A direct thrombin inhibitor, dabigatran etexilate protects from renal fibrosis by inhibiting protease activated receptor-1.

Chronic kidney disease (CKD) involves interstitial fibrosis as an influential underlying pathological process associated with compromised renal function regardless of etiological cause of the injury. The tubulointerstitial fibrosis is found to be well correlated with declining renal function and its subsequent culmination into renal failure. Given the prominent role of thrombin in multiple diseases, it was tempting for us to investigate the outcome of a direct thrombin inhibitor in renal injury. We investigated the involvement of thrombin in renal injury and fibrosis by using an FDA approved orally active, direct thrombin inhibitor, dabigatran etexilate (DB). We used a robust experimental model of unilateral ureteral obstruction (UUO)-induced renal injury which shows progressive tubulointerstitial fibrosis (TIF) along with tubular injury and inflammation. The obstructed kidney showed severe TIF as compared to control kidneys. The administration of DB significantly inhibited UUO-induced collagen-1 and TIF by inhibition of thrombin activated protease activated receptor (PAR)-1 expression in fibrotic kidney. In addition, DB administration improved histoarchitecture of obstructed kidney, inhibited TGF-ß and SNAI2-induced epithelial-mesenchymal transition (EMT) program. Our study highlights the importance of thrombin signalling in TIF and provides strong evidences to support the notion that a direct thrombin inhibitor ameliorates TIF by PAR-1 mediated mechanism.

Crocin, an active constituent of Crocus sativus ameliorates cerulein induced pancreatic inflammation and oxidative stress.

Acute pancreatitis (AP) is a disorder of the pancreas marked by profound inflammation and oxidative stress. Phytoconstituents presents an important toolbox of preventive strategies to combat inflammatory disorders. To this end, we selected the active constituent of Crocus sativus, crocin for evaluation against cerulein-induced AP, owing to its promising antiinflammatory activity in acute as well as chronic inflammatory conditions. The animals were randomly divided into five groups comprising of normal control, cerulein control, crocin low dose (30 mg/kg), crocin high dose (100 mg/kg), and crocin control (100 mg/kg). Various biochemical parameters and the levels of inflammatory cytokines and p65-NFκB were measured. The mechanism was investigated by histology and immunohistochemistry. We found that crocin significantly reduced the pancreatic edema, amylase, and lipase levels. It abrogated the oxidative stress incurred by cerulein challenge. We found that crocin modulated the pancreatic inflammatory cytokine levels. Crocin perturbed the nuclear translocation of p65-NFκB. Crocin reverted the pancreatic histology associated with AP. Furthermore, it upregulated the expression of Nrf-2 and downregulated the expression of IL-6, TNF-α, nitrotyrosine, and NFκB. Cumulatively, these results indicate that crocin has promising potential to prevent cerulein induced AP and regular intake of saffron can prove beneficial for the pancreatic health.

Nimbolide ameliorates unilateral ureteral obstruction-induced renal fibrosis by inhibition of TGF-ß and EMT/Slug signalling.

Chronic kidney disease (CKD) involves interstitial fibrosis as an underlying pathological process associated with compromised renal function irrespective of etiological cause of the injury. The transforming growth factor-ß (TGF-ß) plays a pivotal role in progression of renal fibrosis. TGF-ß transduces its downstream signalling by phosphorylation of smad2/3 and also regulates epithelial-mesenchymal-transition (EMT), a program centrally involved in activation of fibroblasts. Renal fibrosis was induced in Swiss albino mice by unilateral ureteral obstruction of animals. Kidney tissues were evaluated for fibrotic protein expression by western blot and immunohistochemistry. The administration of nimbolide (NB) to UUO animals reduced the oxidative stress, expression of ECM proteins, TGF-ß, p-smad and EMT program. Further, NB administration also improved histoarchitecture of obstructed kidney and reduced the collagen deposition in kidney. Our results provided compelling evidence to support antifibrotic activity of NB by reduction in oxidative stress, TGF-ß, and EMT program in fibrotic kidney. The administration of NB in animals blunted the UUO-induced renal injury, inflammation and reduced fibrogenesis in obstructed kidney.

Visnagin attenuates acute pancreatitis via Nrf2/NFκB pathway and abrogates associated multiple organ dysfunction.

Acute pancreatitis (AP) is an exocrine dysfunction of the pancreas where oxidative stress and inflammatory cytokines play a key role in induction and progression of the disease. Studies have demonstrated that antioxidant phytochemicals have been effective in improving pancreatitis condition, but there are no clinically approved drugs till date. Our study aims to assess the preventive activity of visnagin, a novel phytochemical isolated from Ammi visnaga against cerulein induced AP. Male Swiss albino mice were divided into six groups (n = 6, each group) comprising of normal control, cerulein control, seven day pre-treatment with visnagin at three dose levels; visnagin low dose (10 mg/kg), visnagin mid dose (30 mg/kg), visnagin high dose (60 mg/kg) and visnagin control (60 mg/kg). AP was induced by six injections of cerulein (50 µg/kg, i.p.) on the 7th day and the animals were sacrificed after 6 h of last cerulein dose. Various markers of pancreatic function, oxidative stress and inflammation were assessed. Visnagin was found to be effective in reducing plasma amylase and lipase levels, reduced cerulein induced oxidative stress. Visnagin dose dependently decreased the expression of IL-1ß, IL-6, TNF-α and IL-17. It attenuated the levels of nuclear p65-NFκB. Visnagin improved the antioxidant defence by improving Nrf2 expression and halted pancreatic inflammation by suppressing NFκB and nitrotyrosine expression in the acinar cells. Further, it attenuated the expression of markers of multiple organ dysfunction syndrome and reduced inflammatory cytokines in lungs and intestine. Cumulatively, these findings indicate that visnagin has substantial potential to prevent cerulein induced AP.