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Lanfranco R P Troncone - One of the best experts on this subject based on the ideXlab platform.
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phoneutria nigriventer Spider Toxin tx2 6 induces priapism in mice even after cavernosal denervation
Toxicon, 2017Co-Authors: Katherine Garcia Ravelli, Adriana T Ramos, Luana Baracho Goncalves, Fabio Carlos Magnoli, Lanfranco R P TronconeAbstract:The Phoneutria nigriventer Spider Toxin Tx2-6 causes priapism in humans and mice. This Toxin produces a delay in Sodium channel inactivation, generalized vascular congestion and death by respiratory failure. NO-Synthase inhibitors seem to abolish Toxin-induced priapism. The understanding of the ultimate molecular mechanism involved in Toxin-induced priapism may shed light on aspects of erectile function/dysfunction. This study investigates if cavernosal denervation can abolish the Toxin-induced priapism. Surgical cavernosal nerve excision/denervation was performed in mice and confirmed by infertility, histological assessment of fibrosis and immunohistochemical staining for synaptophysin. Denervated mice showed intense fibrosis of the cavernosal tissue as well as absence of synaptophysin IHC staining; surprisingly mice showed Toxin-induced priapism when tested 15, 30 or 60 days after denervation. While sham-operated mice presented full priapism, denervated animals showed only partial priapism possibly due to the fibrosis. These results reveal that erection caused by Tx2-6 Toxin may not depend on cavernosal nerves integrity. The effect of this Toxin on sodium channels seem not directly involved in priapism as many Toxins have identical effects but do not induce priapism. Discussion approaches the many different potential sites of intervention listed in the signaling cascades of NO/cGMP, RhoA/Rho-Kinase, as well as the emerging new gasotransmitter H2S. The pharmacological inhibition of Rho-kinase and Toxin Tx2-6 have similar effects in vivo.
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Phoneutria nigriventer Spider Toxin Tx2-6 causes priapism and death: a histopathological investigation in mice.
Toxicon, 2012Co-Authors: Katia R. M. Leite, Adriana T Ramos, Fabio Carlos Magnoli, Enrico Andrade, Miguel Srougi, Lanfranco R P TronconeAbstract:Phoneutria nigriventer Spider bite causes priapism, an effect attributed to the peptide Toxins Tx2-5 and Tx2-6 and involving nitric oxide. Tx2-6 (MW = 5287) is known to delay the inactivation of Sodium channels in the same fashion as many other venom Toxins. In the present study we evaluated the i.p. dose that induces priapism and the other symptoms in mice. Animals killed by the Toxin or crude venom (0.85 mg/kg) were autopsied and a pathological study of brain, lung, kidney, liver and heart was undertaken using standard techniques. The same protocol was employed with animals injected with crude venom. Results showed that priapism is the first sign of intoxication, followed by piloerection, abundant salivation and tremors. An i.p. injection of about 0.3 μg/kg induced only priapism with minimal side-effects. The most remarkable histological finding was a general vascular congestion in all organs studied. Penis showed no necrosis or damage. Lungs showed vascular congestion and alveolar hemorrhage. Heart showed also sub-endothelial hemorrhage. Brain showed only a mild edema and vascular congestion. Results obtained with crude venom closely resemble those of purified Toxin. We conclude that Tx2-6 have profound effects on the vascular bed especially in lungs and heart, which may be the cause of death. Interestingly brain tissue was less affected and the observed edema may be attributed to respiratory impairment. To the best of our knowledge this is the first histopathological investigation on this Toxin and venom suggesting a possible cause of death.
