Gastroenterology
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Inflammation In the absence of pathogens occurs in all tissues in response to a wide range of stimuli that cause tissue stress and injury. Such sterile inflammation (SI) is a key process in drug-induced liver injury, nonalcoholic steatohepatitis, and alcoholic steatohepatitis and is a major determinant of fibrosis and carcinogenesis. In SI, endogenous damage-associated molecular patterns (DAMPS), which are usually hidden from the extracellular environment, are released on tissue injury and activate receptors on immune cells. ⋯ DAMPS result in the assembly of a cytosolic protein complex termed the inflammasome, which activates the serine protease caspase-1, resulting in activation and secretion of interleukin-1β and other cytokines. SI-driven liver diseases are responsible for the majority of liver pathology in industrially developed countries and lack specific therapy. Identification of DAMPS, their receptors, signaling pathways, and cytokines now provides a wide range of therapeutic targets for which many antagonists are already available.
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Estrogen has been proposed to modulate gut inflammation through an effect on estrogen receptors found on gastrointestinal epithelial and immune cells. The role of postmenopausal hormone therapy on risk of Crohn's disease (CD) and ulcerative colitis (UC) is unclear. ⋯ In a large prospective cohort of women, postmenopausal hormone therapy was associated with an increased risk of UC but not CD. These findings indicate that pathways related to estrogens might mediate the pathogenesis of UC.
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We aimed to characterize offers of organs to candidates awaiting liver transplantation (LT). ⋯ Most candidates for LT who died or were removed from the list received 1 or more offers of a liver beforehand, and 55% received 1 or more offers of a high-quality liver. These findings indicate that a substantial proportion of wait-list mortality results in part from declined livers, rather than lack of opportunity, for transplantation. Understanding the real-time factors involved in the complex decision to accept a liver offer is vital to reducing wait-list mortality for LT candidates.
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The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T cells (NFAT) in development of AP in mice. ⋯ NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice and might be a therapeutic target.
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The pathogenesis of cirrhosis, a disabling outcome of defective liver repair, involves deregulated accumulation of myofibroblasts derived from quiescent hepatic stellate cells (HSCs), but the mechanisms that control transdifferentiation of HSCs are poorly understood. We investigated whether the Hedgehog (Hh) pathway controls the fate of HSCs by regulating metabolism. ⋯ Hedgehog signaling controls the fate of HSCs by regulating metabolism. These findings might be applied to diagnosis and treatment of patients with cirrhosis.