Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties.

Novel antibiotics are urgently needed to combat multidrug-resistant pathogens. Venoms represent previously untapped sources of novel drugs. Here we repurposed mastoparan-L, the toxic active principle derived from the venom of the wasp Vespula lewisii, into synthetic antimicrobials. We engineered within its N terminus a motif conserved among natural peptides with potent immunomodulatory and antimicrobial activities. The resulting peptide, mast-MO, adopted an α-helical structure as determined by NMR, exhibited increased antibacterial properties comparable to standard-of-care antibiotics both in vitro and in vivo, and potentiated the activity of different classes of antibiotics. Mechanism-of-action studies revealed that mast-MO targets bacteria by rapidly permeabilizing their outer membrane. In animal models, the peptide displayed direct antimicrobial activity, led to enhanced ability to attract leukocytes to the infection site, and was able to control inflammation. Permutation studies depleted the remaining toxicity of mast-MO toward human cells, yielding derivatives with antiinfective activity in animals. We demonstrate a rational design strategy for repurposing venoms into promising antimicrobials.

Wasp venom-induced acute kidney injury: current progress and prospects.

Wasp venom can trigger local and systemic reactions, with the kidneys being commonly affected, potentially causing acute kidney injury (AKI). Despite of the recent advances, our knowledge on the underlying mechanisms of toxicity and targeted therapies remain poor. AKI can result from direct nephrotoxic effects of the wasp venom or secondary rhabdomyolysis and intravascular hemolysis, which will release myoglobin and free hemoglobin. Inflammatory responses play a central role in these pathological mechanisms. Noteworthily, the successful establishment of a suitable experimental model can assist in basic research and clinical advancements related to wasp venom-induced AKI. The combination of therapeutic plasma exchange and continuous renal replacement therapy appears to be the preferred treatment for wasp venom-induced AKI. In addition, studies on cilastatin and varespladib for wasp venom-induced AKI treatment have shown their potential as therapeutic agents. This review summarizes the available evidence on the mechanisms and treatment of wasp venom-induced AKI, with a particular focus on the role of inflammatory responses and potential targets for therapeutic drugs, and, therefore, aiming to support the development of clinical treatment against wasp venom-induced AKI.

Macroscopic hematuria in wasp sting patients: a retrospective study.

BACKGROUND: Macroscopic hematuria after wasp sting has been reported in Asia to occur before acute kidney injury (AKI), and is often used by clinicians as a sign indicating the need for intensive care and blood purification therapy. However, there is no study on the clinical characteristics and prognosis of this symptom. METHODS: The clinical data of 363 patients with wasp sting admitted to Suining Central Hospital from January 2016 to December 2018 were retrospectively analyzed. At admission, the poisoning severity score (PSS) was used as the criterion for severity classification. According to the presence of macroscopic hematuria, the patients were divided into macroscopic hematuria and non-macroscopic hematuria group. RESULTS: Of the 363 wasp sting patients, 219 were male and 144 were female, with a mean age of 55.9 ± 16.3 years. Fifty-one (14%) had macroscopic hematuria, 39 (10.7%) had AKI, 105 (28.9%) had rhabdomyolysis, 61 (16.8%) had hemolysis, 45 (12.4%) went on to received hemodialysis, and 14 (3.9%) died. The incidence of AKI in macroscopic hematuria group was 70.6%, and oliguric renal failure accounted for 72.2%. Patients with macroscopic hematuria had significantly higher PSS (2.2 ± 0.5 vs. 1.1 ± 0.3, p < .001). CONCLUSION: Macroscopic hematuria can be regarded as a surrogate marker of deteriorating clinical outcome following wasp stings. In wasp sting patients with symptoms of macroscopic hematuria or serum LDH higher than 463.5 u/L upon admission, the risk of AKI increases significantly, therefore hemodialysis should be considered. The PSS is helpful in early assessment of the severity of wasp sting patients.

Effect of natural toxins and adipokinetic hormones on the activity of digestive enzymes in the midgut of the cockroach Periplaneta americana.

