International Journal of Biological Macromolecules, May 1, 2021
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
The venom from the scorpion Tityus serrulatus (Ts) has been extensively studied mainly because of... more The venom from the scorpion Tityus serrulatus (Ts) has been extensively studied mainly because of its rich cocktail of neurotoxins. Neurotoxins are the major and the most known components based on their modulation of voltage-gated ion channels. Until now, electrophysiological studies demonstrated that the Ts venom comprises toxins that affect Nav and Kv channels. However, although many studies have been conducted in this field, many peptides from Ts venom await further studies, including Ts8 toxin. Here we report the isolation and electrophysiological study of Ts8. The toxin Ts19 Frag-II was used as negative control. Ts8 demonstrates, among 20 tested channels, to be a selective modulator of Kv4.2 channels. Based on studies investigating the involvement of Kv4.2 on controlling nociception, we further investigated the modulation of pain by Ts8. Using intraplantar injections, Ts8 induced overt nociception (licking and lifting behaviors) and decreased the mechanical nociceptive threshold (hyperalgesia). Furthermore, the hyperalgesia was prolonged when intrathecal injections were performed. Independent of the severity, most of the victims stung by Ts scorpions report an intense and persistent pain as the major manifestation. The new role of Ts8 on nociception could explain, at least partially, this phenomenon. Additionally, our study also stresses the involvement of toxins specific to Nav channels and inflammatory mediators on the Ts painful sting. This work provides useful insights for a better understanding of the prolonged and intense pain associated with Ts envenoming for the development of specific therapies.
Animal-derived venoms are complex mixtures of toxins triggering important biological effects duri... more Animal-derived venoms are complex mixtures of toxins triggering important biological effects during envenomings. Although venom-derived toxins are known for their potential of causing harm to victims, toxins can also act as pharmacological agents. During the COVID-19 pandemic, there was observed an increase in in-depth studies on antiviral agents, and since, to date, there has been no completely effective drug against the global disease. This review explores the crosstalk of animal toxins and COVID-19, aiming to map potential therapeutic agents derived from venoms (e.g., bees, snakes, scorpions, etc.) targeting COVID-19.
Antibiotics are often administered with antivenom following snakebite envenomings in order to avo... more Antibiotics are often administered with antivenom following snakebite envenomings in order to avoid secondary bacterial infections. However, to this date, no studies have evaluated whether antibiotics may have undesirable potentiating effects on snake venom. Herein, we demonstrate that four commonly used antibiotics affect the enzymatic activities of proteolytic snake venom toxins in two different in vitro assays. Similar findings in vivo could have clinical implications for snakebite management and require further examination.
Neutrophil extracellular traps (NETs) are an important mechanism for defense against pathogens. T... more Neutrophil extracellular traps (NETs) are an important mechanism for defense against pathogens. Their overproduction can be harmful since excessive NET formation promotes inflammation and tissue damage in several diseases. Nucleases are capable to degrade NET on basis of their DNA hydrolysis activity, including the CdcPDE, a nuclease isolated from Crotalus durissus collilineatus snake venom. Here, we report a new finding about CdcPDE activity, demonstrating its efficiency in degrading cell-free DNA from NETs, being a potential candidate to assist in therapies targeting inflammatory diseases.
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
cosmeceuticals and atypical therapies (bee venom and leech therapies) are also reported. The leve... more cosmeceuticals and atypical therapies (bee venom and leech therapies) are also reported. The level of cumulative and detailed information provided in this review may help pharmacists, physicians, biotechnologists, pharmacologists, and scientists interested in toxinology, drug discovery, and development of toxin-based products.
