Multi-drug resistance protein (Mrp) 3 may be involved in resveratrol protection against methotrexate-induced testicular damage

El-Sheikh, Azza A. K.; Morsy, Mohamed A.; Al‐Taher, Abdulla

doi:10.1016/j.lfs.2014.10.015

Cited by 16 publications

(24 citation statements)

References 46 publications

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“…After acclimatization, animals were weighed and divided into four groups ( n = 8). The RES‐treated group received oral RES for 8 consecutive days in a dose of 10 mg/kg/day , while the MTX‐treated group received a single intraperitoneal injection of MTX in a dose of 20 mg/kg at day 4, before the termination of the experiment with 5 days . The MTX/RES‐treated group received a combination of both treatments, whereas the control group received vehicles of RES (saline) and MTX (distilled water) in the same volume by the same route of administration.…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, RES was shown to exhibit profound multiorgan protective effects, as in the cardiovascular system, liver, and neurons , although many of RES‐induced in vivo positive effects are only achieved at relatively high doses and long treatment periods, probably due to its extensive metabolism. We have recently shown that RES also has testicular protective effects against the toxicity of the anticancer drug methotrexate (MTX) in vivo, at least in part through upregulation of multidrug resistance protein (MRP) 3 transporter . In the kidney, RES has been reported to have renal protective effects against diabetic nephropathy, as well as aldosterone‐induced, ischemia/reperfusion‐mediated, and sepsis‐related injuries .…”

Section: Introductionmentioning

confidence: 99%

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Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2

El-Sheikh

Morsy

Al‐Taher

2016

Fundamemntal Clinical Pharma

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Resveratrol (RES) is a well-known polyphenol antioxidant. We have previously shown that testicular protective effect of RES against the anticancer drug methotrexate (MTX)-induced toxicity involves transporter-mediated mechanisms. Here, we investigated the effect of RES on MTX-induced nephrotoxicity. Rats were administered RES (10 mg/kg/day) for 8 days, with or without a single MTX dose (20 mg/kg i.p.) at day 4 of the experiment. MTX induced nephrotoxicity, as evidenced by a significant increase in serum blood urea nitrogen and creatinine compared to the control, as well as distortion of kidney microscopic structure. MTX also significantly increased renal nitric oxide level along with inducible nitric oxide synthase, fas ligand, and caspase 3 expressions. Administering RES prior to MTX significantly improved kidney function and microscopic picture and also significantly decreased nitrosative and apoptotic markers compared to MTX alone. RES, but not MTX, caused a significant increase in expression of breast cancer resistance protein (BCRP), an apical efflux renal transporter that participates in urinary elimination of both MTX and RES. Interestingly, concomitant MTX and RES caused further upregulation of renal BCRP compared to RES alone. Using Human BCRP ATPase assay, both RES and MTX exhibited a dose-dependent increase in ATPase activity, with Km values of 0.52 ± 0.03 and 30.9 ± 4.2 μm, respectively. Furthermore, combined RES and MTX caused ATPase activity which was significantly less than maximum ATPase activity attained by the positive control, sulfasalazine (12.5 μm). In conclusion, RES exerted nephroprotection against MTX-induced toxicity through antinitrosative and anti-apoptotic effects, as well as via upregulation of renal BCRP.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2

El-Sheikh

Morsy

Al‐Taher

2016

Fundamemntal Clinical Pharma

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“…Using image J 1.41 (freeware; rsbweb.nih.gov/ij), the immunopositive cells and total number of cells in a field was calculated. [ 17 ] Results were the average of counting three sections from each rat and were expressed as percent of immunopositive cells compared to total number of cells.…”

