Interleukin 1 Inhibitors The pathogenesis of ALD involves upregulation of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-), interleukin 1 (IL-1) and IL-8 [7,159]. AH [47]. 3.2.5. MicroRNAs (MiR-155 and MiR- 223) MicroRNAs (miRNAs) are small (less than 50 nucleotides) noncoding RNAs that regulate the expression of their respective target messenger RNA (mRNAs), and encoded proteins at the posttranscriptional (-)-Borneol level [85]. Within the liver, miRNAs influence a wide array of critical biological processes including hepatocyte regeneration, metabolism, immunity, bile secretion, fibrosis and hepatocellular carcinoma (HCC) [86]. In addition to being housed intracellularly, miRNAs can also be detected extracellularly in the serum, plasma and other body fluids (saliva, urine). The high stability and easy detection of miRNAs in the circulation make them attractive as a potential biomarker for (-)-Borneol the liver diseases [48]. MiR-155 is usually a multifunctional miRNA located within the third exon on chromosome 21. A recent study [87] found that miR-155 deficiency attenuates chronic alcohol-induced steatosis, oxidative stress, and liver injury in the liver. The study showed that alcohol produces both M1 (classical activation) and M2 (alternatively activated profibrotic) macrophage activation in mice. In addition to macrophage activation, AH is also characterized by (-)-Borneol neutrophil infiltration to the liver. Neutrophil infiltration has been shown to correlate with the severity of acute AH [88]. Alcohol diet also resulted in an infiltration of neutrophils (CD11b + Ly6Ghi) in the livers of wild type mice. However, neutrophil infiltration was prevented in miR-155 KO mice after alcohol-fed diet. Collectively, miR-155 seems to play a promoting Rabbit Polyclonal to RGS1 role in the occurrence and development of ALD. MiR-223 (encoded on chromosome 12) is one of the most abundant miRNAs in the neutrophils. Previous studies [89] have shown that this upregulation of miR-223 plays a crucial role in terminating the acute neutrophilic response and could be a therapeutic target for the treatment of acetaminophen (APAP) induced liver failure. One study showed that alcoholics had elevated serum miR-223 levels compared with healthy controls [49]. In addition, in a chronic-plus-binge alcohol-fed mouse model, the levels of miR-223 were increased both in the serum and the neutrophils. However, another study found that the serum miR-223 levels increased while miR-223 levels in the neutrophils decreased in human alcoholics [50]. Another recent study showed that microRNA122 regulated by GRLH2 protects livers of mice and patients from ALD [90]. These discrepant findings suggested that this levels of hepatic neutrophils might be a critical factor for determining the outcome of potential therapeutic implications of miR-223 for diagnosing/treating ALD, making it more sensitive in patients with AH as compared to other manifestations of ALD. 3.3. Biomarkers of Metabolic Changes Alcoholic liver disease leads to a range of metabolic disturbances, some of which can be assessed to determine the severity and prognosis of the hepatocellular damage [91]. A few such biomarkers, which have been gaining interest in ALD are listed below. 3.3.1. Stearoyl-CoA Desaturase 1 (SCD1) One of the histopathological findings in alcohol-induced liver injury is usually steatosis. This has been attributed to alcohol consumption that alters several metabolic processes, especially fatty acid metabolism leading to steatohepatitis. Alcohol is broken down via alcohol dehydrogenase to acetaldehyde, which thereafter is usually converted to acetate by acetaldehyde dehydrogenase altering the NADH/NAD ratio [92]. This imbalance of NADH to NAD results in the diversion of acetyl CoA toward ketogenesis and fatty acid synthesis [93]. Another mechanism that could contribute to the steatosis is the augmented response of sterol regulatory element-binding protein 1 (SREBP-1) in.