Grape Seed Proanthocyanidin Extract Ameliorates Cardiac Remodelling After Myocardial Infarction Through PI3K/AKT Pathway in Mice.

Myocardial infarction is one of the most serious fatal diseases in the world, which is due to acute occlusion of coronary arteries. Grape seed proanthocyanidin extract (GSPE) is an active compound extracted from grape seeds that has anti-oxidative, anti-inflammatory and anti-tumor pharmacological effects. Natural products are cheap, easy to obtain, widely used and effective. It has been used to treat numerous diseases, such as cancer, brain injury and diabetes complications. However, there are limited studies on its role and associated mechanisms in myocardial infarction in mice. This study showed that GSPE treatment in mice significantly reduced cardiac dysfunction and improved the pathological changes due to MI injury. In vitro, GSPE inhibited the apoptosis of H9C2 cells after hypoxia culture, resulting in the expression of Bax decreased and the expression of Bcl-2 increased. The high expression of p-PI3K and p-AKT was detected in MI model in vivo and in vitro. The use of the specific PI3K/AKT pathway inhibitor LY294002 regressed the cardio-protection of GSPE. Our results showed that GSPE could improve the cardiac dysfunction and remodeling induced by MI and inhibit cardiomyocytes apoptosis in hypoxic conditions through the PI3K/AKT signaling pathway.

Endoplasmic reticulum stress serves an important role in cardiac ischemia/reperfusion injury (Review).

Although acute myocardial infarction is one of the most common fatal diseases worldwide, the understanding of its underlying pathogenesis continues to develop. Myocardial ischemia/reperfusion (I/R) can restore myocardial oxygen and nutrient supply. However, a large number of studies have demonstrated that recovery of blood perfusion after acute ischemia causes reperfusion injury to the heart. With progress made in the understanding of the underlying mechanisms of myocardial I/R and oxidative stress, a novel area of research that merits greater study has been identified, that of I/R-induced endoplasmic reticulum (ER) stress (ERS). Cardiac I/R can alter the function of the ER, leading to the accumulation of unfolded/misfolded proteins. The resulting ERS then induces the activation of signal transduction pathways, which in turn contribute to the development of I/R injury. The mechanism of I/R injury, and the causal relationship between I/R and ERS are reviewed in the present article.

Correction：Diagnostic Accuracy of Chest Computed Tomography Scans for Suspected Patients With COVID-19: Receiver Operating Characteristic Curve Analysis.

[This corrects the article DOI: 10.2196/19424.].

Diagnostic Accuracy of Chest Computed Tomography Scans for Suspected Patients With COVID-19: Receiver Operating Characteristic Curve Analysis.

BACKGROUND: Computed tomography (CT) scans are increasingly available in clinical care globally. They enable a rapid and detailed assessment of tissue and organ involvement in disease processes that are relevant to diagnosis and management, particularly in the context of the COVID-19 pandemic. OBJECTIVE: The aim of this paper is to identify differences in the CT scan findings of patients who were COVID-19 positive (confirmed via nucleic acid testing) to patients who were confirmed COVID-19 negative. METHODS: A retrospective cohort study was proposed to compare patient clinical characteristics and CT scan findings in suspected COVID-19 cases. A multivariable logistic model with LASSO (least absolute shrinkage and selection operator) selection for variables was used to identify the good predictors from all available predictors. The area under the curve (AUC) with 95% CI was calculated for each of the selected predictors and the combined selected key predictors based on receiver operating characteristic curve analysis. RESULTS: A total of 94 (56%) patients were confirmed positive for COVID-19 from the suspected 167 patients. We found that elderly people were more likely to be infected with COVID-19. Among the 94 confirmed positive patients, 2 (2%) patients were admitted to an intensive care unit. No patients died during the study period. We found that the presence, distribution, and location of CT lesions were associated with the presence of COVID-19. White blood cell count, cough, and a travel history to Wuhan were also the top predictors for COVID-19. The overall AUC of these selected predictors is 0.97 (95% CI 0.93-1.00). CONCLUSIONS: Taken together with nucleic acid testing, we found that CT scans can allow for the rapid diagnosis of COVID-19. This study suggests that chest CT scans should be more broadly adopted along with nucleic acid testing in the initial assessment of suspected COVID-19 cases, especially for patients with nonspecific symptoms.

Inhibition of TGFß-activated protein kinase 1 ameliorates myocardial ischaemia/reperfusion injury via endoplasmic reticulum stress suppression.

Transforming growth factor ß-activated protein kinase 1 (TAK1) involves in various biological responses and is a key regulator of cell death. However, the role of TAK1 on acute myocardial ischaemia/reperfusion (MI/R) injury is unknown. We observed that TAK1 activation increased significantly after MI/R and hypoxia/reoxygenation (H/R), and we hypothesized that TAK1 has an important role in MI/R injury. Mice (TAK1 inhibiting by 5Z-7-oxozeaenol or silencing by AAV9 vector) were exposed to MI/R injury. Primary cardiomyocytes (TAK1 silencing by siRNA; and overexpressing TAK1 by adenovirus vector) were used to induce H/R injury model in vitro. Inhibition of TAK1 significantly decreased MI/R-induced myocardial infarction area, reduced cell death and improved cardiac function. Mechanistically, TAK1 silencing suppressed MI/R-induced myocardial oxidative stress and attenuated endoplasmic reticulum (ER) stress both in vitro and in vivo. In addition, the inhibition of ROS by NAC partially reversed the damage of TAK1 in vitro. Our study presents the first direct evidence that inhibition of TAK1 mitigated MI/R injury, and TAK1 mediated ROS/ER stress/apoptosis signal pathway is important for the pathogenesis of MI/R injury.

