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Anti-inflammatory activities of arthropod peptides: a systematic review

Abstract

Peptides obtained from different animal species have gained importance recently due to research that aims to develop biopharmaceuticals with therapeutic potential. In this sense, arthropod venoms have drawn attention, not only because of their toxicity but mainly for the search for molecules with various bioactivities, including anti-inflammatory activity. The purpose of the present study is to gather data available in the literature on new peptides derived from arthropod species with anti-inflammatory potential. This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Studies on peptides from arthropods that display anti-inflammatory activity were retrieved from PubMed, Scopus, Web of Science, and Google Scholar databases. The bibliographic research started in 2020 and searched papers without a limit on the publication date. The articles were analyzed using a search string containing the following terms: “Peptides” and “Anti-inflammatory”, in combinations such as “Ant”, “Bee”, “Wasp”, “Crab”, “Shrimp”, “Scorpion”, “Spider”, “Tick” and “Centipedes”. Besides, a search was carried out in the databases with the terms: “Peptides”, “Antitumor”, or “Anticancer”, and “Arthropods”. Articles that met the inclusion and exclusion criteria totalized 171, and these served for data extraction. Additionally, the present review included anti-inflammatory peptides with anticancer properties. Peptides with confirmed anti-inflammatory activity were from insects (ants, bees, and wasps), crustaceans (shrimp and crabs), arachnids (scorpions, spiders, and ticks), and centipedes. These arthropod peptides act mainly by decreasing pro-inflammatory cytokines as analyzed in vitro and in vivo. Some showed significant antineoplastic activity, working in essential cellular pathways against malignant neoplasms.

Keywords:
Venom; Peptides; Anti-inflammatory; Arthropods

Background

The use of enzymes and polypeptides for medicinal purposes has attracted considerable interest due to their high specificity and selectivity. They are also less likely to interfere with cellular processes that are not the aimed therapeutic targets. Protein drugs are composed of bioactive polypeptides with significant therapeutic potential [11. Perumal Samy R, Stiles BG, Franco OL, Sethi G, Lim LHK. Animal venoms as antimicrobial agents. Biochem Pharmacol. 2017 Jun 15;134:127-38. doi: 10.1016/j.bcp.2017.03.005. PubMed PMID: 28288817.
https://doi.org/10.1016/j.bcp.2017.03.00...
]. Although animal venoms have toxic effects, they are extensively studied to find pharmacologically active molecules [22. Harvey AL. Toxins and drug discovery. Toxicon. 2014 Dec 15;92:193-200. doi: 10.1016/j.toxicon.2014.10.020. PubMed PMID: 25448391.
https://doi.org/10.1016/j.toxicon.2014.1...
]. A known example of an isolated venom component that served as a template for developing the anti-hypertensive drug captopril belongs to the bradykinin-potentiating peptide (BPP) family found in the venom of Bothrops jararaca [33. Waheed H, Moin SF, Choudhary MI. Snake venom: from deadly toxins to life-saving therapeutics. Curr Med Chem. 2017;24(17):1874-91. doi: 10.2174/0929867324666170605091546. PubMed PMID: 28578650.
https://doi.org/10.2174/0929867324666170...
].

Arthropods comprise one of the largest groups of animals on Earth, with diverse species being venomous. These species contain complex mixtures of components in their venoms with various families of toxins that exert numerous biological effects on target organisms and systems, testified by a growing number of reported studies available in public databases. This kind of natural chemical and peptide library provides excellent potential for discovering new compounds and activities for alternative or adjuvant therapies based on the mimetic modulation of pharmacological activities of endogenous (poly)peptides in the body [44. Calderon LA, Juliana Sobrinho C, Zaqueo KD, de Moura AA, Grabner AN, Mazzi MV, Marcussi S, Nomizo A, Fernandes CF, Zuliani JP, Carvalho BMA, da Silva SL, Stábeli RG, Soares AM. Antitumoral activity of snake venom proteins: new trends in cancer therapy. Biomed Res Int. 2014;2014:203639. doi: 10.1155/2014/203639. PubMed PMID: 24683541; PMCID: PMC3943284.
https://doi.org/10.1155/2014/203639...
-66. Bondaryk M, Staniszewska M, Zielińska P, Urbańczyk-Lipkowska Z. Natural antimicrobial peptides as inspiration for design of a new generation antifungal compounds. J Fungi (Basel). 2017 Aug 26;3(3):46. doi: 10.3390/jof3030046. PubMed PMID: 29371563; PMCID: PMC5715947.
https://doi.org/10.3390/jof3030046...
]. More than 400 toxins from various animals have activities reported in the literature, and around 3400 reported proteins are from arthropods [77. Uniprot. Universal Protein [Internet]. 2020 [cited 2020 Aug 30]. Available from: Available from: https://www.uniprot.org/ .
https://www.uniprot.org/...
].

Natural products comprise an essential source of bioactive substances, and they have contributed significantly to the manufacture of old and new drugs for diverse therapeutic purposes. In recent years, of all the molecules approved by the U. S. Food and Drug Administration (FDA), a third of them are natural products and derivatives from mammals and microbes [88. Patridge E, Gareiss P, Kinch MS, Hoyer D. An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discov Today. 2016 Feb;21(2):204-7. doi: 10.1016/j.drudis.2015.01.009. PubMed PMID: 25617672.
https://doi.org/10.1016/j.drudis.2015.01...
]. However, arthropod venoms as sources of new pharmaceutically functional molecules are yet to be deeply explored [99. Bonfanti AP, Barreto N, Munhoz J, Caballero M, Cordeiro G, Rocha-E-Silva T, Sutti R, Moura F, Brunetto S, Ramos CD, Thomé R, Verinaud L, Rapôso C. Spider venom administration impairs glioblastoma growth and modulates immune response in a non-clinical model. Sci Rep. 2020 Apr 03;10(1):5876. doi: 10.1038/s41598-020-62620-9. PubMed PMID: 32246025.
https://doi.org/10.1038/s41598-020-62620...
]. Many arthropod venom peptides represent an opportunity by which venom components could be converted into “pharmaceutical gold” [1010. Trim SA, Trim CM. Venom: the sharp end of pain therapeutics. Br J Pain. 2013 Nov;7(4):179-88. doi: 10.1177/2049463713502005. PubMed PMID: 265165; PMCID: PMC4590164.
https://doi.org/10.1177/2049463713502005...
,1111. Pountos I, Panteli M, Lampropoulos A, Jones E, Calori GM, Giannoudis PV. The role of peptides in bone healing and regeneration: a systematic review. BMC Med. 2016 Jul 11;14:103. doi: 10.1186/s12916-016-0646-y. PubMed PMID: 27400961; PMCID: PMC4940902.
https://doi.org/10.1186/s12916-016-0646-...
,1212. Lamiyan AK, Dalal R, Kumar NR. Venom peptides in association with standard drugs: a novel strategy for combating antibiotic resistance- an overview. J Venom Anim Toxins incl Trop Dis. 2020 Aug 10;26: e20200001 doi: 10.1590/1678-9199-JVATITD-2020-0001. PubMed PMID: 32843888.
https://doi.org/10.1590/1678-9199-JVATIT...
]. The production of a drug derived from venoms also includes the characterization of synthetic or recombinant peptide forms. Examples include peptides capable of modulating and/or regulating pain [1313. Monge-Fuentes V, Arenas C, Galante P, Gonçalves JC, Mortari MR, Schwartz EF. Arthropod toxins and their antinociceptive properties: from venoms to painkillers. Pharmacol Ther. 2018 Aug;188:176-85. doi: 10.1016/j.pharmthera.2018 Aug.03.007. PubMed PMID: 29605457.
https://doi.org/10.1016/j.pharmthera.201...
].

This review presents examples of peptides from various arthropod species, mainly focused on biologically active peptides found in arthropod venom with anti-inflammatory potential.

Methods

Investigation plan

This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [1414. Liberati A, Altma DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009 Jul 21;6(7): e1000100. doi: 10.1371/journal.pmed.1000100. PubMed PMID: 19621070.
https://doi.org/10.1371/journal.pmed.100...
]. The search of published articles on the topic of arthropod-derived peptides with anti-inflammatory activity was through PubMed, Scopus, Web of Science, and Google Scholar electronic databases. The bibliographic retrieval started in August 2020 and finished in March 2021. The search did not limit the date of publication. The publications were analyzed using a search string containing terms: “Peptides” and “Anti-inflammatory”, in combinations such as “Ant”, “Bee”, “Wasp”, “Crab”, “Shrimp”, “Scorpion”, “Spider”, “Tick” and “Centipede”. In addition, a search was carried out in the databases with the terms: “Peptides”, “Antitumor”, or “Anticancer”, and “Arthropods”.

Selection of the literature

The studies were selected by the coauthors’ ATS and GSC through Mendeley software (version 1803, 2020) and verified by GRB, ensuring the review work’s inclusion. The selected literature adhered to the following criteria: full research articles that have been conducted in vitro or in vivo experimental studies and evaluated the anti-inflammatory effects of peptides derived from arthropod venoms or their crude extract. Besides, included in this review are ethnopharmacological data related to the topic covered. The criteria used to exclude studies were: repeated articles, editorials, letters to the editor, thesis, dissertations, reports, and articles that are out of the scope of this review.

Data collection

According to the required criteria, the studies selected for inclusion in this systematic review were chosen by the authors’ ATS and GSC. The information collected from the literature contains the following information: authors, affiliation, year of publication, applied methodology, characterized compound, and main results.

Results

After searching the databases, 171 original and review articles were selected out of 769 published papers and utilized to prepare the current review. The flow diagram (Figure 1) depicts the details of the selection process in the databases. Also, general information was obtained, referring to the article’s title, authorship, and publication year.

Figure 1.
PRISMA flowchart showing the research design process of the study.

Reading the material in its entirety made it possible to identify specific information about the animal species involved in the study, the peptide structure identified as a potential anti-inflammatory agent, and the anti-inflammatory activity described more precisely. Table 1 summarizes the collection of this information.

Table 1.
Examples of peptides from the Uniprot database with anti-inflammatory activies.