The biological activity of Rhinella icterica parotoid secretion (RIPS) and some of its chromatogr... more The biological activity of Rhinella icterica parotoid secretion (RIPS) and some of its chromatographic fractions (RI18, RI19, RI23, and RI24) was evaluated in the current study. Mass spectrometry of these fractions indicated the presence of sarmentogenin, argentinogenin, (5β,12β)-12,14-dihydroxy-11-oxobufa-3,20,22-trienolide, marinobufagin, bufogenin B, 11α,19-dihydroxy-telocinobufagin, bufotalin, monohydroxylbufotalin, 19-oxo-cinobufagin, 3α,12β,25,26-tetrahydroxy-7-oxo-5β-cholestane-26-O-sulfate, and cinobufagin-3-hemisuberate that were identified as alkaloid and steroid compounds, in addition to marinoic acid and N-methyl-5-hydroxy-tryptamine. In chick brain slices, all fractions caused a slight decrease in cell viability, as also seen with the highest concentration of RIPS tested. In chick biventer cervicis neuromuscular preparations, RIPS and all four fractions significantly inhibited junctional acetylcholinesterase (AChE) activity. In this preparation, only fraction RI23 compl...
Scorpion venom may cause severe medical complications and untimely death if injected into the hum... more Scorpion venom may cause severe medical complications and untimely death if injected into the human body. Neurotoxins are the main components of scorpion venom that are known to be responsible for the pathological manifestations of envenoming. Besides neurotoxins, a wide range of other bioactive molecules can be found in scorpion venoms. Advances in separation, characterization, and biotechnological approaches have enabled not only the development of more effective treatments against scorpion envenomings, but have also led to the discovery of several scorpion venom peptides with interesting therapeutic properties. Thus, scorpion venom may not only be a medical threat to human health, but could prove to be a valuable source of bioactive molecules that may serve as leads for the development of new therapies against current and emerging diseases. This review presents both the detrimental and beneficial properties of scorpion venom toxins and discusses the newest advances within the dev...
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Journal of Venomous Animals and Toxins including Tropical Diseases, 2018
Background: In recent decades, snake venom disintegrins have received special attention due to th... more Background: In recent decades, snake venom disintegrins have received special attention due to their potential use in anticancer therapy. Disintegrins are small and cysteine-rich proteins present in snake venoms and can interact with specific integrins to inhibit their activities in cell-cell and cell-ECM interactions. These molecules, known to inhibit platelet aggregation, are also capable of interacting with certain cancer-related integrins, and may interfere in important processes involved in carcinogenesis. Therefore, disintegrin from Crotalus durissus collilineatus venom was isolated, structurally characterized and evaluated for its toxicity and ability to interfere with cell proliferation and migration in MDA-MB-231, a human breast cancer cell line. Methods: Based on previous studies, disintegrin was isolated by FPLC, through two chromatographic steps, both on reversed phase C-18 columns. The isolated disintegrin was structurally characterized by Tris-Tricine-SDS-PAGE, mass spectrometry and N-terminal sequencing. For the functional assays, MTT and wound-healing assays were performed in order to investigate cytotoxicity and effect on cell migration in vitro, respectively. Results: Disintegrin presented a molecular mass of 7287.4 Da and its amino acid sequence shared similarity with the disintegrin domain of P-II metalloproteases. Using functional assays, the disintegrin showed low cytotoxicity (15% and 17%, at 3 and 6 μg/mL, respectively) after 24 h of incubation and in the wound-healing assay, the disintegrin (3 μg/mL) was able to significantly inhibit cell migration (24%, p < 0.05), compared to negative control. Conclusion: Thus, our results demonstrate that non-RGD disintegrin from C. d. collilineatus induces low cytotoxicity and inhibits migration of human breast cancer cells. Therefore, it may be a very useful molecular tool for understanding ECM-cell interaction cancer-related mechanisms involved in an important integrin family that highlights molecular aspects of tumorigenesis. Also, non-RGD disintegrin has potential to serve as an agent in anticancer therapy or adjuvant component combined with other anticancer drugs.
