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1.
Biochem Biophys Res Commun ; 438(1): 198-204, 2013 Aug 16.
Article in English | MEDLINE | ID: mdl-23880341

ABSTRACT

Melatonin is a pineal hormone that regulates circadian and seasonal rhythms. The chronobiotic role of melatonin corresponds with a repertoire of pharmacological properties. Besides, it has a wide range of therapeutic applications. However, recent studies have demonstrated its direct interaction with platelets: at physiological concentration it promotes platelet aggregation; on the other hand, at pharmacological doses it raises intracellular Ca(2+) leading to platelet activation, thrombus formation and cardiovascular disorders. In order to further probe its effects on platelets, the current study targeted platelet apoptosis and melatonin was found to stimulate apoptosis. The mitochondrial pathway of apoptosis was mainly investigated because of its susceptibility to oxidative stress-inducing factors including therapeutic and dietary elements. Melatonin significantly increased the generation of intracellular ROS and Ca(2+), facilitating mitochondrial membrane depolarization, cytochrome c release, caspase activation, protein phosphorylation and phosphatidylserine externalization. Further, the overall toxicity of melatonin on platelets was confirmed by MTT and lactate dehydrogenase assays. The elevated rate of platelet apoptosis has far reaching consequences including thrombocytopenia. Besides, platelets undergoing apoptosis release microparticles, which fuel thrombus formation and play a significant role in the pathophysiology of a number of diseases. In many parts of the world melatonin is an over-the-counter dietary supplement and alternative medicine. Since, melatonin displays platelet proapoptotic effect at a concentration attainable through therapeutic dosage, the present study sends a warning signal to the chronic use of melatonin as a therapeutic drug and questions its availability without a medical prescription.


Subject(s)
Apoptosis/drug effects , Blood Platelets/physiology , Hydrogen Peroxide/metabolism , Melatonin/toxicity , Mitochondria/physiology , Mitophagy/physiology , Reactive Oxygen Species/metabolism , Apoptosis/physiology , Blood Platelets/drug effects , Blood Platelets/ultrastructure , Cells, Cultured , Humans , Mitochondria/drug effects , Mitochondria/ultrastructure , Mitophagy/drug effects
2.
J Pharm Pharmacol ; 65(4): 604-14, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23488790

ABSTRACT

OBJECTIVES: This study investigated the protective efficacy of crocin against hepatotoxicity induced by cyclophosphamide (CP) in Wistar rats. METHODS: The experimental rats were treated with crocin orally at a dose of 10 mg/kg for 6 consecutive days after the administration of a single intraperitoneal dose of CP (150 mg/kg). The ameliorative effect of crocin on organ toxicity was studied by evaluating oxidative stress enzymes, inflammatory cytokines and histological sections. KEY FINDINGS: A single intraperitoneal CP injection significantly elevated endogenous reactive oxygen species and oxidation of lipids and proteins, which are the hallmarks of oxidative damage in liver and serum. In consequence, the primary defensive reduced glutathione, total thiol and antioxidant enzymes such as superoxide dismutase, catalase, glutathione-S-transferase and glutathione peroxidase, were significantly reduced. In addition, liver and serum aspartate aminotransferase and alanine aminotransferase along with acid and alkaline phosphatase were considerably increased. Oral administration of crocin significantly rejuvenated all the above altered markers to almost normal state. The protective efficacy of crocin was further supported by the histological assessment and restoration of CP-induced inflammatory cytokines and enzyme levels compared with the control drug. CONCLUSION: The results obtained suggest the protective nature of crocin against CP-induced oxidative damage/inflammation and organ toxicity.


Subject(s)
Antineoplastic Agents, Alkylating/antagonists & inhibitors , Antioxidants/therapeutic use , Carotenoids/therapeutic use , Chemical and Drug Induced Liver Injury/prevention & control , Cyclophosphamide/antagonists & inhibitors , Cytokines/blood , Liver/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antineoplastic Agents, Alkylating/adverse effects , Biomarkers/blood , Biomarkers/metabolism , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Cyclophosphamide/adverse effects , Food Coloring Agents/therapeutic use , Hydrogen Peroxide/metabolism , Lipid Peroxidation/drug effects , Liver/immunology , Liver/metabolism , Liver/pathology , Oxidative Stress/drug effects , Oxidoreductases/metabolism , Protein Carbonylation/drug effects , Protein Processing, Post-Translational/drug effects , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism
3.
Eur J Nutr ; 52(7): 1787-99, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23269651

