---

Background&Objective: Lead toxicity is a common popular problem. Many researches were performed about this toxicity both in-vivo and in-vitro since 100 years ago.Those studies showed that lead have toxic effects such as behavioral disorders, decrease of IQ and decrease of learning and memory. Also lead has neurotoxic effects such as decrease of neuronal density in visual cortex of monkey, cell death in hippocampus and decrease of acetylcolin in rat’s hippocampus. In this study we examin neurotoxic effects of lead on rat’s radial nerve because radial nerve is a mix nerve. Materials&Methods: 24 adult male rats were divided in six groups. Groups I and II received lead acetate 4% and 2%, groups III and IV received disttiled water and normal water for one month.After this time, we killed rats and exposed radial nerve from behind of arm.Then studied them with light and electron microscopy. Results: In experimental groups we saw decrease of myelin sheath diameter and decrease of nuclear density in schwann cell. Also we saw many granules in mitochondrial matrix, active macrophage, edema and disarrangement of myelin sheath layers. Conclusion: We suggest that lead neurophaty is due to schwann cell injury and this lesion lead to decrease of myelin sheath.

---

Background & Objective: Diclofenac is a non-steroidal, anti-inflamatory drug that is prescribed as an analgesic. However, there is little known about the effects of diclofenac on the neural cells. In this study, we investigated the effects of diclofenac as sodium salt on the proliferation and differentiation of PC12 cells.

 

Materials & Methods: This expeimental study was done in Kerman neuroscience research center during 2004. The cell proliferation was evaluated by using XTT assay in the both free-serum neurobasal medium supplemented with B27 supplement and DMEM/F12 medium containing 10% FBS. The nerve growth factor(NGF) – induced differentiation was assessed  by measuring the neurite length for each treatment.

 

Results: The drug toxicity was exhibited at the higher concentrations of 310 mM in the supplemented neurobasal medium. The treatment of cells in the DMEM/F12 medium increased their sensitivity to diclofenac, with 40 and 85% growth inhibition at the 155 and 310 mM concentrations, respectively. The different generics of drug exhibited a equal toxic effects on the PC12 cells. The NGF- induced differentiation was not reduced by toxic and subtoxic concentrations of diclofenac.

 

Conclusion: This study indicated that diclofenac may be able to exhibit its neurotoxic effects through growth inhibition, but not differentiation inhibition. B27 supplement has several antioxidant compounds. Therefore, the difference of diclofenac cytotoxic effects in two culture media suggest that drug cytotoxicity may be related to the oxidative stress.

---

Background & Objective: Tetra Carbon Cholride has been known as reference hepatotoxin because it can cause necrosis, fatty change, cirrhosis and cancer liver. Silymarin has hepatoprotective and anti hepatoxin effect. This study was done to determine the protective effect of Silymarin in acute hepatotoxicity of CCl4 in rats.

Materials & Methods: In this experimental study, we chose 25ml/kg dose of CCl4 (in mineral oil solvent) as an optimum dose. The hepatotoxic effects of intraperiotoneal injection of CCl4 for obtaining parameters of toxicity and therapeutic effects have been examined. According to enzymatic results (increase in ALT and AST) and histopathologic changes (grading the changes in liver including cytoplasmic granularity, cloudy swelling, necrosis and fatty change), the interval between prescribing silymarin and sampling  was determined. Silymarin as a suspension in propylene glycol CMC 2% (3/2 ratio) has been prescribed in 50, 200 and 800mg/kg doses and serum and liver samples were obtained. Negative control group received silymarin vehicle in CCl4 solvent, drug control received 800 mg/kg of silymarin in CCl4 solvent and positive control received silymarin vehicle after injecting CCl4.

Results: The results showed that prescribing 50mg/kg silymarin one hour after injecting CCl4, in addition to inhibiting transaminase activity, prevents progress of liver injury up to 50% of positive control group. Cellular repair and regeneration are also enhanced, So the grade 3necrosis in positive control group is decreased to grade 0.5 in silymarin gourp in 48 hours prescribing silymarin (50mg/kg).

Conclusion: This study showed that up to six hours after injecting CCl4 significantly prevents hepatotoxicity, and cause acceleration in repair of liver injuries.

