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Thermally processed Buthus martensii Karsch scorpions are a traditional Chinese medical material for treating various diseases. However, their pharmacological foundation remains unclear. Here, a new degraded peptide of scorpion toxin was identified in Chinese scorpion medicinal material by proteomics. It was named BmK86-P1 and has six conserved cysteine residues. Homology modeling and circular dichroism spectra experiments revealed that BmK86-P1 not only contained representative disulfide bond-stabilized α-helical and β-sheet motifs but also showed remarkable stability at test temperatures from 20–95 °C. Electrophysiology experiments indicated that BmK86-P1 was a highly potent and selective inhibitor of the hKv1.2 channel with IC50 values of 28.5 ± 6.3 nM. Structural and functional dissection revealed that two residues of BmK86-P1 (i.e., Lys19 and Ile21) were the key residues that interacted with the hKv1.2 channel. In addition, channel chimeras and mutagenesis experiments revealed that three amino acids (i.e., Gln357, Val381 and Thr383) of the hKv1.2 channel were responsible for BmK86-P1 selectivity. This research uncovered a new bioactive peptide from traditional Chinese scorpion medicinal material that has desirable thermostability and Kv1.2 channel-specific activity, which strongly suggests that thermally processed scorpions are novel peptide resources for new drug discovery for the Kv1.2 channel-related ataxia and epilepsy diseases.
Chenhu Qin; Xuhua Yang; Zheng Zuo; Liuting Yang; Fan Yang; Zhijian Cao; Zongyun Chen; Yingliang Wu. BmK86-P1, a New Degradation Peptide with Desirable Thermostability and Kv1.2 Channel-Specific Activity from Traditional Chinese Scorpion Medicinal Material. Toxins 2021, 13, 610 .
AMA StyleChenhu Qin, Xuhua Yang, Zheng Zuo, Liuting Yang, Fan Yang, Zhijian Cao, Zongyun Chen, Yingliang Wu. BmK86-P1, a New Degradation Peptide with Desirable Thermostability and Kv1.2 Channel-Specific Activity from Traditional Chinese Scorpion Medicinal Material. Toxins. 2021; 13 (9):610.
Chicago/Turabian StyleChenhu Qin; Xuhua Yang; Zheng Zuo; Liuting Yang; Fan Yang; Zhijian Cao; Zongyun Chen; Yingliang Wu. 2021. "BmK86-P1, a New Degradation Peptide with Desirable Thermostability and Kv1.2 Channel-Specific Activity from Traditional Chinese Scorpion Medicinal Material." Toxins 13, no. 9: 610.
The NLRP3 inflammasome, a critical component of the innate immune system, induces caspase-1 activation and interleukin-1β maturation and drives cell fate towards pyroptosis. However, the mechanism of NLRP3 inflammasome activation still remains elusive. Here we provide evidence that AKT regulates NLRP3 inflammasome activation. Upon NLRP3 activation, AKT activity is inhibited by second stimulus-induced ROS. In contrast, AKT activation leads to NLRP3 inhibition and improved mitochondrial fitness. Mechanistically, AKT induces the phosphorylation of the DDX3X (DEAD-box helicase 3, X-linked), a recently identified NLRP3 inflammasome component, and impairs the interaction between DDX3X and NLRP3. Furthermore, an AKT agonist reduces NLRP3-dependent inflammation in two in vivo models of LPS-induced sepsis and Alum-induced peritonitis. Altogether, our study highlights an important role of AKT in controlling NLRP3 inflammasome activation.
Xingchen Guo; Sheng Chen; Weiwei Yu; Zhexu Chi; Zhen Wang; Ting Xu; Jian Zhang; Danlu Jiang; Yuxian Guo; Hui Fang; Kailian Zhang; Mobai Li; Dehang Yang; Qianzhou Yu; Qizhen Ye; Di Wang; Xue Zhang; Yingliang Wu. AKT controls NLRP3 inflammasome activation by inducing DDX3X phosphorylation. FEBS Letters 2021, 1 .
AMA StyleXingchen Guo, Sheng Chen, Weiwei Yu, Zhexu Chi, Zhen Wang, Ting Xu, Jian Zhang, Danlu Jiang, Yuxian Guo, Hui Fang, Kailian Zhang, Mobai Li, Dehang Yang, Qianzhou Yu, Qizhen Ye, Di Wang, Xue Zhang, Yingliang Wu. AKT controls NLRP3 inflammasome activation by inducing DDX3X phosphorylation. FEBS Letters. 2021; ():1.
Chicago/Turabian StyleXingchen Guo; Sheng Chen; Weiwei Yu; Zhexu Chi; Zhen Wang; Ting Xu; Jian Zhang; Danlu Jiang; Yuxian Guo; Hui Fang; Kailian Zhang; Mobai Li; Dehang Yang; Qianzhou Yu; Qizhen Ye; Di Wang; Xue Zhang; Yingliang Wu. 2021. "AKT controls NLRP3 inflammasome activation by inducing DDX3X phosphorylation." FEBS Letters , no. : 1.
The scorpion venom system plays a critical role in capturing prey and defending against predators. In this study, the rapid developmental process of the first instar telson was first presented. The small amount of venom in the first instar could be stored well by the distorted and blocked venom ducts, which disappeared in the older scorpions. This special developmental process of the first instar telson revealed the notable survival ability of scorpions.
Songryong Li; UnChol Ri; Chenhu Qin; Yiyuan Guo; Changho Ri; Wenxin Li; Zhijian Cao; Yingliang Wu. The rapid development of the first instar telson with venom secretion highlights the remarkable survival ability of scorpions. Toxicon 2021, 200, 198 -202.