Insect peptides

Ants

Insects possess a multitude of unexplored toxins with presumed potent biological activities. For instance, ants (Insecta class, Hymenoptera order, Formicidae family) are mostly venomous and express several types of peptides in their venoms, therefore emerging as an essential source of bioactive peptides [1515. Heep J, Skaljac M, Grotmann J, Kessel T, Seip M, Schmidtberg H, Vilcinskas A. Identification and functional characterization of a novel insecticidal decapeptide from the myrmicine ant manica rubida. Toxins. 2019 Sep 25;11(10):562. doi: 10.3390/toxins11100562. PubMed PMID: 31557881.
https://doi.org/10.3390/toxins11100562...
]. Not so long ago, investigating the biological effects of isolated peptide toxins from insects was hampered by the size of these majorly tiny animals. With the advent of omics technology, the discovery and characterization of novel peptides progressed [1616. Gonçalves Peterson Fox E, Solis DR, Delazari dos Santos L, dos Santos Pinto JRA, da Silva Menegasso AR, Costa Silva RCM, Palma MS, Correa Bueno O, de Alcântara Machado E. A simple, rapid method for the extraction of whole fire ant venom (insecta: Formicidae: Solenopsis). Toxicon. 2012 Apr;65:5-8. doi: 10.1016/j.toxicon.2012.12.009. PubMed PMID: 23333648.
https://doi.org/10.1016/j.toxicon.2012.1...
]. Initial studies aimed to unveil a way to alleviate the secondary effects caused by these animals’ bites, with ants belonging to the genera Solenopsis, Pachycondyla spp, and Myrmecia the most studied [1717. Nelder MP, Paysen ES, Zungoli PA, Benson EP. Emergence of the introduced ant Pachycondyla chinensis (Formicidae: Ponerinae) as a public health threat in the southeastern United States. J Med Entomol. 2006 Sep 1;43(5):1094-5. doi: 10.1093/jmedent/43.5.1094.
https://doi.org/10.1093/jmedent/43.5.109...
, 1818. Wanandy T, Wilson R, Gell D, Rose HE, Gueven N, Davies NW, Brown SGA, Wiese MD. Towards complete identification of allergens in Jack Jumper (Myrmecia pilosula) ant venom and their clinical relevance: an immunoproteomic approach. Clin Exp Allergy. 2018 Sep;48(9):1222-34. doi: 10.1111/cea.13224. PubMed PMID: 29975807.
https://doi.org/10.1111/cea.13224...
]. In crude and isolated forms, the characterization and verification of several bioactive peptides from the venom of Pseudomyrmex species, such as the mirmexin peptide, proved to have a potent antidematogenic activity [1919. Pan J, Hink WF. Isolation and characterization of myrmexins, six isoforms of venom proteins with anti-inflammatory activity from the tropical ant, Pseudomyrmex triplarinus. Toxicon. 2000 Oct;38(10):1403-13. doi: 10.1016/s0041-0101(99)00233-0. PubMed PMID: 10758275.
https://doi.org/10.1016/s0041-0101(99)00...
-2121. Barassé V, Touchard A, Téné N, Tindo M, Kenne M, Klopp C, Dejean A, Bonnafé E, Treilhou M. The peptide venom composition of the fierce stinging ant Tetraponera aethiops (Formicidae: Pseudomyrmecinae). Toxins (Basel). 2019 Dec 14;11(12):732. doi: 10.3390/toxins11120732. PMID: 31847368; PubMed PMCID: PMC6950161.
https://doi.org/10.3390/toxins11120732...
]. As observed in vivo, poneratoxin, a 25-residue peptide from the bullet ant Paraponera clavate, and some Formicidae peptides, can reduce edema, besides their antinociceptive activity [2222. Rykaczewska-Czerwińska M, Radosz A, Konopinska D, Wrobel M, Plech A. Antinociceptive effect of poneratoxin [PoTX] in rats. Pestycydy. 2008;1-2:135-41.]. In the context of ethnopharmacology, there are reports about the topical use of macerated giant ants Dinopera quadriceps for the treatment of back pain and rheumatic cases [2323. Costa Neto EM, Ramos-Elorduy J, Pino JM. Los insectos medicinales de Brasil: primeros resultados. Bol Soc Entomol Aragonesa. 2006;1(38):395-414.]. These studies have shown that the crude extracts reduced paw edema, leukocyte migration, malonaldehyde, and nitrite content, ameliorating acute peritonitis in vivo and in vitro. This extract contained modulator molecules of cellular oxidant/antioxidant mechanisms involved in acute inflammation elicited by zymosan, but more specific mechanisms of action have not been described [2424. Lopes KS, Rios ERV, Lima CNC, Linhares MI, Torres AFC, Havt A, Quinet YP, Fonteles MMF, Martins AMC. The effects of the brazilian ant Dinoponera quadriceps venom on chemically induced seizure models. Neurochem Int. 2013 Sep;63(3):141-5. doi: 10.1016/j.neuint.2013.06.001. PubMed PMID: 23747963.
https://doi.org/10.1016/j.neuint.2013.06...
,2525. Madeira JC, Quinet YP, Nonato DTT, Sousa PL, Chaves EMC, Honório Júnior JER, Pereira MG, Assreuy AMS. Novel pharmacological properties of Dinoponera quadriceps giant ant venom. Nat Prod Commun. 2015 Sep;10(9):1607-9. doi: 10.1177/1934578X1501000930. PubMed PMID: 26594770.
https://doi.org/10.1177/1934578X15010009...
]. The crude venom of this species has the potential to reduce nociception and interleukin-1β (IL-1β), which suggests that it suppresses inflammatory mediators such as cyclooxygenase-2 (COX-2) and prostaglandin-2 (PGE-2) involved with pain [2626. Sousa PL, Quinet Y, Ponte EL, do Vale JF, Torres AFC, Pereira MG, Assreuy MAS. Venom's antinociceptive property in the primitive ant Dinoponera quadriceps. J Ethnopharmacol. 2012 Oct 31;144(1):213-6. doi: 10.1016/j.jep.2012.08.033. PubMed. PMID: 22960549.
https://doi.org/10.1016/j.jep.2012.08.03...
,2727. Sousa PL, Quinet YP, Brizeno LAC, Sampaio TL, Torres AFC, Martins AMC, Assreuy AMS. The acute inflammatory response induced in mice by the venom of the giant ant Dinoponera quadriceps involves macrophage and interleukin-1β. Toxicon. 2016 Jul;117:22-9. doi: 10.1016/j.toxicon.2016.03.009. PubMed PMID: 27018043.
https://doi.org/10.1016/j.toxicon.2016.0...
]. The Brachyponera sennaarensisare (Samsum ant) ant-derived toxins modulate not only pain but also the immune response. The B. sennaarensisare toxins regulate the expression of MHC-II, CD80, and CD-86, as well as interferon- γ (IFN-γ) and interleukin-17 (IL-17), mediators that are involved in various chronic pathologies and cancer as demonstrated after in vivo tests [2828. Ebaid H, Abdel-Salam B, Alhazza I, Al-Tamimi J, Hassan I, Rady A, Mashaly A, Mahmoud A, Sammour R. Samsum ant venom modulates the immune response and redox status at the acute toxic dose in vivo. J Venom Anim Toxins incl Trop Dis. 2019 Dec 2;25: e20190020. doi: 10.1590/1678-9199-JVATITD-2019-0020. PubMed PMCID: PMC6892565.
https://doi.org/10.1590/1678-9199-JVATIT...
]. Furthermore, these peptides can regulate the nuclear factor kappa B (NF-kB), kinase IkB upward, and suppress nuclear transcription factor-α (TNF-α) and the cell surface death receptor (Fas), although the mechanism involved in anti-inflammatory activity has not been fully elucidated [2929. Al-Tamimi J, Alhazza IM, Al-Khalifa M, Metwalli A, Rady A, Ebaid H. Potential effects of samsum ant, Brachyponera sennaarensis, venom on TNF-α/NF-κB mediated inflammation in CCL4-toxicity in vivo. Lipids Health Dis. 2016 Nov 18;15(1):198. doi: 10.1186/s12944-016-0364-7. PubMed PMID: 27863485; PMCID: PMC5116174.
https://doi.org/10.1186/s12944-016-0364-...
,3030. Ebaid H, Al-Khalifa M, Isa AM, Gadoa S. Bioactivity of samsum ant (Pachycondyla sennaarensis) venom against lipopolysaccharides through antioxidant and upregulation of Akt1 signaling in rats. Lipids Health Dis. 2012 Jul 23;11:93. doi: 10.1186/1476-511X-11-93. PubMed PMID: 22824368; PMCID: PMC3416678.
https://doi.org/10.1186/1476-511X-11-93...
].

Bees

Bees are part of the class Insecta, order Hymenoptera, family Apoidea, and clade Anthophilia. In Brazil, bee venom is commonly found and consists of various bioactive agents that induce allergic reactions when injected into the human body [3131. Czarnetzki BM, Thiele T, Rosenbach T. Immunoreactive leukotrienes in nettle plants (Urtica urens). Int Arch Allergy Appl Immunol. 1990;91(1):43-6. doi: 10.1159/000235087. PubMed PMID: 2155878.
https://doi.org/10.1159/000235087...
]. However, its use for medicinal purposes was documented approximately 6,000 years ago [3232. Raghuraman H, Chattopadhyay A. Melittin: a membrane-active peptide with diverse functions. Biosci Rep. 2007 Oct;27(4-5):189-223. doi: 10.1007/s10540-006-9030-z. PubMed PMID: 17139559.
https://doi.org/10.1007/s10540-006-9030-...
]. Bee venom therapy (BV) is a form of medicine native to ancient Greece and China [3333. Hwang DS, Kim SK, Bae H. Therapeutic effects of bee venom on immunological and neurological diseases. Toxins (Basel). 2015 Jun 29;7(7):2413-21. doi: 10.3390/toxins7072413. PubMed PMID: 26131770; PMCID: PMC4516920.
https://doi.org/10.3390/toxins7072413...
]. In recent years, bee-based therapy has become a new treatment option. An increasing body of scientific evidence has demonstrated the therapeutic potential of bee venom [3434. Romero-Curiel A, López-Carpinteyro D, Gamboa C, De la Cruz F, Zamudio S, Flores G. Apamin induces plastic changes in hippocampal neurons in senile Sprague-Dawley Rats. Synapse. 2011 Oct;65(10):1062-72. doi: 10.1002/syn.20938. PubMed PMID: 21465567.
https://doi.org/10.1002/syn.20938...
]. In traditional medicine in Asia, BV was used in conjunction with acupuncture to treat some anti-inflammatory diseases. Furthermore, combination therapy can reduce inflammation in amyotrophic lateral sclerosis (ALS) due to the disease’s side effects on the liver, kidney, and spleen [3535. Fan AY, Lao L, Zhang RX, Zhou AN, Wang LB, Moudgil KD, Lee DYW, Ma ZZ, Zhang WY, Berman BM. Effects of an acetone extract of Boswellia carterii Birdw. (Burseraceae) gum resin on adjuvant-induced arthritis in lewis rats. J Ethnopharmacol. 2005 Oct 3;101(1-3):104-9. doi: 10.1016/j.jep.2005.03.033. PubMed PMID: 15970410.
https://doi.org/10.1016/j.jep.2005.03.03...
]. Combination acupuncture and BV therapy (i.e., Apis mellifera crude venom) were also favorable to treat respiratory inflammation accompanied by leukocyte, myeloperoxidase (MPO), and IL-1 suppression, using a carrageenan-induced pleurisy mouse model [3636. Choi HS, Kang SY, Roh DH, Choi SR, Ryu Y, Lee JH. Bee venom stimulation of a lung meridian acupoint reduces inflammation in carrageenan-induced pleurisy: an alternative therapeutic approach for respiratory inflammation. J Vet Sci. 2018 Sep 30;19(5):708-15. doi: 10.4142/jvs.2018.19.5.708. PubMed PMID: 29929357.
https://doi.org/10.4142/jvs.2018.19.5.70...
].

The inflammation suppression mechanism of European honey bee Apis mellifera BV, observed in previous studies with animal models, also reduces the formation of atherosclerotic lesions by decreasing the intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule- 1 (VCAM -1), and transforming growth factor-β1 (TGF-β1) [3737. Lee WR, Kim SJ, Park JH, Kim KH, Chang YC, Park YY, Lee KG, Han SM, Yeo JH, Pak SC, Park KK. Bee venom reduces atherosclerotic lesion formation via anti-inflammatory mechanism. Am J Chin Med. 2010;38(6):1077-92. doi: 10.1142/S0192415X10008482. PubMed PMID: 21061462.
https://doi.org/10.1142/S0192415X1000848...
]. Furthermore, the reduction of inflammation induced by apitoxins - a venom bee peptide (A. mellifera) component, is due to the decrease in apoptotic levels mediated by Bcl-2 and Bcl-xL and activating BCL2-associated X protein (Bax) and caspase-3 [3838. Chung KS, An HJ, Cheon SY, Kwon KR, Lee KH. Bee venom suppresses testosterone-induced benign prostatic hyperplasia by regulating the inflammatory response and apoptosis. Exp Biol Med (Maywood). 2015 Dec;240(12):1656-63. doi: 10.1177/1535370215590823. PubMed PMID: 26085572; PMCID: PMC4935329.
https://doi.org/10.1177/1535370215590823...
]. The application of bee venoms (A. mellifera) extends to reduce inflammatory lesions caused by the bacteria Propionibacterium acnes through decreasing TNF-α, interleukin-8 (IL-8), and IFN-γ, while also blocking the expression of Toll-like receptor 2 (TLR2) in human keratinocytes and monocytes [3939. Kim JY, Lee WR, Kim KH, An HJ, Chang YC, Han SM, Park YY, Pak SC, Park KK. Effects of bee venom against Propionibacterium acnes-induced inflammation in human keratinocytes and monocytes. Int J Mol Med. 2015 Jun;35(6):1651-6. doi: 10.3892/ijmm.2015.2180. PubMed PMID: 25872535.
https://doi.org/10.3892/ijmm.2015.2180...
].

Based on previous studies, bee venom toxins from A. mellifera and A. cerana indica act by regulating NF-kB signaling; the antiarthritic effect has been explored to reduce the levels of inflammatory mediators directly involved in the pathophysiology of rheumatoid arthritis, similarly to standard drugs such as methotrexate [4040. Darwish SF, El-Bakly WM, Arafa HM, El-Demerdash E. Targeting TNF-α and NF-κB activation by bee venom: role in suppressing adjuvant induced arthritis and methotrexate hepatotoxicity in rats. PLoS One. 2013 Nov 20;8(11):e79284. doi: 10.1371/journal.pone.0079284. PubMed PMID: 24278124; PMCID: PMC3835890.
https://doi.org/10.1371/journal.pone.007...
-4646. Nipate SS, Bhandarkar AA. Anti-inflammatory, antinociceptive and antiar-thritic potential of apis cerana indica bee venom by reducing pain and degeneration of articular cartilage in adjuvant and collagen induced rat models of arthritis. J Orthop Muscular Syst. 2020 Mar 25;3(1):1-10.]. The compound bee venom’s potential extends to reducing pain, acting as an antinociceptive agent by modulating the α2-adrenergic receptor and cyclooxygenase-2, accompanied by suppressing edema [4747. Calixto MC, Trichês KM, Calixto JB. Analysis of the inflammatory response in the rat paw caused by the venom of Apis melifera bee. Inflamm Res. 2003 Mar;52(3):132-9. doi: 10.1007/s000110300026. PubMed PMID: 12755378.
https://doi.org/10.1007/s000110300026...
-5151. Jeong CH, Cheng WN, Bae H, Lee KW, Han SM, Petriello MC, Lee HG, Seo HG, Han SG. Bee venom decreases LPS-induced inflammatory responses in bovine mammary epithelial cells. J Microbiol Biotechnol. 2017 Oct 28;27(10):1827-36. doi: 10.4014/jmb.1706.06003. PubMed PMID: 28813781.
https://doi.org/10.4014/jmb.1706.06003...
]. BV has a broad spectrum of activities. Its effects are not limited only to joint diseases and respiratory diseases, promoting an improvement in the allergic condition by suppressing inflammatory cytokines when tested in an allergic chronic rhinosinusitis mouse model [5252. Shin SH, Ye MK, Choi SY, Park KK. Anti-inflammatory effect of bee venom in an allergic chronic rhinosinusitis mouse model. Mol Med Rep. 2018 May;17(5):6632-8. doi: 10.3892/mmr.2018.8720. PubMed PMID: 29532888.
https://doi.org/10.3892/mmr.2018.8720...
].

Bee venom is a complex mixture that includes proteins and peptides such as melittin, apamin, phospholipase A2, phospholipase B, hyaluronidase, phosphatase, α-glucosidase, MDC peptide, and adolapin, among other minor components [5353. Son DJ, Lee JW, Lee YH, Song HS, Lee CK, Hong JT. Therapeutic application of anti-arthritis, pain-releasing, and anti-cancer effects of bee venom and its constituent compounds. Pharmacol Ther. 2007 Aug;115(2):246-70. doi: 10.1016/j.pharmthera.2007.04.004. PubMed PMID: 17555825.
https://doi.org/10.1016/j.pharmthera.200...
,5454. Ye X, Guan S, Liu J, Ng CCW, Chan GHH, Sze SCW, Zhang KY, Naude R, Rolka K, Wong JH, Ng TB. Activities of venom proteins and peptides with possible therapeutic applications from bees and WASPS. Protein Pept Lett. 2016;23(8):748-55. doi: 10.2174/0929866523666160618120824. PubMed PMID: 27323949.
https://doi.org/10.2174/0929866523666160...
]. Secretory phospholipase A2 (PLA2- Apis mellifera), a prototype enzyme in bee venom, hydrolyze fatty acids while also having a role in protecting liver damage by producing anti-inflammatory cytokines in mice and reducing neuroinflammation by reducing phosphorylation of STAT3 and inflammatory mediators, including p-STAT3 [5555. Monti MC, Casapullo A, Santomauro C, D'Auria MV, Riccio R, Gomez-Paloma L. The molecular mechanism of bee venom phospholipase A2 inactivation by bolinaquinone. Chembiochem. 2006 Jun;7(6):971-80. doi: 10.1002/cbic.200500454. PubMed PMID: 16671124.
https://doi.org/10.1002/cbic.200500454...
,5656. Kim H, Keum DJ, Kwak Jw, Chung HS, Bae H. Bee venom phospholipase A2 protects against acetaminophen-induced acute liver injury by modulating regulatory T cells and IL-10 in mice. PLoS One. 2014 Dec 5;9(12):e114726. doi: 10.1371/journal.pone.0114726. PubMed PMID: 25478691; PMCID: PMC4257707.
https://doi.org/10.1371/journal.pone.011...
]. Bee venom phospholipase A2 ameliorates amyloidogenesis and neuroinflammation by inhibiting signal transducer and activating the transcription-3 pathway in Tg2576 mice [5757. Ham HJ, Han SB, Yun J, Yeo IJ, Ham YW, Kim SH, Park PH, Choi DY, Hong JT. Bee venom phospholipase A2 ameliorates amyloidogenesis and neuroinflammation through inhibition of signal transducer and activator of transcription-3 pathway in Tg2576 mice. Transl Neurodegener. 2019 Oct 2;8:26. doi: 10.1186/s40035-019-0167-7. PubMed PMID: 31592103; PMCID: PMC6774221.
https://doi.org/10.1186/s40035-019-0167-...
].

