Int J Curr Pharm Res, Vol 14, Issue 1, 1-14Review Article

SNAKE VENOM-DERIVED PEPTIDES AS PROSPECTIVE PHARMACOLOGICAL TOOLS: RECENT TRENDS

**SHEEJA S. RAJAN¹, PERUMAL SUBRAMANIAN^1*, J. P. JOSE MERLIN²**

¹Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608002, Tamil Nadu, India, ²Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA
Email: psub@rediffmail.com

Received: 12 Sep 2021, Revised and Accepted: 15 Nov 2021

ABSTRACT

Small peptides from snake venom are studied as exceedingly selective, specific, effective and harmless therapeutics. This review article critically analyzes with numerous examples for the use of snake venom components as a potential therapeutic tool against various illnesses. The active components from numerous venoms are isolated, purified and used in assays to identify the specific therapeutic components that were categorized based on their biological goal and mechanism of action. This has paved the ways to use peptides from venom as therapeutic drugs. Peptide toxins are usually active orally, via subcutaneous, intramuscular or intravenous administrations. These peptides are targeting a wide range of membrane-bound protein channels and receptors. Peptides are recovered from the venom of diverse animals and most of these possess the possible prospects of safety after isolation and purification and venom-obtained peptides that can become practical drugs effectively, in future.

Keywords: Peptides, Venom toxin, L-amino acid oxidases, Phospholipase A2, Therapeutic tools

© 2022 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijcpr.2022v14i1.44106 Journal homepage: https://innovareacademics.in/journals/index.php/ijcpr

INTRODUCTION

Nature has been always an intriguing source of drug design investigations [1]. It is well known that various bioactive proteins and peptides have been reported that the venom from different species of snakes, conus, scorpions, centipedes, lizards, spiders, sea anemones, bees, and octopus [2, 3]. In this present review, snake venom components, which are of importance for the treatment of various diseases, are considered. Venomous snakes are in focus of investigations and many pharmacologically useful molecules, which have already been isolated and characterized [4]. Epidemiological data estimates that 4.5–5.4 million peoples got bitten by snakes in every year and results about 1.8-2.7 million snakebites envenomation and 81,000 to 138,000 deaths in every year [5]. Hence, snakebite is one of the major public health issues in South Asia, South-east Asia, Sub-Saharan Africa, and Latin America [6, 7]. Venomous snakes with medical importance are mainly belongs to three families: Atractaspididae, Elapidae, and Viperidae [8]. Snakes from the Viperidae family are also further divided into two subfamilies; Viperinae and Crotalinae. In these families, the venom produced in specialized glands are typically delivered to the target organism throughout the modified teeth [9]. Many victims are inflicted with permanent physical injuries due to psychological sequelae, hemorrhage, nephrotoxicity, and tissue necrosis [10].

Snake venom is composed of 90-95% of proteins, which are mostly enzymes [11]. Snake venom is extremely modified with snake’s saliva [12], which containing a complex mixture of amino acids, nucleic acids, carbohydrates, lipids, proteins, and peptides [13, 14]. The composition of snake venom has been illustrated (fig. 1). Proteins and polypeptides are classified into enzymes, and non-enzymatic substances [15]. The most common enzymes of snake venom are phospholipases A2 (2), serine proteases (SVSP), metalloproteases (SVMP), acetylcholinesterases (AChEs), L-amino acid oxidases (LAAO), nucleotidases (5’-nucleotidases, ATPases, phosphodiesterases, and DNases), and hyaluronidases [16]. The most common non-enzymes of snake venom are three-finger toxins (3FTx), Kunitz peptides (KUN), and disintegrins () (fig. 1). The composition of snake venoms may varies depends on the variety of factors, which includes snake family, genus and species, geographical location, typical prey type, age and size of the snakes [9].

The composition of snake venom proteins may undergo distinct qualitative and quantitative variation in populations and individuals of the same species [17]. Variations in protein expression of venom components may also be observed in the same specimen with different ontogeny [18]. Diversification of proteins present in the venom, which is directly reflects its toxicity, pathophysiologic effects, and may represent an evolutionary arms race, by the adaptation of venom composition to improve the ability of subduing different predator’s preys, and also to overcome the resistance of some prey species to the venom [19]. Elapidae and Viperidae venom proteins are produced and secreted by oral exocrine glands, which present in the basal-central lumen, where the venom is stored until its delivery [20]. The production of toxins will be activated by morphological and biochemical changes in secretory epithelial cells after venom injection [21]. Many regulatory mechanisms are carried out in the snakes, to effect protein compositions in their venom, such as mutations affecting gene expression [22], duplication, and loss of toxin-related genes [23], post-transcriptional microRNAs regulation [24], and proteolytic processing [25]. Based on their compositional importance and ubiquity; there are 59 protein families that have been classified into five groups [26], including group I-dominant protein families such as PLA2, SVMP, SVSP, and 3FTx; group II-secondary protein families, which are much smaller amounts than the dominant families such as KUN, LAAO, cysteine-rich secretory protein (CRiSP), C-type lectin (CTL), disintegrin (DIS), and natriuretic peptide (NP); group III-minor protein families such as acetylcholinesterase, hyaluronidase, 5’ nucleotidase, phosphodiesterase, phospholipase B, nerve growth factor (NGF), and vascular endothelial growth factor (VEGF); group IV-rare proteins including 36 families, and; group V-unique protein families such as defensins, waglerin, maticotoxin, and cystatins, which are restricted to the snake species specifically [26, 27].

Snake venom proteins

Snake venom proteins are classified into numerous families, which is based on the structural and functional similarities in the organization of these molecules.

Enzymatic proteins in venoms

Phospholipases A2

Phospholipase A2 (PLA2) plays an important role in the neurotoxic and myotoxic effects of snakebites [28]. These proteins have molecular masses of 13–15 kDa, classified into groups I and II, which are found as major components in the venoms of Elapidae and Viperidae, respectively [12, 28]. There is a third group of PLA2s, which is termed as IIE, has been predominately recovered from the venom of non-front fanged snakes, although their importance in the venom arsenal is still remains unclear [29]. Studies reconstructing the evolutionary history of the multi-locus gene family and after translocation, each of these PLA2s types (I, II, and IIE) has been independently recruited into snake venom systems [30, 31]. Inflammation is induced by non-neurogenic and neurogenic components of PLAs [32]. The non-neurogenic components are especially mediate hydrolysis of membrane lipids, which generates potent pro-inflammatory lipid mediators [33].

Fig. 1: Generalized composition of snake venom

L-amino acid oxidases

L-amino acid oxidases (LAAO) catalyze the stereospecific oxidative deamination of L-amino acid into the corresponding α-keto acid, hydrogen peroxide, and ammonia, which are flavin adenine dinucleotide (FAD) enzymes containing homo-dimeric proteins [34]. LAAOs are produced by different organisms, which ranging from bacteria, algae, and fungi to insects, mammals, mollusks, and certain snake species [35]. Venoms from Viperidae, Crotalinae, and Elapidae species contains relatively high levels of LAAOs, which represent up to ~25% of total protein in the venom; especially in B. caerulus (common krait) [36, 37]. LAAOs along with hyaluronidase and phosphodiesterase enzymes originate in snake venoms are not well studied as other snake venom proteins such as snake venom proteases [38]. LAAOs exhibit a conserved dinucleotide binding fold with other enzymes, which requires FAD as a cofactor, including monoamine oxidase and tryptophan 2-monooxygenase, although phylogenetic comparisons have been revealed a distant relationship with these enzymes [39]. LAAOs usually exist as homodimers, which contribute, in part, to the cytotoxic effects of snake venom [40]. A wide range of biological effects have been attributed to the activity of LAAO, which could activate and/or inhibit platelet aggregation [41], hemorrhage, myonecrosis, and edema [42].

Metalloproteases

Metalloproteases (SVMPs) are zinc-dependent proteinases, which ranges from 20 to 110 kDa in size; and are categorized into three major classes P-I, P-II, and P-III classes, according to their structural domains [43]. These toxins are the major components of viper venoms, which play an important role in the toxicity of these snake venoms [8]. Venom SVMPs have evolved from disintegrin and metalloproteinase (ADAM) proteins, specifically ADAM28, with the PIII being the most basal structural variants, including of metalloproteinase, disintegrin-like, and cysteine-rich domains [44]. The multifunctional properties of SMVPs have been well described. Class P-III SVMPs tend to display stronger hemorrhagic activity when compared to P-I, and P-II SVMPs, possibly due to the disintegrin-like and cysteine-rich domains enabling them to bind with relevant targets in the extracellular matrix of capillary vessels. The functions of these domains have been investigated in inflammation, revealing that these domains are sufficient to induce pro-inflammatory cytokines TNF-α, IL-1b, and IL-6 via leukocyte migration [45].

Serine proteases

Serine proteases (SVSP) belong to the S1 family of serine proteinases and the molecular masses ranging from 26 to 67 kDa with two distinct structural domains [46]. These venom toxins have been evolved from kallikrein-related serine proteases and, following their recruitment for use in the venom gland, which have undergone gene duplication events, ultimately giving rise to various isoforms [46]. SVSPs catalyze the cleavage of polypeptide chains on the C-terminal side, which is positively charged or hydrophobic amino acid residues [47]. Similarly, SVSPs have been described in the venom of wide varieties of snake families, although they are typically abundant in viper venoms and less in other types of venoms of elapid and colubrid snakes (colubridae) [48]. SVSPs are well known for their ability to rupture capillary vessels of SVSPs, which execute their primary toxicity by altering the hemostatic system of their victims by inducing edema and hyperalgesia [49].

Hyaluronidases

Snake venom hyaluronidases are the glycoproteins ranging from the molecular mass 28 to 70 kDa, and the optimum enzyme activity was detected around pH 5.5 [50]. Venom hyaluronidases are known to hydrolyze hyaluronan, which is the major glycosaminoglycan of the interstitial matrix specially found in the extracellular matrix of mammalian cells [51]. They have the capacity to hydrolyze glycosidic linkages β-1-4 residues of N-acetyl-β-D-glucosamine and D-glucuronate from hyaluronan producing tetra and hexasaccharides [52]. During envenomation, hyaluronidases facilitate the venom diffusion in the victim's tissue due to hydrolysis, which make the venom to spread faster in the body and enhance the toxins effect [21].

Nucleotidases

Snake venom nucleotidases comprise of 5′-nucleotidase, ATPase, and ADPase. 5′-nucleotidase is a metalloenzyme with a high molecular mass ranging from 73 to 100 kDa [53]. Gulland and Jackson have identified the 5′-nucleotidase activity in snake venoms, which increase the anticoagulant effect of ADPases, phospholipases A2, and disintegrins by acting synergistically with these specific toxins [54, 55]. ATPases are initially described by Zeller and are known to hydrolyze ATP, which releases adenosine and pyrophosphate. Based on the reaction conditions, ATPases could cleave ATP into AMP and pyrophosphate/phosphate [56, 57]. The only ADPase isolated from snake venom (D. acutus, hundred-pace viper) has a molecular mass of 94 kDa in it’s purified from. This snake venom is known to inhibit platelet aggregation in platelet-rich plasma, which is induced by various molecules, but it does not inhibit thrombin-induced aggregation in platelet-poor plasma [58].

Acetylcholinesterase

Acetylcholinesterase (AChE) plays a crucial role in cholinergic transmission by rapidly inactivating the neurotransmitter and acetylcholine. AChE belongs to the family cholinesterase, which includes butyrylcholinesterase (BuChE) [59]. Both the enzymes hydrolyze choline esters faster than any other substrates, which inhibit physostigmine. AChE is differing from BuChE, it is more active on acetylcholine than propionyl or butyrylcholine. It is also characterized by excess substrate inhibition, which is not observed by BuChE [59]. In addition, these two enzymes may be distinguished by their sensitivity to reversible inhibitors, specifically either AChE or BuChE. The catalytic center of AChE is traditionally considered as a composition of an esterase subsite and an anionic subsite [59]. Earlier study has been suggested that amino acid residues present in the first and second loop of the toxins are involved in the inhibition of enzyme activity [60]. In all Elapidae venoms, AChE is known to be present [2].

Phosphodiesterase

Phosphodiesterase hydrolyzes phosphodiester bonds consecutively from the 30 termini of polynucleotides to produce 5-mononucleotides in the venom of P. flavoviridis (pit viper). In addition, phosphodiesterase activity has been found virtually in all snake venoms, although in general, there is a greater activity associated with Viperidae venoms [38]. Several transcriptome studies from snake venoms indicated that typically less than a few percent of the transcriptomes are comprised of transcripts for phosophodiesterases [61].

