Comparative assessment of two biodegradable chelants, S,S-ethylenediamine disuccinic acid and nitrilotriacetic acid, in facilitating Cd remediation by lesser swine cress (Coronopus didymus, Brassicaceae).

Chemically assisted phytoremediation is suggested as an effective approach to amplify the metal-remediating potential of hyperaccumulators. The current study assessed the efficiency of two biodegradable chelants (S,S-ethylenediamine disuccinic acid, EDDS; nitrilotriacetic acid, NTA) in enhancing the remediation of Cd by Coronopus didymus (Brassicaceae). C. didymus growing in Cd-contaminated soil (35-175 mg kg-1 soil) showed increased growth and biomass due to the hormesis effect, and chelant supplementation further increased growth, biomass, and Cd accumulation. A significant interaction with chelants and different Cd concentrations was observed, except for Cd content in roots and Cd content in leaves, which exhibited a non-significant interaction with chelant addition. The effect of the NTA amendment on the root dry biomass and shoot dry biomass was more pronounced than EDDS at all the Cd treatments. Upon addition of EDDS and NTA, bio-concentration factor values were enhanced by ~184-205 and ~ 199-208, respectively. The tolerance index of root and shoot increased over the control upon the addition of chelants, with NTA being better than EDDS. With chelant supplementation, bio-accumulation coefficient values were in the order Cd35 + NTA (~163%) > Cd105 + NTA (~137%) > Cd35 + EDDS (~89%) > Cd175 + NTA (~85%) > Cd105 + EDDS (~62%) > Cd175 + EDDS (~40%). The translocation factor correlated positively (r ≥ 0.8) with tolerance index and Cd accumulation in different plant parts. The study demonstrated that chelant supplementation enhanced Cd-remediation efficiency in C. didymus as depicted by improved plant growth and metal accumulation, and NTA was more effective than EDDS in reclaiming Cd.

Therapeutic role of nitroglycerin against copper-nitrilotriacetate induced hepatic and renal damage.

Earlier we have shown that exposure to copper-nitrilotriacetate (Cu-NTA) manifests toxicity by generating oxidative stress and potent induction of proliferative reaction in the liver and kidney. In the study, we look at the impact of nitroglycerin (GTN) administration on Cu-NTA-induced oxidative stress and hyperproliferative response in the liver and kidney. GTN administration intraperitoneally to male Wistar rats after Cu-NTA administration intraperitoneally caused substantial protection against Cu-NTA-induced tissue injury, oxidative stress and hyperproliferative response. Cu-NTA administration at a dose of 4.5 mg/kg body weight produces significant (p < .001) elevation in biochemical parameters including aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine (CREA) with a concomitant increase in microsomal lipid peroxidation. Along with these alterations, we discovered a substantial increment in [3H]thymidine incorporation into hepatic and renal DNA synthesis (p < .001). Cu-NTA-induced tissue damage and lipid peroxidation in hepatic and renal tissues were inhibited by GTN treatment in a dose-dependent manner (p < .05-0.001). Furthermore, GTN can suppress the hyperproliferative response elicited by Cu-NTA by down-regulating the rate of [3H]thymidine incorporation into hepatic and renal DNA (p < .01-0.001). Protective effect of GTN against Cu-NTA was also confirmed by histopathological changes in liver and kidney. This result suggests that GTN may serve as a scavenger for reactive oxygen species (ROS) and reduces toxic metabolites of Cu-NTA, thereby avoiding tissue injury and oxidative stress. Further, administration of NO inhibitor, NG-Nitroarginine methyl ester (L-NAME), exacerbated Cu-NTA induced oxidative tissue damage and cell proliferation. Overall, GTN reduces Cu-NTA-induced tissue damage, oxidative stress, and proliferative response in the rat liver and kidney, according to these findings. On the basis of the above results, present study suggests that GTN may be a potential therapeutic agent for restoration of oxidative damage and proliferation to liver and kidney.

