established THP-1-derived testing state macrophages(M0),M1 macrophages,and alternately activated macrophages(M2).Real-time fluorescence quantitative PCR was used to verify the expression of marker genes and the expression of lnc_000048 in macrophages.Flow cytometry was used to detect phenotypic proteins(CD11b,CD38,CD80).We generated cell lines with lentivirus-mediated upregulation or downregulation of lnc_000048.Flow cytometry,western blot,and real-time fluorescence quantitative PCR results showed that down-regulation of lnc_000048 reduced M1 macrophage polarization and the inflammation response,while over-expression of lnc_000048 led to the opposite effect.Western blot results indicated that lnc_000048 enhanced the activation of the STAT1 pathway and mediated the M1 macrophage polarization.Moreover,catRAPID prediction,RNA-pull down,and mass spectrometry were used to identify and screen the protein kinase RNA-activated(PKR),then catRAPID and RPIseq were used to predict the binding ability of lnc_000048 to PKR.Immunofluorescence(IF)-RNA fluorescence in situ hybridization(FISH)double labeling was performed to verify the subcellular colocalization of lnc_000048 and PKR in the cytoplasm of M1 macrophage.We speculate that lnc_000048 may form stem-loop structure-specific binding and activate PKR by inducing its phosphorylation,leading to activation of STAT1 phosphorylation and thereby enhancing STAT1 pathway-mediated polarization of THP-1 macrophages to M1 and inflammatory factor expression.Taken together,these results reveal that the lnc_000048/PKR/STAT1 axis plays a crucial role in the polarization of M1 macrophages and may be a novel therapeutic target for atherosclerosis alleviation in stroke.展开更多
BACKGROUND This study presents a case of rapidly developing respiratory failure due to antisynthetase syndrome(AS)following coronavirus disease 2019(COVID-19)in a 33-year-old man diagnosed with Klinefelter syndrome(KS...BACKGROUND This study presents a case of rapidly developing respiratory failure due to antisynthetase syndrome(AS)following coronavirus disease 2019(COVID-19)in a 33-year-old man diagnosed with Klinefelter syndrome(KS).CASE SUMMARY A 33-year-old man with a diagnosis of KS was admitted to the Department of Pulmonary and Critical Care Medicine of a tertiary hospital in China for fever and shortness of breath 2 wk after the onset of COVID-19.Computed tomography of both lungs revealed diffuse multiple patchy heightened shadows in both lungs,accompanied by signs of partial bronchial inflation.Metagenomic next-generation sequencing of the bronchoalveolar lavage fluid suggested absence of pathogen.A biopsy specimen revealed organizing pneumonia with alveolar septal thickening.Additionally,extensive auto-antibody tests showed strong positivity for anti-SSA,anti-SSB,anti-Jo-1,and anti-Ro-52.Following multidisciplinary discussions,the patient received a final diagnosis of AS,leading to rapidly progressing respiratory failure.CONCLUSION This study underscores the clinical progression of AS-associated interstitial lung disease subsequent to viral infections such as COVID-19 in patients diagnosed with KS.展开更多
Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most count...Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.展开更多
Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is ...Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is limited research on the relationship between CRABP2 and immunotherapy response.This study found that negative correlations of CRABP2 and immune checkpoint markers(PD-1,PD-L1,and CTLA-4)were observed in breast invasive carcinoma(BRCA),skin cutaneous melanoma(SKCM),stomach adenocarcinoma(STAD)and testicular germ cell tumors(TGCT).In particular,in SKCM patients who were treated with PD-1 inhibitors,high levels of CRABP2 predicted poor prognosis.Additionally,CRABP2 expression was elevated in cancer-associated fibroblasts(CAFs)at the single-cell level.The expression of CRABP2 was positively correlated with markers of CAFs,such as MFAP5,PDPN,ITGA11,PDGFRα/βand THY1 in SKCM.To validate the tumor-promoting effect of CRABP2 in vivo,SKCM xenograft mice models with CRABP2 overexpression have been constructed.These models showed an increase in tumor weight and volume.Enrichment analysis indicated that CRABP2 may be involved in immunerelated pathways of SKCM,such as extracellular matrix(ECM)receptor interaction and epithelial-mesenchymal transition(EMT).The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs.In conclusion,this study provides new insights into the role of CRABP2 in immunotherapy response.The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients.Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.展开更多
BACKGROUND N6-methyladenosine(m6A)methylation modification exists in Epstein-Barr virus(EBV)primary infection,latency,and lytic reactivation.It also modifies EBV latent genes and lytic genes.EBV-associated gastric can...BACKGROUND N6-methyladenosine(m6A)methylation modification exists in Epstein-Barr virus(EBV)primary infection,latency,and lytic reactivation.It also modifies EBV latent genes and lytic genes.EBV-associated gastric cancer(EBVaGC)is a distinctive molecular subtype of GC.We hypothesized EBV and m6A methylation regulators interact with each other in EBVaGC to differentiate it from other types of GC.AIM To investigate the mechanisms of m6A methylation regulators in EBVaGC to determine the differentiating factors from other types of GC.METHODS First,The Cancer Gene Atlas and Gene Expression Omnibus databases were used to analyze the expression pattern of m6A methylation regulators between EBVaGC and EBV-negative GC(EBVnGC).Second,we identified Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional enrichment of m6A-related differentially expressed genes.We quantified the relative abundance of immune cells and inflammatory factors in the tumor microenvironment(TME).Finally,cell counting kit-8 cell proliferation test,transwell test,and flow cytometry were used to verify the effect of insulin-like growth factor binding protein 1(IGFBP1)in EBVaGC cell lines.RESULTS m6A methylation regulators were involved in the occurrence and development of EBVaGC.Compared with EBVnGC,the expression levels of m6A methylation regulators Wilms tumor 1-associated protein,RNA binding motif protein 15B,CBL proto-oncogene like 1,leucine rich pentatricopeptide repeat containing,heterogeneous nuclear ribonucleoprotein A2B1,IGFBP1,and insulin-like growth factor 2 binding protein 1 were significantly downregulated in EBVaGC(P<0.05).The overall survival rate of EBVaGC patients with a lower expression level of IGFBP1 was significantly higher(P=0.046).GO and KEGG functional enrichment analyses showed that the immunity pathways were significantly activated and rich in immune cell infiltration in EBVaGC.Compared with EBVnGC,the infiltration of activated CD4+T cells,activated CD8+T cells,monocytes,activated dendritic cells,and plasmacytoid dendritic cells were significantly upregulated in EBVaGC(P<0.001).In EBVaGC,the expression level of proinflammatory factors interleukin(IL)-17,IL-21,and interferon-γ and immunosuppressive factor IL-10 were significantly increased(P<0.05).In vitro experiments demonstrated that the expression level of IGFBP1 was significantly lower in an EBVaGC cell line(SNU719)than in an EBVnGC cell line(AGS)(P<0.05).IGFBP1 overexpression significantly attenuated proliferation and migration and promoted the apoptosis levels in SNU719.Interfering IGFBP1 significantly promoted proliferation and migration and attenuated the apoptosis levels in AGS.CONCLUSION m6A regulators could remodel the TME of EBVaGC,which is classified as an immune-inflamed phenotype and referred to as a“hot”tumor.Among these regulators,we demonstrated that IGFBP1 affected proliferation,migration,and apoptosis.