CP-treated Rats Research Articles

Neuroprotective mechanisms and ameliorative activities of quercetin in cisplatin-induced cerebellum neurotoxicity in rat models

Cisplatin (CP) is a highly effective antitumor agent, but its clinical use is limited due to critical adverse reactions including neurotoxicity. Quercetin (QC) is a naturally occurring phytochemical with promising bioactive effects. This study investigated the Neuroprotective mechanisms and ameliorative activities of quercetin in cisplatin-induced cerebellum neurotoxicity in rat models.The rats were randomly divided into five groups of six (n = 6) rats. Group A, served as control. Group B, received a single dose of 10 mg/kg body weight (bwt) of CP (i.p.) on the first day. Group C received 30 mg/kg bwt of QC. Group D received a single dose of 10 mg/kg bwt CP on the first day followed by 30 mg/kg bwt of QC. Group E received 30 mg/kg bwt of QC per day followed by a single dose of 10 mg/kg bwt of CP on the last day. The treatment lasted for 35 days after which the novel-object recognition memory test (NORT) was used to assess non-spatial memory function. Brain neurochemical status was assessed and brain tissues were processed for histology.Quercetin increased weight loss and cognitive performance in CP-treated rats by enhancing the exploration of unfamiliar objects. Quercetin protects the brain from CP-mediated alterations in oxidative status, as well as brain metabolic enzyme indicators. It also decreased IL-6, IL-1, and TNF-α, and NF-ĸB expression, restored brain metabolic enzyme activities, increased neurotransmitters, and prevented neuromorphological alterations.In conclusion, quercetin protects rats’ brains against CP-induced cerebellum neurotoxicity via oxidative stress inhibition and down-regulation of inflammation.

Icariin inhibits cisplatin-induced ovarian toxicity via modulating NF-κB and PTEN/AKT/mTOR/AMPK axis.

Cisplatin (CP) is a highly effective broad-spectrum chemotherapeutic agent for several solid tumors. However, its clinical use is associated with ovarian toxicity. Icariin (ICA) is a bioactive flavonoid of Epimedium brevicornum with reported protective activities against inflammation, oxidative stress and ovarian failure. This study aimed to explore the protective effects of ICA against CP-associated ovarian toxicity in rats. Rats were randomized into five groups and treated for 17 days: control, ICA (10 mg/kg/day, for 17 days. p.o.), CP (6 mg/kg, i.p. on days 7 and 14), CP + ICA (CP 6 mg/kg i.p. on days 7 and 14 and ICA 5 mg/kg p.o. daily), and CP + ICA (CP 6 mg/kg i.p. on days 7 and 14 and ICA 10 mg/kg p.o. daily). Our results indicated that ICA effectively improved ovarian reserve as indicated by attenuating CP-induced histolopathological changes and enhancing serum anti-müllerian hormone (AMH). Furthermore, co-administration of ICA with CP showed restoration of the oxidant-anti-oxidant balance in ovarian tissues, evidenced by decreased malondialdehyde (MDA) concentrations and elevated superoxide dismutase (SOD) and catalase (CAT) activities. Also, ICA suppressed ovarian inflammation as evidenced by down-regulation of the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB). ICA inhibited ovarian apoptosis in CP-treated rats by down-regulation of CASP3 and Bax and up-regulation of Bcl-2 mRNA expression. Further, ICA enhanced PTEN, p-AKT, p-mTOR, and p-AMPKα expression. In conclusion, ICA possesses a protective activity against CP-induced ovarian toxicity in rats by exhibiting antioxidant, antiinflammatory, anti-apoptotic activities and modulating NF-κB expression and PTEN/AKT/mTOR/AMPK axis in ovarian tissues.

Magnolin alleviates cyclophosphamide-induced oxidative stress, inflammation, and apoptosis via Nrf2/HO-1 signaling pathway.

