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Sample records for hgcl2 induced toxicity

  1. Cardiac dysfunction in HgCl2-induced nephrotic syndrome.

    Science.gov (United States)

    Moreira-Rodrigues, Mónica; Henriques-Coelho, Tiago; Moura, Cláudia; Vasques-Nóvoa, Francisco; Sampaio-Maia, Benedita; Pestana, Manuel; Leite-Moreira, Adelino F

    2010-03-01

    The experimental model of HgCl(2) injection is characterized by a systemic autoimmune disease which leads to the development of nephrotic syndrome (NS). NS seems to be accompanied by cardiovascular alterations, since patients with NS present an increased incidence in cardiac disease. The aim of our work was to study the effects of HgCl(2)-induced NS on myocardial function and morphometry. Normotensive Brown-Norway rats were injected with HgCl(2) (1 mg/kg, HgCl(2) group; n = 6, subcutaneous) or the vehicle (control group; n = 6, subcutaneous) on days 0, 2, 4, 7, 9 and 11. The animals were placed in metabolic cages for evaluation of urinary excretion of noradrenaline, sodium, total proteins, albumin and creatinine. Fourteen and 21 days after the first HgCl(2) injection, left ventricle (LV) hemodynamics was evaluated through pressure micromanometers in basal and isovolumetric heartbeats. The heart and gastrocnemius muscle weights and tibial length were also examined. In an additional group of animals cardiac dimensions and ejection fraction were assessed by echocardiography and LV apoptosis and fibrosis were studied. HgCl(2)-injected rats presented proteinuria, albuminuria, hyperlipidemia, anemia, sodium retention and ascites at day 14. These alterations were accompanied by LV hemodynamic changes only in isovolumetric heartbeats. Similarly, on day 21, HgCl(2)-injected rats presented proteinuria, albuminuria, hyperlipidemia, anemia, but no sodium retention or ascites. These animals presented LV systolic and diastolic dysfunction in both basal and isovolumetric heartbeats, as well as cardiac atrophy, LV fibrosis and an increase in myocyte apoptosis. In conclusion, HgCl(2)-induced NS is accompanied by LV dysfunction and can be a promising model for studying the link between NS and cardiac disease.

  2. Toxic effects of HgCl2 on the growth and oogonium formation in Oedogonium hatei.

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    Singh, H V

    2001-01-01

    The effect of mercuric chloride on the germination and growth of swarmers and subsequent induction of oogonia was studied in Oedogonium hatei Kam. (Oedogoniales, Chorophyceae). HgCl2 within the concentration range of 0.01 to 1.0 mg/l produced a progressive increase in the initiation of germination and reduction in the growth of the alga. The percentage of oogonia formed, and mature oogonia developed, decreased linearly with a rise in the concentrations of HgCl2 employed. The results showed that 1 mg/l HgCl2 was highly toxic to the growth and/or multiplication of zoospores and further development of sexual structures in O. hatei. The germination of zoospores and growth of germlings were so severely affected that induction of oogonia remained completely inhibited at 1 mg/l HgCl2. Moreover, 2 mg/l of HgCl2 was lethal to the asexual zoospores.

  3. Rhubarb Anthraquinones Protect Rats against Mercuric Chloride (HgCl2-Induced Acute Renal Failure

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    Dan Gao

    2016-03-01

    Full Text Available Mercury (Hg causes severe nephrotoxicity in subjects with excess exposure. This work attempted to identify whether a natural medicine—rhubarb—has protective effects against mercuric chloride (HgCl2-induced acute renal failure (ARF, and which of its components contributed most to the treatment. Total rhubarb extract (TR were separated to the total anthraquinones (TA, the total tannins (TT and remaining component extract (RC. Each extract was orally pre-administered to rats for five successive days followed by HgCl2 injection to induce kidney injury. Subsequently, renal histopathology and biochemical examinations were performed in vitro to evaluate the protective effects. Pharmacological studies showed that TR and TA, but not TT or RC manifested significant protection activity against HgCl2-induced ARF. There were also significant declines of serum creatine, urea nitrogen values and increases of total protein albumin levels in TR and TA treated groups compared to HgCl2 alone (p < 0.05. At last, the major components in TA extract were further identified as anthraquinones by liquid chromatography coupled mass spectroscopy. This study thus provides observational evidences that rhubarb could ameliorate HgCl2-induced ARF and its anthraquinones in particular are the effective components responsible for this activity in rhubarb extract.

  4. Zuotai and HgS differ from HgCl2 and methyl mercury in Hg accumulation and toxicity in weanling and aged rats.

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    Zhang, Bin-Bin; Li, Wen-Kai; Hou, Wei-Yu; Luo, Ya; Shi, Jing-Zhen; Li, Cen; Wei, Li-Xin; Liu, Jie

    2017-09-15

    Mercury sulfides are used in Ayurvedic medicines, Tibetan medicines, and Chinese medicines for thousands of years and are still used today. Cinnabar (α-HgS) and metacinnabar (β-HgS) are different from mercury chloride (HgCl2) and methylmercury (MeHg) in their disposition and toxicity. Whether such scenario applies to weanling and aged animals is not known. To address this question, weanling (21d) and aged (450d) rats were orally given Zuotai (54% β-HgS, 30mg/kg), HgS (α-HgS, 30mg/kg), HgCl2 (34.6mg/kg), or MeHg (MeHgCl, 3.2mg/kg) for 7days. Accumulation of Hg in kidney and liver, and the toxicity-sensitive gene expressions were examined. Animal body weight gain was decreased by HgCl2 and to a lesser extent by MeHg, but unaltered after Zuotai and HgS. HgCl2 and MeHg produced dramatic tissue Hg accumulation, increased kidney (kim-1 and Ngal) and liver (Ho-1) injury-sensitive gene expressions, but such changes are absent or mild after Zuotai and HgS. Aged rats were more susceptible than weanling rats to Hg toxicity. To examine roles of transporters in Hg accumulation, transporter gene expressions were examined. The expression of renal uptake transporters Oat1, Oct2, and Oatp4c1 and hepatic Oatp2 was decreased, while the expression of renal efflux transporter Mrp2, Mrp4 and Mdr1b was increased following HgCl2 and MeHg, but unaffected by Zuotai and HgS. Thus, Zuotai and HgS differ from HgCl2 and MeHg in producing tissue Hg accumulation and toxicity, and aged rats are more susceptible than weanling rats. Transporter expression could be adaptive means to reduce tissue Hg burden. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Preventive effect of CuCl₂ on behavioral alterations and mercury accumulation in central nervous system induced by HgCl2 in newborn rats.

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    Moraes-Silva, L; Siqueira, L F; Oliveira, V A; Oliveira, C S; Ineu, R P; Pedroso, T F; Fonseca, M M; Pereira, M E

    2014-07-01

    This study investigated the benefits of Cu preexposition on Hg effects on behavioral tests, acetylcholinesterase (AChE) activity and Hg, and essential metal contents in the cerebrum and cerebellum of neonate rats. Wistar rats received (subcutaneous) saline or CuCl2 ·2H2O (6.9 mg/kg/day) when they were 3 to 7 days old and saline or HgCl2 (5.0 mg/kg/day) when they were 8 to 12 days old. Mercury exposure reduced the performance of rats in the negative geotaxis (3-13 days) and beaker test (17-20 days), inhibited cerebellum AChE activity (13 days), increased cerebrum and cerebellum Hg (13 days), cerebrum Cu (13 days), and cerebrum and cerebellum Zn levels (33 days). The performance of rats in the tail immersion and rotarod tests as well as Fe and Mg levels were not altered by treatments. Copper prevented all alterations induced by mercury. These results are important to open a new perspective of prevention and/or therapy for mercury exposure.

  6. Insulin-like growth factor-1 (IGF-1) enhances recovery from HgCl2-induced acute renal failure: the effects on renal IGF-1, IGF-1 receptor, and IGF-binding protein-1 mRNA.

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    Friedlaender, M; Popovtzer, M M; Weiss, O; Nefesh, I; Kopolovic, J; Raz, I

    1995-04-01

    Several growth factors have been found to play an important role in the recovery from acute renal failure (ARF). The effect of the continuous subcutaneous infusion of human recombinant insulin-like growth factor (IGF)-1 (125 micrograms daily by osmotic minipumps) in a rat model of mercuric chloride (HgCl2)-induced ARF was examined. HgCl2 (4 mg/kg) induced ARF with a mortality that was unaffected by IGF-1. However, IGF-1 significantly enhanced functional and histologic recovery in the survivors, as measured by serum creatinine and creatinine clearance and by histologic scoring. Solution hybridization RNAase protection assays showed that renal IGF-1 mRNA, IGF-1 receptor (IGF-1R) mRNA, and IGF-binding protein-1 (IGFBP-1) mRNA were unaffected by exogenous IGF-1, but this treatment significantly increased renal IGF-1 in ARF rats compared with normal rats and ARF rats not receiving IGF-1. After ARF renal mRNA for IGF-1 was decreased, IGF-1R was unchanged and IGFBP-1 was increased. Similar changes occurred in IGF-1-infused ARF rats. Thus, (1) IGF-1 enhances recovery from nephrotoxic ARF both functionally and histologically; (2) in nephrotoxic ARF, there is (a) a reduction in IGF-1 mRNA expression that is not prevented by IGF-1 infusion, and (b) an increase in renal IGFBP-1 mRNA. This may allow a significant increase in renal IGF-1 levels in IGF-1-infused ARF rats, despite the decrease in renal IGF-1 mRNA. A local increase in renal IGFBP-1 and IGF-1 may explain the accelerated recovery from ATN in this model. It was concluded that HgCl2-induced ARF is amenable to improvement by IGF-1 infusion and that the increase in renal IGFBP-1 mRNA may be an important modulator in the recovery of the kidney.

  7. Mangiferin, a Dietary Xanthone Protects Against Mercury-Induced Toxicity in HepG2 Cells

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    Agarwala, Sobhika; Rao, B. Nageshwar; Mudholkar, Kaivalya; Bhuwania, Ridhirama; Rao, B. S. Satish

    2012-01-01

    Mercury is one of the noxious heavy metal environmental toxicants and is a cause of concern for human exposure. Mangiferin (MGN), a glucosylxanthone found in Mangifera indica, reported to have a wide range of pharmacological properties. The objective of this study was to evaluate the cytoprotective potential of MGN, against mercury chloride (HgCl2) induced toxicity in HepG2 cell line. The cytoprotective effect of MGN on HgCl2 induced toxicity was assessed by colony formation assay, while antiapoptotic effect by fluorescence microscopy, flow cytometric DNA analysis, and DNA fragmentation pattern assays. Further, the cytoprotective effect of MGN against HgCl2 toxicity was assessed by using biochemical parameters like reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) by spectrophotometrically, mitochondrial membrane potential by flowcytometry and the changes in reactive oxygen species levels by DCFH-DA spectrofluoremetric analysis. A significant increase in the surviving fraction was observed with 50 µM of MGN administered two hours prior to various concentrations of HgCl2. Further, pretreatment of MGN significantly decreased the percentage of HgCl2 induced apoptotic cells. Similarly, the levels of ROS generated by the HgCl2 treatment were inhibited significantly (P < 0.01) by MGN. MGN also significantly (P < 0.01) inhibited the HgCl2 induced decrease in GSH, GST, SOD, and CAT levels at all the post incubation intervals. Our study demonstrated the cytoprotective potential of MGN, which may be attributed to quenching of the ROS generated in the cells due to oxidative stress induced by HgCl2, restoration of mitochondrial membrane potential and normalization of cellular antioxidant levels. PMID:20629087

  8. PROTECTIVE EFFECTS OF CALCIUM ANTAGONIST ON VASCULAR SYSTEM AGAINST TOXICITY INDUCED BY MERCURIC CHLORIDE

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    马欣; 厉英倩; 白宇飞; 刘明

    2004-01-01

    Objective To explore the toxic effects of mercuric chloride (HgCl2) on vascular smooth muscle as well as its relationship to calcium antagonist. Methods By using isolated vascular tension methods, we studied the effect of HgCl2 on isolated rabbit aortic rings. Results HgCl2 (1-100μmol*L-1) caused a concentration-dependent contraction of rabbit aortic rings, which did not change with phentolamin or without endothelium. In KH solution with Ca2+ , the maximum contraction amplitude reduced by(61.2±3.3)%. Nifedipine produced a concentration-dependent decrease of the maximum contraction amplitude. Conclusion Calcium antagonist has protective effects on vascular smooth muscle against damage induced by HgCl2.

  9. Assessment of mercury chloride-induced toxicity and the relevance of P2X7 receptor activation in zebrafish larvae.

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    Cruz, Fernanda Fernandes; Leite, Carlos Eduardo; Pereira, Talita Carneiro Brandão; Bogo, Maurício Reis; Bonan, Carla Denise; Battastini, Ana Maria Oliveira; Campos, Maria Martha; Morrone, Fernanda Bueno

    2013-09-01

    Zebrafish (Danio rerio) has been adopted as a model for behavioral, immunological and toxicological studies. Mercury is a toxic heavy metal released into the environment. There is evidence indicating that heavy metals can modulate ionotropic receptors, including the purinergic receptor P2X7. Therefore, this study evaluated the in vivo effects of acute exposure to mercury chloride (HgCl2) in zebrafish larvae and to investigate the involvement of P2X7R in mercury-related toxicity. Larvae survival was evaluated for 24 h after exposure to HgCl2, ATP or A740003. The combination of ATP (1 mM) and HgCl2 (20 μg/L) decreased survival when compared to ATP 1 mM. The antagonist A740003 (300 and 500 nM) increased the survival time, and reversed the mortality caused by ATP and HgCl2 in association. Quantitative real time PCR showed a decrease of P2X7R expression in the larvae treated with HgCl2 (20 μg/L). Evaluating the oxidative stress our results showed decreased CAT (catalase) activity and increased MDA (malondialdehyde) levels. Of note, the combination of ATP with HgCl2 showed an additive effect. This study provides novel evidence on the possible mechanisms underlying the toxicity induced by mercury, indicating that it is able to modulate P2X7R in zebrafish larvae.

  10. Eruca sativa seeds possess antioxidant activity and exert a protective effect on mercuric chloride induced renal toxicity.

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    Sarwar Alam, M; Kaur, Gurpreet; Jabbar, Zoobi; Javed, Kaleem; Athar, Mohammad

    2007-06-01

    Mercuric chloride (HgCl(2)) is a well-known nephrotoxic agent. Increasing number of evidences suggest the role of oxidative stress in HgCl(2) induced nephrotoxicity. Eruca sativa is widely used in folklore medicines and has a good reputation as a remedy of renal ailments. In the present study, the antioxidant potential of ethanolic extract of E. sativa seeds was determined and its protective effect on HgCl(2) induced renal toxicity was investigated. The extract was found to possess a potent antioxidant effect, with a large amount of polyphenols and a high reducing ability. HPLC analysis of the extract revealed glucoerucin and flavonoids to be the major antioxidants present in it. E. sativa extract significantly scavenged several reactive oxygen species (ROS) and reactive nitrogen species (RNS). Feeding of the extract to rats afforded a significant protection against HgCl(2) induced renal toxicity. Subcutaneous administration of 4 mg/kg body weight HgCl(2) induced renal injury evident as a marked elevation in serum creatinine and blood urea nitrogen levels, and histopathological changes such as necrosis, oedema and congestion of stroma and glomeruli. Oxidative modulation of renal tissues following HgCl(2) exposure was evident from a significant elevation in lipid peroxidation and attenuation in glutathione (GSH) contents and activities of antioxidant enzymes viz., catalase (CAT), glutathione peroxidase (GPX), superoxide dismutase (SOD) and glutathione reductase (GR). Oral administration of E. sativa extract to rats at a dose regimen: 50-200 mg/kg body weight for 7 days prior to HgCl(2) treatment significantly and dose dependently protected against alterations in all these diagnostic parameters. The data obtained in the present study suggests E. sativa seeds to possess a potent antioxidant and renal protective activity and preclude oxidative damage inflicted to the kidney.

  11. Effects of mercury chloride (HgCl2) on Betta splendens aggressive display.

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    Mansur, Bruno de Matos; Cavalcante, Caio Neno Silva; dos Santos, Bruno Rodrigues; Gouveia Júnior, Amauri

    2012-03-01

    Mercury chloride (HgCl2) is a toxic mercury salt and a major pollutant, that can be found in soil, water and air, with influences on behavior, physiology and adaptation to the environment. In this study two experiments were designed to examine interactions and effects of HgCl2 on some behavioral patterns of Siamese fighting fish (Betta splendens). In the first experiment we tested the effect of a progressive dose (five 0.04 mg) on aggressive display with exposure to a mirror, whereas in the second experiment we tested the effect of an acute dose (0.2 mg) on the aggressive display with exposure to a mirror. The experiments were performed on 5 consecutive sessions at intervals of 18 hours between sessions. Differences of performance were shown by subjects in the acute and progressive treatments when compared with a control treatment in the majority of behaviors evaluated, namely Floating, Slow Swimming, Wavy Swimming, Emerging, Bend, Square Move and Motor Display Components. Acute treatment was different from control only on Show Body, while the progressive group differed on Resting, Horizontal Display and Appropriate Display Components. Differences between Correlate Display Components and Total were also shown. Both the acute and progressive contamination with HgCl2 decrease the motor activity in the aggressive display, mirror-image test of Betta splendens, mainly on the progressive dose. This implies an impairment on feeding behavior, predator avoidance, reproductive behavior, mate choice and territoriality. These results suggest that in this fish species, the progressive dose has a greater effect on behavior in general and that both the acute and progressive contamination with mercury chloride affect many other aspects of behavior.

  12. Developmental toxicity from exposure to various forms of mercury compounds in medaka fish (Oryzias latipes) embryos

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    Liu, Jie; Wei, Lixin; Jingfeng, Yang; Chernick, Melissa; Hinton, David E.

    2016-01-01

    This study examined developmental toxicity of different mercury compounds, including some used in traditional medicines. Medaka (Oryzias latipes) embryos were exposed to 0.001–10 µM concentrations of MeHg, HgCl2, α-HgS (Zhu Sha), and β-HgS (Zuotai) from stage 10 (6–7 hpf) to 10 days post fertilization (dpf). Of the forms of mercury in this study, the organic form (MeHg) proved the most toxic followed by inorganic mercury (HgCl2), both producing embryo developmental toxicity. Altered phenotypes included pericardial edema with elongated or tube heart, reduction of eye pigmentation, and failure of swim bladder inflation. Both α-HgS and β-HgS were less toxic than MeHg and HgCl2. Total RNA was extracted from survivors three days after exposure to MeHg (0.1 µM), HgCl2 (1 µM), α-HgS (10 µM), or β-HgS (10 µM) to examine toxicity-related gene expression. MeHg and HgCl2 markedly induced metallothionein (MT) and heme oxygenase-1 (Ho-1), while α-HgS and β-HgS failed to induce either gene. Chemical forms of mercury compounds proved to be a major determinant in their developmental toxicity. PMID:27635309

  13. Developmental toxicity from exposure to various forms of mercury compounds in medaka fish (Oryzias latipes embryos

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    Wu Dong

    2016-08-01

    Full Text Available This study examined developmental toxicity of different mercury compounds, including some used in traditional medicines. Medaka (Oryzias latipes embryos were exposed to 0.001–10 µM concentrations of MeHg, HgCl2, α-HgS (Zhu Sha, and β-HgS (Zuotai from stage 10 (6–7 hpf to 10 days post fertilization (dpf. Of the forms of mercury in this study, the organic form (MeHg proved the most toxic followed by inorganic mercury (HgCl2, both producing embryo developmental toxicity. Altered phenotypes included pericardial edema with elongated or tube heart, reduction of eye pigmentation, and failure of swim bladder inflation. Both α-HgS and β-HgS were less toxic than MeHg and HgCl2. Total RNA was extracted from survivors three days after exposure to MeHg (0.1 µM, HgCl2 (1 µM, α-HgS (10 µM, or β-HgS (10 µM to examine toxicity-related gene expression. MeHg and HgCl2 markedly induced metallothionein (MT and heme oxygenase-1 (Ho-1, while α-HgS and β-HgS failed to induce either gene. Chemical forms of mercury compounds proved to be a major determinant in their developmental toxicity.

  14. Glutamate‑mediated effects of caffeine and interferon‑γ on mercury-induced toxicity.

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    Engin, Ayse Basak; Engin, Evren Doruk; Golokhvast, Kirill; Spandidos, Demetrios A; Tsatsakis, Aristides M

    2017-05-01

    The molecular mechanisms mediating mercury‑induced neurotoxicity are not yet completely understood. Thus, the aim of this study was to investigate whether the severity of MeHg‑ and HgCl2‑mediated cytotoxicity to SH‑SY5Y human dopaminergic neurons can be attenuated by regulating glutamate‑mediated signal‑transmission through caffeine and interferon‑γ (IFN‑γ). The SH‑SY5Y cells were exposed to 1, 2 and 5 µM of either MeHgCl2 or HgCl2 in the presence or absence of L‑glutamine. To examine the effect of adenosine receptor antagonist, the cells were treated with 10 and 20 µM caffeine. The total mitochondrial metabolic activity and oxidative stress intensity coefficient were determined in the 1 ng/ml IFN‑γ‑ and glutamate‑stimulated SH‑SY5Y cells. Following exposure to mercury, the concentration‑dependent decrease in mitochondrial metabolic activity inversely correlated with oxidative stress intensity. MeHg was more toxic than HgCl2. Mercury‑induced neuronal death was dependent on glutamate‑mediated excitotoxicity. Caffeine reduced the mercury‑induced oxidative stress in glutamine-containing medium. IFN‑γ treatment decreased cell viability and increased oxidative stress in glutamine‑free medium, despite caffeine supplementation. Although caffeine exerted a protective effect against MeHg-induced toxicity with glutamate transmission, under co‑stimulation with glutamine and IFN‑γ, caffeine decreased the MeHg‑induced average oxidative stress only by half. Thereby, our data indicate that the IFN‑γ stimulation of mercury‑exposed dopaminergic neurons in neuroinflammatory diseases may diminish the neuroprotective effects of caffeine.

  15. Dosage selection of HgCl2 in measuring TFe in iron ore by SnCl2 - HgCl2-K2Cr2O7 volumetry%SnCl2-HgCl2-K2Cr2O7容量法测定铁矿石中TFe时HgCl2用量的选择

    Institute of Scientific and Technical Information of China (English)

    胡祖忠

    2001-01-01

    To retain many advantages of traditional meth od of measuring TFewith the existence of HgCl2 and reduce the pollution of the environment caused by HgCl2, theory about dosage selection of HgCl2 reduced from 5 ml to 2 ml has been studied and results of experiments have been satisfied.%为了保持应用已久的有汞测铁经典方法中的许多优点而减轻HgCl2对环境的污染的缺点,对方法中HgCl2的用量由5ml[1]减少为2ml进行理论上的探讨,并以试验结果加以论证.

  16. Improvement of mercuric chloride-induced testis injuries and sperm quality deteriorations by Spirulina platensis in rats.

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    Gaber E El-Desoky

    Full Text Available The present study was undertaken to investigate the protective effect of the filamentous cyanobacterium Spirulina platensis (S. platensis on mercury (II chloride (HgCl(2-induced oxidative damages and histopathological alterations in the testis of Wistar albino rats. The animals were divided into four equal groups, i control, ii HgCl(2, iii S. platensis and iv combination of HgCl(2+S. platensis. Oxidative stress, induced by a single dose of HgCl(2 (5 mg/kg, bw; subcutaneously, s.c., substantially decreased (P<0.01 the activity level of testicular key enzymatic antioxidant biomarkers (superoxide dismutase, SOD; catalase, CAT and glutathione peroxidase, GPx, oxidative stress makers (blood hydroperoxide; testicular reduced glutathione, GSH and malondialdehyde, MDA, and testicular mercury levels. Moreover, HgCl(2 administration resulted in a significant (P<0.01 increase in the number of sperms with abnormal morphology and decrease in epididymal sperm count, motility, plasma testosterone level and testicular cholesterol. Furthermore, HgCl(2 exposure induced histopathological changes to the testis including morphological alterations of the seminiferous tubules, and degeneration and dissociation of spermatogenic cells. Notably, oral pretreatment of animals with Spirulina (300 mg/kg, bw lowered the extent of the observed HgCl(2-mediated toxicity, whereby significantly reducing the resulting lipid peroxidation products, mercury accumulation in the testis, histopathological changes of the testes and spermatozoal abnormalities. In parallel, the pretreatment with Spirulina also completely reverted the observed Hg-Cl(2-induced inhibition in enzymatic activities of antioxidant biomarkers (SOD, CAT and GPx back to control levels. The pretreatment of rats with S. platensis significantly recovered the observed HgCl(2-mediated decrease in the weight of accessory sex organs. Taken together, our findings clearly highlight the role of S. platensis as a protective

  17. Improvement of Mercuric Chloride-Induced Testis Injuries and Sperm Quality Deteriorations by Spirulina platensis in Rats

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    El-Desoky, Gaber E.; Bashandy, Samir A.; Alhazza, Ibrahim M.; Al-Othman, Zeid A.; Aboul-Soud, Mourad A. M.; Yusuf, Kareem

    2013-01-01

    The present study was undertaken to investigate the protective effect of the filamentous cyanobacterium Spirulina platensis (S. platensis) on mercury (II) chloride (HgCl2)-induced oxidative damages and histopathological alterations in the testis of Wistar albino rats. The animals were divided into four equal groups, i) control, ii) HgCl2, iii) S. platensis and iv) combination of HgCl2+S. platensis. Oxidative stress, induced by a single dose of HgCl2 (5 mg/kg, bw; subcutaneously, s.c.), substantially decreased (P<0.01) the activity level of testicular key enzymatic antioxidant biomarkers (superoxide dismutase, SOD; catalase, CAT and glutathione peroxidase, GPx), oxidative stress makers (blood hydroperoxide; testicular reduced glutathione, GSH and malondialdehyde, MDA), and testicular mercury levels. Moreover, HgCl2 administration resulted in a significant (P<0.01) increase in the number of sperms with abnormal morphology and decrease in epididymal sperm count, motility, plasma testosterone level and testicular cholesterol. Furthermore, HgCl2 exposure induced histopathological changes to the testis including morphological alterations of the seminiferous tubules, and degeneration and dissociation of spermatogenic cells. Notably, oral pretreatment of animals with Spirulina (300 mg/kg, bw) lowered the extent of the observed HgCl2-mediated toxicity, whereby significantly reducing the resulting lipid peroxidation products, mercury accumulation in the testis, histopathological changes of the testes and spermatozoal abnormalities. In parallel, the pretreatment with Spirulina also completely reverted the observed Hg-Cl2-induced inhibition in enzymatic activities of antioxidant biomarkers (SOD, CAT and GPx) back to control levels. The pretreatment of rats with S. platensis significantly recovered the observed HgCl2-mediated decrease in the weight of accessory sex organs. Taken together, our findings clearly highlight the role of S. platensis as a protective modulator of HgCl2

  18. C-HCl(-) hydrogen bonds in solution and in the solid-state: HgCl2 complexes with cyclen-based cryptands.

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    Ikeda, Mari; Sah, Ajay Kumar; Iwase, Miki; Murashige, Rina; Ishi-I, Jun-Ichi; Hasegawa, Masatoshi; Kachi-Terajima, Chihiro; Park, Ki-Min; Kuwahara, Shunsuke; Habata, Yoichi

    2017-03-21

    Structural evidence is reported for C-HCl(-) hydrogen bonds in solution and in the solid state of HgCl2 complexes with cyclen-based cryptands. These cyclen-based cryptands (1) and (2) are bridged by di- and triethylene glycol units, respectively, between two aromatic rings. The X-ray structure indicates that the 2/HgCl2 complex contains an acetonitrile molecule in the cavity.

  19. Crystal structures of three mercury(II complexes [HgCl2L] where L is a bidentate chiral imine ligand

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    Guadalupe Hernández

    2015-12-01

    Full Text Available The crystal structures of three complexes [HgCl2L] were determined, namely, (S-(+-dichlorido[1-phenyl-N-(pyridin-2-ylmethylideneethylamine-κ2N,N′]mercury(II, [HgCl2(C14H14N2], (S-(+-dichlorido[1-(4-methylphenyl-N-(pyridin-2-ylmethylideneethylamine-κ2N,N′]mercury(II, [HgCl2(C15H16N2], and (1S,2S,3S,5R-(+-dichlorido[N-(pyridin-2-ylmethylideneisopinocampheylamine-κ2N,N′]mercury(II, [HgCl2(C16H22N2]. The complexes consist of a bidentate chiral imine ligand coordinating to HgCl2 and crystallize with four independent molecules in the first complex and two independent molecules in the other two. The coordination geometry of mercury is tetrahedral, with strong distortion towards a disphenoidal geometry, as a consequence of the imine bite angle being close to 70°. The Cl—Hg—Cl angles span a large range, 116.0 (2–138.3 (3°, which is related to the aggregation state in the crystals. For small Cl—Hg—Cl angles, complexes have a tendency to form dimers, via intermolecular Hg...Cl contacts. These contacts become less significant in the third complex, which features the largest intramolecular Cl—Hg—Cl angles.

  20. Oral administration of Moringa oleifera oil but not coconut oil prevents mercury-induced testicular toxicity in rats.

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    Abarikwu, S O; Benjamin, S; Ebah, S G; Obilor, G; Agbam, G

    2017-02-01

    This study was conducted to compare the effects of administration of coconut oil (CO) and Moringa oleifera oil (MO) on testicular oxidative stress, sperm quality and steroidogenesis parameters in rats treated with mercury chloride (HgCl2 ). After 15 days of oral administration of CO (2 ml kg(-1) body weight) and MO (2 ml kg(-1) body weight) along with intraperitoneal (i.p.) administration of HgCl2 (5 mg kg(-1) body weight) alone or in combination, we found that CO treatment did not protect against HgCl2 -induced poor sperm quality (motility, count) as well as decreased testosterone level and 17β-hydroxysteroid dehydrogenase (17β-HSD) activity. Treatment with CO alone decreased glutathione (GSH), and glutathione peroxidase (GSH-Px) activities and increased malondialdehyde (MDA) level in rat's testis, whereas MO did not change these parameters. Cotreatment with MO prevented HgCl2 -induced testicular catalase (CAT) and superoxide dismutase (SOD) activities, poor sperm quality and low testosterone level and also blocks the adverse effect of CO+HgCl2 (2 ml kg(-1) body weight + 5 mg kg(-1) body weight) on the investigated endpoints. In conclusion, MO and not CO decreased the deleterious effects of HgCl2 on sperm quality and steroidogenesis in rats and also strengthen the antioxidant defence of the testes. Therefore, MO is beneficial as an antioxidant in HgCl2 -induced oxidative damage.

  1. Toxic encephalopathy induced by capecitabine.

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    Niemann, B; Rochlitz, C; Herrmann, R; Pless, M

    2004-01-01

    Toxic encephalopathy is a rarely described side effect of 5-fluorouracil which usually presents with cerebellar, neuropsychiatric, and focal neurological symptoms. Magnetic resonance imaging findings are described as patchy white matter alterations. We report the 1st case of capecitabine-induced toxic encephalopathy with epilepsy-like symptoms and diffuse white matter alterations on magnetic resonance imaging.

  2. Sparfloxacin induced toxic epidermal necrolysis

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    Ramesh M

    2003-05-01

    Full Text Available Toxic epidermal necrolysis (TEN is a life-threatening cutaneous adverse drug reaction. TEN is known to occur with the fluoroquinolone class of antibiotics, but only four cases of sparfloxacin induced TEN have been reported to the WHO database. This is another case report of sparfloxacin induced TEN.

  3. [Experimental Research of Hg (II) Removal from Aqueous Solutions of HgCl2 with Nano-TiO2].

    Science.gov (United States)

    Zhou, Xiong; Zhang, Jin-yang; Wang, Ding-yong; Qin, Cai-qing; Xu, Feng; Luo Cheng-zhong; Yang, Xi

    2016-01-15

    Mercury removal from aqueous solutions of HgCl2 was studied by indoor simulation experiments, and the effects of three different diameter of particles of Nano-TiO2 ( Nano-Titanium Dioxide) at different dosage, pH, adsorption time and the initial concentration of Hg2+ on the mercury adsorption from simulated wastewater were investigated. The single factor experiments showed that the optimal conditions were: 7.5 g x L(-1) of 5 nm TiO2 or 2.0 g x L(-1) of 100 nm TiO2, pH 8.0, initial concentration of Hg2+ 15 x mg x L(-1) adsorption time 5 min, and under these conditions the adsorption rates reached 99.5% and 99.3%, relatively. When the content of 25 nm TiO2 was 10 g x L(-1), and the other conditions were pH 8.0, initial concentration of Hg2+ 15 mg x L(-1), adsorption time 60 min, the adsorption rate was 62.8%. The Hg(II) removal effects of the TiO2 particles with different diameters followed the order of 100 nm TiO2 > 5 nm TiO2 > 25 nm TiO2. Component adsorption results showed that the 5 nm TiO2 component adsorption effect was superior to its single adsorption effect, while there was little difference between 100 nm TiO2 component adsorption effect and its single adsorption effect. The results of orthogonal experiments indicated that the influencing factors of the adsorption rate followed the order of pH > the initial concentration of Hg2+ > time > dosage. The optimal experiment scheme was: pH 8.0, a dosage of 100 nm Nano-TiO2 of 2.0 g x L(-1) an initial Hg2+ concentration of 25 mg x L(-1) and adsorption time of 10 min. Under the experimental conditions, the maximum adsorption rate reached 99.9%, at the same time, the equilibrium concentration of Hg(II) was 0.033 mg x L(-1) adsorptive capacity was 26.95 mg x g(-1). The adsorption isotherm was in line with the Langmuir isotherm equation, indicating that the Hg(II) uptake by 100 nm Nano-TiO2 was typical monolayer adsorption.

  4. Ceftriaxone-induced toxic hepatitis

    Institute of Scientific and Technical Information of China (English)

    Erdal Peker; Eren Cagan; Murat Dogan

    2009-01-01

    Toxic hepatitis or drug-induced liver injury encompasses a spectrum of clinical disease ranging from mild biochemical abnormalities to acute liver failure. The advantages of a long half-life, wide spectrum, high tissue penetration rate, and a good safety profile,make ceftriaxone, a third-generation cephalosporin,a frequent choice in the treatment of childhood infections. Previous studies have reported a few cases of high aspartate aminotransferase and alanine aminotransferase levels, along with three cases ofhepatitis caused by ceftriaxone. Here, we report a case of drug-induced toxic hepatitis in a patient who was treated with ceftriaxone for acute tonsillitis.

  5. Cytopathology induced by mercuric chloride and methylmercury in cultured renal cells of the Atlantic spotted dolphin (Stenella plagiodon).

    Science.gov (United States)

    Wang, A; Pfeiffer, C J

    2001-01-01

    High mercury concentrations have been reported in various tissues of cetaceans, but the toxicological effects of mercury on cetaceans remain unclear. In vivo study is difficult due to the endangered status of these marine mammals and co-exposure to both mercury and selenium (antagonist of mercury) in the oceanic environment. The present data are the first ultrastructural information on dolphin renal cells exposed to mercury in vitro. Multiple organelle changes were observed in Atlantic spotted dolphin (Stenella plagiodon) renal cells treated with mercuric chloride (HgCl2) or methylmercury chloride (MeHgCl2). Mitochondria and rough endoplasmic reticula were swollen after treatment with HgCl2 or MeHgCl. Mitochondrial dense bodies and small cytoplasmic spherical granules of high electron density were also observed after exposure to MeHgCl. Cytoplasmic vacuoles and myelin-like figures were induced by both HgCl2 and MeHgCl. Nuclear changes included karyolysis, nuclear buds, and a novel observation in mercury-treated cells, vacuolization of (micro-)nucleoli after treatment with HgCl2. These morphological changes (multiple organelle damage and nuclear budding) indicated mercury-treated dolphin renal cells underwent oncosis and necrosis, and supported earlier pathophysiologic findings of diverse toxic actions on genetic, respiratory and other cellular functions.

  6. Abacavir-induced liver toxicity

    Directory of Open Access Journals (Sweden)

    Maria Diletta Pezzani

    Full Text Available Abstract Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.

  7. Abacavir-induced liver toxicity.

    Science.gov (United States)

    Pezzani, Maria Diletta; Resnati, Chiara; Di Cristo, Valentina; Riva, Agostino; Gervasoni, Cristina

    2016-01-01

    Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.

  8. Doxorubicin-induced ovarian toxicity

    Directory of Open Access Journals (Sweden)

    Rizel Shulamith

    2010-03-01

    Full Text Available Abstract Background Young cancer patients may occasionally face infertility and premature gonadal failure. Apart from its direct effect on follicles and oocytes, chemotherapy may induce ovarian toxicity via an impact on the entire ovary. The role of doxorubicin in potential ovarian failure remains obscure. Our intention was to elucidate doxorubicin-related toxicity within ovaries. Methods Female mice were injected intraperitoneally with 7.5 or 10 mg/kg doxorubicin and their ovaries were visualized in vivo by high resolution MRI, one day and one month following treatment. Ovaries of other treated mice were excised and weighed at the same post-treatment intervals. Ovarian histological sections were stained for TUNEL or active caspase-3 and follicles were counted and categorized. Ovulation rates were evaluated in superovulated female mice treated with doxorubicin. Results A single injection of doxorubicin resulted in a major reduction in both ovarian size and weight that lasted even one month post treatment. A dramatic reduction in ovulation rate was observed one week after treatment, followed by a partial recovery at one month. Histological examination revealed positive staining of TUNEL and active caspase-3. We observed a significant reduction in the population of secondary and primordial follicles one month following treatment. Conclusions Our results may imply a mechanism of chemotherapy-induced ovarian toxicity, manifested by reduced ovulation and accompanied by a reduction in ovarian size, caused probably by an acute insult to the ovary.

  9. Interaction of ABC transport proteins with toxic metals at the level of gene and transport activity in the PLHC-1 fish cell line.

    Science.gov (United States)

    Della Torre, Camilla; Zaja, Roko; Loncar, Jovica; Smital, Tvrtko; Focardi, Silvano; Corsi, Ilaria

    2012-06-25

    The aim of this study was to investigate the interaction of four toxic metals with ABC transport proteins in piscine cell line PLHC-1. Cells were exposed for 24 h to 0.01-1 μM of CdCl(2), HgCl(2), As(2)O(3), or K(2)Cr(2)O(7) and the expression of a series of ABC genes (abcb1, abcc1-4) was determined using qRT-PCR. Using the fluorescent model substrates calcein-AM and monochlorbimane we measured interaction of metals with the transport activity of ABC transporters. P-glycoprotein (P-gp) activity was measured in PLHC-1/dox (P-gp overexpressing cells) while activity and interactions of metals with MRPs was measured in PLHC-1/wt cells. After 24 h exposure, abcc2-4 genes were dose-dependently up-regulated by all metals, while abcb1 and abcc1 were less affected. Up-regulation of abcc2 was more pronounced, with up to 8-fold increase in expression. Abcc3 and abcc4 were moderately inducible by HgCl(2) with 3.3-fold and 2.2-fold, respectively. All metals caused a significant inhibition of both P-gp (2.9- to 4-fold vs. controls) and MRP (1.3- to 1.8-fold) transport activities. Modulation of ABC genes and transport activities was further investigated in PLHC-1/wt cells exposed to 1 μM HgCl(2) for 72 h and in Hg resistant cells selected by long term cultivation of PLHC-1/wt cells in increasing concentrations of HgCl(2). Exposure to HgCl(2) for 72 h induced MRP genes expression and efflux activity. The long term cultivation of PLHC-1/wt cells in HgCl(2), did not cause prolonged up-regulation of the tested abc genes but resulted in higher MRP transport activities as determined by the increased sensitivity of these cells to MK571 (MRP specific inhibitor). Results of the present study indicated specific interaction of metals with selected ABC transport proteins. Modulation of ABC transporters takes place at both transcriptional and functional level. An active involvement of efflux pumps in Hg clearance in fish is suggested. Copyright © 2012 Elsevier Ireland Ltd. All rights

  10. Egg white-derived peptides prevent male reproductive dysfunction induced by mercury in rats.

    Science.gov (United States)

    Rizzetti, Danize Aparecida; Martinez, Caroline Silveira; Escobar, Alyne Goulart; da Silva, Taiz Martins; Uranga-Ocio, José Antonio; Peçanha, Franck Maciel; Vassallo, Dalton Valentim; Castro, Marta Miguel; Wiggers, Giulia Alessandra

    2017-02-01

    Oxidative stress in known to contribute to the male reproductive dysfunction induced by mercury (Hg). Our study tested the hypothesis that the egg white hydrolysate (EWH), a potent antioxidant in vitro, is able to prevent the effects of prolonged Hg exposure on male reproductive system in rats. For this, rats were treated for 60 days with: a) Untreated - saline solution (i.m.); b) Hydrolysate - EWH (1 g/kg/day, gavage); c) Mercury - HgCl2 (1st dose 4.6 μg/kg, subsequent doses 0.07 μg/kg/day, i.m.); d) Hydrolysate-Mercury. At the end of the treatment, sperm motility, count and morphological studies were performed; Reactive Oxygen Species (ROS) levels, lipid peroxidation, antioxidant capacity, histological and immunohistochemical assays on testis and epididymis were also carried out. As results, HgCl2-treatment decreased sperm number, increased sperm transit time in epididymis and impaired sperm morphology. However, these harmful effects were prevented by EWH. HgCl2-treatment also increased ROS levels, lipid peroxidation and antioxidant capacity in testis and epididymis as well as promoted testicular inflammation and histological changes in epididymis. EWH improved histological and immunohistochemical alterations, probably due to its antioxidant property. In conclusion, the EWH could represent a powerful natural alternative to protect the male reproductive system against Hg-induced sperm toxicity.

  11. Hydroxycut-induced Liver Toxicity

    African Journals Online (AJOL)

    hanumantp

    Keywords: Hydroxycut, Liver toxicity, Nutritional supplements. Access this article ... presumed notion of safety with over the counter and so called natural weight ... increasing basal metabolic rate and decreasing total body fat. However, there ...

  12. Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity

    Science.gov (United States)

    Yang, Daqian; Tan, Xiao; Lv, Zhanjun; Liu, Biying; Baiyun, Ruiqi; Lu, Jingjing; Zhang, Zhigang

    2016-01-01

    Inorganic mercury, though a key component of pediatric vaccines, is an environmental toxicant threatening human health via accumulating oxidative stress in part. Luteolin has been of great interest because of its antiinflammatory, anticarcinogenic and antioxidative effects. Here we hypothesized that luteolin would attenuate hepatotoxicity induced by acute inorganic mercury exposure. Kunming mice were treated with luteolin (100 mg/kg) 24 h after administration of 4 mg/kg mercuric chloride (HgCl2). The results showed that luteolin ameliorated HgCl2 induced anemia and hepatotoxicity, regulating radical oxygen species (ROS) production and hepatocyte viability in vitro and oxidative stress and apoptosis in vivo. Furthermore, luteolin reversed the changes in levels of inflammation- and apoptosis-related proteins involving NF-κB, TNF-α, Sirt1, mTOR, Bax, p53, and Bcl-2, and inhibited p38 MAPK activation. Luteolin enhanced antioxidant defense system based on Keap1, Nrf2, HO-1, NQO1, and KLF9. Moreover, luteolin did not affect miRNA-146a expression. Collectively, our findings, for the first time, elucidate a precise mechanism for attenuation of HgCl2-induced liver dysfunction by dietary luteolin via regulating Sirt1/Nrf2/TNF-α signaling pathway, and provide a foundation for further study of luteolin as a novel therapeutic agent against inorganic mercury poisoning. PMID:27853236

  13. Dexrazoxane exacerbates doxorubicin-induced testicular toxicity.

    Science.gov (United States)

    Levi, Mattan; Tzabari, Moran; Savion, Naphtali; Stemmer, Salomon M; Shalgi, Ruth; Ben-Aharon, Irit

    2015-10-01

    Infertility induced by anti-cancer treatments pose a major concern for cancer survivors. Doxorubicin (DXR) has been previously shown to exert toxic effects on the testicular germinal epithelium. Based upon the cardioprotective traits of dexrazoxane (DEX), we studied its potential effect in reducing DXR-induced testicular toxicity. Male mice were injected with 5  mg/kg DXR, 100  mg/kg DEX, combination of both or saline (control) and sacrificed either 1, 3 or 6 months later. Testes were excised and further processed. Glutathione and apoptosis assays were performed to determine oxidative stress. Immunohistochemistry and confocal microscopy were used to study the effects of the drugs on testicular histology and on spermatogonial reserve. DXR and the combined treatment induced a striking decline in testicular weight. DEX prevented DXR-induced oxidative stress, but enhanced DXR-induced apoptosis within the testes. Furthermore, the combined treatment depleted the spermatogonial reserve after 1 month, with impaired recovery at 3 and 6 months post-treatment. This resulted in compromised sperm parameters, testicular and epididymal weights as well as significantly reduced sperm motility, all of which were more severe than those observed in DXR-treated mice. The activity of DEX in the testis may differ from its activity in cardiomyocytes. Adding DEX to DXR exacerbates DXR-induced testicular toxicity.

  14. Oral and intramuscular toxicity of inorganic and organic mercury chloride to growing quail

    Science.gov (United States)

    Hill, E.F.; Soares, J.H.

    1987-01-01

    The lethal toxicity of inorganic (HgCl2) and organic (CH3HgCl) mercury chloride was compared for Coturnix (Japanese quail, Coturnix japonica) of different ages from hatch through adulthood by single-dose acute oral and intramuscular injections and by a 5-d dietary trial. Sublethal mercury toxicity was studied by evaluation of plasma and brain cholinesterase activity. CH3HgCl was more toxic than HgCl2 in all tests at each age tested. LD50s consistently increased over the first 4 wk for both acute methods and both mercurials and then stabilized. The striking difference between single-dose acute and 5-d dietary tests was that CH3HgCl averaged about twice as toxic as HgCl2 by both acute methods, compared to 100 times as toxic by the dietary method. For example, at 2 wk of age, the oral LD50s for CH3HgCl and HgCl2 were 18 and 42 mg/kg and the dietary LC50s were 47 and 5086 ppm. When birds were fed HgCl2 and developed clinical signs of intoxication, they could recover once treatment was withdrawn; however, on CH3HgCl, clinical signs often commenced after treatment was withdrawn, and then actually intensified for several days and culminated in death.

  15. Drug-Induced Oxidative Stress and Toxicity

    Directory of Open Access Journals (Sweden)

    Damian G. Deavall

    2012-01-01

    Full Text Available Reactive oxygen species (ROS are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

  16. Toxic and drug-induced myopathies.

    Science.gov (United States)

    Dalakas, M C

    2009-08-01

    Drugs used for therapeutic interventions either alone or in combination may sometimes cause unexpected toxicity to the muscles, resulting in a varying degree of symptomatology, from mild discomfort and inconvenience to permanent damage and disability. The clinician should suspect a toxic myopathy when a patient without a pre-existing muscle disease develops myalgia, fatigue, weakness or myoglobinuria, temporally connected to the administration of a drug or exposure to a myotoxic substance. This review provides an update on the drugs with well-documented myocytoxicity and cautions the clinicians to be alert for the potential toxicity of newly marketed drugs; highlights the clinical features and pathomechanisms of the induced muscle disease; and offers guidance on how best to treat and distinguish toxic myopathies from other acquired or hereditary muscle disorders. Practical issues regarding the diagnosis and management of statin-induced myopathies are emphasized. Myotoxicity resulting from direct insertion of transgenes to the muscle, an exciting new tool currently tested for treatment of muscular dystrophies, is also discussed.

  17. Butachlor-induced acute toxic hepatitis.

    Science.gov (United States)

    Daryani, Nasser Ebrahimi; Hosseini, Parviz; Bashashati, Mohammad; Haidarali, Mona; Sayyah, Alireza

    2007-01-01

    Butachlor is a highly effective herbicidal substance widely used by farmers. We report a 60-year-old man with exfoliative dermatitis, jaundice, increase in liver enzymes and eosinophilia one day after accidental dermal exposure to butachlor toxin. The diagnostic workup showed no other cause and liver histology was consistent with substance-induced toxic hepatitis. Within two weeks of conservative therapy, his liver function tests returned to normal.

  18. Mechanisms of chemotherapy-induced behavioral toxicities.

    Science.gov (United States)

    Vichaya, Elisabeth G; Chiu, Gabriel S; Krukowski, Karen; Lacourt, Tamara E; Kavelaars, Annemieke; Dantzer, Robert; Heijnen, Cobi J; Walker, Adam K

    2015-01-01

    While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms) of chemotherapy include (i) cognitive deficiencies such as problems with attention, memory and executive functioning; (ii) fatigue and motivational deficit; and (iii) neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence, neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs) activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

  19. Mechanisms of chemotherapy-induced behavioral toxicities

    Directory of Open Access Journals (Sweden)

    Elisabeth G Vichaya

    2015-04-01

    Full Text Available While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms of chemotherapy include (i cognitive deficiencies such as problems with attention, memory and executive functioning; (ii fatigue and motivational deficit; and (iii neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

  20. Do toxic ions induce hormesis in plants?

    Science.gov (United States)

    Poschenrieder, Charlotte; Cabot, Catalina; Martos, Soledad; Gallego, Berta; Barceló, Juan

    2013-11-01

    The concept of hormesis in plants is critically reviewed, taking growth stimulation by low concentrations of toxic trace elements as a reference. The importance of both non-adaptive and adaptive mechanisms underlying ion-induced hormetic growth responses is highlighted. The activation of defense mechanisms by metal ions and pathogenic elicitors and the cross talk between the signals induced by metal ions and biotic stressors are considered. The production of reactive oxygen species and, consequently, the induction of stress-induced antioxidants, are key mechanisms in metal ion-induced hormesis in plants. It is concluded that in the current scientific literature, hormesis is used as an "umbrella" term that includes a wide range of different mechanisms. It is recommended that the term hormesis be used in plant toxicology as a descriptive term for the stimulated phase in growth response curves that is induced by low concentrations of toxic metal ions without evidence of the underlying mechanisms. If the mechanisms underlying the stimulated growth phase have been identified, specific terms, such as amelioration, defense gene activation, priming or acclimation, should be used. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  1. Carbamzepine-induced toxic epidermal necrolysis

    Directory of Open Access Journals (Sweden)

    Nithyananda K Chowta

    2011-01-01

    Full Text Available Toxic epidermal necrolysis (TEN, also known as Lyell′s syndrome, is a widespread life-threatening mucocutaneous disease where there is extensive detachment of the skin and mucous membrane. Many factors involved in the etiology of TEN including adverse drug reactions. Here we are reporting a case of toxic epidermal necrolysis in an adult male patient after receiving carbamazepine in a 38 year old male. On the18th day of carbamazepine, patient developed blisters which first appeared on the trunk, chest and arms. The erythematous rash was covering almost all over the body with epidermal detachment of 70% body surface area. There was loss of eye lashes, congestion of conjunctiva with mucopurulent discharge and exposure keratitis. The clinical impression was TEN induced by carbamazepine. Carbamazepine was stopped immediately. He was treated with high dose intravenous betamethasone and systemic and topical antibiotics. After one month, the progression of the skin lesions halted and he was discharged.

  2. Modelling toxicity induced Neurological disorders in Zebrafish

    Directory of Open Access Journals (Sweden)

    Benin Joseph

    2012-03-01

    Full Text Available Neurological disorders have become more common and prevalent. Cellular pathology and behavioural symptoms in neurodegenerative diseases although connected are still a mystery to solve with no complete cure available yet. Central pathways in neurodegeneration involves impaired ubiquitin-proteasome machinery, autophagy and mitochondrial oxidative stress. In the case of neurodevlopmental disorders, environmental toxins and genetic factors are main causative agents. We aim to create a toxicity induced zebrafish model of neurological disease focussing on cognition, movement and hyperactivity disorders. Zebra fish embryos at 48 hr post fertilization were treated with different doses of lead, cholesterol and acetyl choline and by 7 days post fertilization pectoral fin movement, swimming behaviour and touch response were compromised in parallel with apoptosis identified in the brain by acridine orange fluorescent staining. A marked window is observed, therefore promising for a drug screening platform. Further characterization of pathology associated protein expression and specific behavioural studies could render this as a simple promising toxic model for preclinical drug screening.

  3. Erdosteine against acetaminophen induced renal toxicity.

    Science.gov (United States)

    Isik, Bunyamin; Bayrak, Reyhan; Akcay, Ali; Sogut, Sadik

    2006-07-01

    Acetaminophen (APAP) induced toxicities have been a major problem in clinical practice. The aim of the present study was to demonstrate a possible protective role of erdosteine, a mucolytic agent having antioxidant properties via its active metabolites, on APAP induced renal damage in rats. Female Wistar Albino rats were divided into groups including control, erdosteine (150 mg/kg, oral), APAP (1 g/kg, oral) APAP+erdosteine (150 mg/kg, oral) and APAP+erdosteine (300 mg/kg, oral). APAP treatment caused lipid peroxidation as well as high NO level in renal tissue. Also, APAP treated rats had decreased activities of CAT and GSH-Px, but not SOD. In addition, tubular epithelial degeneration, vacuolization and cell desquamation were clearly observed in the APAP treated rats. The cellular debris in the proximal tubules and cortical interstitial congestions were prominent in the kidneys of APAP treated rats. BUN and creatinine levels were increased after APAP administration. All these pathological changes were reversed after erdosteine treatments. Erdosteine treated APAP groups showed milder tubular degeneration, epithelial vacuolization in the proximal tubules, lesser cellular desquamation and better morphology when compared with APAP groups. In conclusion, erdosteine may be a choice of preventive treatment against APAP induced nephrotoxicity.

  4. Mangiferin: A xanthone attenuates mercury chloride induced cytotoxicity and genotoxicity in HepG2 cells.

    Science.gov (United States)

    Kaivalya, Mudholkar; Nageshwar Rao, B N; Satish Rao, B S

    2011-01-01

    Mangiferin (MGN), a dietary C-glucosylxanthone present in Mangifera indica, is known to possess a spectrum of beneficial pharmacological properties. This study demonstrates antigenotoxic potential of MGN against mercuric chloride (HgCl2)-induced genotoxicity in HepG2 cell line. Treatment of HepG2 cells with various concentrations of HgCl2 for 3 h caused a dose-dependent increase in micronuclei frequency and elevation in DNA strand breaks (olive tail moment and tail DNA). Pretreatment with MGN significantly (p inhibited HgCl2 -induced (20 µM for 30 h) DNA damage. An optimal antigenotoxic effect of MGN, both in micronuclei and comet assay, was observed at a concentration of 50 µM. Furthermore, HepG2 cells treated with various concentrations of HgCl2 resulted in a dose-dependent increase in the dichlorofluorescein fluorescence, indicating an increase in the generation of reactive oxygen species (ROS). However, MGN by itself failed to generate ROS at a concentration of 50 µM, whereas it could significantly decrease HgCl2 -induced ROS. Our study clearly demonstrates that MGN pretreatment reduced the HgCl2-induced DNA damage in HepG2 cells, thus demonstrating the genoprotective potential of MGN, which is mediated mainly by the inhibition of oxidative stress.

  5. Bactericidal antibiotics induce programmed metabolic toxicity

    Directory of Open Access Journals (Sweden)

    Aislinn D. Rowan

    2016-03-01

    Full Text Available The misuse of antibiotics has led to the development and spread of antibiotic resistance in clinically important pathogens. These resistant infections are having a significant impact on treatment outcomes and contribute to approximately 25,000 deaths in the U.S. annually. If additional therapeutic options are not identified, the number of annual deaths is predicted to rise to 317,000 in North America and 10,000,000 worldwide by 2050. Identifying therapeutic methodologies that utilize our antibiotic arsenal more effectively is one potential way to extend the useful lifespan of our current antibiotics. Recent studies have indicated that modulating metabolic activity is one possible strategy that can impact the efficacy of antibiotic therapy. In this review, we will address recent advances in our knowledge about the impacts of bacterial metabolism on antibiotic effectiveness and the impacts of antibiotics on bacterial metabolism. We will particularly focus on two studies, Lobritz, et al. (PNAS, 112(27: 8173-8180 and Belenky et al. (Cell Reports, 13(5: 968–980 that together demonstrate that bactericidal antibiotics induce metabolic perturbations that are linked to and required for bactericidal antibiotic toxicity.

  6. Methotrexate-induced acute toxic leukoencephalopathy

    Directory of Open Access Journals (Sweden)

    Parag R Salkade

    2012-01-01

    Full Text Available Acute lymphoblastic leukemia (ALL is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX, as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS. Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced ′acute toxic leukoencephalopathy′ has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non-stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted and FLAIR (Fluid-Attenuated Inversion recovery sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up

  7. Methotrexate-induced acute toxic leukoencephalopathy.

    Science.gov (United States)

    Salkade, Parag R; Lim, Teh Aun

    2012-01-01

    Acute lymphoblastic leukemia (ALL) is one of the most common malignancies of childhood, which is treated with high doses of methotrexate (MTX), as it crosses the blood-brain barrier and can be administered intravenously and via intrathecal route to eradicate leukemic cells from central nervous system (CNS). Additionally, high doses of MTX not only prevent CNS recurrence but also hematologic relapses. Although, standard treatment protocol for ALL includes multimodality therapy, MTX is usually associated with neurotoxicity and affects periventricular deep white matter region. Methotrexate-induced 'acute toxic leukoencephalopathy' has varying clinical manifestations ranging from acute neurological deficit to seizures or encephalopathy. Diffusion weighted magnetic resonance imaging (DW-MRI) is widely available and routinely used in clinical practice to identify acute stroke and also to distinguish acute stroke from non-stroke like conditions. We report a local teenage Chinese girl who developed 2 discrete episodes of left upper and lower limb weakness with left facial nerve paresis after receiving the 2 nd and 3 rd cycle of high dose of intravenous and intrathecal methotrexate, without having cranial irradiation. After each episode of her neurological deficit, the DW-MRI scan showed focal restricted diffusion in right centrum semiovale. Her left sided focal neurological deficit and facial nerve paresis almost completely subsided on both these occasions within 3 days of symptom onset. Follow-up DW-MRI, after her neurological recovery, revealed almost complete resolution of previously noted restricted diffusion in right centrum semiovale, while the lesion was not evident on concurrent T2W (T2-weighted) and FLAIR (Fluid-Attenuated Inversion recovery) sequences, nor showed any post contrast enhancement on post gadolinium enhanced T1W (T1-weighted) sequences. No residual neurological deficit or intellectual impairment was identified on clinical follow up over a 2 year

  8. Simvastatin-induced Toxic Epidermal Necrolysis

    Institute of Scientific and Technical Information of China (English)

    Emmanouil Petrou; Vasiliki Karali; Emmanouil Papadakis

    2014-01-01

    Toxic epidermal necrolysis comprises a severe immune-complex mediated hypersensitivity reaction that typically involves the skin and mucous membranes.Herein, we describe a68-year -old man who presented with the condition after simvastatin administration.

  9. Simvastatin-induced Toxic Epidermal Necrolysis

    Directory of Open Access Journals (Sweden)

    Emmanouil Petrou

    2014-01-01

    Full Text Available Toxic epidermal necrolysis comprises a severe immune-complex mediated hypersensitivity reaction that typically involves the skin and mucous membranes. Herein, we describe a 68-year -old man who presented with the condition after simvastatin administration.

  10. Amiodarone-induced acute lung toxicity in an ICU setting.

    Science.gov (United States)

    Skroubis, G; Skroubis, T; Galiatsou, E; Metafratzi, Z; Karahaliou, A; Kitsakos, A; Nakos, G

    2005-04-01

    Amiodarone is a highly effective antiarrhythmic drug, albeit notorious for its serious pulmonary toxicity. The incidence of amiodarone-induced pulmonary toxicity (APT) appears to be 1% per year (1). We report a case of very acute APT in a man suffering from postoperative atrial fibrillation.

  11. Carbamate pesticide induced toxic epidermal necrolysis

    Directory of Open Access Journals (Sweden)

    Rajendran N

    2001-09-01

    Full Text Available A 36-year-old male alleged to have consumed carbamate pesticide liquid (Baygon@ developed toxic epidermal necrolysis (TEN within twenty-four hours of intake. Though drugs have been commonly incriminated as offending agents for TEN, carbamate pesticide was found to be the causative agent in our case.

  12. Current issues with paracetamol induced toxicity

    Directory of Open Access Journals (Sweden)

    Erdinc Cakir

    2011-06-01

    Full Text Available Paracetamol (acetaminophen; APAP, a commonly-used analgesic and anti-pyretic drug, is usually safe when administered at therapeutic doses in children. However, at overdoses, APAP has the potential for causing fulminant hepatic necrosis and nephrotoxicity in both humans and animals. In pre-school children, many poisonings are due to chemical or pharmaceutical preparations like APAP which is an important example for poisoning with pharmaceutics. Liver has an important role in the metabolism of toxic chemicals, certain drugs and environmental pollutants. Using the cytochrome P450 pathway, APAP is converted to a highly toxic metabolite, namely N–acetyl–p–benzoquinamine (NAPQI. By this way, ... [J Exp Integr Med 2011; 1(3.000: 165-166

  13. Oxidative stress-induced autophagy: Role in pulmonary toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Malaviya, Rama [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2014-03-01

    Autophagy is an evolutionarily conserved catabolic process important in regulating the turnover of essential proteins and in elimination of damaged organelles and protein aggregates. Autophagy is observed in the lung in response to oxidative stress generated as a consequence of exposure to environmental toxicants. Whether autophagy plays role in promoting cell survival or cytotoxicity is unclear. In this article recent findings on oxidative stress-induced autophagy in the lung are reviewed; potential mechanisms initiating autophagy are also discussed. A better understanding of autophagy and its role in pulmonary toxicity may lead to the development of new strategies to treat lung injury associated with oxidative stress. - Highlights: • Exposure to pulmonary toxicants is associated with oxidative stress. • Oxidative stress is known to induce autophagy. • Autophagy is upregulated in the lung following exposure to pulmonary toxicants. • Autophagy may be protective or pathogenic.

  14. Glyphosate induces cardiovascular toxicity in Danio rerio.

    Science.gov (United States)

    Roy, Nicole M; Ochs, Jeremy; Zambrzycka, Ewelina; Anderson, Ariann

    2016-09-01

    Glyphosate is a broad spectrum herbicide used aggressively in agricultural practices as well as home garden care. Although labeled "safe" by the chemical industry, doses tested by industry do not mimic chronic exposures to sublethal doses that organisms in the environment are exposed to over long periods of time. Given the widespread uses of and exposure to glyphosate, studies on developmental toxicity are needed. Here we utilize the zebrafish vertebrate model system to study early effects of glyphosate on the developing heart. Treatment by embryo soaking with 50μg/ml glyphosate starting at gastrulation results in structural abnormalities in the atrium and ventricle, irregular heart looping, situs inversus as well as decreased heartbeats by 48h as determined by live imaging and immunohistochemistry. Vasculature in the body was also affected as determined using fli-1 transgenic embryos. To determine if the effects noted at 48h post fertilization are due to early stage alterations in myocardial precursors, we also investigate cardiomyocyte development with a Mef2 antibody and by mef2ca in situ hybridization and find alterations in the Mef2/mef2ca staining patterns during early cardiac patterning stages. We conclude that glyphosate is developmentally toxic to the zebrafish heart.

  15. Exposure of cultured human proximal tubular cells to cadmium, mercury, zinc and bismuth: toxicity and metallothionein induction.

    Science.gov (United States)

    Rodilla, V; Miles, A T; Jenner, W; Hawksworth, G M

    1998-08-14

    The kidney, in particular the proximal convoluted tubule, is a major target site for the toxic effects of various metals. However, little is known about the early effects of these metals after acute exposure in man. In the present study we have evaluated the toxicity of several inorganic metal compounds (CdCl2, HgCl2, ZnCl2, and Bi(NO3)3) and the induction of metallothionein by these compounds in cultured human proximal tubular (HPT) cells for up to 4 days. The results showed that bismuth was not toxic even at the highest dose (100 microM) used, while zinc, cadmium and mercury exhibited varying degrees of toxicity, zinc being the least toxic and mercury the most potent. A significant degree of interindividual variation between the different isolates used in these experiments was also observed. All metals used in the present study induced MT, as revealed by immunocytochemistry. All metals showed maximal induction between 1 and 3 days after treatment. Although a certain amount of constitutive MT was present in the cultures, the intensity of the staining varied with time in culture and between the different isolates studied. No correlation could be made between the intensity of the staining in control cultures (indicating total amount of constitutive MT) and the susceptibility of a given isolate to metal toxicity. Furthermore, no correlation could be made between metal-induced MT and the susceptibility of a given isolate to that particular metal.

  16. Protective effects of propolis on inorganic mercury induced oxidative stress in mice.

    Science.gov (United States)

    Zhao, Jun-Quan; Wen, Yi-Fei; Bhadauria, Monika; Nirala, Satendra Kumar; Sharma, Abhilasha; Shrivastava, Sadhana; Shukla, Sangeeta; Agrawal, Om Prakash; Mathur, Ramesh

    2009-04-01

    Protective potential of propolis was evaluated against mercury induced oxidative stress and antioxidant enzymatic alterations in mice liver. Exposure to mercuric chloride (HgCl2; 5 mg/kg; ip) induced oxidative stress by increasing lipid peroxidation and oxidized glutathione level along with concomitant decrease in glutathione and various antioxidant enzymes. Mercury intoxication deviated the activity of liver marker enzymes in serum. Conjoint treatment of propolis (200 mg/kg; po) inhibited lipid peroxidation and oxidized glutathione level, whereas increased glutathione level. Activities of antioxidants enzymes, i.e., superoxide dismutase, catalase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase were also restored concomitantly towards control after propolis administration. Release of serum transaminases, alkaline phosphatase, lactate dehydrogenase and y-glutamyl transpeptidase were significantly restored towards control after propolis treatment. Results suggest that propolis augments the antioxidants defense against mercury induced toxicity and provides evidence that it has therapeutic potential as hepatoprotective agent.

  17. Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond.

    Science.gov (United States)

    Di Lisi, Daniela; Madonna, Rosalinda; Zito, Concetta; Bronte, Enrico; Badalamenti, Giuseppe; Parrella, Paolo; Monte, Ines; Tocchetti, Carlo Gabriele; Russo, Antonio; Novo, Giuseppina

    2017-01-15

    Cardiotoxicity induced by chemotherapeutic agents and radiotherapy is a growing problem. In recent years, an increasing number of new drugs with targeted action have been designed. These molecules, such as monoclonal antibodies and tyrosine kinase inhibitors, can cause different type of toxicities compared to traditional chemotherapy. However, they can also cause cardiac complications such as heart failure, arterial hypertension, QT interval prolongation and arrhythmias. Currently, a field of intense research is the vascular toxicity induced by new biologic drugs, particularly those which inhibit vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) and other tyrosine kinases. In this review, we aim at focusing on the problem of vascular toxicity induced by new targeted therapies, chemotherapy and radiotherapy, and describe the main mechanisms and emphasizing the importance of early diagnosis of vascular damage, in order to prevent clinical complications.

  18. [Teratogenesis and medication induced fetal toxicity].

    Science.gov (United States)

    Elefant, Elisabeth; Bavoux, Françoise

    2003-11-15

    The administration of pharmacological treatments during pregnancy always arouses concerns, shared both by the medical body and the general public. The drama of thalidomide, the main cause, has been followed by a number of efforts to develop some knowledge on the reality, nature and frequency of risk of malformation and foeto-toxicity, in particular from medications. A more rational approach to pharmacotherapy in the pregnant woman has come about following a position that was less supported and more alarmist. The principal idea that emerges consists of defending a more realistic evaluation of the risk:benefit ratio of pharmacotherapy in a sick pregnant woman, against the temptation of not treating or giving a maladaptive treatment. The second notion, essential in chronic pathologies, consists of supporting the efforts of multidisciplinary teams working in the pharmacotherapeutic management of pregnant women, to avoid errors of strategy that may be both medical and human.

  19. Effect of Semecarpus anacardium against lead induced toxicity in rats.

    Science.gov (United States)

    Abirami, N; Raju, V Shanmuga; Rajathi, K

    2007-10-01

    The present study was carried out to understand the antioxidant and protective effect of Semecarpus anacardium against lead acetate induced toxicity. This was done by analyzing the phytochemicals (Flavanoids, alkaloids, resins, tannins, carbohydrates, proteins, etc.) present in the plant and by assessing the hepatoprotective efficacy of the plant against lead acetate induced albino rats. Histopathological examination was also carried out to have a supporting evidence for the study. It was observed that the nut milk extract contains flavanoids, phenols and carbohydrates and the drug was effective against lead acetate induced toxicity. The levels of the marker enzymes were increased in the lead acetate induced rats and after the treatment of Semecarpus anacardium the liver damage decreased.

  20. Antidotal Effects of Curcumin Against Agents-Induced Cardiovascular Toxicity.

    Science.gov (United States)

    Farkhondeh, Tahereh; Samarghandian, Saeed

    Curcumin, the major phenolic compound in turmeric, shows preventive effects in various diseases. Curcumin is commonly found in rhizome of the Curcuma species and traditionally used in herbal medicine. Numeros studies has indicated that curcumin posses protective effects against toxic agents in various systems including cardiovascular. This study found that curcumin may be effective in cardiovascular diseases induced by toxic agents including Streptozotocin, Doxorubicin, Cyclosporin A, Methotrexate, Isoproterenol, Cadmium, Diesel exhaust particle, Nicotine, Hydrogen peroxide, and tert- Butyl hydroperoxide. However, due to the lake of information on human, further studies are needed to determine the efficacy of curcumin as an antidote agent. The present study aimed to critically review the recent literature data from that regarding the protective effects of curcumin against agents-induced cardiovascular toxicity.

  1. Inorganic and organic mercury chloride toxicity to Coturnix: Sensitivity related to age and quantal assessment of physiologic responses

    Science.gov (United States)

    Hill, E.F.

    1982-01-01

    The toxicities of mercuric chloride (HgCl(,2)) and methylmercuric chloride (CH(,3)HgCl) were compared for coturnix (Coturnix coturnix japonica) from hatching to adulthood. Comparisons were based on: (1) Median lethal dosages (LD50) derived by administering single peroral and single intramuscular dosages of mercury, (2) median lethal concentrations (LC50) derived by feeding mercury for 5 days, (3) median toxic concentrations (TC50) derived by feeding mercury 9 weeks and measuring plasma enzyme activity, plasma electrolytes, and other blood constituents, and (4) transient changes of various blood chemistries following a single peroral dose of mercury. Acute peroral and intramuscular LD50s for HgCl(,2) and CH(,3)HgCl increased by two- to threefold for coturnix chicks from hatching to 4 weeks of age. Concomitantly, the LC50s also increased, but the important difference between test procedures was that with both single dose routes of exposure the toxicity ratios, i.e., HgCl(,2)/CH(,3)HgCl, at each age were about 2 to 2.5 compared to about 100 for the LC50s. For example, at 2 weeks of age the peroral LD50s for HgCl(,2) and CH(,3)HgCl were 42 and 18 mg/kg; the dietary LC50s were 5086 and 47 ppm for HgCl(,2) and CH(,3)HgCl. The 9 week feeding trial was not associated with gross effects from either HgCl(,2) at 0.5 to 32 ppm or CH(,3)HgCl at 0.125 to 8 ppm. However, subtle responses were detected for the plasma enzymes aspartate aminotransferase, lactate dehydrogenase, and ornithine carbamoyl transferase and could be quantified by probit analysis. This quantal procedure was based on establishment of a normal value for each enzyme and classing outliers as respondents. A 'hazard index' based on the TC50 for an enzyme divided by the LD50 or LC50 was introduced. The single oral dosages of HgCl(,2) and CH(,3)HgCl showed that ratios of alanine aminotransferase, lactate dehydrogenase, and orinthine carbamoyl transferase for the liver and kidneys of adult coturnix were opposite from

  2. The fungicide mancozeb induces toxic effects on mammalian granulosa cells

    Energy Technology Data Exchange (ETDEWEB)

    Paro, Rita [Department of Health Sciences, University of L' Aquila, Via Vetoio, L' Aquila (Italy); Tiboni, Gian Mario [Department of Medicine and Aging, Section of Reproductive Sciences, University “G. D' Annunzio”, Chieti-Pescara (Italy); Buccione, Roberto [Tumor Cell Invasion Laboratory, Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti (Italy); Rossi, Gianna; Cellini, Valerio [Department of Health Sciences, University of L' Aquila, Via Vetoio, L' Aquila (Italy); Canipari, Rita [Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Section of Histology and Embryology, School of Pharmacy and Medicine, “Sapienza” University of Rome, Rome (Italy); Cecconi, Sandra, E-mail: sandra.cecconi@cc.univaq.it [Department of Health Sciences, University of L' Aquila, Via Vetoio, L' Aquila (Italy)

    2012-04-15

    The ethylene-bis-dithiocarbamate mancozeb is a widely used fungicide with low reported toxicity in mammals. In mice, mancozeb induces embryo apoptosis, affects oocyte meiotic spindle morphology and impairs fertilization rate even when used at very low concentrations. We evaluated the toxic effects of mancozeb on the mouse and human ovarian somatic granulosa cells. We examined parameters such as cell morphology, induction of apoptosis, and p53 expression levels. Mouse granulosa cells exposed to mancozeb underwent a time- and dose-dependent modification of their morphology, and acquired the ability to migrate but not to proliferate. The expression level of p53, in terms of mRNA and protein content, decreased significantly in comparison with unexposed cells, but no change in apoptosis was recorded. Toxic effects could be attributed, at least in part, to the presence of ethylenthiourea (ETU), the main mancozeb catabolite, which was found in culture medium. Human granulosa cells also showed dose-dependent morphological changes and reduced p53 expression levels after exposure to mancozeb. Altogether, these results indicate that mancozeb affects the somatic cells of the mammalian ovarian follicles by inducing a premalignant-like status, and that such damage occurs to the same extent in both mouse and human GC. These results further substantiate the concept that mancozeb should be regarded as a reproductive toxicant. Highlights: ► The fungicide mancozeb affects oocyte spindle morphology and fertilization rate. ► We investigated the toxic effects of mancozeb on mouse and human granulosa cells. ► Granulosa cells modify their morphology and expression level of p53. ► Mancozeb induces a premalignant-like status in exposed cells.

  3. Unique copper-induced oligomers mediate alpha-synuclein toxicity.

    Science.gov (United States)

    Wright, Josephine A; Wang, Xiaoyan; Brown, David R

    2009-08-01

    Parkinson's disease and a number of other neurodegenerative diseases have been linked to either genetic mutations in the alpha-synuclein gene or show evidence of aggregates of the alpha-synuclein protein, sometimes in the form of Lewy bodies. There currently is no clear evidence of a distinct neurotoxic species of alpha-synuclein to explain the death of neurons in these diseases. We undertook to assess the toxicity of alpha-synuclein via exogenous application in cell culture. Initially, we showed that only aggregated alpha-synuclein is neurotoxic and requires the presence copper but not iron. Other members of the synuclein family showed no toxicity in any form and inherited point mutations did not alter the effective toxic concentration of alpha-synuclein. Through protein fractionation techniques, we were able to isolate an oligomeric species responsible for the toxicity of alpha-synuclein. This oligomeric species has a unique stellate appearance under EM and again, requires association with copper to induce cell death. The results allow us to suggest that the toxic species of alpha-synuclein in vivo could possibly be these stellate oligomers and not fibrils. Our data provide a link between the recently noted association of copper and alpha-synuclein and a potential role for the combination in causing neurodegeneration.

  4. Melatonin attenuates doxorubicin-induced testicular toxicity in rats.

    Science.gov (United States)

    Lee, K-M; Lee, I-C; Kim, S-H; Moon, C; Park, S-H; Shin, D-H; Kim, S-H; Park, S-C; Kim, H-C; Kim, J-C

    2012-05-01

    This study investigated the protective effects of melatonin (MLT) against doxorubicin (DXR)-induced testicular toxicity and oxidative stress in rats. DXR was given as a single intraperitoneal dose of 10 mg kg(-1) body weight to male rats at 1 h after MLT treatment on day 6 of the study. MLT at 15 mg kg(-1) body weight was administered daily by gavage for 5 days before DXR treatment followed by an additional dose for 5 days. Sperm analysis, histopathological examination and biochemical methods were used for this investigation. DXR caused a decrease in the weight of seminal vesicles, epididymal sperm count and motility and an increase in the incidence of histopathological changes of the testis. In addition, an increased malondialdehyde (MDA) concentration and decreased glutathione content, glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase activities were observed. On the contrary, MLT treatment significantly ameliorated DXR-induced testicular toxicity in rats. Moreover, MDA concentration and GR, GST and SOD activities were not affected when MLT was administered in conjunction with DXR. These results indicate that MLT had a protective effect against DXR-induced testicular toxicity and that the protective effects of MLT may be due to both the inhibition of lipid peroxidation and increased antioxidant activity.