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide,paralleling the rising pandemic of obesity and type 2 diabetes.Due to the growing global health...Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide,paralleling the rising pandemic of obesity and type 2 diabetes.Due to the growing global health burden and com-plex pathogenesis of MASLD,a multifaceted and innovative therapeutic approach is needed.Incretin receptor agonists,which were initially developed for diabetes management,have emerged as promising candidates for MASLD treatment.This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists:glucagon-like peptide-1 receptor agonists,glucose-dependent insulinotropic polypeptide receptor agonists,and glucagon receptor agonists.Incretins and glucagon directly or indirectly impact various organs,including the liver,brain,pancreas,gastro-intestinal tract,and adipose tissue.Thus,these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis.Importantly,this study provides a summary of clinical trials analyzing the effect-iveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function,hepatic steatosis,and intrahepatic inflammation.There are emerging challenges associated with the use of these medications in the real world,particularly adverse events,drug-drug interactions,and barriers to access,which are discussed in detail.Additionally,this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.展开更多
Obesity-induced type 2 diabetes is mainly due to excessive free fatty acids leading to insulin resistance.Increasing thermogenesis is regarded as an effective strategy for hypolipidemia and hypoglycemia.Ginsenoside is...Obesity-induced type 2 diabetes is mainly due to excessive free fatty acids leading to insulin resistance.Increasing thermogenesis is regarded as an effective strategy for hypolipidemia and hypoglycemia.Ginsenoside is a natural active component in Panax ginseng C.A.Meyer,and some of them enhance thermogenesis.However,there are few studies on the mechanism and target of ginsenosides enhancing thermogenesis.Using thermogenic protein uncoupling protein 1(UCP1)-luciferase reporter assay,we identifi ed ginsenoside F1 as a novel UCP1 activator in the ginsenosides library.Using pull down assay and inhibitor interference,we found F1 binds toβ3-adrenergic receptors(β3-AR)to enhance UCP1 expression via cAMP/PKA/CREB pathway.We also investigated the ability of F1 on energy metabolism in obesity-induced diabetic mice,including body weight,body composition and energy expenditure.The results of proteomics showed that F1 signifi cantly up-regulated thermogenesis proteins and lipolytic proteins,but down-regulated fatty acid synthesis proteins.Ginsenoside F1 increased thermogenesis and ameliorated insulin resistance specifi cally by promoting the browning of white adipose tissue in obese mice.Additionally,ginsenoside F1 improves norepinephrine-induced insulin resistance in adipocytes and hepatocytes,and shows a stronger mitochondria respiration ability than norepinephrine.These fi ndings suggest that ginsenoside F1 is a promising lead compound in the improvement of insulin resistance.展开更多
Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TA...Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TAM activators.Cyclin D1b is a highly oncogenic splice variant of cyclin D1.We previously reported that cyclin D1b enhances the invasiveness of breast cancer cells by inducing EMT.However,the role of cyclin D1b in inducing macrophage differentiation toward tumor-associated macrophage-like cells remains unknown.This study aimed to explore the relationship between breast cancer cells overexpressing cyclin Dlb and TAMs.Methods:Mouse breast cancer 4T1 cells were transfected with cyclin D1b variant and co-cultured with macrophage cells in a Transwell coculture system.The expression of characteristic cytokines in differentiated macrophages was detected using qRT-PCR,ELISA and zymography assay.Tumor-associated macrophage distribution in a transplanted tumor was detected by immunofluorescence staining.The proliferation and migration ability of breast cancer cells was detected using the cell counting kit-8(CCK-8)assay,wound healing assay,Transwell invasion assay,and lung metastasis assay.Expression levels of mRNAs were detected by qRT-PCR.Protein expression levels were detected by Western blotting.The integrated analyses of The Cancer Genome Atlas(TCGA)datasets and bioinformatics methods were adopted to discover gene expression,gene coexpression,and overall survival in patients with breast cancer.Results:After co-culture with breast cancer cells overexpressing cyclin D1b,RAW264.7 macrophages were differentiated into an M2 phenotype.Moreover,differentiated M2-like macrophages promoted the proliferation and migration of breast cancer cells in turn.Notably,these macrophages facilitated the migration of breast cancer cells in vivo.Further investigations indicated that differentiated M2-like macrophages induced EMT of breast cancer cells accompanied with upregulation of TGF-β1 and integrinβ3 expression.Conclusion:Breast cancer cells transfected with cyclin D1b can induce the differentiation of macrophages into a tumor-associated macrophage-like phenotype,which promotes tumor metastasis in vitro and in vivo.展开更多
BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1(VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colo...BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1(VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colorectal cancer(CRC). Knockdown of VASH1 enhanced transforming growth factor-β1(TGF-β1)/Smad3 pathway activity and type Ⅰ/Ⅲ collagen production. Our previous findings suggest that ELL-associated factor 2(EAF2) may play a tumor suppressor and protective role in the development and progression of CRC by regulating signal transducer and activator of transcription 3(STAT3)/TGF-β1 signaling pathway. However, the functional role and mechanism of VASH1-mediated TGF-β1 related pathway in CRC has not been elucidated.AIM To investigate the expression of VASH1 in CRC and its correlation with the expression of EAF2. Furthermore, we studied the functional role and mechanism of VASH1 involved in the regulation and protection of EAF2 in CRC cells in vitro.METHODS We collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein and VASH1 protein in patients with advanced CRC. Following, we investigated the effect and mechanism of EAF2 and VASH1 on the invasion, migration and angiogenesis of CRC cells in vitro using plasmid transfection.RESULTS Our findings indicated that EAF2 was down-regulated and VASH1 was upregulated in advanced CRC tissue compared to normal colorectal tissue. KaplanMeier survival analysis showed that the higher EAF2 Level group and the lower VASH1 Level group had a higher survival rate. Overexpression of EAF2 might inhibit the activity of STAT3/TGF-β1 pathway by up-regulating the expression of VASH1, and then weaken the invasion, migration and angiogenesis of CRC cells.CONCLUSION This study suggests that EAF2 and VASH1 may serve as new diagnostic and prognostic markers for CRC, and provide a clinical basis for exploring new biomarkers for CRC. This study complements the mechanism of EAF2 in CRC cells, enriches the role and mechanism of CRC cellderived VASH1, and provides a new possible subtype of CRC as a therapeutic target of STAT3/TGF-β1 pathway.展开更多
Phytophthora root and stem rot of soybean caused by Phytophthora sojae(P.sojae)is a devastating disease that affects soybean[Glycine max(L.)Merr.]all over the world.S-phase kinase-associated protein 1(SKP1)proteins ar...Phytophthora root and stem rot of soybean caused by Phytophthora sojae(P.sojae)is a devastating disease that affects soybean[Glycine max(L.)Merr.]all over the world.S-phase kinase-associated protein 1(SKP1)proteins are key members of the SKP1/Cullin/F-box protein(SCF)ubiquitin ligase complex and play diverse roles in plant biology.However,the role of SKP1 in soybean against the phytopathogenic oomycete P.sojae remains unclear.In this study,a novel member of the soybean SKP1 gene family,GmSKP1 which was significantly induced by P.sojae,was reported.The expression of GmSKP1 was simultaneously induced by methyl jasmonate(MeJA),salicylic acid(SA)and ethylene(ET),which might suggest an important role for GmSKP1 of plant in responses to hormone treatments.Functional analysis using GmSKP1 overexpression lines showed that GmSKP1 enhanced resistance to P.sojae in transgenic soybean plants.Further analyses showed that GmSKP1 interacted with a homeodomain-leucine zipper protein transcription factor(GmHDL56)and a WRKY transcription factor(GmWRKY31),which could positively regulate responses to P.sojae in soybean.Importantly,several pathogenesis-related(PR)genes were constitutively activated,including GmPR1a,GmPR2,GmPR3,GmPR4,GmPR5a and GmPR10,in GmSKP1-OE soybean plants.Taken together,these results suggested that GmSKP1 enhanced resistance to P.sojae in soybean,possibly by activating the defense-related PR genes.展开更多
Yes-associated protein 1(YAP1)is a downstream effector of the Hippo signaling pathway,and it is involved in tumorigenesis,tissue repair,growth,and development.In this review,the biological roles and the mechanisms of ...Yes-associated protein 1(YAP1)is a downstream effector of the Hippo signaling pathway,and it is involved in tumorigenesis,tissue repair,growth,and development.In this review,the biological roles and the mechanisms of YAP1 in mediating stem cell fate decisions are discussed,including cell proliferation,differentiation,and apoptosis.In general,YAP1 promotes the proliferation and differentiation of stem cells,including embryonic stem cells and adult stem cells.It inhibits apoptosis by binding to the transcription factors,e.g.,transcriptional enhanced associate domain(TEAD),Smad,runt-related transcription factor 1/2,p73,p63,and Erb84,to maintain tissue homeostasis.The translocalization of YAP1 in cellular nuclei and the phosphorylation in the cytoplasm work as important and unusual events for the activation of YAP1.Moreover,YAP1 serves as the crosstalk for the Hippo pathway and other signaling pathways,including the Wnt and Notch pathways.It is highlighted in this review that YAP1 is an essential regulator for stem cells that have significant applications in regenerative medicine and reproductive medicine.展开更多
Background:Colorectal cancer(CRC)is one of the most common malignancies.Early diagnosis is the key to effective treatment of CRC.Since microRNAs(miRNAs)can be used as biomarkers of CRC,the objective of this work was t...Background:Colorectal cancer(CRC)is one of the most common malignancies.Early diagnosis is the key to effective treatment of CRC.Since microRNAs(miRNAs)can be used as biomarkers of CRC,the objective of this work was to examine the effect of miR-520f-3p,which targets YAP1(Yes-associated protein 1),on the ability of CRC cells to proliferate,invade,migrate,and undergo epithelial-mesenchymal transition(EMT).Methods:A miR-520f-3p mimic was used to overexpress miR-520f-3p in HT29 cells.To establish the tumor-bearing mouse model,transfected HT29 cells were subcutaneously implanted into BALB/c-nu nude mice,and YAP1 and miR-520f-3p levels were determined using qRT‒PCR.The viability,invasion ability,and migration ability of cells were evaluated by CCK-8,Transwell,and wound healing assays.Apoptosis was detected by flow cytometry and TUNEL assays.The regulatory link between miR-520f-3p and the YAP1 gene was examined by dual-luciferase reporter assay.Tumor tissues with positive Ki-67 expression were identified by immunohistochemistry.Vimentin,E-cadherin,and YAP1 expression were evaluated by western blotting.Results:MiR-520f-3p overexpression could inhibit proliferation,invasion,migration,and EMT and induce apoptosis in HT29 cells.YAP1 was found as a target of miR-520f-3p.The inhibitory effects of miR-520f-3p on proliferation,invasion,migration,and EMT may be reversed by overexpressing YAP1.In tumor-bearing mice,miR-520f-3p overexpression reduced the Ki-67 level,increased apoptosis,and prevented tumor development and spread.Conclusion:By targeting YAP1,miR-520f-3p may be capable of suppressing CRC cell proliferation,invasion,migration,and EMT,providing a novel therapeutic target for the disease.展开更多
Objective:Deleted in liver cancer 1(DLC1)is a GTPase-activating protein that is reported as a suppressor in certain human cancers.However,the detailed biological function of DLC1 is still unclear in human prostate can...Objective:Deleted in liver cancer 1(DLC1)is a GTPase-activating protein that is reported as a suppressor in certain human cancers.However,the detailed biological function of DLC1 is still unclear in human prostate cancer(PCa).In the present study,we aimed to explore the function of DLC1 in PCa cells.Methods:Silencing and overexpression of DLC1 were induced in an androgen-sensitive PCa cell line(LNCaP)using RNA interference and lentiviral vector transduction.The Cell Counting Kit-8 assay was performed to determine cell proliferation.The cell cycle was examined by performing a propidium iodide staining assay.Results:Our results indicated that DLC1 overexpression markedly suppressed the proliferation and cell cycle progression of LNCaP cells.Moreover,DLC1 expression was negatively correlated with Rho-associated protein kinase(ROCK)expression in LNCaP cells.Importantly,this study showed that the ROCK inhibitor Y27632 restored the function of DLC1 in LNCaP cells and reduced the tumorigenicity of LNCaP cells in vivo.Conclusion:Our results indicated that DLC1 overexpression markedly suppressed the proliferation and cell cycle progression of PCa cells and negatively correlated with ROCK expression in PCa cells and tissue.展开更多
