Candoxatril

Recently, the development of natural polysaccharides for ameliorating immunity and gut metabolism has attracted extensive attention. This study used Holothuria leucospilota polysaccharides (HLP) to explore the improvement mechanism in ulcerative colitis rats on perspectives of immunity and metabolism. The results showed that HLP increased goblet cells’ number and the content of tight junction proteins (zona occludens 1 and occludin) and improved intestinal barrier permeability. The levels of immune cytokines (IL‐4, IL‐6, IL‐10, IL‐18, TNF‐α, and IL‐1β) and the activity of oxidative stress‐related enzymes (superoxide dismutase, catalase, malondialdehyde, and glutathione peroxidase) were regulated. HLP regulated the related genes and proteins expression of immune cytokines, MAPK, and NLRP3 inflammasome. Furthermore, HLP treatment increased the concentration of short‐chain fatty acids (SCFAs) and regulated serum metabolic disorders by regulating amino acid metabolism, SCFA metabolism, and energy metabolism. These results provide a new perspective for developing HLP as a promising functional food for preventing and mitigating colitis.

Kidney fibrosis is the common pathophysiological mechanism in end-stage renal disease characterized by excessive accumulation of myofibroblast-derived extracellular matrix. Natriuretic peptides have been demonstrated to have cyclic guanosine monophosphate (cGMP)-dependent anti-fibrotic properties likely due to interference with pro-fibrotic tissue growth factor β (TGF-β) signaling. However, in vivo, natriuretic peptides are rapidly degraded by neutral endopeptidases (NEP). In a unilateral ureteral obstruction (UUO) mouse model for kidney fibrosis we assessed the anti-fibrotic effects of SOL1, an orally active compound that inhibits NEP and endothelin-converting enzyme (ECE). Mice (n=10 per group) subjected to UUO were treated for 1 week with either solvent, NEP-/ECE-inhibitor SOL1 (two doses), reference NEP-inhibitor candoxatril or the angiotensin II receptor type 1 (AT1)-antagonist losartan. While NEP-inhibitors had no significant effect on blood pressure, they did increase urinary cGMP levels as well as endothelin-1 (ET-1) levels. Immunohistochemical staining revealed a marked decrease in renal collagen (∼55% reduction, P<0.05) and α-smooth muscle actin (α-SMA; ∼40% reduction, P<0.05). Moreover, the number of α-SMA positive cells in the kidneys of SOL1-treated groups inversely correlated with cGMP levels consistent with a NEP-dependent anti-fibrotic effect. To dissect the molecular mechanisms associated with the anti-fibrotic effects of NEP inhibition, we performed a ‘deep serial analysis of gene expression (Deep SAGE)’ transcriptome and targeted metabolomics analysis of total kidneys of all treatment groups. Pathway analyses linked increased cGMP and ET-1 levels with decreased nuclear receptor signaling (peroxisome proliferator-activated receptor [PPAR] and liver X receptor/retinoid X receptor [LXR/RXR] signaling) and actin cytoskeleton organization. Taken together, although our transcriptome and metabolome data indicate metabolic dysregulation, our data support the therapeutic potential of NEP inhibition in the treatment of kidney fibrosis via cGMP elevation and reduced myofibroblast formation.