AIM:To investigate the impact of core 1 β3-galactosyltransferase-specific molecular chaperone(COSMC)on the stem cell-like properties of gastric adenocarcinoma cells,and to elucidate its underlying mechanism.METHODS:GEPIA(Gene Expression Profiling Interactive Analysis),TIMER(Tumor IMmune Estimation Resource),Wei Sheng Xin platform,UALCAN(University of Alabama at Birmingham Cancer Data Analysis Portal)and UCSC(Uni-versity of California,Santa Cruz)Xena databases were employed to analyze COSMC expression levels across various carci-noma types.The COSMC expression in gastric cancer tissues and cell lines was evaluated using Western blot analysis.Transfection of small interfering RNA was used to knock down COSMC in MKN-45 cell line.In vitro experiments were con-ducted to explore the relationship between the COSMC expression and the stem cell-like properties of gastric cancer.The qPCR,sphere formation assay,soft agar colony formation assay and CCK-8 assay were used to evaluate the effect of COSMC on the stem cell-like properties of gastric cancer cells.Tn+and Tn-cells were isolated using Vicia villosa lectin(VVL)-conjugated immunomagnetic beads to investigate the influence of Tn structure on the stem cell-like characteristics of gastric cancer cells.Finally,the effect of COSMC knockdown on the mitogen-activated protein kinase(MAPK)signal-ing pathway was evaluated by Western blot analysis.RESULTS:(1)The COSMC exhibited differential expression across pancarcinoma,gastric cancer tissues and gastric cancer cell lines,with elevated expression levels in gastric cancer tissues and gastric cancer cell lines compared with normal tissues and gastric epithelial cell line.(2)Knockdown of COSMC sig-nificantly down-regulated the mRNA levels of stem cell markers NANOG,OCT-4 and CD44 in gastric cancer cells,re-duced the efficiency of soft agar colony formation and sphere formation,and increased the sensitivity of the cells to 5-fluo-rouracil(5-FU).(3)The efficiency of tumor sphere formation and soft agar colony formation in Tn-cells,and the resis-tance to 5-FU were significantly higher than those in Tn+cells.(4)Knockdown of COSMC decreased the protein levels of MAPK signaling pathway-related molecules,including c-Jun N-terminal kinase(JNK),p38 and phosphorylated extracel-lular signal-regulated kinase(p-ERK).CONCLUSION:The COSMC has the potential to enhance the stem cell-like properties of gastric cancer cells,which was likely mediated through the activation of the MAPK signaling pathway.