---

L-glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). It contribute in various physiological conditions such as brain development, synaptic plasticity, memory and learning. However, increasing of the extracellular glutamate concentration and overactivation of glutamate receptors in particular ionotropic subtypes leads to excitotoxicity which is the fundamental pathological pathway of neuronal injury. Due to lack of extracellular enzymatic destruction, the removal of released glutamate is achieved through the excitatory amino acid transporters (EAATs) which are distributed in glia that tightly surround the synaptic clefts, as well as in neurons. EAATs which known as Na+-dependent high-affinity glutamate transporters are the main responsible for maintaining extracellular glutamate concentration below excitotoxic levels. Moreover another membrane transporters regulating the flux of glutamate in different areas of the CNS. This system is cystine-glutamate exchanger (XCG-) that is Na+-independent system. Dysfunction of EAATs has been implicated in both acute insults e.g. stroke, trauma and chronic neurological and neuropsychiatric disorders e.g. amyotrophic lateral sclerosis, epilepsy, schizophrenia and Alzheimer's disease. Therefore, the purpose of this review article is to explain the pathway of glutamate biosynthesis, its release into CNS, discribing and elaborating Glutamate transporters, activites and their role in excitoxcity in CNS.

---

Background and Objective: The anthracyclin drug doxorubicin (Adriamycin) is one of the most effective antineoplastic agents, and widely used to treat a number of malignancies. However, its use has been restricted due to the dose-dependent cardiotoxicity. The mechanisms of Doxorubicin - induced cardiotoxicity is not entirely clear. This study investigates the effect of Doxorubicin on Bcl2 and Bax genes expression as key molecules that involve in intrinsic pathway of apoptosis in rat heart. Materials and Methods: In this experimental study Doxorubicin administration, male Wistar rats were exposed to intraperitoneal injections (2.5 mg/kg, six times for 2 weeks, n=20). Animals were randomly assigned to the healthy untreated control (n=10) and to the Doxorubicin treatment groups (n=10). Three weeks after completion of treatment myocardial fibrosis, Bcl2 and Bax genes expression were investigated by Masson’s trichrome staining and Real Time- PCR analysis respectively. Statistical analysis was performed using the SPSS-16 and independent samples t-test, Mann-Whitney and Kaplan-Meyer method. Results: Masson’s trichrome staining showed that Doxorubicin increased fibrosis in the cardiac muscle (16.4±1) in compare to control group (1±0.79). Real Time- PCR analysis showed that Doxorubicin decreased Bcl2 expression levels (0.1±0.07) and increased Bax expression levels (2.1±0.1) in the myocardium in compare to control group (P<0.01). Conclusion: This study showed that administration of Doxorubicin increase interstitial fibrosis of myocardium and Bax expression levels and decrease Bcl2 expression that are the key genes of mitochondria-dependent apoptotic pathway.

---

Background and Objective: Mirtazapine is a norepinephrine and serotonergic antidepressant that is used in the theraphy of major depressive disorders. This study was carried out to determine the genotoxic and cytotoxic effect of mirtazapine using chromosome aberration and mitotic index tests in human peripheral blood lymphocytes. Methods: In this descriptive -analytic study genotoxic and cytotoxic effect of mirtazapine at 24 and 48 hours treatment periods on four concentration (10, 25, 40, and 55µg/ml) was performed on peripheral blood lymphocyte of four subjects. Results: Mirtazapine significantly reduced the mitotic index in the all concentrations but it non-significantly increased the chromosome aberration at 24-hours and 48-hours treatment periods. Conclusion: Mirtazapine has cytotoxic effect but it has no genotoxic effect on human lymphocyte.

---

Background and Objective: Iron oxide nanoparticles have wide applications such as MRI contrast agent and drug delivery. Nevertheless, their effects on human health have not been fully investigated yet. After cellulose, chitin is one of the most abundant organic materials in nature which is widely used in food industry, cosmetics, agriculture, medicine and the environment. This study was done to evaluate the effect of iron oxide nanoparticles coated with chitosan on renal functional indeces in rat.

Methods: In this experimental study, 60 adult female Wistar rats were allocated into 10 equal groups. Concentrations of 50, 100 and 150 mg/kg/bw from chitosan, iron oxide nanoparticles and chitosan coated nanoparticles were intraperitoneally injected into 9 groups and animals in control group were received normal saline. Blood samples were collected directly from the rat heart in the days 15 and 30 post after injection and renal functional indeces including urea, creatinine, uric acid, sodium, potassium and total protein were measured.