BACKGROUND Clinical prognosis often worsens due to high recurrence rates following radical surgery for colon cancer.The examination of high-risk recurrence factors post-surgery provides critical insights for disease e...BACKGROUND Clinical prognosis often worsens due to high recurrence rates following radical surgery for colon cancer.The examination of high-risk recurrence factors post-surgery provides critical insights for disease evaluation and treatment planning.AIM To explore the relationship between metastasis-associated factor-1 in colon cancer(MACC1)and vacuolar ATP synthase(V-ATPase)expression in colon cancer tissues,and recurrence rate in patients undergoing radical colon cancer surgery.METHODS We selected 104 patients treated with radical colon cancer surgery at our hospital from January 2018 to June 2021.Immunohistochemical staining was utilized to assess the expression levels of MACC1 and V-ATPase in these patients.RESULTS The rates of MACC1 and V-ATPase positivity were 64.42%and 67.31%,respe-ctively,in colon cancer tissues,which were significantly higher than in paracan-cerous tissues(P<0.05).Among patients with TNM stage III,medium to low differentiation,and lymph node metastasis,the positive rates of MACC1 and V-ATPase were significantly elevated in comparison to patients with TNM stage I-II,high differentiation,and no lymph node metastasis(P<0.05).The rate of MACC1 positivity was 76.67%in patients with tumor diameters>5 cm,notably higher than in patients with tumor diameters≤5 cm(P<0.05).We observed a positive correlation between MACC1 and V-ATPase expression(rs=0.797,P<0.05).The positive rates of MACC1 and V-ATPase were significantly higher in patients with recurrence compared to those without(P<0.05).Logistic regression analysis revealed TNM stage,lymph node metastasis,MACC1 expression,and V-ATPase expression as risk factors for postoperative colon cancer recurrence(OR=6.322,3.435,2.683,and 2.421;P<0.05).CONCLUSION The upregulated expression of MACC1 and V-ATPase in colon cancer patients appears to correlate with clinicopathological features and post-radical surgery recurrence.展开更多
基金the financial support from Shandong Traditional Chinese Medicine Science and Technology Project(No.2020M139)the Scientific Research Project of Shandong College of Traditional Chinese Medicine(No.2021FY02)the Development Plan of Laizhou Science and Technology Project(No.2022L01).
文摘Background:The DNA damage repair mechanism plays a crucial role in the occurrence and development of hepatocellular carcinoma(HCC),and RAD51-associated protein 1(RAD51AP1)has received increasing attention as an important protein in the homologous recombination repair pathway.However,the role of RAD51AP1 and its molecular regulatory mechanism in HCC still need further investigation.Methods:We first analysed RAD51AP1 expression,functional enrichment and prognostic value in HCC.Then,the miRWalk,miRDB,and Encyclopedia of RNA Interactomes databases were used to predict the corresponding microRNAs and long noncoding RNAs of RAD51AP1,and their expression levels and prognostic value were analysed.Results:RAD51AP1 was upregulated in the majority of cancers include HCC.The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that RAD51AP1 was mainly involved in pathways related to the cell cycle and repair in HCC.Moreover,the expression level of RAD51AP1 was significantly correlated with T stage,pathologic stage,histologic grade and the level of alpha-fetoprotein.In addition,RAD51AP1 was an independent risk factor significantly and had a high predictive value in HCC.Based on ceRNA network,RAD51AP1 may be regulated by upstream MSC-AS1 and hsa-miR-23c to affect the HCC occurrence and development.Conclusions:High expression of RAD51AP1 plays an important biological role in the cell cycle and repair pathways,and has important diagnostic and prognostic value in HCC.Based on the regulatory mechanism of ceRNA network,we speculate that lncRNA MSC-AS1 acts on hsa-miR-23c and regulates DNA damage repair of HCC through RAD51AP1.It provides a new perspective for further study of DNA damage repair mechanism and potential related treatment of HCC.
基金funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico(426196/2018-0)supported by a scholarship from the Conselho Nacional de Desenvolvimento Científico e Tecnológico(127049/2019-3 and 115208/2020-8)
文摘Human T-cell lymphotropic virus type 1(HTLV-1)is associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis(HAM/TSP).It has been reported that the HTLV-1 proteins(specifically TAX and HBZ)can modulate FOXp3,resulting in an immune imbalance that can favor the progression of HAM/TSP.This review aims to summarize the literature in order to clarify the relationship between the expression of HTLV-1 m RNAs and/or viral proteins(TAX and HBZ)with the expression of mRNA and/or protein FOXp3 and their correlation with HAM/TSP development.This systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis.The search strategy was performed on the Medical Literature Analysis and Retrieval System Online and Latin American and Caribbean Literature in Health Sciences Platform using subject descriptors.After screening,six articles were included in this review.The studies suggested that TAX and HBZ have a directly proportional correlation with FOXp3 in individuals with HAM/TSP,which also presented an increased expression of FOXp3 compared to asymptomatic controls and/or healthy donors.This systematic review indicates that TAX and HBZ can interact with FOXp3 and that interaction may influence HAM/TSP development.
文摘Human T-cell lymphotropic virus type 1(HTLV-1)-associated myelopathy/tropical spastic paraparesis(HAM/TSP) is a slowly progressive neurodegenerative disorder in which lesions of the central nervous system cause progressive weakness, stiffness, and a lower limb spastic paraparesis. In some cases, polymyositis, inclusion bodymyositis, or amyotrophic lateral sclerosis-like syndromes are associated with HTLV-1. TSP was first described in Jamaica in 1888 and known as Jamaican peripheral neuritis before TSP was related to HTLV-1 virus, the first retrovirus being identified, and the disease is since named HAM/TSP. There is no established treatment program for HAM/TSP. Prevention is difficult in lowincome patients(i.e., HTLV-1 infected breast feeding mothers in rural areas, sex workers). Thus, there is a need for new therapeutic avenues. Therapeutic approaches must be based on a better understanding, not only of clinical and clinicopathological data, but also of the pathophysiology of the affection. Consequently, a better understanding of existing or newly developed animal models of HAM/TSP is a prerequisite step in the development of new treatments.