AIM:To investigate the effects of lactylation at the K197 site of peroxiredoxin 1(PRDX1)on the proliferation and migration of glioblastoma cells.METHODS:(1)Immunofluorescence and lactylation pan-antibody techniques were adopted to compare the differences in PRDX1 lactylation modification level between glioblastoma tissues and adjacent normal tissues.High-throughput mass spectrometry and modificomics analysis were utilized to select PRDX1 protein and its K197 site as the focus.(2)Cell experiments were conducted using lactate(5,10 and 15 mmol/L),glu-cose(5,10 and 25 mmol/L)and glycolysis inhibitor 2-deoxy-D-glucose(2-DG;1,5,10 and 15 mmol/L)to treat human glioblastoma U87MG and LN229 cells.Cell proliferation was detected by EdU proliferation staining,and PRDX1 expres-sion was detected in U87MG,LN229 and glial cells via immunoprecipitation and Western blot.The PRDX1 expression and lactylation levels were further examined in 10 mmol/L lactic acid-treated and untreated cells using immunoprecipita-tion and Western blot.(3)The U87MG and LN229 cells were transfected with constructed lactate dehydrogenase A(LDHA)siRNA(si-LDHA)plasmids and negative control(si-Con)plasmids,and the lactylation level of PRDX1 was as-sessed by immunoprecipitation and Western blot.(4)Similarly,the U87MG and LN229 cells were transfected with PRDX1 shRNA(sh-PRDX1)plasmids and negative control(sh-Con)plasmids,and PRDX1 expression was determined by Western blot.(5)The PRDX1 K197R mutant and PRDX1 wild-type(WT)plasmids were constructed and transfected into U87MG and LN229 cells.The PRDX1 expression and lactylation levels were determined by immunoprecipitation and Western blot.The CCK-8 and EdU assays were used to measure cell viability and proliferation,and Transwell assay was performed to assess the migration of U87MG and LN229 cells transfected with PRDX1 K197R mutant and PRDX1 WT plasmids.(6)A tumor formation model in nude mice was established.The LN229 cells with or without PRDX1 K197R mutation were used in the tumor formation experiment with 6 nude mice per group.After 18 d,the nude mice were eutha-nized,and tumor tissues were harvested.Histological changes were observed by HE staining,the lactylation modification leve was detected by immunofluorescence,and immunohistochemistry method was adopted for checking Ki67,a prolifera-tion marker,in tumor tissues.RESULTS:The PRDX1 level in glioblastoma tissues was significantly higher than that in adjacent tissues(P＜0.05).In cell experiments,the addition of lactate and glucose significantly promoted the proliferation and migration of glioblastoma cells and increased the lactylation level of PRDX1(P＜0.05).In contrast,the glycolysis in-hibitor 2-DG inhibited these effects.The si-LDHA transfection experiment showed that knockdown of LDHA reduced the lactylation level of PRDX1(P＜0.05).Importantly,the K197R point mutation in PRDX1 significantly decreased the lacty-lation level of PRDX1 and inhibited the proliferation and migration of glioblastoma cells(P＜0.05).Nude mouse tumori-genesis experiments further confirmed that tumor growth in PRDX1 K197R group was significantly reduced,and the Ki67 proliferation index and lactylation level were decreased(P＜0.05).CONCLUSION:Lactoylation at the K197 site of PRDX1 promotes the proliferation and migration of glioblastoma cells.

Colorectal cancer(CRC)is currently the third most prevalent tumor and the second leading cause of cancer-related mortality.Abnormal Wnt/β-catenin signaling pathway is one of the key signaling pathways leading to the occurrence and development of CRC.The Dickkopf family,consisting of secreted proteins,acts as antagonists to this sig-naling pathway and significantly influences the progression of CRC.The family includes Dickkopf-1 to Dickkopf-4 secret-ed proteins,with each member exhibiting distinct roles in the context of CRC.This article aimed to provide a comprehen-sive overview of the research advancements concerning the secreted Dickkopf family's role in CRC.

AIM:The aim of our study is to investigate the metabolic profile differences during cervical lesion progression and evaluate their potential clinical value in assisting the diagnosis of cervical cancer(CC).METHODS:Ul-tra-high-performance liquid chromatography coupled with high-resolution mass spectrometry(UHPLC-HRMS)was em-ployed to conduct non-targeted metabolomic analysis of cervical swab samples from 43 CC patients,34 high-grade squa-mous intraepithelial lesion(HSIL)patients,and 43 healthy controls.Based on the distinct features among the three groups,principal component analysis(PCA)was used to identify the metabolic differences among CC,HSIL and healthy groups.MetaboAnalyst 5.0 was then employed to perform KEGG pathway enrichment analysis on the differential metabo-lites.Finally,random forest machine learning algorithm was used to construct classification prediction models for distin-guishing CC from healthy,HSIL from healthy,and CC from HSIL.The performance of these models was evaluated using receiver operating characteristic(ROC)curve analysis.RESULTS:A total of 1 543 metabolites were identified across the healthy,HSIL and CC groups after filtration,with 407 metabolites differing between the groups.The study found that metabolite PGE2 was present in all three groups,with its expression levels progressively increasing with the progression of cervical lesions.Differential metabolite enrichment analysis demonstrated that CC is associated with specific cancer-relat-ed metabolic pathways,including the tricarboxylic acid cycle,tyrosine metabolism,tryptophan metabolism,and the pen-tose phosphate pathways.Additionally,the study developed three prediction models based on metabolic products for diag-nosing HSIL and CC:the full model,the simplified model,and the PGE2 model.The results indicated that metabolites ex-hibited strong diagnostic efficiency.Both the full model and the simplified model effectively distinguished CC from HSIL,CC from healthy,and HSIL from healthy.The AUC values for the full model were 0.90,0.92 and 0.84,respectively,while those for the simplified model were 0.81,0.95 and 0.85,respectively.Furthermore,the PEG2 model achieved AUC values of 0.74 and 0.80 for distinguishing CC from healthy and HSIL from healthy,respectively.CONCLUSION:The metabolic profiles of cervical cancer exhibit significant differences during the progression of cervical cancer,and these metabolites hold potential clinical value as biomarkers for cervical lesions.

