88 results on '"Zhang, Jinghai"'
Search Results
2. Size effect of mesoporous silica nanoparticles on regulating the immune effect of oral influenza split vaccine.
- Author
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Liu Z, Lu H, Li S, Liu B, Zhao Q, Gao Y, Mao Y, Zhang J, and Wang S
- Subjects
- Animals, Administration, Oral, Porosity, Mice, Adjuvants, Immunologic chemistry, Adjuvants, Immunologic pharmacology, Adjuvants, Immunologic administration & dosage, Mice, Inbred BALB C, Female, Immunity, Mucosal drug effects, Surface Properties, Silicon Dioxide chemistry, Influenza Vaccines immunology, Influenza Vaccines chemistry, Influenza Vaccines administration & dosage, Nanoparticles chemistry, Particle Size
- Abstract
Mucosal immunization is a powerful weapon against viral infection. In this paper, large pore mesoporous silica nanoparticles (LMSN) with different particle sizes were synthesized for loading influenza split vaccine (SV) to explore the effect of nanoparticle sizes on mucosal immunization and adjuvant efficacy. Interestingly, it was found that among the three particle sizes of nanoparticles, only LMSN-M with around 250 nm could significantly enhance the mucosal immune effect of SV, possessing adjuvant effect. The results indicated that particle size affected the adjuvant effect of LMSN. There was no apparent difference in vaccine loading capacity of LMSN with different particle sizes, but the release of SV depended on the pore length of LMSN. The adjuvant effect of LMSN-M was attributed to its higher cellular uptake performance, intestine absorption and transport efficiency, and the ability to stimulate the maturation of dendritic cells. Simultaneously, compared with LMSN-S and LMSN-L, the more retention of LMSN-M in mesenteric lymph nodes increased the chance of interaction between vaccine and immune system, resulting in the enhanced immunity. This is the first time to study the impact of particle size of LMSN adjuvant on improving mucosal immunity of oral influenza vaccine, and the present work provides a scientific reference for adjuvant design of oral vaccine., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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3. NhaA: A promising adjuvant target for colistin against resistant Escherichia coli.
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Wang X, Cui Y, Wang Z, Jiang H, Ma L, Li W, Yang X, Zhang J, Zhao Y, and Li G
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- Animals, Anti-Bacterial Agents pharmacology, Microbial Sensitivity Tests, Drug Resistance, Bacterial drug effects, Mice, Escherichia coli Infections drug therapy, Escherichia coli Infections microbiology, Colistin pharmacology, Escherichia coli drug effects, Escherichia coli Proteins metabolism
- Abstract
The emergence and widespread of multidrug-resistant Gram-negative bacteria have posed a severe threat to human health and environmental safety, escalating into a global medical crisis. Utilization of antibiotic adjuvants is a rapid approach to combat bacterial resistance effectively since the development of new antimicrobial agents is a formidable challenge. NhaA, driven by proton motive force, is a crucial secondary transporter on the cytoplasmic membrane of Escherichia coli. We found that 2-Aminoperimidine (2-AP), which is a specific inhibitor of NhaA, could enhance the activity of colistin against sensitive E. coli and reverse the resistance in mcr-1 positive E. coli. Mechanistic studies indicated that 2-AP induced dysfunction in cytoplasmic membrane through the suppression of NhaA, leading to metabolic inhibition and ultimately enhancing the sensitivity of E. coli to colistin. Moreover, 2-AP restored the efficacy of colistin against resistant E. coli in two animal infection models. Our findings reveal the potential of NhaA as a novel target for colistin adjuvants, providing new possibilities for the clinical application of colistin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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4. Glucose-responsive insulin microneedle patches for long-acting delivery and release visualization.
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He Y, Chen N, Zang M, Zhang J, Zhang Y, Lu H, Zhao Q, Mao Y, Yuan Y, Wang S, and Gao Y
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- Humans, Mice, Animals, Needles, Drug Delivery Systems, Insulin, Glucose, Administration, Cutaneous, Diabetes Mellitus, Experimental drug therapy
- Abstract
Limited drug loading and incomplete drug release are two major obstacles that traditional polymeric microneedles (MNs) have to overcome. For smart controlled-release MNs, since drug release duration is uncertain, a clear indication of the finish of drug release is also important for patient guidance on the timing of the next dose. In this study, MN with a triple structure of a glucose-responsive shell, loaded insulin powders and a colored propelling inner core (inspired by the mechanism of osmotic pump) was innovatively constructed. The MN patch could release insulin according to blood glucose levels (BGLs) and had excellent drug loading, more complete drug release, and good drug stability, which significantly prolonged the normoglycemic time. An approximately 0.3 cm
2 patch has a hypoglycemic effect on diabetic mice for up to 24 h. Moreover, the fading of the inner core could indicate the release process of the loaded drug and can help to facilitate uninterrupted closed loop therapy for patients. The designed triple MN structure is also suitable, and can be used in the design of other smart MN drug delivery systems to further improve their drug loading capacity and simultaneously achieve more complete, smart controlled and visualized drug release., Competing Interests: Declaration of competing interest Authors declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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5. Erratum: Author correction to "Immune-awakening Saccharomyces -inspired nanocarrier for oral target delivery to lymph and tumors" [Acta Pharmaceutica Sinica B 12 (2022) 4501-4518].
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Mao Y, Wang X, Chen C, Zhao Q, Liu Y, Zhang J, and Wang S
- Abstract
[This corrects the article DOI: 10.1016/j.apsb.2022.04.018.]., (© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)
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- 2024
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6. Current trends in gas-synergized phototherapy for improved antitumor theranostics.
