Inflammatory and fibrotic mechanisms in NAFLD—Implications for new treatment strategies

Non-alcoholic fatty liver disease is comprised of either simple steatosis (non-alcoholic fatty liver) or a more advanced inflammatory and fibrogenic stage (non-alcoholic steatohepatitis [NASH]). NASH affects a growing proportion of the global adult and pediatric population, leading to rising rates of liver fibrosis and hepatocellular carcinoma. NASH is a multifactorial disease that is part of a systemic metabolic disorder. Here, we provide an overview of the metabolic underpinnings of NASH pathogenesis and established drivers of inflammation and fibrosis. Clarification of underlying fibrogenic and inflammatory mechanisms will advance the development of novel treatment strategies as there are no approved therapies at present. We discuss emerging experimental approaches and potential novel investigational strategies derived from animal models including the inflammasome, epigenetic reprogramming, Hippo signaling, Notch signaling, engineered T cells to remove fibrogenic HSCs, and HSC-specific targeting therapies. Recently completed and ongoing clinical trials and antifibrotics are discussed, illuminating the growing expectation that one or more therapies will yield clinical benefit in NASH in the coming years.     

ATC/DDD体系指标用于质子泵抑制剂使用管理效果评价

目的为质子泵抑制剂(PPI)的临床规范使用提供参考。方法采用ATC/DDD体系的分类法查询并计算各PPI的限定日剂量(DDD)值,回顾性分析医院2015年至2017年使用PPI的品种、消耗数量、科室分布、用药频度(DDDs)、使用强度(AUD)及使用率等相关指标。结果医院PPI的DDDs、AUD及使用率,各科室PPI的DDDs、AUD及使用率排名相对稳定;住院患者PPI的DDDs呈上升趋势,PPI销售金额排前10名的科室波动不大,PPI使用率总体略有下降,但仍较高。结论以ATC/DDD评价系统为基础制订各临床科室PPI使用指标具有可行性,可为医疗机构规范PPI的临床应用提供参考。     

Effect of imidazoline-1 receptor agonists on renal dysfunction in rats associated with chronic,sequential fructose and ethanol administration

Insulin resistance and chronic alcoholism are risk factors for renal dysfunction. This study investigated the therapeutic effects of two imidazoline-1 receptor (I1R) agonists on renal dysfunction in rats after chronic, sequential fructose and ethanol administration. Daily drinking water was supplemented with fructose (10%, w/v) for 12 weeks and then with ethanol (20%, v/v) for another 8 weeks. Rats were treated with rilmenidine and clonidine in the last two weeks of the study. Blood glucose and serum insulin (sIns) levels, lipid profiles, kidney function and renal histopathology were evaluated at the end of the experiment. Additionally, renal gene expression of nischarin, phosphatidylcholine-specific phospholipase C (PC-PLC) and prostaglandin E2 (PGE2) were measured. Renal levels of superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and total NO (tNO) were detected, and we determined the relative renal gene expression levels of alpha smooth muscle actin (α-SMA), hydroxyproline, interleukin 10 (IL-10), tumour necrosis factor alpha (TNF-α) and caspase-3. The results showed significant deterioration of blood glucose, sIns, lipid profiles, kidney function and renal histopathology in fructose/ethanol-fed rats. Additionally, markers of inflammation, fibrosis, apoptosis and oxidative stress were upregulated. The administration of rilmenidine or clonidine significantly improved blood glucose and sIns levels and reduced renal dysfunction. Our work showed that chronic, sequential fructose and ethanol administration induced fasting hyperglycaemia and renal impairment, and these effects were ameliorated by I1R agonists.