Cyclophosphamide-induced Oxidative Stress Research Articles

Olea europaea leaf extract up-regulates Nrf2/ARE/HO-1 signaling and attenuates cyclophosphamide-induced oxidative stress, inflammation and apoptosis in rat kidney

Olive leaf extract (OLE) has potential health benefits and protects against cytotoxicity in different organs. However, nothing has yet been reported on its potential to prevent cyclophosphamide (CP)-induced nephrotoxicity. This study investigated the possible protective effect of OLE on CP-induced kidney injury in rats, focusing on oxidative stress, inflammation, apoptosis and Nrf2/ARE/HO-1 signaling. Rats received 100 or 200 mg/kg body weight OLE for 15 days and a single injection of 150 mg/kg CP at day 16. CP induced kidney injury evidenced by the significantly increased serum creatinine and urea, and histopathological alterations, including glomerular atrophy, interstitial hemorrhage, dilated urinary space and necrosis. CP-induced rats exhibited increased kidney lipid peroxidation, protein carbonyl, nitric oxide (NO) and pro-inflammatory cytokines, and up-regulated NF-κB, Bax, cytochrome c and caspase-3. OLE ameliorated kidney function markers and prevented CP-induced tissue damage. In addition, OLE significantly prevented oxidative stress, inflammation and apoptosis by enhancing the antioxidant defenses and Bcl-2 expression, and suppressing the pro-inflammatory and pro-apoptotic markers NF-κB, Bax, cytochrome c and caspase-3. OLE up-regulated Nrf2, HO-1 and NQO-1 expression in the kidney of CP-induced rats. In conclusion, OLE has a substantial protective role against CP-induced nephrotoxicity in rats by up-regulating the Nrf2/ARE/HO-1 signaling, enhancing the antioxidant activity and attenuating inflammation and apoptosis.

Camel milk exosomes modulate cyclophosphamide-induced oxidative stress and immuno-toxicity in rats.

Camel milk proteins exhibit many beneficial properties including immuno-modulatory and anti-oxidant effects. Recent studies demonstrated that most of these properties are ascribed to the presence of extracellular nanovesicles known as exosomes. Therefore, the current study aimed to investigate the effect of the immuno-modulatory and anti-oxidant properties of camel milk exosomes on the immuno-toxicity and oxidative stress induced by cyclophosphamide (CTX) in albino rats. Exosomes were isolated from camel milk and exosomal kappa casein and lactoferrin mRNAs were detected and then sequenced. CTX was used to induce immunosuppression in rats, which were further treated with camel milk and its exosomes. The alterations in biochemical parameters, antioxidant status, cytokine profile, spleen histopathology and flow cytometric analysis were detected. Treatment with CTX resulted in a significant decrease in total protein, albumin, globulin, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels associated with a significant increase in the levels of malondialdehyde (MDA) when compared with the control group. Moreover, CTX depleted lymphocytes in the spleen tissue, significantly reduced the expression of interferon gamma (IFN-γ) in the spleen cells and decreased the CD4+ and CD8+ cell percentages in the blood and spleen, while it induced a significant increase in the expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Co-administration of camel milk exosomes was able to normalize the antioxidant status and most of the biochemical and immunological parameters. This study clarifies that camel milk and its exosomes successfully ameliorate immunosuppression and oxidative stress induced by CTX in rats.

Boric acid protects against cyclophosphamide-induced oxidative stress and renal damage in rats

The worldwide increase in the rate of cancer incidence also leads to a significant increase in the use of chemotherapeutic agents. Unfortunately, the optimal clinical usefulness of these agents is heavy restricted by a high incidence of several organ toxicity and as well reason oxidative stress and bring about changing in antioxidant status. Kidney toxicity is a side effect often encountered with cyclophosphamide (CPM) which is commonly used in most cancer chemotherapy. The present study aims on the assessment of the probable defensive efficacy of Boric acid (BA) against CPM-induced oxidative stress and renal damage in rats. Based upon our investigation results with oxidative stress markers and light microscopic findings, it can be concluded that BA significantly reduced CPM induced oxidative stress and renal damage. As far as we know, high dose (200 mg/kg) of BA are the first study on the prevention of kidney damage caused by CPM. It is thought that the renoprotective effects of BA may be due to an increase in the activity of the antioxidant protection system and also inhibition of lipid per oxidation.

