Bone morphogenetic protein 10, a rising star in the field of diabetes and cardiovascular disease.

Early research suggested that bone morphogenetic protein 10 (BMP10) is primarily involved in cardiac development and congenital heart disease processes. BMP10 is a newly identified cardiac-specific protein. In recent years, reports have emphasized the effects of BMP10 on myocardial apoptosis, fibrosis and immune response, as well as its synergistic effects with BMP9 in vascular endothelium and role in endothelial dysfunction. We believe that concentrating on this aspect of the study will enhance our knowledge of the pathogenesis of diabetes and the cardiovascular field. However, there have been no reports of any reviews discussing the role of BMP10 in diabetes and cardiovascular disease. In addition, the exact pathogenesis of diabetic cardiomyopathy is not fully understood, including myocardial energy metabolism disorders, microvascular changes, abnormal apoptosis of cardiomyocytes, collagen structural changes and myocardial fibrosis, all of which cause cardiac function impairment directly or indirectly and interact with one another. This review summarizes the research results of BMP10 in cardiac development, endothelial function and cardiovascular disease in an effort to generate new ideas for future research into diabetic cardiomyopathy.

Effects of once-weekly glucagon-like peptide-1 receptor agonists on type 2 diabetes mellitus complicated with coronary artery disease: Potential role of the renin-angiotensin system.

AIM: To investigate the potential mechanism of once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RA) in the treatment of type 2 diabetes mellitus (T2DM) complicated with coronary artery disease (CAD). METHODS: We searched both Chinese and English databases for randomized controlled trials related to once-weekly GLP-1 RA for T2DM complicated with CAD to verify the safety and efficacy of GLP-1 RA. The underlying mechanism was analysed by network pharmacology. RESULTS: In total, 13 studies with 35 563 participants were included in the analysis. The pooled analysis found that dulaglutide, exenatide and semaglutide outperformed placebo in cardiovascular outcomes in patients with T2DM, with a significant reduction in the incidence of non-fatal stroke (p < .00). Levels of cardiovascular risk factors were significantly reduced in the once-weekly GLP-1 RA group compared with the conventional treatment group (glycated haemoglobin: p < .00; fasting blood glucose: p < .00; weight: p < .00; systolic blood pressure: p < .00; total cholesterol: p < .00; low-density lipoprotein cholesterol: p < .00). Network pharmacology results were enriched to the renin-angiotensin system, and matrix metalloproteinase 2 and renin (REN) may be the key targets. In addition, four key targets of dulaglutide, five key targets of exenatide and two key targets of semaglutide were enriched. CONCLUSIONS: Our study suggests that once-weekly GLP-1 RA may have a potential protective effect on cardiovascular events in patients with T2DM combined with CAD, possibly through the renin-angiotensin system. However, further research is needed to confirm these findings and determine cause and effect.

Sub-chronic ecotoxicity of triphenyl phosphate to earthworms (Eisenia fetida) in artificial soil: Oxidative stress and DNA damage.

As a flame retardant, triphenyl phosphate (TPHP) is commonly added to various daily products. Due to its easy diffusion, TPHP pollution has become a global concern. Despite the wide focus on environmental risk, the sub-chronic ecotoxicity of TPHP in soil organisms remains unclear. In this study, the artificial soil exposure method was used to analyze the oxidative stress and DNA damage in earthworms with 0, 20, 40, 60 and 80 mg/kg TPHP treatments through the response of reactive oxygen species (ROS), antioxidant and detoxifying enzymes, malondialdehyde (MDA) and olive tail moment (OTM) at 7, 14, 21 and 28 days. Throughout the experimental period, the results showed that the ROS content in earthworms treated with 20, 40, 60 and 80 mg/kg TPHP treatments increased by 9.43-18.37 %, 6.07-25.73 %, 7.71-42.61 % and 8.22-46.70 %, respectively, compared to the control treatment. Meanwhile, the activities of antioxidant and detoxification enzymes in earthworms with all TPHP treatments were significantly activated after exposure for 7 and 14 days, and then inhibited at 21 and 28 days. Despite the protection of antioxidant enzymes and detoxification enzymes, MDA content in earthworms with the 20 mg/kg treatment still significantly increased at 7 and 14 days of exposure, as well as in the other three treatments. Compared to the control treatment, the obviously higher OTM values in earthworms with TPHP treatments possibly indicated a genotoxicity of TPHP in earthworms. Furthermore, the integrated biomarker response index (IBRv2) revealed that earthworms showed an obvious biochemical response TPHP-contaminated soil, which was strongly correlated with TPHP concentrations and exposure time. This study provides insights into the TPHP hazard in the soil environment and offers a reference to assess its environmental risk to soil ecosystems.

