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  • 1.

    【2hr】Stemness in Liver Cancer

    包量

    机译 肝癌中的梗阻
    摘要：Cancer cells possessing “stemness,” or stem-cell properties, are referred to as cancer stem cells (CSC) or cancer-initiating cells. The concept that these cells rest at the apex of the cancer hierarchy is an evolving theme in cancer research. These cells are by definition primarily responsible for initiation and propagation of tumors as well as relapse after therapy, and they are therefore of major scientific interest. Several studies indicate that hepatocellular carcinomas (HCC) that harbor phenotypic features of stem cells and progenitor cells constitute a subclass of therapeutically challenging cancers that are associated with a particularly poor prognosis. We have recently demonstrated tha any cell type in the mouse hepatic lineage can undergo oncogenic reprogramming into a CSC by activating different cell type–specific pathways (). Identification of common and cell of origin–specific phenotypic and genetic changes could provide new therapeutic targets for liver cancer.
  • 2.

    【2hr】The role of Inflammation in the mechanisms of bile acid-induced liver damage

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    机译 炎症在胆汁酸引起的肝损伤机制中的作用
    摘要：Background:The mechanism by which bile acids induce liver injury in cholestasis remains controversial. Although high levels of bile acids are toxic when applied to liver cells, the level of toxic bile acids in the liver of most cholestatic animals and patients is <10 μM, indicating there must be alternative mechanisms. Recent studies suggest that the inflammatory response may play an important role in bile acid-induced liver injury, as pro-inflammatory cytokine expression is stimulated by bile acids in mouse hepatocyte cultures. To elucidate the mechanisms of bile acid-induced liver injury, we assessed signs of liver damage and gene expression in Abcb4−/− mice, a well-known model for cholestasis.
  • 3.

    【2hr】Role of the Intestinal Microbiome in Cholestatic Liver Disease

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    机译 肠道微生物组在胆汁淤积性肝病中的作用
    摘要：Hepatobiliary health and disease is influenced by multiple factors including genetics, epigenetics, and the environment. Recently, multiple lines of evidence suggest that the microbiome also plays a central role in the initiation and/or progression of several liver diseases. Our current understanding of the dynamic interplay between microbes, microbial products and liver health and pathophysiology is incomplete. However, exciting insights are continually being made that support both a central role of the microbiome and a need for further interrogation of the microbes or microbe-associated molecules involved in the initiation and progression Of Select liver diseases.
  • 4.

    【2hr】Intestinal FXR and TGR5 signaling in metabolic regulation

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    机译 肠道FXR和TGR5信号在代谢调节中的作用
    摘要：Bile acids play a critical role in regulation of glucose, lipid and energy metabolisms through activating the nuclear bile acid receptor farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1 aka TGR5) signaling. Paradoxical roles of FXR in regulation of glucose and lipid metabolism and metabolic disorder have been reported recently. Activation or inhibition of intestinal FXR signaling have been shown to improve insulin and glucose sensitivity and energy metabolism to prevent diabetes, obesity and non-alcoholic fatty liver disease (NAFLD). TGR5 has an anti-inflammatory function in the intestine and stimulates glucagon-like peptide-1 (GLP-1) secretion in the intestine to stimulate insulin secretion from the pancreas. The role of TGR5 in metabolism and metabolic regulation is not clear and warrants further study. FXR and TGR5 are co-expressed in the ileum and colon. These two bile acid-activated receptors may cooperate to stimulate GLP-1 secretion and improve hepatic metabolism. FXR and TGR5 dual agonists may have therapeutic potential for treating diabetes and NAFLD.
  • 5.

    【2hr】FXR an emerging target to combat obesity

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    机译 FXR成为对抗肥胖的新兴目标
    摘要：Obesity and its associated diseases, including type 2 diabetes, has reached epidemic levels world-wide. However, available treatment options are limited and ineffective in managing the disease. There is therefore an urgent need for the development of new pharmacological solutions. The bile acid receptor FXR, has recently emerged as an attractive candidate. Initially described for their role in lipid and vitamin absorption from diet, bile acids are hormones with powerful effects on whole body lipid and glucose metabolism. In this review, we focus on FXR and how two decades of work on this receptor, both in rodents and humans, have led to the development of drug agonists with potential use in humans for treatment of conditions ranging from obesity associated diseases to bile acid dysregulation.
  • 6.

