Effect of l-carnitine on cardiotoxicity and apoptosis induced by imatinib through PDGF/ PPARγ /MAPK pathways.

A tyrosine kinase inhibitor Imatinib (IM) is used in the treatment of different varieties of cancers. The current study was designed to explore the beneficial role of l-carnitine against IM-induced cardiotoxicity in rats. Male albino rats received IM (40 mg/kg, i.p.) either alone or/in combination with l-carnitine (100 mg/kg, i.p.) for 7 days. IM increased serum inflammatory cytokines, concomitant with activation of cardiac MAPK, α-SMA, malondialdehyde (MDA) and nitric oxide(NO), decreased cardiac peroxisome proliferator-activated receptor-γ (PPAR-γ) level, superoxide dismutase (SOD) activity, and glutathione (GSH) content. The expression levels of Bcl-2 and PDGF were significantly decreased, while the expression levels of CTGF and BAX were significantly increased in the IM group. The l-carnitine treatment successfully protected the heart as indicated by the improvement of the biochemical and histopathological parameters. l-carnitine didn't affect the serum concentration of IM and increased intracellular concentration in the combination-treated group as measured by the mass spectrometer. Conclusion: l-carnitine abrogated IM-induced cardiac damage and apoptosis via PDGF/PPARγ/MAPK pathways.

Evaluation of aromatase inhibitor on radiation induced pulmonary fibrosis via TGF- ß/Smad 3 and TGF- ß/PDGF pathways in rats.

Radiation-induced pulmonary fibrosis (RIPF) is a known complication in cancer patients after getting thoracic radiotherapy. Aromatase inhibitors (AIs) as anastrozole have been used instead of tamoxifen for adjuvant endocrine treatment of postmenopausal women with hormone sensitive breast cancer. This study is to evaluate the concurrent treatment of anastrozole and RIPF in rats. Twenty four female Wistar rats were distributed into 4 groups: Control (C), Radiation group (R) (total dose 30 Gy in 10 fractions, 5 fractions/week), anastrozole group (A) (0.003 mg/200 g body weight) orally for 14 consecutive days, and Radiation + anastrozole group (R + A). Radiation exposure resulted in a significant increase (p < 0.05) in pulmonary Transforming growth factor-beta 1 (TGF-ß), SMAD family member 3 (Smad3), Platelet-derived growth factor (PDGF), malondialdehyde (MDA), Total nitrate/nitrite (NO), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) compared to the control group. While, significant decreases (p < 0.05) in superoxide dismutase (SOD) activity, reduced glutathione (GSH) and connective tissue growth factor (CTGF) were observed in lung tissue. These alterations were minimized by anastrozole intervention. Also, anastrozole markedly hindered the lung histopathological changes observed after radiation. Concomitant use of anastrozole with radiation seems to attenuate radiation-induced pulmonary toxicity via TGF-ß/Smad 3 and TGF-ß/PDGF pathways in rats.

Metformin and/or low dose radiation reduces cardiotoxicity and apoptosis induced by cyclophosphamide through SIRT-1/SOD and BAX/Bcl-2 pathways in rats.

Cyclophosphamide (CP) is a nitrogen mustard alkylating agent with effective antineoplastic, immunomodulatory and immunosuppressive properties. Despite its vast therapeutic uses, it is known to trigger strict cardiac toxicity. The objective of the current study was to examine the protective role of metformin (MET) and/or low dose radiation (LDR) on cardiotoxicity and apoptosis induced by CP in rats. CP (200 mg/kg i.p) induces cardiotoxicity and apoptosis as indicated by elevation of troponin, cardiac caspase-3 and Endothelin-I (ET-1). While, treatment with MET (150 mg/kg, orally for 14 days) and/or LDR (0.5 Gy) before CP hindered CP-induced toxicity. By estimating the apoptotic index (BAX/Bcl-2 ratio) CP showed significantly the highest BAX/Bcl-2 ratio. Administration of MET and/or LDR showed a significant improvement in oxidative stress indices and reverse the inhibitory effect of CP on SIRT-1. Also, Histological examination of cardiac tissues showed a sign of necrosis of myocardium after CP treatment. Conclusions: The results revealed that MET and/or LDR attenuate CP-induced cardiotoxicity by inhibiting oxidative stress and preserving the activity of antioxidant enzymes through SIRT-1/SOD and BAX/Bcl-2 pathways.