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Yan Z, Liu Z, Zhang H, Guan X, Xu H, Zhang J, Zhao Q, and Wang S
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- Humans, Precision Medicine, Phototherapy methods, Gases therapeutic use, Combined Modality Therapy, Cell Line, Tumor, Neoplasms pathology, Photochemotherapy, Nanoparticles therapeutic use
- Abstract
Phototherapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), has been considered an elegant solution to eradicate tumors due to its minimal invasiveness and low systemic toxicity. Nevertheless, it is still challenging for phototherapy to achieve ideal outcomes and clinical translation due to its inherent drawbacks. Owing to the unique biological functions, diverse gases have attracted growing attention in combining with phototherapy to achieve super-additive therapeutic effects. Specifically, gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H
2 S) have been proven to kill tumor cells by inducing mitochondrial damage in synergy with phototherapy. Additionally, several gases not only enhance the thermal damage in PTT and the reactive oxygen species (ROS) production in PDT but also improve the tumor accumulation of photoactive agents. The inflammatory responses triggered by hyperthermia in PTT are also suppressed by the combination of gases. Herein, we comprehensively review the latest studies on gas-synergized phototherapy for cancer therapy, including (1) synergistic mechanisms of combining gases with phototherapy; (2) design of nanoplatforms for gas-synergized phototherapy; (3) multimodal therapy based on gas-synergized phototherapy; (4) imaging-guided gas-synergized phototherapy. Finally, the current challenges and future opportunities of gas-synergized phototherapy for tumor treatment are discussed. STATEMENT OF SIGNIFICANCE: 1. The novelty and significance of the work with respect to the existing literature. (1) Strategies to design nanoplatforms for gas-synergized anti-tumor phototherapy have been summarized for the first time. Meanwhile, the integration of various imaging technologies and therapy modalities which endow these nanoplatforms with advanced theranostic capabilities has been summarized. (2) The mechanisms by which gases synergize with phototherapy to eradicate tumors are innovatively and comprehensively summarized. 2. The scientific impact and interest. This review elaborates current trends in gas-synergized anti-tumor phototherapy, with special emphases on synergistic anti-tumor mechanisms and rational design of therapeutic nanoplatforms to achieve this synergistic therapy. It aims to provide valuable guidance for researchers in this field., Competing Interests: Declaration of Competing Interest The authors declare there is no conflict of interests., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)- Published
- 2024
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7. Biosynthesis of Vanillin by Rational Design of Enoyl-CoA Hydratase/Lyase.
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Ye Q, Xu W, He Y, Li H, Zhao F, Zhang J, and Song Y
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- Enoyl-CoA Hydratase genetics, Benzaldehydes, Amino Acids, Lyases
- Abstract
Vanillin holds significant importance as a flavoring agent in various industries, including food, pharmaceuticals, and cosmetics. The CoA-dependent pathway for the biosynthesis of vanillin from ferulic acid involved feruloyl-CoA synthase (Fcs) and enoyl-CoA hydratase/lyase (Ech). In this research, the Fcs and Ech were derived from Streptomyces sp. strain V-1. The sequence conservation and structural features of Ech were analyzed by computational techniques including sequence alignment and molecular dynamics simulation. After detailed study for the major binding modes and key amino acid residues between Ech and substrates, a series of mutations (F74W, A130G, A130G/T132S, R147Q, Q255R, ΔT90, ΔTGPEIL, ΔN1-11, ΔC260-287) were obtained by rational design. Finally, the yield of vanillin produced by these mutants was verified by whole-cell catalysis. The results indicated that three mutants, F74W, Q147R, and ΔN1-11, showed higher yields than wild-type Ech. Molecular dynamics simulations and residue energy decomposition identified the basic residues K37, R38, K561, and R564 as the key residues affecting the free energy of binding between Ech and feruloyl-coenzyme A (FCA). The large changes in electrostatic interacting and polar solvating energies caused by the mutations may lead to decreased enzyme activity. This study provides important theoretical guidance as well as experimental data for the biosynthetic pathway of vanillin.
- Published
- 2023
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8. Butein, a potential drug for the treatment of bone cancer pain through bioinformatic and network pharmacology.
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Liu X, Zhao S, Zhao Q, Chen Y, Jia S, Xiang R, Zhang J, Sun J, Xu Y, and Zhao M
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- Humans, Network Pharmacology, Molecular Docking Simulation, Quality of Life, Computational Biology, Cancer Pain, Bone Neoplasms drug therapy, Bone Neoplasms genetics, Osteosarcoma, Drugs, Chinese Herbal
- Abstract
Bone cancer pain is a difficult-to-treat pathologic condition that impairs the patient's quality of life. The effective therapy options for BCP are restricted due to the unknown pathophysiology. Transcriptome data were obtained from the Gene Expression Omnibus database and differentially expressed gene extraction was performed. DEGs integrated with pathological targets found 68 genes in the study. Butein was discovered as a possible medication for BCP after the 68 genes were submitted to the Connectivity Map 2.0 database for drug prediction. Moreover, butein has good drug-likeness properties. To collect the butein targets, we used the CTD, SEA, TargetNet, and Super-PRED databases. Furthermore, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed butein's pharmacological effects, indicating that butein may aid in treating BCP by altering the hypoxia-inducible factor, NF-kappa B, angiogenesis, and sphingolipid signaling pathways. Moreover, the pathological targets integrated with drug targets were obtained as the shared gene set A, which was analyzed by ClueGO and MCODE. Biological process analysis and MCODE algorithm further analyzed that BCP related targets were mainly involved in signal transduction process and ion channel-related pathways. Next, we integrated targets related to network topology parameters and targets of core pathways, identified PTGS2, EGFR, JUN, ESR1, TRPV1, AKT1 and VEGFA as butein regulated hub genes by molecular docking, which play a critical role in its analgesic effect. This study lays the scientific groundwork for elucidating the mechanism underlying butein's success in the treatment of BCP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)
- Published
- 2023
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9. Voltage-gated sodium channels, potential targets of Tripterygium wilfordii Hook. f. to exert activity and produce toxicity.
- Author
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Xu Y, Li W, Wen R, Sun J, Liu X, Zhao S, Zhang J, Liu Y, and Zhao M
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- Tripterygium, Cardiotoxicity, Triterpenes, Voltage-Gated Sodium Channels
- Abstract
Ethnopharmacology Relevance: Tripterygium wilfordii Hook. f. has been widely used in clinical practice due to its good anti-inflammatory and analgesic activities. However, its application is limited by potential toxicity and side effects., Aim of the Study: The study aimed to identify the mechanisms responsible for the pharmacological activity and cardiotoxicity of the main monomers of Tripterygium wilfordii., Materials and Methods: Database analysis predicted that ion channels may be potential targets of Tripterygium wilfordii. The regulatory effects of monomers (triptolide, celastrol, demethylzeylasteral, and wilforgine) on protein Nav1.5 and Nav1.7 were predicted and detected by Autodock and patch clamping. Then, we used the formalin-induced pain model and evaluated heart rate and myocardial zymograms to investigate the analgesic activity and cardiotoxicity of each monomer in vivo., Results: All four monomers were able to bind to Nav1.7 and Nav1.5 with different binding energies and subsequently inhibited the peak currents of both Nav1.7 and Nav1.5. The monomers all exhibited analgesic effects on formalin-induced pain; therefore, we hypothesized that Nav1.7 is one of the key analgesic targets. Demethylzeylasteral reduced heart rate and increased the level of creatine kinase-MB, thus suggesting a potential cardiac risk; data suggested that the inhibitory effect on Nav1.5 might be an important factor underlying its cardiotoxicity., Conclusion: Our findings provide an important theoretical basis for the further screening of active monomers with higher levels of activity and lower levels of toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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10. Immune-awakenin g Saccharomyces -inspired nanocarrier for oral target delivery to lymph and tumors.
