The effects of carnitine supplementation on clinical characteristics of patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials

ObjectiveThe beneficial effects of carnitine supplementation on nonalcoholic fatty liver disease are unclear. We conducted a systematic review and meta-analysis to evaluate the effects of carnitine supplementation on liver function, lipid profile, body mass index, body weight, and homeostasis model assessment of insulin resistance in patients with nonalcoholic fatty liver disease.MethodsA comprehensive search of PubMed, Web of Science, Scopus, Cochrane Library, and Google Scholar databases were performed. Only randomized placebo-controlled human studies that examined the effects of carnitine supplementation on liver function, lipid profile, body mass index, body weight, and homeostasis model assessment of insulin resistance up to September 2019 were included. Fixed effects or random-effects models were applied to compute the pooled effect size. Heterogeneity assessments were performed using Cochran’s Q test and I-squared statistics. The quality of the studies was assessed using the Jaded scale.ResultsA total of 5 articles were selected, including 334 individuals (167 in control and 167 in intervention groups). The results demonstrated that carnitine supplementation significantly reduced homeostasis model assessment of insulin resistance (HOMA-IR) (WMD: −0.91; 95 % CI: −1.11, −0.72; p < 0.001, I² = 0.0 %) and the levels of aspartate aminotransferase (AST) (WMD: −16.62; 95 % CI: −28.11, −5.14; IU/l; p = 0.005, I² = 93.5 %), alanine aminotransferase (ALT) (WMD: -33.39; 95 % CI: −45.13, −21.66; IU/l; p < 0.001, I² = 93.4 %), and triglycerides (TG) (WMD: −22.13; 95 % CI: −38.91, −5.34; mg/dl; p = 0.01; I² = 0.0 %). However, the results of the pooled effect size did not show any significant effect of carnitine supplementation on body mass index (BMI) (WMD: 0.07; 95 % CI: −0.15, 0.29; p = 0.55; I² = 0.0 %), body weight (WMD: −0.28; 95 % CI: −2.23, 1.68; p = 0.78; I² = 45.7 %), the levels of gamma-glutamyl transferase (γGT) (WMD: −11.31; 95 % CI: −24.35, 1.73; IU/l; p = 0.09, I² = 61.1 %), cholesterol (WMD: −13.58; 95 % CI: −46.77, 19.60; mg/dl; p = 0.42; I² = 94.9 %), high-density lipoprotein-cholesterol (HDL-C) (WMD: 1.36; 95 % CI: −0.96, 3.68; mg/dl; p = 0.25; I² = 64.7 %), and low density lipoprotein-cholesterol (LDL-C) (WMD: −14.85; 95 % CI: −45.43, 15.73; mg/dl; p = 0.34; I² = 96.4 %).ConclusionsThis analysis shows that carnitine supplementation for patients with nonalcoholic fatty liver disease demonstrates a reduction in AST, ALT, TG levels and HOMA-IR. However, no significant effect of carnitine supplementation was observed on BMI, body weight, the levels of γGT, TC, HDL-cholesterol and LDL-cholesterol.     

利用规律间隔成簇短回文重复序列/相关蛋白9系统敲减α2δ1对人肝癌细胞系Hep-12干性的影响

目的 通过规律间隔成簇短回文重复序列/相关蛋白9(CRISPR/Cas9)系统敲减人肝癌细胞系Hep12中电压依赖性钙离子通道 α2δ1的表达，观察α2δ1敲减后对肝癌细胞干性的影响。方法 设计3对靶向α2δ1的向导 (sgRNA)，长度为20 bp，构建到lenti CRISPRv2-puro载体上，然后在体外检测sgRNA切割活性，利用慢病毒包装系统包装含有sgRNA的重组质粒，将包装好的病毒感染Hep-12细胞，2 d后加入嘌呤霉素筛选。利用Western blotting验证α2δ1的敲减效果和干性相关基因的表达。通过成球实验检测其体外自我更新能力的变化。结果 测序结果显示，sgRNA成功插入载体质粒；体外切割实验显示，3条sgRNA均有切割活性；Western blotting结果显示，α2δ1基因的表达显著降低，干性相关基因B细胞特异性莫洛尼白血病病毒插入位点1(BMI1)和Nanog的表达显著被抑制；无血清培养基成球实验结果表明，敲减α2δ1导致Hep-12细胞的体外自我更新能力减弱。结论 利用CRISPR/Cas9技术成功构建敲除α2δ1基因的Hep-12细胞系；敲除α2δ1基因后能抑制Hep-12细胞肿瘤干细胞样特性。     