An additive hazards frailty model with semi-varying coefficients.

Proportional hazards frailty models have been extensively investigated and used to analyze clustered and recurrent failure times data. However, the proportional hazards assumption in the models may not always hold in practice. In this paper, we propose an additive hazards frailty model with semi-varying coefficients, which allows some covariate effects to be time-invariant while other covariate effects to be time-varying. The time-varying and time-invariant regression coefficients are estimated by a set of estimating equations, whereas the frailty parameter is estimated by the moment method. The large sample properties of the proposed estimators are established. The finite sample performance of the estimators is examined by simulation studies. The proposed model and estimation are illustrated with an analysis of data from a rehospitalization study of colorectal cancer patients.

Effect of dapagliflozin on diabetic patients with cardiovascular disease via MAPK signalling pathway.

Clinical studies have shown that dapagliflozin can reduce cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM), but the exact mechanism is unclear. In this study, we used the molecular docking and network pharmacology methods to explore the potential mechanism of dapagliflozin on T2DM complicated with cardiovascular diseases (CVD). Dapagliflozin's potential targets were predicted via the Swiss Target Prediction platform. The pathogenic targets of T2DM and CVD were screened by the Online Mendelian Inheritance in Man (OMIM) and Gene Cards databases. The common targets of dapagliflozin, T2DM and CVD were used to establish a protein-protein interaction (PPI) network; the potential protein functional modules in the PPI network were found out by MCODE. Metascape tool was used for Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analysis. A potential protein functional module with the best score was obtained from the PPI network and 9 targets in the protein functional module all showed good binding properties when docking with dapagliflozin. The results of KEGG pathway enrichment analysis showed that the underlying mechanism mainly involved AGE-RAGE signalling pathway in diabetic complications, TNF signalling pathway and MAPK signalling pathway. Significantly, the MAPK signalling pathway was considered as the key pathway. In conclusion, we speculated that dapagliflozin played a therapeutic role in T2DM complicated with CVD mainly through MAPK signalling pathway. This study preliminarily reveals the possible mechanism of dapagliflozin in the treatment of T2DM complicated with CVD and provides a theoretical basis for future clinical research.

The Remission Rate of Type 2 Diabetes Outpatients with Premixed Insulin: The Result of a 5-Year Prospective Study.

The aim of the study was to evaluate the remission rate with short-term premixed insulin therapy in newly diagnosed type 2 diabetes outpatients and investigate predictors contributing to the remission rate. A 5-year prospective study was conducted with a total of 170 patients enrolled. Patients were treated with premixed insulin monotherapy or insulin in combination with one or two oral drugs. After glucose levels were well controlled, insulin and oral drugs were discontinued in a stepwise manner. The prolonged and partial remission rates were calculated and the possible factors contributing to remission were also analyzed. A total of 164 subjects completed the research study. The prolonged remission, partial remission and non-remission rates at the 5-year follow-up were 9.8, 59.8, and 30.5%, respectively. The remission rate was negatively correlated with disease duration (r=0.39). The combined rate of remission (prolonged and partial remission) significantly decreased when the duration was longer than 16 days, and reduced to approximately 50% after 1 month. Moreover, 75% of prolonged remission patients had duration of < 16 days. At the 5-year follow-up, the prolonged remission rate was 9.8% and the partial remission rate was 59.8%. Furthermore, the duration after diagnosis is an independent predictor of remission rate, and initiation of short-term premixed insulin therapy within the first 16 days of diabetes diagnosis is very important for remission. This is the first study to evaluate the remission rate associated with short-term premixed insulin therapy in recently diagnosed type 2 diabetes outpatients. At the 5-year follow-up, the prolonged remission rate was 9.8% and the partial remission rate was 59.8%. The duration of diabetes was identified as an independent predictor of drug-free remission. The initiation of short-term premixed insulin therapy within 15 days of diabetes onset is particular importance for remission.