AIM:This study aims to investigate the role of histone methyltransferase SET and MYND domain containing 2(SMYD2)in facilitating renal fibrosis through the macrophage-myofibroblast transition in diabetic kidney dis-ease(DKD).METHODS:(1)C57BL/6J mice were intraperitoneally administered 55 mg/kg of streptozotocin to induce diabetes mellitus(DM).The experimental groups were categorized as follows:normal control,DM(20 weeks),DM(28 weeks),and DM(36 weeks).Blood glucose(BG),serum creatinine(SCr)and blood urea nitrogen(BUN)levels were determined using a biochemical analyzer.Hematoxylin-eosin(HE)staining and Masson staining were performed to assess morphological and fibrotic changes in renal tissues.Western blot analysis was used to measure the protein levels of SMYD2,histone H3 lysine 4 trimethylation(H3K4me3),arginase-1,matrix metalloproteinase 9(MMP9),collagen type Ⅰ(Col Ⅰ)and α-smooth muscle actin(α-SMA).Immunofluorescence staining was conducted to examine the localization and expression of F4/80,α-SMA,SMYD2,CD86,CD206 and CD163.(2)Mouse monocyte/macrophage RAW264.7 cells were cultured in vitro and assigned to groups as follows:normal glucose(NG)+negative control siRNA(siNC),high glucose(HG)+siNC,NG+SMYD2 siRNA(siSMYD2),and HG+siSMYD2.Western blot analysis was used to assess the expression of relevant proteins.RESULTS:(1)Compared with normal control group,the levels of BG,SCr and BUN were significantly elevated in DM(28 weeks)and DM(36 weeks)groups(P＜0.05).Renal tissue exhibited tubular atro-phy,dilation,and collagen fiber deposition.The levels of H3K4me3,arginase-1,MMP9,Col Ⅰ and α-SMA proteins were up-regulated(P＜0.05).The CD86,CD206,CD163 and F4/80 were primarily localized in the interstitial macrophages of the renal tubules,α-SMA was predominantly detected in the renal interstitium,and SMYD2 was mainly expressed in renal tubular epithelial cells and the renal interstitium.(2)Compared with NG+siNC group,the protein levels of SMYD2,H3K4me3,arginase-1,CD163,Col Ⅰ,α-SMA,transforming growth factor-β1(TGF-β1)and p-Smad3 in the cells of HG+siNC group were significantly increased(P＜0.05).Knockdown of SMYD2 resulted in a reduction of these indicators(P＜0.05).CONCLUSION:The SMYD2 protein appears to facilitate renal fibrosis in DKD by promoting the macrophage-myofibroblast transition,potentially through the modulation of TGF-β1/Smad3 signaling pathway.