    【2hr】Intestinal Farnesoid X Receptor Signaling Modulates Metabolic Disease

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    机译 肠道法尼醇X受体信号调节代谢性疾病
    摘要：Farnesoid X receptor (FXR) regulates the synthesis, transport and enterohepatic circulation of bile acids (BA) by modulating the expression of related genes in the liver and small intestine. The composition of the gut microbiota is correlated with metabolic diseases, notably obesity and non-alcoholic fatty acid disease (NAFLD). Recent studies revealed that bacterial metabolism of BA can modulate FXR signaling in the intestine by altering the composition and concentrations of FXR agonist and antagonist. FXR agonist enhances while FXR antagonist suppresses obesity, NAFLD and insulin resistance. The role of intestinal FXR in metabolic disease was firmly established by the analysis of mice lacking FXR that are metabolic resistant to HFD-induced metabolic disease. This is mediated by FXR modulating in part the expression of genes involved in ceramide synthesis in the small intestine. In ileum of obese mice due to the presence of endogenous FXR agonists produced in the liver, these genes are activated, while in mice with altered levels of specific gut bacteria, levels of an FXR antagonist, tauro-β-muricholic acid (T-β-MCA) increase and FXR signaling and ceramide synthesis are repressed. T-β-MCA, which is metabolized in wild-type mice, led to the discovery of glycine-β-muricholic acid (Gly-MCA) that is stable in the intestine and a potent inhibitor of FXR signaling. These studies reveal that ceramides produced in the ileum under the control of FXR, influence metabolic disease, and suggest that novel FXR antagonist such as Gly-MCA that specifically inhibit intestine FXR, could serve as potential drug for the treatment of metabolic disease.
  • 7.

    【2hr】Impact of Fibroblast Growth Factors 19 and 21 in Bariatric Metabolism

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    机译 成纤维细胞生长因子19和21对肥胖代谢的影响
    摘要：Background:Bariatric surgery is a popular and effective therapeutic intervention for obesity, which is an abnormal health condition that is prevalent worldwide. Metabolic improvements that precede weight loss after bariatric surgery may be mediated, in part, through the fibroblast growth factor (FGF) 15/19 and FGF21 signaling pathways. Both FGF15/19 and FGF21 are hormone-like members of the FGF family and exert their metabolic effects in an endocrine manner. Enhanced bile acid recycling after bariatric surgery leads to increased circulating levels of FGF15/19 in the distal small intestine. Synthesis of FGF21 is upregulated predominately in the fasting state through peroxisome proliferator-activated receptor pathways and to a lesser extent by FGF15/19.
  • 8.

    【2hr】Roles of ileal ASBT and OSTα-OSTβ in regulating bile acid signaling

    包量

    机译 回肠ASBT和OSTα-OSTβ在调节胆汁酸信号中的作用
    • 作者：Paul A. Dawson
    • 刊名：Digestive Diseases (Basel, Switzerland)
    • 2017年第3期
    摘要：BackgroundIn addition to their classical role as detergents, bile acids function as signaling molecules to regulate gastrointestinal physiology, carbohydrate and lipid metabolism, and energy expenditure. The pharmacodynamic potential of bile acids is dependent in part on the tight pharmacokinetic control of their concentration and metabolism, properties governed by their hepatic synthesis, enterohepatic cycling, and biotransformation via host and gut microbiota-catalyzed pathways.
  • 9.

    【2hr】New Developments on the Treatment of Liver Fibrosis

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    机译 肝纤维化治疗的新进展
    摘要：Liver fibrosis results from many chronic injuries, and often progresses to cirrhosis, liver failure, portal hypertension, and hepatocellular carcinoma. Liver transplantation is the only treatment available for patients with advanced stages of liver fibrosis. Therefore, new strategies for anti-fibrotic therapy are required. Various kinds of hepatocyte damage result in inflammation which leads to activation of hepatic stellate cells (HSCs), which are the major source of myofibroblasts in the liver. Myofibroblasts proliferate in response to various kinds of cytokines, chemokines, and growth factors and produce extracellular matrix proteins (ECMs), which forms the fibrous scar. Myofibroblasts undergo apoptosis and inactivation when the underlying causative etiologies are cleared. Here we describe our current knowledge of targeting the steps in HSC activation as therapeutic target for liver fibrosis.
  • 10.