Effects of endothelial progenitor cells transplantation on hyperlipidemia associated kidney damage in ApoE knockout mouse model.

BACKGROUND: Hyperlipidaemia causes kidney damage over the long term. We investigated the effect of the administration of endothelial progenitor cells (EPCs) on the progression of kidney damage in a mouse model of hyperlipidaemia. METHODS: Apolipoprotein E-knockout (ApoE-/-) mice were treated with a high-cholesterol diet after spleen resection. Twenty-four weeks later, the mice were divided into two groups and intravenously injected with PBS or EPCs. Six weeks later, the recruitment of EPCs to the kidney was monitored by immunofluorescence. The lipid, endothelial cell, and collagen contents in the kidney were evaluated by specific immunostaining. The protein expression levels of transforming growth factor-ß (TGF-ß), Smad2/3, and phospho-Smad3 (p-smad3) were detected by western blot analysis. RESULTS: ApoE-/- mice treated with a high-fat diet demonstrated glomerular lipid deposition, enlargement of the glomerular mesangial matrix, endothelial cell enlargement accompanied by vacuolar degeneration and an area of interstitial collagen in the kidney. Six weeks after EPC treatment, only a few EPCs were detected in the kidney tissues of ApoE-/- mice, mainly in the kidney interstitial area. No significant differences in TGF-ß, p-smad3 or smad2/3 expression were found between the PBS group and the EPC treatment group (TGF-ß expression, PBS group: 1.06 ± 0.09, EPC treatment group: 1.09 ± 0.17, P = 0.787; p-smad3/smad2/3 expression: PBS group: 1.11 ± 0.41, EPC treatment group: 1.05 ± 0.33, P = 0.861). CONCLUSIONS: Our findings demonstrate that hyperlipidaemia causes basement membrane thickening, glomerulosclerosis and the vascular degeneration of endothelial cells. The long-term administration of EPCs substantially has limited effect in the progression of kidney damage in a mouse model of hyperlipidaemia.

ATP-binding cassette sub-family a member1 gene mutation improves lipid metabolic abnormalities in diabetes mellitus.

BACKGROUND: Patients with diabetes mellitus were often accompanied with hyperlipidemia. ATP-binding cassette sub-family A member1 (ABCA1) promotes the efflux of lipids and thereby mediates the metabolism of cholesterol. The aim of our study was to determine the associations of ABCA1 gene polymorphisms with the risks of diabetes mellitus and dyslipidemia in diabetic patients. METHODS: We retrieved literature about the relationship between ABCA1 gene polymorphisms (C69T and R230C) and the risk of diabetes through PubMed, Web of Science, EMBASE, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Cochrane database. Weighted mean difference (WMD) and odds ratio (OR) were used to compare continuous and dichotomous variables, respectively, accompanied by their 95% confidence interval (CI). RESULTS: A total of 1746 diabetic patients and 1292 non-diabetic controls were enrolled. All subjects were Caucasians. ABCA1 R230C T allele was significantly associated with reduced the risk of diabetes (OR = 0.75, 95% CI = 0.57-0.98, P = 0.04). There was no association of ABCA1 C69T gene polymorphisms with the risk of diabetes. However, subgroup analyses showed that the ABCA1 C69T gene mutation significantly reduced the risk of hypertriglyceridemia in diabetic patients as compared with that in non-diabetic subjects (dominant model: WMD =0.66, 95% CI = 0.52-0.8, P < 0.0001; recessive model: WMD = 0.47, 95%CI = 0.11-0.83, P = 0.01). CONCLUSIONS: ABCA1 R230C T allele gene mutation is a protective in decreasing the risk of diabetes in Caucasians and ABCA1 C69T gene mutation markedly influences the level of lipid metabolism in diabetic patients.

Construction and biocompatibility of a thin type I/II collagen composite scaffold.