Comparative study of the protective effects of chicken embryo amniotic fluid, vitamin C and coenzyme Q10 on cyclophosphamide-induced oxidative stress in mice ovaries.

Cyclophosphamide is a chemotherapy drug for the treatment of cancer. Chicken embryo amniotic fluid, vitamin C and coenzyme Q10 have anti-oxidant properties. Total of 70 adult female mice were selected and divided into seven groups. The first group that received 2 ml kg-1 of inactivated amniotic fluid subcutaneously. The second group treated with 75 mg kg-1of cyclophosphamide by intraperitoneal injection. Third to fifth groups received 1, 2, and 4 ml kg-1 of chicken embryo amniotic fluid, respectively. The sixth group received vitamin C at a dose of 0.2 mg g-1 of body weight by oral gavages. Seventh group received 10 mg kg-1 coenzyme Q10 intraperitoneally. All cyclophosphamide treated groups (3-7) received 75 mg kg-1 of cyclophosphamide intraperitoneal on day 22. The mice were euthanized on day 29 and ovarian tissue antioxidant enzymes including glutathione peroxidase, superoxide dismutase and catalase activities and malondialdehyde (MDA) were evaluated. Activities of above mentioned enzymes in treatment groups (3-7) was significantly higher than patient control group (2). The results also revealed that MDA levels were higher in the control group in comparison to other treatment groups. Therefore, it is concluded that the chick embryo amniotic fluid and coenzyme Q10 can compete with compounds like vitamin C in increasing the anti-oxidant level in ovarian tissue.

Protective Effects of Selenium on Cyclophosphamide-Induced Oxidative Stress and Kidney Injury.

Cyclophosphamide (CP) is a common anticancer drug, but its use in cancer treatment is limited due to its severe toxicities induced mainly by oxidative stress in normal cells. Reactive oxygen species (ROS) lead to multiple organ injuries, including the kidneys. Selenium (Se) is a nutritionally essential trace element with antioxidant properties. In the present study, the possible protective effect of Se on CP-induced acute nephrotoxicity was investigated. Forty-two Sprague-Dawley rats were equally divided into six groups of seven rats in each. The control group received saline, and other groups were injected with CP (150mg/kg), Se (0.5 or 1mg/kg), or CP + Se intraperitoneally. Total antioxidant capacity (TAC), total oxidant state (TOS), oxidative stress index (OSI), creatinine, and cystatin C (Cys C) levels were measured in the sera. In addition, kidney tissues were examined histologically. In the CP alone treated rats, creatinine, Cys C, TOS, and OSI levels increased, while TAC level decreased. CP-induced histological damages were decreased by co-treatment of Se and biochemical results supported the microscopic observations. In conclusion, our study points to the therapeutic potential of Se and indicates a significant role of ROS in CP-induced kidney toxicity.

Pretreatment with melatonin protects against cyclophosphamide-induced oxidative stress and renal damage in mice.

Cyclophosphamide (CP) is widely used in treatment of different cancers. Nephrotoxicity is one of the dose-limiting side effects of CP. This study was carried out to investigate the effect of melatonin (MEL) on CP-induced nephrotoxicity in mice. In this study, 50 Swiss albino mice (20-25g) were randomly divided into five groups. Mice were pretreated with MEL intraperitoneally (i.p) in doses of 5, 10 and 20mg/kg for five consecutive days, and CP (200mg/kg, i.p) was administrated on the 5th day 1h after the last dose of MEL. Then on day 6, blood samples were collected to determine serum creatinine (Cr) and blood urea nitrogen (BUN) levels. The kidneys were used for histological examination, biochemical assays and real-time PCR studies. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), nitric oxide (NO) level, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activity were assessed in renal tissue. In addition, the expression of SOD2 and PGx1 was measured using real-time PCR method in renal tissue. Results showed that CP administration significantly increases Cr, BUN, MDA, PC, NO level and MPO activity. It also decreases renal GSH level, SOD, GPx and CAT activity. Pretreatment with MEL (especially 20mg/kg, i.p.) for 5days prevented these changes; however, it did not affect the SOD activity. Our results revealed that MEL might be useful for prevention of the nephrotoxicity induced by CP through ameliorative effects on biochemical indices and oxidative stress parameters.