Evaluation of the Effects of Nitrilotriacetic Acid as a Chelating Agent on the Biochemical Toxicity of Lead in Oreochromis niloticus.

In the present research, the effects of sublethal lead (Pb) concentrations on total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI) levels, enzyme activities (aspartate transaminase, AST; alanine transaminase, ALT; lactate dehydrogenase, LDH), ion levels (magnesium, Mg; sodium, Na; potassium, K; chlorine, Cl; calcium, Ca), and some metabolite levels (cholesterol, triglyceride, HDL, LDL, albumin, total protein) in the blood serum of Oreochromis niloticus and the protective function of nitrilotriacetic acid (NTA) due to its chelating characteristic were investigated. O. niloticus, which has an important position in the food chain and is often preferred in toxicological studies, was exposed to 0.1 ppm Pb, 0.1 ppm Pb + 0.3 ppm NTA, 1 ppm Pb, and 1 ppm Pb + 3 ppm NTA concentrations for 7 and 21 days. At the end of the duration, serum TAS and TOS levels were measured spectrophotometrically with Rel Assay Diagnostics; other enzyme activities, ion levels, and metabolite parameters were done by an autoanalyzer using commercial kits. Depending on the exposure periods and concentrations, the changes in the parameters were determined. It is determined that, under the influence of high ambient concentration of lead, TOS, OSI, AST, ALT, LDH, LDL, triglyceride, and Mg levels increased, while TAS, albumin, and K levels decreased after 21 days. These increases/decreases in all serum biochemical parameters were generally higher in fish treated with Pb alone compared to fish treated with a mixture of Pb + NTA. This study shows that these changes in serum parameters could be used as an indicator to assess on metal toxicity.

Nitrilotriacetic Acid-Functionalized Glucose-Responsive Complex Micelles for the Efficient Encapsulation and Self-Regulated Release of Insulin.

Insulin plays a significant role in diabetes treatment. Although a huge number of insulin-loaded, glucose-responsive nanocarriers have been developed in past decades, most of them showed a lower loading capacity and efficiency due to the weak interaction between insulin and nanocarriers. In this work, a novel insulin-encapsulated glucose-responsive polymeric complex micelle (CM) is devised, showing (i) enhanced insulin-loading efficiency owing to the zinc ions' chelation by nitrilotriacetic acid (NTA) groups of NTA-functioned glycopolymer and the histidine imidazole of insulin, (ii) the glucose-triggered pulse release of insulin, and (iii) long stability under physiological conditions. This CM was fabricated by the self-assembly of block copolymer PEG- b-P(Asp- co-AspPBA) and glycopolymer P(Asp- co-AspGA- co-AspNTA), resulting in complex micelles with a PEG shell and a cross-linked core composed of phenylboronic acid (PBA)/glucose complexations. Notably, the modified nitrilotriacetic acid (NTA) groups of CM could specifically bind insulin via chelated zinc ions, thus enhancing the loading efficacy of insulin compared to that of nonmodified CM. The dynamic PBA/glucose complexation core of CM dissociates under the trigger of high glucose concentration (>2 g/L) while being quite stable in low glucose concentrations (<2 g/L), as demonstrated by the pulse release of insulin in vitro. Finally, in a murine model of type 1 diabetes, NTA-modified complex micelles loading an insulin (NTA-CM-INS) group exhibited a long hypoglycemic effect which is superior to that of free insulin in the PBS (PBS-INS) group and insulin-loaded complex micelles without an NTA modification (CM-INS) group. This long-term effect benefited from Zn(II) chelation by NTA-modified complex micelles and could avoid hypoglycemia caused by the burst release of insulin. Taken together, this constitutes a highly effective way to encapsulate insulin and release insulin via an on-demand manner for blood glucose control in diabetes.

Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model.

Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh-deficient mice in comparison to wild-type mice (7.1%). Fe-NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe-NTA treatment in both the genotypes. Renal tumor-free survival after Fe-NTA treatment was marginally different (P = 0.157) between the two genotypes. Array-based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16INKA inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe-NTA-induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.