AMA StyleSongryong Li, UnChol Ri, Chenhu Qin, Yiyuan Guo, Changho Ri, Wenxin Li, Zhijian Cao, Yingliang Wu. The rapid development of the first instar telson with venom secretion highlights the remarkable survival ability of scorpions. Toxicon. 2021; 200 ():198-202.
Chicago/Turabian StyleSongryong Li; UnChol Ri; Chenhu Qin; Yiyuan Guo; Changho Ri; Wenxin Li; Zhijian Cao; Yingliang Wu. 2021. "The rapid development of the first instar telson with venom secretion highlights the remarkable survival ability of scorpions." Toxicon 200, no. : 198-202.
Novel degraded potassium channel-modulatory peptides were recently found in thermally processed scorpions, but their pharmacological properties remain unclear. Here, we identified a full-length scorpion toxin (i.e., BmKcug2) and its four truncated analogs (i.e., BmKcug2-P1, BmKcug2-P2, BmKcug2-P3 and BmKcug2-P4) with three conserved disulfide bonds in processed scorpion medicinal material by mass spectrometry. The pharmacological experiments revealed that the recombinant BmKcug2 and BmKcug2-P1 could selectively inhibit the human Kv1.2 and human Kv1.3 potassium channels, while the other three analogs showed a much weaker inhibitory effect on potassium channels. BmKcug2 inhibited hKv1.2 and hKv1.3 channels, with IC50 values of 45.6 ± 5.8 nM and 215.2 ± 39.7 nM, respectively, and BmKcug2-P1 inhibited hKv1.2 and hKv1.3, with IC50 values of 89.9 ± 9.6 nM and 1142.4 ± 64.5 nM, respectively. The chromatographic analysis and pharmacological properties of BmKcug2 and BmKcug2-P1 boiled in water for different times further strongly supported their good thermal stability. Structural and functional dissection indicated that one amino acid, i.e., Tyr36, determined the differential affinities of BmKcug2 and four BmKcug2 analogs. Altogether, this research investigated the different pharmacological properties of BmKcug2 and its truncated analogs, and the findings highlighted the diversity of K+ channel blockers from various scorpion species through thermal processing.
Chenhu Qin; Xiuping Wan; Songryong Li; Fan Yang; Liuting Yang; Zheng Zuo; Zhijian Cao; Zongyun Chen; Yingliang Wu. Different pharmacological properties between scorpion toxin BmKcug2 and its degraded analogs highlight the diversity of K+ channel blockers from thermally processed scorpions. International Journal of Biological Macromolecules 2021, 178, 143 -153.
AMA StyleChenhu Qin, Xiuping Wan, Songryong Li, Fan Yang, Liuting Yang, Zheng Zuo, Zhijian Cao, Zongyun Chen, Yingliang Wu. Different pharmacological properties between scorpion toxin BmKcug2 and its degraded analogs highlight the diversity of K+ channel blockers from thermally processed scorpions. International Journal of Biological Macromolecules. 2021; 178 ():143-153.
Chicago/Turabian StyleChenhu Qin; Xiuping Wan; Songryong Li; Fan Yang; Liuting Yang; Zheng Zuo; Zhijian Cao; Zongyun Chen; Yingliang Wu. 2021. "Different pharmacological properties between scorpion toxin BmKcug2 and its degraded analogs highlight the diversity of K+ channel blockers from thermally processed scorpions." International Journal of Biological Macromolecules 178, no. : 143-153.
Methotrexate (MTX) has been widely used for the treatment of many types of autoimmune diseases, such as rheumatoid arthritis, psoriasis and dermatomyositis. However, its pharmacological mechanism is still unclear completely. In this study, we found that MTX is a potent and selective inhibitor of the Kv1.3 channel, a class of potassium channels highly associated with autoimmune diseases. Electrophysiological experiments showed that MTX inhibited human Kv1.3 channel with an IC50 of 41.5 ± 24.9 nM, and 1 μM MTX inhibited 32.6 ± 1.3% and 25.6 ± 2.2% of human Kv1.1 and Kv1.2 channel currents, respectively. These data implied the unique selectivity of MTX towards the Kv1.3 channel. Excitingly, using channel activation and chimeric experiments, we found that MTX bound to the outer pore region of Kv1.3 channel. Mutagenesis experiments in the Kv.3 channel extracellular pore region further showed that the Dsp371, Thr373 and His399 residues of outer pore region of Kv1.3 channel played important roles in MTX inhibiting activities. In conclusion, MTX inhibited Kv1.3 channel by targeting extracellular pore region, which is different form all the report small molecules, such as PAP-1 and 4-AP, but similar with many natural animal toxin peptides, such as ChTX, ShK and BmKTX. To the best of our knowledge, MTX is the first small molecular scaffold targeting the Kv1.3 channel extracellular pore region, suggesting its potential applications for designing novel Kv1.3 lead drugs and treating Kv1.3 channel-associated autoimmune diseases.
Zili Xie; Yonghui Zhao; Weishan Yang; Wenxin Li; Yingliang Wu; Zongyun Chen. Methotrexate, a small molecular scaffold targeting Kv1.3 channel extracellular pore region. Biochemical and Biophysical Research Communications 2020, 532, 265 -270.
AMA StyleZili Xie, Yonghui Zhao, Weishan Yang, Wenxin Li, Yingliang Wu, Zongyun Chen. Methotrexate, a small molecular scaffold targeting Kv1.3 channel extracellular pore region. Biochemical and Biophysical Research Communications. 2020; 532 (2):265-270.