Articular cartilage injury is a common type of damage observed in clinical practice. A matrix-induced autologous chondrocyte implant was developed to repair articular cartilage as an advancement on the autologous chondrocyte implant procedure. Here, we establish a thin double layer of collagen as a novel and effective bioscaffold for the regeneration of cartilaginous lesions. We created a collagen membrane with double layers using a cover slip, a cover slip, and the collagen was then freeze-dried under vacuum. Carbodiimide as a crosslinking agent was used to obtain a relatively stable collagen construction. The thickness of the knee joint cartilage from grown rabbits was measured from a frozen section. Both type I and type II collagens were characterized using Sodium dodecylsulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and ultraviolet absorption peaks. The aperture size of the scaffold was observed using a scanning electron microscope (SEM). The degradation of the scaffolds in vitro was tested through digestion using collagenase solution. The mechanical capacity of the scaffolds was assessed under dynamic compression. The influence of the scaffold on chondrocyte proliferation was assessed using the methyl thiazolyl tetrazolium (MTT) colourimetric assay and scanning electron microscopy. The frozen sections of the rabbit femoral condyle showed that the thickness of the weight-bearing area of the articular cartilage was less than 1 mm. The results of the SDS-PAGE and ultraviolet absorption peaks of the collagens were in agreement with the standard photographs in the references. SEM showed that the aperture size of the cross-linked scaffold was 82.14 ± 15.70 µm. The in vitro degradation studies indicated that Carbodiimide cross-linking can effectively enhance the biostability of the scaffolds. The Carbodiimide cross-linking protocol resulted in a mean value for the samples that ranged from 8.72 to 15.95 MPa for the compressive strength. The results of the MTT demonstrated that the scaffold had promoted chondrocyte proliferation and SEM observations showed that the scaffold was a good adhesive and growth material for chondrocytes. Thin type I/II collagen composite scaffold can meet the demands of cartilage tissue engineering and have good biocompatibility.

Efficacy of statins in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials.

BACKGROUND: The effects of statins in patients with diabetic nephropathy are controversial. With increasing interest in the potential therapeutic role of statins in diabetic nephropathy, it is essential to evaluate its real effects. METHODS: PubMed, EMBASE, Web of Science databases, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure were systematically searched for randomized controlled trials (RCTs) of statins in patients with diabetic nephropathy. RESULTS: Fourteen trials with 2866 participants were included in our meta-analysis. Compared with placebo, albuminuria and urinary albumin excretion rates in the statin group were reduced by 0.46 [95 % confidence interval (CI),-0.68 to -0.25, P < 0.0001] and 1.68 (95 % CI, -3.23 to -0.12, P = 0.03), respectively. The reduction of albuminuria was greater in patients of type 2 diabetes mellitus with diabetic nephropathy [standardized mean difference (SMD), -0.56; 95 % CI, -0.80 to -0.32, P < 0.00001] and the decrease was significant during the 1 to 3 years period of statin therapy (SMD, -0.57; 95 % CI, -0.95 to -0.19, P = 0.003). Subgroup analysis demonstrated the effects of statins were much stronger in subjects with pathologic albuminuria: change of -0.71 (95 % CI, -1.09 to -0.33, P = 0.0003) for those with urinary protein excretion 30 to 300 mg/day, -0.37 (95 % CI, -0.67 to -0.06, P = 0.02) for those with excretion more than 300 mg/day and -0.29 (95 % CI, -0.78 to 0.21, P = 0.26) for those with excretion less than 30 mg/day. In contrast, statins did not significantly reduce estimated glomerular filtration rate, serum creatinine and blood urea nitrogen levels. CONCLUSIONS: Statins decrease the albuminuria and urinary albumin excretion rates significantly. The efficacy of statins on renal function is time dependent and better in type 2 diabetic patients with nephropathy.

Microbispora bryophytorum sp. nov., an actinomycete isolated from moss (Bryophyta).