The Natural Product Curcumin as a Potential Coadjuvant in Alzheimer's Treatment.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive cognitive impairment of patients, affecting around 12% of people older than 65 years old. WHO estimated that over 48.6 million all over the world suffer this disease. On the basis of cumulative results on our research, we have postulated the neuroimmunomodulation hypothesis that appears to provide a reasonable explanation of both the preclinical and clinical observations. In this context, the long-term activation of the innate immune system triggers an anomalous cascade of molecular signals, finally leading to tau oligomerization in the pathway to neuronal degeneration. In the present scenario of the failure of many anti-AD drugs, nutraceutical compounds provide an avenue for AD prevention and possibly as coadjuvants in the treatment of this disease. Recent discoveries point to the relevance of curcumin, a natural anti-inflammatory agent, in controlling oxidative stress and improving cholinergic function in the brain, even though the mechanisms underlying these actions are unknown. We investigated the effects of curcumin in cultures of neuronal cells. For this study, we exposed cells to prooxidant conditions, both in the presence and absence of curcumin. Our data reveal that curcumin exert a strong neuroprotective effect in N2a cells, thus preventing toxicity by oxidative agents H2O2 and Fe+3. This is supported by results that indicate that curcumin control the neurodegenerative effects of both oxidative agents, relieving cells from the loss of neuritogenic processes induced by prooxidants. In addition, curcumin was able to slow down the tau aggregation curve and disassemble tau pathological oligomeric structures. Data suggest that curcumin could be a potential compound for prevention of cognitive disorders associated with AD.

Synthesis and anti-diabetic activity of new N,N-dimethylphenylenediamine-derivatized nitrilotriacetic acid vanadyl complexes.

Vanadium compounds are promising anti-diabetic agents. However, reducing the metal toxicity while keeping/improving the hypoglycemic effect is still a big challenge towards the success of anti-diabetic vanadium drugs. To improve the therapeutic potency using the anti-oxidative strategy, we synthesized new N,N-dimethylphenylenediamine (DMPD)-derivatized nitrilotriacetic acid vanadyl complexes ([VO(dmada)]). The in vitro biological evaluations revealed that the DMPD-derivatized complexes showed improved antioxidant capacity and lowered cytotoxicity on HK-2 cells than bis(maltolato)oxidovanadium (IV) (BMOV). In type II diabetic mice, [VO(p-dmada)] (0.15mmolkg-1/day) exhibited better hypoglycemic effects than BMOV especially on improving glucose tolerance and alleviating the hyperglycemia-induced liver damage. These insulin enhancement effects were associated with increased expression of peroxisome proliferator-activated receptor α and γ (PPARα/γ) in fat, activation of Akt (v-Akt murine thymoma viral oncogene)/PKB (protein kinase-B) in fat and liver, and inactivation of c-Jun NH2-terminal protein kinases (JNK) in liver. Moreover, [VO(p-dmada)] showed no tissue toxicity at the therapeutic dose in diabetic mice and the oral acute toxicity (LD50) was determined to be 1640mgkg-1. Overall, the experimental results indicated that [VO(p-dmada)] can be a potent insulin enhancement agent with improved efficacy-over- toxicity index for further drug development. In addition, the results on brain Tau phosphorylation suggested necessary investigation on the effects of vanadyl complexes on the pathology of the Alzheimer's disease in the future.

Chemomodulatory effect Melastoma Malabathricum Linn against chemically induced renal carcinogenesis rats via attenuation of inflammation, oxidative stress, and early markers of tumor expansion.