Non-enzymatic proteins in venoms

Three-finger toxins

The non-enzymatic proteins, such as 3FTxs family of polypeptides, comprised of 60–74 amino acid residues. These peptides showed diverse functionalities, which possesses a conserved structure [62]. Distinct structural features of 3FTxs are unique fold, including three loops, which emerge from a hydrophobic globular core [62]. Proteomic and transcriptomic analyses have shown that the ratio of 3FTxs might be higher relative to other toxins in the Elapidae venoms, for example, venom of N. ashei (spitting cobra), M. pyrrhocryptus (coral snake), and M. tschudii (desert coral snake) [63]. 3FTxs constitute more than 60% of the venom compositions of cobra snakes [64, 65], while there has been a wide range of distributions of relative abundance of 3FTxs among different krait species, ranging from 1.3% in B. fasciatus [66,67] and 60% in L. colubrina (a sea krait) [68, 69].

Cysteine-rich secretory proteins

Cysteine-rich secretory proteins (CRiSPs) are non-enzymatic components, which are presents in various organisms. These enzymes are also found in snake venoms, but their function in envenoming have not yet been fully understood so far [70, 71]. CRiSPs are single-chain proteins with molecular mass ranging from 20 to 30 kDa. These enzymes have been displayed sixteen highly conserved cysteine residues that can form eight disulfide bonds [72]. CRiSPs are largely distributed among Viperidae and Elapidae families from different continents [21, 72]. There are several reports suggesting the isolation and cloning of three snake venom CRiSPs from O. hannah (king cobra), and C. atrox (diamondback rattlesnake), piscivorin, ophanin, and catrin, respectively. Other CRiSPs, including triflin, ablomin, latisemin, and tigrin are isolated from the venoms of P. flavoviridis, L. semifasciata (black-banded sea krait), and R. tigrinus (tiger keelback) [21, 72].

Disintegrins

Disintegrins (DIS) are cysteine-rich peptides that result from the post-translational cleavage of SVMPs, which are phylogenetically related to ADAMs. The possible function and activity of disintegrins in snake venoms are assigned to support the distribution of other toxins throughout the prey tissues by binding integrins and inhibiting platelet aggregation direct upon envenomation [73]. Disintegrins are found in the venoms of Crotalidae and Viperidae snakes, which constitute approximately 17% and 18% of total venom proteins [8]. Disintegrins might exist as monomers, homodimers, and/or heterodimers. The monomers include short (49–51 amino acid residues and four disulfide bonds), medium (70 amino acids and six disulfide bonds), and long disintegrins (84 amino acids and seven disulfide bonds). Most of the disintegrins belong to the monomeric type [74].

Natriuretic peptides

Natriuretic peptides (NPs) are mostly found in Viperidae than Elapidae [75]. NPs constitute only 3% of the venom proteome of Dendroaspis polyepis and 37% of B. nigroviridis [75]. NPs are found in vertebrates, which play an important role in natriuresis. Moreover, the homologous peptide has been reported in plants and bacteria [76]. Three mammalian NPs are well known, such as atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These NPs regulate the functions of cardiovascular and renal systems, which render them by forming a complex and binding to the natriuretic peptide receptor [76]. For example, ANP and BNP could act in an endocrine manner to maintain blood pressure and volume. Both ANP and BNP might be released by cardiomyocytes in response to elevated blood pressure and hypervolemia [77,78] and CNP is produced by endothelial cells [79]. Nowadays, NPs seem to be great, as they support the development of therapeutics and medical procedures for the treatment and diagnosis of unfortunate physiological conditions such as heart failure and hypertension [80].

Protease inhibitors

The first protease inhibitors are found by documenting the isolation of potent kunitz type protease inhibitors from the venom of D. russelli [81]. The occurrence of the protease inhibitors is reported in Elapidae and Viperidae snake venoms [82, 83]. Snake venoms are the interesting sources of protease inhibitors, although these molecules represent in a small proportion of snake venoms. Further, the chemical reactions of the body is sustained and controlled by the antagonism of: (i) proteases, which play key functions in different systems and biochemical pathways and (ii) the correspondent protease inhibitors, which is responsible for controlling protease activities [84].

Kunitz inhibitors

The first identified Kunitz inhibitor is from Australian elapid venoms O. scutellatus by Possani et al. 1992 [85]. Kunitz inhibitors are mainly found in different animals and are characterized by conserved folds consisting of approximately 60 amino acids, which are stabilized by three disulfide bonds [86]. Protease inhibitory activities are conferred by the binding of these highly specific Kunitz inhibitors to the active site of the serine protease in a substrate-like manner. A major contact is formed between a peptide bond of the inhibitors and the active site of the protease, but in contrast to the usual substrate, these peptides bond only with limited and extremely slow hydrolysis [87]. Sequence analysis of the snake venom Kunitz inhibitors has revealed that the amino acids are highly conserved at the core and in the N-terminal surface area but not at the anti-proteinase site [84]. This suggests that Kunitz inhibitors have been retained the same overall fold but evolved to have various functions [84].

Growth factors

The “growth factor” is conventionally associated with growth and cell proliferation. Later, however, other cellular responses are attributed to these neurotrophins, including cell differentiation, transformation, synthesis, secretions, death, and motility [88]. The first identified growth factor is a nerve growth factor (NGF) from mouse sarcoma 180 in the 1950s [89]. NGF is isolated in 1956 from the venom of A. piscivorus (black water viper) [90]. NGFs are participated in neuronal differentiation, synaptic plasticity, and neuroprotection in peripheral and central nervous systems [91]. NGF is also acts on no neuronal cells, but especially on hematopoietic stem cells. However, most of these effects are already reported for murine NGF [92]. It has been described that the part of the sv-NGF is injected at the bite site of N. atra (Chinese cobra) might reach the circulation, which could lead to some physiological activities on non-neuronal cells or tissues. NGF from N. atra exerts important systemic effects in the envenoming, including plasma extraction and histamine release, which could result in tissue vulnerability and facilitate toxin diffusion in the prey organisms [92]. VEGF is formerly designated as vascular permeability factor, which stimulates vasculogenesis, angiogenesis, and lymphangiogenesis. The VEGF family is divided into seven groups, which is designated as VEGF-A to VEGF-F and placental growth factor (PGF) [93]. Snake venom glands are present as at least three different VEGF-Fs with unique features and with distinct receptors selectivity, designated as VEGF-F1 to VEGF-F3. Additionally, VEGF-A-like transcripts have been identified in some snake venoms [94].

Prospective pharmacological tools of snake venom

As new peptides of venom source are recognized and characterized, this can be considered as a new era of medicine. Several drugs produced in venom of various organisms, which are currently being used in the treatment of human disorders. Furthermore, as the competence and price of both commercial production and recombinant expression of peptides endure to progress, it is possible that more of these composite peptide drugs will be produced in the future [95]. Table 1 depicts the prospective pharmacological effect of snake venom peptide in various diseases.

Table 1: Prospective pharmacological influences of snake venom proteins/peptides

Family	Scientific name	Venom peptides/proteins	Experimental model	Observation	Reference
Cancer
Viperidae	Bothrops jararaca	Jararhagin	Human melanoma cell lines (SK-Mel-28)	Increase in the expression of cell cycle and apoptosis	[99]
Elapidae	Naja naja atra	Cardiotoxin III	Human breast cancer cell lines (MDA-MB-231)	Suppression of EGF-induced cell invasion and, migration	[100]
Viperidae	Cerastes vipera	L-amino acid oxidase	Human breast cancer cell lines (MCF-7)	Increase in H₂O₂ and TBARS levels by depletion of catalase activity	[101]
Viperidae	Calloselasma rhodostoma	L-amino acid oxidase	Human colon cancer cell lines (SW480, SW620)	Significant increase in the activity of caspase-3, and reduction in Bcl-2 levels	[13]
Viperidae	Cryptelytrops purpureomaculatus	L-amino acid oxidase	Human colon cancer cell lines (SW480, SW620)	Significant increase in the activity of caspase-3, and reduction in Bcl-2 levels	[102]
Viperidae	Daboia russelii	L-amino acid oxidase (Rusvinoxidase)	Human breast cancer cell lines (MCF-7)	Induction of apoptosis in both intrinsic and extrinsic pathways	[103]
Viperidae	Crotalus durissus	Crotoxin	Human lung squamous carcinoma cell lines (SK-MES-1)	Expression of p-JNK and p17 increased during apoptosis	[104]
Viperidae	Macrovipera lebetina	Snake venom toxin	Human lung cancer cell lines (A549 and NCI-H460)	Induction of caspase-3, 8, 9, Bax, p21, p53, and reduction of cIAP, Bcl2 expression	[105]
Elapidae	Naja oxiana	Cytotoxin I and II	Human cancer cell lines: breast cancer (MCF-7), hepatocellular carcinoma (HepG2) prostate carcinoma (DU145), and promyelocytic leukemia (HL-60)	Activation of apoptotic pathways	[106]
Viperidae	Bothrops pauloensis	L-amino acid oxidase (BnSP-6, a Lys-49)	Human breast cancer cell lines (MDA-MB-231)	Involved in signaling pathways of apoptosis, and autophagy	[107]
Cardiovascular disease
Viperidae	Bothrops marajoensis	Phospholipase A₂	Wistar rats (WTs)	Induction of hypotension, and bradycardia while simultaneously blocking electrical conduction in the heart	[110]
Viperidae	Bitis Arietans, Bitis gabonica, Bitis rhinoceros, Bitis nasicornis	Crude venom	Wistar rats (WTs)	Leads to hypotensive shock, and require special attention in cases of envenoming	[111]
Viperidae	Bothrops jararaca	Proline-rich oligopeptide (Bj-PRO-10c)	Spontaneously hypertensive rats (SHRs)	Modulates gene expression of key enzymes in NO production	[112]
Elapidae	Ophiophagus hannah	Cobra venom factor	Mongrel dogs	Alteration of cardiac performance, collateral blood flow to the clotting system	[113]
Elapidae	Ophiophagus hannah	Cobra venom factor	Feral baboons	Reduction of PMN recruitment, and activate myocardial ischemia, and coronary reperfusion to reduce tissue injury	[114]
Viperidae	Bothrops jararaca	Bradykinin potentiating peptides (BPP-5a)	Spontaneously hypertensive rats (SHRs)	Antihypertensive, and vasorelaxation effects are due to an endothelium, and NO-dependent mechanism	[115]
Elapidae	Bungarus candidus	Crude venom	Wistar rats (WTs)	Involved in autonomic reflex, and vascular nitric oxide mechanisms	[116]
Viperidae	Bitis rhinoceros	Serine protease	Human plasma	Reduction of the risk of human haemostatic disorders, such as heart attacks, and strokes	[117]
Renal disease
Elapidae	Dendroaspis angusticeps	Mambaquaretin-1	pcy mice	Inhibition of dDAVP, and induction of cAMP production	[122]
Viperidae	Trimeresurus flavoviridis	Crude venom	Sprague dawley rats	Correlation of both ECM production, and degradation systems involved in repair process	[123]
Viperidae	Trimeresurus flavoviridis	Crude venom	182 sato mice (TIE2/lZ)	Glomerular endothelial cell turnover, and regeneration of glomerular microvasculature	[124]
Viperidae	Agkistrodon acutus	Crude venom	ddY mice	Inhibition of effect on glomerular disease	[125]
Viperidae	Bothrops alternatus	Crude venom	Wistar-Hannover rats	Induce morphological, and functional renal alterations with enhanced Na+/K+-ATPase expression, and activity in the early phase of renal damage	[126]
Viperidae	Bothrops moojeni	Crude venom	Wistar rats (WTs)	Induced intense alterations in renal physiology, including a drop in RVR associated with diuresis, natriuresis, and kaliuresis	[127]
Viperidae	Bothrops marajoensis	L-amino acid oxidase	MadineDarby Canine Kidney cell lines (MDCK)	Responsible for nephrotoxicity, and renal cytotoxicity	[128]
Elapidae	Micrurus browni, Micrurus laticollaris	Crude venom	Monkey Kidney epithelial cell lines (LLC-MK2), Wistar rats (WTs)	Alteration of renal physiological parameters, and cause nephrotoxic effects, with the involvement of oxidative stress	[129]
Pulmonary disease
Viperidae	Agkistrodon acutus	Fibrinolytic enzyme	Rabbits	Reduction of thrombi, which restores blood flow in the lung, and improving cardiovascular function	[134]
Viperidae	Bothrops jararaca	Jararhagin	CD-1 mice	Affect lung microvessels by proteolytic activity, and also inhibits action of plasma proteinase inhibitors	[135]
Viperidae	Agkistrodon acutus	Recombinant fibrinogenase II	Severe acute pancreatitis rats (SAP)	Degradation of TNF-a	[136]
Viperidae	Bothrops caribbaeus	P-III (snake venom metalloprotease) SVMP	CD-1 mice	Induction of pulmonary hemorrhage, and thrombocytopenia, and increased FDP, without causing blood incoagulability	[137]
Neurodegenerative disease
Viperidae	Bothrops atrox	Glu-Val-Trp (p-BTX-I)	PC12 cell lines	Action via trkA receptor, and PI3K-AKT and MAPK-ERK pathways by NGF	[141]
Viperidae	Bothrops jararaca	Crude venom (CV), Low molecular weight fractions (LMWF)	Hippocampal cell lines	Shows neuroprotective activity in cultured hippocampal cells in oxidative stress induced by H₂O₂	[142]
Elapidae, Viperidae	Naja annulifera, Naja nivea, Dendroaspis jamesoni kaimosae, Vipera ammodytes	Crude venom (CV)	On-line microfluidic profiling	Useful in direct post-column analysis	[143]
Elapidae	Dendroaspis angusticeps (Eastern green mamba)	Fasciculin 2	Acetylcholinesterase in human	Treatment of cognitive impairments associated with Alzheimer’s disease	[144]
Elapidae	Naja kaouthia	Metalloproteinase	Human Nerve growth factor (NGF)	Regulation of platelet reactivity through inhibition of GPVI/sheddase activity	[145]
Viperidae	Daboia russelli russelli	β-amyloid (Aβ)	Human neuroblastoma cell lines (SH-SY5Y)	Inhibition of amyloidosis from cell viability against toxicity, and destabilization of amyloid to monomeric entities	[146]
Diabetes mellitus
Elapidae	Naja naja atra	Crude venom (CV)	Wistar rats (WTs)	Reduces hyperglycemia, decreases urinary protein, improvement renal function, and prevention inflammatory factor infiltration	[149]
Viperidae	Agkistrodon halys	Protein C activators (PCA)	Sprague Dawley rats (SD)	Potential to anti-fibrotic activities, such as the balance between inflammatory cytokine levels and collagen content, and modulates MMP expression	[150]
Viperidae	Trimeresurus flavoviridis	Vascular endothelial growth factor (VEGF)	Spontaneously diabetic Torii rats (SDT)	Enhance β cell injury, microvascular failure, and diabetes	[151]
Elapidae	Naja nigricollis	Phospholipase A2 (PLA₂)	Rat clonal β-cell lines (BRIN-BD11)	Identified isoforms of phospholipase A₂ and effectively stimulate insulin release from BRIN-BD11 cells	[152]
Arthritis
Elapidae	Naja kaouthia	Crude venom (CV)	Albino Wistar rats	Protection against arthritis induced oxidative damages	[155]
Elapidae	Naja naja	NN-32	Albino Wistar rats	Targets complex pathophysiological processes such as cancer, arthritis, and inflammation	[156]
Viperidae	Crotalus durissus	Phospholipase A2 (PLA₂)	Human plasma	Increase in the levels of PLA₂ in patients with rheumatoid arthritis than in those with osteoarthritis	[157]
Elapidae	Naja naja	Phospholipase A2 (PLA₂)	Rats	Correlation of acute inflamed joints bathed in synovial fluids containing high levels of PLA₂ in patients with rheumatoid arthritis	[158]
Elapidae	Naja kaouthia	Cytotoxin I	Albino Wistar rats	Protective activity of nanogold conjugated with snake venom protein toxin, NKCT1, against osteoarthritis	[159]
Viperidae	Bothrops asper	Metalloproteinase BaP1	Wistar rats (WTs)	Metalloproteinase BaP1 has pro-nociceptive activity in joints	[160]
Inflammation
Elapidae	Hydrophis cyanocinctus	Hydrostatin-SN1 (H-SN1)	Human embryonic kidney cell lines (HEK293), human colon cancer cell lines (HT29), normal fibroblast cell lines (L929), and BALB/c mice	Significant anti-inflammatory activity under in vitro and in vivo conditions	[163]
Viperidae	Bothrops jararaca, Bothrops jararacussu	Crude venom (CV)	Swiss mice	Reduction in the inflammatory response to the venom injection	[164]
Viperidae	Bothrops jararacussu	Crude venom (CV)	Mice	Increased productionof IL-1β, COX-2 expression, and neutrophil chemotaxis induced by venom	[165]
Viperidae	Crotalus durissus terrificus	Crotoxin B secreted phospholipase A₂ (CB-sPLA₂)	Swiss mice	Lipid droplets recognition acute phase of inflammation, which involved in both development, and resolution of the inflammatory process	[166]
Viperidae	Bothrops moojeni	Metalloprotease (BmooMP-alpha-I)	C57BL/6 mice	A novel perspective to treat intestinal inflammatory diseases	[167]
Elapidae	Hydrophis cyanocinctus	Hydrostatin-TL1 (H-TL1)	Normal fibroblast cell lines (L929), BALB/c mice	For the development of new agents to treat IBD, sepsis acute shock, and other inflammatory diseases associated with TNF-α	[168]
Analgesic
Viperidae	Gloydius ussuriensis	Gln49 phospholipase A₂ (Gln49-PLA₂)	Kunming white mice	Function of voltage-dependent ion channels, blocking neuronal signal transduction, and the blockade of potassium channels in nerve terminal	[171]
Viperidae	Bothrops asper	Crude venom (CV)	CD-1 mice	An alternative to reduces the pain, and distress of animals	[172]
Viperidae	Bothrops atrox	Crude venom (CV)	Swiss Webster mice	Signal reduction in edema and nociception	[173]

