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Ebrahimkhani M.R.,Northumbria University | Ebrahimkhani M.R.,Center for Environmental Health science | Oakley F.,Northumbria University | Murphy L.B.,Northumbria University | And 16 more authors.
Nature Medicine

Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood 1. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT 2B) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT 2B enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT 2B or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT 2B attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT 2B is clinically safe in humans and may be therapeutic in chronic liver disease. Source

Beamer G.L.,Tufts University | Seaver B.P.,University of Montana | Jessop F.,University of Montana | Jessop F.,Center for Environmental Health science | And 3 more authors.
Frontiers in Immunology

Numerous studies have examined the relationship between alveolar macrophages (AMs) and crystalline silica (SiO2) using in vitro and in vivo immunotoxicity models; however, exactly how exposure to SiO2 alters the functionality of AM and the potential consequences for immunity to respiratory pathogens remains largely unknown. Because recognition and clearance of inhaled particulates and microbes are largely mediated by pattern recognition receptors (PRRs) on the surface of AM, we hypothesized that exposure to SiO2 limits the ability of AM to respond to bacterial challenge by altering PRR expression. Alveolar and bone marrow-derived macrophages downregulate TLR2 expression following acute SiO2 exposure (e.g., 4 h). Interestingly, these responses were dependent on interactions between SiO2 and the class A scavenger receptor CD204, but not MARCO. Furthermore, SiO2 exposure decreased uptake of fluorescently labeled Pam2CSK4 and Pam3CSK4, resulting in reduced secretion of IL-1β, but not IL-6. Collectively, our data suggest that SiO2 exposure alters AM phenotype, which in turn affects their ability to uptake and respond to bacterial lipoproteins. © 2016 Beamer, Seaver, Jessop, Shepherd and Beamer. Source

Shaw J.R.,Indiana University Bloomington | Shaw J.R.,Mt Desert Island Biological Laboratory | VanderHeide J.,Mt Desert Island Biological Laboratory | LaCasse T.,Mt Desert Island Biological Laboratory | And 3 more authors.
Aquatic Toxicology

Seawater acclimation in killifish, Fundulus heteroclitus, is mediated in part by a rapid (1h) translocation of CFTR Cl- channels from an intracellular pool to the plasma membrane in gill and increased CFTR-mediated Cl- secretion. This effect is mediated by serum and glucocorticoid-inducible kinase 1 (SGK1), which is stimulated by plasma hypertonicity rather than cortisol. Since arsenic exposure prevents acclimation to seawater by decreasing CFTR protein levels we tested the hypothesis that arsenic (as sodium arsenite) blocks acclimation to seawater by down regulating SGK1 expression. Freshwater adapted killifish were exposed to arsenic (48h) and transferred to seawater containing arsenic, and SGK and CFTR expression were measured. Arsenic reduced the seawater induced increase in SGK1 mRNA and protein abundance, and reduced both the total amount of CFTR and the amount of CFTR in the plasma membrane. The decrease in membrane CFTR reduced Cl- secretion. Arsenic also increased the amount of ubiquitinated CFTR and its degradation by the lysosome. Thus, we propose a model whereby arsenic reduces the ability of killifish to acclimate to seawater by blocking the seawater induced increase in SGK1, which results in increased ubiquitination and degradation of CFTR. © 2010 Elsevier B.V. Source

Tsuji T.,Kyoto Prefectural University of Medicine | Naito Y.,Kyoto Prefectural University of Medicine | Takagi T.,Kyoto Prefectural University of Medicine | Kugai M.,Kyoto Prefectural University of Medicine | And 17 more authors.
International Journal of Molecular Medicine

Metallothioneins (MTs) are a family of cysteine-rich low molecular-weight proteins that can act as reactive oxygen species scavengers. Although it is known that the induction of MT expression suppresses various inflammatory disorders, the role of MTs in intestinal inflammation remains unclear. In this study, we investigated the effects of dextran sulfate sodium (DSS) administration in mice with targeted deletions of the MT-I/II genes. Acute colitis was induced by 2% DSS in male MT-I/II double knockout (MT-null) and C57BL/6 (wild-type) mice. The disease activity index (DAI) was determined on a daily basis for each animal, and consisted of a calculated score based on changes in body weight, stool consistency and intestinal bleeding. Histology, colon length, myeloperoxidase (MPO) activity and colonic mRNA expression and the concentration of inflammatory cytokines were evaluated by real-time-PCR and enzyme-linked immunosorbent assay (ELISA). The localization of MTs and macrophages was determined by immunohistological and immunofluorescence staining. To investigate the role of MTs in macrophages, peritoneal macrophages were isolated and their responses to lipopolysaccharide were measured. Following DSS administration, the DAI score increased in a time-dependent manner and was significantly enhanced in the MT-I/II knockout mice. Colonic MPO activity levels and inflammatory cytokines [tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-17] production increased following DSS administration, and these increases were significantly enhanced in the MT-I/II knockout mice compared with the wild-type mice. MT-positive cells were detected in the lamina propria and submucosal layer by immunohistochemical and immunofluorescence staining, and were mainly co-localized in F4/80-positive macrophages. The production of inflammatory cytokines (TNF-α, IFN-γ and IL-17) from isolated peritoneal macrophages increased following lipopolysaccharide stimulation, and these increases were significantly enhanced in the macrophages obtained from the MT-I/II knockout mice. These data indicate that MTs play an important role in the prevention of colonic mucosal inflammation in a mouse model of DSS-induced colitis, thus suggesting that endogenous MTs play a protective role against intestinal inflammation. Source

Brown B.D.,University of Montana | Harris J.L.,University of Montana | Parker M.,Rocky Boy Tribal Health | Ricci C.,University of Montana | Noonan C.,Center for Environmental Health science
Diabetes Educator

Purpose The purpose of this study was to use a community-based participatory research (CBPR) approach to translate the original Diabetes Prevention Program (DPP) to be age and culturally specific for American Indian (AI) youth. Methods Tribally enrolled members on 2 Montana Indian reservations conducted focus groups and interviews to discuss community members' perspectives of factors that encouraged or were barriers to healthy diet and exercise behaviors in AI youth. In total, 31 community members, aged 10 to 68 years old, participated in 4 focus groups and 14 individual interviews. Participants were self-identified as elder, cultural expert, tribal health worker, educator, parent/guardian, youth, or school food service worker. Researchers analyzed transcripts based on inductive methods of grounded theory. Results Data analysis revealed translating the DPP to youth was contingent on the lessons incorporating cultural strategies for healthy behaviors in youth such as berry picking, gardening, horseback riding, and dancing; improving knowledge and access to healthy foods and physical activity for youth and their parents; having interactive, hands-on learning activities for healthy lifestyles in the DPP lessons; using a group format and tribal members to deliver the DPP lessons; and having tribal elders talk to youth about the importance of adopting healthy behaviors when they are young. Conclusions A CBPR approach engaged community members to identify strategies inherent in their culture, tradition, and environment that could effectively translate the DPP to Montana Indian youth living in rural reservation communities. © 2010 The Author(s). Source

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