UNLABELLED: Clinicians rely upon the severity of liver fibrosis to segregate patients with well-compensated nonalcoholic fatty liver disease (NAFLD) into subpopulations at high- versus low-risk for eventual liver-related morbidity and mortality. We compared hepatic gene expression profiles in high- and low-risk NAFLD patients to identify processes that distinguish the two groups and hence might be novel biomarkers or treatment targets. Microarray analysis was used to characterize gene expression in percutaneous liver biopsies from low-risk, "mild" NAFLD patients (fibrosis stage 0-1; n = 40) and high-risk, "severe" NAFLD patients (fibrosis stage 3-4; n = 32). Findings were validated in a second, independent cohort and confirmed by real-time polymerase chain reaction and immunohistochemistry (IHC). As a group, patients at risk for bad NAFLD outcomes had significantly worse liver injury and more advanced fibrosis (severe NAFLD) than clinically indistinguishable NAFLD patients with a good prognosis (mild NAFLD). A 64-gene profile reproducibly differentiated severe NAFLD from mild NAFLD, and a 20-gene subset within this profile correlated with NAFLD severity, independent of other factors known to influence NAFLD progression. Multiple genes involved with tissue repair/regeneration and certain metabolism-related genes were induced in severe NAFLD. Ingenuity Pathway Analysis and IHC confirmed deregulation of metabolic and regenerative pathways in severe NAFLD and revealed overlap among the gene expression patterns of severe NAFLD, cardiovascular disease, and cancer. CONCLUSION: By demonstrating specific metabolic and repair pathways that are differentially activated in livers with severe NAFLD, gene profiling identified novel targets that can be exploited to improve diagnosis and treatment of patients who are at greatest risk for NAFLD-related morbidity and mortality.
Asymptomatic Diseases , Fatty Liver/diagnosis , Fatty Liver/genetics , Liver/metabolism , Severity of Illness Index , Transcriptome , Adult , Biopsy , Diagnosis, Differential , Fatty Liver/metabolism , Female , Humans , Liver/pathology , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Regeneration/genetics , Male , Metabolism/genetics , Middle Aged , Non-alcoholic Fatty Liver Disease , Prognosis , Risk Factors , Tissue Array Analysis
Many commonly used non-steroidal anti-inflammatory drugs (NSAIDs) also cause gastrointestinal toxicity, including the development of life-threatening peptic ulcers. We report that mast cell-deficient mice have an extremely high incidence of severe peptic ulceration when exposed to the NSAID piroxicam. This enhanced ulcer susceptibility can be reversed by reconstitution with mast cells. Furthermore, wild type mice treated with diphenhydramine hydrochloride, a commonly used antihistamine that blocks histamine H1 receptors, develop a similarly high incidence of peptic ulcers following piroxicam exposure. The protective effect of mast cells is independent of TNF, blockade of H2 receptors, or acid secretion. These data indicate a critical role for mast cells and the histamine that they produce in prevention and/or repair of piroxicam-induced gastric mucosal injury. Additional studies will be required to determine whether this represents a NSAID class effect that can be exploited to develop novel therapeutic strategies to limit the incidence of NSAID-induced side effects in humans.
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Mast Cells/physiology , Peptic Ulcer/physiopathology , Piroxicam/toxicity , Animals , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase Inhibitors/toxicity , Diphenhydramine/toxicity , Dose-Response Relationship, Drug , Drug Synergism , Gastric Mucosa/metabolism , Gastric Mucosa/pathology , Gastric Mucosa/physiopathology , Histamine/metabolism , Humans , Mast Cells/metabolism , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Peptic Ulcer/chemically induced , Peptic Ulcer/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
Genomic imprinting results in parent-of-origin-dependent, monoallelic expression of genes. The functional haploid state of these genes has far-reaching consequences. Not only has imprinting been implicated in accelerating mammalian speciation, there is growing evidence that it is also involved in the pathogenesis of several human conditions, particularly cancer and neurological disorders. Epigenetic regulatory mechanisms govern the parental allele-specific silencing of imprinted genes, and many theories have attempted to explain the driving force for the evolution of this unique form of gene control. This review discusses the evolution of imprinting in Therian mammals, and the importance of imprinted genes in human health and disease.