基金Supported by The Key Research & Development and Transformation Project of Qinghai Province for 2018(No.2018-SF-113)
文摘BACKGROUND Melanotic Xp11-associated tumors are rare mesenchymal-derived tumors. So far,most primary melanotic Xp11-associated tumors have been reported in the kidney, and reports of this tumor in the gastrointestinal tract are rare.CASE SUMMARY Here we describe the case of a 25-year-old woman who presented with a melanotic Xp11-associated tumor in the sigmoid colon. Colonoscopy revealed a large mucosal bulge in the sigmoid colon, approximately 32 cm inside the anus.The surface was rough with local erosion. The tumor was brittle on biopsy and bled easily. Computed tomography revealed thickening of the rectal wall with edema. Postoperative pathology indicated the likelihood of a perivascular epithelioid cell tumor. Histologically, the tumor comprised plump epithelioid cells with abundant clear to lightly eosinophilic cytoplasm and round nuclei arranged in an alveolar or trabecular pattern. The tumor cells were strongly positive for HMB-45, Melan-A, Cathepsin K, and TFE3 but negative for vimentin,smooth muscle actin, S100 protein, CD10, CK20, and desmin. The tumor cells had a low Ki-67 labeling index(approximately 2%). Fluorescence in situ hybridization revealed TFE3 fracture. Based on these histologic and immunohistochemical features, a diagnosis of melanotic Xp11-associated tumor of the sigmoid colon was made.CONCLUSION In summary, we report the clinicopathological features of a primary tumor that is extremely rare in the sigmoid colon and review the clinicopathological characteristics of melanotic Xp11-associated tumors, compatible with the very rare tumor termed "melanotic Xp11 translocation renal cancer" in all aspects.
文摘Neurofibromatosis type 1(NF-1) is commonly associated with benign or malignant tumors in both the central and peripheral nervous systems. However, rare cases of NF-1-associated multiplerectal neuroendocrine tumors have been reported. This report describes a case of a 39 year old female with NF-1 and intermittent hematochezia as a primary symptom. Physical examination showed multiple subcutaneous nodules and café au lait spots with obvious scoliosis of the back. Imaging examinations and colonoscopy found malformation of the left external iliac vein and multiple gray-yellow nodules with varying sizes and shapes in the rectal submucosal layer. Histological and immunohistochemical results suggested multiple rectal neuroendocrine tumors, a rare disease with few appreciable symptoms and a particularly poor prognosis. The patient with NF-1 presented here had not only multiple rectal neuroendocrine neoplasms but also vascular malformations, scoliosis and other multiple system lesions. This case therefore contributes to improving clinical understanding, diagnosis and treatment of related complications for patients with NF-1 who present with associated medical conditions.
文摘Pancreatic neuroendocrine tumors(PNTs) are relatively uncommon although these neoplasms have been noted to grow in occurrence in recent decades.Surgical removal of locally advanced PNTs involving major vessels and adjacent organs is warranted by reason of an appreciably more favorable prognosis as compared to exocrine pancreas cancer.We are reporting a case of successful multi-organ resection combined with a wide excision of the superior mesenteric,common,proper,left and right hepatic arteries(in the presence of the hepatomesenteric trunk variant of aberrant arterial anatomy) for multifocal PNTs in the setting of multiple neuroendocrine neoplasia type 1 syndrome.The procedure resulted in pain abolition,a significant improvement in the patient's life quality and allowed her to return to work.Follow-up computed tomography at 15 mo post-surgery showed no evidence of disease recurrence.
基金supported by the Natural Science Foundation of Shandong Province,No.ZR2020MH138(to XZ).
文摘Our previous study has demonstrated that lnc_000048 is upregulated in large-artery atherosclerotic stroke and promotes atherosclerosis in ApoE^(-/-)mice.However,little is known about the role of lnc_000048 in classically activated macrophage(M1)polarization.In this study,we established THP-1-derived testing state macrophages(M0),M1 macrophages,and alternately activated macrophages(M2).Real-time fluorescence quantitative PCR was used to verify the expression of marker genes and the expression of lnc_000048 in macrophages.Flow cytometry was used to detect phenotypic proteins(CD11b,CD38,CD80).We generated cell lines with lentivirus-mediated upregulation or downregulation of lnc_000048.Flow cytometry,western blot,and real-time fluorescence quantitative PCR results showed that down-regulation of lnc_000048 reduced M1 macrophage polarization and the inflammation response,while over-expression of lnc_000048 led to the opposite effect.Western blot results indicated that lnc_000048 enhanced the activation of the STAT1 pathway and mediated the M1 macrophage polarization.Moreover,catRAPID prediction,RNA-pull down,and mass spectrometry were used to identify and screen the protein kinase RNA-activated(PKR),then catRAPID and RPIseq were used to predict the binding ability of lnc_000048 to PKR.Immunofluorescence(IF)-RNA fluorescence in situ hybridization(FISH)double labeling was performed to verify the subcellular colocalization of lnc_000048 and PKR in the cytoplasm of M1 macrophage.We speculate that lnc_000048 may form stem-loop structure-specific binding and activate PKR by inducing its phosphorylation,leading to activation of STAT1 phosphorylation and thereby enhancing STAT1 pathway-mediated polarization of THP-1 macrophages to M1 and inflammatory factor expression.Taken together,these results reveal that the lnc_000048/PKR/STAT1 axis plays a crucial role in the polarization of M1 macrophages and may be a novel therapeutic target for atherosclerosis alleviation in stroke.
基金Supported by the Natural Science Foundation of Jiangxi Province,No.20202BAB206002 and No.20224BAB216084.
文摘BACKGROUND This study presents a case of rapidly developing respiratory failure due to antisynthetase syndrome(AS)following coronavirus disease 2019(COVID-19)in a 33-year-old man diagnosed with Klinefelter syndrome(KS).CASE SUMMARY A 33-year-old man with a diagnosis of KS was admitted to the Department of Pulmonary and Critical Care Medicine of a tertiary hospital in China for fever and shortness of breath 2 wk after the onset of COVID-19.Computed tomography of both lungs revealed diffuse multiple patchy heightened shadows in both lungs,accompanied by signs of partial bronchial inflation.Metagenomic next-generation sequencing of the bronchoalveolar lavage fluid suggested absence of pathogen.A biopsy specimen revealed organizing pneumonia with alveolar septal thickening.Additionally,extensive auto-antibody tests showed strong positivity for anti-SSA,anti-SSB,anti-Jo-1,and anti-Ro-52.Following multidisciplinary discussions,the patient received a final diagnosis of AS,leading to rapidly progressing respiratory failure.CONCLUSION This study underscores the clinical progression of AS-associated interstitial lung disease subsequent to viral infections such as COVID-19 in patients diagnosed with KS.