A novel endophytic actinomycete, designated strain NEAU-TX2-2(T), was isolated from moss and characterized using a polyphasic approach. The isolate was found to have morphological characteristics typical of the genus Microbispora . The isolate formed longitudinally paired spores on the tips of short sporophores that branched from aerial hyphae. Analysis of the 16S rRNA gene sequence supported the assignment of the novel strain to the genus Microbispora , and strain NEAU-TX2-2(T) exhibited 99.08 and 98.62% gene sequence similarities to Microbispora amethystogenes JCM 3021(T) and Microbispora rosea subsp. rosea JCM 3006(T), respectively. However two tree-making algorithms supported the position that strain NEAU-TX2-2(T) formed a distinct clade with M. rosea subsp. rosea JCM 3006(T). A low level of DNA-DNA relatedness allowed the isolate to be differentiated from M. amethystogenes JCM 3021(T) and M. rosea subsp. rosea JCM 3006(T). Moreover, strain NEAU-TX2-2(T) could also be distinguished from its closest phylogenetic relatives by morphological and physiological characteristics. Therefore, it is proposed that strain NEAU-TX2-2(T) represents a novel species of the genus Microbispora for which the name Microbispora bryophytorum sp. nov. is proposed. The type strain is NEAU-TX2-2(T) ( = CGMCC 4.7138(T) = DSM 46710(T)).

Ubiquitination and regulation of Smad7 in the TGF-ß1/Smad signaling of aristolochic acid nephropathy.

Aristolochic acid I (AAI) affects TGF-ß1/Smad signaling, which causes AA nephropathy (AAN), but the mechanisms are not fully understood. We aimed to clarify whether Arkadia and UCH37 participate in TGF-ß1/Smad signaling via Smad7, and the regulatory mechanisms of Smad7. One side, mice and cultured mouse renal tubular epithelial cells (RTECs) were treated with various AAI doses and concentrations, respectively; on the other side, RTECs were transfected with small interfering RNA (siRNA) expression vectors against Arkadia and UCH37 and then treated with 10 µg/ml AAI. And then detect the mRNA and protein levels of Smad7, UCH37, Arkadia and any other relative factors by RT-PCR and Western blotting. In kidney tissues and RTECs, the mRNA and protein levels of Smad7 decreased with increasing AAI doses concentrations by real-time PCR and Western blotting, whereas those of Arkadia, UCH37, Smad2, Smad3 and TßRI increased. Cells transfected with the Arkadia siRNA expression vector showed reduced mRNA and protein levels of vimentin, α-SMA, Smad2, Smad3 and TßRI after AAI treatment, while those of CK18 and Smad7 increased compared with those of untransfected RTECs. Conversely, cells transfected with the UCH37 siRNA expression vector showed the opposite effect on analyzed signaling molecules after AAI treatment. Arkadia and UCH37 participate in TGF-ß1/Smad signaling-mediated renal fibrosis, and Smad7 blocks TGF-ß1 signaling by inhibiting Smad2/Smad3 phosphorylation and enhancing the degradation of TßRI.

[Effects of Acupuncture on Neurofunction and Neuropsychological Factors of Chronic Alcoholic Peripheral Neuropathy Patients].