Cancer

Cancer, the second leading cause of mortality across the world, according to global statistics in 2018 ranges about 18.1 million new cases, and 9.6 million deaths [96]. Animal venom toxins exhibit effective anticancer properties, and are possible therapeutic drugs for cancer [97]. Toxins that are purified from various snake venoms are very effective in cancer cell multiplication, migration, invasion, apoptosis, and neo-vascularization [98]. Several studies suggested that low dose of jararhagin induced antiproliferation and induction of apoptosis in SKMel-28 cells, which also increased the expression of cell cycle checkpoint and apoptosis [98, 99]. Another study revealed that CTX III could inhibit the EGF-mediated endothelial-mesenchymal transition (EMT) in MDAMB-231 cells, which could suppress the EGF-induced cell invasion, migration over EGFR-mediated PI3K/Akt, and ERK1/2 signaling pathways [100]. C. vipera (Sahara sand viper)-LAAO has been triggered anti-proliferative activity through H2O2 generation, which could increase H2O2 and TBARS levels accompanied by the depletion of catalase activity in MCF-7 treated cells [101]. Further data provides evidences that the anticancer activity of LAAO from C. rhodostoma (Malayan pit viper) venom in human colon cancer by significant increase in the activity of caspase-3 and reduction in Bcl-2 levels in human colon cancer tissues [13]. In another study same authors demonstrated same results with the venom of C. purpureomaculatus (Shore pit viper) [102]. Moreover, rusvinoxidase induces apoptosis by intrinsic and extrinsic pathways in MCF-7 cells by DNA fragmentation due to activation of caspase-7 rather than caspase-3 [103]. Another study evidenced that the expression of p-JNK and p17 increased apoptosis induced by crotoxin in SK-MES-1 cells [104]. Demonstration of SVT inhibition in lung cancer cells through induction of apoptosis by up-regulation of caspase-3, 8, 9, Bax, p21, and p53, but decreased cIAP and Bcl2 expression has also been documented [105]. Furthermore, CTX-I and CTX-II isolated form N. oxiana (Ladle snake) venom exert their cytotoxic effect in cytosol, which accumulates in lysosomes, and leading to the activation of apoptotic pathways in cancer cells [106]. Induction of apoptosis and autophage by PLA2 and BnSP-6 apoptosis and autography in MDA-MB-231 cells has also been noticed [107].

Cardiovascular disease

Cardiovascular diseases have been considered as a disease of men, which has translated into a lack of awareness and risk in women at the health policy and clinical level. Globally, cardiovascular disease is the most leading cause of death in both women and men [108]. Snakes use their venom to immobilize preys, and to defend against predators. Snake venoms target physiological systems, especially circulation, respiratory and locomotion that evolved to target cardiovascular, neuromuscular systems and locomotion [109]. 2 purified from B. marajoensis (Marajo lancehead) venom induced hypotension, bradycardia and at the same time simultaneously blocks the electrical conduction in the heart in Wistar rats [110]. Another study suggested that the venom of the Bitis species can be considered as an arsenal of molecules, which leads the victim of hypotensive shock, and requires special attention in cases of an envenoming [111]. Further, Bj-PRO-10c is known to induce NO production, and the gene expression of arginiosuccinate synthetase (ASS), and endothelial NOS in the brains of spontaneously hypertensive rats, by improving baroreflex sensitivity, which may reveal novel approaches for treating diseases with impaired baroreflex function [112]. Snake venom factors do not alter cardiac performance, collateral blood flow to the clotting system but decrease the myocardium in mongrel dogs [113]. Snake venom factors could reduce polymorphonuclear (PMN) recruitment and activate myocardial ischemia, and coronary reperfusion to reduce tissue injury in feral baboons [114]. Evidences accumulate that the anti-hypertensive and vasorelaxation effects of BPP-5α in spontaneous hypertensive rats could be due to endothelial and nitric oxide (NO) dependent mechanism, which are unrelated to the inhibition of the hydrolytic activities of ACE [115]. Cardiovascular disturbance observed after envenoming by Malayan krait might be involved in autonomic reflex and vascular nitric oxide mechanisms in rats [116]. Better understanding about the sequence, structure, and functional relationships of B. rhinoceros (Gabino viper) could lead to clinical studies and to investigate the potential application of this components or venom furthermore to being used to treat human haemostatic disorders, including heart attack, strokes, and hypotension [117].

Renal disease

Polycystic kidney disease is one of the life-threatening genetic diseases characterized by multiple fluid-filled cysts present in the kidney [118]. Cyst formation and enlargement progressively compromise normal renal parenchyma functions and, with time, further severely distort the entire kidney, which lead to end-stage renal failure [118]. Snake venoms, which have greater phospholipase activity, might induce myotoxicity with myoglobinuria could be results in renal lesions [119, 120]. Although investigations have been performed on the direct nephrotoxic effect of coral snake venoms the studies are still insufficient in the literature [121]. Renoprotective effect of mambaquaretin-1 showed the lowering of cAMP levels of V2R expressing cells, which inhibited the dDAVP (1-deamino-8D-arginine vasopressin) and could induce cAMP production in a dose-dependent manner in polycystic kidney disease (pcy) mice [122]. HSV-induced glomerulonephritis is correlated with both ECM production and degradation systems in Sprague Dawley rats, which is particularly important for the repair process [123]. More findings indicated that the bone marrow-derived from the endothelial cells can contribute glomerular endothelial cell turnover and also to the regeneration of the glomerular microvasculature by the same venom in pathologic conditions in TIE2/lZ mice model [124]. Another study stated that venom of D. acutus with Chinese herbal medicine (P-19) could possess inhibitory effect on glomerular disease in ddY mice [125]. Moreover, B. alternatus (crossed pit viper) venom was known to morphological and functional changes in Wistar-Hannover rats renal tissue, with enhanced Na+/K+-ATPase expression and activity subsequently could attenuate renal dysfunction during venom-induced damage [126]. B. moojeni (Brazilian lancehead) venom induced in Wistar rats was known to cause extreme changes in renal physiology, including a drop in RVR associated with diuresis, natriuresis, and kaliuresis [127]. Furthermore, LAAO from B. marajoensis venom might be responsible for the nephrotoxicity and renal cytotoxicity in MDCK renal cell lines [128], and thus could be used for the treatment of renal cancer. Recent study suggested that M. latticolaris and M. browni (Brown’s coral snake) venoms could alters the renal physiological parameters and cause nephrotoxic effects with the involvement of oxidative stress in Wistar rats [129].

Pulmonary disease

Chronic obstructive pulmonary disease (COPD) is the third chief cause of death in worldwide [130]. COPD is one of the most commonly disease results in chronic cigarette smoking and it is increasingly recognized, which the early life lung development, health, exposure to airway pollutants, and social deprivation are the major risk factors to develop COPD [130]. Several studies has been described that the harmful effects of venoms are due to the enzymatic activities of the venoms, which could cause endothelial damage or activation, rather than a direct pro-coagulant effect [131-133]. The therapeutic effect of FIIa could be by reducing thrombi, which could restore blood flow in the lung and improve cardiovascular function in rabbits by D. acutus venom [134]. Another investigation revealed that jararhagin from B. jararaca (Yarara snake) can induce pulmonary bleeding after intravenous injection in CD-1 mice. Under certain conditions coagulation tests may not be affected. Jararhagin affects lung microvessels by proteolytic activity and also inhibits the action of plasma proteinase inhibitors [135]. Further, rFII isolated from D. acutus venom has a protective effect on taurocholate-induced SAP in rats is mainly depending on the direct degradation of TNF-α [136]. Moreover, P-III SVMPs from the venom of B. caribbaeus (Saint Lucia viper) was known to induce pulmonary hemorrhage and thrombocytopenia in CD-1 mice, with increased FDP, and without causing blood incoagulability [137].