Modulation of bleomycin-induced oxidative stress and pulmonary fibrosis by N-acetylcysteine in rats via AMPK/SIRT1/NF-κß.

The efficacy of bleomycin (BLM) as an antineoplastic drug is limited to the development of dose and time-dependent pulmonary fibrosis. This study was intended to investigate the effect of N-acetylcysteine (NAC) on BLM-induced pulmonary fibrosis in rats. Twenty rats were randomly divided to the following four groups: Group one served as control; group two received BLM (15 mg/kg, intraperitoneal (ip)) for five consecutive days; group three received NAC (200 mg/kg, ip) for five consecutive days; and group four received NAC 1 hour before BLM for 5 days. The expression of connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), silent information regulator l (SIRT1), AMP-activated protein kinase (AMPK) were determined by qRT-PCR in lung tissues. The changes in transforming growth factor-beta1 (TGF-ß1), tumour necrosis factor-α (TNF-α), interleukin-ß1 (IL-ß1) and nuclear factor kappa-ß (NF-κß) in serum were measured by ELISA. The tissue antioxidant status was determined biochemically. BLM administration caused pulmonary fibrosis as evidenced by increased levels of inflammatory mediators (TGF-ß1, TNF-α, IL-ß1 and NF-κß) in serum (P < .05), elevated lipid peroxidation and nitric oxide and depleted endogenous antioxidants in lung tissue (P < .05). The expression levels of SIRT1 and AMPK were significantly decreased (P < .05), while the expression levels of CTGF and PDGF were increased significantly in the BLM group as compared to the control group (P < .05). These alterations were normalized by NAC intervention. NAC markedly attenuated the lung histopathological changes and reduced collagen deposition. These results suggest that NAC exerted an ameliorative effect against BLM-induced oxidative damage and pulmonary fibrosis via SIRT1/ AMPK/ NF-κß pathways.

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.

Metformin and low dose radiation modulates cisplatin-induced oxidative injury in rat via PPAR-γ and MAPK pathways.

Cisplatin (CIS) is a chemotherapeutic agent used for therapy of many tumors and has been limited by its toxicity. The aim of this study was to investigate the role of Peroxisome proliferator-activated receptor-gamma (PPAR-γ), mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B(NFkB) in the pathogenesis of hepatic damage induced by CIS, and investigated the modulatory effect of metformin (MET) and/or low dose gamma radiation (LDR) on CIS-induced hepatotoxicity in rats. CIS(7.5 mg/kg, i.p.) hepatotoxicity was evidenced by alteration of serum hepatic indices (ALT and AST) accompanied with decreased hepatic PPAR-γ, superoxide dismutase (SOD) activities and reduced glutathione (GSH) content, whereas the levels of malondialdehyde (MDA), total nitrate/nitrite (NOx) and NFkB significantly increased as well as MAPK activity compared with the control, MET and LDR groups. Furthermore, CIS induces apoptosis as indicated by an elevation of hepatic caspase-3. Treatment with MET (150 mg/kg, orally for 14 days) and/or LDR (0.5 Gy), prior to CIS alleviates CIS-induced hepatic damage by mitigating oxidative/ nitrosative stress and PPAR-γ activity reduction, hepatic caspase-3 elevation, and inhibition of NFκB, and MAPK activity levels. CONCLUSIONS: Modulation of PPAR-γ, MAPK and NFkB might contribute to amelioration of CIS-induced hepatic toxicity.

Pharmacological investigation of new niclosamide-based isatin hybrids as antiproliferative, antioxidant, and apoptosis inducers.