文摘Metabolic dysfunction-associated fatty liver disease(MAFLD)is a hepatic manifestation of the metabolic syndrome.It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries.MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma.Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis.The mechanisms involved in maintaining gut-liver axis homeostasis are complex.One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gutliver axis functionality.An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis.Moreover,alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)are a class of drugs developed for the treatment of type 2 diabetes mellitus.They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis.The mechanisms reported to be involved in this effect include an improved regulation of glycemia,reduced lipid synthesis,β-oxidation of free fatty acids,and induction of autophagy in hepatic cells.Recently,multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment.A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD.This review presents the current understanding of the role of the gutliver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.
基金supported by grants from the Natural Science Foundation of Hunan Province(2022JJ80044)the Youth Science Foundation of Xiangya Hospital(2019Q13).
文摘Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is limited research on the relationship between CRABP2 and immunotherapy response.This study found that negative correlations of CRABP2 and immune checkpoint markers(PD-1,PD-L1,and CTLA-4)were observed in breast invasive carcinoma(BRCA),skin cutaneous melanoma(SKCM),stomach adenocarcinoma(STAD)and testicular germ cell tumors(TGCT).In particular,in SKCM patients who were treated with PD-1 inhibitors,high levels of CRABP2 predicted poor prognosis.Additionally,CRABP2 expression was elevated in cancer-associated fibroblasts(CAFs)at the single-cell level.The expression of CRABP2 was positively correlated with markers of CAFs,such as MFAP5,PDPN,ITGA11,PDGFRα/βand THY1 in SKCM.To validate the tumor-promoting effect of CRABP2 in vivo,SKCM xenograft mice models with CRABP2 overexpression have been constructed.These models showed an increase in tumor weight and volume.Enrichment analysis indicated that CRABP2 may be involved in immunerelated pathways of SKCM,such as extracellular matrix(ECM)receptor interaction and epithelial-mesenchymal transition(EMT).The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs.In conclusion,this study provides new insights into the role of CRABP2 in immunotherapy response.The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients.Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.
基金Supported by the Sub-Project of the National Key Research and Development Program,No.2021YFC2600263.
文摘BACKGROUND N6-methyladenosine(m6A)methylation modification exists in Epstein-Barr virus(EBV)primary infection,latency,and lytic reactivation.It also modifies EBV latent genes and lytic genes.EBV-associated gastric cancer(EBVaGC)is a distinctive molecular subtype of GC.We hypothesized EBV and m6A methylation regulators interact with each other in EBVaGC to differentiate it from other types of GC.AIM To investigate the mechanisms of m6A methylation regulators in EBVaGC to determine the differentiating factors from other types of GC.METHODS First,The Cancer Gene Atlas and Gene Expression Omnibus databases were used to analyze the expression pattern of m6A methylation regulators between EBVaGC and EBV-negative GC(EBVnGC).Second,we identified Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional enrichment of m6A-related differentially expressed genes.We quantified the relative abundance of immune cells and inflammatory factors in the tumor microenvironment(TME).Finally,cell counting kit-8 cell proliferation test,transwell test,and flow cytometry were used to verify the effect of insulin-like growth factor binding protein 1(IGFBP1)in EBVaGC cell lines.RESULTS m6A methylation regulators were involved in the occurrence and development of EBVaGC.Compared with EBVnGC,the expression levels of m6A methylation regulators Wilms tumor 1-associated protein,RNA binding motif protein 15B,CBL proto-oncogene like 1,leucine rich pentatricopeptide repeat containing,heterogeneous nuclear ribonucleoprotein A2B1,IGFBP1,and insulin-like growth factor 2 binding protein 1 were significantly downregulated in EBVaGC(P<0.05).The overall survival rate of EBVaGC patients with a lower expression level of IGFBP1 was significantly higher(P=0.046).GO and KEGG functional enrichment analyses showed that the immunity pathways were significantly activated and rich in immune cell infiltration in EBVaGC.Compared with EBVnGC,the infiltration of activated CD4+T cells,activated CD8+T cells,monocytes,activated dendritic cells,and plasmacytoid dendritic cells were significantly upregulated in EBVaGC(P<0.001).In EBVaGC,the expression level of proinflammatory factors interleukin(IL)-17,IL-21,and interferon-γ and immunosuppressive factor IL-10 were significantly increased(P<0.05).In vitro experiments demonstrated that the expression level of IGFBP1 was significantly lower in an EBVaGC cell line(SNU719)than in an EBVnGC cell line(AGS)(P<0.05).IGFBP1 overexpression significantly attenuated proliferation and migration and promoted the apoptosis levels in SNU719.Interfering IGFBP1 significantly promoted proliferation and migration and attenuated the apoptosis levels in AGS.CONCLUSION m6A regulators could remodel the TME of EBVaGC,which is classified as an immune-inflamed phenotype and referred to as a“hot”tumor.Among these regulators,we demonstrated that IGFBP1 affected proliferation,migration,and apoptosis.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most common chronic liver disease worldwide,paralleling the rising pandemic of obesity and type 2 diabetes.Due to the growing global health burden and com-plex pathogenesis of MASLD,a multifaceted and innovative therapeutic approach is needed.Incretin receptor agonists,which were initially developed for diabetes management,have emerged as promising candidates for MASLD treatment.This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists:glucagon-like peptide-1 receptor agonists,glucose-dependent insulinotropic polypeptide receptor agonists,and glucagon receptor agonists.Incretins and glucagon directly or indirectly impact various organs,including the liver,brain,pancreas,gastro-intestinal tract,and adipose tissue.Thus,these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis.Importantly,this study provides a summary of clinical trials analyzing the effect-iveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function,hepatic steatosis,and intrahepatic inflammation.There are emerging challenges associated with the use of these medications in the real world,particularly adverse events,drug-drug interactions,and barriers to access,which are discussed in detail.Additionally,this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.
基金supported by the National Natural Science Foundation of China[31872674]the Jilin Talent Development Foundation Grant[20200301018RQ]the Fundamental Research Funds for the Central Universities[CGZH202206].
文摘Obesity-induced type 2 diabetes is mainly due to excessive free fatty acids leading to insulin resistance.Increasing thermogenesis is regarded as an effective strategy for hypolipidemia and hypoglycemia.Ginsenoside is a natural active component in Panax ginseng C.A.Meyer,and some of them enhance thermogenesis.However,there are few studies on the mechanism and target of ginsenosides enhancing thermogenesis.Using thermogenic protein uncoupling protein 1(UCP1)-luciferase reporter assay,we identifi ed ginsenoside F1 as a novel UCP1 activator in the ginsenosides library.Using pull down assay and inhibitor interference,we found F1 binds toβ3-adrenergic receptors(β3-AR)to enhance UCP1 expression via cAMP/PKA/CREB pathway.We also investigated the ability of F1 on energy metabolism in obesity-induced diabetic mice,including body weight,body composition and energy expenditure.The results of proteomics showed that F1 signifi cantly up-regulated thermogenesis proteins and lipolytic proteins,but down-regulated fatty acid synthesis proteins.Ginsenoside F1 increased thermogenesis and ameliorated insulin resistance specifi cally by promoting the browning of white adipose tissue in obese mice.Additionally,ginsenoside F1 improves norepinephrine-induced insulin resistance in adipocytes and hepatocytes,and shows a stronger mitochondria respiration ability than norepinephrine.These fi ndings suggest that ginsenoside F1 is a promising lead compound in the improvement of insulin resistance.