Section: Methodsmentioning

confidence: 99%

Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats

2016

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Background:Intestinal toxicity is a serious side effect in methotrexate (MTX) chemotherapy.Objective:To investigate the mechanisms by which the anticancer drug MTX-induced intestinal damage could be prevented by thymoquinone (TQ), an active ingredient of Nigella sativa.Materials and Methods:TQ was given orally for 10 days, and MTX toxicity was induced at the end of day 3 of the experiment, with or without TQ pretreatment.Results:MTX caused intestinal damage, represented by distortion in normal intestinal histological structure, with significant oxidative stress, exhibited as decrease in reduced glutathione concentration and catalase activity, along with significant increase in malondialdehyde level compared to control group. MTX also caused nitrosative stress evident by increased intestinal nitric oxide (NO) level, with up-regulation of inducible NO synthase expression shown in immunohistochemical staining. Furthermore, MTX caused inflammatory effects as evident by up-regulation of intestinal necrosis factor-kappa beta and cyclooxygenase-2 expressions, which were confirmed by increased intestinal tumor necrosis factor-alpha level via enzyme-linked immunosorbent assay. Moreover, MTX caused apoptotic effect, as it up-regulated intestinal caspase 3 expression. Concomitant TQ significantly reversed the MTX-induced intestinal toxic effects by reversing intestinal microscopic damage, as well as significantly improving oxidative/nitrosative stress, inflammatory and apoptotic markers tested compared to MTX alone.Conclusion:TQ may possess beneficial intestinal protective effects as an adjuvant co-drug against MTX intestinal toxicity during cancer chemotherapy. TQ protection is conferred via antioxidant, anti-nitrosative, anti-inflammatory, and anti-apoptotic mechanisms.SUMMARY Methotrexate induces oxidative and nitrosative stress in intestinal tissuesMethotrexate also initiates inflammatory and apoptotic intestinal injuryThymoquinone co-administration ameliorates methotrexate-induced intestinal toxicityThymoquinone has antioxidative, anti-nitrosative, anti-inflammatory, and anti-apoptotic mechanisms. Abbreviations used: COX-2: Cyclooxygenase-2, ELISA: Enzyme-linked immunosorbent assay, H and E: Hematoxylin and eosin, iNOS: Inducible nitric oxide synthase, MDA: Malondialdehyde, MTX: Methotrexate, NO: Nitric oxide, NF-κB: Nuclear factor-κB, GSH: Reduced glutathione, TQ: Thymoquinone, TNF-α: Tumor necrosis factor-alpha

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“…As testosterone is indicative of the level of spermatogenesis in males, serum testosterone was used as a marker of testicular function. Testosterone is required for the continues production of different generation of germ cells in the seminiferous tubules (El‐Sheikh, Morsy, & Al‐Taher, ). We observed that in plasma the testosterone levels in AOM group were significantly lower than in the control group ( p < .05).…”

Section: Discussionmentioning

confidence: 99%

Preventive effects of Resveratrol against azoxymethane-induced testis injury in rats

et al. 2016

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To evaluate the protective effects of Resveratrol (RES) on azoxymethane (AOM)-induced testicular damage using histopathology and biochemical analyses, 28 male rats were randomly divided into four groups. Groups were control, RES, AOM and ARES. At the end of the 7 weeks, following routine tissue processing procedure, testis sections were stained with haematoxylin-eosin and Masson's trichrome. The blood samples were taken for biochemical analysis of testosterone, total oxidative stress, total antioxidant status and oxidative stress index. Degenerative changes in the seminiferous tubules such as atrophy, loss in the number of germ cells and arrested spermatogenic cell, and increase in the connective tissue of the tunica albuginea in the groups with AOM treatment were found. RES treatment (ARES) reduced the number of affected seminiferous tubules significantly (p < .05) compared to AOM alone. The testosterone levels in AOM group were significantly lower than in the control group (p < .05). The total oxidative stress levels were significantly higher in AOM group compared to control group (p < .05). The total antioxidant status levels in ARES group were significantly higher than in the AOM group (p < .05). This study results suggest that an antioxidant like Resveratrol may be useful for decreasing the harmful effects of azoxymethane.

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Multi-drug resistance protein (Mrp) 3 may be involved in resveratrol protection against methotrexate-induced testicular damage

Cited by 16 publications

References 46 publications

Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2

Protective mechanisms of resveratrol against methotrexate‐induced renal damage may involve BCRP/ABCG2

Protective mechanisms of thymoquinone on methotrexate-induced intestinal toxicity in rats

Preventive effects of Resveratrol against azoxymethane-induced testis injury in rats

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