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1.
Toxins (Basel) ; 13(5)2021 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-34067049

RESUMEN

Prostate cancer is one of the most common cancers in men. Despite the development of a variety of therapeutic agents to treat either metastatic hormone-sensitive prostate cancer, advanced prostate cancer, or nonmetastatic/metastatic castration-resistant prostate cancer, the progression or spread of the disease often cannot be avoided. Additionally, the development of resistance of prostate cancer cells to available therapeutic agents is a well-known problem. Despite extensive and cost-intensive research over decades, curative therapy for metastatic prostate cancer is still not available. Therefore, additional therapeutic agents are still needed. The animal kingdom offers a valuable source of natural substances used for the treatment of a variety of diseases. Bee venom of the honeybee is a mixture of many components. It contains proteins acting as enzymes such as phospholipase A2, smaller proteins and peptides such as melittin and apamin, phospholipids, and physiologically active amines such as histamine, dopamine, and noradrenaline. Melittin has been shown to induce apoptosis in different cancer cell lines, including prostate cancer cell lines. It also influences cell proliferation, angiogenesis, and necrosis as well as motility, migration, metastasis, and invasion of tumour cells. Hence, it represents an interesting anticancer agent. In this review article, studies about the effect of bee venom components on prostate cancer cells are discussed. An electronic literature research was performed utilising PubMed in February 2021. All scientific publications, which examine this interesting subject, are discussed. Furthermore, the different types of application of these promising substances are outlined. The studies clearly indicate that bee venom or melittin exhibited anticancer effects in various prostate cancer cell lines and in xenografts. In most of the studies, a combination of bee venom or the modified melittin with another molecule was utilised in order to avoid side effects and, additionally, to target selectively the prostate cancer cells or the surrounding tissue. The studies showed that systemic side effects and unwanted damage to healthy tissue and organs could be minimised when the anticancer drug was not activated until binding to the cancer cells or the surrounding tissue. Different targets were used, such as the matrix metalloproteinase 2, hormone receptors expressed by prostate cancer cells, the extracellular domain of PSMA, and the fibroblast activation protein occurring in the stroma of prostate cancer cells. Another approach used loaded phosphate micelles, which were cleaved by the enzyme secretory phospholipase A2 produced by prostate cancer cells. In a totally different approach, targeted nanoparticles containing the melittin gene were used for prostate cancer gene therapy. By the targeted nonviral gene delivery, the gene encoding melittin was delivered to the prostate cancer cells without systemic side effects. This review of the scientific literature reveals totally different approaches using bee venom, melittin, modified melittin, or protoxin as anticancer agents. The toxic agents acted through several different mechanisms to produce their anti-prostate cancer effects. These mechanisms are not fully understood yet and more experimental studies are necessary to reveal the complete mode of action. Nevertheless, the researchers have conducted pioneering work. Based on these results, further experimental and clinical studies about melittin and modifications of this interesting agent deriving from nature are necessary and could possibly lead to a complementary treatment option for prostate cancer.


Asunto(s)
Antineoplásicos/farmacología , Venenos de Abeja/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Apamina/aislamiento & purificación , Apamina/farmacología , Apoptosis/efectos de los fármacos , Venenos de Abeja/administración & dosificación , Venenos de Abeja/química , Abejas , Humanos , Masculino , Meliteno/aislamiento & purificación , Meliteno/farmacología , Fosfolipasas A2/aislamiento & purificación , Fosfolipasas A2/farmacología , Neoplasias de la Próstata/patología
3.
Toxins (Basel) ; 11(6)2019 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-31248167

RESUMEN

Bee venom contains a number of pharmacologically active components, including enzymes and polypeptides such as phospholipase A2 (PLA2) and melittin, which have been shown to exhibit therapeutic benefits, mainly via attenuation of inflammation, neurotoxicity, and nociception. The individual components of bee venom may manifest distinct biological actions and therapeutic potential. In this study, the potential mechanisms of action of PLA2 and melittin, among different compounds purified from honey bee venom, were evaluated against Parkinson's disease (PD). Notably, bee venom PLA2 (bvPLA2), but not melittin, exhibited neuroprotective activity against PD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-induced behavioral deficits were also abolished after bvPLA2 treatment, depending on the PLA2 content. Further, bvPLA2 administration activated regulatory T cells (Tregs) while inhibiting inflammatory T helper (Th) 1 and Th17 cells in the MPTP mouse model of PD. These results indicate that bvPLA2, but not melittin, protected against MPTP and alleviated inflammation in PD. Thus, bvPLA2 is a promising and effective therapeutic agent in Parkinson's disease.