Carvacrol attenuates cyclophosphamide-induced oxidative stress in rat kidney.

Cyclophosphamide (CP) is an antineoplastic drug that induces kidney damage via producing oxidative stress. Carvacrol (CAR) has antioxidative effect and we postulated that it can be protective against CP-induced nephrotoxicity. Six groups (n = 7) of rats (control, 100 mg/kg CP, CP+5 mg/kg CAR, CP+10 mg/kg CAR, 5 mg/kg CAR, and 10 mg/kg CAR) were injected intraperitoneally. Serum malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), creatinine (CRE), total antioxidant capacity (TAC), and total oxidant state (TOS) were measured, and oxidative stress indexes (OSI) were calculated. Kidneys were also analyzed histologically. In CP-alone group MDA, CRE, TOS, and OSI levels increased whereas GSH, SOD, CAT, and TAC levels decreased compared with control group. In CP plus CAR groups, MDA, TOS, and OSI levels decreased whereas GSH, SOD, CAT, and TAC levels increased compared with CP-alone group. However, CRE levels were similar in CP-alone and CP+5 CAR group whereas decreased in CP+10 CAR group. CP+10 CAR group was significantly different in all parameters (except TAC) from CP+5 CAR group. Kidney microscopy was showed lower tissue damage in CP plus CAR groups. In conclusion, 10 mg/kg CAR is more effective than 5 mg/kg CAR in prevention of CP-induced oxidative damage on kidney.

Neuroprotective effect of Decalepis hamiltonii on cyclophosphamide-induced oxidative stress in the mouse brain.

Cyclophosphamide (CP), one of the most widely used antineoplastic drugs, causes toxic side effects on vital organs including brain. In this study, we have investigated neuroprotective potential of the aqueous extract of the roots of Decalepis hamiltonii (DHA) against CP-induced oxidative stress in the mouse brain. Swiss albino male mice were pre-treated with DHA (50 and 100 mg/kg b.w.) for 10 consecutive days followed by an injection with CP intraperitoneally (25 mg/kg b.w.) for 10 days 1 h after DHA treatment; 16 h later, they were euthanized, their brains were immediately removed, and biochemical and molecular analyses were conducted. The results indicated that injection of CP induced oxidative stress in the mouse brain as evident from the increased lipid peroxidation, reactive oxygen species, depletion of glutathione and reduced activities of the antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase. Treatment with DHA significantly mitigated the CP-induced oxidative stress. Moreover, expression of genes for the antioxidant enzymes was downregulated by CP treatment which was reversed by DHA. In conclusion, DHA protected the brain from oxidative stress induced by CP, and therefore, it could be a promising nutraceutical as a supplement in cancer chemotherapy in order to ameliorate the toxic side effects of cancer drugs.

Antioxidative effect of ginseng stem-leaf saponins on oxidative stress induced by cyclophosphamide in chickens

Previous investigation demonstrated that oral administration of ginseng stem-leaf saponins in chickens could enhance the immune response. The present study was designed to evaluate the effects of ginseng stem-leaf saponins on oxidative stress induced by cyclophosphamide in chickens. One hundred and twenty chickens were randomly divided into 5 groups. Groups 1 to 4 received intramuscular injection of cyclophosphamide to induce oxidative stress while group 5 was injected with saline solution and served as control. Following administration of cyclophosphamide, groups 1 to 3 were orally administered ginseng stem-leaf saponins at 2.5, 5, and 10 mg/kg BW in drinking water for 7 d, respectively. After that, the spleen, thymus, bursa, and serum were collected to measure the indices of the organs and oxidative parameters. The results showed that ginseng stem-leaf saponins significantly inhibited cyclophosphamide-induced oxidative stress by increasing the organ indices, total antioxidant capacity, and the levels of glutathione, ascorbic acid, and α-tocopherol, while elevating the activity of total superoxide dismutase, catalase, and glutathione peroxidase, as well as decreasing the protein carbonyl content and malondialdehyde. Therefore, ginseng stem-leaf saponins could be a promising agent against oxidative stress in the poultry industry.

Enhancement of cancer chemotherapeutic efficacy of cyclophosphamide by Curculigo orchioides Gaertn and its ameliorative effects on cyclophosphamide-induced oxidative stress.

