Thymol and carvacrol prevent cisplatin-induced nephrotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats.

The aim of the present study is to assess the possible protective effects of thymol and carvacrol against cisplatin (CP)-induced nephrotoxicity. A single dose of CP {6 mg/kg, intraperitoneally (i.p.)} injected to male rats revealed significant increases in serum urea, creatinine, and tumor necrosis factor alpha levels. It also increased kidney contents of malondialdehyde and caspase-3 activity with significant reduction in serum albumin, kidney content of reduced glutathione as well as catalase, and superoxide dismutase activity as compared to that of the control group. In contrast, administration of thymol {20 mg/kg, orally (p.o.)} and/or carvacrol (15 mg/kg, p.o.) for 14 days before CP injection and for 7 days after CP administration restored the kidney function and examined oxidative stress parameters. In conclusion, thymol was more effective nephroprotective than carvacrol. Moreover, a combination of thymol and carvacrol had a synergistic nephroprotective effect that might be attributed to antioxidant, anti-inflammatory, and antiapoptotic activities.

Genotoxic evaluation of chloroacetonitrile in murine marrow cells and effects on DNA damage repair gene expressions.

Although chloroacetonitrile (CAN), a disinfection by-product of chlorination of drinking water, is considered a rodent carcinogen that induces lung adenomas in mice, previous studies on its genotoxicity have yielded inconclusive results. Thus, its cancer mode of action has not been clearly defined. We evaluated CAN-induced genotoxicity in mice using mouse bone marrow micronucleus test, comet assays and expression of genes associated with DNA damage repair. Mice exposed to CAN at 8.75, 17.5, 35 and 52.5mg/kg for 7 days did not exhibit any significant increases in the incidence of micronuclei formation at 24 and 48h after last exposure. However, CAN caused significant suppressions of erythroblast proliferation at the highest dose. In the alkaline comet assay, there was a significant increase in the incidence of DNA strand breaks in mice killed after 3h of last treatment with 35 and 52.5mg/kg/day CAN, while no significant difference in the DNA strand breaks was found in mice killed after 24h of the last treatment. However, slight (but significant) CAN-induced oxidative DNA damage was detected following Fpg digestion at 3-h sampling time, digestion with EndoIII resulted in considerable increases in oxidative DNA damage at 3 and 24h after the last exposure to 35 and 52.5mg/kg/day CAN as detected by oxidative comet assays. The expression of DNA repair genes OGG1 , Apex1, PARP1 and p53 were up-regulated in mice given 35mg/kg/day CAN at 3h but not in 24h after the last treatment except OGG1 . However, the significant up-regulation of OGG1 at 24h after the last treatment further indicates the occurrence of oxidative DNA damage. Overall, CAN exposure is associated with up-regulation of DNA repair gene expression and the induction of oxidative DNA damage, which may be at least partially responsible for CAN-induced genotoxicity and eventually cause carcinogenicity.

Salubrious effects of dexrazoxane against teniposide-induced DNA damage and programmed cell death in murine marrow cells.

The intention of the present study was to answer the question whether the catalytic topoisomerase-II inhibitor, dexrazoxane, can be used as a modulator of teniposide-induced DNA damage and programmed cell death (apoptosis) in the bone marrow cells in vivo. The alkaline single cell gel electrophoresis, scoring of chromosomal aberrations, micronuclei and mitotic activity were undertaken in the current study as markers of DNA damage. Apoptosis was analysed by the occurrence of a hypodiploid DNA peak and caspase-3 activity. Oxidative stress marker such as intracellular reactive oxygen species production, lipid peroxidation, reduced and oxidised glutathione were assessed in bone marrow as a possible mechanism underlying this amelioration. Dexrazoxane was neither genotoxic nor apoptogenic in mice at the tested dose. Moreover, for the first time, it has been shown that dexrazoxane affords significant protection against teniposide-induced DNA damage and apoptosis in the bone marrow cells in vivo and effectively suppresses the apoptotic signalling triggered by teniposide. Teniposide induced marked biochemical alterations characteristic of oxidative stress including accumulation of intracellular reactive oxygen species, enhanced lipid peroxidation, accumulation of oxidised glutathione and reduction in the reduced glutathione level. Prior administration of dexrazoxane ahead of teniposide challenge ameliorated these biochemical alterations. It is thus concluded that pretreatment with dexrazoxane attenuates teniposide-induced oxidative stress and subsequent DNA damage and apoptosis in bone marrow cells. Based on our data presented, strategies can be developed to decrease the teniposide-induced DNA damage in normal cells using dexrazoxane. Therefore, dexrazoxane can be a good candidate to decrease the deleterious effects of teniposide in the bone marrow cells of cancer patients treated with teniposide.

The impact of ofloxacin on rat testicular DNA: application of image analysis.

Ofloxacin induces its antibacterial action mainly by inhibition of DNA gyrase which is equivalent to topoisomerase II in mammalian cells. The present study was focused on the impact of ofloxacin on rat testicular DNA ploidy in a dose-response relationship using an image analysis technique on testicular sections following Fuelgen DNA staining. Sperm count and motility as well as sperm head abnormality tests were also investigated. Ofloxacin was given p.o. in doses of 36, 72 and 360 mg kg(-1) day(-1) for 15 consecutive days. The animals were then left to live safely to day 60 from starting the experiment to give them a chance to complete the cycle of spermatogenesis. Results revealed that ofloxacin significantly decreased the percentage of haploid cells in a dose-dependent manner with concomitant increase in the percentage of diploid cells. Sperm count and motility was also markedly decreased in a dose-dependent fashion. Sperm head abnormality showed no marked change following ofloxacin treatment. In conclusion, ofloxacin induced a marked disturbance in rat testicular DNA ploidy, which may be explained on the basis of cross-reactivity to topoisomerase II.

