Abstract: The aim of this study was to investigate the protective action of licorice in diabetic nephropathy in male rats. Diabetes was induced in male Wistar rats by using streptozotocin (60 mg/kg body weight). Daily oral ingestion (1 g/kg body weight) of licorice extract for 60 days after the onset of diabetes reversed the adverse effect of diabetes on rats. Licorice extract alleviated blood glucose levels, restored renal function, and attenuated body-weight loss. In addition, licorice extract modulated the adverse effect of diabetes on renal malondialdehyde, glutathione, superoxide dismutase, and catalase activity. Further, licorice extract restored the total antioxidant capacity of diabetic rat kidneys. The biochemical analyses were reinforced by histologic investigations, where focal segmental glomerulosclerosis, tubular damage, and hyperemic kidney were the histologic changes seen in diabetic, but not in treated, rats. In conclusion, the biochemical analysis and the histologic investigations of diabetic rat k...

Abstract: Sulforaphane (SFN) is a naturally occurring isothiocyanate found in cruciferous vegetables, such as broccoli, cabbage, cauliflower, etc. SFN has received a great deal of attention because of its ability to inhibit cell proliferation and induce apoptosis in several tumor cell lines. Previously, we have demonstrated that SFN inhibits the metastasis of B16F-10 melanoma cells in both in vivo and in vitro models. Melanomas are among the aggressive tumor types because of their notorious resistance to treatment and their high tendency to metastasize. In this study, we investigated the influence of SFN on the induction of apoptosis in B16F-10 melanoma cells, which was evidenced by morphological changes such as membrane blebbing, presence of apoptotic bodies, DNA condensation, and also by nuclear DNA fragmentation. SFN-induced apoptosis was associated with the activation of caspases 3 and 9, Bax, and p53 and the downregulation of Bcl-2, caspase-8, Bid, and NF-kB. Caspase-3 is a most likely candidate to mediate SFN-induced apoptosis. In addition to the caspase-dependent pathway, our results also showed the involvement of proinflammatory cytokines, namely tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, IL-12p40, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the nuclear translocation of factors kappa B (NF-κB) p65, NF-κB p50, NF-κB c-Rel, c-FOS, ATF-2, and CREB-1 in SFN-induced apoptosis. These results raise the possibility that SFN may be a promising candidate for molecular-targeting chemotherapy against melanoma.

Abstract: Lipopolysaccharide (LPS) is a glycolipid component of the cell wall of Gram-negative bacteria, which induces a deleterious effect on several organs, including the heart, eventually leading to septic shock and death. Endotoxemia-induced cardiotoxicity is characterized by disturbed intracellular redox balance, excessive reactive oxygen species (ROS) accumulation, inducing DNA, protein, and membrane lipid damage. Resveratrol (trans-3,5,4' trihydroxystilbene; RVT) is a phytoalexin polyphenol that exhibits antioxidant and -inflammatory properties. We investigated the putative effect of a subacute treatment with this natural compound on LPS-induced cardiotoxicity in the rat. We found that resveratrol counteracted LPS-induced lipoperoxidation and decreased superoxide dismutase (SOD) activity, but had no effect on the LPS-induced decrease in catalase (CAT) nor on the increase in peroxidase (POD) activity. Resveratrol also reversed LPS-induced myocardial nitric oxide (NO) elevation. More important, LPS-induced iron depletion from plasma to the myocardial compartment was abolished upon resveratrol treatment. All these data suggest that resveratrol is capable of alleviating LPS-induced cardiotoxicity, and that its mode of action may involve iron-shuttling proteins.