Melittin (Apis mellifera), one of the main peptides in bee venom, comprises 26 amino acid residues with an overall amphipathic character. Administration in high doses of this apitoxin can trigger an allergic reaction, causing local itching and pain. In low doses, it may have an anti-inflammatory role by inhibiting the enzymatic activity of PLA2. Synthetic melittin inhibited the enzymatic activity of secretory phospholipase A2 (PLA2) from various sources, including bee and snake venoms, bovine pancreas, and synovial fluid from rheumatoid arthritis patients. Based on melittin’s hydrophobic nature and its capacity to bind to PLA2, melittin could act as a carrier for PLA2 to translocate it to the membrane. Melittin inhibits the bee venom PLA2 noncompetitively by binding to the enzyme domain other than the catalytic site. [5858. Saini SS, Peterson JW, Chopra AK. Melittin binds to secretory phospholipase A2 and inhibits its enzymatic activity. Biochem Biophys Res Commun. 1997 Sep 18;238(2):436-42. doi: 10.1006/bbrc.1997.7295. PubMed PMID: 9299527.
https://doi.org/10.1006/bbrc.1997.7295...
]. The protective effect of melittin on inflammation and apoptosis was also observed in acute liver failure; the treatment with melittin attenuated the increase of inflammatory cytokines and significantly inhibited caspase expression Bax protein levels, as well as cytochrome c release in vivo [5959. Park JH, Kim KH, Lee WR, Han SM, Park KK. Protective effect of melittin on inflammation and apoptosis in acute liver failure. Apoptosis. 2012 Jan;17(1):61-9. doi: 10.1007/s10495-011-0659-0. PubMed PMID: 21928088.
https://doi.org/10.1007/s10495-011-0659-...
,6060. Nam KW, Je KH, Lee JH, Han HJ, Lee HJ, Kang SK, Mar W. Inhibition of COX-2 activity and proinflammatory cytokines (TNF-alpha and IL-1beta) production by water-soluble sub-fractionated parts from bee (Apis mellifera) venom. Arch Pharm Res. 2003 May;26(5):383-8. doi: 10.1007/BF02976695. PubMed PMID: 12785734.
https://doi.org/10.1007/BF02976695...
].

Moreover, the JNK-dependent inactivation of NF-kB caused by melittin may prevent the release of inflammatory mediators involved in oxidative stress and the generation of pain [6161. Park HJ, Lee HJ, Choi MS, Son DJ, Song HS, Song MJ, Lee JM, Han SB, Kim Y, Hong JT. JNK pathway is involved in the inhibition of inflammatory target gene expression and NF-kappaB activation by melittin. J Inflamm (Lond). 2008 May 29;5:7. doi: 10.1186/1476-9255-5-7. PubMed PMID: 18507870; PMCID: PMC2442592.
https://doi.org/10.1186/1476-9255-5-7...
]. Melittin-induced inhibition of this signaling pathway, which included the ERK and AkT cascade, and suppression of the inflammatory mediators upregulated in periodontitis, a chronic inflammatory disease, was observed in P. gingivalis LPS-stimulated human keratinocytes [6262. Kim WH, An HJ, Kim JY, Gwon MG, Gu H, Jeon M, Kim MK, Han SM, Park KK. Anti-inflammatory effect of melittin on Porphyromonas gingivalis LPS-stimulated human keratinocytes. Molecules. 2018 Feb 5;23(2):332. doi: 10.3390/molecules23020332. PubMed PMID: 29401750; PMCID: PMC6017529.
https://doi.org/10.3390/molecules2302033...
]. Melittin also reduced the release of pro-inflammatory cytokines by monocytes after contact with P. acnes. It is also an effective agent that prevents liver fibrosis by inhibiting inflammation by interrupting the NF-κB signaling pathway [6363. Lee WR, Kim KH, An HJ, Kim JY, Han SM, Lee KG, Park KK. Protective effect of melittin against inflammation and apoptosis on Propionibacterium acnes-induced human THP-1 monocytic cell. Eur J Pharmacol. 2014 Oct 5;740:218-26. doi: 10.1016/j.ejphar.2014.06.058.
https://doi.org/10.1016/j.ejphar.2014.06...
-6464. Park JH, Kum YS, Lee TI, Kim SJ, Lee WR, Kim BI, Kim HS, Kim KH, Park KK. Melittin attenuates liver injury in thioacetamide-treated mice through modulating inflammation and fibrogenesis. Exp Biol Med (Maywood). 2011 Nov;236(11):1306-13. doi: 10.1258/ebm.2011.011127. Epub 2011 Oct 3. PMID: 21969711.
https://doi.org/10.1258/ebm.2011.011127...
]. Moreover, melittin modulated inflammation, having better activity and less toxicity when associated with glutathione S-transferase while in vitro. When using doses that exceed the toxic concentration, it still retains its inflammatory properties [6565. Rayahin JE, Buhrman JS, Gemeinhart RA. Melittin-glutathione S-transferase fusion protein exhibits anti-inflammatory properties and minimal toxicity. Eur J Pharm Sci. 2014 Dec 18;65:112-21. doi: 10.1016/j.ejps.2014.09.012. Epub 2014 Sep 21. PMID: 25240321; PMCID: PMC4253680.
https://doi.org/10.1016/j.ejps.2014.09.0...
]. A study reports its beneficial effect in treating inflammatory diseases, including skin inflammation, neuroinflammation, atherosclerosis, arthritis, and liver inflammation [6666. Lee G, Bae H. Anti-inflammatory applications of melittin, a major component of bee venom: detailed mechanism of action and adverse effects. Molecules. 2016 May 11;21(5):616. doi: 10.3390/molecules21050616. PMID: 27187328; PMCID: PMC6273919.
https://doi.org/10.3390/molecules2105061...
].

Apamine is another toxin that constitutes bee venom. It is an 18 amino acid-residue neurotoxic peptide. Despite its neurotoxicity, apamine helps treat Parkinson’s disease or learning deficits [6767. Ovcharov R, Shkenderov S. Anti-inflammatory effects of apamin. Toxicon. 1976; 14:441-7. doi: 10.1016/0041-0101(76)90060-x. PubMed PMID: 1014033.
https://doi.org/10.1016/0041-0101(76)900...
]. Moreover, apamine, as an anti-inflammatory peptide, reduced the paw’s volume and the haptoglobin and seromucoid contents in vivo [6868. Messier C, Mourre C, Bontempi B, Sif J, Lazdunski M, Destrade C. Effect of apamin, a toxin that inhibits Ca(2+)-dependent K+ channels, on learning and memory processes. Brain Res. 1991 Jun 14;551(1-2):322-6. doi: 10.1016/0006-8993(91)90950-z. PubMed PMID: 1913161.
https://doi.org/10.1016/0006-8993(91)909...
,6969. Alvarez-Fischer D, Noelker C, Vulinović F, Grünewald A, Chevarin C, Klein C, Oertel WH, Hirsch EC, Michel PP, Hartmann A. Bee venom and its component apamin as neuroprotective agents in a Parkinson disease mouse model. PLoS One. 2013 Apr 18;8(4):e61700. doi: 10.1371/journal.pone.0061700. PubMed PMID: 23637888; PMCID: PMC3630120.
https://doi.org/10.1371/journal.pone.006...
]. This bee venom peptide was efficient in treating atopic dermatitis. The Apamin inhibits TNF-α- and IFN-γ-induced inflammatory cytokines and chemokines via suppressions of NF-κB signaling pathway and STAT in human keratinocytes [7070. Kim WH, An HJ, Kim JY, Gwon MG, Gu H, Lee SJ, Park JY, Park KD, Han SM, Kim MK, Park KK. Apamin inhibits TNF-α- and IFN-γ-induced inflammatory cytokines and chemokines via suppressions of NF-κB signaling pathway and STAT in human keratinocytes. Pharmacol Rep. 2017 Oct;69(5):1030-5. doi: 10.1016/j.pharep.2017.04.006. PubMed PMID: 28958612.
https://doi.org/10.1016/j.pharep.2017.04...
]. Apamine showed anti-inflammatory effects in mice with gouty arthritis by inhibiting pro-inflammatory cytokine production and inflammasome formation [7171. Lee YM, Cho SN, Son E, Song CH, Kim DS. Apamin from bee venom suppresses inflammation in a murine model of gouty arthritis. J Ethopharmacol. 2020 Jul 15;257(15): 112860. doi: 10.1016/j.jep.2020.112860.
https://doi.org/10.1016/j.jep.2020.11286...
].

Adolapin, from A. mellifera venom, is another bee venom peptide with potent anti-inflammatory effects but not as well studied as melittin. It reduces the edema of the paw in mice, the levels of prostaglandins, cyclooxygenase 2, in addition to inhibiting PLA2 activity. The anti-inflammatory activity of adolapin is evident in carrageenin models, prostaglandin, rat hind paw edemas, and adjuvant polyarthritis. The adolapin effects are presumably due to its capacity to inhibit the prostaglandin synthase system, following a biphasic dose-response relationship. Likely, among the central mechanisms, one involved an analgesic action of adolapin [7272. Shkenderov S, Koburova K. Adolapin--a newly isolated analgetic and anti-inflammatory polypeptide from bee venom. Toxicon. 1982;20(1):317-21. doi: 10.1016/0041-0101(82)90234-3. PubMed PMID: 7080045.
https://doi.org/10.1016/0041-0101(82)902...
]. Peptide 401 (mast cell degranulating peptide - MCD peptide), with 22 amino acid residues, considered a potent degranulation factor for bee venom mast cells, substantially inhibited the edema caused in rats and attenuated the inflammatory process at the affected site [7373. Banks BE, Dempsey CE, Vernon CA, Warner JA, Yamey J. Anti-inflammatory activity of bee venom peptide 401 (mast cell degranulating peptide) and compound 48/80 results from mast cell degranulation in vivo. Br J Pharmacol. 1990 Feb;99(2):350-4. doi: 10.1111/j.1476-5381.1990.tb14707.x. PMID: 2328399; PMCID: PMC1917405.
https://doi.org/10.1111/j.1476-5381.1990...
,7474. Hanson JM, Morley J, Soria-Herrera C. Anti-inflammatory property of 401 (MCD-peptide), a peptide from the venom of the bee Apis mellifera (L.). Br J Pharmacol. 1974 Mar;50(3):383-92. doi: 10.1111/j.1476-5381.1974.tb09613.x. PMID: 4152780; PMCID: PMC1776661.
https://doi.org/10.1111/j.1476-5381.1974...
].

Wasps

Like bees, wasps (Insecta, Hymenoptera, Apocrita) have complex mixtures of toxins in their venoms and have attracted interest as a potential arthropod source of bioactive substances. Wasps belong to the family Vespidae, and members include the genus Dolichovespula (wasp), Vespula (yellow wasps), and Polistes (paper wasps) [75 75. Chen L, Chen W, Yang H, Lai R. A novel bioactive peptide from wasp venom. J Venom Res. 2010 Sep 30;1:43-7. PubMed PMID: 21544181; PMCID: PMC3086190.]. When injected, the wasp toxins trigger local adverse effects such as pain, edema, erythema, and immune reactions such as anaphylaxis [7676. Chen DM, Lee PT, Chou KJ, Fang HC, Chung HM, Chen DM, Chang LK. Descending aortic thrombosis and cerebral infarction after massive wasp stings. Am J Med. 2004 Apr 15;116(8):567-9. doi: 10.1016/j.amjmed.2003.08.036. PubMed PMID: 15063823.
https://doi.org/10.1016/j.amjmed.2003.08...
,7777. Yuan H, Lu L, Gao Z, Hu F. Risk factors of acute kidney injury induced by multiple wasp stings. Toxicon. 2020 Jul 30;182:1-6. doi: 10.1016/j.toxicon.2020.05.002. PubMed PMID: 32387349.
https://doi.org/10.1016/j.toxicon.2020.0...
]. In general, wasps’ venom comprises a cocktail of hydrophobic peptides, including amines, peptides, enzymes, allergens, and toxins [7878. Yang H, Xu X, Ma D, Zhang K, Lai R. A phospholipase A1 platelet activator from the wasp venom of vespa magnifica (smith). Toxicon. 2008 Feb;51(2):289-96. doi: 10.1016/j.toxicon.2007.10.003. PubMed PMID: 18023835.
https://doi.org/10.1016/j.toxicon.2007.1...
,7979. Graaf DC, Aerts M, Danneels E, Devreese B. Bee, wasp and ant venomics pave the way for a component-resolved diagnosis of sting allergy. J Proteomics. 2009 Mar 6;72(2):145-54. doi: 10.1016/j.jprot.2009.01.017. PubMed PMID: 19344653.
https://doi.org/10.1016/j.jprot.2009.01....
]. For example, mastoparan is an amphipathic, 14-amino acid residue, and it was the first peptide isolated from wasps. This toxin is found in the genera Vespa, Parapolybia, Protonectarina, Polistes, Protopolybia [8080. Moreno M, Giralt E. Three valuable peptides from bee and wasp venoms for therapeutic and biotechnological use: melittin, apamin and mastoparan. Toxins (Basel). 2015 Apr 1;7(4):1126-50. doi: 10.3390/toxins7041126. PubMed PMID: 25835385; PMCID: PMC4417959.
https://doi.org/10.3390/toxins7041126...
].

