Diallyl sulfide alleviates cyclophosphamide-induced nephropathic encephalopathy in rats.

Diallyl sulfide (DAS) is a garlic-derived organosulfur compound. The current study was planned to evaluate the protecting effects of DAS against cyclophosphamide (CP)-induced nephropathic encephalopathy. DAS (100 mg/kg) was orally administered for 4 days, 60 min after the last dose, rats were injected with CP (150 mg/kg). DAS treatment before CP significantly decreased serum urea, creatinine, sodium, potassium, calcium, blood urea nitrogen (BUN), C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor-alpha (TNF-α) compared with CP-treated rats. DAS treatment decreased malondialdehyde (MDA) and increased superoxide dismutase (SOD) and reduced glutathione (GSH) levels in the renal tissues and significantly attenuated the elevated neurotransmitters N-methyl-D-aspartate/adenosine triphosphate (NMDA), γ-aminobutyric acid (GABA) levels and remarkably restored neuronal nitric oxide (NO) level and nitric oxide synthase (nNOS) activity in the brain compared to CP-treated rats. DAS for 4 consecutive days before CP showed moderate positive immunohistochemically expression of the glial fibrillary acidic protein (GFAP) in the brain and kidney tissues comparable to CP-treated rats. DAS afforded renal and neuroprotection against CP-induced nephropathic encephalopathy due to its capacity to ameliorates the afore-mentioned biochemical parameters which were supported by histopathological and immunohistochemically examination.

Ameliorative Effect of Coenzyme Q10 and/or Candesartan on Carboplatin-Induced Nephrotoxicity: Roles of Apoptosis, Transforming Growth Factor-Β1, Nuclear Factor Kappa-B And The Nrf2/HO-1 Pathway

Background: Carboplatin is a drug that is used for treatment of many types of cancer. However, it may produce serious nephrotoxicity. Candesartan is angiotensin II receptor antagonist employed mainly for control of hypertension. Coenzyme Q10 (CoQ10) is a fat-soluble substance which was proven to have potent antioxidant and anti-inflammatory properties. Aim: Our aim was to study the effects of candesartan and/or CoQ10 on carboplatin-induced nephrotoxicity in mice. Methods: Sixty mice were divided into 6 equal groups: Control untreated; carboplatin; carboplatin + candesartan; carboplatin + CoQ10; carboplatin + carboxymethyl cellulose; and carboplatin + candesartan + CoQ10 group. Kidney weight/body weight ratio, blood urea, serum creatinine, creatinine clearance, urinary N-acetyl beta-D-glucosaminidase (NAG), gamma glutamyl transpeptidase (GGT) and the urinary albumin excretion rate (UAER) were determined. Renal tissue catalase (CAT), glutathione reductase (GR), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), transforming growth factor beta-1 (TGF-ß1), tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were also determined, along with mitochondrial complex I activity. In addition, portions of the kidney were subjected to histopathological and immunohistochemical examination. Results: Candesartan and/or CoQ10 induced significant improvement of renal and mitochondrial functions with significant increase in tissue CAT, GR, Nrf2 and HO-1 content associated with significant decrease in the kidney weight/body weight ratio, tissue TGF-ß1, TNF-α and IL-6 and alleviation of the histopathological and immunohistochemical changes as compared to carboplatin alone group. These effects were more significant in candesartan/CoQ10 combination group compared to either candesartan or CoQ10 alone. Conclusion: Candesartan/CoQ10 combination might represent a beneficial therapeutic modality for amelioration of carboplatin-induced nephrotoxicity.

Targeting proinflammatory cytokines, oxidative stress, TGF-ß1 and STAT-3 by rosuvastatin and ubiquinone to ameliorate trastuzumab cardiotoxicity.