Cyclophosphamide (CTX) is a synthetic antineoplastic drug with severe and life-threatening side effects. Studies in search of protective agents, preferably natural products, that can alleviate these side effects are valuable because they can contribute to improve current chemotherapeutic treatment strategies. Curculigo orchioides Gaertn (family Hypoxidaceae) is well known for its medicinal use in the Indian Ayurvedic system of medicine, and various studies have been reported that proved its immunomodulatory and anti-inflammatory properties. In this study, the tumor reduction capacity of CTX in combination with C orchioides methanolic extract was studied using Dalton's lymphoma ascites-induced solid tumor models. Effect of C orchioides on the reversal of the damage induced by CTX administration (intraperitoneally) was also determined in this study. For this, solid tumor volume, serum cytokine levels, hematolological parameters, intestinal histopathology, and serum and tissue biochemical parameters (Glutathione [GSH], alkaline phosphatase [ALP], glutamate pyruvate transaminase [GPT], lipid peroxidation [LPO]) were analyzed. Immune suppression and increased serum proinflammatory cytokine levels caused by CTX administration (25 mg/kg body weight) were reversed by C orchioides (20 mg/kg body weight). The alcoholic extract enhanced the tumor reduction capacity of CTX and reduced GPT and ALP levels in liver and serum, which were elevated by CTX administration. The LPO level was also lower in the CTX-administered animals when treated with the C orchioides extract. In conclusion, the plant extract when administered in combination with CTX, can result in enhanced anticancer properties; it also ameliorates the toxic side effects of CTX.

The effects of tempol on cyclophosphamide-induced oxidative stress in rat micturition reflexes.

We hypothesized that cyclophosphamide- (CYP-) induced cystitis results in oxidative stress and contributes to urinary bladder dysfunction. We determined (1) the expression of oxidative stress markers 3-nitrotyrosine (3-NT), reactive oxygen species (ROS)/reactive nitrogen species (RNS), inflammatory modulators, neuropeptides calcitonin gene-related peptide (CGRP), substance P (Sub P), and adenosine triphosphate (ATP) that contribute to the inflammatory process in the urinary tract and (2) the functional role of oxidative stress in urinary bladder dysfunction with an antioxidant, Tempol, (1 mM in drinking water) combined with conscious cystometry. In CYP-treated (4 hr or 48 hr; 150 mg/kg, i.p.) rats, ROS/RNS and 3-NT significantly (P ≤ 0.01) increased in urinary bladder. CYP treatment increased ATP, Sub P, and CGRP expression in the urinary bladder and cystometric fluid. In CYP-treated rats, Tempol significantly (P ≤ 0.01) increased bladder capacity and reduced voiding frequency compared to CYP-treated rats without Tempol. Tempol significantly (P ≤ 0.01) reduced ATP expression, 3-NT, and ROS/RNS expression in the urinary tract of CYP-treated rats. These studies demonstrate that reducing oxidative stress in CYP-induced cystitis improves urinary bladder function and reduces markers of oxidative stress and inflammation.

Investigation of antigenotoxic potential of Syzygium cumini extract (SCE) on cyclophosphamide-induced genotoxicity and oxidative stress in mice

The present study investigated the protective effects of Syzygium cumini extract (SCE; 100 and 200 mg/kg) against genotoxicity and oxidative stress (OS) induced by cyclophosphamide (CP) in mice. Animals were received 14 days pretreatment (oral) of SCE, followed by induction of genotoxicity by CP (40 mg/kg), 24 hours before sacrifice. Mice bone marrow chromosomal aberration assay, micronucleus assay, and sperm abnormality assay were employed for the study. Activities of hepatic antioxidant enzymes were also investigated. Phytochemical investigation was done to determine total phenolic and flavonoid content in SCE. Results showed that CP produced a significant increase in average percentage of aberrant metaphases and chromosomal aberrations (CAs) excluding gap, and micronuclei (MN) formation in polychromatic erythrocytes produced cytotoxicity in mouse bone marrow cells and induced abnormal sperms in a male germ line. CP also markedly inhibited the activities of superoxide dismutase (SOD), catalase (CAT), and reduced glutahione (GSH) and increased malondialdehyde (MDA) content. Pretreatments with SCE significantly inhibited the frequencies of aberrant metaphases, CAs, MN formation, and cytotoxicity in mouse bone marrow cells induced by CP. SCE also produced a significant reduction of abnormal sperm and antagonized the reduction of CP-induced SOD, CAT, and GSH activities and inhibited increased MDA content in the liver. Total phenolic content present in SCE was 24.68%, whereas total flavonoids were calculated as 3.80%. SCE has a protective effect against genotoxicity and OS induced by CP.