Abstract: Polyethylene glycol 400 (PEG-400) has been used in injections. However, limited data are available concerning the toxicity of a high dose of PEG-400 following intravenous (i.v.) injection. The aim of the present study was to estimate the systemic toxicity and toxicokinetics of a high dose of PEG-400 in dogs following i.v. injection. Twenty-four dogs were divided into four groups: a control group receiving normal saline and three test groups receiving 4.23, 6.34, and 8.45 g/kg of PEG-400, respectively, by i.v. injection once a day for 30 days. The repeated-dose toxicity of PEG-400 was assessed. Toxicokinetic parameters of PEG-400 in dogs were estimated on days 1 and 30. Dry mouth and dry nasal mucus membrane were observed in dogs treated with 6.34 and 8.45 g/kg of PEG-400. Cloudy swelling of kidney cell and increased glomerular volume were observed in dogs treated with 8.45 g/kg of PEG-400 when the animals were sacrificed 24 hours after the last injection. No significant histological changes were found 21 days later. Repeated dosing did not affect the toxicokinetic profile of PEG-400 in dogs. This study has shown that the toxicity of a high dose of PEG-400 following repeated intravenous injections is low, and alterations produced are reversible.

Abstract: In this study, we investigated the effect of vernolide-A on the induction of apoptosis as well as its regulatory effect on the activation of transcription factors in B16F-10 melanoma cells. Treatment of B16F-10 cells with nontoxic concentrations of vernolide-A showed the presence of apoptotic bodies and induced DNA fragmentation in a dose-dependent manner. Cell-cycle analysis and TUNEL assays also confirmed the observation. The proapoptotic genes, p53, Bax, caspase-9, and caspase-3, were upregulated in vernolide-A-treated cells, whereas the antiapoptotic gene, Bcl-2, was downregulated. vernolide-A treatment also showed a downregulation of cyclin D1 expression and upregulated p21 and p27 gene expression in B16F-10 melanoma cells. The study also reveals that vernolide-A treatment could alter the production and expression of proinflammatory cytokines and could inhibit the activation and nuclear translocation of p65, p50, and c-Rel subunits of nuclear factor-κB and other transcription factors, such as c-fos, activated transcription factor-2, and cyclic adenosine monophosphate response-element-binding protein in B16F-10 melanoma cells. These results suggest that vernolide-A induces apoptosis via activation of p53-induced, caspase-3-mediated proapoptotic signaling and suppression of NF-κB-induced, bcl-2-mediated survival signaling.

Abstract: Ebselen is a seleno compound whose antioxidant properties have been attributed to its thiol-peroxidase and thioredoxin-like activity. However, the excessive oxidation of thiols can be potentially toxic. Thus, this work investigated whether lactate dehydrogenase (LDH) can be a possible in vitro target to the toxicity of ebselen, in comparison with diphenyl diselenide [(PhSe)2] and diphenyl ditelluride [(PhTe)2]. Ebselen was the most potent inhibitor of LDH. A maximal inhibitory effect was obtained at 2 μM to LDH purified and at 20 μM to LDH from heart and liver homogenates. Moreover, (PhSe)2, followed by (PhTe)2, also presented a significant inhibitory effect on LDH activity. DL-dithiothreitol (DTT) was able to revert the inhibition of LDH induced by all compounds tested, confirming the involvement of essential thiol groups on LDH inhibition by organochalcogens. In conclusion, our results show that liver and heart LDH may be a possible target for the toxicity of organochalcogens at relative low concentrati...

Abstract: The phototoxicity of ultraviolet A irradiation (UVA) can be enhanced by photosensitizing agents, such as titanium dioxide nanoparticles (100 nm in diameter, "normal-TiO₂"). Nano-TiO₂ treatment in the absence of UVA caused a slight decrease in cell viability, but in the presence of UVA, it caused a significant decrease in cell viability. In the presence of UVA, nano-TiO₂ also significantly increased the percentage of the cell population in the sub-G₁ phase, induced activation of the proapoptotic proteins, caspase-9, caspase-3, and poly(ADP)ribose polymerase, significantly increased the production of reactive oxygen species (ROS), and induced the loss of the mitochondrial membrane potential (MMP), suggesting that UVA and nano-TiO₂ synergistically promoted apoptosis via a mitochondrial pathway. In the presence of UVA, but not in its absence, nano-TiO₂ treatment also caused a significant increase in DNA damage. Normal-TiO₂ used at the same concentrations did not cause DNA damage, induce ROS generation, trigger mitochondrial membrane depolarization, or increase apoptotic cell death, regardless of UVA exposure. Taken together, these results suggest that nano-TiO₂ and UVA synergistically promote rapid ROS generation and MMP collapse, triggering apoptosis. Additionally, they show that small TiO₂ particles are more phototoxic than larger ones.