    【2hr】PATHOGENESIS AND MANAGEMENT OF ALCOHOLIC LIVER DISEASE

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    机译 酒精性肝病的病原学和治疗
    摘要：Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality. ALD encompasses a spectrum of disorders ranging from asymptomatic steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis and its related complications. Moreover, patients can develop an acute-on-chronic form of liver failure called alcoholic hepatitis (AH). Most patients are diagnosed at advanced stages of the disease with higher rates of complications and mortality. The mainstream of therapy of ALD patients, regardless of the disease stage, is prolonged alcohol abstinence. The current therapeutic regimens for AH (i.e. prednisolone) have limited efficacy and targeted therapies are urgently needed. The development of such therapies requires translational studies in human samples and suitable animal models that reproduce clinical and histological features of AH. In recent years, new animal models that simulate some of the features of human AH have been developed, and translational studies using human samples have identified potential pathogenic factors and histological parameters that predict survival. In this review, we discuss the pathogenesis and management of ALD, focusing on AH, its current therapies and potential treatment targets.
  • 11.

    【2hr】Environment and Genes: What Is the Interaction?

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    机译 环境与基因：什么是相互作用？
    • 作者：Richard S. Blumberg
    • 刊名：Digestive Diseases (Basel, Switzerland)
    • 2016年第1-2期
    摘要：Inflammatory bowel disease (IBD) results from a continuum of complex interactions between a quartet of host-derived and external elements that involve various aspects of the intestinal microbiota, the immune system that is centered around the intestinal epithelial cell barrier, the genetic composition of the host and specific environmental factors. Recent studies into the complexity of these arrangements increasingly support the syndromic nature of this disorder and involve a wide range of interacting biologic pathways that affect innate immunity, adaptive immunity, endoplasmic reticulum stress and autophagy as well as metabolic pathways associated with cellular homeostasis. It is further likely that all of the aforementioned host factors including the microbiota, which is as much a part of ourselves as is any organ system, are under the influence of yet-to-be-understood environmental factors that predispose to and precipitate IBD. Notwithstanding the importance of genetic predisposition, these environmental influences are no doubt central to disease pathogenesis in light of the rapid emergence of IBD throughout the world and assumption of disease in migrating populations from low to high risk environments. It can thus be anticipated that environmental factors that modify the risk for development of IBD have the common attribute of affecting the relationship between the commensal microbiota and the immune system in a manner that intersects with the functionally relevant immuno-genetic pathways, and potentially modifies them through epigenetic effects, in a manner that are uniquely operative within a particular syndromic context of IBD and occur sequentially and in a reiterative fashion, perhaps beginning in early life.
  • 12.

    【2hr】From Reflux Esophagitis to Esophageal Adenocarcinoma

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    机译 从反流性食管炎到食管腺癌
    • 作者：Rhonda F. Souza
    • 刊名：Digestive Diseases (Basel, Switzerland)
    • 2016年第5期
    摘要：Reflux esophagitis causes Barrett's metaplasia, an abnormal esophageal mucosa predisposed to adenocarcinoma. Medical therapy for reflux esophagitis focuses on decreasing gastric acid production with proton pump inhibitors. We have reported that reflux esophagitis in a rat model develops from a cytokine-mediated inflammatory injury, not from a caustic chemical (acid) injury. In this model, refluxed acid and bile stimulate the release of inflammatory cytokines from esophageal squamous cells, recruiting lymphocytes first to the submucosa and later to the luminal surface. Emerging studies on acute reflux esophagitis in humans support this new concept, suggesting that reflux-induced cytokine release may be a future target for medical therapies. Sometimes, reflux esophagitis heals with Barrett's metaplasia, a process facilitated by reflux-related nitric oxide (NO) production and Sonic Hedgehog secretion by squamous cells. We have shown that NO reduces expression of genes that promote a squamous cell phenotype, while Hedgehog signaling induces genes that mediate the development of the columnar cell phenotypes of Barrett's metaplasia. Agents targeting esophageal NO production or Hedgehog signaling conceivably could prevent the development of Barrett's esophagus. Persistent reflux promotes cancer in Barrett's metaplasia. We have reported that acid and bile salts induce DNA damage in Barrett's cells. Bile salts also cause NF-κB activation in Barrett's cells, enabling them to resist apoptosis in the setting of DNA damage, and likely contributing to carcinogenesis. Oral treatment with ursodeoxycholic acid prevents the esophageal DNA damage and NF-κB activation induced by toxic bile acids. Altering bile acid composition might be another approach to cancer prevention.
  • 13.

