Background: Scorpion neurotoxins such as those that modify the mammalian voltage-gated sodium ion channels (Nav) are the main responsible for scorpion envenomation. Their neutralization is crucial in the production of antivenoms against scorpion stings.
Methods: In the present study, two in silico designed genes - one that codes for a native neurotoxin from the venom of the Anatolian scorpion Androctonus crassicauda, named Acra 4 - and another non-native toxin - named consensus scorpion toxin (SccTx) obtained from the alignment of the primary structures of the most toxic neurotoxins from the Middle Eastern and North African scorpions - were recombinantly expressed in E. coli Origami.
Results: Following bacterial expression, the two expressed neurotoxins, hereafter named HisrAcra4 and HisrSccTx, were obtained from inclusion bodies. Both recombinant neurotoxins were obtained in multiple Cys-Cys isoforms. After refolding, the active protein fractions were identified with molecular masses of 8,947.6 and 9,989.1 Da for HisrAcra4 and HisrSccTx, respectively, which agreed with their expected theoretical masses. HisrAcra4 and HisrSccTx were used as antigens to immunize two groups of rabbits, to produce either anti-HisrAcra4 or anti-HisrSccTx serum antibodies, which in turn could recognize and neutralize neurotoxins from venoms of scorpion species from the Middle East and North Africa. The antibodies obtained from rabbits neutralized the 3LD50 of Androctonus australis, Leiurus quinquestriatus hebraeus and Buthus occitanus venoms, but they did not neutralize A. crassicauda and A. mauritanicus venoms. In addition, the anti-HisrAcra4 antibodies did not neutralize any of the five scorpion venoms tested. However, an antibody blend of anti-HisrAcra4 and anti-HisrSccTx was able to neutralize A. crassicauda and A. mauritanicus venoms.
Conclusions: Two recombinant Nav neurotoxins, from different peptide families, were used as antigens to generate IgGs for neutralizing scorpion venoms of species from the Middle East and North Africa.
Background: A combination of pharmacological and biomedical assays was applied in this study to examine the bioactivity of Conus virgo crude venom in order to determine the potential pharmacological benefit of this venom, and its in vivo mechanism of action.
Methods: Two doses (1/5 and 1/10 of LC50, 9.14 and 4.57 mg/kg) of the venom were used in pharmacological assays (central and peripheral analgesic, anti-inflammatory and antipyretic), while 1/2 of LC50 (22.85 mg/kg) was used in cytotoxic assays on experimental animals at different time intervals, and then compared with control and reference drug groups.
Results: The tail immersion time was significantly increased in venom-treated mice compared with the control group. Also, a significant reduction in writhing movement was recorded after injection of both venom doses compared with the control group. In addition, only the high venom concentration has a mild anti-inflammatory effect at the late inflammation stage. The induced pyrexia was also decreased significantly after treatment with both venom doses. On the other hand, significant increases were observed in lipid peroxidation (after 4 hours) and reduced glutathione contents and glutathione peroxidase activity, while contents of lipid peroxidation and nitric oxide (after 24 hours) and catalase activity were depleted significantly after venom administration.
Conclusion: These results indicated that the crude venom of Conus virgo probably contain bioactive components that have pharmacological activities with low cytotoxic effects. Therefore, it may comprise a potential lead compound for the development of drugs that would control pain and pyrexia.
A new concept of multisystem disease has emerged as a long-term condition following mild-severe COVID-19 infection. The main symptoms of this affection are breathlessness, chest pain, and fatigue. We present here the clinical case of four COVID-19 patients during hospitalization and 60 days after hospital discharge. Physiological impairment of all patients was assessed by spirometry, dyspnea score, arterial blood gas, and 6-minute walk test 60 days after hospital discharge, and computed tomographic scan 90 days after discharge. All patients had fatigue, which was not related to hypoxemia or impaired spirometry values, and interstitial lung alterations, which occurred in both mechanically ventilated and non-mechanically ventilated patients. In conclusion, identifying the prevalence and patterns of permanent lung damage is paramount in preventing and treating COVID-19-induced fibrotic lung disease. Additionally, and based on our preliminary results, it will be also relevant to establish long-term outpatient programs for these individuals.
