Protective role of Roflumilast against cadmium-induced cardiotoxicity through inhibition of oxidative stress and NF-κB signaling in rats.

Cadmium (Cd), a potent cardiotoxic environmental heavy metal, induces oxidative stress and membrane disturbances in cardiac myocytes. Phosphodiesterase (PDEs) retards the positive inotropic effects of ß-adrenoceptor activation by decreasing levels of cAMP via degradation. Hence, PDE inhibitors sensitize the heart to catecholamine and are therefore, used as positive inotropic agents. The present study was designed to probe the potential attenuating effects of the selective PDE4 inhibitor (Roflumilast, ROF), on cardiac biomarkers, lipid profile, lipid peroxidation products, antioxidant status and histology of cardiac tissues against Cd-induced cardiotoxicity in rats. Rats were randomly distributed into four different groups: group 1, served as the normal control group. Group 2, served as the toxic control group and were administered Cd (3 mg/kg, i.p.) for next 7 days. Groups 3 and 4, served as treatment groups that received Cd with concomitant oral administration of ROF doses (0.5 and 1.5 mg/kg), respectively for 7 days. Serum samples of toxic control group rats resulted in significant (P < 0.001) increase in lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total cholesterol (TC), triglycerides (TG) and low density lipoproteins (LDL) levels with concomitant decrease in high density lipoproteins (HDL) levels in serum which were found reversed with both of ROF treatment groups. Cd also causes significant increased (P < 0.001) in myocardial malondialdehyde (MDA) contents while cardiac glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) enzyme activities were found decreased whereas both doses of ROF, significantly reversed these oxidative stress markers and antioxidant enzymes. Cardiotoxicity induced by Cd also resulted in enhanced expression of non-phosphorylated and phosphorylated form of NF-κB p65 and decreased expression of glutathione-S-transferase (GST) and NQO1 which were found reversed with ROF treatments, comparable to normal control group. Histopathological changes were also improved by ROF administration as compared to Cd treated rats alone. In conclusion, Roflumilast exhibited attenuating effect against Cd-induced cardiac toxicity.

The Protective Effect of Naringenin on Oxaliplatin-Induced Genotoxicity in Mice.

Oxaliplatin is a third generation platinum based anti-cancer drug used against various human malignancies but displays genotoxic properties against normal cells. Naringenin is a naturally occurring bioflavonoid that possesses anti-oxidant properties and has protective effects against DNA damage. The aim of this study is to examine the protective effects of naringenin on oxaliplatin-induced DNA damage in mice. A total of 50, male BALB/c mice were randomly divided equally into five groups. Oxaliplatin toxicity was induced by a single dose (7 mg/kg body weight (b.w.)) injection (intraperitoneally (i.p.)) of oxaliplatin. Naringenin was given orally for ten consecutive days at two doses, 20 mg/kg b.w. (dose I) and 40 mg/kg b.w. (dose II), to group I and group II, respectively. On the tenth day of the experiment, animals in groups III, IV, and V were given a single i.p. injection of oxaliplatin (7 mg/kg b.w.). All the animals were sacrificed 24 h after oxaliplatin treatment. The extent of genotoxicity was assessed by multiple genotoxicity assays (8-hydroxydeoxy-guanosine marker, comet, micronucleus and chromosomal aberration assays, oxidative stress-marker Glutathione evaluation) in order to determine diverse kinds of DNA damage. The results indicated that naringenin administration significantly reduced the DNA damage induced by oxaliplatin possibly due to its strong anti-oxidant properties. The results suggest that naringenin is a potential candidate for future development as a chemoprotective agent against chemotherapy associated complications.

Mechanism behind the anti-tumour potential of saffron (Crocus sativus L.): The molecular perspective.