OBJECTIVE: To observe the effects of acupuncture on neurofunction and neuropsychological factors of chronic alcoholic peripheral neuropathy (CAPN) patients. METHODS: Totally 120 CAPN patients were assigned to the common treatment group, acupuncture group A, and acupuncture group B according to random digit table, 40 in each group. All patients recieved conventional drug therapy. Besides, patients in the acupuncture group A were additionally needled at Pishu (BL20), Weishu (BL21), Xuehai (SP10), Yinlingquan (SP9), Zusanli (ST36), Yanglingquan (GB34), Jiexi (ST41), Xuanzhong (GB39), Xiangu (ST43),Taixi (KI3), Quchi (LI11), Waiguan (SJ5), Hegu (LI4), and so on. On these bases patients in the acupuncture group B were needled at Sishencong (EX-HN1), Yintang (EX-HN3), Neiguan (PC6), Taichong (LR3), Sanyinjiao (SP6), and Taiyang (EX-HN5). Acupuncture was performed once a day, 14 times as a course; and then once on every other day, 14 times in total for 4 weeks. All treatment lasted for 8 successive weeks. Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Neurological Severity Score (NSS), Hamilton Depression Scale (HAMD), and Hamilton Anxiety Scale (HAMA) were assessed, motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) were detected before and after treatment. RESULTS: After 8 weeks of treatment the scores of NIS-LL and NSS significantly decreased in the 3 groups, with statistical difference as compared with before treatment (P < 0.05). Scores of NIS-LL and NSS decreased more in acupuncture groups A and B than in the common treatment group (P < 0.05), and more obvious in acupuncture group B (P < 0.05). Compared with the same group before treatment, MCV and SCV of median nerve, ulnar nerve, common peroneal nerve and tibial nerve increased in acupuncture treatment group A and B after 8-week treatment (P < 0.05). MCV of median nerve, MCV and SCV of common peroneal nerve and tibial nerve significantly increased in the common treatment group (P < 0.05). Compared with the common treatment group, SCV of median nerve, MCV and SCV of ulnar nerve, common peroneal nerve and tibial nerve obviously increased in acupuncture treatment groups A and B after treatment (P < 0.05). MCV of ulnar nerve, MCV and SCV of common peroneal nerve and tibial nerve obviously increased more in acupuncture treatment group A than in acupuncture treatment group B (P < 0.05). At week 8 after treatment scores of HAMD and HAMA were obviously lowered in acupuncture groups A and B, with statistical difference as compared with before treatment (P < 0.05). The scores of HAMD were also decreased in the common treatment group, as compared with before treatment (P < 0.05). At week 8 after treatment scores of HAMD and HAMA were obviously lowered more in acupuncture treatment group B than in acupuncture treatment group A (P < 0.05). CONCLUSION: Acupuncture therapy could effectively improve the neurofunction of CAPN patients, and improve complicated anxiety and depression by additionally needling at Sishencong (EX-HN1), Yintang (EX-HN3), Taichong (LR3), Sanyinjiao (SP6), and Taiyang (EX-HN5).

Expression of histone deacetylase-1 and p300 in aristolochic acid nephropathy models.

Aristolochic acid nephropathy (AAN) is mainly caused by aristolochic acid I (AAI), but the actual mechanism is still uncertain. The current study explored the correlation among the expression of Smad7, p300, histone deacetylase-1 (HDAC1) and the development of AAN using transmission electron microscopy (TEM), RT-PCR, and western blotting in the AAN mouse model and in the AAN cell model. TEM revealed that the renal tubular epithelial cells from the AAI-treated mice presented organelle damages and nuclear deformation. We found that a certain dose of AAI caused renal fibrosis and induced renal tubular epithelial cells to differentiate into myofibroblasts. There was a gradual increase in the expression of HDAC1 mRNA and protein observed using RT-PCR and western blotting in the AAN cell model compared with the control group. Gradual decrease in the expression of Smad7 and p300 mRNA and protein was revealed in the AAN mouse and cell models compared with the control group. These results suggest that AAI dose dependently contributed to the development of AAN, and HDAC1 and p300 participate in the modulation of TGF-ß/Smad pathway-mediated renal interstitial fibrosis.

Clinical study on the efficacy of postural control combined with electroacupuncture in treating dysphagia after stroke.

Objective: To evaluate the clinical effectiveness of combining postural control with electroacupuncture in the treatment of dysphagia following stroke, with the goal of establishing a solid clinical foundation for this therapeutic approach and investigating potential mechanisms to stimulate additional research and progress in post-stroke dysphagia management. Methods: 138 patients who met the diagnostic and inclusion criteria were enrolled and divided into control group and observation group. Both groups received conventional rehabilitation training. Additionally, the control group received swallowing training and diet optimize, while the observation group received swallowing training, diet optimize, posture control as well as electroacupuncture therapy. After four weeks, swallowing function was assessed and compared between the two groups using the Standardized Swallowing Assessment (SSA) score and water swallowing test (WST). Results: Patients who underwent postural control therapy in combination with electroacupuncture demonstrated significantly higher treatment efficacy compared to the control group. Notably, The SSA score and WST score in both groups decreased significantly, and the observation group showed more improvements in aspiration compared to the control group. Conclusion: The integration of posture control, electroacupuncture, and conventional rehabilitation training can effectively lower the degree of post-stroke swallowing disorders, restore swallowing function, and significantly reduce the occurrence of complications such as aspiration, fever, and nutritional disorders. Moreover, this approach significantly improves the quality of life of patients and is more effective than conventional rehabilitation training in treating post-stroke swallowing disorders. Clinical trial registration: https://www.chictr.org.cn/, Identifier ChiCTR2300075870.