  5. Cannabidiol Rescues Acute Hepatic Toxicity and Seizure Induced by Cocaine

    Directory of Open Access Journals (Sweden)

    Luciano Rezende Vilela

    2015-01-01

    Full Text Available Cocaine is a commonly abused illicit drug that causes significant morbidity and mortality. The most severe and common complications are seizures, ischemic strokes, myocardial infarction, and acute liver injury. Here, we demonstrated that acute cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate. Considering the protective role of the endocannabinoid system against cell toxicity, we hypothesized that treatment with an anandamide hydrolysis inhibitor, URB597, or with a phytocannabinoid, cannabidiol (CBD, protects against cocaine toxicity. URB597 (1.0 mg/kg abolished cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg reduced acute liver inflammation and damage induced by cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic drug (acetaminophen increased seizure and lethality induced by cocaine intoxication, linking hepatotoxicity to seizure dynamics. These findings suggest that activation of cannabinoid system may have protective actions on both liver and brain induced by cocaine, minimizing inflammatory injury promoted by cocaine, supporting its further clinical application in the treatment of cocaine abuse.

  6. Mechanisms of Nanoparticle-Induced Oxidative Stress and Toxicity

    Directory of Open Access Journals (Sweden)

    Amruta Manke

    2013-01-01

    Full Text Available The rapidly emerging field of nanotechnology has offered innovative discoveries in the medical, industrial, and consumer sectors. The unique physicochemical and electrical properties of engineered nanoparticles (NP make them highly desirable in a variety of applications. However, these novel properties of NP are fraught with concerns for environmental and occupational exposure. Changes in structural and physicochemical properties of NP can lead to changes in biological activities including ROS generation, one of the most frequently reported NP-associated toxicities. Oxidative stress induced by engineered NP is due to acellular factors such as particle surface, size, composition, and presence of metals, while cellular responses such as mitochondrial respiration, NP-cell interaction, and immune cell activation are responsible for ROS-mediated damage. NP-induced oxidative stress responses are torch bearers for further pathophysiological effects including genotoxicity, inflammation, and fibrosis as demonstrated by activation of associated cell signaling pathways. Since oxidative stress is a key determinant of NP-induced injury, it is necessary to characterize the ROS response resulting from NP. Through physicochemical characterization and understanding of the multiple signaling cascades activated by NP-induced ROS, a systemic toxicity screen with oxidative stress as a predictive model for NP-induced injury can be developed.

  7. Mechanisms of zidovudine-induced mitochondrial toxicity and myopathy.

    Science.gov (United States)

    Scruggs, Erin R; Dirks Naylor, Amie J

    2008-01-01

    Zidovudine (3-azido-3'-deoxythymidine), also referred to as azidothymidine (AZT), has become an integral component in highly active antiretroviral therapy, and has also been used in the treatment of cancer. The clinical effectiveness of AZT is constrained due to its association with increased adverse effects, such as myopathy. There are numerous potential mechanisms that may contribute to AZT-induced myopathy. The first hypothesized mechanism to explain AZT-induced toxicity was mtDNA depletion due to inhibition of DNA polymerase gamma. Although mtDNA depletion is present in patients with myopathy, current data suggests that alternative mechanisms may play a more direct role in the myotoxicity. These mechanisms include AZT-induced oxidative stress, direct inhibition of mitochondrial bioenergetic machinery, and mitochondrial depletion of L-carnitine. Furthermore, we hypothesize that apoptosis may play a role in AZT-induced myopathy.

  8. Glutamine: A novel approach to chemotherapy-induced toxicity

    Directory of Open Access Journals (Sweden)

    Kumar Gaurav

    2012-01-01

    Full Text Available Treatment of cancer is associated with short- and long-term side-effects. Cancer produces a state of glutamine deficiency, which is further aggravated by toxic effects of chemotherapeutic agents leading to increased tolerance of tumor to chemotherapy as well as reduced tolerance of normal tissues to the side-effects of chemotherapy. This article reviews the possible role of glutamine supplementation in reducing the serious adverse events in patients treated with anticancer drugs. The literature related to the possible role of glutamine in humans with cancer and the supportive evidence from animal studies was reviewed. Searches were made and the literature was retrieved using PUBMED, MEDLINE, COCHRANE LIBRARY, CENAHL and EMBASE, with a greater emphasis on the recent advances and clinical trials. Glutamine supplementation was found to protect against radiation-induced mucositis, anthracycline-induced cardiotoxicity and paclitaxel-related myalgias/arthralgias. Glutamine may prevent neurotoxicity of paclitaxel, cisplatin, oxaplatin bortezomib and lenolidamide, and is beneficial in the reduction of the dose-limiting gastrointestinal toxic effects of irinotecan and 5-FU-induced mucositis and stomatitis. Dietary glutamine reduces the severity of the immunosuppressive effect induced by methotrexate and improves the immune status of rats recovering from chemotherapy. In patients with acute myeloid leukemia requiring parenteral nutrition, glycyl-glutamine supplementation could hasten neutrophil recovery after intensive myelosuppressive chemotherapy. Current data supports the usefulness of glutamine supplementation in reducing complications of chemotherapy; however, paucity of clinical trials weakens the clear interpretation of these findings.

  9. Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects

    KAUST Repository

    Papsdorf, Katharina

    2015-09-03

    Background Protein aggregation and its pathological effects are the major cause of several neurodegenerative diseases. In Huntington’s disease an elongated stretch of polyglutamines within the protein Huntingtin leads to increased aggregation propensity. This induces cellular defects, culminating in neuronal loss, but the connection between aggregation and toxicity remains to be established. Results To uncover cellular pathways relevant for intoxication we used genome-wide analyses in a yeast model system and identify fourteen genes that, if deleted, result in higher polyglutamine toxicity. Several of these genes, like UGO1, ATP15 and NFU1 encode mitochondrial proteins, implying that a challenged mitochondrial system may become dysfunctional during polyglutamine intoxication. We further employed microarrays to decipher the transcriptional response upon polyglutamine intoxication, which exposes an upregulation of genes involved in sulfur and iron metabolism and mitochondrial Fe-S cluster formation. Indeed, we find that in vivo iron concentrations are misbalanced and observe a reduction in the activity of the prominent Fe-S cluster containing protein aconitase. Like in other yeast strains with impaired mitochondria, non-fermentative growth is impossible after intoxication with the polyglutamine protein. NMR-based metabolic analyses reveal that mitochondrial metabolism is reduced, leading to accumulation of metabolic intermediates in polyglutamine-intoxicated cells. Conclusion These data show that damages to the mitochondrial system occur in polyglutamine intoxicated yeast cells and suggest an intricate connection between polyglutamine-induced toxicity, mitochondrial functionality and iron homeostasis in this model system.

  10. Protective Effects of Quercetin Against HgCl₂-Induced Nephrotoxicity in Sprague-Dawley Rats.

    Science.gov (United States)

    Shin, Yu Jin; Kim, Jeong Jun; Kim, Ye Ji; Kim, Won Hee; Park, Eun Young; Kim, In Young; Shin, Han-Seung; Kim, Kyeong Seok; Lee, Eui-Kyung; Chung, Kyu Hyuck; Lee, Byung Mu; Kim, Hyung Sik

    2015-05-01

    Mercury is a well-known environmental pollutant that can cause nephropathic diseases, including acute kidney injury (AKI). Although quercetin (QC), a natural flavonoid, has been reported to have medicinal properties, its potential protective effects against mercury-induced AKI have not been evaluated. In this study, the protective effect of QC against mercury-induced AKI was investigated using biochemical parameters, new protein-based urinary biomarkers, and a histopathological approach. A 250 mg/kg dose of QC was administered orally to Sprague-Dawley male rats for 3 days before administration of mercury chloride (HgCl2). All animals were sacrificed at 24 h after HgCl2 treatment, and biomarkers associated with nephrotoxicity were measured. Our data showed that QC absolutely prevented HgCl2-induced AKI, as indicated by biochemical parameters such as blood urea nitrogen (BUN) and serum creatinine (sCr). In particular, QC markedly decreased the accumulation of Hg in the kidney. Urinary excretion of protein-based biomarkers, including clusterin, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein-1 (MCP-1), tissue inhibitor of metalloproteinases 1 (TIMP-1), and vascular endothelial growth factor (VEGF) in response to HgCl2 administration were significantly decreased by QC pretreatment relative to that in the HgCl2-treated group. Furthermore, urinary excretion of metallothionein and Hg were significantly elevated by QC pretreatment. Histopathological examination indicated that QC protected against HgCl2-induced proximal tubular damage in the kidney. A TUNEL assay indicated that QC pretreatment significantly reduced apoptotic cell death in the kidney. The administration of QC provided significant protective effects against mercury-induced AKI.

  11. Diazinon-Induced Ovarian Toxicity and Protection by Vitamins E

    Directory of Open Access Journals (Sweden)

    Zinat Sargazi

    2014-09-01

    Full Text Available Background: DZN (diazinon is an organophosphate insecticide that had been used in agriculture and for domestic and veterinary use for several years and caused many negative effects on plants and animal species, especially on human. The aim of present study was to evaluate the effects of DZN on MDA (malondialdehyde and GSH (glutathione levels in female rat reproductive tissue (ovary and to assess the protective role of vitamin E. Methods: A total of 30 adult female Wistar rats were divided into five groups: control group (without any intervention, sham group (received only pure corn oil, as solvent, experimental group 1 (DZN+corn oil, 60 mg/kg, experimental group 2 (vitamin E, 200 mg/kg, and experimental group 3 (DZN+vitamin E, the same dosage. All drugs were injected intraperitoneally, except vitamin E which was administrated by gavage. The animals were scarified after two weeks and MDA as a marker of lipid peroxidation and GSH content were measured in ovarian tissue. Results: DZN reduced GSH content and increased MDA level in ovary compared with the control group (P<0.001. Vitamin E plus DZN increased GSH content but decreased DZN-induced MDA elevation in rat ovarian tissue. Conclusion: Oxidative stress contributes to DZN-induced ovarian toxicity. The results of this study suggested that vitamin E may have a protective effect on DZN-induced ovarian toxicity.

  12. Specific Conditions for Resveratrol Neuroprotection against Ethanol-Induced Toxicity

    Directory of Open Access Journals (Sweden)

    Brigitte Gonthier

    2012-01-01

    Full Text Available Aims. 3,5,4′-Trihydroxy-trans-stilbene, a natural polyphenolic compound present in wine and grapes and better known as resveratrol, has free radical scavenging properties and is a potent protector against oxidative stress induced by alcohol metabolism. Today, the mechanism by which ethanol exerts its toxicity is still not well understood, but it is generally considered that free radical generation plays an important role in the appearance of structural and functional alterations in cells. The aim of this study was to evaluate the protective action of resveratrol against ethanol-induced brain cell injury. Methods. Primary cultures of rat astrocytes were exposed to ethanol, with or without a pretreatment with resveratrol. We examined the dose-dependent effects of this resveratrol pretreatment on cytotoxicity and genotoxicity induced by ethanol. Cytotoxicity was assessed using the MTT reduction test. Genotoxicity was evidenced using single cell gel electrophoresis. In addition, DNA staining with fluorescent dyes allowed visualization of nuclear damage using confocal microscopy. Results. Cell pretreatment with low concentrations of trans-resveratrol (0.1–10 μM slowed down cell death and DNA damage induced by ethanol exposure, while higher concentrations (50–100 μM enhanced these same effects. No protection by cis-resveratrol was observed. Conclusion. Protection offered by trans-resveratrol against ethanol-induced neurotoxicity was only effective for low concentrations of this polyphenol.

  13. Basal autophagy protects cardiomyocytes from doxorubicin-induced toxicity.

    Science.gov (United States)

    Pizarro, Marcela; Troncoso, Rodrigo; Martínez, Gonzalo J; Chiong, Mario; Castro, Pablo F; Lavandero, Sergio

    2016-08-31

    Doxorubicin (Doxo) is one of the most effective anti-neoplastic agents but its cardiotoxicity has been an important clinical limitation. The major mechanism of Doxo-induced cardiotoxicity is associated to its oxidative capacity. However, other processes are also involved with significant consequences for the cardiomyocyte. In recent years, a number of studies have investigated the role of autophagy on Doxo-induced cardiotoxicity but to date it is not clear how Doxo alters that process and its consequence on cardiomyocytes viability. Here we investigated the effect of Doxo 1uM for 24h of stimulation on cultured neonatal rat cardiomyocytes. We showed that Doxo inhibits basal autophagy. This inhibition is due to both Akt/mTOR signaling pathway activation and Beclin 1 level decrease. To assess the role of autophagy on Doxo-induced cardiomyocyte death, we evaluated the effects 3-methyladenine (3-MA), bafilomycin A1 (BafA), siRNA Beclin 1 (siBeclin 1) and rapamycin (Rapa) on cell viability. Inhibition of autophagy with 3-MA, BafA and siBeclin 1 increased lactate dehydrogenase (LDH) release but, when autophagy was induced by Rapa, Doxo-induced cardiomyocyte death was decreased. These results suggest that Doxo inhibits basal autophagy and contributes to cardiomyocyte death. Activation of autophagy could be used as a strategy to protect the heart against Doxo toxicity.

  14. Lidocaine-induced CNS toxicity--a case report.

    Science.gov (United States)

    Chiang, Y Y; Tseng, K F; Lih, Y W; Tsai, T C; Liu, C T; Leung, H K

    1996-12-01

    Lidocaine is the first local anesthetic of the amide type to be introduced to clinical practice. It is a versatile drug and in anesthesia, is the most commonly used local anesthetic because of its aptness of potency, rapid onset, moderate duration of action and topical activity. It is relatively safe and useful in many other clinical settings. Unfortunately, systemic intoxication and psychotic reaction associated with its use often occur because of its popularity and wider safety margin, for which guide in use is often ignored and overdose becomes commonplace. Moreover, due to its universality in use seldom reports have recently dealt with lidocaine, particularly regarding its toxic reaction. Here, we present a case of lidocaine intoxication occurring during circumcision for a reviewal of the problem. A healthy young male, weighing 65 kg, underwent circumcision for phimosis under penile block with 2% lidocaine which totaled 600 mg. Twenty minutes after injection the patient developed headache, tinnitus, visual and auditory disturbances. Muscle twitching over the mouth angles, trismus and rigidity of extremities were also noted. Later in the course he became restless, agitative, hallucinative, talkative, and verbose with repetitious words. The whole course of the disorder lasted about 5 h. It was believed that lidocaine-induced CNS intoxication, manifested by psychotic reaction broke out. Treatment with thiopental was not very impressive. Also, we took this opportunity to discuss and review the toxic reaction associated with the use of lidocaine, its risk factors, mechanism, treatment and prevention. The complicated associations of lidocaine-induced CNS toxic reaction with central control of behavior and the neurotransmitter systems (adrenergic, dopaminergic and serotonin) were also touched.

  15. Textile dyes induce toxicity on zebrafish early life stages.

    Science.gov (United States)

    de Oliveira, Gisele Augusto Rodrigues; de Lapuente, Joaquín; Teixidó, Elisabet; Porredón, Constança; Borràs, Miquel; de Oliveira, Danielle Palma

    2016-02-01

    Textile manufacturing is one of the most polluting industrial sectors because of the release of potentially toxic compounds, such as synthetic dyes, into the environment. Depending on the class of the dyes, their loss in wastewaters can range from 2% to 50% of the original dye concentration. Consequently, uncontrolled use of such dyes can negatively affect human health and the ecological balance. The present study assessed the toxicity of the textile dyes Direct Black 38 (DB38), Reactive Blue 15 (RB15), Reactive Orange 16 (RO16), and Vat Green 3 (VG3) using zebrafish (Danio rerio) embryos for 144 h postfertilization (hpf). At the tested conditions, none of the dyes caused significant mortality. The highest RO16 dose significantly delayed or inhibited the ability of zebrafish embryos to hatch from the chorion after 96 hpf. From 120 hpf to 144 hpf, all the dyes impaired the gas bladder inflation of zebrafish larvae, DB38 also induced curved tail, and VG3 led to yolk sac edema in zebrafish larvae. Based on these data, DB38, RB15, RO16, and VG3 can induce malformations during embryonic and larval development of zebrafish. Therefore, it is essential to remove these compounds from wastewater or reduce their concentrations to safe levels before discharging textile industry effluents into the aquatic environment.

  16. Glioprotective Effects of Ashwagandha Leaf Extract against Lead Induced Toxicity

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    Praveen Kumar

    2014-01-01

    Full Text Available Withania somnifera (Ashwagandha, also known as Indian Ginseng, is a well-known Indian medicinal plant due to its antioxidative, antistress, antigenotoxic, and immunomodulatory properties. The present study was designed to assess and establish the cytoprotective potential of Ashwagandha leaf aqueous extract against lead induced toxicity. Pretreatment of C6 cells with 0.1% Ashwagandha extract showed cytoprotection against 25 μM to 400 μM concentration of lead nitrate. Further pretreatment with Ashwagandha extract to lead nitrate exposed cells (200 μM resulted in normalization of glial fibrillary acidic protein (GFAP expression as well as heat shock protein (HSP70, mortalin, and neural cell adhesion molecule (NCAM expression. Further, the cytoprotective efficacy of Ashwagandha extract was studied in vivo. Administration of Ashwagandha extract provided significant protection to lead induced altered antioxidant defense that may significantly compromise normal cellular function. Ashwagandha also provided a significant protection to lipid peroxidation (LPx levels, catalase, and superoxide dismutase (SOD but not reduced glutathione (GSH contents in brain tissue as well as peripheral organs, liver and kidney, suggesting its ability to act as a free radical scavenger protecting cells against toxic insult. These results, thus, suggest that Ashwagandha water extract may have the potential therapeutic implication against lead poisoning.

  17. Serotonin deficiency exacerbates acetaminophen-induced liver toxicity in mice.

    Science.gov (United States)

    Zhang, Jingyao; Song, Sidong; Pang, Qing; Zhang, Ruiyao; Zhou, Lei; Liu, Sushun; Meng, Fandi; Wu, Qifei; Liu, Chang

    2015-01-29

    Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.

  18. Bosutinib induced pleural effusions: Case report and review of tyrosine kinase inhibitors induced pulmonary toxicity

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    Natalia I. Moguillansky, MD

    2017-01-01

    Full Text Available Tyrosine kinase inhibitors are known to cause pulmonary complications. We report a case of bosutinib related bilateral pleural effusions in a patient with chronic myeloid leukemia. Characteristics of the pleural fluid are presented. We also discuss other tyrosine kinase inhibitors induced pulmonary toxicities, including pulmonary hypertension and interstitial lung disease.

  19. Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants

    Energy Technology Data Exchange (ETDEWEB)

    Huang Qihong; Jin Xidong; Gaillard, Elias T.; Knight, Brian L.; Pack, Franklin D.; Stoltz, James H.; Jayadev, Supriya; Blanchard, Kerry T

    2004-05-18

    Microarray technology continues to gain increased acceptance in the drug development process, particularly at the stage of toxicology and safety assessment. In the current study, microarrays were used to investigate gene expression changes associated with hepatotoxicity, the most commonly reported clinical liability with pharmaceutical agents. Acetaminophen, methotrexate, methapyrilene, furan and phenytoin were used as benchmark compounds capable of inducing specific but different types of hepatotoxicity. The goal of the work was to define gene expression profiles capable of distinguishing the different subtypes of hepatotoxicity. Sprague-Dawley rats were orally dosed with acetaminophen (single dose, 4500 mg/kg for 6, 24 and 72 h), methotrexate (1 mg/kg per day for 1, 7 and 14 days), methapyrilene (100 mg/kg per day for 3 and 7 days), furan (40 mg/kg per day for 1, 3, 7 and 14 days) or phenytoin (300 mg/kg per day for 14 days). Hepatic gene expression was assessed using toxicology-specific gene arrays containing 684 target genes or expressed sequence tags (ESTs). Principal component analysis (PCA) of gene expression data was able to provide a clear distinction of each compound, suggesting that gene expression data can be used to discern different hepatotoxic agents and toxicity endpoints. Gene expression data were applied to the multiplicity-adjusted permutation test and significantly changed genes were categorized and correlated to hepatotoxic endpoints. Repression of enzymes involved in lipid oxidation (acyl-CoA dehydrogenase, medium chain, enoyl CoA hydratase, very long-chain acyl-CoA synthetase) were associated with microvesicular lipidosis. Likewise, subsets of genes associated with hepatotocellular necrosis, inflammation, hepatitis, bile duct hyperplasia and fibrosis have been identified. The current study illustrates that expression profiling can be used to: (1) distinguish different hepatotoxic endpoints; (2) predict the development of toxic endpoints; and

  20. Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons

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    Shan Liu

    2014-01-01

    Full Text Available Tumor necrosis factor-α (TNF-α is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.

  1. Necroptosis mediates TNF-induced toxicity of hippocampal neurons.

    Science.gov (United States)

    Liu, Shan; Wang, Xing; Li, Yun; Xu, Lei; Yu, Xiaoliang; Ge, Lin; Li, Jun; Zhu, Yongjin; He, Sudan

    2014-01-01

    Tumor necrosis factor-α (TNF-α) is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.

  2. Propolis attenuates doxorubicin-induced testicular toxicity in rats.

    Science.gov (United States)

    Rizk, Sherine M; Zaki, Hala F; Mina, Mary A M

    2014-05-01

    Doxorubicin (Dox), an effective anticancer agent, can impair testicular function leading to infertility. The present study aimed to explore the protective effect of propolis extract on Dox-induced testicular injury. Rats were divided into four groups (n=10). Group I (normal control), group II received propolis extract (200 mg kg(-1); p.o.), for 3 weeks. Group III received 18 mg kg(-1) total cumulative dose of Dox i.p. Group IV received Dox and propolis extract. Serum and testicular samples were collected 48 h after the last treatment. In addition, the effects of propolis extract and Dox on the growth of solid Ehrlich carcinoma in mice were investigated. Dox reduced sperm count, markers of testicular function, steroidogenesis and gene expression of testicular 3β-hydroxysteroid dehydrogenase (3β-HSD), 17β-hydroxysteroid dehydrogenase (17β-HSD) and steroidogenic acute regulatory protein (StAR). In addition, it increased testicular oxidative stress, inflammatory and apoptotic markers. Morphometric and histopathologic studies supported the biochemical findings. Treatment with propolis extract prevented Dox-induced changes without reducing its antitumor activity. Besides, administration of propolis extract to normal rats increased serum testosterone level coupled by increased activities and gene expression of 3ß-HSD and 17ß-HSD. Propolis extract may protect the testis from Dox-induced toxicity without reducing its anticancer potential. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Aceclofenac induced Stevens-Johnson/toxic epidermal necrolysis overlap syndrome

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    Kaderthambi Hajamohideen Nooru Ameen

    2013-01-01

    Full Text Available The purpose of this paper is to report a rare occurrence of Stevens-Johnson/Toxic epidermal necrolysis (SJS/TEN overlap syndrome after the use of aceclofenac. A 38 year old healthy adult male presented with rapidly evolving rash over face and upper body with ulceration of buccal mucosa and breathlessness after taking aceclofenac tablet. Naranjo score for this adverse drug event was six, thereby making it a probable adverse drug reaction. Despite aggressive fluid resuscitation and use of antihistamines and systemic steroids, patient′s health rapidly worsened and died within six hours of presentation. Aceclofenac induced SJS/TEN overlap is an extremely rare clinical association previously reported only once in medical literature. To the best of our knowledge, this is the first case report of such an association in the Indian population. We are presenting this case to highlight the serious adverse reactions possible from a routinely prescribed drug.

  4. Toxicidad ocular medicamentosa Ocular toxicity induced by medication

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    A. Garralda

    2008-01-01

    Full Text Available En el presente trabajo se analiza la toxicidad ocular inducida por cuatro grupos de fármacos sistémicos: tamoxifeno, cloroquina y derivados, anticolinérgicos y tamsulosina. El objetivo principal es dar unas normas prácticas que sirvan para el manejo diario de los pacientes sometidos a estos tratamientos, más que profundizar en los mecanismos de acción de cada uno de ellos.This paper analyses ocular toxicity induced by four groups of systemic medicines: tamoxifen, chloroquine and derivatives, anticholinergics and tamsulosin. Our main aim is to provide some practical rules that will be of use in the everyday management of patients receiving these treatments, rather than to examine the mechanisms by which each of these medicines act.

  5. Amelioration of mercuric chloride induced oxidative stress by Hygrophila auriculata (K.Schum Heine via modulating the oxidant - antioxidant imbalance in rat liver.

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    Metharmitla Perumal Naidu Sridhar

    2013-07-01

    Full Text Available Normal 0 false false false EN-US X-NONE X-NONE Medicinal plants and their phytochemical constituents are considered as paramount entity to treat various human ailments. The present study was designed to investigate the effect of ethanolic extract of Hygrophila auriculata on mercury induced oxidative damage in rat liver. Mercuric chloride (HgCl2 (1mg/kg b.w, i.p was administered three times in a week for two weeks to induce mercury toxicity. Mercury damage to the liver was evident from increase in the activities of marker enzymes such as alanine transaminase (ALT, aspartate transaminase (AST, alkaline phosphatase (ALP and acid phosphatase (ACP in serum. The level of lipid peroxidation (LPO was increased in liver tissue with concomitant decrease in both the enzymic and non-enzymic antioxidants such as superoxide dismutase (SOD, catalase (CAT, glutathione peroxidase (GPx, reduced glutathione (GSH, vitamin C and vitamin E. The  glutathione  metabolizing  enzymes  viz.,  glutathione  reductase (GR,  glucose-6- phosphatase dehydrogenase  (G6PD and glutathione  -S- transferase  (GST were also found to be decreased. Interestingly post treatment with ethanolic extract of Hygrophila auriculata (100 mg/kg b.w, p.o for 10 days after mercury induction significantly ameliorated the mercury induced oxidative damage which is evidenced by the reduction in the marker enzymes, lipid peroxidation and increase in the antioxidant enzymes and glutathione metabolizing enzymes. Thus, this remarkable hepatoprotective activity of ethonolic extact of the plant could be due to the antioxidant  nature, which scavenge excessive free radicals that were involved in the acceleration of  per-oxidation  reaction  and  the potent membrane protective property which ultimately  render protection to the liver against HgCl2 induced oxidative damage.

  6. Environmental toxicants-induced immune responses in the olfactory mucosa

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    Fumiaki Imamura

    2016-11-01

    Full Text Available Olfactory sensory neurons (OSNs are the receptor cells for the sense of smell. Although cell bodies are located in the olfactory mucosa of the nasal cavity, OSN axons directly project to the olfactory bulb that is a component of the central nervous system (CNS. Because of this direct and short connection from this peripheral tissue to the CNS, the olfactory system has attracted attention as a port-of-entry for environmental toxicants that may cause neurological dysfunction. Selected viruses can enter the olfactory bulb via the olfactory mucosa, and directly affect the CNS. On the other hand, environmental toxicants may induce inflammatory responses in the olfactory mucosa, including infiltration of immune cells and production of inflammatory cytokines. In addition, these inflammatory responses cause the loss of OSNs that are then replaced with newly generated OSNs that re-connect to the olfactory bulb after inflammation has subsided. It is now known that immune cells and cytokines in the olfactory mucosa play important roles in both degeneration and regeneration of OSNs. Thus, the olfactory system is a unique neuroimmune interface where interaction between nervous and immune systems in the periphery significantly affects the structure, neuronal circuitry, and immunological status of the CNS. The mechanisms by which immune cells regulate OSN loss and the generation of new OSNs are, however, largely unknown. To help develop a better understanding of the mechanisms involved, we have provided a review of key research that has investigated how the immune response in the olfactory mucosa affects the pathophysiology of OSNs.

  7. Effects of HgCl2 stress on the upper leaf necroses and water use efficiency of oriental hybrid lilies%HgCl2胁迫对东方百合叶烧指数和水分利用效率的影响

    Institute of Scientific and Technical Information of China (English)

    杨爽; 袁晓娜; 王中轩; 祝璞; 贾桂霞

    2016-01-01

    东方百合部分品种在冬季栽培中极易发生叶烧,成为影响百合切花和盆花质量的主要因素之一。叶烧的发生与水分代谢有关,为探寻百合叶烧的发生是否和水通道蛋白相关,本文采用3种不同浓度的水通道蛋白抑制剂HgCl2(50、100和200μmol/L),对叶烧敏感程度不同的2个东方百合品种进行灌根处理,结果表明:随着HgCl2浓度增加,‘Sorbonne '的叶烧指数分别比对照增加了13.56%、36.06%和42.19%;‘Siberia '分别比对照增加了7.20%、12.15%和18.00%。‘Sorbonne'和‘Siberia'的株高、茎粗、叶面积、茎生根长度、茎生根厚度和根系活力、净光合速率和蒸腾速率都受到了不同程度的抑制。其中,HgCl2处理对根系活力的抑制作用最大,3种不同浓度的HgCl2处理后‘Sorbonne'的根系活力分别比对照降低了41.9%、54.7%和67.5%;‘Siberia'的根系活力分别比对照降低了4.8%、33.5%和38.2%。从水分利用效率情况来看,随着HgCl2浓度增加,‘Sorbonne'的水分利用效率分别比对照降低了14.00%、19.23%和46.06%;‘Siberia '的水分利用效率分别比对照降低了8.62%、17.60%和28.71%。由此可知,不同浓度HgCl2胁迫处理抑制了‘Sorbonne'和‘Siberia'的水分运输,显著增加了植物叶烧指数,初步推测百合叶烧发生的程度与植物水通道蛋白的表达有一定的相关性。%Some of the oriental hybrid lily cultivars are prone to upper leaf necrosis ( ULN) , which has become a major threat to the quality of cut and pot lilies. The ULN of oriental lily is believed to relate with water metabolism. In order to explore the relationship between ULN of lilies and the aquaporin, we used three different concentrations of aquaporin inhibitor HgCl2 ( 50, 100 and 200 μmol/L ) to irrigate two lily cultivars which are different in sensitivity to ULN. The result showed that with the increasing concentrations of HgCl2 , the ULN indexes of the cultivar ‘Sorbonne ' were increased by 13. 56%, 36. 06% and 42. 19%, respectively, compared with the contrast; for the cultivar ‘Siberia', the ULN indexes were increased by 7. 20%, 12. 15% and 18. 00%, respectively. The height, stem diameter, leaf area, root length, activity of stem shooting roots, net photosynthetic rate and transpiration rate of‘Sorbonne' and ‘Siberia' were inhibited to varying degrees, especially for the root activity. The root activities of ‘Sorbonne' were reduced by 41. 9%, 54. 7% and 67. 5%, respectively, compared to the contrast after treated with three concentrations of HgCl2; for ‘Siberia' , the root activities were reduced by 4. 8%, 33. 5% and 38. 2%, respectively. The WUEs of ‘Sorbonne' were decreased by 14. 00%, 19. 23% and 46. 06% after HgCl2 treatment, while those of ‘Siberia ' were decreased by 8. 62%, 17. 60% and 28. 71%, respectively. The following conclusions could be drawn: with different levels of HgCl2 stress, the water transportation of ‘Sorbonne' and ‘Siberia' was inhibited, and the ULN indexes were increased. We initially speculate that the degree of ULN of lilies is related to the expression of plant aquaporins.

  8. Antioxidant protection from HIV-1 gp120-induced neuroglial toxicity

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    Walsh Kimberley A

    2004-05-01

    Full Text Available Abstract Background The pathogenesis of HIV-1 glycoprotein 120 (gp120 associated neuroglial toxicity remains unresolved, but oxidative injury has been widely implicated as a contributing factor. In previous studies, exposure of primary human central nervous system tissue cultures to gp120 led to a simplification of neuronal dendritic elements as well as astrocytic hypertrophy and hyperplasia; neuropathological features of HIV-1-associated dementia. Gp120 and proinflammatory cytokines upregulate inducible nitric oxide synthase (iNOS, an important source of nitric oxide (NO and nitrosative stress. Because ascorbate scavenges reactive nitrogen and oxygen species, we studied the effect of ascorbate supplementation on iNOS expression as well as the neuronal and glial structural changes associated with gp120 exposure. Methods Human CNS cultures were derived from 16–18 week gestation post-mortem fetal brain. Cultures were incubated with 400 μM ascorbate-2-O-phosphate (Asc-p or vehicle for 18 hours then exposed to 1 nM gp120 for 24 hours. The expression of iNOS and neuronal (MAP2 and astrocytic (GFAP structural proteins was examined by immunohistochemistry and immunofluorescence using confocal scanning laser microscopy (CSLM. Results Following gp120 exposure iNOS was markedly upregulated from undetectable levels at baseline. Double label CSLM studies revealed astrocytes to be the prime source of iNOS with rare neurons expressing iNOS. This upregulation was attenuated by the preincubation with Asc-p, which raised the intracellular concentration of ascorbate. Astrocytic hypertrophy and neuronal injury caused by gp120 were also prevented by preincubation with ascorbate. Conclusions Ascorbate supplementation prevents the deleterious upregulation of iNOS and associated neuronal and astrocytic protein expression and structural changes caused by gp120 in human brain cell cultures.

  9. Identification and Categorization of Liver Toxicity Markers Induced by a Related Pair of Drugs

    OpenAIRE

    Fuscoe, James C.; Tao Han; Chen, James J; Beland, Frederick A.; Hines, Wade M.; Ching-Wei Chang

    2011-01-01

    Drug-induced liver injury (DILI) is the primary adverse event that results in the withdrawal of drugs from the market and a frequent reason for the failure of drug candidates in the pre-clinical or clinical phases of drug development. This paper presents an approach for identifying potential liver toxicity genomic biomarkers from a liver toxicity biomarker study involving the paired compounds entacapone (“non-liver toxic drug”) and tolcapone (“hepatotoxic drug”). Molecular analysis of the rat...

  10. The efficacy of Pistacia Terebinthus soap in the treatment of cetuximab-induced skin toxicity.

    Science.gov (United States)

    Tastekin, Didem; Tambas, Makbule; Kilic, Kemal; Erturk, Kayhan; Arslan, Deniz

    2014-12-01

    This open-labeled phase II, efficacy-finding study evaluated the efficiency and safety of Pistacia terebinthus soap in metastatic colorectal cancer patients who developed cetuximab induced skin toxicity. Patients who received cetuximab plus chemotherapy and developed Grade 2 or 3 skin toxicity were treated twice daily with a soap made of oil extracted from Pistacia terebinthus. During treatment, no topical or oral antibiotics, corticosteroids or other moisturizers were used. Patients were examined 1 week later and their photographs were taken. Fifteen mCRC patients who developed skin toxicity while receiving first-line CTX in combination with chemotherapy were included into the study. Eight patients were male and the median age was 58 (25-70). Sixty percent of the patients (n:9) had Grade 3 skin toxicity. Complete response rates in patients with Grade 2 and Grade 3 skin toxicities were 100 and 33%, respectively. In the remaining patients with Grade 3 toxicity the skin toxicity regressed to Grade 1. The objective response rate was 100%, and no delay, dose reduction or discontinuation of CTX treatment due to skin toxicity was necessary. Skin toxicity reoccurred in all patients when patients stopped administering the soap and therefore they used it throughout the cetuximab treatment. Pistacia terebinthus soap seemed to be used safely and effectively in the treatment of skin toxicity induced by Cetuximab.

  11. Permethrin-induced oxidative stress and toxicity and metabolism. A review.

    Science.gov (United States)

    Wang, Xu; Martínez, María-Aránzazu; Dai, Menghong; Chen, Dongmei; Ares, Irma; Romero, Alejandro; Castellano, Victor; Martínez, Marta; Rodríguez, José Luis; Martínez-Larrañaga, María-Rosa; Anadón, Arturo; Yuan, Zonghui

    2016-08-01

    Permethrin (PER), the most frequently used synthetic Type I pyrethroid insecticide, is widely used in the world because of its high activity as an insecticide and its low mammalian toxicity. It was originally believed that PER exhibited low toxicity on untargeted animals. However, as its use became more extensive worldwide, increasing evidence suggested that PER might have a variety of toxic effects on animals and humans alike, such as neurotoxicity, immunotoxicity, cardiotoxicity, hepatotoxicity, reproductive, genotoxic, and haematotoxic effects, digestive system toxicity, and cytotoxicity. A growing number of studies indicate that oxidative stress played critical roles in the various toxicities associated with PER. To date, almost no review has addressed the toxicity of PER correlated with oxidative stress. The focus of this article is primarily to summarise advances in the research associated with oxidative stress as a potential mechanism for PER-induced toxicity as well as its metabolism. This review summarises the research conducted over the past decade into the reactive oxygen species (ROS) generation and oxidative stress as a consequence of PER treatments, and ultimately their correlation with the toxicity and the metabolism of PER. The metabolism of PER involves various CYP450 enzymes, alcohol or aldehyde dehydrogenases for oxidation and the carboxylesterases for hydrolysis, through which oxidative stress might occur, and such metabolic factors are also reviewed. The protection of a variety of antioxidants against PER-induced toxicity is also discussed, in order to further understand the role of oxidative stress in PER-induced toxicity. This review will throw new light on the critical roles of oxidative stress in PER-induced toxicity, as well as on the blind spots that still exist in the understanding of PER metabolism, the cellular effects in terms of apoptosis and cell signaling pathways, and finally strategies to help to protect against its oxidative

  12. Cephazolin-Induced Toxic Epidermal Necrolysis Treated with Intravenous Immunoglobulin and N-Acetylcysteine

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    Carlos Saavedra

    2012-01-01

    Full Text Available Toxic epidermal necrolysis is the most severe form of drug-induced skin reaction and includes denudation of >30% of total body surface area. The mechanism of disease is not completely understood, but immunologic mechanisms, cytotoxic reactions, and delayed hypersensitivity seem to be involved. We report a case of cephazolin-induced toxic epidermal necrolysis treated with intravenous immunoglobulin and N-acetylcysteine with excellent response.

  13. Microbially-induced Carbonate Precipitation for Immobilization of Toxic Metals.

    Science.gov (United States)

    Kumari, Deepika; Qian, Xin-Yi; Pan, Xiangliang; Achal, Varenyam; Li, Qianwei; Gadd, Geoffrey Michael

    2016-01-01

    Rapid urbanization and industrialization resulting from growing populations contribute to environmental pollution by toxic metals and radionuclides which pose a threat to the environment and to human health. To combat this threat, it is important to develop remediation technologies based on natural processes that are sustainable. In recent years, a biomineralization process involving ureolytic microorganisms that leads to calcium carbonate precipitation has been found to be effective in immobilizing toxic metal pollutants. The advantage of using ureolytic organisms for bioremediating metal pollution in soil is their ability to immobilize toxic metals efficiently by precipitation or coprecipitation, independent of metal valence state and toxicity and the redox potential. This review summarizes current understanding of the ability of ureolytic microorganisms for carbonate biomineralization and applications of this process for toxic metal bioremediation. Microbial metal carbonate precipitation may also be relevant to detoxification of contaminated process streams and effluents as well as the production of novel carbonate biominerals and biorecovery of metals and radionuclides that form insoluble carbonates. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Predictive Factors of Radiation-Induced Lung Toxicity in Lung Cancer Patients: A Retrospective Study

    Directory of Open Access Journals (Sweden)

    Maher Soliman

    2016-07-01

    Full Text Available Background: Radiation-induced lung toxicity is an important dose-limiting toxicity in lung cancer radiotherapy, for which there are no generally accepted predictive factors. This study seeks to identify risk factors associated with the development of severe radiation-induced lung toxicity using clinical and dosimetric parameters. Methods: We reviewed the medical records of 54 patients with histologically proven stage III non-small cell lung cancer treated with three dimensional-conformal radiotherapy at Alexandria Main University Hospital between January 2008 and December 2011. The original treatment plans for those patients were restored and imported to a treatment planning system. Lung dose–volume histograms and various dosimetric parameters were calculated. Univariate and multivariate logistic regression analyses were performed. Results: The following grades of radiation-induced lung toxicity were observed in patients - grade 0: 17 (31.5%, grade 1: 5 (9.3%, grade 2: 13 (24.1%, grade 3: 15 (27.8%, and grade 5: 4 (7.4%. A total of 19 (35.2% patients developed grade ≥3 and were considered to have an event. Univariate analysis showed that age, presence of chronic obstructive pulmonary disease and location of the primary tumor had significant associations with severe radiation-induced lung toxicity. Other dosimetric variables such as tumor side, histology, forced expiratory volume in 1 s, smoking, and gender showed no significant correlations with severe radiation-induced lung toxicity. Multivariate analysis showed that the presence of chronic obstructive pulmonary disease (P=0.001 and location of the primary tumor (P=0.010 were the only predictive factors for severe radiation-induced lung toxicity. Conclusion: This study demonstrates that patients with chronic obstructive pulmonary disease and lower lung lobe tumors have a high risk of severe radiationinduced lung toxicity when treated with combined chemoradiotherapy. These easily obtained

  15. Sulforaphane mitigates cadmium-induced toxicity pattern in human peripheral blood lymphocytes and monocytes.

    Science.gov (United States)

    Alkharashi, Nouf Abdulkareem Omer; Periasamy, Vaiyapuri Subbarayan; Athinarayanan, Jegan; Alshatwi, Ali A

    2017-10-01

    Cadmium (Cd) is a highly toxic and widely distributed heavy metal that induces various diseases in humans through environmental exposure. Therefore, alleviation of Cd-induced toxicity in living organisms is necessary. In this study, we investigated the protective role of sulforaphane on Cd-induced toxicity in human peripheral blood lymphocytes and monocytes. Sulforaphane did not show any major reduction in the viability of lymphocytes and monocytes. However, Cd treatment at a concentration of 50μM induced around 69% cell death. Treatment of IC10-Cd and 100μM sulforaphane combination for 24 and 48h increased viability by 2 and 9% in cells subjected to Cd toxicity, respectively. In addition, IC25 of Cd and 100μM sulforaphane combination recovered 17-20% of cell viability. Cd induced apoptotic and necrotic cell death. Sulforaphane treatment reduced Cd-induced cell death in lymphocytes and monocytes. Our results clearly indicate that when the cells were treated with Cd+sulforaphane combination, sulforaphane decreased the Cd-induced cytotoxic effect in lymphocytes and monocytes. In addition, sulforaphane concentration plays a major role in the alleviation of Cd-induced toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Fenthion induced toxicity and histopathological changes in gill ...

    African Journals Online (AJOL)

    Tersoo

    2015-06-23

    Jun 23, 2015 ... control of insect pests. The present study investigated the toxic effect of fenthion and the ... A great propor- tion of acute poisoning cases are caused by exposure to .... Inc., Chicago, Illinois, USA) and Duncan's multiple range test was used to determine ..... composite nitrogen fertilizers. Ecotoxicol. Environ.

  17. [Rizatriptan-induced liver toxicity. Report of a case].

    Science.gov (United States)

    Fernandez-Atutxa, Alberto; Vergara, Mercedes; Gil, Montserrat; Dalmau, Blai; Miquel, Mireia; Sanchez-Delgado, Jordi; Casas, Meritxell

    2013-04-01

    Triptans are a class of drugs with proven efficacy in the acute treatment of migraine headache. The first component of these drugs was sumatriptan, with various derivatives subsequently emerging. Until now, there has only been one reported case of liver toxicity with zolmitriptan. We now present a case of hepatotoxicity related to another drug in this group: rizatriptan.

  18. Hesperidin alleviates acetaminophen induced toxicity in Wistar rats by abrogation of oxidative stress, apoptosis and inflammation.

    Science.gov (United States)

    Ahmad, Shiekh Tanveer; Arjumand, Wani; Nafees, Sana; Seth, Amlesh; Ali, Nemat; Rashid, Summya; Sultana, Sarwat

    2012-01-25

    Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but at high dose it leads to undesirable side effects, such as hepatotoxicity and nephrotoxicity. The present study demonstrates the comparative hepatoprotective and nephroprotective activity of hesperidin (HD), a naturally occurring bioflavonoid against APAP induced toxicity. APAP induces hepatotoxicity and nephrotoxicity as was evident by abnormal deviation in the levels of antioxidant enzymes. Moreover, APAP induced renal damage by inducing apoptotic death and inflammation in renal tubular cells, manifested by an increase in the expression of caspase-3, caspase-9, NFkB, iNOS, Kim-1 and decrease in Bcl-2 expression. These results were further supported by the histopathological examination of kidney. All these features of APAP toxicity were reversed by the co-administration of HD. Therefore, our study favors the view that HD may be a useful modulator in alleviating APAP induced oxidative stress and toxicity.

  19. Reactive nitrogen species in acetaminophen-induced mitochondrial damage and toxicity in mouse hepatocytes.

    Science.gov (United States)

    Burke, Angela S; MacMillan-Crow, Lee Ann; Hinson, Jack A

    2010-07-19

    Acetaminophen (APAP) toxicity in primary mouse hepatocytes occurs in two phases. The initial phase (0-2 h) occurs with metabolism to N-acetyl-p-benzoquinoneimine which depletes glutathione, and covalently binds to proteins, but little toxicity is observed. Subsequent washing of hepatocytes to remove APAP and reincubating in media alone (2-5 h) results in toxicity. We previously reported that the reincubation phase occurs with mitochondrial permeability transition (MPT) and increased oxidative stress (dichlorodihydrofluorescein fluorescence) (DCFH(2)). Since DCFH(2) may be oxidized by multiple oxidative mechanisms, we investigated the role of reactive nitrogen species (RNS) leading to 3-nitrotyrosine in proteins by ELISA and by immunoblots. Incubation of APAP with hepatocytes for 2 h did not result in toxicity or protein nitration; however, washing hepatocytes and reincubating in media alone (2-5 h) resulted in protein nitration which correlated with toxicity. Inclusion of the MPT inhibitor, cyclosporine A, in the reincubation media eliminated toxicity and protein nitration. The general nitric oxide synthase (NOS) inhibitor L-NMMA and the neuronal NOS (NOS1) inhibitor, 7-nitroindazole, added in the reincubation media decreased toxicity and protein nitration; however, neither the inducible NOS (NOS2) inhibitors L-NIL (N6-(1-iminoethyl)-L-lysine) nor SAIT (S-(2-aminoethyl)isothiourea) decreased protein nitration or toxicity. The RNS scavengers, N-acetylcysteine, and high concentrations of APAP, added in the reincubation phase decreased toxicity and protein nitration. 7-Nitroindazole and cyclosporine A inhibited the APAP-induced loss of mitochondrial membrane potential when added in the reincubation phase. The data indicate a role for RNS in APAP induced toxicity.

  20. Amiodaron-induced pulmonary toxicity with fatal outcome

    Energy Technology Data Exchange (ETDEWEB)

    Brachtel, D.; Krischel, W.

    1984-12-01

    Three month after initiation of amiodarone treatment wih 1000 mg daily a 62 years old man with refractory ventricular tachycardia developed increasing dyspnea. Chest X-ray findings consisted of patchy alveolar infiltrates and interstitial changes. Despite withdrawal of amiodarone and institution of prednisolone treatment the patient died of cardiorespiratory failure. Chest X-ray examinations at frequent intervals should be performed during the first year of high dose amiodarone therapy to detect early signs of pulmonary toxicity.

  1. Cephalosporin Induced Toxic Epidermal Necrolysis and Subsequent Penicillin Drug Exanthem

    OpenAIRE

    Amanda Lam; Inderpal Randhawa; William Klaustermeyer

    2008-01-01

    Background: Drug hypersensitivity is classically divided into IgE mediated and non-IgE mediated disease. We report a rare case of consequent IgE mediated and non-IgE mediated reactions within the beta lactam class of antibiotics. Case Summary: An 84-year-old man developed toxic epidermal necrolysis (TEN) due to ceftriaxone, a third generation cephalosporin, involving 72% of the body surface area. The patient recovered but within weeks subsequently developed an acute IgE mediated allergic r...

  2. Toxic Epidermal Necrolysis induced by rarely implicated drugs

    Directory of Open Access Journals (Sweden)

    Sujit Rajagopalan

    2012-01-01

    Full Text Available Toxic Epidermal Necrolysis (TEN and Steven-Johnson Syndrome (SJS are serious disorders commonly caused as idiosyncratic reactions to drugs, the most common ones being oxicams, anticonvulsants, allopurinol, and sulfonamides. We present a case of TEN in a patient who developed the lesions after ingesting multiple drugs including paracetamol, metoclopramide, antihistamines, and multivitamins. These drugs have rarely been implicated in this disorder. The suspected drugs in this case were paracetamol and metoclopramide. However, the role of other drugs could not be ruled out definitely. The patient was managed with antibiotics, corticosteroids, and parenteral fluids and recovered well.

  3. Toxicity induced by Basic Violet 14, Direct Red 28 and Acid Red 26 in zebrafish larvae.

    Science.gov (United States)

    Shen, Bing; Liu, Hong-Cui; Ou, Wen-Bin; Eilers, Grant; Zhou, Sheng-Mei; Meng, Fan-Guo; Li, Chun-Qi; Li, Yong-Quan

    2015-12-01

    Basic Violet 14, Direct Red 28 and Acid Red 26 are classified as carcinogenic dyes in the European textile ecology standard, despite insufficient toxicity data. In this study, the toxicity of these dyes was assessed in a zebrafish model, and the underlying toxic mechanisms were investigated. Basic Violet 14 and Direct Red 28 showed acute toxicity with a LC50 value at 60.63 and 476.84 µg ml(-1) , respectively, whereas the LC50 of Acid Red 26 was between 2500 and 2800 µg ml(-1) . Treatment with Basic Violet 14, Direct Red 28 and Acid Red 26 resulted in common developmental abnormalities including delayed yolk sac absorption and swimming bladder deflation. Hepatotoxicity was observed in zebrafish treated with Basic Violet 14, and cardiovascular toxicity was found in zebrafish treated with Acid Red 26 at concentrations higher than 2500 µg ml(-1) . Basic Violet 14 also caused significant up-regulation of GCLC gene expression in a dose-dependent manner whereas Acid Red 26 induced significant up-regulation of NKX2.5 and down-regulation of GATA4 at a high concentration in a dose-dependent manner. These results suggest that Basic Violet 14, Direct Red 28 and Acid Red 26 induce developmental and organ-specific toxicity, and oxidative stress may play a role in the hepatotoxicity of Basic Violet 14, the suppressed GATA4 expression may have a relation to the cardiovascular toxicity of Acid Red 26. Copyright © 2015 John Wiley & Sons, Ltd.

  4. Assessing and managing toxicities induced by kinase inhibitors.

    Science.gov (United States)

    Castoldi, Raffaella E; Pennella, Giulia; Saturno, Grazia S; Grossi, Pietro; Brughera, Marco; Venturi, Miro

    2007-01-01

    Currently, several protein kinase-modulating compounds have received market approval across a range of diverse therapeutic indications. Furthermore, a large number of chemical and biological protein kinase-modulating compounds are undergoing testing at the preclinical and clinical level. Protein kinases are both major pharmacological targets and diagnostically useful. Progression of kinase modulators toward clinically viable therapies is aided by a reversible mechanism of action, short treatment durations and patient-compliant administration routes. However, the physiological role and essential functional activity of protein kinases in many organs and tissues complicates, to different extents, the development of useful, highly potent protein kinase modulators. In this review, we will highlight common problems in the development of these compounds and lessons learned from the extensive preclinical and clinical characterization of some key protein kinase modulators, some of which have either entered and successfully completed clinical trials or have been abandoned as a consequence of unacceptable toxicity issues. We will ultimately explore how molecular profiling tools combined with histopathological endpoints can be adopted to address and further understand these toxicities in humans and understand their relevance and characterization when identified during early animal experiments.

  5. The use of antioxidants in radiotherapy-induced skin toxicity.

    Science.gov (United States)

    Amber, Kyle T; Shiman, Michael I; Badiavas, Evangelos V

    2014-01-01

    Radiation-induced skin damage is one of the most common complications of radiotherapy. In order to combat these side effects, patients often turn to alternative therapies, which often include antioxidants. Antioxidants such as those in the polyphenol chemical class, xanthine derivatives, tocepherol, sucralfate, and ascorbate have been studied for their use in either preventing or treating radiotherapy-induced skin damage. Apart from their known role as free radical scavengers, some of these antioxidants appear to alter cytokine release affecting cutaneous and systemic changes. We review the role of antioxidants in treating and preventing radiation-induced skin damage as well as the possible complications of using such therapy.

  6. Contribution of oxidative stress to TiO2 nanoparticle-induced toxicity.

    Science.gov (United States)

    Song, Bin; Zhou, Ting; Yang, WenLong; Liu, Jia; Shao, LongQuan

    2016-12-01

    With the rapid development of nanotechnology, titanium dioxide nanoparticles (TNPs) are widely used in many fields. People in such workplaces or researchers in laboratories are at a higher risk of being exposed to TNPs, so are the consumers. Moreover, increasing evidence revealed that the concentrations of TNPs are elevated in animal organs after systematic exposure and such accumulated TNPs could induce organ dysfunction. Although cellular responses such as oxidative stress, inflammatory response, apoptosis, autophagy, signaling pathways, and genotoxic effects contribute to the toxicity of TNPs, the interrelationship among them remains obscure. Given the pivotal role of oxidative stress, we summarized relevant articles covering the involvement of oxidative stress in TNPs' toxicity and found that TNP-induced oxidative stress might play a central role in toxic mechanisms. However, available data are far from being conclusive and more investigations should be performed to further confirm whether the toxicity of TNPs might be attributed in part to the cascades of oxidative stress. Tackling this uncertain issue may help us to comprehensively understand the interrelationship among toxic cellular responses induced by TNPs and might shed some light on methods to alleviate toxicity of TNPs.

  7. Influence of soil moisture on linear alkylbenzene sulfonate-induced toxicity in ammonia-oxidizing bacteria.

    Science.gov (United States)

    Nielsen, Klaus B; Brandt, Kristian K; Jacobsen, Anne-Marie; Mortensen, Gerda K; Sørensen, Jan

    2004-02-01

    Moisture affects bioavailability and fate of pollutants in soil, but very little is known about moisture-induced effects on pollutant toxicity. We here report on a modifying effect of moisture on degradation of linear alkylbenzene sulfonates (LASs) and on their toxicity towards ammonia-oxidizing bacteria (AOB) in agricultural soil. In soil spiked with two LAS levels (250 or 1,000 mg/kg) and incubated at four different moisture levels (9-100% of water-holding capacity), degradation was strongly affected by both soil moisture and initial LAS concentration, resulting in degradation half-lives ranging from 13 to more than 160 d. Toxicity towards AOB assessed by a novel Nitrosomonas europaea luxAB-reporter assay was correlated to total LAS concentration, indicating that LAS remained bioavailable over time without accumulation of toxic intermediates. Toxicity towards indigenous AOB increased with increasing soil moisture. The results indicate that dry soil conditions inhibit LAS degradation and provide protection against toxicity within the indigenous AOB, thus allowing for a rapid recovery of this population when LAS degradation is resumed and completed after rewetting. We propose that the protection of microbial populations against toxicity in dry soil may be a general phenomenon caused primarily by limited diffusion and thus a low bioavailability of the toxicant.

  8. Studies on subacute toxicity of Wansheng Huafeng Dan in rats%万胜化风丹对大鼠亚急性毒性的研究

    Institute of Scientific and Technical Information of China (English)

    彭芳; 杨虹; 吴芹; 刘杰; 时京珍

    2012-01-01

    Objective: To compare sub-acute toxic effects of cinnabar and Wansheng Huafeng Dan with mercury chloride and methyl-mercury. Method: Healthy SD rats were orally administered with Wansheng Huafeng Dan (0.42 g·kg-1), cinnabar (0. 15 g ·kg-1), HgS(0. 15g·kg-1), HgCl2(0.02g·kg-1'), MeHg (0.001 g·kg-1) and saline for 21 days under observed and then-weights were monitored. After the final administration, they were decapitated and their blood, liver, kidney and brain tissues were collected for calculating hepatic and renal indexes and detecting the contents of serum glutamic pyruvic rransamina.se, urea nitrogen and crealinine and the mercury accumulation in liver, kidney and brain tissues. Besides, relative expressions of liver metallothionein-1 (MT-1) and cytochrome P450 gene subtypes (Cyplal, Cyp2bl, Cyp2el, Cyp3a2, Cyp4alO) mRNA. Result: HgCl2 caused obvious weight lose in rats. Mercury contents in liver and kidney were markedly increased by HgClj and MeHg, and MeHg markedly increased mercury contents of brain either, but these advent effects were not notable in Wansheng Huafeng Dan and cinnabar groups. However, blood biochemistry and histopathology did not show significant changes in all groups. The expression of rat hepatic MT-1 mRNA was remarkably induced by both HgCl2 and MeHg. The expression of hepatic Cyp3a2 was increased by Wansheng Huafeng Dan and cinnabar, while the expression of Cyp2el was inhibited by HgCl2 and MeHg. Conclusion: The administration of Wansheng Huafeng Dan with equivalent dose for three weeks shows a much low sub-acute toxicity than HgCl2 and MeHg in rats.%目的:比较朱砂及万胜化风丹与氯化汞、甲基汞的亚急性毒性作用.方法:健康SD大鼠连续每天分别灌胃万胜化风丹(0.42 g·kg-1)、朱砂(0.15 g·kg-1)、硫化汞(0.15 g·kg-1)、氯化汞(0.02 g·kg-1)、甲基汞(0.001 g·kg-1),以及生理盐水21 d,观察大鼠一般情况,监测体重,于末次给药后断头取血、肝脏、肾脏和脑组织,计

  9. Vaccination with non-toxic mutant toxic shock syndrome toxin-1 induces IL-17-dependent protection against Staphylococcus aureus infection.

    Science.gov (United States)

    Narita, Kouji; Hu, Dong-Liang; Asano, Krisana; Nakane, Akio

    2015-06-01

    Toxic shock syndrome toxin-1 (TSST-1) is one of superantigens produced by Staphylococcus aureus. We have previously demonstrated that vaccination with non-toxic mutant TSST-1 (mTSST-1) develops host protection to lethal S. aureus infection in mice. However, the detailed mechanism underlying this protection is necessary to elucidate because the passive transfer of antibodies against TSST-1 fails to provide complete protection against S. aureus infection. In this study, the results showed that interleukin-17A (IL-17A)-producing cells were increased in the spleen cells of mTSST-1-vaccinated mice. The main source of IL-17A in mTSST-1-vaccinated mice was T-helper 17 (Th17) cells. The protective effect of vaccination was induced when the vaccinated wild type but not IL-17A-deficient mice were challenged with S. aureus. Gene expression of chemokines, CCL2 and CXCL1, and infiltration of neutrophils and macrophages were increased in spleens and livers of vaccinated mice after infection. The IL-17A-dependent immune response was TSST-1 specific because TSST-1-deficient S. aureus failed to induce the response. The present study suggests that mTSST-1 vaccination is able to provide the IL-17A-dependent host defense against S. aureus infection which promotes chemokine-mediated infiltration of phagocytes into the infectious foci.

  10. Protective Effect of Vitamins E and C on Endosulfan-Induced Reproductive Toxicity in Male Rats

    Directory of Open Access Journals (Sweden)

    Hussain Kargar

    2012-09-01

    Full Text Available Background: The role of oxidative stress in endosulfan-induced reproductive toxicity has been implicated. This study was performed to evaluate the possible protective effect of vitamins E and C, against endosulfan-induced reproductive toxicity in rats.Methods: Fifty adult male Sprague–Dawley rats were randomly divided into five groups (n=10 each. The groups included a control receiving vehicle, a group treated with endosulfan (10 mg/kg/day alone, and three endosulfan-treated group receiving vitamin C (20 mg/kg/day, vitamin E (200 mg/kg/day, or vitamine C+vitamin E at the same doses. After 10 days of treatment, sperm parameters, plasma lactate dehydrogenase (LDH, plasma testosterone and malondialdehyde (MDA levels in the testis were determined. Results: Oral administration of endosulfan caused a reduction in the sperm motility, viability, daily sperm production (DSP and increased the number of sperm with abnormal chromatin condensation. Endosulfan administration increased testis MDA and plasma LDH. Supplementation of vitamin C and vitamin E to endosulfan-treated rats reduced the toxic effect of endosulfan on sperm parameters and lipid peroxidation in the testis. Vitamin E was more protective than vitamin C in reducing the adverse effects of the endosulfan.Conclusion: The findings data suggest that administration of vitamins C and E ameliorated the endosulfan-induced oxidative stress and sperm toxicity in rat. The effect of vitamin E in preventing endosulfan-induced sperm toxicity was superior to that of vitamin C.

  11. Methamphetamine-induced toxicity: The role of autophagy?

    Science.gov (United States)

    Roohbakhsh, Ali; Shirani, Kobra; Karimi, Gholamreza

    2016-12-25

    Methamphetamine (METH) is a highly potent and addictive drug with major medical, psychiatric, cognitive, socioeconomic, and legal consequences. It is well absorbed following different routes of administration and distributed throughout the body. METH is known as psychomotor stimulant with potent physiological outcomes on peripheral and central nervous systems, resulting in physical and psychological disorders. Autophagy is a highly conserved and regulated catabolic pathway which is critical for maintaining cellular energy homeostasis and regulating cell growth. The mechanism of autophagy has attracted considerable attention in the last few years because of its recognition as a vital arbiter of death/survival decisions in cells and as a critical defense mechanism in undesirable physiological conditions. The purpose of the current article was to review available evidence to find a relationship between METH toxicity and mechanisms associated with autophagy in different organs.

  12. GDNF-induced cerebellar toxicity: A brief review.

    Science.gov (United States)

    Luz, Matthias; Mohr, Erich; Fibiger, H Christian

    2016-01-01

    Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson's disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000μg/month). No cerebellar toxicity was observed at lower doses (450 and 900μg/month) in the same study, or at similar or higher doses (up to 10,000μg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed.

  13. Virgin coconut oil supplementation ameliorates cyclophosphamide-induced systemic toxicity in mice.

    Science.gov (United States)

    Nair, S S; Manalil, J J; Ramavarma, S K; Suseela, I M; Thekkepatt, A; Raghavamenon, A C

    2016-02-01

    Virgin coconut oil (VCO) is an unrefined kernal oil, prepared from Cocos nucifera L., having substantial nutritional and medicinal value. Experimental studies have suggested its antioxidant, anti-inflammatory, immunostimulatory and hypolipidemic effects. The present study assesses its effect on formalin-induced chronic inflammation and cyclophosphamide (CTX)-induced systemic toxicity in murine models. Oral administration of VCO effectively reduced formalin-induced paw oedema in mice with more or less similar efficacy as that of diclofenac. The CTX-induced hike in blood urea, creatinine, thiobarbituric acid reactive substances (TBARS) and liver marker enzymes in mice was marginally decreased by VCO (8 g/kg body weight) ingestion orally. The liver and kidney catalase, superoxide dismutase and glutathione peroxidase activities, together with cellular glutathione and TBARS levels, were found to be improved in these animals. Overall the study reveals the protective efficacy of VCO against secondary toxicity induced by CTX possibly through its antioxidant and anti-inflammatory properties.

  14. Attenuating effect of daidzein on polychlorinated biphenyls-induced oxidative toxicity in mouse testicular cells

    Institute of Scientific and Technical Information of China (English)

    Da-lei ZHANG; Yu-ling MI; Kai-ming WANG; Wei-dong ZENG; Cai-qiao ZHANG

    2008-01-01

    The attenuating effect of daidzein (DAD on oxidative toxicity induced by Aroclor 1254 (A 1254) was investigated in mouse testicular cells. Cells were exposed to A1254 alone or with DAI. The oxidative damage was estimated by measuring malondialdehyde (MDA) formation, superoxide dismutase (SOD) activity and glutathione (GSH) content. Results show that A 1254 induced a decrease of germ cell number, an elevation in thiobarbituric acid reactive substances (TBARS) but a decrease in SOD activity and GSH content. However, simultaneous supplementation with DAI decreased TBARS level and increased SOD activity and GSH content. Consequently, dietary DAI may restore the intracellular antioxidant system to attenuate the oxidative toxicity of A1254 in testicular cells.

  15. Triphenyl phosphate-induced developmental toxicity in zebrafish: Potential role of the retinoic acid receptor

    Energy Technology Data Exchange (ETDEWEB)

    Isales, Gregory M.; Hipszer, Rachel A.; Raftery, Tara D. [Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC (United States); Chen, Albert; Stapleton, Heather M. [Division of Environmental Sciences and Policy, Nicholas School of the Environment, Duke University, Durham, NC (United States); Volz, David C., E-mail: volz@mailbox.sc.edu [Department of Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC (United States)

    2015-04-15

    Highlights: • Triphenyl phosphate-induced toxicity in zebrafish embryos is enhanced in the presence of a retinoic acid receptor antagonist. • Triphenyl phosphate uptake or metabolism within zebrafish embryos is not altered in the presence of a retinoic acid receptor antagonist. • Triphenyl phosphate decreases expression of cytochrome P450 26a1 in zebrafish embryos. • Triphenyl phosphate inhibits retinoic acid-induced activation of human retinoic acid receptors. - Abstract: Using zebrafish as a model, we previously reported that developmental exposure to triphenyl phosphate (TPP) – a high-production volume organophosphate-based flame retardant – results in dioxin-like cardiac looping impairments that are independent of the aryl hydrocarbon receptor. Using a pharmacologic approach, the objective of this study was to investigate the potential role of retinoic acid receptor (RAR) – a nuclear receptor that regulates vertebrate heart morphogenesis – in mediating TPP-induced developmental toxicity in zebrafish. We first revealed that static exposure of zebrafish from 5–72 h post-fertilization (hpf) to TPP in the presence of non-toxic concentrations of an RAR antagonist (BMS493) significantly enhanced TPP-induced toxicity (relative to TPP alone), even though identical non-toxic BMS493 concentrations mitigated retinoic acid (RA)-induced toxicity. BMS493-mediated enhancement of TPP toxicity was not a result of differential TPP uptake or metabolism, as internal embryonic doses of TPP and diphenyl phosphate (DPP) – a primary TPP metabolite – were not different in the presence or absence of BMS493. Using real-time PCR, we then quantified the relative change in expression of cytochrome P450 26a1 (cyp26a1) – a major target gene for RA-induced RAR activation in zebrafish – and found that RA and TPP exposure resulted in a ∼5-fold increase and decrease in cyp26a1 expression, respectively, relative to vehicle-exposed embryos. To address whether TPP may

  16. Exploring BSEP Inhibition-Mediated Toxicity with a Mechanistic Model of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Jeffrey L Woodhead

    2014-11-01

    Full Text Available Inhibition of the bile salt export pump (BSEP has been linked to incidence of drug-induced liver injury (DILI, presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors

  17. Protective Effect of Morocco Carob Honey Against Lead-Induced Anemia and Hepato-Renal Toxicity

    Directory of Open Access Journals (Sweden)

    Aicha Fassi Fihri

    2016-06-01

    Full Text Available Background/Aims: Natural honey has many biological activities including protective effect against toxic materials. The aim of this study was to evaluate the protective effect of carob honey against lead-induced hepato-renal toxicity and lead-induced anemia in rabbits. Methods: Twenty four male rabbits were allocated into four groups six rabbits each; group 1: control group, received distilled water (0.1 ml / kg.b.wt /daily; group 2: received oral lead acetate (2 g/kg.b.wt/daily; group 3: treated with oral honey (1g /kg.b.wt/daily and oral lead (2 g/kg.b.wt/daily, and group 4: received oral honey (1 g/kg.b.wt/daily. Honey and lead were given daily during 24 days of experimentation. Laboratory tests and histopathological evaluations of kidneys were done. Results: Oral administration of lead induced hepatic and kidney injury and caused anemia during three weeks of the exposure. Treatment with honey prevented hepato-renal lead toxicity and ameliorated lead-induced anemia when honey was given to animals during lead exposure. Conclusion: It might be concluded that honey has a protective effect against lead-induced blood, hepatic and renal toxic effects.

  18. Assessing atrazine-induced toxicities in Bufo bufo gargarizans Cantor.

    Science.gov (United States)

    Sai, Linlin; Wu, Qingbo; Qu, Binpeng; Bo, Cunxiang; Yu, Gongchang; Jia, Qiang; Xie, Lin; Li, Yuezhong; Guo, Qiming; Ng, Jack C; Peng, Cheng

    2015-02-01

    Atrazine (AZ), a widely used herbicide has drawn attentions for its potential impacts on amphibians. This study aims to investigate the toxicity of AZ in Bufo bufo gargarizans Cantor (B. bufo gargarizans), a species of toad commonly found in China and countries in East Asia. We treated tadpoles with 0.1, 1, 10 and 100 μg/L AZ for 85 days and examined related parameters. The results showed that the mortality of the toads in the treatment group increased dramatically in a U-shaped dose-response relationship. The hindlimb extension and metamorphosis rate of the toads were significantly inhibited by AZ at 10 and 100 μg/L. Under the same condition, there were significant progressive changes in the testicular structures. Moreover, we found that AZ has no significant effects on growth, sex ratios, gonadal morphology, forelimb emergence and histology in the ovaries. Our results support the idea that environmental contaminants including AZ may be relevant to global amphibian decline.

  19. Lead toxicity thresholds in 17 Chinese soils based on substrate-induced nitrification assay.

    Science.gov (United States)

    Li, Ji; Huang, Yizong; Hu, Ying; Jin, Shulan; Bao, Qiongli; Wang, Fei; Xiang, Meng; Xie, Huiting

    2016-06-01

    The influence of soil properties on toxicity threshold values for Pb toward soil microbial processes is poorly recognized. The impact of leaching on the Pb threshold has not been assessed systematically. Lead toxicity was screened in 17 Chinese soils using a substrate-induced nitrification (SIN) assay under both leached and unleached conditions. The effective concentration of added Pb causing 50% inhibition (EC50) ranged from 185 to >2515mg/kg soil for leached soil and 130 to >2490mg/kg soil for unleached soil. These results represented >13- and >19-fold variations among leached and unleached soils, respectively. Leaching significantly reduced Pb toxicity for 70% of both alkaline and acidic soils tested, with an average leaching factor of 3.0. Soil pH and CEC were the two most useful predictors of Pb toxicity in soils, explaining over 90% of variance in the unleached EC50 value. The relationships established in the present study predicted Pb toxicity within a factor of two of measured values. These relationships between Pb toxicity and soil properties could be used to establish site-specific guidance on Pb toxicity thresholds.

  20. Ceftriaxone-induced toxic epidermal necrolysis mimicking burn injury: a case report

    Directory of Open Access Journals (Sweden)

    Billig Allan

    2009-12-01

    Full Text Available Abstract Introduction Toxic epidermal necrolysis is a rare exfoliative disorder with a high mortality rate. Case presentation We present a 70-year-old woman of Iranian descent who presented with toxic epidermal necrolysis that was initially diagnosed as a scald burn. Further anamnesis prompted by spread of the lesions during hospitalization revealed that the patient had been receiving ceftriaxone for several days. To the best of our knowledge, this is the first case of ceftriaxone-induced toxic epidermal necrolysis in the English literature. Conclusion Toxic epidermal necrolysis is an acute, life-threatening, exfoliative disorder with a high mortality rate. High clinical suspicion, prompt recognition, and initiation of supportive care is mandatory. Thorough investigation of the pathogenetic mechanisms is fundamental. Optimal treatment guidelines are still unavailable.

  1. Bovine colostrum modulates myeloablative chemotherapy-induced gut toxicity in piglets

    DEFF Research Database (Denmark)

    Pontoppidan, Peter Erik Lotko; Shen, René Liang; Cilieborg, Malene Skovsted;

    2015-01-01

    BACKGROUND: Intensive chemotherapy frequently results in gut toxicity, indicated by oral and intestinal mucositis, resulting in poor treatment outcomes and increased mortality. There are no effective preventive strategies against gut toxicity and the role of diet is unknown. OBJECTIVE: We...... hypothesized that the severity of chemotherapy-induced gut toxicity in early life is diet-dependent, and that intake of bovine colostrum (BC) provides better gut protection than an artificial milk replacer (MR). METHODS: A total of 37 3-d-old pigs received for 6 d either intravenous saline control......-BC), and milk replacer plus busulfan and cyclophosphamide chemotherapy (BUCY-MR). The gut was collected for analysis 11 d after the start of chemotherapy. RESULTS: Relative to the control groups, both busulfan and cyclophosphamide chemotherapy (BUCY) groups showed signs of gut toxicity, with oral ulcers...

  2. Photo-induced toxicity of Deepwater Horizon slick oil to blue crab (Callinectes sapidus) larvae.

    Science.gov (United States)

    Alloy, Matthew M; Boube, Idrissa; Griffitt, Robert J; Oris, James T; Roberts, Aaron P

    2015-09-01

    The 2010 Deepwater Horizon oil spill resulted in the accidental release of approximately 700 million L of crude oil into the Gulf of Mexico. Photo-induced toxicity after co-exposure to ultraviolet (UV) radiation is 1 mechanism by which polycyclic aromatic hydrocarbons (PAHs) from oil spills may exert toxicity. Blue crab are an important commercial and ecological resource in the Gulf of Mexico, and their largely transparent larvae may make them sensitive to PAH photo-induced toxicity. The goal of the present study was to examine the sensitivity of early lifestage blue crab (Callinectes sapidus) zoea to slick oil collected during the Deepwater Horizon spill. Blue crab zoea were exposed to 1 of several dilutions of water accommodated fractions from 1 of 2 sources of oil and gradations of natural sunlight in a factorial design. Two 7-h solar exposures were carried out with a recovery period (dark) in between. Survival was found to be UV- and PAH-dependent. Toxicity was observed within the range of surface PAH concentrations reported in the Gulf of Mexico during the Deepwater Horizon spill. These findings indicate that early lifestage blue crab are sensitive to photo-induced toxicity from Deepwater Horizon slick oil. © 2015 SETAC.

  3. Alpha-linolenic acid protects against gentamicin induced toxicity

    Directory of Open Access Journals (Sweden)

    Priyadarshini M

    2012-11-01

    Full Text Available Medha Priyadarshini, Mohammad Aatif, Bilqees BanoDepartment of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, IndiaBackground: Recent studies indicate that reactive oxygen species are the major culprits behind the renal damage induced by gentamicin, an aminoglycoside antibiotic used to treat serious and life threatening Gram-negative infections. Experimental evidence suggests a protective role of alpha-linolenic acid supplementation against oxidative stress. The aim of the present study was to investigate the possible beneficial role of alpha-linolenic acid against gentamicin induced renal distress.Methods: Male Wistar rats were divided into three groups of eight rats each, with the first group serving as a control. The other groups were treated intraperitoneally with gentamicin 100 mg/kg body weight per day for 10 days ± alpha-linolenic acid and vitamin E (each given as 250 mg/kg body weight per day. Concentrations of creatinine, urea, cholesterol, inorganic phosphate in serum, malondialdehyde and total sulfhydryl levels, and glutathione-S-transferase, superoxide dismutase, and catalase activity in kidney tissues were determined.Results: Administration of gentamicin to rats induced marked renal failure, characterized by a profound increase in serum creatinine, urea, and cholesterol concentrations, accompanied by significant lowering of renal alkaline phosphatase and acid phosphatase activity, an increase in malondialdehyde, a decline in total sulfhydryl levels, and lowered superoxide dismutase, catalase, and glutathione-S-transferase activity. Cotreatment with alpha-linolenic acid produced amelioration in these biochemical indices of nephrotoxicity in serum as well as in tissue. Further histopathological and human studies are necessary to demonstrate the beneficial effects of alpha-linolenic acid in renal disease.Conclusion: Alpha-linolenic acid may represent a nontoxic and effective intervention strategy in

  4. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

    Science.gov (United States)

    Phan, Carole; Seferian, Andrei; Huertas, Alice; Thuillet, Raphaël; Sattler, Caroline; Le Hiress, Morane; Tamura, Yuichi; Jutant, Etienne-Marie; Chaumais, Marie-Camille; Bouchet, Stéphane; Manéglier, Benjamin; Molimard, Mathieu; Rousselot, Philippe; Sitbon, Olivier; Simonneau, Gérald; Montani, David; Humbert, Marc

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development. PMID:27482885

  5. Protective effects of berberine against amyloid beta-induced toxicity in cultured rat cortical neurons

    Institute of Scientific and Technical Information of China (English)

    Jing Wang; Yanjun Zhang; Shuai Du; Mixia Zhang

    2011-01-01

    Berberine, a major constituent of Coptidis rhizoma, exhibits neural protective effects. The present study analyzed the potential protective effect of berberine against amyloid G-induced cytotoxicity in rat cerebral cortical neurons. Alzheimer's disease cell models were treated with 0.5 and 2 μmol/Lberberine for 36 hours to inhibit amyloid G-induced toxicity. Methyl thiazolyl tetrazolium assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining results showed that berberine significantly increased cell viability and reduced cell apoptosis in primary cultured rat cortical neurons. In addition, western blot analysis revealed a protective effect of berberine against amyloid β-induced toxicity in cultured cortical neurons, which coincided with significantly decreased abnormal up-regulation of activated caspase-3. These results showed that berberine exhibited a protective effect against amyloid 13-induced cytotoxicity in cultured rat cortical neurons.

