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.

Cancer stem cells (CSCs) are proposed to account for the progression, metastasis, and recurrence of diverse malignancies. However, the disorganized vasculars in tumors hinder the accumulation and penetration of nanomedicines, posing a challenge in eliminating CSCs located distantly from blood vessels. Herein, a pair of twin-like small-sized nanoparticles, sunitinib (St)-loaded ROS responsive micelles (RM@St) and salinomycin (SAL)-loaded GSH responsive micelles (GM@SAL), are developed to normalize disordered tumor vessels and eradicate CSCs. RM@St releases sunitinib in response to the abundant ROS in the tumor extracellular microenvironment for tumor vessel normalization, which improved intratumor accumulation and homogeneous distribution of small-sized GM@SAL. Sequentially, GM@SAL effectively accesses CSCs and achieves reduction-responsive drug release at high GSH concentrations within CSCs. More importantly, RM@St significantly extends the window of vessel normalization and enhances vessel integrity compared to free sunitinib, thus further amplifying the anti-tumor effect of GM@SAL. The combination therapy of RM@St plus GM@SAL produces considerable depression of tumor growth, drastically reducing CSCs fractions to 5.6% and resulting in 78.4% inhibition of lung metastasis. This study offers novel insights into rational nanomedicines designed for superior therapeutic effects by vascular normalization and anti-CSCs therapy.

Objective:To investigate the influence of varied oxygen (O 2) concentration environments on the phenotypic transformation of pulmonary artery smooth muscle cells (PASMC) and the mechanism of pulmonary hypertension. Methods:Primary rat PASMC were isolated and cultured through the process of enzymatic digestion. Following identification, the stable passaged PASMC were subjected to a 6-hour incubation in sealed containers with normal O 2 content (group C) and relative O 2 content comprising 55% (group H55), 75% (group H75), and 95% (group H95). mRNA and protein expression of α-Actin (α-SMA), smooth muscle 22α (SM22α), osteopontin (OPN), and matrix metalloproteinase-2 (MMP-2) were measured using real-time quantitative PCR and western blot analysis. Results:The H55 group displayed no significant difference from the C group in terms of mRNA and relative protein expression levels for α-SMA, SM22α, OPN, and MMP-2 (all P>0.05). On the other hand, groups H75 and H95 exhibited a reduction in mRNA and relative protein expression of α-SMA and SM22α, along with an increase in mRNA and relative protein expression of OPN and MMP-2 when compared with both the C and H55 groups (all P<0.05). The H95 group showed a higher relative mRNA expression of MMP-2 as compared to the H75 group ( P<0.05). Conclusions:Oxygen concentration environments of 75% or higher can serve as the foundation for the pathogenesis of pulmonary hypertension, essentially by inducing a phenotypic transformation in PASMC towards adopting a robust secretory function. This induction is contingent upon the concentration of oxygen present.

Objective:To observe the construction of mobile health management model for elderly patients with coronary heart disease, and to conduct empirical research.Methods:A total of 86 elderly patients with coronary heart disease treated in Henan Provincial People's Hospital from January 2019 to January 2021 were selected.They were randomly divided into 2 groups: the control group receiving routine intervention(n=43), and the observation group receiving mobile health management mode as an add-on to routine interventions(n=43).After 3 months of intervention in control versus observation groups, angina, readmission risk factors were assessed, and status of target criteria for low-density lipoprotein cholesterol(LDL-C), resting heart rate, systolic, and diastolic blood pressure as readmission risk factors were evaluated.Before and 3 months after intervention, the self-care ability of patients was evaluated.Results:Number of angina pectoris attacks was less in observation(0.53±0.18)than in control group(0.64±0.15)( t=3.079, P=0.003).Duration of the angina pectoris was shorter in observation(2.72±0.40)min than in control group(3.06±0.55)min, ( t=3.278, P=0.002).Rate of achieving effectiveness of indicators for the risk factors of readmission was higher in observation group than in control group as following data: LDL-C(90.7% and 72.1%, χ2=4.914, P=0.027), resting heart rate(95.4% and 81.4%, χ2=4.074, P=0.044), systolic blood pressure(86.1% and 60.5%, χ2=7.182, P=0.007)and diastolic blood pressure(88.4% and 67.4%, χ2=5.472, P=0.019).The scores of self responsibility, health knowledge, self-care skills and self-concept were higher in the observation group than in the control group, with a statistical significant difference(all P<0.05). Conclusions:The construction of mobile health management model and its application in elderly patients with coronary heart disease are beneficial to improve the symptoms of angina pectoris, reduce the risk factors of readmission and improve the ability of self-care of patients.