Possible protective effect of melatonin and/or desferrioxamine against streptozotocin-induced hyperglycaemia in mice.

There is a clear link between diabetes and oxidative stress. Hyperglycaemia leads to free radical generation and alteration of endogenous antioxidants. The present study is an attempt to evaluate the possible protective effect of melatonin (MLT) and/or desferrioxamine (DF) against streptozotocin (STZ)-induced hyperglycaemia in mice. Serum lipid profile, pancreatic tissue contents of glutathione (GSH) and malondialdehyde (MDA) were determined. MLT and/or DF were given p.o. in doses of 5 mg kg(-1)day(-1)and 250 mg kg(-1) day(-1), respectively for 15 consecutive days prior to STZ treatment (60 mg kg(-1) day(-1) i.p.) for 3 consecutive days. Results revealed that STZ induced a marked increase in serum glucose, serum triglycerides (TG), cholesterol (CHO) and LDL-cholesterol. On the contrary HDL-cholesterol was markedly decreased in STZ-treated group. Moreover, STZ induced a significant decrease in the pancreatic content of GSH with concomitant increase in MDA content. Administration of MLT or (MLT+DF) prior to STZ treatment revealed a marked decrease in serum glucose level by 35.6 and 31.6%, respectively as compared to STZ-treated group. Furthermore, MLT pretreatment of STZ-induced hyperglycemic mice, has not only normalized GSH content of pancreatic tissues but also increased its level more than that of control animals by 110%. On the contrary, MDA content of pancreatic tissues was markedly decreased even lower than normal control group. MLT also, induced a marked protection in terms of decreasing serum CHO, LDL, TG by 21.8, 83.8 and 82.2%, respectively, while HDL was increase by 56% as compared to STZ treated group. DF was found to be less effective than MLT in the protection against STZ-induced hyperglycemia. In conclusion, these data suggest that MLT protects against the damaging consequences induced by hyperglycemia either systemically or in the pancreatic tissues.

Adverse testicular effects of some quinolone members in rats.

In the last few years, a marked decrease in male fertility has been reported. Environmental factors were recently suspected for this effect. Among those factors is the misuse of drugs and in particular antibiotics. Quinolones are a group of antibacterial agents with broad-spectrum activity. Testicular impairment of some quinolone members is controversial; a matter which stimulated our attention to investigate the adverse testicular effects of the most familiar quinolone members, namely: ofloxacin, ciprofloxacin and pefloxacin. They were given to rats in doses of 72, 135 and 72 mg kg(-1) day(-1) p.o., respectively, for 15 consecutive days. Ofloxacin was also used to establish a dose-response relationship in doses of 36, 72 and 360 mg kg(-1) day(-1) p.o. for 15 consecutive days. Results revealed that ofloxacin, ciprofloxacin and pefloxacin reduced testicular LDH-X activity by 39.8%, 62.7% and 60.7%, respectively. Moreover, sperm count, motility and daily sperm production were markedly decreased. Ofloxacin induced a dose-dependent decrease in testicular LDH-X activity, sperm count and motility. Furthermore, daily sperm production showed a marked reduction which amounted to 26.1% and 40. 0% following administration of ofloxacin (72, 360 mg kg(-1) day(-1) x 15 days), respectively. Moreover, administration of ofloxacin resulted in marked testicular histopathological changes. It is concluded that, ofloxacin, ciprofloxacin and pefloxacin significantly impaired both testicular function and structure in rats.

Possible functional immunotoxicity of acrylonitrile (VCN).

Acrylonitrile (vinyl cyanide, VCN), an environmental pollutant, has been shown to be an animal and human carcinogen particularly for the GIT. In a previous work done in our laboratory, VCN induced immunosuppressive effects as indicated by a decrease in plaque forming cell (PFC) response to SRBCs (sheep red blood cell) immunization, a marked depletion of spleen lymphocyte subsets by flow cytometric analysis as well as bacterial translocation of the normal flora leading to brachial lymph node abscess. This work was carried out to evaluate the systemic and/or local immunotoxic potential of VCN. Acrylonitrile (2.7 mg kg-1 day-1) was given to CD-1 mice once daily for 5, 10 and 15 days. Immunohistochemical assessment of the number of cells capable of producing IgA in different intestinal compartments (duodenum, jejunum and ileum) revealed a significant decrease following VCN treatment. On the contrary, Bromodeoxyuridine (BrdU) incorporation in gut epithelial cells (duodenum and ileum) showed a significant increase in the same VCN-treated groups of animals. On the other hand, [3H]thymidine uptake was significantly decreased in splenocytes stimulated with phytohemaglutinin (PHA), Concanavalin-A (Con-A) and Lipopolysaccharide (LPS) and derived from animals treated with VCN. The effects of VCN were started after 5 days and increased up to 15 days of daily treatment in most of the investigated parameters. The results suggested that VCN has a profound immunosuppressive effect either systemically or locally which could be a contributing factor in its GIT carcinogenicity.