  6. Aflatoxin B1 Induced Systemic Toxicity in Poultry and Rescue Effects of Selenium and Zinc.

    Science.gov (United States)

    Mughal, Muhammad Jameel; Peng, Xi; Kamboh, Asghar Ali; Zhou, Yi; Fang, Jing

    2017-08-01

    Among many challenges, exposure to aflatoxins, particularly aflatoxin B1 (AFB1), is one of the major concerns in poultry industry. AFB1 intoxication results in decreased meat/egg production, hepatotoxicity, nephrotoxicity, disturbance in gastrointestinal tract (GIT) and reproduction, immune suppression, and increased disease susceptibility. Selenium (Se) and zinc (Zn), in dietary supplementation, offer easy, cost-effective, and efficient ways to neutralize the toxic effect of AFB1. In the current review, we discussed the impact of AFB1 on poultry industry, its biotransformation, and organ-specific noxious effects, along with the action mechanism of AFB1-induced toxicity. Moreover, we explained the biological and detoxifying roles of Se and Zn in avian species as well as the protection mechanism of these two trace elements. Ultimately, we discussed the use of Se and Zn supplementation against AFB1-induced toxicity in poultry birds.

  7. AMELIORATIVE EFFECT OF PUNICA GRANATUM ETHANOLIC EXTRACT IN CYCLOPHOSPHAMIDE INDUCED TESTICULAR TOXICITY IN MALE WISTAR RATS

    Directory of Open Access Journals (Sweden)

    Divya Bhargavan

    2015-07-01

    Full Text Available Aim: To explore the potential role of Punica granatum ethanolic extract (PGEE in Cyclophosphamide (CP induced testicular toxicity. Methods: Healthy male Wistar rats were allotted to 4 groups (N=6, each Group I: Control, Group II: CP 15mg/kg twice a week, Group III: PGEE 100mg/kg, Group IV: CP and PGEE for 28 days. At the end of the treatment period, organ weight, body weight, epididymal sperm count, motility, morphology, SOD, catalase, GSH, ACP & testosterone level in the testis were evaluated. Results: The CP treated rats showed toxicity evidenced by decreased organ and body weight, decreased sperm quality and testosterone level also increase in MDA and decrease in antioxidants SOD, GSH indicating oxidative stress. In contrast PGEE co-treatment with CP resulted in significant restoration of the above mentioned parameters. Conclusion: These results indicate that PGEE attenuates CP induced testicular toxicity through its ROS scavenging activity.

  8. Doxorubicin-Induced Gut Toxicity in Piglets fed Bovine Milk and Colostrum

    DEFF Research Database (Denmark)

    Shen, René Liang; Rathe, Mathias; Jiang, Pingping

    2016-01-01

    OBJECTIVE: Chemotherapy-induced intestinal toxicity is a common adverse effect of cancer treatment. We hypothesized that a milk diet containing bovine colostrum (BC) would reduce intestinal toxicity in doxorubicin-treated piglets. METHODS: Study 1 investigated intestinal parameters nine days after...... a single dose of doxorubicin (1 × 75 mg/m) in piglets fed bovine milk enriched with whey protein (BM). In Study 2, responses to doxorubicin treatment were investigated in piglets receiving either seven BC feedings per day (Only-BC, n = 13), four BC feedings (High-BC, n = 13), two BC feedings (Low-BC, n...... = 14) or no BC (only BM, n = 13). RESULTS: Doxorubicin treatment induced clinical signs of intestinal toxicity with diarrhea and weight loss, relative to controls (P 

  9. Cephalosporin Induced Toxic Epidermal Necrolysis and Subsequent Penicillin Drug Exanthem

    Directory of Open Access Journals (Sweden)

    Amanda Lam

    2008-01-01

    Discussion: This case demonstrates the complexity of drug hypersensitivity reactions. While it is accepted that IgE mediated penicillin allergy is a predisposition to cephalosporin allergy, this case displays an unusual correlation between drug hypersensitivity and drug class. There have been few studies that evaluate the cross reactivity with penicillin or other beta-lactams in subjects with primary hypersensitivity to cephalosporins. This clinical scenario emphasizes the need of more studies on cephalosporin allergy in particular as shown by this case of sequential non-IgE mediated cephalosporin induced TEN reaction pursuant by an IgE mediated penicillin allergy.

  10. Attenuating effect of daidzein on polychlorinated biphenyls-induced oxidative toxicity in mouse testicular cells*

    OpenAIRE

    Zhang, Da-lei; Mi, Yu-ling; Wang, Kai-Ming; Zeng, Wei-dong; Zhang, Cai-qiao

    2008-01-01

    The attenuating effect of daidzein (DAI) on oxidative toxicity induced by Aroclor 1254 (A1254) was investigated in mouse testicular cells. Cells were exposed to A1254 alone or with DAI. The oxidative damage was estimated by measuring malondialdehyde (MDA) formation, superoxide dismutase (SOD) activity and glutathione (GSH) content. Results show that A1254 induced a decrease of germ cell number, an elevation in thiobarbituric acid reactive substances (TBARS) but a decrease in SOD activity and ...

  11. Amiodarone-induced pulmonary toxicity - Predisposing factors, clinical symptoms and treatment

    NARCIS (Netherlands)

    Jessurun, GAJ; Boersma, WG; Crijns, HJGM

    1998-01-01

    Amiodarone is frequently used for the treatment of cardiac arrhythmias. Although the therapeutic efficacy of amiodarone has been established, its use is limited by its safety profile. Amiodarone-induced pulmonary toxicity is one of the most life-threatening complications of this therapy. It is a rel

  12. Drug-induced liver toxicity and prevention by herbal antioxidants: an overview

    Directory of Open Access Journals (Sweden)

    Divya eSingh

    2016-01-01

    Full Text Available The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for medication instigated liver danger. Endorsed medications (counting acetaminophen represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group (ALFSG of the patients admitted in 17 US healing facilities. Albeit different studies are accessible uncovering the mechanistic aspects of medication prompted hepatotoxicity, we are in the dilemma about the virtual story. The expanding prevalence and effectiveness of Ayurveda and herbal products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several plant products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less side reactions of the herbs provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed on the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication.

  13. Amiodarone-Induced Pulmonary Toxicity – A Frequently Missed Complication

    Science.gov (United States)

    Sweidan, Alexander J.; Singh, Navneet K.; Dang, Natasha; Lam, Vinh; Datta, Jyoti

    2016-01-01

    INTRODUCTION Amiodarone is often used in the suppression of tachyarrhythmias. One of the more serious adverse effects includes amiodarone pulmonary toxicity (APT). Several pulmonary diseases can manifest including interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome, diffuse alveolar hemorrhage, pulmonary nodules or masses, and pleural effusion. Incidence of APT varies from 5–15% and is correlated to dosage, age of the patient, and preexisting lung disease. DESCRIPTION A 56-year-old male with a past medical history of coronary artery disease and chronic obstructive pulmonary disease was admitted for a coronary artery bypass graft. Post-operatively, the patient was admitted to the ICU for ventilator management and continued to receive his home dose of amiodarone 400 mg orally twice daily, which he had been taking for the past 3 months. The patient was found to be hypoxemic with a PaO2 52 mmHg and bilateral infiltrates on chest x-ray. Patient also complained of new onset dyspnea. Physical exam found bilateral rhonchi with bibasilar crackles and subcutaneous emphysema along the left anterior chest wall. Daily chest x-rays showed worsening of bilateral interstitial infiltrates and pleural effusions. A chest high-resolution computed tomography on post-operative day 3 showed extensive and severe bilateral ground glass opacities. APT was suspected and amiodarone was discontinued. A course of oral prednisone without antibiotics was initiated, and after one week of treatment the chest film cleared, the PaO2 value normalized and dyspnea resolved. DISCUSSION APT occurs via cytotoxic T cells and indirectly by immunological reaction. Typically the lungs manifest a diffuse interstitial pneumonitis with varying degrees of fibrosis. Infiltrates with a ‘ground-glass’ appearance appreciated on HRCT are more definitive than chest x-ray. Pulmonary nodules can be seen, frequently in the upper lobes. These are postulated to be accumulations of

  14. Relationship between coumarin-induced hepatocellular toxicity and mitochondrial function in rats.

    Science.gov (United States)

    Tanaka, Yasuhiro; Fujii, Wataru; Hori, Hisako; Kitagawa, Yoshinori; Ozaki, Kiyokazu

    2016-04-01

    The manifestation of coumarin-induced hepatocellular toxicity may differ and depends on the frequency of administration to rats. A single coumarin dose induces hepatocellular necrosis while repeated doses induce only hepatocyte degeneration. However, the mechanism underlying these effects remains unclear. Therefore, we investigated the mechanism of coumarin-induced hepatotoxicity in rats. Coumarin was administered to male rats as a single dose or for 4 consecutive days, and samples were obtained 4 or 24 h after a single dose or 24 h after the repeated doses. A single coumarin dose significantly induced hepatocellular necrosis in rats; however, toxicity was attenuated after repeated dosing. With a single dose, hepatocellular necrosis was preceded by increased mitochondrial number and size and decreased mitochondrial function. An increased expression of granular cytochrome P450 (CYP) 2E1 protein was observed in the cytoplasm and mitochondria of coumarin-treated rats compared to the expression in the untreated controls. Nevertheless, repeated dosing showed mitochondrial function that was equivalent to that of the control while enlarged CYP2E1 protein droplets were distributed outside the mitochondria. These results suggest that mitochondrial function and CYP2E1 expression might be involved in coumarin-induced hepatocellular toxicity in rats. A reduction in mitochondrial CYP2E1 might be implicated in the acquisition of coumarin resistance after repeated doses.

  15. Chemopreventive effect of natural dietary compounds on xenobiotic-induced toxicity

    Directory of Open Access Journals (Sweden)

    Jia-Ching Wu

    2017-01-01

    Full Text Available Contaminants (or pollutants that affect human health have become an important issue, spawning a myriad of studies on how to prevent harmful contaminant-induced effects. Recently, a variety of biological functions of natural dietary compounds derived from consumed foods and plants have been demonstrated in a number of studies. Natural dietary compounds exhibited several beneficial effects for the prevention of disease and the inhibition of chemically-induced carcinogenesis. Contaminant-induced toxicity and carcinogenesis are mostly attributed to the mutagenic activity of reactive metabolites and the disruption of normal biological functions. Therefore, the metabolic regulation of hazardous chemicals is key to reducing contaminant-induced adverse health effects. Moreover, promoting contaminant excretion from the body through Phase I and II metabolizing enzymes is also a useful strategy for reducing contaminant-induced toxicity. This review focuses on summarizing the natural dietary compounds derived from common dietary foods and plants and their possible mechanisms of action in the prevention/suppression of contaminant-induced toxicity.

  16. Neuroprotective effect of thalidomide on MPTP-induced toxicity.

    Science.gov (United States)

    Palencia, Guadalupe; Garcia, Esperanza; Osorio-Rico, Laura; Trejo-Solís, Cristina; Escamilla-Ramírez, Angel; Sotelo, Julio

    2015-03-01

    Thalidomide is a sedative with unique pharmacological properties; studies on epilepsy and brain ischemia have shown intense neuroprotective effects. We analyzed the effect of thalidomide treatment on the neurotoxicity caused by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahidropyridine (MPTP) in mice. Thalidomide was administered at two times; before and after the exposure to MPTP. In both circumstances thalidomide improved the neurotoxicity induced by MPTP as seen by a significant raise of the striatal contents of dopamine and simultaneous decrease of monoamine-oxidase-B (MAO-B). These results indicate that in the experimental model of Parkinson's disease the administration of thalidomide improves the functional damage on the nigrostriatal cell substratum as seen by the production of dopamine. This neuroprotective effect seems to be mediated by inhibition of excitotoxicity. Our results suggest that thalidomide could be investigated as potential adjuvant therapy for Parkinson's disease.

  17. Hypothesis for synergistic toxicity of organophosphorus poisoning-induced cholinergic crisis and anaphylactoid reactions

    Energy Technology Data Exchange (ETDEWEB)

    Cowan, F.M.; Shih, T.M.; Lenz, D.E.; Madsen, J.M.; Broomfield, C.A.

    1996-08-01

    The neurotoxicity of organophosphorus (OP) compounds Involves the Inhibition of acetylchollnesterase (AChE), causing accumulation of acetyicholine (ACh) at synapses. However, cholinergic crisis may not be the sole mechanism of OP toxicity. Adverse drug reactions caused by synergistic toxicity between drugs with distinct pharmacological mechanisms are a common problem. Likewise, the multiple pharmacological activities of a single molecule might also contribute to either toxicity or efficacy. For example, certain OP compounds (e.g. soman) exhibit anti-AChE activity and also act as secretagogues by inducing mast cell degranulation with associated autacoid release and anaphylactoid reactions. Anaphylactoid shock can produce a lethal syndrome with symptoms of respiratory failure and circulatory collapse similar to the physiological sequelae observed for OP poisoning. Moreover, the major classes of drugs used as antidotes for OP intoxication can affect anaphylaxis. Acetylcholine can act as an agonist of autacoid release, and autacoids such as histamine can augment soman-Induced bronchial spasm. In concert with the demonstrably critical role of cholinergic crisis In OP toxicity, the precepts of neuroimmunology indicate that secondary adverse reactions encompassing anaphylactold reactions may complicate OP toxicity.

  18. Acute toxicity and anticonvulsant activity of liposomes containing nimodipine on pilocarpine-induced seizures in mice.

    Science.gov (United States)

    Moreno, Lina Clara Gayoso e Almendra Ibiapina; Cavalcanti, Isabella Macário Ferro; Satyal, Prabodh; Santos-Magalhães, Nereide Stela; Rolim, Hercília Maria Lins; Freitas, Rivelilson Mendes

    2015-01-12

    Nimodipine has been shown to have an inhibitory action on seizures and brain damage in rodents. However, the pharmaceutical applicability of this drug is limited by its low solubility in gastrointestinal fluids and high first-pass effect in the liver, which leads to low bioavailability. These difficulties can be overcome through the use of liposomes. The aim of the present study is to evaluate the toxicity and anticonvulsant activity of liposomes containing nimodipine (NMD-Lipo) on pilocarpine-induced seizures. NMD-Lipo was prepared using the lipid-film hydration method. Central nervous system toxicity of NMD-Lipo was assessed by Hippocratic screening. Systemic toxicity was evaluated by analyses of biochemical and hematological parameters and by observing possible signs of toxicity. The possible anticonvulsant activity was tested by the pilocarpine model. The administration of the NMD-Lipo at doses of 0.1, 1, and 10 mg/kg caused no toxicity in animals. Furthermore, NMD-Lipo prevented the installation of 100% of the pilocarpine-induced seizures and prevented the death of 100% of the mice treated with pilocarpine. These data shown that NMD-Lipo has an anticonvulsant activity significantly superior to free NMD, suggesting that the liposomes promoted a drug controlled release by improving its bioavailability and consequently increasing its pharmacological activity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Arsenic toxicity induced endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible nitric oxide synthase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Sharma, Bhupesh, E-mail: drbhupeshresearch@gmail.com; Sharma, P.M.

    2013-11-15

    Arsenic toxicity has been reported to damage all the major organs including the brain and vasculature. Dementia including Alzheimer's disease (AD) and vascular dementia (VaD) are posing greater risk to the world population as it is now increasing at a faster rate. We have investigated the role of sodium butyrate, a selective histone deacetylase (HDAC) inhibitor and aminoguanidine, a selective inducible nitric oxide synthase (iNOS) inhibitor in pharmacological interdiction of arsenic toxicity induced vascular endothelial dysfunction and dementia in rats. Arsenic toxicity was done by administering arsenic drinking water to rats. Morris water-maze (MWM) test was used for assessment of learning and memory. Endothelial function was assessed using student physiograph. Oxidative stress (aortic superoxide anion, serum and brain thiobarbituric acid reactive species, brain glutathione) and nitric oxide levels (serum nitrite/nitrate) were also measured. Arsenic treated rats have shown impairment of endothelial function, learning and memory, reduction in serum nitrite/nitrate and brain GSH levels along with increase in serum and brain TBARS. Sodium butyrate as well as aminoguanidine significantly convalesce arsenic induced impairment of learning, memory, endothelial function, and alterations in various biochemical parameters. It may be concluded that arsenic induces endothelial dysfunction and dementia, whereas, sodium butyrate, a HDAC inhibitor as well as aminoguanidine, a selective iNOS inhibitor may be considered as potential agents for the management of arsenic induced endothelial dysfunction and dementia. - Highlights: • As has induced endothelial dysfunction (Edf) and vascular dementia (VaD). • As has increased oxidative stress, AChE activity and decreased serum NO. • Inhibitors of HDAC and iNOS have attenuated As induced Edf and VaD. • Both the inhibitors have attenuated As induced biochemical changes. • Inhibitor of HDAC and iNOS has shown good potential

  20. Tomato ( Lycopersicon esculentum prevents lead-induced testicular toxicity

    Directory of Open Access Journals (Sweden)

    Emmanuel O Salawu

    2009-01-01

    Full Text Available Background: Lead, an example of heavy metals, has, for decades, being known for its adverse effects on various body organs and systems such that their functions are compromised. Aim: In the present study, the ability of lead to adversely affect the male reproductive system was investigated and tomato ( Lycopersicon esculentum : Source of antioxidants paste (TP was administered orally to prevent the adverse effects of Pb. Materials and Methods: Fifteen Sprague Dawley rats, randomised into three groups (n = 5, were used for this study. Animals in Group A served as the control and were drinking distilled water. Animals in Groups B and C were drinking 1% Pb (II acetate (LA. Group C animals were, in addition to drinking LA, treated with 1.5 ml of TP/day. All treatments were for 8 weeks. Statistical Analysis Used: A Mann-Whitney U -test was used to analyse the results obtained. Results: The obtained results showed that Pb caused a significant reduction in the testicular weight, sperm count, life-death ratio, sperm motility, normal sperm morphology, and plasma and tissue superoxide dismutase and catalase activity, but a significant increase in plasma and tissue malondialdehyde concentration. But, Pb did not cause any significant change in the serum testosterone level. TP, however, significantly reduced these adverse effects of Pb. Conclusion: These findings lead to the conclusion that TP significantly lowered the adverse effects of Pb exposure on the kidney as well as Pb-induced oxidative stress.

  1. Scientific validation of polyherbal hepatoprotective formulation against paracetamol induced toxicity

    Institute of Scientific and Technical Information of China (English)

    Beerendra Kumar Saroj; Dayanandan Mani; Sunil Kumar Mishra

    2012-01-01

    Objective: This polyherbal formulation has been traditionally used in the Indian system of medicine as a chief formulation for the treatment of hepatic diseases as hepatoprotective. The aim of the study was to study hepatoprotective activity which will be scientific validation of traditional knowledge claimed about this polyherbal formulation. Methods: Hepatotoxicity was induced by administration of paracetamol (300mg/kg) to the animals. The levels of liver enzymes (SGOT, SGPT, Alkaline phosphatase, Serum Bilirubin), lipid profiles (triglyceride, cholesterol, HDL, LDL), creatinine, urea levels and histopathological parameters were measured in order to evaluate hepatoprotective activity of polyherbal formulation. Results: The polyherbal formulation produced a significant hepatoprotective activity of the decoction of polyherbal formulation. The polyherbal formulation (PHF = 1) shows good hepatoprotective activity by lowering the levels of SGOT, alkaline phosphatase, bilirubin parameters (P<0.05), lipid profiles - cholesterol, triglyceride, LDL and histopathological evaluations shows that PHF = 1 and PHF = 3 formulations have significantly hepatoprotective activity (P<0.05). Conclusions: The study validates that polyherbal formulation has a good hepatoprotective activity. Further standardization processes may be performed in order to make it a beneficial hepatoprotective formulation.

  2. Toxicity and EROD-inducing potency of 24 polycyclic aromatic hydrocarbons (PAHs) in chick embryos

    Energy Technology Data Exchange (ETDEWEB)

    Brunstroem, B. (Uppsala Univ. (Sweden). Dept. of Zoophysiology); Broman, D. (Stockholm Univ. (Sweden). Dept. of Zoology); Naef, C. (Stockholm Univ. (Sweden). Dept. of Analytical Chemistry)

    1991-08-01

    The toxicities (embryolethality) of 24 polycyclic aromatic hydrocarbons (PAHs) were determined in chick embryos using a 72-h test. The substances, dissolved in peanut oil, were injected into the air sacs of eggs preincubated for 7 days. LD{sub 50} values were determined for the four most toxic of the 24 compounds. Benzo(k)fluoranthene was the most potent, with an LD{sub 50} of 14 {mu}g (56 nmol)/kg egg. Dibenz(a,h)anthracene, benz(a)lanthracene and benzol(b)naphtho(2,3-d)thiophene were a few times less toxic (LD{sub 50} = 39 {mu}g (140 nmol)/kg, 79 {mu}g (349 nmol)/kg and 82 {mu}g (350 nmol)/kg, respectively). The LD{sub 50} of benzo(k)fluoranthene was only about 5 times higher than that previously found for the most potent coplanar polychlorinated biphenyl (PCB), 3,3',4,4',5-pentachlorobiphenyl (LD{sub 50} = 3.1 {mu}g (9.4 nmol)/kg), in the same kind of test. The toxicities of 18 of the PAHs in this study have also been evaluated previously using a 2-week test in chick embryos. Dibenz(a,h)anthracene, which had not been studied earlier in the 2-week test, proved to be almost as toxic as previously found for benzo(k)fluoranthene in that test. Several of the PAHs studied induced EROD activity in chick embryos, and, in general, the most toxic PAHs were also the most potent inducers of EROD. The highest enzyme activities were found after treatment with indeno(1,2,3-c,d)pyrene (12 times the control value) and dibenz(a,h)anthracene (8 times the control value). However, due to the high toxicity of dibenz(a,h)anthracene, the dose used was 7 times lower than that of indeno(1,2,3-c,d)pyrene. Following injection of PAHs on day 7, the EROD activities on day 10 were considerably lower than those obtained after a corresponding treatment with coplanar PCBs in an earlier study. Of the PAHs studied, some exhibited very high embryotoxicity. The most toxic PAHs induced EROD activity, suggesting that their toxicity was at least partly mediated via binding to the Ah receptor

  3. Myrica nagi attenuates cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in Swiss albino mice.

    Science.gov (United States)

    Alam, A; Iqbal, M; Saleem, M; Ahmed, S; Sultana, S

    2000-05-01

    In recent years, considerable efforts have been made to identify new chemopreventive agents which could be useful for man. Myrica nagi, a subtropical shrub, has been shown to possess significant activity against hepatotoxicity and other pharmacological and physiological disorders. We have shown a chemopreventive effect of Myrica nagi on cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in mice. Cumene hydroperoxide treatment at a dose level of 30 mg/animal/0.2 ml acetone enhances susceptibility of cutaneous microsomal membrane for iron-ascorbate-induced lipid peroxidation and induction of xanthine oxidase activity which are accompanied by decrease in the activities of cutaneous antioxidant enzymes such as catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and depletion in the level of cutaneous glutathione. Parallel to these changes a sharp decrease in the activities of phase II metabolizing enzymes such as glutathione S-transferase and quinone reductase has been observed. Application of Myrica nagi at doses of 2.0 mg and 4.0 mg/kg body weight in acetone prior to that of cumene hydroperoxide (30 mg/animal/0.2 ml acetone) treatment resulted in significant inhibition of cumene hydroperoxide-induced cutaneous oxidative stress and toxicity in a dose-dependent manner. Enhanced susceptibility of cutaneous microsomal membrane for lipid peroxidation induced by iron ascorbate and xanthine oxidase activities were significantly reduced (Pcumene hydroperoxide-induced cutaneous oxidative stress and toxicity.

  4. Protective Effect of Troxerutin on Nickel-Induced Testicular Toxicity in Wistar Rats.

    Science.gov (United States)

    Elangovan, Perumal; Jalaludeen, Abdulkadhar Mohamed; Ramakrishnan, Ramalingam; Pari, Leelavinothan

    2016-01-01

    Nickel (Ni)-induced oxidative damage is a serious problem that leads to reproductive system failure through testicular damage. The present investigation was carried out to determine the effect of troxerutin (Txn) on testicular toxicity induced by Ni in experimental rat testes. The oral administration of Txn (100 mg/kg body weight [bw]) showed a significant (p glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PD), reduced glutathione, ascorbate, total sulphydryl groups, and testis-organ weight. Subsequently, the administration of Txn also significantly reduced the accumulation of Ni, lipid peroxidation products, and protein carbonyl levels in Txn-treated animals. Testicular protection in the experimental animals by Txn is further substantiated by a remarkable reduction of Ni, which was revealed through testicular tissue histopathology. These studies suggest that Txn could prevent oxidative damage and testicular toxicity induced by Ni in experimental animals.

  5. Antioxidative effects of berberine pre-treatment on hydrogen peroxide-induced PC12 cell toxicity

    Institute of Scientific and Technical Information of China (English)

    Daohua Xu; Chenhui Zhou

    2010-01-01

    Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease.Oxidative damage could be prevented by augmenting the endogenous defense capacity against oxidative stress by antioxidant intake.As an effective alkaloid component of Chinese herbal medicine Rhizoma coptidis extract,berberine exhibits antioxidative properties and ameliorates memory impairment in a rat model of Alzheimer's disease.The present study investigated the protective effects of berberine on H2O2-induced PC12 cell toxicity.Results demonstrated that berbedne protects PC12 cells from H2O2-induced apoptosis and increases PC12 cell viability.Lactate dehydrogenase release,reactive oxygen content,and malonyl dialdehyde levels were significantly decreased(P < 0.01).The protective effects of berberine on H2O2-induced PC12 cell toxicity were achieved via the antioxidative effects of berberine.

  6. The role of apoptosis in MCLR-induced developmental toxicity in zebrafish embryos

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Cheng [College of Fisheries, Huazhong Agricultural University, Wuhan 430070 (China); Sun, Hong [Hubei Maternal and Child Health Hospital, Wuhan 430070 (China); Xie, Ping [Donghu Experimental Station of Lake Ecosystems, State Key Laboratory for Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, The Chinese Academy of Sciences, Wuhan 430072 (China); Wang, Jianghua; Zhang, Guirong; Chen, Nan [College of Fisheries, Huazhong Agricultural University, Wuhan 430070 (China); Yan, Wei, E-mail: Yanwei75126@163.com [Institute of Agricultural Quality Standards and Testing Technology, Hubei Academy of Agricultural Sciences, Wuhan 430064 (China); Li, Guangyu, E-mail: ligy2001@163.com [College of Fisheries, Huazhong Agricultural University, Wuhan 430070 (China); Freshwater Aquaculture Collaborative Innovation Center of Hubei Province, Wuhan 430070 (China)

    2014-04-01

    Highlights: • MCLR-induced apoptosis in the heart of developing embryos leads to the growth delay in zebrafish. • MCLR-triggered apoptosis might be induced by ROS. • P53–Bax–Bcl-2 and caspase-dependent apoptotic pathway contribute greatly to MCLR-induced apoptosis. Abstract: We previously demonstrated that cyanobacteria-derived microcystin–leucine–arginine (MCLR) is able to induce developing toxicity, such as malformation, growth delay and also decreased heart rates in zebrafish embryos. However, the molecular mechanisms by which MCLR induces its toxicity during the development of zebrafish remain largely unknown. Here, we evaluate the role of apoptosis in MCLR-induced developmental toxicity. Zebrafish embryos were exposed to various concentrations of MCLR (0, 0.2, 0.5, 2, and 5.0 mg L⁻¹ for 96 h, at which time reactive oxygen species (ROS) was significantly induced in the 2 and 5.0 mg L⁻¹ MCLR exposure groups. Acridine orange (AO) staining and terminal deoxynucleotide transferase-mediated deoxy-UTP nick end labelling (TUNEL) assay showed that MCLR exposure resulted in cell apoptosis. To test the apoptotic pathway, the expression pattern of several apoptotic-related genes was examined for the level of enzyme activity, gene and protein expression, respectively. The overall results demonstrate that MCLR induced ROS which consequently triggered apoptosis in the heart of developing zebrafish embryos. Our results also indicate that the p53–Bax–Bcl-2 pathway and the caspase-dependent apoptotic pathway play major roles in MCLR-induced apoptosis in the developing embryos.

  7. Glucuronidation of drugs and drug-induced toxicity in humanized UDP-glucuronosyltransferase 1 mice.

    Science.gov (United States)

    Kutsuno, Yuki; Itoh, Tomoo; Tukey, Robert H; Fujiwara, Ryoichi

    2014-07-01

    UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl-glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and drug-induced toxicity in humans.

  8. Hepatoprotective effect of leaves of Erythroxylum monogynum Roxb. on paracetamol induced toxicity

    Institute of Scientific and Technical Information of China (English)

    Sabeena Hussain Syed; Ajay Gajanan Namdeo

    2013-01-01

    Objective: To investigate the hepatoprotective activity of methanolic extract of leaves ofErythroxylum monogynum Methods: Methanolic extract of leaves of E. monogynum was given in doses of 100 mg/kg, 200 mg/kg and 400 mg/kg for 7 d and toxicity was induced by paracetamol (2 mg/kg) on Day 8. Silymarin (50 mg/kg) was used as reference standard. After 24 h of toxicity induction blood samples were collected from retro-orbital plexsus and analyzed for serum parameters like serum glutamic pyruvic transaminase, serum glutamic oxaloacetate transaminse, alkaline phosphatase and total bilirubin. Livers isolated were studied for histopathological changes. (E. monogynum) on paracetamol induced toxicity. Results: Phytochemical analysis of methanolic extract of E. monogynum leaves showed the presence of carbohydrates, flavonoids, phenols and saponins. Prior administration of this extract restored the elevated levels serum markers as compared to toxic group which is also confirmed by the histopathological changes observed.Conclusions:The present study showed that methanolic extract of leaves of E. monogynum possess hepatoprotective action against paracetamol induced hepatotoxicity.

  9. Propylthiouracyl-induced severe liver toxicity: An indication for alanine aminotransferase monitoring?

    Institute of Scientific and Technical Information of China (English)

    M Benyounes; C Sempoux; C Daumerie; J Rahier; AP Geubel

    2006-01-01

    Propylthiouracyl (PTU)-related liver toxicity is likely to occur in about 1% of treated patients. In case of acute or subacute hepatitis, liver failure may occur in about one third. We report two further cases of PTU-induced subacute hepatitis, in whom the delay between occurrence of liver damage after the initiation of treatment, the underestimation of its severity and the delayed withdrawal of the drug were all likely responsible for liver failure.The high incidence of liver toxicity related to PTU, its potential severity and delayed occurrence after initiation of treatment are in favor of monthly alanine aminotransferase monitoring, at least during the first six months of therapy.

  10. Ameliorative Effect of Ocimum Sanctum on Meloxicam Induced Toxicity in Wistar Rats

    OpenAIRE

    Mahaprabhu, R.; Bhandarkar, A. G.; Jangir, Babu Lal; Rahangadale, S. P.; Kurkure, N. V.

    2011-01-01

    An ameliorating effect of Ocimum sanctum on the toxic effect of meloxicam, a new non-steroidal anti-inflammatory drug was studied by evaluating haemato-biochemical parameters, oxidative stress, gross and histopathological changes in various organs of Wistar rats. A total of thirty-six male rats were divided in six experimental groups each comprising of six rats and numbered from G1 to G6. Meloxicam toxicity was induced by oral feeding of meloxicam at 1.2 mg/kg and 2.4 mg/kg body weight in G2 ...

  11. Beneficial effects of Bacopa monnieri extract on opioid induced toxicity.

    Science.gov (United States)

    Shahid, Muhammad; Subhan, Fazal; Ullah, Ihsan; Ali, Gowhar; Alam, Javaid; Shah, Rehmat

    2016-02-01

    The present study examined the hepatotoxicity and nephrotoxicity of morphine and illicit street heroin and their amelioration by a standardized methanolic extract of Bacopa monnieri (L.) (mBME) in rats. Morphine or street heroin was administered at a dose of 20 mg/kg for 14 and 21 days. mBME (40 mg/kg) or ascorbic acid (50 mg/kg) was administered two hours before morphine or street heroin. High performance liquid chromatography (HPLC) was used for the standardization of bacoside-A major components in mBME. The antioxidant potential of mBME was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. Administration of morphine and street heroin resulted in marked elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine. Histopathological changes induced by morphine and street heroin after 14 days were of reversible nature while treatment for 21 days was associated with irreversible changes. Pretreatment with mBME or ascorbic acid restored the elevation of serum ALT, AST and creatinine and protected liver and kidneys from the toxicological influence of morphine and street heroin. HPLC analysis showed that mBME contained bacoside-A major components i.e. bacoside-A3 (37.5 μg/mg), bacopaside-II (4.62 μg/mg) and bacopasaponin-C (1.91 μg/mg). The EC50 for the DPPH free radical scavenging assay revealed that mBME possessed strong antioxidant potential. These results concluded that as compared to morphine, street heroin was associated with severe biochemical and histopathological changes in the liver and kidneys. Bacopa monnieri having strong antioxidant potential may provide a beneficial herbal remedy for the efficient management of opioid related hepatotoxicity and nephrotoxicity.

  12. Beneficial effects of Bacopa monnieri extract on opioid induced toxicity

    Directory of Open Access Journals (Sweden)

    Muhammad Shahid

    2016-02-01

    Full Text Available The present study examined the hepatotoxicity and nephrotoxicity of morphine and illicit street heroin and their amelioration by a standardized methanolic extract of Bacopa monnieri (L. (mBME in rats. Morphine or street heroin was administered at a dose of 20 mg/kg for 14 and 21 days. mBME (40 mg/kg or ascorbic acid (50 mg/kg was administered two hours before morphine or street heroin. High performance liquid chromatography (HPLC was used for the standardization of bacoside-A major components in mBME. The antioxidant potential of mBME was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH free radical scavenging assay. Administration of morphine and street heroin resulted in marked elevation of serum alanine aminotransferase (ALT, aspartate aminotransferase (AST and creatinine. Histopathological changes induced by morphine and street heroin after 14 days were of reversible nature while treatment for 21 days was associated with irreversible changes. Pretreatment with mBME or ascorbic acid restored the elevation of serum ALT, AST and creatinine and protected liver and kidneys from the toxicological influence of morphine and street heroin. HPLC analysis showed that mBME contained bacoside-A major components i.e. bacoside-A3 (37.5 μg/mg, bacopaside-II (4.62 μg/mg and bacopasaponin-C (1.91 μg/mg. The EC50 for the DPPH free radical scavenging assay revealed that mBME possessed strong antioxidant potential. These results concluded that as compared to morphine, street heroin was associated with severe biochemical and histopathological changes in the liver and kidneys. Bacopa monnieri having strong antioxidant potential may provide a beneficial herbal remedy for the efficient management of opioid related hepatotoxicity and nephrotoxicity.

  13. The Preventive Effect of Vitamin C on Styrene-Induced Toxicity in Rat Liver and Kidney

    Directory of Open Access Journals (Sweden)

    Ahmadizadeh

    2015-04-01

    Full Text Available Background Styrene (ST is widely used as an organic solvent in many industrial settings. Increasing evidence indicated that ST induced toxicity in human and animals. Occupational exposure to ST can result in multiple-organ toxicity. Objectives The aim of the present study was to investigate the preventive effect of vitamin C (Vit C on ST- induced toxicity in rat liver and kidney. Materials and Methods Adult male rats were pretreated with 300 mg/kg Vit C intraperitoneally. Control rats received vehicle only (distilled water, D H2O. Thirty minutes later, animals were given different doses (0, 200, 400, or 600 mg/kg of ST. Twenty-four hours later, animals were killed and their blood samples were processed for determination of biochemical parameters. Liver damage was estimated by measuring serum aspartate aminotransferase (AST, alanine aminotransferase (ALT, and alkaline phosphatase (ALP activity. nephrotoxicity was evaluated by measuring blood urea nitrogen (BUN and creatinine (CR concentrations. Liver and kidney tissues were removed, fixed and processed for light microscopy. Results Styrene induced a dose-dependent elevation in the AST, ALT, ALP, BUN, and CR levels when compared to those of the control animals. The liver and kidney tissues were intact in control rats. Moreover, ST provoked a dose-dependent injury in the liver and kidney tissues. Vitamin C significantly decreased all biochemical parameters and protected liver and kidney cells against ST-induced toxicity. Conclusions The results of this study showed that Vit C has potential to protect rat liver and kidney tissues against styrene toxicity.

  14. Repeated dose oral toxicity of inorganic mercury in wistar rats: biochemical and morphological alterations

    Directory of Open Access Journals (Sweden)

    M. D. Jegoda

    2013-06-01

    Full Text Available Aim: The study was conducted to find out the possible toxic effect of mercuric chloride (HgCl2 at the histological, biochemical, and haematological levels in the wistar rats for 28 days. Materials and Methods: The biochemical and hematological alteration were estimated in four groups of rat (each group contain ten animals, which were treated with 0 (control, 2, 4, and 8 mg/kg body weight of HgCl2 through oral gavage. At the end of study all rats were sacrificed and subjected for histopathology. Result: A significantly (P < 0.05 higher level of serum alanine amino transferase (ALT, gamma Glutamyle Transferase, and creatinine were recorded in treatment groups, while the level of alkaline phosphtase (ALP was significantly decreased as compared to the control group. The toxic effect on hematoclogical parameter was characterized by significant decrease in hemoglobin, packed cell volume, total erythrocytes count, and total leukocyte count. Gross morphological changes include congestion, severe haemorrhage, necrosis, degenerative changes in kidneys, depletion of lymphocyte in spleen, decrease in concentration of mature spermatocyte, and edema in testis. It was notable that kidney was the most affected organ. Conclusion: Mercuric chloride (HgCl caused dose-dependent toxic effects on blood parameters and kidney. [Vet World 2013; 6(8.000: 563-567

  15. Diethylene glycol-induced toxicities show marked threshold dose response in rats

    Energy Technology Data Exchange (ETDEWEB)

    Landry, Greg M., E-mail: Landry.Greg@mayo.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Dunning, Cody L., E-mail: cdunni@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu [Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Latimer, Brian, E-mail: blatim@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Orchard, Elysse, E-mail: eorcha@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA (United States); McMartin, Kenneth E., E-mail: kmcmar@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States)

    2015-02-01

    Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

  16. Zinc asparaginate supplementation induces redistribution of toxic trace elements in rat tissues and organs

    Directory of Open Access Journals (Sweden)

    Skalny Andrey A.

    2015-09-01

    Full Text Available The primary objective of the current study was the investigation of the influence of zinc asparaginate supplementation for 7 and 14 days on toxic metal and metalloid content in rat organs and tissues. Rats obtained zinc asparaginate in doses of 5 and 15 mg/kg/day for 7 and 14 days. At the end of the experiment rat tissues and organs (liver, kidney, heart, m. gastrocnemius, serum, and hair were collected for subsequent analysis. Estimation of Zn, Al, As, Li, Ni, Sn, Sr content in the harvested organs was performed using inductively coupled plasma mass spectrometry at NexION 300D. The obtained data showed that intragastric administration of zinc significantly increased liver, kidney and serum zinc concentrations. Seven-day zinc treatment significantly affected the toxic trace element content in the animals’ organs. Zinc supplementation significantly decreased particularly liver aluminium, nickel, and tin content, whereas lead tended to increase. Zinc-induced changes in kidney metal content were characterized by elevated lithium and decreased nickel concentration. Zinc-induced alteration of myocardical toxic element content was multidirectional. Muscle aluminium and lead concentration were reduced in response to zinc supplementation. At the same time, serum and hair toxic element concentrations remained relatively stable after 7-day zinc treatment. Zinc asparaginate treatment of 14 days significantly depressed liver and elevated kidney lithium content, whereas a significant zinc-associated decrease was detected in kidney strontium content. Zinc supplementation for 14 days resulted also in multidirectional changes in the content of heart toxic elements. At the same time, significant zinc-associated decrease in muscle lithium and nickel levels was observed. Fourteen-day zinc treatment resulted in significantly increased serum arsenic and tin concentrations, whereas hair trace element content remained relatively stable. Generally, the obtained data

  17. Silver nanoparticles and silver nitrate induce high toxicity to Pseudokirchneriella subcapitata, Daphnia magna and Danio rerio

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Fabianne, E-mail: ribeiro.f@ua.pt [Department of Biology and CESAM, University of Aveiro. Campus Universitario de Santiago, 3810-193. Aveiro (Portugal); Gallego-Urrea, Julián Alberto [Department of Chemistry and Molecular Biologyx, University of Gothenburg, Kemivägen 4, 41296 Gothenburg (Sweden); Jurkschat, Kerstin; Crossley, Alison [Department of Materials, Oxford University Begbroke Science Park OX5 1PF (United Kingdom); Hassellöv, Martin [Department of Chemistry and Molecular Biologyx, University of Gothenburg, Kemivägen 4, 41296 Gothenburg (Sweden); Taylor, Cameron [Department of Materials, Oxford University Begbroke Science Park OX5 1PF (United Kingdom); Soares, Amadeu M.V.M.; Loureiro, Susana [Department of Biology and CESAM, University of Aveiro. Campus Universitario de Santiago, 3810-193. Aveiro (Portugal)

    2014-01-01

    Silver nanoparticles (AgNP) have gained attention over the years due to the antimicrobial function of silver, which has been exploited industrially to produce consumer goods that vary in type and application. Undoubtedly the increase of production and consumption of these silver-containing products will lead to the entry of silver compounds into the environment. In this study we have used Pseudokirchneriella subcapitata, Daphnia magna and Danio rerio as model organisms to investigate the toxicity of AgNP and AgNO{sub 3} by assessing different biological endpoints and exposure periods. Organisms were exposed following specific and standardized protocols for each species/endpoints, with modifications when necessary. AgNP were characterized in each test-media by Transmission Electron Microscopy (TEM) and experiments were performed by Dynamic Light Scattering (DLS) to investigate the aggregation and agglomeration behavior of AgNP under different media chemical composition and test-period. TEM images of AgNP in the different test-media showed dissimilar patterns of agglomeration, with some agglomerates inside an organic layer, some loosely associated particles and also the presence of some individual particles. The toxicity of both AgNO{sub 3} and AgNP differ significantly based on the test species: we found no differences in toxicity for algae, a small difference for zebrafish and a major difference in toxicity for Daphnia magna. - Highlights: •Effects of silver nanoparticles and nitrate were compared in three aquatic species. •The presence of food on the immobilization assay for Daphnia magna significantly decreased AgNP toxicity. •AgNP and AgNO{sub 3} differ in toxicity according to the test species and endpoint. •AgNP and AgNO{sub 3} induced dissimilar abnormalities on zebrafish embryos' development. •AgNP behavior in the test media will rule its bioavailability and uptake and therefore toxicity.

  18. Fipronil-induced enantioselective developmental toxicity to zebrafish embryo-larvae involves changes in DNA methylation.

    Science.gov (United States)

    Qian, Yi; Wang, Cui; Wang, Jinghua; Zhang, Xiaofeng; Zhou, Zhiqiang; Zhao, Meirong; Lu, Chensheng

    2017-05-23

    Enantioselectivity in the aquatic toxicity of chiral pesticides has been widely investigated, while the molecular mechanisms remain unclear. Thus far, few studies has focused on genomic expression related to selective toxicity in chiral pesticide, nor on epigenetic changes, such as DNA methylation. Here, we used fipronil, a broad-spectrum insecticide, as a model chemical to probe its enantioselective toxicity in embryo development. Our results showed that S-(+)-fipronil caused severer developmental toxicity in embryos. The MeDIP-Seq analysis demonstrated that S-(+)-fipronil dysregulated a higher level of genomic DNA methylation than R-(-)-fipronil. Gene Ontology analysis revealed that S-(+)-fipronil caused more differentially methylated genes that are involved in developmental processes. Compared with R-(-)-fipronil, S-(+)-fipronil significantly disrupted 7 signaling pathways (i.e., mitogen-activated protein kinases, tight junctions, focal adhesion, transforming growth factor-β, vascular smooth muscle contraction, and the hedgehog and Wnt signaling pathways) by hyper-methylation of developmentally related genes, which further induced the downregulation of those genes. Together, these data suggest that differences in DNA methylation may partly explain the enantioselectivity of fipronil to zebrafish embryos. The application of epigenetics to investigate the enantioselective toxicity mechanism of chiral chemicals would provide a further understanding of their stereoselectivity biological effects.

  19. Male mice deficient in microsomal epoxide hydrolase are not susceptible to benzene-induced toxicity.

    Science.gov (United States)

    Bauer, Alison K; Faiola, Brenda; Abernethy, Diane J; Marchan, Rosemarie; Pluta, Linda J; Wong, Victoria A; Gonzalez, Frank J; Butterworth, Byron E; Borghoff, Susan J; Everitt, Jeffrey I; Recio, Leslie

    2003-04-01

    Enzymes involved in benzene metabolism are likely genetic determinants of benzene-induced toxicity. Polymorphisms in human microsomal epoxide hydrolase (mEH) are associated with an increased risk of developing leukemia, specifically those associated with benzene. This study was designed to investigate the importance of mEH in benzene-induced toxicity. Male and female mEH-deficient (mEH-/-) mice and background mice (129/Sv) were exposed to inhaled benzene (0, 10, 50, or 100 ppm) 5 days/week, 6 h/day, for a two-week duration. Total white blood cell counts and bone marrow cell counts were used to assess hematotoxicity and myelotoxicity. Micronucleated peripheral blood cells were counted to assess genotoxicity, and the p21 mRNA level in bone marrow cells was used as a determinant of the p53-regulated DNA damage response. Male mEH-/- mice did not have any significant hematotoxicity or myelotoxicity at the highest benzene exposure compared to the male 129/Sv mice. Significant hematotoxicity or myelotoxicity did not occur in the female mEH-/- or 129/Sv mice. Male mEH-/- mice were also unresponsive to benzene-induced genotoxicity compared to a significant induction in the male 129/Sv mice. The female mEH-/- and 129/Sv mice were virtually unresponsive to benzene-induced genotoxicity. While p21 mRNA expression was highly induced in male 129/Sv mice after exposure to 100-ppm benzene, no significant alteration was observed in male mEH-/- mice. Likewise, p21 mRNA expression in female mEH-/- mice was not significantly induced upon benzene exposure whereas a significant induction was observed in female 129/Sv mice. Thus mEH appears to be critical in benzene-induced toxicity in male, but not female, mice.

  20. Evaluation the protective effect of diphenhydramine against acute toxicity induced by levamisole in male mice

    Directory of Open Access Journals (Sweden)

    M.Y. Matti

    2015-06-01

    Full Text Available The aim of this study was to evaluate the protective effect of different doses of diphenhydramine against acute toxicosis with Levamisole. The Mechanism of levamisole induced acute toxicity and that of protective effect of diphenhydramine against Levamisole toxicosis also examined on the level of cholinesterase (ChE activity. Subcutanous injection of 100mg/kg levamisole in male mice with induced cholinergic over stimulation and death in 100% of animals. The Toxicosis was not related to the significantly decreased in plasma, red blood cells and brain ChE activity. Injection low dose of diphenhydramin 2.5mg/kg S.C. 15 min before levamisole produced protective effect against acute toxicity with levamisole. Significantly decreased the severity of toxicosis and increased survival rates to 100%. Diphenhydramine at low dose alone or with acute dose of levamisole did not Produced Significantly inhibition in ChE activity.The data suggested that the toxic effect of Levamisole was not related to inhibition of ChE. The low dose of diphenhydramine protected mice from Levamisole toxicity. The antidoatal effect of diphenhydramine not at the level of protection from ChE inhibition. There was no adverse interaction between two drugs.

  1. Risks of herbalism: a case report of Mexican poppy (Argemone mexicana L induced liver toxicity

    Directory of Open Access Journals (Sweden)

    Carlos Alfredo Meléndez González

    2013-08-01

    Full Text Available The increasing consumption of alternative medicines has lead to a greater awareness about the deleterious effects and interactions that these products can induce. Consequently, medical literature reports liver toxicity from Aloe, Camellia sinensis (green tea, Rhammus purshianus, Aesculus hippocastanum (buckeye and Valeriana officinalis (valerian, among others. This article reports a female patient who twice consumed Mexican poppy (Argemone mexicana L with a one-year interval between ingestions. Both times she developed diarrhea, jaundice and general malaise with impaired liver function tests. Other causes of liver disease were ruled out. Questionnaires were used to assess the possibility of drug-induced liver damage. Clinical information was collected from the patient’s medical record and the literature on the subject was reviewed. We conclude that, at least in this case, the most likely cause of liver toxicity was Argemone mexicana L consumption.

  2. Protective effect of Hibiscus sabdariffa Linn. calyx extract on tetracycline induced testicular toxicity in mice

    Directory of Open Access Journals (Sweden)

    Nawaphat Taweebot

    2010-07-01

    Full Text Available Aqueous Hibiscus sabdariffa Linn. (Malvaceae calyx extract (HSE was evaluated for theprotective effect against testicular toxicity induced by tetracycline dose of 20 mg/100 gBW for 14 daysin mice. The extract doses of 20, 50 and 100 mg/100 gBW used in pretreatment by oral administrationfor 4 days and subsequent co-treatment with tetracycline for 14 days had the protective effectexhibiting significantly increasing quality of seminal fluid including an increase in total sperm count,percentage of mobile sperms and viable sperms when compared to the tetracycline treated group (p H. Sabdariffa. calyx extract may be used as protective agent againsttetracycline-induced reproductive toxicity in mice.

  3. Chlorfenapyr-Induced Toxic Leukoencephalopathy with Radiologic Reversibility: A Case Report and Literature Review.

    Science.gov (United States)

    Baek, Byung Hyun; Kim, Seul Kee; Yoon, Woong; Heo, Tae Wook; Lee, Yun Young; Kang, Heoung Keun

    2016-01-01

    Chlorfenapyr is a widely used, moderately hazardous pesticide. Previous reports have indicated that chlorfenapyr intoxication can be fatal in humans. We reported the first non-fatal case of chlorfenapyr-induced toxic leukoencephalopathy in a 44-year-old female with resolution of extensive and abnormal signal intensities in white matter tracts throughout the brain, brain stem, and spinal cord on serial magnetic resonance imaging.

  4. Chlorfenapyr-Induced Toxic Leukoencephalopathy with Radiologic Reversibility: A Case Report and Literature Review

    OpenAIRE

    Baek, Byung Hyun; Kim, Seul Kee; Yoon, Woong; Heo, Tae Wook; Lee, Yun Young; Kang, Heoung Keun

    2016-01-01

    Chlorfenapyr is a widely used, moderately hazardous pesticide. Previous reports have indicated that chlorfenapyr intoxication can be fatal in humans. We reported the first non-fatal case of chlorfenapyr-induced toxic leukoencephalopathy in a 44-year-old female with resolution of extensive and abnormal signal intensities in white matter tracts throughout the brain, brain stem, and spinal cord on serial magnetic resonance imaging.

  5. Chlorfenapyr-induced toxic leukoencephalopathy with radiologic reversibility: A case report and literature review

    Energy Technology Data Exchange (ETDEWEB)

    Baek, Byung Hyun; Kim, Seul Kee; Yoon, Woong; Heo, Tae Wook; Lee, Yun Young [Dept. of Radiology, Chonnam National University Hospital, Gwangju (Korea, Republic of); Kang, Heonung Keun [Dept. of Radiology, Chonnam National University Hwasun Hospital, Hwasun (Korea, Republic of)

    2016-04-15

    Chlorfenapyr is a widely used, moderately hazardous pesticide. Previous reports have indicated that chlorfenapyr intoxication can be fatal in humans. We reported the first non-fatal case of chlorfenapyr-induced toxic leukoencephalopathy in a 44-year-old female with resolution of extensive and abnormal signal intensities in white matter tracts throughout the brain, brain stem, and spinal cord on serial magnetic resonance imaging.

  6. Pleiotropic protective roles of melatonin against aluminium-induced toxicity in rats.

    Science.gov (United States)

    Allagui, Mohamed S; Hachani, Rafik; Saidi, Saber; Feriani, Anouer; Murat, Jean C; Kacem, Kamel; El feki, Abdelfatteh

    2015-10-01

    This study aimed to investigate the potential effects of melatonin on aluminium-induced toxicity in a rat model using a set of biochemical, inflammatory, oxidant, lipid profile criteria and hepatic integrity (verified by hematoxylin-eosin staining). The results indicated that AlCl3 administration during 60 days (100 mg/kg b.w.) significantly increased the activities of transaminases AST and ALT by 46% (p aluminium-intoxication.

  7. Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats

    Directory of Open Access Journals (Sweden)

    Azza A El-Sheikh

    2016-01-01

    Full Text Available Background: Intestinal toxicity is a serious side effect in methotrexate (MTX chemotherapy. Objective: To investigate the mechanisms by which the anticancer drug MTX-induced intestinal damage could be prevented by thymoquinone (TQ, an active ingredient of Nigella sativa. Materials and Methods: TQ was given orally for 10 days, and MTX toxicity was induced at the end of day 3 of the experiment, with or without TQ pretreatment. Results: MTX caused intestinal damage, represented by distortion in normal intestinal histological structure, with significant oxidative stress, exhibited as decrease in reduced glutathione concentration and catalase activity, along with significant increase in malondialdehyde level compared to control group. MTX also caused nitrosative stress evident by increased intestinal nitric oxide (NO level, with up-regulation of inducible NO synthase expression shown in immunohistochemical staining. Furthermore, MTX caused inflammatory effects as evident by up-regulation of intestinal necrosis factor-kappa beta and cyclooxygenase-2 expressions, which were confirmed by increased intestinal tumor necrosis factor-alpha level via enzyme-linked immunosorbent assay. Moreover, MTX caused apoptotic effect, as it up-regulated intestinal caspase 3 expression. Concomitant TQ significantly reversed the MTX-induced intestinal toxic effects by reversing intestinal microscopic damage, as well as significantly improving oxidative/nitrosative stress, inflammatory and apoptotic markers tested compared to MTX alone. Conclusion: TQ may possess beneficial intestinal protective effects as an adjuvant co-drug against MTX intestinal toxicity during cancer chemotherapy. TQ protection is conferred via antioxidant, anti-nitrosative, anti-inflammatory, and anti-apoptotic mechanisms.

  8. Critical Duration of Exposure for Developmental Chlorpyrifos-Induced Neurobehavioral Toxicity

    OpenAIRE

    Sledge, Damiyon; Yen, Jerry; Morton, Terrell; Dishaw, Laura; Petro, Ann; Donerly, Susan; Linney, Elwood; Levin, Edward D.

    2011-01-01

    Developmental exposure of rats to the pesticide chlorpyrifos (CPF) causes persistent neurobehavioral impairment. In a parallel series of studies with zebrafish, we have also found persisting behavioral dysfunction after developmental CPF exposure. We have developed a battery of measures of zebrafish behavior, which are reliable and sensitive to toxicant-induced damage. This study determined the critical duration of developmental CPF exposure for causing persisting neurobehavioral effects. Tes...

  9. Hepatoprotective activity of Tephrosia purpurea against arsenic induced toxicity in rats

    OpenAIRE

    Ravuri Halley Gora; Sushma Lalita Baxla; Priscilla Kerketta; Subhasree Patnaik; Birendra Kumar Roy

    2014-01-01

    Aim: The present study was conducted to evaluate the hepatoprotective activity of Tephrosia purpurea (TP) against sodium arsenite (NaAsO2) induced sub-acute toxicity in rats. Materials and Methods: Twenty four wistar albino rats of either sex were randomly divided into three groups. Group II and III were orally administered with sodium arsenite (10 mg/kg) daily in drinking water for 28 days. Additionally Group III was orally treated with hydro-alcoholic extract of Tephrosia purpurea (TP) ...

  10. Drug-induced linear IgA bullous dermatosis simulating toxic epidermal necrolysis.

    Science.gov (United States)

    Nasr, Joanna; Ammoury, Alfred; Chouairy, Camil; Mégarbané, Halal; El Habr, Constantin

    2014-01-01

    Linear IgA bullous dermatosis (LAD) is an autoimmune subepidermal blistering disorder. LAD may be either idiopathic or drug related; the most common drug being vancomycin. The clinical presentations of both idiopathic and drug-related LAD are variable and may mimic other blistering disorders. We report a case of a 76-year-old man known to have a renal cell carcinoma who presented a vancomycin-induced LAD that clinically mimicked toxic epidermal necrolysis (TEN).

  11. Protective effect of pomegranate flower extract against gentamicin-induced renal toxicity in male rats

    OpenAIRE

    Sadeghi, Ferdos; Nematbakhsh, Mehdi; Noori-Diziche, Ali; Eshraghi-Jazi, Fatemeh; Talebi, Ardeshir; Nasri, Hamid; Mansouri, Azam; Dehghani, Aghdas; Saberi, Shadan; Shirdavani, Soheila; Ashrafi, Farzaneh

    2015-01-01

    Introduction: Gentamicin (GM) as an antibiotic is used in clinic. However, its administration is limited by side effects such as nephrotoxicity. Herbal extracts could be used in therapeutic approaches. Objectives: The present study was planned to investigate whether pomegranate flower extract (PFE) could ameliorate GM-induced renal toxicity in male rats. Materials and Methods: Twenty eight male Wistar rats were divided into 5 groups. Groups 1 and 2 respectively received PFE 25 and 50 mg/kg fo...

  12. ERK1/2 activation modulates pyocyanin-induced toxicity in A549 respiratory epithelial cells.

    Science.gov (United States)

    Forbes, Amanda; Davey, Andrew K; Perkins, Anthony V; Grant, Gary D; McFarland, Amelia J; McDermott, Catherine M; Anoopkumar-Dukie, Shailendra

    2014-02-01

    Pyocyanin (PCN), a virulence factor produced by Pseudomonas aeruginosa, has many damaging effects on mammalian cells. Several lines of evidence suggest that this damage is primarily mediated by its ability to generate oxidative stress. However mechanisms underlying PCN-induced oxidative injury remain unclear. Although oxidative stress and subsequent MAPK signaling has been shown to modulate cell death in other models, its role in PCN-induced cytotoxicity remains unknown. Therefore the aim of this study was to investigate the role of redox-sensitive MAPK in PCN-induced toxicity in A549 cells. Here we show that PCN (50μM) rapidly increased ERK1/2 phosphorylation after 5min. Pre-treatment of A549 cells with the MEK1/2 inhibitor U0126 (10μM) decreased PCN-induced ERK1/2 phosphorylation and protected cells against apoptosis and cell injury suggesting a role for ERK signalling. In contrast, JNK and p38 MAPK phosphorylation remained unchanged following exposure to PCN and pretreatment with either the JNK or p38 MAPK inhibitors (10μM SP600125 and 10μM SB203580, respectively) did not afford protection against PCN toxicity. This would suggest that PCN-induced cytotoxicity appears to occur independently of JNK and p38 MAPK signaling pathways. Finally, although we confirm that oxidative stress contributes to PCN-induced toxicity, our data suggest the contribution of oxidative stress is independent of ERK1/2 signaling. These findings may provide insight for novel targeted therapies to reduce PCN-mediated lung injury in patients with chronic P. aeruginosa respiratory infections.

  13. The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease

    Energy Technology Data Exchange (ETDEWEB)

    Spincemaille, Pieter [Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee (Belgium); Pham, Duc-Hung [Laboratory for Molecular Biodiscovery, KU Leuven, Campus Gasthuisberg, Herestraat 49, O and N2, 3000 Leuven (Belgium); Chandhok, Gursimran [Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster (Germany); Verbeek, Jef [Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven (Belgium); Zibert, Andree [Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster (Germany); Libbrecht, Louis [Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven (Belgium); Department of Pathology, University Hospital Ghent, De Pintelaan 185, 9000 Ghent (Belgium); Schmidt, Hartmut [Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster (Germany); Esguerra, Camila V.; Witte, Peter A.M. de [Laboratory for Molecular Biodiscovery, KU Leuven, Campus Gasthuisberg, Herestraat 49, O and N2, 3000 Leuven (Belgium); Cammue, Bruno P.A., E-mail: bruno.cammue@biw.kuleuven.be [Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee (Belgium); Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent (Belgium); Cassiman, David [Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven (Belgium); Thevissen, Karin [Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee (Belgium)

    2014-10-15

    Background: Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD. Methods: The effect of OSIP108 was evaluated on viability of various cell lines in the presence of excess Cu, on liver morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae. Results: OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B{sup H1069Q}, but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology and decreased Cu-induced production of reactive oxygen species. Conclusions: OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. General significance: All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment. - Highlights: • Wilson disease (WD) is characterized by accumulation of toxic copper (Cu). • OSIP108 increases viability of Cu-treated cellular models applicable to WD. • OSIP108 injections preserve liver morphology of Cu-treated zebrafish larvae. • OSIP108 injections into zebrafish larvae abrogates Cu-induced oxidative stress.

  14. Melamine-induced renal toxicity is mediated by the gut microbiota.

    Science.gov (United States)

    Zheng, Xiaojiao; Zhao, Aihua; Xie, Guoxiang; Chi, Yi; Zhao, Linjing; Li, Houkai; Wang, Congrong; Bao, Yuqian; Jia, Weiping; Luther, Mike; Su, Mingming; Nicholson, Jeremy K; Jia, Wei

    2013-02-13

    Melamine poisoning has become widely publicized after a recent occurrence of renal injury in infants and children exposed to melamine-tainted milk in China. This renal damage is believed to result from kidney stones formed from melamine and uric acid or from melamine and its cocrystallizing chemical derivative, cyanuric acid. However, the composition of the stones and the mechanism by which the stones are formed in the renal tubules are unknown. We report that cyanuric acid can be produced in the gut by microbial transformation of melamine and serves as an integral component of the kidney stones responsible for melamine-induced renal toxicity in rats. Melamine-induced toxicity in rats was attenuated and melamine excretion increased after antibiotic suppression of gut microbial activity [corrected]. We further demonstrated that melamine is converted to cyanuric acid in vitro by bacteria cultured from normal rat feces; Klebsiella was subsequently identified in fecal samples by 16S ribosomal DNA sequencing. In culture, Klebsiella terrigena was shown to convert melamine to cyanuric acid directly. Rats colonized by K. terrigena showed exacerbated melamine-induced nephrotoxicity. Cyanuric acid was detected in the kidneys of rats administered melamine alone, and the concentration after Klebsiella colonization was increased. These findings suggest that the observed toxicity of melamine may be conditional on the exact composition and metabolic activities of the gut microbiota.

  15. Phytopreventative effects of Gynostemma pentaphyllum against acute Indomethacin-induced gastrointestinal and renal toxicity in rats.

    Science.gov (United States)

    Hesse, Cristina; Razmovski-Naumovski, Valentina; Duke, Colin C; Davies, Neal M; Roufogalis, Basil D

    2007-06-01

    In the present study, the phytoprotective effects of gypenosides from Gynostemma pentaphyllum throughout the gastrointestinal tract and kidney were examined in indomethacin-treated rats. Indomethacin induced gastric and intestinal damage as well as renal toxicity after a single toxicological dose (10 mg/kg) in rats. Acute oral administration of the gypenoside extract (200 mg/kg) significantly reduced gastric and intestinal toxicity induced by indomethacin as measured by ulceration, caecal haemoglobin and plasma haptoglobin. A significant decrease in small intestinal lactose fermenting enterobacteria was evident in animals treated with indomethacin and those pre-treated with G. pentaphyllum then indomethacin. In the renal system, kidney toxicity was evident after indomethacin and in animals pre-treated with indomethacin plus G. pentaphyllum with an increase in urinary N-acetyl-beta-glucosaminidase and a decrease in urinary sodium and chloride electrolyte output. However, a significant increase in urinary microprotein in indomethacin-treated animals was not present in indomethacin plus G. pentaphyllum-treated animals. These studies demonstrate the efficacy of Gynostemma pentaphyllum in lowering gastrointestinal damage induced by indomethacin. The results suggest further investigations of Gynostemma gypenosides are warranted to examine the mechanisms of this phytoprotective activity. (c) 2007 John Wiley & Sons, Ltd.

  16. Chronic fluoride exposure-induced testicular toxicity is associated with inflammatory response in mice.

    Science.gov (United States)

    Wei, Ruifen; Luo, Guangying; Sun, Zilong; Wang, Shaolin; Wang, Jundong

    2016-06-01

    Previous studies have indicated that fluoride (F) can affect testicular toxicity in humans and rodents. However, the mechanism underlying F-induced testicular toxicity is not well understood. This study was conducted to evaluate the sperm quality, testicular histomorphology and inflammatory response in mice followed F exposure. Healthy male mice were randomly divided into four groups with sodium fluoride (NaF) at 0, 25, 50, 100 mg/L in the drinking water for 180 days. At the end of the exposure, significantly increased percentage of spermatozoa abnormality was found in mice exposed to 50 and 100 mg/L NaF. Disorganized spermatogenic cells, vacuoles in seminiferous tubules and loss and shedding of sperm cells were also observed in the NaF treated group. In addition, chronic F exposure increased testicular interleukin-17(IL-17), interleukin-17 receptor C (IL-17RC), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in transcriptional levels, as well as IL-17 and TNF-α levels in translational levels. Interestingly, we observed that F treated group elevated testicular inducible nitric oxide synthase (iNOS) mRNA level and nitric oxide (NO) concentration. Taken together, these results indicated that testicular inflammatory response could contribute to chronic F exposure induced testicular toxicity in mice.

  17. Inhibition of histone deacetylases prevents cytokine-induced toxicity in beta cells

    DEFF Research Database (Denmark)

    Larsen, L; Tonnesen, M; Ronn, S G

    2007-01-01

    AIMS/HYPOTHESIS: The immune-mediated elimination of pancreatic beta cells in type 1 diabetes involves release of cytotoxic cytokines such as IL-1beta and IFNgamma, which induce beta cell death in vitro by mechanisms that are both dependent and independent of nitric oxide (NO). Nuclear factor kappa...... deacetylases (HDAC), and positive effects of HDAC inhibition have been obtained in several inflammatory diseases. Thus, the aim of this study was to investigate whether HDAC inhibition protects beta cells against cytokine-induced toxicity. MATERIALS AND METHODS: The beta cell line, INS-1, or intact rat islets...

  18. Protective effects of Moringa oleifera Lam. leaves against arsenic-induced toxicity in mice

    Science.gov (United States)

    Sheikh, Afzal; Yeasmin, Fouzia; Agarwal, Smita; Rahman, Mashiur; Islam, Khairul; Hossain, Ekhtear; Hossain, Shakhawoat; Karim, Md Rezaul; Nikkon, Farjana; Saud, Zahangir Alam; Hossain, Khaled

    2014-01-01

    Objective To evaluate the protective role of leaves of Moringa oleifera (M. oleifera) Lam. against arsenic-induced toxicity in mice. Methods Swiss albino male mice were divided into four groups. The first group was used as non-treated control group while, the second, third, and fourth groups were treated with M. oleifera leaves (50 mg/kg body weight per day), sodium arsenite (10 mg/kg body weight per day) and sodium arsenite plus M. oleifera leaves, respectively. Serum indices related to cardiac, liver and renal functions were analyzed to evaluate the protective effect of Moringa leaves on arsenic-induced effects in mice. Results It revealed that food supplementation of M. oleifera leaves abrogated the arsenic-induced elevation of triglyceride, glucose, urea and the activities of alkaline phospatase, aspartate aminotransferase and alanine aminotransferase in serum. M. oleifera leaves also prevented the arsenic-induced perturbation of serum butyryl cholinesterase activity, total cholesterol and high density lipoprotein cholesterol. Conclusions The results indicate that the leaves of M. oleifera may be useful in reducing the effects of arsenic-induced toxicity. PMID:25183111

  19. Protective effects of Moringa oleifera Lam. leaves against arsenic-induced toxicity in mice

    Institute of Scientific and Technical Information of China (English)

    Afzal Sheikh; Zahangir Alam Saud; Khaled Hossain; Fouzia Yeasmin; Smita Agarwal; Mashiur Rahman; Khairul Islam; Ekhtear Hossain; Shakhawoat Hossain; Md Rezaul Karim; Farjana Nikkon

    2014-01-01

    Objective: To evaluate the protective role of leaves of Moringa oleifera (M. oleifera) Lam. against arsenic-induced toxicity in mice.Methods:non-treated control group while, the second, third, and fourth groups were treated with M.oleifera leaves (50 mg/kg body weight per day), sodium arsenite (10 mg/kg body weight per day) and sodium arsenite plus M. oleifera leaves, respectively. Serum indices related to cardiac, liver and renal functions were analyzed to evaluate the protective effect of Moringa leaves on arsenic-induced effects in mice.Results:Swiss albino male mice were divided into four groups. The first group was used as induced elevation of triglyceride, glucose, urea and the activities of alkaline phospatase, aspartate aminotransferase and alanine aminotransferase in serum. M. oleifera leaves also prevented the arsenic-induced perturbation of serum butyryl cholinesterase activity, total cholesterol and high density lipoprotein cholesterol.Conclusions:The results indicate that the leaves of M. oleifera may be useful in reducing the It revealed that food supplementation of M. oleifera leaves abrogated the arsenic-effects of arsenic-induced toxicity.

  20. S-Allyl-Cysteines Reduce Amelioration of Aluminum Induced Toxicity in Rats

    Directory of Open Access Journals (Sweden)

    Sadhana Shrivastava

    2011-01-01

    Full Text Available Problem statement: Aluminum (Al is a trivalent cation found in its ionic form in most kinds of animal tissues and in natural waters everywhere. Approach: It is a potent neurotoxin and has been associated in the pathogenesis of several clinical disorders including Alzheimer’s disease. Results: The aim of the study was to demonstrate the protective effect of S-Allyl-Cysteines (SAC against Al-induced toxicity in rat model on certain biochemical parameters, lipid peroxidation and oxidative stress enzymes of white albino rats. Six rats per group were divided into various treatment groups. Group one rats were given normal saline and served as control group. Group two animals received Al as aluminum nitrate 32.5 mg (i.p. for the induction of toxicity. Group three to five received different doses of SAC (25, 50 and 100 mg kg-1 for 3 days after 24 h of Al toxicity. Rats were orally administered their respective doses every day for 3 days. Evaluations were made in blood and tissues. The activity of Acetylcholinesterase (AchE was inhibited in all the parts of brain after Al intoxication. Significant rise were observed the Activities of Serum Transaminases (AST and ALT after toxicant exposure. The activity of â-Aminolevulinic acid Dehydratase (ALAD in blood and â-Aminolevulinic Acid Synthetase (ALAS in brain was decreased after Al exposure. Al significant increased cholesterol, triglyceride, creatinine and urea level in serum. TBARS level was significantly higher and GSH content were significantly lower during toxicity. Total and esterified cholesterol in liver, kidney and brain were increased after Al exposure. Histopathological changes in liver, kidney and brain were also recouped with the therapy. Conclusion/Recommendations: Our data proved that SAC which is a bioactive and bioavailable component of garlic has organosulfur compounds which regulates the thiol status of the cell and scavenges free radicals and work as an antioxidant. Thus SAC

  1. MDR1 overexpression inhibits chemotherapy-induced toxicity of granulosa cells

    Science.gov (United States)

    Salih, Sana M

    2011-01-01

    OBJECTIVE To protect granulosa cells from chemotherapy-induced toxicity by retrovirus-mediated multidrug resistance gene (MDR1) transfection. DESIGN Laboratory study. SETTING Academic research laboratory in a university hospital. INTERVENTION(S) KK15 immortalized murine granulosa cell line was transiently transduced with sf91m3 retrovirus vector carrying MDR1 cDNA that encodes P-glycoprtoein (P-gp). Transduced cells were selected with colchicine and treated with doxorubicin or paclitaxel for 24–72 hours. The expression and function of MDR1 and the mRNA expression of selected steroidogenesis enzymes were evaluated by flow cytometry, cell viability assays, Western blot, and RT-PCR. MAIN OUTCOME MEASURE(S) Viability of sf91m3-transduced KK15 cells after treatment with doxorubicin and paclitaxel. RESULT(S) sf91m3-transduced KK15 demonstrated high expression of biologically active MDR1 as shown by flow cytometry analysis and immunoblotting using P-gp monoclonal antibody and Rhodamine 123 efflux assays. sf91m3-transduced KK15 exhibited significant resistance to toxicity of 10uM paclitaxel(p≤0.001). MDR1-transduced KK15 cells were also protected from doxorubicin toxicity (10nM to 2.5uM) as shown by cell viability assay (p≤0.02). Both flow cytometry and cell viability assay showed that the protection of KK15 from doxorubicin toxicity was lost at 5 uM of doxorubicin; equivalent to 500 times LD50 (p≥0.05). sf91m3-transduced KK15 showed normal mRNA expression of a panel of selected steroidogenesis enzymes. CONCLUSION(S) Retroviral gene delivery of human MDR1 inhibited chemotherapy- induced granulosa cell toxicity and offered chemoprotection in an in vitro model. PMID:21316663

  2. Protective effect of riboflavin on cisplatin induced toxicities: a gender-dependent study.

    Science.gov (United States)

    Naseem, Imrana; Hassan, Iftekhar; Alhazza, Ibrahim M; Chibber, Sandesh

    2015-01-01

    The toxicity exerted by the anticancer drug, cisplatin in vivo is functional to many factors such as dose, duration, gender and age etc. The present study is aimed to investigate if ameliorative potential of riboflavin on cisplatin induced toxicity is gender dependent. Eighty four adult mice from male and female sex were divided into seven groups (n=6) for both sexes. They were treated with riboflavin (2mg/kg), cisplatin (2mg/kg) and their two different combinations (cisplatin at 2mg/kg with 1mg/kg and 2mg/kg of riboflavin) under photoillumination with their respective controls for the combination groups without photoillumination. After treatment, all groups were sacrificed and their kidney, liver and serum were collected for biochemical estimations, comet assay and histopathology. In the present investigation, it was evident from antioxidant and detoxification studies (SOD, CAT, GSH, GST, MDA and carbonyl level) that the female mice exhibited better tolerance towards cisplatin inducted toxicity and the ameliorative effect of riboflavin against cisplatin toxicity was found stronger in their combination groups as compared to the male groups as the activity of all antioxidant enzymes were found better concomitant with lower level of MDA and carbonyl contents in the female combination groups than their male counterparts. Furthermore, single cell gel electrophoresis and histopathological examination confirmed that restoration of normal nuclear and cellular integrity was more prominent in female with respect to the males after treatment in the combination groups in a dose-dependent manner. Hence, this study reveals that cisplatin is more toxic in male mice and the ameliorative effect of riboflavin against cisplatin toxicity is stronger in female mice.

