Mohamed M. Al-Harbi

Doxorubicin Toxicity can be Ameliorated during Antioxidant L-Carnitine Supplementation

Doxorubicin is an antibiotic broadly used in treatment of different types of solid tumors. The present study investigates whether L-carnitine, antioxidant agent, can reduce the hepatic damage induced by doxorubicin. Male Wistar albino rats were divided into six groups: group 1 was intraperitoneal injected with normal saline for 10 consecutive days; group 2, 3 and 4 were injected every other day with doxorubicin (3 mg/kg, i.p.), to obtain treatments with cumulative doses of 6, 12 and 18 mg/kg. The fifth group was injected with L-carnitine (200 mg/kg, i.p.) for 10 consecutive days and the sixth group was received doxorubicin (18 mg/kg) and L-carnitine (200 mg/kg). High cumulative dose of doxorubicin (18 mg/kg) significantly increases the biochemical levels of alanine transaminase, alkaline phosphatase, total bilirubin, thiobarbituric acid reactive substances (TBARs), total nitrate/nitrite (NOx) p < 0.05 and decrease in glutathione (GSH ), superoxide dismutase (SOD), glutathione peroxidase (GSHP x), glutathione-s-transferase (GST), glutathione reductase (GR) and catalase (CAT) activity p < 0.05. The effect of doxorubicin on the activity of antioxidant genes was confirmed by real time PCR in which the expression levels of these genes in liver tissue were significantly decrease compared to control p < 0.05. Interestingly, L-carnitine supplementation completely reversed the biochemical and gene expression levels induced by doxorubicin to the control values. In conclusion, data from this study suggest that the reduction of antioxidant defense during doxorubicin administration resulted in hepatic injury could be prevented by L-carnitine supplementation by decreasing the oxidative stress and preserving both the activity and gene expression level of antioxidant enzymes.

Airway and systemic oxidant-antioxidant dysregulation in asthma: a possible scenario of oxidants spill over from lung into blood.

Asthma is characterized by repeated episodes of airway obstruction and an ongoing cycle of airway inflammation. Reactive oxygen species (ROS) produced by inflammatory cells in the lung play a key role in the pathogenesis as well as amplification of inflammation in asthmatic airways. Several enzymatic and non-enzymatic antioxidants are available in the lung and systemic circulation to counteract ROS-mediated damage on various biomolecules such as lipid membranes, proteins, and DNA; however during asthmatic inflammation these defenses are overwhelmed due to excessive production of ROS thereby leading to inflammatory events in the airways/systemic circulation. ROS-mediated damage may result in increased vascular permeability, mucus hypersecretion, smooth muscle contraction, epithelial shedding and impairment in the responsiveness of β-adrenergic receptors. Strategies aimed to boost the endogenous antioxidants either through dietary or pharmacological intervention to redress oxidant-antioxidant imbalance in asthma is the current area of research in many laboratories throughout the world. This review aims at providing a comprehensive overview of the available literature on oxidative stress and antioxidants imbalance in asthma with a focus both on lung and blood components and bring forth correlations between lung/blood oxidative stress/antioxidant parameters and lung function.

Prevention of doxorubicin-induced myocardial and haematological toxicities in rats by the iron chelator desferrioxamine

SummaryBiochemical and histopathological evaluations of the protective effects of the iron-chelator desferrioxamine against the cardiac and haematological toxicities of doxorubicin in normal rats were carried out. A single dose of doxorubicin (15 mg/kg, i. v.) caused myocardial damage that manifested biochemically as an elevation of serum cardiac enzyme [glutamic oxaloacetic transaminase (GOT), lactic dehydrogenase (LDH) and creatine phosphokinase (CPK)] and cardiac isoenzyme levels and histopathologically as a swelling and separation of cardiac muscle fibers. Doxorubicin caused severe leucopenia and decreases in red blood cell counts and haemoglobin concentrations at 72 h after its administration. Desferrioxamine treatment (250 mg/kg, i.p.) carried out 30 min before doxorubicin administration protected the heart and blood elements from the toxic effects of doxorubicin as indicated by the recovery of levels of cardiac enzymes and isoenzymes and of red blood cell counts to normal values and by the absence of significant myocardial lesions. The findings of this study suggest that desferrioxamine can potentially be used clinically to prevent doxorubicin-induced cardiac and haematological toxicities.