Background: Snakebite envenoming can be a life-threatening condition, for which emergency care is essential. The Bothrops (lancehead) genus is responsible for most snakebite-related deaths and permanent loss of function in human victims in Latin America. Bothrops spp. venom is a complex mixture of different proteins that are known to cause local necrosis, coagulopathy, and acute kidney injury. However, the long-term effects of these viper envenomings have remained largely understudied.
Case presentation: Here, we present a case report of a 46-years old female patient from Las Claritas, Venezuela, who was envenomed by a snake from the Bothrops genus. The patient was followed for a 10-year period, during which she presented oliguric renal failure, culminating in kidney failure 60 months after the envenoming.
Conclusion: In Latin America, especially in Brazil, where there is a high prevalence of Bothrops envenoming, it may be relevant to establish long-term outpatient programs. This would reduce late adverse events, such as chronic kidney disease, and optimize public financial resources by avoiding hemodialysis and consequently kidney transplantation.
Background: The relationship between slow loris (Nycticebus spp.) venom (BGE protein) and the major cat allergen (Fel d 1) from domestic cat (Felis catus) is known for about two decades. Along this time, evidence was accumulated regarding convergences between them, including their almost identical mode of action.
Methods: Large-scale database mining for Fel d 1 and BGE proteins in Felidae and Nycticebus spp., alignment, phylogeny proposition and molecular modelling, associated with directed literature review were assessed.
Results: Fel d 1 sequences for 28 non-domestic felids were identified, along with two additional loris BGE protein sequences. Dimer interfaces are less conserved among sequences, and the chain 1 shows more sequence similarity than chain 2. Post-translational modification similarities are highly probable.
Conclusions: Fel d 1 functions beyond allergy are discussed, considering the great conservation of felid orthologs of this protein. Reasons for toxicity being found only in domestic cats are proposed in the context of domestication. The combination of the literature review, genome-derived sequence data, and comparisons with the venomous primate slow loris may point to domestic cats as potentially poisonous mammals.
Background: Certain environmental toxins permanently damage the thymic epithelium, accelerate immune senescence and trigger secondary immune pathologies. However, the exact underlying cellular mechanisms and pathways of permanent immune intoxication remain unknown. The aim of the present study was to demonstrate gene expressional changes of apoptosis-related cellular pathways in human thymic epithelial cells following exposure to snake venom from Bitis gabonica and Dendroaspis angusticeps.
Methods: Snake venoms were characterized by analytical methods including reversed phase high-performance liquid chromatography and sodium dodecyl sulphate-polyacrylamide gel electrophoresis, then applied on human thymic epithelial cells (1889c) for 24 h at 10 μg/mL (as used in previous TaqMan Array study). Gene expressional changes restricted to apoptosis were assayed by TaqMan Array (Human Apoptosis Plate).
Results: The most prominent gene expressional changes were shown by CASP5 (≈ 2.5 million-fold, confirmed by dedicated quantitative polymerase chain reaction) and CARD9 (0.016-fold) for B. gabonica, and BIRC7 (6.46-fold) and CASP1 (0.30-fold) for D. angusticeps.
Conclusion: The observed apoptotic environment suggests that pyroptosis may be the dominant pathway through which B. gabonica and D. angusticeps snake venoms trigger thymic epithelial apoptosis following envenomation.
Background: Resistance to apoptosis in chronic myeloid leukemia (CML) is associated with constitutive tyrosine kinase activity of the Bcr-Abl oncoprotein. The deregulated expression of apoptosis-related genes and alteration in epigenetic machinery may also contribute to apoptosis resistance in CML. Tyrosine kinase inhibitors target the Bcr-Abl oncoprotein and are used in CML treatment. The resistance of CML patients to tyrosine kinase inhibitors has guided the search for new compounds that may induce apoptosis in Bcr-Abl+ leukemic cells and improve the disease treatment.