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regional brain c fos activation associated with penile erection and other symptoms induced by the Spider Toxin tx2 6
Toxicon, 2011Co-Authors: Lanfranco R P Troncone, Katherine Garcia Ravelli, Fabio Carlos Magnoli, Ivo Lebrun, Debora C Hipolide, Roger Raymond, Jose N NobregaAbstract:Brain areas expressing c-fos messenger RNA were mapped by quantitative in situ hybridization after 1–2 h of intoxication with 10 mg/kg Tx2-6, a Toxin obtained from the venom of the Spider Phoneutria nigriventer. Relative to saline-treated controls, brains from Toxin-treated animals showed pronounced c-fos activation in many brain areas, including the supraoptic nucleus, the paraventricular nucleus of the hypothalamus, the motor nucleus of the vagus, area postrema, paraventricular and paratenial nuclei of the thalamus, locus coeruleus, central amydaloid nucleus and the bed nucleus of the stria terminalis. The paraventricular hypothalamus and the bed nucleus of the stria terminalis have been implicated in erectile function in other studies. A possible role for central NO is considered. Acute stress also activates many brain areas activated by Tx2-6 as well as with NOstimulated Fos transcription. Brain areas that appear to be selectively activated by Tx2-6, include the paratenial and paraventricular thalamic nuclei, the bed nucleus of the stria terminalis and the area postrema and the dorsal motor n. of vagus in the medulla. However, direct injections of different doses of the Toxin into the paraventricular hypothalamic n. failed to induce penile erection, arguing against CNS involvement in this particular effect.
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blockade of neuronal nitric oxide synthase abolishes the toxic effects of tx2 5 a lethal phoneutria nigriventer Spider Toxin
Toxicon, 2004Co-Authors: C M Yonamine, Lanfranco R P Troncone, M A P CamilloAbstract:The primary goal of this study was to determine whether Tx2-5, a sodium channel selective Toxin obtained from the venom of the Spider Phoneutria nigriventer, produced penile erection by means of nitric oxide mechanism. Toxin identity was analyzed by MALDI-TOF, ES-MS and N-terminal amino acid sequencing. Pretreating mice with the non-selective nitric oxide synthase (NOS) inhibitor Nv-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and the selective neuronal-NOS inhibitor 7-Nitroindazole (7-NI) prior to Tx2-5 i.p. (10 mg/25 g mouse) injection challenged the hypothesis above. Controls were injected with the D-isomer or DMSO or saline. Results demonstrated that L-NAME inhibited penile erections in about half the animals treated, while 7-NI completely abolished this effect. Interestingly 7-NI also abolished all the other symptoms of intoxication induced by Tx2-5, including salivation, respiratory distress and death. Tx2-5 killed all the animals of the control group and no one in the 7-NI-treated group. We conclude that (1) intraperitoneal injections of Tx2-5 induce a toxic syndrome that include penile erection, hypersalivation and death by respiratory distress or pulmonary edema; (2) pretreatment with the non-selective NOS inhibitor L-NAME reduces the penile erection and partially protects from the lethal effects of Tx2-5; (3) pretreatment with the nNOS-selective inhibitor 7-NI completely abolishes all the toxic effects of Tx2-5, including penile erection and death suggesting that nNOS is the major player in this intoxication; (4) Toxins from other animals that affect sodium channels in the same way as Tx2-5 and induce similar toxic syndromes may have as a major common target, the activation of nitric oxide synthases. q 2004 Elsevier Ltd. All rights reserved.
Jan Tytgat - One of the best experts on this subject based on the ideXlab platform.
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phoneutria nigriventer Spider Toxin pntx2 1 δ cteniToxin pn1a is a modulator of sodium channel gating
Toxins, 2018Co-Authors: Steve Peigneur, Ana Luiza Bittencourt Paiva, Maria Elena De Lima, Marcia Helena Borges, Marcelo Ribeiro Vasconcelos Diniz, Jan TytgatAbstract:: Spider venoms are complex mixtures of biologically active components with potentially interesting applications for drug discovery or for agricultural purposes. The Spider Phoneutria nigriventer is responsible for a number of envenomations with sometimes severe clinical manifestations in humans. A more efficient treatment requires a comprehensive knowledge of the venom composition and of the action mechanism of the constituting components. PnTx2-1 (also called δ-cteniToxin-Pn1a) is a 53-amino-acid-residue peptide isolated from the venom fraction PhTx2. Although PnTx2-1 is classified as a neuroToxin, its molecular target has remained unknown. This study describes the electrophysiological characterization of PnTx2-1 as a modulator of voltage-gated sodium channels. PnTx2-1 is investigated for its activity on seven mammalian NaV-channel isoforms, one insect NaV channel and one arachnid NaV channel. Furthermore, comparison of the activity of both PnTx2-1 and PnTx2-6 on NaV1.5 channels reveals that this family of Phoneutria Toxins modulates the cardiac NaV channel in a bifunctional manner, resulting in an alteration of the inactivation process and a reduction of the sodium peak current.
