Responses of circulating fish phagocytes to paper mill effluent exposure.
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Animals↗
Biomedical subjects
M Athar
Publications and source records attributed to M Athar.
Attenuation of iron-nitrilotriacetate (Fe-NTA)-mediated renal oxidative stress, toxicity and hyperproliferative response by the prophylactic treatment of rats with garlic oil.
Iron nitrilotriacetate (Fe-NTA) is a potent nephrotoxic agent. In this communication we show that Fe-NTA-mediated nephrotoxicity is diminished by 1 wk of oral daily pretreatment of male albino Wistar rats with garlic oil given by gavage at 50 or 100 mg/kg body weight/ml corn oil. Intraperitoneal Fe-NTA treatment at a dose level of 9 mg Fe/kg body weight/10 ml enhances renal microsomal lipid peroxidation and hydrogen peroxide generation which are accompanied by a decrease in the activities of renal antioxidant enzymes (e.g. catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase), and a 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 (ODC) activity and increases [3H]thymidine incorporation into renal DNA. Prophylactic treatment of animals with garlic oil before the administration of Fe-NTA resulted in the diminution of Fe-NTA mediated injury. The enhancement of renal lipid peroxidation and hydrogen peroxide generation was decreased. In addition, there was recovery of glutathione depletion and inhibition of the activities of antioxidant enzymes. Similarly, in animals given the higher dose of garlic oil (100 mg/kg body weight) the enhanced blood urea nitrogen and serum creatinine levels, which are indicative of renal injury, showed a reduction of about 30% and 40%, respectively, in comparison with the group treated with Fe-NTA alone. Pretreatment with garlic oil also ameliorated the Fe-NTA-mediated induction of ODC activity and enhancement of [3H]thymidine incorporation into DNA in a dose-dependent manner. Our data suggest that garlic oil is a potent chemopreventive agent and may suppress Fe-NTA-induced nephrotoxicity.
Administration, Oral↗
Ferric nitrilotriacetate promotes N-diethylnitrosamine-induced renal tumorigenesis in the rat: implications for the involvement of oxidative stress.
Ferric nitrilotriacetate (Fe-NTA) is a known complete renal carcinogen. In this study we show that Fe-NTA is a potent inducer of renal ornithine decarboxylase (ODC) activity and DNA synthesis and promoter of N-diethylnitrosamine (DEN)-induced renal tumorigenesis in rat. Fe-NTA induced renal ODC activity several fold as compared with saline-treated rats. Renal DNA synthesis, measured as [3H]thymidine incorporation into DNA, was increased after Fe-NTA treatment. Similar to other known tumor promoters, Fe-NTA also depleted the antioxidant armory of the tissue. It depleted glutathione (GSH) levels to approximately 55% of saline-treated controls. It also led to a dose-dependent decrease in the activities of glutathione reductase and glutathione S-transferase. Similarly, activities of catalase, glutathione peroxidase and glucose 6-phosphate dehydrogenase decreased significantly (45-65%). In contrast, gamma-glutamyl transpeptidase activity showed an increase. The maximum changes in activities of these enzymes could be observed at 12 h following Fe-NTA treatment. In addition, Fe-NTA augmented renal microsomal lipid peroxidation >150% over saline-treated controls, which was concomitant with the alterations in GSH metabolizing enzymes and depletion of the antioxidant armory. These effects were alleviated in rats which received a pretreatment with an antioxidant, BHA or BHT. Fe-NTA promoted DEN-induced renal tumorigenesis. In saline alone- and DEN alone-treated animals no tumors could be recorded, whereas in Fe-NTA alone-treated animals 17% tumor incidence was observed. However, in DEN-initiated and Fe-NTA-promoted animals tumor incidence increased to 71%. Our results show that Fe-NTA induces oxidative stress in the kidney and decreases antioxidant defenses, as indicated by the fall in GSH level and in the activities of glutathione peroxidase and catalase. Concomitantly, Fe-NTA increases ODC activity and DNA synthesis, which may be compensatory changes following oxidative injury to renal cells in addition to providing a strong stimulus for renal tumor promotion. Thus oxidative stress and impaired antioxidant defenses induced by Fe-NTA in the kidney may contribute to the observed nephrotoxicity and carcinogenicity.
Adenocarcinoma↗
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.
Animals↗
Evidence that Fe-NTA-induced renal prostaglandin F2 alpha is responsible for hyperplastic response in kidney: implications for the role of cyclooxygenase-dependent arachidonic acid metabolism in renal tumor promotion.