Melastoma malabathricum Linn (MM) has high valued for its commercial significance. Indian market (northeast) has great demand for the plants, which extended, its use as a traditional home remedy due to its anti-inflammatory effects. In this study, we scrutinize the therapeutic and protective effect of MM against diethylnitrosamine (DEN) and ferric nitrilotriacetate (Fe-NTA)-induced renal carcinogenesis, renal hyperproliferation, and oxidative stress in rats. Liquid chromatography mass spectroscopy (LC-MS) was used for identification of phytoconstituents. Administration of DEN confirmed the initiation the renal carcinogenesis via enhancing the expansion of tumor incidence. Intraperitoneally, administration of Fe-NTA boost the antioxidant enzymes (phase I), viz., superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and phase II, viz., quinone reductase (QR) and glutathione-S-transferase (GST). It also increased the content of renal lipid peroxidation (LPO), hydrogen peroxidase (H2O2) with decrease content in glutathione content (GSH). It also increased the renal biochemical and non-biochemical parameter. It also confirmed the augment the level of thymidine [3H] incorporation into renal DNA, ornithine decarboxylase (ODC) activity and increased the generation of proinflammatory (TNF-α, IL-6 and IL-ß) and inflammatory mediator (PGE2). We also analyzed the macroscopic and histologic of renal tissue. In addition, the effect of phytoconstituent of MM extract was evaluated in silico and free radical scavenging activity against the DPPH and ABTS free radicals. LC-MS confirmed the presence of quercetin >gallic acid in MM extract. Renal carcinogenesis rats treated with MM (100, 250, and 500 mg/kg) confirmed the significantly (P < 0.001) protective effect via reduction the antioxidant (phase I and phase II) enzymes, biochemical parameter and restore the proinflammatory and inflammatory mediator at dose dependent manner. MM altered the ODC and thymidine activity in renal DNA. The chemoprotective effect of MM was confirmed via decreased the renal tumor incidence, which was confirmed by the macroscopic and histopathological observation. Consequently, our result suggests that MM is a potent chemoprotective agent and suppresses DEN+ Fe-NTA-induced renal carcinogenesis, inflammatory reaction, and oxidative stress injury in Wister rats.

In vitro organo-protective effect of bark extracts from Syzygium guineense var macrocarpum against ferric-nitrilotriacetate-induced stress in wistar rats homogenates.

BACKGROUND: Overconsumption of oxygen in mammalian cells often lead to the production of reactive oxygen species (ROS) resulting from different mechanisms. Escape of scavenging enzymes/components or nutritional failure are the most important origins. Plant-derived molecules may protect biological molecules either by quenching free radicals, delaying or preventing the ROS formation or by restoring antioxidant enzymes activities. The present study assessed the antioxidant, phenolic profile and protective effect of barks extracts of Syzyguim guineense var macrocarpum against ferric nitriloacetate-induced stress in the liver, heart kidney and brain tissues of wistar rat homogenates. METHODS: Three extracts (aqueous, ethanol and aqueous-ethanol) from the barks of S. guineense var macrocarpum were used in this study. The spectrophotometric standardized methods were used to determine the free radical scavenging and antioxidant potential of the extracts. The protective properties of these plant extracts were also investigated as well as the quantification of secondary metabolites content (total phenolic, flavonoids and flavonols content). The HPLC method helped for characterizing phenolic compounds present in these extracts. RESULTS AND DISCUSSION: All the extracts exhibited a free radical scavenging potential in a concentration dependent manner which varied from 15.18 ± 0.80 to 97.15 ± 0.71 % depending to the type of extract and the method used. The ethanol extract had the higher phenolic content (432.85 mg QE/g extract), including total flavonoids (961.66 mg QE/g extract) and flavonols content (25.12 mg QE/g extract) and higher total antioxidant capacity. Among the phenolic compounds present in the extracts, the HLPC profile revealed the presence of syringic acid and apigenin in all the extracts. The extracts demonstrated their protective effect mostly in liver and brain homogenates by delaying or preventing lipid peroxidation, restoring enzymatic activities and enhancing glutathione levels. CONCLUSION: The overall results demonstrated that the extracts exhibited significant antioxidant and protective effects in liver and brain liver homogenates.

Antioxidant and nephroprotective potential of butylated hydroxyanisole against ferric nitrilotriacetate-induced oxidative stress and early tumor events.

