Unraveling snake venom phospholipase A2: an overview of its structure, pharmacology, and inhibitors.

Snake bite is a neglected disease that affects millions of people worldwide. WHO reported approximately 5 million people are bitten by various species of snakes each year, resulting in nearly 1 million deaths and an additional three times cases of permanent disability. Snakes utilize the venom mainly for immobilization and digestion of their prey. Snake venom is a composition of proteins and enzymes which is responsible for its diverse pharmacological action. Snake venom phospholipase A2 (SvPLA2) is an enzyme that is present in every snake species in different quantities and is known to produce remarkable functional diversity and pharmacological action like inflammation, necrosis, myonecrosis, hemorrhage, etc. Arachidonic acid, a precursor to eicosanoids, such as prostaglandins and leukotrienes, is released when SvPLA2 catalyzes the hydrolysis of the sn-2 positions of membrane glycerophospholipids, which is responsible for its actions. Polyvalent antivenom produced from horses or lambs is the standard treatment for snake envenomation, although it has many drawbacks. Traditional medical practitioners treat snake bites using plants and other remedies as a sustainable alternative. More than 500 plant species from more than 100 families reported having venom-neutralizing abilities. Plant-derived secondary metabolites have the ability to reduce the venom's adverse consequences. Numerous studies have documented the ability of plant chemicals to inhibit the enzymes found in snake venom. Research in recent years has shown that various small molecules, such as varespladib and methyl varespladib, effectively inhibit the PLA2 toxin. In the present article, we have overviewed the knowledge of snake venom phospholipase A2, its classification, and the mechanism involved in the pathophysiology of cytotoxicity, myonecrosis, anticoagulation, and inflammation clinical application and inhibitors of SvPLA2, along with the list of studies carried out to evaluate the potency of small molecules like varespladib and secondary metabolites from the traditional medicine for their anti-PLA2 effect.

Plant-Derived Toxin Inhibitors as Potential Candidates to Complement Antivenom Treatment in Snakebite Envenomations.

Snakebite envenomations (SBEs) are a neglected medical condition of global importance that mainly affect the tropical and subtropical regions. Clinical manifestations include pain, edema, hemorrhage, tissue necrosis, and neurotoxic signs, and may evolve to functional loss of the affected limb, acute renal and/or respiratory failure, and even death. The standard treatment for snake envenomations is antivenom, which is produced from the hyperimmunization of animals with snake toxins. The inhibition of the effects of SBEs using natural or synthetic compounds has been suggested as a complementary treatment particularly before admission to hospital for antivenom treatment, since these alternative molecules are also able to inhibit toxins. Biodiversity-derived molecules, namely those extracted from medicinal plants, are promising sources of toxin inhibitors that can minimize the deleterious consequences of SBEs. In this review, we systematically synthesize the literature on plant metabolites that can be used as toxin-inhibiting agents, as well as present the potential mechanisms of action of molecules derived from natural sources. These findings aim to further our understanding of the potential of natural products and provide new lead compounds as auxiliary therapies for SBEs.

Bioactive Molecules Derived from Snake Venoms with Therapeutic Potential for the Treatment of Thrombo-Cardiovascular Disorders Associated with COVID-19.

As expected, several new variants of Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2) emerged and have been detected around the world throughout this Coronavirus Disease of 2019 (COVID-19) pandemic. Currently, there is no specific developed drug against COVID-19 and the challenge of developing effective antiviral strategies based on natural agents with different mechanisms of action becomes an urgent need and requires identification of genetic differences among variants. Such data is used to improve therapeutics to combat SARS-CoV-2 variants. Nature is known to offer many biotherapeutics from animal venoms, algae and plant that have been historically used in traditional medicine. Among these bioresources, snake venom displays many bioactivities of interest such as antiviral, antiplatelet, antithrombotic, anti-inflammatory, antimicrobial and antitumoral. COVID-19 is a viral respiratory sickness due to SARS-CoV-2 which induces thrombotic disorders due to cytokine storm, platelet hyperactivation and endothelial dysfunction. This review aims to: (1) present an overview on the infection, the developed thrombo-inflammatory responses and mechanisms of induced thrombosis of COVID-19 compared to other similar pathogenesis; (2) underline the role of natural compounds such as anticoagulant, antiplatelet and thrombolytic agents; (3) investigate the management of coagulopathy related to COVID-19 and provide insight on therapeutic such as venom compounds. We also summarize the updated advances on antiviral proteins and peptides derived from snake venoms that could weaken coagulopathy characterizing COVID-19.