Like bee venom, wasps’ venoms have a considerable anti-inflammatory effect, shown inin vitrostudies. These contain toxins that have the potential to inhibit Toll-like receptor 4 (TLR4) mRNA expression, in addition to suppressing TNF-α and interleukin-6 (IL-6) [8181. Yibin G, Jiang Z, Hong Z, Gengfa L, Liangxi W, Guo W, Yongling L. A synthesized cationic tetradecapeptide from hornet venom kills bacteria and neutralizes lipopolysaccharide in vivo and in vitro. Biochem Pharmacol. 2005 Jul 15;70(2):209-19. doi: 10.1016/j.bcp.2005.04.040. PubMed PMID: 15935330.
https://doi.org/10.1016/j.bcp.2005.04.04...
]. Although crude venoms contain several toxins that can trigger a toxic reaction, wasp venoms have powerful anti-inflammatory complexes, as is the case of the crude venom of the wasp Nasonia vitripennis (jewel wasp). The N. vitripennis crude venom reduced the expression of inflammatory cytokines directly involved in inflammatory processes mediated by IL-1β, IL-6, and NF-kB [8282. Danneels EL, Gerlo S, Heyninck K, Craenenbroeck KV, De Bosscher K, Haegeman G, de Graaf DC. How the venom from the ectoparasitoid Wasp nasonia vitripennis exhibits anti-inflammatory properties on mammalian cell lines. PLoS One. 2014 May 12;9(5):e96825. doi: 10.1371/journal.pone.0096825. PMID: 24821138; PMCID: PMC4018385.
https://doi.org/10.1371/journal.pone.009...
,8383. Danneels EL, Formesyn EM, de Graaf DC. Exploring the potential of venom from Nasonia vitripennis as therapeutic agent with high-throughput screening tools. Toxins (Basel). 2015 Jun 3;7(6):2051-70. doi: 10.3390/toxins7062051. PubMed PMID: 26046700; PMCID: PMC4488689.
https://doi.org/10.3390/toxins7062051...
]. In an arthritis model, crude wasp venoms caused the inhibition of the NF-kB pathway. Likewise, Vespa magnifica (murder hornet) and other wasp species’ crude venoms suppressed the expression of mediators involved in hyperalgesia and rheumatoid arthritis [8484. Mortari MR, Cunha AOS, Carolino ROG, Coutinho-Netto J, Tomaz JC, Lopes NP, Coimbra NC, Dos Santos WF. Inhibition of acute nociceptive responses in rats after i.c.v. injection of Thr6 -bradykinin , isolated from the venom of the social wasp , Polybia occidentalis. Br J Pharmacol. 2007 Jul;151(6),860-9. doi: 10.1038/sj.bjp.0707275. PubMed PMID: 17533426.
https://doi.org/10.1038/sj.bjp.0707275...
-8888. Brigatte P, Cury Y, de Souza BM, Baptista-Saidemberg NB, Saidemberg DM, Gutierrez VP, Palma MS. Hyperalgesic and edematogenic effects of peptides isolated from the venoms of honeybee (Apis mellifera) and neotropical social wasps (Polybia paulista and Protonectarina sylveirae). Amino Acids. 2011 Jan;40(1):101-11. doi: 10.1007/s00726-010-0512-8. PubMed PMID: 20177946.
https://doi.org/10.1007/s00726-010-0512-...
].

A study dealing with Vespa tropica (Greater banded hornet) showed that crude venom significantly reduced oxidative stress and the mouse microglial cell line activation, previously stimulated by LPS. Moreover, the peptides purified from the crude venom exhibited potential anti-inflammatory properties, targeting the p38 and MAPK pathways, causing the suppression of NF-κB phosphorylation in LPS-stimulated cells [8989. Kaushik DK, Thounaojam MC, Mitra A, Basu A. Vespa tropica venom suppresses lipopolysaccharide-mediated secretion of pro-inflammatory cyto-chemokines by abrogating nuclear factor-κB activation in microglia. Inflamm Res. 2014 Aug;63(8):657-65. doi: 10.1007/s00011-014-0738-0.
https://doi.org/10.1007/s00011-014-0738-...
].

Crustacean peptides

Prawns/shrimps

Despite not being poisonous, shrimps (Crustacea, Malacostraca, Decapoda) were included here because they do not have an adaptive immune system and therefore rely on their innate immunity bioactive peptide components to deter invading pathogens. Antimicrobial peptides (AMP) are responsible for the immediate host response against invading bacteria, fungi, parasites, and, in some cases, they connect the innate and the adaptive immune response by modulating the expression and release of cytokines. The primary AMPs found in shrimp are grouped into three families of cationic peptides, namely, penaeidins, crustines, and anti-lipopolysaccharide factor (ALF) [9090. Tassanakajon A, Amparyup P, Somboonwiwat K, Supungul P. Cationic antimicrobial peptides in penaeid shrimp. Mar Biotechnol (NY). 2010 Oct;12(5):487-505. doi: 10.1007/s10126-010-9288-9. PubMed PMID: 20379756.
https://doi.org/10.1007/s10126-010-9288-...
]. The ALF, firstly discovered in the horseshoe crab (Limulus polyphemus), was followed by the identification in other crustacean species, like in the black tiger prawnPenaeus monodon, being designated SALF (Shrimp Anti-Factor Lipopolysaccharide) [9090. Tassanakajon A, Amparyup P, Somboonwiwat K, Supungul P. Cationic antimicrobial peptides in penaeid shrimp. Mar Biotechnol (NY). 2010 Oct;12(5):487-505. doi: 10.1007/s10126-010-9288-9. PubMed PMID: 20379756.
https://doi.org/10.1007/s10126-010-9288-...
,9191. Zhou L, Li G, Jiao Y, Huang D, Li A, Chen H, Liu Y, Li S, Li H, Wang C. Molecular and antimicrobial characterization of a group G anti- lipopolysaccharide factor (ALF) from Penaeus monodon. Fish Shellfish Immunol. 2019 Nov;94:149-56. doi: 10.1016/j.fsi.2019.08.066. PubMed PMID: 31465873.
https://doi.org/10.1016/j.fsi.2019.08.06...
]. It is a precursor molecule with a signal sequence of 22 to 28 residues, followed by a mature peptide that contains two conserved cysteine residues. ALF’s functional domain is named lipopolysaccharide-binding domain (LPS-BD) and contains the primary amino acids involved in recognizing and binding LPS and other components of Gram-positive bacteria and fungi [9292. Matos GM, Schmitt P, Barreto C, Farias ND, Toledo-Silva G, Guzmán F, Destoumieux-Garzón D, Perazzolo LM, Rosa RD. Massive gene expansion and sequence diversification is associated with diverse tissue distribution, regulation and antimicrobial properties of anti-lipopolysaccharide factors in shrimp. Mar Drugs. 2018 Oct 11;16(10):381. doi: 10.3390/md16100381. PubMed PMID: 30314303; PMCID: 6213531.
https://doi.org/10.3390/md16100381...
].

P. monodon shrimp contain eleven ALF isoforms distributed in seven groups (Group A to Group G). Likewise, these isoforms can be found in the shrimp speciesFarfantepenaeus aztecus (brown shrimp),L. vannamei (pacific white shrimp or king prawn), andMarsupenaeus japonicus(known as the kuruma shrimp, kuruma prawn, or Japanese tiger prawn) [9191. Zhou L, Li G, Jiao Y, Huang D, Li A, Chen H, Liu Y, Li S, Li H, Wang C. Molecular and antimicrobial characterization of a group G anti- lipopolysaccharide factor (ALF) from Penaeus monodon. Fish Shellfish Immunol. 2019 Nov;94:149-56. doi: 10.1016/j.fsi.2019.08.066. PubMed PMID: 31465873.
https://doi.org/10.1016/j.fsi.2019.08.06...
,9292. Matos GM, Schmitt P, Barreto C, Farias ND, Toledo-Silva G, Guzmán F, Destoumieux-Garzón D, Perazzolo LM, Rosa RD. Massive gene expansion and sequence diversification is associated with diverse tissue distribution, regulation and antimicrobial properties of anti-lipopolysaccharide factors in shrimp. Mar Drugs. 2018 Oct 11;16(10):381. doi: 10.3390/md16100381. PubMed PMID: 30314303; PMCID: 6213531.
https://doi.org/10.3390/md16100381...
]. LPS is an endotoxin present in the outer cell membrane of Gram-negative bacteria. When in contact with the host, it binds to pathogen recognition receptors that recognize this pathogen-associated molecular pattern (PAMP) and activates the signaling pathways that initiate the inflammatory process [9393. Lin MC, Pan CY, Hui CF, Chen JY, Wu JL. Shrimp anti-lipopolysaccharide factor (SALF), an antimicrobial peptide, inhibits proinflammatory cytokine expressions through the MAPK and NF-κB pathways in LPS-induced HeLa cells. Peptides. 2013 Feb;40,42-8. doi: 10.1016/j.peptides.2012.11.010. PubMed PMID: 23247147.
https://doi.org/10.1016/j.peptides.2012....
]. Recent studies show that SALF, besides antimicrobial activity, plays an essential role in neutralizing LPS and preventing its binding to the TLR-4 type Toll-like receptor (TLR). This peptide could inhibit or reduce the inflammatory response, disrupting the mitogen-activated protein (MAP) pathway by regulating and reducing the release of pro-inflammatory cytokines after in vitro tests with different cell lines [9393. Lin MC, Pan CY, Hui CF, Chen JY, Wu JL. Shrimp anti-lipopolysaccharide factor (SALF), an antimicrobial peptide, inhibits proinflammatory cytokine expressions through the MAPK and NF-κB pathways in LPS-induced HeLa cells. Peptides. 2013 Feb;40,42-8. doi: 10.1016/j.peptides.2012.11.010. PubMed PMID: 23247147.
https://doi.org/10.1016/j.peptides.2012....
-9696. Lin MC, Hui CF, Chen JY, Wu JL. The antimicrobial peptide, shrimp anti-lipopolysaccharide factor (SALF), inhibits proinflammatory cytokine expressions through the MAPK and NF-κB pathways in Trichomonas vaginalis adherent to HeLa cells. Peptides. 2012 Dec;38(2):197-207. doi: 10.1016/j.peptides.2012.10.003. PubMed PMID: 23088922.
https://doi.org/10.1016/j.peptides.2012....
].

Among studies about the efficacy of SALF as an anti-inflammatory agent, the effects of Penaeus monodon (giant tiger prawn) SALF on the production and release of tumor necrosis factor (TNF) were reported. This peptide showed suppression of inflammation in a dose-dependent manner in LPS-stimulated cervical cancer HeLa cells. Although the results have been promising, the mechanism involved in anti-inflammatory activity has not been fully elucidated [9393. Lin MC, Pan CY, Hui CF, Chen JY, Wu JL. Shrimp anti-lipopolysaccharide factor (SALF), an antimicrobial peptide, inhibits proinflammatory cytokine expressions through the MAPK and NF-κB pathways in LPS-induced HeLa cells. Peptides. 2013 Feb;40,42-8. doi: 10.1016/j.peptides.2012.11.010. PubMed PMID: 23247147.
https://doi.org/10.1016/j.peptides.2012....
]. The SALF peptides’ protective role includes an anti-inflammatory effect in response to LPS, as observed in cervical cancer epithelial cells (HELA cells). SALF fragments inhibited inflammatory cytokines production, including TNF, interleukin IL-1 β, IL-6, IL-1, and monocyte chemoactive protein (MCP-1). SALF also suppressed IL-6, IL-8, IL-1, and MPC-1e mRNA levels and regulated vaginal epithelial cell immune responses through MAPK (mitogen-activated protein kinases) and NF-κβ (nuclear factor kappa B) pathways [9393. Lin MC, Pan CY, Hui CF, Chen JY, Wu JL. Shrimp anti-lipopolysaccharide factor (SALF), an antimicrobial peptide, inhibits proinflammatory cytokine expressions through the MAPK and NF-κB pathways in LPS-induced HeLa cells. Peptides. 2013 Feb;40,42-8. doi: 10.1016/j.peptides.2012.11.010. PubMed PMID: 23247147.
https://doi.org/10.1016/j.peptides.2012....
].

In addition to the SALF response to bacterial LPS, this peptide modulates the inflammatory responses provoked by the protozoan Trichomonas vaginalis, an etiological agent of Trichomoniasis that affects the cervicovaginal mucosa. When vaginal cells were subjected to stimulation byT. vaginalis, SALF inhibited the release of pro-inflammatory cytokines such as TNF-α, IL-6, IL-8, and MCP-1 through the MAPK pathways and NF-κβ [9696. Lin MC, Hui CF, Chen JY, Wu JL. The antimicrobial peptide, shrimp anti-lipopolysaccharide factor (SALF), inhibits proinflammatory cytokine expressions through the MAPK and NF-κB pathways in Trichomonas vaginalis adherent to HeLa cells. Peptides. 2012 Dec;38(2):197-207. doi: 10.1016/j.peptides.2012.10.003. PubMed PMID: 23088922.
https://doi.org/10.1016/j.peptides.2012....
]. These reports exemplify the promising profile of SALF as an anti-inflammatory agent.