Boric acid enhances in vivo Ehrlich ascites carcinoma cell proliferation in Swiss albino mice

The influence of boric acid, a boron carrier, on Ehrlich ascites carcinoma (EAC) cell-bearing mice was investigated in view of its importance in the boron neutron capture therapy and the influence of boron on proliferation and progression of cancer cells mediated by proteoglycans and collagen. The present study included the evaluation of boric acid for the effects on total count and viability of EAC cells in addition to their non-protein sulfhydryls (NP-SH) and malondialdehyde (MDA) contents as parameters for conjugative detoxication potency and possible oxidative damage. The EAC cell-bearing animals were also observed for the effect on survival, body weight changes, and histopathological evaluation of the tumors grown at the site of inoculation. The treatment with boric acid significantly increased the total number of peritoneal EAC cells and their viability. A significant increase in the body weight was observed that dose-dependently reached plateau levels by 20 days of treatment. Conversely, a reduction in the duration of survival of these animals was evident with the same protocol. Boric acid treatment resulted in a decrease in NP-SH contents with a concomitant increase in MDA levels in EAC cells as revealed by the results of the biochemical analysis. These data are supported by our results on histopathological investigations, which apparently showed fast growth, in addition to several mitotic figures and mixed inflammatory reaction, after treatment with boric acid. It seems likely that a particular combination of properties of boric acid, rather than a single characteristic alone, will provide useful information on the use of this boron carrier in neutron capture therapy.

Evaluation of the genotoxic, cytotoxic, and antitumor properties ofCommiphora molmol using normal and Ehrlich ascites carcinoma cell-bearing Swiss albino mice

The genotoxic, cytotoxic and antitumor properties ofCommiphora molmol (oleo gum resin) were studied in normal and Ehrlich ascites carcinoma cell-bearing mice. In normal mice, the genotoxic and cytotoxic activity was evaluated on the bases of the frequency of micronuclei and the ratio of polychromatic to normochromatic cells in bone marrow, which was substantiated by the biochemical changes in hepatic cells. The antitumor activity ofC. molmol was evaluated from the total count and viability of Ehrlich ascites carcinoma cells and their nucleic acid, protein, malondialdehyde, and elemental concentrations in addition to observations on survival and the trend of changes in body weight. The tumors at the site of injection were evaluated for histopathological changes. Treatment withC. molmol (125–500 mg/kg) showed no clastogenicity but was found to be highly cytotoxic in normal mice. The results obtained in the Ehrlich ascites carcinoma cell-bearing mice revealed the cytotoxic and antitumor activity ofC. molmol which was found to be equivalent to those of the standard cytotoxic drug cyclophosphamide. On the basis of the nonmutagenic, antioxidative, and cytotoxic potential ofC. molmol as observed in the present study, its use in cancer therapy seems to be appropriate and further investigations are suggested.

Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation.

Psoriasis is one of the most common skin disorders characterized by erythematous plaques that result from hyperproliferative keratinocytes and infiltration of inflammatory leukocytes into dermis and epidermis. Recent studies suggest that IL-23/IL-17A/IL-22 cytokine axis plays an important role in the pathogenesis of psoriasis. The small molecule bromodomain and extraterminal domain (BET) inhibitors, that disrupt interaction of BET proteins with acetylated histones have recently demonstrated efficacy in various models of inflammation through suppression of several pathways, one of them being synthesis of IL-17A/IL-22 which primarily depends on transcription factor, retinoic acid receptor-related orphan receptor C (RORC). However, the efficacy and mechanistic aspect of a BET inhibitor in mouse model of skin inflammation has not been explored previously. Therefore, this study investigated the role of BET inhibitor, JQ-1 in mouse model of psoriasis-like inflammation. Mice were topically applied imiquimod (IMQ) to develop psoriasis-like inflammation on the shaved back and ear followed by assessment of skin inflammation (myeloperoxidase activity, ear thickness, and histopathology), RORC and its signature cytokines (IL-17A/IL-22). JQ-1 suppressed IMQ-induced skin inflammation as reflected by a decrease in ear thickness/myeloperoxidase activity, and RORC/IL-17A/IL-22 expression. Additionally, a RORα/γ agonist SR1078 was utilized to investigate the role of RORC in BET-mediated skin inflammation. SR1078 reversed the protective effect of JQ-1 on skin inflammation at both histological and molecular levels in the IMQ model. The current study suggests that BET bromodomains are involved in psoriasis-like inflammation through induction of RORC/IL-17A pathway. Therefore, inhibition of BET bromodomains may provide a new therapy against skin inflammation.