Oxidative stress in a tissue activates phospholipase A2 which releases free arachidonic acid. In addition, a low grade oxidative tone also stimulates the tissue cyclooxygenase activity. Cyclooxygenase-dependent arachidonic acid metabolites such as PGF 2 alpha are known to play an important role in the development and maintenance of hyperplasia in skin in response to the application of tumor promoters. In this study we show that Fe-NTA, an oxidant renal tumor promoter induces PGF 2 alpha which was maximum at 12 hours after Fe-NTA treatment. However, at all time points studied, the elevated levels of PGF 2 alpha have been observed. As a result of the induction of PGF 2 alpha, the hyperplastic response can also be observed in the histopathology of the tissue. Additionally, an increased incorporation of [3H]thymidine in renal DNA has also been observed. Pretreatment of animals with indomethacin suppresses Fe-NTA-mediated hyperproliferation suggesting a role of cyclooxygenase in Fe-NTA-mediated stimulation of hyperplastic activity. The pretreatment of animals with the chain breaking antioxidants, Vit. E, BHA and BHT were only partially effective in inhibiting Fe-NTA-mediated PGF2 alpha production, further suggesting a role of non-free radical-dependent mechanism in its production. Our data suggest that Fe-NTA-induced PGF2 alpha through the activation of cyclooxygenase is responsible for the development and maintenance of hyperplasia in kidney.
Animals↗
Mechanism of asbestos-mediated DNA damage: role of heme and heme proteins.
Several observations, including studies from this laboratory, demonstrate that asbestos generates free radicals in the biological system that may play a role in the manifestation of asbestos-related cytotoxicity and carcinogenicity. It has also been demonstrated that iron associated with asbestos plays an important role in the asbestos-mediated generation of reactive oxygen species. Exposure to asbestos leads to degradation of heme proteins such as cytochrome P450-releasing heme in cytosol. Our simulation experiments in the presence of heme show that such asbestos-released heme may increase lipid peroxidation and can cause DNA damage. Further, heme and horseradish peroxidase (HRP) can cause extensive DNA damage in the presence of asbestos and hydrogen peroxide/organic peroxide/hydroperoxides. HRP catalyzes oxidation reactions in a manner similar to that of prostaglandin H synthetase. Iron released from asbestos is only partially responsible for DNA damage. However, our studies indicate that DNA damage mediated by asbestos in vivo may be caused by a combination of effects such as the release and participation of iron, heme, and heme moiety of prostaglandin H synthetase in free radical generation from peroxides and hydroperoxides.
Animals↗
Paraquat induced DNA damage by reactive oxygen species.
The redox cycling contact herbicide paraquat (PQ) causes oxidative damage to pulmonary tissue. PQ is reduced enzymatically to PQ radical in lung where it reacts with molecular oxygen, generating reactive oxygen species (ROS). ROS damage various macromolecules including DNA. However, the ability of paraquat to mediate DNA damage is unknown. In this study, Bam H1 site (5'-GGATCC-3') on pBR322 DNA was chosen as the target sequence for a study of the PQ-mediated DNA damage. The incubation of PQ with plasmid DNA in the presence of freshly prepared rat lung microsomes and NADPH resulted in damage to the restriction site. The PQ-treated DNA was not digested with the endonuclease reflected by the digestion pattern of DNA on agarose gels. The effect was dependent on the dose of PQ. The PQ-mediated damage to DNA was comparable to DNA damage caused by ROS generated through the xanthine-xanthine oxidase system. The results of the present study suggest that ROS generated by PQ in vitro under aerobic conditions may lead to a modification of the restriction site on DNA.
DNA Damage↗
Coordination of copperpolyamine complex with imidazoles potentiates it superoxide dismutase mimicking activity and abolishes its interaction with albumin.
Mixed ligand complexes of copper polyamine with biomolecules such as imidazole, substituted imidazoles or pyridine have been synthesized and characterized. These molecules were used because of their low toxicity and high activity. These complexes were found to possess a distorted octahedral microenvironment with a potential SOD mimicking activity. The IC50 values for these complexes were of the order of 2-90 microM. Pyridine and imidazole complexes were most effective as they possess the lowest IC50 values of 2.1 and 6 microM respectively which are higher than the IC50 value of polyamine copper complex. Based on the uric acid estimations, it has also been ascertained that these complexes dismute O2- without inhibiting xanthine oxidase activity. The presence of increasing concentrations of albumin had no effect on the SOD mimicking activity of mixed ligand complexes. Polyamine complex, however lost approximately 80% of SOD mimicking activity in the presence of albumin (1 mg). These results suggest that coordination of polyamine copper complex with imidazoles/pyridine may abolish their binding affinity for albumin while potentiating their SOD mimicking activity.