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Mao Y, Wang X, Chen C, Zhao Q, Liu Y, Zhang J, and Wang S
- Abstract
Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenvironment, in addition to improving oral bioavailability relative to other means of delivery of oral drugs. Here, inspired by the specific invasion route of intestinal microorganisms, we pioneered an immune-awakening Saccharomyces -inspired mesoporous silicon nanoparticle (yMSN) for the ingenious cascade-targeted delivery of therapeutic cancer vaccines and antitumor drugs to lymph and tumors via the intestinal lymphatic pathway. Encouragingly, yMSN high-loaded tumor-specific antigens (OVA, 11.9%) and anti-tumor drugs (Len, 28.6%) with high stability, namely Len/OVA/yMSN, efficiently co-delivered OVA and Len to their desired target sites. Moreover, yMSN concomitantly awakened the innate antitumor immunity of dendritic cells and macrophages, strengthening vaccine-induced adaptive immune responses and reversing macrophage-associated immunosuppression in the tumor microenvironment. Surprisingly, Len/OVA/yMSN treatment resulted in excellent synergistic antitumor efficacy and long-term antitumor memory in OVA-Hepa1-6-bearing mice. This high-performance nanocarrier provides a novel approach for lesion-targeting delivery of oral drugs accompanied with awakening of the innate/adaptive immunity of the lesion environment, and also represents a novel path for the oral delivery of diverse therapeutic agents targeting other lymph-mediated diseases., Competing Interests: The authors have no conflicts of interest to declare., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)
- Published
- 2022
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11. Prediction and verification of potential lead analgesic and antiarrhythmic components in Corydalis yanhusuo W. T. Wang based on voltage-gated sodium channel proteins.
- Author
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Sun J, Liu X, Zhao S, Zhang S, Yang L, Zhang J, Zhao M, and Xu Y
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- Analgesics pharmacology, Analgesics therapeutic use, Anti-Arrhythmia Agents, Molecular Docking Simulation, Pain, Plant Extracts chemistry, Corydalis chemistry, Drugs, Chinese Herbal chemistry, Drugs, Chinese Herbal pharmacology, Voltage-Gated Sodium Channels
- Abstract
Corydalis yanhusuo W. T. Wang, a traditional Chinese herbal medicine, has been used as an analgesic for thousands of years and it also promotes blood circulation. In this study, 33 Corydalis yanhusuo alkaloid active components were acquired from Traditional Chinese Medicine Database and Analysis Platform (TCMSP). A total of 543 pain-related targets, 1774 arrhythmia targets, and 642 potential targets of these active components were obtained using Swiss Target Prediction, GeneCards, Open Target Platform, and Therapeutic Target Database. Fifty intersecting targets were visualized through a Venn diagram, KEGG and GO pathway enrichment analysis. The analysis proposed that sodium ion channels are likely potential targets of Corydalis yanhusuo active components as analgesia and anti-arrhythmia agents. Molecular docking showed that the 33 components could bind to Nav1.7 and Nav1.5 (two subtypes of ion channel proteins) with different binding energies. In a patch clamp study, dihydrosanguinarine and dihydrochelerythrine, two monomers with the strongest binding effects, could inhibit the peak currents and promote both activation and inactivation phases of Nav1.5. Meanwhile, dihydrosanguinarine and dihydrochelerythrine could also inhibit peak currents and promote the activation phase of Nav1.7. Therefore, the findings from this study provide valuable information for future uses of traditional Chinese medicines to treat pain and cardiovascular disease., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
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12. Gangliosides play important roles in the nervous system by regulating ion concentrations.
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Xu Y, Sun J, Yang L, Zhao S, Liu X, Su Y, Zhang J, and Zhao M
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- Brain metabolism, Humans, Nerve Regeneration, Neurons metabolism, Signal Transduction, Gangliosides metabolism, Nervous System Diseases metabolism
- Abstract
Gangliosides are important components of the neuronal cell membrane and play a vital role in the development of neurons and the brain. They participate in neurotransmission and are considered as the structural basis of learning and memory. Gangliosides participate in several and important physiological processes, such as cell differentiation, cell signaling, neuroprotection, nerve regeneration and apoptosis. The stability of ion concentration in excitable cells is particularly important in the maintenance of a steady state of cells and in the regulation of physiological functions. Ion concentration has been found to be related to the ganglioside's regulation in many neurological diseases, and several studies have found that they can stabilize intracellular ion concentration by regulating ion channels, which highlights their important regulatory role in neuronal excitability and synaptic transmission. Gangliosides can influence some forms of ion transport, by directly binding to ion transporters or through indirect binding and activation of transport proteins via appropriate signaling pathways. Therefore, the important and special role of gangliosides in the homeostasis of ion concentration is becoming a hot topic in the field and a theoretical basis in promoting help gangliosides use as key drugs for the treatment of nervous system diseases., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
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13. Analysis of CFTR gene expression as an immunological and prognostic biomarker in pan-cancers.
