0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Piperine inhibits AML-12 hepatocyte EMT and LX-2 HSC activation and alleviates mouse liver fibrosis provoked by CCl 4: roles in the activation of the Nrf2 cascade and subsequent suppression of the TGF-β1/Smad axis

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Piperine inhibits hepatocyte EMT and HSC activation and ameliorates mouse liver fibrosis provoked by CCl 4 via activating Nrf2 and subsequently suppressing TGF-β1/Smad signaling.

          Abstract

          Piperine (PIP) is an alkaloid derived from peppercorns. Herein, we assessed its effects on hepatocyte EMT and HSC activation in vitro and CCl 4-elicited liver fibrosis in mice. Further experiments were performed to unveil the molecular mechanisms underlying the hepatoprotective activity of PIP. We found that PIP inhibited TGF-β1-provoked AML-12 hepatocyte EMT and LX-2 HSC activation. Mechanistically, in AML-12 and LX-2 cells, PIP evoked Nrf2 nuclear translocation and increased transcriptions of Nrf2-responsive antioxidative genes. These events decreased TGF-β1-induced production of ROS. Moreover, PIP increased the expression of Smad7, suppressed phosphorylation and nuclear translocation of Smad2/3, and decreased the transcriptions of Smad2/3-downstream genes. Knockdown of Nrf2 abrogated the protective activity of PIP against TGF-β1. Modulatory effects of PIP on the TGF-β1/Smad cascade were also crippled, which suggested that activation of Nrf2 played critical roles in the regulatory effects of PIP on TGF-β1/Smad signaling. Experiments in vivo unveiled that PIP ameliorated mouse liver fibrosis provoked by CCl 4. PIP modulated the intrahepatic contents of the markers of EMT and HSC activation. In mouse livers, PIP activated Nrf2 signaling and reduced Smad2/3-dependent gene transcriptions. Our findings collectively suggested PIP as a new chemical entity with the capacity of alleviating liver fibrosis. The activation of the Nrf2 cascade and subsequent suppression of the TGF-β1/Smad axis are implicated in the hepatoprotective activity of PIP.

          Related collections

          Most cited references53

          • Record: found
          • Abstract: found
          • Article: not found

          TGF-β: the master regulator of fibrosis.

          Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Dose translation from animal to human studies revisited.

            As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis.

              Wound healing is one of the most complex biological processes to occur in life. Repair of tissue following injury involves dynamic interactions between multiple cell types, growth factors, inflammatory mediators and components of the extracellular matrix (ECM). Aberrant and uncontrolled wound healing leads to a non-functional mass of fibrotic tissue. In the eye, fibrotic disease disrupts the normally transparent ocular tissues resulting in irreversible loss of vision. A common feature in fibrotic eye disease is the transdifferentiation of cells into myofibroblasts that can occur through a process known as epithelial-mesenchymal transition (EMT). Myofibroblasts rapidly produce excessive amounts of ECM and exert tractional forces across the ECM, resulting in the distortion of tissue architecture. Transforming growth factor-beta (TGFβ) plays a major role in myofibroblast transdifferentiation and has been implicated in numerous fibrotic eye diseases including corneal opacification, pterygium, anterior subcapsular cataract, posterior capsular opacification, proliferative vitreoretinopathy, fibrovascular membrane formation associated with proliferative diabetic retinopathy, submacular fibrosis, glaucoma and orbital fibrosis. This review serves to introduce the pathological functions of the myofibroblast in fibrotic eye disease. We also highlight recent developments in elucidating the multiple signaling pathways involved in fibrogenesis that may be exploited in the development of novel anti-fibrotic therapies to reduce ocular morbidity due to scarring.
                Bookmark

                Author and article information

                Contributors
                Journal
                FFOUAI
                Food & Function
                Food Funct.
                Royal Society of Chemistry (RSC)
                2042-6496
                2042-650X
                November 15 2021
                2021
                : 12
                : 22
                : 11686-11703
                Affiliations
                [1 ]School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, Hubei, China
                Article
                10.1039/D1FO02657G
                34730139
                685466a3-a926-451d-a62b-110c22e724b3
                © 2021

                http://rsc.li/journals-terms-of-use

                History

                Comments

                Comment on this article