Neurodegenerative disease

Neurodegenerative diseases are induced by the abnormality in one or more genes that mainly code for proteins of the neuroectoderm and its derivatives [138]. Behavioral changes are well-established features of degenerative diseases such as Parkinson disease, frontotemporal dementia, and Alzheimer disease [139]. Neurodegenerative diseases are characterized by the loss of brain function, which result in motor deficits, tremors, and postural instability [140]. Earlier study revealed that p-BTX-I from B. atrox (common lancehead) could induce neuritogenesis in PC12 cells are mediated by the trkA receptor, PI3K-AKT, and MAPK-ERK pathways which are triggered by NGF, which suggest that synthetic peptides p-BTX-I protects PC12 cells from MPP⁺toxicity [141]. Another study suggested that the LMWF of B. jararaca showed neuroprotective activity in cultured hippocampal cells with oxidative stress induced by H₂O₂ [142]. The advantage of direct post-column analysis of four venom proteomes described by microfluidic on-line screening methodology. The coupling of the miniaturized separation techniques to the microfluidic on-line assay and sensitive fluorescence detections, which showed the multiple, sensitive, and robust analyses are possible in a short time frame with the minimal amount of venom [143]. The snake venom toxin Fasciculin 2 has been reported to act as a potent reversible inhibitor of acetylcholinesterase, which could be further used in the treatment of cognitive impairments is associated with Alzheimer’s disease [144]. The role of NGF is regulating the metalloproteinase-mediated events, parameters like physiological, pathological, and therapeutic concentrations of NGF, relative localization of binding partners and the possible regulation of platelet reactivity through inhibition of GPVI/sheddase activities has been reported [145]. The dual potency of venom protein-derived peptides for inhibition of amyloidosis from the cell viability against the toxicity and destabilization of amyloid to monomeric entities suggests a possibility of good opportunity to explore these molecules as a therapeutic agent for both prevention and maintenance of Alzhemier’s disease [146].

Diabetes mellitus

It is well known that Diabetes mellitus is a serious metabolic disease across worldwide. It is mainly classified into type 1 diabetes and type 2 diabetes and 90-95% diabetic patients are type 2 diabetes mellitus is characterized by insulin resistance, which result in decreasing insulin actions on targeted tissues [147]. Recently, diverse venom peptides have emerged as pharmacological implements and remedial for type 1 diabetes and type 2 diabetes [148]. N. atra venom is known to reduce hyperglycemia, decrease urinary protein, enhance renal function and structure, prevent oxidative stress and lipid metabolism products, and restrict inflammatory factor infiltration in Wistar rats [149]. Further, PCA has the ability of anti-fibrotic activities in diabetic rats, such as modulates the balance between inflammatory cytokine levels and collagen content, modulates MMP expressions, and sustains the MMP-TIMP balance [150]. Enhanced VEGF signaling is in islets could also contribute with β cell injury, microvascular failure, and diabetes in spontaneously diabetic Torii (SDT) rats [151]. Furthermore, phospholipase A2 from N. nigricollis (black-necked spitting cobra) are effectively stimulated insulin, which release from BRIN-BD11 cells at the concentration of 1 μM, which is not cytotoxic to the cells and suggesting that the possible therapy for Type 2 diabetes [152].

Arthritis

Arthritis is a type of inflammation which affects the joints. The foremost symptoms of arthritis are joint pain and stiffness which is basically related with increasing age. Osteoarthritis and rheumatoid arthritis are two most common types of arthritis [153]. Cobra venom has a great potential for treating several pathological conditions, including joint pains and other disorders [154]. Earlier study reveals that N. kaouthia (monocled cobra) venom has been showed significant protection against arthritis-induced oxidative damages in male albino rats [155]. The study has proven that NN-32 from N. naja (Indian cobra) venom could targets complex pathophysiological processes such as cancer, arthritis, and inflammation in male albino rats [156]. It is known that there are significantly increasing levels of PLA2 in patients with rheumatoid arthritis than osteoarthritis and the plasma PLA2 is highest in those patients with active rheumatoid arthritis [157]. Further correlation of acute inflamed joints is agreeable in the synovial fluids containing high level of PLA2 in patients with rheumatoid arthritis [158]. The protective activity of nanogold conjugated with snake venom protein toxin, NKCT1 N. kaouthia, against osteoarthritis in albino Wistar rats by limiting the inflammatory markers at the molecular level has been reported [159]. The experiment provides evidence of metalloproteinase BaP1 from B. asper has pro-nociceptive activity in joints. MMPs are involved in the inflammatory joint hyper-nociception and induce COX-2 expression in Wistar rats [160].

Inflammation

Although inflammation is not a disease per se, it is the retort to infection or wound and is perilous for both innate and adaptive immunity in the human body. It is documented as a fragment of the multifaceted biological response of vascular tissues, which are detrimental to stimuli for instance, pathogens, injured cells and irritations [161]. Inflammatory reactions are commonly observed in every victim bitten by venomous snakes, honeybees, and scorpions [162]. Researches reveal that the tumor necrosis factor receptor-1 (TNFR1) and specific binding peptides and Hydrostatin-SN1 (H-SN1), which has been purified from H. cyanocinctus (annulated sea snake) venom glands T7 phage were proven to display the significant changes in anti-inflammatory activities under in vitro and in vivo conditions [163]. Inflammation is part of the responsibility for the tissue damage induced by B. rhinoceros snake venom, which the steroidal anti-inflammatory drug dexamethasone could reduce the myotoxic effects of these venoms and reduce the inflammatory response in Swiss mice [164]. Increased production of IL-1β, COX-2 expression, and neutrophil chemotaxis are induced by B. jararacussu venom in mice could induce an early onset edema dependent on the prostanoid production and neutrophil migration [165]. Phospholipase A2 from snake venom could induce lipid droplets formation in immunocompetent cells and also the inflammatory process [166]. Other findings suggested that the novel perspective to treat intestinal inflammatory diseases, highlighting the potential anti-inflammatory role of metalloproteases in C57BL/6 mice, and its effectiveness as a therapeutic alternative in the immunopathological conditions [167]. Another study documented that H-TL1 from the H. cyanocinctus venom gland T7 phage display library, effectively antagonized the TNF-α/TNFR1 interaction, alleviated the cytotoxicity, and inflammation associated with TNF-α in vitro and in vivo, suggesting promising hopes for the development of new agents to treat inflammatory bowel disease, sepsis acute shock, and other inflammatory diseases, which are associated with elevation of TNF-α [168].

Analgesic

An essential component of the prevention of pain signaling system is binding of some venom-toxins with sensitive receptors, ion channels and thus potentially blocks the signals [169]. Thus, animal toxins act as analgesic properties and manifest healing in experimental arthritis and save from potentially destructive influences of inflammation. Ultimately, these toxins can be used as a new category of anti-inflammatory drugs for basic pain signaling, channelopathies and receptor expression [170]. The investigation has also demonstrated that peptides in venom-derived toxins exhibit improved analgesic potencies and lesser side effects than current therapeutic drugs that are used clinically [170]. The main mechanism of analgesic actions of Gln49-PLA2 from G. ussurensis (Ussuri pit viper) venom is via affecting the function of voltage-dependent ion channels, blocking neuronal signal transduction by the potentiation of sodium channels, and the blockade of potassium channels in the nerve terminal of Kunming white mice [171]. Furthermore, the prophylactic use of the analgesic tramadol does not affect the outcome of the anti-venom potency assay while using B. asper (velvet snake) venom and poly-specific anti-venom. Therefore, represents an alternative way to reduce the pain and distress of animals in this test. Finally, there is a significant correlation between the neutralization of lethality and of coagulant activity of B. asper venom in vitro [172]. More study reveals that CSE is significantly reduced the venom-induced edema and nociception, which could be exhibits a central mechanism for pain inhibition and may also inhibit prostaglandin synthesis in Swiss Webster mice [173].

CONCLUSION

Peptides are recognized for being high selectivity, safe and well tolerated compounds. Due to their high selectivity, the venom peptides can act as effective tools in in vitro as well as in in vivo studies as possible therapeutic agents. Further studies will be need for therapeutic applications of venom peptides linked with protection, pharmacokinetics and distribution. Optimization of the delivery of peptide to exterior and core targets will assist to govern the possibility of using these peptides as potential candidates for effective drug development. This makes a reason for the augmented attention in using peptides for further pharmaceutical research and development and their usage in clinical practices. Peptide therapeutics is at present being appraised in clinical trials. Most of the venoms possess bioactive peptides, which have been already proven potential as effective agents against a number of diseases. An advance in transcriptomics and proteomics research has vividly changed the manner and rate of venom peptide discovery. An emerging trend looks forward the discovery of venom peptides with new structure and unforeseen mechanism of action will be the focus for future research. Simultaneously, this advanced knowledge will be applied for the development of higher throughput strategies targets identification. The present research clearly threw light that venom peptides are the effective tools in the treatment of various disease conditions.

ABBREVIATION

3FTx: Three-finger toxins, AChE: Acetylcholinesterases, ADAM: A disintegrin and metalloproteinase, ANP: Atrial natriuretic peptide, BNP: B-type natriuretic peptide, BuChE: Butyrylcholinesterase, CNP: C-type natriuretic peptide, CRiSP: Cysteine rich secretory protein, CTL: C-type lectin, CTX I: Cross linked C-telopeptide of Type I Collagen, CTX III: Cross linked C-telopeptide of Type III Collagen, DIS: Disintegrins, EGF: Epidermal Growth Factor, FAD: Flavin Adenine Dinucleotide, IL-1b: Interleukin 1 beta, IL-6:Interleukin 6, KUN: Kunitz peptides, LAAO: L-amino acid oxidases, MAPK-ERK: Microtubule associated protein Kinase–Extra cellular Signal, Related Kinases, MCF-7:Michigan Cancer Foundation-7, MPP+:Mitochondrial processing peptidase, NGF: Nerve growth factor, NKCT–1: Naja kaouthia cytotoxin 1, NN-32:Naja naja toxin fraction 32, NP: Natriuretic peptide, P13K-AKT: Phosphatidylinositol 3-Kinase–Protein Kinase B, p-BTX-1:Ptychodiscus brevis toxin 1, PC 12:Pheochromocytoma 12, p-JNK: Phosphorylated c-Jun N-terminal Kinase, PGF: Placental growth factor, PLA2:Phospholipase A2, TBARS: Thiobarbituric Acid Reactive substances, TNF-α: Tumour Necrosis Factor alpha, SVMP: Metalloproteases, SVSP: Serine proteases, VEGF: Vascular endothelial growth factor

ACKNOWLEDGEMENT

This work is funded by Kerala State Council for Science, Technology, and Environment (KSCSTE), and the financial assistance from UGC-SAP and DST-FIST to the Department of Biochemistry and Biotechnology, Annamalai University, Annamalainagar is gratefully acknowledged.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All the authors have contributed equally.

CONFLICT OF INTERESTS

The authors declare there is no conflict of interests.