The present study was aimed to study protective effect of butylated hydroxyanisole (BHA), a phenolic antioxidant used in foods on ferric nitrilotriacetate (Fe-NTA)-induced nephrotoxicity. Male albino rats of Wistar strain (4-6 weeks old) weighing 125-150 g were used in this study. Animals were given a single dose of Fe-NTA (9 mg kg(-1) body weight) after treatment with BHA (1 and 2 mg animal(-1) day(-1)). Fe-NTA treatment enhanced ornithine decarboxylase (ODC) activity to 5.3-fold, and [(3)H]-thymidine incorporation in DNA to 2.5-fold in kidney compared with the corresponding saline-treated control, whereas glutathione (GSH) levels and the activities of antioxidant enzymes decreased to a range of 2- to 2.5-fold in kidney. These changes were reversed significantly in animals receiving a pretreatment of BHA. The enhanced ODC activity and DNA synthesis showed a reduction to 2.12-fold and 1.15-fold, respectively, at a higher dose of 2 mg BHA day(-1) animal(-1), compared with the Fe-NTA-treated groups. Pretreatment with BHA prior to Fe-NTA treatment increased GSH and the activities of antioxidant enzymes to a range of 1.5- to 2-fold in kidney. The results indicate that BHA suppresses Fe-NTA-induced nephrotoxicity in male Wistar rats.

Chemopreventive efficacy of hesperidin against chemically induced nephrotoxicity and renal carcinogenesis via amelioration of oxidative stress and modulation of multiple molecular pathways.

In the present study, chemopreventive efficacy of hesperidin was evaluated against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in wistar rats. Nephrotoxicity was induced by single intraperitoneal injection of Fe-NTA (9 mg Fe/kg b.wt). Renal cancer was initiated by the administration of N-nitrosodiethylamine (DEN 200mg/kg b.wt ip) and promoted by Fe-NTA (9 mg Fe/kg b.wt ip) twice weekly for 16 weeks. Efficacy of hesperidin against Fe-NTA-induced nephrotoxicity was assessed in terms of biochemical estimation of antioxidant enzyme activities viz. reduced renal GSH, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase, superoxide dismutase and renal toxicity markers (BUN, Creatinine, KIM-1). Administration of Fe-NTA significantly depleted antioxidant renal armory, enhanced renal lipid peroxidation as well as the levels of BUN, creatinine and KIM-1. However, simultaneous pretreatment of hesperidin restored their levels in a dose dependent manner. Expression of apoptotic markers caspase-3, caspase-9, bax, bcl-2 and proliferative marker PCNA along with inflammatory markers (NFκB, iNOS, TNF-α) were also analysed to assess the chemopreventive potential of hesperidin in two-stage renal carcinogenesis model. Hesperidin was found to induce caspase-3, caspase-9, bax expression and downregulate bcl-2, NFκB, iNOS, TNF-α, PCNA expression. Histopathological findings further revealed hesperidin's chemopreventive efficacy by restoring the renal morphology. Our results provide a powerful evidence suggesting hesperidin to be a potent chemopreventive agent against renal carcinogenesis possibly by virtue of its antioxidant properties and by modulation of multiple molecular pathways.

Ameliorative effect of butylated hydroxyanisole against ferric nitrilotriacetate-induced hepatotoxicity and oxidative stress in rats.

