Antimutagenic effects of vitamin E on oncology and non oncology hospital nurses by comet assay.

Vitamin E is a natural antioxidant and its most common biologically active form is α-tocopherol. The antiproliferative effects of α-tocopherol have been previously demonstrated. In this study the antimutagenic effects of vitamin E on oncology and non oncology hospital nurses was investigated. A total of 138 female nurses from oncology and non oncology hospitals participated in the study. They received 200 mg/day vitamin E for 2 weeks. The urine samples before and after intake of vitamin E were collected and the nucleus of urothelial cells were evaluated with comet assay. The length of epithelial cells nuclei correlated with increased fracture rate of DNA. Nucleolus length of urine epithelial cells of all nursing staff before and after vitamin E treatment were measured and the data were evaluated by student t-test and SPSS. Our study showed that 20% of nursing staff have apoptosis and DNA fracture in the nucleolus of their urine epithelial cells and DNA damage in the urothelial cells of exposed nurses was significantly higher than the control group (P<0.05).The antimutagenic activity of vitamin E had significant effects on oncology hospital nurses effectively in repairing DNA damage and decreasing their nucleus length in urine epithelial cells.We propose that the higher therapeutic doses of vitamin E and increasing the length of treatment period will be effective against DNA strand breakage and may have more effect on oncology nurses.

Stability analysis of distributed order fractional chen system.

We first investigate sufficient and necessary conditions of stability of nonlinear distributed order fractional system and then we generalize the integer-order Chen system into the distributed order fractional domain. Based on the asymptotic stability theory of nonlinear distributed order fractional systems, the stability of distributed order fractional Chen system is discussed. In addition, we have found that chaos exists in the double fractional order Chen system. Numerical solutions are used to verify the analytical results.

Effect of interactive group discussion among physicians to promote rational prescribing.

This study assessed the effect of an educational intervention (interactive group discussion) on the prescribing behaviour of 51 general physicians from the north-west of Tabriz. Prescriptions were analysed pre-intervention and post-intervention (control and intervention groups) using a proforma with 8 indicators of correct prescribing. The mean number of drugs per prescription pre-intervention was 3.82. The percentage of prescriptions with antibiotics, corticosteroids and injections were 40.8%, 25.9% and 58.0%, respectively. Following the intervention there were slight but not significant changes in the indicators in both intervention and control groups compared with pre-intervention results.

Effect of interactive group discussion among physicians to promote rational prescribing

This study assessed the effect of an educational intervention [interactive group discussion] on the prescribing behaviour of 51 general physicians from the north-west of Tabriz. Prescriptions were analysed pre-intervention and post-intervention [control and intervention groups] using a proforma with 8 indicators of correct prescribing. The mean number of drugs per prescription pre-intervention was 3.82. The percentage of prescriptions with antibiotics, corticosteroids and injections were 40.8%, 25.9% and 58.0%, respectively. Following the intervention there were slight but not significant changes in the indicators in both intervention and control groups compared with pre-intervention results

Chrozophorin: a new acylated flavone glucoside from Chrozophora tinctoria (Euphorbiaceae) / Crozoforina: uma nova flavona glicosilada e acetilada de Chrozophora tinctoria (Euphorbiaceae)

Preparative reversed-phase HPLC analysis of the methanol extract of the aerial parts of Chrozophora tinctoria (Euphorbiaceae) yielded five flavonoid glycosides, quercetin 3-O-rutinoside (1, rutin), acacetin 7-O-rutinoside (2), apigenin 7-O-b-D-[(6-p-coumaroyl)]-glucopyranoside (3), apigenin 7-O- b-D-glucopyranoside (4) and apigenin 7-O-b-D-[6-(3,4-dihydroxybenzoyl)]-glucopyranoside (named, chrozophorin, 5), the last one being a new natural product. The structures of these compounds were elucidated unambiguously by UV spectroscopic analyses using shift reagents, ESIMS, and 1D and 2D NMR spectroscopic techniques. The free-radical scavenging activity of the methanol extract (RC50 = 2.24 x 10-1 mg/mL) as well as the isolated compounds (1-5) (RC50 = 4.38 x 10-3, 2.26 x 10-2, 7.69 x 10-4, 8.71 x 10-3 and 3.19 x 10-4 mg/mL, respectively) were assessed by the DPPH assay.