Chicago/Turabian StyleZili Xie; Yonghui Zhao; Weishan Yang; Wenxin Li; Yingliang Wu; Zongyun Chen. 2020. "Methotrexate, a small molecular scaffold targeting Kv1.3 channel extracellular pore region." Biochemical and Biophysical Research Communications 532, no. 2: 265-270.
Interferon-inducible transmembrane proteins (IFITM1/2/3) have been reported to suppress the entry of a wide range of viruses. However, their antiviral functional residues and specific mechanisms are still unclear. Here, we firstly resolved the topology of IFITM1 on the plasma membrane where N-terminus points into the cytoplasm and C-terminus resides extracellularly. Further, KRRK basic residues of IFITM1 locating at 62–67 of the conserved intracellular loop (CIL) were found to play a key role in the restriction on the Zika virus (ZIKV) and dengue virus (DENV). Similarly, KRRK basic residues of IFITM2/3 also contributed to suppressing ZIKV replication. Finally, IFITM1 was revealed to be capable of restricting the release of ZIKV particles from endosome to cytosol so as to impede the entry of ZIKV into host cells, which was tightly related with the inhibition of IFITM1 on the acidification of organelles. Overall, our study provided topology, antiviral functional residues and the mechanism of interferon-inducible transmembrane proteins.
Fang Sun; Zhiqiang Xia; Yuewen Han; Minjun Gao; Luyao Wang; Yingliang Wu; Jean-Marc Sabatier; Lixia Miao; Zhijian Cao. Topology, Antiviral Functional Residues and Mechanism of IFITM1. Viruses 2020, 12, 295 .
AMA StyleFang Sun, Zhiqiang Xia, Yuewen Han, Minjun Gao, Luyao Wang, Yingliang Wu, Jean-Marc Sabatier, Lixia Miao, Zhijian Cao. Topology, Antiviral Functional Residues and Mechanism of IFITM1. Viruses. 2020; 12 (3):295.
Chicago/Turabian StyleFang Sun; Zhiqiang Xia; Yuewen Han; Minjun Gao; Luyao Wang; Yingliang Wu; Jean-Marc Sabatier; Lixia Miao; Zhijian Cao. 2020. "Topology, Antiviral Functional Residues and Mechanism of IFITM1." Viruses 12, no. 3: 295.
Hepatitis C virus (HCV) infection is a major worldwide health problem which can cause chronic hepatitis, liver fibrosis and hepatocellular carcinoma (HCC). There is still no vaccine to prevent HCV infection. Currently, the clinical treatment of HCV infection mainly relies on the use of direct-acting antivirals (DAAs) which are expensive and have side effects. Here, BmKDfsin3, a scorpion defensin from the venom of Mesobuthus martensii Karsch, is found to dose-dependently inhibit HCV infection at noncytotoxic concentrations and affect viral attachment and post-entry in HCV life cycle. Further experimental results show that BmKDfsin3 not only suppresses p38 mitogen-activated protein kinase (MAPK) activation of HCV-infected Huh7.5.1 cells, but also inhibits p38 activation of Huh7.5.1 cells stimulated by tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) or lipopolysaccharide (LPS). BmKDfsin3 is also revealed to enter into cells. Using an upstream MyD88 dimerization inhibitor ST2345 or kinase IRAK-1/4 inhibitor I, the inhibition of p38 activation represses HCV replication in vitro. Taken together, a scorpion defensin BmKDfsin3 inhibits HCV replication, related to regulated p38 MAPK activation.
Yuting Cheng; Fang Sun; Songryong Li; Minjun Gao; Luyao Wang; Moustafa Sarhan; Mohamed A. Abdel-Rahman; Wenxin Li; Hang Fai Kwok; Yingliang Wu; Zhijian Cao. Inhibitory Activity of a Scorpion Defensin BmKDfsin3 against Hepatitis C Virus. Antibiotics 2020, 9, 33 .
AMA StyleYuting Cheng, Fang Sun, Songryong Li, Minjun Gao, Luyao Wang, Moustafa Sarhan, Mohamed A. Abdel-Rahman, Wenxin Li, Hang Fai Kwok, Yingliang Wu, Zhijian Cao. Inhibitory Activity of a Scorpion Defensin BmKDfsin3 against Hepatitis C Virus. Antibiotics. 2020; 9 (1):33.
Chicago/Turabian StyleYuting Cheng; Fang Sun; Songryong Li; Minjun Gao; Luyao Wang; Moustafa Sarhan; Mohamed A. Abdel-Rahman; Wenxin Li; Hang Fai Kwok; Yingliang Wu; Zhijian Cao. 2020. "Inhibitory Activity of a Scorpion Defensin BmKDfsin3 against Hepatitis C Virus." Antibiotics 9, no. 1: 33.
An increasing number of scorpion fossils indicate that the venomous telson developed from the sharp telson in sea scorpions into the extant scorpion-like telson in aquatic scorpions in the Paleozoic Era and then further evolved into the fetal venom system. This hypothesis led us to evaluate the inhibition of scorpion venom-sensitive potassium channels by hemolymph from the scorpion Mesobuthus martensii. Scorpion hemolymph diluted 1:10 inhibited Kv1.1, Kv1.2, Kv1.3 and SK3 potassium channel currents by 76.4%, 90.2%, 85.8%, and 52.8%, respectively. These discoveries encouraged us to investigate the functional similarity between the more ancient defensin ingredients in hemolymph and the evolved neurotoxins in the venom. In addition to the expression of the representative defensin BmKDfsin3 and BmKDfsin5 in both venomous and non-venomous tissues, NMR analysis revealed structural similarities between scorpion defensin and neurotoxin. Functional experiments further indicated that scorpion defensin used the same mechanism as classical neurotoxin to block the neurotoxin-sensitive Kv1.1, Kv1.2, Kv1.3 and SK3 channels. These findings emphasize the likelihood that scorpion defensins evolved into neurotoxins that were adapted to the emergence of the scorpion telson from the sharp telson of sea scorpions into the extant scorpion-like telson in aquatic scorpions in the Paleozoic Era.