Abstract: This study was conducted to investigate the prophylactic effects of lycopene (LC) and ellagic acid (EA) on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced testicular and spermatozoal toxicity. These toxicological changes are associated with the oxidative stress and apoptosis in male rats. Forty-eight male rats were allocated to one of six groups of 8 rats each: control, LC, EA, TCDD, TCDD+LC, and TCDD+EA. The control group was treated with 0.5 mL/rat slightly alkaline solution+0.5 mL/rat corn oil every other day. The LC group was treated with 0.5 mL/rat slightly alkaline solution+0.5 mL/rat corn oil containing 10 mg/kg of LC every other day. The EA group received 0.5 mL/rat corn oil+0.5 mL/rat slightly alkaline solution containing 2 mg/kg of EA every other day. The TCDD group received 0.5 mL/rat corn oil containing 100 ng/kg/day of TCDD+0.5 mL/rat slightly alkaline solution. The TCDD+LC group was treated with 0.5 mL/rat TCDD+0.5 mL/rat LC. The TCDD+EA group was treated with 0.5 mL/rat TCDD+0.5 mL/rat E...

Abstract: Adriamycin (ADR) causes morphological and functional alterations in mitochondrial structure in the heart. The study′s aim was to determine whether there is a protective effect of selenium (Se) on ADR-induced cardiac damage. Rats were divided into four groups: The first group was injected saline intraperitoneally (i.p.) for 21 days; the second group received 4 mg/kg i.p. ADR every alternate day for 8 days; the third group received 50 µg/kg i.p. Se for 21 days; and the fourth received the Se (for 21 days) and ADR (for 8 days) coadministration i.p. Left ventricular functions, electrocardiography parameters, and blood pressures were assessed. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) level, and thioredoxin reductase (TrxR) activity were determined. Total antioxidant (TAS) and oxidant status (TOS) in cytosol, mitochondria of myocytes, and plasma were measured. Left ventricular data demonstrated left ventricular systolic pressure (LVSP) decreased, left ventricular developed pressure (...

Abstract: Cyclosporine A (CsA) is a potent immunosuppressive agent used for organ transplantations and various autoimmune disorders. However, hepatotoxicity due to CsA remains one of the major side effects. The use of antioxidants reduces the adverse effects of CsA. The aim of this study was to determine the protective effects of erdosteine on CsA-induced liver injury through tissue oxidant/antioxidant parameters and to evaluate light microscopic alterations in rat-liver tissues. Rats were randomly divided into four experimental groups: The control group received sunflower oil (2 mL/kg/day, per orally; p.o.), while the other groups were treated with CsA (25 mg/kg/day, p.o.) or erdosteine (10 mg/kg/day, p.o.) or CsA+erdosteine, respectively. Serum aspartate aminotransferase and alanine aminotransferase levels, tissue malondialdehyde and nitric oxide levels, and superoxide dismutase, glutathione peroxidase and catalase enzyme activities were measured. Histological examination was performed. CsA caused a significant d...

