Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Purpose To investigate the clinicopathological features,differential diagnosis,and prognosis of breast carcinoma within fibroadenoma(FA).Methods A retrospective analysis was performed on the clinical and imaging data of 21 cases of FA-associated carcinoma.HE staining,immunohistochemistry using the EnVision method,and next-generation sequencing were employed to assess the clinicopathological characteristics and genetic alterations,with a review of the relevant literature.Results All patients were female,aged 21-67 years,with a median age of 48 years.Clinically,all lesions presented with well-circumscribed mass lesions.On imaging,12 cases demonstrated punctate or coarse calcifications,while 3 cases exhibited locally indistinct margins.Pathological examination revealed that the tumors had an average maximum diameter of 2.25 cm,with a gray-white nodular cut surface resembling FA.Microscopically,there was proliferation of either epithelial or spindle cells.The pathological diagnosis was FA-associat-ed in situ carcinoma in 16 cases(15 cases of low-grade ductal carcinoma in situ and 1 case of lobular carcinoma in si-tu),and invasive carcinoma in 5 cases(comprising 2 cases of invasive carcinoma-no special type,1 case of invasive lobular carcinoma,1 case of low-grade adenosquamous carcinoma and 1 case of fibromatosis-like metaplastic carcino-ma).In 18 cases,the carcinoma was confined within the FA,whereas in 3 cases the tumor locally extended beyond the FA,and 1 case exhibited ipsilateral axillary lymph node metastasis.Immunophenotypically,tumor cells in in situ carcinomas were negative for CK5/6,while the myoepithelial cells were p63-positive,and both estrogen receptor(ER)and progesterone receptor(PR)were diffusely and consistently positive.In invasive carcinoma,both ductal and lobular subtypes were ER and PR positive and HER2 negative.Conversely,in the low-grade adenosquamous carcinoma and fi-bromatosis-like metaplastic carcinoma,ER,PR,and HER2 were all negative,with p63 and CK5/6 positivity.Two ca-ses were negative for mismatch repair protein PMS2.Six cases had a family or personal history of malignant tumors;a-mong the 5 cases that underwent next-generation sequencing,2 cases harbored germline BRCA2 mutations,2 cases had germline PMS2 mutations,and 1 case exhibited no definitive genetic alteration.Conclusion Carcinoma arising within FA exhibits atypical clinical and imaging features.In patients with high-risk factors for breast cancer or family history of malignancy,or when calcifications are observed on imaging,prompt excision and biopsy are recommended.Recogniz-ing the abnormal morphology within FA and the use of immunohistochemistry are essential for accurate diagnosis,with careful differentiation from spindle cell metaplastic carcinoma and low-grade adenosquamous carcinoma.Overall,the prognosis is relatively favorable,and treatment should be tailored according to tumor type,molecular subtype,and stage.

Objective:To investigate the predictive value of thyroid hormone sensitivity indicators for adverse pregnancy outcomes in pregnant women with gestational diabetes mellitus (GDM) complicated by hypothyroidism.Methods:A cross-sectional study was conducted to retrospectively analyze the clinical data of 80 pregnant women with GDM complicated by hypothyroidism who were admitted to the Department of Obstetrics, Second Affiliated Hospital of Shaanxi University of Chinese Medicine from February 2022 to February 2024. The patients were divided into two groups: the adverse outcome group ( n = 48) and the normal outcome group ( n = 32) based on the occurrence of adverse pregnancy outcomes. Logistic regression analysis was conducted to identify the risk factors for adverse pregnancy outcomes in these women. Additionally, receiver operating characteristic curve analysis was performed to evaluate the predictive value of thyroid hormone sensitivity indicators for adverse pregnancy outcomes. Results:In the adverse outcome group, the proportion of women with a pre-pregnancy body mass index ≥ 24 kg/m2, triglyceride level, activated partial thromboplastin time, fibrinogen level, thyroid-stimulating hormone level, and thyroid-stimulating hormone index were 58.33% (28/48), (5.77 ± 0.25) mmol/L, (31.79 ± 2.68) seconds, (4.39 ± 0.37) g/L, (5.05 ± 1.07) mU/L, and (3.15 ± 0.24), respectively, which were significantly higher than those in the normal outcome group ( χ2 = 4.41, t = -3.56, -3.23, -2.61, -4.17, -9.15, all P < 0.05). Conversely, the levels of free thyroxine, free triiodothyronine, thyrotroph T4 resistance index, and thyroid feedback quantile index in the adverse outcome group were (9.32 ± 1.04) pmol/L, (3.17 ± 0.42) pmol/L, (33.09 ± 4.26), and (0.19 ± 0.07), respectively, which were all significantly lower than those in the normal outcome group ( t = 4.44, 3.51, 4.31, 2.21, all P < 0.05). Logistic regression analysis revealed that pre-pregnancy body mass index [ OR = 2.673, 95% CI(1.057,6.761)], triglyceride level [ OR = 25.623, 95% CI(3.208,204.673)], activated partial thromboplastin time [ OR = 1.365, 95% CI(1.106,1.685)], fibrinogen level [ OR = 3.111, 95% CI(1.257,7.701)], thyroid-stimulating hormone level [ OR = 2.969, 95% CI(1.613,5.465)], free thyroxine level [ OR = 0.441, 95% CI(0.280,0.695)], free triiodothyronine level [ OR = 0.172, 95% CI(0.057,0.516)], thyroid-stimulating hormone index [ OR = 6.298, 95% CI(1.099, 36.094)], thyrotroph T4 resistance index [ OR = 0.799, 95% CI(0.704,0.907)], and thyroid feedback quantile index [ OR = 0.057, 95% CI(0.168,0.478)] were all factors that influence adverse pregnancy outcomes in pregnant women with GDM complicated by hypothyroidism (all P < 0.05). The area under the curve for predicting adverse pregnancy outcomes using the combined thyroid hormone sensitivity indicators was 0.809 [95% CI (0.704, 0.915), P < 0.001], with a sensitivity of 0.896, specificity of 0.687, and a maximum Youden index of 0.583. Conclusions:The thyroid hormone sensitivity indicators have a certain predictive value for adverse pregnancy outcomes in pregnant women with GDM complicated by hypothyroidism. These indicators can provide important reference for clinical prediction and intervention of adverse pregnancy outcomes in this patient population.