Results: There were no significant differences in the level of urea, creatinine, uric acid, sodium, potassium and total protein in the groups whom received chitosan-coated iron oxide nanoparticles compared to control. There was no mortality during the study time.

Conclusion: Short-term using of iron oxide nanoparticles coated with chitosan does not create any toxicity in the rat kidney.

---

Background and Objective: HIV treatment influences the global health and finding new compounds against HIV virus is increased. This study was done to evaluate anti-HIV activity of 8-phenyl-4-quinolone derivatives containing different substituents at position 3.

Methods: In this descriptive study, single cycle replicable (SCR) HIV Virions were produced by co-transfecting HEK 293T cells with pmzNL4-3, pSPAX.2, pMD2.G plasmids. HeLa cells were infected with the SCR virions and then inhibit of virus replication by compounds were measured by p24 Antigen with ELISA kit. The cytotoxicity of these compounds on HeLa cells were measured by XTT method.

Results: All compounds including NPZ_4F, NPZ-2F, NPZ-4CL and NPZ-2CL had the best inhibitory effect at a concentration of 100µM with the inhibition rate of respectively 51%, 48%, 33%, and 25%, respectively. The compounds of NPZ-4F and NPZ-2CL had negligible cellular toxicity and have inhibited HIV replication at the highest concentration. This issue can make them a valuable compound since they are better compounds in therapeutic terms, which at a suitable concentration, they have the lowest rate of cellular toxicity and highest power to inhibit HIV replication.

Conclusion: Novel compounds derived from 8-phenyl-4-quinolone containing different substituents at position 3 can prevent HIV replication which is capable of high anti-viral and low cellular toxicity and suitable candidates for further investigation in antiviral studies.

---

Background and Objective: Curcumin is a combination of active polyphenol from the Curcuma Langa plant, which has extensive biological activities including effects anti-inflammatory, anti-bacterial and cytotoxic markers for multiple cancer cells. Berberine is an alkaloied isokinolin that is present in berberine and suppresses the growth of many tumor cells. This study was designed to determine the antibacterial effect of berberine and indium curcumin and indium diastile curcumin complexes against E-coli and Bacillus pumilus and comparison of their cytotoxicity on the cell lines of the bladder and stomach cancer cells.
Methods: In this descriptive-analytic study, antimicrobial activity and cytotoxicity effect of berberine and indium curcumin and indium diastile curcumin complexes was investigated by MTT and dilution test method respectively. E-coli [BL21 (DE 3)], Bacillus pumilus (PTCC 1529), cell lines of bladder (5637) and stomach (AGS) were evaluated.
Results: The minimum inhibitory concentration (MIC) of berberin for E-coli was determined 5 mM. At 100 micromolar concentration of berberine approximately 100% of the bladder cancer cells have disappeared. Cytotoxic effect of curcumin complexes on two bladder and stomach cancer cell lines showed that both complexes have different inhibitory effects on cell line life. Cytotoxicity of 20μM indium curcumin and indium diastile curcumin complexes for bladder cancer cells were 58% and 55%, respectively, and for stomach cancer cells were 61% and 34 %, respectively. Antibacterial activity of complexes against Bacillus pumilus and E-coli showed that none of the complexes has antimicrobial effect against Bacillus Pamilus, but both complexes inhibited the growth of E-coli bacteria. The bacteria population in the presence of indium curcumin and indium diastile curcumin complexes was reduced to 40% and 24%, respectively.
Conclusion: This study indicated that indium complexes of curcumin and diacetyl curcumin have a potential for anticancer and antibacterial therapy. Furthermore, berberine as an alkaloid has anticancer and antibacterial activity.