Abstract: Persistent organic chemicals, such as perfluorooctanoic acid (PFOA), perfluorooctanesulfonate (PFOS), dioxins, and polychlorinated biphenyls, pose investigative challenges because they are found in virtually everyone (there is no unexposed control group). To overcome this problem, outcome data in some studies are sorted by chemical dose level and findings in low-end dose groups are compared to sequential higher dose groups. An example is the C8 Health Project that evaluated serum PFOA/PFOS (C8) and total cholesterol among 46,294 West Virginia residents who lived, worked, or went to school for at least 1 year in a C8 contaminated drinking-water district and were over age 18 in 2005–2006. The risk for high total cholesterol (>240 mg/dL) measured via odds ratios (ORs) in logistic regression models showed sequential OR increases with PFOA quartile, in comparison to the lowest quartile (OR = 1.00), that were each significantly elevated (OR = 1.21, 1.33, and 1.40, respectively), but age, sex, and body mass inde...

Abstract: Maneb (Manganese ethylene-bis-dithiocarbamate) is a widely used fungicide in agriculture. In order to investigate its effect on male reproductive function, rats were intraperitonealy injected with maneb (1 and 4 mg/kg) for 9 or 18 days. After 6 and 14 days of treatment, the animals received human chorionic gonadotropin (hCG) via a jugular catheter and blood samples were collected at several intervals subsequent to the challenge. They were thereafter decapitated after 9 or 18 days, and organs (i.e., liver, seminal vesicles, and kidneys) were weighed. Leydig cells prepared from rats after 18 days of treatment were incubated with or without different stimulators or precursors [hCG, A23187, 25-OH-cholesterol (25-OH-C), or androstenedione] for 1 hour, and the media were analyzed for testosterone or pregnenolone. Liver glutathione and thiobarbituric acid reactive substances (TBARS) as well as serum alanine aminotransferase (ALT) activity were also measured. Further, Leydig cells and testicular interstitial cells (TICs) prepared from normal rats were incubated with maneb (3-100 µM) for 1 or 2 hours, and testosterone release was assessed. The results showed that administration of maneb (4 mg/kg) for 9 and 18 days did not alter liver function, but resulted in a decrease of basal level of plasma testosterone (P < 0.01). In addition, basal testosterone and pregnenolone release by Leydig cells prepared from maneb 18-day treated animals were significantly reduced (P < 0.05). However, acute in vitro exposure of TIC or Leydig cells to maneb did not alter their testosterone release. These results suggested that maneb alters testosterone production, at least in part, through inhibition of CYP11A1 activitiy.

Abstract: Excretion patterns and rates of ammonium perfluorohexanoate (APFHx) after administration of a single and multiple (14 days) oral dose(s) at 50 mg/kg to male and female mice and rats were examined. The test substance was [14C]-labeled APFHx. After a single oral administration, total excretion was rapid, with mean recoveries of over 90% of the dose at 24 hours after administration, irrespective of gender or species. The major route of elimination was via the urine (means of percentage recovery between 73.0 and 90.2% of the dose), followed by the feces (means of percentage recovery between 7.0 and 15.5% of the dose). Elimination via expired air was negligible. For the multiple dose tests, multiple (13 daily doses) oral administration of APFHx was followed by a single oral administration of [14C]-APFHx. Excretion was rapid, with mean recoveries of over 90% of the administered dose (mean values >95% of the ultimately recovered material) at 24 hours after dosing, irrespective of gender or species. The major rou...