Inhibitory effect of carboxymethylpachymaran on cyclophosphamide-induced oxidative stress in mice

The aim of the present study was to investigate the immunomodulatory effect and antioxidant activity of carboxymethylpachymaran on cyclophosphamide-induced immunosuppression in mice in vivo. The results showed that carboxymethylpachymaran could be used to overcome the cyclophosphamide-induced immunosuppression in mice. Moreover, it significantly increased the thymus and spleen indices, lysozyme, catalase and superoxidase dismutase activities, and total antioxidant capacity. In contrast, it decreased xanthine oxidase activity and malondialdehyde levels. The results indicated that carboxymethylpachymaran might play an important role in the prevention of oxidative damage in the immunological system.

Attenuation of cyclophosphamide-induced neurotoxicity in rat by yellow dye extract from root of Brimstone tree (Morinda lucida)

Cyclophosphamide is an anticancer and immunosuppressant drug that induces reactive oxygen species (ROS) production, so causing malondialdehyde (MDA) production, which is toxic to cells. This study therefore sought to assess the antioxidant and the protective effect of dietary inclusion (0.5 and 1.0%) of yellow dye from root of Brimstone tree (used to enhance the sensory quality of foods and in folk medicine) on cyclophosphamide-induced oxidative stress in brain. Wistar strain albino rats were placed on diet containing 0.5 and 1.0% yellow dye preparation from root of Brimstone tree for 14 days. Intraperitoneal administration of cyclophosphamide (75 mg/kg of body weight) 24 h before the termination of the experiment caused a significant (P<0.05) increase in the brain malondialdehyde (MDA) content (147.2%) and serum activities of aspartate aminotransferase (AST) (21.7 UI/l), alanine amino-transferase (ALT) (29.6 UI/l), alkaline phosphatase (43.8 UI/l) and total bilirubin (1.7 mg/dl). However, there was a significant decrease (P<0.05) in the MDA of content of the brain and serum enzyme activities, in those rats fed diet containing the yellow dye in a dose dependent manner. The inhibition of oxidative stress in brain and serum enzymes and metabolites by the dye could be attributed to its high total phenol content and antioxidant activity as typified by its reducing power, free-radical scavenging ability, Fe(II) chelating ability and inhibition of lipid peroxidation. Therefore, dietary inclusion of the yellow dye from root of Brimstone tree could prevent cyclophosphamide-induced oxidative stress in brain and the associated toxicity to the liver.

Protective effect of aminoguanidine against cyclophosphamide-induced oxidative stress and renal damage in rats

BackgroundCyclophosphamide (CP) is widely used in the treatment of tumors and B-cell malignant disease, such as lymphoma, myeloma, chronic lymphocytic leukemia, and Waldenstrom's macroglobulinemia. Renal damage is one of the dose-limiting side effects of CP. Oxidative stress is reported to play important roles in CP-induced renal damage.AimTo find out whether aminoguanidine (AG) protects against CP-induced oxidative stress and renal damage.MethodRenal damage was induced in the rats by administration of a single injection of CP at a dose of 150 mg/kg body weight intraperitoneally. For the AG pretreatment studies, the rats were injected intraperitoneally with AG at a dose of 200 mg/kg body weight 1 hour before administration of CP. The control rats received AG or saline alone. All the rats were killed 16 hours after the administration of CP or saline. The kidneys were used for histological examination by light microscopy and biochemical assays — malondialdehyde, protein carbonyl content, reduced glutathione (GSH), and the activities of antioxidant enzymes including glutathione peroxidase (GPx), glutathione S transferase (GSTase), catalase, glutathione reductase, and myeloperoxidase (MPO), a marker of neutrophil infiltration.ResultsPretreatment with AG attenuated CP-induced renal damage histologically. Pretreatment with AG prevented CP-induced lipid peroxidation, protein oxidation, depletion of reduced GSH, and loss of activities of the antioxidant enzymes including GPx, catalase, and GSTase and also MPO activity.ConclusionThe results of the present study reveal that AG can prevent CP-induced renal damage by inhibiting oxidative stress. Thus, AG may be useful for prevention of the nephrotoxicity of CP.