Albumins↗
Porphyrin-mediated photosensitization has a weak tumor promoting activity in mouse skin: possible role of in situ-generated reactive oxygen species.
Reactive oxygen species (ROS) have been implicated in skin tumor promotion. Earlier, we showed that porphyrin-mediated cutaneous photosensitization results in the in situ generation of ROS. Recently, we have provided the first in situ evidence for the involvement of ROS in stage I tumor promotion. In this study we further show that in situ-generated ROS act as weak complete tumor promoters in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. Papillomas were induced in Swiss albino mice by a single topical application of DMBA as initiator. The promotion was achieved in these mice by the sustained generation of ROS through dihematoporphyrin ether (DHE)-mediated cutaneous photosensitization, which was done once every day (six times a week) for 24 weeks. The first appearance of visible papillomas could be recorded 24 weeks after the initiation. The highest tumor incidence of 60% occurred at a dose of 2.5 mg/kg body wt DHE. Increasing the dose of DHE produced a decrease in the incidence as well as in the number of papillomas. In contrast, the number of carcinomas/mouse increased with increasing dose of DHE. Histopathology of the tumor samples indicated the formation of in situ carcinoma also in skin. ROS generated through DHE-mediated photosensitization resulted in a approximately 3 fold induction of ODC activity 9 h after photosensitization. DHE-mediated photosensitization enhanced [3H]thymidine incorporation in cutaneous DNA in a dose-dependent manner. A maximum 5-fold induction of [3H]thymidine incorporation was observed at a dose of 10 mg/kg body wt DHE. The longer latency period, low incidence of tumor induction, low tumor yield and low induction of ODC activity as compared with TPA represent the weak but complete tumor promoting potential of in situ-generated ROS. The low tumor incidence and tumor yield observed at higher doses of DHE may be due to the ablation of tumors at early stages due to the strong photodynamic action of DHE.Our data indicate that porphyrin-mediated photosensitization has a weak tumor promoting effect in mouse skin and in situ-generated ROS may play an important role in the development of this response.
9,10-Dimethyl-1,2-benzanthracene↗
Studies on end-to-end colonic anastomosis in the dog: a comparison of techniques.
For end-to-end anastomosis, many techniques suitable for the small intestine end up catastrophically when applied on the colon. An experimental study involving 18 healthy adult dogs was conducted to find a model technique out of the best considered techniques for small intestinal end-to-end anastomosis viz., simple interrupted approximating sutures (group I), double-layer inverting sutures (group II), and Gambee sutures (group III). The results depicted a nonsignificant difference among groups as far as paralytic ileus and omental adhesions are concerned. Similarly, haematologic and physiologic values did not deviate from a normal pattern after any surgical intervention. Barium sulphate radiographs taken at postoperation (PO) day 14 revealed significantly lesser reduction (P < or = 0.001) in lumen diameter (26.14 +/- 1.87%) at the site of anastomosis in group I as compared to 30.16 +/- 1.20% and 38.91 +/- 1.87% reduction in groups III and II, respectively. Similarly, gain in tensile strength was maximum (26.55 +/- 1.33%) in group I and minimum (19.73 +/- 2.62%) in group II on PO day 14. The current study showed superiority of the simple interrupted suture technique for colonic end-to-end anastomosis over the other two techniques studied.
Anastomosis, Surgical↗
Clinical perspectives of intravenous ketamine anaesthesia in peafowl (Pavo cristatus).
A total of 29 peafowl (Pavo cristatus), rectified surgically for infraorbital abscesses (n = 22), lacerated wounds (n = 4), and fractures of tibia (n = 2) and radius (n = 1), were anaesthetized by the intravenous administration of ketamine hydrochloride (Inj. Calypsol, Gedeon Richter, Hungary) in a dose of 15 20 mg/kg body weight. Divided doses (10 mg + 5 mg + 5 mg) were used with an interval of 1-2 min. No premedication was undertaken in any of the birds. Anaesthesia lasted for about 15 min and the birds gained their feet completely after 30 min to 3 hours. The respiration rate was markedly depressed (8-10/min) and the respiratory pattern was deep abdominal. Only a slight increase was observed in the heart rate. Analgesia was incomplete and muscle relaxation was not satisfactory. Mild salivation was also noticed in some of the birds (n = 3). Recovery, although not smooth, was uneventful.