Abstract: Methimazole is the most widely used antithyroid drug in Europe and North America, but it causes several undesirable side effects, such as hematological dysfunctions and immunosuppression. Our aim in this work was to compare, over a time course, markers of oxidative stress, the redox environment, the antioxidant enzymatic system, and the glutathione cycle in the spleen of rats with methimazole- or thyroidectomy-caused hypothyroidism. We used 70-male Wistar rats divided into four groups: 1) euthyroid; 2) sham thyroidectomy; 3) thyroidectomy-caused hypothyroidism, with parathyroid reimplant; and 4) methimazole-caused hypothyroidism. Five rats of the euthyroid- and methimazole-caused hypothyroidism groups were killed at the end of weeks 1, 2, 3, and 4 after treatment, and 5 rats of the sham thyroidectomy and thyroidectomy-caused hypothyroidism groups were killed at the end of weeks 2, 4, and 8 after the surgical procedure. Each spleen was excised and stored at -70°C until oxidative stress, REDOX environment, and the antioxidant enzymatic-system markers were tested. The histological study showed that only methimazole-induced hypothyroidism caused cell damage. This damage was associated with an increase of oxidative-stress markers that were not compensated for by the antioxidant system. The increase of the glutathione-cycle enzymes was insufficient to prevent oxidative-stress markers. Methimazole causes oxidative stress and cell damage in the spleen, whereas hypothyroidism per se does not cause cell damage in this organ. Therefore, it is necessary to develop new antithyroid drugs without causing oxidative stress and cellular damage.

Abstract: Transgenic cloned animals expressing beneficial human nutritional traits offer a new strategy for large-scale production of some kinds of functional substances. In some cases, the required safety testing for genetically modified (GM) foods do not seem appropriate for human food safety, though regulations do not seem to provide alternatives. A 90-day rat feeding study is the core study for the safety assessment of GM foods. The test material in this 90-day study was prepared nonfat milk powder containing recombinant human lactoferrin (rhLF), which was expressed in transgenic cloned cattle. Groups of 10 male and female Sprague-Dawley rats were given a nutritionally balanced purified diet containing 7.5, 15, or 30% transgenic or conventional milk powder for 90 days. A commercial AIN93G diet was used as an additional control group. Clinical, biological, and pathological parameters were compared between groups. The only significant effect of treatment was higher mean ferritin and Fe(+) concentrations for both male and female rats fed the transgenic milk powder diets, as compared to rats fed nontransgenic milk diets or the commercial diet. The results of the present study are consistent with previous research, which indicates that milk powder containing rhLF derived from healthy transgenic cloned cattle is as safe as conventional milk powder.

Abstract: The effect of the environmental contaminant, bisphenol A, on cytosolic free Ca2+ concentrations ([Ca2+]i) in Madin-Darby canine kidney (MDCK) cells is unclear. This study explored whether bisphenol A changed basal [Ca2+]i levels in suspended MDCK cells by using fura-2 as a Ca2+-sensitive fluorescent dye. Bisphenol A, at concentrations between 50 and 300 µM, increased [Ca2+]i in a concentration-dependent manner. The Ca2+ signal was reduced, partly, by removing extracellular Ca2+. Bisphenol A induced Mn2+ influx, leading to quenching of fura-2 fluorescence, suggesting Ca2+ influx. This Ca2+ influx was inhibited by phospholipase A2 inhibitor aristolochic acid, store-operated Ca2+ channel blockers nifedipine and SK&F96365, and protein kinase C inhibitor GF109203X. In Ca2+-free medium, pretreatment with the mitochondrial uncoupler, carbonylcyanide m-chlorophenylhydrazone (CCCP), and the endoplasmic reticulum Ca2+ pump inhibitors, thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ), inhibited bisphenol A–induce...

Abstract: Diclofop-methyl (DM) is a chlorophenoxy derivative used in large quantities for the control of annual grasses in grain and vegetable crops. In this study, the genotoxic effects of DM were investigated by measuring chromosomal aberrations (CAs) in mouse bone-marrow cells and CA and the comet assay in human peripheral lymphocytes. Mice were treated with 15.63, 31.25, 62.5, and 125 mg/kg body weight of DM intraperitoneally for 24 hours, and 15.63-, 31.25-, 62.5-, 125-, and 250-µg/mL concentrations were applied to human lymphocytes for both 24 and 48 hours. In in vivo treatments, DM significantly, but not dose dependently, increased the total chromosome aberrations, compared to both negative and solvent controls. Cell proliferation was significantly, but not dose dependently, affected by all doses. In in vitro treatments, DM (except 15.63 µg/mL) significantly and dose dependently increased the frequency of chromosome aberrations. Also, 250 µg/mL of 48-hour treatment was found to be toxic. Cell proliferation w...