REFERENCES

Utkin YN. Animal venom studies: current benefits and future developments. World J Biol Chem. 2015;6(2):28-33. doi: 10.4331/wjbc.v6.i2.28, PMID 26009701.
Pennington MW, Czerwinski A, Norton RS. Peptide therapeutics from venom: current status and potential. Bioorg Med Chem. 2018;26(10):2738-58. doi: 10.1016/j.bmc.2017.09.029, PMID 28988749.
Munawar A, Ali SA, Akrem A, Betzel C. Snake venom peptides: tools of biodiscovery. Toxins. 2018;10(11):474. doi: 10.3390/toxins10110474, PMID 30441876.
Simoes Silva R, Alfonso J, Gomez A, Holanda RJ, Sobrinho JC, Zaqueo KD, Moreira-Dill LS, Kayano AM, Grabner FP, da Silva SL, Almeida JR, Stabeli RG, Zuliani JP, Soares AM. Snake venom, a natural library of new potential therapeutic molecules: challenges and current perspectives. Curr Pharm Biotechnol. 2018;19(4):308-35. doi: 10.2174/1389201019666180620111025, PMID 29929461.
Longbottom J, Shearer FM, Devine M, Alcoba G, Chappuis F, Weiss DJ, Ray SE, Ray N, Warrell DA, Ruiz de Castaneda R, Williams DJ, Hay SI, Pigott DM. Vulnerability to snakebite envenoming: a global mapping of hotspots. Lancet. 2018;392(10148):673-84. doi: 10.1016/S0140-6736(18)31224-8, PMID 30017551.
Ralph R, Sharma SK, Faiz MA, Ribeiro I, Rijal S, Chappuis F, Kuch U. The timing is right to end snakebite deaths in South Asia. Br Med J. 2019;364:k5317. doi: 10.1136/bmj.k5317, PMID 30670457.
Silva A, Isbister GK. Current research into snake antivenoms, their mechanisms of action and applications. Biochem Soc Trans. 2020;48(2):537-46. doi: 10.1042/BST20190739, PMID 32196542.
Tasoulis T, Isbister GK. A review and database of snake venom proteomes. Toxins (Basel). 2017;9(9):290. doi: 10.3390/toxins9090290, PMID 28927001.
Sanhajariya S, Duffull SB, Isbister GK. Pharmacokinetics of snake venom. Toxins (Basel). 2018;10(2):73. doi: 10.3390/toxins10020073, PMID 29414889.
Cheng CL, Mao YC, Liu PY, Chiang LC, Liao SC, Yang CC. Deinagkistrodon acutus envenomation: a report of three cases. J Venom Anim Toxins Incl Trop Dis. 2017;23:20. doi: 10.1186/s40409-017-0111-1, PMID 28344596.
Chinnasamy S, Selvaraj G, Selvaraj C, Kaushik AC, Kaliamurthi S, Khan A, Singh SK, Wei DQ. Combining in silico and in vitro approaches to identification of potent inhibitor against phospholipase A2 (PLA2). Int J Biol Macromol. 2020;144:53-66. doi: 10.1016/j.ijbiomac.2019.12.091, PMID 31838071.
Ferraz CR, Arrahman A, Xie C, Casewell NR, Lewis RJ, Kool J, Cardoso FC. Multifunctional toxins in snake venoms and therapeutic implications: from pain to hemorrhage and necrosis. Front Ecol Evol. 2019;7(7):218. doi: 10.3389/fevo.2019.00218.
Zainal Abidin SA, Rajadurai P, Chowdhury MEH, Ahmad Rusmili MR, Othman I, Naidu R. Cytotoxic, antiproliferative and apoptosis-inducing activity of L-amino acid oxidase from Malaysian Calloselasma rhodostoma on human colon cancer cells. Basic Clin Pharmacol Toxicol. 2018;123(5):577-88. doi: 10.1111/bcpt.13060, PMID 29908095.
Meier J, Stocker KF. Biology and distributuion of venomous snakes of medical importance and the composition of snake venom. In: Meier J, White J, editors. Handbook of clinical toxicology of animal venoms and proteins. Boca Raton, FL: CRC Press Press; 2008. p. 367-412.
Puzari U, Mukherjee AK. Recent developments in diagnostic tools and bioanalytical methods for analysis of snake venom: A critical review. Anal Chim Acta. 2020;1137:208-24. doi: 10.1016/j.aca.2020.07.054, PMID 33153604.
Nalbantsoy A, Hempel BF, Petras D, Heiss P, Gocmen B, Igci N, Yildiz MZ, Süssmuth RD. Combined venom profiling and cytotoxicity screening of the Radde’s mountain viper (Montivipera raddei) and mount Bulgar viper (Montivipera bulgardaghica) with potent cytotoxicity against human A549 lung carcinoma cells. Toxicon. 2017;135(1):71-83. doi: 10.1016/j.toxicon.2017.06.008, PMID 28625888.
Casewell NR. Venom evolution: gene loss shapes phenotypic adaptation. Curr Biol. 2016;26(18):R849-51. doi: 10.1016/j.cub.2016.07.082, PMID 27676304.
Calvete JJ, Sanz L, Cid P, de la Torre P, Flores Diaz M, Dos Santos MCD, Borges A, Bremo A, Angulo Y, Lomonte B, Alape-Giron A, Gutierrez JM. Snake venomics of the Central American rattlesnake Crotalus simus and the South American Crotalus durissus complex points to neurotoxicity as an adaptive paedomorphic trend along with crotalus dispersal in South America. J Proteome Res. 2010;9(1):528-44. doi: 10.1021/pr9008749, PMID 19863078.
Calvete JJ, Sanz L, Angulo Y, Lomonte B, Gutierrez JM. Venoms, venomics, antivenomics. FEBS Lett. 2009;583(11):1736-43. doi: 10.1016/j.febslet.2009.03.029, PMID 19303875.
Rosenberg HI. Histology, histochemistry, and emptying mechanism of the venom glands of some elapid snakes. J Morphol. 1967;123(2):133-55. doi: 10.1002/jmor.1051230204, PMID 6073683.
Boldrini Franca J, Cologna CT, Pucca MB, Bordon KCF, Amorim FG, Anjolette FAP, Cordeiro FA, Wiezel GA, Cerni FA, Pinheiro Junior EL, Shibao PY, Ferreira IG, de Oliveira IS, Cardoso IA, Arantes EC. Minor snake venom proteins: structure, function and potential applications. Biochim Biophys Acta Gen Subj. 2017;1861(4):824-38. doi: 10.1016/j.bbagen.2016.12.022, PMID 28012742.
Rokyta DR, Wray KP, McGivern JJ, Margres MJ. The transcriptomic and proteomic basis for the evolution of a novel venom phenotype within the timber rattlesnake (Crotalus horridus). Toxicon. 2015;98:34-48. doi: 10.1016/j.toxicon.2015.02.015, PMID 25727380.
Casewell NR, Wagstaff SC, Wuster W, Cook DAN, Bolton FMS, King SI. Medically important differences in snake venom composition are dictated by distinct postgenomic mechanisms. Proc Natl Acad Sci USA 2014;111(25):9205-10.
Durban J, Perez A, Sanz L, Gomez A, Bonilla F, Rodriguez S, Chacon D, Sasa M, Angulo Y, Gutierrez JM, Calvete JJ. Integrated “omics” profiling indicates that miRNAs are modulators of the ontogenetic venom composition shift in the Central American rattlesnake, Crotalus simus simus. BMC Genomics. 2013;14:234. doi: 10.1186/1471-2164-14-234, PMID 23575160.
Boldrini Franca J, Correa Netto C, Silva MMS, Rodrigues RS, De La Torre PDL, Perez A, Soares AM, Zingali RB, Nogueira RA, Rodrigues VM, Sanz L, Calvete JJ. Snake venomics and antivenomics of Crotalus durissus subspecies from Brazil: assessment of geographic variation and its implication on snakebite management. J Proteomics. 2010;73(9):1758-76. doi: 10.1016/j.jprot.2010.06.001, PMID 20542151.
Modahl CM, Mackessy SP. Venoms of rear-fanged snakes: new proteins and novel activities. Front Ecol Evol. 2019;7:279. doi: 10.3389/fevo.2019.00279.
Urra FA, Araya Maturana R. Putting the brakes on tumorigenesis with snake venom toxins: new molecular insights for cancer drug discovery. Semin Cancer Biol. 2020;16(20):30102-4. doi: 10.1016/j.semcancer.2020.05.006, PMID 32428714.
Harris JB, Scott Davey T. Secreted phospholipases A2 of snake venoms: effects on the peripheral neuromuscular system with comments on the role of phospholipases A2 in disorders of the CNS and their uses in industry. Toxins (Basel). 2013;5(12):2533-71. doi: 10.3390/toxins5122533, PMID 24351716.
Perry BW, Card DC, Mcglothlin JW, Pasquesi GIM, Adams RH, Schield DR, Hales NR, Corbin AB, Demuth JP, Hoffmann FG, Vandewege MW, Schott RK, Bhattacharyya N, Chang BSW, Casewell NR, Whiteley G, Reyes Velasco J, Mackessy SP, Gamble T, Storey KB, Biggar KK, Passow CN, Kuo CH, McGaugh SE, Bronikowski AM, de Koning APJ, Edwards SV, Pfrender ME, Minx P, Brodie ED, Brodie ED, Warren WC, Castoe TA. Molecular adaptations for sensing and securing prey and insight into amniote genome diversity from the garter snake genome. Genome Biol Evol. 2018;10(8):2110-29. doi: 10.1093/gbe/evy157, PMID 30060036.
Fry BG, Scheib H, de L M Junqueira de Azevedo I, Silva DA, Casewell NR. Novel transcripts in the maxillary venom glands of advanced snakes. Toxicon. 2012;59(7-8):696-708. doi: 10.1016/j.toxicon.2012.03.005, PMID 22465490.
Junqueira-De-Azevedo IL, Bastos CM, Ho PL, Luna MS, Yamanouye N, Casewell NR. Venom-related transcripts from Bothrops jararaca tissues provide novel molecular insights into the production and evolution of snake venom. Mol Biol Evol. 2015;32(3):754-66. doi: 10.1093/molbev/msu337, PMID 25502939.
Zhang CC, Medzihradszky KF, Sanchez EE, Basbaum AI, Julius D. Lys49 myotoxin from the Brazilian lancehead pit viper elicits pain through regulated ATP release. Proc Natl Acad Sci USA. 2017;114(12):E2524-32. doi: 10.1073/pnas.1615484114, PMID 28265084.
Costa SKP, Camargo EA, Antunes E. Inflammatory action of secretory phospholipases A2 from snake venoms. Toxinology. 2017:35-52. doi: 10.1007/978-94-007-6452-1_10.
Moustafa IM, Foster S, Lyubimov AY, Vrielink A. Crystal structure of LAAO from Calloselasma rhodostoma with an L-phenylalanine substrate: insights into structure and mechanism. J Mol Biol. 2006;364(5):991-1002. doi: 10.1016/j.jmb.2006.09.032, PMID 17046020.
Hossain GS, Li J, Shin HD, Du G, Liu L, Chen J. L-amino acid oxidases from microbial sources: types, properties, functions, and applications. Appl Microbiol Biotechnol. 2014;98(4):1507-15. doi: 10.1007/s00253-013-5444-2, PMID 24352734.
Guo C, Liu S, Yao Y, Zhang Q, Sun MZ. Past decade study of snake venom L-amino acid oxidase. Toxicon. 2012;60(3):302-11. doi: 10.1016/j.toxicon.2012.05.001, PMID 22579637.
More S, Kiran K, Veena S, Gadag J. Purification of an L-amino acid oxidase from Bungarus caeruleus (Indian krait) venom. J Venom Anim Toxins Incl Trop Dis. 2010;16(1):60-76. doi: 10.1590/S1678-91992010005000002.
Fox JW. A brief review of the scientific history of several lesser-known snake venom proteins: l-amino acid oxidases, hyaluronidases and phosphodiesterases. Toxicon. 2013;62:75-82. doi: 10.1016/j.toxicon.2012.09.009, PMID 23010165.
Tan KK, Bay BH, Gopalakrishnakone P. L-amino acid oxidase from snake venom and its anticancer potential. Toxicon. 2018;144:7-13. doi: 10.1016/j.toxicon.2018.01.015, PMID 29407871.
Georgieva D, Murakami M, Perband M, Arni R, Betzel C. The structure of a native l-amino acid oxidase, the major component of the Vipera ammodytes ammodytes venomic, reveals dynamic active site and quaternary structure stabilization by divalent ions. Mol Biosyst. 2011;7(2):379-84. doi: 10.1039/c0mb00101e, PMID 20938508.
Naumann GB, Silva LF, Silva L, Faria G, Richardson M, Evangelista K, Kohlhoff M, Gontijo CM, Navdaev A, de Rezende FF, Eble JA, Sanchez EF. Cytotoxicity and inhibition of platelet aggregation caused by an l-amino acid oxidase from Bothrops leucurus venom. Biochim Biophys Acta. 2011;1810(7):683-94. doi: 10.1016/j.bbagen.2011.04.003, PMID 21539897.
Pessatti M, Fontana JD, Furtado MF, Guimaraes MF, Zanette LR, Costa WT, Baron M. Screening of Bothrops snake venoms for L-amino acid oxidase activity. Appl Biochem Biotechnol. 1995;51-52:197-210. doi: 10.1007/BF02933424, PMID 7668847.