International Journal of Biological Macromolecules, 2019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Snake venom L-amino acid oxidases (svLAAOs) are an interesting class of enzymes with important bi... more Snake venom L-amino acid oxidases (svLAAOs) are an interesting class of enzymes with important biological activities. Their participation in key metabolic processes, including pathological disorders, suggest that svLAAOs are potential lead compounds in drug discovery. However, their short-term stability defies their applications. This paper describes the stability studies together with functional and structural characterization of the LAAO bordonein-L. It has 498 amino acid residues, one N-glycosylation site and two disulfide bonds, revealed by high-resolution MS/MS. Molecular modeling approach showed its monomer folds into three conserved domains: FAD, substrate and helical domains. Differential scanning fluorimetry showed the enzyme tends to destabilize from neutral to basic pHs and in presence of mono/bivalent ions and it is highly stabilized by acid pHs and its substrates. However, high concentrations of L-amino acids decrease bordonein-L enzyme activity. Dynamic light scattering revealed bordonein-L remains in the dimeric and monodisperse form, so aggregation does not cause the rapidly decrease of enzyme activity. In vitro, the enzyme exhibited cytotoxicity against fibroblast cell line and killed Leishmania amazonensis promastigotes, intensified by substrate addition. Concluding, our results provide biochemistry and biophysical insights to improve LAAOs stability and better approaches to long-term storage. Moreover, our study emphasizes the importance of proper buffers choice mainly in cell-based assays.
Journal of Venomous Animals and Toxins including Tropical Diseases, 2019
Scorpion venoms are natural sources of molecules that have, in addition to their toxic function, ... more Scorpion venoms are natural sources of molecules that have, in addition to their toxic function, potential therapeutic applications. In this source the neurotoxins can be found especially those that act on potassium channels. Potassium channels are responsible for maintaining the membrane potential in the excitable cells, especially the voltagedependent potassium channels (Kv), including Kv1.3 channels. These channels (Kv1.3) are expressed by various types of tissues and cells, being part of several physiological processes. However, the major studies of Kv1.3 are performed on T cells due its importance on autoimmune diseases. Scorpion toxins capable of acting on potassium channels (KTx), mainly on Kv1.3 channels, have gained a prominent role for their possible ability to control inflammatory autoimmune diseases. Some of these toxins have already left bench trials and are being evaluated in clinical trials, presenting great therapeutic potential. Thus, scorpion toxins are important natural molecules that should not be overlooked in the treatment of autoimmune and other diseases.
International Journal of Biological Macromolecules, May 1, 2021
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
The venom from the scorpion Tityus serrulatus (Ts) has been extensively studied mainly because of... more The venom from the scorpion Tityus serrulatus (Ts) has been extensively studied mainly because of its rich cocktail of neurotoxins. Neurotoxins are the major and the most known components based on their modulation of voltage-gated ion channels. Until now, electrophysiological studies demonstrated that the Ts venom comprises toxins that affect Nav and Kv channels. However, although many studies have been conducted in this field, many peptides from Ts venom await further studies, including Ts8 toxin. Here we report the isolation and electrophysiological study of Ts8. The toxin Ts19 Frag-II was used as negative control. Ts8 demonstrates, among 20 tested channels, to be a selective modulator of Kv4.2 channels. Based on studies investigating the involvement of Kv4.2 on controlling nociception, we further investigated the modulation of pain by Ts8. Using intraplantar injections, Ts8 induced overt nociception (licking and lifting behaviors) and decreased the mechanical nociceptive threshold (hyperalgesia). Furthermore, the hyperalgesia was prolonged when intrathecal injections were performed. Independent of the severity, most of the victims stung by Ts scorpions report an intense and persistent pain as the major manifestation. The new role of Ts8 on nociception could explain, at least partially, this phenomenon. Additionally, our study also stresses the involvement of toxins specific to Nav channels and inflammatory mediators on the Ts painful sting. This work provides useful insights for a better understanding of the prolonged and intense pain associated with Ts envenoming for the development of specific therapies.
Animal-derived venoms are complex mixtures of toxins triggering important biological effects duri... more Animal-derived venoms are complex mixtures of toxins triggering important biological effects during envenomings. Although venom-derived toxins are known for their potential of causing harm to victims, toxins can also act as pharmacological agents. During the COVID-19 pandemic, there was observed an increase in in-depth studies on antiviral agents, and since, to date, there has been no completely effective drug against the global disease. This review explores the crosstalk of animal toxins and COVID-19, aiming to map potential therapeutic agents derived from venoms (e.g., bees, snakes, scorpions, etc.) targeting COVID-19.