---

Background and Objective: Increasing interest has been devoted to the design and discovery of more effective anticancer agents in current medicinal chemistry because of the high prevalence of cancer in different societies and resistance occurrence to existing anticancer drugs. The aim of this study was to evaluate the anticancer activity of two novel quinoline compounds (RQ1 and RQ2) on human gastric cancer cells.
Methods: In this descriptive - analytic study, the anticancer effects of the compounds were evaluated by MTT assay. This test was performed on two categories of gastric cancer cells sensitive to Danorubicin (EPG85-257P) and resistant to Danorubicin (EPG85-257RDB). The arresting mechanism in the G2 / M phase of the cell cycle and the induction of apoptosis by the compounds was investigated using the PI test and flow cytometric analysis.
Results: Novel quinoline derivatives RQ1 and RQ2 showed good anticancer effects on both sensitive and resistant human gastric cancer cells (IC50=25-38mM). Compound RQ2 showed the most cytotoxic activity on the Danorubicin-sensitive cancer cell line with IC50=25mM. The percentage of Danorubicin resistant gastric cancer cells (EPG85-257RDB) in the G2 / M phase at 25mm concentration of RQ1 and RQ2 was 35.95 and 34.88, respectively, and 41.1% and 42.89% of these cells, after treatment with 50mm concentration of RQ1 and RQ2 arrested at the G2 / M phase respectively.
Conclusion: The two novel quinoline compounds, RQ1 and RQ2 showed strong anticancer effect on both sensitive and resistant human gastric cancer cell lines.

---

Background and Objective: Multiwall carbon nanotubes nowadays have multiple uses in the field of drug and gene delivery and other biological fields, and it is necessary to study their potential toxicity on organisms due to unique properties of these nanostructures. This study was conducted to determine the toxicity of multi-wall carbon nanotubes functionalized with carboxylic groups on the function and structure of the rats liver tissue.
Methods: In this experimental study, 50 mature female Wistar Rats were randomly allocated into five groups including the control group of normal saline and Tween and treatment groups 2.5, 5, 10, 20 mg/kg/bw concentrations of multi-wall carbon nanotubes functionalized with carboxylic group with diameter less than 8 nm and length 30 micrometers that was received in 8 steps, intraperitoneally. Blood sampling was performed in two steps (The first stage was one day after the last injection and the second stage was 20 days after the last injection). The level of activity of the aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) enzymes and the amount of malondialdehyde were measured in serum. By preparing the tissue sections of the liver, a number of rats in each group (after 20 days from the last injection) with hematoxylin-eosin staining, the tissue structure of the liver was examined by optical microscopy. Animals were weighed before and after treatment.
Results: In the first stage, only the mean of AST activity at 5 mg/kg/bw concentration was significantly increased (P<0.05). In the second stage, ALP activity was significantly reduced (P<0.05) in all doses higher than 2.5 mg/kg/bw and the activity of AST and ALT in doses of 5 and 10 mg/kg/bw was significantly reduced (P<0.05) and in the dose of 2.5 mg/kg/bw was significantly increased (P<0.05). Histologic studies revealed disturbances such as degeneration of the vein wall of the lobular center, degeneration of the nucleus and hepatocyte lysis with severe atrophy, irregularity and dilatation of the sinusoids and accumulation of inflammatory cells in the treatment groups in dose-dependent manner. Based on the above findings the most disturbances were related to the 20 mg/kg/bw concentration.
Conclusion: It seems that multi-wall carbon nanotubes functionalized with carboxylic group, even in small amounts (2.5 and 5 mg/kg/bw) after 20 days, are toxic on the liver and cause liver tissue and function impairment.

---

Background and Objective: Copper oxide nanoparticles, in addition to useful applications, may have adverse effects on the organisms.This study was done to determine the effect of copper oxide nanoparticles on liver toxicity, enzymes changes and liver histological structure of rats.
Methods: In this experimental study, 40 Wistar male rats were randomly allocated into 4 groups. During 10 days, five times (one day interval), 3 groups of rats were received 10, 20 and 30 mg/kg of copper oxide nanoparticles with a diameter of less than 50 nm and purity of 99% and a surface of 80 m²/g intraperitoneally, respectively. One group was considered as the control group. Activity of Lactate dehydrogenase (LDH), Alkaline phosphatase (ALP), Aspartate transaminase (AST) and Alanine aminotransferase (ALT) enzymes were tested in two stages (one day and 15 days after treatment). Also, liver tissue sections were prepared and stained with hematoxylin-eosin.
Results: No significant alterations of AST enzyme activity were not seen between different groups in two stages. The activity of ALT, ALP, and LDH enzymes in the first stage showed a significant increase in all treatment groups compared to control and returned to normal after 15 days. Rat's weight changes were not statistically significant between different groups. Histological studies revealed multiple tissue injuries in dose-dependent in treatment groups which included mild and severe hyperemia, hepatocytes degeneration, hyperplasia and inflammation.
Conclusion: Injection of low doses of copper oxide nanoparticles, after 15 days, although changes in enzyme activity return to normal, but significant disturbances observes in the structure of the liver tissue.