Evaluation of teratogenic potential of khat (catha edulis forsk.) In rats

The embryotoxic and teratogenic effects of khat (Catha edulis Forsk.), a plant chewed by the people of Eastern Africa and Southern Arabia to attain a state of euphoria and stimulation, was studied in Wistar rats. Methanolic extract of khat was administered orally by gavage to rats during days from 6 to 15 of gestation at doses of 0, 125, 250 and 500 mg/kg. body weight/day. Khat reduced the food consumption and maternal weight gain and also lowered the food efficiency index, as compared to control mothers. On day 20 of gestation, all dams were sacrificed by cervical dislocation, cesarean sections were performed and maternal and fetal toxicities were assessed. The administration of khat had no effect on fetal sex ratio. However, at a dose of 125 mg/kg body weight and above, it produced a significant increase in resorptions and fetal wastage. Khat administration in utero also reduced the litter size and caused intrauterine growth retardation. External, visceral and skeletal examination of the fetus of treated dams showed several types of malformations and variations in all the groups of animals. However, a consistent tendency of abnormalities was observed in the highest dosed (500 mg/kg) group. The data of the present study revealed that khat retarded fetal growth and induced terata. The present observations indicate that khat possesses both embryotoxic as well as teratogenic properties. The developmental toxicities of khat are dose-related.

Association between Paraoxonases Gene Expression and Oxidative Stress in Hepatotoxicity Induced by CCl4

Objectives. The purpose of the study is to evaluate the hepatoprotective effect of rutin in carbon tetrachloride- (CCl4-) induced liver injuries in rat model. Methods. Forty male Wistar albino rats were divided into four groups. Group I was the control group and received dimethyl sulphoxide (DMSO) and olive oil. Group II received rutin. Groups III was treated with CCl4. Group IV was administered rutin after 48 h of CCl4 treatment. Liver enzymes level, lipid profile, lipid peroxidation, and hydrogen peroxide were measured. The genes expression levels were monitored by real time RT-PCR and western blot techniques. Results. CCl4 group showed significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), thiobarbituric acid reactive substances (TBAR), hydrogen peroxide (H2O2), and lipid profile and a significant decrease in glutathione peroxidase (GPx), glutathione S transferase (GST), catalase (CAT), paraoxonase-1 (PON-1), paraoxonase-3 (PON-3), peroxisome proliferator activated receptor delta (PPAR-δ), and ATP-binding cassette transporter 1 (ABAC1) genes expression levels. Interestingly, rutin supplementation completely reversed the biochemical and gene expression levels induced by CCl4 to control values. Conclusion. CCl4 administration causes aberration of genes expression levels in oxidative stress pathway resulting in DNA damage and hepatotoxicity. Rutin causes hepatoprotective effect through enhancing the antioxidant genes.

Desferrioxamine Attenuates Doxorubicin-Induced Acute Cardiotoxicity through TFG-β/Smad p53 Pathway in Rat Model

Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy. Accordingly, this study has been initiated to investigate the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX-induced acute cardiotoxicity in rats. Male Wistar albino rats were divided into four groups and were injected intraperitoneally (I.P.) with normal saline, a single dose of DOX (15 mg/kg), a single dose of DFX (250 mg/kg) and a combined treatment with DFX (250 mg/kg) 30 min prior to a single dose of DOX, (15 mg/kg). A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels. Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels. Data from this study suggest that (1) DOX induces its acute cardiotoxicity secondary to increasing genes expression of TGF-β/Smad pathway. (2) DOX increases apoptosis through upregulation of CDKN2A and p53 and downregulation of Mdm2 gene expression. (3) The preventive effect of DFX against DOX-induced cardiotoxicity is mediated via the TGF-β1/Smad pathway.

Inhibition of gastric mucosal damage by methylglyoxal pretreatment in rats.

The effect of methylglyoxal pretreatment on gastric mucosal injuries caused by 80% ethanol, 25% NaCl and 0.2 M NaOH, was investigated in rats. The effects caused by pylorous ligation accumulated gastric acid secretions and ethanol-induced changes in gastric mucus secretions, levels of proteins, nucleic acid, malondialdehyde (MDA) and non-protein sulfhydryl groups were also investigated. Methylglyoxal pretreatment at oral doses of 50, 100 and 200 mg/kg body weight was found to provide a dose-dependent protection against the ulcerogenic effects of different necrotizing agents used. With the same dose regimen methylglyoxal offered significant protection against ethanol-induced damage on the parameters evaluated for histopathology. Furthermore, the pretreatment afforded a dose-dependent inhibition of pylorous ligated accumulation of gastric acid secretions and ethanol-induced depletion of stomach wall mucus, proteins, nucleic acids, NP-SH contents and an increase in the MDA levels in gastric tissue. The protective effect of methylglyoxal against ethanol-induced damage to the gastric wall mucosa may be mediated through its effect on mucous production, proteins, nucleic acids, NP-SH groups and its free-radical scavenging property under the influence of polyamines stimulated by ornithine decarboxylase activity (ODC).