  3. Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Jain, Anil K.; Tewari-Singh, Neera; Inturi, Swetha; Kumar, Dileep [Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); Orlicky, David J. [Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); Agarwal, Chapla [Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States); White, Carl W. [Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045USA (United States); Agarwal, Rajesh, E-mail: Rajesh.Agarwal@UCDenver.edu [Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045 (United States)

    2015-05-15

    Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2 mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants. - Highlights: • Silibinin treatment attenuated nitrogen mustard (NM)-induced skin injury. • Silibinin affects pathways associated with DNA damage, inflammation and vesication. • The efficacy of silibinin could also be associated with oxidative stress. • These results support testing and optimization of

  4. Renal Toxicity of Mercuric Chloride at Different Time Intervals in Rats

    Directory of Open Access Journals (Sweden)

    W.A. Al-Madani

    2009-01-01

    Full Text Available This study was undertaken to study the renal toxicity of mercuric chloride in rats at different periods of time. The following groups of rats were studied: i control, ii placebo, iii rats injected with a single ip dose of 100 mg/kg body weight of 2, 3 dimercapto- 1-propanesulfonic acid, iv rats injected with a single ip dose of 100 mg/kg body weight of 2, 3 dimercapto-1-propanesulfonic acid (DMPS followed by a single dose ip of 2.0 mg HgCl2/kg body weight one hour after DMPS injection v rats injected with a single ip dose of 2.0 mg HgCl2/kg body weight. Results indicate that mercuric chloride was more toxic after 48 hours of its administration when compared to 24 hours. Mercuric chloride administration caused an impairment of renal function which was evident from a significant decrease in urine volume, urinary excretion of urea, creatinine and glomerular filteration rate (P < 0.001 when compared to other treated groups. There was an increased excretion of protein, albumin and γ—glutamyltransferase in the urine of mercuric chloride treated rats. Administration of 2, 3 dimercapto-1-propanesulfonic acid before mercuric chloride treatment caused the altered indices to return to near normal levels.

  5. Ketamine induces toxicity in human neurons differentiated from embryonic stem cells via mitochondrial apoptosis pathway

    Science.gov (United States)

    Bosnjak, Zeljko J.; Yan, Yasheng; Canfield, Scott; Muravyeva, Maria Y.; Kikuchi, Chika; Wells, Clive; Corbett, John; Bai, Xiaowen

    2013-01-01

    Ketamine is widely used for anesthesia in pediatric patients. Growing evidence indicates that ketamine causes neurotoxicity in a variety of developing animal models. Our understanding of anesthesia neurotoxicity in humans is currently limited by difficulties in obtaining neurons and performing developmental toxicity studies in fetal and pediatric populations. It may be possible to overcome these challenges by obtaining neurons from human embryonic stem cells (hESCs) in vitro. hESCs are able to replicate indefinitely and differentiate into every cell type. In this study, we investigated the toxic effect of ketamine on neurons differentiated from hESCs. Two-week-old neurons were treated with different doses and durations of ketamine with or without the reactive oxygen species (ROS) scavenger, Trolox. Cell viability, ultrastructure, mitochondrial membrane potential (ΔΨm), cytochrome c distribution within cells, apoptosis, and ROS production were evaluated. Here we show that ketamine induced ultrastructural abnormalities and dose- and time-dependently caused cell death. In addition, ketamine decreased ΔΨm and increased cytochrome c release from mitochondria. Ketamine also increased ROS production and induced differential expression of oxidative stress-related genes. Specifically, abnormal ultrastructural and ΔΨm changes occurred earlier than cell death in the ketamine-induced toxicity process. Furthermore, Trolox significantly decreased ROS generation and attenuated cell death caused by ketamine in a dose-dependent manner. In conclusion, this study illustrates that ketamine time- and dose-dependently induces human neurotoxicity via ROS-mediated mitochondrial apoptosis pathway and that these side effects can be prevented by the antioxidant agent Trolox. Thus, hESC-derived neurons might provide a promising tool for studying anesthetic-induced developmental neurotoxicity and prevention strategies. PMID:22873495

  6. Exposure to Chlorinated Biphenyls Causes Polymorphonucleocytes to Induce Progenitor Cell Toxicity in Culture

    Directory of Open Access Journals (Sweden)

    Tanika V. Martin

    2006-03-01

    Full Text Available Progenitor cells (PC are the precursors for many developmental structures and are sensitive to a variety of toxic agents including the environmental contaminants, polychlorinated biphenyls (PCBs. The mechanism(s that contributes to the development of PCB-induced progenitor cell-related fetotoxicities are not completely understood. However, several studies have demonstrated an important role for neutrophils (polymorphonucleocytes in the development of PCB induced toxicities. Our recent findings have indicated that conditioned medium collected from PC (CMPC exposed to a single dose of the PCB mixture, Aroclor 1248, can activate isolated neutrophil populations. Because of our recent findings, this study was conducted to determine if conditioned medium from PC treated with a PCB mixture causes neutrophils to injure PC in culture. Isolated PC were cultured and treated with different concentrations of Aroclor 1248 for 24 hours. The resulting PC-derived conditioned media was collected and its affect on neutrophil activity was analyzed. Conditioned medium from PC treated with Aroclor 1248 was chemotactic for neutrophils. The conditioned medium from Aroclor 1248 treated-PC also stimulated neutrophils to release super oxide anion, cathepsin G and elastase into culture medium. Furthermore, the conditioned medium from Aroclor 1248 treated- PC was able to stimulate neutrophils to cause progenitor cell toxicity in co-cultures. The conditioned medium from Aroclor 1248 treated-PC was not toxic to individual neutrophil cultures or PC cultures. Moreover, the addition of a protease inhibitor to the co-cultures containing neutrophils and PC, afforded protection against neutrophil-induced cytotoxicity of PC. These data suggest that a PCB mixture can cause progenitor cells to produce a factor(s that activates neutrophils and stimulates them to damage PC populations in culture.

  7. Mitigating effect of Indian propolis against mitomycin C induced bone marrow toxicity.

    Science.gov (United States)

    Kumari, Sandhya; Naik, Prashantha; Vishma, B L; Salian, Sujith Raj; Devkar, Raviraj Anand; Khan, Saleemulla; Mutalik, Srinivas; Kalthur, Guruprasad; Adiga, Satish Kumar

    2016-10-01

    A major drawback with cancer chemotherapy is its severe toxic effects on non-target tissues. Assessment of natural products for their protective effect against anticancer drugs-induced toxicity is gaining importance in cancer biology. The present study was aimed at assessing the protective effect of hydroethanolic extract of Indian propolis (HEIP) against mitomycin C (MMC)-induced genotoxicity and cytotoxicity. Swiss albino mice were injected with various doses of HEIP (100, 200, 300, 400, 600 and 800 mg/kg b. wt., i.p) 1 h prior to MMC (8 mg/kg, i.p.) injection. The geno- and cyto-toxicities were evaluated in mice by performing bone marrow micronucleus and TUNEL assays. In vitro antioxidant and lipid peroxidation inhibitory assays were carried out to understand the mechanism of the protective effects. The significant increase in the frequency of micronculeated cells (12.51 ± 0.48), apoptotic cells (23.43 ± 1.86) and reduction in P/N ratio (0.69 ± 0.04) compared with control indicated the potential geno- and cytotoxic effects of MMC in bone marrow. Pretreatment with HEIP resulted in the significant recovery of the toxic effects induced by MMC. HEIP at 400 mg/kg b. wt. was found to be the optimum dose imparting the maximum protective effects. The in vitro antioxidant and lipid peroxidation inhibitory assays suggest that the extract possesses substantial free radical scavenging activities. In conclusion, HEIP possesses substantial geno- and cyto-protective properties against MMC, which could be mediated through efficient free radical scavenging and inhibitory effect on lipid peroxidation.

  8. Effects of Colloidal Oatmeal Lotion on Symptoms of Dermatologic Toxicities Induced by Epidermal Growth Factor Receptor Inhibitors.

    Science.gov (United States)

    Ke, Ya-Ting; Kuo, Chia-Chi

    2017-01-01

    The common adverse effects associated with targeted therapy for cancer, such as epidermal growth factor receptor inhibitors (EGFRIs), are dermatologic toxicities that cause the patient physical discomfort and affect treatment. Colloidal oatmeal lotion (COL) has been proven to help prevent dermatitis and xerosis. Evidence of its effect on EGFRI-induced dermatologic toxicities, however, is limited. The purpose of this study was to explore the effect of COL on EGFRI-induced dermatologic toxicities. This study used a 1-group pretest-posttest design with a convenience sample of 30 patients with cancer who developed EGFRI-induced dermatologic toxicities from a medical center in southern Taiwan. All participants applied topical COL 3 to 5 times a day for 4 consecutive weeks and received a pretest and 4 posttests. A generalized estimating equation was used to assess the impact of demographics, disease characteristics, and weeks of COL use on dermatologic toxicity severity, body surface area affected, and level of pruritus. Significant differences were found between the pretest and all posttests after using COL with regard to the severity, body surface area affected, and level of pruritus in participants who developed EGFRI-induced dermatologic toxicities (P dermatologic toxicities. Based on the study results, COL could improve the symptoms of dermatologic toxicities in those receiving EGFRIs with no adverse effects. Therefore, the authors suggest the use of COL in clinical settings.

  9. Ozonides: intermediates in ozone-induced toxicity. A study on their mechanism of toxic action and detoxification by antioxidants

    NARCIS (Netherlands)

    Hempenius, R.A.

    2000-01-01

    Ozone is a major constituent of photochemical smog. The toxicity of ozone is well documented and has been related to its strong oxidative potential. The principal target organ for ozone toxicity is the respiratory system. Unsaturated fatty acids, which are present in both the lipids of the lung lini

  10. Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode

    Directory of Open Access Journals (Sweden)

    Magd A. Kotb

    2012-07-01

    Full Text Available Ursodeoxycholic acid (UDCA is a steroid bile acid approved for primary biliary cirrhosis (PBC. UDCA is reported to have “hepato-protective properties”. Yet, UDCA has “unanticipated” toxicity, pronounced by more than double number of deaths, and eligibility for liver transplantation compared to the control group in 28 mg/kg/day in primary sclerosing cholangitis, necessitating trial halt in North America. UDCA is associated with increase in hepatocellular carcinoma in PBC especially when it fails to achieve biochemical response (10 and 15 years incidence of 9% and 20% respectively. “Unanticipated” UDCA toxicity includes hepatitis, pruritus, cholangitis, ascites, vanishing bile duct syndrome, liver cell failure, death, severe watery diarrhea, pneumonia, dysuria, immune-suppression, mutagenic effects and withdrawal syndrome upon sudden halt. UDCA inhibits DNA repair, co-enzyme A, cyclic AMP, p53, phagocytosis, and inhibits induction of nitric oxide synthatase. It is genotoxic, exerts aneugenic activity, and arrests apoptosis even after cellular phosphatidylserine externalization. UDCA toxicity is related to its interference with drug detoxification, being hydrophilic and anti-apoptotic, has a long half-life, has transcriptional mutational abilities, down-regulates cellular functions, has a very narrow difference between the recommended (13 mg/kg/day and toxic dose (28 mg/kg/day, and it typically transforms into lithocholic acid that induces DNA strand breakage, it is uniquely co-mutagenic, and promotes cell transformation. UDCA beyond PBC is unjustified.

  11. Reproductive toxicity and gender differences induced by cadmium telluride quantum dots in an invertebrate model organism

    Science.gov (United States)

    Yan, Si-Qi; Xing, Rui; Zhou, Yan-Feng; Li, Kai-Le; Su, Yuan-Yuan; Qiu, Jian-Feng; Zhang, Yun-Hu; Zhang, Ke-Qin; He, Yao; Lu, Xiao-Ping; Xu, Shi-Qing

    2016-09-01

    Sexual glands are key sites affected by nanotoxicity, but there is no sensitive assay for measuring reproductive toxicity in animals. The aim of this study was to investigate the toxic effects of cadmium telluride quantum dots (CdTe-QDs) on gonads in a model organism, Bombyx mori. After dorsal vein injection of 0.32 nmol of CdTe-QDs per individual, the QDs passed through the outer membranes of gonads via the generation of ROS in the membranes of spermatocysts and ovarioles, as well as internal germ cells, thereby inducing early germ cell death or malformations via complex mechanisms related to apoptosis and autophagy through mitochondrial and lysosomal pathways. Histological observations of the gonads and quantitative analyses of germ cell development showed that the reproductive toxicity was characterized by obvious male sensitivity. Exposure to QDs in the early stage of males had severe adverse effects on the quantity and quality of sperm, which was the main reason for the occurrence of unfertilized eggs. Ala- or Gly-conjugated QDs could reduce the nanotoxicity of CdTe-QDs during germ cell development and fertilization of their offspring. The results demonstrate that males are preferable models for evaluating the reproductive toxicity of QDs in combined in vivo/in vitro investigations.

  12. In Vitro Protective Potentials of Annona muricata Leaf Extracts Against Sodium Arsenite-induced Toxicity.

    Science.gov (United States)

    George, Vazhappilly Cijo; Kumar, Devanga Ragupathi Naveen; Suresh, Palamadai Krishnan; Kumar, Rangasamy Ashok

    2015-01-01

    Sodium arsenite (NaAsO2) is a metalloid which is present widely in the environment and its chronic exposure can contribute to the induction of oxidative stress, resulting in disturbances in various metabolic functions including liver cell death. Hence, there is a need to develop drugs from natural sources, which can reduce arsenic toxicity. While there have been reports regarding the antioxidant and protective potentials of Annona muricataleaf extracts, our study is the first ofits kind to extend these findings by specifically evaluating its ability to render protection against sodium arsenite (NaAsO2) induced toxicity (10 μM) in WRL-68 (human hepatic cells) and human erythrocytes by employing XTT and haemolysis inhibition assays respectively. The methanolic extract exhibited higher activity than the aqueous extract in both assays. The results showed a dose-dependent decrease in arsenic toxicity in both WRL-68 cells and erythrocytes, suggesting the protective nature of Annona muricatato mitigate arsenic toxicity. Hence the bioactive extracts can further be scrutinized for the identification and characterization of their principal contributors.

  13. Reproductive toxicity and gender differences induced by cadmium telluride quantum dots in an invertebrate model organism

    Science.gov (United States)

    Yan, Si-Qi; Xing, Rui; Zhou, Yan-Feng; Li, Kai-Le; Su, Yuan-Yuan; Qiu, Jian-Feng; Zhang, Yun-Hu; Zhang, Ke-Qin; He, Yao; Lu, Xiao-Ping; Xu, Shi-Qing

    2016-01-01

    Sexual glands are key sites affected by nanotoxicity, but there is no sensitive assay for measuring reproductive toxicity in animals. The aim of this study was to investigate the toxic effects of cadmium telluride quantum dots (CdTe-QDs) on gonads in a model organism, Bombyx mori. After dorsal vein injection of 0.32 nmol of CdTe-QDs per individual, the QDs passed through the outer membranes of gonads via the generation of ROS in the membranes of spermatocysts and ovarioles, as well as internal germ cells, thereby inducing early germ cell death or malformations via complex mechanisms related to apoptosis and autophagy through mitochondrial and lysosomal pathways. Histological observations of the gonads and quantitative analyses of germ cell development showed that the reproductive toxicity was characterized by obvious male sensitivity. Exposure to QDs in the early stage of males had severe adverse effects on the quantity and quality of sperm, which was the main reason for the occurrence of unfertilized eggs. Ala- or Gly-conjugated QDs could reduce the nanotoxicity of CdTe-QDs during germ cell development and fertilization of their offspring. The results demonstrate that males are preferable models for evaluating the reproductive toxicity of QDs in combined in vivo/in vitro investigations. PMID:27669995

  14. Amide hydrolysis of a novel chemical series of microsomal prostaglandin E synthase-1 inhibitors induces kidney toxicity in the rat

    National Research Council Canada - National Science Library

    Bylund, Johan; Annas, Anita; Hellgren, Dennis; Bjurström, Sivert; Andersson, Håkan; Svanhagen, Alexander

    2013-01-01

    A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats...

  15. Supplementary Material for: Polyglutamine toxicity in yeast induces metabolic alterations and mitochondrial defects

    KAUST Repository

    Papsdorf, Katharina

    2015-01-01

    Abstract Background Protein aggregation and its pathological effects are the major cause of several neurodegenerative diseases. In Huntingtonâ s disease an elongated stretch of polyglutamines within the protein Huntingtin leads to increased aggregation propensity. This induces cellular defects, culminating in neuronal loss, but the connection between aggregation and toxicity remains to be established. Results To uncover cellular pathways relevant for intoxication we used genome-wide analyses in a yeast model system and identify fourteen genes that, if deleted, result in higher polyglutamine toxicity. Several of these genes, like UGO1, ATP15 and NFU1 encode mitochondrial proteins, implying that a challenged mitochondrial system may become dysfunctional during polyglutamine intoxication. We further employed microarrays to decipher the transcriptional response upon polyglutamine intoxication, which exposes an upregulation of genes involved in sulfur and iron metabolism and mitochondrial Fe-S cluster formation. Indeed, we find that in vivo iron concentrations are misbalanced and observe a reduction in the activity of the prominent Fe-S cluster containing protein aconitase. Like in other yeast strains with impaired mitochondria, non-fermentative growth is impossible after intoxication with the polyglutamine protein. NMR-based metabolic analyses reveal that mitochondrial metabolism is reduced, leading to accumulation of metabolic intermediates in polyglutamine-intoxicated cells. Conclusion These data show that damages to the mitochondrial system occur in polyglutamine intoxicated yeast cells and suggest an intricate connection between polyglutamine-induced toxicity, mitochondrial functionality and iron homeostasis in this model system.

  16. Chelidonium majus 30C and 200C in induced hepato-toxicity in rats.

    Science.gov (United States)

    Banerjee, Antara; Pathak, Surajit; Biswas, Surjyo Jyoti; Roy-Karmakar, Susanta; Boujedaini, Naoual; Belon, Philippe; Khuda-Bukhsh, Anisur Rahman

    2010-07-01

    Homeopathy is a popular form of complementary and alternative medicine and is used to treat for certain liver ailments. To analyze the efficacy of homeopathic Chelidonium majus (Chel) 30C and 200C in amelioration of experimentally induced hepato-toxicity in rats. Rats were randomized into six sub-groups: negative control; negative control+EtOH; positive control; positive control+EtOH group; Chel 30; Chel 200. Rats were sacrificed at day 30, 60, 90 and 120; various toxicity biomarkers and pathological parameters were evaluated. Gelatin zymography for determination of metalloproteinases activity and Western blot of p53 and Bcl-2 proteins were also employed. All analyses were observer blind. Chronic feeding of p-dimethyl amino azo benzene (p-DAB) and phenobarbital (PB) elevated the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH), triglyceride, cholesterol, creatinine and bilirubin and lowered the levels of glutathione (GSH), glucose-6-phosphate dehydrogenase (G-6-PD), catalase and HDL-cholesterol. There were statistically significant modulations of these parameters in the treated animals, compared to positive controls. In both treated groups, there was downregulation of metalloproteinases, p53 and Bcl-2 proteins compared to over-expression in the positive control groups. Both the potencies of Chel exhibited anti-tumor and anti-oxidative stress potential against artificially induced hepatic tumors and hepato-toxicity in rats. More studies are warranted. 2010 Elsevier Ltd. All rights reserved.

  17. Changes in Gut Microbiota May Be Early Signs of Liver Toxicity Induced by Epoxiconazole in Rats.

    Science.gov (United States)

    Xu, Cheng; Liu, Qian; Huan, Fei; Qu, Jianhua; Liu, Wei; Gu, Aihua; Wang, Yubang; Jiang, Zhaoyan

    2014-01-01

    The gut microbiome is essential for human health due to its effects on disease development, drug metabolism and the immune system. It may also play a role in the interaction with environmental toxicants. However, the effect of epoxiconazole, a fungicide active ingredient from the class of azoles developed to protect crops, on the abundance and composition of the gut microbiome has never been studied. We put forward the hypothesis that changes in gut microbiota may be early signs of toxicity induced by epoxiconazole. In this study, female rats were fed with epoxiconazole-adulterated diets (0, 4 and 100 mg/kg/day) for 90 days. The gut microbiome was determined by 16S rRNA gene sequencing. Body and organ weight, and blood biochemistry were also measured after 90 days of oral epoxiconazole exposure. Interestingly, the abundance of gut Firmicutes decreased, and Bacteroidetes and Proteobacteria increased. At family level, Lachnospiraceae and Enterobacteriaceae were selectively enriched following epoxiconazole exposure. Our results indicate that epoxiconazole exposure may induce changes in the gut microbiome and potential liver toxicity. Changes in the gut microbiome may be used as early indicators for monitoring the health risk of the host. © 2015 S. Karger AG, Basel

  18. Melatonin prevents gentamicin-induced testicular toxicity and oxidative stress in rats.

    Science.gov (United States)

    Kim, S-H; Lee, I-C; Baek, H-S; Shin, I-S; Moon, C; Kim, S-H; Yun, W-K; Nam, K-H; Kim, H-C; Kim, J-C

    2014-01-01

    This study investigated the protective effects of melatonin (MT) against gentamicin (GM)-induced testicular toxicity and oxidative damage in rats. GM (100 mg kg(-1) ) was injected intraperitoneally (i.p.) to rats for 6 days. MT (15 mg kg(-1) ) was administered i.p. to rats for 6 days at 1 hr after the GM treatment. GM caused a decrease in prostate and seminal vesicle weights, sperm count and sperm motility. Histopathological examination showed various morphological alterations in the testis, characterised by degeneration of spermatogonia/spermatocytes, decrease in the number of early spermatogenic cells and vacuolisation. In addition, an increased malondialdehyde concentration and decreased glutathione content and glutathione reductase, catalase and glutathione-S-transferase activities were found in the testis. In contrast, MT treatment significantly attenuated the testicular toxicity of GM, including decreased reproductive organ weights, sperm count, and sperm motility and increased histopathological alterations. MT also had an antioxidant benefit by decreasing the lipid peroxidative product malondialdehyde and increasing the level of the antioxidant glutathione and the activities of antioxidant enzymes in the testis. These results indicate that MT prevents testicular toxicity induced by GM in rats, presumably due to its potent antioxidant activity, and its ability to inhibit lipid peroxidation, and restore antioxidant enzyme activity.

  19. Arsenic-induced bone marrow toxicity: ultrastructural and electron-probe analysis

    Energy Technology Data Exchange (ETDEWEB)

    Feussner, J.R.; Shelburne, J.D.; Bredehoeft, S.; Cohen, H.J.

    1979-05-01

    A patient with severe arsenic poisoning that resulted in marked peripheral blood and bone marrow abnormalities, including megaloblastic erythropoiesis experienced many of the previously reported hematologic complications of arsenic poisoning: leukopenia, granulocytopenia, absolute eosinophilia, and profound anemia. In this study we report an ultrastructural and electron-proble analysis of the bone marrow. Although megaloblastic anemia associated with arsenic poisoning has been described rarely, the presence of arsenic in the local bone marrow milieu has not been demonstrated previously. The ultrastructural features of arsenic-induced bone marrow toxicity are similar to those described in other dyserythropoietic states and include marked nuclear aberrations involving shape, chromatin distribution, and nuclear envelope. Using the technique of energy-dispersive x-ray analysis (electron probe) we demonstrated arsenic in bone marrow spicules; this supports the contention that arsenic can cause megaloblastic anemia. We suggest that this technique may be a useful tool in further studies that attempt to explore the mechanism of arsenic-induced hematologic toxicity. Finally, we suggest that arsenic has a direct toxic effect on DNA synthesis that results in marked disturbances of nuclear division. We recommend that the most appropriate screening procedure to evaluate possible arsenic poisoning is tissue arsenic measurements (hair and nails) rather than 24-hr urinary measurements.

  20. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity.

    Science.gov (United States)

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-09-02

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered.

  1. Integrated proteomics and metabolomics analysis of rat testis: Mechanism of arsenic-induced male reproductive toxicity

    Science.gov (United States)

    Huang, Qingyu; Luo, Lianzhong; Alamdar, Ambreen; Zhang, Jie; Liu, Liangpo; Tian, Meiping; Eqani, Syed Ali Musstjab Akber Shah; Shen, Heqing

    2016-09-01

    Arsenic is a widespread metalloid in environment, whose exposure has been associated with a broad spectrum of toxic effects. However, a global view of arsenic-induced male reproductive toxicity is still lack, and the underlying mechanisms remain largely unclear. Our results revealed that arsenic exposure decreased testosterone level and reduced sperm quality in rats. By conducting an integrated proteomics and metabolomics analysis, the present study aims to investigate the global influence of arsenic exposure on the proteome and metabolome in rat testis. The abundance of 70 proteins (36 up-regulated and 34 down-regulated) and 13 metabolites (8 increased and 5 decreased) were found to be significantly altered by arsenic treatment. Among these, 19 proteins and 2 metabolites were specifically related to male reproductive system development and function, including spermatogenesis, sperm function and fertilization, fertility, internal genitalia development, and mating behavior. It is further proposed that arsenic mainly impaired spermatogenesis and fertilization via aberrant modulation of these male reproduction-related proteins and metabolites, which may be mediated by the ERK/AKT/NF-κB-dependent signaling pathway. Overall, these findings will aid our understanding of the mechanisms responsible for arsenic-induced male reproductive toxicity, and from such studies useful biomarkers indicative of arsenic exposure could be discovered.

  2. The ameliorative effect of propolis against methoxychlor induced ovarian toxicity in rat.

    Science.gov (United States)

    El-Sharkawy, Eman E; Kames, Amany O G; Sayed, S M; Nisr, Neveen A E L; Wahba, Nahed M; Elsherif, Walaa M; Nafady, Allam M; Abdel-Hafeez, M M; Aamer, A A

    2014-12-01

    A study was designed to evaluate ameliorative effect of propolis against methoxychlor (MXC) induced ovarian toxicity in rat. The organochlorine pesticide (MXC) is a known endocrine disruptor with estrogenic, anti-estrogenic, and anti-androgenic properties. To investigate whether chronic exposure to MXC could cause ovarian dysfunction, two groups of Sprague-Dawley adult female rats were exposed to MXC alone in a dose of 200mg/kg, twice/weekly, orally or MXC dose as previous plus propolis in a dose of 200mg/l/day, in drinking water for 10 months. Another two groups of rat were given corn oil (control) or propolis. Multiple reproductive parameters, ovarian weight, serum hormone levels, ovarian oxidative status and ovarian morphology were examined. In MXC-exposed group, there is a significant decrease in body and ovarian weight vs. control. MXC decreases serum estradiol and progesterone levels. A significant increase in the levels of lipid peroxidation was obtained while a significant decrease of the total antioxidant was recorded. Ovarian histopathology showed primary, secondary and vesicular follicles displaying an atretic morphology. Increase in the ovarian surface epithelium height accompanied with vacuolated, pyknotic oocytes were obtained. The previous toxic effects were neutralized by the administration of propolis in MXC+propolis group. The present results suggest that propolis may be effective in decreasing of MXC-induced ovarian toxicity in rat.

  3. Rat liver arginase system under acetaminophen-induced toxic injury and protein deprivation

    Directory of Open Access Journals (Sweden)

    H. P. Kopylchuk

    2017-04-01

    Full Text Available Arginase activity and L-arginine content in both cytosolic and mitochondrial fractions of rat liver cells under the conditions of toxic injury on the background of protein deprivation was studied. The most significant reduction of arginase activity in liver cells and depletion of L-arginine pool was found in rats with toxic acetaminophen-induced liver injury maintained on the ration balanced by all nutrients as well as in protein deficiency rats. It was concluded that reduction of the arginase activity in the cytosolic fraction of rat liver cells, combined with simultaneous decrease of L-arginine content, may be considered as one of the mechanisms of ornithine cycle disturbance. The decline of activity of mitochondrial isoform of arginase II, for certain, is related with activation of NO-synthase system.

  4. Protective Role of Spirulina platensis against Acute Deltamethrin-Induced Toxicity in Rats

    Science.gov (United States)

    Abdel-Daim, Mohamed M.; Abuzead, Said M. M.; Halawa, Safaa M.

    2013-01-01

    Deltamethrin is a broad-spectrum synthetic pyrethroid insecticide and acaricide widely used for agricultural and veterinary purposes. However, its human and animal exposure leads to hepatonephrotoxicity. Therefore, the present study was undertaken to examine the hepatonephroprotective and antioxidant potential of Spirulina platensis against deltamethrin toxicity in male Wistar albino rats. Deltamethrin treated animals revealed a significant increase in serum biochemical parameters as well as hepatic and renal lipid peroxidation but caused an inhibition in antioxidant biomarkers. Spirulina normalized the elevated serum levels of AST, ALT, APL, uric acid, urea and creatinine. Furthermore, it reduced deltamethrin-induced lipid peroxidation and oxidative stress in a dose dependent manner. Therefore, it could be concluded that spirulina administration able to minimize the toxic effects of deltamethrin by its free radical-scavenging and potent antioxidant activity. PMID:24039839

  5. Caenorhabditis elegans as a Model System for Studying Drug Induced Mitochondrial Toxicity.

    Directory of Open Access Journals (Sweden)

    Richard de Boer

    Full Text Available Today HIV-1 infection is recognized as a chronic disease with obligatory lifelong treatment to keep viral titers below detectable levels. The continuous intake of antiretroviral drugs however, leads to severe and even life-threatening side effects, supposedly by the deleterious impact of nucleoside-analogue type compounds on the functioning of the mitochondrial DNA polymerase. For detailed investigation of the yet partially understood underlying mechanisms, the availability of a versatile model system is crucial. We therefore set out to develop the use of Caenorhabditis elegans to study drug induced mitochondrial toxicity. Using a combination of molecular-biological and functional assays, combined with a quantitative analysis of mitochondrial network morphology, we conclude that anti-retroviral drugs with similar working mechanisms can be classified into distinct groups based on their effects on mitochondrial morphology and biochemistry. Additionally we show that mitochondrial toxicity of antiretroviral drugs cannot be exclusively attributed to interference with the mitochondrial DNA polymerase.

  6. Therapeutic Down-Modulators of Staphylococcal Superantigen-Induced Inflammation and Toxic Shock

    Directory of Open Access Journals (Sweden)

    Teresa Krakauer

    2010-07-01

    Full Text Available Staphylococcal enterotoxin B (SEB and related superantigenic toxins are potent stimulators of the immune system and cause a variety of diseases in humans, ranging from food poisoning to toxic shock. These toxins bind directly to major histocompatibility complex (MHC class II molecules on antigen-presenting cells and specific Vb regions of T-cell receptors (TCR, resulting in hyperactivation of both monocytes/macrophages and T lymphocytes. Activated host cells produce massive amounts of proinflammatory cytokines and chemokines, activating inflammation and coagulation, causing clinical symptoms that include fever, hypotension, and shock. This review summarizes the in vitro and in vivo effects of staphylococcal superantigens, the role of pivotal mediators induced by these toxins in the pathogenic mechanisms of tissue injury, and the therapeutic agents to mitigate the toxic effects of superantigens.

  7. T-2 Toxin-induced Toxicity in Pregnant Mice and Rats

    Directory of Open Access Journals (Sweden)

    Shinya Sehata

    2008-11-01

    Full Text Available T-2 toxin is a cytotoxic secondary fungal metabolite that belongs to the trichothecene mycotoxin family. This mycotoxin is a well known inhibitor of protein synthesis through its high binding affinity to peptidyl transferase, which is an integral part of the ribosomal 60s subunit, and it also inhibits the synthesis of DNA and RNA, probably secondary to the inhibition of protein synthesis. In addition, T-2 toxin is said to induce apoptosis in many types of cells bearing high proliferating activity. T-2 toxin readily passes the placenta and is distributed to embryo/fetal tissues, which include many component cells bearing high proliferating activity. This paper reviews the reported data related to T-2 toxin-induced maternal and fetal toxicities in pregnant mice and rats. The mechanisms of T-2 toxin-induced apoptosis in maternal and fetal tissues are also discussed in this paper.

  8. Involvement of oxidative stress in 4-vinylcyclohexene-induced toxicity in Drosophila melanogaster.

    Science.gov (United States)

    Abolaji, Amos Olalekan; Kamdem, Jean Paul; Lugokenski, Thiago Henrique; Nascimento, Thallita Kalar; Waczuk, Emily Pansera; Farombi, Ebenezer Olatunde; Loreto, Élgion Lúcio da Silva; Rocha, João Batista Teixeira

    2014-06-01

    4-Vinylcyclohexene (VCH) is a dimer of 1,3-butadiene produced as a by-product of pesticides, plastic, rubber, flame retardants, and tire production. Although, several studies have reported the ovotoxicity of VCH, information on a possible involvement of oxidative stress in the toxicity of this occupational chemical is scarce. Hence, this study was carried out to investigate further possible mechanisms of toxicity of VCH with a specific emphasis on oxidative stress using a Drosophila melanogaster model. D. melanogaster (both genders) of 1 to 3 days old were exposed to different concentrations of VCH (10 µM-1 mM) in the diet for 5 days. Subsequently, the survival and negative geotaxis assays and the quantification of reactive oxygen species (ROS) generation were determined. In addition, we evaluated RT-PCR expressions of selected oxidative stress and antioxidant mRNA genes (HSP27, 70, and 83, SOD, Nrf-2, MAPK2, and catalase). Furthermore, catalase, glutathione-S-transferase (GST), delta aminolevulinic acid dehydratase (δ-ALA-D), and acetylcholinesterase (AChE) activities were determined. VCH exposure impaired negative geotaxic behavior and induced the mRNA of SOD, Nrf-2, and MAPK2 genes expressions. There were increases in catalase and ROS production, as well as inhibitions of GST, δ-ALA-D, and AChE activities (Pmelanogaster is a useful model for investigating the toxicity of VCH exposure, and here, we have provided further insights on the mechanism of VCH-induced toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate-induced toxicity in rat kidney.

    Science.gov (United States)

    Sawada, Stefanie; Oberemm, Axel; Buhrke, Thorsten; Merschenz, Julia; Braeuning, Albert; Lampen, Alfonso

    2016-06-01

    3-Chloropropane-1,2-diol (3-MCPD) and its fatty acid esters are formed during thermal treatment of fat-containing foodstuff in the presence of salt. Toxicological studies indicate a carcinogenic potential of 3-MCPD, pointing to the kidney as the main target organ. It is assumed that the toxicological property of 3-MCPD esters is constituted by the release of 3-MCPD during digestion. In a repeated-dose 28-day oral toxicity study using Wistar rats, animals were treated with equimolar doses of either 3-MCPD (10 mg/kg body weight) or 3-MCPD dipalmitate (53 mg/kg body weight). A lower dose of 3-MCPD dipalmitate (13.3 mg/kg body weight) was also applied. No histopathologically visible toxicity was observed in the study. To address molecular mechanisms leading to toxicity of 3-MCPD and its esters, kidney samples were analyzed by a comparative, two-dimensional gel electrophoresis/mass spectrometry proteomic approach. After either 3-MCPD or 3-MCPD dipalmitate treatment, alterations in proteins related to various metabolic pathways, including carbohydrate, amino acid, and fatty acid metabolism, were detected. These findings confirm and complement previous data on the inhibition of glucose metabolism by 3-MCPD. Altogether, broad overlap of 3-MCPD- and 3-MCPD dipalmitate-induced proteomic changes was observed. Further analyses revealed that the observed induction of glutathione S-transferase pi 1 (Gstp1) occurred at the transcriptional level and was not related to nuclear factor (erythroid-derived 2)-like 2 activation. Overall, the results indicate common mechanisms of toxicity for 3-MCPD and its dipalmitate ester. Furthermore, data suggest Gstp1 as a sensitive marker for early 3-MCPD-induced effects in rat kidney.

  10. Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11).

    Science.gov (United States)

    Chen, Shujuan; Yueh, Mei-Fei; Bigo, Cyril; Barbier, Olivier; Wang, Kepeng; Karin, Michael; Nguyen, Nghia; Tukey, Robert H

    2013-11-19

    Camptothecin (CPT)-11 (irinotecan) has been used widely for cancer treatment, particularly metastatic colorectal cancer. However, up to 40% of treated patients suffer from severe late diarrhea, which prevents CPT-11 dose intensification and efficacy. CPT-11 is a prodrug that is hydrolyzed by hepatic and intestinal carboxylesterase to form SN-38, which in turn is detoxified primarily through UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed glucuronidation. To better understand the mechanism associated with toxicity, we generated tissue-specific Ugt1 locus conditional knockout mouse models and examined the role of glucuronidation in protecting against irinotecan-induced toxicity. We targeted the deletion of the Ugt1 locus and the Ugt1a1 gene specifically in the liver (Ugt1(ΔHep)) and the intestine (Ugt1(ΔGI)). Control (Ugt1(F/F)), Ugt1(ΔHep), and Ugt1(ΔGI) adult male mice were treated with different concentrations of CPT-11 daily for four consecutive days. Toxicities were evaluated with regard to tissue glucuronidation potential. CPT-11-treated Ugt1(ΔHep) mice showed a similar lethality rate to the CPT-11-treated Ugt1(F/F) mice. However, Ugt1(ΔGI) mice were highly susceptible to CPT-11-induced diarrhea, developing severe and lethal mucositis at much lower CPT-11 doses, a result of the proliferative cell loss and inflammation in the intestinal tract. Comparative expression levels of UGT1A1 in intestinal tumors and normal surrounding tissue are dramatically different, providing for the opportunity to improve therapy by differential gene regulation. Intestinal expression of the UGT1A proteins is critical toward the detoxification of SN-38, whereas induction of the UGT1A1 gene may serve to limit toxicity and improve the efficacy associated with CPT-11 treatment.

  11. Protective effect of some plant oils on diazinon induced hepatorenal toxicity in male rats

    Directory of Open Access Journals (Sweden)

    Atef M. Al-Attar

    2017-09-01

    Full Text Available Environmental pollution and exposure to environmental pollutants are still some of the major global health issues. Pesticides have been linked to a wide range of health hazards. The toxicity of pesticides depends on several factors such as its chemical properties, doses, exposure period, exposure methods, gender, genetics, age, nutritional status and physiological case of exposed individuals. Medicinal plants, natural products and nutrition continue to play a central role in the healthcare system of large proportions of the world’s population. Alternative medicine plays an important role in health services around the world. The aim of this study was to investigate the effect of olive, sesame and black seed oils on hepatorenal toxicity induced by diazinon (DZN in male rats. The experimental animals were divided into nine groups. The first group served as control. The second group was exposed to DZN. The third group was treated with olive oil and DZN. Rats of the fourth group were subjected to sesame oil and DZN. Rats of the fifth group were exposed to black seed oil and DZN. The sixth, seventh and eighth groups were supplemented with olive, sesame and black seed oils respectively. Rats of the ninth group were treated with corn oil. Levels of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase, total bilirubin, creatinine, blood urea nitrogen and malondialdehyde were significantly increased in rats exposed to DZN. Moreover, levels of serum glutathione and superoxide dismutase were significantly decreased. Several histopathological changes were observed in the structures of liver and kidney due to DZN exposure. This study showed that these oils attenuated the physiological disturbances and histopathological alterations induced by DZN intoxication. Moreover, the antioxidant properties of these oils support the bioactive roles of its protective effects on DZN toxicity. This study therefore

  12. Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin

    Science.gov (United States)

    Jain, Anil K; Tewari-Singh, Neera; Inturi, Swetha; Kumar, Dileep; Orlicky, David J; Agarwal, Chapla; White, Carl W; Agarwal, Rajesh

    2015-01-01

    Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2 mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51% reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants. PMID:25791923

  13. Inorganic carbon acquisition in potentially toxic and non-toxic diatoms: the effect of pH-induced changes in the seawater carbonate chemistry

    DEFF Research Database (Denmark)

    Trimborn, S; Lundholm, Nina; Thoms, S;

    2008-01-01

    The effects of pH-induced changes in seawater carbonate chemistry on inorganic carbon (C-i) acquisition and domoic acid (DA) production were studied in two potentially toxic diatom species, Pseudo-nitzschia multiseries and Nitzschia navis-varingica, and the non-toxic Stellarima stellaris. In vivo......, it was about 55% in P. multiseries and only approximately 30% in N. navis-varingica. The intracellular content of DA increased in P. multiseries and N. navis-varingica with increasing pH. Based on our data, we propose a novel role for eCA acting as C-i-recycling mechanism. With regard to p...

  14. Cardioprotective Effect of Grape Seed Extract on Chronic Doxorubicin-Induced Cardiac Toxicity in Wistar Rats

    Directory of Open Access Journals (Sweden)

    Nasser Razmaraii

    2016-09-01

    Full Text Available Purpose: The aim of the present study was to determine the ability of grape seed extract (GSE as a powerful antioxidant in preventing adverse effect of doxorubicin (DOX on heart function. Methods: Male rats were divided into three groups: control, DOX (2 mg/kg/48h, for 12 days and GSE (100 mg/kg/24h, for 16 days plus DOX. Left ventricular (LV function and hemodynamic parameters were assessed using echocardiography, electrocardiography and a Millar pressure catheter. Histopathological analysis and in vitro antitumor activity were also evaluated. Results: DOX induced heart damage in rats through decreasing the left ventricular systolic and diastolic pressures, rate of rise/decrease of LV pressure, ejection fraction, fractional shortening and contractility index as demonstrated by echocardiography, electrocardiography and hemodynamic parameters relative to control group. Our data demonstrated that GSE treatment markedly attenuated DOX-induced toxicity, structural changes in myocardium and improved ventricular function. Additionally, GSE did not intervene with the antitumor effect of DOX. Conclusion: Collectively, the results suggest that GSE is potentially protective against DOX-induced toxicity in rat heart and maybe increase therapeutic index of DOX in human cancer treatment.

  15. Cardioprotective Effect of Grape Seed Extract on Chronic Doxorubicin-Induced Cardiac Toxicity in Wistar Rats.

    Science.gov (United States)

    Razmaraii, Nasser; Babaei, Hossein; Mohajjel Nayebi, Alireza; Assadnassab, Gholamreza; Ashrafi Helan, Javad; Azarmi, Yadollah

    2016-09-01

    Purpose: The aim of the present study was to determine the ability of grape seed extract (GSE) as a powerful antioxidant in preventing adverse effect of doxorubicin (DOX) on heart function. Methods: Male rats were divided into three groups: control, DOX (2 mg/kg/48h, for 12 days) and GSE (100 mg/kg/24h, for 16 days) plus DOX. Left ventricular (LV) function and hemodynamic parameters were assessed using echocardiography, electrocardiography and a Millar pressure catheter. Histopathological analysis and in vitro antitumor activity were also evaluated. Results: DOX induced heart damage in rats through decreasing the left ventricular systolic and diastolic pressures, rate of rise/decrease of LV pressure, ejection fraction, fractional shortening and contractility index as demonstrated by echocardiography, electrocardiography and hemodynamic parameters relative to control group. Our data demonstrated that GSE treatment markedly attenuated DOX-induced toxicity, structural changes in myocardium and improved ventricular function. Additionally, GSE did not intervene with the antitumor effect of DOX. Conclusion: Collectively, the results suggest that GSE is potentially protective against DOX-induced toxicity in rat heart and maybe increase therapeutic index of DOX in human cancer treatment.

  16. Combined effects of gallic acid and propolis on beryllium-induced hepatorenal toxicity.

    Science.gov (United States)

    Nirala, Satendra K; Li, Peiqiang; Bhadauria, Monika; Guo, Guangqin

    2008-09-01

    The combined effect of gallic acid (3,4,5-trihydroxy benzoic acid; GA; 50 mg kg(-1) i.p.) and propolis (200 mg kg(-1) p.o.) was evaluated against beryllium-induced biochemical and morphological alterations in the liver and kidney. Female albino rats were exposed to beryllium nitrate (1 mg kg(-1) i.p.) daily for 28 days followed by treatment with the above mentioned therapeutic agents either individually or in combination for five consecutive days. Exposure to beryllium increased its concentration in the serum, liver and kidney and caused significant alterations in cytochrome P450 enzymes, microsomal lipid peroxidation and protein contents. Beryllium administration significantly altered the aspartate aminotransaminase, alanine aminotransaminase, lactate dehydrogenase, γ-grutamy1 transpeptidase, bilirubin, creatinine and urea in serum, and the activity of acid phosphatase, alkaline phosphatase, adenosine triphosphatase, glucose-6-phophatase and succinic dehydrogenase, triglycerides, cholesterol, protein contents, glycogen contents, lipid peroxidation and glutathione level in the liver and kidney. Beryllium exposure induced severe alterations in hepatorenal morphology, revealing its toxic consequences at a cellular level. Individual administration of GA and propolis reduced the effects on the studied parameters to a degree. Interestingly, GA in conjunction with propolis reversed the alterations in all of the variables examined, highlighting the beneficial effects of combined therapy over monotherapy in the alleviation of beryllium-induced systemic toxicity. © 2008 ISZS, Blackwell Publishing and IOZ/CAS.

  17. Mechanisms of carbon nanotube-induced toxicity: Focus on oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Shvedova, Anna A., E-mail: ats1@cdc.gov [Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, University of Rome “Tor Vergata”, Rome (Italy); Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, University of Rome “Tor Vergata”, Rome (Italy); Pietroiusti, Antonio [Department of Biopathology, University of Rome “Tor Vergata”, Rome (Italy); Fadeel, Bengt [Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden); Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA (United States); Kagan, Valerian E. [Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA (United States)

    2012-06-01

    Nanotechnologies are emerging as highly promising technologies in many sectors in the society. However, the increasing use of engineered nanomaterials also raises concerns about inadvertent exposure to these materials and the potential for adverse effects on human health and the environment. Despite several years of intensive investigations, a common paradigm for the understanding of nanoparticle-induced toxicity remains to be firmly established. Here, the so-called oxidative stress paradigm is scrutinized. Does oxidative stress represent a secondary event resulting inevitably from disruption of biochemical processes and the demise of the cell, or a specific, non-random event that plays a role in the induction of cellular damage e.g. apoptosis? The answer to this question will have important ramifications for the development of strategies for mitigation of adverse effects of nanoparticles. Recent examples of global lipidomics studies of nanoparticle-induced tissue damage are discussed along with proteomics and transcriptomics approaches to achieve a comprehensive understanding of the complex and interrelated molecular changes in cells and tissues exposed to nanoparticles. We also discuss instances of non-oxidative stress-mediated cellular damage resulting from direct physical interference of nanomaterials with cellular structures. -- Highlights: ► CNT induced non-random oxidative stress associated with apoptosis. ► Non-oxidative mechanisms for cellular toxicity of carbon nanotubes. ► Biodegradation of CNT by cells of innate immune system. ► “Omics”-based biomarkers of CNT exposures.

  18. Pharmacokinetics and toxicodynamics of pralidoxime effects on paraoxon-induced respiratory toxicity.

    Science.gov (United States)

    Houzé, Pascal; Mager, Donald E; Risède, Patricia; Baud, Frédéric J

    2010-08-01

    Empirical studies suggest that the antidotal effect of pralidoxime depends on plasma concentrations with therapeutic effects associated with concentrations above 4 mg/l. The purpose of this study was to determine the pharmacokinetic-toxicodynamic (PK-TD) relationships for the antidotal effect of pralidoxime on paraoxon-induced toxicity in rats. Diethylparaoxon inactivation of whole-blood cholinesterase activity was studied both in vitro and in male Sprague-Dawley rats. Toxin-induced respiratory effects were measured via whole-body plethysmography in control and pralidoxime-treated animals (50 mg/kg im injection). In the in vitro analysis, cholinesterase reactivation by pralidoxime in blood-poisoned diethylparaoxon (10nM) was proportional to the logarithm of drug concentrations. A mechanism-based TD model was developed, which well described the inhibition of cholinesterases by diethylparaoxon and reactivation with pralidoxime. The in vitro pralidoxime EC(50) was estimated to be 4.67 mg/l. Animals exposed to diethylparaoxon exhibited a decrease in respiratory rate and an increase in expiratory time, and pralidoxime treatment resulted in a rapid complete but transient (antidotal effects, which explained the complex relationship between drug exposure and pharmacological response profile. This study provides insights into the role of oxime-rescue of paraoxon-induced toxicity, and the final PK-TD model might prove useful in optimizing the design and development of such therapy.

  19. Penicillin induced toxic epidermal necrolysis with secondary impetiginization: a rare case

    Directory of Open Access Journals (Sweden)

    Hari Babu Ramineni

    2015-02-01

    Full Text Available Drug induced allergic reactions can be categorized into IgE-mediated and non-IgE mediated hypersensitivity reactions. Symptoms of IgE-mediated reactions are angioedema, bronchospasm, anaphylaxis, and urticaria that appears within 72 hours and those which are Non-IgE mediated hypersensitivity reactions include morbilliform eruptions, interstitial nephritis, hemolytic anemia, serum sickness, thrombocytopenia, and erythema multiforme, after 72 hours. TEN is defined as an extensive detachment of full-thickness epidermis most often related to an adverse drug reaction. We report a rare case of penicillin induced toxic epidermal necrolysis with Secondary Impetigination in a 38-year-old male patient with complaints of rashes all over the body, chest pain and dry tongue since seven days. Based on history and clinical examination patient was diagnosed as of penicillin induced toxic epidermal necrolysis with secondary impetigination and was successfully treated with antihistamines, parenteral antibiotics and corticosteroids. [Int J Res Med Sci 2015; 3(2.000: 511-512

  20. Protective effect of ginger against toxicity induced by chromate in rats.

    Science.gov (United States)

    Krim, Meriem; Messaadia, Amira; Maidi, Imen; Aouacheri, Ouassila; Saka, Saad

    2013-01-01

    The evaluation of the effect of ginger on the modulation of toxic effects induced by chromate is the objective of our study. 50 male rats Albinos Wistar were divided to five groups as follow: group I (T) is served as control, received a mineral water by gavage (per os); group II (G) received an experimental diet with 2% of ginger; group III (Cr) received an oral dose of potassium dichromate (15 mg/kg) and normal diet; group IV (CrG): received an oral dose of potassium dichromate (15 mg/kg) and an experimental diet containing 2% ginger; and group V (Cr(+)G) received an oral dose of potassium dichromate (25 mg/kg) and an experimental diet with 2% of ginger. The results of this study indicate that the chromate provoked a haematoxic effect (anemia), nephrotoxic, hepatotoxic, and also a perturbation in lipids profile. In addition, chromate has a pro-oxidant effect, which was indicated by decrease of reduced glutathione (GSH) levels in different tissues. However, the administration of ginger revealed a reduction of the intensity of oxidative stress induced by the chromate resulting in the decrease of the majority of the previous parameters concentrations. In conclusion we demonstrated that ginger has potent antioxidants activity, revealed by the amelioration of chromate's toxic effects. We can say that ginger has a protective effect towards damages induced by the chromate.

  1. The effect of N6-Cyclopentyladenosine on ouabain-Induced toxicity: isolated guinea pig atria

    Directory of Open Access Journals (Sweden)

    Bakhtiarian A

    2009-04-01

    Full Text Available "nBackground: Adenosine receptors play an important role in the treatment of paroxysmal supraventricular tachycardia in cardiovascular system. This effect is through interaction with A1 type of G-protein-coupled adenosine receptors. The effect of N6-cyclopentyladenosine (CPA, an A1-selective adenosine agonist, was studied on ouabain-induced toxicity in spontaneously beating isolated guinea pig atria. "nMethods: In the beginning the isolated guinea pig atria were mounted on the organ bath containing modified krebs and contractile responses in the four groups (shame, CPA, ouabain, CPA- ouabain were measured. "nResults: CPA (2-16nM produced a dose-dependent decrease in the force of contractions (34%-51% and in the rate of contractions (22%-48%. CPA significantly increased the time of onset of arrhythmia (toxicity induced by ouabain (1.2µM when it was administered 10 min before ouabain was added in organ bath. Ouabain (1.2µM alone produced arrhythmia at 7 min and either asystole or standstill at 22 min. CPA (8nM increased the time required to produce arrhythmia to 27.5 min and prolonged beating atria to more than 63 min and prevented the occurrence of asystole. "nConclusion: CPA produces direct cardiac action, probably due the inhibition of cardiac Ca2+ channel and membrane hyperpolarization of atrium cells in guinea pig atria. Moreover, our results suggest that CPA may reduce the membrane conduction through inhibition of ionic channels, which decrease ouabain- induced toxicity.

  2. Lutein alleviates arsenic-induced reproductive toxicity in male mice via Nrf2 signaling.

    Science.gov (United States)

    Li, S G; Xu, S Z; Niu, Q; Ding, Y S; Pang, L J; Ma, R L; Jing, M X; Wang, K; Ma, X M; Feng, G L; Liu, J M; Zhang, X F; Xiang, H L; Li, F

    2016-05-01

    This study aims to investigate the mechanisms involved in the action of lutein (LU) alleviating arsenic-induced reproductive toxicity using mice model. Forty male Kunming mice were received following treatments by gavage: normal saline solution (control), arsenic trioxide (ATO; 5 mg/kg/day), LU (40 mg/kg/day), and ATO + LU (5 mg/kg/day + 40 mg/kg/day). At the end, the mice were killed by cervical dislocation and weighed. Pathological examination was done on the testis. The biomedical parameters including superoxide dismutase (SOD), glutathione (GSH), total antioxidative capability, malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reproductive indexes were analyzed. The messenger RNA (mRNA) and protein expression of Nrf2, heme oxygenase 1 (HO-1), glutathione S-transferase (GST), nicotinamide adenine dinucleotide phosphate dehydrogenase, quinone 1 (NQO1) in testis were detected by real-time polymerase chain reaction and Western blot. We found that there was a decrease in sperm count; testis somatic index; the activities of SOD, GSH, total antioxidative capacity (p treated mice, while there was an increase in the levels of sperm abnormalities, MDA, and 8-OHdG than control (p treated with ATO + LU showed recovery of the measured parameters between those of ATO or saline-treated group. The antagonized interaction between ATO and LU was statistically significant (p treated with ATO + LU also showed greater mRNA expression of Nrf2, HO-1, NQO1, and GST than ATO or saline-treated groups. These findings suggest that LU alleviates reproductive toxicity induced by arsenic in male mice via Nrf2 signaling, which implicates a possible mechanism of LU in preventing the reproductive injury, and elucidates that consuming the rich plant sources of LU will alleviate the reproductive toxicity induced by chemicals.

  3. Thioacetamide-induced acute liver toxicity in rats treated with Balanites roxburghii extracts

    Institute of Scientific and Technical Information of China (English)

    Mallikarjuna Rao Talluri; Rajananda Swamy Tadi; Ganga Rao Battu

    2016-01-01

    Objective: To evaluate the antioxidant and thioacetamide induced liver toxicity using extracts of aerial parts of Balanites roxburghii (B. roxburghii). Methods: The in-vitro antioxidant activity was estimated for different extracts on super-oxide, hydroxyl and 1,1-diphenyl-2-picrylhydrazyl free radicals and the hepatoprotective activity of the selected plant extracts was evaluated by using thioacetamide-induced liver intoxication in rats model. Results: There were no visible signs of toxicity, mortality and no behavioral changes were observed for the selected plant extracts (hydroalcoholic, ethyl acetate and hexane) at 2 000 mg/kg body weight. The plant extracts showed dose-dependent effectiveness in the inhibition of free radicals generation and hepatoprotective nature. The hydroalcoholic extract showed more scavenging activity as compared to other extracts with IC50 values of (332.50 ± 1.30) mg, (302.00 ± 1.50) mg and (230.40 ± 1.10) mg on superoxide, hy-droxyl and 1,1-diphenyl-2-picrylhydrazyl free radicals. Aerial parts of B. roxburghii at three dose levels such as 125 mg/kg, 250 mg/kg and 500 mg/kg showed dose dependent percentage protection as standard drugs and on enhancement activities of serum biomarker enzymes (aspartate aminotransferase, alanine transaminase, alkaline phos-phatase, total bilirubin and total protein) observed in thioacetamide-induced hepatotox-icity. The hydroalcoholic extract showed significant results at 500 mg/kg body weight as compared to other extracts (P Conclusions: It was observed that the B. roxburghii plant extracts are non-toxic and have capacity to restore the physiological changes caused by the hepatotoxic compounds.

  4. Autophagy of metallothioneins prevents TNF-induced oxidative stress and toxicity in hepatoma cells.

    Science.gov (United States)

    Ullio, Chiara; Brunk, Ulf T; Urani, Chiara; Melchioretto, Pasquale; Bonelli, Gabriella; Baccino, Francesco M; Autelli, Riccardo

    2015-01-01

    Lysosomal membrane permeabilization (LMP) induced by oxidative stress has recently emerged as a prominent mechanism behind TNF cytotoxicity. This pathway relies on diffusion of hydrogen peroxide into lysosomes containing redox-active iron, accumulated by breakdown of iron-containing proteins and subcellular organelles. Upon oxidative lysosomal damage, LMP allows relocation to the cytoplasm of low mass iron and acidic hydrolases that contribute to DNA and mitochondrial damage, resulting in death by apoptosis or necrosis. Here we investigate the role of lysosomes and free iron in death of HTC cells, a rat hepatoma line, exposed to TNF following metallothionein (MT) upregulation. Iron-binding MT does not normally occur in HTC cells in significant amounts. Intracellular iron chelation attenuates TNF and cycloheximide (CHX)-induced LMP and cell death, demonstrating the critical role of this transition metal in mediating cytokine lethality. MT upregulation, combined with starvation-activated MT autophagy almost completely suppresses TNF and CHX toxicity, while impairment of both autophagy and MT upregulation by silencing of Atg7, and Mt1a and/or Mt2a, respectively, abrogates protection. Interestingly, MT upregulation by itself has little effect, while stimulated autophagy alone depresses cytokine toxicity to some degree. These results provide evidence that intralysosomal iron-catalyzed redox reactions play a key role in TNF and CHX-induced LMP and toxicity. The finding that chelation of intralysosomal iron achieved by autophagic delivery of MT, and to some degree probably of other iron-binding proteins as well, into the lysosomal compartment is highly protective provides a putative mechanism to explain autophagy-related suppression of death by TNF and CHX.

  5. Amelioratory effect of coenzyme Q10 on potential human carcinogen Microcystin-LR induced toxicity in mice.

    Science.gov (United States)

    Lone, Yaqoob; Bhide, Mangla; Koiri, Raj Kumar

    2017-04-01

    Microcystins are a group of cyclic heptapeptide toxins produced by cyanobacteria. More than 100 microcystin analogues have been detected, among which microcystin-LR is the most abundant and toxic variant. Present study was designed to reveal whether potential human carcinogen microcystin-LR could imbalance the glycolytic-oxidative-nitrosative status of heart, kidney and spleen of mice and also to explore the amelioratory effect of coenzyme Q10 on microcystin-LR induced toxicity. Microcystin-LR was administered at a dose of 10 μg/kg bw/day, ip for 14 days in male mice. In microcystin-LR treated mice as compared to control, significant increase in the level of lipid peroxidation, hydrogen peroxide, lactate dehydrogenase, nitric oxide with a concomitant decrease in the level of glutathione was observed, suggesting microcystin-LR induced toxicity via induction of oxidative-nitrosative-glycolytic pathway. Although several studies have evaluated numerous antioxidants but still there is no effective chemoprotectant against microcystin-LR induced toxicity. When microcystin-LR treated mice were co-administered coenzyme Q10 (10 mg/kg bw/day, im) for 14 days, it was observed that coenzyme Q10 ameliorates microcystin-LR induced toxicity via modulation of glycolytic-oxidative-nitrosative stress pathway. Thus, the results suggest that coenzyme Q10 has a potential to be developed as preventive agent against microcystin-LR induced toxicity.

  6. Ameliorative potential of Tephrosia purpurea extract against arsenic induced toxicity in wistar rats

    OpenAIRE

    Birendra kumar Roy; Naveen Kumar; Reetu Toppo; Priscilla Kerketta; Sushma Lalita Baxla; Ravuri Halley Gora

    2013-01-01

    Aim: The present investigation has been conducted to evaluate the protective activity of Tephrosia purpurea extract (TPE) against arsenic induced toxicity. Materials and Methods: For this study, twenty four wistar albino rats were taken. Control group, group – I rats were given sodium arsenite @ 10 mg/kg and group – II rats were treated with TPE @ 500 mg/kg along with sodium arsenite @ 10 mg/kg (daily oral for 28 days). On 29th day animals were slaughtered and various parameters were determin...

  7. Partial purification and characterization of an escherichia coli toxic factor that induces morphological cell alterations.

    OpenAIRE

    Caprioli, A; Falbo, V.; Roda, L G; Ruggeri, F. M.; Zona, C

    1983-01-01

    A factor produced by several strains of Escherichia coli isolated from enteritis-affected children has been shown to produce both a necrotizing effect on rabbit skin and striking morphological alterations on CHO, Vero, and HeLa cells. The same strains were found to have hemolytic activity on sheep erythrocytes. The toxic, cell-altering factor was demonstrated to be different from both heat-labile and heat-stable enterotoxins and from Vero toxin. The main effect induced by the isolated factor ...

  8. Mercury induces inflammatory mediator release from human mast cells

    Directory of Open Access Journals (Sweden)

    Peterson Erika

    2010-03-01

    Full Text Available Abstract Background Mercury is known to be neurotoxic, but its effects on the immune system are less well known. Mast cells are involved in allergic reactions, but also in innate and acquired immunity, as well as in inflammation. Many patients with Autism Spectrum Disorders (ASD have "allergic" symptoms; moreover, the prevalence of ASD in patients with mastocytosis, characterized by numerous hyperactive mast cells in most tissues, is 10-fold higher than the general population suggesting mast cell involvement. We, therefore, investigated the effect of mercuric chloride (HgCl2 on human mast cell activation. Methods Human leukemic cultured LAD2 mast cells and normal human umbilical cord blood-derived cultured mast cells (hCBMCs were stimulated by HgCl2 (0.1-10 μM for either 10 min for beta-hexosaminidase release or 24 hr for measuring vascular endothelial growth factor (VEGF and IL-6 release by ELISA. Results HgCl2 induced a 2-fold increase in β-hexosaminidase release, and also significant VEGF release at 0.1 and 1 μM (311 ± 32 pg/106 cells and 443 ± 143 pg/106 cells, respectively from LAD2 mast cells compared to control cells (227 ± 17 pg/106 cells, n = 5, p 2 (0.1 μM to the proinflammatory neuropeptide substance P (SP, 0.1 μM had synergestic action in inducing VEGF from LAD2 mast cells. HgCl2 also stimulated significant VEGF release (360 ± 100 pg/106 cells at 1 μM, n = 5, p 6 cells, and IL-6 release (466 ± 57 pg/106 cells at 0.1 μM compared to untreated cells (13 ± 25 pg/106 cells, n = 5, p 2 (0.1 μM to SP (5 μM further increased IL-6 release. Conclusions HgCl2 stimulates VEGF and IL-6 release from human mast cells. This phenomenon could disrupt the blood-brain-barrier and permit brain inflammation. As a result, the findings of the present study provide a biological mechanism for how low levels of mercury may contribute to ASD pathogenesis.

  9. The cathepsin B inhibitor, z-FA-CMK is toxic and readily induced cell death in human T lymphocytes

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    Liow, K.Y.; Chow, S.C., E-mail: chow.sek.chuen@monash.edu

    2013-11-01

    The cathepsin B inhibitor, benzyloxycarbonyl-phenylalanine-alanine-chloromethylketone (z-FA-CMK) was found to be toxic and readily induced cell death in the human T cell line, Jurkat, whereas two other analogs benzyloxycarbonyl-phenylalanine-alanine-fluoromethylketone (z-FA-FMK) and benzyloxycarbonyl-phenylalanine-alanine-diazomethylketone (z-FA-DMK) were not toxic. The toxicity of z-FA-CMK requires not only the CMK group, but also the presence of alanine in the P1 position and the benzyloxycarbonyl group at the N-terminal. Dose–response studies showed that lower concentrations of z-FA-CMK induced apoptosis in Jurkat T cells whereas higher concentrations induced necrosis. In z-FA-CMK-induced apoptosis, both initiator caspases (-8 and -9) and effector caspases (-3, -6 and -7) were processed to their respective subunits in Jurkat T cells. However, only the pro-form of the initiator caspases were reduced in z-FA-CMK-induced necrosis and no respective subunits were apparent. The caspase inihibitor benzyloxycarbonyl-valine-alanine-aspartic acid-(O-methyl)-fluoromehylketone (z-VAD-FMK) inhibits apoptosis and caspase processing in Jurkat T cells treated with low concentration of z-FA-CMK but has no effect on z-FA-CMK-induced necrosis and the loss of initiator caspases. This suggests that the loss of initiator caspases in Jurkat T cells during z-FA-CMK-induced necrosis is not a caspase-dependent process. Taken together, we have demonstrated that z-FA-CMK is toxic to Jurkat T cells and induces apoptosis at low concentrations, while at higher concentrations the cells die of necrosis. - Highlights: • z-FA-CMK is toxic and induce cell death in the human T cells. • z-FA-CMK toxicity requires the CMK group, alanine and the benzyloxycarbonyl group. • z-FA-CMK induced apoptosis at low concentration and necrosis at high concentration.

  10. Expression of miRNA-122 Induced by Liver Toxicants in Zebrafish

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    Hyun-Sik Nam

    2016-01-01

    Full Text Available MicroRNA-122 (miRNA-122, also known as liver-specific miRNA, has recently been shown to be a potent biomarker in response to liver injury in mammals. The objective of this study was to examine its expression in response to toxicant treatment and acute liver damage, using the zebrafish system as an alternative model organism. For the hepatotoxicity assay, larval zebrafish were arrayed in 24-well plates. Adult zebrafish were also tested and arrayed in 200 mL cages. Animals were exposed to liver toxicants (tamoxifen or acetaminophen at various doses, and miRNA-122 expression levels were analyzed using qRT-PCR in dissected liver, brain, heart, and intestine, separately. Our results showed no significant changes in miRNA-122 expression level in tamoxifen-treated larvae; however, miRNA-122 expression was highly induced in tamoxifen-treated adults in a tissue-specific manner. In addition, we observed a histological change in adult liver (0.5 μM and cell death in larval liver (5 μM at different doses of tamoxifen. These results indicated that miRNA-122 may be utilized as a liver-specific biomarker for acute liver toxicity in zebrafish.

  11. Crataegus Monogyna Aqueous Extract Ameliorates Cyclophosphamide-Induced Toxicity in Rat Testis: Stereological Evidences

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    Hassan Malekinejad

    2012-01-01

    Full Text Available Cyclophosphamide (CP is extensively used as an antineoplastic agent for the treatment of various cancers, as well as an immunosuppressive agent. However, despite its wide spectrum of clinical uses, CP is known to cause several adverse effects including reproductive toxicity. Crataegus monogyna is one of the oldest pharmaceutical plants that have been shown to be cytoprotective by scavenging free radicals. The present study was conducted to assess whether Crataegus monogyna fruits aqueous extract with anti-oxidant properties, could serve as a protective agent against reproductive toxicity during CP treatment in a rat model. Male Wistar rats were categorized into four groups. Two groups of rats were administered CP at a dose of 5 mg in 5 ml saline/kg/day for 28 days by oral gavages. One of these groups received Crataegus monogyna aqueous extract at a dose of 20 mg/kg/day orally four hours after cyclophosphamide administration. A vehicle treated control group and a Crataegus monogyna control group were also included. The CP-treated group showed significant decreases in the body, testes and epididymides weights as well as many histological alterations. Stereological parameters and spermatogenic activities (Sertoli cell, repopulation and miotic indices were also significantly decreased by CP treatment. Notably, Crataegus coadministration caused a partial recovery in above-mentined parameters. These findings indicate that Crataegus monogyna may be partially protective against CP-induced testicular toxicity.

  12. Protection of the blood-brain barrier by pentosan against amyloid-β-induced toxicity.

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    Deli, Mária A; Veszelka, Szilvia; Csiszár, Boglárka; Tóth, Andrea; Kittel, Agnes; Csete, Mária; Sipos, Aron; Szalai, Anikó; Fülöp, Lívia; Penke, Botond; Abrahám, Csongor S; Niwa, Masami

    2010-01-01

    Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer's disease. Amyloid-β (Aβ) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Aβ showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic organelles and tight junctions could be observed in brain endothelial cells. Treatment with Aβ1-42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Aβ fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Aβ1-42. Sulfated polysaccharide pentosan could decrease the toxic effects of Aβ peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer's disease.

  13. The Effect of Ascorbic Acid on Mancozeb-Induced Toxicity in Rat Thymocytes.

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    Pavlovic, V; Cekic, S; Kamenov, B; Ciric, M; Krtinic, D

    2015-01-01

    Mancozeb, as a dithiocarbamate fungicide, has been found to exhibit toxicological manifestations in different cells, mainly by generation of free radicals which may alter antioxidant defence systems in cells. The effect of mancozeb on the cells of a primary lymphoid organ has not been studied. In the present study, the effects of mancozeb (0.2, 2 and 5 μg/ml) or mancozeb+ascorbic acid (100 μg/ml), or ascorbic acid alone or control medium alone on the levels of cell viability, apoptosis, intracellular reactive oxygen species production (ROS), mitochondrial membrane potential (MMP) and ATP levels in rat thymocytes were examined in vitro. Cells treated with mancozeb displayed a concentration-dependent increase of hypodiploid cells and ROS production followed by markedly decreased viability of the cells, MMP and ATP levels. Application of ascorbic acid significantly reduced cytotoxicity in cell cultures treated with 0.2 and 2 μg/ml of mancozeb, together with significantly decreased ROS levels and increased MMP and ATP levels. In cells treated with 5 μg/ml of mancozeb, ascorbic acid failed to reduce toxicity while simultaneously increasing the apoptosis rate of thymocytes. These results suggest that ROS plays a significant role in mancozeb-induced toxicity, through alteration of mitochondrial function. Ascorbic acid administration reduced the toxicity rate in cells treated with lower mancozeb concentrations, while it may have the ability to shift cells from necrosis to apoptosis in the presence of highest mancozeb concentrations.

  14. An alternative antidote therapy in amitriptyline-induced rat toxicity model: theophylline.

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    Oransay, Kubilay; Kalkan, Sule; Hocaoglu, Nil; Arici, Aylin; Tuncok, Yesim

    2011-01-01

    We planned this study in order to investigate the effects of theophylline on cardiovascular parameters in an anaesthetized rat model of amitriptyline toxicity. In the preliminary study, we tested theophylline as 1 mg/kg of bolus, followed by a 0.5-mg/kg infusion. Toxicity was induced by the infusion of 0.94 mg/kg/min of amitriptyline up to the point of a 40-45% inhibition of mean arterial pressure (MAP). The rats were randomized to two groups: a group of 5% dextrose bolus followed by 5% dextrose infusion, and another group with theophylline bolus followed by infusion. Amitriptyline caused a significant decrease in MAP and prolongation in QRS; however, it did not alter heart rate (HR). When compared to the dextrose group, theophylline administration increased MAP, shortened prolonged QRS duration, and increased HR (P  0.05). Bolus doses followed by a continuous infusion of theophylline were found to be effective in reversing the hypotension and QRS prolongation seen in amitriptyline toxicity. One of the possible explanations of this beneficial effect is nonselective adenosine antagonism of theophylline. Further studies are needed to reveal the exact mechanism of the observed effect.

  15. LINEAR ALKYL BENZENE SULPHONATE, A DETERGENT INDUCED TOXICITY ON THE GILL OF PUNTIUS TICTO FISH

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    Jain Varsha

    2011-10-01

    Full Text Available Detergents are common household products used for cleaning of domestic materials. The ‘after wash’ of the detergents are either drained into the aquatic environment such as ponds, lakes, rivers, streams, etc. or they find their way into the aquatic environment by natural sewage. Hence in the present study, the acute toxic and histopathological effects of a detergent, “Linear Alkyl Benzene Sulphonate” (LABS on the gill of Puntius ticto (a teleost fish were evaluated. For acute toxicity study, the fishes were exposed to LABS (Henko in graded concentrations (20-28 mg/L, except 22 mg/L for 24, 48, 72 and 96 hr duration. All 30 (100% fishes were died in the Henko concentration of 28 mg/L at 24 hr, indicating that the acute toxicity of LABS is dose dependent. The LC50 of Henko was found to be 25.5 mg/L. For histopathological study, the fishes were exposed to 2 mg/L Henko for one month. The histopathological examination of Henko-treated fish gill revealed severe changes in the epithelial lining of gill arch, gill rakers and gill filaments, suggesting that the LABS may induce the abnormal cellular structure in gill.

  16. Effects of Bee Venom on Glutamate-Induced Toxicity in Neuronal and Glial Cells

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    Sang Min Lee

    2012-01-01

    Full Text Available Bee venom (BV, which is extracted from honeybees, is used in traditional Korean medical therapy. Several groups have demonstrated the anti-inflammatory effects of BV in osteoarthritis both in vivo and in vitro. Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS. Changes in glutamate release and uptake due to alterations in the activity of glutamate transporters have been reported in many neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. To assess if BV can prevent glutamate-mediated neurotoxicity, we examined cell viability and signal transduction in glutamate-treated neuronal and microglial cells in the presence and absence of BV. We induced glutamatergic toxicity in neuronal cells and microglial cells and found that BV protected against cell death. Furthermore, BV significantly inhibited the cellular toxicity of glutamate, and pretreatment with BV altered MAP kinase activation (e.g., JNK, ERK, and p38 following exposure to glutamate. These findings suggest that treatment with BV may be helpful in reducing glutamatergic cell toxicity in neurodegenerative diseases.

  17. Green Tea Protects Testes against Atrazine-induced Toxicity in Rat

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    Reza Kheirandish

    2017-06-01

    Full Text Available Background: Atrazine (ATZ is a common herbicide in agriculture for control of grass and broad-leaved weeds. It persists in the environment and causes reproductive problems in both human and animals. The present study was aimed at protective effect of green tea against ATZ toxicity in the reproductive system of male rats. Methods: The present study was performed in Veterinary School, Shahid Bahonar University of Kerman in 2016. ATZ and treatment groups received ATZ daily 200 mg/kg BW orally for 14 d. In addition, 0.2% methanolic green tea extract was administrated in the treatment group. Results: In histopathologic investigation, number of germinal layers reduced in the most seminiferous tubules in the ATZ group and spermatids were absence. Necrotic spermatocytes, spermatids, and spermatozoa were evident in the testicular tubules. In the morphometric measurements, tubular diameter, germinal epithelium height, and meiosis index decreased significantly. Conclusion: Green tea extract had reduced testicular toxicity of atrazine significantly. ATZ induces toxicity through oxidative damage and green tea extract can protect the testes due to antioxidant activity of its polyphenols especially flavonoids.

  18. A comparison of potency differences among thyroid peroxidase (TPO) inhibitors to induce developmental toxicity and other thyroid gland-linked toxicities in humans and rats.

    Science.gov (United States)

    Motonaga, Kozo; Ota, Mika; Odawara, Kyoko; Saito, Shoji; Welsch, Frank

    2016-10-01

    The potencies of resorcinol, 6-propylthiouracil (PTU) and methimazole (MMI) for inducing developmental toxicity and neurotoxicity were compared in pregnant rats, regarded as valid model for human thyroid toxicity. Profound differences on maternal thyroid hormone levels (THs), maternal toxicity as well as developmental and neurotoxicity sequelae occurred. Resorcinol affected none of those end points. PTU and MMI caused significant effects. Therapy with either PTU or MMI during the first trimester of human pregnancy can cause reductions of maternal THs, accompanied by disruptions of prenatal development. Clinical MMI studies show sporadic evidence of teratogenic effects, with equivocal relation to thyroid peroxidase (TPO) inhibition. In recent decades no MMI associated prenatal toxicity has been reported, an outcome possibly related to carefully managed therapy. Orally administered resorcinol was rapidly absorbed, metabolized and excreted and was undetectable in the thyroid. In contrast, PTU or MMI accumulated. Resorcinol's potency to inhibit TPO was profoundly lower than that of PTU or MMI. Quantum chemical calculations may explain low resorcinol reactivity with TPO. Thus, distinctions in the target organ and the TPO inhibitory potency between these chemicals are likely contributing to different reductions of maternal THs levels and affecting the potency to cause developmental toxicity and neurotoxicity. Copyright © 2016. Published by Elsevier Inc.

  19. Protective effect of Juglans nigra on sodium arsenite-induced toxicity in rats

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    Solomon E Owumi

    2013-01-01

    Full Text Available Background: Consumption of arsenic contaminated water has been implicated in metalloid-induced carcinogenesis. Dietary intake of certain plant products with chemoprotective properties may protect against the onset of diseases and promote maintenance of health. Objectives: We investigated the outcome of black walnut Juglans nigra (JN consumption on sodium arsenite (SA-induced toxicity in rats. Materials and Methods: Wister albino rats were treated as follows: Control, SA only (positive control (2.5 mg/kg body weight, JN only (100 mg/kg weight, and JN+SA coadministered. After 5 weeks animals were sacrificed whole blood, femur, liver and testis harvested were assessed for hepatic transaminases and clastogenicity. Histology of the liver, sperm morphology and quality were also assessed. Data were analyzed (ANOVA and expressed as means ±SD. Results: SA treatment elevated hepatic transaminases level in serum (P < 0.05, induced histological changes in liver: fibroplasia and periportal hepatocytes infiltration by mononuclear cells. These changes were ameliorated by JN (P < 0.05 coadministration. SA induced micronuclei formation (P < 0.05. Again JN decreased (P < 0.05 micronuclei formation by 50%. Sperm count and motility decreased (P < 0.05 in all groups compared to control. Conclusion: JN showed no protection against arsenite effect on sperm quality. Hepatoprotective and anticlastogenic effects were apparent suggesting a chemopreventive potential active against arsenite genotoxicity and chromosomal instability which have implication for metalloid-induced carcinogenesis.