Abstract: Polybrominated diphenyl ethers (PBDEs) are commonly used as commercial flame retardants in a variety of products, including plastics and textiles. Previous studies in our laboratory, and in the literature, showed that exposure to a specific PBDE congener (PBDE 47) during a critical period of brain development may lead to developmental delays and hyperactivity in adulthood. To date, the underlying causes of these behavioral alterations are unknown, although in vitro studies linked PBDEs with potential alterations in neurotransmitter levels, particularly acetylcholine (ACh) and dopamine (DA). Alterations in DA function have also been noted in cases of hyperactivity in rodents and humans. The current study examined monoamine levels in male mice acutely exposed to corn oil vehicle or PBDE 47 (1, 10, or 30 mg/kg) on postnatal day (PND) 10. Animals were sacrificed on PND 15, PND 20, and in adulthood (131–159 days old). The cortex, striatum, and cerebellum were isolated and analyzed by high-performance liquid ch...

Abstract: Oxime reactivator HI-6 (asoxime, in some sources) is a potent antidote suitable for treatment of intoxication by nerve agents. Despite the fact that HI-6 is considered for practical application in emergency situations, the impact of HI-6 on patients' bodies has not been established yet. The present experiment was carried out in order to estimate whether HI-6 would be able to trigger or protect from oxidative stress in a BALB/c mice model. HI-6 was applied in doses ranging from 0.2 to 20% of LD₅₀. Ferric-reducing antioxidant power (FRAP), thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), and glutathione reductase (GR) were assayed in the blood, liver, kidney, and brain of treated animals. It was found that HI-6 does not increase GR or TBARS. On the contrary, TBARS levels in the brain and liver were found to be significantly decreased in HI-6-treated animals. Pertinent antioxidant properties of HI-6 were excluded by the FRAP method. Endogenous antioxidants were unchanged, with the exception of the kidney. Low-molecular-weight antioxidants assayed by the FRAP method were significantly decreased in kidneys of animals treated with HI-6. However, GSH partially recovered the loss of the other low-molecular-weight antioxidants and was significantly increased in the kidney of HI-6-exposed mice. HI-6 potential to produce nephropathy is hypothesized. The achieved conclusions were quite surprising and showed a complex impact of HI-6 on the body.

Abstract: Bisphenol F (BPF) is present in the environment and as a contaminant of food Humans may, therefore, be exposed to BPF, and an assessment of this risk is required BPF has been shown to have genotoxic and endocrine-disruptor properties in a human hepatoma cell line (HepG2), which is a model system for studies of xenobiotic toxicity In this study, we investigated the ability of HepG2 cells to biotransform BPF, because metabolism may affect the observed effects of BPF, and we compared this metabolic capacity with that of human hepatocytes Cells were incubated for 24 hours with [3H]-BPF The culture medium was then concentrated and its metabolites were isolated by high-performance liquid chromatography and identified by mass spectrometry BPF was largely metabolized into the corresponding sulfate by the HepG2 cell line BPF was metabolized into both sulfate and glucuronide by human hepatocytes, but with differences between individuals The metabolism of BPF in both HepG2 cells and human hepatocytes suggest

Abstract: Ciprofloxacin is a fluoroquinolone antibiotic that has a relatively low rate of occurence of adverse side effects. However, increasing evidences suggest that ciprofloxacin may cause unexpected severe liver damage. Especially, the risk of hepatotoxicity is significantly higher in elderly men receiving drug for a long time. In this article, 2 cases of unexpected severe hepatoxicity of ciprofloxacin are presented.