Crabs

In recent years, marine organisms have attracted great interest due to their unique constituents with diverse bioactivities. These animals have hemolymph with potent antimicrobial peptides essential for their innate immunity. These peptides are valuable for biomedical applications [9797. Marggraf MB, Panteleev PV, Emelianova AA, Sorokin MI, Bolosov IA, Buzdin AA, Kuzmin DV, Ovchinnikova TV. Cytotoxic potential of the novel horseshoe crab peptide polyphemusin III. Mar Drugs. 2018 Nov 26;16(12):466. doi: 10.3390/md16120466. PubMed PMID: 30486233; PMCID: 6315362.
https://doi.org/10.3390/md16120466...
]. Crabs (Crustacea, Malacostraca, Decapoda, Pleocyemata) have been investigated for the peptides’ antimicrobial activity and their immunomodulatory effects. Purified peptides from various species of crabs such as LALF (The Atlantic horseshoe crab-Limulus polyphemus), M-ALF (kuruma shrimp-Marsupenaeus Japonicus), PtALF, PtALF4, PtALF5, and PtALF8 (horse crab-Portunus trituberculatus) showed an anti-lipopolysaccharide activity [9898. Hoess A, Watson S, Siber GR, Liddington R. Crystal structure of an endotoxin-neutralizing protein from the horseshoe crab, Limulus anti-LPS factor, at 1.5 A resolution. EMBO J. 1993 Sep;12(9):3351-6. PubMed PMID: 8253062; PMCID: 413608.-103103. Vallespi MG, Glaria LA, Reyes O, Garay HE, Ferrero J, Araña MJ. A Limulus antilipopolysaccharide factor-derived peptide exhibits a new immunological activity with potential applicability in infectious diseases. Clin Diagn Lab Immunol. 2000 Jul;7(4):669-75. doi: 10.1128/CDLI.7.4.669-675.2000. PMID: 10882670; PMCID: PMC95932.
https://doi.org/10.1128/CDLI.7.4.669-675...
]. In another example, the β-1,3-glucan binding protein (β-GPB) from the rice paddy crabParatelphusa hydrodromus can trigger an immune response against external aggressors. Additionally, β-GPB also exerts an antioxidant effect, reducing DPPH radicals, in a model of restraining the albumin’s denaturation [104104. Iswarya A, Anjugam M, Vaseeharan B. Role of purified β-1, 3 glucan binding protein (β-GBP) from Paratelphusa hydrodromus and their anti-inflammatory, antioxidant and antibiofilm properties. Fish Shellfish Immunol. 2017 Sep;68:54-64. doi: 10.1016/j.fsi.2017.07.007. PubMed PMID: 28684323.
https://doi.org/10.1016/j.fsi.2017.07.00...
]. Regarding the antioxidant enzymatic profile, enzymes purified from distinct crab species showed an effective antioxidant potential by increasing the activity of superoxide dismutase (SOD) and catalase (CAT) [105105. Liu HP, Chen FY, Gopalakrishnan S, Qiao K, Bo J, Wang KJ. Antioxidant enzymes from the crab Scylla paramamosain: gene cloning and gene/protein expression profiles against LPS challenge. Fish Shellfish Immunol; 2010 May-Jun;28(5-6):862-71. doi: 10.1016/j.fsi.2010.02.008. PubMed PMID: 20153435.
https://doi.org/10.1016/j.fsi.2010.02.00...
,106106. Soundarapandian P, Roy S, Varadharajan D. Antioxidant activity in hard and soft shell crabs of Charybdis lucifera (Fabricius, 1798). J Aquac Res Development. 2014; 5(7):1-5. doi: 10.4172/2155-9546.1000288.
https://doi.org/10.4172/2155-9546.100028...
]. Moreover, crab-derived peptides can restrain the inflammatory process by reducing inflammatory mediators’ levels and modulating the NF-kB pathway, implicated in various inflammatory diseases [107107. Sharma S, Yedery RD, Patgaonkar MS, Selvaakumar C, Reddy KVR. Antibacterial activity of a synthetic peptide that mimics the LPS binding domain of Indian mud crab, Scylla serrata anti-lipopolysaccharide factor (SsALF) also involved in the modulation of vaginal immune functions through NF-kB signaling. Microb Pathog. 2011 Mar-Apr;50(3-4):179-91. doi: 10.1016/j.micpath.2010.12.007. PubMed PMID: 21195157.
https://doi.org/10.1016/j.micpath.2010.1...
]. Besides their role as an anti-inflammatory substance, these crustacean-derived peptides can exert antinociceptive effects, consequently playing a role in pain control as potent COX-2 reducers in vitro [108108. Narayanasamy A, Balde A, Raghavender P, Shashanth D, Abraham J, Joshi I, Nazeer RA. Isolation of marine crab (Charybdis natator) leg muscle peptide and its anti-inflammatory effects on macrophage cells. Bio Agricul Biotec. 2020 May;25:101577. doi: 10.1016/j.bcab.2020.101577.
https://doi.org/10.1016/j.bcab.2020.1015...
].

Arachnida peptides

Scorpions

Venom peptides from scorpion (Chelicerata, Arachnida, Scorpiones) distribute into two main groups: DBPs (disulfide-bridged peptides) and NDBPs (non-disulfide-bridged peptides). DBPs generally target ion channels. Most scorpion DBPs contain three to four disulfide bridges and interact with the Na+, K+, Ca2+, and Cl− channels. In comparison, the NDBP peptides are less abundantly distribute among scorpion venoms and exhibit multiple activities, such as insecticide, antiviral, antimicrobial, hemolytic, antiproliferative, bradykinin-enhancing, and immunomodulatory [109109. Almaaytah A, Albalas Q. Scorpion venom peptides with no disulfide bridges: a review. Peptides. 2014 Jan;51:35-45. doi: 10.1016/j.peptides.2013.10.021. PubMed PMID: 24184590.
https://doi.org/10.1016/j.peptides.2013....
,110110. Daniele-Silva A, Machado RJA, Monteiro NKV, Estrela AB, Santos ECG, Carvalho E, Araújo Júnior RF, Melo-Silveira RF, Rocha HAO, Silva-júnior AA, Fernandes-Pedrosa MF. Stigmurin and TsAP-2 from Tityus stigmurus scorpion venom: assessment of structure and therapeutic potential in experimental sepsis. Toxicon. 2016 Oct;121:10-21. doi: 10.1016/j.toxicon.2016.08.016. PubMed PMID: 27567704.
https://doi.org/10.1016/j.toxicon.2016.0...
].

Dias and collaborators [111111 Dias NB, de Souza BM, Cocchi FK, Chalkidis HM, Dorce VAC, Palma MS. Profiling the short, linear, non-disulfide bond-containing peptidome from the venom of the scorpion Tityus obscurus. J Proteomics. 2018 Jan 6;170:70-79. doi: 10.1016/j.jprot.2017.09.006. PMID: 28918200.
https://doi.org/10.1016/j.jprot.2017.09....
] analyzed 320 non-disulfide bond-containing peptides, of which 27 had their sequences assigned. Among them, thirteen peptides constituting novel toxins inTityus obscurus venom (Amazonian black scorpion). As examples, ToAP3 (FIGMIPGLIGGLISAIK-NH2) and ToAP4 (FFSLIPSLIGGLVSAIK-NH2) NDBPs exerted their effect on immunomodulation and suppression of inflammatory mediators, such as TNF-α and IL-1β. Furthermore, ToAP3 and ToAP4 were associated with the modulation of antigen presentation. They reduced TNF-α and IL-1β at transcriptional and translational levels in bone marrow-derived macrophages (BMDM) and dendritic cells (BMDC). The reduction of TNF-α secretion before LPS- inflammatory stimuli is associated with peptide interaction with TLR-4. ToAP4 increased MHC-II expression in BMDC, while ToAP3 decreased co-stimulatory molecules such as CD80 and CD86 [112112. Veloso Júnior PHH, Simon KS, de Castro RJA, Coelho LC, Erazo FAH, de Souza ACB, das Neves RC, Lozano VF, Schwartz EF, Tavares AH, Mortari MR, Junqueira-Kipnis AP, Silva-Pereira I, Bocca AL. Peptides ToAP3 and ToAP4 decrease release of inflammatory cytokines through TLR-4 blocking. Biomed Pharmacother. 2019 Oct;118:109152. doi: 10.1016/j.biopha.2019.109152. PubMed PMID: 31376652.
https://doi.org/10.1016/j.biopha.2019.10...
]. Stigmurin, a cationic peptide from the scorpion Tityus stigmurus venom (scorpion from the family Buthidae found in Brazil) and TsAP-2 from the scorpion Tityus serrulatus venom (Brazilian yellow scorpion) both reduced the migration of leukocytes and TNF-α release, reducing the inflammatory process. Additionally, the fractions extracted from their respective crude venoms could modulate the expression of the cytokines IL-4, IL-6, IL-13, and IL-13, which are pro and anti-inflammatory [113113. Yaqoo R, Tahir HM, Rasheed A, Ahshan MM, Arshad M. Anti-inflammatory role peptides isolated from venom of Androctonus finitimus (Pocock 1897) (scorpiones: Buthidae). J Anim Plant Sci. 2019; 29(1):334-42. ].

The peptide Ts14 from T. serrulatus modulates critical events occurring in the fibrovascular tissue, i.e., it causes neovascularization, inflammatory cell recruitment, and extracellular matrix deposition induced by polyether-polyurethane sponge implants in mice. Consequently, Ts14 has therapeutic potential in wound healing and ischemic and inflammatory conditions. Furthermore, Ts14 reduced TNF-α levels and neutrophil infiltration, although stimulated macrophage infiltration into implants, as determined by myeloperoxidase (MPO) and N-acetyl-β-d-glucosaminidase (NAG) enzyme activities, respectively [114114. Cassini-Vieira P, Felipetto M, Prado LB, Verano-Braga T, Andrade SP, Santos RAS, Teixeira MM, de Lima ME, Pimenta AMC, Barcelos LS. Ts14 from Tityus serrulatus boosts angiogenesis and attenuates inflammation and collagen deposition in sponge-induced granulation tissue in mice. Peptides. 2017 Dec; 98:63-9. doi: 10.1016/j.peptides.2016.10.002. Epub 2016 Oct 11. PMID: 27732900.
https://doi.org/10.1016/j.peptides.2016....
]. BotAF is a peptide derived from Buthus occitanus tunetanus (common yellow scorpion), another yellow scorpion species that comprises a long chain of 64 amino acid residues, with potent analgesic activity in rodents [115115. Maatoug R, Jebali J, Guieu R, Waard M, Kharrat R. BotAF, a new Buthus occitanus tunetanus scorpion toxin, produces potent analgesia in rodents. Toxicon. 2018 Jul;149:72-85.]. From the Chinese scorpionMesobuthus martensii (Chinese scorpion), 35 scorpion oligopeptides (CMOs) were studied. Specifically, the peptide CMO-1 suppressed inflammation by reducing the production of inflammatory mediators such as nitric oxide (NO), TNF -α, IL-6, and IL-1β in RAW264.7 macrophages cells. Moreover, CMO-1 inhibited the degradation of IkBα and the nuclear translocation of p65. It also suppressed NF-kβ activation and inhibited MAPK phosphorylation of ERK, JNK, and p38 [116116. Zheng M, Ju W, Chen J, Yuan Y, Zhang C, Liu F, Zhang F. Structural characterization and anti-inflammatory potency of Mesobuthus martensii Karsch oligopeptides in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Royal Soc Chem. 2019;9(43):24822-32. doi:10.1039/C9RA01623F.
https://doi.org/10.1039/C9RA01623F...
]. The venom of another species of Mesobuthus (Mesobuthus eupeus- lesser Asian scorpion,the lesser Asian scorpion, or the mottled scorpion) was effective in treating CFA-induced arthritis, in which the edema reduction correlated with the reduction of arthritis [117117. Ahmadi M, Zare MA, Hashemlou M, Hejazi M. Study on anti inflammatory effect of scorpion (Mesobuthus eupeus) venom in adjuvant-induced arthritis in rats. Arch Razi Insti. 2009 Jun;64(1):51-6. ].

Sc20 from the venom of Scorpiops tibetanus is also a potent anti-inflammatory and immunosuppressor. This peptide modulated two important pro-inflammatory factors: the secretion of TNF-α and IFN-γ, displaying a positive effect in delayed hypersensitivity. Similar peptide St20, the first disulfide-bridged toxin peptide from the scorpion S. tibetanus, showed immunosuppressive and anti-inflammatory activities, suggesting that it may be a novel source of venom peptides to treat human disease [118118. Xiao M, Ding L, Yang W, Chai L, Sun Y, Yang X, Li D, Zhang H, Li W, Cao Z, Wu Y, Li J, Li S, Chen Z. St20, a new venomous animal derived natural peptide with immunosuppressive and anti-inflammatory activities. Toxicon. 2017;127:37-43. doi: 10.1016/j.toxicon.2017.01.005. PubMed PMID: 28077339.
https://doi.org/10.1016/j.toxicon.2017.0...
].

The voltage-gated Kv1.3 channel, expressed in memory-efficient T cells, is presently a recognized targeted drug for treating various autoimmune diseases. Scorpion venom possesses Kv1.3 channel peptide blockers that suppress cytokine secretion and alleviate disease in animal models of T-cell-mediated autoimmune diseases [119119. Chen Z, Hu Y, Hu J, Yang W, Sabatier JM, De Waard M, Cao Z, Li W, Han S, Wu Y. Unusual binding mode of scorpion toxin BmKTX onto potassium channels relies on its distribution of acidic residues. Biochem Biophys Res Commun. 2014 Apr 25;447(1):70-6. doi: 10.1016/j.bbrc.2014.03.101. PubMed PMID: 24704423.
https://doi.org/10.1016/j.bbrc.2014.03.1...
]. Thus, to improve the selectivity and activity of these scorpion venom peptides directed at regulating Kv1.3 potassium channels are currently undertaken. A remarkable example is the study of the scorpion toxin BmKTX, isolated from M. martensii [120120. Renisio JG, Romi-Lebrun R, Blanc E, Bornet O, Nakajima T, Darbon H. Solution structure of BmKTX , a K+ blocker toxin from the chinese scorpion Buthus martensi. Proteins. 2000 Jan 1;38(1),70-7. doi: 10.1002/(sici)1097-0134(20000101)38:1<70::aid-prot8>3.0.co;2-5. PubMed PMID: 10651040.
https://doi.org/10.1002/(sici)1097-0134(...
]. Recently, BmKTX analogs such as ADWX-1, BmKTX-D33H, BmKTX-19, and BmKTX-196 demonstrated specific inhibition of the Kv1.3 channel. Most venom-derived peptides have not evolved to target specific mammalian receptors of therapeutic interest; therefore, preparing peptide analogs with higher potency toward specific targets is customary [119119. Chen Z, Hu Y, Hu J, Yang W, Sabatier JM, De Waard M, Cao Z, Li W, Han S, Wu Y. Unusual binding mode of scorpion toxin BmKTX onto potassium channels relies on its distribution of acidic residues. Biochem Biophys Res Commun. 2014 Apr 25;447(1):70-6. doi: 10.1016/j.bbrc.2014.03.101. PubMed PMID: 24704423.
https://doi.org/10.1016/j.bbrc.2014.03.1...
,120120. Renisio JG, Romi-Lebrun R, Blanc E, Bornet O, Nakajima T, Darbon H. Solution structure of BmKTX , a K+ blocker toxin from the chinese scorpion Buthus martensi. Proteins. 2000 Jan 1;38(1),70-7. doi: 10.1002/(sici)1097-0134(20000101)38:1<70::aid-prot8>3.0.co;2-5. PubMed PMID: 10651040.
https://doi.org/10.1002/(sici)1097-0134(...
,121121. Ye F, Hu Y, Yu W, Xie Z, Hu J, Cao Z, Li W, Wu Y. The scorpion toxin analogue BmKTX-D33H as a potential Kv1.3 channel-selective immunomodulator for autoimmune diseases. Toxins (Basel). 2016 Apr 19;8(4):115. doi: 10.3390/toxins8040115. PubMed PMID: 27104568; PMCID: PMC4848641.
https://doi.org/10.3390/toxins8040115...
]. The Vm24 scorpion toxin also showed similar activity to the venom-peptides above, which are blockers of Kv1.3 channels, acting without affecting the T cells’ viability and inhibiting the activation of CD25 and CD40L, as well as the cytokine secretion of pro-inflammatory IFN-γ and TNF [122122. Veytia-Bucheli JI, Jiménez-Vargas JM, Melchy-Pérez EI, Sandoval-Hernández MA, Possani LD, Rosenstein Y. Kv1.3 channel blockade with the Vm24 scorpion toxin attenuates the CD4+ effector memory T cell response to TCR stimulation. Cell Commun Signal. 2018 Aug 14;16(1):45. doi: 10.1186/s12964-018-0257-7. PMID: 30107837; PMCID: PMC6092819.
https://doi.org/10.1186/s12964-018-0257-...
].

