RESUMO
Though systemic and local manifestations of snakebite are considered serious, the relevance of oxidative stress in viper bite pathology is largely denied. However, over the past decade, studies have provided substantial evidence for the presence of persistent oxidative stress in viper bite victims. This review aims at highlighting the disturbances in redox homeostasis soon after viper envenomation and its implications in the pathomechanism of secondary/long term complications including thrombocytopenia, hypopituitarism, infertility, renal abnormalities and persistent local tissue degradation. Both enzymatic and non-enzymatic components of viper venom play a pivotal role in bringing redox turbulence in victims. Venom-induced hemorrhage and necrosis with subsequent release of damage associated molecular pattern (DAMPs) molecules also contribute to sustained oxidative stress and inflammation. Studies have demonstrated that along with anti-venom therapy an antioxidant treatment during the early stages of viper bite and also long term treatment could help to reduce the occurrence of secondary/long term complications. Further, proper knowledge regarding the pathophysiology will allow for exploration of new avenues in the treatment of viper bite.
Assuntos
Inflamação/patologia , Estresse Oxidativo/efeitos dos fármacos , Mordeduras de Serpentes/patologia , Venenos de Víboras/toxicidade , Animais , Antioxidantes/uso terapêutico , Antivenenos/uso terapêutico , Modelos Animais de Doenças , Hemorragia/etiologia , Hemorragia/patologia , Hemorragia/prevenção & controle , Homeostase , Humanos , Hipopituitarismo/etiologia , Hipopituitarismo/patologia , Hipopituitarismo/prevenção & controle , Inflamação/tratamento farmacológico , Inflamação/etiologia , Rim/anormalidades , Rim/patologia , Necrose/etiologia , Necrose/patologia , Necrose/prevenção & controle , Mordeduras de Serpentes/complicações , Mordeduras de Serpentes/tratamento farmacológico , Trombocitopenia/etiologia , Trombocitopenia/patologia , Trombocitopenia/prevenção & controle , Anormalidades Urogenitais/etiologia , Anormalidades Urogenitais/patologia , Anormalidades Urogenitais/prevenção & controleRESUMO
Platelets, once considered mediators of hemostasis and thrombosis, are now known to be involved in wound healing, inflammation, cardiovascular diseases, diabetes, arthritis, and cancer. Recent reports attest that platelets possess the cellular machinery to undergo apoptosis and that platelet apoptosis can be triggered by myriad stimuli including chemical and physical agonists, and pathophysiological conditions. Augmented rate of platelet apoptosis leads to thrombocytopenia, bleeding disorders and microparticle generation. Despite knowing the significant role of platelets in health and disease, and that any alterations in platelet functions can wreak havoc to the health, the offshoot reactions of therapeutic drugs on platelets and the far-reaching consequences are often neglected. The present review focuses on the impact of platelet apoptosis and the role of platelet-derived microparticles on different pathophysiological conditions. It also touches upon the effects of biologicals on platelets, and discusses the need to overcome the adverse effects of pro-apoptotic drugs through auxiliary therapy.
Assuntos
Apoptose , Plaquetas/fisiologia , Apoptose/efeitos dos fármacos , Transtornos Plaquetários/etiologia , Plaquetas/efeitos dos fármacos , Micropartículas Derivadas de Células , HumanosRESUMO
Viper bites cause high morbidity and mortality worldwide and regarded as a neglected tropical disease affecting a large healthy population. Classical antivenom therapy has appreciably reduced the snakebite mortality rate; it apparently fails to tackle viper venom-induced local manifestations that persist even after the administration of antivenom. Recently, viper venom-induced oxidative stress and vital organ damage is deemed as yet another reason for concern; these are considered as postmedicated complications of viper bite. Thus, treating viper bite has become a challenge demanding new treatment strategies, auxiliary to antivenin therapy. In the last decade, several studies have reported the use of plant products and clinically approved drugs to neutralize venom-induced pharmacology. However, very few attempts were undertaken to study oxidative stress and vital organ damage. Based on this background, the present study evaluated the protective efficacy of melatonin in Echis carinatus (EC) venom-induced tissue necrosis, oxidative stress, and organ toxicity. The results demonstrated that melatonin efficiently alleviated EC venom-induced hemorrhage and myonecrosis. It also mitigated the altered levels of inflammatory mediators and oxidative stress markers of blood components in liver and kidney homogenates, and documented renal and hepatoprotective action of melatonin. The histopathology of skin, muscle, liver, and kidney tissues further substantiated the overall protection offered by melatonin against viper bite toxicities. Besides the inability of antivenoms to block local effects and the fact that melatonin is already a widely used drug promulgating a multitude of therapeutic functionalities, its use in viper bite management is of high interest and should be seriously considered.