Abstract: Adverse biological activities of Schiff base (SB) derivatives are well known. In this study, the ligand and its metal complexes have been synthesized and characterized by IR, 1H-NMR spectra, elemental analyses, magnetic susceptibility, UV-Vis spectra, and thermogravimetry/differential thermal analysis. From the elemental analyses data, the complexes were proposed to have the general formula [Mn(L)2(H2O)2], [Co(L)2(H2O)2], and [Ni2(L)(H2O)4(Cl)3]. From the magnetic moment and UV-Vis spectra data, it was found that the geometrical structures of these complexes are octahedral. In the in vivo experiment, adult male rats were injected subcutaneously with a new SB (L) and its [Mn(L)2(H2O)2], [Co(L)2(H2O)2], and [Ni2(L)(H2O)4(Cl)3] complexes (25 mg/kg body weight) and were then sacrificed 16 days later. Effects of these compounds on serum antioxidant vitamins (i.e., vitamins A, E, and C) and malondialdehyde (MDA) levels were measured in blood serum, liver, and kidney tissues. In an in vitro experiment, antiproli...

Abstract: Sesame oil could be considered as a potent antioxidant and dietary supplement. It possesses antimutagenic, anti-inflammatory and anti-cardiac toxicity. In the view of available findings, the current study focused on determining the protective effects of sesame oil on 4-Nitroquinoline-1-oxide (4-NQO) -induced oxidative DNA damage and lipid peroxidation (LPO) in rats. Seven groups of Wistar albino rats each with 6 either sex were used. Groups were given vehicle control and sesame oil alone orally and 4-NQO (30 mg/kg) by intraperitoneal injection. Following the four dose levels (1, 2, 4, and 8 ml/kg orally), sesame oil plus 4-NQO were also tested. After 24 hours of 4-NQO injection, blood samples were drawn by venipuncture. DNA damage (8-hydroxy-2-deoxy guanosine; 8-OHdG) and LPO were estimated. LPO from the 4-NQO-treated group was 2.5-fold higher than that of the control LPO. Pretreatment with sesame oil reduced this by 16–61%. 8-OHdG DNA damage from 4-NQO was found to be 3-fold higher than that of controls....

Abstract: 9-cis-UAB30 is a potential chemopreventative agent that has been shown to be effective on many different types of tumors. The safety and toxicity of 9-cis-UAB30 had not been previously established. These studies were conducted to evaluate the potential toxicity and pharmacokinetics in a rodent and a nonrodent species for the purpose of investigational new drug submission. Oral gavage administration of 9-cis-UAB30 at the doses 0, 3, 15, and 100 mg/kg/day to CD® rats for 28 days showed a dose-dependent (although not dose-proportional) increase in plasma drug levels in week 4. The liver was the target organ for toxicity of 9-cis-UAB30. Hepatomegaly along with increases in serum aspartate-aminotransferase and alkaline-phosphatase levels were seen in rats. Moderate hypoalbuminemia and hyperglobulinemia resulted in a decreased albumin/globulin ratio. Histopathology revealed hepatocellular change consistent with hepatic glycogen deposition. Toxicity studies in dogs did not show treatment-related toxicity at doses as high as 100 mg/kg/day (highest dose tested) administered by capsules for 28 days. No effects on the central nervous system (functional observational battery in rats) or cardiovascular function (safety pharmacology study in telemeterized dogs) were seen. The no observed adverse effect level (NOAEL) in the rat studies was 3 mg/kg/day; however, the adverse effects seen in rats receiving 15 mg/kg/day (the least observed adverse effect level) was a slight, but statistically significant, elevation in fibrinogen and decrease in prothrombin time, which may be a sign of some tendency for increased blood coagulation. The NOAEL in the dog study was at least 100 mg/kg/day.