Atherosclerosis(AS)is a chronic inflammatory disease involving various immune cells and is char-acterized by lipid deposition and inflammatory response.In recent years,the field of exosome research has been rapidly developed,thereby enhancing our comprehension of their role in AS.Immune cell-derived exosomes are extracellular vesi-cles secreted by immune cells that possess specificity,stability,and biocompatibility.These exosomes have the capacity to induce diverse responses including modulating gene transcription and regulating cytokine production,thereby influenc-ing the body's inflammatory and immune response.During AS progression,these exosomes primarily participate in patho-logical processes including endothelial dysfunction,lipid deposition,vascular calcification,and plaque rupture,all of which significantly influence the development of AS.This review is focused on exploring the role of exosomes derived from monocytes,macrophages,neutrophils,lymphocytes,as well as other immune cells(neutrophils,eosinophils,mast cells,and myeloid-derived suppressor cells)in AS,aiming to offer insights for diagnosis and clinical treatment.

Periodontitis is a chronic inflammatory disease primarily triggered by dysregulation of microbial communities and altered host immune response.It is clinically presented by alveolar bone resorption,which is one of the main causes of loosening of teeth and tooth loss.Cathepsin K(CTSK)is a highly expressed collagenase produced by osteo-clasts and can directly degrade matrix collagen proteins and indirectly increase osteoclast activity.The expression level of CTSK fluctuates in response to the progression of periodontal inflammation.The expression of Toll-like receptors is upregu-lated in periodontitis lesions.Pathogen-associated molecular pattern binds to relevant TLRs,initiating downstream im-mune pathways that promote receptor activator of nuclear factor-κB ligand-dependent osteoclastogenesis,along with in-creased expression of CTSK.Intervening in the process of alveolar bone resorption can be achieved through the regulation of CTSK.This paper provides a summary of the pathogenic mechanism of CTSK in periodontitis and highlights the research progress regarding the use of CTSK as a therapeutic target.The aim is to offer insights and references for the treatment of periodontitis.

Multiple myeloma(MM),a common malignancy of plasma cells,remains an incurable disease de-spite significant therapeutic advancements.A defining characteristic of MM is the recurrent occurrence of cytogenetic ab-normalities,particularly the gains of chromosome 1q21(1q21+),which are among the most frequently observed anoma-lies in this condition,affecting approximately 40%of patients with newly diagnosed MM.While numerous studies have identified 1q21+as an independent prognostic marker linked to poor outcomes in MM,its prognostic significance continues to be debated.An increasing number of national and international prognostic stratification systems classify 1q21+as a high-risk factor;however,its predictive value remains contentious.Variations in 1q21 copy numbers significantly impact genomic instability,drug resistance,and the likelihood of early disease progression,highlighting its growing importance in clinical management strategies.Despite the availability of various therapeutic approaches,such as autologous hemato-poietic stem cell transplantation,immunomodulatory drugs,and proteasome inhibitors,the adverse prognostic implica-tions of 1q21+persist unresolved.This review will explore the latest advancements in understanding the 1q21+in MM,fo-cusing on its pathogenesis,prognostic relevance,and implications for clinical management.

Head and neck squamous cell carcinoma(HNSCC)is currently acknowledged as an independent cause of disease.Beyond smoking and heavy alcohol use,persistent infection with high-risk human papillomavirus(HPV)is receiving increased recognition as a newly identified independent cause of this condition.The distinct clinical character-istics of HPV-related HNSCC,which are linked with a better prognosis,and its interaction with the tumor immune micro-environment,are areas of intense research focus.The specific immune response triggered by HPV and the tumor immune microenvironment are vital in the development,progression,and outcome of HNSCC.This review examines the ways HPV positive HNSCC evades the immune system,assesses the influence of HPV on the tumor immune microenvironment in HN-SCC,and explores its interaction with the body's adaptive immunity.This article presents a review on the evaluation of specific immune responses in improving the prognosis of HPV-related HNSCC and discusses the potential value of immune analysis in predicting prognosis.Furthermore,we analyze novel immune therapy strategies,mechanisms,and prognosis in HPV-related HNSCC.