Animal Venom for Medical Usage in Pharmacopuncture in Korean Medicine: Current Status and Clinical Implication.

Animal venoms, widespread throughout the world, are complex mixtures, the composition of which depends on the venom-producing species. The objective of this study was to contribute to the development of animal venom-based medicines by investigating the use of animal venom pharmacopuncture in Korean medicine (KM) institutions. We surveyed 256 public health centers from 1 through 31 October 2019 as guided by the Ministry of Health and Welfare (MoHW). A questionnaire developed by an expert group was distributed and collected for statistical analysis. The survey identified three types of animal venom-based pharmacopuncture: bee, snake, and toad venoms. The medications are based on a single animal venom ingredient and produced in 11 external herbal dispensaries (EHDs). Each animal venom is processed, refined, and freeze-dried in a cleanroom to produce a powder formulation that is later measured, diluted, filtered, filled, sealed, sterilized, and packaged as pharmacopuncture injections used in KM institutions. Bee venom therapy is effective in treating musculoskeletal pain, snake venom therapy is effective in controlling bleeding during surgery, and toad venom therapy is effective in cancer treatment. The study suggests that bee, snake, and toad venoms could be used in medical institutions and have the potential for drug development.

A snake toxin as a theranostic agent for the type 2 vasopressin receptor.

Rationale: MQ1, a snake toxin which targets with high nanomolar affinity and absolute selectivity for the type 2 vasopressin receptor (V2R), is a drug candidate for renal diseases and a molecular probe for imaging cells or organs expressing V2R. Methods: MQ1's pharmacological properties were characterized and applied to a rat model of hyponatremia. Its PK/PD parameters were determined as well as its therapeutic index. Fluorescently and radioactively labeled MQ1 were chemically synthesized and associated with moderate loss of affinity. MQ1's dynamic biodistribution was monitored by positron emission tomography. Confocal imaging was used to observe the labeling of three cancer cell lines. Results: The inverse agonist property of MQ1 very efficiently prevented dDAVP-induced hyponatremia in rats with low nanomolar/kg doses and with a very large therapeutic index. PK (plasma MQ1 concentrations) and PD (diuresis) exhibited a parallel biphasic decrease. The dynamic biodistribution showed that MQ1 targets the kidneys and then exhibits a blood and kidney biphasic decrease. Whatever the approach used, we found a T1/2α between 0.9 and 3.8 h and a T1/2ß between 25 and 46 h and demonstrated that the kidneys were able to retain MQ1. Finally, the presence of functional V2R expressed at the membrane of cancer cells was, for the first time, demonstrated with a specific fluorescent ligand. Conclusion: As the most selective V2 binder, MQ1 is a new promising drug for aquaresis-related diseases and a molecular probe to visualize in vitro and in vivo V2R expressed physiologically or under pathological conditions.

Anti-integrin αv therapy improves cardiac fibrosis after myocardial infarction by blunting cardiac PW1+ stromal cells.

There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1+ cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1+ cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1+ cells (93% ± 1%), predominantly as the αVß1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFß at the surface of cardiac PW1+ cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1+CD51+ cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia.

Anticancer Activity of Toxins from Bee and Snake Venom-An Overview on Ovarian Cancer.

