RESUMO
Organ scarring, referred to as fibrosis, results from a failed wound-healing response to chronic tissue injury and is characterised by the aberrant accumulation of various extracellular matrix (ECM) components. Once established, fibrosis is recognised as a hallmark of stiffened and dysfunctional tissues, hence, various fibrosis-related diseases collectively contribute to high morbidity and mortality in developed countries. Despite this, these diseases are ineffectively treated by currently-available medications. The pro-fibrotic cytokine, transforming growth factor (TGF)-ß1, has emerged as the master regulator of fibrosis progression, owing to its ability to promote various factors and processes that facilitate rapid ECM synthesis and deposition, whilst negating ECM degradation. TGF-ß1 signal transduction is tightly controlled by canonical (Smad-dependent) and non-canonical (MAP kinase- and Rho-associated protein kinase-dependent) intracellular protein activity, whereas its pro-fibrotic actions can also be facilitated by the Wnt/ß-catenin pathway. This review outlines the pathological sequence of events and contributing roles of TGF-ß1 in the progression of fibrosis, and how the Wnt/ß-catenin pathway contributes to tissue repair in acute disease settings, but to fibrosis and related tissue dysfunction in synergy with TGF-ß1 in chronic diseases. It also outlines the anti-fibrotic and related signal transduction mechanisms of the hormone, relaxin, that are mediated via its negative modulation of TGF-ß1 and Wnt/ß-catenin signaling, but through the promotion of Wnt/ß-catenin activity in acute disease settings. Collectively, this highlights that the crosstalk between TGF-ß1 signal transduction and the Wnt/ß-catenin cascade may provide a therapeutic target that can be exploited to broadly treat and reverse established fibrosis.
Assuntos
Relaxina , Humanos , Relaxina/uso terapêutico , beta Catenina/metabolismo , Doença Aguda , Via de Sinalização Wnt , Fator de Crescimento Transformador beta1 , FibroseRESUMO
Activation of acid-sensing ion channel 1a (ASIC1a) plays a major role in mediating acidosis-induced neuronal injury following a stroke. Therefore, the inhibition of ASIC1a is a potential therapeutic avenue for the treatment of stroke. Venom-peptide Hi1a, a selective and highly potent ASIC1a inhibitor, reduces the infarct size and functional deficits when injected into the brain after stroke in rodents. However, its efficacy when administered using a clinically relevant route of administration remains to be established. Therefore, the current investigation aims to examine the efficacy of systemically administered Hi1a, using two different models of stroke in different species. Mice were subjected to the filament model of middle cerebral artery occlusion (MCAO) and treated with Hi1a systemically using either a single- or multiple-dosing regimen. 24 h poststroke, mice underwent functional testing, and the brain infarct size was assessed. Rats were subjected to endothelin-1 (ET-1)-induced MCAO and treated with Hi1a intravenously 2 h poststroke. Rats underwent functional tests prior to and for 3 days poststroke, when infarct volume was assessed. Mice receiving Hi1a did not show any improvements in functional outcomes, despite a trend toward reduced infarct size. This trend for reduced infarct size in mice was consistent regardless of the dosing regimen. There was also a trend toward lower infarct size in rats treated with Hi1a. More specifically, Hi1a reduced the amount of damage occurring within the somatosensory cortex, which was associated with an improved sensorimotor function in Hi1a-treated rats. Thus, this study suggests that Hi1a or more brain-permeable ASIC1a inhibitors are a potential stroke treatment.
RESUMO
Two series of N-(heteroaryl)thiophene sulfonamides, encompassing either a methylene imidazole group or a tert-butylimidazolylacetyl group in the meta position of the benzene ring, have been synthesized. An AT2R selective ligand with a Ki of 42 nM was identified in the first series and in the second series, six AT2R selective ligands with significantly improved binding affinities and Ki values of <5 nM were discovered. The binding modes to AT2R were explored by docking calculations combined with molecular dynamics simulations. Although some of the high affinity ligands exhibited fair stability in human liver microsomes, comparable to that observed with C21 undergoing clinical trials, most ligands displayed a very low metabolic stability with t½ of less than 10 min in human liver microsomes. The most promising ligand, with an AT2R Ki value of 4.9 nM and with intermediate stability in human hepatocytes (t½ = 77 min) caused a concentration-dependent vasorelaxation of pre-contracted mouse aorta.