Carvedilol safeguards against aspirin-induced gastric damage in rats.

This study investigated the effect of carvedilol on aspirin-induced gastric damage. Male Wistar rats were divided into three groups. Control rats received the vehicle, while the aspirin group received aspirin (200 mg/kg) orally for 4 days. Rats of aspirin + carvedilol group were administered aspirin along with carvedilol (5 mg/kg; intraperitoneal) for 4 days. Animals were euthanized at the end of the treatment period, and gastric tissues were collected to perform histopathological and mechanistic studies. The results revealed that aspirin administration induced gastric ulcer as there were remarkable histopathological lesions in the form of marked necrosis, inflammation, hemorrhage, edema, and dysplastic changes. Lipid peroxidative markers such as malondialdehyde, 4-hydroxynonenal, and protein carbonyl were significantly elevated in the aspirin group. This was concurrent with a significant amelioration of antioxidants such as reduced glutathione, superoxide dismutase, and catalase. Furthermore, aspirin increased the immunoexpression of cyclooxygenase (COX) 2 and nuclear factor kappa-B (NF-κB). Aspirin induced elevation in the inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1ß. Aspirin enhanced the immunoexpression of inducible nitric oxide synthetase (iNOS) and increased the level of nitrite/nitrate in gastric tissue. On the other hand, carvedilol treatment reversed all these pathological changes. Carvedilol succeeded to enhance antioxidants in gastric tissue, attenuated lipid peroxidative parameters, and suppressed the release of inflammatory mediators. It attenuated the immunoexpression of COX-2, NF-κB, and iNOS. Collectively, carvedilol has a gastro-protective effect that could be attributed to its antioxidative and anti-inflammatory properties, which modulate NF-κB/COX-2/iNOS pathways.

Modulation of d-galactosamine/lipopolysacharride-induced fulminant hepatic failure by nilotinib.

This investigation was undertaken to test the effect of nilotinib against d-galactosamine (GalN) and lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF). Male Swiss albino mice were orally treated with nilotinib for 3 days prior to GalN/LPS challenge. The results revealed that administration of GalN/LPS caused elevation in the mortality rate. GalN/LPS-induced severe hepatic injury was manifested by increased serum transaminases and alkaline phosphatase (ALP) levels as well as histopathological hepatic necrosis and inflammation. In addition, GalN/LPS increased the hepatic oxidative stress as indicated by increased malondialdehyde level, decreased glutathione content, and superoxide dismutase (SOD) activity. Furthermore, GalN/LPS increased nuclear factor kappa-B activation and the levels of tumor necrosis factor-alpha and interleukin-1ß. These biochemical and histopathological changes were markedly ameliorated by nilotinib pretreatment. On the other hand, the level of toll-like receptor-4 was increased upon GalN/LPS challenge, which was not alleviated by nilotinib pretreatment. These data demonstrate that nilotinib has hepatoprotective activity against GalN/LPS-mediated FHF in mice via anti-oxidative and anti-inflammatory effects.

Nilotinib attenuates endothelial dysfunction and liver damage in high-cholesterol-fed rabbits.

Nilotinib is an oral potent tyrosine kinase inhibitor that has diverse biological activities. However, its effects on hypercholesterolemia and associated disorders have not been studied yet. The present study explored the effect of nilotinib on atherosclerosis progression, endothelial dysfunction, and hyperlipidemia-associated hepatic injury in high-cholesterol (HC)-fed rabbits. Rabbits were classified into four groups: control, nilotinib, HC, and HC + nilotinib groups. Rabbits were fed either a regular diet or an HC-enriched diet for 8 weeks. By the end of the eighth week, blood and tissue samples were obtained for biochemical, histological, immunohistochemical, and in vitro analyses. Results indicated that the HC diet induced a significant elevation in the serum lipid parameters (triglycerides, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), lactate dehydrogenase, and nitric oxide content. Endothelial dysfunction was evident through the impairment of acetylcholine-induced relaxation of isolated aortas and the histopathological lesions of the aortic specimen. Moreover, HC significantly increased serum malondialdehyde. Liver damage was clear through increase in serum transaminases and alkaline phosphatase, and it was further supported by histopathological examination. HC increased the expression of platelet-derived growth factor receptor (PDGFR)-B in both aorta and liver tissues. Interestingly, nilotinib administration retarded atherosclerosis progression and attenuated all of the aforementioned parameters. These data suggest that nilotinib may counteract atherosclerosis development, vascular dysfunction, and hepatic damage in HC-fed rabbits through interfering with PDGF-B.

Agmatine attenuates silica-induced pulmonary fibrosis.

There is a large body of evidence that nitric oxide (NO) formation is implicated in mediating silica-induced pulmonary fibrosis. As a reactive free radical, NO may not only contribute to lung parenchymal tissue injury but also has the ability to combine with superoxide and form a highly reactive toxic species peroxynitrite that can induce extensive cellular toxicity in the lung tissues. This study aimed to explore the effect of agmatine, a known NO synthase inhibitor, on silica-induced pulmonary fibrosis in rats. Male Sprague Dawley rats were treated with agmatine for 60 days following a single intranasal instillation of silica suspension (50 mg in 0.1 ml saline/rat). The results revealed that agmatine attenuated silica-induced lung inflammation as it decreased the lung wet/dry weight ratio, protein concentration, and the accumulation of the inflammatory cells in the bronchoalveolar lavage fluid. Agmatine showed antifibrotic activity as it decreased total hydroxyproline content of the lung and reduced silica-mediated lung inflammation and fibrosis in lung histopathological specimen. In addition, agmatine significantly increased superoxide dismutase (p < 0.001) and reduced glutathione (p < 0.05) activities with significant decrease in the lung malondialdehyde (p < 0.001) content as compared to the silica group. Agmatine also reduced silica-induced overproduction of pulmonary nitrite/nitrate as well as tumor necrosis factor α. Collectively, these results demonstrate the protective effects of agmatine against the silica-induced lung fibrosis that may be attributed to its ability to counteract the NO production, lipid peroxidation, and regulate cytokine effects.