This study examined the effect of two natural toxins (a venom from the parasitic wasp Habrobracon hebetor and destruxin A from the entomopathogenic fungus Metarhizium anisopliae), and one pathogen (the entomopathogenic fungus Isaria fumosorosea) on the activity of basic digestive enzymes in the midgut of the cockroach Periplaneta americana. Simultaneously, the role of adipokinetic hormones (AKH) in the digestive processes was evaluated. The results showed that all tested toxins/pathogens elicited stress responses when applied into the cockroach body, as documented by an increase of AKH level in the central nervous system. The venom from H. hebetor showed no effect on digestive enzyme activities in the ceca and midgut in vitro. In addition, infection by I. fumosorosea caused a decrease in activity of all enzymes in the midgut and a variable decrease in activity in the ceca; application of AKHs did not reverse the inhibition. Destruxin A inhibited the activity of all enzymes in the midgut but none in the ceca in vitro; application of AKHs did reverse this inhibition, and no differences between both cockroach AKHs were found. Overall, the results demonstrated the variable effect of the tested toxins/pathogens on the digestive processes of cockroaches as well as the variable ability of AKH to counteract these effects.

Parasitism and venom of ectoparasitoid Scleroderma guani impairs host cellular immunity.

Venom is a prominently maternal virulent factor utilized by parasitoids to overcome hosts immune defense. With respect to roles of this toxic mixture involved in manipulating hosts immunity, great interest has been mostly restricted to Ichneumonoidea parasitoids associated with polydnavirus (PDV), of which venom is usually considered as a helper component to enhance the role of PDV, and limited Chalcidoidea species. In contrast, little information is available in other parasitoids, especially ectoparasitic species not carrying PDV. The ectoparasitoid Scleroderma guani injects venom into its host, Tenebrio molitor, implying its venom was involved in suppression of hosts immune response for successful parasitism. Thus, we investigated the effects of parasitism and venom of this parasitoid on counteracting the cellular immunity of its host by examining changes of hemocyte counts, and hemocyte spreading and encapsulation ability. Total hemocyte counts were elevated in parasitized and venom-injected pupae. The spreading behavior of both granulocytes and plasmatocytes was impaired by parasitization and venom. High concentration of venom led to more severely increased hemocyte counts and suppression of hemocyte spreading. The ability of hemocyte encapsulation was inhibited by venom in vitro. In addition to immediate effects observed, venom showed persistent interference in hosts cellular immunity. These results indicate that venom alone from S. guani plays a pivotal role in blocking hosts cellular immune response, serving as a regulator that guarantees the successful development of its progenies. The findings provide a foundation for further investigation of the underlying mechanisms in immune inhibitory action of S. guani venom.

The Cytotoxic Effects of Camptothecin and Mastoparan on the Unicellular Green Alga Chlamydomonas reinhardtii.

We have recently reported that protease inhibitors affecting the activity of the proteasome cause necrotic cell death in Chlamydomonas reinhardtii instead of inducing apoptosis as shown for some mammalian cell lines. Therefore, we have studied other well-known inducers of apoptosis in mammalian cells for their effects on C. reinhardtii cells. Mastoparan caused rapid cell death without a prominent lag-phase under all growth conditions, whereas the cytotoxic effect of the topoisomerase I inhibitor camptothecin exclusively occurred during the cell-division phase. Essentially no differences between wall-deficient and wild-type cells were observed with respect to dose-response and time-course of camptothecin and mastoparan. In cultures of the wall-deficient strain, cell death was accompanied by swelling and subsequent disruption of the cells, established markers of necrosis. In case of the wild-type strain, camptothecin and mastoparan caused accumulation of apparently intact, but dead cells instead of cell debris due to the presence of the wall. Both in cultures of the wall-deficient and the wild-type strains, cell death was accompanied by an increase of the protein concentration in the culture medium indicating a lytic process like necrosis. Taking together, we have severe doubts on the existence of an apoptotic program in case of C. reinhardtii.

