In addition, they also partici pate in the pathogenesis of severa

In addition, they also partici pate in the pathogenesis of several CNS diseases such as stroke, Alzheimers disease, neuroinflammation, and malignant glioma. Among members of the MMP family, MMP 9 has been shown to be elevated in var ious brain disorders. thorough Moreover, several pro inflam matory mediators such as interleukin 1b, lipopolysaccharide, bradykinin, and oxidized low density lipoprotein can induce MMP 9 expres sion and activity in cultured rat astrocytes, indi cating that the expression and activation of MMP 9 may be regulated during brain injuries and inflammation. Transforming growth factor b is a multifunc tional cytokine that regulates a broad diversity of phy siological and pathological processes, including tissue wound healing, inflammation, cell proliferation, differen tiation, migration, and extracellualr matrix synth esis.

Accordingly, TGF b family members play an important role in early embryogenesis and in the homeostasis of adult tissues. However, several lines of evidence show that lack of coordination of TGF b dependent signaling often leads to a number of human diseases, including fibrosis, cancer, and autoimmune diseases. Moreover, Inhibitors,Modulators,Libraries TGF b is a key immune system modulator, TGF b1 especially, that may have both pro and anti inflammatory effects in immune system depending on the cell type. Within the CNS, all three isoforms of TGF bs family, i. e. TGF b1, b2, and b3, are produced by both glial and neural cells. Previous reports have suggested a relationship between increased TGF Inhibitors,Modulators,Libraries b1 levels and cerebral ischemic injury.

Following CNS injury, elevated TGF b levels in astrocytes has been proven to be associated with astrocytic scar formation. Emerging evidence has also demonstrated that TGF b1 is a crucial mediator in the pathogenesis of several CNS disorders, such as in organization of glial scars in response to injury and in several neurodegenerative disorders. TGF bs binds Inhibitors,Modulators,Libraries to Inhibitors,Modulators,Libraries two serinethreonine kinase receptors which consist of TGF bRI and TGF bRII. When a ligand binds, TGF bRII phosphorylates TGF bRI and activates Smad dependent intracellular signaling pathways and thus leads to expression of several genes. In addition to activation of Smad dependent pathways, TGF b can affect several signal transduction Inhibitors,Modulators,Libraries pathways in a Smad independent manner, such as mitogen acti vated protein kinases, including extracellular signal related protein kinase, p38 MAPK, and c Jun N terminal kinase.

In human gin gival and skin fibroblasts, inhibitor manufacture both p38 MAPK and Smad3 cooperate in regulating TGF b induced MMP 13 expression, whereas ERK12 cooperates with Smad3 in regulating connective tissue growth factor expression. Recently, increasing evidence has attributed the cellular damage in neurodegenerative disorders to oxidative stress that leads to generation of reactive oxy gen species that are responsible for brain inflam matory disorders and that have deleterious effects during CNS pathogenic processes.

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