Ferric nitrilotriacetate (Fe-NTA) is a known renal carcinogen and has been shown to adversely induce oxidative stress and tissue toxicity after both acute and chronic exposure. Present studies were designed to study the hepatoprotective and antioxidant potential of butylated hydroxyanisole (BHA), a phenolic antioxidant used in foods on ferric nitrilotriacetate (Fe-NTA) induced hepatotoxicity in rats. Male albino rats of Wistar strain (4-6 weeks old) weighing 125-150 g were used in this study. Animals were given a single dose of Fe-NTA (9 mg/kg body weight, intraperitoneal) after a week's treatment with BHA. BHA was administered orally once daily for 7 days at doses of 1 and 2 mg/animal/day. The hepatoprotective activity was assessed using various biochemical parameters as serum transaminases (alanine transaminase (ALT), aspartate transaminase (AST)) and lactate dehydrogenase (LDH). Fe-NTA treatment increased ALT, AST, and LDH levels significantly when compared to the corresponding saline-treated group (p < 0.001). Fe-NTA also depleted the levels of glutathione and the activities of antioxidant enzymes namely glutathione reductase and glutathione-S-tranferase (p < 0.05). Pretreatment with BHA significantly decreased ALT, AST and LDH levels in a dose-dependent manner (p < 0.05). BHA also increased antioxidant enzymes level and decreased lipid peroxidation and hydrogen peroxide generation to 1.3-1.5-fold as compared to Fe-NTA-treated group. The results show the strong hepatoprotective activity of BHA which could be due to its potent antioxidant effects.

MAPKs' status at early stages of renal carcinogenesis and tumors induced by ferric nitrilotriacetate.

Renal cell carcinoma (RCC) is asymptomatic at early stages, and thus, initial diagnosis frequently occurs at advanced or even metastatic stages, leading to a high rate of mortality. Ferric nitrilotriacetate (FeNTA)-induced RCC model is a useful tool to analyze molecular events at different stages of the carcinogenesis process in vivo. MAPKs' alterations seem to play an important role in the development and maintenance of human RCC tumors. Based on the above, p38α/ß/γ, JNK1/2, and ERK1/2 statuses were studied at early stages of FeNTA-induced renal carcinogenesis (1 and 2 months of carcinogen treatment) as well as in tumor tissue. MAPKs showed distinct response along carcinogenesis process, either as total proteins and/or as their phosphorylated forms. While the increase in total and phospho-p38α/ß levels became lower as carcinogenesis progressed, p38γ overexpression grew. Instead, total JNK2 diminished, but JNK1 was elevated at all studied times, and p-JNK1 levels increased at early stages, but not in tumors. In contrast, p-JNK2 rose at 2 months of treatment and in tumor tissue. Increased levels of p-ERK1/2 were observed at all stages analyzed. Very interestingly, at 1 and 2 months of FeNTA treatment, no alterations in MAPKs were found in liver or lung, where no primary tumors are induced with the scheme of FeNTA administration followed here. In conclusion, MAPKs' behavior evolved differentially as renal carcinogenesis advanced, even among isoforms of the same family, but it did not change in other tissues. All this strongly suggests a role of these kinases in FeNTA-induced RCC tumor development and maintenance.

Ameliorative effect of polyphenols from Padina boergesenii against ferric nitrilotriacetate induced renal oxidative damage: With inhibition of oxidative hemolysis and in vitro free radicals.

The aim of this study was to evaluate the antioxidant activities of diethyl ether (DEE) and methanol (M) extracts from brown alga Padina boergesenii using in vitro and in vivo antioxidant assay, which may help to relate the antioxidant properties with the possible outline of its ameliorative effect. M extract showed higher radical scavenging activity through ferric reducing antioxidant power 139.11 µmol tannic acid equivalent/g; DPPH 71.32 ± 0.56%; deoxyribose radical 88.31 ± 0.47%, and total antioxidant activity 0.47 ± 0.02 mg ascorbic acid equivalents/g. Oxidative red blood cell (RBC) hemolysis inhibition rate was significantly higher in M extract (150 mg/kg body weight) in reference to total phenolic content (r = 0.935). Rats administered with DEE and M extracts (150 mg/kg body weight) for seven days before the administration of ferric nitrilotriacetate (9 mg of Fe/mg/kg bodyweight). Rats pretreated with extracts significantly changed the level of renal microsomal lipid peroxidation, glutathione, and antioxidant enzymes in post-mitochondrial supernatant (P < 0.05). Ameliorative effect of extracts against renal oxidative damage was evident in rat kidney through changes in necrotic and epithelial cells. HPTLC technique has identified the presence of rutin with reference to retardation factor (Rf ) in both the extracts. These findings support the source of polyphenols (rutin) from P. boergesenii had potent antioxidant activity; further work on isolation of bioactive compounds can be channeled to develop as a natural antioxidant.