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Phoneutria nigriventer Spider Toxin PnTx2-1 (δ-CteniToxin-Pn1a) Is a Modulator of Sodium Channel Gating
MDPI AG, 2018Co-Authors: Steve Peigneur, Maria Elena De Lima, Marcia Helena Borges, Marcelo Ribeiro Vasconcelos Diniz, Ana Luiza B. Paiva, Jan TytgatAbstract:Spider venoms are complex mixtures of biologically active components with potentially interesting applications for drug discovery or for agricultural purposes. The Spider Phoneutria nigriventer is responsible for a number of envenomations with sometimes severe clinical manifestations in humans. A more efficient treatment requires a comprehensive knowledge of the venom composition and of the action mechanism of the constituting components. PnTx2-1 (also called δ-cteniToxin-Pn1a) is a 53-amino-acid-residue peptide isolated from the venom fraction PhTx2. Although PnTx2-1 is classified as a neuroToxin, its molecular target has remained unknown. This study describes the electrophysiological characterization of PnTx2-1 as a modulator of voltage-gated sodium channels. PnTx2-1 is investigated for its activity on seven mammalian NaV-channel isoforms, one insect NaV channel and one arachnid NaV channel. Furthermore, comparison of the activity of both PnTx2-1 and PnTx2-6 on NaV1.5 channels reveals that this family of Phoneutria Toxins modulates the cardiac NaV channel in a bifunctional manner, resulting in an alteration of the inactivation process and a reduction of the sodium peak current
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solution structure and alanine scan of a Spider Toxin that affects the activation of mammalian voltage gated sodium channels
Journal of Biological Chemistry, 2007Co-Authors: Gerardo Corzo, Jan Tytgat, Frank Bosmans, Elba Villegas, Jennifer K Sabo, Bert Billen, Raymond S. NortonAbstract:Magi 5, from the hexathelid Spider Macrothele gigas, is a 29-residue polypeptide containing three disulfide bridges. It binds specifically to receptor site 4 on mammalian voltage-gated sodium channels and competes with scorpion beta-Toxins, such as Css IV from Centruroides suffusus suffusus. As a consequence, Magi 5 shifts the activation voltage of the mammalian rNav1.2a channel to more hyperpolarized voltages, whereas the insect channel, DmNav1, is not affected. To gain insight into Toxin-channel interactions, Magi 5 and 23 analogues were synthesized. The three-dimensional structure of Magi 5 in aqueous solution was determined, and its voltage-gated sodium channel-binding surfaces were mapped onto this structure using data from electrophysiological measurements on a series of Ala-substituted analogues. The structure clearly resembles the inhibitor cystine knot structural motif, although the triple-stranded beta-sheet typically found in that motif is partially distorted in Magi 5. The interactive surface of Magi 5 toward voltage-gated sodium channels resembles in some respects the Janus-faced atracoToxins, with functionally important charged residues on one face of the Toxin and hydrophobic residues on the other. Magi 5 also resembles the scorpion beta-Toxin Css IV, which has distinct nonpolar and charged surfaces that are critical for channel binding and has a key Glu involved in voltage sensor trapping. These two distinct classes of Toxin, with different amino acid sequences and different structures, may utilize similar groups of residues on their surface to achieve the common end of modifying voltage-gated sodium channel function.
Zhonghua Liu - One of the best experts on this subject based on the ideXlab platform.
