Anti-fibrotic treatments for chronic liver diseases: The present and the future.
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ABSTRACT:
SUBMITTER: Odagiri N
PROVIDER: S-EPMC8273638 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Inflammation involving the innate and adaptive immune systems is a normal response to infection. However, when allowed to continue unchecked, inflammation may result in autoimmune or autoinflammatory disorders, neurodegenerative disease, or cancer. A variety of safe and effective anti-inflammatory agents are available, including aspirin and other nonsteroidal anti-inflammatories, with many more drugs under development. In particular, the new era of anti-inflammatory agents includes "biologicals" such as anticytokine therapies and small molecules that block the activity of kinases. Other anti-inflammatories currently in use or under development include statins, histone deacetylase inhibitors, PPAR agonists, and small RNAs. This Review discusses the current status of anti-inflammatory drug research and the development of new anti-inflammatory therapeutics.
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Project description:Background/aimsEfficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects.MethodsThe effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis.ResultsThe evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl-2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2.ConclusionThe combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.
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Project description:Nintedanib, a Food and Drug Administration-approved drug for the treatment of patients with idiopathic pulmonary fibrosis (IPK), inhibits both tyrosine kinase receptors and non-receptor kinases, and block activation of platelet-derived growth factor receptors, fibroblast growth factor receptor, vascular endothelial growth factor receptors, and Src family kinases. Preclinical and clinical studies have revealed the potent anti-fibrotic effect of nintedanib in IPK in human and animal models. Recent preclinical studies have also demonstrated the inhibitory effect of nintedanib on the development and progression of tissue fibrosis in other organs, including liver, kidney, and skin. The anti-fibrotic actions of nintedanib occur through a number of mechanisms, including blocking differentiation of fibroblasts to myofibroblasts, inhibition of epithelial-mesenchymal transition, and suppression of inflammation and angiogenesis. In this article, we summarize the mechanisms and efficacy of nintedanib in the treatment of fibrotic diseases in animal models and clinical trials, provide an update on recent advances in the development of other novel antifibrotic agents in preclinical and clinical study, and offer our perspective about the possible clinical application of these agents in fibrotic diseases.
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Project description:BackgroundThe possibilities in the field of molecular therapies of neuromuscular diseases have rapidly developed in recent years. First compounds are already available in clinical practice and numerous other substances are in advanced phases of clinical trials. This article gives an exemplary overview of the current state of clinical research in molecular therapies of neuromuscular diseases. It also gives a view into the near future of the clinical application, including the challenges.DiscussionUsing Duchenne muscular dystrophy (DMD) and myotubular myopathy as examples, the principles of gene addition in monogenetic skeletal muscle diseases, which are already manifested in childhood are described. In addition to initial successes, the challenges and setbacks hindering the approval and regular clinical application of further compounds are demonstrated. Furthermore, the state of current clinical research in Becker-Kiener muscular dystrophy (BMD) and the numerous forms of limb-girdle muscular dystrophy (LGMD) are summarized. Numerous new therapeutic approaches and a corresponding outlook are also shown for facioscapulohumeral muscular dystrophy (FSHD), Pompe disease, and myotonic dystrophy.ConclusionClinical research in the field of molecular therapy of neuromuscular diseases is one of the pacesetters of modern precision medicine; however, challenges need to be seen, jointly addressed and overcome in the future.
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Project description:Liver transplantation represents the standard treatment for people with an end-stage liver disease and some liver-based metabolic disorders; however, shortage of liver donor tissues limits its availability. Furthermore, whole liver replacement eliminates the possibility of using native liver as a possible target for future gene therapy in case of liver-based metabolic defects. Cell therapy has emerged as a potential alternative, as cells can provide the hepatic functions and engraft in the liver parenchyma. Various options have been proposed, including human or other species hepatocytes, hepatocyte-like cells derived from stem cells or more futuristic alternatives, such as combination therapies with different cell types, organoids and cell-biomaterial combinations. In this review, we aim to give an overview of the cell therapies developed so far, highlighting preclinical and/or clinical achievements as well as the limitations that need to be overcome to make them fully effective and safe for clinical applications.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.
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