Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study

Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant (p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant (p < 0.05) compared to the control (0.51 ± 0.07). Histology of the liver, spleen and brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment.     

Novel biocompatible nanomaterial for biomedical application: Structural,morphological, magnetic,and in vivo toxicity investigations

Assessing the biocompatibility of magnetic nanoparticles for biomedical applications is highly demanded and attracted an increasing interest in the last years. We, herein report the synthesis, physical characterization, and biocompatibility of CoFe_(2-x-y-z)Gd_xSm_yHo_zO₄ (x = y = z = 0, 0.01) nanoparticles (NPs) synthesized by the auto-combustion method for the first time. The physicochemical and magnetic properties of the synthesized nanoparticles were fully characterized using various techniques including X-ray diffraction (XRD), Fourier transforms infrared spectra (FTIR), scanning electron microscopy (SEM), Transmission electron microscopy (TEM), and vibrating sample magnetometer (VSM). A single-phase with a space group Fd-3m and mixed spinel structure were confirmed by XRD, Rietveld analysis, and the cation distribution study. FTIR confirms the formation of the crystallographic sites of the spinel structure, namely the octahedral site and the tetrahedral site. The nanoparticles exhibited a quasi-spherical shape with size distribution (24–51 nm). VSM measurements reveal that magnetic properties can be tuned by doping for biomedical applications. To evaluate the safety of our nanoparticle sub-chronic toxicity was highlighted in Wistar rats by oral administration at doses of 500, 250,125, and 50 mg/kg and by intraperitoneal injection at doses of 40,20,10, and 5 mg/kg. Results showed no significant changes in the hematological parameters, serum biochemical system, organ weight, and histopathological examination (p > 0,05) for doses below 250 mg/kg and 40 mg/kg administered orally or by intraperitoneal injection respectively. The results of the current study suggesting that treatment with the nanoparticle for 28 days does not produce any significant toxicity in the male and female rats for the either using voices (oral, intraperitoneal) except at high doses. These findings reported here strongly suggest that the as-prepared nanoparticles can be used in several biomedical applications, including separation and purification, drug delivery, imaging (MRI contrast), and therapy (hyperthermia).     

Anti-Inflammatory Effects of 4-Methylcyclopentadecanone on Edema Models in Mice

The present study evaluated the anti-inflammatory effects of 4-methylcyclopentadecanone (4-MCPC) on edema models in mice and aimed to determine the safety of 4-MCPC after acute exposure. The acute toxicity of 4-MCPC was evaluated by oral administration to rats of single doses of 0, 5, 50, 500 and 5000 mg/kg. Toxic symptoms were observed for 14 days. The anti-inflammatory activity was evaluated in xylene-induced mouse ear edema and carrageenan-induced mouse paw edema. The animals were treated with 4-MCPC once every day for seven consecutive days. Edema index, % inhibition, IL-1β, TNF-α, PGE₂ and MPO levels in paws were detected after the treatment with xylene or carrageenan. Our results indicated that the LD₅₀ value of 4-MCPC in rats is greater than 5000 mg/kg. The ED₅₀ of 4-MCPC in xylene-induced mouse ear edema model was 7.5 mg/kg. 4-MCPC (8 or 16 mg/kg) remarkably inhibited carrageenan-induced mouse paw edema. Further study revealed that 4-MCPC treatment also decreased IL-1β, TNF-α, PGE₂ and MPO levels in mice paws. Intragastric administration of 4-MCPC exhibited more significant anti-inflammatory activity than muscone at a dose of 16 mg/kg. Taken together, our results suggest that 4-MCPC has potent anti-inflammatory activity and the mechanisms might be related to the decreases of the levels of IL-1β, TNF-α, PGE₂ and MPO in inflamed paws.     

