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Carfilzomib is a proteasome inhibitor, commonly used in multiple myeloma, but its clinical use may be limited due to cardiotoxicity. This study was aimed to evaluate the influence of rutin in carfilzomib-induced cardiotoxicity in rats. Wistar albino male rats weighing 200-250 g (approximately 10 weeks old) were taken for this study. Animals were divided into four groups of six animals each. Group 1 served as normal control (NC), received normal saline; group 2 animals received carfilzomib (dissolved in 1 % DMSO) alone; group 3 animals received rutin (20 mg/kg) + carfilzomib; and group 4 animals received rutin (40 mg/kg) + carfilzomib. Hematological changes, biochemical changes, oxidative stress, hypertrophic gene expression, apoptotic gene expression, NFκB and IκB-α protein expression and histopathological evaluation were done to confirm the finding of carfilzomib-induced cardiotoxicity. Treatment with rutin decreased the carfilzomib-induced changes in cardiac enzymes such as lactate dehydrogenase, creatine kinase (CK) and CK-MB. For the assessment of cardiotoxicity, we further evaluated cardiac hypertrophic gene and apoptotic gene expression such as α-MHC, β-MHC and BNP and NF-κB and p53 gene expression, respectively, using RT-PCR. Western blot analysis showed that rutin treatment prevented the activation of NF-κB by increasing the expression of IκB-α. Rutin also attenuated the effects of carfilzomib on oxidant-antioxidant including malondialdehyde and reduced glutathione. Histopathological study clearly confirmed that rutin attenuated carfilzomib-induced cardiotoxicity in rats.

Oxidant-antioxidant imbalance plays an important role in repeated cycles of airway inflammation observed in asthma. It is when reactive oxygen species (ROS) overwhelm antioxidant defenses that a severe inflammatory state becomes apparent and may impact vasculature. Several studies have shown an association between airway inflammation and cardiovascular complications; however so far none has investigated the link between airway oxidative stress and systemic/vascular oxidative stress in a murine model of asthma. Therefore, this study investigated the contribution of oxidative stress encountered in asthmatic airways in modulation of vascular/systemic oxidant-antioxidant balance. Rats were sensitized intraperitoneally with ovalbumin (OVA) in the presence of aluminum hydroxide followed by several intranasal (i.n.) challenges with OVA. Rats were then assessed for airway and vascular inflammation, oxidative stress (ROS, lipid peroxides) and antioxidants measured as total antioxidant capacity (TAC) and thiol content. Challenge with OVA led to increased airway inflammation and oxidative stress with a concomitant increase in vascular inflammation and oxidative stress. Oxidative stress in the vasculature was significantly inhibited by antioxidant treatment, N-acetyl cysteine; whereas hydrogen peroxide (H2O2) inhalation worsened it. Therefore, our study shows that oxidative airway inflammation is associated with vascular/systemic oxidative stress which might predispose these patients to increased cardiovascular risk., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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.

This study was undertaken to evaluate the protective effect of thymoquinone (TQ) against acetaminophen-induced hepatotoxicity. Mice were given TQ orally at three different doses (0.5, 1 and 2mg/kg/day) for 5 days before a single hepatotoxic dose of acetaminophen (500 mg/kg i.p.). TQ supplementation dramatically reduced acetaminophen-induced hepatotoxicity, in a dose-dependent manner, as evidenced by decreased serum alanine aminotransferase (ALT) activities. Acetaminophen (500 mg/kg i.p.) resulted in a significant increase in serum ALT and total nitrate/nitrite, hepatic lipid peroxides and a significant decrease in hepatic reduced glutathione (GSH) and ATP in a time-dependent manner. Interestingly, supplementation of TQ (2mg/kg/day) for 5 days before acetaminophen administration resulted in reversal of acetaminophen-induced increase in ALT, total nitrate/nitrite, lipid peroxide and a decrease in GSH and ATP. Moreover, TQ did not affect acetaminophen-induced early decrease in hepatic GSH indicating lack of the effect on the metabolic activation of acetaminophen. In conclusion, TQ is effective in protecting mice against acetaminophen-induced hepatotoxicity possibly via increased resistance to oxidative and nitrosative stress as well as its ability to improve the mitochondrial energy production., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