Assuntos
Melatonina/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Mordeduras de Serpentes/tratamento farmacológico , Animais , Radicais Livres/metabolismo , Hemorragia/prevenção & controle , Mediadores da Inflamação/sangue , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Melatonina/administração & dosagem , Melatonina/farmacologia , Camundongos , Músculo Esquelético/patologia , Necrose/prevenção & controle , Ratos Wistar , Venenos de Víboras/toxicidadeRESUMO
The surfacing of the applied fields of biology such as, biotechnology, pharmacology and drug discovery was a boon to the modern man. However, it had its share of disadvantages too. The indiscriminate use of antibiotics and other biological drugs resulted in numerous adverse reactions including thrombocytopenia. One of the reasons for drug-induced thrombocytopenia could be attributed to an enhanced rate of platelet apoptosis, which is a less investigated aspect. The present essay sheds light on the adverse (pro-apoptotic) effects of some of the commonly used drugs and antibiotics on platelets viz. cisplatin, aspirin, vancomycin and balhimycin. Furthermore, the undesirable reactions resulting from chemotherapy could be attributed at least to some extent to the systemic stress induced by microparticles, which in turn are the byproducts of platelet apoptosis. Thereby, the essay aims to highlight the challenges in the emerging trend of cross-disciplinary implications, i.e., drug-induced platelet apoptosis, which is a nascent field. Thus, the different mechanisms through which drugs induce platelet apoptosis are discussed, which also opens up a new perspective through which the adverse effects of commonly used drugs could be dealt. The drug-associated platelet toxicity is of grave concern and demands immediate attention. Besides, it would also be appealing to examine the platelet pro-apoptotic effects of other commonly used therapeutic drugs.
Assuntos
Apoptose/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Trombocitopenia/induzido quimicamente , Aspirina/efeitos adversos , Plaquetas/ultraestrutura , Cisplatino/efeitos adversos , Humanos , Farmacovigilância , Trombocitopenia/patologia , Vancomicina/efeitos adversos , Vancomicina/análogos & derivadosRESUMO
In current scenario of human health and diseases, drug-induced hepatic injury has been recognized as a serious and unresolved problem. Particularly, chemotherapeutic agents have been reported to induce organ toxicity. The aim of the present study is to evaluate organ toxicity and oxidative damage induced by cyclophosphamide (CP), a chemotherapeutic drug and its amelioration by sesamol, an antioxidant from sesame seeds. CP (150 mg/kg) is injected intraperitonially to experimental rats and from day 2 rats were orally treated with sesamol. Rats were sacrificed to evaluate non-enzymatic and enzymatic oxidative stress parameters in serum and tissue homogenates on day 8. Besides, liver function parameters and pro-inflammatory mediators were assessed. Histopathological studies of liver and kidney were also carried out. Elevated levels of endogenous reactive oxygen species, lipid peroxidation and decreased levels of glutathione, total thiols, along with the reduction in antioxidant enzymes including superoxide dismutase, catalase, glutathione-stransferase and glutathione peroxidase, were evident in CP-intoxicated animals. Pro-inflammatory mediators like tumor necrosis factor - α, interleukin (IL)-1ß, IL-6 and cyclooxygenase-2 were also elevated. Moreover, the levels of liver function markers like serum alanine aminotransferase and aspartate aminotransferase were also altered. Histology of liver and kidney tissues further supported CP-induced organ damage. Altered parameters were significantly restored to normal by oral administration of sesamol (50 mg/kg) suggesting its antioxidative stress, anti-inflammatory and hepatoprotective abilities. The study clearly demonstrated the potentiality of sesamol against CPinduced organ toxicity and oxidative stress suggesting its applicability in treatment regime of cancer and other stress-associated disorders as a supportive/auxiliary therapy.