Lanxia Meng; Yonghui Zhao; Daliang Qu; Zili Xie; Xingchen Guo; Zhanyong Zhu; Zongyun Chen; Longhua Zhang; Wenxin Li; Zhijian Cao; Changlin Tian; Yingliang Wu. Ion channel modulation by scorpion hemolymph and its defensin ingredients highlights origin of neurotoxins in telson formed in Paleozoic scorpions. International Journal of Biological Macromolecules 2020, 148, 351 -363.
AMA StyleLanxia Meng, Yonghui Zhao, Daliang Qu, Zili Xie, Xingchen Guo, Zhanyong Zhu, Zongyun Chen, Longhua Zhang, Wenxin Li, Zhijian Cao, Changlin Tian, Yingliang Wu. Ion channel modulation by scorpion hemolymph and its defensin ingredients highlights origin of neurotoxins in telson formed in Paleozoic scorpions. International Journal of Biological Macromolecules. 2020; 148 ():351-363.
Chicago/Turabian StyleLanxia Meng; Yonghui Zhao; Daliang Qu; Zili Xie; Xingchen Guo; Zhanyong Zhu; Zongyun Chen; Longhua Zhang; Wenxin Li; Zhijian Cao; Changlin Tian; Yingliang Wu. 2020. "Ion channel modulation by scorpion hemolymph and its defensin ingredients highlights origin of neurotoxins in telson formed in Paleozoic scorpions." International Journal of Biological Macromolecules 148, no. : 351-363.
Activated macrophages adapt their metabolic pathways to drive the pro-inflammatory phenotype, but little is known about the biochemical underpinnings of this process. Here, we find that lipopolysaccharide (LPS) activates the pentose phosphate pathway, the serine synthesis pathway, and one-carbon metabolism, the synergism of which drives epigenetic reprogramming for interleukin-1β (IL-1β) expression. Glucose-derived ribose and one-carbon units fed by both glucose and serine metabolism are synergistically integrated into the methionine cycle through de novo ATP synthesis and fuel the generation of S-adenosylmethionine (SAM) during LPS-induced inflammation. Impairment of these metabolic pathways that feed SAM generation lead to anti-inflammatory outcomes, implicating SAM as an essential metabolite for inflammatory macrophages. Mechanistically, SAM generation maintains a relatively high SAM:S-adenosylhomocysteine ratio to support histone H3 lysine 36 trimethylation for IL-1β production. We therefore identify a synergistic effect of glucose and amino acid metabolism on orchestrating SAM availability that is intimately linked to the chromatin state for inflammation.
Weiwei Yu; Zhen Wang; Kailian Zhang; Zhexu Chi; Ting Xu; Danlu Jiang; Sheng Chen; Wenxin Li; Xuyan Yang; Xue Zhang; Yingliang Wu; Di Wang. One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages. Molecular Cell 2019, 75, 1147 -1160.e5.
AMA StyleWeiwei Yu, Zhen Wang, Kailian Zhang, Zhexu Chi, Ting Xu, Danlu Jiang, Sheng Chen, Wenxin Li, Xuyan Yang, Xue Zhang, Yingliang Wu, Di Wang. One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages. Molecular Cell. 2019; 75 (6):1147-1160.e5.
Chicago/Turabian StyleWeiwei Yu; Zhen Wang; Kailian Zhang; Zhexu Chi; Ting Xu; Danlu Jiang; Sheng Chen; Wenxin Li; Xuyan Yang; Xue Zhang; Yingliang Wu; Di Wang. 2019. "One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages." Molecular Cell 75, no. 6: 1147-1160.e5.
The neurotoxins of venomous scorpion act on ion channels. Whether these neurotoxins are retained in processed Buthus martensii Karsch scorpions used in traditional Chinese medicine materials is unknown. Comprehensive mass spectrometry-based proteomic characterization of functionally active toxins in the processed medicinal scorpion material revealed 22 full-length and 44 truncated thermostable potassium channel-modulatory toxins that preserved six conserved cysteine residues capable of forming the three disulfide bonds necessary for toxicity. Additionally, a broad spectrum of degraded toxin fragments was found, indicating their relative thermal instability which enabled toxicity reduction. Furthermore, the suppression of interleukin-2 (IL-2) production in Jurkat cells and the reduced delayed-type hypersensitivity (DTH) response demonstrated that the extracts have immunoregulatory activity both in vitro and in vivo. Our work describes the first “map” of functionally active scorpion toxins in processed scorpion medicinal material, which is helpful to unveil the pharmaceutical basis of the processed scorpion medicinal material in traditional Chinese medicine. Scorpions have been used as medicinal materials in China for more than one thousand years. This is an example of the well-known “Combat poison with poison” strategy common to traditional Chinese medicine. In the past 30 years, extensive investigations of Chinese scorpions have indicated that the neurotoxins in the scorpion venom are the main toxic components and they target various ion channels in cell membranes. However, whether these neurotoxins are retained in processed Buthus martensii Karsch scorpions used for traditional Chinese medicine remains unknown. Our study described the thermal stability and instability of potassium channel-modulatory neurotoxins in processed scorpions and helps to understand the pharmaceutical basis underling the strategy of “combat poison with poison to cure diseases”.