Abscess↗
Metabolic requirements for induction of contact hypersensitivity to immunotoxic polyaromatic hydrocarbons.
Experiments were performed to define the metabolic requirements for induction of contact hypersensitivity to polyaromatic hydrocarbons (PAHs), environmental xenobiotics that are both immunotoxic and carcinogenic. Evidence that conversion of the parent compound to a reactive metabolite was necessary for the development of contact hypersensitivity included the fact 1) that contact hypersensitivity to the polyaromatic hydrocarbon dimethylbenz(a)anthracene (DMBA) only occurred in strains of mice that could metabolize the compound, 2) that among the PAHs, only those that could induce aryl hydrocarbon hydroxylase, the rate-limiting enzyme in the PAH metabolic pathway, were immunogenic, and 3) that inhibitors of PAH metabolism reduced DMBA contact hypersensitivity. Cells from the XS52 Langerhans cell-like dendritic cell line were able to metabolize the PAH benzo(a)pyrene to its diol, quinone, and phenol metabolites. GM-CSF augmented benzo(a)pyrene metabolism in XS52 cells. Finally, in vivo depletion of CD8+, but not CD4+, T cell populations inhibited contact hypersensitivity to DMBA. The implications of these experiments are that at least for some contact allergens, the metabolic status of the host is a key determinant of individual susceptibility to the development of allergic contact dermatitis, and the metabolic pathway of an individual hapten may have ramifications for the T cell subpopulation-CD4 or CD8-that is activated.
Animals↗
Ferric nitrilotriacetate (Fe-NTA) is a potent hepatic tumor promoter and acts through the generation of oxidative stress.
Fe-NTA is a known renal carcinogen. However, little is known about its carcinogenic potential in liver. In this study we for the first time show that Fe-NTA is a potent hepatic tumor promoter. Fe-NTA administration induced dose dependently the hepatic ornithine decarboxylase (ODC) activity several folds as compared to its activity in the saline-treated rats. Similarly, hepatic DNA synthesis which is measured as [3H]thymidine incorporation in DNA is also increased following Fe-NTA treatment. The effects of Fe-NTA were similar to other tumor promoters not only with respect to inducing ODC activity and [3H]thymidine incorporation in DNA but also in depleting antioxidant armory of the tissue. Fe-NTA depleted levels of glutathione to about 35% of the saline-treated control and activities of antioxidant enzymes catalase, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase decreased significantly (45-55% of saline-treated control). Concomitant with the depletion in antioxidant armory, Fe-NTA augmented hepatic microsomal lipid peroxidation more than three folds. The pretreatment of rats with antioxidants BHA or BHT diminished the observed effects of Fe-NTA. Our data indicate that Fe-NTA is a potent hepatic tumor promoter and acts through a mechanism involving oxidative stress.
Animals↗
Evidence that in situ generated reactive oxygen species act as a potent stage I tumor promoter in mouse skin.
A body of indirect evidence has suggested the involvement of reactive oxygen species (ROS) in tumor promotion. However, direct evidence for the involvement of in situ generated ROS in tumor promotion is lacking at present. This study provides the first in situ evidence for the involvement of ROS in stage I tumor promotion. Earlier we have shown that parenteral administration of Photofrin-II (a mixture of porphyrins) to mice followed by their exposure to visible light generates ROS. In this study we further provide E.S.R. spectral evidence that both O2.- and .OH radicals are generated during tissue photosensitization. The free radicals/ROS generation is followed by the development of cutaneous inflammation which is maximum at six hours after photosensitization and develops in a dose dependent manner. The epidermal myeloperoxidase activity which represents neutrophil infiltration is also increased more than 160% of the control value. The histopathology of skin tissues of 7,12 dimethyl benz(a)anthracene initiated mice receiving multiple treatments of Pf-II and light for a period of four weeks indicates pronounced epidermal hyperplasia, glandular hyperplasia, dark basal keratinocytes induction characterized by the high uptake of the dye and frequent neutrophil infiltrations. Our data indicate that ROS generated in situ as a result of porphyrin-mediated cutaneous photosensitization results in the development of changes characteristic of stage I tumor promotion in murine skin.