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Variation of Two S3b Residues in KV4.1–4.3 Channels Underlies Their Different Modulations by Spider Toxin κ-LhTx-1
'Frontiers Media SA', 2021Co-Authors: Zhen Xiao, Song-ping Liang, Piao Zhao, Xiangjin Kong, Ruiwen Wang, Cheng Tang, Zhonghua LiuAbstract:The naturally occurred peptide Toxins from animal venoms are valuable pharmacological tools in exploring the structure-function relationships of ion channels. Herein we have identified the peptide Toxin κ-LhTx-1 from the venom of Spider Pandercetes sp (the Lichen huntsman Spider) as a novel selective antagonist of the KV4 family potassium channels. κ-LhTx-1 is a gating-modifier Toxin impeded KV4 channels’ voltage sensor activation, and mutation analysis has confirmed its binding site on channels’ S3b region. Interestingly, κ-LhTx-1 differently modulated the gating of KV4 channels, as revealed by Toxin inhibiting KV4.2/4.3 with much more stronger voltage-dependence than that for KV4.1. We proposed that κ-LhTx-1 trapped the voltage sensor of KV4.1 in a much more stable resting state than that for KV4.2/4.3 and further explored the underlying mechanism. Swapping the non-conserved S3b segments between KV4.1(280FVPK283) and KV4.3(275VMTN278) fully reversed their voltage-dependence phenotypes in inhibition by κ-LhTx-1, and intensive mutation analysis has identified P282 in KV4.1, D281 in KV4.2 and N278 in KV4.3 being the key residues. Furthermore, the last two residues in this segment of each KV4 channel (P282/K283 in KV4.1, T280/D281 in KV4.2 and T277/N278 in KV4.3) likely worked synergistically as revealed by our combinatorial mutations analysis. The present study has clarified the molecular basis in KV4 channels for their different modulations by κ-LhTx-1, which have advanced our understanding on KV4 channels’ structure features. Moreover, κ-LhTx-1 might be useful in developing anti-arrhythmic drugs given its high affinity, high selectivity and unique action mode in interacting with the KV4.2/4.3 channels
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recombinant paurtx 3 a Spider Toxin inhibits sodium channels and decreases membrane excitability in drg neurons
Biochemical and Biophysical Research Communications, 2020Co-Authors: Minzhi Chen, Shuijiao Peng, Li Wang, Li Yang, Xi Zhou, Yunxiao Zhang, Zhonghua LiuAbstract:Abstract Voltage-gated sodium channels are critical for the generation and propagation of action potentials. Gating modifier Toxins from Spider venom can modulate the gating mechanism of sodium channels and thus have potential as drug leads. Here, we established expression of the gating modifier Toxin PaurTx-3, a sodium channel inhibitor found in the venom of the Spider Phrixotrichus auratus. Whole-cell voltage-clamp recordings indicated that recombinant PaurTx-3 (rPaurTx-3) inhibited Nav1.4, Nav1.5, and Nav1.7 currents with IC50 values of 61 nM, 72 nM, and 25 nM, respectively. Furthermore, rPaurTx-3 irreversibly inhibited Nav1.7 currents, but had 60–70% recovery in Nav1.4 and Nav1.5 after washing with a bath solution. rPaurTx-3 also hyperpolarized the voltage-dependent steady-state inactivation curve and significantly slowed recovery from fast inactivation of Nav1.7. Current-clamp recordings showed that rPaurTx-3 suppressed small DRG neuron activity. The biological activity assay findings for rPaurTx-3 support its potent pharmacological effect in Nav1.7 and small DRG neurons.
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engineering gain of function analogues of the Spider venom peptide hntx i a potent blocker of the hnav1 7 sodium channel
Toxins, 2018Co-Authors: Yunxiao Zhang, Song-ping Liang, Minzhi Chen, Xi Zhou, Qiuchu Yang, Qingfeng Zhang, Dezheng Peng, Zhonghua LiuAbstract:Pain is a medical condition that interferes with normal human life and work and reduces human well-being worldwide. The voltage-gated sodium channel (VGSC) human NaV1.7 (hNaV1.7) is a compelling target that plays a key role in human pain signaling. The 33-residue peptide µ-TRTX-Hhn2b (HNTX-I), a member of NaV-targeting Spider Toxin (NaSpTx) family 1, has shown negligible activity on mammalian VGSCs, including the hNaV1.7 channel. We engineered analogues of HNTX-I based on sequence conservation in NaSpTx family 1. Substitution of Asn for Ser at position 23 or Asp for His at position 26 conferred potent activity against hNaV1.7. Moreover, multiple site mutations combined together afforded improvements in potency. Ultimately, we generated an analogue E1G⁻N23S⁻D26H⁻L32W with >300-fold improved potency compared with wild-type HNTX-1 on hNaV1.7 (IC50 0.036 ± 0.007 µM). Structural simulation suggested that the charged surface and the hydrophobic surface of the modified peptide are responsible for binding affinity to the hNaV1.7 channel, while variable residues may determine pharmacological specificity. Therefore, this study provides a profile for drug design targeting the hNaV1.7 channel.
