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.

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.

[This corrects the article DOI: 10.1016/j.apsb.2022.05.019.].

OBJECTIVE To investigate the protective effect and mechanism of quercetin on the cardiac and renal functions of rats with cardiorenal syndrome （CRS） based on the phosphoinositide 3-kinase （PI3K）/protein kinase B （Akt）/nuclear factor kappa- B （NF-κB） signaling pathway. METHODS CRS model of SD rats was induced by left anterior descending coronary artery ligation combined with acute renal ischemia-reperfusion. Model rats were randomly separated into model group， quercetin low-dose group （35 mg/kg）， quercetin high-dose group （70 mg/kg）， high-dose of quercetin+740Y-P group （70 mg/kg quercetin+3.5 mg/kg PI3K/Akt/ NF-κB signaling pathway activator 740Y-P）， with 12 rats in each group. Another 12 normal rats were selected as sham operation group. They were given relevant drugs， once a day， for 14 consecutive days. After administration， the cardiac function indexes [left ventricular ejection fraction （LVEF）， end-diastolic volume （EDV）， isovolumic relaxation time （IVRT）] and renal function indicators [blood urea nitrogen （BUN）， 24-hour urine protein， and serum creatinine （Scr）] were detected， and fibrosis in the cardiac and renal tissues was observed； the levels of inflammatory indexes [interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α）] in the serum and cardiac and renal tissues as well as the expression of PI3K/Akt/NF-κB pathway-related proteins in the cardiac and renal tissues were detected. RESULTS Compared with sham operation group， the levels of BUN， 24-hour urine protein and Scr， collagen volume fraction of cardiac and renal tissues， the levels of IL-1β and TNF-α in serum and cardiac and renal tissues， and the phosphorylation of PI3K， Akt and NF-κB p65 protein in cardiac and renal tissues were increased significantly in model group （P＜0.05）； the levels of LVEF， IVRT and EDV were reduced significantly （P＜0.05）. Compared with the model group， the above indexes were reversed significantly in quercetin low-dose and high-dose groups （P＜0.05）， and the reversal effect was better in the high-dose group （P＜0.05）. 740Y-P restored the reverse effect of high-dose quercetin on the indexes （P＜0.05）. CONCLUSIONS Quercetin can alleviate cardiac and renal fibrosis and function injury， the mechanism of which may be 20232016） associated with inhibiting the activation of the PI3K/Akt/NF-κB signaling pathway.

Objective To investigate the effects of inhibiting KDM2A gene on the proliferation,invasion and migration of liver cancer cells and its possible regulatory mechanism.Methods Forty pairs of HCC tissues and their adjacent normal counterparts were collected from 2014 to 2017 in Tongji Hospital,Tongji Medical College Affiliated to Huazhong University of Science and Technology.Human liver cancer cell lines HepG2,Huh7,HCCLM3,MHCC-97H and normal liver cells LO2 were cultured in vitro.The mRNA and protein expression levels of KDM2A in HCC tissues and cells were detected by qRT-PCR and Western blotting.Huh7 cells were taken and set up as follows:(1)si-NC group(transfected with si-NC)and si-KDM2A group(transfected with si-KDM2A);(2)mimic-NC group(transfected with mimic-NC),miRNA-29a-3p mimic group(transfected with miRNA-29a-3p mimic),inhibitor-NC group(transfected with inhibitor-NC)and miRNA-29a-3p inhibitor group(transfected with miRNA-29a-3p inhibitor).The mRNA and protein expression levels of KDM2A were detected by qRT-PCR and Western blotting.The invasion and migration of cells were detected by Transwell,the proliferation of cells was detected by CCK-8 methods.The online databases TargetScan,miRDIP,miRWalk,Starbase and miRDB were used to predict the binding sites of KDM2A and miR-29a-3p.The KDM2A 3'-UTR(WT)or KDM2A 3'-UTR(MUT)report plasmid was co-transfected with NC-miRNA or miR-29a-3p mimics respectively for 48 h in 293T cells,and the luciferase activity was detected by the luciferase reporter gene detection system.Results Compared with adjacent normal counterparts,the relative mRNA and protein expression levels of KDM2A in HCC tissues increased significantly(P＜0.05).Compared with LO2,the relative mRNA and protein expression levels of KDM2A in HepG2,Huh7,HCCLM3 and MHCC-97H increased significantly(P＜0.05).Compared with si-NC group,the proliferation,invasion and migration of Huh7 cells in si-KDM2A group decreased significantly(P＜0.05 or P＜0.01).The analysis results of TargetScan,miRDIP,miRWalk,Starbase and miRDB showed that there were binding sites between KDM2A and miR-29a-3p.The results of the dual luciferase reporter assay showed that miR-29a-3p mimic significantly reduced KDM2A-MUT luciferase activity(P＜0.01).After overexpression of miRNA-29a-3p,the relative mRNA and protein expression levels of KDM2A were decreased(P＜0.01),the proliferation,invasion and migration abilities were decreased(P＜0.05)in Huh7 cells.After inhibiting the expression of miRNA-29a-3p,the relative mRNA and protein expression levels of KDM2A were increased(P＜0.05),the proliferation,invasion and migration abilities were enhanced(P＜0.05)in Huh7 cells.Conclusion Inhibiting the expression of KDM2A can reduce the proliferation and migration ability of Huh7 cells.miR-29a-3p may be the upstream regulator of KDM2A and participate in the occurrence and development of hepatocellular carcinoma.