    【2hr】New Biology to New Treatment of Helicobacter pylori-Induced Gastric Cancer

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    机译 幽门螺杆菌诱发的胃癌新疗法的新生物学
    摘要：BackgroundHelicobacter pylori is a bacterial carcinogen and incurs the highest known level of risk for the development of gastric cancer, a disease that claims hundreds of thousands of lives per year. Approximately 89% of the global gastric cancer burden and 5.5% of malignancies worldwide are attributable to H. pylori-induced inflammation and injury. However, only a fraction of colonized persons ever develop neoplasia, and disease risk involves well-choreographed interactions between pathogen and host, which are dependent upon strain-specific bacterial factors, host genotypic traits, and/or environmental conditions.
  • 14.

    【2hr】Links of autophagy dysfunction to inflammatory bowel disease onset

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    机译 自噬功能障碍与炎症性肠病发作的联系
    摘要：IntroductionAutophagy is a cellular stress response that plays key roles in physiological processes, such as adaptation to starvation, degradation of aberrant proteins or organelles, anti-microbial defense, protein secretion, and innate and adaptive immunity. Dysfunctional autophagy is recognized as a contributing factor in many chronic inflammatory diseases, including inflammatory bowel disease (IBD). Genetic studies have identified multiple IBD-associated risk loci that include genes required for autophagy, and several lines of evidence demonstrate that autophagy is impaired in IBD patients. How dysfunctional autophagy contributes to IBD onset is currently under investigation by researchers.
  • 15.

    【2hr】Methotrexate for inflammatory bowel diseases – New developments

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    机译 甲氨蝶呤治疗炎性肠病–新进展
    • 作者：Hans H. Herfarth
    • 刊名：Digestive Diseases (Basel, Switzerland)
    • 2016年第1-2期
    摘要：Methotrexate (MTX) is an established therapy for patients with steroid dependent Crohn’s disease (CD). MTX is also frequently used in combination with anti-TNF agents to suppress anti-drug antibody formation. It has been suggested in the past that MTX lacks any clinical effectiveness in patients with ulcerative colitis (UC), however newer data at least partially contradict this assumption. The following review will discuss recent data for the use of MTX in CD, UC and in combination with anti-TNF agents.
  • 16.

    【2hr】Malignancies in Primary Sclerosing Cholangitis – A Continuing Threat

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    机译 原发性硬化性胆管炎的恶性肿瘤-持续的威胁
    摘要：Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease of unknown etiology, primarily targeting cholangiocytes at any portion of the biliary tree. No effective medical treatments are currently available. A unique feature of PSC is its close association (about 80%) with inflammatory bowel disease (IBD), mainly ulcerative colitis (UC). As in many chronic inflammatory conditions, cancer development can complicate PSC, accounting for >40% of deaths. Cholangiocarcinoma (CCA), gallbladder carcinoma (GBC) and colorectal carcinoma (CRC) have been variably associated to PSC, with a prevalence up to 13–14%. The risk of cancer is one of the most challenging issues in the management of PSC; it raises several questions about cancer surveillance, early diagnosis, prevention and treatment.Key MessagesAmong the different cancers complicating PSC, CCA is the most relevant, because it is more frequent (incidence of 0.5–1.5%) and because the prognosis is poor (5-year survival <10%). Early diagnosis of CCA in PSC can be difficult because lesions may not be evident in radiological studies. Surgical resection provides disappointing results; liver transplantation combined with neoadjuvant chemoradiotherapy is being proposed, but this approach is limited to a highly selected group of patients and is available only in a few specialized centers. Similar to CCA, GBC carries a dismal prognosis. Since it is difficult to discriminate GBC from other gallbladder abnormalities, cholecystectomy has been proposed in all gallbladder lesions detected in PSC, regardless of their size. CRC is a frequent complication of PSC associated to UC; its incidence steadily increases with time of colitis, reaching up to 20–30% of the patients after 20 years. Colonoscopy with extensive histologic sampling at an annual/biannual interval is an effective surveillance strategy. However, when dysplastic lesions are detected, preemptive proctocolectomy should be considered.
  • 17.