Cancer represents the disease of the millennium, a major problem in public health. The proliferation of tumor cells, angiogenesis, and the relationship between the cancer cells and the components of the extracellular matrix are important in the events of carcinogenesis, and these pathways are being used as targets for new anticancer treatments. Various venoms and their toxins have shown possible anticancer effects on human cancer cell lines, providing new perspectives in drug development. In this review, we observed the effects of natural toxins from bee and snake venom and the mechanisms through which they can inhibit the growth and proliferation of cancer cells. We also researched how several types of natural molecules from venom can sensitize ovarian cancer cells to conventional chemotherapy, with many toxins being helpful for developing new anticancer drugs. This approach could improve the efficiency of standard therapies and could allow the administration of decreased doses of chemotherapy. Natural toxins from bee and snake venom could become potential candidates for the future treatment of different types of cancer. It is important to continue these studies concerning therapeutic drugs from natural resource and, more importantly, to investigate their mechanism of action on cancer cells.

Targeting αvß3 and αvß5 integrins inhibits pulmonary metastasis in an intratibial xenograft osteosarcoma mouse model.

Osteosarcoma is an aggressive bone cancer that has a high propensity for metastasis to the lungs. Patients with metastatic disease face a very poor prognosis. Therefore, novel therapeutics, efficiently suppressing the metastatic process, are urgently needed. Integrins play a pivotal role in tumor cell adhesion, motility and metastasis. Here, we evaluated αvß3 and αvß5 integrin inhibition with cilengitide as a novel metastasis-suppressive therapeutic approach in osteosarcoma. Immunohistochemical analysis of αvß3 and αvß5 integrins expression in a tissue microarray of tumor specimens collected from osteosarcoma patients revealed that αvß5 integrin is mainly found on tumor cells, whereas αvß3 is predominantly expressed by stromal cells. In vitro functional assays demonstrated that cilengitide dose-dependently inhibited de novo adhesion, provoked detachment and inhibited migration of osteosarcoma cell lines. Cilengitide induced a decline in cell viability, blocked the cell cycle in the G1 phase and caused anoikis by activation of the Hippo pathway. In a xenograft orthotopic mouse model cilengitide minimally affected intratibial primary tumor growth but, importantly, suppressed pulmonary metastasis. The data demonstrate that targeting αvß3 and αvß5 integrins in osteosarcoma should be considered as a novel therapeutic option for patients with metastatic disease.

The role of intravenous vasodilators in acute heart failure management.

Acute heart failure is a major cause of emergency hospital admission, with significant impact on health resources and patient outcomes. With no new treatments for over 20 years, the advent of new innovative therapies may facilitate a radical change in our approach to such patients. In this article, we examine the current evidence for the use of current intravenous vasodilators in AHF management, and review the potential of novel therapies currently in development.

Standards of care and novel approaches in the management of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Standard therapeutic approaches provide modest improvement in the progression-free and overall survival, necessitating the investigation of novel therapies. We review the standard treatment options for GBM and evaluate the results obtained in clinical trials for promising novel approaches, including the inhibition of angiogenesis, targeted approaches against molecular pathways, immunotherapies, and local treatment with low voltage electric fields.

Effects of snake venom polypeptides on central nervous system.

The nervous system is a primary target for animal venoms as the impairment of its function results in the fast and efficient immobilization or death of a prey. There are numerous evidences about effects of crude snake venoms or isolated toxins on peripheral nervous system. However, the data on their interactions with the central nervous system (CNS) are not abundant, as the blood-brain barrier (BBB) impedes penetration of these compounds into brain. This updated review presents the data about interaction of snake venom polypeptides with CNS. Such data will be described according to three main modes of interactions: - Direct in vivo interaction of CNS with venom polypeptides either capable to penetrate BBB or injected into the brain. - In vitro interactions of cell or sub-cellular fractions of CNS with crude venoms or purified toxins. - Indirect effects of snake venoms or their components on functioning of CNS under different conditions. Although the venom components penetrating BBB are not numerous, they seem to be the most suitable candidates for the leads in drug design. The compounds with other modes of action are more abundant and better studied, but the lack of the data about their ability to penetrate BBB may substantially aggravate the potentials for their medical perspectives. Nevertheless, many such compounds are used for research of CNS in vitro. These investigations may give invaluable information for understanding the molecular basis of CNS diseases and thus lay the basis for targeted drug design. This aspect also will be outlined in the review.

