Vittrupmaddox3303

An increasing percentage of people have or are at risk to develop non-alcoholic fatty liver disease (NAFLD) worldwide. NAFLD comprises different stadia going from isolated steatosis to non-alcoholic steatohepatitis (NASH). NASH is a chronic state of liver inflammation that leads to the transformation of hepatic stellate cells to myofibroblasts. GSK-3 inhibitor These cells produce extra-cellular matrix that results in liver fibrosis. In a normal situation, fibrogenesis is a wound healing process that preserves tissue integrity. However, sustained and progressive fibrosis can become pathogenic. This process takes many years and is often asymptomatic. Therefore, patients usually present themselves with end-stage liver disease e.g., liver cirrhosis, decompensated liver disease or even hepatocellular carcinoma. Fibrosis has also been identified as the most important predictor of prognosis in patients with NAFLD. Currently, only a minority of patients with liver fibrosis are identified to be at risk and hence referred for treatment. This is not only because the disease is largely asymptomatic, but also due to the fact that currently liver biopsy is still the golden standard for accurate detection of liver fibrosis. However, performing a liver biopsy harbors some risks and requires resources and expertise, hence is not applicable in every clinical setting and is unsuitable for screening. Consequently, different non-invasive diagnostic tools, mainly based on analysis of blood or other specimens or based on imaging have been developed or are in development. In this review, we will first give an overview of the pathogenic mechanisms of the evolution from isolated steatosis to fibrosis. This serves as the basis for the subsequent discussion of the current and future diagnostic biomarkers and anti-fibrotic drugs.The intestinal extracellular matrix (ECM) represents a complex network of proteins that not only forms a support structure for resident cells but also interacts closely with them by modulating their phenotypes and functions. More than 300 molecules have been identified, each of them with unique biochemical properties and exclusive biological functions. ECM components not only provide a scaffold for the tissue but also afford tensile strength and limit overstretch of the organ. The ECM holds water, ensures suitable hydration of the tissue, and participates in a selective barrier to the external environment. ECM-to-cells interaction is crucial for morphogenesis and cell differentiation, proliferation, and apoptosis. The ECM is a dynamic and multifunctional structure. The ECM is constantly renewed and remodeled by coordinated action among ECM-producing cells, degrading enzymes, and their specific inhibitors. During this process, several growth factors are released in the ECM, and they, in turn, modulate the deposition of new ECM. In this review, we describe the main components and functions of intestinal ECM and we discuss their role in maintaining the structure and function of the intestinal barrier. Achieving complete knowledge of the ECM world is an important goal to understand the mechanisms leading to the onset and the progression of several intestinal diseases related to alterations in ECM remodeling.Many putative uremic toxins-like indoxyl sulfate, p-cresol sulfate, kynurenic acid, uric acid, and CMPF-are organic anions. Both inter-organ and inter-organismal communication are involved. For example, the gut microbiome is the main source of indole, which, after modification by liver drug metabolizing enzymes (DMEs), becomes indoxyl sulfate. Various organic anion transporters (organic anion transporters, OATs; organic anion-transporting polypeptides, OATPs; multidrug resistance-associated proteins, MRPs, and other ABC transporters like ABCG2)-often termed "drug transporters"-mediate movement of uremic toxins through cells and organs. In the kidney proximal tubule, critical roles for OAT1 and OAT3 in regulating levels of protein-bound uremic toxins have been established using knock-out mice. OATs are important in maintaining residual tubular function in chronic kidney disease (CKD); as CKD progresses, intestinal transporters like ABCG2, which extrude urate and other organic anions into the gut lumen, seem to help restore homeostasis. Uremic toxins like indoxyl sulfate also regulate signaling and metabolism, potentially affecting gene expression in extra-renal tissues as well as the kidney. Focusing on the history and evolving story of indoxyl sulfate, we discuss how uremic toxins appear to be part of an extensive "remote sensing and signaling" network-involving so-called drug transporters and drug metabolizing enzymes which modulate metabolism and signaling. This systems biology view of uremic toxins is leading to a new appreciation of uremia as partly due to disordered remote sensing and signaling mechanisms-resulting from, and causing, aberrant inter-organ (e.g., gut-liver- kidney-CNS) and inter-organismal (e.g., gut microbiome-host) communication.Although platelets and the coagulation factors are components of the blood system, they become part of and contribute to the tumor microenvironment (TME) not only within a solid tumor mass, but also within a hematogenous micrometastasis on its way through the blood stream to the metastatic niche. The latter basically consists of blood-borne cancer cells which are in close association with platelets. At the site of the primary tumor, the blood components reach the TME via leaky blood vessels, whose permeability is increased by tumor-secreted growth factors, by incomplete angiogenic sprouts or by vasculogenic mimicry (VM) vessels. As a consequence, platelets reach the primary tumor via several cell adhesion molecules (CAMs). Moreover, clotting factor VII from the blood associates with tissue factor (TF) that is abundantly expressed on cancer cells. This extrinsic tenase complex turns on the coagulation cascade, which encompasses the activation of thrombin and conversion of soluble fibrinogen into insoluble fibrin. The presence of platelets and their release of growth factors, as well as fibrin deposition changes the TME of a solid tumor mass substantially, thereby promoting tumor progression. Disseminating cancer cells that circulate in the blood stream also recruit platelets, primarily by direct cell-cell interactions via different receptor-counterreceptor pairs and indirectly by fibrin, which bridges the two cell types via different integrin receptors. These tumor cell-platelet aggregates are hematogenous micrometastases, in which platelets and fibrin constitute a particular TME in favor of the cancer cells. Even at the distant site of settlement, the accompanying platelets help the tumor cell to attach and to grow into metastases. Understanding the close liaison of cancer cells with platelets and coagulation factors that change the TME during tumor progression and spreading will help to curb different steps of the metastatic cascade and may help to reduce tumor-induced thrombosis.