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Engineering Gain-of-Function Analogues of the Spider Venom Peptide HNTX-I, A Potent Blocker of the hNaV1.7 Sodium Channel
MDPI AG, 2018Co-Authors: Yunxiao Zhang, Song-ping Liang, Minzhi Chen, Xi Zhou, Qiuchu Yang, Qingfeng Zhang, Dezheng Peng, Zhonghua LiuAbstract:Pain is a medical condition that interferes with normal human life and work and reduces human well-being worldwide. Human voltage-gated sodium channel NaV1.7 (hNaV1.7) is a compelling target that plays a key role in human pain signaling. The 33-residue peptide µ-TRTX-Hhn2b (HNTX-I), a member of NaV-targeting Spider Toxin (NaSpTx) family 1, has shown negligible activity on mammalian voltage-gated sodium channels (VGSCs), including the hNaV1.7 channel. We engineered analogues of HNTX-I based on sequence conservation in NaSpTx family 1. Substitution of Asn for Ser at position 23 or Asp for His at position 26 conferred potent activity against hNaV1.7. Moreover, multiple site mutations combined together afforded improvements in potency. Ultimately, we generated an analogue E1G–N23S–D26H–L32W with >300-fold improved potency compared with wild-type HNTX-I on hNaV1.7 (IC50 0.036 ± 0.007 µM). Structural simulation suggested that the charged surface and the hydrophobic surface of the modified peptide are responsible for binding affinity to the hNaV1.7 channel, while variable residues may determine pharmacological specificity. Therefore, this study provides a profile for drug design targeting the hNaV1.7 channel
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Spider Toxin peptide lycosin i functionalized gold nanoparticles for in vivo tumor targeting and therapy
Theranostics, 2017Co-Authors: Huaxin Tan, Song-ping Liang, Yazhou Huang, Bo Chen, Peng Zhang, Lehui Xiao, Zhonghua LiuAbstract:Cell penetrating peptides (CPPs) are commonly utilized for intracellular delivery of functional materials to circumvent biomembrane barrier. However, further application of CPPs is hindered by lacking selectivity toward targeted cells. The Spider venom peptide, lycosin-I, is a CPP with potent cytotoxicity to cancer cells, which might enable lycosin-I to deliver functional materials into cancer cells selectively. In this study, we demonstrated that the lycosin-I-conjugated spherical gold nanoparticles (LGNPs) not only exhibited efficient cellular internalization efficiency toward cancer cells but also displayed unprecedented selectivity over noncancerous cells. Although LGNPs were removed from the living circulatory system via reticuloendothelial system-dominant clearance modes without noticeable adverse effects to animals, they actually displayed active tumor-targeting effects and efficient accumulation in tumors in vivo. Furthermore, the potential application of this platform for cancer therapy was explored by lycosin-I-conjugated gold nanorods (LGNRs). LGNRs exhibited selective intracellular translocation towards cancer cells and efficient photothermal effect under near infrared (NIR, 808 nm) irradiation, which consequently killed cancer cells in vitro and in vivo effectively. Therefore, the established LGNPs and LGNRs possessed great potential in cancer-targeting delivery and photothermal therapy.
Song-ping Liang - One of the best experts on this subject based on the ideXlab platform.