A group of Niclosamide-linked isatin hybrids (Xo, X1, and X2) was created and examined using IR, 1HNMR, 13C NMR, and mass spectrometry. These hybrids' cytotoxicity, antioxidant, cell cycle analysis, and apoptosis-inducing capabilities were identified. Using the SRB assay, their cytotoxicity against the human HCT-116, MCF-7, and HEPG-2 cancer cell lines, as well as VERO (African Green Monkey Kidney), was evaluated. Compound X1 was the most effective compound. In HCT-116 cells, compound X1 produced cell cycle arrest in the G1 phase, promoted cell death, and induced apoptosis through mitochondrial membrane potential breakdown in comparison to niclosamide and the control. Niclosamide and compound X1 reduced reactive oxygen species generation and modulated the gene expression of BAX, Bcl-2, Bcl-xL, and PAR-4 in comparison to the control. Docking modeling indicated their probable binding modalities with the XIAP BIR2 domain, which selectively binds caspase-3/7, and highlighted their structural drivers of activity for further optimization investigations. Computational in silico modeling of the new hybrids revealed that they presented acceptable physicochemical values as well as drug-like characteristics, which may introduce them as drug-like candidates. The study proved that compound X1 might be a novel candidate for the development of anticancer agents as it presents antiproliferative activity mediated by apoptosis.

Efficacy of lycopene against fluoride toxicity in rats.

CONTEXT: Oxidative damage to cellular components such as lipids and cell membranes by free radicals and reactive oxygen species (ROS) is thought to be associated with the development of degenerative diseases. Fluoride intoxication is associated with oxidative stress and altered anti-oxidant defense mechanism. Lycopene is a lipid-soluble powerful anti-oxidant that scavenges free radicals and ROS. OBJECTIVE: This study was extended to investigate lycopene anti-oxidant efficacy in different organs of fluoride-intoxicated rats. METHODS: Twenty-four adult rats were randomly divided into four groups of six animals each. Rats in group I received daily doses of vehicle. Group II rats were given lycopene (10 mg/kg body weight/day), by tubes, dissolved in 0.5 ml of corn oil for 5 weeks. Group III rats were given sodium fluoride (NaF) (10.3 mg/kg body weight/day), by tubes, for 5 weeks. In group IV rats, lycopene was administered 1 h later and NaF was administered for 5 weeks. RESULTS: NaF administration induced oxidative stress as evidenced by elevated levels of lipid peroxidation (51.3, 65.9 and 67.6%) measured as malondialdehyde and total nitrate/nitrite (61.0, 59.7 and 68.9%) in red blood cells, heart and brain tissues. Moreover, significantly decreased reduced glutathione level, total anti-oxidant capacity and superoxide dismutase activity were observed in the examined tissues. The induced oxidative stress and the alterations in anti-oxidant system were normalized by the oral administration of lycopene treatment. CONCLUSION: Lycopene administration could minimize the toxic effects of fluoride indicating its free-radical scavenging and powerful anti-oxidant activities.

Fasciola gigantica: Parasitological and scanning electron microscopy study of the in vitro effects of ivermectin and/or artemether.

OBJECTIVE: To evaluate the in vitro effects of different concentrations of ivermectin and/or artemether on Fasciolagigantica worms and to study the parasitological changes and tegumental alterations using scanning electron microscopy (SEM). METHODS: Fasciola gigantica worms were incubated in vitro for 24 and 48 h with three concentrations of either ivermectin or artemether (10, 20 and 50 microg/ml) or both in half concentration of either (5, 10 and 25 microg/ml). RESULTS: Exposure of Fasciola worms to 25+25 microg/ml of combined drug regimens or to 50 microg/ml of either ivermectin or artemether for 48 h led to 100%, 41.7% and 75% worm killing which were accompanied by a significant reduction in egg laying capacity and significant increase in dead eggs maximally recorded in combined drug regimens. SEM of the flukes incubated for 48 h with combined drug regimens showed maximal tegumental disruption with swelling of the worm body, roughness, blebbing, sloughing and complete loss of spines. Disruption to the tegument of the flukes induced by artemether was more than that of ivermectin. CONCLUSIONS: Artemether alone or combined with ivermectin in half doses had potent fasciocidal activities. Besides, half doses of combined drug regimens had higher ovicidal effects than each drug alone. In vivo studies are recommended to explore the efficacy of combined regimens against Fasciola infection.

Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats.

The present study was designed to evaluate the radioprotective effect of N- acetylcysteine (NAC) on gamma-radiation induced toxicity in hepatic tissue in rat. The cellular changes were estimated using malondialdehyde (MDA, an index of lipid peroxidation), superoxide dismutase (SOD), glutathione peroxidase (GSHPx), reduced glutathione (GSH), and total nitrate/nitrite (NO(x)) as markers of hepatic oxidative stress in rats following gamma-irradiation. The DNA damage was determined by agarose gel electrophoresis. To achieve the ultimate goal of this study, 40 adult rats were randomly divided into 4 groups of 10 animals each. Group I was injected intraperitoneally with saline solution for 7 consecutive days and served as control group. Group II was irradiated with a single dose of 6Gy gamma-radiation. Group III was daily injected with NAC (1g/kg, i.p.) for 7 consecutive days. Group IV received a daily i.p. injection of NAC (1g/kg, i.p.) for 7 consecutive days and 1h after the last dose, rats were irradiated with a single dose (6Gy) gamma-radiation. The animals were sacrificed after 24h. DNA damage was observed in tissue after total body irradiation with a single dose of 6Gy. Malondialdehyde and total nitrate/nitrite were increased significantly whereas the levels of GSH and antioxidant enzymes were significantly decreased in gamma-irradiated group. Pretreatment with NAC showed a significant decrease in the levels of MDA, NO(x) and DNA damage. The antioxidant enzymes increased significantly along with the levels of GSH. Moreover, histopathological examination of liver tissues confirmed the biochemical data. Thus, our results show that pretreatment with N-acetylcysteine offers protection against gamma-radiation induced cellular damage.

Protective effect of N-acetylcysteine on cyclophosphamide-induced cardiotoxicity in rats.

Cyclophosphamide (CP) is an oxazaphosphorine nitrogen mustard alkylating drug used for the treatment of chronic and acute leukemias, lymphoma, myeloma, and cancers of the breast and ovary. It is known to cause severe cardiac toxicity. This study investigated the protective effect of N-Acetylcysteine (NAC) on CP-induced cardiotoxicity in rats. CP resulted in a significant increase in serum aminotransferases, creatine kinase (CK), lactate dehydrogenase(LDH) enzymes, asymmetric dimethylarginine and tumor necrosis factor-α and significant decrease in total nitrate/nitrite(NOx). In cardiac tissues, a single dose of CP (200mg/kg, i.p.) resulted in significant increase in malondialdehyde and NOx and a significant decrease in reduced glutathione content, glutathione peroxidase, catalase, and superoxide dismutase activities. Interestingly, Administration of NAC (200mg/kg, i.p.) for 5 days prior to CP attenuates all the biochemical changes induced by CP. These results revealed that NAC attenuates CP-induced cardiotoxicity by inhibiting oxidative and nitrosative stress and preserving the activity of antioxidant enzymes.

Early treatment of radiation-induced heart damage in rats by caffeic acid phenethyl ester.