Asunto(s)
Venenos de Abeja/química , Fármacos Neuroprotectores/uso terapéutico , Trastornos Parkinsonianos/tratamiento farmacológico , Fosfolipasas A2/uso terapéutico , Animales , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Masculino , Meliteno/aislamiento & purificación , Meliteno/uso terapéutico , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/aislamiento & purificación , Fosfolipasas A2/aislamiento & purificación , Linfocitos T Reguladores/efectos de los fármacos
4.
J Proteome Res ; 17(11): 3904-3913, 2018 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-30223649

RESUMEN

Jellyfish are a type of poisonous cnidarian invertebrate that secrete lethal venom for predation or defense. Human beings often become victims of jellyfish stings accidentally while swimming or fishing and suffer severe pain, itching, swelling, inflammation, shock, and even death. Jellyfish venom is composed of various toxins, and the lethal toxin is the most toxic and hazardous component of the venom, which is responsible for deaths caused by jellyfish stings and envenomation. Our previous study revealed many toxins in jellyfish venom, including phospholipase A2, metalloproteinase, and protease inhibitors. However, it is still unknown which type of toxin is lethal and how it works. Herein a combined toxicology analysis, proteome strategy, and purification approach was employed to investigate the lethality of the venom of the jellyfish Cyanea nozakii. Toxicity analysis revealed that cardiotoxicity including acute myocardial infarction and a significant decrease in both heart rate and blood pressure is the primary cause of death. Purified lethal toxin containing a fraction of jellyfish venom was subsequently subjected to proteome analysis and bioinformation analysis. A total of 316 and 374 homologous proteins were identified, including phospholipase A2-like toxins and metalloprotease-like toxins. Furthermore, we confirmed that the lethality of the jellyfish venom is related to metalloproteinase activity but without any phospholipase A2 activity or hemolytic activity. Altogether, this study not only provides a comprehensive understanding of the lethal mechanism of jellyfish venom but also provides very useful information for the therapeutic or rescue strategy for severe jellyfish stings.


Asunto(s)
Venenos de Cnidarios/química , Metaloproteasas/aislamiento & purificación , Infarto del Miocardio/inducido químicamente , Fosfolipasas A2/aislamiento & purificación , Proteoma/aislamiento & purificación , Escifozoos/química , Animales , Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Cromatografía Liquida , Venenos de Cnidarios/toxicidad , Femenino , Ontología de Genes , Corazón/efectos de los fármacos , Corazón/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Hígado/efectos de los fármacos , Hígado/fisiopatología , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Masculino , Espectrometría de Masas , Metaloproteasas/química , Metaloproteasas/toxicidad , Ratones , Anotación de Secuencia Molecular , Infarto del Miocardio/fisiopatología , Fosfolipasas A2/química , Fosfolipasas A2/toxicidad , Proteoma/química , Proteoma/clasificación , Proteoma/toxicidad , Proteómica/métodos , Escifozoos/patogenicidad , Escifozoos/fisiología , Bazo/efectos de los fármacos , Bazo/fisiopatología
5.
Toxicon ; 125: 1-12, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27826020

RESUMEN

Jellyfish envenomations are emerging as an important public health concern occurred worldwide. In China, the situation is getting worse with numerous people stung by jellyfish Nemopilema nomurai (N. nomurai) and Cyanea nozakii (C. nozakii) in the summer. However, the proteinaceous mixtures in nematocysts responsible for the symptoms of jellyfish stings were scarcely characterized and understood in view of enzymatic constituents and toxicity. In the present study, enzymatic properties of jellyfish N. nomurai and C. nozakii nematocyst venom were analyzed biochemically and kinetically. The current data revealed that N. nomurai and C. nozakii nematocyst venom exhibited various enzymatic activities, of which metalloproteinases activity and PLA2s-like activity were predominant. Moreover, the catalytic activities of metalloproteinases and PLA2s-like were dependent on different physiochemical conditions such as temperature, pH and divalent ions. Kinetic profiling revealed their catalytic behaviors fitted the Michaelis-Menten equation under specific conditions. Findings suggested jellyfish nematocyst venom possessed diverse enzymatic constituents, which may underlie the extensively characterized bioactivities of jellyfish venom and human envenomations. Hence, our study will contribute to understanding the enzymatic constituents and toxicity of jellyfish nematocyst venom and may afford potential therapeutic targets for developing drugs for jellyfish stings.


Asunto(s)
Venenos de Cnidarios/enzimología , Escifozoos/enzimología , Animales , Venenos de Cnidarios/química , Fibrinógeno/química , Cinética , Metaloproteasas/química , Metaloproteasas/aislamiento & purificación , Metaloproteasas/metabolismo , Fosfolipasas A2/química , Fosfolipasas A2/aislamiento & purificación , Fosfolipasas A2/metabolismo
6.
Toxins (Basel) ; 7(7): 2422-34, 2015 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-26131771

RESUMEN

A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A2 (bvPLA2) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA2, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA2-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA2 treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system.