Cancer is a disorder which has noted a significant rise in incidence worldwide and continues to be the largest cause of mortality. It has a dramatic impact on human life expectancy and quality of life in spite of the increase in technology and the treatments available for cancer patients. These new therapeutic options being chemotherapy, radiotherapy, photolytic therapy and catalytic therapy are known to have many adverse reactions and also no better positive outcomes than before. Hence, research is now focused more on utilizing the vast repertoire of traditional medicinal knowledge i.e. the use of flora for treatment of cancer rather than the use of chemicals. One such herb is the Crocus sativus L., commonly known as Saffron, rich in carotenoids - crocin, crocetin and safranal. Various studies have been carried out over the past few years to confirm the anti-cancer properties of saffron, both in vivo using animal models and in vitro using human malignant cell lines on various types of cancers with positive results. The proposed mechanism of actions has also been worked upon. This review is aimed to provide a brief overview on the anti-tumor potential of saffron focusing on the molecular mechanism involved.

Activation of adenosine A2A receptor signaling regulates the expression of cytokines associated with immunologic dysfunction in BTBR T+ Itpr3tf/J mice.

Autism spectrum disorder (ASD) is neurodevelopmental disorders characterized by stereotypical repetitive behavior, impaired social interaction, and deficits in communication. The BTBR T+ Itpr3tf/J (BTBR) mice have been extensively used as an animal model of the ASD-like phenotype. Adenosine A2A receptors (A2ARs) are considered potential targets in the treatment of neurodegenerative diseases. In this study, we used the A2AR antagonist SCH 5826 (SCH) and the A2AR agonist CGS 21680 (CGS) to investigate the activation of A2AR signaling in immune cells. Further, we examined the effects of A2ARs on the expression of the cytokines interleukin 2 (IL-2), IL-6, IL-9, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and transforming growth factor ß (TGF-ß) in the spleen and in splenic CD4+ T cells. In addition, we assessed the mRNA and protein expression levels of these cytokines in the brain tissue. Our results showed that the levels of IL-2+, IL-6+, IL-9+, IFN-γ+, and TNF-α+ were significantly lower, whereas the levels of TGF-ß+ in the spleen and in splenic CD4+ T cells were significantly higher in the CGS-treated mice than in the BTBR control and SCH-treated mice. In addition, reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis showed a decrease in the mRNA and protein expression levels of IL-2, IL-6, IL-9, IFN-γ+, and TNF-α+ and an increase in the mRNA and protein expression levels of TGF-ß in the CGS-treated mice, while treatment with BTBR alone and SCH resulted in increased Th1 levels and decreased Th2 levels in the brain tissue. Our results suggest that treatment the A2AR agonist CGS may be a promising therapeutic option for neuroimmune dysfunction.

Modulatory effect of Morus indica against two-stage skin carcinogenesis in Swiss albino mice: possible mechanism by inhibiting aryl hydrocarbon hydroxylase.

The modulatory effect of the methanolic extract of Morus indica on 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced oxidative stress and 7,12-dimethylbenz(a)anthracene induced and croton oil (0.5% per mouse/0.2 mL acetone, v/v) promoted skin tumourigenesis in Swiss albino mice was studied. The efficacy of the M. indica extract was also evaluated in-vitro by studying the inhibition of the activity and level of aryl hydrocarbon hydroxylase, cytochrome P450, DNA sugar damage in calf thymus DNA and Fe(++)/ascorbate-induced lipid peroxidation in microsomes of mice. Significant increases in the activity of antioxidant enzymes (P <0.001) and a concomitant decrease (P <0.001) in the cutaneous malondialdehyde level were observed at three doses of plant extract (2.5, 5.0 and 7.5 mg kg(-1)). Application of M. indica 1 h before each application of croton oil showed inhibitory effects on tumour promotion in terms of a reduction in the number of tumours/mouse and percentage of mice with tumours. It was also accompanied by an extension of the tumour latency period. TPA, which resulted in a rapid and transient stimulation of mouse epidermal ornithine decarboxylase activity (P <0.001), was inhibited dose dependently by pre-treatment with M. indica extract (P <0.001). The results suggest that M. indica extract may be useful as a therapeutic agent for cancer control as it blocks or suppresses events associated with chemical carcinogenesis.