Análise das partes aéreas de Chrozophora tinctoria (Euphorbiaceae) através de HPLC preparativa com coluna de fase reversa produziu cinco glicosídeos de flavonóides, quercetina 3-O-rutinosídeo (1, rutina), acacetina 7-O-rutinosídeo (2), apigenina 7-O-b-D-[(6-p-cumaroil)]-glicopiranosídeo (3), apigenina 7-O-b-D-glicopiranosídeo (4) e apigenina 7-O-b-D-[-(3,4-diidroxibenzoil)]-glicopiranosídeo (chamado crozoforina, 5), sendo o último um novo produto natural. As estruturas dessas substâncias foram inequivocamente elucidadas por análise de espectrofotometria de UV com o uso de reagentes de deslocamento, ESIMS, e técnicas de RMN 1D e 2D. A atividade de captura de radicais livres do extrato metanólico (RC50 = 2,24 x 10-1 mg/mL) bem como das substâncias isoladas (1-5) (RC50 = 4,38 x 10-3, 2,26 x 10-2, 7,69 x 10-4, 8,71 x 10-3 e 3,19 x 10-4 mg/mL, respectivamente) foram analisados pelo método DPPH.

Evidence that iron overload plus croton oil induce skin tumours in mice.

Iron overload is known to occur due to different factors including genetic disorders. It has been shown that iron overload predisposes humans to an increased risk of cancer. However, the mechanism by which iron overload enhances chemically induced carcinogenesis is not known. In this report, for the first time it is shown that iron overload acts as a tumour initiator. Female albino Swiss mice were given iron dextran 1 mg/mouse per day intramuscularly for 15 days and croton oil 0.5 mg in 200 microL acetone/mouse topically twice a week for 30 weeks. During this period, the animals were observed for tumour incidence. There were significantly higher yields of tumours in those animals receiving both iron and croton oil. However, the group of animals treated only with acetone, iron, croton oil and 7,12-dimethylbenz(a)anthracene (DMBA) alone did not develop any tumours during 30 weeks of observation. Further, croton oil-mediated induction in cutaneous lipid peroxidation (LPO) level was higher in the iron-overload group. The results of this study suggest that oxidative stress generated by iron overload is responsible for croton oil-mediated skin carcinogenesis.

Effect of chronic and acute administration of fluoxetine and its additive effect with morphine on the behavioural response in the formalin test in rats.

Serotonergic systems are involved in the central regulation of nociceptive sensitivity. Fluoxetine, a selective inhibitor of the reuptake of serotonin (5-hydroxytryptamine, 5-HT), was administered orally (0.16, 0.32, 0.8 mg kg(-1) daily for 7 days), intraperitoneally (0.04, 0.08, 0.16 mg kg(-1) day(-1) for 7 days and a single dose of 0.32 mg kg(-1)) and intracerebroventricularly (10 microg/rat) to rats and nociceptive sensitivity was evaluated using the formalin test (50 microL of 2.5% formalin injected subcutaneously). The effect of fluoxetine was also studied in the presence of 5,7-dihydroxytryptamine creatinine sulfate (5,7-DHT) and after co-administration with morphine. Oral (0.8 mg kg(-1)), intraperitoneal (0.16 and 0.32 mg kg(-1)) and intracerebroventricular (10 microg/rat) fluoxetine induced antinociception in the late phase of the formalin test. Furthermore, intrathecal administration of 5-HT (100 microg/rat) induced an analgesic effect. The analgesic effect of fluoxetine (0.16 and 0.32 mg kg(-1), i.p.) and 5-HT (100 microg/rat, i.t.) was abolished by pre-treatment with 5,7-DHT (100 microg/rat, i.t.). In addition, the analgesic effect of 5-HT (100 microg/rat, i.t.) was decreased by pre-treatment with naloxone (2 mg kg(-1), i.p.). Morphine (5 mg kg(-1), i.p.) induced analgesia that was increased by fluoxetine (0.32 mg kg(-1), i.p.). These results suggest that fluoxetine has an antinociceptive effect in tonic inflammatory pain through functional alteration of the serotonergic system and also potentiates the analgesic effect of morphine.

Role of iron-dextran on 7,12-dimethylbenz(a) anthracene-initiated and croton oil-promoted cutaneous tumorigenesis in normal and pregnant mice.

