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Background: Cyclophosphamide (CP) as an alkylating compound has been widely applied to treat cancer and autoimmune diseases. CP is observed to be nephrotoxic in humans and animals because it produces reactive oxygen species. Gallic Acid (GA), a polyhydroxy phenolic compound, is reported to exhibit antioxidant and anti-inflammatory effects. Objective: The current research aimed at evaluating the GA effect on CP-related renal toxicity. Methods: In total, 35 male mice were assigned to 5 groups. Group1: receiving normal saline, group 2: CP group, receiving one CP injection (200 mg/kg; i.p.) on day 6. Groups 3 and 4: GA+CP, GA (10 and 30 mg/kg; p.o.; respectively) received through six consecutive days plus CP on the 6th day 2 hr after the last dose of GA, group 5: received GA (30 mg/kg; p.o.) for six consecutive days. Then on day 7, blood samples were collected for determining Creatinine (Cr), serum kidney injury molecule-1 (KIM-1), Blood Urea Nitrogen (BUN), and Neutrophil Gelatinase-Associated Lipocalin (NGAL) concentrations. Malondialdehyde (MDA), Nitric Oxide (NO) concentration, Catalase (CAT), Superoxide Dismutase (SOD), Glutathione (GSH), Glutathione Peroxidase (GPx) activities, and IL-1β, TNF-α levels were assessed in renal tissue. Results: CP administration significantly increases KIM-1, NGAL, Cr, BUN, MDA, NO, IL-1β, and TNF-α level. It also decreases GSH concentration, SOD, GPx, and CAT function. Pretreatment with GA prevented these changes. Histopathological assessments approved the GA protective effect. Conclusion: Our results showed that GA is possibly effective as a protective agent in cyclophosphamide- associated toxicities.

Gentamicin is an essential aminoglycoside antibiotic, but it is only used to treat severe bacterial infections due to its high nephrotoxicity in patients. We evaluated the preventive effects of diosmin (as a natural ingredient) on gentamicin-related kidney damage in rats. In this research, 28 male Wistar rats were divided into four groups: control, gentamicin (100 mg/kg (i.p.), daily for 1 week), gentamicin plus diosmin (50 mg/kg, p.o., daily for 2 weeks), and diosmin (50 mg/kg/day, p.o. for 2 weeks). After the final gavage, blood samples were collected for the determination of blood urea nitrogen (BUN) and creatinine. Kidneys are used for biochemical, inflammatory, and histological tests. The concentrations of creatinine, BUN, nitric oxide, malondialdehyde, tumor necrosis factor α (TNF-α), and interleukin 1 beta (IL-1β) were significantly increased. But, the level of glutathione and activities of catalase, glutathione peroxidase, and superoxide dismutase decreased during treatment with gentamicin. On the other hand, the concentrations of creatinine, BUN, nitric oxide, malondialdehyde, TNF-α, and IL-1β were significantly reduced, and the glutathione level, activities of catalase, and glutathione peroxidase were significantly increased via co-administration with diosmin. Diosmin had ameliorative impacts against gentamicin-related kidney injury due to its antioxidant and anti-inflammatory activities.

Mozhdeh Roghani,1 Heibatullah Kalantari,1,2 Mohammad Javad Khodayar,1,2 Layasadat Khorsandi,3 Mojtaba Kalantar,4 Mehdi Goudarzi,5 Hadi Kalantar1,2 1Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 2Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 3Cellular and Molecular Research Center, Department of Anatomical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 4Student Research Committee, Shoushtar University of Medical Sciences, Shoushtar, Iran; 5Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IranCorrespondence: Hadi KalantarDepartment of Toxicology, Faculty of Pharmacy and Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, IranTel/Fax +98-613738378Email Kalantar-h@ajums.ac.irIntroduction: In multiple studies, involvement of oxidative stress in the pathogenesis of methotrexate (MTX)-mediated liver damage has been confirmed. Use of many drugs has been examined experimentally in order to prevent or diminish oxidative stress. However, no study has yet examined the effects of ferulic acid (FA) on MTX-induced liver damage. This study aimed at evaluating the effects of FA on protection against liver damage induced by MTX in mice.Materials and Methods: In this the mice were divided into five groups in a random manner: I) control; II) MTX (20 mg/kg); III and IV) FA (50 and 100 mg/kg) + MTX; and V) FA (100 mg/kg), and we measured serum factors, oxidative stress and inflammatory factors.Results: In the MTX group, accumulation of inflammatory cells, accumulation of red blood cell (RBC), and nuclear pyknosis (NP) were detected in the liver. In line with the histological data, the levels of nitric oxide (NO), malondialdehyde (MDA), interleukin-6 (IL-6), and tumor necrosis factor-α increased (TNF-α), whereas the reduced glutathione (GSH), catalase (CAT), total antioxidant capacity (TAC), superoxide dismutase (SOD), and glutathione peroxidase (GPx) content reduced in the MTX group. However, FA ameliorated these hazardous effects in the antioxidant and anti-inflammatory systems in MTX-treated groups.Conclusion: Based on our findings, oxidative stress impairment and MTX-induced liver damage were ameliorated following FA pretreatment at both histological and biochemical levels. Therefore, FA can be effectively used in abrogation of MTX-induced toxicity.Keywords: methotrexate, oxidative damage, inflammation, ferulic acid, mice