  20. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice

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    Silva-Filho, Saulo Euclides; Cardia, Gabriel Fernando Esteves; Cremer, Edivaldo; Bersani-Amado, Ciomar Aparecida

    2017-01-01

    High doses of acetaminophen (APAP) lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO) activity and nitric oxide (NO) production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP. PMID:28717379

  1. Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage.

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    Belenky, Peter; Ye, Jonathan D; Porter, Caroline B M; Cohen, Nadia R; Lobritz, Michael A; Ferrante, Thomas; Jain, Saloni; Korry, Benjamin J; Schwarz, Eric G; Walker, Graham C; Collins, James J

    2015-11-03

    Understanding how antibiotics impact bacterial metabolism may provide insight into their mechanisms of action and could lead to enhanced therapeutic methodologies. Here, we profiled the metabolome of Escherichia coli after treatment with three different classes of bactericidal antibiotics (?-lactams, aminoglycosides, quinolones). These treatments induced a similar set of metabolic changes after 30 min that then diverged into more distinct profiles at later time points. The most striking changes corresponded to elevated concentrations of central carbon metabolites, active breakdown of the nucleotide pool, reduced lipid levels, and evidence of an elevated redox state. We examined potential end-target consequences of these metabolic perturbations and found that antibiotic-treated cells exhibited cytotoxic changes indicative of oxidative stress, including higher levels of protein carbonylation, malondialdehyde adducts, nucleotide oxidation, and double-strand DNA breaks. This work shows that bactericidal antibiotics induce a complex set of metabolic changes that are correlated with the buildup of toxic metabolic by-products.

  2. Antioxidant activity of Gloriosa superba against paracetamol induced toxicity in experimental rats.

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    Mrs. Indhumathi.T

    2011-12-01

    Full Text Available Paracetamol was chosen to induce hepatotoxicity in rats. Gloriosa superba tubers were extracted and used for the treatment against paracetamol induced toxicity. In this study, the animals weredivided into three groups comprising of six animals each. Group I served as a control, group II animals were administered with paracetamol(200 μg/kg orally for 10 days, group III animals were received Gloriosa superba tubers aqueous extract (500 mg/kg/bw/po for 5 days followed by paracetamol(200 μg/kg orally for 2 days.Level of LPO was found to be increased during paracetamol intoxication with concomitant decrease in the activity of enzymic and non- enzymic antioxidants. The antioxidant enzyme levels were reverted to near normal in Group III rats which results the antioxidant activity of Gloriosa superba.

  3. Quantitative analysis of cytokine-induced vascular toxicity and vascular leak in the mouse brain.

    Science.gov (United States)

    Irwan, Yetty Y; Feng, Yi; Gach, H Michael; Symanowski, James T; McGregor, John R; Veni, Gopalkrishna; Schabel, Matthias; Samlowski, Wolfram E

    2009-09-30

    A storm of inflammatory cytokines is released during treatment with pro-inflammatory cytokines, such as interleukin-2 (IL-2), closely approximating changes initially observed during sepsis. These signals induce profound changes in neurologic function and cognition. Little is known about the mechanisms involved. We evaluated a number of experimental methods to quantify changes in brain blood vessel integrity in a well-characterized IL-2 treatment mouse model. Measurement of wet versus dry weight and direct measurement of small molecule accumulation (e.g. [(3)H]-H(2)O, sodium fluorescein) were not sensitive or reliable enough to detect small changes in mouse brain vascular permeability. Estimation of brain water content using proton density magnetic resonance imaging (MRI) measurements using a 7T mouse MRI system was sensitive to 1-2% changes in brain water content, but was difficult to reproduce in replicate experiments. Successful techniques included use of immunohistochemistry using specific endothelial markers to identify vasodilation in carefully matched regions of brain parenchyma and dynamic contrast enhanced (DCE) MRI. Both techniques indicated that IL-2 treatment induced vasodilation of the brain blood vessels. DCE MRI further showed a 2-fold increase in the brain blood vessel permeability to gadolinium in IL-2 treated mice compared to controls. Both immunohistochemistry and DCE MRI data suggested that IL-2 induced toxicity in the brain results from vasodilation of the brain blood vessels and increased microvascular permeability, resulting in perivascular edema. These experimental techniques provide us with the tools to further characterize the mechanism responsible for cytokine-induced neuropsychiatric toxicity.

  4. Doxorubicin-induced vascular toxicity--targeting potential pathways may reduce procoagulant activity.

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    Irit Ben Aharon

    Full Text Available INTRODUCTION: Previous study in mice using real-time intravital imaging revealed an acute deleterious effect of doxorubicin (DXR on the gonadal vasculature, as a prototype of an end-organ, manifested by a reduction in blood flow and disintegration of the vessel wall. We hypothesized that this pattern may represent the formation of microthrombi. We aimed to further characterize the effect of DXR on platelets' activity and interaction with endothelial cells (EC and to examine potential protectants to reduce DXR acute effect on the blood flow. METHODS: The effect of DXR on platelet adhesion and aggregation were studied in vitro. For in vivo studies, mice were injected with either low molecular weight heparin (LMWH; Enoxaparin or with eptifibatide (Integrilin(© prior to DXR treatment. Testicular arterial blood flow was examined in real-time by pulse wave Doppler ultrasound. RESULTS: Platelet treatment with DXR did not affect platelet adhesion to a thrombogenic surface but significantly decreased ADP-induced platelet aggregation by up to 40% (p<0.001. However, there was a significant increase in GPIIbIIIa-mediated platelet adhesion to DXR-exposed endothelial cells (EC; 5.7-fold; p<0.001 reflecting the toxic effect of DXR on EC. The testicular arterial blood flow was preserved in mice pre-treated with LMWH or eptifibatide prior to DXR (P<0.01. CONCLUSIONS: DXR-induced acute vascular toxicity may involve increased platelet-EC adhesion leading to EC-bound microthrombi formation resulting in compromised blood flow. Anti-platelet/anti-coagulant agents are effective in reducing the detrimental effect of DXR on the vasculature and thus may serve as potential protectants to lessen this critical toxicity.

  5. Photo-induced toxicity of titanium dioxide nanoparticles to Daphnia magna under natural sunlight.

    Science.gov (United States)

    Mansfield, C M; Alloy, M M; Hamilton, J; Verbeck, G F; Newton, K; Klaine, S J; Roberts, A P

    2015-02-01

    Titanium dioxide nanoparticles (TiO2 NP) are one of the most abundantly utilized nanoparticles in the world. Studies have demonstrated the ability of the anatase crystal of TiO2 NP to produce reactive oxygen species (ROS) in the presence of ultraviolet radiation (UVR), a co-exposure likely to occur in aquatic ecosystems. The goal of this study was to examine the photo-induced toxicity of anatase TiO2 NP under natural sunlight to Daphnia magna. D. magna were exposed to a range of UVR intensities and anatase TiO2 concentrations in an outdoor exposure system using the sun as the source of UVR. Different UVR intensities were achieved using UVR opaque and transparent plastics. AnataseTiO2-NP demonstrated the reciprocal relationship seen in other phototoxic compounds such as polycyclic aromatic hydrocarbons (PAHs) at higher UVR treatments. The calculated 8h LC50 of anatase TiO2 NP was 139 ppb under full intensity ambient natural sunlight, 778 ppb under 50% natural sunlight, and >500 ppm under 10% natural sunlight. Mortality was also compared between animals allowed to accumulate a body burden of anatase TiO2 for 1h and organisms whose first exposure to anatase TiO2 aqueous suspensions occurred under UVR. A significantly greater toxic effect was observed in aqueous, low body burden suspensions than that of TiO2 1h body burdens, which is dissimilar from the model presented in PAHs. Anatase TiO2 presents a unique photo-induced toxic model that is different than that of established phototoxic compounds.

  6. Ameliorative efficacy of tetrahydrocurcumin against arsenic induced oxidative damage, dyslipidemia and hepatic mitochondrial toxicity in rats.

    Science.gov (United States)

    Muthumani, M; Miltonprabu, S

    2015-06-25

    Arsenic (As) is a well-known human carcinogen and a potent hepatotoxin. Environmental exposure to arsenic imposes a serious health hazard to humans and other animals worldwide. Tetrahydrocurcumin (THC), one of the major metabolites of curcumin, exhibits many of the same physiological and pharmacological activities as curcumin and in some systems may exert greater antioxidant activity than the curcumin. It has been reported that THC has antioxidant efficacy attributable to the presence of identical β-diketone of 3rd and 5th substitution in heptane moiety. In the present study, rats were orally treated with arsenic alone (5 mg kg(-1) bw/day) with THC (80 mg kg(-1) bw/day) for 28 days. Hepatotoxicity was measured by the increased activities of serum hepatospecific enzymes, namely aspartate transaminase, alanine transaminase, alkaline phosphatase and bilirubin along with increased elevation of lipid peroxidative markers, thiobarbituric acid reactive substances. And also elevated levels of serum cholesterol, triglycerides, free fatty acids and phospholipids were observed in arsenic intoxicated rats. These effects of arsenic were coupled with enhanced mitochondrial swelling, inhibition of cytochrome c oxidase, Ca(2+)ATPase and a decrease in mitochondrial calcium content. The toxic effect of arsenic was also indicated by significantly decreased activities of enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase along with non-enzymatic antioxidant such as reduced glutathione. Administration of THC exhibited significant reversal of arsenic induced toxicity in hepatic tissue. All these changes were supported by the reduction of arsenic concentration and histopathological observations of the liver. These results suggest that THC has a protective effect over arsenic induced toxicity in rat. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. protective effect of tetracycline against dermal toxicity induced by Jellyfish venom.

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    Changkeun Kang

    Full Text Available BACKGROUND: Previously, we have reported that most, if not all, of the Scyphozoan jellyfish venoms contain multiple components of metalloproteinases, which apparently linked to the venom toxicity. Further, it is also well known that there is a positive correlation between the inflammatory reaction of dermal tissues and their tissue metalloproteinase activity. Based on these, the use of metalloproteinase inhibitors appears to be a promising therapeutic alternative for the treatment of jellyfish envenomation. METHODOLOGY AND PRINCIPAL FINDINGS: Tetracycline (a metalloproteinase inhibitor has been examined for its activity to reduce or prevent the dermal toxicity induced by Nemopilema nomurai (Scyphozoa: Rhizostomeae jellyfish venom (NnV using in vitro and in vivo models. HaCaT (human keratinocyte and NIH3T3 (mouse fibroblast incubated with NnV showed decreases in cell viability, which is associated with the inductions of metalloproteinase-2 and -9. This result suggests that the use of metalloproteinase inhibitors, such as tetracycline, may prevent the jellyfish venom-mediated local tissue damage. In vivo experiments showed that comparing with NnV-alone treatment, tetracycline pre-mixed NnV demonstrated a significantly reduced progression of dermal toxicity upon the inoculation onto rabbit skin. CONCLUSIONS/SIGNIFICANCE: It is believed that there has been no previous report on the therapeutic agent of synthetic chemical origin for the treatment of jellyfish venom-induced dermonecrosis based on understanding its mechanism of action except the use of antivenom treatment. Furthermore, the current study, for the first time, has proposed a novel mechanism-based therapeutic intervention for skin damages caused by jellyfish stings.

  8. Gallic acid protects against cyclophosphamide-induced toxicity in testis and epididymis of rats.

    Science.gov (United States)

    Oyagbemi, A A; Omobowale, T O; Saba, A B; Adedara, I A; Olowu, E R; Akinrinde, A S; Dada, R O

    2016-05-01

    The protective role of gallic acid (GA) on reproductive toxicity induced by cyclophosphamide (CPA), an antineoplastic drug, was investigated in male Wistar rats. Sixty rats were grouped into 10 rats per group. Group 1 (control) received distilled water. Rats in groups 2 and 3 received GA alone at 60 and 120 mg kg(-1) for 14 consecutive days, respectively. Group 4 received a single intraperitoneal dose of CPA at 200 mg kg(-1) on day 1. Groups 5 and 6 received a single dose of CPA (200 mg kg(-1) ) intraperitoneally on day 1 followed by treatment with GA at 60 and 120 mg kg(-1) for 14 consecutive days, respectively. In testes and epididymis of the treated rats, CPA administration resulted in significant elevation (P < 0.05) in malondialdehyde (MDA), nitrite and hydrogen peroxide levels. There was a significant decrease in the activities of superoxide dismutase and glutathione-S-transferase. Furthermore, there were significant reductions in plasma luteinising hormone (LH), follicle stimulation hormone (FSH) and testosterone levels, which were accompanied by significant decrease in sperm motility and viability in CPA-treated rats. Histological examination revealed marked testicular and epididymal atrophy in CPA alone treated rats and these aberrations were reversed by GA. In conclusion, GA has capacity to protect against reproductive toxicity induced by cyclophosphamide.

  9. The galactose-induced decrease in phosphate levels leads to toxicity in yeast models of galactosemia.

    Science.gov (United States)

    Machado, Caio M; De-Souza, Evandro A; De-Queiroz, Ana Luiza F V; Pimentel, Felipe S A; Silva, Guilherme F S; Gomes, Fabio M; Montero-Lomelí, Mónica; Masuda, Claudio A

    2017-02-14

    Classic galactosemia is an inborn error of metabolism caused by deleterious mutations in the GALT gene. A number of evidences indicate that the galactose-1-phosphate accumulation observed in patient cells is a cause of toxicity in this disease. Nevertheless, the consequent molecular events caused by the galactose-1-phosphate accumulation remain elusive. Here we show that intracellular inorganic phosphate levels decreased when yeast models of classic galactosemia were exposed to galactose. The decrease in phosphate levels is probably due to the trapping of phosphate in the accumulated galactose-1-phosphate since the deletion of the galactokinase encoding gene GAL1 suppressed this phenotype. Galactose-induced phosphate depletion caused an increase in glycogen content, an expected result since glycogen breakdown by the enzyme glycogen phosphorylase is dependent on inorganic phosphate. Accordingly, an increase in intracellular phosphate levels suppressed the galactose effect on glycogen content and conferred galactose tolerance to yeast models of galactosemia. These results support the hypothesis that the galactose-induced decrease in phosphate levels leads to toxicity in galactosemia and opens new possibilities for the development of better treatments for this disease.

  10. Toxicity and characterization of cholinesterase-inhibition induced by diisopropyl fluorophosphate in Artemia salina larvae.

    Science.gov (United States)

    Sánchez-Fortún, S; Barahona, M V

    2009-03-01

    The acute toxicity of diisopropyl fluorophosphate (DFP) on three age classes of Artemia salina was evaluated. An increase in toxicity of this organophosphorous (OP) compound was found following longer development of A. salina larvae. The effects of pretreatment with the non-selective muscarinic antagonist atropine, the two reversible acetylcholinesterase inhibitors physostigmine and pyridostigmine, and the cholinesterase-reactivating oxime 2-pyridine aldoxime methoiodide (2-PAM), as individual and combined pretreatments, on DFP-induced lethality in 24h Artemia were also investigated. The lethal action of DFP was not prevented by pretreatment of 24h Artemia with atropine, physostigmine, and pyridostigmine, while 2-PAM proved effective against intoxication with this OP compound. The inhibitory effects of combinations of atropine (10(-5)M) plus 2-PAM or physostigmine were greater than those elicited by either drug alone, with the maximum protection afforded being 100%. Pretreatment with 2-PAM (10(-6)M) plus physostigmine or pyridostigmine was ineffective. These results suggest that the combinations of atropine plus 2-PAM or physostigmine are effective in the prevention of the lethal effects induced by DFP in A. salina larvae.

  11. Protection against adriamycin (doxorubicin-induced toxicity in mice by several clinically used drugs.

    Directory of Open Access Journals (Sweden)

    Shinozawa,Shinya

    1987-02-01

    Full Text Available Protective effects of clinically used drugs against adriamycin (ADM-induced toxicity were studied in ICR mice. The control mice, which were administered 15 mg/kg of ADM twice, survived 7.48 +/- 1.99 days (mean +/- S.D.. The survival times of mice treated with the following drugs, expressed as a percent of that of the control group, were 293.6% for coenzyme Q10 (Co Q10, 2 mg/kg, 402.2% for dextran sulfate (MDS, 300 mg/kg, 121.6% for flavin adenine dinucleotide (20 mg/kg, 236.3% for adenosine triphosphate disodium (50 mg/kg, 213.7% for reduced glutathione (100 mg/kg, 121.6% for phytonadione (50 mg/kg, 155.2% for inositol nicotinate (Ino-N, 500 mg/kg, 335.5% for nicomol (1000 mg/kg, 157.5% for nicardipine (10 mg/kg and 123.3% for dipyridamol (50 mg/kg. Anti-hyperlipemic agents such as MDS, nicomol, Ino-N and Co Q10 strongly protected against the ADM-induced toxicity, and the mice administered these drugs lived significantly longer than the control mice. The mechanism of the protective effect was discussed.

  12. Modulation of rifampicin toxicity by 6 MFA, an interferon inducer obtained from fungus Aspergillus ochraceus.

    Science.gov (United States)

    Dhuley, J N; Naik, S R

    1998-06-02

    The effect of 6 MFA (Sixth mycelial fraction of acetone), an interferon inducer obtained from fungus Aspergillus ochraceus, on rifampicin toxicity was studied in rats. Chronic oral administration of rifampicin (1 g/kg per day) for 30 days produced thrombocytopenia, hemolytic anaemia, transient leukopenia and increased nucleated cells in bone marrow and decreased weights of thymus and spleen significantly in male rats. Furthermore, chronic administration of rifampicin induced significant increase in cytochrome P-450 contents, lipid peroxidation (LPO) and superoxide dismutase (SOD) activity in liver and bone marrow. Simultaneous administration of 6 MFA (100 mg/kg; i.p.) on alternate days for a period of 30 days prevented most of the adverse effects of rifampicin, mentioned earlier and also restored the hepatic architecture histologically. The LPO, cytochrome P 450 content, lymphocyte and bone marrow cell counts returned to normal level whereas SOD activity was further increased. The 6 MFA treatment enhanced the SRBC antibody litre in rifampicin-treated rats. Thus, beneficial effects of 6 MFA in the amelioration of mediated rifampicin toxicity observed in the present study may be through induction of interferons and their associated effects.

  13. Ameliorative potential of Tephrosia purpurea extract against arsenic induced toxicity in wistar rats

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    Birendra kumar Roy

    2013-05-01

    Full Text Available Aim: The present investigation has been conducted to evaluate the protective activity of Tephrosia purpurea extract (TPE against arsenic induced toxicity. Materials and Methods: For this study, twenty four wistar albino rats were taken. Control group, group – I rats were given sodium arsenite @ 10 mg/kg and group – II rats were treated with TPE @ 500 mg/kg along with sodium arsenite @ 10 mg/kg (daily oral for 28 days. On 29th day animals were slaughtered and various parameters were determined. Serum biomarkers, haematological parameter analysis and histomorphological examination are carried out with estimation of arsenic concentration in tissues. Results: Oral administration of sodium arsenite @ 10 mg/kg for 28 days resulted in a significant decrease in Hb%, TEC and TLC, significant increase of serum glucose, cholesterol, calcium and significant increase in arsenic accumulation in tissues. Histopathological results of intestine revealed haemorrhagic enteritis along with loss of villi. Treatment with Tephrosia purpurea @ 500 mg/kg significantly decreased the elevated glucose, LDH levels, along with significant increase haematological levels towards normal. There was reduced haemorrhagic enteritis and presence of intact villi, as compared to arsenic treated group. But there was no significant difference in serum calcium, serum cholesterol and arsenic concentration in tissues, when compared with arsenic treated group. Conclusion: The study conclude that supplementation of TPE (500 mg/kg daily oral for 28 days has shown protection against arsenic induced toxicity by its protective effect. [Vet World 2013; 6(8.000: 493-496

  14. Phytoremedial effect of Withania somnifera against arsenic-induced testicular toxicity in Charles Foster rats

    Directory of Open Access Journals (Sweden)

    Arun Kumar

    2015-06-01

    Full Text Available Objective: The main objective of the current study was to observe the ameliorative effect of Withania somnifera on arsenic-induced testicular toxicity by exploring the crucial parameters such as sperm counts, sperm motility, hormonal assay and lipid peroxidation including histopathology. Materials and Methods: In the present study, arsenic in the form of sodium arsenite was administered orally to male Charles Foster rats for 45 days. Thereafter, ethanolic root extract of Withania somnifera was administered for 30 days to observe its ameliorative effect on male reproductive system. Results: The study revealed that after administration of sodium arsenite, there was a decrease in the sperm counts and sperm motility accompanied by an increased incidence of sperm abnormalities and hormonal imbalance leading to infertility. However, after administration of Withania somnifera, there was significant reversal in the parameters denoting that it not only possesses antioxidant and rejuvenating property but also maintains the cellular integrity of testicular cells leading to normal functioning of it. Conclusion: The study concludes that Withania somnifera possesses phytoremedial effect. It is one of the best antidotes against arsenic-induced reproductive toxicity.

  15. Grape Seed Proanthocyanidin Extract Alleviates Arsenic-induced Oxidative Reproductive Toxicity in Male Mice

    Institute of Scientific and Technical Information of China (English)

    LI Shu Gang; GUO Shu Xia; DING Yu Song; NIU Qiang; XU Shang Zhi; PANG Li Juan; MA Ru Lin; JING Ming Xia; FENG Gang Ling; LIU Jia Ming

    2015-01-01

    Objective To determine the ability of grape seed proanthocyanidin extract (GSPE) in alleviating arsenic-induced reproductive toxicity. Methods Sixty male Kunming mice received the following treatments by gavage: normal saline solution (control); arsenic trioxide (ATO; 4 mg/kg); GSPE (400 mg/kg); ATO+GSPE (100 mg/kg);ATO+GSPE (200 mg/kg) and ATO+GSPE (400 mg/kg). Thereafter, the mice were sacrificed and weighed, and the testis was examined for pathological changes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO1), glutathione S-transferase (GST), NAD(P)H dehydrogenase, and quinone 1 (NQO1) expression in the testis was detected by real-time PCR. Superoxide dismutase (SOD), glutathione (GSH), total antioxidative capability (T-AOC), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), and reproductive indexes were analyzed. Results ATO-treated mice showed a significantly decreased sperm count and testis somatic index and activity levels of SOD, GSH, and T-AOC than control group. Compared to the ATO-treated group, ATO+GSPE group showed recovery of the measured parameters. Mice treated with ATO+high-dose GSPE showed the highest level of mRNA expression of Nrf2, HO, NQO1, and GST. Conclusion GSPE alleviates oxidative stress damage in mouse testis by activating Nrf2 signaling, thus counteracting arsenic-induced reproductive toxicity.

  16. Hepatoprotective Effect of Citrus limon Fruit Extract against Carbofuran Induced Toxicity in Wistar Rats

    Directory of Open Access Journals (Sweden)

    Sunil Kumar Jaiswal

    2015-01-01

    Full Text Available Carbofuran (2,3-dihydro-2,2-dimethyl-7-benzofuranol methylcarbamate, is known to induce oxidative stress and to cause inhibition of acetylcholinesterase activity. The present work was envisaged to evaluate the effect of carbofuran on redox indices and its interactions with hepatic markers in rat. The ameliorating effect of Citrus limon fruit extract on carbofuran induced toxicity was also monitored. The results indicated that carbofuran treatment caused significant alterations in the levels of activities of AST, ALT, and LDH in liver tissues and serum. The levels of enzymatic oxidative stress markers such as SOD and catalase and nonenzymatic redox molecules such as total thiol, GSH, and protein thiol also showed significant perturbations in rat liver due to carbofuran treatment. The administration of Citrus limon fruit extract, however, was able to markedly ameliorate the toxicity of carbofuran by protecting the levels of aforesaid biomarkers to near normal levels. The ameliorative effect of Citrus limon fruit extract may be due to the presence of different antioxidants in it which may neutralize the ROS and RNS generated in the body tissue due to pesticide stress. These results suggested that Citrus limon fruit extract may be utilized as a potential supplement in proper management of pesticide intoxication in association with relevant therapeutics.

  17. Ameliorative effect of propolis on the cadmium-induced reproductive toxicity in male albino rats.

    Science.gov (United States)

    Çilenk, Kübra Tuğçe; Öztürk, İsmet; Sönmez, Mehmet Fatih

    2016-10-01

    Propolis is a potent antioxidant and a free radical scavenger. The present study aimed to investigate protective effects of propolis extract on cadmium-induced testicular damage, apoptosis, HIF-1α expression and toxicity in rat's testis tissue. A total of 32 male rats were equally divided into four study groups namely, control, Cd (1mg/kg/day), Cd+propolis (50mg/kg/day) and propolis. The rats were decapitated under ketamine anesthesia and their testes tissues were removed. Serum testosterone, tissue malondialdehyde and HIF-1α levels, HIF-1α expression, apoptosis and histopathological damage scores were then compared. In the Cd group, the diameters of seminiferous tubules, tubular biopsy score of Johnsen and serum testosterone levels were decreased compared control group, but tissue HIF-1α and tissue MDA levels was higher than control group. The immunoreactivity of HIF-1α and the number of apoptotic cells were increased in Cd group. Furthermore, the propolis treated group showed an improved histological appearance in the Cd group. Thus, the results suggest that propolis acts as a potent protective agent against Cd-induced testicular toxicity in rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Chlorogenic and caftaric acids in liver toxicity and oxidative stress induced by methamphetamine.

    Science.gov (United States)

    Koriem, Khaled M M; Soliman, Rowan E

    2014-01-01

    Methamphetamine intoxication can cause acute hepatic failure. Chlorogenic and caftaric acids are the major dietary polyphenols present in various foods. The aim of this study was to evaluate the protective role of chlorogenic and caftaric acids in liver toxicity and oxidative stress induced by methamphetamine in rats. Thirty-two male albino rats were divided into 4 equal groups. Group 1, which was control group, was injected (i.p) with saline (1 mL/kg) twice a day over seven-day period. Groups 2, 3, and 4 were injected (i.p) with methamphetamine (10 mg/kg) twice a day over seven-day period, where groups 3 and 4 were injected (i.p) with 60 mg/kg chlorogenic acid and 40 mg/kg caftaric acid, respectively, one day before methamphetamine injections. Methamphetamine increased serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, cholesterol, low-density lipoprotein, and triglycerides. Also, malondialdehyde in serum, liver, and brain and plasma and liver nitric oxide levels were increased while methamphetamine induced a significant decrease in serum total protein, albumin, globulin, albumin/globulin ratio, brain serotonin, norepinephrine and dopamine, blood and liver superoxide dismutase, and glutathione peroxidase levels. Chlorogenic and caftaric acids prior to methamphetamine injections restored all the above parameters to normal values. In conclusion, chlorogenic and caftaric acids before methamphetamine injections prevented liver toxicity and oxidative stress where chlorogenic acid was more effective.

  19. Intervention of ginger or propolis ameliorates methotrexate-induced ileum toxicity.

    Science.gov (United States)

    Abdul-Hamid, Manal; Salah, Marwa

    2016-02-01

    The long-term clinical use of methotrexate (MTX) is restricted due to its severe intestinal toxicity. The protective effect of ginger or propolis on the toxicity induced by MTX is relatively less understood, so the possible protective effect of ginger or propolis, used separately, was investigated. A total of 60 male albino rats were divided into six groups as follows: (1) control group; (2) ginger group; (3) propolis group; (4) MTX group; (5) ginger + MTX group; and (6) propolis + MTX group. The present results show that MTX caused ileum injury, including shortening and fusion of the villi, inflammatory cell infiltration and goblet cell depletion. Administration of ginger or propolis ameliorated the MTX-induced ileum injury as shown by histological, immunohistochemical and ultrastructural investigations and statistical analysis. This is revealed by intact villi, which shows marked increase in brown colouration of proliferating cell nuclear antigen positive nuclei in the crypts region, improvement in the number of goblet cells and brush border length of ileum. The current results conclude the efficacy and safety of ginger and propolis, which may be due to their antioxidant properties.

  20. Uranium-induced oxidative stress in Arabidopsis thaliana: influence of pH on uranium toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Horemans, N.; Saenen, E.; Vanhoudt, N.; Vandenhove, H.; Biermans, G.; Van Hees, M. [SCK.CEN (Belgium); Vangronsveld, J.; Cuypers, A. [Hasselt University (Belgium)

    2014-07-01

    , the EC50 value for leaf growth reduction at pH 4.5 (27 ± 5.2 μM U) was 2 times lower than the EC50 value observed at pH 7.5 (53 ± 3.5 μM U). This again indicates that U is more toxic at low pH, which was confirmed by the measurement of membrane damage which was present at lower concentrations at pH 4.5 as pH 7.5. These differences in toxicity can possibly be related to the different U species present at both pH levels. In addition, since the U concentration in the leaves is very low, root-to-shoot signalling may be involved in the activation of leaf stress responses. Finally, at both pH levels, ascorbate biosynthesis was induced, possibly indicating an important role for this metabolite in scavenging ROS after U exposure. In conclusion, the pH strongly influences U toxicity, with more toxic effects observed at low pH. To support our data, the U speciation and micro-localization in the plants will be determined in order to define the species of U that are responsible for the toxicity. Document available in abstract form only. (authors)

  1. Elemental changes in hemolymph and urine of Rhodnius prolixus induced by in-vivo exposure to mercury: A study using synchrotron radiation total reflection X-ray fluorescence

    Science.gov (United States)

    Mantuano, Andrea; Pickler, Arissa; Barroso, Regina C.; de Almeida, André P.; Braz, Delson; Cardoso, Simone C.; Gonzalez, Marcelo S.; Figueiredo, Marcela B.; Garcia, Eloi S.; Azambuja, Patricia

    2012-05-01

    In recent years, the effects of pollution on the health of humans and other vertebrates were extensively studied. However, the effects on some invertebrates are comparatively unknown. Recent studies have demonstrated that toxic metals interfere with the reproduction, development and immune defenses of some terrestrial and marine invertebrates. Some environmental conditions including pollution produce chronic and acute effects on different animal's organs and systems. In this work, we investigated changes in the concentrations of Cl, K, Ca, Fe and Zn in Rhodnius prolixus as insect model. The elements were quantified using urine and hemolymph samples collected on different days after feeding the insects with blood containing HgCl2. The synchrotron radiation total reflection X-ray fluorescence measurements were carried at the X-ray fluorescence beamline facility in Brazilian Synchrotron Light Laboratory. The observation reveals that the calcium level was higher in the hemolymph than in urine. On the other hand, the urine collected from insects treated with HgCl2 showed higher level of Cl than hemolymph samples. Ca, Fe and Zn concentrations decrease drastically in urine samples collected after 2 days of HgCl2 treatment. The regulation of triatomines excretion was discussed pointing out the importance of trace elements.

  2. Betanin attenuates paraquat-induced liver toxicity through a mitochondrial pathway.

    Science.gov (United States)

    Han, Junyan; Zhang, Zongju; Yang, Shaobin; Wang, Jun; Yang, Xuelian; Tan, Dehong

    2014-08-01

    We attempted to determine whether betanin (from natural pigments) that has anti-oxidant properties would be protective against paraquat-induced liver injury in Sprague-Dawley rats. Paraquat was injected intraperitoneally into rats to induce liver toxicity. The rats were randomly divided into four groups: a control group, a paraquat group, and two groups that received betanin at doses of 25 and 100mg/kg/day three days before and two days after they were administered paraquat. We evaluated liver histopathology, serum liver enzymatic activities, oxidative stress, cytochrome P450 (CYP) 3A2 mRNA expression, and mitochondrial damage. The rats that were injected with paraquat incurred liver injury, evidenced by histological changes and elevated serum aspartate aminotransferase and alanine aminotransferase levels; paraquat also led to oxidative stress, an increase of cytochrome P450 3A2 mRNA expression, and mitochondrial damage, indicated by mitochondrial membrane swelling, reduced mitochondrial cytochrome C, and apoptosis-inducing factor protein levels. Pathological damage and all of the above mentioned markers were lesser in the animals treated with betanin than in those who received paraquat alone. Betanin had a protective effect against paraquat-induced liver damage in rats. The mechanism of the protection appears to be the inhibition of CYP 3A2 expression and protection of mitochondria.

  3. Hepatoprotective potential of kumaryasava and its concentrate against CCl4-induced hepatic toxicity in Wistar rats

    Science.gov (United States)

    Khan, Mohammad Ahmed; Gupta, Arun; Sastry, J. L. N.; Ahmad, Sayeed

    2015-01-01

    Objective: Kumaryasava (KS) is a marketed Ayurvedic formulation containing Aloe vera as the main ingredient. It has been used widely for the treatment of liver disorders; however, there is a lack of modern scientific data on hepatoprotection. The recommended dose of KS is high and up to 60 mL/day. The present study describes the preparation of new KS concentrate and evaluation of comparative hepatoprotective activity of KS and prepared KS concentrate at one-third of KS dose against CCl4-induced hepatic toxicity. Materials and Methods: Animals were divided into different groups (n = 6). The first group received normal saline (control) 1.0 mL/Kg/day p.o. for 10 days. The second group (toxicant) was given normal saline 1.0 mL/Kg/day p.o. for 10 days with CCl4 in olive oil (1:1 v/v) at 1.0 mL/Kg/day p.o. Third, fourth, and fifth groups received KS, KS concentrate and a marketed formulation as standard) at doses of 5.0 mL/Kg/day p.o., 1.6 mL/Kg/day p.o., and 100 mL/Kg/day p.o. (tablet suspended in water using 0.1% carboxymethyl cellulose) respectively for 10 days along with CCl4 as given to the toxicant group. On the 11th day, blood was withdrawn from retro-orbital plexus and serum was separated for biochemical estimation of serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), and albumin levels. Later, animals were sacrificed under high dose of anesthesia to remove liver tissue, which were removed and washed with ice cold saline for the estimation of lipid peroxidation. Liver tissue from each group was also fixed in 10% formalin for histopathological analysis. Results: Results demonstrated that both KS and KS concentrate showed the protection against CCl4-induced hepatic toxicity. This was evident from the reduction in serum SGOT, SGPT, ALP levels, and elevation in serum albumin levels observed post treatment of CCl4 treated rats with KS and KS concentrate, which were supported by histopathological data

  4. Effect of Physalis peruviana L. on cadmium-induced testicular toxicity in rats.

    Science.gov (United States)

    Othman, Mohamed S; Nada, Ahmed; Zaki, Hassan S; Abdel Moneim, Ahmed E

    2014-06-01

    Cadmium (Cd) stimulates the production of reactive oxygen species and causes tissue damage. We investigated here the protective effect of Physalis peruviana L. (family Solanaceae) against cadmium-induced testes toxicity in rats. Twenty-eight Wistar albino rats were used. They were divided into four groups (n=7). Group 1 was used as control. Group 2 was intraperitoneally injected with 6.5 mg/kg body weight (bwt) of cadmium chloride for 5 days. Group 3 was orally treated with 200 mg/kg bwt of methanolic extract of physalis (MEPh). Group 4 was pretreated with MEPh before cadmium for 5 days. Changes in body and testes weights were determined. Oxidative stress markers, antioxidant enzymes, and testosterone level were measured. Histopathological changes of testes were examined, and the immunohistochemical staining for the proapoptotic (caspase-3) protein was performed. The injection of cadmium caused a significant decrease in body weight, while a significant increase in testes weight and testes weight index was observed. Pretreatment with MEPh was associated with significant reduction in the toxic effects of Cd as shown by reduced testicular levels of malondialdehyde, nitric oxide, and caspase-3 expression and increased glutathione content, and the activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and testosterone were also increased. Testicular histopathology showed that Cd produced an extensive germ cell apoptosis, and the pretreatment of MEPh in Cd-treated rats significantly reduced Cd-induced testicular damage. On the basis of the above results, it can be hypothesized that P. peruviana L. has a protective effect against cadmium-induced testicular oxidative stress and apoptosis in the rat.

  5. Protective role of pectin against cadmium-induced testicular toxicity and oxidative stress in rats.

    Science.gov (United States)

    Koriem, Khaled M M; Fathi, Gamal E; Salem, Huda A; Akram, Nabil H; Gamil, Sofie A

    2013-05-01

    Cadmium has been classified as an environmental pollutant and human carcinogen. Pectin is a family of complex polysaccharides that function as hydrating agents and cementing materials for the cellulosic network. The aim of this study was to evaluate the protective role of pectin against cadmium-induced testicular toxicity and oxidative stress in rats. Forty male Wistar rats were divided into five equal groups. Groups 1 and 2 were injected intraperitoneally (i.p.) saline (1 mg/kg) and pectin (50 mg/kg), respectively, two days/weeks over three weeks period. Groups 3-5 were injected i.p. with 1 mg/kg cadmium two days/week while groups 4 and 5 co-administrated i.p. with 25 and 50 mg/kg pectin, respectively, three days/week over three weeks period. The results of the present work revealed that cadmium-exposed rats showed decrease in serum testosterone, dehydroepiandrosterone sulfate and lactate dehydrogenase. Testicular cholesterol, total protein, glucose-6-phosphate dehydrogenase, 3β-hydroxysteroid dehydrogenase, superoxide dismutase, glutathione peroxidase, catalase, glutathione S-transferase and reduced glutathione levels were also decreased while testicular malondialdehyde level was increased after cadmium injection. On the other hand, serum luteinizing hormone, follicle stimulating hormone, sex hormone binding globulin and γ-glutamyl transpeptidase were increased after cadmium exposure. Cadmium also induced sperms loss. Co-administration of pectin with cadmium restores all the above parameters and sperms to the normal levels where pectin at higher dose was more effective than lower one. These results were supported by histochemical investigations. In conclusion, pectin can counteract the testicular toxicity and oxidative stress induced by cadmium and the effect was dose-dependent.

  6. Effects of ZnO Nanoparticles on Dimethoate-Induced Toxicity in Mice.

    Science.gov (United States)

    Yan, Xincheng; Rong, Rui; Zhu, Shanshan; Guo, Mingchun; Gao, Shang; Wang, Shasha; Xu, Xiaolong

    2015-09-23

    The extensive applications of ZnO nanoparticles (nano ZnO) and dimethoate have increased the risk of people's coexposure to nano ZnO and dimethoate. Therefore, we evaluated in this study the effects of nano or bulk ZnO on dimethoate-induced toxicity in mice. The serum biochemical parameters, biodistributions, oxidative stress responses, and histopathological changes in mice were measured after intragastric administration of nano or bulk ZnO and/or dimethoate for 14 days. Oral administration of nano or bulk ZnO at a dose of 50 mg/kg did not cause obvious injury in mice. In contrast, oral administration of dimethoate at a dose of 15 mg/kg induced observable oxidative damage in mice. Co-administration of nano or bulk ZnO with dimethoate significantly increased Zn accumulation by 30.7 ± 1.7% or 29.7 ± 2.4% and dimethoate accumulation by 42.8 ± 2.1% or 46.6 ± 2.9% in the liver, respectively. The increased accumulations of dimethoate and Zn in the liver reduced its cholinesterase activity from 5.64 ± 0.45 U/mg protein to 4.67 ± 0.42 U/mg protein or 4.76 ± 0.45 U/mg protein for nano or bulk ZnO, respectively. Furthermore, the accumulations of dimethoate and Zn in liver also increased hepatic oxidative stress, resulting in severe liver damage. Both nano and bulk ZnO dissolved quickly in acidic gastric fluid, regardless of particle size; therefore, they had nearly identical enhanced effects on dimethoate-induced toxicity in mice.

  7. Protection by pentoxifylline of diazinon-induced toxic stress in rat liver and muscle.

    Science.gov (United States)

    Amirkabirian, Nasim; Teimouri, Fatemeh; Esmaily, Hadi; Mohammadirad, Azadeh; Aliahmadi, Atousa; Abdollahi, Mohammad

    2007-01-01

    ABSTRACT The effects of diazinon, pentoxifylline, and their combination therapy on plasma glucose, the key enzymes of glycogenolysis and gluconeogenesis, and oxidative stress were studied in rat liver and muscle. Oxidative stress was determined by measuring the concentration of lipid peroxides and assessing total antioxidant capacity. Diazinon (60 mg/kg) and pentoxifylline (100 mg/kg) were administrated by gavage. Administration of diazinon increased blood glucose, hepatic glycogen phosphorylase (GP), and phosphoenol pyruvate carboxykinase (PEPCK) by 160.65%, 117.2%, and 93.5%, respectively, while it decreased plasma cholinesterase (ChE) by 53.82%. Diazinon-induced oxidative stress was demonstrated by decreased total antioxidant capacity and enhanced lipid peroxidation by 52.61% and 280% in liver and by 40.02% and 46.6% in muscle, respectively. Pentoxifylline increased plasma glucose, hepatic GP, and PEPCK by 98.65%, 60%, and 79.86%, respectively, while it did not change plasma ChE, liver and muscle lipid peroxides, and total antioxidant capacity. In combination therapy, pentoxifylline did not alter diazinon-induced change in muscle GP activity but restored a diazinon-induced increase in hepatic and muscle lipid peroxides by 39.18% and 42.35%, respectively. Pentoxifylline also recovered a diazinon-induced decrease in liver and muscle total antioxidant capacity and plasma ChE by 122.33%, 56.44%, and 115.62%, respectively. Pentoxifylline did not affect diazinon-induced hyperglycemia and increased hepatic GP and PEPCK or muscle GP activities. It is concluded that pentoxifylline is a good choice for the alleviation of acute toxic stress of diazinon in muscle and liver and ChE in plasma, while it is unable to recover diazinon-induced hyperglycemia.

  8. Sex differences in apolipoprotein A1 and nevirapine-induced toxicity

    Directory of Open Access Journals (Sweden)

    Aline Marinho

    2014-11-01

    Full Text Available Nevirapine (NVP is associated with severe liver and skin toxicity through sulfotransferase (SULT bioactivation of the phase I metabolite 12-hydroxy-NVP [1–3]. The female sex, a well-known risk factor for NVP-induced toxicity, is associated with higher SULT expression (4 and lower plasma levels of 12-hydroxy-NVP [3]. Interestingly, apolipoprotein A1 (ApoA1 increases SULT2B1 activity and ApoA1 synthesis is increased by NVP [5, 6]. Herein, we explore the effect of ApoA1 levels on NVP metabolism and liver function. The study protocol was firstly approved by the hospitals’ Ethics Committees. All included individuals were HIV-infected patients treated with NVP for at least one month. The plasma concentrations of NVP and its phase I metabolites were quantified by HPLC [7]. ApoA1 levels were assessed by an immunoturbidimetric assay. Forty-nine HIV-infected patients on NVP were included (53% men, 59% Caucasian. NVP plasma levels were correlated with HDL-cholesterol (Spearman r=0.2631; p=0.0441 and ApoA1 (Spearman r=0.3907; p=0.0115. Women had higher ApoA1 levels than men (Student's t Test; p=0.0051. In both sexes, 12-hydroxy-NVP levels were negatively correlated with ApoA1 (male: Spearman r=−0.3810; p=0.0499 female: Spearman r=−0.5944; p=0.0415. In men, ApoA1 was positively correlated with aspartate aminotransferase (AST, Spearman r=0.5507; p=0.0413, while in women ApoA1 was associated (Spearman r=0.6408; p=0.0056 with alanine aminotransferase (ALT. These results show sex differences in NVP-induced ApoA1 synthesis. The higher ApoA1 levels in women might stabilize SULT2B1 [6]. This would explain the lower levels of 12-hydroxy-NVP [3] and the higher hepatotoxicity found in women, due to increased sulfonation of this metabolite. These data support a role for ApoA1 in the sex dimorphic mechanism leading to NVP-induced toxicity.

  9. Nanoparticulate-induced toxicity and related mechanism in vitro and in vivo

    Science.gov (United States)

    Kim, Hye Won; Ahn, Eun-Kyung; Jee, Bo Keun; Yoon, Hyoung-Kyu; Lee, Kweon Haeng; Lim, Young

    2009-01-01

    In urban areas, the quantity of exhaust particles from vehicle emissions is tremendous and has been regarded as the main contributor to particulate matter (PM) pollution. Recently, the nano-sized PM on public health has begun to raise the attention. The increased toxicity of nanoparticulate can be largely explained by their small size, high airborne concentration, extensive surface area and high content of organic carbon and transition metals. We have attempted to address the toxicity of nano sized-particlulate matter by comparing various particulates including micro-SiO2 (mSiO2), nano-SiO2 (nSiO2), micro-TiO2 (mTiO2), and nano-TiO2 (nTiO2) in RAW264.7 cells and in vivo. The cell viability of all particulates decreased dose dependently. 24-h incubation with nSiO2 demonstrated apoptosis in RAW264.7 using Annexin-V binding immunofluorescent microscopy, but not in any other particulates. In vivo, cytotoxicity of nanosized was higher than micro-sized particulates. As higher the concentration of particulates, the more pulmonary injury and neutrophilic infiltration were observed in nano-sized than micro-sized particulates, respectively. Particularly, 5.0 mg/kg of mTiO2 never shows any increase of neutrophile even with high cellularity of total cells and macrophages. From these results, we suggested that particulate-induced respiratory toxicity be influenced by component, size, and dose of particulates including the characteristic nature of the target cells in vitro and in vivo.

  10. Chemoprotective effect of Crataegus monogyna aqueous extract against cyclophosphamide-induced reproductive toxicity

    Directory of Open Access Journals (Sweden)

    Ali Shalizar Jalali

    2011-11-01

    Full Text Available AbstractCyclophosphamide (CP is extensively used as an antineoplastic agent for treatment of various cancers, as well as an immunosuppressive agent. However, despite its wide spectrum of clinical uses, CP is known to cause several adverse effects including reproductive toxicity in humans and experimental animals. Crataegus monogyna is one of the oldest medicinal plant has been shown to be cytoprotective by scavenging free radicals. The present study was conducted to assess whether Crataegus monogyna fruits aqueous extract with anti-oxidant properties could serve as a protective agent against reproductive toxicity during CP treatment in a rat model. Male Wistar rats were categorized into four groups. Two groups of rats were administered CP at a dose of 5 mg in 5 mL saline kg-1 per day for 28 days by oral gavages. One of the groups received Crataegus monogyna aqueous extract at a dose of 20 mg kg-1 per day orally four hours after cyclophosphamide administration. A vehicle-treated control group and a Crataegus monogyna control group were also included. The CP-treated group showed significant decreases in the body and organ weights and spermatogenic activities as well as many histological alterations. CP treatment also caused a significant decrease in sperm count and motility with an increase in dead and abnormal sperms. Moreover, significant decrease in serum levels of testosterone and increased serum concentrations of FSH, LH, LDH, CPK and SGOT were observed in CP-treated rats. Notably, Crataegus coadministration caused a partial recovery in above-mentioned parameters. These findings indicated that Crataegus might be partially protective against CP-induced reproductive toxicity.

  11. Quinone-induced protein handling changes: Implications for major protein handling systems in quinone-mediated toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Rui; Siegel, David; Ross, David, E-mail: david.ross@ucdenver.edu

    2014-10-15

    Para-quinones such as 1,4-Benzoquinone (BQ) and menadione (MD) and ortho-quinones including the oxidation products of catecholamines, are derived from xenobiotics as well as endogenous molecules. The effects of quinones on major protein handling systems in cells; the 20/26S proteasome, the ER stress response, autophagy, chaperone proteins and aggresome formation, have not been investigated in a systematic manner. Both BQ and aminochrome (AC) inhibited proteasomal activity and activated the ER stress response and autophagy in rat dopaminergic N27 cells. AC also induced aggresome formation while MD had little effect on any protein handling systems in N27 cells. The effect of NQO1 on quinone induced protein handling changes and toxicity was examined using N27 cells stably transfected with NQO1 to generate an isogenic NQO1-overexpressing line. NQO1 protected against BQ–induced apoptosis but led to a potentiation of AC- and MD-induced apoptosis. Modulation of quinone-induced apoptosis in N27 and NQO1-overexpressing cells correlated only with changes in the ER stress response and not with changes in other protein handling systems. These data suggested that NQO1 modulated the ER stress response to potentiate toxicity of AC and MD, but protected against BQ toxicity. We further demonstrated that NQO1 mediated reduction to unstable hydroquinones and subsequent redox cycling was important for the activation of the ER stress response and toxicity for both AC and MD. In summary, our data demonstrate that quinone-specific changes in protein handling are evident in N27 cells and the induction of the ER stress response is associated with quinone-mediated toxicity. - Highlights: • Unstable hydroquinones contributed to quinone-induced ER stress and toxicity.

  12. PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS.

    Science.gov (United States)

    Azim, Samy Abdelfatah Abdel; Abdelrahem, Mohamed Taha; Said, Mostafa Mohamed; Khattab, Alshaimaa

    2017-01-01

    Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential.

  13. Nano-sized titanium dioxide-induced splenic toxicity: a biological pathway explored using microarray technology.

    Science.gov (United States)

    Sheng, Lei; Wang, Ling; Sang, Xuezi; Zhao, Xiaoyang; Hong, Jie; Cheng, Shen; Yu, Xiaohong; Liu, Dong; Xu, Bingqing; Hu, Renping; Sun, Qingqing; Cheng, Jie; Cheng, Zhe; Gui, Suxin; Hong, Fashui

    2014-08-15

    Titanium dioxide nanoparticles (TiO2 NPs) have been widely used in various areas, and its potential toxicity has gained wide attention. However, the molecular mechanisms of multiple genes working together in the TiO2 NP-induced splenic injury are not well understood. In the present study, 2.5, 5, or 10mg/kg body weight TiO2 NPs were administered to the mice by intragastric administration for 90 consecutive days, their immune capacity in the spleen as well as the gene-expressed characteristics in the mouse damaged spleen were investigated using microarray assay. The findings showed that with increased dose, TiO2 NP exposure resulted in the increases of spleen indices, immune dysfunction, and severe macrophage infiltration as well as apoptosis in the spleen. Importantly, microarray data showed significant alterations in the expressions of 1041 genes involved in immune/inflammatory responses, apoptosis, oxidative stress, stress responses, metabolic processes, ion transport, signal transduction, cell proliferation/division, cytoskeleton and translation in the 10 mg/kg TiO2 NP-exposed spleen. Specifically, Cyp2e1, Sod3, Mt1, Mt2, Atf4, Chac1, H2-k1, Cxcl13, Ccl24, Cd14, Lbp, Cd80, Cd86, Cd28, Il7r, Il12a, Cfd, and Fcnb may be potential biomarkers of spleen toxicity following exposure to TiO2 NPs.

  14. Effect of a polyherbal formulation, Ambrex, on butylated hydroxy toluene (BHT) induced toxicity in rats.

    Science.gov (United States)

    Devi, R S; Narayan, Shoba; Mohan, K Vijai; Sabitha, K E; Devi, C S Shyamala

    2003-11-01

    Effect of polyherbal formulation Ambrex was evaluated in butylated hydroxytoluene (BHT) induced toxicity of lungs and liver in rats. Toxicity was produced by administering BHT (500 mg/kg/day) for 3 days. Lung damage was evidenced by elevated levels of broncho alveolar lavage fluid (BAL) parameters such as protein, lactate, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), acid phosphatase (ACP) and glucose-6-phosphate dehydrogenase (G6PDH). Liver damage was proved by elevated levels of serum protein and markers such as LDH, ALP, aspartate amino transferase (AST), alanine amino transferase (ALT), decreased level of lipid peroxides (LPO) in serum and glutathione (GSH) in liver. Administration of aqueous suspension of Ambrex (50 mg/kg orally) retained these elevated levels of BAL-protein, lactate, LDH, ALP, ACP, G6PDH and serum-protein, LDH, ALP, AST and ALT at near normal values. Decreased level of liver GSH was retained at near normalcy in Ambrex pretreated BHT-administered animals. There was no change in liver LPO in all the four groups.

  15. The protective role of Gongronema latifolium in acetaminophen induced hepatic toxicity in Wistar rats

    Institute of Scientific and Technical Information of China (English)

    Nnodim Johnkennedy; Emejulu Adamma

    2011-01-01

    Objective: To evaluate the protective effect of leaf extract of Gongronema latifolium (G. latifolium) against acute acetaminophen induced hepatic toxicity in Wistar rats. Methods:Thirty six Wistar rats were divided into 6 groups with 6 rats in each group. Animals in group 1 and 2 were administered with 600 mg/kg b.w. of acetaminophen only and acetaminophen plus 100 mg/kg b.w. of caffeine by oral gavages, respectively. Experimental groups 3 and 4 were treated as in group 1 but in addition received 200 and 400 mg/kg b.w., respectively of the leaf extract of G. latifolium by oral gavages. The experimental groups 5 and 6 were treated as in group 2 and in addition received 200 and 400 mg/kg b.w. of leaf extract of G. latifolium, respectively. The treatment lasted for 14 days. Results: The results obtained showed that the serum glutamic-oxalacetic transaminease (AST), glutamic-pyruvic transaminase (ALT) and alkaline phosphatase (ALP) levels had a greater increase in group 2 than in group 1 but dropped marginally in groups 3 and 4. However, in groups 5 and 6, AST, ALT and ALP were significantly reduced (P<0.05). Similarly, serum protein levels were significantly increased in groups 3, 4, 5 and 6 when compared with group 1 and 2. Conclusions: It can be concluded that extract of G. latifolium offers protection against acetaminophen and caffeinated acetaminophen toxicity in Wistar rats.

  16. Parental exposure to microcystin-LR induced thyroid endocrine disruption in zebrafish offspring, a transgenerational toxicity.

    Science.gov (United States)

    Cheng, Houcheng; Yan, Wei; Wu, Qin; Liu, Chunsheng; Gong, Xiuying; Hung, Tien-Chieh; Li, Guangyu

    2017-11-01

    Microcystin-LR is the most poisonous and commonly encountered hepatotoxin produced by cyanobacteria in an aquatic ecosystem, and it may cause thyroid dysfunction in fish. The present study aimed to reveal the effects of transgenerational toxicity of MCLR on the thyroid endocrine system under sub-chronic exposure conditions. Adult zebrafish (F0) were exposed to environmentally relevant concentrations (1, 5 and 25 μg/L) of MCLR for 45 days. The produced F1 embryos were then tested without further MCLR treatment. In the F0 generation, exposure to 25 μg/L MCLR reduced thyroxine (T4) but not 3, 5, 3'-triiodothyronine (T3) levels in females, while the T4 and T3 levels were unchanged in males. After parental exposure to MCLR, we observed a decreased hatching and growth retardation correlated with reduced thyroid hormone levels in the F1 offspring. The gene transcription and protein expression along the hypothalamic-pituitary-thyroid axis were detected to further investigate the possible mechanisms of MCLR-induced thyroid disruption. Our results indicated MCLR could disturb the thyroid endocrine system under environmentally relevant concentrations and the disrupting effects could be remarkably transmitted to its F1 offspring. We regard these adverse effects as a parental transgenerational toxicity of MCLR. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Scenario-based prediction of Li-ion batteries fire-induced toxicity

    Science.gov (United States)

    Lecocq, Amandine; Eshetu, Gebrekidan Gebresilassie; Grugeon, Sylvie; Martin, Nelly; Laruelle, Stephane; Marlair, Guy

    2016-06-01

    The development of high energy Li-ion batteries with improved durability and increased safety mostly relies on the use of newly developed electrolytes. A detailed appraisal of fire-induced thermal and chemical threats on LiPF6- and LiFSI-based electrolytes by means of the so-called "fire propagation apparatus" had highlighted that the salt anion was responsible for the emission of a non negligible content of irritant gas as HF (PF6-) or HF and SO2 (FSI-). A more thorough comparative investigation of the toxicity threat in the case of larger-size 0.4 kWh Li-ion modules was thus undertaken. A modeling approach that consists in extrapolating the experimental data obtained from 1.3Ah LiFePO4/graphite pouch cells under fire conditions and in using the state-of-the-art fire safety international standards for the evaluation of fire toxicity was applied under two different real-scale simulating scenarios. The obtained results reveal that critical thresholds are highly dependent on the nature of the salt, LiPF6 or LiFSI, and on the cells state of charge. Hence, this approach can help define appropriate fire safety engineering measures for a given technology (different chemistry) or application (fully charged backup batteries or batteries subjected to deep discharge).

  18. Beneficial effect of erdosteine on methotrexate-induced testicular toxicity in mice.

    Science.gov (United States)

    Oktar, Süleyman; Gökçe, Ahmet; Aydin, Mehmet; Davarci, Mürsel; Meydan, Sedat; Oztürk, Oktay Hasan; Koç, Ahmet

    2010-08-01

    Methotrexate is used to treat certain types of cancer of the breast, skin, head and neck, or lung. Methotrexate can cause serious or life-threatening side effects on liver, lungs, kidneys, and immune system. Methotrexate chemotherapy causes testicular damage in humans. The aim of this study was to investigate the possible protective role of erdosteine on testicular toxicity of methotrexate in mice. Twenty-six male mice were divided into four groups as follows: group 1, control; group 2, erdosteine-treated; group 3, methotrexate-treated; and group 4, methotrexate + erdosteine treated. On the first day of experiment, a single dose of methotrexate was intraperitoneally administered to groups 3 and 4, although a daily single dose of erdosteine was orally administered to group 2 and 4 for 7 days. At the end of the experiment, the testes of the animals were removed and weighed. The levels of total antioxidant capacity and total oxidative stress, and myeloperoxidase activity in the methotrexate group were higher than the control group (perdosteine could effectively protect the testes in methotrexate-induced toxicity.

  19. Amelioration of iron toxicity: A mechanism for aluminum-induced growth stimulation in tea plants.

    Science.gov (United States)

    Hajiboland, Roghieh; Barceló, Juan; Poschenrieder, Charlotte; Tolrà, Roser

    2013-11-01

    Tea plants (Camellia sinensis) are well adapted to acid soils with high Al availability. These plants not only accumulate high leaf Al concentrations, but also respond to Al with growth stimulation. Decreased oxidative stress has been associated with this effect. Why tea plants not exposed to Al suffer from oxidative stress has not been clarified. In this study, hydroponically grown tea plants treated with 0 to 300 μM Al were analyzed for growth, Al and Fe accumulation, and Al distribution by means of morin and hematoxylin staining. Roots of control plants stained black with hematoxylin. This indicates the formation of a Fe-hematoxylin complex. Young leaves of controls accumulated more than 1000 mg Fe kg(-1) dry weight. This concentration is above the Fe-toxicity threshold in most species. Supply of Al stimulated growth and reduced Fe uptake and transport. These results indicate that Al-induced growth stimulation might be due to alleviation of a latent Fe toxicity occurring in tea plants without Al supply.

  20. Toxicity of Mineral Dusts and a Proposed Mechanism for the Pathogenesis of Particle-Induced Lung Diseases

    Science.gov (United States)

    Lam, C.-W.; Zeidler-Erdely, P.; Scully, R.R.; Meyers, V.; Wallace, W.; Hunter, R.; Renne, R.; McCluskey, R.; Castranova, V.; Barger, M.; hide

    2015-01-01

    Humans will set foot on the moon again. The lunar surface has been bombarded for 4 billion years by micrometeoroids and cosmic radiation, creating a layer of fine dust having a potentially reactive particle surface. To investigate the impact of surface reactivity (SR) on the toxicity of particles, and in particular, lunar dust (LD), we ground 2 Apollo 14 LD samples to increase their SR and compare their toxicity with those of unground LD, TiO2 and quartz. Intratracheally instilled at 0, 1, 2.5, or 7.5 mg/rat, all dusts caused dose-dependent increases in pulmonary lesions, and enhancement of biomarkers of toxicity assessed in bronchoalveolar lavage fluids (BALF). The toxicity of LD was greater than that of TiO2 but less than that of quartz. Three LDs differed 14-fold in SR but were equally toxic; quartz had the lowest SR but was most toxic. These results show no correlation between particle SR and toxicity. Often pulmonary toxicity of a dust can be attributed to oxidative stress (OS). We further observed dose-dependent and dustcytotoxicity- dependent increases in neutrophils. The oxidative content per BALF cell was also directly proportional to both the dose and cytotoxicity of the dusts. Because neutrophils are short-lived and release of oxidative contents after they die could initiate and promote a spectrum of lesions, we postulate a general mechanism for the pathogenesis of particle-induced diseases in the lung that involves chiefly neutrophils, the source of persistent endogenous OS. This mechanism explains why one dust (e.g., quartz or nanoparticles) is more toxic than another (e.g., micrometer-sized TiO2), why dust-induced lesions progress with time, and why lung cancer occurs in rats but not in mice and hamsters exposed to the same duration and concentration of dust.

  1. Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity

    Institute of Scientific and Technical Information of China (English)

    Wen-Bo Qiao; Yan-Hui Zhao; Yan-Bin Zhao; Rui-Zhi Wang

    2005-01-01

    AIM: To analyze the clinical and dosimetric predictive factors for radiation-induced esophageal injury in patients with non-small-cell lung cancer (NSCLC) during threedimensional conformal radiotherapy (3D-CRT). METHODS: We retrospectively analyzed 208 consecutive patients (146 men and 62 women) with NSCLC treated with 3D-CRT. The median age of the patients was 64 years (range 35-87 years). The clinical and treatment parameters including gender, age, performance status, sequential chemotherapy, concurrent chemotherapy, presence of carinal or subcarinal lymph nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy were studied. Clinical and dosimetric factors for radiation-induced acute and late grade 3-5 esophageal injury were analyzed according to Radiation Therapy Oncology Group (RTOG) criteria.RESULTS: Twenty-five (12%) of the two hundred and eight patients developed acute or late grade 3-5 esophageal injury. Among them, nine patients had both acute and late grade 3-5 esophageal injury, two died of late esophageal perforation. Concurrent chemotherapy and maximal point dose to the esophagus ≥60 Gy were significantly associated with the risk of grade 3-5 esophageal injury. Fifty-four (26%) of the two hundred and eight patients received concurrent chemotherapy. Among them, 25 (46%) developed grade 3-5 esophageal injury (P = 0.0001<0.01). However, nograde 3-5 esophageal injury occurred in patients who received a maximal point dose to the esophagus <60 Gy (P= 0.0001<0.01).CONCLUSION: Concurrent chemotherapy and the maximal esophageal point dose ≥60 Gy are significantly associated with the risk of grade 3-5 esophageal injury in patients with NSCLC treated with 3D-CRT.

  2. INVESTIGATION OF NEPFROPROTECTIVE EFFECT OF SILYMARIN AGAINST METHOTREXATE AND IFOSFAMIDE INDUCED TOXICITY IN RATS.

    Directory of Open Access Journals (Sweden)

    MANOHAR NAIK K

    2015-01-01

    Full Text Available The present study was undertaken to investigate the Nephroprotective effect of silymarin against Methotrexate (MTX induced nephrotoxicity in rats. In MTX model rats of either sex (n=6 were pre-treated with silymarin (50mg/kg, p.o. for 6 days in MTX model, MTX toxicity was induced by administering MTX (20mg/kg on third day by intra-peritoneal route. The influence of prophylactic treatment was analyzed by quantification of Serum/Urinary biomarkers and antioxidants and histopathological observations. Silymarin treatment in presence of MTX was responsible for significant reduction in Serum; Urea, Creatinine, Aspartate transaminase (AST, Alanine transaminase (ALT and Urinary; Total Protein, Sodium and Potassium compared to MTX control group. Silymarin treatment was also responsible for significant increase in Serum Albumin and antioxidants such as superoxide dismutase (SOD, Glutathione (GSH and Catalase activities in kidney tissue homogenate compared to MTX control group. Similarly, there was an increase in the urine volume and decrease in the kidney weight in the silymarin treated groups compared to the MTX control group. Results were further supported by histopathological studies. Investigation witnessed the administration of silymarin 50mg/kg dose was effective in normalizing the abnormal conditions of kidney induced by MTX. Thus investigational finding conclude that silymarin possess potential benefits in treating animals with nephrotoxicity.

  3. Hepatoprotective efficacy of Hypnea muciformis ethanolic extract on CCl4 induced toxicity in rats

    Directory of Open Access Journals (Sweden)

    Giridharan Bupesh

    2012-12-01

    Full Text Available The ethanolic extract of Hypnea muciformis (red algae was tested for hepatoprotective activity against experimentally induced liver damage by Carbon tetrachloride (CCl4 in male albino rats. The levels of serum enzymatic and biochemical parameters such as serum glutamate oxaloacetate transaminase (SGOT, Serum glutamate pyruvate transaminase (SGPT, alkaline phosphatase (ALP, lactate dehydrogenase, 5' nucleotidase, bilirubin, creatinine, urea, triglycerides, lipid peroxides and albumin were determined. The CCI4 induced lesions in the liver significant increased the levels of serum marker enzymes SGPT and SGOT, bilirubin, creatinine and decreased urea. The oral treatment with ethanolic extract of H. muciformis exhibited significant hepatoprotective activity by reducing the CCL4 caused changes in the biochemical parameters such as total protein, total bilirubin, total cholesterol, triglycerides, and urea. These parameters were restored towards the normal levels as shown by the enzymatic tests. In addition, H. muciformis significantly decreased the liver weight of CCl4 intoxicated rats. Apparently the H. muciformis extract interfered with the free radical formation, which resulted in hepatoprotective activity. Acute toxicity studies revealed that the LD50 value was more than 3 g/kg body weight. These results clearly indicated that this seaweed contained some active principles in its ethanolic extract which acted as an antidote against the hepatotoxicity induced by CCl4.

  4. Effects of Roselle and Ginger on cisplatin-induced reproductive toxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Amr Amin; AlaaEldin A. Hamza

    2006-01-01

    Aim: To evaluate the protective effects of Hibiscus sabdariffa (Roselle) and Zingiber officinale (Ginger) against cisplatin-induced reproductive toxicity in rats and to study the mechanisms underlying these effects. Methods:which began 21 days before a single cisplatin I.p. Injection (10 mg/kg body weight). Results: Extracts of H. Sabdariffa and Z. Officinale reduced the extent of cisplatin-induced sperm abnormality and enhanced sperm motility. Both extracts restored the control level of malondialdehyde (MDA) (lipid peroxidation marker) in the cisplatin-treated testis.The cisplatin injection induced decline in the levels of superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT) were significantly reversed to control levels in groups where cisplatin was preceded by the administration of either H. Sabdariffa or Z. Officinale. Conclusion: Both H. Sabdariffa and Z. Officinale treatment increased the activities of testicular antioxidant enzymes and restored sperm motility of cisplatin-treated rats. The protective effects of tested plants are, therefore, suggested to be mediated by their potent antioxidant activities.

  5. Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae Ho; Jenrow, Kenneth A.; Brown, Stephen L. [Dept.of Radiation Oncology, Henry Ford Health System, Detroit (United States)

    2014-09-15

    To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs.

  6. Organochlorine pesticides dieldrin and lindane induce cooperative toxicity in dopaminergic neurons: role of oxidative stress.

    Science.gov (United States)

    Sharma, Heera; Zhang, Ping; Barber, David S; Liu, Bin

    2010-03-01

    Elevated environmental exposure to pesticides has been implicated as a contributing factor in the pathogenesis of Parkinson's disease (PD), a progressive movement disorder resulted from degeneration of the nigrostriatal dopaminergic (DA) pathway. Organochlorine pesticides (OCPs) including dieldrin and lindane remain ubiquitous in the environment and food supply due to their resistance to degradation and bioaccumulation along the food chain. While prior studies have gained insight into the neurotoxic effects of individual OCPs such as dieldrin, the effect of combinations of coexisting OCPs is lacking. In this study, we determined the combined effect of dieldrin and lindane on DA neurons and potential mechanism of action. Combinations of dieldrin and lindane (5-25 microM) were more effective in causing toxicity in immortalized rat N27 DA neurons than when used alone. Mechanistically, dieldrin and lindane combination induced a rapid increase in the levels of intracellular reactive oxygen species, a decrease in mitochondrial membrane potential and activation of caspase 3/7. Pretreatment with antioxidant N-acetyl cysteine blocked the effect of dieldrin and lindane on ROS generation and mitochondrial membrane potential and protected against dieldrin- and lindane-induced neurotoxicity. These results demonstrate that dieldrin and lindane work cooperatively to induce DA neurotoxicity through the induction of oxidative stress and mitochondrial dysfunction. These findings may advance understanding of the role of pesticides in the multi-factorial etiology of PD. Copyright (c) 2009 Elsevier Inc. All rights reserved.

  7. Haemato-biochemical alterations induced by lead acetate toxicity in wistar rats

    Directory of Open Access Journals (Sweden)

    S. G. Suradkar

    Full Text Available An experiment was conducted to study the haemato-biochemical alterations induced by lead acetate toxicity in 48 Wistar rats of either sex, divided uniformly into four different groups. The rats of group I received only deionised water as control while, group II, III and IV were given lead acetate @ 1 PPM, 100 PPM and 1000 PPM, in drinking deionised water respectively for 28 days. In group III and IV dose dependant significant (P<0.05 reductions in TEC, Hb, PCV and TLC were observed. No significant change was observed in neutrophil, eosinophil, basophil and monocyte count in any treatment groups, whereas the lymphocyte count decreased significantly (P<0.05 in group III and IV. A dose dependant significant (P<0.05 increase in AST, ALP, AKP, GGT, BUN and creatinine was experiential while TP and albumin levels were decreased in group III and IV. [Vet World 2009; 2(11.000: 429-431

  8. Suppression of starvation-induced autophagy by recombinant toxic shock syndrome toxin-1 in epithelial cells.

    Directory of Open Access Journals (Sweden)

    Krisana Asano

    Full Text Available Toxic shock syndrome toxin-1 (TSST-1, a superantigen produced from Staphylococcus aureus, has been reported to bind directly to unknown receptor(s and penetrate into non-immune cells but its function is unclear. In this study, we demonstrated that recombinant TSST-1 suppresses autophagosomal accumulation in the autophagic-induced HeLa 229 cells. This suppression is shared by a superantigenic-deficient mutant of TSST-1 but not by staphylococcal enterotoxins, suggesting that autophagic suppression of TSST-1 is superantigenic-independent. Furthermore, we showed that TSST-1-producing S. aureus suppresses autophagy in the response of infected cells. Our data provides a novel function of TSST-1 in autophagic suppression which may contribute in staphylococcal persistence in host cells.

  9. Toxic hepatitis induced by Gymnema sylvestre, a natural remedy for type 2 diabetes mellitus.

    Science.gov (United States)

    Shiyovich, Arthur; Sztarkier, Ignacio; Nesher, Lior

    2010-12-01

    Toxic hepatitis or drug-induced liver injury (DILI) encompasses a spectrum of conditions ranging from mild biochemical abnormalities to acute liver failure. Recent studies report that 35% to 48% of patients with diabetes use some form of complementary and alternative medical therapy. Moreover, >800 plants have been traditionally used for the treatment of diabetes. Despite this widespread use, only few were supported by rigorous clinical evidence. Gymnema sylvestre, also known as gurmar (sugar destroyer in Hindi), is a plant considered to be with potent antidiabetic effects and, hence, widely used in folk, ayurvedic and homeopathic systems in medicine. The authors were unable to find previous reports associating G sylvestre to liver injury. Herein, the authors report a case of DILI in a patient who was treated with G sylvestre for diabetes mellitus and review the literature to suggest possible mechanisms that led to this acute condition.

  10. Lipid emulsion-mediated reversal of toxic-dose aminoamide local anesthetic-induced vasodilation in isolated rat aorta

    OpenAIRE

    Ok, Seong-Ho; Han, Jeong Yeol; Lee, Soo Hee; Shin, Il-Woo; Lee, Heon Keun; Chung, Young-Kyun; Choi, Mun-Jeoung; Sohn, Ju-Tae

    2013-01-01

    Background Intravenous lipid emulsion has been used to treat systemic toxicity of local anesthetics. The goals of this in vitro study were to determine the ability of two lipid emulsions (Intralipid® and Lipofundin® MCT/LCT) to reverse toxic dose local anesthetic-induced vasodilation in isolated rat aortas. Methods Isolated endothelium-denuded aortas were suspended for isometric tension recording. Vasodilation was induced by bupivacaine (3 × 10-4 M), ropivacaine (10-3 M), lidocaine (3 × 10-3 ...

  11. 1H NMR-based serum metabolomics reveals erythromycin-induced liver toxicity in albino Wistar rats

    Directory of Open Access Journals (Sweden)

    Atul Rawat

    2016-01-01

    Full Text Available Introduction: Erythromycin (ERY is known to induce hepatic toxicity which mimics other liver diseases. Thus, ERY is often used to produce experimental models of drug-induced liver-toxicity. The serum metabolic profiles can be used to evaluate the liver-toxicity and to further improve the understanding of underlying mechanism. Objective: To establish the serum metabolic patterns of Erythromycin induced hepatotoxicity in albino wistar rats using 1H NMR based serum metabolomics. Experimental: Fourteen male rats were randomly divided into two groups (n = 7 in each group: control and ERY treated. After 28 days of intervention, the metabolic profiles of sera obtained from ERY and control groups were analyzed using high-resolution 1D 1H CPMG and diffusion-edited nuclear magnetic resonance (NMR spectra. The histopathological and SEM examinations were employed to evaluate the liver toxicity in ERY treated group. Results: The serum metabolic profiles of control and ERY treated rats were compared using multivariate statistical analysis and the metabolic patterns specific to ERY-induced liver toxicity were established. The toxic response of ERY was characterized with: (a increased serum levels of Glucose, glutamine, dimethylamine, malonate, choline, phosphocholine and phospholipids and (b decreased levels of isoleucine, leucine, valine, alanine, glutamate, citrate, glycerol, lactate, threonine, circulating lipoproteins, N-acetyl glycoproteins, and poly-unsaturated lipids. These metabolic alterations were found to be associated with (a decreased TCA cycle activity and enhanced fatty acid oxidation, (b dysfunction of lipid and amino acid metabolism and (c oxidative stress. Conclusion and Recommendations: Erythromycin is often used to produce experimental models of liver toxicity; therefore, the established NMR-based metabolic patterns will form the basis for future studies aiming to evaluate the efficacy of anti-hepatotoxic agents or the hepatotoxicity of new

  12. Age-related differences in susceptibility to cisplatin-induced renal toxicity.

    Science.gov (United States)

    Espandiari, P; Rosenzweig, B; Zhang, J; Zhou, Y; Schnackenberg, L; Vaidya, V S; Goering, P L; Brown, R P; Bonventre, J V; Mahjoob, K; Holland, R D; Beger, R D; Thompson, K; Hanig, J; Sadrieh, N

    2010-03-01

    Limited experimental models exist to assess drug toxicity in pediatric populations. We recently reported how a multi-age rat model could be used for pre-clinical studies of comparative drug toxicity in pediatric populations. The objective of this study was to expand the utility of this animal model, which previously demonstrated an age-dependent sensitivity to the classic nephrotoxic compound, gentamicin, to another nephrotoxicant, namely cisplatin (Cis). Sprague-Dawley rats (10, 25, 40 and 80 days old) were injected with a single dose of Cis (0, 1, 3 or 6 mg kg(-1) i.p.). Urine samples were collected prior and up to 72 h after treatment in animals that were >or= 25 days old. Several serum, urinary and 'omic' injury biomarkers as well as renal histopathology lesions were evaluated. Statistically significant changes were noted with different injury biomarkers in different age groups. The order of age-related Cis-induced nephrotoxicity was different than our previous study with gentamicin: 80 > 40 > 10 > 25 day-old vs 10 >or= 80 > 40 > 25-day-old rats, respectively. The increased levels of kidney injury molecule-1 (Kim-1: urinary protein/tissue mRNA) provided evidence of early Cis-induced nephrotoxicity in the most sensitive age group (80 days old). Levels of Kim-1 tissue mRNA and urinary protein were significantly correlated to each other and to the severity of renal histopathology lesions. These data indicate that the multi-age rat model can be used to demonstrate different age-related sensitivities to renal injury using mechanistically distinct nephrotoxicants, which is reflected in measurements of a variety of metabolite, gene transcript and protein biomarkers.