Isolation and chemical characterization of agelaiatoxin8 (AvTx8) from Agelaia vicina wasp venom and its biological effects on GABA neurotransmission.

Arthropod venoms are sources of molecules that may be useful tools to investigate molecular mechanisms of putative new medicines and laboratory drugs. Here we show the effects of the compound agelaiatoxin-8 (AVTx8), isolated from Agelaia vicina venom, on γ-aminobutyric acid (GABA) neurotransmission in rat brain synaptosomes. Analysis reveals that AvTx8 is composed by 14 amino acid residues with a molecular weight (MW) of 1567 Da. AvTx8 increased GABA release and inhibited GABA uptake in synaptosomes from rat cerebral cortex. AvTx8 inhibited GABA uptake and increased GABA release in the presence of Ca+ , Na+ , and K+ channel blockers, suggesting that it acts directly on GABA transporters. In addition, AvTx8 significantly decreases GABA binding in synaptic membranes from rat brain cortex, suggesting that it also modulates the activity of GABA receptors. Moreover, AvTx8 decreased GAT-1- and GAT-3-mediated GABA uptake in transfected COS-7 cells. Accordingly, we suggest that AvTx8 modulates GABA neurotransmission and might provide a novel entry point for identifying a new class of GABA-modulating neuroprotective drugs.

The role and mechanism of NLRP3 in wasp venom-induced acute kidney injury.

BACKGROUND: Inflammation and pyroptosis have crucial impacts on the development of acute kidney injury (AKI) and have been validated in a variety of existing AKI animal models. However, the mechanisms underlying wasp venom-induced AKI are still unclear. The involvement of nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) in some mouse models of AKI has been extensively documented, and its crucial function in controlling inflammation and pyroptosis has been highlighted. The objective of our study was to investigate the role and mechanism of NLRP3 in inflammation and pyroptosis associated with wasp venom-induced AKI. METHODS: A mouse model of AKI induced by wasp venom pre-injected with an NLRP3 inhibitor was used to study the role and mechanism of NLRP3. To verify the importance of NLRP3, western blotting was performed to assess the expression of NLRP3, caspase-1 p20, and gasdermin D (GSDMD)-N. Additionally, quantitative real-time polymerase was used to determine the expression of NLRP3, caspase-1, and GSDMD. Furthermore, enzyme-linked immunosorbent assay was utilized to measure the levels of interleukin (IL)-1ß and IL-18. RESULTS: NLRP3 was found to be the downstream signal of the stimulator of interferon genes in the wasp sting venom-induced AKI model. The administration of wasp venom in mice significantly upregulated the expression of NLRP3, leading to renal dysfunction, inflammation, and pyroptosis. Treatment with an NLRP3 inhibitor reversed the renal damage induced by wasp venom and attenuated pathological injury, inflammatory response, and pyroptosis. CONCLUSION: NLRP3 activation is associated with renal failure, inflammatory response and pyroptosis in the hyper early phase of wasp venom-induced AKI. The inhibition of NLRP3 significantly weakened this phenomenon. These findings could potentially offer a viable therapeutic approach for AKI triggered by wasp venom.

Modulation of response to braconid wasp venom by adipokinetic hormone in Drosophila melanogaster.