Background Due to the fact that methotrexate is widely used both as an immunosuppressive drug and as a chemotherapy agent, many studies are needed to reduce the side effects of this drug on non-target organs. Purpose This study was designed to investigate the effects of epicatechin (Epi) on MTX (methotrexate)-induced hepatotoxicity in mice. Research Design After 1 week for adaptation, we randomly divided 42 male Naval Medical Research Institute mice into six groups: (I) control; (II) Epi (100 mg/kg, po); (III) MTX (20 mg/kg, i.p.) on the fifth day; and (IV, V, and VI) Epi (25, 50, and 100 mg/kg, po) + MTX (20 mg/kg, i.p.) on the fifth day. At day 10, the mice were sacrificed and serum factors, oxidative stress markers, and inflammatory cytokines were measured. Results MTX increased activity level of serum enzymes (alanine aminotransferase and aspartate aminotransferase), lipid peroxidation marker (malondialdehyde), and inflammatory factors including interleukin-1 beta, tumor necrosis factor-alpha, and nitric oxide. Furthermore, MTX decreased glutathione level and activity level of catalase, superoxide dismutase, and glutathione peroxidase. Epi was able to reduce the destructive effects of oxidative/antioxidant system imbalance and inflammatory reactions and also histopathological damage in MTX intoxicated mice. Epi pretreatment reduced liver dysfunction by improving the antioxidant defense system, anti-inflammatory effects, and alleviation of histopathological damage in MTX hepatotoxicity. Conclusions Accordingly, Epi can be used as a therapeutic agent in hepatotoxicity associated with MTX chemotherapy.

Background: Acetaminophen (APAP) is a common analgesic and antipyretic medicine that can lead to acute liver injury at high doses. Crocin, a Crocus sativus’ ingredient, has potent antioxidant effects. Objectives: This study examined the protective effects of crocin against APAP-induced oxidative stress in mice. Methods: In this study, 56 mice were randomly divided into seven groups (n = 8 per group), including the negative (normal saline, 10 mL/kg) and positive (oral normal saline for five days + a single dose of APAP (300 mg/kg) on day 6th) control groups. The third group (NAC) received normal saline for up to five days, and on the 6th day, immediately after the administration of acetaminophen, received NAC (50 mg/kg). Groups fourth to sixth received respectively 12.5, 25, and 50 mg/kg of crocin (orally for six days), followed by a single dose of APAP (300 mg/kg) on 6th day. The last group received crocin (50 mg/kg) for six days. Then 24 h after the last injection, the animals were sacrificed, and samples were collected for biochemical and histopathological evaluations. Results: The levels of ALT, AST, and MDA increased, and the activity of CAT, GSH, and GPX decreased in the APAP-treated group compared to the control group. In APAP-treated groups, the administration of crocin decreased the serum levels of AST, ALT, and MDA and increased the activity of CAT, GSH, and GPX. Histopathological evaluations confirmed the above findings. Conclusions: According to our results, it seems that crocin has a protective effect against acetaminophen-induced liver toxicity and can be used as a therapeutic agent to treat APAP-induced hepatotoxicity.