Fan Yang; Danya Wang; Yongjia Tong; Chenghu Qin; Liuting Yang; Fei Yu; Xin Huang; Shuang Liu; Zhijian Cao; Lin Guo; Wenxin Li; Yingliang Wu; Xiaolu Zhao. Thermostable potassium channel-inhibiting neurotoxins in processed scorpion medicinal material revealed by proteomic analysis: Implications of its pharmaceutical basis in traditional Chinese medicine. Journal of Proteomics 2019, 206, 103435 .
AMA StyleFan Yang, Danya Wang, Yongjia Tong, Chenghu Qin, Liuting Yang, Fei Yu, Xin Huang, Shuang Liu, Zhijian Cao, Lin Guo, Wenxin Li, Yingliang Wu, Xiaolu Zhao. Thermostable potassium channel-inhibiting neurotoxins in processed scorpion medicinal material revealed by proteomic analysis: Implications of its pharmaceutical basis in traditional Chinese medicine. Journal of Proteomics. 2019; 206 ():103435.
Chicago/Turabian StyleFan Yang; Danya Wang; Yongjia Tong; Chenghu Qin; Liuting Yang; Fei Yu; Xin Huang; Shuang Liu; Zhijian Cao; Lin Guo; Wenxin Li; Yingliang Wu; Xiaolu Zhao. 2019. "Thermostable potassium channel-inhibiting neurotoxins in processed scorpion medicinal material revealed by proteomic analysis: Implications of its pharmaceutical basis in traditional Chinese medicine." Journal of Proteomics 206, no. : 103435.
Scorpion toxins are well-known as the largest potassium channel peptide blocker family. They have been successfully proven to be valuable molecular probes for structural research on diverse potassium channels. The potassium channel pore region, including the turret and filter regions, is the binding interface for scorpion toxins, and structural features from different potassium channels have been identified using different scorpion toxins. According to the spatial orientation of channel turrets with differential sequence lengths and identities, conformational changes and molecular surface properties, the potassium channel turrets can be divided into the following three states: open state with less hindering effects on toxin binding, half-open state or half-closed state with certain effects on toxin binding, and closed state with remarkable effects on toxin binding. In this review, we summarized the diverse structural features of potassium channels explored using scorpion toxin tools and discuss future work in the field of scorpion toxin-potassium channel interactions.
Yonghui Zhao; Zongyun Chen; Zhijian Cao; Wenxin Li; Yingliang Wu. Diverse Structural Features of Potassium Channels Characterized by Scorpion Toxins as Molecular Probes. Molecules 2019, 24, 2045 .
AMA StyleYonghui Zhao, Zongyun Chen, Zhijian Cao, Wenxin Li, Yingliang Wu. Diverse Structural Features of Potassium Channels Characterized by Scorpion Toxins as Molecular Probes. Molecules. 2019; 24 (11):2045.
Chicago/Turabian StyleYonghui Zhao; Zongyun Chen; Zhijian Cao; Wenxin Li; Yingliang Wu. 2019. "Diverse Structural Features of Potassium Channels Characterized by Scorpion Toxins as Molecular Probes." Molecules 24, no. 11: 2045.
Yingliang Wu. Scorpion toxin-potassium channel interactions and their applications. Toxicon 2019, 158, S23 .
AMA StyleYingliang Wu. Scorpion toxin-potassium channel interactions and their applications. Toxicon. 2019; 158 ():S23.
Chicago/Turabian StyleYingliang Wu. 2019. "Scorpion toxin-potassium channel interactions and their applications." Toxicon 158, no. : S23.
Viral infections still threaten human health all over the world, and many people die from viral diseases every year. However, there are no effective vaccines or drugs for preventing or managing most viral diseases. Thus, the discovery and development of broad-spectrum antiviral agents remain urgent. Here, we expressed and purified a venom peptide, Ev37, from the scorpion Euscorpiops validus in a prokaryotic system. We found that rEv37 can inhibit dengue virus type 2 (DENV-2), hepatitis C virus (HCV), Zika virus (ZIKV), and herpes simplex virus type 1 (HSV-1) infections in a dose-dependent manner at noncytotoxic concentrations, but that it has no effect on Sendai virus (SeV) and adenovirus (AdV) infections in vitro. Furthermore, rEv37 alkalized acidic organelles to prevent low pH–dependent fusion of the viral membrane–endosomal membrane, which mainly blocks the release of the viral genome from the endosome to the cytoplasm and then restricts viral late entry. Taken together, our results indicate that the scorpion venom peptide Ev37 is a broad-spectrum antiviral agent with a specific molecular mechanism against viruses undergoing low pH–dependent fusion activation during entry into host cells. We conclude that Ev37 is a potential candidate for development as an antiviral drug.
Fangfang Li; Yange Lang; Zhenglin Ji; Zhiqiang Xia; Yuewen Han; Yuting Cheng; Gaomin Liu; Fang Sun; Yonghui Zhao; Minjun Gao; Zongyun Chen; Yingliang Wu; Wenxin Li; Zhijian Cao. A scorpion venom peptide Ev37 restricts viral late entry by alkalizing acidic organelles. Journal of Biological Chemistry 2019, 294, 182 -194.
AMA StyleFangfang Li, Yange Lang, Zhenglin Ji, Zhiqiang Xia, Yuewen Han, Yuting Cheng, Gaomin Liu, Fang Sun, Yonghui Zhao, Minjun Gao, Zongyun Chen, Yingliang Wu, Wenxin Li, Zhijian Cao. A scorpion venom peptide Ev37 restricts viral late entry by alkalizing acidic organelles. Journal of Biological Chemistry. 2019; 294 (1):182-194.