Assuntos
Antineoplásicos Alquilantes/toxicidade , Antioxidantes/farmacologia , Benzodioxóis/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ciclofosfamida/toxicidade , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Animais , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Citocinas/metabolismo , Peróxido de Hidrogênio/metabolismo , Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Baço/metabolismo , Baço/patologiaRESUMO
Platelets play an indispensable role in human health and disease. Platelets are very sensitive to oxidative stress, as it leads to the damage of mitochondrial DNA, which is the initial step of a sequence of events culminating in the cell death through the intrinsic pathway of apoptosis. Owing to a lot of reports on secondary complications arising from oxidative stress caused by therapeutic drug overdose, the present study concentrated on the influence of sesamol on oxidative stress-induced platelet apoptosis. Sesamol, a phenolic derivative present in sesame seeds is an exceptionally promising drug with lots of reports on its protective functions, including its inhibitory effects on platelet aggregation at concentrations below 100 µM, and its anti-cancer effect at 1 mM. However, the present study explored the toxic effects of sesamol on human platelets. Sesamol at the concentration of 0.25 mM and above induced platelet apoptosis through endogenous generation of ROS, depletion of thiol pool, and Ca(2+) mobilization. It also induced mitochondrial membrane potential depolarization, caspase activation, cytochrome c translocation and phosphatidylserine exposure, thus illustrating the pro-apoptotic effect of sesamol at higher concentration. However, even at high concentration of 2 mM sesamol effectively inhibited collagen/ADP/epinephrine-induced platelet aggregation. The study demonstrates that even though sesamol inhibits platelet aggregation, it has the tendency to elicit platelet apoptosis at higher concentrations. Sesamol has a potential as thrombolytic agent, nevertheless the current work highlights the significance of an appropriate dosage of sesamol when it is used as a therapeutic drug.
Assuntos
Apoptose/efeitos dos fármacos , Benzodioxóis/farmacologia , Estresse Oxidativo , Fenóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes , Plaquetas/metabolismo , Plaquetas/patologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Citocromos c/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologiaRESUMO
Coumarins are a group of natural compounds widely distributed in plants. Of late, coumarins and their derivatives have grabbed much attention from the pharmacological and pharmaceutical arena due to their broad range of therapeutical qualities. A coumarin derivative 4-methylesculetin (4-ME) has known to possess effective antioxidant and radical-scavenging properties. Recently they have also shown to down regulate nuclear factor-kappa B (NF-κB) and protein kinase B (Akt) that play a vital role in inflammation and apoptosis. In view of this, the present study investigated the anti-arthritic potentiality of 4-ME by assessing its ability to inhibit cartilage and bone degeneration, inflammation and associated oxidative stress. Arthritis being a debilitating joint disease, results in the deterioration of extracellular matrix (ECM) of cartilage and synovium. Participation of both enzymatic and non-enzymatic factors in disease perpetuation is well documented. The present study demonstrated the mitigation of augmented serum levels of hyaluronidase and matrix metalloproteinases (MMP-13, MMP-3 and MMP-9) responsible for cartilage degeneration by 4-ME. It also protected bone resorption by reducing the elevated levels of bone-joint exoglycosidases, cathepsin-D and tartrate resistant acid phosphatases. Further, 4-ME significantly ameliorated the upregulated non-enzymatic inflammatory markers like TNF-α, IL-1ß, IL-6, COX-2 and PGE2. Besides, 4-ME effectively stabilized the arthritis-induced oxidative stress by restoring the levels of reactive oxygen species, lipid and hydro peroxides and antioxidant enzymes such as superoxide dismutase, catalase and glutathione-S-transferase. Thus, the study suggests that 4-ME could be an effective agent to treat arthritis and associated secondary complications like oxidative stress.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Osso e Ossos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Umbeliferonas/farmacologia , Animais , Artrite Experimental/patologia , Osso e Ossos/patologia , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Cumarínicos/química , Modelos Animais de Doenças , Inflamação/patologia , Masculino , Ratos , Ratos WistarRESUMO
In the present human health scenario, implication of oxidative stress in numerous pathologies including neurodegenerative, cardiovascular, liver, renal, pulmonary disorders, and cancer has gained attention. N-Acetylcysteine (NAC), a popular thiol antioxidant, has been clinically used to treat various pathophysiological disorders. However, NAC therapy is routine only in paracetamol intoxication and as a mucolytic agent. Over six decades, numerous studies involving NAC therapy have yielded inconsistent results, and this could be due to low bioavailability. In order to overcome the limitations of NAC, an amide derivative N-Acetylcysteine amide (NACA) has been synthesized to improve the lipophilicity, membrane permeability, and antioxidant property. Recent studies have demonstrated the blood-brain barrier permeability and therapeutic potentials of NACA in neurological disorders including Parkinson's disease, Alzheimer's disease, Multiple sclerosis, Tardive dyskinesia, and HIV-associated neurological disorders. In addition, NACA displays protective effect against pulmonary inflammation and antibiotic-induced apoptosis. Forthcoming research on the possible therapeutic properties of NACA and its generics in the management of pathologies associated with extracellular matrix degradation and oxidative stress-related inflammation is highly exiting. Superior bioavailability of NACA is likely to fulfill the promises of NAC as well as a molecule to improve the endurance and resident time of bioscaffolds and biomaterials. Till date, more than 800 reviews on NAC have been published. However, no comprehensive review is available on the therapeutic applications of NACA. Therefore, the current review would be the first to emphasize the therapeutic potentials of NACA and its derivatives.