Background Gentamicin is a crucial aminoglycoside antibiotic but it is used only to treat severe bacterial infections, because of its high nephrotoxicity among patients. We evaluated the preventive effects of diosmin (as a natural ingredient) on gentamicin-related renal damage in rats. MethodsIn this research, 28 male Wistar rats were assigned to 4 groups: control, gentamicin (100 mg/kg, (i.p.), daily for 1 week), and gentamicin plus diosmin (50mg/kg, p.o., daily for two weeks), diosmin (50mg/kg/day, p.o. for two weeks). After, the final gavage, blood specimens were gathered for determining serum blood urea nitrogen (BUN) and creatinine. kidneys used for biochemical, inflammation and histological test.Results Creatinine, BUN, nitric oxide, malondialdehyde, TNF-α and IL-1β concentrations significantly increased and glutathione, catalase, glutathione peroxidase, and superoxide dismutase activities decreased after gentamicin treatment. Creatinine, BUN, nitric oxide, malondialdehyde, tumour necrosis factor α (TNF-α), interleukin 1 beta (IL-1β) concentrations significantly reduced and glutathione level, catalase and glutathione peroxidase activities significantly increased via co-administration with diosmin. ConclusionDiosmin had ameliorative impacts against gentamicin-related kidney injury that can be owing to its antioxidant, and anti-inflammatory activities.

The antineoplastic effects of 5-hydroxytryptamine (5-HT) receptor antagonists have been shown in previous studies. However, the exact underlying mechanisms mediating these antineoplastic effects are unclear. In the present study, we assessed the antineoplastic effects of tropisetron, a 5-HT receptor antagonist, in an experimental model of lung cancer in BALB/c mouse. Lewis lung carcinoma cell line was used to induce lung cancer. Mice were divided into four groups (n = 6) as follows: tumor-bearing mice + tropisetron (5 mg/kg intraperitoneally [IP]), tumor-bearing mice + tropisetron (10 mg/kg IP), tumor-bearing mice + saline, healthy mice + tropisetron (10 mg/kg). Tumor burden, interferon-γ (IFN-γ), interleukin (IL)-4, pathological response, Ki-67, and E-cadherin were assessed using enzyme-linked immunosorbent assay, and real-time polymerase chain reaction. Comet assay was used to assess DNA toxicity. Tropisetrone-treated animals (either 5 or 10 mg/kg) showed significantly lower tumor sizes at the day 24th after tumor induction. Tropisetron received animals also showed significantly higher levels of IFN-γ, E-cadherin, pathologic response, and necrotic cells compared to the saline-treated counterparts. In addition, the levels of IL-4, and Ki-67 were significantly lower in tropisetrone treated mice in comparison with control. Furthermore, tropisteron coadministration signifcantly reduced H2 O2 -induced DNA toxicity while treatment with tropisteron alone showed no adverse effect on DNA. Tropisetrone can be used as a potential antineoplastic drug in lung cancer. This agent can promote its antineoplastic effects in part through modulating inflammatory and proliferating markers.

Background Methotrexate (MTX) is used commonly in the treatment of various cancers and inflammatory diseases; nevertheless, the associated hepatotoxicity has limited its clinical application. Crocin (CRO) is described as a natural carotenoid with analgesic, antioxidant, and antiinflammatory properties. This study aimed to determine the effects of CRO on MTX-induced hepatotoxicity. Methods For pretreatment, CRO at doses of 25 and 50 mg/kg (po), as well as 20 mg/kg (ip) of MTX, was injected in rats. Results MTX led to hepatotoxicity, as confirmed by the significant increase in liver markers, histopathological changes, decreased GSH content, and reduced antioxidant enzyme activity (i.e., CAT, SOD, and GPx). It increased TNF-α, IL-1β, lipid peroxidation, and nitric oxide levels. Nevertheless, by increasing antioxidant defense in hepatic tissues and reducing oxidative stress and proinflammatory mediators, pretreatment with CRO could alleviate hepatotoxicity. Conclusion CRO can inhibit MTX-induced hepatotoxicity through improving antioxidant defense and reducing oxidative stress and inflammation.

Purpose Cyclophosphamide is an alkylating agent with nephrotoxicity that constraints its clinical application. Berberine is an isoquinoline derivative alkaloid with biological functions like antioxidant and anti-inflammatory. The current research intended to examine the nephroprotective impacts of berberine against cyclophosphamide-stimulated nephrotoxicity. Methods Forty animal subjects were randomly separated into five categories of control (Group I). Cyclophosphamide (200 mg/kg, i.p., on 7th day) (Group II), and groups III and IV that received berberine 50 and 100 mg/kg orally for seven days and a single injection of cyclophosphamide on 7th day. Group V as berberine (100 mg/kg, alone). On day 8, blood samples were drawn from the retro-orbital sinus to determine serum levels of blood urea nitrogen (BUN), creatinine (Cr), Neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) as biomarkers for kidney injury. Nitric oxide (NO), malondialdehyde (MDA) and glutathione (GSH) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) activities as oxidative stress factors, tumor necrosis factor- α (TNF-α) and interleukin 1 beta (IL-1β) levels as inflammatory mediators were assessed in kidney tissue. Results The results of this study demonstrated that berberine was able to protect remarkably the kidney from CP-induced injury through decreasing the level of BUN, Cr, NGAL, KIM-1, NO, MDA TNF-α, IL-1β and increasing the level of GSH, CAT, SOD and GPx activities. Conclusion Berberine may be employed as a natural agent to prevent cyclophosphamide-induced nephrotoxicity through anti-oxidant and anti-inflammatory effects.