The minute wasp Habrobracon hebetor venom (HH venom) is a potent cocktail of toxins that paralyzes the victim's muscles and suppresses humoral and cellular immunity. This study examined the effect of HH venom on specific biochemical, physiological, and ultrastructural characteristics of the thoracic and nervous (CNS) tissues of Drosophila melanogaster under in vitro conditions. Venom treatment modulated the activities of superoxide dismutase (SOD) and catalase (CAT), endogenous Drome-AKH level, and affected the relative viability of the cells. Additionally, it reduced the expression of genes related to the immune system in the CNS, including Keap1, Relish, Nox, Eiger, Gadd45, and Domeless, as well as in the thoracic muscles, except for Nox. Besides, venom treatment led to deteriorative changes in the ultrastructure of muscle cells, particularly affecting the mitochondria. When venom and Drosophila melanogaster-adipokinetic hormone (Drome-AKH) were applied together, the effects of the venom alone were often modulated. The harmful effect of the venom on SOD activity was relatively reduced and the activity returned to a level similar to that of the control. In the CNS, the simultaneous application of venom and hormones abolished the suppression of previously reported immune-related genes (except for Gadd45), whereas in the muscles, this was only true for Eiger. Additionally, Drome-AKH restored cell structure to a level comparable to that of the control and lessened the harmful effects of HH venom on muscle mitochondria. These findings suggest a general body response of D. melanogaster to HH venom and a partial defensive role of Drome-AKH in this process.

Venom of the ectoparasitoid, Nasonia vitripennis, influences gene expression in Musca domestica hemocytes.

Insect hosts have evolved potent innate immunity against invasion by parasitoid wasps. Host/parasitoids live in co-evolutionary relationships. Nasonia vitripennis females inject venom into their dipteran hosts just prior to laying eggs on the host's outer integument. The parasitoid larvae are ectoparasitoids because they feed on their hosts within the puparium, but do not enter the host body. We investigated the influence of N. vitripennis venom on the gene expression profile of hemocytes of their hosts, pupae of the housefly, Musca domestica. We prepared venom by isolating venom glands and treated experimental host pupae with venom. We used suppression subtractive hybridization (SSH) to determine the influence of venom on hemocyte gene expression. At 1 h post treatment, we recorded decreases in transcript levels of 133 EST clones derived from forward a subtractive library of host hemocytes and upregulation in transcript levels of 111 EST clones from the reverse library. These genes are related to immune and stress response, cytoskeleton, cell cycle and apoptosis, metabolism, transport, and transcription/translation regulation. We verified the reliability of our data with reverse transcription quantitative real-time PCR analysis of randomly selected genes, and with assays of enzyme activities. These analyses showed that the expression level of all selected genes were downregulated after venom treatment. Outcomes of our experiments support the hypothesis that N. vitripennis venom influences the gene expression in host hemocytes. We conclude that the actions of venom on host gene expression influence host biology in ways that benefit the development and emergence of the next generation of parasitoids.

Wasp venom allergy: effect of anti-IgE antibody on wasp venom anaphylaxis in a mouse model.

BACKGROUND: Although anti-IgE antibody (Ab) therapy was recently shown to be effective in patients with bronchial asthma, no study has reported the effect of IgE therapy in the prevention of wasp venom anaphylaxis. In this study, we used a mouse model of wasp venom allergy to investigate the effect of anti-IgE Ab on wasp venom anaphylaxis. METHODS: We developed a mouse model of wasp venom allergy by intraperitoneally (i.p.) injecting wasp venom into BALB/c mice twice on experimental day (day) 0 and 7. On day 20, a group of mice received an i.p. injection of mouse anti-IgE Ab as a pretreatment, and another group received rat anti-IgG1 Ab. On day 21, the animals were challenged by i.p. injection of wasp venom, and 30 min later, body temperature was measured and serum levels of leukotriene (LT) B4 and LTC4 were determined using enzyme immunoassay. RESULTS: The body temperature of mice treated with anti-IgE Ab and controls before and after wasp venom challenge was 37.8±0.2 vs 37.7± 0.3°C before challenge and 37.8±0.2 vs 37.1± 0.3°C after challenge, respectively, showing that anti-IgE Ab treatment significantly prevented body temperature from falling (p <0.05). Furthermore, anti-IgE Ab treatment reduced total serum IgE levels in the treated mice (42.2±15.9 pg/ml), compared with controls (105.9±23.1 pg/ml, p <0.05), and inhibited the secretion of LTC4 in the treated mice (32.0±18.8 pg/ml), but not in the controls (162.4±12.4 pg/ml, p <0.05), following challenge with wasp venom. CONCLUSION: The results of the present study indicate that anti-IgE Ab treatment is an effective preventive measure against wasp venom-induced anaphylaxis.