Assuntos
Acetilcisteína/análogos & derivados , Antioxidantes/administração & dosagem , Tratamento Farmacológico/métodos , Estresse Oxidativo/efeitos dos fármacos , Acetilcisteína/administração & dosagem , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Viper envenomations are characterized by prominent local and systemic manifestations including hematological alterations. Snake venom metalloproteinases (SVMPs) and phospholipase A2 (PLA2) plays crucial role in the pathophysiology of hemorrhage by targeting/altering the platelets function which may result in thrombocytopenia. Platelets undergo the classic events of mitochondria-mediated apoptotic pathway due to augmented endogenous reactive oxygen species (ROS) levels. The observed anticoagulant effects during viper envenomations could be due to exacerbated platelet apoptosis and thrombocytopenia. Moreover, antivenin treatments are ineffective against the venom-induced oxidative stress; therefore, it necessitates an auxiliary therapy involving antioxidants which can effectively scavenge the endothelium-generated/endogenous ROS and protect the platelets. The present study explored the effects of viper venom on platelet apoptosis and its amelioration by a phytochemical crocin. The study evaluated the Vipera russelli venom-induced apoptotic events including endogenous ROS generation, intracellular Ca(2+) mobilization, mitochondrial membrane depolarization, cyt-c translocation, caspase activation and phosphatidylserine externalization which were effectively mitigated when the venom was pre-treated with crocin. The study highlights one of the less studied features of venom-induced secondary complications i.e. platelet apoptosis and sheds light on the underlying basis for venom-induced thrombocytopenia, systemic hemorrhage and in vivo anticoagulant effect.
Assuntos
Apoptose/efeitos dos fármacos , Plaquetas/metabolismo , Carotenoides/farmacologia , Crocus/química , Mordeduras de Serpentes/tratamento farmacológico , Trombocitopenia/tratamento farmacológico , Venenos de Víboras/toxicidade , Viperidae , Animais , Plaquetas/patologia , Carotenoides/química , Feminino , Humanos , Masculino , Mordeduras de Serpentes/sangue , Mordeduras de Serpentes/patologia , Trombocitopenia/etiologia , Trombocitopenia/metabolismo , Trombocitopenia/patologiaRESUMO
Hyaluronidase inhibitors have immense applications in pathophysiological conditions associated with hyaluronan-hyaluronidase system. The present study demonstrates the inhibitory efficacy of clinically accepted antioxidant N-acetyl cysteine (NAC) against hyaluronidase of serum, testis, and snake and bee venoms. The experimental and molecular dynamic simulation data suggest the non-competitive inhibition and involvement of thiol groups of both NAC and glutathione in exertion of inhibition. The bioavailability, less-toxic and antioxidant nature of NAC and glutathione could become valuable in the management of pathologies triggered by extracellular matrix degradation and to increase the endurance of hyaluronan based biomaterials/supplements, which are highly exciting aspects.