Skin chemical carcinogenesis has been divided into the process of initiation, promotion and progression. Earlier, we showed the role of iron overload in the promotion stage of skin carcinogenesis. In this communication, we report that iron overload does not augment croton oil-mediated tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated pregnant mice skin tumorigenesis. Virgin female Swiss mice were given 1 mg iron/mouse/day parenterally for 2 weeks to induce iron overload. After the last injection, a group of mice was left with male mice for 10 days. These animals showed an increase in cutaneous iron concentration as compared to normal mice. Papillomas were induced in mice skin by a single topical application of DMBA as initiator. A week after the initiation, promoting agent, croton oil was applied twice per week for 20 weeks. The appearance of the first tumor (papilloma), number of tumors/mouse and percentage incidence were recorded. When compared to the iron unloaded control and iron overload pregnant groups, the iron overload virgin animals showed an increased incidence of tumors. In iron overload virgin animals, tumors appeared earlier and also the numbers of tumors/mouse were significantly higher. However, in iron overload pregnant animals, diminished tumor incidence was observed and the numbers of tumors matched the result of normal pregnant animals. Our results show that iron overload in pregnant mice does not participate in the augmentation of DMBA- and croton oil-induced skin tumorigenesis.

Iron overload augments 7,12-dimethylbenz(a)anthracene-initiated and 12-O-tetradecanoylphorbol-13-acetate-promoted skin tumorigenesis.

Reactive oxygen species and free radicals have been implicated in the multistep cutaneous chemical carcinogenesis. Much of the experimental evidence in this regard is indirect and is based on observations that prooxidant status usually enhances and antioxidant treatments generally inhibit tumor yield. Iron overload is known to enhance peroxidative damage and cause oxidative stress. In this study, we report that iron overload augments 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated cutaneous tumor promotion. Female Swiss mice were subjected to iron overload by injecting 1 mg iron/ mouse/day consecutively for 2 weeks. Tumors were initiated by applying a single dose of 7,12-dimethylbenz(a)anthracene and promoted with twice weekly applications of TPA for 20 weeks and the appearance of first tumor (latency period), percent incidence and number of tumors per mouse were recorded. It has been observed that the level of iron in involved (tumor-bearing) skin was about fourfold higher as compared to uninvolved (non-tumor) skin of iron overload animals and about tenfold higher as compared to the iron level in the skin of normal animals. When compared to the iron-unloaded control group, the iron overload mice showed an increased incidence of tumors. In iron overload animals, the tumors appeared 3 weeks earlier and also the number of tumors per mouse was significantly higher (2.5-fold). These data indicate that iron overload augments TPA-mediated tumor promotion. We propose that oxidative stress generated by iron overload may be responsible for the augmentation of cutaneous tumorigenesis.

Effect of iron overload on the benzoyl peroxide-mediated tumor promotion in mouse skin.

In this communication, we report that iron overload augments benzoyl peroxide (BPO)-mediated tumor promotion in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. Female albino Swiss mice were overloaded with iron and tumors were initiated by applying a single topical application of DMBA. A week after the initiation, promoting agent, BPO, was applied three times/week for 46 weeks. The appearance of the first tumor (papilloma) and the number of tumors/mouse were recorded. When compared to the control group, the iron-overloaded mice showed an increased incidence of tumors at various time intervals. In iron-overloaded animals, tumors appeared earlier and also the number of tumors/mouse was significantly higher. These data could be correlated with the iron levels of mouse skin in the two groups. Further, BPO-mediated induction in ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation in cutaneous DNA were higher in the iron overload group. In addition, in iron-overloaded mice, cutaneous lipid peroxidation (LPO) and xanthine oxidase (XOD) activities were higher, whereas catalase activity was reduced. Similar to papilloma induction, a significant increase in carcinoma yield and incidence was observed in iron-overloaded animals. Based on this study, we propose that iron overload significantly increases the tumor promotion and progression potential of BPO. We suggest that oxidative stress generated by iron overload is responsible for the augmentation of BPO-mediated cutaneous tumorigenesis.

alpha-Tocopherol (vitamin-E) ameliorates ferric nitrilotriacetate (Fe-NTA)-dependent renal proliferative response and toxicity: diminution of oxidative stress.