[Toxicology of Hymenoptera venoms]. / Wlasciwosci jadów blonkówek (Hymenoptera).

Hymenoptera venom is a secretion of special poison glands of insects. It serves both as a defensive substance against aggressors, as well as weapon used to paralyze the victim during gaining food. Chemically, the venom is a mixture of biologically active substances of high-, medium-, and small molecular weight with a variety of physiological functions. Individual substances may have toxic effects on stung human contributing to certain clinical signs and symptoms of venom poisoning. In the present paper, chemical structure, physiological role and toxicity of particular components of Hymenoptera venom are described.

Megalin blockade with cilastatin ameliorates multiple wasp sting-induced acute kidney injury in rats.

Cilastatin has been shown to prevent various drug-induced nephrotoxicities and confer renoprotection in a mouse model of glycerol-mediated rhabdomyolysis-induced acute kidney injury (AKI). The present study aimed to investigate whether cilastatin attenuates wasp sting-induced AKI in rats. Male Wistar rats were divided into the control, cilastatin, AKI, and AKI + cilastatin groups. Nephrotoxicity was assessed using renal function, rhabdomyolysis (creatine kinase, CK) and intravascular hemolysis (lactate dehydrogenase, LDH) markers, and histological changes. In addition, tubular injury biomarkers, apoptosis, oxidative stress markers, complement C3 expression, and urine and blood myoglobin levels were examined. Compared with the control or cilastatin group, the AKI group showed significant histological damage, increased levels of CK, LDH, and creatinine, and increased mRNA expression of tubular injury biomarkers. Cilastatin ameliorated wasp venom-induced kidney injury by attenuating oxidative stress and apoptosis. Cilastatin also reduced C3 expression in the renal tubular cells. In addition, cilastatin reduced serum myoglobin levels and increased urine myoglobin concentrations. Therefore, megalin blockade with cilastatin attenuates wasp venom-induced AKI owing to its antioxidative and antiapoptotic properties.

A parasitoid wasp manipulates the drive for walking of its cockroach prey.

The parasitoid wasp A. compressa hunts cockroaches as a live food supply for its offspring. The wasp selectively injects venom into the cerebral ganglia of the prey to induce long-term hypokinesia [1-5], during which the stung cockroach, although not paralyzed, does not initiate spontaneous walking and fails to escape aversive stimuli. This allows the wasp to grab the cockroach by the antenna and walk it to a nest much like a dog on a leash. There, the wasp lays an egg on the prey, seals the nest, and leaves. The stung cockroach, however, does not fight to escape its tomb but rather awaits its fate, being consumed alive by the hatching larva over several days. We investigated whether the venom-induced hypokinesia is a result of an overall decrease in arousal or, alternatively, a specific decrease in the drive to initiate or maintain walking. We found that the venom specifically affects both the threshold for the initiation and the maintenance of walking-related behaviors. Nevertheless, the walking pattern generator itself appears to be intact. We thus report that the venom, rather than decreasing overall arousal, manipulates neuronal centers within the cerebral ganglia that are specifically involved in the initiation and maintenance of walking.

Cell-penetrating peptides, PepFects, show no evidence of toxicity and immunogenicity in vitro and in vivo.