基金supported by the National Natural Science Foundation of China(No.81702920,No.82174020).
文摘Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TAM activators.Cyclin D1b is a highly oncogenic splice variant of cyclin D1.We previously reported that cyclin D1b enhances the invasiveness of breast cancer cells by inducing EMT.However,the role of cyclin D1b in inducing macrophage differentiation toward tumor-associated macrophage-like cells remains unknown.This study aimed to explore the relationship between breast cancer cells overexpressing cyclin Dlb and TAMs.Methods:Mouse breast cancer 4T1 cells were transfected with cyclin D1b variant and co-cultured with macrophage cells in a Transwell coculture system.The expression of characteristic cytokines in differentiated macrophages was detected using qRT-PCR,ELISA and zymography assay.Tumor-associated macrophage distribution in a transplanted tumor was detected by immunofluorescence staining.The proliferation and migration ability of breast cancer cells was detected using the cell counting kit-8(CCK-8)assay,wound healing assay,Transwell invasion assay,and lung metastasis assay.Expression levels of mRNAs were detected by qRT-PCR.Protein expression levels were detected by Western blotting.The integrated analyses of The Cancer Genome Atlas(TCGA)datasets and bioinformatics methods were adopted to discover gene expression,gene coexpression,and overall survival in patients with breast cancer.Results:After co-culture with breast cancer cells overexpressing cyclin D1b,RAW264.7 macrophages were differentiated into an M2 phenotype.Moreover,differentiated M2-like macrophages promoted the proliferation and migration of breast cancer cells in turn.Notably,these macrophages facilitated the migration of breast cancer cells in vivo.Further investigations indicated that differentiated M2-like macrophages induced EMT of breast cancer cells accompanied with upregulation of TGF-β1 and integrinβ3 expression.Conclusion:Breast cancer cells transfected with cyclin D1b can induce the differentiation of macrophages into a tumor-associated macrophage-like phenotype,which promotes tumor metastasis in vitro and in vivo.
基金the Natural Science Foundation of Liaoning Province,No.2023-MS-149.
文摘BACKGROUND As a novel endogenous anti-angiogenic molecule, vasohibin 1(VASH1) is not only expressed in tumor stroma, but also in tumor tissue. Moreover, studies have shown that VASH1 may be a prognostic marker in colorectal cancer(CRC). Knockdown of VASH1 enhanced transforming growth factor-β1(TGF-β1)/Smad3 pathway activity and type Ⅰ/Ⅲ collagen production. Our previous findings suggest that ELL-associated factor 2(EAF2) may play a tumor suppressor and protective role in the development and progression of CRC by regulating signal transducer and activator of transcription 3(STAT3)/TGF-β1 signaling pathway. However, the functional role and mechanism of VASH1-mediated TGF-β1 related pathway in CRC has not been elucidated.AIM To investigate the expression of VASH1 in CRC and its correlation with the expression of EAF2. Furthermore, we studied the functional role and mechanism of VASH1 involved in the regulation and protection of EAF2 in CRC cells in vitro.METHODS We collected colorectal adenocarcinoma and corresponding adjacent tissues to investigate the clinical expression of EAF2 protein and VASH1 protein in patients with advanced CRC. Following, we investigated the effect and mechanism of EAF2 and VASH1 on the invasion, migration and angiogenesis of CRC cells in vitro using plasmid transfection.RESULTS Our findings indicated that EAF2 was down-regulated and VASH1 was upregulated in advanced CRC tissue compared to normal colorectal tissue. KaplanMeier survival analysis showed that the higher EAF2 Level group and the lower VASH1 Level group had a higher survival rate. Overexpression of EAF2 might inhibit the activity of STAT3/TGF-β1 pathway by up-regulating the expression of VASH1, and then weaken the invasion, migration and angiogenesis of CRC cells.CONCLUSION This study suggests that EAF2 and VASH1 may serve as new diagnostic and prognostic markers for CRC, and provide a clinical basis for exploring new biomarkers for CRC. This study complements the mechanism of EAF2 in CRC cells, enriches the role and mechanism of CRC cellderived VASH1, and provides a new possible subtype of CRC as a therapeutic target of STAT3/TGF-β1 pathway.
基金Supported by the NSFC Projects(31971972)the Natural Science Foundation of Heilongjiang Province(ZD2019C001)the Outstanding Talents and Innovative Team of Agricultural Scientific Research。
文摘Phytophthora root and stem rot of soybean caused by Phytophthora sojae(P.sojae)is a devastating disease that affects soybean[Glycine max(L.)Merr.]all over the world.S-phase kinase-associated protein 1(SKP1)proteins are key members of the SKP1/Cullin/F-box protein(SCF)ubiquitin ligase complex and play diverse roles in plant biology.However,the role of SKP1 in soybean against the phytopathogenic oomycete P.sojae remains unclear.In this study,a novel member of the soybean SKP1 gene family,GmSKP1 which was significantly induced by P.sojae,was reported.The expression of GmSKP1 was simultaneously induced by methyl jasmonate(MeJA),salicylic acid(SA)and ethylene(ET),which might suggest an important role for GmSKP1 of plant in responses to hormone treatments.Functional analysis using GmSKP1 overexpression lines showed that GmSKP1 enhanced resistance to P.sojae in transgenic soybean plants.Further analyses showed that GmSKP1 interacted with a homeodomain-leucine zipper protein transcription factor(GmHDL56)and a WRKY transcription factor(GmWRKY31),which could positively regulate responses to P.sojae in soybean.Importantly,several pathogenesis-related(PR)genes were constitutively activated,including GmPR1a,GmPR2,GmPR3,GmPR4,GmPR5a and GmPR10,in GmSKP1-OE soybean plants.Taken together,these results suggested that GmSKP1 enhanced resistance to P.sojae in soybean,possibly by activating the defense-related PR genes.
基金This work was supported by grants from the National Nature Science Foundation of China(32170862,31872845)Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defect in Hunan Province(2019SK1012)+4 种基金Key Grant of Research and Development in Hunan Province(2020DK2002)High-Level Talent Gathering Project in Hunan Province(2018RS3066)Natural Science Foundation of Hunan Province(2020JJ5383,2021JJ40365)Health Commission Foundation of Hunan Province(202104052273,202102050927)Hunan Province College Student Research Learning and Innovative Experiment Project(S202010542084).
文摘Yes-associated protein 1(YAP1)is a downstream effector of the Hippo signaling pathway,and it is involved in tumorigenesis,tissue repair,growth,and development.In this review,the biological roles and the mechanisms of YAP1 in mediating stem cell fate decisions are discussed,including cell proliferation,differentiation,and apoptosis.In general,YAP1 promotes the proliferation and differentiation of stem cells,including embryonic stem cells and adult stem cells.It inhibits apoptosis by binding to the transcription factors,e.g.,transcriptional enhanced associate domain(TEAD),Smad,runt-related transcription factor 1/2,p73,p63,and Erb84,to maintain tissue homeostasis.The translocalization of YAP1 in cellular nuclei and the phosphorylation in the cytoplasm work as important and unusual events for the activation of YAP1.Moreover,YAP1 serves as the crosstalk for the Hippo pathway and other signaling pathways,including the Wnt and Notch pathways.It is highlighted in this review that YAP1 is an essential regulator for stem cells that have significant applications in regenerative medicine and reproductive medicine.
文摘Background:Colorectal cancer(CRC)is one of the most common malignancies.Early diagnosis is the key to effective treatment of CRC.Since microRNAs(miRNAs)can be used as biomarkers of CRC,the objective of this work was to examine the effect of miR-520f-3p,which targets YAP1(Yes-associated protein 1),on the ability of CRC cells to proliferate,invade,migrate,and undergo epithelial-mesenchymal transition(EMT).Methods:A miR-520f-3p mimic was used to overexpress miR-520f-3p in HT29 cells.To establish the tumor-bearing mouse model,transfected HT29 cells were subcutaneously implanted into BALB/c-nu nude mice,and YAP1 and miR-520f-3p levels were determined using qRT‒PCR.The viability,invasion ability,and migration ability of cells were evaluated by CCK-8,Transwell,and wound healing assays.Apoptosis was detected by flow cytometry and TUNEL assays.The regulatory link between miR-520f-3p and the YAP1 gene was examined by dual-luciferase reporter assay.Tumor tissues with positive Ki-67 expression were identified by immunohistochemistry.Vimentin,E-cadherin,and YAP1 expression were evaluated by western blotting.Results:MiR-520f-3p overexpression could inhibit proliferation,invasion,migration,and EMT and induce apoptosis in HT29 cells.YAP1 was found as a target of miR-520f-3p.The inhibitory effects of miR-520f-3p on proliferation,invasion,migration,and EMT may be reversed by overexpressing YAP1.In tumor-bearing mice,miR-520f-3p overexpression reduced the Ki-67 level,increased apoptosis,and prevented tumor development and spread.Conclusion:By targeting YAP1,miR-520f-3p may be capable of suppressing CRC cell proliferation,invasion,migration,and EMT,providing a novel therapeutic target for the disease.
基金This study was supported by the Key Scientific Research Project of Shanghai Municipal Commission of Health and Family Planning(No.201640014)the project of Natural Science Foundation of Jiangxi(No.20171BAB205019)the Special Diseases Program of Pudong New Area Health System(No.PWZzb2017-06).
文摘Objective:Deleted in liver cancer 1(DLC1)is a GTPase-activating protein that is reported as a suppressor in certain human cancers.However,the detailed biological function of DLC1 is still unclear in human prostate cancer(PCa).In the present study,we aimed to explore the function of DLC1 in PCa cells.Methods:Silencing and overexpression of DLC1 were induced in an androgen-sensitive PCa cell line(LNCaP)using RNA interference and lentiviral vector transduction.The Cell Counting Kit-8 assay was performed to determine cell proliferation.The cell cycle was examined by performing a propidium iodide staining assay.Results:Our results indicated that DLC1 overexpression markedly suppressed the proliferation and cell cycle progression of LNCaP cells.Moreover,DLC1 expression was negatively correlated with Rho-associated protein kinase(ROCK)expression in LNCaP cells.Importantly,this study showed that the ROCK inhibitor Y27632 restored the function of DLC1 in LNCaP cells and reduced the tumorigenicity of LNCaP cells in vivo.Conclusion:Our results indicated that DLC1 overexpression markedly suppressed the proliferation and cell cycle progression of PCa cells and negatively correlated with ROCK expression in PCa cells and tissue.
基金The study was reviewed and approved by the Institutional Review Board of The First Affiliated Hospital of Gannan Medical College,No.20141219.
文摘BACKGROUND Clinical prognosis often worsens due to high recurrence rates following radical surgery for colon cancer.The examination of high-risk recurrence factors post-surgery provides critical insights for disease evaluation and treatment planning.AIM To explore the relationship between metastasis-associated factor-1 in colon cancer(MACC1)and vacuolar ATP synthase(V-ATPase)expression in colon cancer tissues,and recurrence rate in patients undergoing radical colon cancer surgery.METHODS We selected 104 patients treated with radical colon cancer surgery at our hospital from January 2018 to June 2021.Immunohistochemical staining was utilized to assess the expression levels of MACC1 and V-ATPase in these patients.RESULTS The rates of MACC1 and V-ATPase positivity were 64.42%and 67.31%,respe-ctively,in colon cancer tissues,which were significantly higher than in paracan-cerous tissues(P<0.05).Among patients with TNM stage III,medium to low differentiation,and lymph node metastasis,the positive rates of MACC1 and V-ATPase were significantly elevated in comparison to patients with TNM stage I-II,high differentiation,and no lymph node metastasis(P<0.05).The rate of MACC1 positivity was 76.67%in patients with tumor diameters>5 cm,notably higher than in patients with tumor diameters≤5 cm(P<0.05).We observed a positive correlation between MACC1 and V-ATPase expression(rs=0.797,P<0.05).The positive rates of MACC1 and V-ATPase were significantly higher in patients with recurrence compared to those without(P<0.05).Logistic regression analysis revealed TNM stage,lymph node metastasis,MACC1 expression,and V-ATPase expression as risk factors for postoperative colon cancer recurrence(OR=6.322,3.435,2.683,and 2.421;P<0.05).CONCLUSION The upregulated expression of MACC1 and V-ATPase in colon cancer patients appears to correlate with clinicopathological features and post-radical surgery recurrence.