In the present study, we investigated the protective effect of magnolin (MAG) against oxidative stress induced by cyclophosphamide (CP) and its role in the Nrf2/HO-1 signaling pathway. Rats were administered MAG (1mg/kg, i.p.) for 14days and CP (75mg/kg, i.p.) on the 14th day. CP administration increased tissue damage, as evidenced by elevated levels of transaminases (aspartate and alanine), alkaline phosphatase, and renal parameters (blood urea nitrogen and creatinine). Additionally, 8-hydroxy-2'-deoxyguanosine and malondialdehyde levels were increased, whereas glutathione levels, along with catalase and superoxide dismutase activities, decreased in CP-treated rats. CP also down-regulated the expression of Bcl-2, HO-1, Nrf2, and NQO-1, while up-regulating Bax, Cas-3, TNF-α, Cox-2, iNOS, IL-6, IL-1β, and NFκB in liver and kidney tissues. In addition, CP treatment caused histopathological changes in heart, lung, liver, kidney, brain, and testis tissues. Treatment with MAG improved biochemical and oxidative stress parameters and prevented histopathological changes in CP-treated rats. Moreover, MAG suppressed the expression of inflammatory cytokines and apoptosis markers. In conclusion, MAG effectively prevented CP-induced toxicity by reducing oxidative stress, inflammation, and apoptosis, with its protective efficacy associated with the up-regulation of Nrf2/HO-1 signaling.

Potential ameliorative effects of bilberry (Vaccinium myrtillus L.) fruit extract on cisplatin-induced reproductive damage in adult male albino rats.

Cisplatin (CP) is a widely used chemotherapeutic agent, but its severe side effects impact testicular function. We investigated the potential protective effects of bilberry extract against CP-induced testicular toxicity. Forty adult male albino rats were divided into four groups. Control animals received a single oral dose of 0.9% saline. Bilberry-treated rats received oral bilberry extract (200 mg/kg body weight [BW] dissolved in 1 mL of saline) daily for 10 consecutive days. CP-treated animals were administered a single intraperitoneal dose (7.5 mg/kg BW). Finally, a bilberry+CP group received oral bilberry extract (200 mg/kg BW) daily for 10 consecutive days, with one intraperitoneal dose of CP (7.5 mg/kg BW) on day 2. We assessed sperm count, motility, viability, and abnormalities, along with testis weight, testis weight-to-BW ratio, antioxidant activity, levels of oxidative stress markers (malondialdehyde [MDA] and hydrogen peroxide [H2O2]), sex hormones (follicle-stimulating hormone [FSH], luteinizing hormone [LH], and testosterone), and apoptotic and anti-apoptotic markers, and DNA damage. Testicular tissue underwent histopathological examination. Among CP-treated rats, significantly lower values were observed for testis weight; testis weight-to-BW ratio; levels of FSH, LH, testosterone, superoxide dismutase, catalase, glutathione S-transferase, glutathione, and B-cell lymphoma 2; and sperm count, motility, and proportion of normal sperm. CP administration was associated with higher MDA, H2O2, p53, Bax, cytochrome c, caspase 9, and caspase 3 levels, along with elevated tail moment. However, bilberry extract administration significantly improved all altered parameters. Bilberry treatment demonstrated protective effects and reduced CP-induced testicular toxicity via antioxidant activity and cytoprotection.

The immune-modulatory role of MSCs exerted by PI3K/AKT signaling pathway in kidney tissue after cyclophosphamide.

Cyclophosphamide (CP) is one of the most effective immunosuppressive agents. To understand the mechanisms used by the CP and MSCs in the kidney, we investigated their effects on some pathways. 4 groups of female rats were used. GI: was the normal control group treated with saline solution. Groups G II, G III, and G IV were treated with CP. G I and G II groups were sacrificed on the fourth day after treatment., G III (Auto healing group) was left without treatment after the CP injection for six days. The G IV group was treated with MSCs on the fourth day after the CP injection. G III and G IV groups were sacrificed six days after treatment, and the kidney was removed and processed. CP induced up-regulation in CD14 and CD21 positive cells and caspase. Significant down-regulation of previous markers in groups III and IV. CP exerted a downregulation effect on AKT/ PI3K, that were ameliorated in groups III and IV. A significant increase in P53, BCL2, as well as VEGF in Group IV (P < 0 05). MSCs play a vital function in the immune inhibition in CP-treated rats through PI3K/AKT pathway.

The protective effect of hydroalcoholic extract of Ephedra pachyclada leaves on ovarian damage induced by cyclophosphamide in rat: An experimental study.

