Abstract
Liver fibrosis is a pathophysiologic process involving the accumulation of extracellular matrix proteins as collagen deposition. Advanced liver fibrosis can evolve in cirrhosis, portal hypertension and often requires liver transplantation. At the cellular level, hepatic fibrosis involves the activation of hepatic stellate cells and their transdifferentiation into myofibroblasts. Numerous pro-fibrogenic mediators including the transforming growth factor-β1, the platelet-derived growth factor, endothelin-1, toll-like receptor 4, and reactive oxygen species are key players in this process. Knowledge of the cellular and molecular mechanisms underlying hepatic fibrosis development need to be extended to find novel therapeutic strategies. Antifibrotic therapies aim to inhibit the accumulation of fibrogenic cells and/or prevent the deposition of extracellular matrix proteins. Natural products from terrestrial and marine sources, including sulfur-containing compounds, exhibit promising activities for the treatment of fibrotic pathology. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans are largely unknown. This review aims to provide a reference collection on experimentally tested natural anti-fibrotic compounds, with particular attention on sulfur-containing molecules. Their chemical structure, sources, mode of action, molecular targets, and pharmacological activity in the treatment of liver disease will be discussed.
Highlights
Liver fibrosis is a pathological process that leads to an excessive accumulation of extracellular matrix (ECM) proteins and the loss of the physiological liver tissue architecture [1]
This review provides the “state of the art” on molecular mechanisms underlying liver fibrosis and the pharmacological potential of natural sulfur-containing compounds as an alternative therapeutic strategy, in order to define new directions in the fight against chronic liver diseases
(RhoA)/Rho-associated protein kinase (ROCK), janus kinase 1 (JAK)/signal transducers of activated transcription (STAT), Ras/Raf leading to the activation of several important transcription factors as the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), STAT1/3 and extracellular signal-regulated kinases 1 and 2 (Erk1/2), which enhance the expression of genes involved in survival, migration and ECM production
Summary
Liver fibrosis is a pathological process that leads to an excessive accumulation of extracellular matrix (ECM) proteins and the loss of the physiological liver tissue architecture [1]. HSCs, promoting their differentiation into myofibroblasts, as well as they can stimulate the epithelial to mesenchymal transition and the recruitment of circulating monocytes and fibrocytes from bone marrow The combination of these events leads to an increased expression and secretion of elastin, collagen, proteoglycans and glycoproteins, causing the accumulation of the ECM and the fibrotic process. The cirrhotic process is associated with the necrosis of hepatocytes, the collapse of the reticular support system with consequent deposition of connective tissue, the subversion of the vascular bed, and the nodular regeneration of the remaining parenchyma This process can take years or decades to develop, a correct staging and an adequate pharmacological therapy of fibrosis are extremely important, for the individual prognostic evaluation of the patient, and for the prevention of disease progression towards cirrhosis and hepatobiliary cancer [5,6]. Since these compounds are powerful antioxidants, due to the unique chemical properties of sulfur atoms, the relationship among reactive oxygen species (ROS)/nitric oxide (NO) production, liver fibrosis and the protective role of sulfur compounds, has been highlighted
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