A mounting body of research suggests that circRNAs significantly contribute to the develop-ment of myocardial fibrosis.The microarray results of human circular RNA expression profile indicated that circHERC4_041 expression increased in the myocardium of patients with heart failure,RT-qPCR a-nalysis confirmed that the myocardial expression level of circHERC4_041 in individuals with heart failure were considerably elevated compared to that in healthy organ donors.Fluorescence in situ hybridization(FISH)confirmed that circHERC4_041 was abundant in the cytoplasm of human cardiomyocyte AC16.Overexpression of circHERC4_041 in mouse myocardial fibroblasts(mCFs)mediated by adenovirus in-hibited the expression of fibrosis-related proteins in mCFs.Experiments involving cell proliferation,wound healing,and Transwell assays demonstrated that overexpression of circHERC4_041 suppressed the growth and mobility of mCFs(P＜0.001).Sequence analysis results suggested that circHERC4_041 con-tains potential ribosome entry sequence(IRES)and open reading frame(ORF).Western blot confirmed that circHERC4_041 could translate the 516 amino acid HERC4-516aa protein,which was mainly located in the cytoplasm of the cell.Cell functional experiments confirmed that circHERC4_041 inhibited the fi-brotic phenotype of mCFs by specifically translating HERC4-516aa(P＜0.05).The specific interaction between HERC4-516aa and transglutaminase 2(TGM2)was confirmed by IP-MS screening and Co-IP i-dentification.Further results found that the degradation of TGM2 was promoted through proteasome path-way.The overexpression of TGM2 in mCFs facilitated by adenoviral vectors could counteract the suppres-sive effects of HERC4-516aa on the fibrotic phenotype of mCFs.Therefore,this study confirmed that the HERC4-516aa protein translated by circHERC4_041 can specifically bind to TGM2 to inhibit the fibrotic phenotype of myocardial fibroblasts.

Rho proteins and the Rho-associated protein kinase(ROCK)signaling pathway are cruci-al components of intracellular signaling cascades.Rho proteins,which belong to the small GTPase family,play a pivotal role in regulating essential elements of the cytoskeleton within cells.ROCK functions as a downstream effector protein kinase of Rho,modulating various biological processes,including cell morphology,migration,and proliferation.Recent studies have underscored the signifi-cance of the ROCK signaling pathway in the replication of a diverse group of viruses.Furthermore,it has been discovered that some viruses disrupt cellular contraction,adhesion,and migration through the Rho/ROCK pathway,subsequently influencing the immune response triggered by vi-ral infections and affecting the tight junctions between cells.This article primarily reviews the re-search progress regarding the Rho/ROCK signaling pathway and its key signaling molecules,Rho and ROCK,in terms of their activation and regulation of viral replication and tight junction pro-teins between cells.

Rho proteins and the Rho-associated protein kinase(ROCK)signaling pathway are cruci-al components of intracellular signaling cascades.Rho proteins,which belong to the small GTPase family,play a pivotal role in regulating essential elements of the cytoskeleton within cells.ROCK functions as a downstream effector protein kinase of Rho,modulating various biological processes,including cell morphology,migration,and proliferation.Recent studies have underscored the signifi-cance of the ROCK signaling pathway in the replication of a diverse group of viruses.Furthermore,it has been discovered that some viruses disrupt cellular contraction,adhesion,and migration through the Rho/ROCK pathway,subsequently influencing the immune response triggered by vi-ral infections and affecting the tight junctions between cells.This article primarily reviews the re-search progress regarding the Rho/ROCK signaling pathway and its key signaling molecules,Rho and ROCK,in terms of their activation and regulation of viral replication and tight junction pro-teins between cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.