Assuntos
Acetilcisteína/farmacologia , Glutationa/farmacologia , Hialuronoglucosaminidase/antagonistas & inibidores , Acetilcisteína/química , Acetilcisteína/metabolismo , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Glutationa/química , Glutationa/metabolismo , Hialuronoglucosaminidase/química , Hialuronoglucosaminidase/metabolismo , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação ProteicaRESUMO
Snakebite is a serious medical and socio-economic problem affecting the healthy individuals and agricultural and farming populations worldwide. In India, Vipera russelli snakebite is common, ensuing high morbidity and mortality. The venom components persuade multifactorial stress phenomenon and alter the physiological setting by causing disruption of the blood cells and vital organs. The present study demonstrates the anti-ophidian property of Crocin (Crocus sativus), a potent antioxidant against viper venom-induced oxidative stress. The in vivo oxidative damage induced by venom was clearly evidenced by the increased oxidative stress markers and antioxidant enzymes/molecules along with the proinflammatory cytokines including IL-1ß, TNF-α and IL-6. Furthermore, venom depleted the hemoglobin, hematocrit, mean corpuscular volume and platelet count in experimental animals. Crocin ameliorated the venom-induced oxidative stress, hematological alteration and proinflammatory cytokine levels. At present, administration of antivenom is an effective therapy against systemic toxicity, but it offers no protection against the rapidly spreading oxidative damage and infiltration of pro-inflammatory mediators. These pathologies will continue even after antivenom administration. Hence, a long-term auxiliary therapy is required to treat secondary as well as neglected complications of snakebite.
Assuntos
Carotenoides/uso terapêutico , Crocus/química , Daboia , Estresse Oxidativo/efeitos dos fármacos , Mordeduras de Serpentes/tratamento farmacológico , Venenos de Víboras/toxicidade , Animais , Carotenoides/farmacologia , Catalase/análise , Avaliação Pré-Clínica de Medicamentos , Eritrócitos/efeitos dos fármacos , Glutationa/análise , Glutationa Transferase/análise , Peróxido de Hidrogênio/análise , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/química , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Fitoterapia , Distribuição Aleatória , Mordeduras de Serpentes/sangue , Mordeduras de Serpentes/patologia , Superóxido Dismutase/análiseRESUMO
Platelets are the key players in the development of cardiovascular diseases as the microparticles generated by apoptotic platelets and platelet aggregation contribute actively towards the disease propagation. Thus, the aim of this study was to demonstrate the effect of a phytochemical which can prevent these two processes and thereby project it as a cardio-protective compound. Crocin, a natural carotenoid exhibits a wide spectrum of therapeutic potentials through its antioxidant property. The study demonstrated its effects on cytoplasmic apoptotic events of mitochondrial pathway in platelets. Collagen/calcium ionophore-A23187 stimulated platelets were treated with crocin and endogenous generation of reactive oxygen species (ROS) and hydrogen peroxide (H(2)O(2)) were measured. H(2)O(2)-induced changes in crocin-pretreated platelets such as intracellular calcium, mitochondrial membrane potential (ΔΨm), caspase activity, phosphatidylserine exposure and cytochrome c translocation were determined. Crocin dose-dependently ameliorated collagen- and A23187-induced endogenous generation of ROS and H(2)O(2). It also abolished the H(2)O(2)-induced events of intrinsic pathway of apoptosis. Further, it hindered collagen-induced platelet aggregation and adhesion. The current piece of work clearly suggests its anti-apoptotic effect as well as inhibitory effects on platelet aggregation. Thus, crocin can be deemed as a prospective candidate in the treatment regime of platelet-associated diseases.
Assuntos
Antioxidantes/farmacologia , Plaquetas/metabolismo , Carotenoides/farmacologia , Aditivos Alimentares/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Apoptose/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Sinalização do Cálcio , Caspase 3/metabolismo , Caspase 9/metabolismo , Adesão Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Citocromos c/metabolismo , Ativação Enzimática/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fosfatidilserinas/metabolismo , Agregação Plaquetária/efeitos dos fármacosRESUMO
Platelets are anuclear blood cells originating from bone megakaryocytes. Despite being anuclear, their number is maintained by apoptosis, a process of programmed cell death. The rate of apoptotic death of platelets is accelerated by oxidative and shear stress, ex vivo storage (blood banking conditions) and certain pathophysiological disorders. These factors initiate apoptotic events through the mitochondria- mediated intrinsic pathway. Besides, apoptotic platelets also release phosphatidylserine-positive membrane fractions called microparticles, which cause fibrin deposition and thrombus formation, and are involved in the promulgation of a host of disease conditions including cardiovascular diseases. In this context, several phytochemicals have been reported to be cardioprotective and work by inhibiting platelet aggregation or by dissolving the fibrin clots. Besides, ample reports focus on the positive effects of phytochemicals on normal physiology of platelets, but do not focus on their adverse effects on platelets. Moreover, platelets are reported to be extremely sensitive to therapeutic components in the blood. For example, resveratrol and thymoquinone are hitherto known compounds to possess proapoptotic effects on platelets. In contrast, cinnamtannin B1 and crocin exhibit antiapoptotic effects. Thus, the current review aims to elucidate the underlying mechanisms through which the phytochemicals mediate their effects on platelet apoptosis. Moreover, the need for scrutiny of therapeutic compounds for their effects on platelet functions before including them in treatment regimen is also being emphasized.