    【2hr】Diet1 is a Regulator of FGF15/19-dependent Bile Acid Synthesis

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    机译 Diet1是FGF15 / 19依赖性胆汁酸合成的调节剂
    摘要：BackgroundA fascinating aspect of bile acid homeostasis is the coordination between bile acid uptake in intestine and hepatic bile acid synthesis. In response to bile acid uptake in enterocytes, FXR is activated and induces transcription of fibroblast growth factor (FGF) 15 in mice, or FGF19 in humans. FGF15/19 is secreted into the enterohepatic circulation, and through activation of hepatic receptors, leads to repression of Cyp7a1, a rate-limiting enzyme for bile acid synthesis. Using a genetic approach, we identified a novel protein, Diet1, as a control point for FGF15/19 production.
  • 18.

    【2hr】Impact of Inhibiting Ileal Apical Versus Basolateral Bile acid Transport on Cholesterol Metabolism and Atherosclerosis in Mice

    包量

    机译 抑制回肠顶端和基底外侧胆汁酸转运对小鼠胆固醇代谢和动脉粥样硬化的影响
    • 作者：Paul A. Dawson
    • 刊名：Digestive Diseases (Basel, Switzerland)
    • 2015年第3期
    摘要：BackgroundBile acid sequestrants have been used for many years to treat hypercholesterolemia by increasing hepatic conversion of cholesterol to bile acids, thereby inducing hepatic LDL receptor expression and clearance of apoB-containing particles. In order to further understand the underlying molecular mechanisms linking gut-liver signaling and cholesterol homeostasis, mouse models defective in ileal apical membrane bile acid transport (Asbt null) and ileal basolateral membrane bile acid transport (Ostα null) were studied under basal and hypercholesterolemic conditions.
  • 19.

    【2hr】Serum Markers in the Clinical Management of Celiac Disease

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    机译 乳糜泻临床治疗中的血清标志物
    摘要：The advent of highly reliable non-invasive celiac diagnostic tests has transformed the field of celiac disease, from diagnosis, to evaluation of epidemiology, to clinical and translational research. Serologic tests in their modern forms are highly sensitive and specific for diagnosis, allowing for consideration of avoidance of diagnostic intestinal biopsy in some settings. On the other hand, as predictors of intestinal damage and for use in monitoring disease activity, currently available non-invasive tests have been disappointing. Serologic tests, while a measure of disease activity, do not correlate well with histology or symptomatology and it is unclear if they predict long-term risk. Additionally, while the many clinically available tests have improved accessibility, tests can have widely different cut-off levels and overall performance, making comparison of levels in individual patients overtime and across populations quite difficult. In the future, we can expect to see improvement in the currently available serologic tests including tTG and DGP with expansion of the dynamic range of the tests and the celiac care community should push for standardization of assays that would simplify research and patient care. Additionally, current serologic tests are measures of the adaptive immune response in celiac disease but do not directly measure intestinal inflammation. Promising work on intestinal-fatty acid binding protein (I-FABP) and other assays which directly measure intestinal damage may compliment traditional serologic tests and further improve our ability to non-invasively diagnose and monitor celiac disease. The coming years hold promise for the continuing evolution of serum based tests in celiac disease with the possibility of substantial improvement of patient care and clinical research.
  • 20.

    【2hr】Acetaminophen - Dose-dependent Drug Hepatotoxicity and Acute Liver Failure in Patients

    包量

    机译 对乙酰氨基酚-剂量依赖性药物的肝毒性和患者的急性肝衰竭
    • 作者：Hartmut Jaeschke
    • 刊名：Digestive Diseases (Basel, Switzerland)
    • 2015年第4期
    摘要：BackgroundDrug-induced liver injury (DILI) is a rare but serious clinical problem. A number of drugs can cause severe liver injury and acute liver failure (ALF) at therapeutic doses in a very limited number of patients (<1:10,000). This idiosyncratic DILI (iDILI), which is currently not predictable in preclinical safety studies, appears to depend on individual susceptibility and the inability to adapt to the cellular stress caused by a particular drug. In striking contrast to iDILI, drugs with dose-dependent hepatotoxicity are mostly detected during preclinical studies and do not reach the market. One notable exception is acetaminophen (APAP, paracetamol), which is a safe drug at therapeutic doses but can cause severe liver injury and ALF after intentional and unintentional overdoses.
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