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Variation of Two S3b Residues in KV4.1–4.3 Channels Underlies Their Different Modulations by Spider Toxin κ-LhTx-1
'Frontiers Media SA', 2021Co-Authors: Zhen Xiao, Song-ping Liang, Piao Zhao, Xiangjin Kong, Ruiwen Wang, Cheng Tang, Zhonghua LiuAbstract:The naturally occurred peptide Toxins from animal venoms are valuable pharmacological tools in exploring the structure-function relationships of ion channels. Herein we have identified the peptide Toxin κ-LhTx-1 from the venom of Spider Pandercetes sp (the Lichen huntsman Spider) as a novel selective antagonist of the KV4 family potassium channels. κ-LhTx-1 is a gating-modifier Toxin impeded KV4 channels’ voltage sensor activation, and mutation analysis has confirmed its binding site on channels’ S3b region. Interestingly, κ-LhTx-1 differently modulated the gating of KV4 channels, as revealed by Toxin inhibiting KV4.2/4.3 with much more stronger voltage-dependence than that for KV4.1. We proposed that κ-LhTx-1 trapped the voltage sensor of KV4.1 in a much more stable resting state than that for KV4.2/4.3 and further explored the underlying mechanism. Swapping the non-conserved S3b segments between KV4.1(280FVPK283) and KV4.3(275VMTN278) fully reversed their voltage-dependence phenotypes in inhibition by κ-LhTx-1, and intensive mutation analysis has identified P282 in KV4.1, D281 in KV4.2 and N278 in KV4.3 being the key residues. Furthermore, the last two residues in this segment of each KV4 channel (P282/K283 in KV4.1, T280/D281 in KV4.2 and T277/N278 in KV4.3) likely worked synergistically as revealed by our combinatorial mutations analysis. The present study has clarified the molecular basis in KV4 channels for their different modulations by κ-LhTx-1, which have advanced our understanding on KV4 channels’ structure features. Moreover, κ-LhTx-1 might be useful in developing anti-arrhythmic drugs given its high affinity, high selectivity and unique action mode in interacting with the KV4.2/4.3 channels
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engineering gain of function analogues of the Spider venom peptide hntx i a potent blocker of the hnav1 7 sodium channel
Toxins, 2018Co-Authors: Yunxiao Zhang, Song-ping Liang, Minzhi Chen, Xi Zhou, Qiuchu Yang, Qingfeng Zhang, Dezheng Peng, Zhonghua LiuAbstract:Pain is a medical condition that interferes with normal human life and work and reduces human well-being worldwide. The voltage-gated sodium channel (VGSC) human NaV1.7 (hNaV1.7) is a compelling target that plays a key role in human pain signaling. The 33-residue peptide µ-TRTX-Hhn2b (HNTX-I), a member of NaV-targeting Spider Toxin (NaSpTx) family 1, has shown negligible activity on mammalian VGSCs, including the hNaV1.7 channel. We engineered analogues of HNTX-I based on sequence conservation in NaSpTx family 1. Substitution of Asn for Ser at position 23 or Asp for His at position 26 conferred potent activity against hNaV1.7. Moreover, multiple site mutations combined together afforded improvements in potency. Ultimately, we generated an analogue E1G⁻N23S⁻D26H⁻L32W with >300-fold improved potency compared with wild-type HNTX-1 on hNaV1.7 (IC50 0.036 ± 0.007 µM). Structural simulation suggested that the charged surface and the hydrophobic surface of the modified peptide are responsible for binding affinity to the hNaV1.7 channel, while variable residues may determine pharmacological specificity. Therefore, this study provides a profile for drug design targeting the hNaV1.7 channel.
