WITHDRAWN: Whole genome sequencing identifies novel NOTCH3 mutations for leukoaraiosis.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Cardio-Protective Role of Gingerol along with Prominent Anti-Diabetic Cardiomyopathy Action in A Streptozotocin-Induced Diabetes Mellitus Rat Model.

OBJECTIVES: Diabetic cardiomyopathy (DCM) is characterized as a coronary heart disease which expands during diabetes due to alterations in the myocardial function and structure. The currentstudy intends to elucidate the protective effect of gingerol on DCM in a streptozotocin (STZ)-induced diabetes mellitus (DM) rat model. MATERIALS AND METHODS: In this experimental study, the animals were divided into three groups: normal control, DM control, and DM+gingerol (10 mg/kg). The body weights of all rats were estimated at regular intervals. The myocardial profile, oxidative stress, and activities of metabolic enzymes were also scrutinized. The proinflammatory cytokine levels together with cellular protein expression connected with apoptosis were estimated via Western blot analysis. RESULTS: The rats that suffered from DCM exhibited abnormal levels of myocardial markers, aberrant metabolic enzymatic activity, elevated concentrations of inflammatory factors, and enhanced oxidative stress parameters along with increased cell death apoptosis. Whereas gingerol showed protective effects on the treated rats by an improved antioxidant defense system. CONCLUSIONS: The current findings suggested that gingerol is effective in the treatment of DCM by inhibition of inflammation and oxidative stress.

Rapid permissive action of dexamethasone on the regulation of blood pressure in a rat model of septic shock.

Glucocorticoids (GCs) play a vital role in the regulation of blood pressure by their permissive effects in potentiating vasoactive responses to catecholamines through glucocorticoid receptors. GCs achieve this function by controlling vascular smooth muscle tone. Clinically, low to moderate doses of GCs are generally used in the treatment of septic shock in recent years. GCs are now known to have both genomic and non-genomic effects. While genomic effects of GCs were well studied, few non-genomic effects were reported, much less the non-genomic mechanisms. One of the most important characters of their non-genomic effects is short latency. The aim of this study was to determine whether GCs can rapidly regulate blood pressure by their permissive action on norepinephrine (NE). Adrenalectomized rats were subjected to cecal ligation and puncture to induce septic shock. The septic rats displayed a significant decrease in the blood pressure response to NE. Dexamethasone (DEX) rapidly restores this hyporeactivity to NE in adrenalectomized septic rats. Further studies showed that DEX potentiates the NE-induced shrinkage and actin cytoskeleton rearrangement of single cell from mesenteric arteries in a short time. These findings suggest that GCs probably exert their permissive actions on the pressure response to NE through rapid non-genomic mechanisms. In this article, we found that as an adjunctive therapy for septic shock, the use of GCs may involve a rapid permissive action, and non-genomic effects of GCs may be involved in these processes.

Dexamethasone induces rapid promotion of norepinephrine­mediated vascular smooth muscle cell contraction.

The aim of the present study was to identify the rapid effect of dexamethasone (Dex) on norepinephrine (NE)­mediated contraction of vascular smooth muscle cells (VSMCs) and to establish the underlying mechanism(s). Rat VSMCs were preincubated with lipopolysaccharide to simulate acute septic shock. Myosin light chain (MLC20) phosphorylation of VSMCs was detected by western blot analysis to observe the effects of Dex on NE­mediated contraction. Activation of the RhoA/ RhoA kinase (ROCK), extracellular signal­regulated kinase (ERK) and p38 signaling pathways was detected by western blot analysis to explore the mechanism. It was identified that Dex rapidly promoted NE­induced phosphorylation of MLC20 in VSMCs and this effect may be non­genomic. The RhoA/ROCK, ERK and p38 pathways were demonstrated to be important for the rapid effect of Dex­induced promotion of NE­mediated contraction in VSMCs. The present results indicate that Dex may rapidly reverse the hyporeactivity of vasoconstriction to NE in vitro and this effect may be mediated by specific non­genomic mechanisms through increased activation of the RhoA/ROCK, ERK and p38 signaling pathways.

Corticosterone rapidly promotes respiratory burst of mouse peritoneal macrophages via non-genomic mechanism.

BACKGROUND: The immunomodulatory effects of glucocorticoids (GCs) have been described as bimodal. High concentration of GCs exerts immunosuppressive effects and low levels of GCs are immunopermissive. While the immunosuppressive mechanisms of GCs have been investigated intensely, the immunopermissive effects of GCs remain unclear. A lot of studies showed GCs could exert rapid non-genomic actions. We herein studied the rapid immunopromoting effects of GCs. METHODS: We observed the rapid (within 30 minutes) effects of corticosterone on respiratory burst of mouse peritoneal macrophages and studied their mechanisms. The superoxide anions were measured by cytochrome C reduction assay. Protein kinase C phosphorylation was measured by Western blotting and membrane fluidity was evaluated by fluorescence polarization measurement. RESULTS: The 10(-8) mol/L and 10(-7) mol/L corticosterone rapidly increased the superoxide anions production by macrophages, which were insensitive to GC-receptor antagonist, mifepristone, and protein-synthesis inhibitor, cycloheximide. Corticosterone coupled to bovine serum albumin was able to mimic the effects of corticosterone. The effects were independent of protein kinase C pathway and the change in membrane fluidity. CONCLUSIONS: The results indicate that corticosterone rapidly promote the superoxide anions production by mouse peritoneal macrophages may through non-genomic mechanisms. This study may contribute to understanding the effects of GCs under stress condition and the physiological significance of nongenomic effects of GCs.

An inhibitory effect of chrysoeriol on platelet-derived growth factor (PDGF)-induced proliferation and PDGF receptor signaling in human aortic smooth muscle cells.

Platelet-derived growth factor (PDGF)-BB is one of the most potent factors in the development and progression of various vascular disorders such as restenosis and atherosclerosis. Chrysoeriol is a flavonoid with antioxidant and anti-inflammatory activities. In this study, we investigated the effect of chrysoeriol on the proliferation of human aortic smooth muscle cells (HASMC). Chrysoeriol significantly inhibited PDGF (20 ng/mL)-induced migration and [(3)H]-thymidine incorporation into DNA at concentrations of 5 and 10 microM without any cytotoxicity. Chrysoeriol also blocked PDGF-stimulated dissociation of actin filament and inhibited PDGF beta-receptor (Rbeta) phosphorylation in a concentration-dependent manner. As a result, the downstream signal transduction pathways of PDGF-Rbeta, including ERK1/2, p38, and Akt phosphorylation, were also inhibited by chrysoeriol in the same pattern. These findings suggest that in addition to its antioxidant and anti-inflammatory activities, chrysoeriol may be used for the prevention and treatment of vascular diseases and during restenosis after coronary angioplasty.