Chicago/Turabian StyleFangfang Li; Yange Lang; Zhenglin Ji; Zhiqiang Xia; Yuewen Han; Yuting Cheng; Gaomin Liu; Fang Sun; Yonghui Zhao; Minjun Gao; Zongyun Chen; Yingliang Wu; Wenxin Li; Zhijian Cao. 2019. "A scorpion venom peptide Ev37 restricts viral late entry by alkalizing acidic organelles." Journal of Biological Chemistry 294, no. 1: 182-194.
Dengue virus (DENV) and Zika virus (ZIKV) have spread throughout many countries in the developing world and infect millions of people every year, causing severe harm to human health and the economy. Unfortunately, there are few effective vaccines and therapies available against these viruses. Therefore, the discovery of new antiviral agents is critical. Herein, a scorpion venom peptide (Smp76) characterized from Scorpio maurus palmatus was successfully expressed and purified in Escherichia coli BL21(DE3). The recombinant Smp76 (rSmp76) was found to effectively inhibit DENV and ZIKV infections in a dose-dependent manner in both cultured cell lines and primary mouse macrophages. Interestingly, rSmp76 did not inactivate the viral particles directly but suppressed the established viral infection, similar to the effect of interferon (IFN)-β. Mechanistically, rSmp76 was revealed to upregulate the expression of IFN-β by activating interferon regulatory transcription factor 3 (IRF3) phosphorylation, enhancing the type-I IFN response and inhibiting viral infection. This mechanism is significantly different from traditional virucidal antimicrobial peptides (AMPs). Overall, the scorpion venom peptide Smp76 is a potential new antiviral agent with a unique mechanism involving type-I IFN responses, demonstrating that natural AMPs can enhance immunity by functioning as immunomodulators.
Zhenglin Ji; Fangfang Li; Zhiqiang Xia; Xingchen Guo; Minjun Gao; Fang Sun; Yuting Cheng; Yingliang Wu; Wenxin Li; Syed Abid Ali; Zhijian Cao. The Scorpion Venom Peptide Smp76 Inhibits Viral Infection by Regulating Type-I Interferon Response. Virologica Sinica 2018, 33, 545 -556.
AMA StyleZhenglin Ji, Fangfang Li, Zhiqiang Xia, Xingchen Guo, Minjun Gao, Fang Sun, Yuting Cheng, Yingliang Wu, Wenxin Li, Syed Abid Ali, Zhijian Cao. The Scorpion Venom Peptide Smp76 Inhibits Viral Infection by Regulating Type-I Interferon Response. Virologica Sinica. 2018; 33 (6):545-556.
Chicago/Turabian StyleZhenglin Ji; Fangfang Li; Zhiqiang Xia; Xingchen Guo; Minjun Gao; Fang Sun; Yuting Cheng; Yingliang Wu; Wenxin Li; Syed Abid Ali; Zhijian Cao. 2018. "The Scorpion Venom Peptide Smp76 Inhibits Viral Infection by Regulating Type-I Interferon Response." Virologica Sinica 33, no. 6: 545-556.
The classical potassium channel inhibitors are toxin peptides from venomous animals, and whether there are peptide inhibitors from other species is an open question. Due to both the independent and interdependent relationships between the spear (peptide inhibitors) and the shield (potassium channels), human defensins were first identified by our group as endogenous potassium channel inhibitors. Encouraged by the discovery of human defensins as potassium channel inhibitors, defensins from invertebrates and fungi were successively found by our group to be potassium channel inhibitors. In addition, a plant defensin was reported to be a potassium channel inhibitor. Since defensins are widely produced by vertebrate, invertebrate, plant and fungi species, the recent work established a new research field on defensin-potassium channel interactions. Here, we review the current work on defensins from vertebrate, invertebrate, plant and fungi species as inhibitors of potassium channels and discuss future work in this research field.
Yonghui Zhao; Zongyun Chen; Zhijian Cao; Wenxin Li; Yingliang Wu. Defensins, a novel type of animal toxin-like potassium channel inhibitor. Toxicon 2018, 157, 101 -105.
AMA StyleYonghui Zhao, Zongyun Chen, Zhijian Cao, Wenxin Li, Yingliang Wu. Defensins, a novel type of animal toxin-like potassium channel inhibitor. Toxicon. 2018; 157 ():101-105.
Chicago/Turabian StyleYonghui Zhao; Zongyun Chen; Zhijian Cao; Wenxin Li; Yingliang Wu. 2018. "Defensins, a novel type of animal toxin-like potassium channel inhibitor." Toxicon 157, no. : 101-105.
Summary Cholesterol metabolism has been linked to immune functions, but the mechanisms by which cholesterol biosynthetic signaling orchestrates inflammasome activation remain unclear. Here, we have shown that NLRP3 inflammasome activation is integrated with the maturation of cholesterol master transcription factor SREBP2. Importantly, SCAP-SREBP2 complex endoplasmic reticulum-to-Golgi translocation was required for optimal activation of the NLRP3 inflammasome both in vitro and in vivo. Enforced cholesterol biosynthetic signaling by sterol depletion or statins promoted NLPR3 inflammasome activation. However, this regulation did not predominantly depend on changes in cholesterol homeostasis controlled by the transcriptional activity of SREBP2, but relied on the escort activity of SCAP. Mechanistically, NLRP3 associated with SCAP-SREBP2 to form a ternary complex which translocated to the Golgi apparatus adjacent to a mitochondrial cluster for optimal inflammasome assembly. Our study reveals that, in addition to controlling cholesterol biosynthesis, SCAP-SREBP2 also serves as a signaling hub integrating cholesterol metabolism with inflammation in macrophages.