The aim of this study was to assess the possible modulatory effects of rosuvastatin and/or ubiquinone on trastuzumab (TRZ)-induced cardiotoxicity in mice. One hundred and twenty mice were divided into six equal groups as follows: control group; TRZ group; TRZ+carboxymethyl cellulose group; TRZ+rosuvastatin group; TRZ+Ubiquinone group and TRZ+rosuvastatin+Ubiquinone group. Serum creatine kinase (CK-MB), lactate dehydrogenase (LDH), troponin I and N-terminal pro-B-type natriuretic peptide (NT-pro BNP) were measured. Also, tissue malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPx), interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-ß1) and signal transducers and activators of transcription-3 (STAT-3) were determined. Also, echocardiography was performed. Parts of the heart were subjected to histopathological, immunohistochemical and electron microscopic examination. Administration of rosuvastatin and/or ubiquinone to TRZ-treated mice induced significant increase in tissue GPx, CAT and STAT-3 with significant decrease in serum CK-MB, LDH, troponin I, NT-pro BNP, tissue MDA, TGF-ß1 and IL-6 and improved the histopathological, immunohistochemical, echocardiographic and electron microscopic changes compared to the group that received TRZ alone. These changes were significant in rosuvastatin/ubiquinone combination group compared to the use of each of these drugs alone. In conclusion, rosuvastatin/ubiquinone combination may represent a new therapeutic modality to ameliorate TRZ-induced cardiotoxicity.

Ameliorative potential of fluoxetine/raloxifene combination on experimentally induced breast cancer.

Breast cancer is one of the most common types of malignancies in females worldwide. Targeting the estrogen receptors alone with raloxifene (RAL) reduces the incidence of estrogen receptor positive tumors. Fluoxetine (FLX) is one of selective serotonin reuptake inhibitors that was proven to have anticancer properties. Our aim was to detect the effects of RAL/FLX combination on experimentally induced breast cancer. Eighty female Wistar rats were divided into four equal groups: 7,12-Dimethyl Benzanthracene (DMBA) induced breast cancer group, DMBA+RAL, DMBA+FLX and DMBA+RAL+FLX. Tumor volume, tissue malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and transforming growth factor beta1 (TGF-ß1) were determined in the tumor tissues. Parts of the tumor were subjected to histopathological examination. RAL or FLX alone or in combination induced significant increase in tumor CAT and SOD with significant decrease in tumor volume, tissue MDA, TNF-α, IL-6 and TGF-ß1 and alleviated the histopathological and immunohistochemical changes compared to DMBA group. In conclusion, RAL/FLX combination had a better effect than each of RAL or FLX alone against DMBA-induced breast cancer in rats which may represent a new therapeutic modality for management of breast cancer.

Anti-cancer and cardioprotective effects of indol-3-carbinol in doxorubicin-treated mice.

Doxorubicin (DOX) is a broad-spectrum antitumor antibiotic used in treatment of cancer. Its effect may be complicated by increased risk of cardiotoxicity. It was suggested that natural compounds with anticancer properties can be used in combination with DOX to decrease its dose and side effects. Indole-3-carbinol (I3C) is one of the phytochemicals that was shown to have anti-cancer effect. Our aim was to detect the possible chemosensitizing effects of I3C in DOX-induced cytotoxicity and the possible cardioprotective effects of I3C in DOX-induced cardiotoxicity. One hundred mice were divided into five equal groups: Control untreated group, solid Ehrlich carcinoma (SEC), SEC + DOX, SEC + I3C, SEC + DOX + I3C. Tumor volume, serum creatinine kinase and lactate dehydrogenase were measured. Also, tissue malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), sphingosine kinase-1 (SphK1) activity and interleukin-6 (IL-6) were determined. Parts of the tumor and cardiac tissues were subjected to histopathological examination. DOX or I3C alone or in combination induced significant increase in tumor CAT and SOD with significant decrease in tumor volume, tumor MDA, SphK1 activity and IL-6 and alleviated the histopathological changes with significant increase in the apoptotic index and significant decrease in tissue bcl2 compared to SEC group. Also, DOX induced cardiotoxicity which was ameliorated by I3C. In conclusion, DOX/I3C combination had a better effect than each of DOX or I3C alone against SEC in mice with marked improvement of the cardiotoxicity induced by DOX.