Background: Polyphenolic compounds have anti-proliferative effects and can trigger apoptosis in cancer cells. Ferulic acid is excessively found in various herbal products and fruits. Ferulic acid plays a role in the treatment of neurodegenerative diseases, cancer, diabetes, cardiovascular disease, inflammation, and bacterial and viral infections. Objectives: The purpose of this study was to evaluate the anticancer effect of ferulic acid on renal carcinoma cells (ACHN). Methods: To assess the anti-proliferative effect of ferulic acid, the renal carcinoma cell line (ACHN) was treated with different ferulic acid concentrations (10, 20, 40, 80, and 160 μM) for 24, 48, and 72 hours. Cell viability was measured using the MTT assay. The apoptosis of cancer cells was evaluated by flow cytometry and real-time PCR. Results: The IC50 of ferulic acid against ACHN cells was determined to be 30 μM at 72 hours with the MTT assay. The treatment of cells with ferulic acid concentrations of 30 and 60 μM caused a significant increase in the apoptosis index. The Bcl-2 gene expression level was significantly lower in the treated group than in the control group, and the Bax gene expression level was significantly higher in the treated group than in the control group (P < 0.001). Conclusions: The results of this study showed the apoptotic activity of ferulic acid against ACHN cells. These results can be helpful in the better understanding of the anticancer mechanism of ferulic acid, suggesting this substance as an alternative drug or in combination with conventional chemical treatments for cancer treatment.

Methotrexate (MTX) is used as an effective chemotherapeutic agent against autoimmune diseases and tumors. Oxidative stress and inflammation are involved in the pathogenesis of MTX-induced damage. This study aimed at examining the ameliorating effects of apigenin (API) as a natural antioxidant on MTX-induced hepatotoxicity. The rats were classified into four groups: group I: normal saline-treated, group II: MTX-treated (20 mg/kg, ip, single dose at day 7), group III: MTX + API-treated (20 mg/kg, po), and group IV: API-treated. API was administrated for 9 days. Alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) were used as biochemical factors of MTX-induced hepatic injury. In hepatic tissues, the levels of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), and activities of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) as oxidative stress markers along with inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) were assessed. Our results showed that MTX administration significantly increased ALP, ASP, ALT, MDA, NO, TNF-α, and IL-1β levels and significantly decreased antioxidant factors such as GSH, CAT, GPx, and SOD. The API pretreatment group showed a significant rise in hepatic antioxidant markers, besides significant reductions in the serum levels of AST, ALT, and ALP and hepatic content of MDA, TNF-α, NO, and IL-1β. In addition, the hepatoprotective effect of API was confirmed by histological evaluation of the liver. API can prevent MTX-induced hepatotoxicity through mitigation of oxidative stress and inflammation.

Hepatotoxicity is one of the major side effects of methotrexate (MTX), which restricts the clinical use of this drug. Berberine (BBR) is a natural compound with multiple pharmacological activities such as antioxidant, antiapoptotic and anti-inflammatory effects. In this study, the effect of BBR on MTX-induced hepatotoxicity was studied. A total number of 28 male Wistar rats were randomly divided into four experimental groups. Rats were pretreated with BBR orally with dose of 100mg/kg for 10 consecutive days and MTX (20mg/kg, intraperitoneally) was administrated on the 9th day. Then on day 11, blood samples were collected to determine serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The extracted livers were used for histological examination, biochemical assays and real time PCR studies. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), nitric oxide (NO) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activities were assessed in hepatic tissue. In addition, the expression of SOD and PGx was measured using real-time PCR method in hepatic tissue. Results showed that MTX administration significantly increases AST, ALT and ALP levels (all p

