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

Correspondence to Dr James J DiNicolantonio; jjdinicol@gmail.com Overview of transforming growth factor-beta signalling Upregulated transforming growth factor-beta (TGFβ) signalling, driving mesenchymal cells to increase their production of ground substance and undergo a transition to a myofibroblast phenotype, is believed to play a pathogenic role in diverse fibrotic disorders, including benign prostatic hyperplasia, scleroderma, pulmonary fibrosis, glomerulosclerosis, tubulointerstial fibrosis, hepatic fibrosis, open angle glaucoma, Peyronie’s disease and the cardiac fibrosis associated with cardiac hypertrophy and heart failure.1–20 It should follow that safe, practical measures which downregulate such signalling may have potential for the prevention and control of these syndromes. [...]the Smad2/3-Smad4 heterodimer quite frequently functions in concert with an AP-1 complex to mediate TGFβ-induced transcription.23–28 Activation of AP-1 reflects concurrent TGFβ-mediated activation of the mitogen-activated protein (MAP) kinases ERK, JNK and p38.29 30 Activation of the MAP kinase kinase kinase TAK1 is upstream from JNK and p38 MAP kinase in this signalling pathway. NOX4-mediated inhibition of tyrosine phosphatase activity (such as PTP1B) may also contribute to NOX4’s impact on TGFβ signalling.40 41 cGMP, oestrogen receptor-β, Nrf2, Sirt1 and hydrogen sulfide can diminish TGFβ signalling TGFβ signalling can be opposed by cGMP, the ligand-bound oestrogen receptor-β (ERβ), activation of the nrf2 transcription factor and the Sirt1 deacetylase. The latter, a metabolic derivative and close homolog of biliverdin, has been found to share the latter’s ability to inhibit certain nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complexes, including those dependent on NOX4.120 121 Oxidative stress, via induction of heme oxygenase-1 (HO-1), promotes generation of biliverdin from heme; this biliverdin is rapidly reduced by biliverdin reductase to yield free bilirubin, which in turn quells oxidative stress by inhibiting NADPH oxidase complexes.122–126 PhyCB, analogously, is reduced by biliverdin reductase to phycocyanorubin, a homolog of bilirubin that shares its ability to inhibit these complexes.127 This likely explains, in large part, why oral administration of PhyCB, spirulina or phycocyanin (the spirulina protein which contains PhyCB as a covalently attached chromophore) has exerted profound antioxidant/anti-inflammatory activity in rodents in a wide vari