- Author
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Wang Q, Jia S, Zheng J, Xiang R, Cui Y, Zhang J, Xu Y, and Zhao M
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- Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Gene Expression, Humans, Prognosis, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Neoplasms genetics, Neoplasms metabolism
- Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride channel that regulates fluid homeostasis via ATP binding and uses energy to transport relevant substrates across cytomembranes. It has been reported that CFTR plays a crucial role in the incidence and development of various types of cancers by regulating proliferation, metastasis, invasion and apoptosis. However, aberrant CFTR gene expression across different cancers makes it difficult to propose CFTR as a possible pan-cancer biomarker. Here, multiple databases (ONCOMINE, PrognoScan, Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA)), were accessed to investigate the relationship between CFTR gene expression with the immunological and prognostic roles in pan-cancers. The results showed higher CFTR gene expression in tumor tissues compared to normal tissues for most cancers except for CHOL, ESCA, KICH, LAML, SKCM and STAD. Higher expression of the CFTR gene directly correlated with better prognosis for BRCA, GBM, COAD, KIRP, LAML, LUAD, PRAD, SARC and STAD, and CFTR gene expression was higher in stage Ⅰ_Ⅱ compared to stage Ⅲ_ Ⅳ. Furthermore, CFTR gene expression levels were significantly associated with immune infiltrates and immunocytes, in particular, immune checkpoints, in COAD, LIHC, LUAD and LUSC. In conclusion, CFTR can be used as a prognostic marker for nine types of cancers examined in this study where CFTR expression levels play a vital role in forecasting the clinical efficacy of immune checkpoint suppression therapy., (Copyright © 2022. Published by Elsevier Ltd.)
- Published
- 2022
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14. A Versatile Hemolin With Pattern Recognitional Contributions to the Humoral Immune Responses of the Chinese Oak Silkworm Antheraea pernyi .
- Author
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He X, Zhou T, Cai Y, Liu Y, Zhao S, Zhang J, Wang X, and Zhang R
- Subjects
- Animals, China, Immunity, Humoral, Immunoglobulins, Insect Proteins, Bombyx, Moths
- Abstract
Hemolin is a distinctive immunoglobulin superfamily member involved in invertebrate immune events. Although it is believed that hemolin regulates hemocyte phagocytosis and microbial agglutination in insects, little is known about its contribution to the humoral immune system. In the present study, we focused on hemolin in Antheraea pernyi ( Ap -hemolin) by studying its pattern recognition property and humoral immune functions. Tissue distribution analysis demonstrated the mRNA level of Ap -hemolin was extremely immune-inducible in different tissues. The results of western blotting and biolayer interferometry showed recombinant Ap -hemolin bound to various microbes and pathogen-associated molecular patterns. In further immune functional studies, it was detected that knockdown of hemolin regulated the expression level of antimicrobial peptide genes and decreased prophenoloxidase activation in the A. pernyi hemolymph stimulated by microbial invaders. Together, these data suggest that hemolin is a multifunctional pattern recognition receptor that plays critical roles in the humoral immune responses of A. pernyi ., Competing Interests: Author YL is employed by Liaoning Applos Biotechnology Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 He, Zhou, Cai, Liu, Zhao, Zhang, Wang and Zhang.)
- Published
- 2022
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15. Methionine 58 is a key residue in the modulation of BmK scorpion toxin AGP-SYPU2 activity through in silico and in vivo studies.
- Author
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Cui Y, Wang T, Hao Z, Zhang J, and Zhao Y
- Subjects
- Amino Acid Sequence, Analgesics chemistry, Analgesics metabolism, Animals, Methionine metabolism, Scorpion Venoms chemistry, Scorpions chemistry, Scorpions metabolism
- Abstract
Protein dynamic networks play an important role in the regulation of many protein systems. Some residues that are far away from the interface between proteins and their targets have a critical role in modulating the activity of some scorpion toxins. Here, conservation analysis combined with an in vivo experiment has reveals that Met58 is a key residue of BmK scorpion toxin AGP-SYPU2 in the modulation of analgesic activity. Molecular dynamics simulations clearly reveal the conformational changes that allow the loop between the β2 and β3 sheets to be exposed on the toxin surface to interact with its targets. Our results emphasize specific roles for the residue Met58 in the NC domain and our work gives valuable information for further modification of scorpion toxins to obtain new analgesic peptides with enhanced activity. Communicated by Ramaswamy H. Sarma.
- Published
- 2022
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16. Analgesic effect of the main components of Corydalis yanhusuo (yanhusuo in Chinese) is caused by inhibition of voltage gated sodium channels.
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Xu Y, Sun J, Li W, Zhang S, Yang L, Teng Y, Lv K, Liu Y, Su Y, Zhang J, and Zhao M
- Subjects
- Analgesics chemistry, Analgesics isolation & purification, Animals, Berberine Alkaloids isolation & purification, Berberine Alkaloids pharmacology, CHO Cells, Cricetulus, Disease Models, Animal, Drugs, Chinese Herbal chemistry, Drugs, Chinese Herbal pharmacology, Formaldehyde, Mice, Pain drug therapy, Patch-Clamp Techniques, Voltage-Gated Sodium Channel Blockers chemistry, Voltage-Gated Sodium Channel Blockers isolation & purification, Voltage-Gated Sodium Channels drug effects, Voltage-Gated Sodium Channels metabolism, Analgesics pharmacology, Corydalis chemistry, Drugs, Chinese Herbal poisoning, Voltage-Gated Sodium Channel Blockers pharmacology
- Abstract
Ethnopharmacology Relevance: Pain often causes a series of abnormal changes in physiology and psychology, which can lead to disease and even death. Drug therapy is the most basic and commonly used method for pain relief and management. Interestingly, at present, hundreds of traditional Chinese medicines have been reported to be used for pain relief, most of which are monomer preparations, which have been developed into new painkillers. Corydalis yanhusuo is a representative of one of these medicines and is available for pain relief., Aim of the Study: This study aims to determine the analgesic effect and the potential targets of the monomers derived from Corydalis yanhusuo, and to explore any possible associated cardiac risk factors., Materials and Methods: In this study, four monomers derived from Corydalis yanhusuo (tetrahydropalmatine, corydaline, protopine, dehydrocorydaline) were tested in vivo, using the formalin-induced pain model to determine their analgesic properties. Their potential targets were also determined using whole cell patch clamp recordings and myocardial enzyme assays., Results: The results showed that all monomers showed analgesic activity and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.7, which indicating that Nav1.7 might be involved in the analgesic mechanism of Corydalis yanhusuo. Protopine increased the level of creatine kinase-MB (CK-MB) and inhibited the peak currents, promoted the activation and inactivation phases of Nav1.5, indicating that Nav1.5 might be involved in the cardiac risk associated with protopine treatment., Conclusion: These data showed that tetrahydropalmatine produced the best analgesic effect and the lowest cardiac risk. Thus, voltage gated sodium channels (VGSCs) might be the main targets associated with Corydalis yanhusuo. This study, therefore, provides valuable information for future studies and use of traditional Chines medicines for the alleviation of pain., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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17. Identification of a novel protective human monoclonal antibody, LXY8, that targets the key neutralizing epitopes of staphylococcal enterotoxin B.
