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  • Understanding and defining these miRNA profiles helps to unc


    Understanding and defining these miRNA profiles helps to uncover the clinical usefulness of miRNAs. Numerous human clinical trials are currently evaluating miRNA therapeutics during various liver diseases, such as targeting miR-122 during chronic hepatitis C infection. Aside from therapeutics, the development of diagnostic tools is of utmost importance, since these tools may be able to detect underlying liver injury that may not otherwise be noticed. However, the reliability and cost-effectiveness of screening for miRNAs pose a significant problem when developing miRNA-based diagnostic approaches. Based on the findings discussed in this review, it is evident that miRNA signatures are associated with diseased states, and these dopamine receptors patterns could provide important clinical benefit. These findings support the critical impact that these small RNAs have on cholangiopathy development.
    Conflict of interest
    Acknowledgements This work was supported in part by the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White, a VA Research Career Scientist Award, a VA Merit award to Dr. Alpini (5I01BX000574), a VA Merit Award (1I01BX003031) to Dr. Francis, a VA Merit Award (5I01BX002192) to Dr. Glaser, and a VA Merit Award (1I01BX001724) to Dr. Meng from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research, a NIH grant DK108959 to Dr. Francis, and the multiple-PIs NIH grants DK058411, DK076898, DK107310 and DK062975 belong to Drs. Alpini, Meng and Glaser. This material is the result of work supported by resources at the Central Texas Veterans Health Care System. The content is the responsibility of the author(s) alone and does not necessarily reflect the views or policies of the Department of Veterans Affairs or the United States Government.
    Introduction Gallstone disease is not only a very prevalent liver disease worldwide, but also a very old human disorder, going back thousands of years, as it has been found in ancient mummies in Egypt and China. Although gallstone disease was not recognized by ancient Chinese, abdominal pain as a result of hepatobiliary diseases and gastric malfunction, jaundice caused by liver diseases, and epigastric colic owing most likely to gallstones or biliary ascariasis were often treated with bear\'s bile. The earliest medical record for these therapeutic interventions was found in Treatise on Properties of Drugs (c. 643 CE or earlier) written by an ancient Chinese doctor Zhen Quan (c. 540 to 643 CE). Modern chemical analysis of the bile of Asian black bears (Ursus thibetanus or Selenarctos thibetanus) and brown bears (Ursus arctos) found that ursodeoxycholic acid (UDCA) is the major composition of the bile acid pool in these animals. Notably, UDCA, a hydrophilic bile acid, is now first-line pharmacological therapy in a subgroup of symptomatic patients with small, radiolucent cholesterol-enriched gallstones. Long-term administration of UDCA promotes the dissolution of cholesterol gallstones, especially in patients with small (≤5 mm in diameter), cholesterol-rich and uncalcified stones (radiolucent on plain X-ray film) in a functioning gallbladder with preserved kinetics and a patent cystic duct. However, the therapeutic effect of UDCA is not always achieved in clinical practice because of a high recurrence rate of gallstones. Although laparoscopic cholecystectomy is nowadays the first choice of treatment options for gallstone disease, it is invasive and can cause surgical complications regarding morbidity and mortality, and not all patients with symptomatic gallstones are candidates for surgery. To reduce the morbidity, mortality and costs of health care associated with gallstones, it is imperative to elucidate the pathogenesis of gallstone disease. This will promote the development of a novel, effective, and noninvasive therapy for patients with gallstones. Since the first gallstone gene, Lith1 was identified by quantitative locus trait (QTL) mapping methods in inbred strains of mice in 1995, a mouse gallstone gene map that contains 25 Lith genes has been established through genetic analysis of cholesterol gallstone formation in different strains of inbred mice fed a lithogenic diet for 8 weeks. This greatly promotes the discovery of human Lith genes because of homologues between human and mouse chromosomes. Such a successful study is the confirmation of ABCG5/G8 as a human Lith gene based on mouse studies. The Abcg5/g8 was first identified as the mouse Lith9 by the QTL mapping methods, and subsequently, two major gallstone-associated variants in ABCG5/G8 (ABCG5-R50C and ABCG8-D19H) were found not only in German and Chilean populations, but also in Chinese and Indian populations. Therefore, based on the mouse gallstone (Lith) gene map, more human Lith genes will be identified and their pathogenic mechanisms will be elucidated in the near future.