Ascorbic acid inhibits ferric nitrilotriacetate induction of ornithine decarboxylase, DNA synthesis, oxidative stress, and hepatotoxicity in rats.

Ascorbic acid (AA) is a naturally occurring phenolic compound with antioxidant properties used in food, cosmetics, and pharmaceutical products. In this study, the effect of AA on ferric nitrilotriacetate (Fe-NTA)-induced hepatotoxicity in rats has been examined. Fe-NTA alone enhances ornithine decarboxylase activity to 4.5-fold and tritiated thymidine incorporation in DNA to 3.6-fold in livers compared with the corresponding saline-treated controls. The enhanced ornithine decarboxylase activity and DNA synthesis showed a reduction to 3.02- and 1.88-fold, respectively, at a higher dose of 2 mg AA per day per animal, compared with the Fe-NTA-treated groups. Fe-NTA treatment also enhanced the hepatic microsomal lipid peroxidation to 1.7-fold compared to saline-treated controls. These changes were reversed significantly in animals receiving pretreatment of AA. The present data shows that AA can reciprocate the toxic effects of Fe-NTA and can serve as a potent chemopreventive agent to suppress oxidant-induced tissue injury and hepatotoxicity in rats.

Desferrioxamine-caffeine (DFCAF) as a cell permeant moderator of the oxidative stress caused by iron overload.

Desferrioxamine (DFO) is a potent iron chelator used in the treatment of iron overload (IO) disorders. However, due to its low cell permeability and fast clearance, DFO administration is usually prolonged and of limited use for the treatment of IO in tissues such as the brain. Caffeine is a safe, rapidly absorbable molecule that can be linked to other compounds to improve their cell permeability. In this work, we successfully prepared and described DFO-caffeine, a conjugate with iron scavenging ability, antioxidant properties and enhanced permeation in the HeLa cell model.

Protective effect of ethanolic extract of Tabernaemontana divaricata (L.) R. Br. against DEN and Fe NTA induced liver necrosis in Wistar Albino rats.

This study is an attempt to evaluate the hepatoprotective activity of Tabernaemontana divaricata against DEN and Fe NTA induced liver necrosis in rats. Ethanolic extract of the whole plant of Tabernaemontana divaricata at doses of 200 and 400 mg/kg body weight and 5-fluorouracil (standard drug) was orally administered to male Wistar Albino rats once daily for 24 weeks, simultaneously treated with the carcinogen DEN and Fe NTA. In simultaneously treated animals, the plant extract significantly decreased the levels of uric acid, bilirubin, AST, ALT, and ALP in serum and increased the levels of liver marker enzymes in liver. Treatment with the extracts resulted in a significant increase in the levels of antioxidants accompanied by a marked reduction in the levels of malondialdehyde when compared to DEN and Fe NTA treated group. When compared with 200 mg/kg bw rats, 400 mg/kg bw rats and 5-fluorouracil treated rats showed better results in all the parameters. The histopathological studies confirmed the protective effects of extract against DEN and Fe NTA induced liver necrosis. Thus, it could be concluded that the use of Tabernaemontana divaricata extract in the treatment of carcinogen induced hepatic necrosis.

Rat model demonstrates a high risk of tremolite but a low risk of anthophyllite for mesothelial carcinogenesis.