- Author
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Hu N, Qiao C, Wang J, Wang Z, Li X, Zhou L, Wu J, Zhang D, Feng J, Shen B, Zhang J, and Luo L
- Subjects
- Animals, CHO Cells, Cell Proliferation, Cell Surface Display Techniques, Cricetulus, Cytokines metabolism, Enterotoxins antagonists & inhibitors, Epitope Mapping, Female, Histocompatibility Antigens Class II metabolism, Humans, Mice, Inbred BALB C, Protein Binding, Receptors, Antigen, T-Cell metabolism, Mice, Antibodies, Bacterial analysis, Antibodies, Monoclonal analysis, Antibodies, Neutralizing analysis, Enterotoxins immunology, Epitopes immunology
- Abstract
Staphylococcal enterotoxin B (SEB), one of the exotoxins produced by Staphylococcus aureus, is the key toxin that causes poisoning reactions and toxic shock syndrome. In the current research work, a novel human antibody named LXY8 was screened from a human phage display antibody library, and LXY8 blocked the interaction between SEB and the T cell receptor (TCR). The binding activity between LXY8 and SEB was 0.525 nM. Furthermore, LXY8 could effectively inhibit the SEB-induced activation of peripheral blood mononuclear cells and release of cytokines. In the BALB/c mouse model, LXY8 effectively neutralized SEB toxicity in vivo. Finally, based on computer-guided molecular modeling, we designed a series of SEB mutation sites; these sites facilitated the determination of the key residues (i.e.
176 EFNN179 ) of SEB recognized by LXY8. The research revealed that the176 EFNN179 residues of SEB are important for specific antibody-antigen recognition. The results may be helpful for the development of antibody-based therapy for SEB-induced toxic shock syndrome., Competing Interests: Declaration of competing interest Long L. Luo, Nai J. Hu, Chun X. Qiao, Jing Wang, Xin Y. Li, Jan N. Feng and Bei F. Shen have submitted patent applications pertaining to anti-SEB antibodies. The other authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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18. Active components of Bupleurum chinense and Angelica biserrata showed analgesic effects in formalin induced pain by acting on Nav1.7.
- Author
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Xu Y, Yu Y, Wang Q, Li W, Zhang S, Liao X, Liu Y, Su Y, Zhao M, and Zhang J
- Subjects
- Analgesics chemistry, Analgesics therapeutic use, Animals, CHO Cells, Cricetulus, Disease Models, Animal, Drugs, Chinese Herbal chemistry, Drugs, Chinese Herbal therapeutic use, Female, Formaldehyde toxicity, Furocoumarins pharmacology, Furocoumarins therapeutic use, Hot Temperature adverse effects, Male, Medicine, Chinese Traditional, Mice, Oleanolic Acid analogs & derivatives, Oleanolic Acid pharmacology, Oleanolic Acid therapeutic use, Pain etiology, Plant Roots chemistry, Saponins pharmacology, Saponins therapeutic use, Sodium physiology, Analgesics pharmacology, Angelica chemistry, Bupleurum chemistry, Drugs, Chinese Herbal pharmacology, NAV1.7 Voltage-Gated Sodium Channel drug effects, Pain drug therapy
- Abstract
Ethnopharmacology Relevance: Pain is an unpleasant sensory and emotional experience, often accompanied by the occurrence of a variety of diseases. More than 800 kinds of traditional Chinese medicines (TCM) has now been reported for pain relief and several monomers have been developed into novel analgesic drugs. Bupleurum chinense and Angelica biserrata were representatives of the TCM that are currently available for the treatment of pain., Aim of the Study: The study aims to detect the potential analgesic activity of each monomer of Bupleurum chinense and Angelica biserrata and to explore whether Nav1.7 is one of the targets for its analgesic activity., Materials and Methods: In this study, five monomers from Bupleurum chinense (Saikosaponin A, Saikosaponin B1, Saikosaponin B2, Saikosaponin C, Saikosaponin D) and five monomers from the Angelica biserrata (Osthole, Xanthotoxin, Imperatorin, Isoimperatorin, Psoralen) were examined by whole-cell patch-clamp on Nav1.7, which was closely associated with pain. Classical mouse pain models were also used to further verify the analgesic activity in vivo., Results: The results showed that monomers of Saikosaponins and Angelica biserrata all inhibited the peak currents of Nav1.7, indicating that Nav1.7 might be involved in the analgesic mechanism of Saikosaponins and Angelica biserrata. Among them, Saikosaponin A and Imperatorin showed the strongest inhibitory effect on Nav1.7. Furthermore, both Saikosaponin A and Imperatorin showed inhibitory effects on thermal pain and formalin-induced pain in phase II in vivo., Conclusion: The results provide valuable information for future studies on the potential of TCM in alleviating pain., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2021
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19. Regulatory effects of non-steroidal anti-inflammatory drugs on cardiac ion channels Nav1.5 and Kv11.1.
- Author
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Xu Y, Li W, Han Y, Liu H, Zhang S, Yan J, Sun J, Liu Y, Zhang J, and Zhao M
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, CHO Cells, Cricetulus, HEK293 Cells, Humans, Ion Channel Gating drug effects, Kinetics, Anti-Inflammatory Agents, Non-Steroidal pharmacology, ERG1 Potassium Channel metabolism, NAV1.5 Voltage-Gated Sodium Channel metabolism
- Abstract
Non-steroidal Anti-inflammatory Drugs (NSAIDs) are widely used because of their excellent anti-inflammatory and analgesic effects. However, NSAIDs could cause certain cardiac side effects, such as myocardial infarction, heart failure, atrial fibrillation, arrhythmia and sudden cardiac death. Therefore, meloxicam, nimesulide, piroxicam, and diclofenac were selected and the whole cell patch clamp technique was used to investigate the electrophysiological regulatory effects of them on the sodium channel hNav1.5 and potassium channel hKv11.1, which were closely associated to the biotoxicity of cardiac, and to explore the potential cardiac risk mechanism. The results showed that the four NSAIDs could inhibit the peak currents of hNav1.5 and hKv11.1. Furthermore, the four NSAIDs could affect both the activation and inactivation processes of hNav1.5 with I-V curves left-shifted to hyperpolarized direction in activation phase. These data indicate that the inhibition effects of Nav1.5 and Kv11.1 by meloxicam, nimesulide, piroxicam, and diclofenac might contribute to their potential cardiac risk. These findings provide a basis for the discovery of other potential cardiac risk targets for NSAIDs., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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20. Trp: a conserved aromatic residue crucial to the interaction of a scorpion peptide with sodium channels.