1. The present study investigated whether propionyl-L-carnitine (PLC) has neuroprotective effects, similar to those reported for acetyl-L-carnitine (AC), against transient forebrain ischaemia-induced neuronal damage and biochemical derangement in the rat hippocampal CA1 region. 2. In total, 105 adult male Wistar albino rats were divided into seven groups of 15 animals each. The first three groups were injected i.p. with normal saline, AC (300 mg/kg) or PLC (300 mg/kg) for 7 successive days. The next three groups were injected i.p. with the same doses of normal saline, AC or PLC immediately after the induction of 10 min forebrain ischaemia and i.p. injections were continued for 7 successive days. Rats in the seventh group were subjected to sham-operated ischaemia and injected with normal saline for 7 successive days. 3. Seven days after treatment, animals were killed and their brains isolated for histopathological examination and biochemical studies. 4. Forebrain ischaemia resulted in a significant decrease in the number of intact neurons (77%), ATP concentration (51%) and glutathione content (32%), whereas there was a significant increase in the production of thiobarbituric acid-reactive substances (TBARS; 71%) and total nitrate/nitrite (NOx; 260%) in hippocampal tissues. 5. Administration of either AC or PLC attenuated forebrain ischaemia-induced neuronal damage, manifested by a greater number of intact neurons, ATP and glutathione, as well as a decrease in TBARS and NOx in hippocampal tissues. 6. Results from the present study suggest, for the first time, that PLC attenuates forebrain ischaemia-induced neuronal injury, oxidative stress and energy depletion in the hippocampal CA1 region. Propionyl-L-carnitine has neuroprotective effects similar to AC and could have a potential use in the treatment of neurodegenerative diseases. 7. The results of the present study will open up new perspectives for the use of PLC in the treatment of neurodegenerative diseases associated with, or secondary to, myocardial ischaemia-reperfusion injury and chronic circulatory failure.

In the present study, we examined whether the powerful antioxidant probucol (a clinically used lipid-lowering drug) would attenuate the oxidative stress and energy starvation in experimental model of heart failure (HF) using isoproterenol. Rats were injected subcutaneously with isoproterenol (2.4 mgkg-1) daily for 1 week, and then treated with probucol (61 mg/kg) daily for 2 weeks. Oxidative stress was assessed by measuring myocardial lipid peroxides level and antioxidant enzymes activities, glutathione peroxidase (GPx) and superoxide dismutase. In addition, cardiac metabolic damage was estimated by measuring myocardial ATP, ADP and AMP levels as well as ATP/ADP ratio. It was found that isoproterenol induced a significant increase in heart rate by approximately 30% as compared with the pre-value. These changes were significantly attenuated by post-treatment of rats with probucol. Also, isoproterenol induced several pathological changes including lymphocyte infiltration, myofibrillar hemorrhage and degeneration, and these changes were attenuated by probucol. In addition, animals treated with isoproterenol showed a significant increase in myocardial lipid peroxides level up to 163% and a significant decrease in myocardial GPx activity by 35% as compared with the control group. Probucol not only counteracted significantly the pronounced oxidative stress effect of isoproterenol but also it induced a significant increase in myocardial GPx as compared with the control group. The major new finding of the present study is that treatment with probucol induced a significant increase in myocardial ATP level (the source of energy) and ATP/ADP ratio. Moreover, there is a significant correlation between ATP/ADP ratio and myocardial probucol level. In conclusion, the cardioprotective effect of probucol in treatment of HF is a result of not only its antioxidant properties and an enhancement of endogenous antioxidant reserve (mainly GPx) but also an enhancement of myocardial energy state.