Antibiotics are often administered with antivenom following snakebite envenomings in order to avo... more Antibiotics are often administered with antivenom following snakebite envenomings in order to avoid secondary bacterial infections. However, to this date, no studies have evaluated whether antibiotics may have undesirable potentiating effects on snake venom. Herein, we demonstrate that four commonly used antibiotics affect the enzymatic activities of proteolytic snake venom toxins in two different in vitro assays. Similar findings in vivo could have clinical implications for snakebite management and require further examination.
Neutrophil extracellular traps (NETs) are an important mechanism for defense against pathogens. T... more Neutrophil extracellular traps (NETs) are an important mechanism for defense against pathogens. Their overproduction can be harmful since excessive NET formation promotes inflammation and tissue damage in several diseases. Nucleases are capable to degrade NET on basis of their DNA hydrolysis activity, including the CdcPDE, a nuclease isolated from Crotalus durissus collilineatus snake venom. Here, we report a new finding about CdcPDE activity, demonstrating its efficiency in degrading cell-free DNA from NETs, being a potential candidate to assist in therapies targeting inflammatory diseases.
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
cosmeceuticals and atypical therapies (bee venom and leech therapies) are also reported. The leve... more cosmeceuticals and atypical therapies (bee venom and leech therapies) are also reported. The level of cumulative and detailed information provided in this review may help pharmacists, physicians, biotechnologists, pharmacologists, and scientists interested in toxinology, drug discovery, and development of toxin-based products.
The biological activity of Rhinella icterica parotoid secretion (RIPS) and some of its chromatogr... more The biological activity of Rhinella icterica parotoid secretion (RIPS) and some of its chromatographic fractions (RI18, RI19, RI23, and RI24) was evaluated in the current study. Mass spectrometry of these fractions indicated the presence of sarmentogenin, argentinogenin, (5β,12β)-12,14-dihydroxy-11-oxobufa-3,20,22-trienolide, marinobufagin, bufogenin B, 11α,19-dihydroxy-telocinobufagin, bufotalin, monohydroxylbufotalin, 19-oxo-cinobufagin, 3α,12β,25,26-tetrahydroxy-7-oxo-5β-cholestane-26-O-sulfate, and cinobufagin-3-hemisuberate that were identified as alkaloid and steroid compounds, in addition to marinoic acid and N-methyl-5-hydroxy-tryptamine. In chick brain slices, all fractions caused a slight decrease in cell viability, as also seen with the highest concentration of RIPS tested. In chick biventer cervicis neuromuscular preparations, RIPS and all four fractions significantly inhibited junctional acetylcholinesterase (AChE) activity. In this preparation, only fraction RI23 compl...
Scorpion venom may cause severe medical complications and untimely death if injected into the hum... more Scorpion venom may cause severe medical complications and untimely death if injected into the human body. Neurotoxins are the main components of scorpion venom that are known to be responsible for the pathological manifestations of envenoming. Besides neurotoxins, a wide range of other bioactive molecules can be found in scorpion venoms. Advances in separation, characterization, and biotechnological approaches have enabled not only the development of more effective treatments against scorpion envenomings, but have also led to the discovery of several scorpion venom peptides with interesting therapeutic properties. Thus, scorpion venom may not only be a medical threat to human health, but could prove to be a valuable source of bioactive molecules that may serve as leads for the development of new therapies against current and emerging diseases. This review presents both the detrimental and beneficial properties of scorpion venom toxins and discusses the newest advances within the dev...