- Author
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Xu Y, Sun J, Yu Y, Kong X, Meng X, Liu Y, Cui Y, Su Y, Zhao M, and Zhang J
- Subjects
- Animals, Female, Humans, Ion Channel Gating, Male, Mice, NAV1.4 Voltage-Gated Sodium Channel genetics, NAV1.5 Voltage-Gated Sodium Channel genetics, NAV1.7 Voltage-Gated Sodium Channel genetics, Peptide Fragments genetics, Scorpion Venoms genetics, Tryptophan genetics, Analgesics pharmacology, NAV1.4 Voltage-Gated Sodium Channel metabolism, NAV1.5 Voltage-Gated Sodium Channel metabolism, NAV1.7 Voltage-Gated Sodium Channel metabolism, Pain drug therapy, Peptide Fragments pharmacology, Scorpion Venoms pharmacology, Tryptophan metabolism
- Abstract
Anti-tumour-analgesic peptide (AGAP), one scorpion toxin purified from Buthus martensii Karsch, was known as its analgesic and anti-tumour activities. Trp38, a conserved aromatic residue of AGAP, might play important roles in its interaction with sodium channels. In this study, a mutant W38F was generated and effects of W38F were examined on hNav1.4, hNav1.5 and hNav1.7 by using whole-cell patch-clamp, which were closely associated to the biotoxicity of skeletal and cardiac muscles and pain signalling. The data showed that W38F decreased the inhibition effects of peak currents of hNav1.7, hNav1.4 and hNav1.5 compared with AGAP, notably, W38F reduced the analgesic activity compared with AGAP. The results suggested that Trp38 be a crucial amino acid involved in the interaction with these three sodium channels. The decreased analgesic activity of W38F might result from its much less inhibition of hNav1.7. These findings provided more information about the relationship between structure and function of AGAP and may facilitate the modification of other scorpion toxins with pharmacological effects., (© Crown copyright 2020.)
- Published
- 2020
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21. Investigation of the Selectivity of L-Type Voltage-Gated Calcium Channels 1.3 for Pyrimidine-2,4,6-Triones Derivatives Based on Molecular Dynamics Simulation.
- Author
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Ye Q, Zhang Z, Zhang W, Ding Y, Zhao F, Zhang J, and Song Y
- Subjects
- Binding Sites, Calcium Channel Blockers chemistry, Calcium Channel Blockers pharmacology, Humans, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Molecular Conformation, Molecular Structure, Protein Binding, Protein Interaction Domains and Motifs, Structure-Activity Relationship, Calcium Channels, L-Type chemistry, Molecular Dynamics Simulation, Pyrimidinones chemistry, Pyrimidinones pharmacology
- Abstract
Human Ca
v 1.3 (hCav 1.3) is of great interest as a potential target for Parkinson's disease. However, common medications like dihydropyridines (DHPs), a kind of classic calcium channel blocker, have poor selectivity to hCav 1.3 in clinical treatment, mainly due to being implicated in cardiovascular side-effects mediated by human Cav 1.2 (hCav 1.2). Recently, pyrimidine-2,4,6-triones (PYTs) have received extensive attention as prominent selective inhibitors to hCav 1.3. In this study, we describe the selectivity mechanism of PYTs for hCav 1.2 and hCav 1.3 based on molecular dynamic simulation methods. Our results reveal that the van der Waals (vdW) interaction was the most important force affecting selectivity. Moreover, the hydrophobic interaction was more conducive to the combination. The highly hydrophobic amino acid residues on hCav 1.3, such as V162 (IR1), L303 (IR2), M481 (IR3), and F484 (IR3), provided the greatest contributions in the binding free energy. On the other hand, the substituents of a halogen-substituted aromatic ring, cycloalkyl and norbornyl on PYTs, which are pertinent to the steric hindrance of the compounds, played core roles in the selectivity and affinity for hCav 1.3, whereas strong polar substituents needed to be avoided. The findings could provide valuable information for designing more effective and safe medicines for Parkinson's disease.- Published
- 2020
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22. A novel hexamerin with an unexpected contribution to the prophenoloxidase activation system of the Chinese oak silkworm, Antheraea pernyi.
- Author
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Liu C, Zhu J, Ma J, Zhang J, Wang X, and Zhang R
- Subjects
- Amino Acid Sequence, Animals, Catechol Oxidase metabolism, DNA, Complementary genetics, Enzyme Precursors metabolism, Insect Proteins chemistry, Insect Proteins immunology, Larva, Phylogeny, Sequence Alignment, Immunity, Innate genetics, Insect Proteins genetics, Moths genetics, Moths immunology
- Abstract
Hexamerin was originally identified as a storage protein but later confirmed to be involved in many physiological processes. In the present study, we cloned and characterized a novel hexamerin complementary DNA sequence from the Chinese oak silkworm, Antheraea pernyi (Ap-hexamerin), which shows high homology with reported insect methionine-rich hexamerins. The tissue distribution and time course of expression demonstrated that Ap-hexamerin was predominantly synthesized in the fat body and the expression level was significantly increased in response to the microbial challenge, suggesting the relevance of Ap-hexamerin to immune responses. In further immune functional studies, Ap-hexamerin was confirmed to take part in the upregulation of prophenoloxidase (PPO) activation in A. pernyi haemolymph triggered by pathogen-associated molecular patterns (PAMPs). Additional molecular interaction analysis revealed that Ap-hexamerin is capable of binding the PAMPs used in the phenoloxidase assay, suggesting hexamerin in A. pernyi may positively regulate haemolymph PPO activation, acting as a pattern recognition protein., (© 2019 Wiley Periodicals, Inc.)
- Published
- 2020
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23. Siglec1 enhances inflammation through miR-1260-dependent degradation of IκBα in COPD.