Abstract: The aim of the present work was to clarify the involvement of free radicals, cytochrome P450 toxic metabolites, and deregulation of calcium homeostasis in the mechanism of diethyldithiocarbamate (DDC) hepatotoxicity. This was elucidated through the preadministration of ascorbic acid (a free radical scavenger), cimetidine (an inhibitor of cytochrome P450 enzymes), or nifedipine (a calcium-blocking agent) before DDC treatment to male albino rats. DDC was administered either as a single dose [800 mg/kg body weight (b.w.), subcutaneously, s.c.] or daily repeated doses for 30 days (400 mg/kg b.w., s.c.). Oxidative stress indicators [e.g., malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase enzyme (SOD)] showed that single or repeated DDC doses induce an increase in MDA level and a decrease in SOD activity in the liver, whereas it causes depletion in hepatic GSH after a single dose and an elevation in its value after repeated doses. Severe histopathological changes were also observed in t...

Abstract: Selective serotonin reuptake inhibitors are widely prescribed drugs without recognized cardiovascular risk. We report the case of a 54-year-old patient who developed QTc interval prolongation, followed by ventricular fibrillation episodes, 10 hours after admission to the ICU, in the setting of a citalopram overdose. Citalopram plasma values dropped from 5.88 to 0.34 mg/L at 9 days postadmission. The patient was treated by oral activated charcoal, and final outcome was favorable.

Abstract: Nitric oxide donor tocopherol analogs were found to be incorporated in low-density lipoprotein to release nitric oxide into the hydrophobic core of the lipoprotein, thus inhibiting lipid oxidation processes associated with atheroma plaque formation. Previously, we studied their cytotoxicity against human and murine macrophages as first selection for in vivo studies. Herein, we examined both the in vitro mutagenic and DNA-damage effects of selected compounds to further evaluate drug potential. While the compounds of interest were nongenotoxics in both experimental tests (Ames and alkaline comet), one of the potential blood metabolites exhibited genotoxicity (alkaline comet test), and the furazan derivative was mutagenic (Ames test). Two selected (nitrooxy and furoxan) compounds were studied in long- and short-term in vivo treatment, and in these conditions, animal toxicity was not evidenced, suggesting the possibility of these compounds as potential antiatherogenic drugs.

Abstract: Soman is a highly neurotoxic chemical warfare agent and inhibits the neural enzyme, acetylcholinesterase (AChE). Protein kinase C (PKC) isozymes regulate a wide range of cellular functions to a variety of extracellular stimuli. However, their exact role in nerve-agent poisoning is not well understood. In the present study, we investigated the effect of soman (80 μg/kg−1, administered subcutaneously) on two PKC isozymes’ immunoreactivity levels and activities of PKC and AChE in different rat-brain areas. Results showed a significant induction in PKC βII and ζ isoenzyme expression levels from 2.5 hours to 14 days post-soman exposure periods in the hippocampus, cerebellum, thalamus and cerebral cortex. The striatum showed reduced expression levels of both the isozymes from 1 to 3 days after soman exposure. PKC activity was increased in the cerebrum and cerebellum up to 7 days post-soman exposure. The toxicity target enzyme, AChE activity remained inhibited in plasma and brain up to 3 days post exposure and t...

Abstract: Styrene is known to be hepatotoxic and pneumotoxic in rodents, and these adverse effects are related to its metabolism. Mice deficient in the enzymes responsible for both the activation and detoxification of styrene are useful in examining this relationship more closely. In the current study, mice deficient in glutathione S-transferase P1P2−/− (GST−/−) were compared with wild-type mice. Similar changes in serum sorbitol dehydrogenase, as an indicator of hepatotoxicity, and bronchioalveolar levels of protein, cells, and lactate dehydrogenase, as indicators of pneumotoxicity, were observed after styrene administration. Glutathione depletion followed a similar pattern. The administration of the toxic metabolite, styrene oxide, which is a direct substrate for glutathione metabolism, and 4-vinylphenol, which is a minor metabolite but is more potent than either styrene oxide, yielded results similar to those of styrene. The results indicate that either other isoforms of glutathione S-transferase are more import...