  13. Life stage-related differences in susceptibility to acrylamide-induced neural and testicular toxicity.

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    Takahashi, Miwa; Inoue, Kaoru; Koyama, Naoki; Yoshida, Midori; Irie, Kaoru; Morikawa, Tomomi; Shibutani, Makoto; Honma, Masamitsu; Nishikawa, Akiyoshi

    2011-09-01

    In order to assess age-dependence of susceptibility to acrylamide (ACR)-induced neural and testicular toxicity, 3- and 7-week-old male SD rats were given ACR at 0, 50, 100, or 200 ppm in the drinking water for 4 weeks, and the nervous and male reproductive systems were examined histopathologically. Testicular genotoxicity was evaluated with the comet assay and the micronucleus (MN) test. Glutathione S-transferase (GST) activity and glutathione (GSH) content in the liver and testis were also measured. In both young and adult animals, neurotoxicity was evident from 100 ppm and increased in proportion to ACR intake per body weight. In the testis, marked degeneration and exfoliation, mainly of spermatids, were observed from 100 ppm limited to young animals. The comet assay revealed ACR to significantly induce DNA damage from 100 ppm in both life stages, while MNs were found only in young rats from 100 ppm. The level of GST activity in the testis of young rats at the end of experiment was significantly lower than that of adult animals, regardless of the ACR treatment. There were no life stage-related differences in GSH contents in the liver and testis. These results suggest that susceptibility to neurotoxicity might not differ between young and adult rats when exposure levels are adjusted for body weight. Regarding testicular toxicity, young animals around puberty proved more susceptible than adult animals, possibly due to their lower level of testicular GST activity than that in adult animals.

  14. An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation.

    Science.gov (United States)

    Xue, Jing; Ideraabdullah, Folami Y

    2016-04-01

    In recent years, the etiology of human disease has greatly improved with the inclusion of epigenetic mechanisms, in particular as a common link between environment and disease. However, for most diseases we lack a detailed interpretation of the epigenetic regulatory pathways perturbed by environment and causal mechanisms. Here, we focus on recent findings elucidating nutrient-related epigenetic changes linked to obesity. We highlight studies demonstrating that obesity is a complex disease linked to disruption of epigenetically regulated metabolic pathways in the brain, adipose tissue and liver. These pathways regulate (1) homeostatic and hedonic eating behaviors, (2) adipocyte differentiation and fat accumulation, and (3) energy expenditure. By compiling these data, we illustrate that obesity-related phenotypes are repeatedly linked to disruption of critical epigenetic mechanisms that regulate key metabolic genes. These data are supported by genetic mutation of key epigenetic regulators, and many of the diet-induced epigenetic mechanisms of obesity are also perturbed by exposure to environmental toxicants. Identifying similarly perturbed epigenetic mechanisms in multiple experimental models of obesity strengthens the translational applications of these findings. We also discuss many of the ongoing challenges to understanding the role of environmentally induced epigenetic pathways in obesity and suggest future studies to elucidate these roles. This assessment illustrates our current understanding of molecular pathways of obesity that are susceptible to environmental perturbation via epigenetic mechanisms. Thus, it lays the groundwork for dissecting the complex interactions between diet, genes and toxicants that contribute to obesity and obesity-related phenotypes. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. IL-2 regulates SEB induced toxic shock syndrome in BALB/c mice.

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    Aslam Ali Khan

    Full Text Available BACKGROUND: Toxic Shock Syndrome (TSS is characterized by fever, rash, hypotension, constitutional symptoms, and multi-organ involvement and is caused by Staphylococcus aureus enterotoxins such as Staphylococcal Enterotoxin B (SEB. SEB binds to the MHC-IIalpha chain and is recognized by the TCRbeta chain of the Vbeta8 TCR(+ T cells. The binding of SEB to Vbeta chain results in rapid activation of T cells and production of inflammatory cytokines, such as Interleukin-2 (IL-2, Interferon-gamma and Tumor Necrosis Factor-alpha which mediate TSS. Although IL2 was originally identified as the T cell growth factor and was proposed to contribute to T cell differentiation, its role in TSS remains unexplored. METHODOLOGY/PRINCIPAL FINDINGS: Mice were injected with D-Gal (25 mg/mouse. One hour after D-Galactosamine (D-Gal injection each mouse was injected with SEB (20 microg/mouse. Mice were then observed for 72 hrs and death was recorded at different times. We tested Interleukin-12, IFNgamma, and IL-2 deficient mice (IL-2(-/-, but only the IL-2 deficient mice were resistant to SEB induced toxic shock syndrome. More importantly reconstitution of IL-2 in IL-2 deficient mice restored the shock. Interestingly, SEB induced IL-2 production from T cells was dependent on p38MAPK activation in macrophages as inhibition of it in macrophages significantly inhibited IL-2 production from T cells. CONCLUSION: This study shows the importance of IL -2 in TSS which has not been previously explored and it also shows that regulating macrophages function can regulate T cells and TSS.

  16. The protective effect of Moringa oleifera leaves against cyclophosphamide-induced urinary bladder toxicity in rats.

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    Taha, Nevine R; Amin, Hanan Ali; Sultan, Asrar A

    2015-02-01

    Cyclophosphamide (CP), an alkylating antineoplastic agent is widely used in the treatment of solid tumors and B-cell malignant disease. It is known to cause urinary bladder damage due to inducing oxidative stress. Moringa oleifera (Mof) is commonly known as drumstick tree. Moringa leaves have been reported to be a rich source of β-carotene, protein, vitamin C, calcium, and potassium. It acts as a good source of natural antioxidants; due to the presence of various types of antioxidant compounds such as ascorbic acid, flavonoids, phenolics and carotenoids. The aim of this work was to test the possible antioxidant protective effects of M. oleifera leaves against CP induced urinary bladder toxicity in rats. Female Wister albino rats were divided into 4 groups. Group I served as control, received orally normal saline, group II received a single dose CP 100mg/kg intraperitoneally, group III and VI both received orally hydroethanolic extract of Mof; 500 mg/kg and 1000 mg/kg respectively daily for a week, 1h before and 4h after CP administration. Rats were sacrificed 24h after CP injection. The bladder was removed, sectioned, and subjected to light, transition electron microscopic studies, and biochemical studies (measuring the parameter of lipid peroxidation; malondialdehyde along with the activities of the antioxidant enzyme reduced glutathione). The bladders of CP treated rats showed ulcered mucosa, edematous, hemorrhagic, and fibrotic submucosa by light microscopy. Ultrastructure observation showed; losing large areas of uroepithelium, extended intercellular gaps, junction complexes were affected as well as damage of mitochondria in the form of swelling and destruction of cristae. Biochemical analysis showed significant elevation of malondialdhyde, while reduced glutathione activity was significantly lowered. From the results obtained in this work, we can say that Moringa leaves play an important role in ameliorating and protecting the bladder from CP toxicity.

  17. Sodium Selenite Protects Against Silver Nanoparticle-Induced Testicular Toxicity and Inflammation.

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    Ansar, Sabah; Abudawood, Manal; Hamed, Sherifa Shaker; Aleem, Mukhtar M

    2017-01-01

    Metal nanomaterials hold great potential and play an important role in consumer products. However, the increasing use of nanomaterials has raised concern over inadvertent exposure and potential risks for human health and the environment. Henceforth, in vivo testing of nanoparticles and protection against its toxicity is required. Using rat as an animal model, effect of sodium selenite (Se), an essential trace element, on rat testes exposed to silver nanoparticles (AgNPs) was evaluated. Male rats were treated with AgNPs (5 mg/kg/b.w) i/p or Se (0.2 mg/kg/b.w) by gavage. AgNP administration decreased Glutathione (GSH) levels and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) and increased levels of malondialdehyde (MDA) and expression of interleukin-1 beta (IL-1β), IL-6, and tumor necrosis factor alpha (TNF-α). However, treatment with Se increased GSH levels and activities of SOD, CAT, and GPx compared with AgNP-treated group and decreased the level of MDA and inflammatory biomarkers significantly (p < 0.05) as compared with AgNP-treated group. Light microscopic analyses also revealed that AgNP induced histopathological changes in testes tissue. Further, protection by Se on biochemical results was confirmed by alleviation of the histopathological changes in the tissue. Results show the adverse effects of AgNPs on the male reproductive tract, particularly spermatogenesis, and suggest that Se possesses significant potential in reducing AgNP-induced testicular toxicity.

  18. The protective role of transferrin in Müller glial cells after iron-induced toxicity.

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    Picard, Emilie; Fontaine, Isabelle; Jonet, Laurent; Guillou, Florian; Behar-Cohen, Francine; Courtois, Yves; Jeanny, Jean-Claude

    2008-05-20

    Transferrin (Tf) expression is enhanced by aging and inflammation in humans. We investigated the role of transferrin in glial protection. We generated transgenic mice (Tg) carrying the complete human transferrin gene on a C57Bl/6J genetic background. We studied human (hTf) and mouse (mTf) transferrin localization in Tg and wild-type (WT) C57Bl/6J mice using immunochemistry with specific antibodies. Müller glial (MG) cells were cultured from explants and characterized using cellular retinaldehyde binding protein (CRALBP) and vimentin antibodies. They were further subcultured for study. We incubated cells with FeCl(3)-nitrilotriacetate to test for the iron-induced stress response; viability was determined by direct counting and measurement of lactate dehydrogenase (LDH) activity. Tf expression was determined by reverse transcriptase-quantitative PCR with human- or mouse-specific probes. hTf and mTf in the medium were assayed by ELISA or radioimmunoassay (RIA), respectively. mTf was mainly localized in retinal pigment epithelium and ganglion cell layers in retina sections of both mouse lines. hTf was abundant in MG cells. The distribution of mTf and hTf mRNA was consistent with these findings. mTf and hTf were secreted into the medium of MG cell primary cultures. Cells from Tg mice secreted hTf at a particularly high level. However, both WT and Tg cell cultures lose their ability to secrete Tf after a few passages. Tg MG cells secreting hTf were more resistant to iron-induced stress toxicity than those no longer secreted hTf. Similarly, exogenous human apo-Tf, but not human holo-Tf, conferred resistance to iron-induced stress on MG cells from WT mice. hTf localization in MG cells from Tg mice was reminiscent of that reported for aged human retina and age-related macular degeneration, both conditions associated with iron deposition. The role of hTf in protection against toxicity in Tg MG cells probably involves an adaptive mechanism developed in neural retina to

  19. Ascorbic acid attenuates antineoplastic drug 5-fluorouracil induced gastrointestinal toxicity in rats by modulating the expression of inflammatory mediators

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    Abdulrahman Khazim Al-Asmari

    2015-01-01

    Full Text Available Damage to the mucous membrane is a serious issue associated with chemotherapy. Gastrointestinal (GI toxicity is complex and multistep process and unregulated production of reactive oxygen species (ROS and inflammatory mediators play vital role in the development of GI toxicity. In the present study we have investigated the attenuating potential of vitamin C (vit. C on 5 fluorouracil (5-FU induced GI toxicity by targeting oxidative stress and inflammatory markers in Sprague Dawley (SD rats. Rats were gavaged with vit. C (500 mg/kg b. wt. or vehicle daily (day 1–10 and were given intraperitoneal injection of 5-FU (150 mg/kg b. wt. or saline (control on day 8 to induce mucositis. We found that vit. C supplementation attenuated 5-FU induced lipid peroxidation, myeloperoxidase (MPO activity, activation of NF-kB and expression of COX-2. Histological observations further supported the protective potential of vit. C against 5-FU induced intestinal anomalies such as neutrophil infiltration, loss of cellular integrity, villus and crypt deformities. Thus the biochemical, molecular and histological findings of the present study demonstrate that oxidative stress and inflammation play vital role in 5-FU induced GI toxicity and the inhibitory potential of vit. C is may be due to the modulation of oxidative stress, activation of redox sensitive transcription factor and also its downstream target molecules.

  20. Comparison of coumarin-induced toxicity between sandwich-cultured primary rat hepatocytes and rats in vivo: a toxicogenomics approach.

    Science.gov (United States)

    Kienhuis, Anne S; Wortelboer, Heleen M; Hoflack, Jean-Christophe; Moonen, Edwin J; Kleinjans, Jos C S; van Ommen, Ben; van Delft, Joost H M; Stierum, Rob H

    2006-12-01

    Sandwich-cultured primary rat hepatocytes are often used as an in vitro model in toxicology and pharmacology. However, loss of liver-specific functions, in particular, the decline of cytochrome P450 (P450) enzyme activity, limits the value of this model for prediction of in vivo toxicity. In this study, we investigated whether a hepatic in vitro system with improved metabolic competence enhances the predictability for coumarin-induced in vivo toxicity by using a toxicogenomics approach. Therefore, primary rat hepatocytes were cultured in sandwich configuration in medium containing a mixture of low concentrations of P450 inducers, phenobarbital, dexamethasone, and beta-naphthoflavone. The toxicogenomics approach used enabled comparison of similar mechanistic end-points at the molecular level between in vitro and in vivo conditions, namely, compound-induced changes in multiple genes and signaling pathways. Toxicant-induced cytotoxic effects and gene expression profiles observed in hepatocytes cultured in modified medium and hepatocytes cultured in standard medium (without inducers) were compared with results from a rat in vivo study. Coumarin was used as a model compound because its toxicity depends on bioactivation by P450 enzymes. Metabolism of coumarin toward active metabolites, coumarin-induced cytotoxicity, and gene expression modulation were more pronounced in hepatocytes cultured in modified medium compared with hepatocytes cultured in standard medium. In addition, more genes and biological pathways were similarly affected by coumarin in hepatocytes cultured in modified medium and in vivo. In conclusion, these experiments showed that for coumarin-induced toxicity, sandwich-cultured hepatocytes maintained in modified medium better represent the situation in vivo compared with hepatocytes cultured in standard medium.

  1. Mercuric Compounds Induce Pancreatic Islets Dysfunction and Apoptosis in Vivo

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    Yi-Chang Su

    2012-09-01

    Full Text Available Mercury is a toxic heavy metal that is an environmental and industrial pollutant throughout the world. Mercury exposure leads to many physiopathological injuries in mammals. However, the precise toxicological effects of mercury on pancreatic islets in vivo are still unclear. Here, we investigated whether mercuric compounds can induce dysfunction and damage in the pancreatic islets of mice, as well as the possible mechanisms involved in this process. Mice were treated with methyl mercuric chloride (MeHgCl, 2 mg/kg and mercuric chloride (HgCl2, 5 mg/kg for more than 2 consecutive weeks. Our results showed that the blood glucose levels increased and plasma insulin secretions decreased in the mice as a consequence of their exposure. A significant number of TUNEL-positive cells were revealed in the islets of mice that were treated with mercury for 2 consecutive weeks, which was accompanied by changes in the expression of the mRNA of anti-apoptotic (Bcl-2, Mcl-1, and Mdm-2 and apoptotic (p53, caspase-3, and caspase-7 genes. Moreover, plasma malondialdehyde (MDA levels increased significantly in the mice after treatment with mercuric compounds for 2 consecutive weeks, and the generation of reactive oxygen species (ROS in the pancreatic islets also markedly increased. In addition, the mRNA expression of genes related to antioxidation, including Nrf2, GPx, and NQO1, were also significantly reduced in these islets. These results indicate that oxidative stress injuries that are induced by mercuric compounds can cause pancreatic islets dysfunction and apoptosis in vivo.

  2. Hepatoprotective effects of licochalcone B on carbon tetrachloride-induced liver toxicity in mice

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    Haifeng Teng

    2016-08-01

    Full Text Available Objective(s: The objective of this study was to investigate the hepatoprotective effect of licochalcone B (LCB in a mice model of carbon tetrachloride (CCl4-induced liver toxicity. Materials and Methods: Hepatotoxicity was induced in mice by a single subcutaneous injection (SC of CCl4. The LCB was administered orally once a day for seven days (PO as pretreatment at three doses of 1, 5, and 25 mg/kg/day. The levels of superoxide dismutase (SOD, malondialdehyde (MDA, glutathione (GSH, glutathione disulfide (GSSG, C-reactive protein (CRP, tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, alanine aminotransferase (ALT and aspartate aminotransferase (AST were analyzed by ELISA. The protein expression degrees of p38 mitogen activated protein kinases (p38 and nuclear factor-k-gene binding (NF-κB were assayed by western blotting. Results: CCl4-induced hepatotoxicity was manifested by an increase in the levels of ALT, AST, MDA, IL-6, CRP, and TNF-ɑ, and a decrease in the SOD level and GSH/GSSG ratio in the serum. The histopathological examination of the liver sections revealed necrosis and inflammatory reactions. Pretreatment with LCB decreased the levels of ALT, AST, MDA, GSSG, IL-6, CRP, TNF-ɑ, and the protein expression of p38 and NF-κB, increased the level of SOD and GSH, and normalized the hepatic histo-architecture. Conclusion: LCB protected the liver from CCl4-induced injury. Protection may be due to inhibition of p38 and NFκB signaling, which subsequently reduced inflammation in the liver.

  3. Galangin Prevents Acute Hepatorenal Toxicity in Novel Propacetamol-Induced Acetaminophen-Overdosed Mice.

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    Tsai, Ming-Shiun; Chien, Chia-Chih; Lin, Ting-Hui; Liu, Chia-Chi; Liu, Rosa Huang; Su, Hong-Lin; Chiu, Yung-Tsung; Wang, Sue-Hong

    2015-11-01

    Acetaminophen (APAP) overdose causes severe liver and kidney damage. APAP-induced liver injury (AILI) represents the most frequent cause of drug-induced liver failure. APAP is relatively insoluble and can only be taken orally; however, its prodrug, propacetamol, is water soluble and usually injected directly. In this study, we examined the time-dependent effects of AILI after propacetamol injection in mice. After analyses of alanine aminotransferase and aspartate aminotransferase activities and liver histopathology, we demonstrated that a novel AILI mouse model can be established by single propacetamol injection. Furthermore, we compared the protective and therapeutic effects of galangin with a known liver protective extract, silymarin, and the only clinical agent for treating APAP toxicity, N-acetylcysteine (NAC), at the same dose in the model mice. We observed that galangin and silymarin were more effective than NAC for protecting against AILI. However, only NAC greatly improved both the survival time and rate consequent to a lethal dose of propacetamol. To decipher the hepatic protective mechanism(s) of galangin, galangin pretreatment significantly decreased the hepatic oxidative stress, increased hepatic glutathione level, and decreased hepatic microsomal CYP2E1 levels induced by propacetamol injection. In addition, propacetamol injection also reproduced the probability of APAP-induced kidney injury (AIKI), appearing similar to a clinical APAP overdose. Only galangin pretreatment showed the protective effect of AIKI. Thus, we have established a novel mouse model for AILI and AIKI using a single propacetamol injection. We also demonstrated that galangin provides significant protection against AILI and AIKI in this mouse model.

  4. Cytoprotective effects of essential oil of Pinus halepensis L. against aspirin-induced toxicity in IEC-6 cells.

    Science.gov (United States)

    Bouzenna, Hafsia; Hfaiedh, Najla; Bouaziz, Mouhamed; Giroux-Metges, Marie-Agnès; Elfeki, Abdelfattah; Talarmin, Hélène

    2017-07-18

    Essential oils from Pinus species have been reported to have various therapeutic properties. This study was undertaken to identify the chemical composition and cytoprotective effects of the essential oil of Pinus halepensis L. against aspirin-induced damage in cells in vitro. The cytoprotection of the oil against toxicity of aspirin on the small intestine epithelial cells IEC-6 was tested. The obtained results have shown that 35 different compounds were identified. Aspirin induced a decrease in cell viability, and exhibited significant damage to their morphology and an increase in superoxide dismutase (SOD) and catalase (CAT) activities. However, the co-treatment of aspirin with the essential oil of Pinus induced a significant increase in cell viability and a decrease in SOD and CAT activities. Overall, these finding suggest that the essential oil of Pinus halepensis L. has potent cytoprotective effect against aspirin-induced toxicity in IEC-6 cells.

  5. Protective effect of Sida cordata leaf extract against CCl(4) induced acute liver toxicity in rats.

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    Mistry, Sunil; Dutt, K R; Jena, J

    2013-04-13

    To investigate the hepatoprotective potential of Sida cordata (Malvaceae) (S. cordata) in experimental rats to validate its traditional claim. Wister albino rats were divided into 6 groups: Group I served as control; Group II served as hepatotoxic (CCl(4) treated) group; Group III, IV and V served as (100, 200 and 400 mg/kg b.w.) S. cordata leaf extract (SCLE) treated groups; Group VI served as positive control (Silymarin) treated group. Liver marker enzymes serum glutamate oxyloacetic transaminase, serum glutamic pyruvic transaminase, pancreatic enzymatic antioxidants superoxide dismutase (SOD), lipid peroxidation, catalase (CAT), reduced glutathione (GSH) were measured and compared along with histopathological studies. Obtained results show that the treatment with SCLE significantly (P<0.05-<0.001) and dose-dependently reduced CCl4 induced elevated serum level of hepatic enzymes. Furthermore, SCLE significantly (up to P<0.001) reduced the lipid peroxidation in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and CAT towards normal levels, which was confirmed by the histopathological studies. The results of this study strongly indicate the protective effect of SCLE against CCl(4) induced acute liver toxicity in rats and thereby scientifically support its traditional use. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  6. Cypermethrin-induced reproductive toxicity in the rat is prevented by resveratrol

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    Poonam Sharma

    2014-01-01

    Full Text Available Aims : The current study was to assess the protective role of resveratrol in cypermethrin-induced reproductive toxicity in male Wistar rats. Materials and Methods : Rats were exposed to cypermethrin (3.83 mg/kg bw for 14 days. Pre- and post-treatment of resveratrol (20 mg/kg bw for 14 days was given to cypermethrin exposed rats. At the end of the experiment, rats were sacrificed, testis and epididymis were removed, sperm characteristics, sex hormones, and various biochemical parameters were studied. Results : Cypermethrin exposure resulted in a significant decrease in weight of testis and epididymis, testicular sperm head counts, sperm motility and live sperm counts and increase in sperm abnormalities. Serum testosterone (T, follicle stimulating hormone (FSH, luteinizing hormone (LH, reduced glutathione (GSH, catalase (CAT, superoxide dismutase (SOD, glutathione S-transferase (GST, glutathione reductase (GR, glutathione peroxidase (GPx and total protein (TP content were decreased and lipid peroxidation (LPO level was increased on cypermethrin exposure. Pre- and post-treatment of resveratrol increased sperm head counts, sperm motility, live sperm counts, T, FSH, LH, GSH, CAT, SOD, GST, GR, GPx and TP contents and decreased LPO. Treatment with resveratrol alone has improved sperm parameters and testicular antioxidant defence system. Conclusion : The study concluded that resveratrol ameliorated cypermethrin-induced testicular damage by reducing oxidative stress and by enhancing the level of sex hormones.

  7. Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage

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    Peter Belenky

    2015-11-01

    Full Text Available Understanding how antibiotics impact bacterial metabolism may provide insight into their mechanisms of action and could lead to enhanced therapeutic methodologies. Here, we profiled the metabolome of Escherichia coli after treatment with three different classes of bactericidal antibiotics (β-lactams, aminoglycosides, quinolones. These treatments induced a similar set of metabolic changes after 30 min that then diverged into more distinct profiles at later time points. The most striking changes corresponded to elevated concentrations of central carbon metabolites, active breakdown of the nucleotide pool, reduced lipid levels, and evidence of an elevated redox state. We examined potential end-target consequences of these metabolic perturbations and found that antibiotic-treated cells exhibited cytotoxic changes indicative of oxidative stress, including higher levels of protein carbonylation, malondialdehyde adducts, nucleotide oxidation, and double-strand DNA breaks. This work shows that bactericidal antibiotics induce a complex set of metabolic changes that are correlated with the buildup of toxic metabolic by-products.

  8. Cypermethrin induced reproductive toxicity in male Wistar rats: protective role of Tribulus terrestris.

    Science.gov (United States)

    Sharma, Poonam; Huq, Amir Ul; Singh, Rambir

    2013-09-01

    The present study was designed to investigate role of ethanolic extract of Tribulus terrestris (EETT) against alpha-cypermethrin induced reproductive toxicity in male Wistar rats. 24 male Wistar rats weighing about 250-300g were divided in four groups. Group-I was control. alpha-cypermethrin (3.38 mg kg-1b.wt.) was given to group-IlI for 28 days. In Group-Ill, alpha-cypermethrin and EETT (100 mg kg -1b.wt.) were administered in combination for 28 days. Rats in group-IV were given EETT for 28 days. At the end of the experiment, rats were sacrificed, testes and epididymis were removed and sperm characteristics, sex hormones and various biochemical parameters were studied. Decrease in weight of testes and epididymis, testicular sperm head count, sperm motility, live sperm count, serum testosterone (T), follicle stimulating hormone (FSH), leutinizing hormone (LH), catalase (CAT), superoxide dismutase (SOD), glutathione S transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), total protein content and increase in sperm abnormalities and lipid peroxidation (LPO) level was observed in rats exposed to cypermethrin. In combination group-Ill, EETT treatment ameliorated alpha-cypermethrin induced damage. EETT treatment in group-IV increased testes and epididymis weight, sperm head counts, sperm motility, live sperm counts, testosterone, FSH, LH, GSH, CAT, SOD, GST, GR, GPx and total protein content. The study suggested that Tribulus terrestris plant possess reproductive system enhancement and antioxidant activity.

  9. Behavioural differentiation induced by environmental variation when crossing a toxic zone in an amoeba

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    Kunita, Itsuki; Ueda, Kei-Ichi; Akita, Dai; Kuroda, Shigeru; Nakagaki, Toshiyuki

    2017-09-01

    Organisms choose from among various courses of action in response to a wide variety of environmental conditions and the mechanism by which various behaviours are induced is an open question. Interesting behaviour was recently reported: that a unicellular organism of slime mold Physarum polycephalum known as an amoeba had multiple responses (crossing, returning, etc) when the amoeba encounters a zone with toxic levels of quinine, even under carefully controlled conditions. We here examined this elegant example in more detail to obtain insight into behavioural differentiation. We found that the statistical distribution of passage times across a quinine zone switch from unimodal to bimodal (with peaks corresponding to fast crossing and no crossing) when a periodic light stimulation to modulate a biorhythm in amoeba is applied homogeneously across the space, even under the same level of chemical stimuli. Based on a mathematical model for cell movement in amoeba, we successfully reproduced the stimulation-induced differentiation, which was observed experimentally. These dynamics may be explained by a saddle structure around a canard solution. Our results imply that the differentiation of behavioural types in amoeba is modified step-by-step via the compounding of stimulation inputs. The complex behaviour like the differentiation in amoeba may provide a basis for understanding the mechanism of behaviour selection in higher animals from an ethological perspective.

  10. Pharmacological intervention of tiferron and propolis to alleviate beryllium-induced hepatorenal toxicity.

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    Nirala, Satendra Kumar; Bhadauria, Monika; Shukla, Sangeeta; Agrawal, Om Prakash; Mathur, Asha; Li, Pei Qiang; Mathur, Ramesh

    2008-08-01

    Intervention of chelating agent tiferron (sodium-4,5-dihydroxy-1,3-benzene disulfonate; 300 mg/kg, intraperitoneal) with propolis (honey beehive product; 200 mg/kg, p.o.) was evaluated to encounter the characteristic biochemical and ultra-morphological alterations following subchronic exposure to beryllium. Female albino rats were challenged with beryllium nitrate (1 mg/kg, i.p.) daily for 28 days followed by treatment of the above-mentioned therapeutic agents either individually or in combination for five consecutive days. Exposure to beryllium increased its concentration in the serum, liver and kidney, and caused significant alterations in cytochrome P450 activity, microsomal lipid peroxidation and proteins. Activities of alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transpeptidase, bilirubin, creatinine and urea in the serum and activity of acid phosphatase, alkaline phosphatase, adenosine triphosphatase, glucose-6-phophatase and succinic dehydrogenase in the liver and kidney were significantly altered after beryllium administration. Beryllium exposure also induced severe hepatorenal alterations at histopathological and ultra-morphological level. Tiferron along with propolis dramatically reversed the alterations in all the variables more towards control rather than their individual treatment. The study concludes that pharmacological intervention of tiferron and propolis is beneficial in attenuating beryllium-induced systemic toxicity.

  11. Differential sensitivity of prefrontal cortex and hippocampus to alcohol-induced toxicity.

    Directory of Open Access Journals (Sweden)

    Anna-Kate Fowler

    Full Text Available The prefrontal cortex (PFC is a brain region responsible for executive functions including working memory, impulse control and decision making. The loss of these functions may ultimately lead to addiction. Using histological analysis combined with stereological technique, we demonstrated that the PFC is more vulnerable to chronic alcohol-induced oxidative stress and neuronal cell death than the hippocampus. This increased vulnerability is evidenced by elevated oxidative stress-induced DNA damage and enhanced expression of apoptotic markers in PFC neurons. We also found that one-carbon metabolism (OCM impairment plays a significant role in alcohol toxicity to the PFC seen from the difference in the effects of acute and chronic alcohol exposure on DNA repair and from exaggeration of the damaging effects upon additional OCM impairment in mice deficient in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR. Given that damage to the PFC leads to loss of executive function and addiction, our study may shed light on the mechanism of alcohol addiction.

  12. Anti-oxidative effect of resveratrol on aluminum induced toxicity in rat cerebral tissue.

    Science.gov (United States)

    Zakaria, M M H; Hajipour, B; Estakhri, R; Saleh, B M

    2017-01-01

    The direct protective effects of resveratrol against oxidative stress have been demonstrated in neuroglial cells, the mechanisms of these effects are not fully understood. The aim of this research was to study the effect of resveratrol on AL induced cerebral injury in rat. We divided the groups as follows with 10 animals each: a) Group I - served as control receiving normal drinking water and diet ad libitum. b) Group II - animals were administered aluminum at a dose level of 100 mg/kg body weight for a period of 6 weeks daily through oral gavage. c) Group III - animals were administered aluminum at a dose level of 100 mg/kg body weight and resveratrol at a dose of 10 mg/kg body weight intraperitoneally for a period of 6 weeks daily. After 6 weeks rats were anesthetized and decapitated. Brains were removed immediately and frozen in liquid nitrogenRESULTS: The levels of SOD and GPx antioxidant enzymes were decreased in all of the groups receiving aluminium, but it was less severe in resveratrol treated group. SOD and GPx levels in aluminium + resveratrol group were higher than in the aluminum group (p resveratrol group compared to aluminum group and the difference was significant (p resveratrol is effective in preventing AL induced toxicity by reducing MDA production in cerebral tissue. Resveratrol also attenuated SOD and GPx suppression in cerebral tissue significantly. Our findings provide the rationale for further studies directed to understanding the mechanism of resveratrol in preventing neurodeterioration (Tab. 1, Ref. 35).

  13. Protective effect of Sida cordata leaf extract against CCl4 induced acute liver toxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Sunil Mistry; KR Dutt; J Jena

    2013-01-01

    Objective: To investigate the hepatoprotective potential of Sida cordata (Malvaceae) (S. cordata) in experimental rats to validate its traditional claim. Methods: Wister albino rats were divided into 6 groups: Group Ⅰ served as control; Group Ⅱ served as hepatotoxic (CCl4 treated) group;Group Ⅲ, Ⅳ and Ⅴ served as (100, 200 and 400 mg/kg b.w.) S. cordata leaf extract (SCLE) treated groups; Group Ⅵ served as positive control (Silymarin) treated group. Liver marker enzymes serum glutamate oxyloacetic transaminase, serum glutamic pyruvic transaminase, pancreatic enzymatic antioxidants superoxide dismutase (SOD), lipid peroxidation, catalase (CAT), reduced glutathione (GSH) were measured and compared along with histopathological studies. Results:Obtained results show that the treatment with SCLE significantly (P<0.05-<0.001) and dose-dependently reduced CCl4 induced elevated serum level of hepatic enzymes. Furthermore, SCLE significantly (up to P<0.001) reduced the lipid peroxidation in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and CAT towards normal levels, which was confirmed by the histopathological studies. Conclusions: The results of this study strongly indicate the protective effect of SCLE against CCl4 induced acute liver toxicity in rats and thereby scientifically support its traditional use.

  14. Lung cell toxicity experimentally induced by a mixed dust from Mexicali, Baja California, Mexico.

    Science.gov (United States)

    Osornio-Vargas, A R; Hernández-Rodríguez, N A; Yáñez-Buruel, A G; Ussler, W; Overby, L H; Brody, A R

    1991-10-01

    Lung disease caused by nonoccupational exposures to inorganic particles from the soil has been reported in several areas of the world. We tested the toxic potential of dust samples from a Mexican city (Mexicali) that is frequently affected by dust storms and is geographically related to the area of San Diego, CA, where constituents of the soil have been reported to be fibrogenic. We found that samples of Mexicali dust are a mixture of approximately 75% potassium aluminum silicates (illite) and approximately 20% silica. Respirable size particles were highly hemolytic and induced lactic dehydrogenase release from alveolar macrophages exposed in vitro. Animals instilled intratracheally with the dust developed a multifocal interstitial lung disease associated with deposits of the aluminum silicates, which were identified by X-ray microanalysis. Inhalation studies in rats demonstrated that the majority of particles were deposited preferentially at the first alveolar duct bifurcations. Twenty-four hours later, numerous particles had been ingested by alveolar macrophages that had migrated to those sites of deposition. It is proposed that alveolar macrophages are attracted to the deposited particles by complement fragments since Mexicali dust is capable of activating complement proteins from both serum and bronchoalveolar lavage. Activation resulted in alveolar macrophage chemotaxis. Mexicali dust induced biological activities and lung changes similar to those of asbestos and silica, suggesting that this material could be an etiologic agent of pulmonary fibrosis in exposed individuals.

  15. Role of GluR2 expression in AMPA-induced toxicity in cultured murine cerebral cortical neurons

    DEFF Research Database (Denmark)

    Jensen, J B; Lund, Trine Meldgaard; Timmermann, D B;

    2001-01-01

    of the Mg(2+) block of the NMDA receptor on AMPA-R stimulation. The involvement of Ca(2+) influx through AMPA-R was also examined. The number of neurons possessing Ca(2+)-permeable AMPA-R increased during culture development, concurrently with an increasing susceptibility for AMPA-induced toxicity during...

  16. p-Methoxyl-diphenyl diselenide protects against cisplatin-induced renal toxicity in mice.

    Science.gov (United States)

    Wilhelm, Ethel A; Bortolatto, Cristiani F; Nogueira, Cristina W

    2012-05-01

    The present study was designed to investigate the effects of p-methoxyl-diphenyl diselenide (OMePhSe)(2) on oxidative stress and renal damage parameters of mice exposed to cisplatin. (OMePhSe)(2) (50 and 100 mg/kg/day) was orally administered to mice for six consecutive days. On the third day after the beginning of (OMePhSe)(2) treatment, the renal toxicity was induced by injecting cisplatin (10 mg/kg intraperitoneal) in mice. (OMePhSe)(2) treatment (50 mg/kg) partially reduced plasma urea and creatinine levels increased by cisplatin. Histopathological examination of kidneys showed that (OMePhSe)(2) ameliorated renal injury caused by cisplatin. (OMePhSe)(2) attenuated the decrease in reduced glutathione (GSH) and ascorbic acid (AA) levels, the inhibition of glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and catalase (CAT) activities caused by cisplatin in kidney. (OMePhSe)(2) treatment partially protected against the inhibition of renal δ-aminolevulinic dehydratase (δ-ALA-D) activity caused by cisplatin. No alteration in renal lipid peroxidation levels was found in cisplatin and/or (OMePhSe)(2) groups. (OMePhSe)(2) was effective against the increase in reactive species (RS) levels caused by the cisplatin exposure. Based on the renoprotective and antioxidant actions of (OMePhSe)(2) we suggest that this organoselenium compound could be considered a feasible candidate to protect against toxicity commonly encountered in cisplatin exposure.

  17. The effect of melatonin on procarbazine induced testicular toxicity on rats.

    Science.gov (United States)

    Alp, Bilal Fırat; Kesik, Vural; Malkoç, Ercan; Yiğit, Nuri; Saldır, Mehmet; Babacan, Oğuzhan; Akgül, Emin Özgür; Poyrazoglu, Yavuz; Korkmazer, Nadir; Gulgun, Mustafa; Erdem, Onur

    2014-12-01

    Procarbazine (P) is an effective chemotherapeutic drug especially used in lymphoma treatment; however testicular toxicity is a limiting factor. Various ways of treatment were tried to preserve testicular function including hormonal treatment, antioxidant treatment, and sperm cryopreservation but resulted with low rates of satisfaction. Procarbazine is a well known agent causing sterility even in the first doses of chemotherapy. Antioxidants such as N acetylcysteine and ascorbate have been used for protective purposes and were very successful. Melatonin (M) is another powerful antioxidant and we aimed to use M for the protection of P induced testicular toxicity in this study. Procarbazine was given peroral by gavage once a week at a dose of 62.5 mg/kg/week for 4 weeks (total dose: 250 mg/kg) (P group) and in procarbazine + melatonin (PM) group, 10 mg/kg melatonin was intraperitoneally administered daily for five days a week for 4 weeks (total 20 days). The experiment ended at day 90. In the P and PM groups the testicle width, length, and weight, sperm A and sperm AB properties (Sperm A: sperms straight line progressive, Sperm B: sperms straight slow progressive, Sperm AB: Sperm A + Sperm B), spermatogonia, Sertoli cells, seminiferous tubule, and germinative layer thickness were lowered as compared with the control group. However, there were no significant differences between the P and PM groups in regard to these parameters. Melatonin preserved Sertoli cell and spermatogonia function. The testosterone and follicle-stimulating hormone (FSH) levels were also preserved. Melatonin significantly decreased malondialdehyde (MDA) levels and preserved the antioxidant enzyme levels such as glutathione peroxidase (GPx) and nitrite nitrate (NO2-/NO3-). Melatonin may protect testicular functions in P treated patients and is open to consideration during chemotherapy since it appears to be without any side effects.

  18. Alleviating anastrozole induced bone toxicity by selenium nanoparticles in SD rats

    Energy Technology Data Exchange (ETDEWEB)

    Vekariya, Kiritkumar K.; Kaur, Jasmine; Tikoo, Kulbhushan, E-mail: tikoo.k@gmail.com

    2013-04-15

    Aromatase inhibitors like anastrozole play an undisputed key role in the treatment of breast cancer, but on the other hand, various side effects like osteoporosis and increased risk of bone fracture accompany the chronic administration of these drugs. Here we show for the first time that selenium nanoparticles, when given in conjugation to anastrozole, lower the bone toxicity caused by anastrozole and thus reduce the probable damage to the bone. Selenium nanoparticles at a dose of 5 μg/ml significantly reduced the cell death caused by anastrozole (1 μM) in HOS (human osteoblast) cells. In addition, our results also highlighted that in female SD rat model, SeNPs (0.25, 0.5, 1 mg/kg/day) significantly prevented the decrease in bone density and increase in biochemical markers of bone resorption induced by anastrozole (0.2 mg/kg/day) treatment. Histopathological examination of the femurs of SeNP treated group revealed ossification, mineralization, calcified cartilaginous deposits and a marginal osteoclastic activity, all of which indicate a marked restorative action, suggesting the protective action of the SeNPs. Interestingly, SeNPs (1 mg/kg/day) also exhibited protective effect in ovariectomized rat model, by preventing osteoporosis, which signifies that bone loss due to estrogen deficiency can be effectively overcome by using SeNPs. - Highlights: ► SeNPs significantly reduce bone toxicity in anastrozole treated rats. ► SeNPs successfully prevented osteoporosis in ovariectomized rats. ► SeNP treatment lowered the levels of TRAP and increased the levels of ALKP.

  19. Cell apoptosis of caprine spleen induced by toxicity of cadmium with different levels of molybdenum.

    Science.gov (United States)

    Gu, Xiaolong; Chen, Rongrong; Hu, Guoliang; Zhuang, Yu; Luo, Junrong; Zhang, Caiying; Guo, Xiaoquan; Huang, Aiming; Cao, Huabin

    2015-07-01

    In order to clarify the effects of the combination of Mo and Cd on goat and relationship between the two elements, combined chronic toxicity of cadmium with different levels of molybdenum in vivo on apoptosis gene and ultrastructure of spleen was evaluated with the methods of RT-qPCR and transmission electron microscopy. A total of thirty-six goats were randomly distributed in equal number into four groups. These groups were randomly assigned with one of three oral treatments of CdCl2 (0.5 mgCd kg(-1)) and [(NH4)6Mo7O24·4H2O] (15 mg Mo kg(-1), group I; 30 mg Mo kg(-1), group II; 45 mg Mo kg(-1), group III), while the control group received deionized water. Spleen tissues were taken from individual goat at different time intervals to measure the levels of apoptosis genes including Bcl-2, Bax, Cyt c, Caspase-3, Smac and ceruloplasmin (Cp). The results revealed that a significant suppression in Bcl-2 expression and increase in Cyt c, Caspase-3 and Cp expression in splenic cells. The Bax expression in group I and II was up-regulated, however, it displayed reduction in group III, whereas no statistical significance was observed on Smac expression. In addition, histopathologic injury revealed remarkable morphplogical changes on the splenocytes in the means of apoptosis including fragmentized nucleus, apoptotic body and vesiculation of cytoplasma and mitochondria. Taken together, combined chronic toxicity of cadmium with different levels of molybdenum induce goat spleen cell apoptosis associated with mitochondrial intrinsic pathway, and the two elements showed possible antergic relationship.

  20. Nano-sized titanium dioxide-induced splenic toxicity: A biological pathway explored using microarray technology

    Energy Technology Data Exchange (ETDEWEB)

    Sheng, Lei [Medical College of Soochow University, Suzhou 215123 (China); Wang, Ling [Library of Soochow University, Suzhou 215123 (China); Sang, Xuezi; Zhao, Xiaoyang; Hong, Jie; Cheng, Shen; Yu, Xiaohong; Liu, Dong; Xu, Bingqing; Hu, Renping; Sun, Qingqing; Cheng, Jie; Cheng, Zhe; Gui, Suxin [Medical College of Soochow University, Suzhou 215123 (China); Hong, Fashui, E-mail: Hongfsh_cn@sina.com [Medical College of Soochow University, Suzhou 215123 (China)

    2014-08-15

    Highlights: • Exposure to TiO{sub 2} NPs could be accumulated in the spleen. • Exposure to TiO{sub 2} NPs caused spleen lesions in mice. • Exposure to TiO{sub 2} NPs resulted in immune dysfunction in mice. • Exposure to TiO{sub 2} NPs caused alteration of 1041 genes expression of known function in the spleen. - Abstract: Titanium dioxide nanoparticles (TiO{sub 2} NPs) have been widely used in various areas, and its potential toxicity has gained wide attention. However, the molecular mechanisms of multiple genes working together in the TiO{sub 2} NP-induced splenic injury are not well understood. In the present study, 2.5, 5, or 10 mg/kg body weight TiO{sub 2} NPs were administered to the mice by intragastric administration for 90 consecutive days, their immune capacity in the spleen as well as the gene-expressed characteristics in the mouse damaged spleen were investigated using microarray assay. The findings showed that with increased dose, TiO{sub 2} NP exposure resulted in the increases of spleen indices, immune dysfunction, and severe macrophage infiltration as well as apoptosis in the spleen. Importantly, microarray data showed significant alterations in the expressions of 1041 genes involved in immune/inflammatory responses, apoptosis, oxidative stress, stress responses, metabolic processes, ion transport, signal transduction, cell proliferation/division, cytoskeleton and translation in the 10 mg/kg TiO{sub 2} NP-exposed spleen. Specifically, Cyp2e1, Sod3, Mt1, Mt2, Atf4, Chac1, H2-k1, Cxcl13, Ccl24, Cd14, Lbp, Cd80, Cd86, Cd28, Il7r, Il12a, Cfd, and Fcnb may be potential biomarkers of spleen toxicity following exposure to TiO{sub 2} NPs.

  1. Ameliorative effect of two Ayurvedic herbs on experimentally induced arsenic toxicity in calves.

    Science.gov (United States)

    Biswas, Suman; Maji, Chinmoy; Sarkar, Prasanta Kumar; Sarkar, Samar; Chattopadhyay, Abichal; Mandal, Tapan Kumar

    2017-02-02

    Chronic arsenic poisoning due to contaminated subsoil water is a threat to society in West Bengal, India and in Bangladesh. The human being may also be affected by the exposed cattle from the affected area by consuming milk, egg, meat and others. In Ayurveda, several herbs like Haridra (turmeric), Shunthi (dried ginger root) and others are used for the management of arsenic poisoning. The study was conducted to find out the ameliorative effect of turmeric and ginger powder against experimentally induced arsenic toxicity in calves. Twenty four calves were divided into four groups (group I, II, III and IV) having six animals in each group. Animals of group I, II and III were orally administered with sodium arsenite at 1mg/kg body weight for 90 days and in addition group II and group III animals were treated orally with turmeric and ginger powder respectively at 10mg/kg body weight from 46th day onwards. Group IV animals were given food and water without drug and served as control. Arsenic content was estimated in faeces, hair, urine and plasma in every 15 days. Bio-chemical, haematological and anti-oxidant parameters were also assessed. Turmeric and ginger powder significantly (Parsenic levels through increased excretion via faeces and urine. Haemoglobin level, TEC and TLC were decreased in groups I, II and III, however these were improved significantly (Parsenic from the body but also give protection from possible damage caused by arsenic exposure, it may be concluded from the present study that turmeric and ginger can be helpful in the therapy of chronic arsenic toxicity in calves. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Ribosomal genes as early targets of cadmium-induced toxicity in Chironomus riparius larvae

    Energy Technology Data Exchange (ETDEWEB)

    Planello, R. [Biologia Ambiental, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia, Senda del Rey 9, 28040, Madrid (Spain); Martinez-Guitarte, J.L. [Biologia Ambiental, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia, Senda del Rey 9, 28040, Madrid (Spain); Morcillo, G. [Biologia Ambiental, Facultad de Ciencias, Universidad Nacional de Educacion a Distancia, Senda del Rey 9, 28040, Madrid (Spain)]. E-mail: gmorcillo@ccia.uned.es

    2007-02-01

    Cadmium is a widespread environmental pollutant that causes severe impacts in organisms. Although the effects of cadmium on aquatic insects have been studied in terms of their toxicity and changes in developmental parameters, little is known about its molecular and genetic effects. We have investigated the alterations in the pattern of gene expression provoked by acute exposure to cadmium in Chironomus riparius Mg. (Diptera, Chironomidae), a sentinel organism widely used in aquatic toxicity testing. The early cytotoxic effects were evaluated using immunocytochemistry and specific fluorescent probes in fourth instar larvae after 12 h of 10 mM cadmium treatments; under these conditions no significant effect on larvae mortality was detected until after 36 h of exposure. The changes in the pattern of gene expression were analysed by means of DNA/RNA hybrid antibodies in the polytene chromosomes from salivary gland cells. A decrease in the activity of the nucleolus is especially remarkable, accompanied by a significant reduction in size and the modification in nucleolar architecture, as shown by FISH. The inhibition of rDNA transcription was further evaluated by Northern blot analysis, which showed a marked decrease in the level of preribosomal rRNA (54% 45S 12 h). However, the BR genes, whose products are the giant polypeptides that constitute the silk-like secretion for constructing housing tubes, remain active. Simultaneously, decondensation and activation take place at some chromosomal regions, especially at the centromeres. The changes observed in the pattern of gene expression do not resemble those found after heat shock or other cell stressors. These data provide the first evidence that cadmium interacts with ribosomal genes and results in a drastic impairment of the functional activity of the nucleolus, an essential organelle for cellular survival. Therefore, the depletion of ribosomes would be a long-term effect of Cd-induced cellular damage. These findings may

  3. Anti-Oxidant and Hepatoprotective Activities of Ziziphus mucronata Fruit Extract Against Dimethoate-Induced Toxicity

    Directory of Open Access Journals (Sweden)

    Kwape Tebogo Elvis

    2013-03-01

    Full Text Available Objective: The study was carried out to evaluate the hepatoprotective and antioxidant potential of Ziziphus mucronata (ZM fruit extract. Methods: The different types of fruit extract were prepared by soaking the dry powdered fruit in different solvents followed by rotary evaporation. Each extract was tested for its phenol content and antioxidant activities. An in vivo study was performed in Sprague- Dawley (SD rats. Thirty adult male SD rats (aged 21 weeks were divided into six groups of five rats each and treated as follows: The normal control (NC received distilled water while the dimethoate control (DC received 6 mg/kg.bw.day-1 dimethoate dissolved in distilled water. The experimental groups E1, E2, E3, and E0 received dimethoate (6 mg/kg.bw + ZMFM (100 mg/kg.bw-1, dimethoate (6 mg/kg.bw + ZMFM (200 mg/kg.bw-1, dimethoate (6 mg/kg.bw + ZMFM (300 mg/kg.bw-1, and ZMFM (300 mg/kg.bw-1 only. Both the normal control and the dimethoate control groups were used to compare the results. After 90 days, rats were sacrificed, blood was collected for biochemical assays, and livers were harvested for histological study. Results: High phenol content was estimated, and 2, 2- diphenyl-1-picryl hydrazyl radical (DPPH spectrophotometric, thin layer chromatography (TLC and 2, 2-Azobis-3-ethyl benzothiazoline-6-sulphonic acid (ABTS assays showed a high antioxidant activity among the extracts. The preventive effects observed in the E1, E2 and E3 groups proved that the extract could prevent dimethoate toxicity by maintaining normal reduced glutathione (GSH, vitamin C and E, superoxide dismutase, catalase, cholineasterase and lipid profiles. The preventive effect was observed to be dose dependent. The EO group showed no extractinduced toxicity. Histological observations agreed with the results obtained in the biochemical studies. Conclusion: The study demonstrated that ZM methanol fruit extract is capable of attenuating dimethoate-induced toxicity because of its

  4. Environmentally toxicant exposures induced intragenerational transmission of liver abnormalities in mice

    Directory of Open Access Journals (Sweden)

    Mohamed A. Al-Griw

    2017-08-01

    Full Text Available Environmental toxicants such as chemicals, heavy metals, and pesticides have been shown to promote transgenerational inheritance of abnormal phenotypes and/or diseases to multiple subsequent generations following parental and/ or ancestral exposures. This study was designed to examine the potential transgenerational action of the environmental toxicant trichloroethane (TCE on transmission of liver abnormality, and to elucidate the molecular etiology of hepatocyte cell damage. A total of thirty two healthy immature female albino mice were randomly divided into three equal groups as follows: a sham group, which did not receive any treatment; a vehicle group, which received corn oil alone, and TCE treated group (3 weeks, 100 μg/kg i.p., every 4th day. The F0 and F1 generation control and TCE populations were sacrificed at the age of four months, and various abnormalities histpathologically investigated. Cell death and oxidative stress indices were also measured. The present study provides experimental evidence for the inheritance of environmentally induced liver abnormalities in mice. The results of this study show that exposure to the TCE promoted adult onset liver abnormalities in F0 female mice as well as unexposed F1 generation offspring. It is the first study to report a transgenerational liver abnormalities in the F1 generation mice through maternal line prior to gestation. This finding was based on careful evaluation of liver histopathological abnormalities, apoptosis of hepatocytes, and measurements of oxidative stress biomarkers (lipid peroxidation, protein carbonylation, and nitric oxide in control and TCE populations. There was an increase in liver histopathological abnormalities, cell death, and oxidative lipid damage in F0 and F1 hepatic tissues of TCE treated group. In conclusion, this study showed that the biological and health impacts of environmental toxicant TCE do not end in maternal adults, but are passed on to offspring

  5. Protective Effects of Diallyl Sulfide and Curcumin Separately against Thallium-Induced Toxicity in Rats

    Directory of Open Access Journals (Sweden)

    Mohamed M. Abdel-Daim

    2015-07-01

    Full Text Available Thallium acetate (TI is a cumulative poison intimately accompanied by an increase in reactive oxygen species (ROS formation that represents an important risk factor for tissue injury and malfunction. This study aims to determine the possible hepatoprotective and antioxidant effects of diallyl sulfide (DAS from garlic and curcumin from turmeric against TI-induced liver injury and oxidative stress (OS in rats. This in vivo animal study divided rats into six groups of 8 rats per group. The first group received saline and served as the control group. The second and third groups received DAS or curcumin only at a dose of 200 mg/kg. The fourth group received TI at a dose of 6.4 mg/kg for 5 consecutive days. The fifth and sixth groups received DAS or curcumin orally 1 hour before TI intoxication at the same dose as the second and third groups. Liver integrity serum enzymes aspartate aminotransferase (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP, lactate dehydrogenase (LDH, and γ-glutamyltransferase (γ-GT were evaluated. Serum and liver tissue homogenate lipid peroxidation and OS biomarkers were measured. The data were analyzed by one-way ANOVA followed by Duncan’s multiple range test for post hoc analysis using SPSS version 16. TI induced marked oxidative liver damage as shown by significantly (P≤0.05 elevated serum AST, ALT, ALP, LDH and γ-GT levels. There were significant (P≤0.05 increases in serum and hepatic malondialdehyde (MDA and serum nitric oxide (NO as well as decreased hepatic glutathione (GSH and catalase (CAT activities. There were significantly (P≤0.05 less serum and hepatic superoxide dismutase (SOD and total antioxidant capacity (TAC. Pre-treatment with DAS or curcumin ameliorated the changes in most studied biochemical parameters. DAS and curcumin effectively reduced TI-induced liver toxicity.

  6. Campomanesia adamantium (Myrtaceae fruits protect HEPG2 cells against carbon tetrachloride-induced toxicity

    Directory of Open Access Journals (Sweden)

    Thaís de Oliveira Fernandes

    2015-01-01

    Full Text Available Campomanesia adamantium (Myrtaceae is an antioxidant compounds-rich Brazilian fruit popularly known as gabiroba. In view of this, it was evaluated the hepatoprotective effects of pulp (GPE or peel/seed (GPSE hydroalcoholic extracts of gabiroba on injured liver-derived HepG2 cells by CCl4 (4 mM. The results showed the presence of total phenolic in GPSE was (60% higher when compared to GPE, associated with interesting antioxidant activity using DPPH·− assay. Additionally, HPLC chromatograms and thin layer chromatography of GPE and GPSE showed the presence of flavonoids. Pretreatment of HepG2 cells with GPE or GPSE (both at 800–1000 μg/mL significantly (p < 0.0001 protected against cytotoxicity induced by CCl4. Additionally, the cells treated with both extracts (both at 1000 μg/mL showed normal morphology (general and nuclear contrasting with apoptotic characteristics in the cells only exposed to CCl4. In these experiments, GPSE also was more effective than GPE. In addition, CCl4 induced a marked increase in AST (p < 0.05 and ALT (p < 0.0001 levels, while GPE or GPSE significantly (p < 0.0001 reduced these levels, reaching values found in the control group. In conclusion, the results suggest that gabiroba fruits exert hepatoprotective effects on HepG2 cells against the CCl4-induced toxicity, probably, at least in part, associated with the presence of antioxidant compounds, especially flavonoids.

  7. Lead Intoxication Synergies of the Ethanol-Induced Toxic Responses in Neuronal Cells--PC12.

    Science.gov (United States)

    Kumar, V; Tripathi, V K; Jahan, S; Agrawal, M; Pandey, A; Khanna, V K; Pant, A B

    2015-12-01

    Lead (Pb)-induced neurodegeneration and its link with widespread neurobehavioral changes are well documented. Experimental evidences suggest that ethanol could enhance the absorption of metals in the body, and alcohol consumption may increase the susceptibility to metal intoxication in the brain. However, the underlying mechanism of ethanol action in affecting metal toxicity in brain cells is poorly understood. Thus, an attempt was made to investigate the modulatory effect of ethanol on Pb intoxication in PC12 cells, a rat pheochromocytoma. Cells were co-exposed to biological safe doses of Pb (10 μM) and ethanol (200 mM), and data were compared to the response of cells which received independent exposure to these chemicals at similar doses. Ethanol (200 mM) exposure significantly aggravated the Pb-induced alterations in the end points associated with oxidative stress and apoptosis. The finding confirms the involvement of reactive oxygen species (ROS)-mediated oxidative stress, and impairment of mitochondrial membrane potential, which subsequently facilitate the translocation of triggering proteins between cytoplasm and mitochondria. We further confirmed the apoptotic changes due to induction of mitochondria-mediated caspase cascade. These cellular changes were found to recover significantly, if the cells are exposed to N-acetyl cysteine (NAC), a known antioxidant. Our data suggest that ethanol may potentiate Pb-induced cellular damage in brain cells, but such damaging effects could be recovered by inhibition of ROS generation. These results open up further possibilities for the design of new therapeutics based on antioxidants to prevent neurodegeneration and associated health problems.

  8. Quercetin attenuates di-(2-ethylhexyl) phthalate-induced testicular toxicity in adult rats.

    Science.gov (United States)

    Abd-Ellah, M F; Aly, H A A; Mokhlis, H A M; Abdel-Aziz, A H

    2016-03-01

    The aim of the present study was to investigate the potential oxidative damage of di-(2-ethylhexyl) phthalate (DEHP) in the rat testis and to further elucidate the potential modulatory effect of quercetin. DEHP was diluted in corn oil and given to rats by oral gavage at doses 0, 300, 600, and 900 mg/kg/day (groups I, III, IV, or V, respectively) for 15 consecutive days. Group VI was pretreated with quercetin (90 mg/kg), 24 h before starting the experiment and then treated with DEHP (900 mg/kg/day) for 15 consecutive days. Group II was treated with quercetin (90 mg/kg/day). The relative testes weight and sperm motility were significantly decreased by treatment with 900 mg/kg of DEHP. Both sperm count and daily sperm production were significantly decreased by DEHP treatment at doses of 600 and 900 mg/kg. Serum testosterone level and prostatic acid phosphatase (ACP) activity and testicular lactate dehydrogenase-X (LDH-X) activity were significantly decreased in animals treated with 900 mg/kg. Serum total ACP activity was significantly increased in animals treated with 600 and 900 mg/kg of DEHP. DEHP treatment induced oxidative stress and histopathological abnormality. These abnormalities were effectively normalized by pretreatment with quercetin except for LDH-X near normalcy. In conclusion, the findings of this study demonstrate that DEHP impairs testicular function at least, in part, by inducing oxidative stress and quercetin has a potent protective effect against DEHP-induced testicular toxicity in rats.

  9. Modulation of copper toxicity-induced oxidative damage by excess supply of iron in maize plants.

    Science.gov (United States)

    Kumar, Praveen; Tewari, Rajesh Kumar; Sharma, Parma Nand

    2008-02-01

    In this study, we examined the modulation of Cu toxicity-induced oxidative stress by excess supply of iron in Zea mays L. plants. Plants receiving excess of Cu (100 microM) showed decreased water potential and simultaneously showed wilting in the leaves. Later, the young leaves exhibited chlorosis and necrotic scorching of lamina. Excess of Cu suppressed growth, decreased concentration of chloroplastic pigments and fresh and dry weight of plants. The activities of peroxidase (EC 1.11.1.7; POD), ascorbate peroxidase (EC 1.11.1.11; APX) and superoxide dismutase (EC 1.15.1.1; SOD) were increased in plants supplied excess of Cu. However, activity of catalase (EC 1.11.1.6; CAT), was depressed in these plants. In gel activities of isoforms of POD, APX and SOD also revealed upregulation of these enzymes. Excess (500 microM)-Fe-supplemented Cu-stressed plants, however, looked better in their phenotypic appearance, had increased concentration of chloroplastic pigments, dry weight, and improved leaf tissue water status in comparison to the plants supplied excess of Cu. Moreover, activities of antioxidant enzymes including CAT were further enhanced and thiobarbituric acid reactive substance (TBARS) and H(2)O(2) concentrations decreased in excess-Fe-supplemented Cu-stressed plants. In situ accumulation of H(2)O(2), contrary to that of O(2)(*-) radical, increased in both leaf and roots of excess-Cu-stressed plants, but Cu-excess plants supplied with excess-Fe showed reduced accumulation H(2)O(2) and little higher of O(2)(*-) in comparison to excess-Cu plants. It is, therefore, concluded that excess-Cu (100 microM) induces oxidative stress by increasing production of H(2)O(2) despite of increased antioxidant protection and that the excess-Cu-induced oxidative damage is minimized by excess supply of Fe.

  10. Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin.

    Science.gov (United States)

    Raghu, Ramanathan; Karthikeyan, Sivanesan

    2016-09-01

    HIV/AIDS patients are more prone for opportunistic TB infections and they are administered the combined regimen of anti-retroviral drug zidovudine (AZT) and isoniazid (INH) for therapy. However, AZT+INH treatment has been documented to induce injury and remedial measures to prevent this adversity are not clearly defined. Silibinin (SBN) is a natural hepatoprotective principle isolated from medicinal plant Silybum marianum and is currently used for therapy of various liver diseases. This study investigate the hepatotoxic potentials of AZT alone, INH alone and AZT+INH treatments and the mitigating potentials of SBN against these drugs induced toxic insults of liver in rats. Separate groups of rats (n=6 in each group) were administered AZT alone (50mg/kg b.w.), INH alone (25mg/kg, b.w.), AZT+INH (50mg/kg, b.w. and 25mg/kg, b.w.), SBN alone (100mg/kg, b.w.) and SBN+AZT+INH daily for sub-chronic period of 45days orally. The control rats received saline/propylene glycol. INH alone and AZT+INH-induced parenchymal cell injury and cholestasis of liver was evidenced by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin, protein, oxidative stress parameters (lipid peroxidation, superoxide dismutase, catalase, reduced glutathione, vitamins C and E) and membrane bound ATPases were evaluated in serum/liver tissue homogenates. Histopathological studies show ballooning degradation, inflammatory lesions, lipid deposition and hydropic changes in the liver tissue. All the above biochemical and pathological changes induced by AZT+INH treatments were mitigated in rats receiving SBN simultaneously with these hepatotoxins, indicating its hepatoprotective and antioxidant potentials against AZT+INH-induced hepatotoxicity. The moderate hepatoprotective and oxidant potentials of SBN could be due to its low bioavailability and this deficiency could be prevented by supplementation of

  11. The efficiency of combined CaO/electrochemical treatment in removal of acid mine drainage induced toxicity and genotoxicity.

    Science.gov (United States)

    Radić, Sandra; Vujčić, Valerija; Cvetković, Želimira; Cvjetko, Petra; Oreščanin, Višnja

    2014-01-01

    Acid mine drainage (AMD) is a by-product of the mining industry that has a detrimental effect on aquatic plant and animal life due to high load of heavy metals and sulfates. In the present study, the toxic and genotoxic potential of AMD prior to and following combination of neutralization/electrocoagulation processes was evaluated using several bioassays and selected parameters. Regardless of pH correction of AMD prior to Daphnia bioassay, high acute toxicity was observed in Daphnia magna. The mine leachate also induced strong phyto-, cyto- and genotoxicity to Allium cepa roots. Short term exposure to AMD inhibited duckweed growth and chlorophyll a content and simultaneously promoted lipid peroxidation and DNA damage despite duckweed capability to upregulate antioxidative defense mechanisms. The results show that observed (geno)toxicity could be related to oxidative stress most probably induced by toxic metal action. However, influence of low pH as a contributing factor in the phytotoxicity of AMD cannot be excluded. The application of combined treatment eliminated genotoxicity and was highly efficient in reducing toxicity of AMD. Thus, the method seems to be suitable for treatment of AMD waters enabling their safe discharge to an aquatic environment.

  12. Aluminum induces neurodegeneration and its toxicity arises from increased iron accumulation and reactive oxygen species (ROS) production.

    Science.gov (United States)

    Wu, Zhihao; Du, Yumei; Xue, Hua; Wu, Yongsheng; Zhou, Bing

    2012-01-01

    The neurotoxicity of aluminum (Al) - the most abundant metal element on earth - has been known for years. However, the mechanism of Al-induced neurodegeneration and its relationship to Alzheimer's disease are still controversial. In particular, in vivo functional data are lacking. In a Drosophila model with chronic dietary Al overloading, general neurodegeneration and several behavioral changes were observed. Al-induced neurodegeneration is independent of β-amyloid or tau-associated toxicity, suggesting they act in different molecular pathways. Interestingly, Drosophila frataxin (dfh), which causes Friedreich's ataxia if mutated in humans, displayed an interacting effect with Al, suggesting Friedreich's ataxia patients might be more susceptible to Al toxicity. Al-treated flies accumulated large amount of iron and reactive oxygen species (ROS), and exhibited elevated SOD2 activity. Genetic and pharmacological efforts to reduce ROS or chelate excess Fe significantly mitigated Al toxicity. Our results indicate that Al toxicity is mediated through ROS production and iron accumulation and suggest a remedial route to reduce toxicity due to Al exposure.

  13. Toxicity and 7-ethoxyresorufin O-deethylase-inducing potency of coplanar polychlorinated biphenyls (PCBs) in chick embryos

    Energy Technology Data Exchange (ETDEWEB)

    Brunstroem, B.; Andersson, L.

    1988-10-01

    The toxicities of the coplanar polychlorinated biphenyls 3,3',4,4'-tetrachlorobiphenyl (TCB), 3,3',4,4',5-pentachlorobiphenyl (PeCB) and 3,3',4,4',5,5'-hexachlorobiphenyl (HCB) were compared in a 72-h study on chick embryos. The substances were injectied into the air sacs of hens's eggs preincubated for 7 days. Mortality was measured 72 h later and corresponding LD/sub 50/ values were calculated. The rank order of toxicity was PeCB>TCB>HCB. Using the same injection procedure, the potencies of these chlorobiphenyls with regard to their induction of hepatic 7-ethoxyresorufin O-deethylase activity were compared. The ranking order of the substances as inducers was the same as their order when ranked according to toxicity. The three coplanar chlorobiphenyls were considerably more toxic and potent as inducers than the non-planar 2,2',4,4',5,5'-hexachlorobiphenyl. In a 2-week toxicity study, PeCB and HCB were injected into the yolks of hens' eggs preincubated for 4 days. PeCB was about 50-fold more potent than HCB in causing embryonic death. Both substances caused abnormalities, including edema, liver lesions, microphthalmia and beak deformities.

  14. Assessment of locomotion behavioral defects induced by acute toxicity from heavy metal exposure in nematode Caenorhabditis elegans

    Institute of Scientific and Technical Information of China (English)

    WANG Dayong; XING Xiaojuan

    2008-01-01

    Locomotion behaviors are susceptible to disruption by a broad spectrum of chemicals and environmental stresses. However, no systematic testing of locomotion behavior defects induced by metal exposure has been conducted in the model organism of nematode Caenorhabditis elegans. In this study, the acute toxicity from heavy metal exposure on the locomotion behaviors was analyzed in nematodes. Endpoints of head thrash, body bend, forward turn, backward turn, and Omega/U turn were chosen to evaluate the locomotion behavioral defects. Our data suggest that the endpoints of head thrash, body bend, and forward turn will be useful for the evaluation of heavy metal toxicity in nematodes. The endpoint of head thrash could detect the toxicity from Cd, Co, Cr, Cu, Hg, and Pb exposures at a low concentration (2.5 μmol/L). The endpoint of body bend could be explored to evaluate the toxicity from all assayed heavy metal exposures at different concentrations, whereas the endpoint of forward turn will be more useful for the evaluation of heavy metal toxicity at high concentrations. Thus, endpoints of these locomotion behaviors establish a fast and economic way to assess the presence of acute toxicity from heavy metal exposure in nematode C. elegans.

  15. Zebrafish on a chip: a novel platform for real-time monitoring of drug-induced developmental toxicity.

    Directory of Open Access Journals (Sweden)

    Yinbao Li

    Full Text Available Pharmaceutical safety testing requires a cheap, fast and highly efficient platform for real-time evaluation of drug toxicity and secondary effects. In this study, we have developed a microfluidic system for phenotype-based evaluation of toxic and teratogenic effects of drugs using zebrafish (Danio rerio embryos and larvae as the model organism. The microfluidic chip is composed of two independent functional units, enabling the assessment of zebrafish embryos and larvae. Each unit consists of a fluidic concentration gradient generator and a row of seven culture chambers to accommodate zebrafish. To test the accuracy of this new chip platform, we examined the toxicity and teratogenicity of an anti-asthmatic agent-aminophylline (Apl on 210 embryos and 210 larvae (10 individuals per chamber. The effect of Apl on zebrafish embryonic development was quantitatively assessed by recording a series of physiological indicators such as heart rate, survival rate, body length and hatch rate. Most importantly, a new index called clonic convulsion rate, combined with mortality was used to evaluate the toxicities of Apl on zebrafish larvae. We found that Apl can induce deformity and cardiovascular toxicity in both zebrafish embryos and larvae. This microdevice is a multiplexed testing apparatus that allows for the examination of indexes beyond toxicity and teratogenicity at the sub-organ and cellular levels and provides a potentially cost-effective and rapid pharmaceutical safety assessment tool.

  16. Nanoscale zerovalent iron (nZVI) at environmentally relevant concentrations induced multigenerational reproductive toxicity in Caenorhabditis elegans.

    Science.gov (United States)

    Yang, Ying-Fei; Chen, Pei-Jen; Liao, Vivian Hsiu-Chuan

    2016-05-01

    Nanoscale zerovalent iron (nZVI) is widely used with large scale for environmental remediation for in situ or ex situ applications. The potential impact of nZVI on biota at environmentally relevant concentrations needs to be elucidated. In this study, the reproductive toxicities of three irons species: carboxymethyl cellulose (CMC)-stabilized nZVI, nanoscale iron oxide (nFe3O4), and ferrous ion (Fe(II)aq) in the soil-dwelling nematode Caenorhabditis elegans were examined. In addition, the generational transfer of reproductive toxicity of CMC-nZVI on C. elegans was investigated. The results showed that CMC-nZVI, nFe3O4, and Fe(II)aq did not cause significant mortality after 24 h exposure at the examined concentrations. Reproductive toxicity assays revealed that CMC-nZVI, nFe3O4, and Fe(II)aq significantly decreased offsprings in parental generation (F0) in accompany with the increased intracellular reactive oxygen species (ROS). Furthermore, the reproductive toxicity of CMC-nZVI at environmentally relevant concentrations was transferrable from the F0 to the F1 and F2 generations, but then recovered in the F3 and F4 generations. Further evidence showed that total irons were accumulated in the F0 and F1 generations of C. elegans after CMC-nZVI parental exposure. This study demonstrated that environmentally relevant concentrations of CMC-nZVI induced multigenerational reproductive toxicity which can be ascribed to its high production of ROS in F0 generation, toxicity of Fe(II)aq, and iron accumulation in C. elegans. Since nZVI is widely used for environmental remediation, considering the multigenerational toxicity, this study thus implicates a potential environmental risk of nZVI-induced nanotoxicity in the environment.

  17. Prospective evaluation of radiation-induced skin toxicity in a race/ethnically diverse breast cancer population.

    Science.gov (United States)

    Wright, Jean L; Takita, Cristiane; Reis, Isildinha M; Zhao, Wei; Lee, Eunkyung; Nelson, Omar L; Hu, Jennifer J

    2016-03-01

    We evaluated predictors of radiation-induced skin toxicity in a prospective study of a tri-racial/ethnic breast cancer population. We evaluated patient demographics, tumor characteristics, and treatment variables in the first 392 patients in a prospective study assessing radiation-induced skin toxicity. Logistic regression analyses were conducted to evaluate potential predictors of skin toxicity. The study consists of 59 non-Hispanic whites (NHW; 15%), 241 Hispanic Whites (HW; 62%), 79 black or African Americans (AA; 20%), and 13 others (3%). Overall, 48% developed grade 0-1 skin toxicity, 49.8% grade 2, and 2.2% grade 3 by the National Cancer Institute's Common Toxicity Criteria for Adverse Events (CTCAE) scale. Twenty-one percent developed moist desquamation. In multivariate analysis, higher body mass index (BMI; OR = 2.09; 95%CI = 1.15, 3.82), higher disease stage (OR = 1.82; 95%CI = 1.06, 3.11), ER-positive/PR-negative status (OR = 2.74; 95%CI = 1.26, 5.98), and conventionally fractionated regimens (OR = 3.25; 95%CI = 1.76, 6.01) were significantly associated with higher skin toxicity grade after adjustment for age, race, ethnicity, ER status, and breast volume. B MI specifically predicted for moist desquamation, but not degree of erythema. In this racially and ethnically diverse cohort of breast cancer patients receiving radiation to the intact breast, risk factors including BMI, disease stage, and conventionally fractionated radiation predicted for higher skin toxicity grade, whereas age, race, ethnicity, and breast volume did not. BMI specifically predicted for moist desquamation, suggesting that preventive measures to address this particular outcome should be investigated. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  18. Heme oxygenase-1 protects against Alzheimer's amyloid-β(1-42)-induced toxicity via carbon monoxide production.

    Science.gov (United States)

    Hettiarachchi, N; Dallas, M; Al-Owais, M; Griffiths, H; Hooper, N; Scragg, J; Boyle, J; Peers, C

    2014-12-11

    Heme oxygenase-1 (HO-1), an inducible enzyme up-regulated in Alzheimer's disease, catabolises heme to biliverdin, Fe2+ and carbon monoxide (CO). CO can protect neurones from oxidative stress-induced apoptosis by inhibiting Kv2.1 channels, which mediates cellular K+ efflux as an early step in the apoptotic cascade. Since apoptosis contributes to the neuronal loss associated with amyloid β peptide (Aβ) toxicity in AD, we investigated the protective effects of HO-1 and CO against Aβ(1-42) toxicity in SH-SY5Y cells, employing cells stably transfected with empty vector or expressing the cellular prion protein, PrP(c), and rat primary hippocampal neurons. Aβ(1-42) (containing protofibrils) caused a concentration-dependent decrease in cell viability, attributable at least in part to induction of apoptosis, with the PrP(c)-expressing cells showing greater susceptibility to Aβ(1-42) toxicity. Pharmacological induction or genetic over-expression of HO-1 significantly ameliorated the effects of Aβ(1-42). The CO-donor CORM-2 protected cells against Aβ(1-42) toxicity in a concentration-dependent manner. Electrophysiological studies revealed no differences in the outward current pre- and post-Aβ(1-42) treatment suggesting that K+ channel activity is unaffected in these cells. Instead, Aβ toxicity was reduced by the L-type Ca2+ channel blocker nifedipine, and by the CaMKKII inhibitor, STO-609. Aβ also activated the downstream kinase, AMP-dependent protein kinase (AMPK). CO prevented this activation of AMPK. Our findings indicate that HO-1 protects against Aβ toxicity via production of CO. Protection does not arise from inhibition of apoptosis-associated K+ efflux, but rather by inhibition of AMPK activation, which has been recently implicated in the toxic effects of Aβ. These data provide a novel, beneficial effect of CO which adds to its growing potential as a therapeutic agent.

  19. Developmental toxicity and DNA damage to zebrafish induced by perfluorooctane sulfonate in the presence of ZnO nanoparticles.

    Science.gov (United States)

    Du, Jia; Wang, Shutao; You, Hong; Jiang, Rui; Zhuang, Changlu; Zhang, Xiaohui

    2016-03-01

    Perfluorooctane sulfonate (PFOS) and ZnO nanoparticles (ZnO-NPs) are frequently detected in the environment, but few studies have assessed their joint toxicity. In this study, the acute toxicity and chronic toxicity to zebrafish (Danio rerio) induced by PFOS in the presence of ZnO-NPs were investigated, including developmental toxicity and DNA damage. The embryos were exposed to PFOS (only) (0.4, 0.8, and 1.6 mg/L) and PFOS plus ZnO-NPs (0.4 + 50, 0.8 + 50, and 1.6 + 50 mg/L) solutions to evaluate mortality (96 h), body length (96 h), hatch rate (72 h), heart rate (48 h),and malformation rate (96 h). The results revealed that the co-treatment could cause more severe developmental toxicity compared with the control and single-treatments, and the toxic effects generally increased in a dose-response manner. In addition, adult zebrafish were exposed to single and mixed solutions of PFOS and ZnO-NPs (at the concentrations mentioned above) for 30 days. DNA damage to zebrafish was evaluated by the comet assay and micronucleus test. We found that the PFOS single-treatment at all doses (0.4, 0.8, and 1.6 mg/L) could strongly induce DNA damage to peripheral blood cells and that ZnO-NPs could aggravate the formation of DNA damage in co-treatments. Histological examination of liver, testicle, and ovary showed that the presence of ZnO-NPs (50 mg/L) could also cause more serious histological damage to adult zebrafish than PFOS alone. As a result, the synergistic effects played an important role during joint exposure. Our observations provide a basic understanding of the joint toxicity of PFOS and ZnO-NPs to aquatic organisms.