Hetlaxin (ISCTGSKQCYDPCKKKTGCPNAKCMNKSCKCYGC) is a DBPs, belonging to the scorpion alpha-toxin family, isolated from the Heterometrus laoticus venom (Vietnam forest scorpion), which possesses a high affinity to the Kv1.3 potassium channel. This isolated H. laoticus venom peptide exerted an anti-inflammatory effect similar or slightly superior to ketoprofen [123123 Hoang AN, Vo HDM, Vo NP, Kudryashova KS, Nekrasova OV, Feofanov AV, Kirpichnikov MP, Andreeva TV, Serebryakova MV, Tsetlin VI, Utkin YN. Vietnamese Heterometrus laoticus scorpion venom: evidence for analgesic and anti-inflammatory activity and isolation of new polypeptide toxin acting on Kv1.3 potassium channel. Toxicon. 2014 Jan;77:40-4. doi: 10.1016/j.toxicon.2013.10.027.
https://doi.org/10.1016/j.toxicon.2013.1...
].

Spiders

Spiders (Chelicerata, Arachnida, Araneae) comprise one of the oldest living animals on Earth that surged approximately 300 million years ago and comprise the most significant number of living species (> 40,000) [124124. Zhang H, Liu H, Chen Y, Yang X, Wang P, Liu T, Deng M, Qin B, Correia C, Lee S, Kim J, Sparks M, Nair AA, Evans DL, Kalari KR, Zhang P, Wang L, You Z, Kaufmann SH, Lou Z, Pei H. A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice. Nat Commun. 2016 Jan 5;7:10201. doi: 10.1038/ncomms10201. PMID: 26727879; PMCID: PMC4728409.
https://doi.org/10.1038/ncomms10201...
]. As in other arthropods, inoculation of their venom causes local discomfort, such as edema, and more severe deleterious effects, like ulcerations, acute renal failure, and even death in the worse cases [125125. Okamoto CK, van den Berg CW, Masashi M, Gonçalves-de-Andrade RM, Tambourgi DV. Tetracycline reduces kidney Damage Induced by Loxosceles Spider Venom. Toxins (Basel). 2017 Mar 2;9(3):90. doi: 10.3390/toxins9030090. PMID: 28257106; PMCID: PMC5371845.
https://doi.org/10.3390/toxins9030090...
,126126. Manzoni-de-Almeida D, Squaiella-Baptistão CC, Lopes PH, van den Berg CW, Tambourgi DV. Loxosceles venom sphingomyelinase D activates human blood leukocytes: role of the complement system. Mol Immunol. 2018 Feb;94:45-53. doi: 10.1016/j.molimm.2017.12.009. PubMed PMID: 29257998.
https://doi.org/10.1016/j.molimm.2017.12...
]. Although arachnids venoms are harmfully toxic to humans, some venom peptides have beneficial bioactivities applicable to biomedicine. In general, arthropod-derived venom’s biochemical targets are excitable neuronal receptors; these include ion channels like voltage-gated sodium channels (Nav) found in neurons, which allow the modulating of pain. Spider peptides that modulate such pharmacological targets serve as molecular templates for the development of analgesic drugs. For example, the Hm1a peptide purified from the venom of Heterosodra maculate (togo starburst baboon spider) can control the hypersensitivity in chronic visceral pain [127127. Dongol Y, Cardoso FC, Lewis RJ. Spider Knottin Pharmacology at Voltage-Gated Pain Pathways. Toxins (Basel). 2019 Oct 29;11(11),1-39. doi: 10.3390/toxins11110626. PMID: 31671792.
https://doi.org/10.3390/toxins11110626...
].

Phlotoxin 1 (Ph1Tx1) is a 34-residue toxin purified from Phlogiellus spider venom, a promising antinociceptive peptide with a high affinity for Pav [128128. Gonçalves TC, Lesport P, Kuylle S, Stura E, Ciolek J, Mourier G, Servent D, Bourinet E, Benoit E, Gilles N. Evaluation of the spider (Phlogiellus genus) phlotoxin 1 and synthetic variants as antinociceptive drug candidates. Toxins (Basel). 2019 Aug 22;11(9):484. doi: 10.3390/toxins11090484. PubMed PMID: 31443554; PMCID: PMC6784069.
https://doi.org/10.3390/toxins11090484...
]. The crude venom of Phoneutria nigriventer (armed spiders), besides its antineoplastic activity, can suppress the IFN-γ release and increase the expression of the anti-inflammatory cytokine IL-10. Phα1β, a peptide purified from the venom of P. nigriventer, has a significant role in the control of the CFA-induced chronic arthritis model. The Phα1β suppressed the inflammatory agent’s side effects while the antinociceptive role acted as the antagonist of the TRAP1 channel [129129. Tonello R, Fusi C, Materazzi S, Marone IM, De Logu F, Benemei S, Gonçalves MC, Coppi E, Castro-Junior CJ, Gomez MV, Geppetti P, Ferreira J, Nassini R. The peptide Phα1β, from spider venom, acts as a TRPA1 channel antagonist with antinociceptive effects in mice. Br J Pharmacol. 2017 Jan;174(1):57-69. doi: 10.1111/bph.13652. PubMed PMID: 27759880; PMCID: PMC5341489.
https://doi.org/10.1111/bph.13652...
-131131. Tenza-Ferrer H, Magno LAV, Romano-Silva MA, da Silva JF, Gomez MV. Phα1β spider toxin reverses glial structural plasticity upon peripheral inflammation. Front Cell Neurosci. 2019 Jul 10;13:306. doi: 10.3389/fncel.2019.00306. PubMed PMID: 31354431; PMCID: PMC6635560.
https://doi.org/10.3389/fncel.2019.00306...
]. Furthermore, other peptides such as Tx3-3, PnTx4, PhKv, and PhTx3-5 from the P. nigriventer venom have important antinociceptive properties as observed in the animal neuropathic inflammatory pain model [132132. Grishin EV, Savchenko GA, Vassilevski AA, Korolkova YV, Boychuk YA, Viatchenko-Karpinski VY, Nadezhdin KD, Arseniev AS, Pluzhnikov KA, Kulyk VB, Voitenko NV, Krishtal OO. Novel peptide from spider venom inhibits P2X3 receptors and inflammatory pain. Ann Neurol. 2010 May;67(5):680-3. doi: 10.1002/ana.21949. PubMed PMID: 20437566.
https://doi.org/10.1002/ana.21949...
-135135. Dalmolin GD, Bannister K, Gonçalves L, Sikandar S, Patel R, Cordeiro MN, Gomez MV, Ferreira J, Dickenson AH. Effect of the spider toxin Tx3-3 on spinal processing of sensory information in naive and neuropathic rats: an in vivo electrophysiological study. Pain Rep. 2017 Jul 6;2(4):e610. doi: 10.1097/PR9.0000000000000610. PubMed PMID: 29392225; PMCID: PMC5741365.
https://doi.org/10.1097/PR9.000000000000...
]. Lycotoxin-Pa4a peptide from Pardosa astrigera venom displays immunomodulatory activity by increasing the expression of IL-10 and suppressing pro-inflammatory mediators such as nitric oxide, nitric oxide-induced synthase (iNOS), IL-1β, TNF-α, in addition to reducing COX-2. In vitro studies with an LPS-stimulated model demonstrated that this peptide could act as a potential antinociceptive modulator [136136. Shin MK, Hwang IW, Kim Y, Kim ST, Jang W, Lee S, Bang WY, Bae CH, Sung JS. Antibacterial and anti-inflammatory effects of novel peptide toxin from the spider Pardosa astrigera. Antibiotics (Basel). 2020 Jul 19;9(7):422. doi: 10.3390/antibiotics9070422. PMID: 32707636; PMCID: PMC7400607.
https://doi.org/10.3390/antibiotics90704...
].

Ticks

Ticks are hematophagous arthropods that rely only on the innate defense to protect themselves against invading microorganisms. Biologically active molecules are also necessary to keep blood fluid during feeding and eliminate the host’s defense mechanisms, such as vasoconstriction, forming a hemostatic plug, activating the coagulation cascade, and initiating inflammatory responses that lead to wound healing and tissue remodeling. Thus, some bioactive molecules have anticoagulant, antiplatelet, vasodilatory, anti-inflammatory, and immunomodulatory activity and are crucial to overcoming the host’s hemostatic and immunological responses, allowing ticks to feed and develop [137137. Kazimírová M, Štibrániová I. Tick salivary compounds: their role in modulation of host defences and pathogen transmission. Front Cell Infect Microbiol. 2013 Aug 20;43(3):43. doi: 10.3389/fcimb.2013.00043. PMID: 23971008; PMCID: PMC3747359.
https://doi.org/10.3389/fcimb.2013.00043...
].

Ornithodoros savignyi (sand tampan, African-eyed tampan, or Kalahari sand tampan) is a tick that parasites cattle and is endemic in arid and semi-arid regions of the African continent. This tick species express antimicrobial peptides (defensins) constitutively in various tissues at low levels and inductively during blood-feeding or in response to bacterial challenge. Defensins are cationic molecules with molecular masses of approximately 4 kDa containing cysteine residues forming three disulfide bonds [138138. Prinsloo L, Naidoo A, Serem J, Taute H, Sayed Y, Bester M, Neitz A, Gaspar A. Structural and functional characterization of peptides derived from the carboxy-terminal region of a defensin from the tick Ornithodoros savignyi. J Pept Sci. 2013 May;19(5):325-32. doi: 10.1002/psc.2505. PMID: 23553969.
https://doi.org/10.1002/psc.2505...
]. Studies on O. savignyi resulted in the cloning and sequencing of defensin isoforms, OsDef1 and OsDef2, derived from the terminal carboxy region. Due to the bactericidal activity isoform 2, this peptide served as a model for the synthesis of the peptide Os (KGIRGYKGGYCKGAFKQTCKCY) and its analog Os-C (KGIRGYKGGY- KGAFKQT- K-Y), with 22 and 19 residues of amino acids, respectively [139139. Malan M, Serem JC, Bester MJ, Neitz AWH, Gaspar ARM. Anti-inflammatory and anti-endotoxin properties of peptides derived from the carboxy-terminal region of a defensin from the tick Ornithodoros savignyi. J Pept Sci. 2016 Jan;22(1):43-51. doi: 10.1002/psc.2838. PMID: 26662999.
https://doi.org/10.1002/psc.2838...
]. Os peptides’ mechanisms of action in bacterial cells’ membrane involve their penetration into the cell and action on intracellular targets. As a result of these findings, Malan et al. [139139. Malan M, Serem JC, Bester MJ, Neitz AWH, Gaspar ARM. Anti-inflammatory and anti-endotoxin properties of peptides derived from the carboxy-terminal region of a defensin from the tick Ornithodoros savignyi. J Pept Sci. 2016 Jan;22(1):43-51. doi: 10.1002/psc.2838. PMID: 26662999.
https://doi.org/10.1002/psc.2838...
] evaluated these peptides’ effects in inflammatory conditions resulting from gram-negative bacteria infection. Thus, Os and Os-C’s showed anti-inflammatory properties on Raw 264.7 macrophages stimulated by LPS and IFN-γ in vitro. Both peptides inhibited the production of TNF-α and NO-induced by LPS in RAW 264.7 cells without appreciable cytotoxic effects. In addition to anti-endotoxin activity and anti-inflammatory properties, Os eliminated NO directly, and both Os and Os-C peptides exhibited antioxidant activity, which together can reduce oxidative stress associated with inflammation [139139. Malan M, Serem JC, Bester MJ, Neitz AWH, Gaspar ARM. Anti-inflammatory and anti-endotoxin properties of peptides derived from the carboxy-terminal region of a defensin from the tick Ornithodoros savignyi. J Pept Sci. 2016 Jan;22(1):43-51. doi: 10.1002/psc.2838. PMID: 26662999.
https://doi.org/10.1002/psc.2838...
].

Wu et al. identified two families of immunoregulatory peptides, hyalomin-A1 and hyalomin-B1, from the salivary glands of the Hyalomma asiaticum tick. The amino acid sequences of hyalomin-A1 and B1 correspond to the sequences QTPRTIGPPYT and TLRTTTGYWTTVEKGNGTTPAANSTEKGNRPYGR, respectively. Hyalomin-A1 and B1 act as immunoregulators, inhibiting the secretion of pro-inflammatory cytokines induced by LPS in vitro and increasing immunosuppressive cytokine, IL-10 [140140. Wu J, Wang Y, Liu H, Yang H, Ma D, Li J, Li D, Lai R, Yu H. Two immunoregulatory peptides with antioxidant activity from tick salivary glands. J Biol Chem. 2010 May 28;285(22):16606-13. doi: 10.1074/jbc.M109.094615. PMID: 20178988; PMCID: PMC2878058.
https://doi.org/10.1074/jbc.M109.094615...
]. Both hyalomin-A1 and B1 could quickly eliminate oxidants in a few seconds. Such antioxidant activities can contribute to immunoregulatory and anti-inflammatory abilities.