---

Background and Objective: In medical sciences, identifying the anticancer properties of plumbagin is of special importance. For this reason, this study investigated the anticancer activity of polymeric nanoparticles loaded by plumbagin against breast cancer cells.
Methods: In this descriptive study, the diblock copolymer mPEG–PCL was synthesized by ring-opening polymerization of caprolactone in the presence of mPEG as the initiator and Sn(oct)2 as the catalyst. The synthesized copolymers were characterized by Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance, gel permeation chromatography, and differential scanning calorimetry. The nanoprecipitation method was used for preparing nanoparticles loaded with plumbagin. The characteristics of these nanoparticles were investigated by various techniques including dynamic light scattering. The cytotoxicity of plumbagin, copolymer, and the nanoparticles loaded with plumbagin on MCF7 and HFF2 cells was evaluated by MTT assay.
Results: The average diameter of the nanoparticles was less than 115 nm. The loading capacity and encapsulation efficiencies were 15.4±0.13% and 79.1±0.65%, respectively. Drug release was slow, controlled, and almost dependent on pH. The results of the MTT assay showed strong and dose-dependent inhibition of cell growth by the plumbagin-loaded micelles compared with plumbagin alone in a way that the half maximal inhibitory concentration of this nanoparticle against MCF7 cells after 48 and 72 hours was 10.78 and 24.03 μM, respectively.
Conclusion: The mPEG-PCL nanoparticles can be an efficient carrier for plumbagin, and plumbagin can be an effective drug on breast cancer cells, without toxicity on healthy cells.
 

---

Background and Objective: Spirulina (Spirulina platensis) has numerous nutritional and therapeutic benefits. This experimental study aimed to investigate the effect of spirulina on changes in the levels of liver enzymes of male BALB/c mice exposed to a high dose of acetaminophen.
Methods: In this experimental study, 42 adult male BALB/c mice were divided into seven groups of six. The toxic dose of acetaminophen 600 mg/kg body weight was considered. The control group received only a standard diet and water. The sham group was gavaged with saline solution. The third to seventh groups were treated as: acetaminophen; spirulina 600 mg/kg/bw, spirulina 300 mg/kg/bw, spirulina 600 mg/kg/bw + acetaminophen, and spirulina 300 mg/kg/bw + acetaminophen, respectively. In all groups, mice were treated with acetaminophen and spirulina powder by gavage for 14 consecutive days. Twenty-four hours after receiving the last dose of medication and deprivation of food (the animals still had access to water), the animals were anesthetized and blood samples were taken from the heart. Activity of liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) was measured by spectrophotometry. Protein concentration was determined by the Lowry method. Catalase activity was assessed using hydrogen peroxide. The amount of malondialdehyde was measured and the total antioxidant capacity was determined by FRAP method by reducing ferric to ferro ions.
Results: The levels of serum transaminases (ALT, AST, ALP) as well as the level of total antioxidant capacity and malondialdehyde of the acetaminophen-treated group increased significantly compared to the control group (P<0.05). The levels of these enzymes in the group treated with S. platensis 300 mg/kg/bw + acetaminophen decreased significantly compared to the group treated with acetaminophen (P<0.05). Catalase activity in the acetaminophen group was significantly decreased compared to the control group (P<0.05).In the group of S. platensis 300 mg/kg/bw + acetaminophen, catalase activity increased significantly compared to the acetaminophen group (P<0.05). The results of experiments in two groups of spirulina and acetaminophen showed that the active ingredients of the algae at a dose of 300 worked better than 600 mg per kg of body weight in response to oxidative stress.
Conclusion: Consuming 300 mg/kg of S. platensis along with a near toxic dose of acetaminophen increases resistance to oxidative stress and injuries caused by drug poisoning by affecting the activity of enzymes and the antioxidant defense system.