Objective:This study aims to compare the antiviral treatment similarities and differences in the population covered by the 2024 version of the World Health Organization's (WHO) hepatitis B prevention and treatment guidelines and the current Chinese hepatitis B prevention and treatment guidelines, so as to explore their impact on the indications for antiviral therapy in Chinese patients with chronic hepatitis B (CHB).Methods:The information of patients with chronic hepatitis B virus infection who did not receive antiviral treatment was collected through the registration database of the China Clinical Research Platform for Hepatitis B Elimination. Descriptive statistics were conducted on the demographic, blood, biochemical, and virological levels of patients according to the treatment recommendations of the two versions of the guidelines. The Mann-Whitney U test and χ2 test were used to compare the differences and proportional distribution of the treatment populations covered by the two guidelines. The χ2 test was used to analyze the coverage rate of different antiviral treatment indications.Results:A total of 21,134 CHB patients without antiviral treatment were enrolled. 69.4% of patients met the 2024 versions of the WHO guidelines' recommendations. 85.0% of patients met the current Chinese hepatitis B prevention and treatment guidelines. The WHO guidelines for antiviral therapy indications were met in younger patients with higher levels of ALT, AST, and APRI scores, as well as greater proportion of patients with higher viral loads (P<0.001). The WHO guidelines recommended a cut-off value of APRI>0.5, which raised the proportion of patients on antiviral therapy from 6.6% to 30.9%. 45.7% of patients met the antiviral indications for HBV DNA >2000 IU/ml with abnormal transaminase (ALT>30 U/L for males and ALT>19 U/L for females). The reduced APRI diagnostic cut-off value and ALT treatment threshold had further increased the treatment coverage rate by 91.6% in patients with chronic HBV infection in line with the 2024 versions of WHO guidelines.Conclusion:The reduction of the APRI diagnostic cut-off value and the ALT treatment threshold, based on the current hepatitis B guidelines of China, will further improve the treatment coverage of CHB patients.

Objective To compare the inhibitory effects of remimazolam and dexmedetomidine on cough during emergence from general anesthesia after thyroid surgery.Methods Patients with 111 cases of thyroid surgery were randomly divided into 3 groups,37 in each group.Group A was given a bolus of 0.1 mg·kg-1 and 0.05 mg·kg-1·h-1 remimazolam intravenous infusion until extubation,group B was given 0.5 μg·kg-1 of the dexmedetomidine over 10 minutes,and group C was given same dose of normal saline.The incidence of cough during emergence from general anesthesia,the moderate and severe cough,the recovery time and extubation time,the Ramsay Sedation Scale(RSS)score,and the heart rate(HR),and mean arterial pressure(MAP)at different time points before and after intervention and before and after extubation were recorded and compared.Results There were significant differences in the incidence of coughing among group A,B and C(37.84％vs.67.57％vs.91.89％,adjusted P＜0.016 7,respectively).The incidence of moderate and severe cough was also lower in group A than in group B and C(8.11％vs.35.14％vs.67.57％,adjusted P＜0.001).The recovery time and extubation time were longer in group B than those of group A and C(adjusted P＜0.001).The RSS scores at the time of extubation and after extubation were higher in group B than in group A and C(adjusted P=0.002 and P=0.007,respectively).After intervention,compared with group C,the HR of group A and B decreased to different degree,and different drugs interacted with time,and the HR of group B patients decreased to a greater extent.Conclusion Remimazolam suppresses the occurrence and reduces the severity coughing during emergence from general anesthesia,and reduce the severity in patients treated with thyroid surgeries.Compared with dexmedetomidine,remimazolam did not prolong recovery time and extubation time,remaining more stable haemodynamics.