Inhibition of Cyclophosphamide-Induced Oxidative Stress in Brain by Dietary Inclusion of Red Dye Extracts from Sorghum (Sorghum bicolor) Stem

The stem of sorghum is used as color additives in cooking meals and taken as beverages when steeped or boiled in water as folklore for the management of anemia and some other diseases. This study sought to assess the antioxidant and neuroprotective potentials of red dye extract from sorghum stem on cyclophosphamide-induced oxidative stress in rat brain. Wistar strain albino rats were fed diet supplemented with the red dye (0.5% and 1.0% inclusion) for 14 days. There was no significant difference (P > .05) in average feed intake and weight gain of rats fed the basal diet and the red dye-supplemented diet. However, intraperitoneal administration of cyclophosphamide (75 mg/kg of body weight) 24 hours prior the termination of the experiment caused a significant (P < .05) increase in the brain malondialdehyde (MDA) content and serum activities of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in those rats fed diet without the dye supplement, whereas there was a significant decrease (P < .05) in brain MDA content and serum enzyme activities in rats fed diet with the dye in a concentration-dependent manner. The protective effect of the red dye against cyclophosphamide-induced oxidative stress could be attributed to the high phenolic content (56.2%) and antioxidant activities of the red dye as typified by 2,2-diphenyl-1-picrylhydrazyl free radical scavenging ability, reducing properties, and Fe(2+) chelating ability. Therefore, dietary inclusion of the red dye from sorghum stem could be harnessed in the management of neurodegenerative diseases associated with oxidative stress.

Oral Glutamine Attenuates Cyclophosphamide-Induced Oxidative Stress in the Bladder but Does Not Prevent Hemorrhagic Cystitis in Rats

Cyclophosphamide (CP) is widely used in the treatment of cancer and non-malignant disease states such as rheumatoid arthritis. Hemorrhagic cystitis is a major dose-limiting side effect of CP. The incidence of this side effect is related to the dosage and can be as high as 75%. Elimination of the side effects of CP can lead to better tolerance of the drug, and a more efficient therapy can be achieved for patients in need of CP treatment. Several studies have demonstrated that oxidative stress and neutrophil infiltration play important roles in CP-induced bladder damage. Glutamine is utilized under clinical conditions for preventing chemotherapeutic drug-induced side effects, based on its ability to attenuate oxidative stress. The aim of the study is to verify whether glutamine prevents CP-induced oxidative stress and bladder damage using a rat model. Adult male rats were administered 150mg/kg body weight of CP intraperitoneally. Glutamine pretreated rats were administered 1g/kg body weight of glutamine orally 2h before the administration of CP. Vehicle/glutamine-treated rats served as controls. All the rats were killed 16h after the dose of CP/vehicle. The urinary bladders were removed and used for light microscopic and biochemical studies. The markers of oxidative stress including malondialdehyde content, protein carbonyl content, protein thiol, and myeloperoxidase activity, a marker of neutrophil infiltration, were measured in bladder homogenates. CP treatment induced hemorrhagic cystitis in the rats. Pretreatment with glutamine significantly reduced CP-induced lipid peroxidation (p < 0.01), protein oxidation (p < 0.01), and increase in myeloperoxidase activity (p < 0.05). However, it did not prevent CP-induced bladder damage. The results of the present study show that glutamine pretreatment does not attenuate CP-induced hemorrhagic cystitis, although it prevents CP-induced oxidative stress and neutrophil infiltration significantly. It is therefore necessary to clarify the utility of glutamine as a chemoprotective agent before it is recommended in the market as a nutrient supplement.

