MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the
*CYTOKINES; *ETHANOL; *FATTY LIVER; *INFLAMMATION; *LEUKOCYTES; Adult; Alanine Transaminase/blood; Alcoholic/genetics/*metabolism/pathology; Alcoholism/*blood/complications; Animals; Aspartate Aminotransferases/blood; Bilirubin/blood; Binge Drinking/*blood/complications; Case-Control Studies; Central Nervous System Depressants/administration & dosage; Down-Regulation; Ethanol/administration & dosage; Female; Humans; Inbred C57BL; Interleukin-6/genetics/metabolism; Liver Diseases; Male; Mice; MicroRNAs/*blood/*genetics; Middle Aged; NADPH Oxidases/genetics/metabolism; Neutrophils/*metabolism; Reactive Oxygen Species/metabolism; Up-Regulation; Young Adult
OBJECTIVES: Chronic-plus-binge ethanol feeding activates neutrophils and exacerbates liver injury in mice. This study investigates how recent excessive drinking affects peripheral neutrophils and liver injury in alcoholics, and how miR-223, one of the most abundant microRNAs (miRNAs) in neutrophils, modulates neutrophil function and liver injury in ethanol-fed mice. DESIGNS: Three hundred alcoholics with (n=140) or without (n=160) recent excessive drinking and 45 healthy controls were enrolled. Mice were fed an ethanol diet for 10 days followed by a single binge of ethanol. RESULTS: Compared with healthy controls or alcoholics without recent drinking, alcoholics with recent excessive drinking had higher levels of circulating neutrophils, which correlated with serum levels of alanine transaminase (ALT) and aspartate transaminase (AST). miRNA array analysis revealed that alcoholics had elevated serum miR-223 levels compared with healthy controls. In chronic-plus-binge ethanol feeding mouse model, the levels of miR-223 were increased in both serum and neutrophils. Genetic deletion of the miR-223 gene exacerbated ethanol-induced hepatic injury, neutrophil infiltration, reactive oxygen species (ROS) and upregulated hepatic expression of interleukin (IL)-6 and phagocytic oxidase (phox) p47(phox). Mechanistic studies revealed that miR-223 directly inhibited IL-6 expression and subsequently inhibited p47(phox) expression in neutrophils. Deletion of the p47(phox) gene ameliorated ethanol-induced liver injury and ROS production by neutrophils. Finally, miR-223 expression was downregulated, while IL-6 and p47(phox) expression were upregulated in peripheral blood neutrophils from alcoholics compared with healthy controls. CONCLUSIONS: miR-223 is an important regulator to block neutrophil infiltration in alcoholic liver disease and could be a novel therapeutic target for the treatment of this malady.
Li Man; He Yong; Zhou Zhou; Ramirez Teresa; Gao Yueqiu; Gao Yanhang; Ross Ruth A; Cao Haixia; Cai Yan; Xu Ming-Jiang; Feng Dechun; Zhang Ping; Liangpunsakul Suthat; Gao Bin
Gut
2017
2017-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1136/gutjnl-2016-311861" target="_blank" rel="noreferrer noopener">10.1136/gutjnl-2016-311861</a>
Maximizing function in Alzheimer's disease: what role for tacrine?
Humans; Treatment Outcome; Aspartate Aminotransferases/blood; Alzheimer Disease/blood/diagnosis/*drug therapy; Cholinesterase Inhibitors/pharmacology/*therapeutic use; Cognition/drug effects; Liver Function Tests; Tacrine/pharmacology/*therapeutic use
As the number of elderly persons continues to increase, family physicians will be caring for more patients with Alzheimer's disease. The treatment plan for patients with this incurable illness should be directed at optimizing their physical and psychosocial functioning and supporting their caregivers. Tacrine is the first medication proven to ameliorate the symptoms of Alzheimer's disease. This drug has been approved by the U.S. Food and Drug Administration for use in patients with mild to moderate Alzheimer's disease as evidenced by a score between 10 and 26 on the Mini-Mental State Examination. Tacrine can produce modest dose-related improvements in cognitive function and global measures of patient function. Such improvements only occur in 25 percent of patients treated with tacrine. On discontinuation of the drug, the patient's cognitive function returns to the level that would be expected if no treatment had been given. Both the degree of cognitive improvement and the severity of cholinergic symptoms increase with higher doses of tacrine. Thus, patients receiving tacrine therapy must be monitored for both clinical efficacy and adverse effects of the medication.
Smucker W D
American Family Physician
1996
1996-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).