贵阳地区儿童重症社区获得性肺炎肺泡灌洗液病原及药敏分析

目的分析贵阳地区儿童重症社区获得性肺炎支气管肺泡灌洗液（BALF）病原学分布及耐药特点。方法收集989例重症社区获得性肺炎患儿临床资料，将支气管肺泡灌液采用支气管镜取出进行细菌培养、病毒以及肺炎支原体(MP)检测。结果（1）989例重症社区获得性肺炎患儿病原检出阳性716例，阳性率72.40%，细菌、病毒、支原体检出率分别33.27% （329例）、22.45%（222例）、31.45%（311例）。（2）细菌感染中的肺炎链球菌、金黄色葡萄球菌为最为常见的革兰阳性菌株(G+)；而肺炎克雷伯菌、大肠埃希菌为最为常见的革兰阴性菌株(G-)。培养菌株对青霉素类、红霉素、第1、2、3代头孢类抗生素有较高的耐药性，对头孢吡肟、拉氧头孢、哌拉西林、左氧氟沙星有较高的敏感性，对亚胺培南、万古霉素、利奈唑烷均无耐药发生。（3）病毒感染检出222例，其中呼吸道合胞病毒131例，腺病毒检测49例，流感病毒6例（A型2例，B型4例），副流感病毒36例（1型3例、2型4例、3型29例），病毒检出率以0～12月龄组最高，RSV、ADV感染主要集中在冬春季节。（4）肺炎支原体检出阳性率31.45%（311例），肺炎支原体检出率以3～5岁组最高。结论贵阳地区重症肺炎中肺炎克雷伯杆菌、肺炎链球菌、大肠埃希菌、金黄色葡萄球菌为重要的细菌病原。重要病毒为腺病毒和呼吸道病毒为主，1～12月龄组的病毒感染检出率比较高。     

Clinical implications,diagnosis,and management of diabetes in patients with chronic liver diseases

Diabetes mellitus(DM) negatively affects the development and progression of chronic liver diseases(CLD) of various etiologies. Concurrent DM and CLD are also associated with worse clinical outcomes with respect to mortality, the occurrence of hepatic decompensation, and the development of hepatocellular carcinoma(HCC). Unfortunately, early diagnosis and optimal treatment of DM can be challenging, due to the lack of established clinical guidelines as well as the medical complexity of this patient population. We conducted an exploratory review of relevant literature to provide an up-to-date review for internists and hepatologists caring for this patient population. We reviewed the epidemiological and pathophysiological associations between DM and CLD, the impact of insulin resistance on the progression and manifestations of CLD, the pathogenesis of hepatogenic diabetes, as well as the practical challenges in diagnosis and monitoring of DM in this patient population. We also reviewed the latest clinical evidence on various pharmacological antihyperglycemic therapies with an emphasis on liver disease-related clinical outcomes. Finally, we proposed an algorithm for managing DM in patients with CLD and discussed the clinical and research questions that remain to be addressed.     

uPAR Controls Vasculogenic Mimicry Ability Expressed by Drug-Resistant Melanoma Cells

Malignant melanoma is a highly aggressive skin cancer characterized by an elevated grade of tumor cell plasticity. Such plasticity allows adaptation of melanoma cells to different hostile conditions and guarantees tumor survival and disease progression, including aggressive features such as drug resistance. Indeed, almost 50% of melanoma rapidly develop resistance to the BRAFV600E inhibitor vemurafenib, with fast tumor dissemination, a devastating consequence for patients’ outcomes. Vasculogenic mimicry (VM), the ability of cancer cells to organize themselves in perfused vascular-like channels, might sustain tumor spread by providing vemurafenibresistant cancer cells with supplementary ways to enter into circulation and disseminate. Thus, this research aims to determine if vemurafenib resistance goes with the acquisition of VM ability by aggressive melanoma cells, and identify a driving molecule for both vemurafenib resistance and VM. We used two independent experimental models of drug-resistant melanoma cells, the first one represented by a chronic adaptation of melanoma cells to extracellular acidosis, known to drive a particularly aggressive and vemurafenib-resistant phenotype, the second one generated with chronic vemurafenib exposure. By performing in vitro tube formation assay and evaluating the expression levels of the VM markers EphA2 and VE-cadherin by Western blotting and flow cytometer analyses, we demonstrated that vemurafenib-resistant cells obtained by both models are characterized by an increased ability to perform VM. Moreover, by exploiting the CRISPR-Cas9 technique and using the urokinase plasminogen activator receptor (uPAR) inhibitor M25, we identified uPAR as a driver of VM expressed by vemurafenib-resistant melanoma cells. Thus, uPAR targeting may be successfully leveraged as a new complementary therapy to inhibit VM in drug-resistant melanoma patients, to counteract the rapid progression and dissemination of the disease.     

基于肠道菌群的中药改善胰岛素抵抗的作用机制研究进展

中医药的特色与优势促进了其治疗与胰岛素抵抗相关的慢性代谢性疾病如肥胖、糖尿病等的发展,但其尚不明确的作用机制极大限制了中药现代化、国际化和产业化。随着2代/3代基因测序技术的飞速发展,肠道菌群已成为中药作用机制研究的热点和新途径。为此,探讨肠道菌群及其代谢产物与胰岛素抵抗的关系,从中药复方、药对、单味药和活性成分不同角度系统分析中药通过调控肠道菌群改善胰岛素抵抗的研究进展,以期为阐释中药的作用机制提供研究思路与参考。