AIM:To investigate the role and underlying mechanisms of NADPH oxidase 4(NOX4)/transient receptor potential channel subfamily C member 6(TRPC6)in the context of podocyte damage in diabetic nephropathya comprehensive investigative study was warranted.METHODS:(1)Male Sprague-Dawley rats were randomly divided in-to four distinct groups:a control group,a diabetic nephropathy group,a NOX4 inhibitor GKT137831-treated group,and a combined diabetic nephropathy with NOX4 inhibitor GKT137831-treated group,each consisting of 8～10 rats.The type 1 diabetes mellitus model was constructed via a single intraperitoneal injection of streptozotocin(STZ)(70 mg/kg),subse-quent to the successful induction of the model,GKT137831(at the dose of 5 mg/kg)was administered intraperitoneally.Regular monitoring of blood glucose levels was conducted,and urinary albumin excretion was quantified after 24 hours.Moreover,blood and kidney tissues were harvested for further analysis.(2)Mouse glomerular podocytes were divided into four distinct groups:a normal control group,a high glucose group,a GKT137831-treated group and a high glucose GKT137831-treated group.These podocytes were subsequently cultivated in vitro under high glucose conditions for 2 weeks.Thereafter,transfection of podocytes was carried out using NOX4 inhibitors and short interfering RNA targeting(siRNA)TRPC6.To detect the expression levels of NOX4 and TRPC6,a battery of techniques including Western blot,Immunohistochemistry,and reverse transcription polymerase chain reaction(RT-qPCR)were employed.(3)The morpho-logical changes of podocyte mitochondria under the condition of high glucose were observed by fluorescence confocal mi-croscopy,and the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1α(PGC1α),mito-chondrial transcription factor A(TFAM),cytochromec oxidase subunit Ⅰ(COX Ⅰ)and cytochromec oxidase subunit Ⅳ(COX Ⅳ)in podocytes were assessed utilizing the Western blot technique.RESULTS:(1)Compared with normal con-trol group,mice with diabetic nephropathy manifested pronounced glomerular hypertrophy,thickening of basement mem-brane,expansion of the mesangial region,and an increased rate of urinary albumin excretion was observed.Analytical techniques such as Western blot and Immunohistochemistry showed a significant upsurge in the expression level of the NOX4 protein in kidney tissue,a diminished expression of glomerular podocyte protein(nephrin),an increased expression of interstitial cell markers(desmin),and an enhanced level of TRPC6 expression(P＜0.05).GKT137831 was assoiated with a reduction in desmin expression in renal tissue,preservation of glomerular nephrin expression,and a decrease in uri-nary albumin excretion(P＜0.05).(2)In vitro podocyte experiment,the expression of NOX4 and TRPC6 in podocyte was significantly increased in the context of high glucose(P＜0.05).Findings from Immunofluorescence and Western blot showed that GKT137831 effectively diminished the expression levels of TRPC6 and desmin while partially rescuing neph-rin expression in podocellular cells(P＜0.05).Western blot results showed that transfection of TRPC6 small interfering RNA could further promote the protective effect of GKT137831 on podiocytes.(3)Under high-glucose conditions,fluores-cence confocal microscopy revealed mitochondrial morphological damage in podocytes.However,therapeutic intervention with GKT137831 and transfection of TRPC6 siRNA partially rescued the mitochondrial structural integrity.Under high glucose conditions,immunoblot analysis demonstrated a marked decrement in the protein expression levels of PGC1α,TFAM,COX Ⅰ,and COX Ⅳ in podocytes.Importantly,GKT137831 and the transfection of TRPC6 siRNA significantly upregulated the levels of PGC1α,TFAM,COX Ⅰ,and COX Ⅳ(P＜0.05).CONCLUSION:In the context of the patho-genesis of diabetic nephropathy,the increased expression of NOX4 in the kidneys contributes to podocyte damage,with the effect being partially mediated via the TRPC6 channel.Inhibiting the NOX4-TRPC6 signaling pathway has the potential to ameliorate mitochondrial dysfunction in podocytes.This finding offers novel perspectives and strategies for the clinical di-agnosis and treatment of diabetic nephropathy.