Proteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction. Osteocrin (OSTN) acts as a novel exercise-responsive myokine and is implicated in various cardiac diseases. Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy (DCM). Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin (STZ, 50 mg/kg) for consecutive 5 days to generate diabetic models. Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro. OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment. Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro. Mechanistically, OSTN treatment restored protein kinase G (PKG)-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro. Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil. OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCM.
We retrospectively collected the clinical data and follow-up information of patients with osteosarcoma who were admitted to Department of Orthopedics, RenMin Hospital of Wuhan University from January 2010 to December 2016 and explore the relationship between red cell distribution width (RDW) and prognosis of patients with osteosarcoma. The present study finally included 271 patients with osteosarcoma with median follow-up time of 24.2 months (3–69 months). According to the RDW median, 135 patients belong to the low RDW group and 136 patients belong to high RDW group. Compared with low RDW group, the high RDW group tend to have metastasis (50 vs 32.6%, P=0.004), higher poor response rate to chemotherapy compared with the low RDW group (24.3 vs 7.4%, P=0.000) and higher C-reactive protein (CRP) (7.6 ± 4.9 vs 5.5 ± 4.5, t = 3.727, P=0.000). There was slightly significant difference in the types of pathology (χ2 = 8.059, P=0.045). The Kaplan–Meier analysis indicated survival curve of high RDW group was poorer than that in the low RDW group (P=0.020). The univariate cox analysis indicated that patients with RDW ≥ median had higher risk of poor prognosis compared with those who had RDW level < median (HR = 2.41, 95% confidence interval (CI): 1.51–3.83, P=0.000). After adjusting some potential cofounding factors, the elevated RDW was still associated with poor prognosis (HR = 1.66, 95% CI: 1.07–2.56, P=0.024). The elevated pretreatment RDW was associated with poor overall survival (OS) in patients with osteosarcoma and can be an independent predictor of prognosis.
The hexosamine biosynthetic pathway (HBP) produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to facilitate O-linked GlcNAc (O-GlcNAc) protein modifications, and subsequently enhance cell survival under lethal stresses. Transcript induced in spermiogenesis 40 (Tisp40) is an endoplasmic reticulum membrane-resident transcription factor and plays critical roles in cell homeostasis. Here, we show that Tisp40 expression, cleavage and nuclear accumulation are increased by cardiac ischemia/reperfusion (I/R) injury. Global Tisp40 deficiency exacerbates, whereas cardiomyocyte-restricted Tisp40 overexpression ameliorates I/R-induced oxidative stress, apoptosis and acute cardiac injury, and modulates cardiac remodeling and dysfunction following long-term observations in male mice. In addition, overexpression of nuclear Tisp40 is sufficient to attenuate cardiac I/R injury in vivo and in vitro. Mechanistic studies indicate that Tisp40 directly binds to a conserved unfolded protein response element (UPRE) of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) promoter, and subsequently potentiates HBP flux and O-GlcNAc protein modifications. Moreover, we find that I/R-induced upregulation, cleavage and nuclear accumulation of Tisp40 in the heart are mediated by endoplasmic reticulum stress. Our findings identify Tisp40 as a cardiomyocyte-enriched UPR-associated transcription factor, and targeting Tisp40 may develop effective approaches to mitigate cardiac I/R injury.
Objective To analyse the incidence and baseline predictors of the left ventricular ejection fraction (LVEF) returning to normal after dilated cardiomyopathy (DCM) following intervention with standard anti-heart failure (HF) medication in postmenopausal women. Methods Data from consecutive postmenopausal women who were first diagnosed with DCM and received anti-HF treatment during 2011 to 2018 were prospectively retrieved. The study population was divided into the LVEF recovery (LVR) group and the LVEF unrecovered (LVU) group according to whether LVEF was > 50%. The primary endpoint was baseline predictors of LVEF returning to normal. Results LVEF returned to normal in 49.3% (210/426) of patients with DCM. LVEF was significantly higher in the LVR group than in the LVU group (57.4% ± 6.9% vs 44.2% ± 5.3%; hazard ratio 1.312, 95% confidence interval 1.015–1.726) at the final follow-up. High systolic pressure, a short history of HF, a short QRS interval, a small left ventricular end-diastolic diameter (LVEDd), and high LVEF at admission were independent predictors of LVEF returning to normal. Conclusions LVEF returning to normal in postmenopausal women with DCM who receive standard anti-HF treatment is associated with systolic pressure, a history of HF, QRS interval, LVEDd, LVEF at admission, and favourable outcome.
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