Inhibition of cyclophosphamide-induced oxidative stress in rat brain by polar and non-polar extracts of Annatto ( Bixa orellana) seeds

Annatto ( Bixa orellana) seeds are widely distributed throughout the Tropics and have been used to provide both colour and flavour to food. This study sought to assess the ability of dietary inclusion of polar (water) and non-polar (chloroform) extracts of Annatto ( B. orellana) seeds on cyclophosphamide-induced oxidative stress in rat brain. The total phenol content and antioxidant activities of polar (water) and non-polar (chloroform) extracts of Annatto seeds were determined in vitro and in vivo. The results of the study showed that intraperitoneal administration of cyclophosphamide (75 mg/kg of body weight) caused a significant increase ( P<0.05) in the malondialdehyde (MDA) content of the brain; however, dietary inclusion of Annatto seed extracts (0.1% and 0.2%) caused dose-dependent significant decrease ( P<0.05) in the MDA content of the brain. Likewise, the extracts also caused dose-dependent inhibition of the elevated serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase and total bilirubin. However, the non-polar extract had significantly higher inhibitory effects on the elevated MDA production in brain and serum liver function markers. This higher protective effect of the non-polar extract could be attributed to its higher antioxidant properties as typified by its significantly higher ( P<0.05) reducing power, free-radical scavenging and Fe (II) chelating ability. Therefore, dietary inclusion of Annato seed extracts as food colourant could prevent oxidative stress occasioned by cyclophosphamide administration, but the non-polar extract is a better protectant.

Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative stress, DNA damage and early hepatocarcinogenesis in rat: Role of Nrf2, p53, p38 and phase-II enzymes

Cyclophosphamide, an alkylating agent, disturbs the oxidant and antioxidant balance that is associated with several unwanted toxic effects and induction of secondary cancers. Astaxanthin is a powerful antioxidant and possess several beneficial effects against various human diseases and physiological disorders. The present study was aimed to investigate the effects of astaxanthin against cyclophosphamide-induced oxidative stress, DNA damage, cell death and induction of GST-P foci in rat liver. Further attempt has been made to study the influence of astaxanthin on antioxidant response element (ARE) and the transcription factor Nrf2 (nuclear factor E 2-related factor 2) in the induction of phase-II enzymes NAD(P)H: quinine oxidoreductase-1(NQO-1) and Hemoxygenase-1 (HO-1). Both pre- and post-treatment with astaxanthin (25 mg/kg) decreased cyclophosphamide-induced oxidative stress and DNA damage in the liver as evident from the restoration in malondialdehyde and glutathione level as well as modified comet assay parameters. Significant decrease in the number as well as area of GST-P foci in rat hepatocytes was observed with astaxanthin post-treatment. Treatment with astaxanthin significantly decreased the expression of p53 and p38 as compared to cyclophosphamide treated group. It was further observed that the level of Nrf2 and phase-II enzymes, i.e. NQO-1 and HO-1 were increased with astaxanthin treatment. The present study confirms that astaxanthin is a potent antioxidant and attenuates oxidative stress, DNA damage, cell death as well as induction of early hepatocarcinogenesis in rat induced by cyclophosphamide. Our results provide the evidence that one of the mechanism of chemoprotection offered by astaxanthin is mediated through Nrf2–ARE pathway.

Cyclophosphamide-induced oxidative stress in brain: Protective effect of hot short pepper (Capsicum frutescens L. var. abbreviatum)

This study sought to characterize the distribution of phenols and antioxidant activities in hot short pepper (Capsicum frutescens var. abbreviatum) and their inhibition of cyclophosphamide-induced oxidative stress in rat's brain. The total phenol content and antioxidant activities of pepper flesh (pericarp) and seeds were determined in vitro and in vivo. The results of the study revealed that intraperitoneal administration of cyclophosphamide (75mg/kg of body weight) caused a significant increase (P<0.05) in the malondialdehyde (MDA) content of the brain; however, there was a significant decrease (P<0.05) in the brain MDA content, in those of rats fed diet containing pepper; the flesh showed a higher inhibitory effect. In addition, dietary inclusion of the pepper (seed and flesh) also caused a dose-dependent inhibition of serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase and total bilirubin; likewise, dietary inclusion of the flesh inhibited MDA production than the seeds. The higher inhibition of oxidative stress in brain and serum enzymes and metabolites by the flesh could be attributed to its significantly higher (P<0.05) total phenol content, reducing power and free-radical scavenging ability. Therefore, dietary hot short pepper (Capsicum frutescens L. var. abbreviatum) could prevent cyclophosphamide-induced oxidative stress in brain; although the flesh is a better protectant, the possible contributory role of the seeds cannot be neglected. However, this protective effect of the pepper could be attributed to their antioxidant properties.