Assuntos
Apoptose/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Benzoquinonas/farmacologia , Humanos , Resveratrol , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologiaRESUMO
Snakebite is a serious medical and socio-economic problem affecting the rural and agricultural laborers of tropical and sub-tropical region across the world leading to high morbidity and mortality. In most of the snakebite incidences, victims usually end up with permanent tissue damage and sequelae with high socioeconomic and psychological impacts. Although, mortality has been reduced markedly due to anti-venom regimen, it is associated with several limitations. Snake venom metalloprotease, hyaluronidase and myotoxic phospholipase A2 are the kingpins of tissue necrosis and extracellular matrix degradation. Thus, inhibition of these enzymes is considered to be the rate limiting step in the management of snakebite. Unfortunately, tissue necrosis and extracellular matrix degradation persists even after the administration of anti-venom. At present, inhibitors from snake serum and plasma, several synthetic compounds and their analogs have been demonstrated to possess anti-snake venom activities, but the use of plant metabolites for this purpose has an added advantage of traditional knowledge and will make the treatment cheaper and more accessible to the affected population. Therefore, the clinical and research forums are highly oriented towards plant metabolites and interestingly, certain phytochemicals are implicated as the antibody elicitors against venom toxicity that can be exploited in designing effective anti-venoms. Based on these facts, we have made an effort to enlist plant based secondary metabolites with antiophidian abilities and their mechanism of action against locally acting enzymes/toxins in particular. The review also describes their functional groups responsible for therapeutic beneficial and certainly oblige in designing potent inhibitors against venom toxins.
Assuntos
Fitoterapia/métodos , Plantas/metabolismo , Mordeduras de Serpentes/tratamento farmacológico , Venenos de Serpentes/toxicidade , Animais , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Humanos , Venenos de Serpentes/enzimologiaRESUMO
The majority of snake venom phospholipases A(2) (svPLA(2)s) are toxic and induce a wide spectrum of biological effects. They are cysteine-rich proteins that contain 119-134 amino acids and share similar structures and functions. About 50% of the residues are incorporated into α-helices, whereas only 10% are in ß-sheets. Fourteen conserved cysteines form a network of seven disulfide bridges that stabilize the tertiary structure. They show a high degree of sequence and structural similarity, and are believed to have a common calcium- dependent catalytic mechanism. Additionally, svPLA(2)s display an array of biological actions that are either dependent or independent of catalysis. The PLA(2)s of mammalian origin also exert potent bactericidal activity by binding to anionic surfaces and enzymatic degradation of phospholipids in the target membranes, preferentially of Gram-positive species. The bactericidal activity against Gram-negatives by svPLA(2) requires a synergistic action with bactericidal/permeability-increasing protein (BPI), but is equally dependent on enzymatic- based membrane degradation. Several hypotheses account for the bactericidal properties of svPLA(2)s, which include "fatal depolarization" of the bacterial membrane, creation of physical holes in the membrane, scrambling of normal distribution of lipids between the bilayer leaflets, and damage of critical intracellular targets after internalization of the peptide. The present review discusses several svPLA(2)s and derived peptides that exhibit strong bactericidal activity. The reports demonstrate that svPLA(2)-derived peptides have the potential to counteract microbial infections. In fact, the C-terminal cationic/hydrophobic segment (residues 115-129) of svPLA(2)s is bactericidal. Thus identification of the bactericidal sites in svPLA(2)s has potential for developing novel antimicrobials.
