Thallium (Tl) is a highly toxic heavy metal though up to now its mechanisms are poorly understood. In this study, we comparatively investigated the cytotoxic mechanisms of Tl(I) and Tl(III) in isolated rat hepatocytes. Both Tl(I) and Tl(III) cytotoxicities were associated with reactive oxygen species (ROS) formation, lipid peroxidation, collapse of mitochondrial membrane potential, activation of caspases cascade, lysosomal membrane leakiness, and cellular proteolysis. Hepatocyte glutathione (GSH) was also rapidly oxidized. GSH-depleted hepatocytes were more resistant to Tl(I)-induced cytotoxicity, ROS formation and lipid peroxidation. This suggests that Tl(I) is reductively activated by GSH. On the other hand, GSH-depleted hepatocytes were much more sensitive to Tl(III)-induced cytotoxicity, ROS formation, and lipid peroxidation. This suggests that GSH only plays an antioxidant role against Tl(III) cytotoxicity. Our results also showed that CYP2E1 involves in Tl(I) and Tl(III) oxidative stress cytotoxicity mechanism and both cations detoxified via methylation. In conclusion, both Tl(I) and Tl(III) cytotoxicities were associated with mutual mitochondrial/lysosomal injuries (cross-talk) initiated by increased ROS formation resulted from metal-CYP2E1 destructive interaction or metal-induced disruption of mitochondrial electron transfer chain.
Cisplatin is widely used chemotherapeutic agent for the treatment of several human malignancies. Dose-related nephrotoxicity is the major adverse effect of cisplatin. The cellular and molecular mechanisms behind the cisplatin nephrotoxicity have not yet been completely understood. In this study, cytotoxic effect of cisplatin on renal proximal tubular (RPT) cells was evaluated. Our results showed that cytotoxic action of cisplatin on RPT cells is mediated by reactive oxygen species (ROS) formation, decline of mitochondrial membrane potential, increase in caspase-3 activity and lysosomal membrane leakiness before cell lysis ensued. All of the above mentioned cisplatin-induced oxidative stress cytotoxicity markers were significantly (p < 0.05) prevented by ROS scavengers, antioxidants, mitochondrial permeability transition (MPT) pore sealing agents, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Our results also showed that CYP2E1 involves in cisplatin oxidative stress cytotoxicity mechanism and intracellular nitric oxide enhancement protects the RPT cells against the cisplatin-induced cytotoxicity. It seems that cisplatin nephrotoxicity is associated with mutual mitochondrial/lysosomal potentiation (cross-talk) of oxidative stress in RPT cells. This cross-talk finally results in release of lysosomal digestive proteases and phospholipases and mitochondrial MPT pore opening leading to cytochrome c release and activation of caspases cascade which signal apoptosis.
The high-performance liquid chromatography-mass spectrometry (LC-MS) technique is widely applied to routine analysis in many matrices. Despite the enormous application of LC/MS, this technique is subjected to drawbacks called matrix...
A new class of pyrazino[1,2-a]benzimidazole derivatives possessing the SO 2 Me pharmacophore at the para position of the C-3 phenyl ring was designed, synthesized, and tested for their cyclooxygenase-2 (COX-2) inhibitory, anti-cancer and anti-platelet aggregation activities. In vitro COX-1/COX-2 inhibition studies showed that 2-(4methylphenyl)-1-methylene-3-(4-(methylsulfonyl)phenyl)-1,2-dihydropyrazino-[1,2a]benzimidazole (5g) was the most potent COX-2 inhibitor (IC 50 = 0.08 μM) and 2-(3,4,5-trimethoxyphenyl)-1-methylene-3-(4-(methylsulfonyl)phenyl)-1,2-dihydropyrazino-[1,2-a]benzimidazole (5m) had the highest selectivity index (SI > 909).Cytotoxicity of the synthesized compounds was also determined against the MCF-7 cell line. Most compounds were cytotoxic against MCF-7 cells and our results showed that compound 5m exhibited the highest anti-proliferative activity compared to the reference compound, cisplatin. Our data also indicated that compound 5k was the most potent platelet aggregation inhibitor according to aggregometry test results. K E Y W O R D S anti-cancer, anti-platelet aggregation, COX-2 inhibitory, docking study, MCF-7, pyrazinobenzimidazole 1 | INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) continue to be one of the most widely used prescription and over-the-counter medications. These drugs interfere with inflammatory mediators (prostaglandins) biosynthesis by inhibiting cyclooxygenase (COX) The pharmacologic effects of NSIADs are attributed to inhibition of COX-1 and COX-2 enzymes. COX-1 produces prostaglandins involved in normal cellular activity such as maintenance of kidney functions and gastric mucosa protection; COX-2 produces prostaglandins at inflammatory sites. [1] Most NSAIDs inhibit both COX-1 and COX-2, but with varying degrees of selectivity. The evidence shows that antiinflammatory activities of NSAIDs are due to the inhibition of COX-2, whereas the ulcerogenic adverse effects are associated with the inhibition of COX-1. The differences in the amino acid sequence of COX-1 and COX-2 binding sites provided valuable strategy for the design of selective COX-2 inhibitors. The main difference involves the presence of a second pocket within COX binding site, which is more available in COX-2, whereas restricted in COX-1 due to the extra steric bulk of Ile 523 in COX-1. The larger volume of COX-2 active site allows larger molecules to enter the active site and inhibit COX-2, selectively. [2] Based upon this, many selective COX-2 inhibitors have been designed and entered the market. These medicines have fewer Arch Pharm Chem Life Sci. 2019;352:e1800265.wileyonlinelibrary.com/journal/ardp
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.