马蹄香对小鼠的急性毒性及对大鼠的亚急性毒性观察

目的观察马蹄香(Valeviana jatamansi Jones)对小鼠的急性毒性及对大鼠的亚急性毒性,以评价其安全性。方法给小鼠灌服5 000、7 500、10 000 mg/kg的马蹄香,对照组灌胃1%羧甲基纤维素钠(CMC),观察小鼠的中毒症状,记录小鼠的死亡数,采用Red-Munchen法计算半数致死量(LD50),并检查小鼠组织和脏器的病理变化;对大鼠分别灌服4 000、1 000和200 mg/kg的马蹄香,连续给药14 d,对照组灌胃CMC水溶液,给药后观察14 d,检测大鼠体重、脏器系数、血常规指标、血生化指标及组织病理变化情况。结果急性毒性试验结果显示,灌胃马蹄香后,小鼠短时间内出现活动减少,而后趋于正常,病理学检测未发现小鼠组织或脏器有明显异常改变,LD50>10 000 mg/kg;亚急性毒性试验结果显示,马蹄香各剂量组大鼠的增重、脏器系数、血常规指标、血生化指标及组织病理变化与对照组比较,差异均无统计学意义(P>0.05)。结论马蹄香具有较好的安全性。     

杀菌剂氟吗啉和多菌灵对蚯蚓的急性毒性

采用自然土和OECD标准人工土研究了氟吗啉和多菌灵对蚯蚓的急性毒性，并对试验过程中蚯蚓的中毒症状和形态、行为变化进行了观察。结果表明，氟吗啉在自然土壤中对蚯蚓的LC50为592．73mg／kg，95％置信区间为562．41～623．80mg／kg；氟吗啉在人工土壤中对蚯蚓的LC50为318．79mg／kg，95％置信区间为181．63-543．79mg／kg。多菌灵在自然土壤中对蚯蚓的LC50为26．53mg／kg，95％置信区间为15．98-42．93mg／kg；多菌灵在人工土壤中对蚯蚓的LC50为5．57mg／kg，95％置信区间为2．48～11．83mg／kg。依据农药对蚯蚓的毒性等级划分标准，氟吗啉在自然土壤和人工土壤中对蚯蚓的毒性均为低毒级；多菌灵在自然土壤中对蚯蚓的毒性为低毒级，而在人工土壤中对蚯蚓的毒性为中毒级。     

The Safety Evaluation of Salvianolic Acid B and Ginsenoside Rg1 Combination on Mice

Our previous study indicated that the combination of salvianolic acid B (SalB) and ginsenoside Rg1 (Rg1), the main components of Salvia miltiorrhizae and Panax notoginseng, improves myocardium structure and ventricular function in rats with ischemia/reperfusion injury. The present study aimed to determine the safety of the combined SalB and Rg1 (SalB-Rg1) in mice. The safety of SalB-Rg1 was evaluated through acute toxicity and repeated-dose toxicity. In the acute toxicity study, the up and down procedure was carried out firstly, and then, the Bliss method was applied. In the toxicity study for seven-day repeated treatment of SalB-Rg1, forty Kunming mice were randomly divided into four groups. The intravenous median lethal dose (LD₅₀) of the SalB-Rg1 combination was 1747 mg/kg using the Bliss method. For both the acute toxicity study and the seven-day repeated toxicity study, SalB-Rg1 did not induce significant abnormality on brain, heart, kidney, liver and lung structure at any dose based on H&E stain. There were no significant changes related to the SalB-Rg1 toxicity detected on biochemical parameters for two kinds of toxicity studies. The LD₅₀ in mice was 1747 mg/kg, which was more than one hundred times higher than the effective dose. Both studies of acute toxicity and seven-day repeated dose toxicity indicated the safety of the SalB-Rg1 combination.     

Metabolic Kinetics of <Emphasis Type="Italic">tert</Emphasis>-Butylhydroquinone and Its Metabolites in Rat Serum after Oral Administration by LC/ITMS

Liquid chromatography–ion trap mass spectrometry (LC/ITMS) was employed for a metabolic kinetics study of tert-butylhydroquinone (TBHQ) and its metabolites in rat serum after oral administration. The mean serum concentration–time data of TBHQ and its four metabolites (M1–M4) in both male and female rats after oral administration of TBHQ at dosages of 7, 350 and 700 mg/kg were all best-fitted by a two-compartment model with first-order absorption. TBHQ was rapidly absorbed, distributed and metabolized. The metabolites were also distributed rapidly except M2, but eliminated more slowly than TBHQ. At the doses of 350 and 700 mg/kg, the total concentrations of TBHQ and its metabolites in serum were much higher for male than female rats during the metabolic process (P < 0.01). In addition, the serum concentrations of M1, M3 and M4 were all much higher for males than for females (P < 0.01) during the metabolic process, while no significant differences between male and female rats were found (P > 0.05) for TBHQ and M2, at the doses of 350 and 700 mg/kg. The exploratory assessment of dose proportionality for TBHQ and its metabolites by the power model indicated that the TBHQ exposure increased in a more-than-dose-proportional manner, but the exposures of the metabolites M1–M4 increased in a less-than-dose-proportional manner, across the dose of 7–700 mg/kg.     