A20 functions as mediator in TNFα-induced injury of human umbilical vein endothelial cells through TAK1-dependent MAPK/eNOS pathway.

A20, a negative regulator of nuclear factor κB signaling, has been shown to attenuate atherosclerotic events. Transforming growth factor beta-activated kinase 1 (TAK1) plays a critical role in TNFα-induced atherosclerosis via endothelial nitric oxide (NO) synthase (eNOS) uncoupling and NO reduction. In the study, we investigated the hypothesis that A20 protected endothelial cell injury induced by TNFα through modulating eNOS activity and TAK1 signalling. Human umbilical vein endothelial cells (HUVECs) were stimulated by TNFα. The impact of A20 on cell apoptosis, eNOS expression and NO production and related TAK1 pathway were detected. Both eNOS and NO production were remarkably reduced. TAK1, p38 MAPK phosphorylation and HUVECs apoptosis were enhanced after TNFα stimulation for 2 hrs. Inhibition of A20 significantly activated TAK1, p38 MAPK phosphorylation, and cell apoptosis, but blocked eNOS expression and NO production. Furthermore, p38 MAPK expression was suppressed by A20 over-expression, but re-enhanced by inhibiting A20 or activation of TAK1. Furtherly, TNFα-induced suppression of eNOS and NO production were largely prevented by silencing p38 MAPK. Collectively, our results suggested that A20-mediated TAK1 inactivation suppresses p38 MAPK and regulated MAPK/eNOS pathway, which contributes to endothelial cell survival and function preservation.

Heparin-based coacervate of bFGF facilitates peripheral nerve regeneration by inhibiting endoplasmic reticulum stress following sciatic nerve injury.

Creating a microenvironment at the injury site that favors axonal regrowth and remyelinationis pivotal to the success of therapeutic reinnervation. The mature myelin sheath of the peripheral nervous system depends on active participation of Schwann cells to form new cytoskeletal components and tremendous amounts of relevant neurotrophic factors. In this study, we utilized a new biomaterial for growth factor delivery consisting of a biocompatible polycation, poly(ethylene argininylaspartatediglyceride) and heparin. It is capable of binding a variety of growth factors to deliver basic fibroblast growth factor (bFGF) through polyvalent ionic interactions for nerve repair. In vitro assays demonstrated that the bFGF loading efficiency reached 10 µg and this delivery vehicle could control the release of bFGF. In vivo, the coacervate enhanced bFGF bioavailability, which improved both motor and sensory function. It could also acceleratemyelinated fiber regeneration and remyelination and promote Schwann cells proliferation. Furthermore, the neuroprotective effect of bFGF-coacervate in sciatic nerve injury was associated with the alleviation of endoplasmic reticulum stress signal. This heparin-based delivery platform leads to increased bFGF loading efficiency and better controls its release, which will provide an effective strategy for peripheral nerve injury regeneration therapy.

miR-600 inhibits cell proliferation, migration and invasion by targeting p53 in mutant p53-expressing human colorectal cancer cell lines.

Mutations of the tumor protein p53 gene, a tumor suppressor, are one of the most frequent genetic alterations observed in cancer. It has been reported that mutations in p53 result in the loss of wild-type p53 activity, and the gain of novel oncogenic properties that promote tumor growth and progression. Recent studies have demonstrated that a number of microRNAs (miRs) are involved in the post-transcriptional regulation of p53. The present study demonstrates that miR-600 is a direct negative regulator of p53 through binding a site in the 3' untranslated region of p53 mRNA in human colorectal cancer (CRC) cells. Overexpression of miR-600 by lentiviral-mediated transduction decreased endogenous levels of p53 protein and inhibited cell proliferation, migration and invasion in mutant p53-expressing human CRC cell lines (SW480, SW620 and DLD-1) in vitro. In addition, silencing of p53 with small interfering RNA led to a similar phenotype. Furthermore, overexpression of miR-600 or p53 knockdown suppressed the expression of matrix metalloproteinase 9, and promoted the expression of E-cadherin and ß-catenin. The results of the current study demonstrate that miR-600 is an important negative regulator of p53, and suggest that targeting mutant p53 using lentiviral-mediated miR-600 overexpression is a promising therapeutic strategy for the treatment of CRCs with p53 mutations.

Loss of TRADD attenuates pressure overload-induced cardiac hypertrophy through regulating TAK1/P38 MAPK signalling in mice.

We investigated the role of tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) on pressure overload-induced cardiac hypertrophy and the underlying molecular mechanisms by using a TRADD deficiency mice model. 6-8 weeks wild-type and TRADD knockout mice were performed to transverse aorta constriction (TAC) or sham operation (6-8 mice for each group). 14 days after TAC, cardiac function was measured by echocardiography, as well as by pathological and molecular analyses of heart samples. The expressions of cardiac hypertrophic and fibrotic markers were detected by qPCR. Phosphorylated and total TAK1, Akt, and p38 MAPK levels were examined by Western blotting. The ratios of lung or heart/body weight, wall thickness/chamber diameter of left ventricular and cross area of cardiomyocyte were significantly reduced in TRADD knockout (KO) mice than those of wild-type mice after TAC. Moreover, cardiac hypertrophic and fibrotic markers were downregulated in TRADD knockout mice than those of wild-type mice following TAC. Protein expression analysis showed phosphorylated TAK1, p38 MAPK and AKT were upregulated after TAC in both wild-type and TRADD KO mice, phosphorylation of TAK1 and p38 MAPK was reduced more remarkably after TRADD deficiency, while phosphorylated AKT expression was similar between TRADD KO and wild-type mice following TAC. Our data suggest that TRADD KO blunts pressure overload-induced cardiac hypertrophy through mediating TAK1/p38 MAPK but not AKT phosphorylation in mice.