Assuntos
Anti-Infecciosos/farmacologia , Fosfolipases A2/farmacologia , Venenos de Serpentes/enzimologia , Animais , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/metabolismo , Peptídeos Catiônicos Antimicrobianos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Proteínas Sanguíneas/metabolismo , Domínio Catalítico , Membrana Celular/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Fosfolipases A2/metabolismo , Fosfolipases A2/uso terapêuticoRESUMO
Articular cartilage degeneration and inflammation are the hallmark of progressive arthritis and is the leading cause of disability in 10-15% of middle aged individuals across the world. Cartilage and synovium are mainly degraded by either enzymatic or non-enzymatic ways. Matrix metalloproteinases (MMPs), hyaluronidases (HAases) and aggrecanases are the enzymatic mediators and inflammatory cytokines and reactive oxygen species being non-enzymatic mediators. In addition, MMPs and HAases generated end-products act as inflammation inducers via CD44 and TLR-4 receptors involved NF-κB pathway. Although several drugs have been used to treat arthritis, numerous reports describe the side effects of these drugs that may turn fatal. On this account several medicinal plants and their isolated molecules have been involved in modern medicine strategies to fight against arthritis. In view of this, the present study investigated the antiarthritic potentiality of Crocin, a dietary colorant carotenoid isolated from stigma of Crocus sativus. Crocin effectively neutralized the augmented serum levels of enzymatic (MMP-13, MMP-3 and MMP-9 and HAases) and non-enzymatic (TNF-α, IL-1ß, NF-κB, IL-6, COX-2, PGE(2) and ROS) inflammatory mediators. Further, Crocin re-established the arthritis altered antioxidant status of the system (GSH, SOD, CAT and GST). It also protected the bone resorption by inhibiting the elevated levels of bone joint exoglycosidases, cathepsin-D and tartrate resistant acid phosphatases. Taken together, Crocin revitalized the arthritis induced cartilage and bone deterioration along with inflammation and oxidative damage that could be accredited to its antioxidant nature. Thus, Crocin could be an effective antiarthritic agent which can equally nullify the arthritis associated secondary complication.
Assuntos
Artrite Experimental/prevenção & controle , Carotenoides/farmacologia , Cartilagem Articular/efeitos dos fármacos , Inflamação/prevenção & controle , Fosfatase Ácida/antagonistas & inibidores , Fosfatase Ácida/metabolismo , Animais , Antioxidantes/metabolismo , Artrite Experimental/sangue , Artrite Experimental/complicações , Western Blotting , Reabsorção Óssea/metabolismo , Reabsorção Óssea/prevenção & controle , Carotenoides/administração & dosagem , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Catepsina D/antagonistas & inibidores , Catepsina D/metabolismo , Citocinas/sangue , Suplementos Nutricionais , Glutationa/sangue , Hialuronoglucosaminidase/sangue , Inflamação/etiologia , Inflamação/metabolismo , Mediadores da Inflamação/sangue , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Metaloproteinase 13 da Matriz/sangue , Metaloproteinase 3 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fosfatase Ácida Resistente a TartaratoRESUMO
The mortality rate due to snakebite is reduced markedly by the use of anti-venoms, which are the only medically approved remedial agents available. The anti-venoms effectively neutralize the systemic toxicity but offer no protection towards local tissue degradation. In viperid snake envenomations, SVMPs and SVHYs are the major agents responsible for brutal local tissue damage as they degrade ECM and basement membrane surrounding the blood vessels. Thus, the usage of inhibitor(s) against ECM degrading enzymes in the treatment of viper bites is an affirmative therapeutic choice. The present study assessed the efficacy of N-acetyl cysteine (NAC) to inhibit gelatinase, hyaluronidase, hemorrhagic and defibrinogenating activities of Vipera russelli and Echis carinatus venoms. NAC inhibited these activities dosedependently, but it did not inhibit the PLA2, 5' nucleotidase, procoagulant and edema inducing activities of both the venoms. NAC showed complete inhibition of hemorrhagic activity when incubated with venom prior to testing. Whereas little inhibition was observed when venom and NAC were injected independently. Inhibition of the basement membrane degradation and accumulation of inflammatory leukocytes at the site of venom injection in histological sections further corroborate the inhibitory property of NAC. The observed inhibition of hemorrhage was likely due to zinc chelation as supported by spectral studies. Further, docking predictions suggested the role of -SH and -NH-CO-CH3 groups of NAC in the inhibition of SVMPs and SVHYs. Future studies related to the protective role of NAC against the venom induced systemic hemorrhage and secondary complications are highly exciting.