Background: Cyclophosphamide (CP) is one of the most popular bifunctional alkylating agents, which is utilized in the treatment of numerous cancer diseases and has toxic side effects such as nephrotoxicity, hematotoxicity, mutagenicity, and immunotoxicity. In this study, Elaeagnus angustifolia fruit extract (EAFE), a natural plant extract, was examined for its antioxidant activity against CP-induced renal oxidative damage in mice. Methods: In this experimental study, 30 male Swiss albino mice (25 - 30 g) were separated into five groups. Group 1 received normal saline for 5 days; group 2 was treated with CP 200 mg/kg single intraperitoneal (i.p) dose only on the 5th day; groups 3 to 5 received EAFE at doses of 100, 200, and 400 mg/kg, respectively, administered orally during 5 days, and CP on the 5th day 1 hour after the last dose of extract administration. Then on the 6th day, the mice were sacrificed. Blood samples were collected to determine serum blood urea nitrogen (BUN) and creatinine (Cr) levels. Levels of malondialdehyde (MDA) and glutathione (GSH) in kidney tissue were also examined. Histological assessment was undertaken on kidney samples taken from all groups. Results: The results obtained from our study showed a significant increase in the levels of MDA, Cr, and BUN and a decrease in GSH following CP injection. Pre-treatment with EAFE showed a decrease in the levels of MDA, Cr, and BUN and an increase in GSH in all doses; however, the most significant reduction was observed at doses of 200 and 400 mg/kg. In addition, the nephroprotective effect of EAFE was confirmed by histological evaluation of the kidneys. Conclusions: Our results indicate that EAFE has protective effects against CP-induced renal damage possibly by amelioration of biochemical indices and oxidative stress parameters. © 2017, Shiraz E-Medical Journal.

Background: Mercury has a variety of industrial applications and is well-known for its hematotoxic, hepatotoxic, neurotoxic, nephrotoxic, and genotoxic effects. Objectives: This study was carried out to assess the protective effects of gallic acid against mercuric chloride-induced oxidative stress in albino rats. Methods: A total of 35 male Wistar rats were divided into 5 groups (7 rats per group). Groups 1 and 2 were used as the negative and positive controls, respectively and received normal saline (2 mL/kg/day, po) and mercuric chloride (0.4 mg/kg/day, po) for 28 days. Group 3 only received gallic acid (200 mg/kg/day, po) for 28 days, whereas groups 4 and 5 received gallic acid (50 and 200 mg/kg/day, respectively) after 1 hour, followed by mercuric chloride (0.4 mg/kg/day, po) for 28 days. Results: The results demonstrated that treatment with gallic acid significantly diminished the mercuric chloride-induced increase in the serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lipid peroxidation in liver tissues. In addition, gallic acid treatment increased the level of glutathione peroxidase, superoxide dismutase, and catalase activity and lowered the glutathione level in liver tissues, compared to the mercuric chloride group. The liver of rats, treated with mercuric chloride, showed degenerated cells (with mild cytoplasmic vacuolation and blebbing), binucleated cells, and significant sinusoidal dilation. Conclusions: It can be concluded that gallic acid restores the activities of antioxidant enzymes and tissue markers in mercuric chloride-treated rats, probably by scavenging free radicals and improving the antioxidant defense mechanisms. © 2017.

Lung fibrosis is a chronic and intermittent pulmonary disease, caused by damage to the lung parenchyma due to inflammation and fibrosis. Epicatechin (Epi) as a flavonoid has antioxidant and anti-inflammatory properties. This study was conducted to evaluate the effect of Epi on oxidative stress, inflammation and pulmonary fibrosis induced by bleomycin (BLM) in mice. Accordingly, animals were randomly assigned into two groups of 7 and 14 days to evaluate the role of Epi in the early oxidative and late fibrotic phases of BLM-induced pulmonary injury, respectively. Each group was divided into six subgroups include control, Epi 100 mg/kg, BLM, and BLM groups pretreated with 25, 50 and 100 mg/kg Epi, respectively, from three days before until 7 or 14 days after BLM. Lung tissue oxidative stress markers including the activity of superoxide dismutase, glutathione peroxidase, catalase and the levels of malondialdehyde and glutathione were determined. Furthermore, alveolitis and inflammation were evaluated by Szapiel grading scores. In addition, fibrotic markers including lung hydroxyproline content, level of transforming growth factor beta and Ashcroft fibrotic grading of lung fibrosis were examined. Epi exerted protective effects against BLM-induced pulmonary injury in a dose-dependent manner in two early and late phases of lung injury. Oxidative stress markers persisted until the late fibrotic phase, as pro-fibrotic events were present in the early oxidative phase of BLM-induced injury. Finally, it is concluded that Epi can protect the lung against BLM-induced pulmonary oxidative stress, inflammation and fibrosis.