Therapeutical targets for revert liver fibrosis [Blancos terapéuticos potenciales para revertir la cirrosis hepática]

Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis and its complications: portal hypertension, liver failure, hepatic encephalopathy, and hepatocellular carcinoma and others. Efficient and well-tolerated antifibrotic drugs are still lacking, and current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Efforts over the past decade have mainly focused on fibrogenic cells generating the scarring response, although promising data on inhibition of parenchymal injury or reduction of liver inflammation have also been obtained. A large number of approaches have been validated in culture studies and in animal models, and several clinical trials are underway or anticipated for a growing number of molecules. This review highlight recent advances in the molecular mechanisms of liver fibrosis and discusses mechanistically based strategies that have recently emerged

[Transforming growth factor-beta as a therapeutic target]

Transforming growth factor-beta (TGF-beta) family members include TGF-beta, activins, and bone morphogenetic proteins (BMP). These proteins are structurally related cytokines secreted in diverse Metazoans. TGF-beta family members regulate cellular functions such as proliferation, apoptosis, differentiation, and migration, and play an important role in organism development. Deregulated TGF-beta family signaling participates in various human pathologies including autoimmune diseases, vascular disorders, fibrotic disease, and cancer. Ligand-induced activation of TGF-beta family receptors with intrinsic serine/threonine kinase activity, triggers phosphorylation of the intracellular effectors of TGF-beta signaling, the Smads proteins. Once these proteins are activated they translocate into the nucleus, where they induce transcription of target genes and regulate cellular processes and functions. Novel therapeutic strategies are currently being developed to correct alterations in pathologies that involve TGF-beta as the main mediator. The English version of this paper is available at: http://www.insp.mx/salud/index.html. [References: 41

Therapeutical targets for revert liver fibrosis [Blancos terapéuticos potenciales para revertir la cirrosis hepética]

Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis and its complications: portal hypertension, liver failure, hepatic encephalopathy, and hepatocellular carcinoma and others. Efficient and well-tolerated antifibrotic drugs are still lacking, and current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Efforts over the past decade have mainly focused on fibrogenic cells generating the scarring response, although promising data on inhibition of parenchymal injury or reduction of liver inflammation have also been obtained. A large number of approaches have been validated in culture studies and in animal models, and several clinical trials are underway or anticipated for a growing number of molecules. This review highlight recent advances in the molecular mechanisms of liver fibrosis and discusses mechanistically based strategies that have recently emerged

Transforming growth factor-β as a therapeutic target [El factor de crecimiento transformante β como blanco terapéutico]

Transforming growth factor-β (TGF-β) family members include TGF-β, activins, and bone morphogenetic proteins (BMP). These proteins are structurally related cytokines secreted in diverse Metazoans. TGF-β family members regulate cellular functions such as proliferation, apoptosis, differentiation, and migration, and play an important role in organism development. Deregulated TGF-β family signaling participates in various human pathologies including autoimmune diseases, vascular disorders, fibrotic disease, and cancer. Ligand-induced activation of TGF-β family receptors with intrinsic serine/threonine kinase activity, triggers phosphorylation of the intracellular effectors of TGF-β signaling, the Smads proteins. Once these proteins are activated they translocate into the nucleus, where they induce transcription of target genes and regulate cellular processes and functions. Novel therapeutic strategies are currently being developed to correct alterations in pathologies that involve TGF-β as the main mediator

[Transforming growth factor-beta as a therapeutic target]

Transforming growth factor-beta (TGF-beta) family members include TGF-beta, activins, and bone morphogenetic proteins (BMP). These proteins are structurally related cytokines secreted in diverse Metazoans. TGF-beta family members regulate cellular functions such as proliferation, apoptosis, differentiation, and migration, and play an important role in organism development. Deregulated TGF-beta family signaling participates in various human pathologies including autoimmune diseases, vascular disorders, fibrotic disease, and cancer. Ligand-induced activation of TGF-beta family receptors with intrinsic serine/threonine kinase activity, triggers phosphorylation of the intracellular effectors of TGF-beta signaling, the Smads proteins. Once these proteins are activated they translocate into the nucleus, where they induce transcription of target genes and regulate cellular processes and functions. Novel therapeutic strategies are currently being developed to correct alterations in pathologies that involve TGF-beta as the main mediator. The English version of this paper is available at: http://www.insp.mx/salud/index.html. [References: 41

Hepatocyte growth factor (HGF) and its therapeutic applications [Factor de crecimiento de hepatocitos (HGF) y sus aplicaciones terapéuticas.]