Furthermore, the results indicated that both hyalomin-A1 and B1 significantly suppressed the LPS-induced activation of the JNK subgroup of the MAPK signaling pathway by blocking JNK phosphorylation and, consequently, led to a reduction in MCP-1, IFN-γ, and tumor necrosis factor-α genes. The in vivo experiments identified that these peptides could inhibit the hind paw’s inflammation in mice depending on the dose administered. These anti-inflammatory functions were significantly present after nine days of administration. At a dose of 5 mg/kg of body weight, the mice could recover to a normal state after 21 days of administration of hyalomin-A1 or B1 [141141. Denisov SS, Ramírez-Escudero M, Heinzmann ACA, Ippel JH, Dawson PE, Koenen RR, Hackeng TM, Janssen BJC, Dijkgraaf I. Structural characterization of anti-CCL5 activity of the tick salivary protein evasin-4. J Biol Chem. 2020 Oct 16;295(42):14367-78. doi: 10.1074/jbc.RA120.013891. PMID: 32817341; PMCID: PMC7573271.
https://doi.org/10.1074/jbc.RA120.013891...
].

Ticks have another mechanism of escape from the host’s defenses related to the presence of evasins, small cysteine-rich binding proteins secreted in their saliva. To neutralize chemokines and their signaling, ticks, such as Rhipicephalus sanguineus (commonly called the brown dog tick, kennel tick, or pantropical dog tick), secrete evasins [142142. Déruaz M, Frauenschuh A, Alessandri AL, Dias JM, Coelho FM, Russo RC, Ferreira BR, Graham GJ, Shaw JP, Wells TNC, Teixeira MM, Power CA, Proudfoot AE. Ticks produce highly selective chemokine binding proteins with antiinflammatory activity. J Exp Med. 2008 Sep 1;205(9):2019-31. doi: 10.1084/jem.20072689. PMID: 18678732; PMCID: PMC2526197.
https://doi.org/10.1084/jem.20072689...
]. Evasin-1 (P0C8E7) inhibits cell recruitment of chemokines CCL3, CCL3L1, and CCL4-mediated chemotaxis in L1.2/CCR5 transfectants in vivo and in vitro. Besides, it also inhibited CCL3-induced granulocyte recruitment in mice. Evasin-3 (P0C8E8) inhibits neutrophil recruitment and reduces inflammation. Treatment with this peptide resulted in inhibiting total cell accumulation in the synovial cavity in a mouse-induced arthritis model. Inhibition of neutrophil infiltration in the knee joint reduced induced hypernociception, reduced production of TNF-α in the periarticular tissues, and inhibition of leukocyte adhesion [142142. Déruaz M, Frauenschuh A, Alessandri AL, Dias JM, Coelho FM, Russo RC, Ferreira BR, Graham GJ, Shaw JP, Wells TNC, Teixeira MM, Power CA, Proudfoot AE. Ticks produce highly selective chemokine binding proteins with antiinflammatory activity. J Exp Med. 2008 Sep 1;205(9):2019-31. doi: 10.1084/jem.20072689. PMID: 18678732; PMCID: PMC2526197.
https://doi.org/10.1084/jem.20072689...
]. The peptide derived from the N-terminal region of evasin-4 (P0C8E9), which had an affinity with the chemokine CCL5, inhibited the activity of CCL5 in monocyte migration assays. This result suggests that evasin-4 derivatives can serve as a starting point for developing anti-inflammatory drugs [142142. Déruaz M, Frauenschuh A, Alessandri AL, Dias JM, Coelho FM, Russo RC, Ferreira BR, Graham GJ, Shaw JP, Wells TNC, Teixeira MM, Power CA, Proudfoot AE. Ticks produce highly selective chemokine binding proteins with antiinflammatory activity. J Exp Med. 2008 Sep 1;205(9):2019-31. doi: 10.1084/jem.20072689. PMID: 18678732; PMCID: PMC2526197.
https://doi.org/10.1084/jem.20072689...
].

Tian et al. [143143. Tian Y, Chen W, Mo G, Chen R, Fang M, Yedid G, Yan X. An immunosuppressant peptide from the hard tick Amblyomma variegatum. Toxins (Basel). 2016 May 3;8(5):133. doi: 10.3390/toxins8050133.
https://doi.org/10.3390/toxins8050133...
] investigated the immunosuppressive peptide amphiregulin from the tick Amblyomma variegatum (the tropical bont tick). This peptide is composed of 40 amino acid residues (HLHMHGNGATQVFKPRLVLKCPNAAQLIQPGKLQRQLLLQ). In rat splenocytes, amphiregulin exerted significant anti-inflammatory effects by inhibiting the secretion of TNF-α, IL-1, IL-8, and IFN-γ in vitro. Compared to LPS, these inflammatory mediators’ inhibition was significant in all tested peptide concentrations (2, 4, and 8 µg/mL). Amphiregulin showed substantial elimination of free radicals and antioxidant activities in specific concentrations (5, 10, and 20 µg/mL) in vitro and also significantly inhibited the paw inflammation induced by adjuvant mice in vivo [143143. Tian Y, Chen W, Mo G, Chen R, Fang M, Yedid G, Yan X. An immunosuppressant peptide from the hard tick Amblyomma variegatum. Toxins (Basel). 2016 May 3;8(5):133. doi: 10.3390/toxins8050133.
https://doi.org/10.3390/toxins8050133...
].

Chilopod peptides

Centipede

Centipedes are part of the subphylum Myriapoda (class Chilopoda). Scolopendra subspinipes mutilans (Chinese red-headed centipede) is a component of natural extract formulation widely used in traditional Chinese and Korean medicine to treat various conditions due to its anti-inflammatory, antimicrobial, and analgesic effects [144144. Hwang L, Ko IG, Jin JJ, Kim SH, Kim CJ, Jeon JW, Han JH. Scolopendra subspinipes mutilans extract suppresses inflammatory and neuropathic pain in vitro and in vivo. Evid based Complement Alternat Med. 2018 Dec 17;2018: 5057372. doi: 10.1155/2018/5057372. PubMed PMID: 30647762.
https://doi.org/10.1155/2018/5057372...
]. It is a stable extract of which studies report its neuroinflammatory activity and efficacy as a mitigating agent of inflammation in rheumatoid arthritis, as well as antitumor and immunostimulant [145145. Liu DY, Zhao HM, Cheng SM, Rao Y, Huang XY, Zuo ZQ, Lei M, Guan YM, Liu HN, Lu AP. Scorpio and Scolopendra attenuate inflammation and articular damage in rats with collagen-induced arthritis. J Ethnopharmacol. 2012 Jun 1;141(2):603-7. doi: 10.1016/j.jep.2011.08.056. PubMed PMID: 21911049.
https://doi.org/10.1016/j.jep.2011.08.05...
,146146. Zhao H, Li Y, Wang Y, Zhang J, Ouyang X, Peng R, Yang J. Antitumor and immunostimulatory activity of a polysaccharide-protein complex from Scolopendra subspinipes mutilans L. Koch in tumor-bearing mice. Food Chem Toxicol. 2012 Aug;50(8):2648-55. doi: 10.1016/j.fct.2012.05.018. PubMed PMID: 22613217.
https://doi.org/10.1016/j.fct.2012.05.01...
]. From the venom ofScolopendra subspinipes mutilans (Chinese redhead), the formyl peptide receptor 2 (FPR2) peptide with a chemo-attractive property for FRP2 on the neutrophils’ surface was isolated. Results evidenced the therapeutic effects of this peptide on rheumatoid arthritis by inhibiting the release of pro-inflammatory cytokines and the recruitment of neutrophils in the joint [147147. Park YJ, Park B, Lee M, Jeong YS, Lee HY, Sohn DH, Song JJ, Lee JH, Hwang JS, Bae YS. A novel antimicrobial peptide acting via formyl peptide receptor 2 shows therapeutic effects against rheumatoid arthritis. Sci Rep. 2018 Oct 2;8(1):14664. doi:10.1038/s41598-018-32963-5.
https://doi.org/10.1038/s41598-018-32963...
]. Scolopendrasin IX, another peptide isolated from the same centipede species, can down-regulate the expression of pro-inflammatory mediators such as TNF-α and IL-6, also having therapeutic effects against rheumatoid arthritis. In mouse neutrophils, peptides from this centipede species’ venom have a high potential to control the inflammatory process due to their targeted effects. However, the mechanism of action has not been clarified yet [147147. Park YJ, Park B, Lee M, Jeong YS, Lee HY, Sohn DH, Song JJ, Lee JH, Hwang JS, Bae YS. A novel antimicrobial peptide acting via formyl peptide receptor 2 shows therapeutic effects against rheumatoid arthritis. Sci Rep. 2018 Oct 2;8(1):14664. doi:10.1038/s41598-018-32963-5.
https://doi.org/10.1038/s41598-018-32963...
].

Discussion

Peptides and antitumor activities

When there is a failure in the inflammatory process’s control mechanism, the condition can evolve into chronic inflammation with consequent mutation and cell proliferation, thus creating an environment conducive to cancer development. In this context, numerous treatments rely on antineoplastic therapy, including chemotherapy, radiotherapy, and immunotherapy [148148. Singh N, Baby D, Rajguru JP, Patil PB, Thakkannavar SS, Pujari VB. Inflammation and cancer. Ann Afr Med. 2019 Jul-Sep;18(3):121-6. doi: 10.4103/aam.aam_56_18. PMID: 31417011; PMCID: PMC6704802.
https://doi.org/10.4103/aam.aam_56_18...
]. These therapeutic options can cause serious side effects and increase resistance to neoplastic cells, therefore continuous research intent to find new therapeutical options. Animal venoms have become an object of interest because they have specific and structurally stable components that can interact with and modulate their molecular targets, making them good therapeutic candidates [149149. Roy A, Jauhari N, Bharadvaja N. Medicinal plants as a potential source of chemopreventive agents. In: Akhtar M, Swamy M, editors. Anticancer plants: natural products and biotechnological implements. Springer, Singapura;2018. p. 109-39. doi: 10.1007/978-981-10-8064-7_6.
https://doi.org/10.1007/978-981-10-8064-...
].

Among the drugable candidates, peptides from different arthropod species can potentially control inflammatory processes and control malignant neoplasms [150150. Tomar V, Kumar N, Tomar R, Sood D, Dhiman N, Dass SK, Prakash S, Madan J, Chandra R. Biological evaluation of noscapine analogues as potent and microtubule-targeted anticancer agents. Sci Rep. 2019 Dec 20;9(1):19542. doi: 10.1038/s41598-019-55839-8.
https://doi.org/10.1038/s41598-019-55839...
]. For instance, among the various ant toxins, solenopsin A (derived from red imported fire ant- Solenopsis invicta) is a potent anti-angiogenic agent that inhibits the phosphorylation of Akt-1 and FOXO1a, a substrate of Akt, thus modulating the Akt signal transduction, phosphatidylinositol-3-kinase in mouse embryos (3T3-L1 and NIH3T3) and zebrafish [151151. Arbiser JL, Kau T, Konar M, Narra K, Ramchandran R, Summers SA, Vlahos CJ, Ye K, Perry BN, Matter W, Fischl A, Cook J, Silver PA, Bain J, Cohen P, Whitmire D, Furness S, Govindarajan B, Bowen JP. Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis. Blood. 2007 Jan 15;109(2):560-5. doi: 10.1182/blood-2006-06-029934. PMID: 16990598; PMCID: PMC1785094.
https://doi.org/10.1182/blood-2006-06-02...
]. In cell cultures of HepG2, MCF-7, and LoVo lines, this peptide proved to be an anti-angiogenic toxin that can reduce the levels of cytokines such as interleukin (IL) -1β, IL-6, IL-8, and NF-κB) [152152. Al-Tamimi J, Semlali A, Hassan I, Ebaid H, Alhazza IM, Mehdi SH, Al-Khalifa M, Alanazi MS. Samsum ant venom exerts anticancer activity through immunomodulation in vitro and in vivo. Cancer Biother Radiopharm. 2018 Mar;33(2):65-73. doi: 10.1089/cbr.2017.2400. PMID: 29634416.
https://doi.org/10.1089/cbr.2017.2400...
]. Table 2 summarizes information regarding some venom peptides with antitumoral and anti-inflammatory activity.

Table 2.
Examples of peptides from the Uniprot database with antineoplastic activities.

In this line, the centipede glycosphingolipid peptide-7 from the millipede - Parafontaria laminata armigera exerts an antiproliferative effect on neoplastic cells and inhibits the focal adhesion kinase (FAK) pathway in addition to the signal-regulated kinase (Erk) 1 and 2, both involved in the proliferation of melanoma cells. This same peptide reduced proteins’ expression related to oral squamous cell carcinoma (cyclin D1) [153153. Sonoda Y, Hada N, Kaneda T, Suzuki T, Ohshio T, Takeda T, Kasahara T. A synthetic glycosphingolipid-induced antiproliferative effect in melanoma cells is associated with suppression of FAK, Akt, and Erk activation. Biol Pharm Bull. 2008 Jun;31(6):1279-83. doi: 10.1248/bpb.31.1279. PMID: 18520069.
https://doi.org/10.1248/bpb.31.1279...
]. Regarding bee venom, melittin (Apis mellifera) is undoubtedly one of the most multifunctional toxins. In the fight against neoplastic cells, melittin can bind calmodulin and prevent cell proliferation, inducing the death of neoplastic cells through the activation of caspases and metalloproteinases (MMPs) [154154. Holle L, Song W, Holle E, Wei Y, Wagner T, Yu X. A matrix metalloproteinase 2 cleavable melittin/avidin conjugate specifically targets tumor cells in vitro and in vivo. Int J Oncol. 2003 Jan;22(1):93-8. doi: 10.3892/ijo.22.1.93. PMID: 12469190.
https://doi.org/10.3892/ijo.22.1.93...
,155155. Moon DO, Park SY, Heo MS, Kim KC, Park C, Ko WS, Choi YH, Kim GY. Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. Int Immunopharmacol. 2006 Dec 5;6(12):1796-1807. doi: 10.1016/j.intimp.2006.07.027. PMID: 17052670.
https://doi.org/10.1016/j.intimp.2006.07...
]. In cells transformed by an oncogene, melittin activates PLA2, which destroys cancer cells and comprises another mechanism that acts as an antineoplastic agent. Through the PLA2-dependent mechanism of activation, melittin is effective in leukemic cell lines that are even resistant to TNF-α [156156. Arora AS, de Groen PC, Croall DE, Emori Y, Gores GJ. Hepatocellular carcinoma cells resist necrosis during anoxia by preventing phospholipase-mediated calpain activation. J Cell Physiol. 1996 Jun;167(3):434-42. doi: 10.1002/(SICI)1097-4652(199606)167:3<434::AID-JCP7>3.0.CO;2-Q. PMID: 8655597.
https://doi.org/10.1002/(SICI)1097-4652(...
, 157157. Wu YL, Jiang XR, Newland AC, Kelsey SM. Failure to activate cytosolic phospholipase A2 causes TNF resistance in human leukemic cells. J Immunol. 1998 Jun 15;160(12):5929-35. PMID: 9637506.].