Cyclophosphamide (CP) is an anticancer drug that acts as an alkylation agent after metabolism in the liver. CP has toxic effects on the body's cells, especially the reproductive system's function, and causes infertility. Moreover, medicinal plants have few side effects and are psychologically acceptable to patients. This study aimed to investigate the impact of Ephedra pachyclada hydroalcoholic extract (EPHE) on ovarian tissue and hypothalamic-pituitary-gonadal axis in rats treated with CP. In this experimental study, 48 adult female Wistar rats (180-200 gr, 9-10 wk) were randomly assigned to 6 experimental groups (n = 8/each): (a) control; (b) sham; (c) CP; (d) CP+250 mg/kg EPHE; (e) CP+500 mg/kg EPHE; (f) CP+1000 mg/kg EPHE. On the 29 day of the experiment, serum was collected; serum concentration of the luteinizing hormone, follicle-stimulating hormone, estrogen, progesterone, and antioxidant activity were measured. The number of ovarian follicles were also counted. In the CP groups, serum concentrations of follicle-stimulating hormone and luteinizing hormone significantly increased, and estrogen and progesterone significantly decreased (p 0.05). EPHE significantly compensated for the complications caused by CP and 1000 mg/kg had the greatest effect. Antioxidant reduction by CP was significantly enhanced by EPHE, especially at higher doses (p 0.05). The number of primordial, primary, secondary, and Graafian follicles showed a significant decrease in CP groups and EPHE groups showed a significant increase compared to the CP. EPHE showed that the concentration of 1000 mg/kg was more effective than other doses (p 0.05). In addition to proving the effect of EPHE on the hypothalamic-pituitary-gonadal axis, our investigation showed antioxidant properties, which can be an effective factor in CP-treated rats.

Micronuclei and nuclear buds in amniotic tissue of rats treated with cyclophosphamide.

Fetal development can be altered by DNA damage caused by maternal exposure to chemical, physical, or biological agents during gestation. One method of assessing genotoxicity is to detect micronuclei (MNs) and/or nuclear abnormalities. This can be performed in vivo and requires only frequently dividing tissues, such as amniotic tissue (AT), which is in contact with the fetal environment and is composed of very thin layers of cells. This study evaluated the presence of MNs, nucleoplasmic bridges, and nuclear buds (NBs) in the fetal AT following maternal exposure to cyclophosphamide (CP) during pregnancy. Pregnant Wistar rats were divided into a negative control group and an experimental group that was orally administered CP (10mg/kg). Daily blood smears were obtained from pregnant rats on days 14-19 of gestation. The rats were dissected, and fetal ATs were obtained on the 19th day of gestation. The MN and NB frequencies in AT cells were analyzed using a fluorescence microscope (100×). Micronucleated erythrocytes in the peripheral blood of the control rats were also assessed. Micronucleated polychromatic erythrocyte frequencies were significantly higher than those in the controls. Polychromatic erythrocyte frequencies were lower in CP-treated rats than in controls at 48-120h. Fetuses in the CP-treated group also showed a significant increase in MNs and NBs in AT cells. In conclusion, AT could be used for analyzing MNs and NBs in rats following maternal exposure to a genotoxic agent and as a viable alternative for analyzing the integrity of fetal DNA during gestation.

Ginger's Antiapoptotic and Antioxidant Effects on Ovaries of Cyclophosphamide-therapied Rats.

In the recent decade, there has been increasing interest in preventing ovarian toxicity after chemotherapy exposure. It has been documented that ginger (Zingiber officinale) might normalize the hormonal balance and control the menstrual cycle.. This study has analyzed whether ginger extract protects against cyclophosphamide (CP)-induced ovarian failure in rats. Rats were distributed into four groups consisting of vehicle, CP, ginger, and CP + ginger. At the end of the treatment, all rats were killed under anesthesia to obtain ovarian tissues and blood samples for histological, molecular, and biochemical experiments. Our results indicated that ginger improves CP-caused histological changes in ovarian tissues and significantly restores serum hormonal abnormalities. Ginger also showed unique antioxidant, anti-inflammatory, and antiapoptotic properties in the ovarian tissues of CP-induced rats. Further, our findings indicated that ginger might activate the Nrf2 and SIRT and inhibit the PI3K/AKT pathway in the ovaries of CP-treated rats. In conclusion, ginger was found to protect against CP-caused ovarian toxicity in rats. The protective impacts of ginger may mediate, at least partly, by alleviating the oxidant state, inhibiting pro-inflammatory conditions, and exhibiting antiapoptotic activities.