Fox JW, Serrano SM. Structural considerations of the snake venom metalloproteinases, key members of the M12 reprolysin family of metalloproteinases. Toxicon. 2005;45(8):969-85. doi: 10.1016/j.toxicon.2005.02.012, PMID 15922769.
Casewell NR. On the ancestral recruitment of metalloproteinases into the venom of snakes. Toxicon. 2012;60(4):449-54. doi: 10.1016/j.toxicon.2012.02.006, PMID 22406471.
Ferreira BA, Deconte SR, De Moura FBR, Tomiosso TC, Clissa PB, Andrade SP, Araujo FA. Inflammation, angiogenesis and fibrogenesis are differentially modulated by distinct domains of the snake venom metalloproteinase jararhagin. Int J Biol Macromol. 2018;119:1179-87. doi: 10.1016/j.ijbiomac.2018.08.051, PMID 30102981.
Vaiyapuri S, Thiyagarajan N, Hutchinson EG, Gibbins JM. Sequence and phylogenetic analysis of viper venom serine proteases. Bioinformation. 2012;8(16):763-72. doi: 10.6026/97320630008763, PMID 23055627.
Serrano SMT. The long road of research on snake venom serine proteinases. Toxicon. 2013;62:19-26. doi: 10.1016/j.toxicon.2012.09.003, PMID 23010164.
Modahl CM, Frietze S, Mackessy SP. Transcriptome-facilitated proteomic characterization of rear-fanged snake venoms reveal abundant metalloproteinases with enhanced activity. J Proteomics. 2018;187:223-34. doi: 10.1016/j.jprot.2018.08.004, PMID 30092380.
Slagboom J, Kool J, Harrison RA, Casewell NR. Haemotoxic snake venoms: their functional activity, impact on snakebite victims and pharmaceutical promise. Br J Haematol. 2017;177(6):947-59. doi: 10.1111/bjh.14591, PMID 28233897.
Wahby AF, el Mahdy el-SM, El-Mezayen HA, Salama WH, Abdel-Aty AM, Fahmy AS. Egyptian horned viper Cerastes cerastes venom hyaluronidase: purification, partial characterization and evidence for its action as a spreading factor. Toxicon. 2012;60(8):1380-9. doi: 10.1016/j.toxicon.2012.08.016, PMID 23000079.
Bordon KCF, Wiezel GA, Amorim FG, Arantes EC. Arthropod venom hyaluronidases: biochemical properties and potential applications in medicine and biotechnology. J Venom Anim Toxins Incl Trop Dis. 2015;21:43. doi: 10.1186/s40409-015-0042-7, PMID 26500679.
Mackessy SP. Handbook of venoms and toxins of reptiles. Taylor & Francis; 2009.
Ouyang C, Huang TF. Inhibition of platelet aggregation by 5′-nucleotidase purified from trimeresurus gramineus snake venom. Toxicon. 1983;21(4):491-501. doi: 10.1016/0041-0101(83)90127-7, PMID 6312633.
Gulland JM, Jackson EM. 5-nucleotidase. Biochem J. 1938;32(3):597-601. doi: 10.1042/bj0320597, PMID 16746659.
Jorge da Silva NJ, Aird SD. Prey specificity, comparative lethality and compositional differences of coral snake venoms. Comp Biochem Physiol C Toxicol Pharmacol. 2001;128(3):425-56. doi: 10.1016/s1532-0456(00)00215-5, PMID 11255115.
Zeller EA. The formation of pyrophosphate from adenosine triphosphate in the presence of a snake venom. Arch Biochem. 1950;28(1):138-9. PMID 14771934.
Iwanaga S, Suzuki T. Enzymes in snake venom, Snake venoms. Springer; 1979. p. 61-158.
Ouyang C, Huang TF. Platelet aggregation inhibitors from Agkistrodon acutus snake venom. Toxicon. 1986;24(11-12):1099-106. doi: 10.1016/0041-0101(86)90136-4, PMID 3031852.
Frobert Y, Creminon C, Cousin X, Remy MH, Chatel JM, Bon S, Bon C, Grassi J. Acetylcholinesterases from Elapidae snake venoms: biochemical, immunological and enzymatic characterization. Biochim Biophys Acta. 1997;1339(2):253-67. doi: 10.1016/s0167-4838(97)00009-5. PMID 9187246.
Kini RM, Doley R. Structure, function and evolution of three-finger toxins: mini proteins with multiple targets. Toxicon. 2010;56(6):855-67. doi: 10.1016/j.toxicon.2010.07.010, PMID 20670641.
Aird SD. The role of purine and pyrimidine nucleosides in snake venoms. In: Mackessy SP, editor, Handbook of venoms and toxins of reptiles. CRC Press; 2009. p. 393-431.
Nirthanan S, Gwee MC. Three-finger alpha-neurotoxins and the nicotinic acetylcholine receptor, forty years on. J Pharmacol Sci. 2004;94(1):1-17. doi: 10.1254/jphs.94.1, PMID 14745112.
Olamendi Portugal T, Batista CVF, Pedraza Escalona M, Restano Cassulini R, Zamudio FZ, Benard Valle M, de Roodt AR, Possani LD. New insights into the proteomic characterization of the coral snake Micrurus pyrrhocryptus venom. Toxicon. 2018;153:23-31. doi: 10.1016/j.toxicon.2018.08.003, PMID 30153434.
Dutta S, Chanda A, Kalita B, Islam T, Patra A, Mukherjee AK. Proteomic analysis to unravel the complex venom proteome of Eastern India Naja naja: correlation of venom composition with its biochemical and pharmacological properties. J Proteomics. 2017;156:29-39. doi: 10.1016/j.jprot.2016.12.018, PMID 28062377.
Slagboom J, Otvos RA, Cardoso FC, Iyer J, Visser JC, van Doodewaerd BR, McCleary RJR, Niessen WMA, Somsen GW, Lewis RJ, Kini RM, Smit AB, Casewell NR, Kool J. Neurotoxicity fingerprinting of venoms using on-line microfluidic achbp profiling. Toxicon. 2018;148:213-22. doi: 10.1016/j.toxicon.2018.04.022, PMID 29730150.
Ziganshin RH, Kovalchuk SI, Arapidi GP, Starkov VG, Hoang AN, Thi Nguyen TT, Nguyen KC, Shoibonov BB, Tsetlin VI, Utkin YN. Quantitative proteomic analysis of Vietnamese krait venoms: neurotoxins are the major components in Bungarus multicinctus and phospholipases a2 in Bungarus fasciatus. Toxicon. 2015;107(B):197-209. doi: 10.1016/j.toxicon.2015.08.026, PMID 26341420.
Rusmili MR, Yee TT, Mustafa MR, Hodgson WC, Othman I. Proteomic characterization and comparison of Malaysian Bungarus candidus and Bungarus fasciatus venoms. J Proteomics. 2014;110:129-44. doi: 10.1016/j.jprot.2014.08.001, PMID 25154052.
Oh AMF, Tan CH, Ariaranee GC, Quraishi N, Tan NH. Venomics of Bungarus caeruleus (Indian krait): comparable venom profiles, variable immunoreactivities among specimens from Sri Lanka, India and Pakistan. J Proteomics. 2017;164:1-18. doi: 10.1016/j.jprot.2017.04.018, PMID 28476572.
Tan CH, Wong KY, Tan KY, Tan NH. Venom proteome of the yellow-lipped sea krait, Laticauda colubrina from Bali: insights into subvenomic diversity, venom antigenicity and cross-neutralization by antivenom. J Proteomics. 2017;166:48-58. doi: 10.1016/j.jprot.2017.07.002, PMID 28688916.
Yamazaki Y, Morita T. Structure and function of snake venom cysteine-rich secretory proteins. Toxicon. 2004;44(3):227-31. doi: 10.1016/j.toxicon.2004.05.023, PMID 15302528.
Utkin YN, Osipov AV. Non-lethal polypeptide components in cobra venom. Curr Pharm Des. 2007;13(28):2906-15. doi: 10.2174/138161207782023757, PMID 17979735.
Yamazaki Y, Hyodo F, Morita T. Wide distribution of cysteine-rich secretory proteins in snake venoms: isolation and cloning of novel snake venom cysteine-rich secretory proteins. Arch Biochem Biophys. 2003;412(1):133-41. doi: 10.1016/s0003-9861(03)00028-6, PMID 12646276.
Saviola AJ, Modahl CM, Mackessy SP. Disintegrins of crotalus simus tzabcan venom: isolation, characterization and evaluation of the cytotoxic and anti-adhesion activities of tzabcanin, a new rgd disintegrin. Biochimie. 2015;116:92-102. doi: 10.1016/j.biochi.2015.07.005, PMID 26163300.
Bilgrami S, Yadav S, Kaur P, Sharma S, Perbandt M, Betzel C, Singh TP. Crystal structure of the disintegrin heterodimer from saw-scaled viper (Echis carinatus) at 1.9 a resolution. Biochemistry. 2005;44(33):11058-66. doi: 10.1021/bi050849y, PMID 16101289.
Kloog Y, Sokolovsky M. Similarities in mode and sites of action of sarafotoxins and endothelins. Trends Pharmacol Sci. 1989;10(6):212-4. doi: 10.1016/0165-6147(89)90261-7, PMID 2549664.
Vink S, Jin AH, Poth KJ, Head GA, Alewood PF. Natriuretic peptide drug leads from snake venom. Toxicon. 2012;59(4):434-45. doi: 10.1016/j.toxicon.2010.12.001, PMID 21147145.
Yoshimura M, Yasue H, Morita E, Sakaino N, Jougasaki M, Kurose M, Mukoyama M, Saito Y, Nakao K, Imura H. Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation. 1991;84(4):1581-8. doi: 10.1161/01.cir.84.4.1581, PMID 1914098.
Kinnunen P, Vuolteenaho O, Ruskoaho H. Mechanisms of atrial and brain natriuretic peptide release from rat ventricular myocardium: effect of stretching. Endocrinology. 1993;132(5):1961-70. doi: 10.1210/endo.132.5.8477647, PMID 8477647.
Suga S, Itoh H, Komatsu Y, Ogawa Y, Hama N, Yoshimasa T, Nakao K. Cytokine-induced C-type natriuretic peptide (CNP) secretion from vascular endothelial cells-evidence for CNP as a novel autocrine/paracrine regulator from endothelial cells. Endocrinology. 1993;133(6):3038-41. doi: 10.1210/endo.133.6.8243333, PMID 8243333.
Koh CY, Kini RM. From snake venom toxins to therapeutics-cardiovascular examples. Toxicon. 2012;59(4):497-506. doi: 10.1016/j.toxicon.2011.03.017, PMID 21447352.
Takahashi H, Iwanaga S, Suzuki T. Isolation of a novel inhibitor of kallikrein, plasmin and trypsin from the venom of Russell’s viper (Vipera russelli). FEBS Lett. 1972;27(2):207-10. doi: 10.1016/0014-5793(72)80621-5, PMID 4541477.
Calvete JJ, Marcinkiewicz C, Sanz L. Snake venomics of Bitis gabonica gabonica. Protein family composition, subunit organization of venom toxins, and characterization of dimeric disintegrins bitisgabonin-1 and bitisgabonin-2. J Proteome Res. 2007;6(1):326-36. doi: 10.1021/pr060494k, PMID 17203976.
Earl STH, Richards R, Johnson LA, Flight S, Anderson S, Liao A, de Jersey J, Masci PP, Lavin MF. Identification and characterisation of kunitz-type plasma kallikrein inhibitors unique to Oxyuranus sp. snake venoms. Biochimie. 2012;94(2):365-73. doi: 10.1016/j.biochi.2011.08.003, PMID 21843588.
Shamsi TN, Parveen R, Fatima S. Characterization, biomedical and agricultural applications of protease inhibitors: a review. Int J Biol Macromol. 2016;91:1120-33. doi: 10.1016/j.ijbiomac.2016.02.069, PMID 26955746.
Possani LD, Martin BM, Yatani A, Mochca Morales J, Zamudio FZ, Gurrola GB, Brown AM. Isolation and physiological characterization of taicatoxin, a complex toxin with specific effects on calcium channels. Toxicon. 1992;30(11):1343-64. doi: 10.1016/0041-0101(92)90511-3, PMID 1485334.
Zupunski V, Kordis D, Gubensek F. Adaptive evolution in the snake venom Kunitz/BPTI protein family. FEBS Lett. 2003;547(1-3):131-6. doi: 10.1016/s0014-5793(03)00693-8, PMID 12860400.
Laskowski M, Kato I. Protein inhibitors of proteinases. Annu Rev Biochem. 1980;49(1):593-626. doi: 10.1146/annurev.bi.49.070180.003113.
Wordinger RJ, Clark AF. Growth factors and neurotrophic factors as targets. In: Yorio T, Clark AF, Wax MB, editors, Ocular therapeutics: Eye on new discoveries. Academic Press; 2008. p. 87-116.
Aloe L. Rita levi-montalcini: the discovery of nerve growth factor and modern neurobiology. Trends Cell Biol. 2004;14(7):395-9. doi: 10.1016/j.tcb.2004.05.011, PMID 15246433.
Cohen S, Levi Montalcini R. A nerve growth-stimulating factor isolated from snake venom. Proc Natl Acad Sci USA. 1956;42(9):571-4. doi: 10.1073/pnas.42.9.571, PMID 16589907.