避蚊胺原药大鼠亚慢性（180d）经口毒性研究

目的：研究避蚊胺原药对大鼠亚慢性（180d）经口毒性,得出最大无作用剂量。方法：按照《农药登记毒理学试验方法》（GB15670—1995）进行试验。观察体重、血液生化、血常规指标、脏器系数及主要脏器组织病理学改变。结果：染毒1-26周各剂量组雌、雄大鼠体重、进食量无显著差异：各剂量组雌、雄大鼠各血液学指标均未见异常;各剂量组雌、雄大鼠生化指标均未见异常;各剂量组大鼠尿常规检测未见异常;各剂量组雌、雄大鼠的各被检脏器系数无显著差异：高剂量组和对照组各主要脏器均未见明显的病理学改变。结论：在本试验条件下,避蚊胺原药对雌、雄大鼠亚慢性（180d）经口毒性试验的最大无作用剂量雌性（206．89±52．01）mg／kg,雄性（179．38±63．87）mg／kg。     

1-Isobutanoil-2-isopropylisothiourea Phosphate,T1082: A Safe and Effective Prevention of Radiotherapy Complications in Oncology

The radioprotective effects of a new 1-isobutanoil-2-isopropylisothiourea derivative named T1082 are presented. Research methods included toxic characteristics, radioprotective activity (Till–McCulloch’s test and 30-day survival test) in γ-ray total-body-irradiated mice, and a clinical and histological study of the effect of T1082 on acute radiation skin reactions (RSR) in rats after a single or fractionated β-ray local irradiation. T1082 is more effective than its analogue, the NOS inhibitor T1023, at low concentrations and doses (1/12–1/8 LD₁₀), both parenterally and intragastrically. In this case, its therapeutic index (LD₅₀/ED₅₀) reaches 30, and the optimal radioprotective doses (ED_84–98—141–224 mg/kg) are an order less than the maximum tolerated doses—1/16–1/10 LD₁₀. These properties allowed T1082, at a low intragastrical dose (160 mg/kg; 1/14 LD10), to significantly limit the severity of acute RSR after single (40 Gy) and fractionated (78 Gy) β-ray irradiation. The results confirm T1082 as one of the safest emergency radioprotectors and indicate the prospects for its further development as a pharmacological agent for the prevention of RT complications.     

Characterization,in vitro bioactivity and biological studies of sol-gel-derived TiO2 substituted 58S bioactive glass

Bioactive glasses (BGs) have been used for bone formation and bone repair processes in recent years. This study investigated the titanium substitution effect on 58S BGs (Ti-BGs) 60SiO₂-(36 − X)CaO-4P₂O₅-XTiO₂ (X = 0, 3, and 5 mol.%) prepared by the sol-gel technique, and the main goal was to find the optimum amount of titanium in Ti-BGs. Synthesized BGs, which were investigated after immersion in simulated body fluid (SBF), were tested by X-ray diffraction (XRD) analysis, Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy. Moreover alkaline phosphate (ALP) activity, 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and antibacterial studies were employed to investigate the biological properties of Ti-BGs. According to the FTIR and XRD test results, hydroxyapatite (HA) formation on Ti-BGs surfaces was confirmed. Meanwhile, the presence of 5 mol.% compared to 3 mol.% increased the HA grain distribution and their size on the Ti-BGs surface. Additionally, MTT and ALP results confirmed that the optimal amount of titanium substitution in BG was 5 mol.%. Since 5 mol.% Ti incorporated BG (BG-5) had the highest biocompatibility level, antibacterial properties, maximum cell proliferation, and ALP activity among the synthesized Ti-BGs, it is presented as the best candidate for further in vivo investigations.     