Chuansheng Guo; Zhexu Chi; Danlu Jiang; Ting Xu; Weiwei Yu; Zhen Wang; Sheng Chen; Li Zhang; Qianyun Liu; Xingchen Guo; Xue Zhang; Wenxin Li; Linrong Lu; Yingliang Wu; Bao-Liang Song; Di Wang. Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages. Immunity 2018, 49, 842 -856.e7.
AMA StyleChuansheng Guo, Zhexu Chi, Danlu Jiang, Ting Xu, Weiwei Yu, Zhen Wang, Sheng Chen, Li Zhang, Qianyun Liu, Xingchen Guo, Xue Zhang, Wenxin Li, Linrong Lu, Yingliang Wu, Bao-Liang Song, Di Wang. Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages. Immunity. 2018; 49 (5):842-856.e7.
Chicago/Turabian StyleChuansheng Guo; Zhexu Chi; Danlu Jiang; Ting Xu; Weiwei Yu; Zhen Wang; Sheng Chen; Li Zhang; Qianyun Liu; Xingchen Guo; Xue Zhang; Wenxin Li; Linrong Lu; Yingliang Wu; Bao-Liang Song; Di Wang. 2018. "Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages." Immunity 49, no. 5: 842-856.e7.
Recent reports have identified defensins as a new type of potassium channel inhibitors; differential binding mechanisms of human β-defensins hBD1 and hBD2 point to complex interactions between human β-defensins and potassium channels. We investigated the inhibitory effects of human defensins hBD3 and hBD4 on potassium channels. The data indicate that hBD3 is a voltage-gated channel subfamily A member 3 (Kv1.3) inhibitor with an IC50 value of 187.6 ± 25.7 nM; 1 μM hBD4 inhibited 34.0 ± 0.2% of Kv1.3 channel currents. Moreover, 1 μM hBD3 inhibited 50.6 ± 3.6% of Kv1.2 channel currents and had smaller effects on Kv1.1, SKCa3, and IKCa channel currents; these effects differed from the Kv1.3 channel-specific inhibitors hBD1 and hBD2. Similar to the pharmacological profiles of hBD1 and hBD2, hBD4 had lower inhibitory effects on Kv1.1, Kv1.2, SKCa3, and IKCa channels. Subsequent mutagenesis and channel activation experiments confirmed that hBD3 binds in a manner similar to that of hBD1, interacting with the outer pore region of the Kv1.3 channel without affecting Kv1.3 channel activation. Thus, the data indicate that the human β-defensin family is a novel group of potassium channel inhibitors with diverse types of human β-defensin-potassium channel interactions.
Yonghui Zhao; Zili Xie; Jing Feng; Wenxin Li; Zhijian Cao; Yingliang Wu. Pharmacological characterization of human beta-defensins 3 and 4 on potassium channels: Evidence of diversity in beta-defensin-potassium channel interactions. Peptides 2018, 108, 14 -18.
AMA StyleYonghui Zhao, Zili Xie, Jing Feng, Wenxin Li, Zhijian Cao, Yingliang Wu. Pharmacological characterization of human beta-defensins 3 and 4 on potassium channels: Evidence of diversity in beta-defensin-potassium channel interactions. Peptides. 2018; 108 ():14-18.
Chicago/Turabian StyleYonghui Zhao; Zili Xie; Jing Feng; Wenxin Li; Zhijian Cao; Yingliang Wu. 2018. "Pharmacological characterization of human beta-defensins 3 and 4 on potassium channels: Evidence of diversity in beta-defensin-potassium channel interactions." Peptides 108, no. : 14-18.
Since there is a symbiotic and competitive relationship between microorganisms in the same ecological niche, fungal defensins have been found to be important resources for antimicrobial peptides. Here, a fungal defensin, triintsin, was characterized in a clinical isolate of Trichophytoninterdigitale from a patient with onychomycosis. The comparison of its genomic and mRNA sequences showed the gene organization and structure of three coding exons separated by two introns. The precursor peptide of triintsin contained 85 amino acid residues, which were composed of three parts including an N-terminal signal domain of 21 residues, a pro-peptide of 47 residues that ended at lysine-arginine and a mature peptide of 38 residues at the C-terminus. The 3D-structure established by homology modeling revealed that triintsin presented a representative typical cysteine-stabilized α-helical and β-sheet fold. The reductive linear peptide of triintsin was obtained by chemical synthesis. After cyclization to form three pairs of disulfide bonds, the oxidative-type peptide displayed broad-spectrum antimicrobial activity against both gram-positive and gram-negative bacteria but also showed anti-fungal activity. Moreover, triintsin can effectively inhibit the growth of clinical strains. Altogether, the peptide is a human pathogenic fungus-derived defensin with broad-spectrum antimicrobial activity.
Bingzheng Shen; Jinchun Song; Yonghui Zhao; Yaoyun Zhang; Gaomin Liu; Xueke Li; Xingchen Guo; Wenxin Li; Zhijian Cao; Yingliang Wu. Triintsin, a human pathogenic fungus-derived defensin with broad-spectrum antimicrobial activity. Peptides 2018, 107, 61 -67.
AMA StyleBingzheng Shen, Jinchun Song, Yonghui Zhao, Yaoyun Zhang, Gaomin Liu, Xueke Li, Xingchen Guo, Wenxin Li, Zhijian Cao, Yingliang Wu. Triintsin, a human pathogenic fungus-derived defensin with broad-spectrum antimicrobial activity. Peptides. 2018; 107 ():61-67.
Chicago/Turabian StyleBingzheng Shen; Jinchun Song; Yonghui Zhao; Yaoyun Zhang; Gaomin Liu; Xueke Li; Xingchen Guo; Wenxin Li; Zhijian Cao; Yingliang Wu. 2018. "Triintsin, a human pathogenic fungus-derived defensin with broad-spectrum antimicrobial activity." Peptides 107, no. : 61-67.