Asunto(s)
Analgésicos/uso terapéutico , Antineoplásicos/efectos adversos , Venenos de Abeja/química , Neuralgia/tratamiento farmacológico , Compuestos Organoplatinos/efectos adversos , Fosfolipasas A2/uso terapéutico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Analgésicos/aislamiento & purificación , Animales , Venenos de Abeja/enzimología , Conducta Animal/efectos de los fármacos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Masculino , Ratones Endogámicos C57BL , Neuralgia/inducido químicamente , Neuralgia/metabolismo , Oxaliplatino , Fosfolipasas A2/aislamiento & purificación , Receptores Adrenérgicos alfa 2/metabolismo
7.
Curr Top Med Chem ; 11(20): 2566-77, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21682680

RESUMEN

Four compounds (isoquercitrin, myricetin-3-O-glucoside, catechin and gallocatechin) were isolated from lyophilized aqueous extract of Schizolobium parahyba leaves by chromatography on Sephadex LH-20, followed by semipreparative HPLC using a C-18 column, and identified by 1H and 13C NMR. The compounds were then, tested against hemorrhagic and fibrinogenolytic activities of Bothrops crude venoms and isolated metalloproteinases. The inhibitors neutralized the biological and enzymatic activities of Bothrops venoms and toxins isolated from B. jararacussu and B. neuwiedi venoms. The results showed that gallocatechin and myricetin-3-O-glucoside are good inhibitors of hemorrhagic and fibrinogenolytic activities of metalloproteinases, respectively. Gallocatechin also inhibited the myotoxic activity of both B. alternatus venom and BnSP-6 (Lys49 PhospholipaseA2 from B. neuwiedi). Circular dichroism and docking simulation studies were performed in order to investigate the possible interaction between BnSP-6 and gallocatechin. This is the first time these compounds and their anti-ophidian properties are reported for S. parahyba species. Forthcoming studies involving X-ray co-crystallization, will be of great importance for the development of new therapeutic agents for the treatment of ophidian accidents and for the better understanding of the structure/function relationship of venom toxins.


Asunto(s)
Antivenenos/farmacología , Bothrops/fisiología , Venenos de Crotálidos/antagonistas & inhibidores , Fabaceae/química , Flavonoides/farmacología , Hemorragia/tratamiento farmacológico , Metaloproteasas/antagonistas & inhibidores , Inhibidores de Fosfolipasa A2 , Mordeduras de Serpientes , Animales , Antivenenos/química , Antivenenos/aislamiento & purificación , Cromatografía de Afinidad , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Venenos de Crotálidos/química , Venenos de Crotálidos/enzimología , Venenos de Crotálidos/aislamiento & purificación , Venenos de Crotálidos/toxicidad , Fibrinolíticos/química , Fibrinolíticos/aislamiento & purificación , Fibrinolíticos/toxicidad , Flavonoides/química , Flavonoides/aislamiento & purificación , Hemorragia/patología , Hemorragia/prevención & control , Espectroscopía de Resonancia Magnética , Masculino , Metaloproteasas/química , Metaloproteasas/aislamiento & purificación , Metaloproteasas/toxicidad , Ratones , Modelos Moleculares , Músculos/efectos de los fármacos , Músculos/patología , Fosfolipasas A2/química , Fosfolipasas A2/aislamiento & purificación , Fosfolipasas A2/toxicidad , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Hojas de la Planta/química
8.
Methods Mol Biol ; 716: 245-65, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21318911

RESUMEN

Wound healing is a complex process involving the integrated actions of numerous cell types, soluble mediators, and extracellular matrix (ECM). In this study, phospholipase A(2) (PLA(2)) purified from crotalid snake venom was found to express in vitro bactericidal activity against a group of clinical human pathogens. Based on the sequence homology of PLA(2), a series of peptides were derived from the C-terminal region of crotalid PLA(2). These short synthetic peptides were found to reproduce the bactericidal activity of its parent molecule. In vitro assays for bactericidal and cytolytic activities of these peptides showed very high microbicidal potency against Gram-negative and Gram-positive (Staphylococcus aureus) bacteria. Variants of the peptides showed reduced toxicity toward normal human cells, while retaining high bactericidal potency. Here we describe the protocol for evaluating the wound healing process by antibacterial peptides. We evaluated the biological roles of the candidate peptides in skin wound healing, using a specific BALB/c mice model. Peptide-treated animals showed accelerated healing of full-thickness skin wounds, with increased reepithelialization, collagen synthesis, and angiogenesis observed during the healing process. Healing wounds in protein/peptide-treated mice had higher densities of neutrophils, macrophages, and fibrocytes. Along with increased leukocyte infiltration, levels of macrophage-derived chemokine expression were also upregulated. These results demonstrate that the protein/peptide derived from snake venoms promotes healing of skin wounds. The primary mechanism seems to be an increase in leukocyte infiltration, leading to locally elevated synthesis and release of collagen and growth factors.


