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Treatment of Non-Alcoholic Steatosis: Preclinical Study of a New Nutraceutical Multitarget Formulation

非酒精性脂肪变性的治疗: 一种新的营养多靶点制剂的临床前研究

  • 影响因子:4.51
  • DOI:10.3390/nu12061819
  • 作者列表:"Laura Micheli","Alessandra Pacini","Lorenzo Di Cesare Mannelli","Elena Trallori","Roberta D’Ambrosio","Carlo Bianchini","Pietro Lampertico","Carla Ghelardini
  • 发表时间:2020-06-19
Abstract

Multifactorial pathogenesis of non-alcoholic steatohepatitis (NASH) disease, a wide-spread liver pathology associated with metabolic alterations triggered by hepatic steatosis, should be hit by multitarget therapeutics. We tested a multicomponent food supplement mixture (AP-NHm), whose components have anti-dislipidemic, antioxidant and anti-inflammatory effects, on in vitro and in vivo models of NASH. In vitro, hepatic cells cultures were treated for 24 h with 0.5 mM oleic acid (OA): in the co-treatment set cells were co-treated with AP-NH mixtures (AP-NHm, 1:3:10 ratio) and in the post-injury set AP-NHm was added for 48 h after OA damage. In vivo, C57BL/6 mice were fed with high-fat diet (HFD) for 12 weeks, inducing NASH at 7th week, and treated with AP-NHm at two dosages (1:3 ratio) in co-treatment or post-injury protocols, while a control group was fed with a standard diet. In in vitro co-treatment protocol, alterations of redox balance, proinflammatory cytokines release and glucose uptake were restored in a dose-dependent manner, at highest dosages also in post-injury regimen. In both regimens, pathologic dyslipidemias were also ameliorated by AP-NHm. In vivo, high-dose-AP-NHm-co-treated-HFD mice dose-dependently gained less body weight, were protected from dyslipidemia, and showed a lower liver weight. Dose-dependently, AP-NHm treatment lowered hepatic LDL, HDL, triglycerides levels and oxidative damage; co-treatment regimen was anti-inflammatory, reducing TNF-α and IL-8 levels. Hepatic lipidic infiltration significantly decreased in co-treated and post-injury-AP-NHm-HFD animals. The multitarget approach with AP-NHm was effective in preventing and reducing NASH-related pathologic features, warranting for the clinical development of this compound.

摘要

非酒精性脂肪性肝炎 (NASH) 疾病的多因素发病机制,是一种与肝脏脂肪变性触发的代谢改变相关的广泛肝脏病理,应通过多靶点治疗来打击。我们在 NASH 的体外和体内模型上测试了一种多组分食品补充剂混合物 (AP-NHm),其组分具有抗血脂、抗氧化和抗炎作用。在体外,用 0.5 mM 油酸 (OA) 处理肝细胞培养物 24 h: 在共处理组中,用 AP-NH 混合物 (AP-NHm,1:3:10 比例) 共处理细胞并在 OA 损伤后 48 h 加入 AP-NHm。体内采用高脂饮食 (HFD) 喂养 C57BL/6 小鼠 12 周,诱导第 7 周 NASH,并在联合治疗或损伤后方案中以两种剂量 (1:3 比例) 用 AP-NHm 治疗,而对照组以标准饮食喂养。在体外联合治疗方案中,氧化还原平衡、促炎细胞因子释放和葡萄糖摄取的改变以剂量依赖性方式恢复,最高剂量也是在损伤后方案中。在这两种方案中,AP-NHm 也改善了病理性血脂异常。在体内,高剂量-AP-NHm-co-treated-HFD 小鼠剂量依赖性地获得较少的体重,免受血脂异常的影响,并表现出较低的肝脏重量。剂量依赖性,AP-NHm 治疗降低肝脏 LDL,HDL,甘油三酯水平和氧化损伤; 共同治疗方案是抗炎,降低 TNF-α 和 IL-8 水平。共处理和损伤后-AP-NHm-HFD 动物的肝脏脂质浸润显著降低。AP-NHm 的多靶点方法有效预防和减少 NASH 相关的病理特征,为该化合物的临床开发提供了保证。

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作者列表:["Moon AM","Jiang Y","Rogal SS","Tapper EB","Lieber SR","Barritt AS 4th"]

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影响因子:3.87
发表时间:2020-02-01
DOI:10.1111/liv.14321
作者列表:["Chen VL","Chen Y","Du X","Handelman SK","Speliotes EK"]

METHODS:BACKGROUND AND AIMS:Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS:We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS:Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS:We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.

翻译标题与摘要 下载文献
影响因子:2.57
发表时间:2020-02-01
DOI:10.1111/eci.13198
作者列表:["Li H","Wieser A","Zhang J","Liss I","Markwardt D","Hornung R","Neumann-Cip AC","Mayerle J","Gerbes A","Steib CJ"]

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