Hepatocyte growth factor (HGF) also known as "scatter factor" (SF), was identified for the first time as a potent mitogen of primary cultured hepatocytes; it has multiple biological responses in a variety of cells including mitogenic, motogenic, morphogenic and antiapoptotic activities. It is secreted as an inactive single chain protein and isproteolitically cleaved to form an active two chain HGF. The hepatocyte growth factor activator (HGFA) is the principal activator of HGF. HGF exerts its biological effects through transmembrane tyrosine kinase receptor (c-Met). HGF is a growth factor displaying a remarkable ability to promote tissue repair and organ regeneration after injury. Therefore attention should be set on the clinical potential of HGF as a treatment for various diseases

Hepatic fibrosis. Role of matrix metalloproteases and TGFβ [Fibrosis hepática. El papel de las metaloproteinasas y deTGF-β]

Liver fibrosis and cirrhosis involve multiple cellular and molecular events that lead to deposition of an excess of extracellular matrix proteins and increase the distortion of normal liver architecture. Etiologies include chronic viral hepatitis, alcohol abuse and drug toxicity. Degradation of these matrix proteins occurs predominantly as a result of a family of enzymes called metalloproteases (MMPs) that specifically degrade collagenous and non-collagenous substrates. Matrix degradation in the liver is due to the action of at least four of the se enzymes: MMP-1, MMP-2, MMP-3 and MMP-9. In the fibrinolytic system, MMPs can be activated through proteolytic cleavage by the action of urokinase plasminogen activator; a second mechanism includes the same metalloproteases. This activity is regulated at many levels in the fibrinolytic system. The main regulator is the PAI-1. This molecule blocks the conversion of plasminogen into plasmin, and the MMP cannot be activated. At a second level, the inhibition is possible by binding to inhibitors called TIMP that can inhibit the proteolitic activity even when the MMPs had been previously activated by plasmin. During abnormal conditions, overexpression of these inhibitors is directed by the transforming growth factor-β that in a fibrotic disease acts as an extremely important adverse factor

[Hepatocyte growth factor (HGF) and its therapeutic applications]

Hepatocyte growth factor (HGF) also known as "scatter factor" (SF), was identified for the first time as a potent mitogen of primary cultured hepatocytes; it has multiple biological responses in a variety of cells including mitogenic, motogenic, morphogenic and antiapoptotic activities. It is secreted as an inactive single chain protein and isproteolitically cleaved to form an active two chain HGF. The hepatocyte growth factor activator (HGFA) is the principal activator of HGF. HGF exerts its biological effects through transmembrane tyrosine kinase receptor (c-Met). HGF is a growth factor displaying a remarkable ability to promote tissue repair and organ regeneration after injury. Therefore attention should be set on the clinical potential of HGF as a treatment for various diseases. [References: 34

Hepatocyte growth factor (HGF) and its therapeutic applications [Factor de crecimiento de hepatocitos (HGF) y sus aplicaciones terapéuticas.]

Hepatocyte growth factor (HGF) also known as "scatter factor" (SF), was identified for the first time as a potent mitogen of primary cultured hepatocytes; it has multiple biological responses in a variety of cells including mitogenic, motogenic, morphogenic and antiapoptotic activities. It is secreted as an inactive single chain protein and isproteolitically cleaved to form an active two chain HGF. The hepatocyte growth factor activator (HGFA) is the principal activator of HGF. HGF exerts its biological effects through transmembrane tyrosine kinase receptor (c-Met). HGF is a growth factor displaying a remarkable ability to promote tissue repair and organ regeneration after injury. Therefore attention should be set on the clinical potential of HGF as a treatment for various diseases