Canagliflozin combined with aerobic exercise protects against chronic heart failure in rats.

To determine the efficacy and potential protective mechanism of canagliflozin combined with aerobic exercise in treating chronic heart failure (CHF). Isoproterenol was injected into rats to create CHF models. The rats were then subsequently divided into saline, canagliflozin (3 mg/kg/d), aerobic exercise training, and canagliflozin combined with aerobic exercise training. Compared to the CHF group, the canagliflozin combined with the aerobic exercise group had superior ventricular remodeling and cardiac function. In rats treated with canagliflozin combined with aerobic exercise, the expression of cytochrome P450 (CYP) 4A3, CYP4A8, COL1A1, COL3A1, and FN1 was reduced, while the expression of CYP26B1, ALDH1A2, and CYP1A1 increased significantly. Additionally, canagliflozin combined with aerobic exercise decreased the phosphorylation of AKT and ERK1/2. Canagliflozin combined with aerobic exercise has a positive effect on the development of CHF via the regulation of retinol metabolism and the AKT/ERK signaling pathway.

Efficacy of polyethylene glycol loxenatide for type 2 diabetes mellitus patients: a systematic review and meta-analysis.

Objective: Some studies have proved that polyethylene glycol loxenatide (PEG-Loxe) has significant effects on controlling blood glucose and body weight in patients with type 2 diabetes mellitus (T2DM), but there is still some controversy over the improvement of blood lipid profiles (BLP) and blood pressure (BP), and more evidences are needed to verify such effects. Therefore, this study was conducted to provide a comprehensive evaluation of the efficacy of PEG-Loxe in improving blood glucose (BG), BLP, BP, body mass index (BMI), and body weight (BW) in patients with T2DM for clinical reference. Methods: Randomized controlled trials (RCT) in which PEG-Loxe was applied to treat T2DM were retrieved by searching PubMed, Cochrane Library, Embase, Medline, Scopus, Web of Science, China National Knowledge Infrastructure, China Scientific Journal, Wanfang Data, and SinoMed databases. Outcome measures included BG, BLP, BP, BMI, and BW. RevMan 5.3 software was used to perform data analysis. Results: Eighteen trials were identified involving 2,166 patients. In experimental group 1,260 patients received PEG-Loxe alone or with other hypoglycemic agents, while in control group 906 patients received placebo or other hypoglycemic agents. In the overall analysis, PEG-Loxe significantly reduced the levels of glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), 2-h postprandial blood glucose (2-h PBG), BMI, and BW compared with control group. However, it had no obvious effect on total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Conclusion: PEG-Loxe has better hypoglycemic effects compared with placebo in patients with T2DM, but could not significantly improved TG, LDL-C, HDL-C, SBP, and DBP. And the combination of conventional hypoglycemic drugs (CHD) and PEG-Loxe could more effectively improve the levels of HbA1c, FPG, 2-h PBG, TC, TG, BMI, and BW compared with CHD in T2DM patients. Systematic Review Registration: www.inplasy.com, identifier INPLASY202350106.

Elucidating the molecular basis of ATP-induced cell death in breast cancer: Construction of a robust prognostic model.