Members of the GADD45 Protein Family Show Distinct Propensities to form Toxic Amyloid-Like Aggregates in Physiological Conditions

The three members (GADD45α, GADD45β, and GADD45γ) of the growth arrest and DNA damage-inducible 45 (GADD45) protein family are involved in a myriad of diversified cellular functions. With the aim of unravelling analogies and differences, we performed comparative biochemical and biophysical analyses on the three proteins. The characterization and quantification of their binding to the MKK7 kinase, a validated functional partner of GADD45β, indicate that GADD45α and GADD45γ are strong interactors of the kinase. Despite their remarkable sequence similarity, the three proteins present rather distinct biophysical properties. Indeed, while GADD45β and GADD45γ are marginally stable at physiological temperatures, GADD45α presents the Tm value expected for a protein isolated from a mesophilic organism. Surprisingly, GADD45α and GADD45β, when heated, form high-molecular weight species that exhibit features (ThT binding and intrinsic label-free UV/visible fluorescence) proper of amyloid-like aggregates. Cell viability studies demonstrate that they are endowed with a remarkable toxicity against SHSY-5Y and HepG2 cells. The very uncommon property of GADD45β to form cytotoxic species in near-physiological conditions represents a puzzling finding with potential functional implications. Finally, the low stability and/or the propensity to form toxic species of GADD45 proteins constitute important features that should be considered in interpreting their many functions.     

Comparative Neuropharmacology and Pharmacokinetics of Methamphetamine and Its Thiophene Analog Methiopropamine in Rodents

Methiopropamine is a novel psychoactive substance (NPS) that is associated with several cases of clinical toxicity, yet little information is available regarding its neuropharmacological properties. Here, we employed in vitro and in vivo methods to compare the pharmacokinetics and neurobiological effects of methiopropamine and its structural analog methamphetamine. Methiopropamine was rapidly distributed to the blood and brain after injection in C57BL/6 mice, with a pharmacokinetic profile similar to that of methamphetamine. Methiopropamine induced psychomotor activity, but higher doses were needed (E_max 12.5 mg/kg; i.p.) compared to methamphetamine (E_max 3.75 mg/kg; i.p.). A steep increase in locomotor activity was seen after a modest increase in the methiopropamine dose from 10 to 12.5 mg/kg, suggesting that a small increase in dosage may engender unexpectedly strong effects and heighten the risk of unintended overdose in NPS users. In vitro studies revealed that methiopropamine mediates its effects through inhibition of norepinephrine and dopamine uptake into presynaptic nerve terminals (IC₅₀ = 0.47 and 0.74 µM, respectively), while the plasmalemmal serotonin uptake and vesicular uptake are affected only at high concentrations (IC₅₀ > 25 µM). In summary, methiopropamine closely resembles methamphetamine with regard to its pharmacokinetics, pharmacodynamic effects and mechanism of action, with a potency that is approximately five times lower than that of methamphetamine.     

Nicotine Neurotoxicity Involves Low Wnt1 Signaling in Spinal Locomotor Networks of the Postnatal Rodent Spinal Cord

The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysiological changes after injury. While low dose nicotine (1 µM) induces neuroprotection, how higher doses affect spinal networks is unknown. Using spinal preparations of postnatal wild-type Wistar rat and Wnt1Cre2:Rosa26Tom double-transgenic mouse, we studied the effect of nicotine (0.5–10 µM) on locomotor networks in-vitro. Nicotine 10 µM induced motoneuron depolarization, suppressed monosynaptic reflexes, and decreased fictive locomotion in rat spinal cord. Delayed fall in neuronal numbers (including motoneurons) of central and ventral regions emerged without loss of dorsal neurons. Conversely, nicotine (0.5–1 µM) preserved neurons throughout the spinal cord and strongly activated the Wnt1 signaling pathway. High-dose nicotine enhanced expression of S100 and GFAP in astrocytes indicating a stress response. Excitotoxicity induced by kainate was contrasted by nicotine (10 µM) in the dorsal area and persisted in central and ventral regions with no change in basal Wnt signaling. When combining nicotine with kainate, the activation of Wnt1 was reduced compared to kainate/sham. The present results suggest that high dose nicotine was neurotoxic to central and ventral spinal neurons as the neuroprotective role of Wnt signaling became attenuated. This also corroborates the risk of cigarette smoking for the foetus/newborn since tobacco contains nicotine.     