UNLABELLED: The study is designed to determine the therapeutic effect of caffeic acid phenethyl ester (CAPE) in minimizing radiation-induced injuries in rats. Rats were exposed to 7Gy gamma radiation, 30min later rats were injected with CAPE (10µmol/kg body, i.p.) for 7 consecutive days. Rats were sacrificed at 8 and 15 days after starting the experiment. Gamma-irradiation induced significant increase in malondialdehyde (MDA) level and xanthine oxidase (XO) and adenosine deaminase (ADA) activities, and significant decrease in total nitrate/nitrite (NO(x)) level and glutathione peroxidise (GPx), superoxide dismutase (SOD) and catalase activities in heart tissue and augmented lipid fractions levels and activities of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and aspartate transaminase (AST) in serum. Irradiated rats early treated with CAPE showed significant decrease in MDA, XO and ADA and significant increase in NO(x) and SOD in heart tissue and in serum enzymes compared with irradiated group. Serum lipid profiles and cardiac enzymes were restored. CONCLUSION: CAPE could exhibits curable effects on gamma irradiation-induced cardiac-oxidative impairment in rats.

Protective role of carnitine ester against radiation-induced oxidative stress in rats.

The aim of this study was to investigate the antioxidant effect of acetyl-L-carnitine (ALC) against gamma-irradiation-induced oxidative damage in liver and lung tissue after total body irradiation with a single dose of 6Gy. To achieve the ultimate goal of this study, 40 adult rats were randomly divided into 4 groups of 10 animals each. Group I was injected intraperitoneally with saline solution for 5 consecutive days and served as control group. Group II was irradiated with a single dose of 6Gy. Group III was daily injected with ALC (250 mg kg(-1), i.p.) for 5 consecutive days. Group IV received a daily i.p. injection of ALC (250 mg kg(-1), i.p.) for 5 consecutive days and 1h after the last dose, rats were irradiated with a single dose (6Gy). The animals were sacrified after 24h. Administration of ALC for 5 consecutive days resulted in a significant increase in the activities of both superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) and the level of reduced glutathione (GSH), in lung and liver tissues which were reduced by radiation treatment. Also, ALC resulted in a significant decrease in total nitrate/nitrite (NO(x)) and malondialdehyde (MDA) levels in both lung and liver tissues and a significant decrease in triglycerides, low-density lipoprotein-cholesterol (LDL), high-density lipoprotein-cholesterol (HDL), total cholesterol, Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels and Gamma glutamyl transpeptidase (GGTP) compared to irradiated group. In conclusion, data obtained from this study indicate that ALC could increase the endogenous antioxidant defense mechanism in rat and there by protect the animals from radiation-induced organs toxicity.

Acetyl-L-carnitine modulates bleomycin-induced oxidative stress and energy depletion in lung tissues.

BACKGROUND AND PURPOSE: The usefulness of Bleomycin (BLM) as an important antineoplastic drug is usually limited to the development of dose and time-dependent interstitial pneumonitis and pulmonary fibrosis. This study has been initiated to investigate the possible protective effects of acetyl-L-carnitine (AC) against BLM-induced lung toxicity at an early stage of its development. MATERIAL AND METHODS: A total of 40 male Sprague-Dawley rats weighing from 200-250 g each, were divided into 4 groups of 10 animals each. The first group received a daily i.p. injection of normal saline (0.5 ml/200 gm body weight) for 5 consecutive days and served as a control. Animals in the second, third and fourth groups were daily injected intraperitoneally (i.p.) with BLM (15 mg/kg body weight), AC (250 mg/kg body weight) and AC (250 mg/kg) 2 hrs before BLM (15 mg/kg) each for 5 consecutive days, respectively. RESULTS: Treatment of rats with BLM (15 mg/kg) resulted in a significant 3.4 and 2.9 folds increase in malondialdehyde (MDA) and nitric oxide (NO) production in lung tissue, respectively and a significant 39%, 35%, 54% and 44% decrease in reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and adenosine triphosphate (ATP), respectively as compared to the control group. Treatment of rats with AC did not lead to any significant change in the mentioned biochemical parameters in the lung tissue. Administration of AC two hours before BLM attenuated BLM-induced increase in MDA and NO and the decrease in GSH, SOD, GSHPx and ATP in lung tissue. CONCLUSION: The present data suggests that the protective effect of AC against BLM-induced acute lung injury could be, at least in part, due to its free radical scavenging properties with the consequent improvement in mitochondrial function and ATP production.