Cell-penetrating peptide based vehicles have been developed for the delivery of different payloads into the cells in culture and in animals. However, several biological features, among which is the tendency to trigger innate immune response, limit the development of highly efficient peptide-based drug delivery vectors. This study aims to evaluate the influence of transportan 10 (TP10) and its chemically modified derivatives, PepFects (PFs), on the innate immune response of the host system. PFs have shown high efficiency in nucleic acid delivery in vitro and in vivo; hence, the estimation of their possible toxic side effects would be of particular interest. In this study, we analyzed cytotoxic and immunogenic response of PF3, PF4, and PF6 peptides in monocytic leukemia and peripheral blood mononuclear cell lines. In comparison with amphipathic PFs, TP10, TAT, stearyl-(RxR)(4) peptides, and the most widely used transfection reagents Lipofectamine 2000 and Lipofectamine RNAiMAX were also analyzed in this study. IL-1ß, IL-18, and TNF-α cytokine release was detected using highly sensitive enzyme-linked immunosorbent assay (ELISA). Cell viability was detected by measuring the activity of cellular enzymes that reduce water-soluble tetrazolium salts to formazan dyes and apoptosis was evaluated by measuring the levels of caspase-1 and caspase-3/7 over untreated cells. All peptides were found to be nontoxic and nonimmunogenic in vitro at the concentrations of 10 µM and 5 µM, respectively, and at a dose of 5 mg/kg in vivo, suggesting that these CPPs exhibit a promising potential in the delivery of therapeutic molecules into the cell without risks of toxicity and inflammatory reactions.

Inhibitory effect of ganglioside on mastoparan-induced cytotoxicity and degranulation in lipid raft of connective tissue type mast cell.

Antihistamine, the most important drug for Hymenoptera stinging, cannot attenuate cytotoxicity and mast cell direct activation by mastoparan that is the most abundant polypeptides in the venoms of social wasps. The aim of this study was to investigate whether gangliosides inhibit the effect of mastoparan on mast cells activation. The degranulation and cytotoxicity in canine cutaneous mastocytoma cells (CM-MC) were done by measurement of ß-hexosaminidase release and MTT assay. Lipid raft was isolated with discontinuous sucrose gradient centrifuge for the analysis of distribution of Gα(q) and Gα(i) protein by western blotting. We found that mastoparan induced the degranulation in (CM-MC) via direct activation of Gα(i) and Gα(q) with a decrease in their amount in lipid raft. Ganglioside G(D1a) (disialoganglioside) and G(M1) (monosialoganglioside) strongly reduced the degranulation and cytotoxicity through stabilizing the structure of lipid raft domain. In addition, mastoparan generated intracellular reactive oxygen species (ROS) independently from cytotoxicity, through arachidonic cascade but not G-protein activations. Crude wasp venom showed cytotoxicity and induction of the release from CM-MC, which were potently reduced by gangliosides. We show here that mastoparan activates both Gα(i) and Gα(q) protein and that the exogenous ganglioside G(D1a) and G(M1) inhibit the degranulation and cytotoxicity through stabilizing lipid raft. Gangliosides have potentials to be therapeutic tool or clinical prophylaxis for wasp stinging.

Pro-inflammatory response induced by the venom of Parachartergus fraternus wasp.

The sting of different wasp species triggers local and systemic reactions in victims that can lead to death. Parachartergus fraternus is responsible for frequent accidents in Latin America; however, few studies have been conducted on this insect and its venom. In this study, the inflammatory process induced by the venom of the P. fraternus wasp (Pfv; 100, 200, and 400 µg/kg) was characterized. Mice were used to assess paw edema, vascular permeability, mast cell degranulation, leukocyte influx, nitric oxide (NO) production, expression of inflammatory genes, and histopathological changes. Pfv triggered edema formation with a peak dose of 200 µg/kg at 10 min. There was an increase in permeability in all periods and doses evaluated, with no differences between them. The 200 µg/kg dose induced mast cell degranulation in all periods, with a peak at 15 min. This same dose induced leukocyte influx with a predominance of mononuclear cells and triggered a peak in NO production in the 12th hour. The increase in COX-2, iNOS, and IFN-γ mRNA expression occurred after 1 and 6 h, and there was an increase in IL-10 expression after 48 h. In addition, Pfv triggered edema and induced an influx of macrophages and mast cells into the injection site. Therefore, Pfv induces an inflammatory process from the first 5 min of inoculation that can persist for up to 48 h.

Comprehensive Analysis and Biological Characterization of Venom Components from Solitary Scoliid Wasp Campsomeriella annulata annulata.