Protective effect of arbutin against cyclophosphamide-induced oxidative stress, inflammation, and hepatotoxicity via Nrf2/HO-1 pathway in rats.

Cyclophosphamide (CP) is a potent anticancer drug widely employed in chemotherapy against various types of cancer. However, CP leads to toxicity to non-targeted organs, including the liver and this limits its clinical use. This study explored the role of arbutin (ARB) against CP-mediated oxidative and inflammatory reactions and hepatotoxicity. Rats were administered ARB (25 and 50 mg/kg) for 14 days and CP (150 mg/kg). CP triggered liver tissue injury with marked increase in serum AST, ALT, ALP, and bilirubin, and hepatic malondialdehyde (MDA) and nitric oxide (NO) coupled with diminution of GSH, SOD, catalase, and GPx. Liver NF-kB p65, NOS, IL-6, TNF-α, Bax and caspase-3 were upregulated by CP injection and IL-10 and Bcl-2 were decreased. ARB prevented liver injury, suppressed MDA, NO, NF-kB p65, inflammatory markers, Bax and caspase-3 in CP-treated rats. ARB restored antioxidants, IL-10 and Bcl-2, and enhanced Nrf2 and hemeoxygenase-1 (HO) both gene and protein in the liver of rats. In conclusion, these results pinpointed the protective role of ARB on oxidative and inflammatory reactions, apoptosis, and hepatotoxicity in rats. This hepatoprotective activity was linked to the ability of ARB to modulate Nrf2/HO-1 pathway.

Combination of metformin and hesperidin mitigates cyclophosphamide-induced hepatotoxicity. Emerging role of PPAR-γ/Nrf-2/NF-κB signaling pathway.

Cyclophosphamide (CP) is widely used as an immunosuppressive and chemotherapeutic drug. However, its therapeutic application is restricted by its adverse effects, particularly hepatotoxicity. Both metformin (MET) and hesperidin (HES) have promising antioxidant, anti-inflammatory, and anti-apoptotic effects. Therefore, the principal aim of the current study is to investigate the hepatoprotective effects of MET, HES, and their combinations on the CP-induced hepatotoxicity model. Hepatotoxicity was evoked by a single (I.P) injection of CP (200mg/kg) on day 7. For this study, 64 albino rats were randomly categorized into eight equal groups; naïve, control vehicle, untreated CP (200mg/kg, IP), and CP 200 groups treated with MET 200, HES 50, HES 100 or a combination of MET 200 with HES 50 and HES 100 respectively orally daily for 12days. At the end of the study, the liver function biomarkers, oxidative stress, inflammatory parameters, histopathological and immunohistochemical analysis of PPAR-γ, Nrf-2, NF-κB, Bcl-2, and caspase3 were assessed. CP significantly increased serum ALT, AST, total bilirubin, hepatic MDA, NO content, NF-κB, and TNF-α. Otherwise, albumin, hepatic GSH content, Nrf-2, and PPAR-γ expression decreased considerably compared to the control vehicle group. The combinations of MET200 with HES50 or HES100 induced pronounced hepatoprotective, anti-oxidative, anti-inflammatory, and anti-apoptotic effects on CP-treated rats. The possible explanation of such hepatoprotective effects may be mediated via upregulation of Nrf-2, PPAR-γ, Bcl-2 expression, hepatic GSH content, and marked suppression of TNF-α and NF-κB expression. In conclusion, the current study showed that combining MET and HES revealed a remarkable hepatoprotective effect against CP-induced hepatotoxicity.

Hesperidin Mitigates Cyclophosphamide-Induced Testicular Dysfunction via Altering the Hypothalamic Pituitary Gonadal Axis and Testicular Steroidogenesis, Inflammation, and Apoptosis in Male Rats.

