Inhibitory effects of curcumin on activity of cytochrome P450 2C9 enzyme in human and 2C11 in rat liver microsomes

Cytochrome P450 2C9 (CYP2C9), one of the most important phase I drug metabolizing enzymes, could catalyze the reactions that convert diclofenanc into diclofenac 4′-hydroxylation. Evaluation of the inhibitory effects of compounds on CYP2C9 is clinically important because inhibition of CYP2C9 could result in serious drug–drug interactions. The objective of this work was to investigate the effects of curcumin on CYP2C9 in human and cytochrome P450 2C11 (CYP2C11) in rat liver microsomes. The results showed that curcumin inhibited CYP2C9 activity (10?µmol?L^–1 diclofenac) with half-maximal inhibition or a half-maximal inhibitory concentration (IC50) of 15.25?µmol?L^–1 and Ki?=?4.473?µmol?L^–1 in human liver microsomes. Curcumin’s mode of action on CYP2C9 activity was noncompetitive for the substrate diclofenanc and uncompetitive for the cofactor NADPH. In contrast to its potent inhibition of CYP2C9 in human, diclofenanc had lesser effects on CYP2C11 in rat, with an IC50 ≥100?µmol L^–1. The observations imply that curcumin has the inhibitory effects on CYP2C9 activity in human. These in vitro findings suggest that more attention should be paid to special clinical caution when intake of curcumin combined with other drugs in treatment.     

依达拉奉对大鼠缺血再灌注心肌的保护作用

目的 探讨依达拉奉对心肌缺血再灌注的保护作用及机制.方法 将50只成年SD大鼠按随机数字表法分为假手术组、再灌注组、低剂量组、中剂量组和高剂量组,每组10只.建立大鼠急性缺血再灌注模型,描记术中心电图变化.假手术组：开胸,分离左冠状动脉并穿线,不结扎,旷置225 min;再灌注组：缺血45 min,再灌注3 h,灌注前1 min将生理盐水按0.2 mL·kg-1经右股静脉注入;低剂量组：再灌注前1 min,将依达拉奉按3 mg·kg-1经右股静脉注入;中剂量组：灌注前1 min将依达拉奉按6 mg·kg-1经右股静脉注入;高剂量组：灌注前1 min将依达拉奉按9 mg·kg-1经右股静脉注入.于再灌注末测定血清肌钙蛋白、心肌组织Ca2＋、SOD、MDA及Na＋-K＋-ATPase 、Ca2＋-ATPase的含量或活性.结果 再灌注组与低剂量组、中剂量组、高剂量组相比,再灌注后ST段回落程度较低、室性心律失常发作例数稍高,但4组间比较差异均无统计学意义（均P＞0.05）.低剂量组、中剂量组和高剂量组的血清肌钙蛋白明显低于再灌注组（均P＜0.05）;中剂量组、高剂量组及再灌注组血清肌钙蛋白明显高于假手术组（P＜0.05或P＜0.01）.与假手术组比较,再灌注组心肌组织MDA活性、Ca2＋含量明显增高,SOD活力及Na＋-K＋-ATP酶、Ca2＋-ATP酶活性明显降低（均P＜0.05）;与再灌注组比较,低剂量组、中剂量组和高剂量组的MDA活力及Ca2＋含量降低,SOD活力及Na＋-K＋-ATP酶、Ca2＋-ATP酶活性明显增加（均P＜0.05）.结论 在再灌注前注射依达拉奉可减轻心肌缺血再灌注损伤.其作用机制是有效地清除氧自由基、提高机体抗氧化应激能力.     

Occupational rehabilitation in the construction industry of Victoria

A survey of construction companies' secondary disability management practices was undertaken in the state of Victoria, Australia. The results indicate that formal rehabilitation and return‐to‐work programmes and practices are not adopted in many companies. Smaller construction firms were less likely to have adopted formal programmes or practices than medium‐to‐large firms. In particular, construction companies reported difficulties in the provision of suitable alternate or light duties for workers returning to work following an injury. Most companies regarded disability management practices to have increased operating costs while yielding little or no benefit in terms of reducing lost workdays. Strategies to overcome some of these impediments to rehabilitation and return‐to‐work in construction are recommended.     

Analyses of systems theory for construction accident prevention with specific reference to OSHA accident reports

To enhance workplace safety in the construction industry it is important to understand interrelationships among safety risk factors associated with construction accidents. This study incorporates the systems theory into Heinrich's domino theory to explore the interrelationships of risks and break the chain of accident causation. Through both empirical and statistical analyses of 9358 accidents which occurred in the U.S. construction industry between 2002 and 2011, the study investigates relationships between accidents and injury elements (e.g., injury type, part of body, injury severity) and the nature of construction injuries by accident type. The study then discusses relationships between accidents and risks, including worker behavior, injury source, and environmental condition, and identifies key risk factors and risk combinations causing accidents. The research outcomes will assist safety managers to prioritize risks according to the likelihood of accident occurrence and injury characteristics, and pay more attention to balancing significant risk relationships to prevent accidents and achieve safer working environments.     

