TGF-β signal shifting between tumor suppression and fibro-carcinogenesis in human chronic liver diseases

Comparative clinical study between the effect of fenofibrate alone and its combination with pentoxifylline on biochemical parameters and liver stiffness in patients with non-alcoholic fatty liver disease

“…The overall results indicate that the combination of fenofibrate plus pentoxifylline results in more improvement in liver fibrosis than fenofibrate alone as indicated by more improvement in indirect markers of hepatic fibrosis (ALT, AST, GGT), a direct marker linked to matrix deposition (HA) and cytokine/growth factor linked to liver fibrosis (TGF-b1) together with more improvement in liver stiffness. This favorable effect of fenofibrate plus pentoxifylline on liver fibrosis may be attributed to the anti-inflammatory effect of both drugs since both drugs can reduce the expression and down-regulate TNF-a [14,15,18], whereas TNF-a activation of receptor tyrosine kinases can convert a cytostatic TGF-beta signal to collagen-producing character in activated hepatic stellate cells under the influence of inflammatory microenvironments [49]. Furthermore, the decrease in liver fibrosis provoked by fenofibrate plus pentoxifylline may be related to the antifibrogenic effect of both drugs on activated hepatic stellate cells, the major cells involved in hepatic fibrosis [51,57,58].…”

“…The production of TNFalpha is one of the primary events in liver injury triggering the production of various cytokines [33] that recruit inflammatory cells which in their turn could damage hepatocytes and induce fibrogenesis. Interestingly, TNF-a and growth factors activation of receptor tyrosine kinases can convert a cytostatic TGF-beta signal to collagen-producing character in activated hepatic stellate cells under the influence of inflammatory microenvironments [49]. The notion that fenofibrate may reduce TGF-b1 expression [50,51] may give logical justification for decreased TGF-b1 level noted in the fenofibrate treated group.…”

Stevioside inhibits experimental fibrosis by down‐regulating profibrotic Smad pathways and blocking hepatic stellate cell activation

“…In this pathway, Smads 2 and 3 are important mediators, serving as transcriptional factors that constantly shuttle between the cytoplasm and the nucleus, once they are complexed to Smad4 and are phosphorylated at the C‐terminal by TβRI. Nevertheless, once this pathway is over‐stimulated, a negative feedback response is released, mediated by Smad7, antagonizing the signalling cascade of TGF‐β1 . There is also a non‐canonical pathway in which PDGF activates JNK, which, in turn, phosphorylates Smad3 in the linker domain to generate p‐Smad3L, which rapidly translocates to the nucleus where it stimulates HSC proliferation .…”

“…In addition, Smad3 plays a major role in fibrogenesis by inducing the production of collagen; thus, these proteins are essential in the fibrogenic process that ultimately leads to cirrhosis. Moreover, proteins involved in HSC proliferation, such as PDGFR, that enhance inflammatory and fibrogenic responses via MAPK, as well as NF‐κB and c‐Myc, a potent mitogen that can be promoted by PDGF and pro‐inflammatory cytokines via pSmad3L, contribute to the exacerbation of the fibrogenic response …”

Transforming Growth Factor-beta 1 Involved in the Pathogenesis of Endometriosis through Regulating Expression of Vascular Endothelial Growth Factor under Hypoxia

“…TGF-β1 is also able to promote cell migration by up-regulating the activity of MMPs. [5859] Other researchers showed that TGF-β1/SMAD2/3 signaling can stimulate human granulosa cell migration by up-regulating connexin 43 expression[60] and regulate insulin gene transcription and pancreatic islet cell function through SMAD2/3 signaling,[61] and this pathway plays a critical role in renal fibrosis and chronic liver disease. [62] However, the effect of TGF-β1/SMAD2/3 signaling on EMs pathogenesis is unclear.…”