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Journal of Venomous Animals and Toxins including Tropical Diseases, 2018
Background: In recent decades, snake venom disintegrins have received special attention due to th... more Background: In recent decades, snake venom disintegrins have received special attention due to their potential use in anticancer therapy. Disintegrins are small and cysteine-rich proteins present in snake venoms and can interact with specific integrins to inhibit their activities in cell-cell and cell-ECM interactions. These molecules, known to inhibit platelet aggregation, are also capable of interacting with certain cancer-related integrins, and may interfere in important processes involved in carcinogenesis. Therefore, disintegrin from Crotalus durissus collilineatus venom was isolated, structurally characterized and evaluated for its toxicity and ability to interfere with cell proliferation and migration in MDA-MB-231, a human breast cancer cell line. Methods: Based on previous studies, disintegrin was isolated by FPLC, through two chromatographic steps, both on reversed phase C-18 columns. The isolated disintegrin was structurally characterized by Tris-Tricine-SDS-PAGE, mass spectrometry and N-terminal sequencing. For the functional assays, MTT and wound-healing assays were performed in order to investigate cytotoxicity and effect on cell migration in vitro, respectively. Results: Disintegrin presented a molecular mass of 7287.4 Da and its amino acid sequence shared similarity with the disintegrin domain of P-II metalloproteases. Using functional assays, the disintegrin showed low cytotoxicity (15% and 17%, at 3 and 6 μg/mL, respectively) after 24 h of incubation and in the wound-healing assay, the disintegrin (3 μg/mL) was able to significantly inhibit cell migration (24%, p < 0.05), compared to negative control. Conclusion: Thus, our results demonstrate that non-RGD disintegrin from C. d. collilineatus induces low cytotoxicity and inhibits migration of human breast cancer cells. Therefore, it may be a very useful molecular tool for understanding ECM-cell interaction cancer-related mechanisms involved in an important integrin family that highlights molecular aspects of tumorigenesis. Also, non-RGD disintegrin has potential to serve as an agent in anticancer therapy or adjuvant component combined with other anticancer drugs.
International Journal of Biological Macromolecules, 2019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Snake venom L-amino acid oxidases (svLAAOs) are an interesting class of enzymes with important bi... more Snake venom L-amino acid oxidases (svLAAOs) are an interesting class of enzymes with important biological activities. Their participation in key metabolic processes, including pathological disorders, suggest that svLAAOs are potential lead compounds in drug discovery. However, their short-term stability defies their applications. This paper describes the stability studies together with functional and structural characterization of the LAAO bordonein-L. It has 498 amino acid residues, one N-glycosylation site and two disulfide bonds, revealed by high-resolution MS/MS. Molecular modeling approach showed its monomer folds into three conserved domains: FAD, substrate and helical domains. Differential scanning fluorimetry showed the enzyme tends to destabilize from neutral to basic pHs and in presence of mono/bivalent ions and it is highly stabilized by acid pHs and its substrates. However, high concentrations of L-amino acids decrease bordonein-L enzyme activity. Dynamic light scattering revealed bordonein-L remains in the dimeric and monodisperse form, so aggregation does not cause the rapidly decrease of enzyme activity. In vitro, the enzyme exhibited cytotoxicity against fibroblast cell line and killed Leishmania amazonensis promastigotes, intensified by substrate addition. Concluding, our results provide biochemistry and biophysical insights to improve LAAOs stability and better approaches to long-term storage. Moreover, our study emphasizes the importance of proper buffers choice mainly in cell-based assays.
Journal of Venomous Animals and Toxins including Tropical Diseases, 2019
Scorpion venoms are natural sources of molecules that have, in addition to their toxic function, ... more Scorpion venoms are natural sources of molecules that have, in addition to their toxic function, potential therapeutic applications. In this source the neurotoxins can be found especially those that act on potassium channels. Potassium channels are responsible for maintaining the membrane potential in the excitable cells, especially the voltagedependent potassium channels (Kv), including Kv1.3 channels. These channels (Kv1.3) are expressed by various types of tissues and cells, being part of several physiological processes. However, the major studies of Kv1.3 are performed on T cells due its importance on autoimmune diseases. Scorpion toxins capable of acting on potassium channels (KTx), mainly on Kv1.3 channels, have gained a prominent role for their possible ability to control inflammatory autoimmune diseases. Some of these toxins have already left bench trials and are being evaluated in clinical trials, presenting great therapeutic potential. Thus, scorpion toxins are important natural molecules that should not be overlooked in the treatment of autoimmune and other diseases.
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