Cilengitide: an RGD pentapeptide ανß3 and ανß5 integrin inhibitor in development for glioblastoma and other malignancies.

Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανß3 and ανß5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.

K+(ATP) channels-independent analgesic action of Crotalus durissus cumanensis venom.

The effect was investigated of the K+ channel blocker, glibenclamide, on the ability of Crotalus durissus cumanensis venom (CDCM) to promote peripheral antinociception. This was measured by formalin-induced nociception in male Swiss mice. CDCM (200 and 300 microg/kg) produced an antinociceptive effect during phase 2 in the formalin test. The effect of CDCM (200 microg/kg) was unaffected by the ATP-sensitive K+ channel blocker glibenclamide (2 mg/kg). These results suggest that CDCM is effective against acute pain. However, the ATP-sensitive K+ channels pathway is not contributable to the antinociceptive mechanism of CDCM.

Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM), a highly invasive and vascular cancer, responds poorly to conventional cytotoxic therapy. Integrins, widely expressed in GBM and tumor vasculature, mediate cell survival, migration and angiogenesis. Cilengitide is a potent alphavbeta3 and alphavbeta5 integrin inhibitor. OBJECTIVE: To summarize the preclinical and clinical experience with cilengitide for GBM. METHODS: Preclinical studies and clinical trials evaluating cilengitide for GBM were reviewed. RESULTS/CONCLUSIONS: Cilengitide is active and synergizes with external beam radiotherapy in preclinical GBM models. In clinical trials for recurrent GBM, single-agent cilengitide has antitumor benefits and minimal toxicity. Among newly diagnosed GBM patients, single-arm studies incorporating cilengitide into standard external beam radiotherapy/temozolomide have shown encouraging activity with no increased toxicity and have led to a planned randomized Phase III trial.

Snake remedies and eosinophilic granuloma complex in cats.

Eosinophilic granuloma complex (EGC) is a syndrome occurring in cats, characterized by lesions affecting the skin and the oral cavity. Conventional treatment is mainly symptomatic and may have undesirable side effects. This paper summarizes homeopathic treatment with snake remedies of cats suffering from EGC. Snake remedies were chosen by individual repertorizations and administered in different dilutions. Reactions were mostly quick, leading to significant improvements, including complete recoveries.

Snake venom as therapeutic agents: from toxin to drug development.

Snake bite injuries and death are socio-medical problems of considerable magnitude. In India a large number of people suffer and die every year due to snake venom poisoning. Snake venom, though greatly feared, is a natural biological resource, containing several components that could be of potential therapeutic value. Use of snake venom in different pathophysiological conditions has been mentioned in Ayurveda, homeopathy and folk medicine. It is well known that snake venom is complex mixture of enzymes, peptides and proteins of low molecular mass with specific chemical and biological activities. Snake venom contains several neurotoxic, cardiotoxic, cytotoxic, nerve growth factor, lectins, disintrigrins, haemorrhagins and many other different enzymes. These proteins not only inflict death to animals and humans, but can also be used for the treatment of thrombosis, arthritis, cancer and many other diseases. An overview of various snake venom components that have prospects in health and diseases are discussed in this review.

Effects of batroxobin on spatial learning and memory disorder of rats with temporal ischemia and the expression of HSP32 and HSP70.

The effect of Batroxobin on spatial memory disorder of left temporal ischemic rats and the expression of HSP32 and HSP70 were investigated with Morri's water maze and immunohistochemistry methods. The results showed that the mean reaction time and distance of temporal ischemic rats in searching a goal were significantly longer than those of the sham-operated rats and at the same time HSP32 and HSP70 expression of left temporal ischemic region in rats was significantly increased as compared with the sham-operated rats. However, the mean reaction time and distance of the Batroxobin-treated rats were shorter and they used normal strategies more often and earlier than those of ischemic rats. The number of HSP32 and HSP70 immune reactive cells of Batroxobin-treated rats was also less than that of the ischemic group. In conclusion, Batroxobin can improve spatial memory disorder of temporal ischemic rats; and the down-regulation of the expression of HSP32 and HSP70 is probably related to the attenuation of ischemic injury.