Translocator Protein Modulation by 4′-Chlorodiazepam and NO Synthase Inhibition Affect Cardiac Oxidative Stress,Cardiometabolic and Inflammatory Markers in Isoprenaline-Induced Rat Myocardial Infarction

The possible cardioprotective effects of translocator protein (TSPO) modulation with its ligand 4′-Chlorodiazepam (4′-ClDzp) in isoprenaline (ISO)-induced rat myocardial infarction (MI) were evaluated, alone or in the presence of L-NAME. Wistar albino male rats (b.w. 200–250 g, age 6–8 weeks) were divided into 4 groups (10 per group, total number N = 40), and certain substances were applied: 1. ISO 85 mg/kg b.w. (twice), 2. ISO 85 mg/kg b.w. (twice) + L-NAME 50 mg/kg b.w., 3. ISO 85 mg/kg b.w. (twice) + 4′-ClDzp 0.5 mg/kg b.w., 4. ISO 85 mg/kg b.w. (twice) + 4′-ClDzp 0.5 mg/kg b.w. + L-NAME 50 mg/kg b.w. Blood and cardiac tissue were sampled for myocardial injury and other biochemical markers, cardiac oxidative stress, and for histopathological evaluation. The reduction of serum levels of high-sensitive cardiac troponin T hs cTnT and tumor necrosis factor alpha (TNF-α), then significantly decreased levels of serum homocysteine Hcy, urea, and creatinine, and decreased levels of myocardial injury enzymes activities superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as lower grades of cardiac ischemic changes were demonstrated in ISO-induced MI treated with 4′-ClDzp. It has been detected that co-treatment with 4′-ClDzp + L-NAME changed the number of registered parameters in comparison to 4′-ClDzp group, indicating that NO (nitric oxide) should be important in the effects of 4′-ClDzp.     

Effects of particulate matter on the pulmonary and vascular system: time course in spontaneously hypertensive rats

Background  

This study was performed within the scope of two multi-center European Commission-funded projects (HEPMEAP and PAMCHAR) concerning source-composition-toxicity relationship for particulate matter (PM) sampled in Europe. The present study aimed to optimize the design for PM in vivo toxicity screening studies in terms of dose and time between a single exposure and the determination of the biological responses in a rat model mimicking human disease resulting in susceptibility to ambient PM. Dust in thoracic PM size-range (aerodynamic diameter <10 μm) was sampled nearby a road tunnel (RTD) using a high volume cascade impactor. Spontaneously hypertensive rats were exposed to urban dust collected in Ottawa, Canada (EHC-93 10 mg/kg of body weight; reference PM) or different RTD doses (0.3, 1, 3, 10 mg/kg of body weight) by intratracheal instillation. Necropsy was performed at 4, 24, or 48 hr after exposure.     

硫丹毒性研究

硫丹（ｅｎｄｏｓｕｌｆａｎ）原药和３５％乳油对ＳＤ大鼠的急性经口和经皮毒性属于高毒到中等毒范围，两种染毒途径均具有明显的性别差异，对雌性的毒性大。中毒表现主要为神经系统症状，部分动物死于肺水肿。对小鼠有中等蓄积毒性。对家兔皮肤、眼粘膜有轻度刺激作用。Ａｍｅｓ试验，小鼠骨髓胞微核试验和睾丸初级精母细胞染色体畸变试验结果均匀为阴性。     