PLA2 (Apis mellifera) is a toxin that negatively regulates transduction pathways related to cell survival and tumor invasion. Moreover, treatment with this peptide decreased epidermal growth factor (EGFr) [158158. Putz T, Ramoner R, Gander H, Rahm A, Bartsch G, Thurnher M. Antitumor action and immune activation through cooperation of bee venom secretory phospholipase A2 and phosphatidylinositol-(3,4)-bisphosphate. Cancer Immunol Immunother. 2006 Nov;55(11):1374-83. doi: 10.1007/s00262-006-0143-9. PMID: 16485125.
https://doi.org/10.1007/s00262-006-0143-...
]. BV is efficient in killing K1735M2 and B16 melanoma cells, halting the cell cycle at the G1 stage and, therefore, inhibiting cancer cells’ proliferation in a dose-dependent manner. Furthermore, BV treatment stimulated Bax production, a pro-apoptotic protein, and reduced the expression of Bcl-2, resulting in the formation of dimers with Bax and the consequent cell death [159159. Wolff H, Saukkonen K, Anttila S, Karjalainen A, Vainio H, Ristimäki A. Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res. 1998 Nov 15;58(22):4997-5001. PMID: 9823297., 160160. Jang MH, Shin MC, Lim S, Han SM, Park HJ, Shin I, Lee JS, Kim KA, Kim EH, Kim CJ. Bee venom induces apoptosis and inhibits expression of cyclooxygenase-2 mRNA in human lung cancer cell line NCI-H1299. J Pharmacol Sci. 2003 Feb;91(2):95-104. doi: 10.1254/jphs.91.95. PMID: 12686753.
https://doi.org/10.1254/jphs.91.95...
].

Mastoparan is a peptide isolated from wasp Polybia paulista, which alone can induce mitochondrial permeability; however, it does not have specificity in malignant cells. Though, when encapsulated in a liposome, this peptide could release cytochrome in human chronic myeloid leukemia cells [161161. de Souza BM, da Silva AVR, Resende VMF, Arcuri HA, dos Santos Cabrera MP, Ruggiero Neto J, Palma MS. Characterization of two novel polyfunctional mastoparan peptides from the venom of the social wasp Polybia paulista. Peptides. 2009 Aug;30(8):1387-95. doi: 10.1016/j.peptides.2009.05.008. Epub 2009 May 20. PMID: 19463874.
https://doi.org/10.1016/j.peptides.2009....
]. Isolated from Polybia paulista, the Polybia MPI peptide has cytotoxicity against leukemic T lymphocytes, in addition to being able to reach the cells of the lipid membranes creating channels that provoke ionic permeabilization, depolarization, and consequent cell death [162162. Pal P, Roy S, Chattopadhyay S, Pal TK. Medicinal value of animal venom for treatment of cancer in humans-a review. World Sci News. 2015;22: 91-107.].

Although spiders are a widespread species within the arthropod group, toxins that act as antineoplastic agents are understudied. Research has shown that the crude venom from Macrothele raven (Araneae, Hexathelidae) can arrest cancer cells via caspase 3 in treated cells, leading to the HeLa cell’s cell death. In breast cancer cells, the crude venom of this species caused cell death, in addition to causing a cell arrest in the G2/M and G0/ G1 cycles [163163. Gao L, Shan BE, Chen J, Liu JH, Song DX, Zhu BC. Effects of spider Macrothele raven venom on cell proliferation and cytotoxicity in HeLa cells. Acta Pharmacol Sin. 2005 Mar;26(3):369-76. doi: 10.1111/j.1745-7254.2005.00052.x. PMID: 15715936.
https://doi.org/10.1111/j.1745-7254.2005...
, 164164. Gao L, Yu S, Wu Y, Shan B. Effect of spider venom on cell apoptosis and necrosis rates in MCF-7 cells. DNA Cell Biol. 2007 Jul;26(7): 485-9. doi: 10.1089/dna.2007.0579. PMID: 17630852.
https://doi.org/10.1089/dna.2007.0579...
].

The toxins obtained from the Chinese bird spider Haplopelma hainanum showed antitumor activity in a liver cancer cell line, decreasing cell growth, mitochondrial membrane potential, in addition to stimulating the production of caspase 3 and 9 and inducing apoptosis through a dependent mitochondrial pathway [165165. Lian W, Lian H, Li Q, Hu A, Liu S. The venom of spider Haplopelma hainanum suppresses proliferation and induces apoptosis in hepatic cancer cells by caspase activation in vitro. J Ethnopharmacol. 2018 Oct 28;225:169-177. doi: 10.1016/j.jep.2018.06.022. PMID: 29928971.
https://doi.org/10.1016/j.jep.2018.06.02...
].

Scorpion venoms have been a promising target in cancer treatment, the most interesting being the long-chain toxins that act on K +, Cl-, and ion channels. For example, human breast cancer MCF-7 cells treated with Buthus matensii karsch toxin extract could induce apoptosis by producing caspase 3 and down-regulating Bcl-2. In in vitro studies, gonoearrestide, a peptide found in the fat-tailed scorpion Androctonus mauritanicus and A. australis, was able to kill neoplastic cells by arresting the cell cycle in the G1 phase due to inhibition of cyclin-dependent kinase 4 (CDK4) and increased cell expression of cycle regulators and inhibitors cyclin D3, p27, and p21 [166166. Li W, Li Y, Zhao Y, Yuan J, Mao W. Inhibition effects of scorpion venom extracts (Buthus matensii Karsch) on the growth of human breast cancer MCF-7 cells. Afr J Tradit Complement Altern Med. 2014 Aug 23;11(5):105-10. doi: 10.4314/ajtcam.v11i5.17. PMID: 25395713; PMCID: PMC4202526.
https://doi.org/10.4314/ajtcam.v11i5.17...
]. Also, this species' venom was able to block the cell cycle from the G0/G1 phase to the S phase [167167. Li B, Lyu P, Xi X, Ge L, Mahadevappa R, Shaw C, Kwok HF. Triggering of cancer cell cycle arrest by a novel scorpion venom-derived peptide-gonearrestide. J Cell Mol Med. 2018 Sep;22(9):4460-73. doi: 10.1111/jcmm.13745. PMID: 29993185; PMCID: PMC6111814.
https://doi.org/10.1111/jcmm.13745...
].

Chlorotoxin (Cltx) is found in the venom of the Palestine yellow scorpion Leiurus quinquestriatus. In vitro studies showed that Cltx binds to glioma cells without affecting normal cells; Cltx can bind endogenously to MMP-2 expressed in glioma cells, thus generating a loss of the gelatinase activity of the glioma and decreasing the expression of MMP2. PBITx1, extracted from the burrowing thick tail scorpion Parabuthus schlechteri, is a selective toxin of the Na+ channel and structurally similar to Cltx, suggesting that it could act on chloride channels and arrest cancer cells [168168. Mamelak AN, Rosenfeld S, Bucholz R, Raubitschek A, Nabors LB, Fiveash JB, Shen S, Khazaeli MB, Colcher D, Liu A, Osman M, Guthrie B, Schade-Bijur S, Hablitz DM, Alvarez VL, Gonda MA. Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J Clin Oncol. 2006 Aug 1;24(22):3644-50. doi: 10.1200/JCO.2005.05.4569. PMID: 16877732.
https://doi.org/10.1200/JCO.2005.05.4569...
-170170. Tytgat J, Debont T, Rostoll K, Müller GJ, Verdonck F, Daenens P, van der Walt JJ, Possani LD. Purification and partial characterization of a 'short' insectotoxin-like peptide from the venom of the scorpion Parabuthus schlechteri. FEBS Lett. 1998 Dec 28;441(3):387-91. doi: 10.1016/s0014-5793(98)01589-0. PMID: 9891977.
https://doi.org/10.1016/s0014-5793(98)01...
]. This synthesized peptide showed low toxicity in clinical trials, inhibiting angiogenesis, a possible candidate to combat gliomas [171 171. El-Ghlban S, Kasai T, Shigehiro T, Yin HX, Sekhar S, Ida M, Sanchez A, Mizutani A. Chlorotoxin-Fc fusion inhibits release of MMP-2 from pancreatic cancer cells. Biomed Res Int. 2014;2014:152659. doi: 10.1155/2014/152659. Epub 2014 Jan 6. PMID: 24511528; PMCID: PMC3910484.
https://doi.org/10.1155/2014/152659...
].

Work limitations

Arthropods comprise a large phylum of invertebrate animals, and their particular biological and ecological characteristics vary according to each species. It is worth mentioning that numerous species have bioactive peptides in their venoms with anti-inflammatory activity, as observed in studies conducted in vivo and in vitro. Thus, we selected certain arthropods groups that provided more publications related to the theme when inquiring databases. We expected the present review to glimpse the theme and attract the audience's attention to this exciting research topic. A limitation of the study is about some elusive mechanisms of action of venom peptides reported by different laboratories that can be further explored for peptide drug development. Despite this, a handful of information allowed describing the peptides' significant “anti-inflammatory effects” from venom components of numerous arthropod species.

Conclusion

Considerable diversity of bioactive molecules under investigation can be developed as therapeutic agents to treat numerous human diseases. Various research groups have studied different peptides identified in arthropod venoms to unravel their potential as anti-inflammatory agents. The selected examples listed herein comprise peptides found in the venom and hemolymph of diverse species of arthropods. Included in this review were arthropods related to insects (ants, bees, and wasps), crustaceans (shrimp and crabs), arachnids (scorpions and spiders), and chilopods (centipedes), all of them containing in their venom peptides with important anti-inflammatory activity. Peptides derived from arthropod venoms act on different inflammatory pathways, reducing pro-inflammatory cytokines both in in vitro and in vivo models. It is known that inflammation at an advanced stage can trigger malignant neoplasms and contribute to their exacerbation. Thus, multifunctional venom peptides that act on inflammatory pathways and pathways related to cancer deserve considerable attention in the present and future natural drug development programs. Consequently, arthropod venom peptides, which evolved over millions of years, comprise a rich source for discovering and developing peptides with potent pharmacological efficacy to treat inflammatory and malignant diseases. The disclosure of their specific mechanisms of action and application potential as therapeutic agents should continue in the years to come.

Abbreviations

ALF: anti-lipopolysaccharide factor; ALS: amyotrophic lateral sclerosis; BAX: BCL2-associated X protein; BCL: B-cell lymphoma; BV: bee venom therapy; CAT: catalase; CD: cluster of differentiation; CMO: scorpion oligopeptides; COX: cyclooxygenase; DBPs: disulfide-bridged peptides; DPPH: 2,2-diphenyl-1-picrylhydrazyl; ERK: extracellular signal-regulated kinase; FAZ: cell surface death receptor; FDA: U.S. Food and Drug Administration; FPR-2: formyl peptide receptor-2; ICAM-1: intercellular adhesion molecule 1; IFN- γ: interferon gama; IL-1: interleukin 1; IL-1β: interleukin beta; IL-4: interleukin 4; IL-6: interleukin 6; IL-8: interleukin 8; IL-10: interleukin 10; IL-13: interleukin 13; iNOS: nitric oxide-induced synthase; JNK: c-Jun N-terminal kinases; LALF: limulus anti-lipopolysaccharide factor; LPS-BD: lipopolysaccharide-binding domain; LPS: anti-lipopolysaccharide; M-ALF: marsupenaeus anti-lipopolysaccharide factor; MAP: mitogen-activated protein; MAPK: mitogen-activated protein kinase; MHC-II: major histocompatibility complex 2; MPC: monocyte chemoactive protein; MPO: myeloperoxidase; NDBPs: non-disulfide-bridged peptides; NF-kβ: nuclear factor kappa beta; PAM: antimicrobial peptides; PAMP: pathogen-associated molecular pattern; PRISMA: preferred reporting items for systematic reviews and meta-analysis; PGE: prostaglandin; PLA2: phospholipase A2; PtALF: portunus trituberculatus anti-lipopolysaccharide factor; SALF: shrimp anti-lipopolysaccharide factor; SOD: superoxide dismutase; TGF-β1: transforming growth factor-β1; TLR: toll-like receptor; TNF- α: nuclear transcription factor-alpha; TRAP1: transient receptor potential ankyrin; VCAM: vascular adhesion molecule; β-GPB: guanine nucleotide-binding protein subunit beta.

Acknowledgments

The authors would like to thank Arnold Wesly Cartagena (The Open University, United Kingdom) for the translation of this manuscript.

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  • Availability of data and materials

    Not applicable.
  • Funding

    This research received external funding from the Cearense Foundation for Scientific and Technological Development Support (FUNCAP), and the Coordination for the Improvement of Higher Education Personnel (CAPES).
  • Ethics approval

    Not applicable.
  • Consent for publication

    Not applicable

Publication Dates

  • Publication in this collection
    22 Oct 2021
  • Date of issue
    2021

History

  • Received
    02 Nov 2020
  • Accepted
    09 Apr 2021
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