Asunto(s)
Antibacterianos/uso terapéutico , Evaluación Preclínica de Medicamentos/métodos , Péptidos/uso terapéutico , Fosfolipasas A2/uso terapéutico , Enfermedades Cutáneas Bacterianas/tratamiento farmacológico , Cicatrización de Heridas/efectos de los fármacos , Animales , Antibacterianos/aislamiento & purificación , Bacterias/efectos de los fármacos , Bothrops/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Péptidos/aislamiento & purificación , Fosfolipasas A2/aislamiento & purificación , Piel/efectos de los fármacos , Piel/patología , Enfermedades Cutáneas Bacterianas/patología , Venenos de Serpiente/enzimología
9.
J Appl Toxicol ; 31(8): 720-9, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21319174

RESUMEN

Phyllorhiza punctata (P. punctata) is a jellyfish native to the southwestern Pacific. Herewith we present the biochemical and pharmacological characterization of an extract of the tentacles of P. punctata. The tentacles were subjected to three freeze-thaw cycles, homogenized, ultrafiltered, precipitated, centrifuged and lyophilized to obtain a crude extract (PHY-N). Paralytic shellfish poisoning compounds such as saxitoxin, gonyautoxin-4, tetrodotoxin and brevetoxin-2, as well as several secretory phospholipase A(2) were identified. PHY-N was tested on autonomic and somatic neuromuscular preparations. In mouse vas deferens, PHY-N induced phasic contractions that reached a peak of 234 ± 34.7% of control twitch height, which were blocked with either 100 µ m of phentolamine or 1 m m of lidocaine. In mouse corpora cavernosa, PHY-N evoked a relaxation response, which was blocked with either L-N(G) -Nitroarginine methyl ester (0.5 m m) or 1 m m of lidocaine. PHY-N (1, 3 and 10 µg ml(-1) ) induced an increase in tonus of the biventer-cervicis neuromuscular preparation that was blocked with pre-treatment of galamine (10 µ m). Administration of 6 mg kg(-1) PHY-N intramuscularly produced death in broilers by spastic paralysis. In conclusion, PHY-N induces nerve depolarization and nonspecifically increases neurotransmitter release.


Asunto(s)
Venenos de Cnidarios/toxicidad , Unión Neuromuscular/efectos de los fármacos , Escifozoos/química , Transmisión Sináptica/efectos de los fármacos , Animales , Pollos , Venenos de Cnidarios/aislamiento & purificación , Lidocaína/metabolismo , Masculino , Toxinas Marinas , Ratones , Unión Neuromuscular/metabolismo , Oxocinas/aislamiento & purificación , Oxocinas/toxicidad , Fentolamina/metabolismo , Fosfolipasas A2/aislamiento & purificación , Fosfolipasas A2/toxicidad , Saxitoxina/análogos & derivados , Saxitoxina/aislamiento & purificación , Saxitoxina/toxicidad , Manejo de Especímenes , Tetrodotoxina/aislamiento & purificación , Tetrodotoxina/toxicidad , Conducto Deferente/efectos de los fármacos
10.
Toxicon ; 51(8): 1548-53, 2008 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-18466944

RESUMEN

A compound (AIPLAI (Azadirachta indica PLA(2) inhibitor)) purified from the methanolic leaf extract of A. indica (Neem) inhibits the cobra and Russell's viper venoms (RVVs) phospholipase A(2) enzymes in a dose-dependent manner. Inhibition of catalytic and tested pharmacological properties of cobra venom (Naja naja and Naja kaouthia) PLA(2) enzymes by AIPLAI is significantly higher (P<0.05) compared to the inhibition of PLA(2) enzymes of crude RVV (Daboia russelli) when tested under the same condition. Kinetic study reveals that in in vitro condition, AIPLAI inhibits the purified N. kaouthia PLA(2) enzymes in a non-competitive manner. The AIPLAI is quite stable at room temperature. The present study shows that AIPLAI holds good promise for the development of novel anti-snake venom drug in future.


Asunto(s)
Azadirachta/química , Venenos Elapídicos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Fosfolipasa A2 , Extractos Vegetales/farmacología , Venenos de Víboras/química , Animales , Cromatografía Líquida de Alta Presión , Elapidae , Inhibidores Enzimáticos/aislamiento & purificación , Cinética , Fosfolipasas A2/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta/química , Daboia
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