Ferric nitrilotriacetate (Fe-NTA) is a potent nephrotoxic agent. In this communication, we show the modulatory effect of DL-alpha-tocopherol (Vitamin-E) on ferric nitrilotriacetate (Fe-NTA)-induced renal oxidative stress, toxicity and hyperproliferative response in rats. Fe-NTA-treatment enhances the susceptibility of renal microsomal membrane for iron-ascorbate-induced lipid peroxidation and hydrogen peroxide generation which are accompanied by a decrease in the activities of renal antioxidant enzymes, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase and depletion in the level of renal glutathione. Parallel to these changes, a sharp increase in blood urea nitrogen and serum creatinine has been observed. In addition, Fe-NTA-treatment also enhances renal ornithine decarboxylase activity (ODC) and increases [3H]thymidine incorporation in renal DNA. Prophylactic treatment of animals with Vit.E daily for 1 week prior to the administration of Fe-NTA resulted in the diminution of Fe-NTA-mediated damage. Enhanced susceptibility of renal microsomal membrane for lipid peroxidation induced by iron-ascorbate and hydrogen peroxide generation were significantly reduced (P < 0.05). In addition, the depleted level of glutathione and inhibited activities of antioxidant enzymes recovered to significant levels (P < 0.05). Similarly, the enhanced blood urea nitrogen and serum creatinine levels which are indicative of renal injury showed a reduction of about 50% at a higher dose of Vit.E. The pretreatment of rats with Vit.E reduced the Fe-NTA-mediated induction in ODC activity and enhancement in [3H]thymidine incorporation in DNA. The protective effect of Vit.E was dose dependent. In summary, our data suggest that Vit.E is an effective chemopreventive agent in kidney and may suppress Fe-NTA-induced renal toxicity.

Evidence that iron-overload promotes 7,12-dimethylbenz(a)anthracene- induced skin tumorigenesis in mice.

Iron overload is known to occur in West European and American populations due to the consumption of an iron-rich diet. There are also genetic disorders which lead to body iron overload. It has been shown that iron overload predisposes humans to an increased risk of cancer. In experimental animals, iron overload is known to enhance intestinal, colon, hepatic, pulmonary and mammary carcinogenesis. However, the mechanism by which iron overload enhances chemically-induced carcinogenesis is not known. In this study, we show that iron overload acts as a mild tumor promoter in mouse skin. Female albino swiss mice were given 1 mg iron/mouse parenterally for 2 weeks to induce iron overload. These animals showed a three-fold increase in cutaneous iron concentration as compared to normal mice. Tumors were initiated by topically applying 7,12-dimethylbenz(a)anthracene (DMBA). Appearance of the first tumor (latency period), percent tumor incidence and number of tumors/mouse were recorded. When compared to the control group, iron overload mice showed an increased incidence of tumors, from 25%-55% by week 20, and tumors appeared 4 weeks earlier. The number of tumors per mouse was four-fold higher in the iron overload group. The induction of cutaneous ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation in cutaneous DNA were higher in iron overload groups as compared to normal control animals. Similar to other oxidant tumor promoters, iron overload enhanced cutaneous lipid peroxidation and xanthine oxidase activity and decreased catalase activity. Our results indicate that iron overload exerts a mild tumor promoting activity in mouse skin. Our data also show that oxidative stress generated by iron overload plays an important role in the augmentation of cutaneous tumorigenesis. These data may also have implications for the enhanced risk of cancer-induction following UVB exposure of human populations with iron overload.

Glutathione metabolizing enzymes and oxidative stress in ferric nitrilotriacetate mediated hepatic injury.

Glutathione (GSH) plays several important roles in the protection of cells against oxidative damage, particularly following exposure to xenobiotics. Ferric nitrilotriacetate (Fe-NTA) is a potent depletor of GSH and also enhances tissue lipid peroxidation. In this study, we show the effect of Fe-NTA treatment on hepatic GSH and some of the glutathione metabolizing enzymes, oxidant generation and liver damage. The level of hepatic GSH and the activities of glutathione reductase, glutathione S-transferase, glutathione peroxidase, and glucose 6-phosphate dehydrogenase all decrease following Fe-NTA administration. In these parameters the maximum decrease occurred at 12 h following Fe-NTA treatment. In contrast, γ-glutamyl transpeptidase was increased at this time. Not surprisingly, the increase in the activity of γ-glutamyl transpeptidase and decreases in GSH, glutathione peroxidase, glutathione reductase, glucose 6-phosphate dehydrogenase and glutathione S-transferase were found to be dependent on the dose of Fe-NTA administered. Fe-NTA administration also enhances the production of H2O2 and increases hepatic lipid peroxidation. Parallel to these changes, Fe-NTA enhances liver damage as evidenced by increases in serum transaminases. Once again, the liver damage is dependent on the dose of Fe-NTA and is maximal at 12 h. Pretreatment of animals with antioxidant, butylated hydroxy anisole (BHA), protects against Fe-NTA-mediated hepatotoxicity further supporting the involvement of oxidative stress in Fe-NTA-mediated hepatic damage. In aggregate, our results indicate that Fe-NTA administration eventuates in decreased hepatic GSH, a fall in the activities of glutathione metabolizing enzymes and excessive production of oxidants, all of which are involved in the cascade of events leading to iron-mediated hepatic injury.