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Engineering Gain-of-Function Analogues of the Spider Venom Peptide HNTX-I, A Potent Blocker of the hNaV1.7 Sodium Channel
MDPI AG, 2018Co-Authors: Yunxiao Zhang, Song-ping Liang, Minzhi Chen, Xi Zhou, Qiuchu Yang, Qingfeng Zhang, Dezheng Peng, Zhonghua LiuAbstract:Pain is a medical condition that interferes with normal human life and work and reduces human well-being worldwide. Human voltage-gated sodium channel NaV1.7 (hNaV1.7) is a compelling target that plays a key role in human pain signaling. The 33-residue peptide µ-TRTX-Hhn2b (HNTX-I), a member of NaV-targeting Spider Toxin (NaSpTx) family 1, has shown negligible activity on mammalian voltage-gated sodium channels (VGSCs), including the hNaV1.7 channel. We engineered analogues of HNTX-I based on sequence conservation in NaSpTx family 1. Substitution of Asn for Ser at position 23 or Asp for His at position 26 conferred potent activity against hNaV1.7. Moreover, multiple site mutations combined together afforded improvements in potency. Ultimately, we generated an analogue E1G–N23S–D26H–L32W with >300-fold improved potency compared with wild-type HNTX-I on hNaV1.7 (IC50 0.036 ± 0.007 µM). Structural simulation suggested that the charged surface and the hydrophobic surface of the modified peptide are responsible for binding affinity to the hNaV1.7 channel, while variable residues may determine pharmacological specificity. Therefore, this study provides a profile for drug design targeting the hNaV1.7 channel
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Spider Toxin peptide lycosin i functionalized gold nanoparticles for in vivo tumor targeting and therapy
Theranostics, 2017Co-Authors: Huaxin Tan, Song-ping Liang, Yazhou Huang, Bo Chen, Peng Zhang, Lehui Xiao, Zhonghua LiuAbstract:Cell penetrating peptides (CPPs) are commonly utilized for intracellular delivery of functional materials to circumvent biomembrane barrier. However, further application of CPPs is hindered by lacking selectivity toward targeted cells. The Spider venom peptide, lycosin-I, is a CPP with potent cytotoxicity to cancer cells, which might enable lycosin-I to deliver functional materials into cancer cells selectively. In this study, we demonstrated that the lycosin-I-conjugated spherical gold nanoparticles (LGNPs) not only exhibited efficient cellular internalization efficiency toward cancer cells but also displayed unprecedented selectivity over noncancerous cells. Although LGNPs were removed from the living circulatory system via reticuloendothelial system-dominant clearance modes without noticeable adverse effects to animals, they actually displayed active tumor-targeting effects and efficient accumulation in tumors in vivo. Furthermore, the potential application of this platform for cancer therapy was explored by lycosin-I-conjugated gold nanorods (LGNRs). LGNRs exhibited selective intracellular translocation towards cancer cells and efficient photothermal effect under near infrared (NIR, 808 nm) irradiation, which consequently killed cancer cells in vitro and in vivo effectively. Therefore, the established LGNPs and LGNRs possessed great potential in cancer-targeting delivery and photothermal therapy.
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a novel Spider peptide Toxin suppresses tumor growth through dual signaling pathways
Current Molecular Medicine, 2012Co-Authors: Zhiqiang Liu, Mi Deng, J W Xiang, Y Zhao, Song-ping LiangAbstract:Spider venom is a large pharmacological repertoire containing many biologically active peptides, which may have a potent therapeutic implication. Here we investigated a peptide Toxin, named lycosin-I, isolated from the venom of the Spider Lycosa singoriensis. In contrast to most Spider peptide Toxins adopting inhibitor cystine knot (ICK) motif, lycosin-I shows a linear amphipathic alpha-helical conformation, common to α-helical host defense peptides. Lycosin-I displays strong ability to inhibit cancer cell growth in vitro and can effectively suppresses tumor growth in vivo. Mechanistically, it activates the mitochondrial death pathway to sensitize cancer cells for apoptosis, as well as up-regulates p27 to inhibit cell proliferation. Taken together, our results provide the first evidence that a Spider Toxin can effectively suppress tumorigenesis through activation of dual signaling pathways. In addition, lycosin-I may be a useful structural lead for the development of novel anticancer drugs.
Fabio Carlos Magnoli - One of the best experts on this subject based on the ideXlab platform.