- Author
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Li S, Jiang L, Yang Y, Cao J, Zhang Q, Zhang J, Wang R, Deng X, and Li Y
- Subjects
- 3' Untranslated Regions genetics, Animals, Cell Line, Cytokines metabolism, Disease Models, Animal, Down-Regulation genetics, Lung metabolism, Lung pathology, Male, MicroRNAs genetics, Protein Binding, RNA, Messenger genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Inflammation genetics, MicroRNAs metabolism, NF-KappaB Inhibitor alpha metabolism, Proteolysis, Pulmonary Disease, Chronic Obstructive genetics, Sialic Acid Binding Ig-like Lectin 1 metabolism
- Abstract
It has been documented that sialic acid-binding Ig-like lectin 1 (Siglec1) is a cell surface protein with a variety of functions in the immune system. In the present study, we evaluated whether Siglec1 plays a role in chronic obstructive pulmonary disease (COPD). Results show that the expression of Siglec1 was increased in the lung of COPD rats, and that Siglec1 overexpression greatly enhanced the expression of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6 in cigarette smoke extract (CSE)-treated NR8383 cells, a rat lung-derived macrophage cell line. Notably, the proinflammatory effect of Siglec1 was totally inhibited by overexpression of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α (IκBα). Importantly, Siglec1 overexpression increased miR-1260, which then degraded IκBα through its 3' untranslated region (3'UTR). Further study demonstrated that miR-1260 inhibitor attenuated inflammation in CSE-induced rat COPD lung and in CSE-treated NR8383 cells. Finally, the inhibitory effect of miR-1260 on inflammation was totally lost when IκBα was inhibited. In summary, the present study demonstrated that Siglec1 exerts its proinflammatory effects through increasing miR-1260, leading to decreased expression of IκBα., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2020
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24. Voltage-gated sodium channels β3 subunit promotes tumorigenesis in hepatocellular carcinoma by facilitating p53 degradation.
- Author
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Li S, Han J, Guo G, Sun Y, Zhang T, Zhao M, Xu Y, Cui Y, Liu Y, and Zhang J
- Subjects
- Carcinoma, Hepatocellular metabolism, Cell Cycle, Cell Proliferation, Cellular Senescence, Gene Knockdown Techniques, Hep G2 Cells, Humans, Liver Neoplasms metabolism, Proto-Oncogene Proteins c-mdm2 metabolism, Ubiquitination, Voltage-Gated Sodium Channel beta-3 Subunit deficiency, Voltage-Gated Sodium Channel beta-3 Subunit genetics, Carcinogenesis, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology, Proteolysis, Tumor Suppressor Protein p53 metabolism, Voltage-Gated Sodium Channel beta-3 Subunit metabolism
- Abstract
The voltage-gated sodium channels (VGSCs) are aberrantly expressed in a variety of tumors and play an important role in tumor growth and metastasis. Here, we show that VGSCs auxiliary β3 subunit, encoded by the SCN3B gene, promotes proliferation and suppresses apoptosis in HepG2 cells by promoting p53 degradation. β3 significantly increases HepG2 cell proliferation, promotes tumor growth in mouse xenograft models, and suppresses senescence and apoptosis. We found that β3 knockdown stabilizes p53 protein, leading to potentiation of p53-induced cell cycle arrest, senescence, and apoptosis. Mechanistic studies revealed that β3 could bind to p53, promoting p53 ubiquitination and degradation by stabilizing the p53/MDM2 complex. Our results suggest that β3 is a novel negative regulator of p53 and a potential oncogenic factor., (© 2019 Federation of European Biochemical Societies.)
- Published
- 2020
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25. The diversity of pattern recognition receptors (PRRs) involved with insect defense against pathogens.
- Author
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Wang X, Zhang Y, Zhang R, and Zhang J
- Subjects
- Animals, Bacteria, Biological Coevolution, Immunity, Innate, Insecta immunology, Insecta microbiology, Receptors, Pattern Recognition immunology
- Abstract
Through evolution, selection pressures cause both insects and the pathogens attacking them to adapt so that they will both survive and this has been called the co-evolutionary 'arms race'. Insects expand their repertoire of pattern recognition receptors (PRRs), a fundamental and core component of their immune systems, to adapt to the constantly changing and unpredictable diversity of pathogens. In this review, we discuss the diversity of PRRs based on studies conducted in recent years. The strategies associated with PRR diversity summarized here are genetic evolution, isoform diversity based on alternative splicing, 'part-time' PRRs, PRRs with opsonin function, and regulation of complex signaling pathways. Taken together, these data indicate that the function of PRRs in insect immunity is far more complex and possesses more features than originally thought., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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26. Enhanced interaction between SEC2 mutant and TCR Vβ induces MHC II-independent activation of T cells via PKCθ/NF-κB and IL-2R/STAT5 signaling pathways.
- Author
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Fu X, Xu M, Song Y, Li Y, Zhang H, Zhang J, and Zhang C
- Subjects
- Animals, Cell Proliferation, Enterotoxins metabolism, Female, Gene Expression Regulation immunology, Histocompatibility Antigens Class II metabolism, Interleukin-2 metabolism, Mice, Mice, Inbred BALB C, NF-kappa B metabolism, Phosphorylation, Protein Kinase C-theta metabolism, Receptors, Interleukin-2 metabolism, STAT5 Transcription Factor metabolism, Spleen immunology, T-Lymphocytes cytology, Enterotoxins genetics, Lymphocyte Activation, Mutation, Receptors, Antigen, T-Cell metabolism, Signal Transduction, T-Lymphocytes immunology
- Abstract
SEC2, a major histocompatibility complex class II (MHC II)-dependent T-cell mitogen, binds MHC II and T-cell receptor (TCR) Vβs to induce effective co-stimulating signals for clonal T-cell expansion. We previously characterized a SEC2 mutant with increased recognition of TCR Vβs, ST-4, which could intensify NF-κB signaling transduction, leading to IL-2 production and T-cell activation. In this study, we found that in contrast to SEC2, ST-4 could induce murine CD4
+ T-cell proliferation in a Vβ8.2- and Vβ8.3-specific manner in the absence of MHC II+ antigen-presenting cells (APCs). Furthermore, although IL-2 secretion in response to either SEC2 or ST-4 stimulation was accompanied by up-regulation of protein kinase Cθ (PKCθ), inhibitor of κB (IκB), α and β IκB kinase (IKKα/β), IκBα, and NF-κB in mouse splenocytes, only ST-4 could activate CD4+ T cells in the absence of MHC II+ APCs through the PKCθ/NF-κB signaling pathway. The PKCθ inhibitor AEB071 significantly suppressed SEC2/ST-4-induced T-cell proliferation, CD69 and CD25 expression, and IL-2 secretion with or without MHC II+ APCs. Further, SEC2/ST-4-induced changes in PKCθ/NF-κB signaling were significantly relieved by AEB071 in a dose-dependent manner. Using Lck siRNA, we found that Lck controlled SEC2/ST-4-induced phosphorylation of PKCθ. We also demonstrated that the IL-2R/STAT5 pathway is essential for SEC2/ST-4-induced T-cell activation. Collectively, our data demonstrate that an enhanced ST-4-TCR interaction can compensate for lack of MHC II and stimulate MHC II-free CD4+ T-cell proliferation via PKCθ/NF-κB and IL-2R/STAT5 signaling pathways. Compared with SEC2, intensified PKCθ/NF-κB and IL-2R/STAT5 signals induced by ST-4 lead to enhanced T-cell activation. The results of this study will facilitate better understanding of TCR-based immunotherapies for cancer., (© 2018 Fu et al.)- Published
- 2018
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27. Occurrence state of co-existing arsenate and nickel ions at the ferrihydrite-water interface: Mechanisms of surface complexation and surface precipitation via ATR-IR spectroscopy.
