Search results for: cytoprotection

Authors: B. Yermekbayeva, A. Gulyayaev, T. Nurgozhin, C. Bektur

Abstract:

Cytisine aminophosphonate under the name "Cytafat" was approved for clinical trials in Republic of Kazakhstan as a putative liver protecting drug for the treatment of acute toxic hepatitis. A method of conducting the clinical trial is a double blind study. Total number of patients -71, aged from 16 to 56 years. Research on healthy volunteers determined the maximal tolerable doze of "Cytafat" as 200 mg/kg. Side effects when administered at high dozes (100-200 mg/kg) are tachycardia and increase of arterial blood pressure. The drug is tested in the treatment of 28 patients with a syndrome of hepatocellular failure (a poisoning with substitutes of alcohol, rat poison, or medical products). "Cytafat" was intravenously administered at a dose of 10 mg/kg in 200 ml of 5 % glucose solution once daily. The number of administrations: 1-3. In the comparison group, 23 patients were treated intravenously once a day with “Essenciale H” at a dose of 10 ml. 20 patients received a placebo (10 ml of glucose intravenously). In all cases of toxic hepatopathology the significant positive clinical effect of the testing drug distinguishable from placebo and surpassing the alternative was observed. Within a day after administration a sharp reduction of cytolitic syndrome parameters (ALT, AST, alkaline phosphatase, thymol turbidity test, GGT) was registered, a reduction of the severity of cholestatic syndrome (bilirubin decreased) was recorded, significantly decreased indices of lipid peroxidation. The following day, in all cases the positive dynamics was determined with ultrasound study (reduction of diffuse changes and events of reactive pancreatitis), hepatomegaly disappeared. Normalization of all parameters occurred in 2-3 times faster, than when using the drug "Essenciale H" and placebo. Average term of elimination of toxic hepatopathy when using the drug "Cytafat" -2,8 days, "Essenciale H" -7,2 days, and placebo -10,6 days. The new drug "Cytafat" has expressed cytoprotective properties.

Keywords: cytisine, cytoprotection, hepatopathy, hepatoprotection

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Authors: Rajapaksha Gedara Prasad Tharanga Jayasooriya, Matharage Gayani Dilshara, Yung Hyun Choi, Gi-Young Kim

Abstract:

Camptothecin (CPT) is a quinolone alkaloid which inhibits DNA topoisomerase I that induces cytotoxicity in a variety of cancer cell lines. We previously showed that CPT effectively inhibited invasion of prostate cancer cells and also combined treatment with subtoxic doses of CPT and TNF-related apoptosis-inducing ligand (TRAIL) potentially enhanced apoptosis in a caspase-dependent manner in hepatoma cancer cells. Here, we found that treatment with CPT caused an irreversible cell cycle arrest in the G2/M phase. CPT-induced cell cycle arrest was associated with a decrease in protein levels of cell division cycle 25C (Cdc25C) and increased the level of cyclin B and p21. The CPT-induced decrease in Cdc25C was blocked in the presence of proteasome inhibitor MG132, thus reversed the cell cycle arrest. In addition to that treatment of CPT-increased phosphorylation of Cdc25C was the resulted of activation of checkpoint kinase 2 (Chk2), which was associated with phosphorylation of ataxia telangiectasia-mutated. Interestingly CPT induced G2/M phase of the cell cycle arrest is reactive oxygen species (ROS) dependent where ROS inhibitors NAC and GSH reversed the CPT-induced cell cycle arrest. These results further confirm by using transient knockdown of nuclear factor-erythroid 2-related factor 2 (Nrf2) since it regulates the production of ROS. Our data reveal that treatment of siNrf2 increased the ROS level as well as further increased the CPT induce G2/M phase cell cycle arrest. Our data also indicate CPT-enhanced cell cycle arrest through the extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal kinase (JNK) pathway. Inhibitors of ERK and JNK more decreased the Cdc25C expression and protein expression of p21 and cyclin B. These findings indicate that Chk2-mediated phosphorylation of Cdc25C plays a major role in G2/M arrest by CPT.

Keywords: camptothecin, cell cycle, checkpoint kinase 2, nuclear factor-erythroid 2-related factor 2, reactive oxygen species

Procedia PDF Downloads 404

Authors: Gaweł Magdalena, Lipkowska Anna, Olbert Magdalena, Frąckiewicz Ewelina, Librowski Tadeusz, Nowak Gabriel, Pilc Andrzej

Abstract:

Heme oxygenase-1 (HO-1), also known as heat shock protein 32 (HSP32), has been shown to be implicated in cytoprotection in various organs. Its activation plays a significant role in acute and chronic inflammation, protecting cells from oxidative injury and apoptosis. This inducible isoform of HO catalyzes the first and rate-limiting step in heme degradation to produce equimolar quantities of biologically active products: carbon monoxide (CO), free iron and biliverdin. CO has been reported to possess anti-apoptotic properties. Moreover, it inhibits the production of proinflammatory cytokines and stimulates the synthesis of the anti-inflammatory interleukin-10 (IL-10), as well as promotes vasodilatation at sites of inflammation. The second product of catalytic HO-1 activity, free cytotoxic iron, is promptly sequestered into the iron storage protein ferritin, which lowers the pro-oxidant state of the cell. The third product, biliverdin, is subsequently converted by biliverdin reductase into the bile pigment bilirubin, the most potent endogenous antioxidant among the constituents of human serum, which modulates immune effector functions and suppresses inflammatory response. Furthermore, being one of the so-called stress proteins, HO-1 adaptively responds to different stressors, such as reactive oxygen species (ROS), inflammatory cytokines and heavy metals and thus protects cells against such conditions as ischemia, hemorrhagic shock, heat shock or hypoxia. It is suggested that pharmacologic modulation of HO-1 may represent an effective strategy for prevention of stress and drug-induced gastrointestinal toxicity. HO-1 is constitutively expressed in normal gastric, intestinal and colonic mucosa and up-regulated during inflammation. It has been proven that HO-1 up-regulated by hemin, heme and cobalt-protoporphyrin ameliorates experimental colitis. In addition, the up-regulation of HO-1 partially explains the mechanism of action of 5-aminosalicylic acid (5-ASA), which is used clinically as an anti-colitis agent. In 2009 Ueda et al. has reported for the first time that mucosal protection by Polaprezinc, a chelate compound of zinc and L-carnosine used as an anti-ulcer drug in Japan, is also attributed to induction of HO-1 in the stomach. Since then, inducers of HO-1 are desired subject of research, as they may constitute therapeutically effective anti-ulcer drugs.

Keywords: heme oxygenase-1, gastric lesions, gastroprotection, Polaprezinc

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