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phoneutria nigriventer Spider Toxin tx2 6 induces priapism in mice even after cavernosal denervation
Toxicon, 2017Co-Authors: Katherine Garcia Ravelli, Adriana T Ramos, Luana Baracho Goncalves, Fabio Carlos Magnoli, Lanfranco R P TronconeAbstract:The Phoneutria nigriventer Spider Toxin Tx2-6 causes priapism in humans and mice. This Toxin produces a delay in Sodium channel inactivation, generalized vascular congestion and death by respiratory failure. NO-Synthase inhibitors seem to abolish Toxin-induced priapism. The understanding of the ultimate molecular mechanism involved in Toxin-induced priapism may shed light on aspects of erectile function/dysfunction. This study investigates if cavernosal denervation can abolish the Toxin-induced priapism. Surgical cavernosal nerve excision/denervation was performed in mice and confirmed by infertility, histological assessment of fibrosis and immunohistochemical staining for synaptophysin. Denervated mice showed intense fibrosis of the cavernosal tissue as well as absence of synaptophysin IHC staining; surprisingly mice showed Toxin-induced priapism when tested 15, 30 or 60 days after denervation. While sham-operated mice presented full priapism, denervated animals showed only partial priapism possibly due to the fibrosis. These results reveal that erection caused by Tx2-6 Toxin may not depend on cavernosal nerves integrity. The effect of this Toxin on sodium channels seem not directly involved in priapism as many Toxins have identical effects but do not induce priapism. Discussion approaches the many different potential sites of intervention listed in the signaling cascades of NO/cGMP, RhoA/Rho-Kinase, as well as the emerging new gasotransmitter H2S. The pharmacological inhibition of Rho-kinase and Toxin Tx2-6 have similar effects in vivo.
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Phoneutria nigriventer Spider Toxin Tx2-6 causes priapism and death: a histopathological investigation in mice.
Toxicon, 2012Co-Authors: Katia R. M. Leite, Adriana T Ramos, Fabio Carlos Magnoli, Enrico Andrade, Miguel Srougi, Lanfranco R P TronconeAbstract:Phoneutria nigriventer Spider bite causes priapism, an effect attributed to the peptide Toxins Tx2-5 and Tx2-6 and involving nitric oxide. Tx2-6 (MW = 5287) is known to delay the inactivation of Sodium channels in the same fashion as many other venom Toxins. In the present study we evaluated the i.p. dose that induces priapism and the other symptoms in mice. Animals killed by the Toxin or crude venom (0.85 mg/kg) were autopsied and a pathological study of brain, lung, kidney, liver and heart was undertaken using standard techniques. The same protocol was employed with animals injected with crude venom. Results showed that priapism is the first sign of intoxication, followed by piloerection, abundant salivation and tremors. An i.p. injection of about 0.3 μg/kg induced only priapism with minimal side-effects. The most remarkable histological finding was a general vascular congestion in all organs studied. Penis showed no necrosis or damage. Lungs showed vascular congestion and alveolar hemorrhage. Heart showed also sub-endothelial hemorrhage. Brain showed only a mild edema and vascular congestion. Results obtained with crude venom closely resemble those of purified Toxin. We conclude that Tx2-6 have profound effects on the vascular bed especially in lungs and heart, which may be the cause of death. Interestingly brain tissue was less affected and the observed edema may be attributed to respiratory impairment. To the best of our knowledge this is the first histopathological investigation on this Toxin and venom suggesting a possible cause of death.
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regional brain c fos activation associated with penile erection and other symptoms induced by the Spider Toxin tx2 6
Toxicon, 2011Co-Authors: Lanfranco R P Troncone, Katherine Garcia Ravelli, Fabio Carlos Magnoli, Ivo Lebrun, Debora C Hipolide, Roger Raymond, Jose N NobregaAbstract:Brain areas expressing c-fos messenger RNA were mapped by quantitative in situ hybridization after 1–2 h of intoxication with 10 mg/kg Tx2-6, a Toxin obtained from the venom of the Spider Phoneutria nigriventer. Relative to saline-treated controls, brains from Toxin-treated animals showed pronounced c-fos activation in many brain areas, including the supraoptic nucleus, the paraventricular nucleus of the hypothalamus, the motor nucleus of the vagus, area postrema, paraventricular and paratenial nuclei of the thalamus, locus coeruleus, central amydaloid nucleus and the bed nucleus of the stria terminalis. The paraventricular hypothalamus and the bed nucleus of the stria terminalis have been implicated in erectile function in other studies. A possible role for central NO is considered. Acute stress also activates many brain areas activated by Tx2-6 as well as with NOstimulated Fos transcription. Brain areas that appear to be selectively activated by Tx2-6, include the paratenial and paraventricular thalamic nuclei, the bed nucleus of the stria terminalis and the area postrema and the dorsal motor n. of vagus in the medulla. However, direct injections of different doses of the Toxin into the paraventricular hypothalamic n. failed to induce penile erection, arguing against CNS involvement in this particular effect.