Cyclophosphamide (CP) is a cytotoxic, cell cycle, non-specific, and antiproliferative drug. This study aimed to address the toxic effects of CP on male fertility and the possible ameliorative role of hesperidin (HSP). Thirty-two adult albino rats were randomly divided into four groups, namely, the negative control, HSP, CP-treated, and CP+HSP-treated groups. The CP-treated rats showed a significant reduction in the levels of serum LH, FSH, testosterone, prolactin, testicular glutathione peroxidase (GPx), and total antioxidant capacity (TAC) with an elevation in levels of malondialdehyde (MDA), and p53, and iNOS immune expression, compared to the control group. A significant downregulation in hypothalamic KISS-1, KISS-1r, and GnRH, hypophyseal GnRHr, and testicular mRNA expression of steroidogenesis enzymes, PGC-1α, PPAR-1, IL10, and GLP-1, as well as a significant upregulation in testicular mRNA of P53 and IL1β mRNA expression, were detected in the CP-treated group in comparison to that in the control group. The administration of HSP in CP-treated rats significantly improved the levels of serum LH, FSH, testosterone, prolactin, testicular GPx, and TAC, with a reduction in levels of MDA, and p53, and iNOS immune expression compared to the CP-treated group. A significant upregulation in hypophyseal GnRHr, and testicular mRNA expression of CYP19A1 enzymes, PPAR-1, IL10, and GLP-1, as well as a significant downregulation in testicular mRNA of P53 and IL1β mRNA expression, were detected in the CP+HSP-treated group in comparison to that in the CP-treated group. In conclusion, HSP could be a potential auxiliary agent for protection from the development of male infertility.

Biochemical, Histological, and Ultrastructural Studies of the Protective Role of Vitamin E on Cyclophosphamide-Induced Cardiotoxicity in Male Rats

Cyclophosphamide (CP) (Cytoxan or Endoxan) is an efficient anti-tumor agent, widely used for the treatment of various neoplastic diseases. The study aimed to investigate the protective role of vitamin E (vit E) in improving cardiotoxicity in rats induced by CP. Forty male Wistar rats were divided randomly into four experimental groups (each consisting of ten rats); the control group was treated with saline. The other three groups were treated with vit E, CP, and the combination of vit E and CP. Serum lipid profiles, enzyme cardiac biomarkers, and cardiac tissue antioxidants were evaluated, as well as histological and ultrastructure investigations. CP-treated rats showed a significant increase in serum levels of cardiac markers (troponin, CK, LDH, AST, and ALT), lipid profiles, a reduction in the antioxidant enzyme activities (CAT, SOD, and GPx), and an elevation in the level of lipid peroxidation (LPO). The increase in the levels of troponin, LDH, AST, ALP, and triglycerides is a predominant indicator of cardiac damage due to the toxic effect of CP. The biochemical changes parallel cardiac injuries such as myocardial infarction, myocarditis, and heart failure. Vitamin E played a pivotal role, as it attenuated most of these changes because of its ability to scavenge free radicals and reduce LPO. In addition, vit E was found to improve the histopathological alterations caused by CP where no evidence of damage was observed in the cardiac architecture, and the cardiac fibers had regained their normal structure with minimal hemorrhage. As a result of its antioxidant activity and its stabilizing impact on the cardiomyocyte membranes, vit E is recommended as a potential candidate in decreasing the damaging effects of CP.

Effects of chemical and green nano-zinc oxide on histological changes, oxidative stress, and apoptosis in rat kidney associated with cisplatin

Cisplatin (CP) is used to treat various tumors. A main restriction of cisplatin is nephrotoxicity. This study aimed to evaluate the protective effects of ZnONPs on cisplatin-induced oxidative stress and rat kidney tissue damage. Eighty adult male Wistar rats (250g-270g) were divided into ten groups: Control (CON), Sham (SH), Bulk ZnO (BZnO), Chemical ZnONPs (ChZnONPs), Green ZnONPs (GrZnONPs), Cisplatin (CP), Cisplatin+BulkZnO (CP+BZnO), Cisplatin+Green ZnONPs (CP+GrZnONPs), Cisplatin+Chemical ZnONPs (CP+ChZnONPs), Cisplatin+Explant (CP+EX). CP was i.p administered 5mg/kg/week and BZnO, ChZnONPs and GrZnONPs were i.p administered at a dose of 5mg/kg/day. After 30 days of the treatment, the expression of apoptosis/anti apoptosis related genes oxidant/antioxidant factors and histological changes in the were studied. The CP-treated group showed a decrease in body weight, while the Co-administration of ZGNPs to CP-treated rats showed a significant increase compared to the CP group. The results showed that the increased mRNA level of bax, MDA and the decreased mRNA level of bcl2, SOD and CAT activities in kidney of CP group were improved when animals were treated with ZnO NPs. Our results showed that GrZnONPs, ChZnONPs and BZnO had the potential to protect against oxidative stress and cisplatin-induced neurotoxicity that this protective effect was more evident in GrZnONPs.

Protective effects of asperuloside against cyclophosphamide-induced urotoxicity and hematotoxicity in rats

Abstract Cyclophosphamide (CP) is a highly efficacious chemotherapy drug for treating cancers and autoimmune disorders, but it is also notable for its deleterious side effects including urotoxicity in cancer patients, which has been extensively linked to CP-induced oxidative/inflammatory cascades. Herein, we investigated the protective effects of asperuloside (ASP) against CP-induced urotoxicity. Rats received oral administration of ASP (20 and 40 mg/kg bw/day) for 35 days and were injected with weekly CP (100 mg/kg bw, i.p.) for 4 weeks to induce acute bladder toxicity. CP acutely altered haematological parameters and significantly reduced body weight gain, bladder glutathione peroxidase, reduced glutathione, catalase, and superoxide dismutase activities. Furthermore, CP caused an upward surge in bladder malondialdehyde, nuclear factor-kappa B, tumour necrosis factor-α, interleukin-1β, and interleukin 6 concentrations. ASP supplementation ameliorated CP-induced haematological derangement and bladder urotoxicity through the restoration of oxidative and inflammatory parameters in CP-treated rats. These findings suggested that ASP could be valorised as a possible therapeutic agent against chemotherapy-related toxicities as well as oxidative damage disorders.

Hydroethanolic extract of Ixora coccinea leaves inhibits testicular and epididymal toxicity associated with antitumor drug Cisplatin in rats

Cisplatin (Cp) is one of the most effective chemotherapy antineoplastic drugs. Nevertheless, it causes numerous injurious effects on numerous organs, precisely the testes. Ixora coccinea (IC) is a well-known medicinal herb and has a long history of medicinal use as a tonic to promote health. This study revealed the inhibitory effects of hydroethanolic extract of IC leaves (HEICL) on CP-induced testicular damage in male Wistar rats. Thirty (30) adult male Wistar rats were used and divided into six groups of five rats. These groups were treated as followed: Group 1(control group) and 2 were administered (0.9% saline) and CP (10 mg/kg. b.wt) intraperitoneal (IP) route respectively, and groups 3 and 4 were administered HEICL at 150 mg/kg and 300 mg/kg and 5 and 6 were co-treated with Cp + HEICL (150 and 300 mg/kg) respectively. The treatment duration was 28 days. Spermatological profiles and testicular histopathology were assessed. Cp-treated rats showed a significant (p&lt;0.05) reduction in relative organ weight and sperm parameters. On the other hand, Cp treatment increased the percentage of sperm abnormalities relative to the control and the groups administered HEICL only. These results were confirmed by histopathological analysis. Contrarily, there were modulations in cp-induced spermiotoxic and testicular damage following the HEICL pretreatment. Our research showed that CP treatment exerts damaging consequences on sperm parameters, testicular tissues, and accessory sex organs in rats. Pre-treatment with HEICL for 26 days at doses of 200 and 400 mg/kg bodyweight had a protective role against testicular damage brought on by CP.

Amaranthus hybridus (Amaranthaceae) prevents the detrimental effects of cyclophosphamide on ovarian function in Wistar rats: An experimental study.

BackgroundCyclophosphamide (CP) is an anticancer agent, but its chronic administration induces ovarian toxicity.ObjectiveWe evaluated the effects of aqueous extract (AE) and methanol extract (ME) of Amaranthus hybridus (A. hybridus) on CP-induced ovarian toxicity in rats.Materials and Methods40 female Wistar rats (10 wk, 170-200 gr) were distributed into 8 groups (n = 5/each) as follows: 1) healthy control; 2) CP+distilled water (10 ml/kg/d); 3) CP+3%-tween 80 (10 mL/kg/d); 4) CP+clomiphene citrate (2 mg/kg/d); 5, 6) CP+AE of A. hybridus (55 and 110 mg/kg/d); and 7, 8) CP+ME of A. hybridus (55 and 110 mg/kg/d). After 28 days of treatment, estrus cyclicity, ovarian and uterine weights as well as estradiol levels and ovarian histology were determined.ResultsCP induced ovarian toxicity after 28 days of exposure. More specifically, CP disturbed the estrus cycle, decreased ovary and uterus weights (p = 0.04), and the 17-β estradiol level (p = 0.04), and induced severe ovarian damages. Remarkably, A. hybridus significantly increased (p = 0.03) the ovarian weight (AE and ME at all doses) and uterus weight (ME at 110 mg/kg/d), compared with the CP-treated rats. Moreover, the 17-β estradiol level was significantly elevated (p = 0.02) in rats given clomiphene citrate and A. hybridus (AE 110 mg/kg/d; ME 55 mg/kg/d). Finally, the ovaries of rats given plant extracts had many corpus luteum and normal follicles, and no cystic follicles.Conclusionprevented the detrimental effects of CP on ovarian function, which could support its traditional use as a fertility enhancer.

LCZ696 (sacubitril/valsartan) protects against cyclophosphamide-induced nephrotoxicity in adult male rats: Up-regulation of Apelin-13/ACE2, miR-200, and down-regulation of TGF-β/SMAD 2/3 and miR-192

BackgroundCyclophosphamide (CP) is a widely used chemotherapeutic drug. However, the associated nephrotoxicity restricts its clinical use. AimThe present research was designed to study the impact of LCZ696 (LCZ); which is a combination of Sacubitril/Valsartan compared to valsartan (VAL) on CP-induced nephrotoxicity. Main methodsSixty adult male Wistar rats were randomly and equally assigned into 6 groups as follows: Control, LCZ (30 mg/kg, p.o.), VAL (15 mg/kg, p.o.), CP (200 mg/kg, single dose, i.p.), CP/LCZ, and CP/VAL groups. LCZ and VAL were given once daily for 6 days prior to CP (groups 5 & 6). At the end of the experiment, kidney functions, oxidants/antioxidants, inflammatory and fibrotic biomarkers in renal tissues were assessed. Further, immunohistochemical, and histomorphometric analyses were carried out. Key findingsIn comparison with CP-treated rats, LCZ resulted in a significant reduction in serum urea (26.6 %) and creatinine (63 %), moreover it decreased renal content of reactive oxygen species (ROS), zinc finger E-box-binding homeobox (ZEB)-1, SMAD2/3, plasminogen activator inhibitor (PAI)-1, fibronectin, histone deacetylase (HDAC)-4, nuclear factor-kappa B (NF-κB) and miR-192 expression by ~40–60 % as well as the immunohistological expressions of transforming growth factor-β (TGF-β) and anti-phospho Histone (H2AX) by ~75 % reduction. Whereas the renal total antioxidant capacity (TAC), apelin-13, miR-200 expression, and the immunoreactivity of angiotensin-converting enzyme 2 (ACE2) were enhanced by ~3–4-folds. Noteworthy, the prophylactic effect of LCZ was superior to VAL on the histomorphometric and immunohistological levels. SignificanceProphylactic administration of LCZ protected against CP-induced nephrotoxicity via up-regulating apelin-13/ACE2, miR-200, and down-regulating TGF-β/SMAD 2/3 and miR-192.

TLRs-JNK/ NF-κB Pathway Underlies the Protective Effect of the Sulfide Salt Against Liver Toxicity.

Hydrogen sulfide (H2S) is an endogenously gas transmitter signaling molecule with known antioxidant, anti-inflammatory, and cytoprotective properties. Although accumulating evidence shows the therapeutic potential of H2S in various hepatic diseases, its role in cyclophosphamide (CP)-induced hepatotoxicity remains elusive. The present study was undertaken to investigate the impact of endogenous and exogenous H2S on toll-like receptors (TLRs)-mediated inflammatory response and apoptosis in CP-induced hepatotoxicity. Either an H2S donor (NaHS (100 μM/kg) or an H2S blocker [dl-propargylglycine (PAG) (30 mg/kg, i. p.)], was administered for 10 days before a single ip injection of CP (200 mg/kg). NaHS attenuated conferred hepatoprotection against CP-induced toxicity, significantly decreasing serum hepatic function tests and improving hepatic histopathology. Additionally, NaHS-treated rats exhibited antioxidant activity in liver tissues compared with the CP group. The upregulated hepatic levels of TLR2/4 and their downstream signaling molecules including c-Jun N-terminal kinase (JNK) and nuclear factor-kappa B (NF-κB) were also suppressed by NaHS protective treatment. NaHS showed anti-inflammatory and antiapoptotic effects; reducing hepatic level tumor necrosis factor-alpha (TNF-α) and caspase-3 expression. Interestingly, the cytotoxic events induced in CP-treated rats were not significantly altered upon the blocking of endogenous H2S. Taken together, the present study suggested that exogenously applied H2S rather than the endogenously generated H2S, displayed a hepatoprotective effect against CP-induced hepatotoxicity that might be mediated by TLRs-JNK/NF-κB pathways.

Silymarin ameliorates cisplatin-induced nephrotoxicity by downregulating TNF-α and NF-kB and by upregulating IL-10

Cisplatin (CP) is one of the antineoplastic agents used to treat many types of cancers. Besides these effects of CP, it causes various side effects such as nephrotoxicity. Inflammation is considered to be one of the main pathogeneses of CP-induced nephrotoxicity. Silymarin (SIL) is a flavonoid with beneficial pharmacological properties such as antioxidant and anti-inflammatory. The current study aimed to investigate the beneficial effects of Silymarin against CP-induced nephrotoxicity. Albino Wistar male rats were randomly divided into four groups (n=7): Control group was administered saline (0.5 ml) for 10 days intraperitoneally (IP), CP group was received CP (a single dose of 8 mg/kg, IP), CP+ SIL group was administered saline (0.5 ml) for 10 days and was received CP (a single dose of 8 mg/kg). To measure the inflammatory response, TNF-α, NF-kB and IL-10 expressions were performed. As a result, TNF-α and NF-kB expressions significantly increased while IL-10 expression decreased in the kidney of the CP group compared to the control group. However, SIL treatment significantly decreased TNF-α and NF-kB expressions and increased IL-10 expression in kidney CP-treated rats. These findings reveal that SIL may ameliorates the CP-induced nephrotoxicity in rats by inducing downregulation of TNF-α and NF-kB expressions and upregulation of IL-10 expression.

Unravelling the Protective Effects of Emodin Against Cyclophosphamide Induced Gonadotoxicity in Male Wistar Rats.

BackgroundOver the past few decades, cyclophosphamide (CP) has been extensively used as a broad-spectrum alkylating agent for the treatment of various cancers and solid tumors. However, the therapeutic actions on CP are not limited to only cancer cells, as it simultaneously exerts significant toxicities on healthy cells through the instigation of oxidative stress and oxidative damages. CP induced testicular toxicity is associated with impaired spermatogenesis, reduced sperm functionality, reproductive hormone and testicular weight. This study was aimed at unravelling the protective effects of emodin (EMD) on testicular toxicity following CP treatment.MethodsTwenty-four male Wistar rats were allotted into 4 groups as normal control group (NCG), CP control group (CPCG), EMD25+CP (25 mg/kg in 5% tween 80) and EMD50+CP groups (50 mg/kg in 5% tween 80). EMD was orally administered for 35 consecutive days, while four doses of CP (100 mg/kg/week) were administered intraperitoneally from the second to fifth week of treatment. Thereafter, the animals were sacrificed and histopathological examination of the testes as well as serum/testicular biochemical assays were conducted.ResultsThe results revealed that CP significantly impeded sperm function parameters including sperm count, viability and motility as well as decreased reproductive hormones (testosterone, LH and FSH) levels. In addition, CP enhanced testicular oxidative stress and proinflammatory markers (MDA, IL-6 and TNF-α), while simultaneously decreasing testicular antioxidant enzymes (GSH, GPx, SOD and CAT). Evidence of marked histopathological alterations was also observed in the H&E stained testicular tissues of CP treated rats. EMD significantly prevented these CP induced negative effects.ConclusionThis study provides a basis for the potential use of EMD in counteracting chemotherapy induced testicular toxicity. The results further suggest that EMD testicular protective effects in CP-treated rats may be mediated through its modulatory role on oxidative stress and inflammation.