9,10-Dimethyl-1,2-benzanthracene↗
Augmentation of chrysotile-induced oxidative stress by BHA in mice lungs.
Asbestos is known to induce oxidative stress in the lung. The consumption of butylated hydroxyanisole (BHA) in preserved food and soft drinks is increasing in the general population, which includes workers in asbestos factories. Because there is no information on the effect of co-exposure to chrysotile and BHA, the time-dependent effects of a single intratracheal dose of chrysotile (1 mg per mouse) and a single ip dose of BHA (350 mg/kg body weight) on various indices of oxidative stress such as lipid peroxidation, hydrogen peroxide generation, glutathione peroxidase (GPX), glutathione reductase (GR), catalase, glucose-6-phosphate dehydrogenase (G6PDH) and glutathione (GSH) were followed for up to 14 days. Microsomal lipid peroxidation (as well as that induced by NADPH) was significantly enhanced by BHA in the chrysotile-exposed group. GPX and GR activities in the same group were gradually decreased by BHA. Non-significant modulation of catalase activity by BHA was also noted. BHA induces GSH to a significant extent in lungs exposed with chrysotile. An increase in the G6PDH activity was maximal (19%; P < 0.05) at day 3. The results clearly demonstrate that BHA enhances chrysotile-induced oxidative stress in the lung.
Animals↗
Crude extracts of hepatoprotective plants, Solanum nigrum and Cichorium intybus inhibit free radical-mediated DNA damage.
The presence of plant extracts of Solanum nigrum and Cichorium intybus in the reaction mixture containing calf thymus DNA and free radical generating system protect DNA against oxidative damage to its deoxyribose sugar moiety. The effect was dependent on the concentration of plant extracts. However, the effect of Cichorium intybus was much pronounced as compared to the effect of Solanum nigrum. These studies suggest that the observed hepatoprotective effect of these crude plant extracts may be due to their ability to suppress the oxidative degradation of DNA in the tissue debris.
Acetates↗
Differential role of hydrogen peroxide and organic peroxides in augmenting asbestos-mediated DNA damage: implications for asbestos induced carcinogenesis.
The incubation of asbestos with DNA in presence of peroxides augmented DNA damage several fold as compared to the damage caused by individual treatments. Asbestos in presence of hydrogen peroxide causes DNA double strand breaks, damage to its deoxyribose sugar moiety and enhanced DNA fidelity. However, only DNA double strand breaks and enhanced DNA fidelity could be recorded in presence of organic hydroperoxide/peroxide but no DNA sugar damage could be observed. Further, the extent of DNA damage could be correlated to the carcinogenic potential of asbestos fibre. Crocidolite, the most carcinogenic variety of asbestos, produces maximum damage to DNA in presence of both hydrogen peroxide and organic hydroperoxide/peroxide while chrysolite which is only a co-carcinogen produces significantly less DNA damage. The observed differences in DNA damage by hydrogen peroxide and organic hydroperoxide/peroxide have been ascribed to the differential reactivity of DNA with hydroxyl and alkoxy/aryloxy free radicals produced respectively from these inorganic and organic peroxides.
Animals↗
ras protein p21 processing enzyme farnesyltransferase in chemical carcinogen-induced murine skin tumors.
Farnesylation of ras protein p21 is crucial for the protein's membrane localization, which is essential for its cell-transforming activity, which in turn is thought to be critical for the ultimate induction of cancer. The cytosolic enzyme farnesyltransferase plays a major role in posttranslational modification of p21, but the level of farnesyltransferase activity in mammalian tumors and its relationship to the processing of cytosolic p21 that leads to tumorigenesis are unknown. We report here that farnesyltransferase activity was significantly higher in chemical carcinogen-induced benign skin papillomas in SENCAR mice than in the epidermises of control animals. The enzyme is primarily epidermal in origin, and kinetic studies with cytosol from epidermis and papillomas showed that the reaction was linear with respect to time, substrate concentration, and protein content. Skin papillomas showed significantly elevated levels of both cytosolic and membrane-bound Ha-ras p21, whereas far lesser cytosolic and almost negligible amounts of membrane-bound p21 were present in the epidermis of control mice. There was a positive correlation between increased enzyme activity in papilloma cytosol and the processing of overexpressed cytosolic Ha-ras p21 for its localization to membrane.
Alkyl and Aryl Transferases↗