Purpose: Cancer rates have been increased among women of reproductive age nowadays. Hence, many young female will be exposed to chemotherapeutic agents as cyclophosphamide (CP), carrying the hazards on female fertility. Cilostazol is a selective phosphodiesterase-3 inhibitor drug which exhibits antioxidant, anti-inflammatory, and anti-apoptotic activities. We aimed in this study to explore the possible protective effects of cilostazol against CP-induced ovarian damage in female rats. Methods: Cilostazol (10 mg/kg/day) was administered orally for 10 days in presence and absence of CP (150 mg/kg IP single dose) treatment. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), and anti-Müllerian hormone (AMH) levels were determined. Ovarian oxidative stress parameters along with inflammatory biomarkers were measured. 3,5-Cyclic adenosine monophosphate (cAMP) ovarian level was detected. Ovarian histopathological examination and caspase-3 immunohistochemical study were evaluated. Results: CP-treated rats showed a significant increase in serum levels of FSH and LH with decreased serum E2 and AMH levels with an increase in the ovarian inflammatory and oxidative stress biomarkers besides a significant decrease in cAMP ovarian level with an evident histopathological picture of ovarian damage and a high caspase-3 immunoexpression. Cilostazol pretreatment significantly restored the distributed hormonal levels, the oxidative stress and inflammatory biomarkers to their normal levels with marked improvement in histopathological picture of ovarian damage with a significant decrease in caspase-3 immunoexpression. Conclusions: These data suggest that cilostazol protects against CP- induced ovarian damage, which may be related to an increase in cAMP with subsequent anti-inflammatory, antioxidant, and anti-apoptotic properties. [ABSTRACT FROM AUTHOR]

1. The present study investigated the possible protective effects of thymoquinone (TQ), a compound derived from Nigella sativa with strong anti-oxidant properties, against gentamicin (GM)-induced nephrotoxicity. 2. A total of 40 adult male Wistar albino rats was divided into four groups. Rats in the first group were injected daily with normal saline (2.5 mL/kg, i.p.) for 8 consecutive days, whereas rats in the second group received TQ (50 mg/L in drinking water) for 8 consecutive days. Animals in the third group were injected daily with GM (80 mg/kg, i.p.) for 8 consecutive days, whereas animals in the fourth group received a combination of GM (80 mg/kg, i.p.) and TQ (50 mg/L in drinking water) for 8 consecutive days. 3. Gentamicin resulted in a significant increase in serum creatinine, blood urea nitrogen (BUN), thiobarbituric acid-reactive substances (TBARS) and total nitrate/nitrite (NOx) and a significant decrease in reduced glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT) and ATP levels in kidney tissues. 4. Interestingly, TQ supplementation resulted in a complete reversal of the GM-induced increase in BUN, creatinine, TBARS and NOx and decrease in GSH, GPx, CAT and ATP to control values. Moreover, histopathological examination of kidney tissues confirmed the biochemical data, wherein TQ supplementation prevents GM-induced degenerative changes in kidney tissues. 5. Data from the present study suggest that TQ supplementation prevents the development of GM-induced acute renal failure by a mechanism related, at least in part, to its ability to decrease oxidative stress and to preserve the activity of the anti-oxidant enzymes, as well as it ability to prevent the energy decline in kidney tissues. [ABSTRACT FROM AUTHOR]

Abstract: Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion and/or action. One of the most important complications of this metabolic disease is diabetic nephropathy. Hyperglycemia promotes oxidative stress and hence generation of reactive oxygen species (ROS), which is known to play a crucial role in the pathogenesis of diabetic nephropathy. Recent studies have established that metformin, an oral hypoglycemic drug, possesses antioxidant effects. However, whether metformin can protect against diabetic nephropathy has not been reported before. The overall objectives of the present study are to elucidate the potential nephroprotective effect of metformin in a rat diabetic nephropathy model and explore the exact underlying mechanism(s) involved. The effect of metformin on the biochemical changes associated with hyperglycemia induced by streptozotocin was investigated in rat kidney tissues. In addition, energy nucleotides (AMP and ATP), and Acetyl-CoA in the kidney homogenates and mitochondria, and the mRNA expression of oxidative stress and pro-inflammatory mediators were assessed. Our results showed that treatment of normoglycemic rats with metformin caused significant increase in ATP, Acetyl-CoA, and CoA-SH contents in kidney homogenates and mitochondria along with profound decrease in AMP level. On the other hand, treatment of diabetic nephropathy rats with metformin normalized all biochemical changes and the energy status in kidney tissues. At the transcriptional levels, metformin treatment caused significant restoration in diabetic nephropathy-induced oxidative stress mRNA levels, particularly GSTα, NQO1, and CAT genes, whereas inhibited TNF-α and IL-6 pro-inflammatory genes. Our data lend further credence for the contribution of metformin in the nephroprotective effect in addition to its well known hypoglycemic action. [Copyright &y& Elsevier]