MicroRNA-378 Alleviates Cerebral Ischemic Injury by Negatively Regulating Apoptosis Executioner Caspase-3

miRNAs have been linked to many human diseases, including ischemic stroke, and are being pursued as clinical diagnostics and therapeutic targets. Among the aberrantly expressed miRNAs in our previous report using large-scale microarray screening, the downregulation of miR-378 in the peri-infarct region of middle cerebral artery occluded (MCAO) mice can be reversed by hypoxic preconditioning (HPC). In this study, the role of miR-378 in the ischemic injury was further explored. We found that miR-378 levels significantly decreased in N2A cells following oxygen-glucose deprivation (OGD) treatment. Overexpression of miR-378 significantly enhanced cell viability, decreased TUNEL-positive cells and the immunoreactivity of cleaved-caspase-3. Conversely, downregulation of miR-378 aggravated OGD-induced apoptosis and ischemic injury. By using bioinformatic algorithms, we discovered that miR-378 may directly bind to the predicted 3′-untranslated region (UTR) of Caspase-3 gene. The protein level of caspase-3 increased significantly upon OGD treatment, and can be downregulated by pri-miR-378 transfection. The luciferase reporter assay confirmed the binding of miR-378 to the 3′-UTR of Caspase-3 mRNA and repressed its translation. In addition, miR-378 agomir decreased cleaved-caspase-3 ratio, reduced infarct volume and neural cell death induced by MCAO. Furthermore, caspase-3 knockdown could reverse anti-miR-378 mediated neuronal injury. Taken together, our data demonstrated that miR-378 attenuated ischemic injury by negatively regulating the apoptosis executioner, caspase-3, providing a potential therapeutic target for ischemic stroke.     

Correlations of Hepatic Hemodynamics,Liver Function,and Fibrosis Markers in Nonalcoholic Fatty Liver Disease: Comparison with Chronic Hepatitis Related to Hepatitis C Virus

The progression of chronic liver disease differs by etiology. The aim of this study was to elucidate the difference in disease progression between chronic hepatitis C (CHC) and nonalcoholic fatty liver disease (NAFLD) by means of fibrosis markers, liver function, and hepatic tissue blood flow (TBF). Xenon computed tomography (Xe-CT) was performed in 139 patients with NAFLD and 152 patients with CHC (including liver cirrhosis (LC)). The cutoff values for fibrosis markers were compared between NAFLD and CHC, and correlations between hepatic TBF and liver function tests were examined at each fibrosis stage. The cutoff values for detection of the advanced fibrosis stage were lower in NAFLD than in CHC. Although portal venous TBF (PVTBF) correlated with liver function tests, PVTBF in initial LC caused by nonalcoholic steatohepatitis (NASH-LC) was significantly lower than that in hepatitis C virus (C-LC) (p = 0.014). Conversely, the liver function tests in NASH-LC were higher than those in C-LC (p < 0.05). It is important to recognize the difference between NAFLD and CHC. We concluded that changes in hepatic blood flow occurred during the earliest stage of hepatic fibrosis in patients with NAFLD; therefore, patients with NAFLD need to be followed carefully.     

Resveratrol Attenuates Acute Inflammatory Injury in Experimental Subarachnoid Hemorrhage in Rats via Inhibition of TLR4 Pathway

Toll-like receptor 4 (TLR4) has been proven to play a critical role in neuroinflammation and to represent an important therapeutic target following subarachnoid hemorrhage (SAH). Resveratrol (RSV), a natural occurring polyphenolic compound, has a powerful anti-inflammatory property. However, the underlying molecular mechanisms of RSV in protecting against early brain injury (EBI) after SAH remain obscure. The purpose of this study was to investigate the effects of RSV on the TLR4-related inflammatory signaling pathway and EBI in rats after SAH. A prechiasmatic cistern SAH model was used in our experiment. The expressions of TLR4, high-mobility group box 1 (HMGB1), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB) were evaluated by Western blot and immunohistochemistry. The expressions of Iba-1 and pro-inflammatory cytokines in brain cortex were determined by Western blot, immunofluorescence staining, or enzyme-linked immunosorbent assay. Neural apoptosis, brain edema, and neurological function were further evaluated to investigate the development of EBI. We found that post-SAH treatment with RSV could markedly inhibit the expressions of TLR4, HMGB1, MyD88, and NF-κB. Meanwhile, RSV significantly reduced microglia activation, as well as inflammatory cytokines leading to the amelioration of neural apoptosis, brain edema, and neurological behavior impairment at 24 h after SAH. However, RSV treatment failed to alleviate brain edema and neurological deficits at 72 h after SAH. These results indicated that RSV treatment could alleviate EBI after SAH, at least in part, via inhibition of TLR4-mediated inflammatory signaling pathway.     

Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI.