Cyclophosphamide-induced Toxicity Research Articles

Olive Oil's protective potential against cyclophosphamide-induced nephrotoxicity in Swiss albino rats

Background: Cyclophosphamide is a widely used chemotherapy drug, known for its cytotoxic and mutagenic effects on mammalian tissues and cells. Olive oil, rich in antioxidants, has potential protective effects against drug-induced organ damage. This study investigates the protective role of olive oil against cyclophosphamide-induced toxicity in mice. Objective: To evaluate the protective effects of olive oil against cyclophosphamide-induced kidney toxicity in rats. Material and Method: Male albino mice (n=9) were divided into three groups: Control, Cyclophosphamide (150 mg/kg), and Cyclophosphamide (150 mg/kg) + Olive Oil (200 mg/kg). After one week of treatment, kidney tissues were collected and stained with hematoxylin and Eosin for histopathological analysis. Results: The administration of olive oil led to a significant decrease in cellular damage of the kidney tissue. In this study the histopathological examination revealed marked improvement in kidney tissue architecture, with reduced cellular damage, inflammation, and fibrosis compared to the group treated with cyclophosphamide alone. These findings suggest that olive oil has a protective effect against cyclophosphamide-induced hepatic and renal toxicity in mice. Conclusion: Cyclophosphamide caused significant histopathological damage to kidney tissues in mice. Co-administration of olive oil mitigated these adverse effects, likely due to its antioxidant properties. This suggests that olive oil may serve as a protective adjunct in cyclophosphamide chemotherapy.

Surfactin from Bacillus subtilis enhances immune response and contributes to the maintenance of intestinal microbial homeostasis.

The potential of surfactin as a microbial surfactant extends beyond its surfactant properties, impacting immune regulation and gut health. As the need for alternatives to traditional antibiotics continues to grow, surfactin's ability to enhance host defense mechanisms against common pathogens without directly targeting them with antibiotics offers a strategic advantage. Understanding how surfactin shapes the immune landscape and the gut microbiome can inform innovative interventions against immunosuppression and intestinal impairment, particularly in contexts such as cyclophosphamide-induced toxicity.

Preliminary proteomic analysis of mouse lung tissue treated with cyclophosphamide and Venetin-1

Cyclophosphamide (CPAm) is a widely used chemotherapeutic agent that exhibits potent anti-cancer properties but is often associated with debilitating side effects. Despite its efficacy, the management of CPAm-induced toxicities remains a significant clinical challenge. There has been growing interest in exploring complementary and alternative therapies to mitigate these adverse effects in recent years, and this may be a chance for the earthworm-derived preparation, Venetin-1. Its rich composition of bioactive compounds has demonstrated promising pharmacological properties, including anti-inflammatory, antioxidant, and immunomodulatory effects. These properties suggest its potential to counteract various systemic toxicities induced by CPAm. We conducted a comprehensive study to investigate the effect of Venetin-1 on cyclophosphamide-induced toxicity. Mice were administered CPAm for four days, followed by application of the earthworm preparation in two doses (50 mg/kg and 100 mg/kg b.w). Importantly, the preparation did not cause any side effects in all mice, ensuring the safety of the intervention. We then determined global changes in the proteome using proteomics and quantitative SWATH-MS analysis, which is a robust and reliable method. This allowed us to identify up- and downregulated proteins in each studied group, providing valuable insights into the mechanism of action of Venetin-1. As shown by the results, Venetin-1 had a significant effect on the proteome of mouse lung tissue. It was possible to determine quantitative changes in 400 proteins, and the analysis after administration of Venetin-1 showed a change in the global proteomic profile from upregulated to down-regulated. The stimulating properties of the preparation concerning the complement system were also confirmed in a separate validation experiment. Venetin-1 shows promise in reducing the harmful effects of cyclophosphamide on lung tissue. It encourages tissue regeneration, reduces inflammation, supports autophagy, and boosts the immune system. However, more research is needed to thoroughly elucidate and describe the benefits of Venetin-1.

Ameliorative effects of thistle and thyme honeys on cyclophosphamide-induced toxicity in mice

Abstract Cyclophosphamide (CP) is a potent anticancer agent widely used to treat various malignancies and autoimmune diseases after organ transplantation. However, its therapeutic benefits are often accompanied by severe toxicity, primarily attributable to oxidative stress. In contrast, Moroccan honey, including varieties, such as thyme and thistle, is known for its multifaceted medicinal properties, including potent antioxidant activity. This study sought to investigate the protective potential of Moroccan honey against CP-induced genotoxic and cytotoxic effects in mouse bone marrow cells. The results revealed a significant increase in genotoxicity and cytotoxicity following CP administration (20 mg/kg), as evidenced by elevated micronuclei frequency and a reduced ratio of polychromatic to normochromatic erythrocytes. However, pretreatment with Moroccan honey (1 g/kg) for a duration of 6 days effectively attenuated these adverse effects. Furthermore, biochemical analysis demonstrated that mice receiving honey exhibited notable improvements in liver function, as indicated by decreased levels of alanine aminotransferase, aspartate aminotransferase, and uric acid. Histological examination revealed reduced hepatic damage characterized by diminished steatosis, apoptosis, necrosis, and inflammatory cell infiltration. These findings underscore the potential of thyme and thistle honeys, as a promising adjunctive therapy to mitigate the deleterious effects associated with CP treatment, offering potential applications in complementary chemotherapeutic strategies.

In Vitro Antitumor and Antioxidant Capacity as well as Ameliorative Effects of Fermented Kefir on Cyclophosphamide-Induced Toxicity on Cardiac and Hepatic Tissues in Rats.

Fermented prebiotic and probiotic products with kefir are very important to slow down and prevent the growth of tumors and to treat cancer by stimulating the immune response against tumor cells. Cyclophosphamide (CPx) is widely preferred in cancer treatment but its effectiveness in high doses is restricted because of its side effects. The aim of this study was to investigate the protective effects of kefir against CPx-induced heart and liver toxicity. In an experiment, 42 Wistar albino rats were divided into six treatment groups: the control (Group 1), the group receiving 150 mg/kg CPx (Group 2), the groups receiving 5 and 10 mg/kg kefir (Groups 3 and 4) and the groups receiving 5 and 10 mg/kg kefir + CPx (Group 5 and 6). Fermented kefirs obtained on different days by traditional methods were mixed and given by gavage for 12 days, while a single dose of CPx was administered intraperitoneally (i.p.) on the 12th day of the experiment. It was observed that alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), creatinine kinase-MB (CK-MB), ischemia modified albumin (IMA) and Troponin I values, which indicate oxidative stress, increased in the CPx-administered group, and this level approached that of the control in the CPx + kefir groups. Likewise, as a result of the kefir, the rats' CPx-induced histopathological symptoms were reduced, and their heart and liver tissue were significantly improved. In conclusion, it was observed that kefir had a cytoprotective effect against CPx-induced oxidative stress, hepatotoxicity and cardiotoxicity, bringing their biochemical parameters closer to those of the control by suppressing oxidative stress and reducing tissue damage.

Therapeutic effects of Medicago sativa against cyclophosphamide-induced toxicity in rats.

Medicago sativa (M. sativa) has been traditionally used for treating anemia; therefore, M. sativa hydro-ethanolic extract therapeutic effects against cyclophosphamide (CP) -induced hematologic and liver toxicity were examined. Thirty male Wistar rats were randomly divided to control (saline); CP (100 mg/kg, day 1-3, subcutaneously); CP+ M. sativa 200 mg/kg (MS 200); CP+ M. sativa 400 mg/kg (MS 400); CP+ dexamethasone (0.1 mg/kg), (all groups n=6). Treated animals received M. sativa or dexamethasone by gavage from days 7-14. On days 0, 7, and 14, hematologic parameters, and on the 14th day, serum and liver tissue oxidative stress markers including nitric oxide, malondialdehyde (MDA) and total thiol levels, superoxide dismutase (SOD) and catalase (CAT) activities, serum lipids, and liver enzymes were measured. Animal weight, platelet, white blood cells, and red blood cells counts, hemoglobin and hematocrit as well as thiol, SOD, and CAT activities in serum and liver tissue were significantly reduced, but serum nitric oxide, MDA, total cholesterol, triglycerides, low-density lipoproteins levels, and liver enzymes were increased in the CP group compared to the control group (p<0.05 to p<0.001). Administering M. sativa extract (400 mg/kg) significantly enhanced platelet count, and SOD and CAT activities and inhibited all of the CP toxic effects, while dexamethasone improved platelet count and oxidative stress markers compared to the CP group (p<0.05 to p<0.001). The extract of M. sativa (400 mg/kg) showed therapeutic effects against the CP-induced myelosuppression and thrombocytopenia and improved oxidative stress markers which were comparable to the effect of dexamethasone.

Ameliorative Effects of the Methanol Extract of Phyllantus amarus on Cyclophosphamide-Induced Toxicity in Mice

Ameliorative Effects of the Methanol Extract of Phyllantus amarus on Cyclophosphamide-Induced Toxicity in Mice

Preventive Effects of Traditional Plant Concoction “Combo” on the Cyclophosphamide-Induced Ovarian Toxicity in Wistar Rats

Exposure to chemotherapeutic agents like cyclophosphamide (a drug for cancer treatment), leads to infertility due to its toxic effect on the ovaries. Combo, “a commonly used plant concoction in traditional medicine for the treatment of infertility” is composed of Clove (dried flower), garlic (bulb), ginger (rhizome), and turmeric (rhizome). The aim of this study was to evaluate the possible prophylactic effects of Combo therapy in cyclophosphamide-induced ovarian toxicity in female Wistar rats. Female Wistar rats were divided into 6 groups (A-F) of 6 animals each. Group A (normal control) received distilled water only. Group B (negative control) received 200mg/kg of cyclophosphamide only, while group C (positive control) received only 29mg/kg of Combo. On the other hand, groups D, E and F were pretreated with Combo doses of (15, 29, and 290 mg/kg) and were later treated with 200mg/kg of cyclophosphamide after 7 days. All administrations were done orally. The reproductive hormones assayed were oestrogen and progesterone, while the oxidative stress biomarkers evaluated include glutathione, malondialdehyde, and nitric oxide. Their levels were used as diagnostic markers for assessing the reproductive functions of the ovaries. Combo pre-treatment significantly (p&lt;0.05) decreased the levels of malondialdehyde and nitric oxide, and significantly (p&lt;0.05) increased glutathione, oestrogen and progesterone levels when compared with cyclophosphamide group. Histopathological investigation showed that Combo mitigated degenerative cells in follicles, stromal oedema, and atresia of the follicles when compared with cyclophosphamide group. In conclusion, Combo has fertility potentials and can protect against ovarian degeneration in cyclophosphamide-induced toxicity.

1H NMR-based urinary metabolic analysis of high-dose cyclophosphamide-induced toxicity in mice

Cyclophosphamide (CP) is widely used in clinical fields. Beside its therapeutic effects, CP shows toxicity depending on dose and administration schedule. In this study, the urinary metabolic profiles were investigated in mice intraperitoneally injected with high-dose CP (150 mg/kg body weight) once a week over four weeks using nuclear magnetic resonance (NMR)-based metabolomics. Twenty-six metabolites were identified as potential biomarkers by multivariate statistical analysis. A decrease in isoleucine, alanine, N-acetylglutamic acid, proline, methionine, valine, phenylacetylglulamine, dimethylamine, hippurate, acetic acid, lactate, α-oxoglutarate, citrate, malonic acid, creatinine, niacin, β-hydroxybutyrate, and betaine, whereas an increase in leucine, glutamate, glycine, taurine, phenylacetylglycine, glucose, creatine, and choline were observed in the urine of high-dose CP-treated mice. Metabolites related to amino acid metabolism, energy metabolism, and gut microbial metabolism were changed markedly in the urine. Further metabolic pathway analysis suggested that seven metabolic pathways, including alanine, aspartate, and glutamate metabolism, arginine biosynthesis, glyoxylate, and dicarboxylate metabolism, glycine, serine and threonine metabolism, d-glutamine and d-glutamate metabolism, arginine, and proline metabolism, citrate cycle, as well as the gut microbiota metabolism, were significantly involved in response to high-dose CP treatment. These findings help to predict the toxicity of CP and understand the biological mechanism of the toxicity of CP.

Altered hallmarks of DNA double-strand breaks, oxidative DNA damage and cytogenotoxicity by piperlongumine in hippocampus and hepatocytes of rats intoxicated with cyclophosphamide

AimCyclophosphamide is an effective anti-tumor agent, however, it induces genomic instability and tissue toxicity in clinical application. This study aims to evaluate the action of piperlongumine against cyclophosphamide-induced toxicity. Main methodsThe action was investigated in rodent model of genomic instability, where piperlongumine (50 mg/kg) was orally co-administered with cyclophosphamide (5 mg/kg) for 28 days to Wistar albino rats. Further, piperlongumine was also examined for acute and sub-acute toxicity. Key findingsPiperlongumine significantly reversed genotoxicity in high-proliferation tissue (bone marrow: p < 0.05) as well as in vital tissues (hippocampus: p < 0.01 and hepatocytes: p < 0.05), calculated as micronuclei formation and %DNA fragmentation. It also restored the redox homeostasis, counteracted the formation of oxidative DNA damage product and DNA double-strand break in vital tissues, indicated by reduction of 8-OHdG and γH2AX. TUNEL assay revealed that piperlongumine diminished the cyclophosphamide-associated apoptotic cell death in hippocampus as well as in liver tissue and conferred cytoprotection to the host. These findings were finally corroborated with the histopathological findings, where piperlongumine treatment restored the cellular viability of liver and hippocampus. Further, piperlongumine did not produce any toxic effects to rats in systemic toxicity studies. SignificancePiperlongumine possesses genome stabilizing effect and reduces cyclophosphamide-associated DNA damage, oxidative stress, hepato-, and neurotoxicity, diminishes the DNA damage response pathway in the rat model, at the same time, conserves the micro-architectural details of liver and hippocampus. The findings are significant in terms of reducing genotoxic impact of chemotherapy-receiving patients.

Evaluation of Argyreia speciosa root extract as a protective agent against cyclophosphamide-induced toxicities

Evaluation of Argyreia speciosa root extract as a protective agent against cyclophosphamide-induced toxicities

Efficacy of Carob Leaves and Pods in Reducing Cyclophosphamide-Induced Toxicity on Bone Marrow and Peripheral Blood Leukocytes

Cyclophosphamide is one of the chemotherapeutics for cancer, however this drug has severe side effects in multiple organs and is a well-known mutagenic agent. In this work the protective activity of antioxidant-rich Carob (Ceratonia siliqua L.) pods and leaves extracts against cyclophosphamide induced genotoxicity was studied. Safety of these extracts was evaluated in acute and subacute toxicity tests at a dose of 1500 mg/kg/day in albino rats. Both extracts exhibited no mortality or significant changes in rats' general behavior. Moreover, organ weights and blood chemistry revealed no toxic effects of these extracts (p&gt;0.05).The anti-mutagenic potential of carob pods and leaves extracts were evaluated using in vivo bone marrow chromosomal aberration and micronucleus assays and in vitro comet assay for peripheral blood white cells. Results showed that rats that were treated with cyclophosphamide along with carob pods had a significant decrease in chromosomal aberrations when compared with cyclophosphamide-treated rats (p&lt;0.05). Pods extract also showed significant reduction in cyclophosphamide-induced DNA migration (p&lt;0.05). There were also highly statistically significant differences in the means of micronuclei (MNs) in immature red blood cells between cyclophosphamide group and carob leaves group (p&lt;0.01).It could be concluded that Carob extracts had protective effect against cyclophosphamide- induced genotoxicity and may be considered as anti-mutagenic agent after conducting more studies.

Evaluation of the protective effect of coenzyme Q10 on the growth process of embryos from in vitro fertilization in laboratory mice treated with cyclophosphamide

"Cyclophosphamide is an anticancer drug that acts as an alkylating agent after metabolism in the liver. Despite its many clinical applications in cancer treatment, this drug has toxic effects on the body's organs, especially the genitals. One of the most critical side effects is a change in the function of the female reproductive system, which can lead to infertility. This study aimed to investigate the antioxidant effects of coenzyme Q10 on cyclophosphamide-induced toxicity in vitro fertilized embryos in mice. In this experimental study, 24 female mice weighing 25 g 4 groups of 6 were divided and treated for 21 days. The first group (control group), solvent (cyclophosphamide) including DMSO and PBS (0.1 ml intraperitoneally), the second group (sham group), cyclophosphamide at a dose of 10 mg/kg was injected as a single dose, and the third group (experimental group), along with single-dose cyclophosphamide, coenzyme Q10 at a dose of 200 mg/kg/day was injected intraperitoneally and the fourth group (positive control group), only coenzyme Q10 at a dose of 200 mg/kg/day was injected intraperitoneally. At the end of the treatment period, ovulation stimulation was performed using PMSG and HCG hormones. Six adult male mice were used to prepare normal sperm. The animals were facilitated after anesthesia. After extraction of regular eggs and sperm and fertilization in HTF + 4 mg BSA medium, the fertilized eggs were incubated for 120 hours, and the embryonic developmental stages were examined during this period. Were analyzed by ANOVA and comparison of ratios. Cyclophosphamide significantly reduced oocyte quality, fertilization rate, pre-implantation embryonic development, and embryo quality. Coenzyme Q10 (Co Q10) significantly reduced the adverse effects of cyclophosphamide. The present study showed that crocin could protect the fertility of the female sex against damage caused by cyclophosphamide. "

Protective effect of alogliptin against cyclophosphamide-induced lung toxicity in rats: Impact on PI3K/Akt/FoxO1 pathway and downstream inflammatory cascades

Cyclophosphamide (CP)-induced lung toxicity is a remaining obstacle against the beneficial use of this chemotherapeutic agent. More considerations were given to the role of Alogliptin (ALO) in ameliorating CP-induced toxicities in many tissues. We designed this study to clarify the protective potential of ALO against CP-induced lung toxicity in rats. ALO was administered for 7 days. Single-dose CP was injected on the 2nd day (200 mg/kg: i.p.) to induce lung toxicity. Rats were divided into four groups: control, ALO-treated, CP-treated and ALO + CP-treated group. Leucocytic count, total proteins, LDH activity, TNF-α, and IL-6 were estimated in the bronchoalveolar lavage fluid (BALF). The oxidative/antioxidants (MDA, Nrf2, TAO and GSH), inflammatory (NFκB), fibrotic (TGF-β1) and apoptotic (PI3K/Akt/FoxO1) markers in pulmonary homogenates were biochemically evaluated. Rat lung sections were examined histologically (light and electron microscopic examination) and immunohistochemically (for iNOS and CD68 positive alveolar macrophages). CP significantly increased oxidative stress, inflammation, fibrosis, and apoptosis markers as well as deteriorated the histopathological pulmonary architecture. These hazardous effects were significantly ameliorated by ALO treatment. ALO protected against CP-induced lung toxicity by mitigating the oxidative, inflammatory and fibrotic impacts making it a promising pharmacological therapy for mitigating CP-induced lung toxicity.Graphical abstract

Simvastatin cardioprotection in cyclophosphamide-induced toxicity via the modulation of inflammasome/caspase1/interleukin1β pathway.

Drug-induced cardiotoxicity is a serious adverse effect that occurs during the administration of chemotherapeutic agents such as cyclophosphamide (CYC). Therefore, there is a critical need to find cardioprotective agents to keep the heart healthy. The current study aimed to investigate the protective effect of simvastatin (SIM) against CYC-induced heart damage and evaluate different mechanisms involved in mediating this effect, including the inflammasome/caspase1/interleukin1β (IL1β) pathway and endothelial nitric oxide synthase (eNOS). 36 rats were randomly assigned to one of four groups: a control group that received only vehicles, a CYC group that received CYC (150mg/kg/day) i.p. on the fourth and fifth days, a CYC+SIM group that received SIM (10mg/kg/day) orally for 5 days and CYC (150mg/kg/day) i.p. on the fourth and fifth days, and a CYC+SIM+ Nitro- ω-L-arginine (L-NNA) group that received L-NNA (25mg/kg/day, SIM (10mg/kg/day) orally for 5 days and CYC (150mg/kg/day) i.p. on the 4th and 5th days. The CYC group revealed an obvious elevation in cardiac enzymes and heart weights with toxic histopathological changes. Moreover, there was an increase in malondialdehyde (MDA), tumor necrosis factor-alpha (TNFα) levels, and up-regulation of the NLRP3inflammasome/caspase1/IL1β pathway. In addition, total antioxidant capacity (TAC), eNOS, reduced glutathione (GSH), and superoxide dismutase (SOD) significantly decreased. CYC-induced cardiotoxicity was most properly reversed by SIM through its anti-oxidant, anti-inflammatory, and anti-apoptotic actions with the stimulation of eNOS. The co-administration of L-NNA diminished the protective effect of SIM, indicating the essential role of eNOS in mediating this effect. Therefore, SIM ameliorated CYC-induced cardiotoxicity.

Liposomal Ellagic Acid Alleviates Cyclophosphamide-Induced Toxicity and Eliminates the Systemic Cryptococcus neoformans Infection in Leukopenic Mice.

Cryptococcus neoformans infections rose sharply due to rapid increase in the numbers of immunocompromised individuals in recent years. Treatment of Cryptococcosis in immunocompromised persons is largely very challenging and hopeless. Hence, this study aimed to determine the activity of ellagic acid (EA) in the treatment of C. neoformans in cyclophosphamide injected leukopenic mice. A liposomal formulation of ellagic acid (Lip-EA) was prepared and characterized, and its antifungal activity was assessed in comparison to fluconazole (FLZ). The efficacy of the drug treatment was tested by assessing survival rate, fungal burden, and histological analysis in lung tissues. The safety of the drug formulations was tested by investigating hepatic, renal function, and antioxidant levels. The results of the present work demonstrated that Lip-EA, not FLZ, effectively eliminated C. neoformans infection in the leukopenic mice. Mice treated with Lip-EA (40 mg/kg) showed 70% survival rate and highly reduced fungal burden in their lung tissues, whereas the mice treated with FLZ (40 mg/kg) had 20% survival rate and greater fungal load in their lungs. Noteworthy, Lip-EA treatment alleviated cyclophosphamide-induced toxicity and restored hepatic and renal function parameters. Moreover, Lip-EA treatment restored the levels of superoxide dismutase and reduced glutathione and catalase in the lung tissues. The effect of FLZ or EA or Lip-EA against C. neoformans infection was assessed by the histological analysis of lung tissues. Lip-EA effectively reduced influx of inflammatory cells, thickening of alveolar walls, congestion, and hemorrhage. The findings of the present study suggest that Lip-EA may prove to be a promising therapeutic formulation against C. neoformans in immunocompromised persons.

Evaluating the role of GSTP1 genetic polymorphism (rs1695, 313A>G) as a predictor in cyclophosphamide-induced toxicities.

The association between Glutathione S-transferase Pi 1(GSTP1) genetic polymorphism (rs1695, 313A>G) and cyclophosphamide-induced toxicities has been widely investigated in previous studies, however, the results were inconsistent. This study was performed to further elucidate the association.A comprehensive search was conducted in PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and Wan Fang database up to January 5, 2020. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were used to estimate the association between GSTP1 rs1695 polymorphism and cyclophosphamide-induced hemotoxicity, gastrointestinal toxicity, infection, and neurotoxicity.A total of 13 studies were eventually included. Compared with the GSTP1 rs1695 AA genotype carriers, patients with AG and GG genotypes had an increased risk of cyclophosphamide-induced gastrointestinal toxicity (RR, 1.61; 95% CI, 1.18–2.19; P = .003) and infection (RR, 1.57; 95% CI, 1.00–2.48; P = .05) in the overall population. In the subgroup analyses, there were significant associations between GSTP1 rs1695 polymorphism and the risk of cyclophosphamide-induced myelosuppression (RR, 2.10; 95% CI, 1.60–2.76; P < .00001), gastrointestinal toxicity (RR, 1.77; 95%CI, 1.25–2.53; P = .001), and infection (RR, 2.01; 95% CI, 1.14–3.54; P = .02) in systemic lupus erythematosus (SLE) or lupus nephritis syndrome patients, but not in cancer patients.Our results confirmed an essential role for the GSTP1 rs1695 polymorphism in the prediction of cyclophosphamide-induced myelosuppression, gastrointestinal toxicity, and infection in SLE or lupus nephritis syndrome patients. More studies are necessary to validate our findings in the future.

Ulmus macrocarpa Hance Reduces Cyclophosphamide-induced Toxicity in Mouse Liver

Ulmus macrocarpa Hance Reduces Cyclophosphamide-induced Toxicity in Mouse Liver

The possible protective effect of captopril on liver and bone marrow after cyclophosphamide-induced toxicity in adult albino rats

Cyclophosphamide (CP) is commonly used in regimen of treatment of cancers and autoimmune diseases as systemic lupus. Hepatotoxicity and bone marrow depression are acute side effects of CP through inducing oxidative stress. The concomitant use of captopril ameliorates these side effects. This study aimed to evaluate the possible protective effects of captopril against hepatotoxicity and bone marrow depression induced by CP in adult albino rats. In this experimental study, 60 rats were divided into 4 groups;, the captopril treated group (capoten tablet 50 mg/kg for 5 days orally), CP treated group (150 mg/kg, a single dose intraperitoneal administration) and the captopril-CP treated group received captopril (50mg/kg for 5 days orally) followed by CP (150 mg/kg, a single dose intraperitoneally). The liver tissues and bone marrow of rats in all groups were subjected to light and electron microscopic studies. The serum levels of liver function markers such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in blood samples of each group as indicators of liver damage. The results showed that the injection of CP elevated serum ALT and AST compared to the control group. Concomitant treatment of captopril and CP decreases serum levels of ALT and AST. CP treated group showed diffuse lesion of liver tissue and bone marrow. The captopril-CP treated group showed minimal hepatic congestion and decreased adipose tissue in bone marrow. The current study provided that captopril has protective effect against cyclophosphamide induced hepatotoxicity and myelotoxicity.

Nephroprotective effect of exogenous hydrogen sulfide donor against cyclophosphamide-induced toxicity is mediated by Nrf2/HO-1/NF-κB signaling pathway

AimCyclophosphamide (CP) is an effective anticancer and immunosuppressive agent. However, it induces nephrotoxicity that limits its use. This study explored the effect of H2S, an important biological signaling molecule with a cytoprotective activity, on CP-induced nephrotoxicity. MethodsMale Wistar rats were treated with saline or NaHS (100 μM/kg/day, H2S donor) or dl-propargylglycine (PAG) (30 mg/kg/day, H2S blocker) for 10 days before a single i.p injection of CP (200 mg/kg). Then, rats were sacrificed, and renal functions were assessed in serum. Histopathological changes, as well as oxidant defenses, inflammatory and apoptotic markers in the renal tissue, were evaluated. Key findingsPretreatment with NaHS significantly reduced the urea and creatinine levels that were elevated in CP-intoxicated rats. NaHS increased the expression of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2) and its subsequent antioxidant proteins; heme oxygenase-1 (HO-1), NAD(P) H quinone oxidoreductase 1 (NQO1), reduced glutathione (GSH) and superoxide dismutase (SOD). Moreover, NaHS prohibited the histopathological damage induced by CP. The inhibition of caspase-3 and nuclear factor kappa B (NF-κB) supported the protective role of H2S against CP-induced kidney damage. On the other hand, blocking endogenous H2S did not provide a more significant deterioration in CP-induced nephrotoxicity in terms of oxidative stress or inflammatory status. SignificanceExogenous H2S donors exhibited a protective effect against CP-induced nephrotoxicity, which may be mediated via the Nrf2/HO-1/NF-κB signaling pathway. However, endogenous H2S may be insufficient to protect the cell against the induced oxidative damage. This approach provides a novel target to prevent nephrotoxicity of CP.