Venoms of solitary wasps are utilized for prey capture (insects and spiders), paralyzing them with a stinger injection to be offered as food for their larvae. Thus, the identification and characterization of the components of solitary wasp venoms can have biotechnological application. In the present study, the venom components profile of a solitary scoliid wasp, Campsomeriella annulata annulata, was investigated through a comprehensive analysis using LC-MS and -MS/MS. Online mass fingerprinting revealed that the venom extract contains 138 components, and MS/MS analysis identified 44 complete sequences of the peptide components. The peptides are broadly divided into two classes: bradykinin-related peptides, and linear α-helical peptides. Among the components of the first class, the two main peptides, α-campsomerin (PRLRRLTGLSPLR) and ß-campsomerin (PRLRRLTGLSPLRAP), had their biological activities evaluated. Both peptides had no effects on metallopeptidases [human neprilysin (NEP) and angiotensin-converting enzyme (ACE)] and acetylcholinesterase (AChE), and had no cytotoxic effects. Studies with PC12 neuronal cells showed that only α-campsomerin was able to enhance cell viability, while ß-campsomerin had no effect. It is noteworthy that the only difference between the primary structures from these peptides is the presence of the AP extension at the C-terminus of ß-campsomerin, compared to α-campsomerin. Among the linear α-helical peptides, annulatin (ISEALKSIIVG-NH2) was evaluated for its biological activities. Annulatin showed histamine releasing activity from mast cells and low hemolytic activity, but no antimicrobial activities against all microbes tested were observed. Thus, in addition to providing unprecedented information on the whole components, the three peptides selected for the study suggest that molecules present in solitary scoliid wasp venoms may have interesting biological activities.

Biological and Inflammatory Effects of Antigen 5 from Polybia paulista (Hymenoptera, Vespidae) Venom in Mouse Intraperitoneal Macrophages.

The social wasp Polybia paulista (Hymenoptera, Vespidae) is highly aggressive, being responsible for many medical occurrences. One of the most allergenic components of this venom is Antigen 5 (Poly p 5). The possible modulation of the in vitro immune response induced by antigen 5 from P. paulista venom, expressed recombinantly (rPoly p 5), on BALB/c mice peritoneal macrophages, activated or not with LPS, was assessed. Here, we analyzed cell viability changes, expression of the phosphorylated form of p65 NF-κB subunit, nitric oxide (NO), proinflammatory cytokines production, and co-stimulatory molecules (CD80, CD86). The results suggest that rPoly p 5 does not affect NO production nor the expression of co-stimulatory molecules in mouse peritoneal macrophages. On the other hand, rPoly p 5 induced an increase in IL-1ß production in non-activated macrophages and a reduction in the production of TNF-α and MCP-1 cytokines in activated macrophages. rPoly p 5 decreased the in vitro production of the phosphorylated p65 NF-κB subunit in non-activated macrophages. These findings suggest an essential role of this allergen in the polarization of functional M2 macrophage phenotypes, when analyzed in previously activated macrophages. Further investigations, mainly in in vivo studies, should be conducted to elucidate Polybia paulista Ag5 biological role in the macrophage functional profile modulation.

Sweet as honey, bitter as bile: Mitochondriotoxic peptides and other therapeutic proteins isolated from animal tissues, for dealing with mitochondrial apoptosis.

Mitochondria are subcellular organelles involved in cell metabolism and cell life-cycle. Their role in apoptosis regulation makes them an interesting target of new drugs for dealing with cancer or rare diseases. Several peptides and proteins isolated from animal and plant sources are known for their therapeutic properties and have been tested on cancer cell-lines and xenograft murine models, highlighting their ability in inducing cell-death by triggering mitochondrial apoptosis. Some of those molecules have been even approved as drugs. Conversely, many other bioactive compounds are still under investigation for their proapoptotic properties. In this review we report about a group of peptides, isolated from animal venoms, with potential therapeutic properties related to their ability in triggering mitochondrial apoptosis. This class of compounds is known with different names, such as mitochondriotoxins or mitocans.