ABSTRACT

PURPOSE: The dietary sesamol is one of the important constituent of sesame seed that has been mainly claimed to combat cardiovascular disease and diabetes, which are the major secondary complications of arthritis. Thus, the present study was designed to evaluate the anti-arthritic, anti-inflammatory and anti-stress potentials of sesamol. METHODS: Arthritis was induced using Freund's complete adjuvant to hind paw of experimental rats. The physical and biochemical alterations and its recovery by sesamol were assessed by measuring enzymatic and non-enzymatic mediators. Arthritis-induced inflammation, oxidative stress and their protective by sesamol were measured by determining the levels of pro-inflammatory cytokines and oxidative stress markers. RESULTS: In the present study, sesamol was demonstrated to alleviate arthritis-induced cartilage degeneration by mitigating augmented serum levels of hyaluronidase and matrix metalloproteinases (MMP-13, MMP-3 and MMP-9). It also protected bone resorption by reducing the elevated levels of bone joint exoglycosidases, cathepsin D and tartarate-resistant acid phosphatases. Sesamol also abrogated the non-enzymatic inflammatory markers (TNF, IL-1ß, IL-6, COX-2, PGE2, ROS, and H2O2,) effectively. In addition, sesamol neutralizes arthritis-induced oxidative stress by restoring the levels of reactive oxygen species, lipid and hydro peroxides and sustained antioxidant homeostasis by re-establishing altered activities of superoxide dismutase, catalase and glutathione-s-transferase. CONCLUSION: Taken together, the study demonstrated the anti-arthritic, anti-inflammatory, anti-oxidative stress and chondro-protective potentials of sesamol in vivo. Thus, sesamol could be a single bullet that can fight arthritis as well as the secondary complications of arthritis such as cardio vascular disorders and diabetes.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Antioxidants/administration & dosage , Arthritis, Experimental/drug therapy , Benzodioxoles/administration & dosage , Extracellular Matrix/metabolism , Inflammation Mediators/metabolism , Phenols/administration & dosage , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Catalase/metabolism , Cyclooxygenase 2/metabolism , Glutathione Transferase/metabolism , Hydrogen Peroxide/metabolism , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Matrix Metalloproteinase 13/genetics , Matrix Metalloproteinase 13/metabolism , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Oxidative Stress/drug effects , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism , Tumor Necrosis Factor-alpha/metabolism
4.
Basic Clin Pharmacol Toxicol ; 109(4): 292-9, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21729242

ABSTRACT

Viper envenomation undeniably induces brutal local manifestations such as haemorrhage, oedema and necrosis involving massive degradation of extracellular matrix at the bitten region and many a times results in dangerous systemic haemorrhage including pulmonary shock. Snake venom metalloproteases (SVMPs) are being considered to be the primary culprits for the venom-induced haemorrhage. As a consequence, the venom researchers and medical practitioners are in deliberate quest of SVMP inhibitors. In this study, we evaluated the inhibitory effect of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (DFD) on viper venom-induced haemorrhagic and PLA(2) activities. DFD effectively neutralized the haemorrhagic activity of the medically important viper venoms such as Echis carinatus, Echis ocelatus, Echis carinatus sochureki, Echis carinatus leakeyi and Crotalus atrox in a dose-dependent manner. The histological examinations revealed that the compound DFD effectively neutralizes the basement membrane degradation, and accumulation of inflammatory leucocytes at the site of Echis carinatus venom injection further confirms the inhibition of haemorrhagic activity. In addition, DFD dose dependently inhibited the PLA(2) activities of Crotalus atrox and E. c. leakeyi venoms. According to the docking studies, DFD binds to hydrophobic pocket of SVMP with the ki of 19.26 × 10(-9) (kcal/mol) without chelating Zn(2+) in the active site. It is concluded that the clinically approved inhibitors of haemorrhagins could be used as a potent first-aid agent in snakebite management. Furthermore, a high degree of structural and functional homology between SVMPs and their relatives, the MMPs, suggests that DFD analogues may find immense value in the regulation of multifactorial pathological conditions like inflammation, cancer and wound healing.


Subject(s)
Benzofurans/pharmacology , Enzyme Inhibitors/pharmacology , Hemorrhage/drug therapy , Viper Venoms/antagonists & inhibitors , Animals , Citalopram/analogs & derivatives , Dose-Response Relationship, Drug , Erythrocytes/drug effects , Hemolysis , Hemorrhage/chemically induced , Humans , Male , Mice , Phospholipases A/antagonists & inhibitors , Protein Binding , Skin/drug effects , Skin/pathology , Viper Venoms/enzymology , Viper Venoms/toxicity
5.
Immunopharmacol Immunotoxicol ; 31(4): 607-15, 2009.
Article in English | MEDLINE | ID: mdl-19874230

ABSTRACT

Snakebites in rural areas of tropical and subtropical regions are commonly treated with medicinal plants. In this report, we have studied the ability of Anacardium occidentale bark extract to neutralize enzymatic as well as pharmacological effects induced by Vipera russelii venom. The extract neutralized the viper venom hydrolytic enzymes such as phospholipase, protease, and hyaluronidase in a dose dependent manner. These enzymes are responsible for both local effects of envenomation such as local tissue damage, inflammation and myonecrosis, and systemic effects including dysfunction of vital organs and alteration in the coagulation components. In addition, extract neutralized the pharmacological effects such as edema, hemorrhage, and myotoxic effects including lethality, induced by venom. Since, it inhibits both hydrolytic enzymes and pharmacological effects; it may be used as an alternative treatment to serum therapy and, in addition, as a rich source of potential inhibitors of hydrolytic enzymes involved in several physiopathological diseases.


Subject(s)
Anacardium/physiology , Immunosuppressive Agents/pharmacology , Plant Bark/physiology , Plant Extracts/pharmacology , Snakes , Viper Venoms/antagonists & inhibitors , Anacardium/chemistry , Animals , Dose-Response Relationship, Immunologic , Immunosuppressive Agents/chemistry , Male , Mice , Plant Bark/chemistry , Plant Extracts/isolation & purification , Snakes/immunology , Viper Venoms/enzymology
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