A nutraceutical strategy for downregulating TGFβ signalling: prospects for prevention of fibrotic disorders, including post-COVID-19 pulmonary fibrosis

Abstract

transcription is induced in this manner codes for NOX4, which constitutively generates superoxide/hydrogen peroxide. NOX4 induction plays a key role in upregulating TGF signalling, as inhibitors of this enzyme notably blunt TGF activity. 1 36-38 This is at least partially attributable to the fact that nuclear NOX4 generates hydrogen peroxide which reversibly inhibits MAP kinase phosphatase-1. This latter enzyme functions to deactivate both JNK and p38 MAP kinase; its inactivation by NOX4 hence upregulates JNK and p38 activation, thereby boosting the TGF signal. NOX4-mediated inhibition of tyrosine phosphatase activity (such as PTP1B) may also contribute to NOX4's impact on TGF signalling. 40 41 CGMP, OESTROGEN RECEPTOR-, NRF2, SIRT1 AND HYDROGEN SULFIDE CAN DIMINISH TGF SIGNALLING TGF signalling can be opposed by cGMP, the ligandbound oestrogen receptor- (ER), activation of the nrf2 transcription factor and the Sirt1 deacetylase. The effect of cGMP in this regard is mediated by protein kinase G-1a (PKG-1a). This kinase phosphorylates the TGF-activated Smad3 (pSmad3) in such a way as to prevent the translocation of pSmad3/Smad4 heterodimers to the nucleus. 42 43 Once phosphorylated by PKG-1a, Smad3 has a high affinity for cytosolic beta2-tubulin, resulting in its sequestration in the cytoplasm. Other research suggests that PKG activity may interfere with TGF signalling by promoting the proteasomal degradation of Smad3. Not surprisingly, agents with boost cellular levels of cGMP have also been shown to oppose tissue fibrosis and TGF activity. 42 43 46-56 Ligand-bound activated ER has been found to downregulate TGF-mediated transcription by a direct interaction with AP-1 complexes that blocks their transactivational activity. 57 58 This interaction does not involve binding of ER to oestrogen response elements on DNA, but rather to c-Jun. 0] Moreover, polymorphisms of the ER gene (but not that of the ER gene) have been linked to increased risk for POAG. 74 75 7] This effect of Nrf2 is indirect, reflecting its ability to decrease protein on July 12,

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