BACKGROUND: Breast cancer is a multifaceted and formidable disease with profound public health implications. Cell demise mechanisms play a pivotal role in breast cancer pathogenesis, with ATP-triggered cell death attracting mounting interest for its unique specificity and potential therapeutic pertinence. AIM: To investigate the impact of ATP-induced cell death (AICD) on breast cancer, enhancing our understanding of its mechanism. METHODS: The foundational genes orchestrating AICD mechanisms were extracted from the literature, underpinning the establishment of a prognostic model. Simultaneously, a microRNA (miRNA) prognostic model was constructed that mirrored the gene-based prognostic model. Distinctions between high- and low-risk cohorts within mRNA and miRNA characteristic models were scrutinized, with the aim of delineating common influence mechanisms, substantiated through enrichment analysis and immune infiltration assessment. RESULTS: The mRNA prognostic model in this study encompassed four specific mRNAs: P2X purinoceptor 4, pannexin 1, caspase 7, and cyclin 2. The miRNA prognostic model integrated four pivotal miRNAs: hsa-miR-615-3p, hsa-miR-519b-3p, hsa-miR-342-3p, and hsa-miR-324-3p. B cells, CD4+ T cells, CD8+ T cells, endothelial cells, and macrophages exhibited inverse correlations with risk scores across all breast cancer subtypes. Furthermore, Kyoto Encyclopedia of Genes and Genomes analysis revealed that genes differentially expressed in response to mRNA risk scores significantly enriched 25 signaling pathways, while miRNA risk scores significantly enriched 29 signaling pathways, with 16 pathways being jointly enriched. CONCLUSION: Of paramount significance, distinct mRNA and miRNA signature models were devised tailored to AICD, both potentially autonomous prognostic factors. This study's elucidation of the molecular underpinnings of AICD in breast cancer enhances the arsenal of potential therapeutic tools, offering an unparalleled window for innovative interventions. Essentially, this paper reveals the hitherto enigmatic link between AICD and breast cancer, potentially leading to revolutionary progress in personalized oncology.

Oxidative stress and DNA damage in earthworms induced by methyl tertiary-butyl ether in natural soils.

Adverse effects of methyl tertiary-butyl ether (MTBE) have been noticed at different trophic levels by international researchers. However, there was unclear evidence about its effects on oxidative stress and DNA damage in earthworms. In this study, earthworms were cultivated in various doses of MTBE (0.0 mg/kg, 10.0 mg/kg, 30.0 mg/kg, and 60.0 mg/kg) contaminated agricultural soil for 7 days, 14 days, 21 days, and 28 days, respectively. The result showed that the reactive oxygen species (ROS) content of earthworms significantly increased in MTBE treatment groups compared to the control group. In MTBE treatment groups, the activities of superoxide dismutase, catalase, peroxidase, and glutathione S-transferase were significantly activated at the exposure of 7 days, which increased by 36.3-78.9%, 51.8-97.3%, 36.5-61.9%, and 12.0-54.8%, respectively. Then, the activities of these defense enzymes showed various changes following the changes in exposure times and MTBE concentrations. Especially in the 60.0 mg kg-1 group, both antioxidant enzymes and GST were still significantly activated at the exposure of 14 days and then significantly inhibited at the exposure of 28 days. The analysis of olive tail moment showed significant DNA damage in the 10.0 mg kg-1 group at the exposure of 28 days, and this damage in 30.0 mg/kg and 60.0 mg/kg groups was found at the exposure of 7 days. This result was consistent with the malondialdehyde accumulation in earthworms. Additionally, the analysis of IBRv2 showed the effects of MTBE treatments on earthworms in dose- and time-dependent manners. This study helps better to understand the effects of MTBE on soil invertebrate animals and provide theoretical support for soil protection in governing MTBE application.

The Efficacy of Microfracture Combined with Extracorporeal Shock Wave Therapy for Treating Osteochondral Lesion of the Talus and the Quality of Regenerated Cartilage: A Retrospective Cohort Study and MRI Assessment.

BACKGROUND: osteochondral lesion of the talus (OLT) is a common disease in the physically active population, and extracorporeal shock wave therapy (ESWT) is a noninvasive treatment. We hypothesized that microfracture (MF) combined with ESWT may have great potential to become a novel combination treatment of OLT. METHODS: the OLT patients who received MF + ESWT or MF + platelet-rich plasma (PRP) injection were retrospectively included, with a minimal follow up of 2y. The daily activating VAS, exercising VAS, and American Orthopedic Foot and Ankle Society Ankle-Hindfoot Score (AOFAS) were used to assess the efficacy and functional outcome, and ankle MRI T2 mapping was used to evaluate the quality of regenerated cartilage in the OLT patients. RESULTS: only transient synovium-stimulated complications were found during the treatment sessions; the complication rate and daily activating VAS did not have differences between groups. MF + ESWT had a higher AOFAS and a lower T2 mapping value than MF + PRP at the 2y follow up. CONCLUSIONS: the MF + ESWT had superior efficacy for treating OLT, which resulted in better ankle function and more hyaline-like regenerated cartilage, superior to the traditional MF + PRP.