Objective:To compare the efficacy of percutaneous vertebroplasty (PVP) under enhanced regional and conventional anesthesia for multisegmental acute symptomatic osteoporotic thoracolumbar fractures (m-ASOTLF).Methods:A retrospective cohort study was conducted to analyze the data of 91 patients with m-ASOTLF who were admitted to Honghui Hospital of Xi′an Jiaotong University from January 2021 to December 2022, including 36 males and 55 females, aged 55-80 years [(67.4±7.3)years]. According to American Society of Anesthesiologists (ASA) classification system, 18 patients were classified as grade I, 52 grade II, and 21 grade III. Injured segments included T 6-T 10 in 23 patients, T 11-L 2 in 47 and L 3-L 5 in 21. All the patients were treated with PVP, among whom 45 were given enhanced regional anesthesia (enhanced anesthesia group) and 46 regional conventional anesthesia (conventional anesthesia group). The following indicators were compared between the two groups: the operation time, intraoperative bleeding, intraoperative heart rate, intraoperative mean arterial pressure (MAP), number of intraoperative fluoroscopies, and total amount of bone cement injected; the visual analogue scale (VAS) and Oswestry dysfunction index (ODI) before surgery, at 1 day, 1 month after surgery and at the last follow-up; the mini-mental state examination (MMSE) before surgery, at 1, 6, and 12 hours after surgery; the anterior vertebrae height (AVH), middle vertebrae height (MVH), and vertebral kyphosis angle (VKA) before and at 1 day after surgery; the incidence of complications such as bone cement leakage. Results:All the patients were followed up for 12-20 months [(15.8±2.6)months]. There were no significant differences between the two groups in the operation time, intraoperative bleeding, intraoperative heart rate, intraoperative MAP, number of intraoperative fluoroscopies or total amount of bone cement injected ( P>0.05). No significant differences were found between the two groups in VAS or ODI before surgery and at the last follow-up ( P>0.05). The VAS scores in the enhanced anesthesia group were (2.5±0.4)points and (1.8±0.3)points at 1 day and 1 month postoperatively respectively, which were both lower than (3.5±0.4)points and (2.0±0.5)points in the conventional anesthesia group ( P<0.01). The ODI values in the enhanced anesthesia group were 39.8±3.3 and 26.5±5.0 at 1 day and 1 month postoperatively respectively, which were both lower than 43.8±7.5 and 30.3±6.4 in the conventional anesthesia group ( P<0.01). The VAS and ODI at all postoperative time points decreased in both groups compared with those before surgery, with significant differences among those at all postoperative time points ( P<0.05). There was no significant difference between the two groups in the MMSE scores before, at 1, 6, and 12 hours after surgery ( P>0.05). The MMSE scores at 1 and 6 hours postoperatively were lower than that preoperatively in both groups ( P<0.05), and it was increased at 6 hours compared with that at 1 hour postoperatively ( P<0.05). There was no significant difference between the MMSE scores at 12 hours postoperatively and preoperatively in both groups ( P>0.05). The differences between the two groups in AVH, MVH, or VKA preoperatively were not statistically significant ( P>0.05). The AVH and MVH at 1 day postoperatively in the enhanced anesthesia group were (22.4±4.2)mm and (22.7±3.7)mm respectively, which were both higher than those in the conventional anesthesia group [(19.3±3.7)mm and (20.1±6.3)mm] ( P<0.05 or 0.01); the VKA at 1 day postoperatively in the enhanced anesthesia group was (13.9±3.7)°, which was lower than that in the conventional anesthesia group (15.8±4.1)° ( P<0.05). The AVH, MVH, and VKA in both groups were all improved at 1 day postoperatively compared with those preoperatively ( P<0.05). The incidence of bone cement leakage in the enhanced anesthesia group was 6.7% (3/45), which was lower than 21.7% (10/46) in the conventional anesthesia group ( P<0.05). Conclusion:Compared with conventional regional anesthesia, PVP under enhanced regional anesthesia for m-ASOTLF has more advantages in early postoperative pain relief, improvement of spinal function, restoration of vertebral height and reduction of bone cement leakage.