Methods: In the present study, we investigated whether the L-amino acid oxidase isolated from Bothrops moojeni snake venom (BmooLAAO-I) (i) was cytotoxic to Bcr-Abl+ cell lines (HL-60.Bcr-Abl, K562-S, and K562-R), HL-60 (acute promyelocytic leukemia) cells, the non-tumor cell line HEK-293, and peripheral blood mononuclear cells (PBMC); and (ii) affected epigenetic mechanisms, including DNA methylation and microRNAs expression in vitro.
Results: BmooLAAO-I induced ROS production, apoptosis, and differential DNA methylation pattern of regulatory apoptosis genes. The toxin upregulated expression of the pro-apoptotic genes BID and FADD and downregulated DFFA expression in leukemic cell lines, as well as increased miR-16 expression - whose major predicted target is the anti-apoptotic gene BCL2 - in Bcr-Abl+ cells.
Conclusion: BmooLAAO-I exerts selective antitumor action mediated by H2O2 release and induces apoptosis, and alterations in epigenetic mechanisms. These results support future investigations on the effect of BmooLAAO-I on in vivo models to determine its potential in CML therapy.
Background: Acute kidney injury (AKI) is a frequent complication of snakebite envenomation, which is still little known in sub-Saharan Africa. This study aims to describe the clinical, biological and ultrasonographic aspects of AKI following severe snakebite envenomation managed in the intensive care unit.
Method: A prospective observational survey was performed in Benin over a period of 18 months. All patients suffering severe snakebite envenomation (SBE) were included. The diagnosis of AKI was made using the KDIGO criteria. Kidney ultrasound exam was performed in all patients to assess internal bleeding and morphological and structural abnormalities of the kidneys.
Results: Fifty-one cases of severe SBE were included. All patients presented inflammatory syndrome and showed abnormal WBCT whereas bleeding was found in 46 of them (90%). The median time to hospital presentation was three days. The majority of patients were male (M/F sex ratio = 1.55) and the median age was 26. Sixteen patients (31%) showed AKI according to the KDIGO criteria. Severe AKI (KDIGO stage 2 and 3) was observed in three patients, including one stage 2 and two stage 3. Kidney ultrasound revealed three cases of kidney capsular hematoma (6%), two cases of kidney hypertrophy (3%), three cases of kidney injury (4%), two stage 1 KDIGO and one stage 2 KDIGO. Only one patient benefited from hemodialysis. All patients showing AKI recovered without sequels. The median duration of hospital stays was four days. Seven patients died (14%) including four among the 16 AKI patients. Antivenom has been administered to 41 patients (80%). The comparison between patients without and with AKI did not show any significant difference except gender (p = 10-2).
Conclusion: AKI is a common complication of severe snakebite envenomation. Resulting from inflammatory and hemorrhagic disorders, AKI may prove to be a short-term life-threatening factor.
Background: Snake venom phospholipases A2 (svPLA2) are biologically active toxins, capable of triggering and modulating a wide range of biological functions. Among the svPLA2s, crotoxin (CTX) has been in the spotlight of bioprospecting research due to its role in modulating immune response and hemostasis. In the present study, novel anticoagulant mechanisms of CTX, and the modulation of inflammation-induced coagulation were investigated.
Methods: CTX anticoagulant activity was evaluated using platelet poor plasma (PPP) and whole blood (WB), and also using isolated coagulation factors and complexes. The toxin modulation of procoagulant and pro-inflammatory effects was evaluated using the expression of tissue factor (TF) and cytokines in lipopolysaccharide (LPS)-treated peripheral blood mononuclear cells (PBMC) and in WB.
Results: The results showed that CTX impaired clot formation in both PPP and WB, and was responsible for the inhibition of both intrinsic (TF/factor VIIa) and extrinsic (factor IXa/factor VIIIa) tenase complexes, but not for factor Xa and thrombin alone. In addition, the PLA2 mitigated the prothrombinase complex by modulating the coagulation phospholipid role in the complex. In regards to the inflammation-coagulation cross talk, the toxin was capable of reducing the production of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α, and was followed by decreased levels of TF and procoagulant activity from LPS-treated PBMC either isolated or in WB.
Conclusion: The results obtained in the present study recognize the toxin as a novel medicinal candidate to be applied in inflammatory diseases with coagulation disorders.
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