Mannion RJ, Costigan M, Decosterd I, Amaya F, Ma QP, Holstege JC, Ji RR, Acheson A, Lindsay RM, Wilkinson GA, Woolf CJ. Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc Natl Acad Sci USA. 1999;96(16):9385-90. doi: 10.1073/pnas.96.16.9385, PMID 10430952.
Kostiza T, Meier J. Nerve growth factors from snake venoms: chemical properties, mode of action and biological significance. Toxicon. 1996;34(7):787-806. doi: 10.1016/0041-0101(96)00023-2, PMID 8843580.
Otrock ZK, Makarem JA, Shamseddine AI. Vascular endothelial growth factor family of ligands and receptors: review [review]. Blood Cells Mol Dis. 2007;38(3):258-68. doi: 10.1016/j.bcmd.2006.12.003, PMID 17344076.
Yamazaki Y, Morita T. Molecular and functional diversity of vascular endothelial growth factors. Mol Divers. 2006;10(4):515-27. doi: 10.1007/s11030-006-9027-3, PMID 16972015.
Pennington MW, Czerwinski A, Norton RS. Peptide therapeutics from venom: current status and potential. Bioorg Med Chem. 2018;26(10):2738-58. doi: 10.1016/j.bmc.2017.09.029, PMID 28988749.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. doi: 10.3322/caac.21492, PMID 30207593.
Al-Sadoon MK, Abdel-Maksoud MA, Rabah DM, Badr G. Induction of apoptosis and growth arrest in human breast carcinoma cells by a snake (Walterinnesia aegyptia) venom combined with silica nanoparticles: crosstalk between Bcl2 and caspase 3. Cell Physiol Biochem. 2012;30(3):653-65. doi: 10.1159/000341446, PMID 22854437.
Neda A, Neda SK, Ata G, Ahmad TM, Mohamad G, Mohammad HP. A. crassicauda, M. eupeus and H. Lepturus scorpion venoms initiate a strong in vivo anticancer immune response in CT26-tumor mice model. Toxicon 2020;180:31-8.
Klein A, Capitanio JS, Maria DA, Ruiz IRG. Gene expression in SK-Mel-28 human melanoma cells treated with the snake venom jararhagin. Toxicon. 2011;57(1):1-8. doi: 10.1016/j.toxicon.2010.09.001, PMID 20851711.
Tsai PC, Fu YS, Chang LS, Lin SR. Taiwan cobra cardiotoxin III suppresses EGF/EGFR-mediated epithelial-to-mesenchymal transition and invasion of human breast cancer MDA-MB-231 cells. Toxicon. 2016;111:108-20. doi: 10.1016/j.toxicon.2016.01.051, PMID 26774845.
Salama WH, Ibrahim NM, El Hakim AE, Bassuiny RI, Mohamed MM, Mousa FM, Ali MM. L-amino acid oxidase from Cerastes vipera snake venom: isolation, characterization and biological effects on bacteria and tumor cell lines. Toxicon. 2018;150:270-9. doi: 10.1016/j.toxicon.2018.06.064, PMID 29898379.
Zainal Abidin SAZ, Rajadurai P, Hoque Chowdhury ME, Othman I, Naidu R. Cytotoxic, anti-proliferative and apoptosis activity of l-amino acid oxidase from Malaysian Cryptelytrops purpureomaculatus (CP-LAAO) venom on human colon cancer cells. Molecules. 2018;23(6):1388. doi: 10.3390/molecules23061388.
Mukherjee AK, Saviola AJ, Burns PD, Mackessy SP. Apoptosis induction in human breast cancer (MCF-7) cells by a novel venom L-amino acid oxidase (Rusvinoxidase) is independent of its enzymatic activity and is accompanied by caspase-7 activation and reactive oxygen species production. Apoptosis. 2015;20(10):1358-72. doi: 10.1007/s10495-015-1157-6, PMID 26319994.
Wang JH, Xie Y, Wu JC, Han R, Reid PF, Qin ZH, He JK. Crotoxin enhances the antitumor activity of gefinitib (Iressa) in SK-MES-1 human lung squamous carcinoma cells. Oncol Rep. 2012;27(5):1341-7. doi: 10.3892/or.2012.1677, PMID 22322185.
Lee HL, Park MH, Son DJ, Song HS, Kim JH, Ko SC, Song MJ, Lee WH, Yoon JH, Ham YW, Han SB, Hong JT. Anti-cancer effect of snake venom toxin through down regulation of AP-1 mediated PRDX6 expression. Oncotarget. 2015;6(26):22139-51. doi: 10.18632/oncotarget.4192, PMID 26061816.
Ebrahim K, Shirazi FH, Mirakabadi AZ, Vatanpour H. Cobra venom cytotoxins; apoptotic or necrotic agents? Toxicon. 2015;108:134-40. doi: 10.1016/j.toxicon.2015.09.017, PMID 26482932.
Azevedo FVPV, Lopes DS, Cirilo Gimenes SNC, Ache DC, Vecchi L, Alves PT, Guimaraes Dde O, Rodrigues RS, Goulart LR, Rodrigues Vde M, Yoneyama KA. Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA₂ homologue from Bothrops pauloensis venom. Int J Biol Macromol. 2016;82:671-7. doi: 10.1016/j.ijbiomac.2015.10.080, PMID 26519876.
Geraghty L, Figtree GA, Schutte AE, Patel S, Woodward M, Arnott C. Cardiovascular disease in women: From pathophysiology to novel and emerging risk factors. Heart Lung Circ 2021;30(1):9-17.
Kini RM, Koh CY. Snake venom three-finger toxins and their potential in drug development targeting cardiovascular diseases. Biochem Pharmacol. 2020;181:114105. doi: 10.1016/j.bcp.2020.114105.
Evangelista IL, Martins AMC, Nascimento NRF, Havt A, Evangelista JSAM, de Noroes TBS, Toyama MH, Diz-Filho EB, Toyama Dde O, Fonteles MC, Monteiro HS. Renal and cardiovascular effects of Bothrops marajoensis venom and phospholipase A2. Toxicon. 2010;55(6):1061-70. doi: 10.1016/j.toxicon.2009.12.004, PMID 20036276.
Kodama RT, Cajado Carvalho D, Kuniyoshi AK, Kitano ES, Tashima AK, Barna BF, Takakura AC, Serrano SM, Dias-Da-Silva W, Tambourgi DV, Portaro FV. New proline-rich oligopeptides from the venom of African adders: insights into the hypotensive effect of the venoms. Biochim Biophys Acta. 2015;1850(6):1180-7. doi: 10.1016/j.bbagen.2015.02.005, PMID 25688758.
Lameu C, Pontieri V, Guerreiro JR, Oliveira EF, da Silva CA, Giglio JM, Melo RL, Campos RR, de Camargo AC, Ulrich H. Brain nitric oxide production by a proline-rich decapeptide from Bothrops jararaca venom improves baroreflex sensitivity of spontaneously hypertensive rats. Hypertens Res. 2010;33(12):1283-8. doi: 10.1038/hr.2010.208, PMID 21132021.
Maroko PR, Carpenter CB, Chiariello M, Fishbein MC, Radvany P, Knostman JD, Hale SL. Reduction by cobra venom factor of myocardial necrosis after coronary artery occlusion. J Clin Invest. 1978;61(3):661-70. doi: 10.1172/JCI108978, PMID 641147.
Crawford MH, Grover FL, Kolb WP, McMahan CA, O’Rourke RA, McManus LM, Pinckard RN. Complement and neutrophil activation in the pathogenesis of ischemic myocardial injury. Circulation. 1988;78(6):1449-58. doi: 10.1161/01.cir.78.6.1449, PMID 3191598.
Ianzer D, Xavier CH, Fraga FC, Lautner RQ, Guerreiro JR, Machado LT, Mendes EP, de Camargo AC, Santos RA. BPP-5a produces a potent and long-lasting NO-dependent antihypertensive effect. Ther Adv Cardiovasc Dis. 2011;5(6):281-95. doi: 10.1177/1753944711427318, PMID 22032921.
Chaisakul J, Rusmili MRA, Hodgson WC, Hatthachote P, Suwan K, Inchan A, Chanhome L, Othman I, Chootip K. A pharmacological examination of the cardiovascular effects of Malayan krait (Bungarus candidus) venoms. Toxins (Basel). 2017;9(4):122. doi: 10.3390/toxins9040122, PMID 28353659.
Vaiyapuri S, Harrison RA, Bicknell AB, Gibbins JM, Hutchinson G. Purification and functional characterisation of rhinocerase, a novel serine protease from the venom of Bitis gabonica rhinoceros. PLOS ONE. 2010;5(3):e9687. doi: 10.1371/journal.pone.0009687, PMID 20300193.
Sun Y, Zhou H, Yang BX. Drug discovery for polycystic kidney disease. Acta Pharmacol Sin. 2011;32(6):805-16. doi: 10.1038/aps.2011.29, PMID 21642949.
De Roodt AR, Lago NR, Stock RP. Myotoxicity and nephrotoxicity by micrurus venoms in experimental envenomation. Toxicon. 2012;59(2):356-64. doi: 10.1016/j.toxicon.2011.11.009, PMID 22133570.
Faiz A, Ghose A, Ahsan F, Rahman R, Amin R, Hassan MU, Chowdhury AW, Kuch U, Rocha T, Harris JB, Theakston RD, Warrell DA. The greater black krait (Bungarus niger), a newly recognized cause of neuro-myotoxic snake bite envenoming in Bangladesh. Brain. 2010;133(11):3181-93. doi: 10.1093/brain/awq265, PMID 20855420.
Lomonte B, Rey Suarez P, Fernandez J, Sasa M, Pla D, Vargas N, Benard Valle M, Sanz L, Correa Netto C, Nunez V, Alape Giron A, Alagon A, Gutierrez JM, Calvete JJ. Venoms of Micrurus coral snakes: evolutionary trends in compositional patterns emerging from proteomic analyses. Toxicon. 2016;122:7-25. doi: 10.1016/j.toxicon.2016.09.008, PMID 27641749.
Ciolek J, Reinfrank H, Quinton L, Viengchareun S, Stura EA, Vera L, Sigismeau S, Mouillac B, Orcel H, Peigneur S, Tytgat J, Droctove L, Beau F, Nevoux J, Lombes M, Mourier G, De Pauw E, Servent D, Mendre C, Witzgall R, Gilles N. Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease. Proc Natl Acad Sci USA. 2017;114(27):7154-9. doi: 10.1073/pnas.1620454114, PMID 28630289.
Kawazu T, Nishino T, Obata Y, Furusu A, Miyazaki M, Abe K, Koji T, Kohno S. Production and degradation of extracellular matrix in reversible glomerular lesions in rat model of habu snake venom-induced glomerulonephritis. Med Mol Morphol. 2012;45(4):190-8. doi: 10.1007/s00795-011-0559-y, PMID 23224597.
Abe Yoshio Y, Abe K, Miyazaki M, Furusu A, Nishino T, Harada T, Koji T, Kohno S. Involvement of bone marrow-derived endothelial progenitor cells in glomerular capillary repair in habu snake venom-induced glomerulonephritis. Virchows Arch. 2008;453(1):97-106. doi: 10.1007/s00428-008-0618-5, PMID 18551312.
Sugimoto K, Fujise Y, Shibata K, Komori Y, Nikai T, Sugihara H, Sakurai N. Effects of a prescription of Chinese herbal medicine on snake venom-induced nephropathy in mice. Biol Pharm Bull. 1996;19(4):587-92. doi: 10.1248/bpb.19.587, PMID 8860964.
Linardi A, Rocha e Silva TAA, Miyabara EH, Franco Penteado CF, Cardoso KC, Boer PA, Moriscot AS, Gontijo JA, Joazeiro PP, Collares Buzato CB, Hyslop S. Histological and functional renal alterations caused by Bothrops alternatus snake venom: expression and activity of Na+/K+-ATPase. Biochim Biophys Acta. 2011;1810(9):895-906. doi: 10.1016/j.bbagen.2011.06.006, PMID 21704674.
Barbosa PSF, Havt A, Faco PEG, Sousa TM, Bezerra ISAM, Fonteles MC, Toyama MH, Marangoni S, Novello JC, Monteiro HS. Renal toxicity of Bothrops moojeni snake venom and its main myotoxins. Toxicon. 2002;40(10):1427-35. doi: 10.1016/s0041-0101(02)00156-3, PMID 12368112.
Dantas RT, Jorge ARC, Jorge RJB, de Menezes RRPPB, Lima DB, Torres AFC, Toyama MH, Monteiro HS, Martins AM. L-amino acid oxidase from Bothrops marajoensis causes nephrotoxicity in isolated perfused kidney and cytotoxicity in MDCK renal cells. Toxicon. 2015;104:52-6. doi: 10.1016/j.toxicon.2015.08.007, PMID 26263888.
Braga JRM, Jorge ARC, Marinho AD, Silveira JAM, Nogueira Junior FA, Valle MB, Alagon A, de Menezes RRPPB, Martins AMC, Feijao LX, Monteiro HSA, Jorge RJB. Renal effects of venoms of mexican coral snakes Micrurus browni and Micrurus laticollaris. Toxicon. 2020;181:45-52. doi: 10.1016/j.toxicon.2020.04.095, PMID 32339535.
Ramakrishnan S, Bafadhel M, Russell R. Chronic obstructive pulmonary disease: management of chronic disease. Medicine. 2020;48(5):333-6. doi: 10.1016/j.mpmed.2020.02.002.
Gutierrez JM, Sanz L, Escolano J, Fernandez J, Lomonte B, Angulo Y, Rucavado A, Warrell DA, Calvete JJ. Snake venomics of the lesser antillean pit vipers Bothrops caribbaeus and Bothrops lanceolatus: correlation with toxicological activities and immunoreactivity of a heterologous antivenom. J Proteome Res. 2008;7(10):4396-408. doi: 10.1021/pr8003826, PMID 18785768.