This article reported a successful cesarean section performed on a woman with 37 +6 weeks of gestation after heart-lung transplantation (HLTx) at the Second Xiangya Hospital of Central South University. The patient was a 29-year-old woman with singleton pregnancy who underwent HLTx seven years ago. During pregnancy, she was treated with azathioprine and tacrolimus to suppress immune rejection. The patient was in New York Heart Association (NYHA) class Ⅰ and had no fever or shortness of breath. Prenatal examinations indicated that the mother and the fetus were in good condition. A baby girl was delivered successfully at full term by a transverse lower-segment cesarean section under spinal anesthesia. Both the mother and the child were healthy at follow-up of 42 d after discharge.

Objective:To evaluate the effect of orexin A on morphine-induced gastrointestinal dysfunction in mice.Methods:Forty SPF C57B/6 mice, aged 6-8 weeks, half male and half female, weighing 18-22 g, were divided into 5 groups ( n=8 each) using a random number table method: control group (group C), morphine group (group M) and morphine + different doses of orexin A groups (MOH, MOM and MOL groups). Normal saline 8 ml/kg was subcutaneously injected daily in group C, morphine 6 mg/kg was subcutaneously injected daily in the other four groups, and orexin A 75, 50 and 25 μg/kg were subcutaneously injected daily for 10 days at the same time in MOH, MOM and MOL groups.The fetal water content was calculated and averaged daily.After the last administration, the mice were gavaged with black nutrient paste, and the gastric emptying rate and small intestinal propulsion rate were detected 30 min later.Blood samples were collected from the orbit, and the concentration of serum gastrin (GAS) was detected by enzyme-linked immunosorbent assay.The mice were then sacrificed, and colon tissues were removed for determination of c-kit positive cell area (by immunohistochemistry) and expression of c-kit, substance P (SP) and neural nitric oxide synthase (nNOS) in colon tissues (by Western blot). Results:Compared with group C, the rate of fecal water content, gastric emptying rate, small intestinal propulsion rate and serum GAS concentration were significantly decreased, the area of c-kit positive cells was decreased, and the expression of c-kit and SP was down-regulated, and the expression of nNOS was up-regulated in group M ( P<0.05). Compared with group M, the small intestinal propulsive rate and serum GAS concentration were significantly increased, and the area of c-kit positive cells was increased, and the expression of c-kit was up-regulated in group MOH, the rate of fecal water content, gastric emptying rate, small intestinal propulsion rate and serum GAS concentration were significantly increased, the area of c-kit positive cells was increased, and the expression of c-kit and SP was up-regulated, and the expression of nNOS was down-regulated in group MOM, and the serum GAS concentration and c-kit positive cell area were significantly increased in group MOL ( P<0.05). Conclusions:Orexin A 50 μg/kg can effectively alleviate the gastrointestinal dysfunction induced by morphine in mice, and the mechanism may be related to promotion of GAS secretion, interstitial cells of Cajal growth and SP release and inhibition of NO release.

Objective:To evaluate the effect of canagliflozin on intrarenal fat content and oxygenation in newly-diagnosed type 2 diabetes patients.Methods:Twenty-three newly-diagnosed type 2 diabetes patients were divided into canagliflozin( n=11) and glimepiride control( n=12) groups .Both groups received MRI scanning with Dixon MRI and BOLD MRI sequence to assess patients′ intrarenal fat content, oxygenation level before treatment and 24 weeks after treatment. Fasting blood glucose, glycosylated hemoglobin, blood uric acid, blood lipids, blood pressure, weight, and other metabolic index were also tested before and after treatment. Furthermore, the relationship between body mass index(BMI) and intrarenal fat content and the correlation between changes in intrarenal fat content and improvement in renal hypoxia were analyzed. Results:No significant differences were found in baseline age, body weight, fasting blood glucose, glycosylated hemoglobin, blood lipid, and serum uric acid between the two groups. There was no significant difference in fasting blood glucose, glycosylated hemoglobin, cholesterol(CHO), low-density lipoprotein-cholesterol(LDL-C), and triglycerides(TG) levels in both groups after 12 and 24 weeks of treatment. The decrease in body weight, blood uric acid level, and diastolic blood pressure from baseline in the canagliflozin group was greater than those in the control group( P<0.05). Two groups of patients with type 2 diabetes at baseline had no obvious difference in intrarenal fat content, and the patients′ BMI showed no obvious correlation with degree of intrarenal fat accumulation. Canagliflozin treatment for 24 weeks could reduce intrarenal fat content, which was higher than that of control group. The R2 * values of renal cortex and medulla in the canagliflozin group decreased from baseline by 19.22% and 22.63% respectively( P<0.05), whereas no significant difference was seen in the glimepiride control group. The decrease of intrarenal fat content in the canagliflozin group was related to the improvement of renal cortex and medulla oxygenation. Conclusion:Canagliflozin can reduce intrarenal fat accumulation and improve renal cortical hypoxia in newly diagnosed type 2 diabetes patients with normal renal function.