Asbestos was abundantly used in industry during the last century. Currently, asbestos confers a heavy social burden due to an increasing number of patients with malignant mesothelioma (MM), which develops after a long incubation period. Many studies have been conducted on the effects of the asbestos types that were most commonly used for commercial applications. However, there are few studies describing the effects of the less common types, or minor asbestos. We performed a rat carcinogenesis study using Japanese tremolite and Afghan anthophyllite. Whereas more than 50% of tremolite fibers had a diameter of < 500 nm, only a small fraction of anthophyllite fibers had a diameter of < 500 nm. We intraperitoneally injected 1 or 10 mg of asbestos into F1 Fischer-344/Brown-Norway rats. In half of the animals, repeated intraperitoneal injections of nitrilotriacetate (NTA), an iron chelator to promote Fenton reaction, were performed to evaluate the potential involvement of iron overload. Tremolite induced MM with a high incidence (96% with 10 mg; 52% with 1 mg), and males were more susceptible than females. Histology was confirmed using immunohistochemistry, and most MMs were characterized as the sarcomatoid or biphasic subtype. Unexpectedly NTA showed an inhibitory effect in females. In contrast, anthophyllite induced no MM after an observation period of 550 days. The results suggest that the carcinogenicity of anthophyllite is weaker than formerly reported, whereas that of tremolite is as potent as major asbestos as compared with our previous data.

Consumption of hydrogen-rich water protects against ferric nitrilotriacetate-induced nephrotoxicity and early tumor promotional events in rats.

The aim of this work was to test whether consumption with hydrogen-rich water (HW) alleviated renal injury and inhibited early tumor promotional events in Ferric nitrilotriacetate (Fe-NTA)-treated rats. Rats were injected with Fe-NTA solution (7.5mg Fe/kg body weight) intraperitoneally to induce renal injury and simultaneously treated with HW (1.3 ± 0.2mg/l). We found that consumption with HW ameliorated Fe-NTA-induced renal injuries including suppressing elevation of serum creatinine and blood urea nitrogen and inhibited early tumor promotional events including decreasing ornithine decarboxylase activity and incorporation of [3H]thymidine into renal DNA. Consumption with HW suppressed Fe-NTA-induced oxidative stress through decreasing formation of lipid peroxidation and peroxynitrite and activities of NADPH oxidase and xanthine oxidase, increasing activity of catalase, and restoring mitochondrial function in kidneys. Consumption with HW suppressed Fe-NTA-induced inflammation marked by reduced NF-κB, IL-6, and MCP-1 expression and macrophage accumulating in kidneys. In addition, consumption with HW suppressed VEGF expression, STAT3 phosphorylation and PCNA expression in kidneys of Fe-NTA-treated rats. Consumption with HW decreased the incidence of renal cell carcinoma and suppressed tumor growth in Fe-NTA-treated in rats. In conclusion, drinking with HW attenuated Fe-NTA-induced renal injury and inhibited early tumor promotional events in rats.

Role of ascorbic acid in counteracting ferric nitrilotriacetate-induced nephrotoxicity in rats.

CONTEXT: Ascorbic acid (AA) is a naturally occurring organic compound with antioxidant properties. It is necessary for normal growth and development, and has been shown to protect against tissue toxicity and oxidative stress. OBJECTIVE: The protective effect of AA against nephrotoxicity induced in albino rats by ferric nitrilotriacetate (Fe-NTA) was evaluated. MATERIALS AND METHODS: Male albino rats of Wistar strain (4-6 weeks old) weighing 125-150 g were used in this study. Animals were given a single dose of Fe-NTA (9 mg/kg body weight, intraperitoneal) after a week of treatment with AA (1 and 2 mg/animal/day). RESULTS: Fe-NTA treatment enhanced microsomal lipid peroxidation (LPO) and hydrogen peroxide (H2O2) generation to 1.7- to 2.2-fold, glutathione (GSH) levels were decreased by two-fold and the activities of GSH metabolizing enzymes decreased to a range of 2.2- to 2.5-fold in renal tissue. These changes were reversed significantly in animals receiving pretreatment of AA. Treatment of rats with AA prior to the treatment with Fe-NTA decreased microsomal LPO and H2O2 generation to 124 and 172%, and also resulted in the recovery of reduced levels of GSH, GSH-metabolizing enzymes to almost 92% at the higher dose level of AA. DISCUSSION AND CONCLUSION: AA protects against Fe-NTA-induced nephrotoxicity and renal damage. AA has a beneficial impact on Fe-NTA-induced toxicity due to its scavenging and antioxidant effect in albino rats.