Biocompatibility of Graphene Oxide

Herein, we report the effects of graphene oxides on human fibroblast cells and mice with the aim of investigating graphene oxides' biocompatibility. The graphene oxides were prepared by the modified Hummers method and characterized by high-resolution transmission electron microscope and atomic force microscopy. The human fibroblast cells were cultured with different doses of graphene oxides for day 1 to day 5. Thirty mice divided into three test groups (low, middle, high dose) and one control group were injected with 0.1, 0.25, and 0.4 mg graphene oxides, respectively, and were raised for 1 day, 7 days, and 30 days, respectively. Results showed that the water-soluble graphene oxides were successfully prepared; graphene oxides with dose less than 20 μg/mL did not exhibit toxicity to human fibroblast cells, and the dose of more than 50 μg/mL exhibits obvious cytotoxicity such as decreasing cell adhesion, inducing cell apoptosis, entering into lysosomes, mitochondrion, endoplasm, and cell nucleus. Graphene oxides under low dose (0.1 mg) and middle dose (0.25 mg) did not exhibit obvious toxicity to mice and under high dose (0.4 mg) exhibited chronic toxicity, such as 4/9 mice death and lung granuloma formation, mainly located in lung, liver, spleen, and kidney, almost could not be cleaned by kidney. In conclusion, graphene oxides exhibit dose-dependent toxicity to cells and animals, such as inducing cell apoptosis and lung granuloma formation, and cannot be cleaned by kidney. When graphene oxides are explored for in vivo applications in animal or human body, its biocompatibility must be considered.     

Subchronic Toxicity of Copper Oxide Nanoparticles and Its Attenuation with the Help of a Combination of Bioprotectors

In the copper metallurgy workplace air is polluted with condensation aerosols, which a significant fraction of is presented by copper oxide particles <100 nm. In the scientific literature, there is a lack of their in vivo toxicity characterization and virtually no attempts of enhancing organism’s resistance to their impact. A stable suspension of copper oxide particles with mean (±SD) diameter 20 ± 10 nm was prepared by laser ablation of pure copper in water. It was being injected intraperitoneally to rats at a dose of 10 mg/kg (0.5 mg per mL of deionized water) three times a week up to 19 injections. In parallel, another group of rats was so injected with the same suspension against the background of oral administration of a “bio-protective complex” (BPC) comprising pectin, a multivitamin-multimineral preparation, some amino acids and fish oil rich in ω-3 PUFA. After the termination of injections, many functional and biochemical indices for the organism’s status, as well as pathological changes of liver, spleen, kidneys, and brain microscopic structure were evaluated for signs of toxicity. In the same organs we have measured accumulation of copper while their cells were used for performing the Random Amplification of Polymorphic DNA (RAPD) test for DNA fragmentation. The same features were assessed in control rats infected intraperitoneally with water with or without administration of the BPC. The copper oxide nanoparticles proved adversely bio-active in all respects considered in this study, their active in vivo solubilization in biological fluids playing presumably an important role in both toxicokinetics and toxicodynamics. The BPC proposed and tested by us attenuated systemic and target organs toxicity, as well as genotoxicity of this substance. Judging by experimental data obtained in this investigation, occupational exposures to nano-scale copper oxide particles can present a significant health risk while the further search for its management with the help of innocuous bioprotectors seems to be justified.     

Investigation of Ifosfamide Toxicity Induces Common Upstream Regulator in Liver and Kidney

Ifosfamide is an alkylating agent, a synthetic analogue of cyclophosphamide, used to treat various solid cancers. In this study, the toxicity of ifosfamide was evaluated using single-and multiple-dose intraperitoneal administration in rats under Good Laboratory Practice guidelines, and an additional microarray experiment was followed to support toxicological findings. A single dose of ifosfamide (50 mg/kg) did not induce any pathological changes. Meanwhile, severe renal toxicity was observed in the 7 and 28 days consecutively administered groups, with significant increases in blood urea nitrogen and creatinine levels. In the tox-list analysis, cholesterol synthesis-related genes were mostly affected in the liver and renal failure-related genes were affected in the kidney after ifosfamide administration. Moreover, interferon regulatory factor 7 was selected as the main upstream regulator that changed in both the liver and kidney, and was found to interact with other target genes, such as ubiquitin specific peptidase 18, radical S-adenosyl methionine domain containing 2, and interferon-stimulated gene 15, which was further confirmed by real-time RT-PCR analysis. In conclusion, we confirmed kidney-biased ifosfamide organ toxicity and identified identically altered genes in both the liver and kidney. Further comprehensive toxicogenomic studies are required to reveal the exact relationship between ifosfamide-induced genes and organ toxicity.