The human defensins are recently discovered to inhibit potassium channels, which are classical targets of the animal toxins. Whether other vertebrate defensins are potassium channel inhibitors remains unknown. In this work, we reported that the mouse β-defensin 3 (mBD3) was a novel inhibitor of both endogenous and exogenous potassium channels. The structural analysis showed that mBD3 is the most identical to human Kv1.3 channel-sensitive human β-defensin 2 (hBD2). However, the pharmacological profiles indicated that the recombinant mBD3 (rmBD3) weakly inhibited the mouse and human Kv1.3 channels. Different from the pharmacological features of human β-defensins, mBD3 more selectively inhibited the mouse Kv1.6 and human KCNQ1/KCNE1 channels with IC50 values of 0.6 ± 0.4 μM and 1.2 ± 0.8 μM, respectively. The site directed mutagenesis experiments indicated that the extracellular pore region of mouse Kv1.6 channel was the interaction site of rmBD3. In addition, the minor effect on the channel conductance-voltage relationship curves implied that mBD3 might bind the extracellular transmembrane helices S1-S2 linker and/or S3-S4 linker of mouse Kv1.6 channel. Together, these findings not only revealed mBD3 as a novel inhibitor of both endogenous and exogenous potassium channels, but also provided a clue to investigate the role of mBD3-Kv1.6 channel interaction in the physiological and pathological field in the future.
Yaoyun Zhang; Yonghui Zhao; Hongyue Liu; Weiwei Yu; Fan Yang; Wenhua Li; Zhijian Cao; Yingliang Wu. Mouse β-Defensin 3, A Defensin Inhibitor of Both Its Endogenous and Exogenous Potassium Channels. Molecules 2018, 23, 1489 .
AMA StyleYaoyun Zhang, Yonghui Zhao, Hongyue Liu, Weiwei Yu, Fan Yang, Wenhua Li, Zhijian Cao, Yingliang Wu. Mouse β-Defensin 3, A Defensin Inhibitor of Both Its Endogenous and Exogenous Potassium Channels. Molecules. 2018; 23 (6):1489.
Chicago/Turabian StyleYaoyun Zhang; Yonghui Zhao; Hongyue Liu; Weiwei Yu; Fan Yang; Wenhua Li; Zhijian Cao; Yingliang Wu. 2018. "Mouse β-Defensin 3, A Defensin Inhibitor of Both Its Endogenous and Exogenous Potassium Channels." Molecules 23, no. 6: 1489.
Scorpion toxins are invaluable pharmacological tools for studying ion channels and potential drugs for channelopathies. The long-chain toxins from scorpion venom with four disulfide bridges exhibit their unusual bioactivity or biotoxicity by acting on the sodium channels. However, the functional properties of most toxins are still unclear due to their tiny amounts in crude venom and their challenging production by chemical and gene engineering techniques. Here, we expressed one of the long-chain α-toxins, BmKM9, found in the venom of the scorpion Buthus martensii Karsch and characterized its pharmacological properties on sodium channels. Unlike previous toxin production, the recombinant BmKM9 (rBmKM9) possessed no additional amino acid residues such as the His-tag and thrombin cleavage site. The refolded toxin could inhibit the inactivation of rNav1.4, hNav1.5 and hNav1.7 sodium channels. Dose-response experiments were further conducted on these channels. The calculated EC50 values were 131.7±6.6nM for rNav1.4, 454.2±50.1nM for hNav1.5 and 30.9±10.3μM for hNav1.7. The channel activation experiments indicated that the rBmKM9 toxin could shift the activation curves of rNav1.4 and hNav1.5 channels toward a more negative direction and present the typical features of a β-toxin. However, instead of the same activation property on sodium channels, the rBmKM9 toxin could result in different inactivation shift capabilities on rNav1.4 and hNav1.5 channels. The V1/2 values of the steady-state inactivation were altered to be more positive for rNav1.4 and more negative for hNav1.5. Moreover, the recovery of the hNav1.5 channel from inactivation was more significantly delayed than that of the rNav1.4 channel by exposure to rBmKM9. Together, these findings highlighted that the rBmKM9 toxin presents the pharmacological properties of both α- and β-toxins, which would increase the challenge to the classical classification of scorpion toxins. Furthermore, the expression method and functional information on sodium channels would promote the potential application of toxins and contribute to further channel structural and functional studies.
Fan Yang; Shuang Liu; Yaoyun Zhang; Chenhu Qin; Lingna Xu; Wenhua Li; Zhijian Cao; Wenxin Li; Yingliang Wu. Expression of recombinant α-toxin BmKM9 from scorpion Buthus martensii Karsch and its functional characterization on sodium channels. Peptides 2018, 99, 153 -160.
AMA StyleFan Yang, Shuang Liu, Yaoyun Zhang, Chenhu Qin, Lingna Xu, Wenhua Li, Zhijian Cao, Wenxin Li, Yingliang Wu. Expression of recombinant α-toxin BmKM9 from scorpion Buthus martensii Karsch and its functional characterization on sodium channels. Peptides. 2018; 99 ():153-160.
Chicago/Turabian StyleFan Yang; Shuang Liu; Yaoyun Zhang; Chenhu Qin; Lingna Xu; Wenhua Li; Zhijian Cao; Wenxin Li; Yingliang Wu. 2018. "Expression of recombinant α-toxin BmKM9 from scorpion Buthus martensii Karsch and its functional characterization on sodium channels." Peptides 99, no. : 153-160.