Disease/genetics , Evolution, Molecular , Genomic Imprinting , Mammals/genetics , Animals , Humans
Inflammatory bowel disease (IBD) is a T cell driven inflammatory condition of the gut. Following solid organ transplantation (SOT), de novo IBD has been reported despite anti-T cell therapy for the prevention of organ rejection. This paradox is illustrated with a case report, highlighting the difficult diagnostic criteria, the potential role of Damage or Pathogen Associated Molecular Pattern Molecules [DAMPs and PAMPs] that drives aspects of ongoing inflammation within the transplanted organ as well as the intestine, and the therapeutic strategies applied. Recurrent IBD is more common than de novo IBD following transplantation, with cumulative risks ten years after orthotopic liver transplantation of 70% and 30%, respectively. Furthermore, the annual incidence of de novo IBD following solid organ transplantation has been estimated to be 206 cases/100,000 or ten times the expected incidence of IBD in the general population (approximately 20 cases/100,000). The association of IBD with other autoimmune conditions such as primary sclerosing cholangitis and autoimmune hepatitis, both common indications for liver transplantation, may play a contributory role, particularly in view of the observation that IBD is more common following liver transplant than other solid organ transplants. Recurrent IBD following transplant appears to run a more aggressive course than de novo IBD, with a higher proportion requiring colectomy for medically refractory disease. Risk factors that have been associated with development of post-transplant IBD include acute CMV infection and the use of tacrolimus.
Hepatitis, Autoimmune/surgery , Immunosuppressive Agents/therapeutic use , Inflammatory Bowel Diseases/etiology , Liver Transplantation , Adult , Cytokines/immunology , Cytokines/metabolism , Cytomegalovirus , Female , Hepatitis, Autoimmune/drug therapy , Humans , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/epidemiology , Postoperative Complications , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
The evolution of barriers to gene exchange is centrally important to speciation. We used the crickets Allonemobius fasciatus and A. socius to investigate the genetic architecture of conspecific sperm precedence (CSP), a postinsemination prezygotic reproductive barrier. With amplified fragment-length polymorphism (AFLP) markers and controlled crosses we constructed linkage maps and estimated positions of QTL associated with CSP. The majority of QTL have low to moderate effects, although a few QTL exist in A. socius with large effects, and the numbers of QTL are comparable to numbers of genes accounting for species differences in other studies. The QTL are spread across many unlinked markers, yet QTL placed with linked markers are on a small number of linkage groups that could reflect the role of the large Allonemobius sex chromosome in prezygotic isolation. Although many QTL had positive effects on conspecific sperm utilization several QTL also exerted negative effects, which could be explained by intraspecific sexual conflict, sperm competition, or epistasis of introgressed genes on novel backgrounds. One unexpected outcome was that A. socius CSP alleles have a stronger effect than those from A. fasciatus in hybrid females, causing hybrids to behave like A. socius with regard to sperm utilization. Implications of this asymmetry in the Allonemobius hybrid zone are discussed.
Crosses, Genetic , Gryllidae/genetics , Quantitative Trait Loci , Spermatozoa/physiology , Animals , Climate , Female , Gryllidae/classification , Male , North America , Pedigree , Population Density , Reproduction/genetics
An intriguing aspect of the current renaissance in investigations of the genetics of reproductive isolation is that it has been dominated by studies that resemble work done in the 1930s, 1940s, and 1950s. The dominant model organism (Drosophila), research approaches, and traits of interest (sterility and inviability of hybrids) all harken back to this earlier era. Herein, we explore the factors that led to a rebirth of interest in the genetics of reproductive isolation and to the adoption of the approaches of an earlier generation of biologists. At the same time, we appeal for more intensive investigations of traits that reproductively isolate closely related species, inclusion of a greater range of organisms in studies of reproductive isolation, and focus on a broader range of questions surrounding speciation. We end with a description of ongoing quantitative trait loci (QTL) studies of conspecific sperm precedence in the ground crickets Allonemobius fasciatus and Allonemobius socius. We have found several QTL with large effects on variance in patterns of sperm utilization in backcross females. Moreover, some QTL have an antagonistic effect on conspecific sperm, a finding that lends support to the hypothesis that rapid evolution of conspecific sperm precedence is a by-product of sexual conflict.