  20. Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice.

    Directory of Open Access Journals (Sweden)

    Emil Schüler

    Full Text Available The kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after 177Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity.C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys. At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a global transcriptional variations in kidney tissues, (b morphological changes in the kidneys, (c changes in white and red blood cell count as well as blood levels of urea, and (d changes in renal function using 99mTc-DTPA/99mTc-DMSA scintigraphy.In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99mTc-DTPA after 150 MBq, an increased uptake of 99mTc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months.Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for 177Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm applicability of these

  1. Gene networks and toxicity pathways induced by acute cadmium exposure in adult largemouth bass (Micropterus salmoides)

    Energy Technology Data Exchange (ETDEWEB)

    Mehinto, Alvine C., E-mail: alvinam@sccwrp.org [Southern California Coastal Water Research Project, Costa Mesa, CA 92626 (United States); Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Prucha, Melinda S. [Department of Human Genetics, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322 (United States); Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Colli-Dula, Reyna C.; Kroll, Kevin J.; Lavelle, Candice M.; Barber, David S. [Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Vulpe, Christopher D. [Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720 (United States); Denslow, Nancy D. [Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States)

    2014-07-01

    Highlights: • Low-level acute cadmium exposure elicited tissue-specific gene expression changes. • Molecular initiating events included oxidative stress and disruption of DNA repair. • Metallothionein, a marker of metal exposure, was not significantly affected. • We report effects of cadmium on cholesterol metabolism and steroid synthesis. • Diabetic complications and impaired reproduction are potential adverse outcomes. - Abstract: Cadmium is a heavy metal that can accumulate to toxic levels in the environment leading to detrimental effects in animals and humans including kidney, liver and lung injuries. Using a transcriptomics approach, genes and cellular pathways affected by a low dose of cadmium were investigated. Adult largemouth bass were intraperitoneally injected with 20 μg/kg of cadmium chloride (mean exposure level – 2.6 μg of cadmium per fish) and microarray analyses were conducted in the liver and testis 48 h after injection. Transcriptomic profiles identified in response to cadmium exposure were tissue-specific with the most differential expression changes found in the liver tissues, which also contained much higher levels of cadmium than the testis. Acute exposure to a low dose of cadmium induced oxidative stress response and oxidative damage pathways in the liver. The mRNA levels of antioxidants such as catalase increased and numerous transcripts related to DNA damage and DNA repair were significantly altered. Hepatic mRNA levels of metallothionein, a molecular marker of metal exposure, did not increase significantly after 48 h exposure. Carbohydrate metabolic pathways were also disrupted with hepatic transcripts such as UDP-glucose, pyrophosphorylase 2, and sorbitol dehydrogenase highly induced. Both tissues exhibited a disruption of steroid signaling pathways. In the testis, estrogen receptor beta and transcripts linked to cholesterol metabolism were suppressed. On the contrary, genes involved in cholesterol metabolism were highly

  2. Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients.

    Science.gov (United States)

    van der Schoot, Gabriela G F; Westerink, Nico-Derk L; Lubberts, Sjoukje; Nuver, Janine; Zwart, Nynke; Walenkamp, Annemiek M E; Wempe, Johan B; Meijer, Coby; Gietema, Jourik A

    2016-05-01

    Bleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic variants of the HFE gene induces altered iron metabolism and may contribute to toxicity. We investigated the association between two common allelic variants of the HFE gene, H63D and C282Y, with development of pulmonary and renal toxicity during and after treatment with bleomycin- and cisplatin-containing chemotherapy. In 369 testicular cancer patients treated with bleomycin and cisplatin at the University Medical Center Groningen between 1978 and 2006, H63D and/or C282Y genotypes were determined with an allelic discrimination assay. Data were collected on development of BIP, pulmonary function parameters, renal function, and survival. BIP developed more frequently in patients who were heterozygote (16 in 75, 21%) and homozygote (2 in 4, 50%) for the H63D variant, compared with those who had the HFE wild-type gene (31 in 278, 11%) (p = 0.012). Overall survival, testicular cancer-related survival, and change in renal function were not associated with the H63D variant. We observed an association between presence of one or both H63D alleles and development of BIP in testicular cancer patients treated with bleomycin combination chemotherapy. In patients heterozygote and homozygote for the H63D variant, BIP occurred more frequently compared with wild-type patients. When validated and confirmed, HFE H63D genotyping may be used to identify patients with increased risk for pulmonary bleomycin toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Critical role of surface chemical modifications induced by length shortening on multi-walled carbon nanotubes-induced toxicity

    Directory of Open Access Journals (Sweden)

    Bussy Cyrill

    2012-11-01

    Full Text Available Abstract Given the increasing use of carbon nanotubes (CNT in composite materials and their possible expansion to new areas such as nanomedicine which will both lead to higher human exposure, a better understanding of their potential to cause adverse effects on human health is needed. Like other nanomaterials, the biological reactivity and toxicity of CNT were shown to depend on various physicochemical characteristics, and length has been suggested to play a critical role. We therefore designed a comprehensive study that aimed at comparing the effects on murine macrophages of two samples of multi-walled CNT (MWCNT specifically synthesized following a similar production process (aerosol-assisted CVD, and used a soft ultrasonic treatment in water to modify the length of one of them. We showed that modification of the length of MWCNT leads, unavoidably, to accompanying structural (i.e. defects and chemical (i.e. oxidation modifications that affect both surface and residual catalyst iron nanoparticle content of CNT. The biological response of murine macrophages to the two different MWCNT samples was evaluated in terms of cell viability, pro-inflammatory cytokines secretion and oxidative stress. We showed that structural defects and oxidation both induced by the length reduction process are at least as responsible as the length reduction itself for the enhanced pro-inflammatory and pro-oxidative response observed with short (oxidized compared to long (pristine MWCNT. In conclusion, our results stress that surface properties should be considered, alongside the length, as essential parameters in CNT-induced inflammation, especially when dealing with a safe design of CNT, for application in nanomedicine for example.

  4. A pharmacologically-based array to identify targets of cyclosporine A-induced toxicity in cultured renal proximal tubule cells

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    Sarró, Eduard, E-mail: eduard.sarro@vhir.org [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Jacobs-Cachá, Conxita, E-mail: conxita.jacobs@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Itarte, Emilio, E-mail: emili.itarte@uab.es [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Meseguer, Anna, E-mail: ana.meseguer@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Departament de Bioquimica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain)

    2012-01-15

    Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule cells (PTC), a comprehensive view of events occurring after CsA exposure remains to be described. For this purpose, we applied a pharmacologic approach based on the use of known activities of a large panel of potentially protective compounds and evaluated their efficacy in preventing CsA toxicity in cultured mouse PTC. Our results show that compounds that blocked protein synthesis and apoptosis, together with the CK2 inhibitor DMAT and the PI3K inhibitor apigenin, were the most efficient in preventing CsA toxicity. We also identified GSK3, MMPs and PKC pathways as potential targets to prevent CsA damage. Additionally, heparinase-I and MAPK inhibitors afforded partial but significant protection. Interestingly, antioxidants and calcium metabolism-related compounds were unable to ameliorate CsA-induced cytotoxicity. Subsequent experiments allowed us to clarify the hierarchical relationship of targeted pathways after CsA treatment, with ER stress identified as an early effector of CsA toxicity, which leads to ROS generation, phenotypical changes and cell death. In summary, this work presents a novel experimental approach to characterizing cellular responses to cytotoxics while pointing to new targets to prevent CsA-induced toxicity in proximal tubule cells. Highlights: ► We used a novel pharmacological approach to elucidate cyclosporine (CsA) toxicity. ► The ability of a broad range of compounds to prevent CsA toxicity was evaluated. ► CsA toxicity was monitored using LDH release assay and PARP cleavage. ► Protein synthesis, PI3K, GSK3, MMP, PKC and caspase inhibitors prevented CsA toxicity. ► We also identified ER

  5. Lipid Emulsions Enhance the Norepinephrine-Mediated Reversal of Local Anesthetic-Induced Vasodilation at Toxic Doses

    Science.gov (United States)

    Lee, Soo Hee; Sung, Hui-Jin; Ok, Seong-Ho; Yu, Jongsun; Choi, Mun-Jeoung; Lim, Jin Soo

    2013-01-01

    Purpose Intravenous lipid emulsions have been used to treat the systemic toxicity of local anesthetics. The goal of this in vitro study was to examine the effects of lipid emulsions on the norepinephrine-mediated reversal of vasodilation induced by high doses of levobupivacaine, ropivacaine, and mepivacaine in isolated endothelium-denuded rat aorta, and to determine whether such effects are associated with the lipid solubility of local anesthetics. Materials and Methods The effects of lipid emulsions (0.30, 0.49, 1.40, and 2.61%) on norepinephrine concentration-responses in high-dose local anesthetic (6×10-4 M levobupivacaine, 2×10-3 M ropivacaine, and 7×10-3 M mepivacaine)-induced vasodilation of isolated aorta precontracted with 60 mM KCl were assessed. The effects of lipid emulsions on local anesthetic- and diltiazem-induced vasodilation in isolated aorta precontracted with phenylephrine were also assessed. Results Lipid emulsions (0.30%) enhanced norepinephrine-induced contraction in levobupivacaine-induced vasodilation, whereas 1.40 and 2.61% lipid emulsions enhanced norepinephrine-induced contraction in both ropivacaine- and mepivacaine-induced vasodilation, respectively. Lipid emulsions (0.20, 0.49 and 1.40%) inhibited vasodilation induced by levobupivacaine and ropivacaine, whereas 1.40 and 2.61% lipid emulsions slightly attenuated mepivacaine (3×10-3 M)-induced vasodilation. In addition, lipid emulsions attenuated diltiazem-induced vasodilation. Lipid emulsions enhanced norepinephrine-induced contraction in endothelium-denuded aorta without pretreatment with local anesthetics. Conclusion Taken together, these results suggest that lipid emulsions enhance the norepinephrine-mediated reversal of local anesthetic-induced vasodilation at toxic anesthetic doses and inhibit local anesthetic-induced vasodilation in a manner correlated with the lipid solubility of a particular local anesthetic. PMID:24142661

  6. Strain difference of cadmium-induced testicular toxicity in inbred Wistar-Imamichi and Fischer 344 rats

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Hideaki; Narumi, Rika [Kumamoto University, Faculty of Education, Kumamoto (Japan); Nagano, Masaaki; Yasutake, Akira [National Institute for Minamata Disease, Biochemistry Section, Kumamoto (Japan); Waalkes, Michael P. [National Cancer Institute at the National Institute of Environmental Health Sciences, Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, Research Triangle Park, NC (United States); Imamura, Yorishige [Kumamoto University, Graduate School of Pharmaceutical Sciences, Kumamoto (Japan)

    2009-07-15

    Previously, we reported that Wistar-Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced lethality and hepatotoxicity compared to Fischer 344 (F344) rats. Since the testes are one of the most sensitive organs to acute Cd toxicity, we examined possible strain-related differences in Cd-induced testicular toxicity between inbred WI and F344 rats. Rats were treated with a single dose of 0.5, 1.0 or 2.0 mg Cd/kg, as CdCl{sub 2}, sc and killed 24 h later. Cd at doses of 1.0 and 2.0 mg/kg induced severe testicular hemorrhage, as assessed by pathological and testis hemoglobin content, in F344 rats, but not WI rats. After Cd treatment (2.0 mg/kg), the testicular Cd content was significantly lower in WI rats than in the F344 rats, indicating a toxiokinetic mechanism for the observed strain difference. Thus, the remarkable resistance to Cd-induced testicular toxicity in WI rats is associated, at least in part, with lower testicular accumulation of Cd. When zinc (Zn; 10 mg/kg, sc) was administered in combination with Cd (2.0 mg/kg) to F344 rats, the Cd-induced increase in testicular hemoglobin content, indicative of hemorrhage, was significantly reduced. Similarly, the testicular Cd content was significantly decreased with Zn co-treatment compared to Cd treatment alone. Thus, it can be concluded that the testicular Cd accumulation partly competes with Zn transport systems and that these systems may play an important role in the strain-related differences in Cd-induced testicular toxicity between WI and F344 rats. (orig.)

  7. Hesperidin attenuates benzo[alpha] pyrene-induced testicular toxicity in rats via regulation of oxidant/antioxidant balance.

    Science.gov (United States)

    Arafa, H M M; Aly, H A A; Abd-Ellah, M F; El-Refaey, H M

    2009-07-01

    Benzo[alpha]pyrene (BaP) is one of the polycyclic aromatic hydrocarbons, which has shown carcinogenic, teratogenic, and mutagenic potentials. The reproductive toxicity of BaP in male was not well investigated. Thereby, we have addressed in the current study the testicular toxicity of BaP and the postulate whether or not the citrus flavonoid, hesperidin (HDN), could ameliorate such toxicity in male Swiss albino rats. In this sense, animals were challenged with BaP (50 mg/kg/day, orally) for 10 consecutive days. HDN (200 mg/kg/day, orally) was administered ahead of BaP challenge for 10 consecutive days. BaP induced testicular toxicity that was well characterized histologically and biochemically. It decreased the relative testis weight and induced pyknosis and necrobiotic changes as well as chromatolysis in the nuclei of the spermatocytes in the seminiferous tubules. It also markedly deteriorated epididymal function as shown by decreased sperm count, motility, and daily sperm production. The polyaromatic hydrocarbon also reduced the testicular activities of lactate dehydrogenase (LDH-X), superoxide dismutase (SOD), and glutathione-S-transferase (GST). Besides, it decreased the testicular reduced glutathione (GSH) but increased malondialdehyde (MDA) contents. Prior administration of HDN ahead of BaP challenge ameliorated all the histological and biochemical alterations induced by BaP. It improved the epididymal function and mitigated the injurious effects of BaP on the seminiferous tubules. In conclusion, HDN has proven protective effects in BaP-induced testicular toxicity paradigm, and this protection resides, at least in part, on its antioxidant properties.

  8. Assessing benzene-induced toxicity on wild type Euglena gracilis Z and its mutant strain SMZ.

    Science.gov (United States)

    Peng, Cheng; Arthur, Dionne M; Sichani, Homa Teimouri; Xia, Qing; Ng, Jack C

    2013-11-01

    Benzene is a representative member of volatile organic compounds and has been widely used as an industrial solvent. Groundwater contamination of benzene may pose risks to human health and ecosystems. Detection of benzene in the groundwater using chemical analysis is expensive and time consuming. In addition, biological responses to environmental exposures are uninformative using such analysis. Therefore, the aim of this study was to employ a microorganism, Euglena gracilis (E. gracilis) as a putative model to monitor the contamination of benzene in groundwater. To this end, we examined the wild type of E. gracilis Z and its mutant form, SMZ in their growth rate, morphology, chlorophyll content, formation of reactive oxygen species (ROS) and DNA damage in response to benzene exposure. The results showed that benzene inhibited cell growth in a dose response manner up to 48 h of exposure. SMZ showed a greater sensitivity compared to Z in response to benzene exposure. The difference was more evident at lower concentrations of benzene (0.005-5 μM) where growth inhibition occurred in SMZ but not in Z cells. We found that benzene induced morphological changes, formation of lipofuscin, and decreased chlorophyll content in Z strain in a dose response manner. No significant differences were found between the two strains in ROS formation and DNA damage by benzene at concentrations affecting cell growth. Based on these results, we conclude that E. gracilis cells were sensitive to benzene-induced toxicities for certain endpoints such as cell growth rate, morphological change, depletion of chlorophyll. Therefore, it is a potentially suitable model for monitoring the contamination of benzene and its effects in the groundwater.

  9. Neuroprotective effect of carvedilol against aluminium induced toxicity: possible behavioral and biochemical alterations in rats.

    Science.gov (United States)

    Kumar, Anil; Prakash, Atish; Dogra, Samrita

    2011-01-01

    Aluminium, is a trace element available in the Earth's crust naturally and has a toxic potential for humans. It has been suggested as a contributing factor in the pathogenesis of Alzheimer's disease. β-Adrenoceptor blocking agents (β-blockers) have been established as therapeutics for the treatment of patients with hypertension, ischemic heart diseases, chronic heart failure, arrhythmias and glaucoma. Over the years, however, β-blockers have been associated with an incidence, albeit low, of central nervous system (CNS) side effects. In addition, noradrenergic receptors play a modulatory role in many nerve functions, including vigilance, attention, reward, learning and memory. Therefore, the present study has been designed to explore the possible role of carvedilol, an adrenergic antagonist against aluminium chloride-induced neurotoxicity in rats. Aluminium chloride (100 mg/kg) was administered daily for six weeks that significantly increased cognitive dysfunction in the Morris water maze and oxidative damage as indicated by a rise in lipid peroxidation and nitrite concentration and depleted reduced glutathione, superoxide dismutase, catalase and glutathione S-transferase activity compared to sham treatment. Chronic aluminium chloride treatment also significantly increased acetylcholinesterase activity and the aluminium concentration in brain compared to sham. Chronic administration of carvedilol (2.5 and 5 mg/kg, po) daily to rats for a period of 6 weeks significantly improved the memory performance tasks of rats in the Morris water maze test, attenuated oxidative stress (reduced lipid peroxidation, nitrite concentration and restored reduced glutathione, superoxide dismutase, catalase and glutathione S-transferase activity), decreased acetylcholinesterase activity and aluminium concentration in aluminium-treated rats compared to control rats (p aluminium chloride-induced cognitive dysfunction and oxidative damage.

  10. Prion-induced and spontaneous formation of transmissible toxicity in PrP transgenic Drosophila.

    Science.gov (United States)

    Thackray, Alana M; Di, Ying; Zhang, Chang; Wolf, Hanna; Pradl, Lydia; Vorberg, Ina; Andréoletti, Olivier; Bujdoso, Raymond

    2014-10-01

    Prion diseases are fatal transmissible neurodegenerative diseases of various mammalian species. Central to these conditions is the conversion of the normal host prion protein PrP(C) into the abnormal prion conformer PrP(Sc). Mature PrP(C) is attached to the plasma membrane by a glycosylphosphatidylinositol anchor, whereas during biosynthesis and metabolism cytosolic and secreted forms of the protein may arise. The role of topological PrP(C) variants in the mechanism of prion formation and prion-induced neurotoxicity during prion disease remains undefined. In the present study we investigated whether Drosophila transgenic for ovine PrP targeted to the plasma membrane, to the cytosol or for secretion, could produce transmissible toxicity following exposure to exogenous ovine prions. Although all three topological variants of PrP were efficiently expressed in Drosophila, cytosolic PrP was conformationally distinct and required denaturation before recognition by immunobiochemical methods. Adult Drosophila transgenic for pan neuronally expressed ovine PrP targeted to the plasma membrane, to the cytosol or for secretion exhibited a decreased locomotor activity after exposure at the larval stage to ovine prions. Proteinase K-resistant PrP(Sc) was detected by protein misfolding cyclic amplification in prion-exposed Drosophila transgenic for membrane-targeted PrP. Significantly, head homogenate from all three variants of prion-exposed PrP transgenic Drosophila induced a decreased locomotor activity when transmitted to PrP recipient flies. Drosophila transgenic for PrP targeted for secretion exhibited a spontaneous locomotor defect in the absence of prion exposure that was transmissible in PrP transgenic flies. Our data are consistent with the formation of transmissible prions in PrP transgenic Drosophila.

  11. Selenium in the Prevention of Anthracycline-Induced Cardiac Toxicity in Children with Cancer

    Directory of Open Access Journals (Sweden)

    Nurdan Tacyildiz

    2012-01-01

    Full Text Available High cumulative doses of anthracyclines (300–500 mg/m2 used in the treatment of children with cancer may result in cardiotoxicity, a major long-term adverse effect that limits clinical usefulness of this class of chemotherapeutic agents. We assessed anthracycline-induced cardiotoxicity by measuring Pro-BNP levels and echocardiographic (ECHO findings and investigated potential protective effect of selenium (Se supplementation in a group of pediatric cancer patients. Plasma level of Pro-BNP was measured, and ECHO was performed in 67 patients (45 boys, 22 girls; ages 2–18 years; median age 12 years after they completed anthracycline-containing chemotherapy. Serum Se level was measured in 37 patients. Eleven patients had high Pro-BNP levels and/or cardiac failure with Pro-BNP levels of 10–8,022 pg/mL (median 226.3 pg/mL; laboratory normal level is less than 120 pg/mL. Serum Se levels were low (20–129 mcg/L, median 62 mcg/L in ten of these eleven patients. Eight of 10 patients with low Se and high Pro-BNP levels were supplemented with Se 100 mcg/day for a period of 4–33 months (median 6 months which resulted in improvement in Pro-BNP and/or ECHO findings. These results suggest that Se supplementation may have a role in protection against anthracycline-induced cardiac toxicity.

  12. Protective effects of thymoquinone and l-cysteine on cadmium-induced reproductive toxicity in rats

    Directory of Open Access Journals (Sweden)

    Manal M. Sayed

    2014-01-01

    Full Text Available This study was conducted to investigate the possible protective role of thymoquinone (TQ and l-cysteine on the reproductive toxicity of male rats induced by cadmium chloride (CdCl2. Forty rats were divided into four even groups. The first group served as untreated control. The second, third and fourth groups received CdCl2, CdCl2 and TQ, and CdCl2 and l-cysteine, respectively for 56 days. Cd exposure caused spermatological damage (decrease sperm count and motility and increased the rates of sperm abnormalities, decrease serum testosterone level and increased oxidative stress. Histological alterations were also observed in the form of vascular and cellular changes in CdCl2 treated rats. The vascular changes were congestion of the blood vessels with interstitial edema in the testes, epididymis, seminal vesicle and prostate. The cellular changes were in the form of degenerative changes with presence of multinucleated giant cells in the lumen of seminiferous tubules, vacuolation and sloughing of the lining epithelium of the epididymis, seminal vesiculitis and prostatitis. Co-administration of TQ and l-cysteine with CdCl2 increased glutathione (GSH, superoxide dismutase (SOD, catalase (CAT and testosterone and reduced lipid peroxidation (LPO activity. In conclusion, our results showed that TQ and l-cysteine can ameliorate the deleterious effects of CdCl2 probably by activating testicular endocrine and antioxidant systems.

  13. Effective analgesic doses of tramadol or tapentadol induce brain, lung and heart toxicity in Wistar rats.

    Science.gov (United States)

    Faria, Juliana; Barbosa, Joana; Leal, Sandra; Afonso, Luís Pedro; Lobo, João; Moreira, Roxana; Queirós, Odília; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

    2017-06-15

    Tramadol and tapentadol are extensively prescribed for the treatment of moderate to severe pain. Although these drugs are very effective in pain treatment, the number of intoxications and deaths due to both opioids is increasing, and the underlying toxic mechanisms are not fully understood. The present work aimed to study the potential biochemical and histopathological alterations induced by acute effective (analgesic) doses of tramadol and tapentadol, in Wistar rats. Forty-two male Wistar rats were divided into different groups: a control, administered with normal saline solution, and tramadol- or tapentadol-treated groups (10, 25 or 50mg/kg - typical effective analgesic dose, intermediate and maximum recommended doses, respectively). 24h after intraperitoneal administration, biochemical and oxidative stress analyses were performed in blood, and specimens from brain, lung and heart were taken for histopathological and oxidative stress studies. Both drugs caused an increase in the AST/ALT ratio, in LDH, CK and CK-MB activities in serum samples, and an increase in lactate levels in serum and brain samples. Oxidative damage, namely protein oxidation, was found in heart and lung tissues. In histological analyses, tramadol and tapentadol were found to cause alterations in cell morphology, inflammatory cell infiltrates and cell death in all tissues under study, although tapentadol caused more damage than tramadol. Our results confirmed the risks of tramadol exposure, and demonstrated the higher risk of tapentadol, especially at high doses. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Assessment of Pulmonary Toxicity Induced by Inhaled Toner with External Additives

    Directory of Open Access Journals (Sweden)

    Taisuke Tomonaga

    2017-01-01

    Full Text Available We investigated the harmful effects of exposure to a toner with external additives by a long-term inhalation study using rats, examining pulmonary inflammation, oxidative stress, and histopathological changes in the lung. Wistar rats were exposed to a well-dispersed toner (mean of MMAD: 2.1 μm at three mass concentrations of 1, 4, and 16 mg/m3 for 22.5 months, and the rats were sacrificed after 6 months, 12 months, and 22.5 months of exposure. The low and medium concentrations did not induce statistically significant pulmonary inflammation, but the high concentration did, and, in addition, a histopathological examination showed fibrosis in the lung. Although lung tumor was observed in one sample of high exposure for 22.5 months, the cause was not statistically significant. On the other hand, a persistent increase in 8-OHdG was observed in the high exposure group, indicating that DNA damage by oxidative stress with persistent inflammation leads to the formation of tumorigenesis. The results of our studies show that toners with external additives lead to pulmonary inflammation, oxidative stress, and fibrosis only at lung burdens beyond overload. These data suggest that toners with external additives may have low toxicity in the lung.

  15. Amla as an antihyperglycemic and hepato-renal protective agent in fluoride induced toxicity

    Directory of Open Access Journals (Sweden)

    Rupal A Vasant

    2012-01-01

    Full Text Available Purpose of the study was to examine the antihyperglycemic and hepato-renal protective effects of Emblica officinalis (Eo fruit as a food supplement in fluoride induced toxicity. Eo fruit powder was incorporated into the diet (2.5, 5 and 10 gm % of fluoride exposed animals for a duration of 30 days. Fluoride exposure caused significant elevation in plasma glucose, serum glutamate oxaloacetate transaminase (SGOT, serum glutamate pyruvate transaminase (SGPT, acid phosphatase (ACP, alkaline phosphatase (ALP activities, hepatic glucose-6-phosphatase (G-6-Pase and decreased hepatic glycogen content, hexokinase activity and antioxidant profiles (hepatic and renal. An inclusion of Eo fruit powder significantly reduced plasma glucose levels, SGOT, SGPT, ACP and ALP activities, hepatic G-6-Pase activity and increased hepatic glycogen content and hexokinase activity. Hepatic and renal antioxidant status of fluoride exposed animals improved upon feeding Eo fruit powder. We, therefore, conclude that E. officinalis fruit could be useful in regulating hyperglycemia and enhances antioxidant status of fluoride exposed animals.

  16. [Group A streptococcus-induced toxic shock syndrome in pregnancy: a case report of cesarean section].

    Science.gov (United States)

    Yamada, Kumiko; Fukuda, Taeko; Kimura, Maiko; Hagiya, Keiichi; Danmura, Masato; Nakayama, Shin; Ogura, Tsuyoshi; Tanaka, Makoto

    2012-12-01

    Group A streptococcus (GAS)-induced toxic shock syndrome (TSS) in pregnancy is rare, but its clinical course is fulminant. The mortality rates of mother and fetus are reported to be 58 and 66%, respectively. We report a case of GAS-TSS after cesarean section. A 38-year-old pregnant woman of 38 weeks gestation was admitted to our hospital because of vomiting, fever of 39 degrees C, and continuous abdominal pain with scanty genital bleeding. She had complained of sore throat several days before. One hour after admission, external fetal monitoring revealed periodic pulse deceleration to 90 x beats min(-1). The emergent cesarean section was performed under general anesthesia. Approximately 8 hours after the cesarean section, she developed coma, shock and respiratory insufficiency requiring intubation. Streptococcus pyogens were isolated from her blood sample and the patient met criteria for GAS-TSS. She was treated with antibiotics (penicillin and clindamycin), antithrombin III, recomodulin, catecholamins, and continuous hemodialysis with filtration of toxins. Although the patient recovered and was discharged on 63rd day, the infant died on postpartum day 4. Early recognition and intensive treatment for GAS is recommended in a late stage pregnancy with an episode of sore throat, vomiting, high fever, strong labor pain, and DIC signs.

  17. A smartphone metabolomics platform and its application to the assessment of cisplatin-induced kidney toxicity.

    Science.gov (United States)

    Kwon, Hyuknam; Park, Jooeun; An, Yongjin; Sim, Jaeho; Park, Sunghyouk

    2014-10-03

    The application of smartphones to medical devices has been gaining attention in addressing accessibility and cost issues in healthcare, and the detection of medically relevant compounds has been demonstrated using customized smartphone hardware and/or software. Metabolomics, a newly rising omics field, has also spawned many medical applications but requires highly sophisticated and expensive equipment. Here, we describe a portable smartphone platform, built with readily available and affordable materials, that can perform all of the critical aspects of metabolomics. Excluding the smartphone itself, the total materials for the platform were obtained at less than US $20. For spectral data acquisition, the system utilized visible light (400-700 nm) and a built-in camera. All of the data processing, statistical analysis, and final-visualization components necessary for decision making were implemented in the smartphone platform. The platform is generally applicable as long as the analytes absorb visible light. We provide a proof-of-concept example wherein the metabolomics platform was applied to the assessment of cisplatin-induced kidney toxicity in a rat model, correctly predicting 7 out of 8 test samples. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Hepatoprotective activity of Tephrosia purpurea against arsenic induced toxicity in rats

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    Ravuri Halley Gora

    2014-01-01

    Full Text Available Aim: The present study was conducted to evaluate the hepatoprotective activity of Tephrosia purpurea (TP against sodium arsenite (NaAsO2 induced sub-acute toxicity in rats. Materials and Methods: Twenty four wistar albino rats of either sex were randomly divided into three groups. Group II and III were orally administered with sodium arsenite (10 mg/kg daily in drinking water for 28 days. Additionally Group III was orally treated with hydro-alcoholic extract of Tephrosia purpurea (TP @ 500 mg/kg daily for the same time period, whereas only deionized water was given to Group I (control. Serum biomarker levels, oxidative stress parameters and arsenic concentration were assessed in liver. Histopathology was also conducted. Results: It has been seen that TPE (500 mg/kg significantly (P < 0.01 reduced serum ALT, AST, ALP activity and increased total protein and reduced necrosis and inflammation in liver of group III compared to group II. A significantly (P < 0.01 higher LPO and lower GSH levels without change in SOD activity in liver was also observed in group II compared to group III, though there was no significant difference in arsenic accumulation between them. The plant extract also protects the animals of group III from significant (P < 0.01 reduction in body weight. Conclusion: Our study shows that supplementation of Tephrosia purpurea extract (500 mg/kg could ameliorate the hepatotoxic action of arsenic.

  19. The Protective effect of Ellagic acid on rats’ ovarian fetus toxicity induced by cyclophosphamide

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    M Mousavi M

    2015-10-01

    Full Text Available Background & aim: Cyclophosphamide, an alkylating agent used in the treatment of cancer that has many side effects on different organs, including the gonads .The purpose of this study was to investigate the effects of an antioxidant Ellagic acid on cyclophosphamide -induced toxicity in rat fetal ovarian tissue. Methods: Forty two pregnant  female Wistar rats weighing 250-200 gr were randomly divided into seven groups.The first, second, third, fourth, fifth and sixth 5 mg/ kg cyclophosphamide on days 1, 13 and 18 were given intraperitoneal remote pregnancy .The fourth, fifth and sixth groups hour after receiving cyclophosphamide, Ellagic acid (10 mg/kg has received in the course of pregnancy.Control groups and seven group (normal during pregnancy daily orally received 0.5 mL of saline. After postpartum, Neonatal rats were anesthetized with ether. Animals were dissects, then Ovaries were removed and transferred to 10% formalin solution. After tissue processing, tissue sections were prepared and H&E stained.Data were analyzed by SPSSsoftware and One- way ANOVA test. Results: The groups that were exposed to cyclophosphamide ovarian mean of diameter, primordial follicle diameter and number of follicular cell of primordialin control group compared to ellagic acid treatments showed a significant decrease. Conclusion: The results showed that Ellagic acid due to its antioxidant properties could reduce the harmful effects caused by cyclophosphamide in the fetal ovary.

  20. Protective effect of cactus (Opuntia ficus indica) cladode extract upon nickel-induced toxicity in rats.

    Science.gov (United States)

    Hfaiedh, Najla; Allagui, Mohamed Salah; Hfaiedh, Mbarka; Feki, Abdelfattah El; Zourgui, Lazhar; Croute, Françoise

    2008-12-01

    The purpose of this study carried out on male Wistar rats, was to evaluate the protective effects of regular ingestion of juice from the prickly pear cactus (Opuntia ficus indica) cladodes against nickel chloride toxicity. Rats were given either normal tap water or water containing 25% of cactus juice for one month. Then, rats of each group were injected daily, for 10 days, with either NiCl(2) solution (4mg (30micromol)/kg body weight) or with the same volume of saline solution (300mM NaCl). Significant increases of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase activities and of cholesterol, triglycerides and glucose levels were observed in blood of nickel-treated rats. In the liver, nickel chloride was found to induce an oxidative stress evidenced by an increase in lipid peroxidation and changes in antioxidant enzymes activities. Superoxide-dismutase (SOD) activity was found to be increased whereas glutathione peroxidase and catalase activities were decreased. These changes did not occur in animals previously given cactus juice, demonstrating a protective effect of this vegetal extract.

  1. Curcumin inhibits adenosine deaminase and arginase activities in cadmium-induced renal toxicity in rat kidney

    Directory of Open Access Journals (Sweden)

    Ayodele Jacob Akinyemi

    2017-04-01

    Full Text Available In this study, the effect of enzymes involved in degradation of renal adenosine and l-arginine was investigated in rats exposed to cadmium (Cd and treated with curcumin, the principal active phytochemical in turmeric rhizome. Animals were divided into six groups (n = 6: saline/vehicle, saline/curcumin 12.5 mg/kg, saline/curcumin 25 mg/kg, Cd/vehicle, Cd/curcumin 12.5 mg/kg, and Cd/curcumin 25 mg/kg. The results of this study revealed that the activities of renal adenosine deaminase and arginase were significantly increased in Cd-treated rats when compared with the control (p < 0.05. However, co-treatment with curcumin inhibits the activities of these enzymes compared with Cd-treated rats. Furthermore, Cd intoxication increased the levels of some renal biomarkers (serum urea, creatinine, and electrolytes and malondialdehyde level with a concomitant decrease in functional sulfhydryl group and nitric oxide (NO. However, co-treatment with curcumin at 12.5 mg/kg and 25 mg/kg, respectively, increases the nonenzymatic antioxidant status and NO in the kidney, with a concomitant decrease in the levels of malondialdehyde and renal biomarkers. Therefore, our results reinforce the importance of adenosine deaminase and arginase activities in Cd poisoning conditions and suggest some possible mechanisms of action by which curcumin prevent Cd-induced renal toxicity in rats.

  2. Copper toxicity induced hepatocerebral and neurodegenerative diseases: an urgent need for prognostic biomarkers.

    Science.gov (United States)

    Pal, Amit

    2014-01-01

    Copper (Cu) has been the subject of intensive research over several decades as numerous evidence robustly support the involvement of excess Cu induced neurotoxicity in hepatocerebral (Wilson's disease) and neurodegenerative disorders (especially Alzheimer's disease and Parkinson's disease); notwithstanding, the ideal Cu neurotoxicity biomarker/s for early prognosis remains elusive. Non-ceruloplasmin bound Cu is a biological marker of Wilson's disease and recent studies have shown that its levels are also increased in Alzheimer's disease. Copper chaperone for superoxide dismutase seems to be the other most promising biomarker of Cu toxicity (subject to its validation). Serum/plasma Cu, urine Cu and ceruloplasmin concentrations, most widely used laboratory indicators to diagnose Wilson's disease, are not specific for Cu excess milieu as these are also influenced by age, sex, inflammation and hormonal status. High inter-individual variability, nonexistence of standardized assays and non-specificity limit the use of other cuproenzymes as biomarkers of Cu neurotoxicity. The majority of Cu neurotoxicity biomarker research has focused in plasma/serum where other factors including inflammation, oxidative stress, dietary and environmental factors influence the Cu condition being studied. Proteomics study of cerebrospinal fluid, due to its high specificity and sensitivity represents an alternative approach to study early peripheral Cu neurotoxicity biomarker/s in experimental animals. In addition, network biology, transcriptomics in conjunction with novel in vivo Cu imaging techniques allow us to explore other potential candidates and propose new targets to be studied for chronic Cu neurotoxicity biomarker/s, and for possible therapeutic interventions.

  3. Roles of miRNAs in microcystin-LR-induced Sertoli cell toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Yuan [Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); Wang, Hui [The Centre for Individualized Medication, Linköping University Hospital, Linköping University, Linköping SE-58185 (Sweden); Wang, Cong [Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); Qiu, Xuefeng [Department of Urology, Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210008 (China); Benson, Mikael [The Centre for Individualized Medication, Linköping University Hospital, Linköping University, Linköping SE-58185 (Sweden); Yin, Xiaoqin [Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); Xiang, Zou [Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, University of Gothenburg, Gothenburg (Sweden); Li, Dongmei, E-mail: lidm@nju.edu.cn [Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); and others

    2015-08-15

    Microcystin (MC)-LR, a cyclic heptapeptide, is a potent reproductive system toxin. To understand the molecular mechanisms of MC-induced reproductive system cytotoxicity, we evaluated global changes of miRNA and mRNA expression in mouse Sertoli cells following MC-LR treatment. Our results revealed that the exposure to MC-LR resulted in an altered miRNA expression profile that might be responsible for the modulation of mRNA expression. Bio-functional analysis indicated that the altered genes were involved in specific cellular processes, including cell death and proliferation. Target gene analysis suggested that junction injury in Sertoli cells exposed to MC-LR might be mediated by miRNAs through the regulation of the Sertoli cell-Sertoli cell pathway. Collectively, these findings may enhance our understanding on the modes of action of MC-LR on mouse Sertoli cells as well as the molecular mechanisms underlying the toxicity of MC-LR on the male reproductive system. - Highlights: • miRNAs were altered in Sertoli cells exposed to MC-LR. • Alerted genes were involved in different cell functions including the cell morphology. • MC-LR adversely affected Sertoli cell junction formation through the regulating miRNAs.

  4. Lesser celandine (pilewort) induced acute toxic liver injury:The first case report worldwide

    Institute of Scientific and Technical Information of China (English)

    Bulent Yilmaz; Bars Yilmaz; Bora Aktas; Ozan Unlu; Emir Charles Roach

    2015-01-01

    Lesser celandine, also known as Ranunculus ficaria , isa herbaceous perennial plant that commonly utilizespiles and is taken either internally or used externally.The causality assessment of several reports providedevidence for the existence of Greater Celandinehepatotoxicity. However, there hasn't been any casereport published thus far, about lesser celandineinduced liver injury. Here, we present a case of36-year-old woman admitted to the hospital with acutehepatitis and jaundice on her sclera with no historyof drug abuse or alcohol consumption. However, thepatient had a recent history of lesser celandine extractconsumption for hemorrhoids, for about 10 d, prior tothe admission. Viral hepatitis, autoimmune hepatitis,and drug induced toxic hepatitis were ruled out byfurther imaging studies and laboratory analysis. Usingthe Council for International Organizations of MedicalSciences scale, the type of liver injury was assumedas hepatocellular and was scored as 7 which showsprobable causality. Immediate discontinuation of lessercelandine extract resulted in rapid decrease of theelevated enzymes. Herbs have been reported to causeliver injury and therefore should be suspected in thecase of acute hepatitis with an unknown etiology. Thiscase is important to be the first to explain hepatotoxicitycaused by lesser celandine. Physicians should considerlesser celandine as a causative agent for hepatotoxicity.

  5. Role of GluR2 expression in AMPA-induced toxicity in cultured murine cerebral cortical neurons

    DEFF Research Database (Denmark)

    Jensen, Jette Bisgaard; Lund, Trine Meldgaard; Timmermann, Daniel B.

    2001-01-01

    alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R)-mediated neurotoxicity was studied in relation to subunit expression and the presence of Ca(2+)-permeable receptor channels. AMPA-mediated toxicity had two components: 1) a direct AMPA-R-mediated component, which was not due...... of the Mg(2+) block of the NMDA receptor on AMPA-R stimulation. The involvement of Ca(2+) influx through AMPA-R was also examined. The number of neurons possessing Ca(2+)-permeable AMPA-R increased during culture development, concurrently with an increasing susceptibility for AMPA-induced toxicity during...... development. GluR2(R) levels also increased during development, and channel blockers of Ca(2+)-permeable AMPA-R lacking the GluR2(R) subunit (spermine and philanthotoxin) failed to prevent neurotoxicity or increases in [Ca(2+)](i). Thus, the direct AMPA-R-mediated toxicity may be explained by initiation...

  6. Protective efficacy of folic acid and vitamin B12 against nicotine-induced toxicity in pancreatic islets of the rat

    Directory of Open Access Journals (Sweden)

    Bhattacharjee Ankita

    2015-06-01

    Full Text Available Although cigarette smoking is associated with insulin resistance and an increased risk for type 2 diabetes, few studies have examined the effect of nicotine on the adult endocrine pancreas. In this study, male Wister rats were treated with nicotine (3 mg/kg body weight/day with or without supplementation of folic acid (36 μg/kg body weight/day or vitamin B12 (0.63 μg/kg body weight/day alone or in combination. Fasting blood glucose, insulin and HBA1C level and different oxidative and anti-oxidative stress parameters were measured and pancreatic tissue sections were stained with eosin-haematoxylene. Data were analysed by nonparametric statistics. The results revealed that nicotine induced prediabetes condition with subsequent damage to pancreatic islets in rats. Nicotine also caused oxidative stress in pancreatic tissue as evidenced by increased nitric oxide and malondialdehyde level and decreased superoxide dismutase, catalase and reduced glutathione level. Compared to vitamin B12 supplementation, folic acid blunted the nicotine-induced toxicity in pancreatic islets with higher efficacy. Further, folic acid and vitamin B12 in combination were able to confer significant protection on pancreatic islets against nicotine induced toxicity. These results suggest that supplementation of folic acid and vitamin B12 in combination may be a possible strategy of detoxification against nicotine-induced toxicity in pancreatic islets of the rat.

  7. Protective efficacy of folic acid and vitamin B12 against nicotine-induced toxicity in pancreatic islets of the rat

    Science.gov (United States)

    Bhattacharjee, Ankita; Prasad, Shilpi Kumari; Pal, Swagata; Maji, Bithin; Syamal, Alak Kumar; Banerjee, Arnab

    2015-01-01

    Although cigarette smoking is associated with insulin resistance and an increased risk for type 2 diabetes, few studies have examined the effect of nicotine on the adult endocrine pancreas. In this study, male Wister rats were treated with nicotine (3 mg/kg body weight/ day) with or without supplementation of folic acid (36 μg/kg body weight/day) or vitamin B12 (0.63 μg/kg body weight/day) alone or in combination. Fasting blood glucose, insulin and HBA1C level and different oxidative and anti-oxidative stress parameters were measured and pancreatic tissue sections were stained with eosin-haematoxylene. Data were analysed by nonparametric statistics. The results revealed that nicotine induced prediabetes condition with subsequent damage to pancreatic islets in rats. Nicotine also caused oxidative stress in pancreatic tissue as evidenced by increased nitric oxide and malondialdehyde level and decreased superoxide dismutase, catalase and reduced glutathione level. Compared to vitamin B12 supplementation, folic acid blunted the nicotine-induced toxicity in pancreatic islets with higher efficacy. Further, folic acid and vitamin B12 in combination were able to confer significant protection on pancreatic islets against nicotine induced toxicity. These results suggest that supplementation of folic acid and vitamin B12 in combination may be a possible strategy of detoxification against nicotine-induced toxicity in pancreatic islets of the rat. PMID:27486368

  8. The effects of taurine on vigabatrin, high light intensity and mydriasis induced retinal toxicity in the pigmented rat.

    Science.gov (United States)

    Rasmussen, Allan D; Truchot, Nathalie; Pickersgill, Nigel; Thale, Zia Irene; Rosolen, Serge G; Botteron, Catherine

    2015-01-01

    The overall purpose of this study was to establish a model that may be used for examining the effect of Vigabatrin-induced retinal toxicity in pigmented rats, and subsequently examine the possible effects of taurine on the retinal toxicity. In the first part of the study, pigmented Long Evans rats were subjected to combinations of induced mydriasis, low/high light intensities (40/2000 lx) and oral administration of near-MTD (Maximum Tolerated Dose) doses (200 mg/kg/day) of Vigabatrin for up to 6 weeks. The combination of mydriasis and high light intensity applied to Long Evans rats resulted in retinal damage that was increased by the administration of Vigabatrin. In the second part of the study Long Evans rats were subjected to combinations of induced mydriasis and high/low light intensity (40/2000 lx) while being orally administered low (30 mg/kg/day) or high (200 mg/kg/day) doses of Vigabatrin for up to 6 weeks. In addition, selected groups of animals were administered taurine via the drinking water (20 mg/ml), resulting in systemic taurine concentrations of approximately threefold the endogenous concentration. The combined results of the studies demonstrate that retinal damage can be induced in pigmented animals when combining mydriasis and high light intensity. Retinal damage was functionally evaluated by electroretinography (ERG), then confirmed by histopathology. While depending on mydriasis and high light intensity, administration of Vigabatrin increased the retinal toxicity and resulted in the formation of rosette-like structures in the retina in a dose-related manner. Administration of taurine did not alleviate the Vigabatrin-induced retinal toxicity, as demonstrated either functionally by ERG or morphologically, although systemic concentrations of 3-fold the endogenous levels were reached, and it was thus not possible to demonstrate a protective effect of taurine in these pigmented animals. Copyright © 2014 Elsevier GmbH. All rights reserved.

  9. Antioxidant compounds in the seaweed Gelidiella acerosa protects human Peripheral Blood Mononuclear Cells against TCDD induced toxicity.

    Science.gov (United States)

    Ilavarasi, K; Chermakani, P; Arif Nisha, S; Sheeja Malar, D; Pandima Devi, K

    2015-04-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental toxin formed as an unintentional by-product of incomplete combustion. Several therapeutic approaches have evolved to combat its toxicity since it elicits immunotoxicity, neurotoxicity, hepatotoxicity, carcinogenicity and lethality. Search for drugs from natural resources especially from seaweeds has become intense due to their enormous pharmacological potential. Hence, the present study aims at revealing the protective effect of methanolic extract of G. acerosa (MEGA) in Peripheral Blood Mononuclear Cells (PBMC) against TCDD induced toxicity, by assessing the antioxidant, anti-apoptotic and cytoprotective activities. The results of antioxidant assays suggests that MEGA reverted TCDD induced toxicity by causing an alteration in the levels of antioxidant enzymes (Catalase [CAT], Superoxide dismutase [SOD], Glutathione peroxidase [GPx], Glutathione-S-transferase [GST]) and Glutathione [GSH]. The results of lipid peroxidation assay and protein carbonyl content reveal that MEGA protects PBMC from TCDD induced macromolecular damage. MEGA was found to exhibit significant (p TCDD induced oxidative DNA damage. Levels of phase-I detoxification enzymes determined by EROD assay and semi-quantitative RT-PCR showed that TCDD up-regulates the expression of CYP1A1 and upon co-treatment with MEGA, the expression got slightly decreased suggesting its protective role. Preliminary phytochemical analysis demonstrates that the extract is rich in cardiac glycosides and terpenoids. LC-MS analysis revealed the presence of antioxidants including caffeic acid, phytol and mannoheptulose in MEGA, which could be attributed for the observed protective effect against TCDD induced toxicity.

  10. Effect of Marine Omega 3 Fatty Acids on Methylmercury-Induced Toxicity in Fish and Mammalian Cells In Vitro

    Directory of Open Access Journals (Sweden)

    O. J. Nøstbakken

    2012-01-01

    Full Text Available Methylmercury (MeHg is a ubiquitous environmental contaminant which bioaccumulates in marine biota. Fish constitute an important part of a balanced human diet contributing with health beneficial nutrients but may also contain contaminants such as MeHg. Interactions between the marine n-3 fatty acids eicosapentaenoic acid (20:5n-3, EPA and docosahexaenoic acid (22:6n-3, DHA with MeHg-induced toxicity were investigated. Different toxic and metabolic responses were studied in Atlantic salmon kidney (ASK cell line and the mammalian kidney-derived HEK293 cell line. Both cell lines were preincubated with DHA or EPA prior to MeHg-exposure, and cell toxicity was assessed differently in the cell lines by MeHg-uptake in cells (ASK and HEK293, proliferation (HEK293 and ASK, apoptosis (ASK, oxidation of the red-ox probe roGFP (HEK293, and regulation of selected toxicological and metabolic transcriptional markers (ASK. DHA was observed to decrease the uptake of MeHg in HEK293, but not in ASK cells. DHA also increased, while EPA decreased, MeHg-induced apoptosis in ASK. MeHg exposure induced changes in selected metabolic and known MeHg biomarkers in ASK cells. Both DHA and MeHg, but not EPA, oxidized roGFP in HEK293 cells. In conclusion, marine n-3 fatty acids may ameliorate MeHg toxicity, either by decreasing apoptosis (EPA or by reducing MeHg uptake (DHA. However, DHA can also augment MeHg toxicity by increasing oxidative stress and apoptosis when combined with MeHg.

  11. Arsenic Induced Toxicity in Broiler Chicks and Its Amelioration with Ascorbic Acid: Clinical, Hematological and Pathological Study

    Directory of Open Access Journals (Sweden)

    Rabia Sharaf, Ahrar Khan*, Muhammad Zargham Khan, Iftikhar Hussain, Rao Zahid Abbas, S. T. Gul, Fazal Mahmood and Muhammad Kashif Saleemi

    2013-07-01

    Full Text Available This study was conducted to observe the arsenic (As toxicity lesions in birds and to know either Vit C ameliorates these toxic effects or not. One-day-old broilers chicks (n=72 procured from a local hatchery were randomly divided into four equal groups. First group was kept as control and second group was given As (50 mg/kg BW via crop tubing. Third group received in addition to As, Vit C (250 mg/kg BW whereas fourth group received only Vit C. Killing by neck dislocation of randomly selected six birds from each group was carried out on experimental days 0, 16 and 32 for collection of blood and tissues specimens. Arsenic treated birds showed clinical signs of toxicity throughout the experiment than all other groups. These clinical signs included decreased body weight and feed intake, dullness, open mouth breathing, increased thirst, ruffled feathers, pale comb, skin irritation and watery diarrhea which were not significant in any other group. As treated group showed a significant (P<0.05 decrease in hematological parameters. Severe gross and histopathological changes were observed in intestines, spleen and lungs of birds fed with As than all other groups. Decreased height of villi of middle portion of small intestines was also observed in As treated birds. Villi height in Vit C treated group increased as compared to control group. It was concluded that As induces severe toxic effects in broiler birds; however, these toxic effects can be partially ameliorated by Vit C.

  12. Study on the stem's disinfection and bud inducement of Aglaonema commutatum%粗勒草茎段的消毒灭菌和不定芽诱导的研究

    Institute of Scientific and Technical Information of China (English)

    刘俊仙; 龙明华; 朱顺莲; 徐小雁

    2009-01-01

    研究不同灭菌处理、不同基本培养基、不同激素种类及浓度对粗勒草"黑美人"和"银皇后"两品种茎段不定芽诱导的影响,结果表明:"黑美人":以75%酒精1min+0.1%HgCl2 20min的灭菌效果最佳,污染率为25.56%;以MS+6-BA 4.0mg/L+NAA 0.05mg/L的诱导效果最好;"银皇后":以75%酒精1min+0.1%HgCl2 22min的灭菌效果最佳,污染率为29.6%;以MS+6-BA 4.0mg/L+NAA0.1mg/L的诱导效果最好.%The effect of different sterilization treatments, basic mediums, hormone kinds and concentrations on bud inducement of two AgLaonema commutatum varieties was studie.The result indicates that in AgLaonema commutatum "Treubii" : 75%C2HsOH 1min+0.1% HgCl2 20mins had the best sterilization effect, whose contamination rate was 25.56%, and MS+6-BA 4.0mg/L +NAA 0.05mg/L had the highest inductivity. While in Aglaonema commutatum "Malay fieauty":75%C2H5OH 1min+0.1% HgCl2 22mins had the best sterilization effect, whose contamination rate was 29.6% ,and MS+6- BA4.0mg/L+NAA0.1mg/L had the highest inductivity.

  13. Precision-cut intestinal slices as an in vitro model to predict NSAID induced intestinal toxicity

    NARCIS (Netherlands)

    Niu, Xiaoyu; van der Bijl, Henk; Groothuis, Geny; de Graaf, Inge

    2013-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with high prevalence of gastro-intestinal side-effects. In vivo studies suggest that uncoupling of oxidative phosphorylation is an important cause of the toxicity and that the toxicity is aggravated by enterohepatic circulation. Precision

  14. Bovine colostrum modulates myeloablative chemotherapy-induced gut toxicity in piglets

    DEFF Research Database (Denmark)

    Pontoppidan, Peter Erik Lotko; Shen, René Liang; Cilieborg, Malene Skovsted

    2015-01-01

    BACKGROUND: Intensive chemotherapy frequently results in gut toxicity, indicated by oral and intestinal mucositis, resulting in poor treatment outcomes and increased mortality. There are no effective preventive strategies against gut toxicity and the role of diet is unknown. OBJECTIVE: We hypothe...

  15. Monitoring and assessment of toxic metals in Gulf War oil spill contaminated soil using laser-induced breakdown spectroscopy.

    Science.gov (United States)

    Hussain, T; Gondal, M A

    2008-01-01

    Laser-induced breakdown spectroscopy (LIBS) was applied for the detection of toxic metals in oil spill contaminated soil (OSCS). The OSCS samples were collected from Khursania Saudi Arabia along the coast of Persian Gulf exposed to oil spills in 1991 Gulf war. Environmentally important elements like Aluminum Magnesium, Calcium, Chromium, Titanium, Strontium, Iron, Barium, Sodium, potassium, Zirconium and Vanadium from the contaminated soil have been detected. Optimal experimental conditions for analysis were investigated. The LIBS system was calibrated using standard samples containing these trace elements. The results obtained using Laser-Induced Breakdown Spectroscopy (LIBS) were compared with the results obtained using Inductively Coupled Plasma Emission Spectroscopy (ICP). The concentrations of some elements (Ba and Cr) were found higher than permissible safe limits. Health risks associated with exposure to such toxic elements are also discussed.

  16. Involvement of PINK1/parkin-mediated mitophagy in ZnO nanoparticle-induced toxicity in BV-2 cells

    Science.gov (United States)

    Wei, Limin; Wang, Jianfeng; Chen, Aijie; Liu, Jia; Feng, Xiaoli; Shao, Longquan

    2017-01-01

    With the increasing application of zinc oxide nanoparticles (ZnO NPs) in biological materials, the neurotoxicity caused by these particles has raised serious concerns. However, the underlying molecular mechanisms of the toxic effect of ZnO NPs on brain cells remain unclear. Mitochondrial damage has been reported to be a factor in the toxicity of ZnO NPs. PINK1/parkin-mediated mitophagy is a newly emerging additional function of autophagy that selectively degrades impaired mitochondria. Here, a PINK1 gene knockdown BV-2 cell model was established to determine whether PINK1/parkin-mediated mitophagy was involved in ZnO NP-induced toxicity in BV-2 cells. The expression of total parkin, mito-parkin, cyto-parkin, and PINK1 both in wild type and PINK1−/− BV-2 cells was evaluated using Western blot analysis after the cells were exposed to 10 μg/mL of 50 nm ZnO NPs for 2, 4, 8, 12, and 24 h. The findings suggested that the downregulation of PINK1 resulted in a significant reduction in the survival rate after ZnO NP exposure compared with that of control cells. ZnO NPs were found to induce the transportation of parkin from the cytoplasm to the mitochondria, implying the involvement of mitophagy in ZnO NP-induced toxicity. The deletion of the PINK1 gene inhibited the recruitment of parkin to the mitochondria, causing failure of the cell to trigger mitophagy. The present study demonstrated that apart from autophagy, PINK1/parkin-mediated mitophagy plays a protective role in ZnO NP-induced cytotoxicity. PMID:28331313

  17. Poor Baseline Pulmonary Function May Not Increase the Risk of Radiation-Induced Lung Toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jingbo [Department of Radiation Oncology, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States); Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Cao, Jianzhong [Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Yuan, Shuanghu [Department of Radiation Oncology, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States); Ji, Wei [Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Arenberg, Douglas [Department of Internal Medicine, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States); Dai, Jianrong [Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Stanton, Paul; Tatro, Daniel; Ten Haken, Randall K. [Department of Radiation Oncology, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States); Wang, Luhua, E-mail: wlhwq@yahoo.com [Department of Radiation Oncology, Cancer Hospital, Chinese Academic Medical Sciences and Peking Union Medical College, Beijing (China); Kong, Feng-Ming, E-mail: fengkong@med.umich.edu [Department of Radiation Oncology, University of Michigan/Ann Arbor Veterans Health System, Ann Arbor, Michigan (United States)

    2013-03-01

    Purpose: Poor pulmonary function (PF) is often considered a contraindication to definitive radiation therapy for lung cancer. This study investigated whether baseline PF was associated with radiation-induced lung toxicity (RILT) in patients with non-small cell lung cancer (NSCLC) receiving conformal radiation therapy (CRT). Methods and Materials: NSCLC patients treated with CRT and tested for PF at baseline were eligible. Baseline predicted values of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), and diffusion capacity of lung for carbon monoxide (DLCO) were analyzed. Additional factors included age, gender, smoking status, Karnofsky performance status, coexisting chronic obstructive pulmonary disease (COPD), tumor location, histology, concurrent chemotherapy, radiation dose, and mean lung dose (MLD) were evaluated for RILT. The primary endpoint was symptomatic RILT (SRILT), including grade ≥2 radiation pneumonitis and fibrosis. Results: There was a total of 260 patients, and SRILT occurred in 58 (22.3%) of them. Mean FEV1 values for SRILT and non-SRILT patients were 71.7% and 65.9% (P=.077). Under univariate analysis, risk of SRILT increased with MLD (P=.008), the absence of COPD (P=.047), and FEV1 (P=.077). Age (65 split) and MLD were significantly associated with SRILT in multivariate analysis. The addition of FEV1 and age with the MLD-based model slightly improved the predictability of SRILT (area under curve from 0.63-0.70, P=.088). Conclusions: Poor baseline PF does not increase the risk of SRILT, and combining FEV1, age, and MLD may improve the predictive ability.

  18. Potato crop as a source of emetic Bacillus cereus and cereulide-induced mammalian cell toxicity.

    Science.gov (United States)

    Hoornstra, Douwe; Andersson, Maria A; Teplova, Vera V; Mikkola, Raimo; Uotila, Liisa M; Andersson, Leif C; Roivainen, Merja; Gahmberg, Carl G; Salkinoja-Salonen, Mirja S

    2013-06-01

    Bacillus cereus, aseptically isolated from potato tubers, were screened for cereulide production and for toxicity on human and other mammalian cells. The cereulide-producing isolates grew slowly, the colonies remained small (~1 mm), tested negative for starch hydrolysis, and varied in productivity from 1 to 100 ng of cereulide mg (wet weight)(-1) (~0.01 to 1 ng per 10(5) CFU). By DNA-fingerprint analysis, the isolates matched B. cereus F5881/94, connected to human food-borne illness, but were distinct from cereulide-producing endophytes of spruce tree (Picea abies). Exposure to cell extracts (1 to 10 μg of bacterial biomass ml(-1)) and to purified cereulide (0.4 to 7 ng ml(-1)) from the potato isolates caused mitochondrial depolarization (loss of ΔΨm) in human peripheral blood mononuclear cells (PBMC) and keratinocytes (HaCaT), porcine spermatozoa and kidney tubular epithelial cells (PK-15), murine fibroblasts (L-929), and pancreatic insulin-producing cells (MIN-6). Cereulide (10 to 20 ng ml(-1)) exposed pancreatic islets (MIN-6) disintegrated into small pyknotic cells, followed by necrotic death. Necrotic death in other test cells was observed only after a 2-log-higher exposure. Exposure to 30 to 60 ng of cereulide ml(-1) induced K(+) translocation in intact, live PBMC, keratinocytes, and sperm cells within seconds of exposure, depleting 2 to 10% of the cellular K(+) stores within 10 min. The ability of cereulide to transfer K(+) ions across biological membranes may benefit the producer bacterium in K(+)-deficient environments such as extracellular spaces inside plant tissue but is a pathogenic trait when in contact with mammalian cells.

  19. Effects of Sodium Selenite on Formaldehyde Induced Renal Toxicity in Mice

    Directory of Open Access Journals (Sweden)

    Shabnam Mohammadi 1,2 * , Maryam Moghimian 3, Hanieh Torabzadeh 4, Mahla Langari 4, Roghayeh Nazeri 4, Zahra Karimi 4, Elham Sangari 4, Najmeh Jagarmi 5, Alireza Mohammad Zadeh 3, Mehdi Karimi 7, Kamyar Tavakkoli 8, Ali Delshad 9, Fatemeh Mohammadzadeh 3, Majid Ghayour-Mobarhan 10

    2016-12-01

    Full Text Available Background: Formaldehyde is widely used for industrial applications. Renal injury is an adverse effect associated with formaldehyde. Few studies have explored the potential benefits of protective factors on formaldehyde induced renal toxicity. This study evaluated the dose dependent effects of sodium selenite on the biochemical and histopathological effects of formaldehyde on murine kidney. Methods: Forty eight adult Balb/c male mice were randomized into six groups: a control group, a formaldehyde group and experimental III-VI groups. Formaldehyde group was injected with 10 mg/kg formaldehyde and groups III-VI received intraperitoneally doses of 0.1, 0.2, 0.4, 0.8 mg/kg selenium. After two weeks, a stereological study was done in accordance with the principle of Cavalieri and serum concentrations of urea and creatinine were measured. Data were analyzed using ANOVA and SPSS software. Results: Glomerosclerosis, necrosis and vacuolization were observed in the convoluted tubules of animals treated with formaldehyde. The biochemical markers, volume and count of glomeruli in the group treated with formaldehyde was significantly difference compared to the control group (P<0.05. The volume of the glomeruli in the group treated with 0.2 and 0.4 mg selenium and urea level in the group treated with 0.4 and 0.1 mg/kg selenium was significantly difference compared to the control group (P <0.05. The count of glomeruli and creatinine level in the selenium group was significantly difference compared to the control group (P ≤ 0.0001. Conclusions: A dose of 0.2 mg/kg of sodium selenite caused partial protective effect on the renal tissue and function in exposed to formaldehyde.

  20. Protective effect of pretreatment with thymoquinone against Aflatoxin B1 induced liver toxicity in mice

    Directory of Open Access Journals (Sweden)

    A Nili-Ahmadabadi

    2011-10-01

    Full Text Available "n  Background and the purpose of the study: Thymoquinone (TQ is one of the active components of Nigella sativa. The plant has been used in herbal medicine for treatment of many diseases including liver complications. The present study aimed to investigate protective effects of TQ on Aflatoxin B1 (AFB1 induced liver toxicity in mice. "n  Methods: Animals were divided into six groups and treated intraperitoneally. Group 1 (blank served as vehicle, group 2 (positive control received AFB1, Group 3 was treated with 9 mg/kg of TQ, Groups 4, 5 and 6 were treated with 4.5, 9 and 18 mg/kg of TQ, respectively. After three consecutive days, except for groups 1 and 3, animals were administered with a single dose of AFB1 (2 mg/kg. All the animals were killed 24 hrs following the AFB1 administration under ether anesthesia. Biochemical parameters including AST, ALT and ALP in serum samples and glutathione (GSH and malondialdehyde (MDA contents in liver homogenates were determined. Liver sections were collected for histopathological examination. "n  Results: Findings of this study showed that AST, ALT, ALP and MDA levels were significantly lower in the TQ treated animals as compared to AFB1 group (group 2. Furthermore, TQ was able to recover glutathione content (GSH of liver tissue. The best response, however, was observed with the dose of 9 mg/kg. Liver sections of AFB1 intoxicated mice showed inflammation, necrosis, hyperplasia of kupffer and infiltration of mononuclear cells, dilation of sinusoids and disruption of hepatocytes, while treatment with TQ helped to normalize liver architecture in accordance to biochemical findings. "n  Conclusion: Taken collectively, TQ has a protective role with optimum dose of 9 mg/kg in AFB1 hepatotoxicity.

  1. Cadmium-Induced Toxicity and the Hepatoprotective Potentials of Aqueous Extract of Jessiaea Nervosa Leaf

    Directory of Open Access Journals (Sweden)

    Ama Udu Ibiam

    2013-08-01

    Full Text Available Purpose: Hepatoprotective potentials of Jussiaea nervosa leaf extract against Cadmium-induced hepatotoxicity were investigated. Methods: Forty albino rats were randomly assigned into groups A-G with 4 rats in each of the groups A-F. Group A served as control and were given feed only while rats in groups B-F were orally exposed to varying concentrations of cadmium for six weeks. Effects of cadmium were most significant at 12 mg/Kg body weight (BW, and this dose was used for subsequent test involving oral administration of Jussiaea nervosa leaf extracts. In this segment, group G (n= 16 was sub-divided into four: G1-G4, with each sub-group containing four rats. Rats in sub-group G1 were given cadmium and feed only and served as positive control. Rats in sub-groups G2, G3, and G4 were given cadmium and 20, 50 and 100g/kg BW of Jussiaea nervosa extract, respectively, for six weeks. Blood and liver were analysed using standard laboratory techniques and methods. Results: Liver function parameters (ALT, AST, ALP, bilirubin were significantly (p<0.05 elevated in exposed rats in comparison to the controls, except for total protein and albumin, which were significantly decreased. Histopathological assessment reveals renal pathology in exposed rats in sharp contrast with the controls. Jussiaea nervosa extract however lowered the values of liver function parameters with 100mg/Kg BW dose producing the highest ameliorative effects. Similarly, the serum albumin and total protein significantly (p<0.05 improved with normal liver architecture. Conclusion: The results show the hepatoprotective potentials of Jussiaea nervosa extract against Cd toxicity.

  2. Molecular, Biochemical and Ultrastructural Changes Induced by Pb Toxicity in Seedlings of Theobroma cacao L.

    Science.gov (United States)

    Reis, Graciele Santos Monteiro; de Almeida, Alex-Alan Furtado; de Almeida, Nicolle Moreira; de Castro, Andressa Vieira; Mangabeira, Pedro Antonio Oliveira; Pirovani, Carlos Priminho

    2015-01-01

    Pb is a metal which is highly toxic to plants and animals, including humans. High concentrations of Pb have been observed in beans of T. cacao, as well as in its products. In this work, we evaluated the molecular, biochemical, and ultrastructural alterations in mature leaves and primary roots of seedlings of two progenies of T. cacao, obtained from seed germination in different concentrations of Pb (0, 0.05, 0.1, 0.2, 0.4, 0.8 g L(-1)), in the form of Pb(NO3)2. The progenies resulted from self-fertilization of Catongo and a cross of CCN-10 x SCA-6. The Pb, supplied via seminal, caused alterations in the ultrastructures of the mesophyll cells and in the amount of starch grains in the chloroplasts. The dosage of substances reactive to thiobarbituric acid showed that Pb induced lipid peroxidation. The activity of guaiacol peroxidases and the expression of genes associated to synthetase of phytochelatin, SODcyt and PER increased in response to Pb. In addition, there was alteration in the expression of stress-related proteins. The progeny of CCN-10 x SCA-6 was more tolerant to Pb stress when compared to Catongo, since: (i) it accumulated more Pb in the roots, preventing its translocation to the shoot; (ii) it presented higher activity of peroxidases in the roots, which are enzymes involved in the elimination of excess of reactive oxygen species; and (iii) increased expression of the gene in the phytochelatin biosynthesis route. The results of the proteomic analysis were of paramount importance to differentiate the defense mechanisms used by both progenies of T. cacao.

  3. Screening for Small Molecule Inhibitors of Statin-Induced APP C-terminal Toxic Fragment Production.

    Science.gov (United States)

    Poksay, Karen S; Sheffler, Douglas J; Spilman, Patricia; Campagna, Jesus; Jagodzinska, Barbara; Descamps, Olivier; Gorostiza, Olivia; Matalis, Alex; Mullenix, Michael; Bredesen, Dale E; Cosford, Nicholas D P; John, Varghese

    2017-01-01

    Alzheimer's disease (AD) is characterized by neuronal and synaptic loss. One process that could contribute to this loss is the intracellular caspase cleavage of the amyloid precursor protein (APP) resulting in release of the toxic C-terminal 31-amino acid peptide APP-C31 along with the production of APPΔC31, full-length APP minus the C-terminal 31 amino acids. We previously found that a mutation in APP that prevents this caspase cleavage ameliorated synaptic loss and cognitive impairment in a murine AD model. Thus, inhibition of this cleavage is a reasonable target for new therapeutic development. In order to identify small molecules that inhibit the generation of APP-C31, we first used an APPΔC31 cleavage site-specific antibody to develop an AlphaLISA to screen several chemical compound libraries for the level of N-terminal fragment production. This antibody was also used to develop an ELISA for validation studies. In both high throughput screening (HTS) and validation testing, the ability of compounds to inhibit simvastatin- (HTS) or cerivastatin- (validation studies) induced caspase cleavage at the APP-D720 cleavage site was determined in Chinese hamster ovary (CHO) cells stably transfected with wildtype (wt) human APP (CHO-7W). Several compounds, as well as control pan-caspase inhibitor Q-VD-OPh, inhibited APPΔC31 production (measured fragment) and rescued cell death in a dose-dependent manner. The effective compounds fell into several classes including SERCA inhibitors, inhibitors of Wnt signaling, and calcium channel antagonists. Further studies are underway to evaluate the efficacy of lead compounds - identified here using cells and tissues expressing wt human APP - in mouse models of AD expressing mutated human APP, as well as to identify additional compounds and determine the mechanisms by which they exert their effects.

  4. Metalloproteins and phytochelatin synthase may confer protection against zinc oxide nanoparticle induced toxicity in Caenorhabditis elegans.

    Science.gov (United States)

    Polak, Natasa; Read, Daniel S; Jurkschat, Kerstin; Matzke, Marianne; Kelly, Frank J; Spurgeon, David J; Stürzenbaum, Stephen R

    2014-03-01

    Zinc oxide nanoparticles (ZnONPs) are used in large quantities by the cosmetic, food and textile industries. Here we exposed Caenorhabditis elegans wild-type and a metal sensitive triple knockout mutant (mtl-1;mtl-2;pcs-1) to ZnONPs (0-50mg/L) to study strain and exposure specific effects on transcription, reactive oxygen species generation, the biomolecular phenotype (measured by Raman microspectroscopy) and key endpoints of the nematode life cycle (growth, reproduction and lifespan). A significant dissolution effect was observed, where dissolved ZnO constituted over 50% of total Zn within a two day exposure to the test medium, suggesting that the nominal exposure to pure ZnONPs represents in vivo, at best, a mixture exposure of ionic zinc and nanoparticles. Nevertheless, the analyses provided evidence that the metallothioneins (mtl-1 and mtl-2), the phytochelatin synthase (pcs-1) and an apoptotic marker (cep-1) were transcriptionally activated. In addition, the DCFH-DA assay provided in vitro evidence of the oxidative potential of ZnONPs in the metal exposure sensitive triple mutant. Raman spectroscopy highlighted that the biomolecular phenotype changes significantly in the mtl-1;mtl-2;pcs-1 triple knockout worm upon ZnONP exposure, suggesting that these metalloproteins are instrumental in the protection against cytotoxic damage. Finally, ZnONP exposure was shown to decrease growth and development, reproductive capacity and lifespan, effects which were amplified in the triple knockout. By combining diverse toxicological strategies, we identified that individuals (genotypes) housing mutations in key metalloproteins and phytochelatin synthase are more susceptible to ZnONP exposure, which underlines their importance to minimize ZnONP induced toxicity.

  5. In vitro immunopotentiating properties and tumour cell toxicity induced by Lophophora williamsii (peyote) cactus methanolic extract.

    Science.gov (United States)

    Franco-Molina, M; Gomez-Flores, R; Tamez-Guerra, P; Tamez-Guerra, R; Castillo-Leon, L; Rodríguez-Padilla, C

    2003-11-01

    Lophophora williamsii, also known as peyote, is found primarily in dry regions from Central Mexico, including the Mexican States of Nayarit, San Luis Potosí, Zacatecas, Nuevo León, Chihuahua, Coahuila and Tamaulipas, to Texas particularly in regions along Rio Grande. Peyote extracts have been associated with stimulating the central nervous system and regulating blood pressure, sleep, hunger and thirst. However, there is no evidence of any effect of peyote on the immune system or against tumour cell growth. The present study was designed to evaluate the in vitro effects of peyote methanolic extracts on some parameters of mouse and human leukocyte immunocompetence and tumour cell growth. Peyote extract (0.18-18 micro g/mL) activated nitric oxide production by murine macrophages, and stimulated up to 2.4-fold proliferation of murine thymic lymphocytes. In addition, peyote extract induced up to 1.85-, 2.29- and 1.89-fold increases in mRNA signal of IL-1, IL-6 and IL-8 by human leukocytes. Also examined were the effects of peyote extracts on murine lymphoma L5178Y-R and fi broblastoma L929, and human myeloid U937 and mammary gland MCF7 tumour cell growth using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT). Peyote extracts were toxic for MCF7, L5178Y-R, U937 and L929 (18 mg/mL peyote extract caused 1.3%, 8%, 45% and 60% viability respectively) cell lines.

  6. Screening for Small Molecule Inhibitors of Statin-Induced APP C-terminal Toxic Fragment Production

    Science.gov (United States)

    Poksay, Karen S.; Sheffler, Douglas J.; Spilman, Patricia; Campagna, Jesus; Jagodzinska, Barbara; Descamps, Olivier; Gorostiza, Olivia; Matalis, Alex; Mullenix, Michael; Bredesen, Dale E.; Cosford, Nicholas D. P.; John, Varghese

    2017-01-01

    Alzheimer’s disease (AD) is characterized by neuronal and synaptic loss. One process that could contribute to this loss is the intracellular caspase cleavage of the amyloid precursor protein (APP) resulting in release of the toxic C-terminal 31-amino acid peptide APP-C31 along with the production of APPΔC31, full-length APP minus the C-terminal 31 amino acids. We previously found that a mutation in APP that prevents this caspase cleavage ameliorated synaptic loss and cognitive impairment in a murine AD model. Thus, inhibition of this cleavage is a reasonable target for new therapeutic development. In order to identify small molecules that inhibit the generation of APP-C31, we first used an APPΔC31 cleavage site-specific antibody to develop an AlphaLISA to screen several chemical compound libraries for the level of N-terminal fragment production. This antibody was also used to develop an ELISA for validation studies. In both high throughput screening (HTS) and validation testing, the ability of compounds to inhibit simvastatin- (HTS) or cerivastatin- (validation studies) induced caspase cleavage at the APP-D720 cleavage site was determined in Chinese hamster ovary (CHO) cells stably transfected with wildtype (wt) human APP (CHO-7W). Several compounds, as well as control pan-caspase inhibitor Q-VD-OPh, inhibited APPΔC31 production (measured fragment) and rescued cell death in a dose-dependent manner. The effective compounds fell into several classes including SERCA inhibitors, inhibitors of Wnt signaling, and calcium channel antagonists. Further studies are underway to evaluate the efficacy of lead compounds – identified here using cells and tissues expressing wt human APP – in mouse models of AD expressing mutated human APP, as well as to identify additional compounds and determine the mechanisms by which they exert their effects.

  7. Quinones and aromatic chemical compounds in particulate matter induce mitochondrial dysfunction: implications for ultrafine particle toxicity.