Malbranque S, Piercecchi Marti MD, Thomas L, Barbey C, Courcier D, Bucher B, Ridarch A, Smadja D, Warrell DA. Fatal diffuse thrombotic microangiopathy after a bite by the “Fer-de-Lance” pit viper (Bothrops lanceolatus) of martinique. Am J Trop Med Hyg. 2008;78(6):856-61. PMID 18541759.
Terra RMS, Pinto AF, Guimaraes JA, Fox JW. Proteomic profiling of snake venom metalloproteinases (SVMPs): insights into venom induced pathology. Toxicon. 2009;54(6):836-44. doi: 10.1016/j.toxicon.2009.06.010, PMID 19539639.
Lin X, Liang XX, Tang JJ, Chen JS, Qiu PX, Yan GM. The effect of the fibrinolytic enzyme FIIa from Agkistrodon acutus venom on acute pulmonary thromboembolism. Acta Pharmacol Sin. 2011;32(2):239-44. doi: 10.1038/aps.2010.193, PMID 21293476.
Escalante T, Nunez J, Moura da Silva AM, Rucavado A, Theakston RDG, Gutierrez JM. Pulmonary hemorrhage induced by jararhagin, a metalloproteinase from Bothrops jararaca snake venom. Toxicol Appl Pharmacol. 2003;193(1):17-28. doi: 10.1016/s0041-008x(03)00337-5, PMID 14613713.
Luo S, Wang R, Jiang W, Lin X, Qiu P, Yan G. A novel recombinant snake venom metalloproteinase from Agkistrodon acutus protects against taurocholate-induced severe acute pancreatitis in rats. Biochimie. 2010;92(10):1354-61. doi: 10.1016/j.biochi.2010.06.018, PMID 20600562.
Herrera C, Rucavado A, Warrell DA, Gutierrez JM. Systemic effects induced by the venom of the snake Bothrops caribbaeus in a murine model. Toxicon. 2013;63:19-31. doi: 10.1016/j.toxicon.2012.10.023, PMID 23159397.
Vallat JM, Goizet C, Tazir M, Couratier P, Magy L, Mathis S. Classifications of neurogenetic diseases: an increasingly complex problem. Rev Neurol (Paris). 2016;172(6-7):339-49. doi: 10.1016/j.neurol.2016.04.005, PMID 27240993.
Wexler E. Clinical neurogenetics: behavioral management of inherited neurodegenerative disease. Neurol Clin. 2013;31(4):1121-44. doi: 10.1016/j.ncl.2013.04.016, PMID 24176427.
Yu S, Wang X, He X, Wang Y, Gao S, Ren L, Shi Y. Curcumin exerts anti-inflammatory and antioxidative properties in 1-methyl-4-phenylpyridinium ion (MPP (+))-stimulated mesencephalic astrocytes by interference with TLR4 and downstream signaling pathway. Cell Stress Chaperones. 2016;21(4):697-705. doi: 10.1007/s12192-016-0695-3, PMID 27164829.
Bernardes CP, Santos NAG, Sisti FM, Ferreira RS, Santos Filho NA, Cintra ACO, Cilli EM, Sampaio SV, Santos AC. A synthetic snake-venom-based tripeptide (Glu–Val–Trp) protects PC12 cells from MPP+toxicity by activating the NGF-signaling pathway. Peptides. 2018;104:24-34. doi: 10.1016/j.peptides.2018.04.012, PMID 29684590.
Querobino SM, Carrettiero DC, Costa MS, Alberto Silva C. Neuroprotective property of low molecular weight fraction from B. jararaca snake venom in H2O2-induced cytotoxicity in cultured hippocampal cells. Toxicon. 2017;129:134-43. doi: 10.1016/j.toxicon.2017.02.015, PMID 28216408.
Heus F, Vonk F, Otvos RA, Bruyneel B, Smit AB, Lingeman H, Richardson M, Niessen WM, Kool J. An efficient analytical platform for on-line microfluidic profiling of neuroactive snake venoms towards nicotinic receptor affinity. Toxicon. 2013;61:112-24. doi: 10.1016/j.toxicon.2012.11.002, PMID 23159399.
Waqar M, Batool S. In silico analysis of binding of neurotoxic venom ligands with acetylcholinesterase for therapeutic use in treatment of Alzheimer’s disease. J Theor Biol. 2015;372:107-17. doi: 10.1016/j.jtbi.2015.02.028, PMID 25747777.
Wijeyewickrema LC, Gardiner EE, Gladigau EL, Berndt MC, Andrews RK. Nerve growth factor inhibits metalloproteinase-disintegrins and blocks ectodomain shedding of platelet glycoprotein VI. J Biol Chem. 2010;285(16):11793-9. doi: 10.1074/jbc.M110.100479, PMID 20164177.
Bhattacharjee P, Bhattacharyya D. Factor V activator from Daboia russelli russelli venom destabilizes β-amyloid aggregate, the hallmark of Alzheimer disease. J Biol Chem. 2013;288(42):30559-70. doi: 10.1074/jbc.M113.511410, PMID 23986449.
Yuzefovych LV, Musiyenko SI, Wilson GL, Rachek LI. Mitochondrial DNA damage and dysfunction, and oxidative stress are associated with endoplasmic reticulum stress, protein degradation and apoptosis in high fat diet-induced insulin resistance mice. PLOS ONE. 2013;8(1):e54059. doi: 10.1371/journal.pone.0054059, PMID 23342074.
Deplazes E. Molecular simulations of venom peptide-membrane interactions: progress and challenges. Pept Sci. 2018;110(3):1-9. doi: 10.1002/pep2.24060.
Dai GL, He JK, Xie Y, Han R, Qin ZH, Zhu LJ. Therapeutic potential of Naja naja atra venom in a rat model of diabetic nephropathy. Biomed Environ Sci. 2012;25(6):630-8. doi: 10.3967/0895-3988.2012.06.004, PMID 23228832.
Li S, Hong Y, Jin X, Zhang G, Hu Z, Nie L. A new Agkistrodon halys venom-purified protein C activator prevents myocardial fibrosis in diabetic rats. Croat Med J. 2015;56(5):439-46. doi: 10.3325/cmj.2015.56.439, PMID 26526881.
Mukai E, Ohta T, Kawamura H, Lee EY, Morita A, Sasase T, Miyajima K, Inagaki N, Iwanaga T, Miki T. Enhanced vascular endothelial growth factor signaling in islets contributes to β cell injury and consequential diabetes in spontaneously diabetic torii rats. Diabetes Res Clin Pract. 2014;106(2):303-11. doi: 10.1016/j.diabres.2014.08.023, PMID 25262109.
Conlon JM, Attoub S, Musale V, Leprince J, Casewell NR, Sanz L, Calvete JJ. Isolation and characterization of cytotoxic and insulin-releasing components from the venom of the black-necked spitting cobra Naja nigricollis (Elapidae). Toxicon X. 2020;6:100030. doi: 10.1016/j.toxcx.2020.100030.
Lee YM, Cho SN, Son E, Song CH, Kim DS. Apamin from bee venom suppresses inflammation in a murine model of gouty arthritis. J Ethnopharmacol. 2020;257:112860. doi: 10.1016/j.jep.2020.112860.
Pal SK, Gomes A, Dasgupta SC, Gomes A. Snake venom as therapeutic agents: from toxin to drug development. Indian J Exp Biol. 2002;40(12):1353-8. PMID 12974396.
Gomes A, Bhattacharya S, Chakraborty M, Bhattacharjee P, Mishra R, Gomes A. Anti-arthritic activity of Indian monocellate cobra (Naja kaouthia) venom on adjuvant induced arthritis. Toxicon. 2010;55(2-3):670-3. doi: 10.1016/j.toxicon.2009.10.007, PMID 19825384.
Gomes A, Datta P, Das T, Biswas AK, Gomes A. Anti arthritic and anti inflammatory activity of a cytotoxic protein NN-32 from Indian spectacle cobra (Naja naja) venom in male albino rats. Toxicon. 2014;90:106-10. doi: 10.1016/j.toxicon.2014.07.002, PMID 25026566.
Smith GM, Ward RL, McGuigan L, Rajkovic IA, Scott KF. Measurement of human phospholipase A2 in arthritis plasma using a newly developed sandwich ELISA. Br J Rheumatol. 1992;31(3):175-8. doi: 10.1093/rheumatology/31.3.175, PMID 1540785.
Vadas P, Pruzanski W, Kim J, Fornasier V. The proinflammatory effect of intra-articular injection of soluble human and venom phospholipase A2. Am J Pathol. 1989;134(4):807-11. PMID 2705507.
Gomes A, Saha PP, Bhowmik T, Dasgupta AK, Dasgupta SC. Protection against osteoarthritis in experimental animals by nanogold conjugated snake venom protein toxin gold nanoparticle-Naja kaouthia cytotoxin 1. Indian J Med Res. 2016;144(6):910-7. doi: 10.4103/ijmr.IJMR_1078_14, PMID 28474628.
Fernandes CM, Pereira Teixeira Cde F, Leite ACRM, Gutierrez JM, Rocha FAC. The snake venom metalloproteinase BaP1 induces joint hypernociception through TNF-α and PGE2-dependent mechanisms. Br J Pharmacol. 2007;151(8):1254-61. doi: 10.1038/sj.bjp.0707351, PMID 17592506.
Strbo N, Yin N, Stojadinovic O. Innate and adaptive immune responses in wound epithelialization. Adv Wound Care (New Rochelle). 2014;3(7):492-501. doi: 10.1089/wound.2012.0435, PMID 25032069.
Echeverría S, Leiguez E, Guijas C, do Nascimento NG, Acosta O, Teixeira C, Leiva LC, Rodriguez JP. Evaluation of pro-inflammatory events induced by Bothrops alternatus snake venom. Chem Biol Interact. 2018;281:24-31. doi: 10.1016/j.cbi.2017.12.022, PMID 29248447.
Zheng Z, Jiang H, Huang Y, Wang J, Qiu L, Hu Z, Ma X, Lu Y. Screening of an anti-inflammatory peptide from Hydrophis cyanocinctus and analysis of its activities and mechanism in DSS-induced acute colitis. Sci Rep. 2016;6:25672. doi: 10.1038/srep25672, PMID 27158082.
Patrao Neto FC, Tomaz MA, Strauch MA, Monteiro Machado M, Rocha JR, Borges PA, Calil Elias S, Melo PA. Dexamethasone antagonizes the in vivo myotoxic and inflammatory effects of bothrops venoms. Toxicon. 2013;69:55-64. doi: 10.1016/j.toxicon.2013.01.023. PMID 23416798.
Wanderley CWS, Silva CMS, Wong DVT, Ximenes RM, Morelo DFC, Cosker F, Aragao KS, Fernandes C, Palheta Junior RC, Havt A, Brito GA, Cunha FQ, Ribeiro RA, Lima Junior RC. Bothrops jararacussu snake venom-induces a local inflammatory response in a prostanoid- and neutrophil-dependent manner. Toxicon. 2014;90:134-47. doi: 10.1016/j.toxicon.2014.08.001, PMID 25127849.
Giannotti KC, Leiguez E, de Carvalho AEZd, Nascimento NG, Matsubara MH, Fortes Dias CL, Moreira V, Teixeira C. A snake venom group IIA PLA₂ with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ2 in macrophages. Sci Rep. 2017;7(1):4098. doi: 10.1038/s41598-017-04498-8.
Silva MC, Sales Campos H, Oliveira CJF, Silva TL, França FBF, Oliveira F, Mineo TWP, Mineo JR. Treatment with a zinc metalloprotease purified from Bothrops moojeni snake venom (BmooMP-alpha-I) reduces the inflammation in an experimental model of dextran sulfate sodium-induced colitis. Mediators Inflamm. 2019;2019:5195134. doi: 10.1155/2019/5195134.
Wang N, Huang Y, Li A, Jiang H, Wang J, Li J, Qiu L, Li K, Lu Y. Hydrostatin-TL1, an anti-inflammatory active peptide from the venom gland of Hydrophis cyanocinctus in the South China sea. Int J Mol Sci. 2016;17(11):1940. doi: 10.3390/ijms17111940, PMID 27879679.
Upadhyay RK. Animal venom derived toxins are novel analgesics for treatment of arthritis. J Mol Sci. 2018;2:6-13.
Gazerani P, Cairns BE. Venom-based biotoxins as potential analgesics. Expert Rev Neurother. 2014;14(11):1261-74. doi: 10.1586/14737175.2014.962518, PMID 25234848.
Zhang Y, Jiang B, Li W, Zhou C, Ji F, Xie Q, Sun X, An L, Bao Y. Mechanisms of analgesic action of Gln49-PLA(2) from gloydius ussurensis snake venom. Appl Biochem Biotechnol. 2010;160(3):773-9. doi: 10.1007/s12010-009-8573-4, PMID 19277489.
Chacon F, Oviedo A, Escalante T, Solano G, Rucavado A, Gutierrez JM. The lethality test used for estimating the potency of antivenoms against Bothrops asper snake venom: pathophysiological mechanisms, prophylactic analgesia, and a surrogate in vitro assay. Toxicon. 2015;93:41-50. doi: 10.1016/j.toxicon.2014.11.223, PMID 25447772.
Picanço LC, Bittencourt JAHM, Henriques SVC, Da Silva JS, Oliveira JMS, Ribeiro JR, Sanjay AB, Carvalho JC, Stien D, Silva JO. Pharmacological activity of costus spicatus in experimental Bothrops atrox envenomation. Pharm Biol. 2016;54(10):2103-10. doi: 10.3109/13880209.2016.1145703, PMID 27306958.