Radical oxygen species and bile secretion

Oxidative stress is a common feature in most hepatopathies. Accumulating evidences indicate that reactive oxygen species (ROS) induce a number of functional changes either deleterious or adaptive in the capability of the hepatocytes to produce bile and to secrete exogenous and endogenous compounds. This review is aimed to describe the mechanisms involved in these changes. For this purpose, we will summarize: 1. The current evidence that acutely induced oxidative stress is cholestatic, by describing the mechanisms underlying the hepatocyte secretory failure, including the disorganization of the actin cytoskeleton and its most noticeable consequences, that is, the impairment of tight-junctional structures and the endocytic internalization of canalicular transporters relevant to bile formation. 2. The role for oxidative-stress-activated signalling pathways in the pathomechanisms described above, particularly those involving Ca2+ elevation and its consequent activation via Ca2+ of “classical” and “novel” PKC isoforms. 3. The mechanisms involved in the adaptive response against oxidative stress mediated by ROS-responsive transcription factors, such as upregulation of GSH synthesis pathway, antioxidant enzymes, and hepatocellular efflux pumps. 4. The consequences on hepatocellular secretory function when this adaptive response can be surpassed by the sustained/high production of ROS. This deleterious effects include transcriptional and posttranscriptional changes in the expression of transporters relevant to bile formation, as has been shown to occur, for example, after long-term administration of aluminum to rats, in the Long-Evans Cinnamon rat (a model of chronic hepatic copper accumulation mimicking Wilson’s disease), and in ischemia-reperfusion injury.Fil: Basiglio, Cecilia Lorena. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE‑CONICET); Argentina.Fil: Toledo, Flavia D. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE‑CONICET); Argentina.Fil: Sánchez Pozzi, Enrique J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE‑CONICET); Argentina.Fil: Roma, Marcelo Gabriel. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental (IFISE‑CONICET); Argentina

Differential sensitivity to pro-oxidant exposure in two populations of killifish (Fundulus heteroclitus)

New Bedford Harbor (MA, U.S.A.; NBH) is a Superfund site inhabited by Atlantic killifish (Fundulus heteroclitus) with altered aryl hydrocarbon receptor (Ahr) signaling, leading to resistance to effects of polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The Ahr is a transcription factor that regulates gene expression of many Phase I and II detoxifying enzymes and interacts with Nrf2, a transcription factor that regulates the response to oxidative stress. This study tested the hypothesis that PCB-resistant killifish exhibit altered sensitivity to oxidative stress. Killifish F(1) embryos from NBH and a clean reference site (Scorton Creek, MA, U.S.A.; SC) were exposed to model pro-oxidant and Nrf2-activator, tert-butylhydroquinone (tBHQ). Embryos were exposed at specific embryonic developmental stages (5, 7, and 9 days post fertilization) and toxicity was assessed, using a deformity score, survival, heart rate, and gene expression to compare sensitivity between PCB-resistant and PCB-sensitive (reference) populations. Acute exposure to tBHQ resulted in transient reduction in heart rate in NBH and SC F(1) embryos. However, embryos from NBH were more sensitive to tBHQ, with more frequent and severe deformities, including pericardial edema, tail deformities, small body size, and reduced pigment and erythrocytes. NBH embryos had lower basal expression of antioxidant genes catalase and glutathione-S-transferase alpha (gsta), and upon exposure to tBHQ, exhibited lower levels of expression of catalase, gsta, and superoxide dismutase compared to controls. This result suggests that adaptation to tolerate PCBs has altered the sensitivity of NBH fish to oxidative stress during embryonic development, demonstrating a cost of the PCB resistance adaptation

Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics.

Africa is the ultimate source of modern humans and as such harbors more genetic variation than any other continent. For this reason, studies of the patterns of genetic variation in African populations are crucial to understanding how genes affect phenotypic variation, including disease predisposition. In addition, the patterns of extant genetic variation in Africa are important for understanding how genetic variation affects infectious diseases that are a major problem in Africa, such as malaria, tuberculosis, schistosomiasis, and HIV/AIDS. Therefore, elucidating the role that genetic susceptibility to infectious diseases plays is critical to improving the health of people in Africa. It is also of note that recent and ongoing social and cultural changes in sub-Saharan Africa have increased the prevalence of non-communicable diseases that will also require genetic analyses to improve disease prevention and treatment. In this review we give special attention to many of the past and ongoing studies, emphasizing those in Sub-Saharan Africans that address the role of genetic variation in human disease