    Science.gov (United States)

    Xia, Tian; Korge, Paavo; Weiss, James N; Li, Ning; Venkatesen, M Indira; Sioutas, Constantinos; Nel, Andre

    2004-10-01

    Particulate pollutants cause adverse health effects through the generation of oxidative stress. A key question is whether these effects are mediated by the particles or their chemical compounds. In this article we show that aliphatic, aromatic, and polar organic compounds, fractionated from diesel exhaust particles (DEPs), exert differential toxic effects in RAW 264.7 cells. Cellular analyses showed that the quinone-enriched polar fraction was more potent than the polycyclic aromatic hydrocarbon (PAH)-enriched aromatic fraction in O2 .- generation, decrease of membrane potential (Delta-Psi m), loss of mitochondrial membrane mass, and induction of apoptosis. A major effect of the polar fraction was to promote cyclosporin A (CsA)-sensitive permeability transition pore (PTP) opening in isolated liver mitochondria. This opening effect is dependent on a direct effect on the PTP at low doses as well as on an effect on Delta-Psi m at high doses in calcium (Ca2+)-loaded mitochondria. The direct PTP effect was mimicked by redox-cycling DEP quinones. Although the aliphatic fraction failed to perturb mitochondrial function, the aromatic fraction increased the Ca2+ retention capacity at low doses and induced mitochondrial swelling and a decrease in Delta-Psi m at high doses. This swelling effect was mostly CsA insensitive and could be reproduced by a mixture of PAHs present in DEPs. These chemical effects on isolated mitochondria could be reproduced by intact DEPs as well as ambient ultrafine particles (UFPs). In contrast, commercial polystyrene nanoparticles failed to exert mitochondrial effects. These results suggest that DEP and UFP effects on the PTP and Delta-Psi m are mediated by adsorbed chemicals rather than the particles themselves.

  8. Developmental toxicity and oxidative stress induced by gamma irradiation in zebrafish embryos

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Miao; Hu, Nan; Ding, Dexin; Zhao, Weichao; Feng, Yongfu; Zhang, Hui; Li, Guangyue; Wang, Yongdong [University of South China, Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, Hengyang, Hunan Province (China)

    2016-11-15

    This study aimed to evaluate the biological effects of gamma irradiation on zebrafish embryos. Different doses of gamma rays (0.01, 0.05, 0.1, 0.5 and 1 Gy) were used to irradiate zebrafish embryos at three developmental stages (stage 1, 6 h post-fertilization (hpf); stage 2, 12 hpf; stage three, 24 hpf), respectively. The survival, malformation and hatching rates of the zebrafish embryos were measured at the morphological endpoint of 96 hpf. The activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and glutathione S-transferase (GST) were assayed. Morphology analysis showed that gamma irradiation inhibited hatching and induced developmental toxicity in a dose-dependent manner. Interestingly, after irradiation the malformation rate changed not only in a dose-dependent manner but also in a developmental stage-dependent manner, indicating that the zebrafish embryos at stage 1 were more sensitive to gamma rays than those at other stages. Biochemical analysis showed that gamma irradiation modulated the activities of antioxidant enzymes in a dose-dependent manner. A linear relationship was found between GPx activity and irradiation dose in 0.1-1 Gy group, and GPx was a suitable biomarker for gamma irradiation in the dose range from 0.1 to 1 Gy. Furthermore, the activities of SOD, CAT, GR and GPx of the zebrafish embryos at stage 3 were found to be much higher than those at other stages, indicating that the zebrafish embryos at stage 3 had a greater ability to protect against gamma rays than those at other stages, and thus the activities of antioxidant enzymes changed in a developmental stage-dependent manner. (orig.)

  9. Development of a laser induced breakdown spectrometer for detection of toxic elements in cosmetic products

    Science.gov (United States)

    Maganda, Yasin Wandhami

    In this research work we developed a highly sensitive analytical Laser Induced Breakdown Spectrometer to detect toxic elements in commercially available cosmetic products. These products are frequently used by many all over the world, therefore there is an increasing demand to determine concentration levels of toxic elements present in them because they cause dangerous diseases and most of them are highly carcinogenic and life threatening. Laser Induced Breakdown Spectroscopy (LIBS) was applied for spectroscopic analysis of cosmetic products such as tooth paste, synthetic hair dye, kohl eyeliners and talcum powder samples. These samples were purchased from the local market within the kingdom of Saudi Arabia. The LIBS method is based on spectroscopic analysis of plasma resulting from the interaction of a high power pulsed laser radiations with a sample medium. In order to improve the sensitivity of the spectrometer, the dependence of the LIBS signal intensity and plasma parameters such as temperature (T) and electron density (ne) on gate/time delay, laser fluence and wavelength of the excitation source for plasma generated under ambient conditions were studied. During this work Nd: YAG lasers having 266nm, 532 nm and 1064 nm wavelengths operating in Q-switch mode were used as the excitation sources in combination with a spectrograph having a gated ICCD camera. Boltzmann plots and stark broadening for the recorded spectral lines were used to estimate the plasma temperature and electron density respectively. Temporal evolution of the plasma temperature and electron density showed a t-2 dependence. On the other hand plasma temperature and electron density increased with increase in laser fluence but leveled off at higher fluencies. It is worth noting that in both cases 266 nm and 1064 nm excitation wavelengths consistently had the highest and lowest values respectively. Therefore a 266 nm wavelength Nd: YAG laser excitation source was selected to develop a highly

  10. Toxicity induced by dieldrin and chlorpyrifos in the freshwater crayfish Cambarellus montezumae (Cambaridae

    Directory of Open Access Journals (Sweden)

    Sandra Díaz-Barriga Arceo

    2015-03-01

    Full Text Available The toxicity induced by insecticides in aquatic organisms is of utmost relevance because it may give a clue about the degree of health or damage of the involved ecosystem. In the present report, we determined the effect of dieldrin (DD and chlorpyrifos (CP on the freshwater crayfish, Cambarellus montezumae. The organisms (4-6cm in diameter were collected in the Ignacio Ramírez Reservoir, situated at 50km Northeast of Mexico City, in the Rio Lerma Basin. Initially, we determined the LC50 value with the Probit method, then the DNA damage with single cell gel electrophoresis (comet assay applied at 24, 48, and 72h of exposure to the brain and hepatopancreas of animals exposed (in reconstituted water to 0.05 and 0.5µg/L of each insecticide. In the hepatopancreas of the same organisms, we determined the lipid peroxidation by applying the TBARS test. DNA damage and lipid peroxidation were also evaluated with the same methods to organisms exposed in water from the reservoir. In regard to the LC50 at 72h of exposure, we found a value of 5.1µg/L and a value of 5.62µg/L for DD and CP, respectively. The comet assay applied at different exposure times showed significant DNA damage to both organs, with respect to the control level. In the case of DD, statistical significance was observed for the two doses in the whole evaluated schedule. CP was genotoxic in the brain with the high dose at 72h, and in the hepatopancreas with the two tested doses at all evaluated exposure times. Also, a significant lipid peroxidation increase was detected with the two doses of insecticides. In the study with water from the reservoir, a more pronounced DNA damage was detected. Our results showed strong DNA damage induced by both insecticides in the crayfish, as well as a correlation with the lipid peroxidation effect, suggesting that oxidative stress is involved in the genotoxic alteration. Our results also showed the usefulness of the studied organism as well as the

  11. Toxicity induced by dieldrin and chlorpyrifos in the freshwater crayfish Cambarellus montezumae (Cambaridae).

    Science.gov (United States)

    Díaz, Sandra; Arceo, Barriga; Martínez-Tabche, Laura; Alvarez-González, Isela; López López, Eugenia; Madrigal-Bujaidar, Eduardo

    2015-03-01

    The toxicity induced by insecticides in aquatic organisms is of utmost relevance because it may give a clue about the degree of health or damage of the involved ecosystem. In the present report, we determined the effect of dieldrin (DD) and chlorpyrifos (CP) on the freshwater crayfish, Cambarellus montezumae. The organisms (4-6 cm in diameter) were collected in the Ignacio Ramirez Reservoir, situated at 50 km Northeast of Mexico City, in the Rio Lerma Basin. Initially, we determined the LC50 value with the Probit method, then the DNA damage with single cell gel electrophoresis (comet assay applied at 24, 48, and 72 h of exposure) to the brain and hepatopancreas of animals exposed (in reconstituted water) to 0.05 and 0.5 microg/L of each insecticide. In the hepatopancreas of the same organisms, we determined the lipid peroxidation by applying the TBARS test. DNA damage and lipid peroxidation were also evaluated with the same methods to organisms exposed in water from the reservoir. In regard to the LC50, at 72 h of exposure, we found a value of 5.1 microg/L and a value of 5.62 microg/L for DD and CP, respectively. The comet assay applied at different exposure times showed significant DNA damage to both organs, with respect to the control level. In the case of DD, statistical significance was observed for the two doses in the whole evaluated schedule. CP was genotoxic in the brain with the high dose at 72 h, and in the hepatopancreas with the two tested doses at all evaluated exposure times. Also, a significant lipid peroxidation increase was detected with the two doses of insecticides. In the study with water from the reservoir, a more pronounced DNA damage was detected. Our results showed strong DNA damage induced by both insecticides in the crayfish, as well as a correlation with the lipid peroxidation effect, suggesting that oxidative stress is involved in the genotoxic alteration. Our results also showed the usefulness of the studied organism as well as the

  12. Protective Effects of Some Medicinal Plants from Lamiaceae Family Against Beta-Amyloid Induced Toxicity in PC12 Cell

    Directory of Open Access Journals (Sweden)

    S Saeidnia

    2012-10-01

    Full Text Available Background: Excessive accumulation of beta-amyliod peptide (Aβ, the major component of senile plaques in Alzheimer's disease (AD, causes neuronal cell death through induction of oxidative stress. Therefore, antioxidants may be of use in the treatment of AD. The medicinal plants from the Lamiaceae family have been widely used in Iranian traditional medicine. These plants contain compounds with antioxidant activity and some species in this family have been reported to have neuroprotective properties. In the present study, methanolic extract of seven plants from salvia and satureja species were evaluated for their protective effects against beta-amyloid induced neurotoxicity.Methods: Aerial parts of the plants were extracted with ethyl acetate and methanol, respectively, by percolation at room temperature and subsequently, methanolic extracts of the plants were prepared. PC12 cells were incubated with different concentrations of the extracts in culture medium 1h prior to incubation with Aβ. Cell toxicity was assessed 24h after addition of Aβ by MTT assay.Results: Satureja bachtiarica, Salvia officinalis and Salvia macrosiphon methanolic extracts exhibited high protective effects against Aβ induced toxicity (P<0.001. Protective effects of Satureja bachtiarica and Salvia officinalis were dose-dependent.Conclusion: The main constituents of these extracts are polyphenolic and flavonoid compounds such as rosmarinic acid, naringenin, apigenin and luteolin which have antioxidant properties and may have a role in neuroprotection. Based on neuroprotective effect of these plants against Aβ induced toxicity, we recommend greater attention to their use in the treatment of Alzheimer disease.

  13. Neuroprotective effects of triterpene glycosides from glycine max against glutamate induced toxicity in primary cultured rat cortical cells.

    Science.gov (United States)

    Moon, Hyung-In; Lee, Jai-Heon

    2012-01-01

    To examine the neuroprotective effects of Glycine max, we tested its protection against the glutamate-induced toxicity in primary cortical cultured neurons. In order to clarify the neuroprotective mechanism(s) of this observed effect, isolation was performed to seek and identify active fractions and components. From such fractionation, two triterpene glycosides, 3-O-[α-l-rhamnopyranosyl(1-2)-β-d-glucopyranosyl(1-2)-β-d-glucuronopyranosyl]olean-12-en-3β,22β,24-triol (1) and 3-O-[β-d-glucopyranosyl(1-2)-β-d-galactopyranosyl(1-2)-β-d-glucuronopyranosyl]olean-12-en-3β,22β,24-triol (2) were isolated with the methanol extracts with of air-dried Glycine max. Among these compounds, compound 2 exhibited significant neuroprotective activities against glutamate-induced toxicity, exhibiting cell viability of about 50% at concentrations ranging from 0.1 μM to 10 μM. Therefore, the neuroprotective effect of Glycine max might be due to the inhibition of glutamate-induced toxicity by triterpene glycosides.

  14. Local anaesthetic toxicity in a pregnant patient undergoing lignocaine-induced intravenous regional anaesthesia.

    LENUS (Irish Health Repository)

    Coleman, M

    2012-02-03

    A pregnant patient at 38 weeks\\' gestation developed symptoms of local anaesthetic toxicity following intravenous regional anaesthesia (IVRA) for hand surgery, using a standard dose of lignocaine. Reports suggest that a number of factors, both physiological and pharmacological, combine to increase the likelihood of local anaesthetic (LA) toxicity in pregnancy despite employment of a conventional "safe" IVRA technique. It is suggested that for IVRA, pregnant patients are premedicated with a benzodiazepine, the tourniquet time is increased and the concentration of LA is decreased to reduce the risks of LA toxicity.

  15. Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7 model

    Directory of Open Access Journals (Sweden)

    Ajayi Abiodun

    2012-07-01

    Full Text Available Abstract Background Spinocerebellar ataxia type 7 (SCA7 is one of nine inherited neurodegenerative disorders caused by polyglutamine (polyQ expansions. Common mechanisms of disease pathogenesis suggested for polyQ disorders include aggregation of the polyQ protein and induction of oxidative stress. However, the exact mechanism(s of toxicity is still unclear. Results In this study we show that expression of polyQ expanded ATXN7 in a novel stable inducible cell model first results in a concomitant increase in ROS levels and aggregation of the disease protein and later cellular toxicity. The increase in ROS could be completely prevented by inhibition of NADPH oxidase (NOX complexes suggesting that ATXN7 directly or indirectly causes oxidative stress by increasing superoxide anion production from these complexes. Moreover, we could observe that induction of mutant ATXN7 leads to a decrease in the levels of catalase, a key enzyme in detoxifying hydrogen peroxide produced from dismutation of superoxide anions. This could also contribute to the generation of oxidative stress. Most importantly, we found that treatment with a general anti-oxidant or inhibitors of NOX complexes reduced both the aggregation and toxicity of mutant ATXN7. In contrast, ATXN7 aggregation was aggravated by treatments promoting oxidative stress. Conclusion Our results demonstrates that oxidative stress contributes to ATXN7 aggregation as well as toxicity and show that anti-oxidants or NOX inhibition can ameliorate mutant ATXN7 toxicity.

  16. EVALUATION OF NEPHRO-PROTECTIVE AND ANTI-NEPHRO-TOXIC PROPERTIES OF RAKTA PUNARNAVA ROOTS (Boerhaavia diffusa, L. GOKSHUR FRUITS (Tribulus terrestris, L. IN DRUG INDUCED NEPHROTOXICITY

    Directory of Open Access Journals (Sweden)

    Kulkarni Yogini Ramachandra

    2012-07-01

    Full Text Available Kwath of Rakta Punarnava roots (Boerhaavia diffusa, L. and Gokshur fruits (Tribulus terrestris,L. were tried for their Nephro-protective and anti-nephro-toxic properties by using Gentamycin induced Nephro-toxic model in Wistar strain Albino Rats. The effects were assessed on the basis of Biochemical and Histo-pathological investigations. Both the selected drugs have proven statistically significant results as Nephro-protective agent whereas Punarnava has got pronounced anti-nephro-toxic action too.

  17. Neuropeptide Y promotes neurogenesis and protection against methamphetamine-induced toxicity in mouse dentate gyrus-derived neurosphere cultures.

    Science.gov (United States)

    Baptista, Sofia; Bento, Ana Rita; Gonçalves, Joana; Bernardino, Liliana; Summavielle, Teresa; Lobo, Andrea; Fontes-Ribeiro, Carlos; Malva, João O; Agasse, Fabienne; Silva, Ana P

    2012-06-01

    Methamphetamine (METH) is a psychostimulant drug of abuse that causes severe brain damage. However, the mechanisms responsible for these effects are poorly understood, particularly regarding the impact of METH on hippocampal neurogenesis. Moreover, neuropeptide Y (NPY) is known to be neuroprotective under several pathological conditions. Here, we investigated the effect of METH on dentate gyrus (DG) neurogenesis, regarding cell death, proliferation and differentiation, as well as the role of NPY by itself and against METH-induced toxicity. DG-derived neurosphere cultures were used to evaluate the effect of METH or NPY on cell death, proliferation or neuronal differentiation. Moreover, the role of NPY and its receptors (Y(1), Y(2) and Y(5)) was investigated under conditions of METH-induced DG cell death. METH-induced cell death by both apoptosis and necrosis at concentrations above 10 nM, without affecting cell proliferation. Furthermore, at a non-toxic concentration (1 nM), METH decreased neuronal differentiation. NPY's protective effect was mainly due to the reduction of glutamate release, and it also increased DG cell proliferation and neuronal differentiation via Y(1) receptors. In addition, while the activation of Y(1) or Y(2) receptors was able to prevent METH-induced cell death, the Y(1) subtype alone was responsible for blocking the decrease in neuronal differentiation induced by the drug. Taken together, METH negatively affects DG cell viability and neurogenesis, and NPY is revealed to be a promising protective tool against the deleterious effects of METH on hippocampal neurogenesis.

  18. "Ecstasy"-induced toxicity in SH-SY5Y differentiated cells: role of hyperthermia and metabolites.

    Science.gov (United States)

    Barbosa, Daniel José; Capela, João Paulo; Silva, Renata; Ferreira, Luísa Maria; Branco, Paula Sério; Fernandes, Eduarda; Bastos, Maria Lourdes; Carvalho, Félix

    2014-02-01

    3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a recreational hallucinogenic drug of abuse known to elicit neurotoxic properties. Hepatic formation of neurotoxic metabolites is thought to play a major role in MDMA-related neurotoxicity, though the mechanisms involved are still unclear. Here, we studied the neurotoxicity mechanisms and stability of MDMA and 6 of its major human metabolites, namely α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) and their correspondent glutathione (GSH) and N-acetyl-cysteine (NAC) conjugates, under normothermic (37 °C) or hyperthermic conditions (40 °C), using cultured SH-SY5Y differentiated cells. We showed that MDMA metabolites exhibited toxicity to SH-SY5Y differentiated cells, being the GSH and NAC conjugates more toxic than their catecholic precursors and MDMA. Furthermore, whereas the toxicity of the catechol metabolites was potentiated by hyperthermia, NAC-conjugated metabolites revealed higher toxicity under normothermia and GSH-conjugated metabolites-induced toxicity was temperature-independent. Moreover, a time-dependent decrease in extracellular concentration of MDMA metabolites was observed, which was potentiated by hyperthermia. The antioxidant NAC significantly protected against the neurotoxic effects of MDMA metabolites. MDMA metabolites increased intracellular glutathione levels, though depletion in thiol content was observed in MDMA-exposed cells. Finally, the neurotoxic effects induced by the MDMA metabolite N-Me-α-MeDA involved caspase 3 activation. In conclusion, this study evaluated the stability of MDMA metabolites in vitro, and demonstrated that the catechol MDMA metabolites and their GSH and NAC conjugates, rather than MDMA itself, exhibited neurotoxic actions in SH-SY5Y differentiated cells, which were differently affected by hyperthermia, thus highlighting a major role for reactive metabolites and hyperthermia in MDMA's neurotoxicity.

  19. Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Langsenlehner, Tanja; Thurner, Eva-Maria; Kapp, Karin S. [Medical Univ. of Graz (Austria). Dept. of Therapeutic Radiology and Oncology; Renner, Wilfried [Medical Univ. of Graz (Austria). Clinical Inst. of Medical and Chemical Lab. Diagnostics; Gerger, Armin; Hofmann, Guenter [Medical Univ. of Graz (Austria). Division of Oncology; Langsenlehner, Uwe [GKK Outpatient Dept. Graz (Austria). Division of Internal Medicine

    2011-12-15

    Vascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients. The association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG {>=}2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5'-nuclease (TaqMan) assays. Within a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan-Meier analysis, carriers of the VEGF -7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349-5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade {>=}2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes. We conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer.

  20. Protective effects of a by-product of the pecan nut industry (Carya illinoensis) on the toxicity induced by cyclophosphamide in rats Carya illinoensis protects against cyclophosphamide-induced toxicity.

    Science.gov (United States)

    Benvegnú, D; Barcelos, R C S; Boufleur, N; Reckziegel, P; Pase, C S; Müller, L G; Martins, N M B; Vareli, C; Bürger, M E

    2010-01-01

    This study investigated the antioxidant effects of pecan nut (Carya illinoensis) shell aqueous extract (AE) on toxicity induced by cyclophosphamide (CP) in the heart, kidney, liver, bladder, plasma and erythrocytes of rats. Rats were treated with water or pecan shell AE (5%) ad libitum, replacing drinking water for 37 days up to the end of the experiment. On day 30, half of each group received a single administration of vehicle or CP 200 mg/kg-ip. After 7 days, the organs were removed. Rats treated with CP showed an increase in lipid peroxidation (LP) and decrease in reduced glutathione (GSH) levels in all structures. Catalase (CAT) activity was increased in the heart and decreased in liver and kidney. Besides, CP treatment decreased plasmatic vitamin C (VIT C) levels and induced bladder macroscopical and microscopical damages. In contrast, co-treatment with pecan shell AE prevented the LP development and the GSH depletion in all structures, except in the heart and plasma, respectively. CAT activity in the heart and liver as well as the plasmatic VIT C levels remained unchanged. Finally, AE prevented CP-induced bladder injury. These findings revealed the protective role of pecan shell AE in CP-induced multiple organ toxicity.

  1. Prediction of clinical toxicity in localized cervical carcinoma by radio-induced apoptosis study in peripheral blood lymphocytes (PBLs

    Directory of Open Access Journals (Sweden)

    Lara Pedro C

    2009-11-01

    Full Text Available Abstract Background Cervical cancer is treated mainly by surgery and radiotherapy. Toxicity due to radiation is a limiting factor for treatment success. Determination of lymphocyte radiosensitivity by radio-induced apoptosis arises as a possible method for predictive test development. The aim of this study was to analyze radio-induced apoptosis of peripheral blood lymphocytes. Methods Ninety four consecutive patients suffering from cervical carcinoma, diagnosed and treated in our institution, and four healthy controls were included in the study. Toxicity was evaluated using the Lent-Soma scale. Peripheral blood lymphocytes were isolated and irradiated at 0, 1, 2 and 8 Gy during 24, 48 and 72 hours. Apoptosis was measured by flow cytometry using annexin V/propidium iodide to determine early and late apoptosis. Lymphocytes were marked with CD45 APC-conjugated monoclonal antibody. Results Radiation-induced apoptosis (RIA increased with radiation dose and time of incubation. Data strongly fitted to a semi logarithmic model as follows: RIA = βln(Gy + α. This mathematical model was defined by two constants: α, is the origin of the curve in the Y axis and determines the percentage of spontaneous cell death and β, is the slope of the curve and determines the percentage of cell death induced at a determined radiation dose (β = ΔRIA/Δln(Gy. Higher β values (increased rate of RIA at given radiation doses were observed in patients with low sexual toxicity (Exp(B = 0.83, C.I. 95% (0.73-0.95, p = 0.007; Exp(B = 0.88, C.I. 95% (0.82-0.94, p = 0.001; Exp(B = 0.93, C.I. 95% (0.88-0.99, p = 0.026 for 24, 48 and 72 hours respectively. This relation was also found with rectal (Exp(B = 0.89, C.I. 95% (0.81-0.98, p = 0.026; Exp(B = 0.95, C.I. 95% (0.91-0.98, p = 0.013 for 48 and 72 hours respectively and urinary (Exp(B = 0.83, C.I. 95% (0.71-0.97, p = 0.021 for 24 hours toxicity. Conclusion Radiation induced apoptosis at different time points and radiation

  2. Common synonymous variants in ABCA4 are protective for chloroquine induced maculopathy (toxic maculopathy)

    OpenAIRE

    Weber, Bernhard H. F.; Bergholz, Richard; Mändl, Julia; Jägle, Herbert; Ruether, Klaus; Grassmann, Felix

    2015-01-01

    Background Chloroquine (CQ) and hydroxychloroquine (HCQ) are used to treat auto-immune related diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Both drugs however can cause retinal toxicity eventually leading to irreversible maculopathy and retinopathy. Established risk factors are duration and dosage of treatment while the involvement of genetic factors contributing to toxic maculopathy is largely unclear. To address the latter issue, this study aimed to expand on ...

  3. Peumus boldus (Boldo) Aqueous Extract Present Better Protective Effect than Boldine Against Manganese-Induced Toxicity in D. melanogaster.

    Science.gov (United States)

    Bianchini, Matheus Chimelo; Gularte, Claudia Ortiz Alves; Escoto, Dandara Fidélis; Pereira, Geovana; Gayer, Mateus Cristofari; Roehrs, Rafael; Soares, Félix Alexandre Antunes; Puntel, Robson L

    2016-10-01

    The cellular, intracellular and molecular mechanism(s) underlying the toxicity of Mn are still incompletely understood, although several points concerning Mn neurotoxicity have been addressed. Importantly, oxidative changes have been reported to be involved in Mn-induced toxicity. As a consequence, antioxidants are expected to offer protection in Drosophila melanogaster exposed to this metal. So, in this study we evaluated the hypothesis that the aqueous extract of boldo (Peumus boldus), and its alkaloids boldine, could prevent/ameliorate behavioral and oxidative alterations induced by Mn in a D. melanogaster intoxication model. Adult wild-type flies were concomitantly exposed to Mn (3 mM) and boldo aqueous extract (5 mg/mL) or boldine (327.37 µg/mL) in the food during 9 days. Mn-fed flies had a worse performance in the negative geotaxis assay and in the open-field test, as well as a higher incidence of mortality and TBARS levels in head and body, when compared to control group. Boldo aqueous extract was found to reduce the mortality rate of the flies exposed to Mn. In turn, boldine was ineffective against Mn-induced mortality and significantly increases mortality per se. Additionally, Mn-induced locomotors dysfunction were fully ameliorated by boldo crude extract and only partially ameliorated by boldine. Likewise, boldo completely normalize head and body TBARS levels, whereas boldine only partially normalize in body. Finally, we found that flies treated with Mn presented significantly decrease in dopamine levels. Our results suggest that boldo crude extract can exert protective effect against Mn-induced toxicity in D. melanogaster, whereas boldine do not. Moreover, our data confirm the utility of this model to investigate potential therapeutic strategies on movement disorders, such as that caused by Mn.

  4. Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity.

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    Cheng, Jie; Ma, Xiaochao; Krausz, Kristopher W; Idle, Jeffrey R; Gonzalez, Frank J

    2009-08-01

    Acetaminophen (APAP) is safe at therapeutic levels but causes hepatotoxicity via N-acetyl-p-benzoquinone imine-induced oxidative stress upon overdose. To determine the effect of human (h) pregnane X receptor (PXR) activation and CYP3A4 induction on APAP-induced hepatotoxicity, mice humanized for PXR and CYP3A4 (TgCYP3A4/hPXR) were treated with APAP and rifampicin. Human PXR activation and CYP3A4 induction enhanced APAP-induced hepatotoxicity as revealed by hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities elevated in serum, and hepatic necrosis after coadministration of rifampicin and APAP, compared with APAP administration alone. In contrast, hPXR mice, wild-type mice, and Pxr-null mice exhibited significantly lower ALT/AST levels compared with TgCYP3A4/hPXR mice after APAP administration. Toxicity was coincident with depletion of hepatic glutathione and increased production of hydrogen peroxide, suggesting increased oxidative stress upon hPXR activation. Moreover, mRNA analysis demonstrated that CYP3A4 and other PXR target genes were significantly induced by rifampicin treatment. Urinary metabolomic analysis indicated that cysteine-APAP and its metabolite S-(5-acetylamino-2-hydroxyphenyl)mercaptopyruvic acid were the major contributors to the toxic phenotype. Quantification of plasma APAP metabolites indicated that the APAP dimer formed coincident with increased oxidative stress. In addition, serum metabolomics revealed reduction of lysophosphatidylcholine in the APAP-treated groups. These findings demonstrated that human PXR is involved in regulation of APAP-induced toxicity through CYP3A4-mediated hepatic metabolism of APAP in the presence of PXR ligands.

  5. Fluoxetine prevents Aβ1-42-induced toxicity via a paracrine signaling mediated by Transforming-Growth-Factor-β1

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    Filippo Caraci

    2016-10-01

    Full Text Available Selective reuptake inhibitors (SSRIs, such as fluoxetine and sertraline, increase circulating Transforming-Growth-Factor-β1 (TGF-ß1 levels in depressed patients,and are currently studied for their neuroprotective properties in Alzheimer’s disease (AD. TGF-β1 is an anti-inflammatory cytokine that exerts neuroprotective effects against ß-amyloid (Aβ-induced neurodegeneration.In the present work the SSRI, fluoxetine, was tested for the ability to protect cortical neurons against 1µM oligomeric Aß1-42-induced toxicity. At therapeutic concentrations (100nM-1µM, fluoxetine significantly prevented Aβ-induced toxicity in mixed glia-neuronalcultures, but not in pure neuronal cultures. Though to a lesser extent, also sertraline was neuroprotective in mixed cultures, whereas serotonin (10nM-10µM did not mimick fluoxetine effects.Glia-conditioned medium collected from astrocytes challenged with fluoxetine protected pure cortical neurons against Aβ toxicity. The effect was lost in the presence of a neutralizing antibody against TGF-ß1 in the conditioned medium, or when the specific inhibitor of type-1 TGF-β1 receptor, SB431542, was added to pure neuronal cultures. Accordingly, a 24 hr treatment of cortical astrocytes with fluoxetine promoted the release of active TGF-β1 in the culture media through the conversion of latent TGF-ß1 to mature TGF-ß1.Unlike fluoxetine, both serotonin and sertraline did not stimulate the astrocyte release of active TGF-β1. We conclude that fluoxetine is neuroprotective against Aß toxicity via a paracrine signaling mediated by TGFβ-1, which does not result from a simplistic SERT blockade.

  6. Current view of zinc as a hepatoprotective agent in conditions of chlorpyrifos induced toxicity.

    Science.gov (United States)

    Malhotra, Anshoo; Dhawan, D K

    2014-06-01

    Human population bears the brunt of deadly hepatotoxic, neurodegenerative, behavioural and various other developmental disorders due to pesticide toxicity through environmental or occupational exposures. The application of pesticides to control pests in land and water has posed potential health hazards to live stock and wildlife including fishes, mammals, birds and humans. Therefore, various scientific approaches are being considered to tackle the problem of pesticide poisoning especially in developing economies. The role of essential trace elements as the promising and efficient preventive prophylactic agents without any toxicity and side effects in attenuating the adverse effects caused by pesticides, have been reported by various scientists, the world over. In this perspective, zinc, a key constituent of more than 300 mammalian enzymes and many transcription factors has proved its protective potential in various models of animal toxicity. The hepato-protective potential of zinc has been proved during various toxic states including pesticide toxicity. However, zinc warrants further examination with regard to documentation of specific molecular pathways to establish the exact mechanisms for zinc-mediated protection during pesticide toxicity. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Impact of solar UV radiation on toxicity of ZnO nanoparticles through photocatalytic reactive oxygen species (ROS) generation and photo-induced dissolution

    Science.gov (United States)

    The present study investigated the impact of solar UV radiation on ZnO nanoparticle toxicity through photocatalytic ROS generation and photo-induced dissolution. Toxicity of ZnO nanoparticles to Daphnia magna was examined under laboratory light versus simulated solar UV radiatio...

  8. A suite of recombinant luminescent bacterial strains for the quantification of bioavailable heavy metals and toxicity testing

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    Kahru Anne

    2009-05-01

    Full Text Available Abstract Background Recombinant whole-cell sensors have already proven useful in the assessment of the bioavailability of environmental pollutants like heavy metals and organic compounds. In this work 19 recombinant bacterial strains representing various Gram-positive (Staphylococcus aureus and Bacillus subtilis and Gram-negative (Escherichia coli, Pseudomonas fluorescens bacteria were constructed to express the luminescence encoding genes luxCDABE (from Photorhabdus luminescens as a response to bioavailable heavy metals ("lights-on" metal sensors containing metal-response elements, 13 strains or in a constitutive manner ("lights-off" constructs, 6 strains. Results The bioluminescence of all 13 "lights-on" metal sensor strains was expressed as a function of the sub-toxic metal concentrations enabling the quantitative determination of metals bioavailable for these strains. Five sensor strains, constructed for detecting copper and mercury, proved to be target metal specific, whereas eight other sensor strains were simultaneously induced by Cd2+, Hg2+, Zn2+and Pb2+. The lowest limits of determination of the "lights-on" sensor strains for the metals tested in this study were (μg l-1: 0.002 of CH3HgCl, 0.03 of HgCl2, 1.8 of CdCl2, 33 of Pb(NO32, 1626 of ZnSO4, 24 of CuSO4 and 340 of AgNO3. In general, the sensitivity of the "lights-on" sensor strains was mostly dependent on the metal-response element used while the selection of host bacterium played a relatively minor role. In contrast, toxicity of metals to the "lights-off" strains was only dependent on the bacterial host so that Gram-positive strains were remarkably more sensitive than Gram-negative ones. Conclusion The constructed battery of 19 recombinant luminescent bacterial strains exhibits several novel aspects as it contains i metal sensor strains with similar metal-response elements in different host bacteria; ii metal sensor strains with metal-response elements in different copies and iii

  9. Protective Effect of the Plant Extracts of Erythroxylum sp. against Toxic Effects Induced by the Venom of Lachesis muta Snake

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    Eduardo Coriolano de Oliveira

    2016-10-01

    Full Text Available Snake venoms are composed of a complex mixture of active proteins that induce toxic effects, such as edema, hemorrhage, and death. Lachesis muta has the highest lethality indices in Brazil. In most cases, antivenom fails to neutralize local effects, leading to disabilities in victims. Thus, alternative treatments are under investigation, and plant extracts are promising candidates. The objective of this work was to investigate the ability of crude extracts, fractions, or isolated products of Erythroxylum ovalifolium and Erythroxylum subsessile to neutralize some toxic effects of L. muta venom. All samples were mixed with L. muta venom, then in vivo (hemorrhage and edema and in vitro (proteolysis, coagulation, and hemolysis assays were performed. Overall, crude extracts or fractions of Erythroxylum spp. inhibited (20%–100% toxic effects of the venom, but products achieved an inhibition of 4%–30%. However, when venom was injected into mice before the plant extracts, hemorrhage and edema were not inhibited by the samples. On the other hand, an inhibition of 5%–40% was obtained when extracts or products were given before venom injection. These results indicate that the extracts or products of Erythroxylum spp. could be a promising source of molecules able to treat local toxic effects of envenomation by L. muta venom, aiding in the development of new strategies for antivenom treatment.

  10. Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Song, SungWon; Miranda, Carlos J; Braun, Lyndsey; Meyer, Kathrin; Frakes, Ashley E; Ferraiuolo, Laura; Likhite, Shibi; Bevan, Adam K; Foust, Kevin D; McConnell, Michael J; Walker, Christopher M; Kaspar, Brian K

    2016-04-01

    Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non-cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte-mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity.

  11. Voluntary Ingestion of Natural Cocoa Extenuated Hepatic Damage in Rats with Experimentally Induced Chronic Alcoholic Toxicity

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    Godwin Sokpor

    2012-05-01

    Full Text Available Background: Chronic ethanol ingestion causes hepatic damage imputable to an increasedoxidative stress engendered by alcoholic toxicity. Polyphenols in cocoa have antioxidant properties, and natural cocoa powder (NCP contains the highest levels of total antioxidant capacity when compared to all other kinds of edible cocoa products. This study tested the hypothesis that dietary supplementation with NCP mitigates hepatic injury resulting from chronic ethanol consumption. Three groups of eight randomized Sprague-Dawley rats were fed standardrat food and treated daily for 12 weeks as follows: (i the Ethanol-water group was given unrestricted access to 40% (v/v ethanol for 12 hours (at night followed by water for the remaining 12 hours (daytime, (ii the Ethanol-cocoa group had similarly unrestricted access to 40% ethanol for 12 hours followed by 2% (w/v NCP for 12 hours, and (iii the control group was not given alcohol and had unrestricted access to only water which was synchronously replenished every 12 hours as it was for the ethanol treated animals.Results: Qualitative structural liver damage evidenced by hepatocyte cytoplasmic fatty accumulation, nuclear alterations, and disruption of general liver micro-architecture, was severe in the ethanol-water group when compared with the ethanol-cocoa group of rats. Design-based stereologic assessment yielded a significantly greater volume (Tukey’s HSD, p = 0.0005 ofundamaged hepatocytes (9.61 ml, SD 2.18 ml in the ethanol-cocoa group as opposed to theethanol-water group of rats (2.34 ml, SD 1.21 ml. Control rats had 10.34 ml (SD 1.47 ml of undamaged hepatocytes, and that was not significantly greater (Tukey’s HSD, p=0.659 than the value for the ethanol-cocoa group of rats. Relative to controls, therefore, histomorphometryFunctional Foods in Health and Disease 2012, 2(5:166- 187 showed 93% hepatocyte preservation from alcoholic injury in rats that voluntarily imbibed NCP suspension compared with 23% in

  12. BIOCHEMICAL STUDIES ON HEPATO AND NEPHROPROTECTIVE EFFECT OF BUTTERFLY TREE (BAUHINIA PURPUREA LINN. AGAINST ACETAMINOPHEN INDUCED TOXICITY

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    T. Sivanagi Reddy

    2012-06-01

    Full Text Available The present study was carried out to evaluate the hepato and nephroprotective activity of ethanolic extract of stem bark of Bauhinia purpurea against paracetamol induced toxicity in rats. 100, 200 and 400 mg/kg, Oral doses of ethanolic extract of stem bark of Bauhinia purpurea was administered to group of animals for 14 days. Silymarin (25 mg/kg served as a standard and paracetamol suspension at a dose of 750 mg/kg, Body weight, was used to induce liver and kidney damage. Parameters of study were glutamate oxaloacetate transaminase (GOT, glutamate pyruvate transaminase (GPT, alkaline phosphatase (ALP, bilirubin, triglycerides and total protein as liver function tests, blood urea nitrogen (BUN, creatinine and urea as kidney function tests. Biochemical studies showed increase in the levels of serum GOT, GPT, ALP, total bilirubin, triglycerides, BUN, creatinine and urea and reduction in the levels of total protein in paracetamol induced groups. These values are retrieved significantly (p< 0.05 in a dose dependant manner by treatment with ethanolic extracts of Bauhinia purpurea stem bark at three different doses. The overall result suggests that the ethanolic extract of stem bark of Bauhinia purpurea possesses hepato and nephroprotective activity against paracetamol induced toxicity.

  13. Phosphoproteome Analysis Reveals the Molecular Mechanisms Underlying Deoxynivalenol-Induced Intestinal Toxicity in IPEC-J2 Cells

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    Zhang, Zhi-Qi; Wang, Song-Bo; Wang, Rui-Guo; Zhang, Wei; Wang, Pei-Long; Su, Xiao-Ou

    2016-01-01

    Deoxynivalenol (DON) is a widespread trichothecene mycotoxin that commonly contaminates cereal crops and has various toxic effects in animals and humans. DON primarily targets the gastrointestinal tract, the first barrier against ingested food contaminants. In this study, an isobaric tag for relative and absolute quantitation (iTRAQ)-based phosphoproteomic approach was employed to elucidate the molecular mechanisms underlying DON-mediated intestinal toxicity in porcine epithelial cells (IPEC-J2) exposed to 20 μM DON for 60 min. There were 4153 unique phosphopeptides, representing 389 phosphorylation sites, detected in 1821 phosphoproteins. We found that 289 phosphopeptides corresponding to 255 phosphoproteins were differentially phosphorylated in response to DON. Comprehensive Gene Ontology (GO) analysis combined with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that, in addition to previously well-characterized mitogen-activated protein kinase (MAPK) signaling, DON exposure altered phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase/signal transducer, and activator of transcription (JAK/STAT) pathways. These pathways are involved in a wide range of biological processes, including apoptosis, the intestinal barrier, intestinal inflammation, and the intestinal absorption of glucose. DON-induced changes are likely to contribute to the intestinal dysfunction. Overall, identification of relevant signaling pathways yielded new insights into the molecular mechanisms underlying DON-induced intestinal toxicity, and might help in the development of improved mechanism-based risk assessments in animals and humans. PMID:27669298

  14. Phosphoproteome Analysis Reveals the Molecular Mechanisms Underlying Deoxynivalenol-Induced Intestinal Toxicity in IPEC-J2 Cells

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    Zhi-Qi Zhang

    2016-09-01

    Full Text Available Deoxynivalenol (DON is a widespread trichothecene mycotoxin that commonly contaminates cereal crops and has various toxic effects in animals and humans. DON primarily targets the gastrointestinal tract, the first barrier against ingested food contaminants. In this study, an isobaric tag for relative and absolute quantitation (iTRAQ-based phosphoproteomic approach was employed to elucidate the molecular mechanisms underlying DON-mediated intestinal toxicity in porcine epithelial cells (IPEC-J2 exposed to 20 μM DON for 60 min. There were 4153 unique phosphopeptides, representing 389 phosphorylation sites, detected in 1821 phosphoproteins. We found that 289 phosphopeptides corresponding to 255 phosphoproteins were differentially phosphorylated in response to DON. Comprehensive Gene Ontology (GO analysis combined with Kyoto Encyclopedia of Genes and Genomes (KEGG pathway enrichment revealed that, in addition to previously well-characterized mitogen-activated protein kinase (MAPK signaling, DON exposure altered phosphatidylinositol 3-kinase/Akt (PI3K/Akt and Janus kinase/signal transducer, and activator of transcription (JAK/STAT pathways. These pathways are involved in a wide range of biological processes, including apoptosis, the intestinal barrier, intestinal inflammation, and the intestinal absorption of glucose. DON-induced changes are likely to contribute to the intestinal dysfunction. Overall, identification of relevant signaling pathways yielded new insights into the molecular mechanisms underlying DON-induced intestinal toxicity, and might help in the development of improved mechanism-based risk assessments in animals and humans.

  15. In vitro approaches to evaluate toxicity induced by organotin compounds tributyltin (TBT), dibutyltin (DBT), and monobutyltin (MBT) in neuroblastoma cells.

    Science.gov (United States)

    Ferreira, Martiña; Blanco, Lucía; Garrido, Alejandro; Vieites, Juan M; Cabado, Ana G

    2013-05-01

    The toxic effects of the organotin compounds (OTCs) monobutyltin (MBT), dibutyltin (DBT), and tributyltin (TBT) were evaluated in vitro in a neuroblastoma human cell line. Mechanisms of cell death, apoptosis versus necrosis, were studied by using several markers: inhibition of cell viability and proliferation, F-actin, and mitochondrial membrane potential changes as well as reactive oxygen species (ROS) production and DNA fragmentation. The most toxic effects were detected with DBT and TBT even at very low concentrations (0.1-1 μM). In contrast, MBT induced lighter cytotoxic changes at the higher doses tested. None of the studied compounds stimulated propidium iodide uptake, although the most toxic chemical, TBT, caused lactate dehydrogenase release at the higher concentrations tested. These findings suggest that in neuroblastoma, OTC-induced cytotoxicity involves different pathways depending on the compound, concentration, and incubation time. A screening method for DBT and TBT quantification based on cell viability loss was developed, allowing a fast detection alternative to complex methodology.

  16. Effect of Apitherapy Formulations against Carbon Tetrachloride-Induced Toxicity in Wistar Rats after Three Weeks of Treatment

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    Calin Vasile Andritoiu

    2014-08-01

    Full Text Available The human body is exposed nowadays to increasing attacks by toxic compounds in polluted air, industrially processed foods, alcohol and drug consumption that increase liver toxicity, leading to more and more severe cases of hepatic disorders. The present paper aims to evaluate the influence of the apitherapy diet in Wistar rats with carbon tetrachloride-induced hepatotoxicity, by analyzing the biochemical determinations (enzymatic, lipid and protein profiles, coagulation parameters, minerals, blood count parameters, bilirubin levels and histopathological changes at the level of liver, spleen and pancreas. The experiment was carried out on six groups of male Wistar rats. Hepatic lesions were induced by intraperitoneal injection of carbon tetrachloride (dissolved in paraffin oil, 10% solution. Two mL per 100 g were administered, every 2 days, for 2 weeks. Hepatoprotection was achieved with two apitherapy diet formulations containing honey, pollen, propolis, Apilarnil, with/without royal jelly. Biochemical results reveal that the two apitherapy diet formulations have a positive effect on improving the enzymatic, lipid, and protein profiles, coagulation, mineral and blood count parameters and bilirubin levels. The histopathological results demonstrate the benefits of the two apitherapy diet formulations on reducing toxicity at the level of liver, spleen and pancreas in laboratory animals.

  17. Protective Effect of Virgin Olive Oil (Olea europea L. Against Oxidative Damage Induced by Mercuric Chloride in Rat Albinos Wistar

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    Youcef Necib

    2014-03-01

    Full Text Available Olive oil is beneficial effects are not only related to its high content of oleic acid, but also to the antioxidant potential of its polyphenols. In this study, we assess the effects of virgin olive oil on mercuric chloride induced oxidative damage in the liver of rats. Adult male Albinos Wistar rats randomly divided into four groups, were the first was served as a control, whereas the remaining groups respectively treated with: virgin olive oil (2ml/ kg b.w; by gavage, mercuric chloride (0.5 mg/kg body weight i.p and combination of virgin olive oil and HgCl2. Change in liver enzyme activities, thiobarbituric acid reactive substances (TBARS level, antioxidants and reduced glutathione (GSH contents were determined after 2 weeks of experimental period. Exposure of rats to mercuric chloride caused a significant increase the lipid peroxidation level along with corresponding decrease in the reduced glutathione and various antioxidant enzymes in liver. And increase in serum: glucose level, APL and transaminases activities and decreased in total protein and albumin levels. Furthermore, treatment with mercuric chloride caused a marked elevation of liver weight and decreased body weight. Supplementation of virgin olive oil resulted in decreased of lipid peroxidation level and in the serum: AST, ALT and APL activities were decreased along with increase in total protein, albumin and liver GSH levels. The activities of antioxidants enzymes: glutathione peroxidase (GSH-Px and glutathione –S-transferase (GST were also concomitantly restored to near normal level by virgin olive oil supplementation to mercuric chloride intoxicated rats. Liver histological studies have confirmed the changes observed in biochemical parameters and proved the beneficial role of virgin olive oil. The results clearly demonstrate that virgin olive oil treatment augments the antioxidants defense mechanism in mercuric chloride induced toxicity and provides evidence that it may have a

  18. Therapeutic effect of ozone and rutin on adriamycin-induced testicular toxicity in an experimental rat model.

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    Salem, E A; Salem, N A; Hellstrom, W J

    2017-02-01

    To evaluate the cytoprotective effects of rutin, ozone and their combination on adriamycin (ADR)-induced testicular toxicity, 50 male albino rats were classified into five groups of ten animals each as follows: placebo group; ADR group; ADR + rutin group; ADR + ozone group and ADR + rutin + ozone group. Sperm functions, testosterone (T), luteinising hormone (LH), follicle stimulating hormone (FSH), testicular enzymes, oxidant/antioxidant status, C-reactive protein, monocyte chemoattractant proteins-1 and leukotriene B4 were determined. After ADR injection, a decline in sperm functions was observed. FSH and LH levels were increased, T level and testicular enzymes were decreased, significant enhancement in oxidative stress with subsequent depletion in antioxidants was detected and inflammatory markers were significantly elevated. Treatment with rutin and/or ozone, however, improved the aforementioned parameters. Ozone therapy alone almost completely reversed the toxic effects of ADR and restored all parameters to normal levels.

  19. Zinc reduces copper toxicity induced oxidative stress by promoting antioxidant defense in freshly grown aquatic duckweed Spirodela polyrhiza L.

    Science.gov (United States)

    Upadhyay, RishiKesh; Panda, Sanjib Kumar

    2010-03-15

    The mechanism by which Zn promotes Cu toxicity in duckweed Spirodela polyrhiza L. was investigated in order to understand the possible interaction between these two metals. Cu uptake was gradually declined by Zn. The induction of oxidative stress is shown by increased levels of lipid peroxidation, total peroxide, superoxide anion and lipoxygenase activity. Zn interaction reduced the oxidative damage. However, only Zn-treated plants did not show alteration in the above observed parameters. The activities of antioxidant enzymes catalase, ascorbate peroxidase and peroxidase showed a very high increase in activity in Cu+Zn treatment as compared to Cu or Zn alone-treated plants. Thus, this study demonstrates that zinc reversed the effect of copper, combating against Cu induced oxidative damage and improvement of duckweed's growth and toxicity under natural condition.

  20. Problems associated with glucose toxicity: Role of hyperglycemia-induced oxidative stress

    Institute of Scientific and Technical Information of China (English)

    Shinji Kawahito; Hiroshi Kitahata; Shuzo Oshita

    2009-01-01

    Glucose homeostasis deficiency leads to a chronic increase in blood glucose concentration. In contrast to physiological glucose concentration, chronic superphysiological glucose concentration negatively affects a large number of organs and tissues. Glucose toxicity means a decrease in insulin secretion and an increase in insulin resistance due to chronic hyperglycemia. It is now generally accepted that glucose toxicity is involved in the worsening of diabetes by affecting the secretion of β-cells. Several mechanisms have been proposed to explain the adverse effects of hyperglycemia.It was found that persistent hyperglycemia caused the functional decline of neutrophils. Infection is thus the main problem resulting from glucose toxicity in the acute phase. In other words, continued hyperglycemia is a life-threatening risk factor, not only in the chronic but also the acute phase, and it becomes a risk factor for infection, particularly in the perioperative period.

  1. Problems associated with glucose toxicity: Role of hyperglycemia-induced oxidative stress

    Science.gov (United States)

    Kawahito, Shinji; Kitahata, Hiroshi; Oshita, Shuzo

    2009-01-01

    Glucose homeostasis deficiency leads to a chronic increase in blood glucose concentration. In contrast to physiological glucose concentration, chronic superphysiological glucose concentration negatively affects a large number of organs and tissues. Glucose toxicity means a decrease in insulin secretion and an increase in insulin resistance due to chronic hyperglycemia. It is now generally accepted that glucose toxicity is involved in the worsening of diabetes by affecting the secretion of β-cells. Several mechanisms have been proposed to explain the adverse effects of hyperglycemia. It was found that persistent hyperglycemia caused the functional decline of neutrophils. Infection is thus the main problem resulting from glucose toxicity in the acute phase. In other words, continued hyperglycemia is a life-threatening risk factor, not only in the chronic but also the acute phase, and it becomes a risk factor for infection, particularly in the perioperative period. PMID:19725147

  2. N-acetyl cysteine mitigates the acute effects of cocaine-induced toxicity in astroglia-like cells.

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    Ramesh B Badisa

    Full Text Available Cocaine has a short half-life of only about an hour but its effects, predominantly on the central nervous system (CNS, are fairly long-lasting. Of all cells within the CNS, astrocytes may be the first to display cocaine toxicity owing to their relative abundance in the brain. Cocaine entry could trigger several early response changes that adversely affect their survival, and inhibiting these changes could conversely increase their rate of survival. In order to identify these changes and the minimal concentrations of cocaine that can elicit them in vitro, rat C6 astroglia-like cells were treated with cocaine (2-4 mM for 1h and assayed for alterations in gross cell morphology, cytoplasmic vacuolation, viability, reactive oxygen species (ROS generation, glutathione (GSH levels, cell membrane integrity, F-actin cytoskeleton, and histone methylation. We report here that all of the above identified features are significantly altered by cocaine, and may collectively represent the key pathology underlying acute toxicity-mediated death of astroglia-like cells. Pretreatment of the cells with the clinically available antioxidant N-acetyl cysteine (NAC, 5 mM for 30 min inhibited these changes during subsequent application of cocaine and mitigated cocaine-induced toxicity. Despite repeated cocaine exposure, NAC pretreated cells remained highly viable and post NAC treatment also increased viability of cocaine treated cells to a smaller yet significant level. We show further that this alleviation by NAC is mediated through an increase in GSH levels in the cells. These findings, coupled with the fact that astrocytes maintain neuronal integrity, suggest that compounds which target and mitigate these early toxic changes in astrocytes could have a potentially broad therapeutic role in cocaine-induced CNS damage.

  3. Decorporation and therapeutic efficacy of liposomal-DTPA against thorium-induced toxicity in the Wistar rat.

    Science.gov (United States)

    Kumar, Amit; Sharma, Pragya; Ali, Manjoor; Pandey, Badri Narain; Mishra, Kaushala Prasad

    2012-03-01

    This study examined the effect of liposomal encapsulation of (99m)Tc-labeled diethylenetriaminepentaacetic acid (metastable technetium labeled DTPA) on its organ distribution and therapeutic effect of optimized neutral liposomal-DTPA against thorium ((232)Th)-induced liver toxicity and its accumulation in rat animal model. (99m)Tc-DTPA was encapsulated in neutral (dipalmitoylphosphatidylcholine:cholesterol) and positively (dipalmitoylphosphatidylcholine:cholesterol:stearylamine) charged liposomes using thin film hydration method. Comparative efficacy of liposomal and free DTPA (11.2 mg/kg) was examined in terms of its effect on (232)Th accumulation and subsequent toxicity in the liver and blood of rat administered with (232)Th-nitrate (600 μg/kg). Organ distribution of free or liposomal (99m)Tc-DTPA was determined by solid scintillation counting and (232)Th accumulation by Inductively Coupled Plasma-Atomic Emission Spectroscopy. Neutral liposomes encapsulated with (99m)Tc-DTPA showed more uptake in liver, spleen and blood than with positively charged liposomal- and free- (99m)Tc-DTPA. Administration of (232)Th-nitrate to rat significantly increased the levels of liver toxicity markers and of oxidative injury, which were found to be restored more significantly by neutral liposomal-DTPA than free-DTPA. The accumulation of (232)Th in liver and blood of contaminated mice was found to be decreased more significantly by neutral liposomal-DTPA than by free-DTPA. Decorporation and consequent mitigation of (232)Th induced toxicity may be significantly improved by liposomal encapsulation of DTPA, a chelating agent.

  4. Protective activity of andrographolide and arabinogalactan proteins from Andrographis paniculata Nees. against ethanol-induced toxicity in mice.

    Science.gov (United States)

    Singha, Prajjal K; Roy, Somenath; Dey, Satyahari

    2007-04-20

    To find out the active principles against ethanol-induced toxicity in mice, Andrographis paniculata Nees. (Ap) was chosen and isolated andrographolide (ANDRO) and arabinogalactan proteins (AGPs). ANDRO was detected by HPTLC, FTIR and quantified by HPLC (10mg/g of Ap powder). AGPs was detected by beta-glucosyl Yariv staining of SDS-PAGE gel, FTIR and quantified by single radial gel diffusion assay with beta-glucosyl Yariv reagent (0.5mg/g Ap powder). The mice are pretreated intra-peritoneally (i.p.) with different doses (62.5, 125, 250, and 500mg/kg) of body weight of mice] of ANDRO and AGPs for 7 days and then ethanol (7.5g/kg of body weight) was injected, i.p. Besides, silymarin was used as standard hepatoprotective agent for comparative study with ANDRO and AGPs. The ameliorative activity of ANDRO and AGP against hepatic renal alcohol toxicity was measured by assessing GOT, GPT, ACP, ALP and LP levels in liver and kidney. It has been observed that pretreatment of mice with ANDRO and AGPs at 500mg/kg of body weight and 125mg/kg of body weight respectively could able to minimize the toxicity in compare to ethanol treated group as revealed by the different enzymatic assay in liver and kidney tissues and the results were comparable with silymarin. Hence, out of several ill-defined compounds present in Ap, ANDRO and AGPs are the potential bioactive compounds responsible for protection against ethanol-induced toxicity.

  5. Racial variations in radiation-induced skin toxicity severity: data from a prospective cohort receiving postmastectomy radiation.

    Science.gov (United States)

    Wright, Jean L; Takita, Cristiane; Reis, Isildinha M; Zhao, Wei; Lee, Eunkyung; Hu, Jennifer J

    2014-10-01

    Radiation-induced skin toxicity is one of the most symptomatic side effects of postmastectomy radiation therapy (PMRT). We sought to determine whether the severity of acute skin toxicity was greater in black patients in a prospective cohort receiving PMRT and to identify other predictors of more severe skin toxicity. We evaluated the first 110 patients in an ongoing prospective study assessing radiation-induced skin toxicity in patients receiving PMRT. We recorded patient demographics, body mass index (BMI), and disease and treatment characteristics. Logistic regression analyses were conducted to evaluate the effect of potential predictors on the risk of skin toxicity. A total of 23.6% respondents self-identified as black, 5.5% as non-Hispanic white, 69.1% as Hispanic white, and 1.8% as other; 57% were postmenopausal, and 70.9% had BMI of >25. Median chest wall dose was 50 Gy, and mastectomy scar dose was 60 Gy. Most patients, 95.5%, were treated with a 0.5-cm bolus throughout treatment. There were no significant differences in patient characteristics in black versus non-black patients. At RT completion, moist desquamation was more common in black patients (73.1% vs 47.6%, respectively, P=.023), in postmenopausal patients (63.5% vs 40.4%, respectively, P=.016), and in those with BMI of ≥25 (60.3% vs 37.5%, respectively, P=.030). On multivariate analysis, the effects of black race (odds ratio [OR] = 7.46, P=.031), BMI ≥25 (OR = 2.95, P=.043) and postmenopausal status (OR = 8.26, P=.004) remained significant risk factors for moist desquamation. In this prospectively followed, racially diverse cohort of breast cancer patients receiving PMRT delivered in a uniform fashion, including the routine use of chest wall boost and bolus, black race, higher BMI, and postmenopausal status emerged as significant predictors of moist desquamation. There was a high frequency of moist desquamation, particularly in those patients with elevated risk. Continued study of patient

  6. Racial Variations in Radiation-Induced Skin Toxicity Severity: Data From a Prospective Cohort Receiving Postmastectomy Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Wright, Jean L., E-mail: jwrigh71@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, Maryland (United States); Takita, Cristiane [Department of Radiation Oncology, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida (United States); Reis, Isildinha M. [Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (United States); Department of Public Health Sciences, University of Miami, Miami, Florida (United States); Zhao, Wei; Lee, Eunkyung [Department of Public Health Sciences, University of Miami, Miami, Florida (United States); Hu, Jennifer J. [Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (United States); Department of Public Health Sciences, University of Miami, Miami, Florida (United States)

    2014-10-01

    Purpose: Radiation-induced skin toxicity is one of the most symptomatic side effects of postmastectomy radiation therapy (PMRT). We sought to determine whether the severity of acute skin toxicity was greater in black patients in a prospective cohort receiving PMRT and to identify other predictors of more severe skin toxicity. Methods and Materials: We evaluated the first 110 patients in an ongoing prospective study assessing radiation-induced skin toxicity in patients receiving PMRT. We recorded patient demographics, body mass index (BMI), and disease and treatment characteristics. Logistic regression analyses were conducted to evaluate the effect of potential predictors on the risk of skin toxicity. Results: A total of 23.6% respondents self-identified as black, 5.5% as non-Hispanic white, 69.1% as Hispanic white, and 1.8% as other; 57% were postmenopausal, and 70.9% had BMI of >25. Median chest wall dose was 50 Gy, and mastectomy scar dose was 60 Gy. Most patients, 95.5%, were treated with a 0.5-cm bolus throughout treatment. There were no significant differences in patient characteristics in black versus non-black patients. At RT completion, moist desquamation was more common in black patients (73.1% vs 47.6%, respectively, P=.023), in postmenopausal patients (63.5% vs 40.4%, respectively, P=.016), and in those with BMI of ≥25 (60.3% vs 37.5%, respectively, P=.030). On multivariate analysis, the effects of black race (odds ratio [OR] = 7.46, P=.031), BMI ≥25 (OR = 2.95, P=.043) and postmenopausal status (OR = 8.26, P=.004) remained significant risk factors for moist desquamation. Conclusions: In this prospectively followed, racially diverse cohort of breast cancer patients receiving PMRT delivered in a uniform fashion, including the routine use of chest wall boost and bolus, black race, higher BMI, and postmenopausal status emerged as significant predictors of moist desquamation. There was a high frequency of moist desquamation, particularly in those

  7. Chemoprotective role of quercetin in manganese-induced toxicity along the brain-pituitary-testicular axis in rats.

    Science.gov (United States)

    Adedara, Isaac A; Subair, Temitayo I; Ego, Valerie C; Oyediran, Oluwasetemi; Farombi, Ebenezer O

    2017-02-01

    Reproductive dysfunction in response to manganese exposure has been reported in humans and animals. Quercetin, a bioflavonoid widely distributed in fruits, vegetables and beverages has been shown to possess antioxidant, anti-inflammatory and anti-apoptotic activities in different experimental model systems. However, there is dearth of scientific information on the influence of quercetin on manganese-induced reproductive toxicity. This study was designed to evaluate the influence of quercetin on manganese-induced functional alterations along the brain-pituitary- testicular axis in rats. Manganese was administered alone at 15 mg/kg body weight or orally co-treated with quercetin at 10 and 20 mg/kg body weight for 45 consecutive days. Results indicated that quercetin co-treatment significantly (p manganese-induced elevation in biomarkers of oxidative stress whereas it increased antioxidant enzymes activities and glutathione level in the brain, testes and epididymis of the treated rats. Furthermore, quercetin mediated suppression of inflammatory indices and caspase-3 activity was accompanied by preservation of histo-architectures of the brain, testes and epididymis in manganese-treated rats. The significant reversal of manganese-induced decreases in reproductive hormones (i.e. luteinizing hormone, follicle-stimulating hormone and testosterone) and testicular activities of acid phosphatase, alkaline phosphatase and lactate dehydrogenase by quercetin was complemented by an increase in sperm quality and quantity in the treated rats. Collectively, quercetin modulated manganese-induced toxicity along the brain-pituitary-testicular axis in rats via its intrinsic antioxidant, anti-inflammatory and anti-apoptotic activities, and may thus represent a potential pharmacological agent against manganese-induced male reproductive deficits in humans.

  8. Photo-induced toxicity and oxidative stress responses in Tigriopus japonicus exposed to nitro-polycyclic aromatic hydrocarbons and artificial light.

    Science.gov (United States)

    Onduka, Toshimitsu; Ojima, Daisuke; Ito, Katsutoshi; Mochida, Kazuhiko; Ito, Mana; Koyama, Jiro; Fujii, Kazunori

    2017-02-01

    Photo-induced toxicity is an important phenomenon in ecotoxicology because sunlight reaches many organisms in their natural habitats. To elucidate whether sunlight enhances the toxicity of nitro-polycyclic aromatic hydrocarbons (nitro-PAHs), the acute toxicities of 10 nitro-PAHs and the related compound 1-nitropyrene (1-NP) to Tigriopus japonicus were assessed in darkness or under light conditions. In addition, the relationships among the toxicity of 1-NP to T. japonicus, lighting condition, and the concentration of reactive oxygen species (ROS) formed were investigated in the presence or absence of the ROS scavenger ascorbic acid in the test solutions. Light irradiation increased the toxicity of all tested nitro-PAHs except 1,5-dinitronaphthalene. Among the compounds tested, 1-NP was the most phototoxic: it was more than 1000 times more toxic under the light conditions than in darkness. In contrast, at the same light levels, pyrene was not phototoxic. Light irradiation induced the generation of ROS in the 1-NP exposure groups, and the immobilization rate of T. japonicus increased with the amount of ROS produced. The addition of ascorbic acid to the test solutions suppressed both the generation of ROS and the light-induced immobilization of T. japonicus. To accurately assess the ecotoxicologic risk of nitro-PAHs, their overall photo-induced toxicity must be considered.

  9. Protective effect of cysteine and vitamin E, Crocus sativus and Nigella sativa extracts on cisplatin-induced toxicity in rats.

    Science.gov (United States)

    el Daly, E S

    1998-01-01

    Cisplatin [cis-dichlorodiammineplatinum (II)] is a widely used chemotherapeutic drug that is toxic to the kidney. Concurrent administration of cysteine together with vitamin E, Crocus sativus and Nigella sativa reduced the toxicity of cisplatin in rats. When administered i.p. for 5 alternate days with 3 mg/kg cisplatin, cysteine (20 mg/kg) together with vitamin E (2 mg/rat) an extract of Crocus sativus stigmas (50 mg/kg) and Nigella sativa seed (50 mg/kg) significantly reduced blood urea nitrogen (BUN) and serum creatinine levels as well as cisplatin-induced serum total lipids increases. In contrast, the protective agents given together with cisplatin led to an even greater decrease in blood glucose than that seen with cisplatin alone. The serum activities of alkaline phosphatase, lactate dehydrogenase, malate dehydrogenase, aspartate aminotransferase and alanine aminotransferase of cisplatin-treated rats were significantly decreased, whereas the activities of glutathione reductase and isocitrate dehydrogenase were significantly increased. Addition of cysteine and vitamin E, Crocus sativus and Nigella sativa in combination with cisplatin partially prevented many changes in the activities of serum enzymes. In cisplatin-treated rats, the liver activities of isocitrate dehydrogenase and aspartate aminotransferase were significantly increased, whereas much greater changes were found in the kidneys, with increased activity of glucose-6-phosphate dehydrogenase and decreased activities of alkaline phosphatase, isocitrate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase and gamma-glutamyl transferase, as well as a decreased phosphorylation to oxidation ratio in the mitochondria, indicating reduced adenosine triphosphate production. Also, administration of cysteine and vitamin E, Crocus sativus and Nigella sativa together with cisplatin partially reversed many of the kidney enzymes changes induced by cisplatin

  10. Achillea millefolium inflorescence aqueous extract ameliorates cyclophosphamide-induced toxicity in rat testis: stereological evidences%Achillea millefolium inflorescence aqueous extract ameliorates cyclophosphamide-induced toxicity in rat testis:stereological evidences

    Institute of Scientific and Technical Information of China (English)

    Ali Shalizar Jalali; Shapour Hasanzadeh; Hassan Malekinejad

    2012-01-01

    Cyclophosphamide (CP) is extensively used for the treatment of various cancers,as well as an immunosuppressive agent.However,CP is known to cause several adverse effects including reproductive toxicity.Achillea millefolium,a widely distributed medicinal plant,is highly regarded for its medicinal activities,including antioxidant and anti-inflammatory properties.The present study was conducted to assess whether Achillea millefolium inflorescences aqueous extract with antioxidant and anti-inflammatory activities could serve as a protective agent against reproductive toxicity during CP treatment.Male Wistar rats were categorized into four groups.Two groups of rats were administered CP at a dose of 5mg·kg-1·d-1 for 28 d by oral gavages.One of these groups received Achillea aqueous extract at a dose of 1.2 g·kg-1·d-1 orally 4 h after cyclophosphamide administration.A vehicle treated control group and an Achillea control group were also included.Thc CP-trcatcd group showed significant decreases in the body,testes and epididymides weights as well as many histological alterations.Stereological parameters,spermatogenic activities and testicular antioxidant capacity along with epididymal sperm count and serum testosterone concentration were also significantly decreased by CP treatment.Notably,Achillea co-administration caused a partial recovery in above-mentioned parameters.These findings indicate that Achillea millefolium inflorescence aqueous extract may be partially protective against CP-induced testicular toxicity.

  11. Differential effects of grape juice on gastric emptying and renal function from cisplatin-induced acute adverse toxicity.

    Science.gov (United States)

    Ko, J-L; Tsai, C-H; Liu, T-C; Lin, M-Y; Lin, H-L; Ou, C-C

    2016-08-01

    Grape skin and seeds contain large amounts of phytochemicals such as polyphenols, resveratrol, and proanthocyanidins, which possess antioxidant activities. Cisplatin is widely used in the treatment of cancer. High doses of cisplatin have also been known to produce acute adverse effects. The aim of this study was to investigate the protective effects of antioxidant properties of whole grape juice (with skin and seeds) on cisplatin-induced acute gastrointestinal tract disorders and nephrotoxicity in Wistar rats. Gastric emptying is significantly increased in whole grape juice-pretreated rats when compared to cisplatin treatment alone. The expression of ghrelin mRNA of stomach is increased in rats with whole grape juice. However, pretreatment with whole grape juice did not reduce renal function markers in acute renal toxicity. No significant changes were recorded in the oxidative stress/antioxidant status parameters of any study group. In contrast, pretreatment with whole grape juice slightly improved tubular cell vacuolization, tubular dilatation, and cast formation in renal tubules. These results show that consumption of whole grape juice induces somewhat beneficial effects in preventing cisplatin-mediated dyspepsia but does not offer protection against cisplatin-induced acute renal toxicity. © The Author(s) 2015.

  12. Fluorometric assessment of acetaminophen-induced toxicity in rat hepatocyte spheroids seeded on micro-space cell culture plates.

    Science.gov (United States)

    Sanoh, Seigo; Santoh, Masataka; Takagi, Masashi; Kanayama, Tatsuya; Sugihara, Kazumi; Kotake, Yaichiro; Ejiri, Yoko; Horie, Toru; Kitamura, Shigeyuki; Ohta, Shigeru

    2014-09-01

    Hepatotoxicity induced by the metabolic activation of drugs is a major concern in drug discovery and development. Three-dimensional (3-D) cultures of hepatocyte spheroids may be superior to monolayer cultures for evaluating drug metabolism and toxicity because hepatocytes in spheroids maintain the expression of various metabolizing enzymes and transporters, such as cytochrome P450 (CYP). In this study, we examined the hepatotoxicity due to metabolic activation of acetaminophen (APAP) using fluorescent indicators of cell viability and intracellular levels of glutathione (GSH) in rat hepatocyte spheroids grown on micro-space cell culture plates. The mRNA expression levels of some drug-metabolizing enzymes were maintained during culture. Additionally, this culture system was compatible with microfluorometric imaging under confocal laser scanning microscopy. APAP induced a decrease in intracellular ATP at 10mM, which was blocked by the CYP inhibitor 1-aminobenzotriazole (ABT). APAP (10mM, 24h) decreased the levels of both intracellular ATP and GSH, and GSH-conjugated APAP (APAP-GSH) were formed. All three effects were blocked by ABT, confirming a contribution of APAP metabolic activation by CYP to spheroid toxicity. Fluorometric imaging of hepatocyte spheroids on micro-space cell culture plates may allow the screening of drug-induced hepatotoxicity during pharmaceutical development.

  13. An overview of data mining algorithms in drug induced toxicity prediction.

    Science.gov (United States)

    Omer, Ankur; Singh, Poonam; Yadav, N K; Singh, R K

    2014-04-01

    The growth in chemical diversity has increased the need to adjudicate the toxicity of different chemical compounds raising the burden on the demand of animal testing. The toxicity evaluation requires time consuming and expensive undertaking, leading to the deprivation of the methods employed for screening chemicals pointing towards the need to develop more efficient toxicity assessment systems. Computational approaches have reduced the time as well as the cost for evaluating the toxicity and kinetic behavior of any chemical. The accessibility of a large amount of data and the intense need of turning this data into useful information have attracted the attention towards data mining. Machine Learning, one of the powerful data mining techniques has evolved as the most effective and potent tool for exploring new insights on combinatorial relationships among various experimental data generated. The article accounts on some sophisticated machine learning algorithms like Artificial Neural Networks (ANN), Support Vector Machine (SVM), k-mean clustering and Self Organizing Maps (SOM) with some of the available tools used for classification, sorting and toxicological evaluation of data, clarifying, how data mining and machine learning interact cooperatively to facilitate knowledge discovery. Addressing the association of some commonly used expert systems, we briefly outline some real world applications to consider the crucial role of data set partitioning.

  14. Toxicogenomic assessment of 6-OH-BDE47 induced developmental toxicity in chicken embryo

    Science.gov (United States)

    Hydroxylated and methoxylated polybrominated diphenyl ethers (OH-/MeO-PBDEs) are analogs of PBDEs with hundreds of possible structures and many of them can activate aryl hydrocarbon receptor (AhR), however, the in vivo evidence on the toxicity of OH-/MeO-PBDEs are still very limi...

  15. [Protective effect of diclofenac towards the oxidative stress induced by paracetamol toxicity in rats].

    Science.gov (United States)

    Aouacheri, W; Saka, S; Djafer, R; Lefranc, G

    2009-01-01

    Association of paracetamol (PARA) and diclofenac (DiCF) is the aim of our study. 60 male rats "Albinos wistar" were treated by oral gavage (per os) during seven days. A control group was treated by mineral water (0+0) mg/kg and a second group was treated with only a toxic dose of 100 mg/kg of PARA (100+0). Remaining lots were treated with a combination of different toxic doses of PARA and a therapeutic dose of DiCF (15+3, 100+3, 200+3 and 400+3) mg/kg. Plasma concentration of amiotransferases (ASAT, ALAT), alkalines phosphatase (ALP), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione (GSH), glucose, cholesterol, creatinin, direct and total bilirubin, significantly varied in the treated rats regarding to the witness's rats. The toxicity of PARA revealed by a dose dependant blood increases of ASAT, ALAT, ALP, GPx, GR, glucose, creatinin, bilirubin, and by decreases of cholesterol concentration and tissue GSH in comparisons to controls. The depletion of GSH and the increase of the oxidative stress enzymes (GPx and GR) suggest a detoxification function of the glutathione system. The association (PARA + DiCF) revealed a protective effect, resulting in the increase of the concentrations of ASAT, ALAT, ALP, GPx, GR, bilirubin and the increase of GSH. Regarding to all these results, it has been suggested that DiCF has a protective action towards the toxic effects of PARA.

  16. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

    Science.gov (United States)

    Funk, Juergen; Robbins, Justin B.; Crogan-Grundy, Candace; Presnell, Sharon C.; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level. PMID:27387377

  17. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

    Directory of Open Access Journals (Sweden)

    Deborah G Nguyen

    Full Text Available Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI. This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM. Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

  18. The Relationship between Common Genetic Markers of Breast Cancer Risk and Chemotherapy-Induced Toxicity: A Case-Control Study

    Science.gov (United States)

    Kar, Siddhartha; Michailidou, Kyriaki; Hiller, Louise; Vallier, Anne-Laure; Ingle, Susan; Hardy, Richard; Bowden, Sarah J.; Dunn, Janet A.; Twelves, Chris; Poole, Christopher J.; Caldas, Carlos; Earl, Helena M.; Pharoah, Paul D. P.; Abraham, Jean E.

    2016-01-01

    Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment. PMID:27392074

  19. System-based identification of toxicity pathways associated with multi-walled carbon nanotube-induced pathological responses

    Energy Technology Data Exchange (ETDEWEB)

    Snyder-Talkington, Brandi N. [Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Dymacek, Julian [Lane Department of Computer Science and Electrical Engineering, West Virginia University, Morgantown, WV 26506-6070 (United States); Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300 (United States); Porter, Dale W.; Wolfarth, Michael G.; Mercer, Robert R. [Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Pacurari, Maricica [Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300 (United States); Denvir, James [Department of Biochemistry and Microbiology, Marshall University, Huntington, WV 25755 (United States); Castranova, Vincent [Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Qian, Yong, E-mail: yaq2@cdc.gov [Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26505 (United States); Guo, Nancy L., E-mail: lguo@hsc.wvu.edu [Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300 (United States)

    2013-10-15

    The fibrous shape and biopersistence of multi-walled carbon nanotubes (MWCNT) have raised concern over their potential toxicity after pulmonary exposure. As in vivo exposure to MWCNT produced a transient inflammatory and progressive fibrotic response, this study sought to identify significant biological processes associated with lung inflammation and fibrosis pathology data, based upon whole genome mRNA expression, bronchoaveolar lavage scores, and morphometric analysis from C57BL/6J mice exposed by pharyngeal aspiration to 0, 10, 20, 40, or 80 μg MWCNT at 1, 7, 28, or 56 days post-exposure. Using a novel computational model employing non-negative matrix factorization and Monte Carlo Markov Chain simulation, significant biological processes with expression similar to MWCNT-induced lung inflammation and fibrosis pathology data in mice were identified. A subset of genes in these processes was determined to be functionally related to either fibrosis or inflammation by Ingenuity Pathway Analysis and was used to determine potential significant signaling cascades. Two genes determined to be functionally related to inflammation and fibrosis, vascular endothelial growth factor A (vegfa) and C-C motif chemokine 2 (ccl2), were confirmed by in vitro studies of mRNA and protein expression in small airway epithelial cells exposed to MWCNT as concordant with in vivo expression. This study identified that the novel computational model was sufficient to determine biological processes strongly associated with the pathology of lung inflammation and fibrosis and could identify potential toxicity signaling pathways and mechanisms of MWCNT exposure which could be used for future animal studies to support human risk assessment and intervention efforts. - Highlights: • A novel computational model identified toxicity pathways matching in vivo pathology. • Systematic identification of MWCNT-induced biological processes in mouse lungs • MWCNT-induced functional networks of lung

  20. The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.

    KAUST Repository

    Zheng, Ming

    2015-02-03

    We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.ABCB5 alleles alter susceptibility to