- Author
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Wang C, Cui Y, Zhang J, Gomez M, Wang S, and Jia Y
- Subjects
- Arsenates chemistry, Ferric Compounds chemistry, Nickel chemistry, Spectroscopy, Fourier Transform Infrared methods, Water adverse effects
- Abstract
Arsenic and nickel are common contaminants that usually co-exist in many contaminated natural and mining environments. More research on the interaction of these two contaminants is needed such as their coordination structure and occurrence state at mineral-water interfaces. In this study, we investigated the structure of surface complexes and surface precipitates formed by co-existing As(V) and Ni(II) ions at the ferrihydrite-water interface by varying the order of adsorption processes, pH, aging time and Ni(II) concentration using attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). ATR-FTIR analysis revealed the presence of complexed AsONi bonds which produced ternary surface complexes. These ternary AsONi surface complexes formed through a layer by layer alternative coordination on top of the binary AsOFe surface site complexes of ferrihydrite. Such multilayer surface complexes formed as initial surface precipitates which were found to refine their surface structure from amorphous to crystalline phases and were a function of incubation time, coverage of multilayer surface complexes, Ni(II) concentration and pH. Our results presented here can well explain the formation process of surface precipitates on the molecular scale and are of use to forecast the fate and mobility of commonly As(V) and Ni(II) species at the ferrihydrite-water interface commonly found in natural or mine tailings water-soil environments., (Copyright © 2018. Published by Elsevier Ltd.)
- Published
- 2018
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28. A novel peptidoglycan recognition protein involved in the prophenoloxidase activation system and antimicrobial peptide production in Antheraea pernyi.
- Author
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Zhao S, Wang X, Cai S, Zhang S, Luo H, Wu C, Zhang R, and Zhang J
- Subjects
- Animals, Antimicrobial Cationic Peptides immunology, Bacteria immunology, Larva immunology, Larva microbiology, Moths microbiology, Receptors, Pattern Recognition immunology, Recombinant Proteins immunology, Carrier Proteins immunology, Catechol Oxidase immunology, Enzyme Activation immunology, Enzyme Precursors immunology, Insect Proteins immunology, Moths immunology
- Abstract
Pattern recognition receptors (PRRs) are employed in insects to defend against infectious pathogens by triggering various immune responses. Peptidoglycan recognition proteins (PGRPs), a vital family of PRRs, are widely distributed and highly conserved from vertebrates to invertebrates. To date, five PGRP genes have been identified in Antheraea pernyi, but their biochemical roles still remain unknown. In this study, we focused on the immune functions of PGRP-SA in A. pernyi (ApPGRP-SA), which was confirmed to be immune-related according to its significantly up-regulated expression level post microbial injection. In addition, the binding properties of ApPGRP-SA were investigated using a recombinant protein produced in a prokaryotic expression system, revealing that rApPGRP-SA displayed a multi-binding ability to various microbes, including the Gram-positive bacteria Staphylococcus aureus and Micrococcus luteus, Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, and fungus Candida albicans, together with their surface pathogen associated molecular patterns (PAMPs). Further studies showed that after recognition, the mixture of rApPGRP-SA/PAMP remarkably stimulated prophenoloxidase (PPO) activation in the hemolymph of A. pernyi in vitro, while the ds-PGRP-SA-treated hemolymph exhibited a lower sensitivity to PAMPs in comparison to the native sample. Moreover, the transcriptional level of the three antimicrobial peptides was also decreased in PGRP-SA knock-down larvae in response to immune-challenge. In summary, we conclude that ApPGRP-SA is a novel identified PGRP in A. pernyi that might act as a broad-spectrum pattern recognition receptor and is involved in the PPO activation system as well as antimicrobial peptide production., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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29. The role of the arginine residue in site RC for the analgesic activity of the recombinant Chinese scorpion Buthus martensii Karsch, BmK AGP-SYPU1.
- Author
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Cui Y, Wang Y, Wang X, Zhang Z, Zhang J, and Zhao Y
- Subjects
- Analgesics administration & dosage, Analgesics chemistry, Animals, Arginine chemistry, Arginine genetics, China, Female, Injections, Intraperitoneal, Male, Mice, Mice, Inbred Strains, Models, Molecular, Mutagenesis, Site-Directed, Recombinant Proteins administration & dosage, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Analgesics pharmacology, Arginine pharmacology, Scorpions chemistry
- Abstract
Scorpion venom is composed of a large number of bioactive peptides which display important pharmacological activities. In this study we have carried out a study of the functional role of the arginine residue at position 58 in the site RC comprising the reverse turn (8-12) and C-terminal residues 58-64. A polymerase chain reaction was used to substitute this arginine residue with a single amino acid such as alanine, glycine and lysine. The mutants were expressed in soluble form in E. coli, and purified by affinity chromatography. After target peptide purity identification, the recombinant peptides underwent a circular dichroism analysis and a study of their analgesic activity in mice. The results indicated that a single residue modification can affect the pharmacological activity. Our efforts establish a sound basis for further study of the structure-function determinants of the analgesic effect., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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30. Scorpion Toxins Targeting Voltage-gated Sodium Channels Associated with Pain.
- Author
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Xu Y, Sun J, Liu H, Sun J, Yu Y, Su Y, Cui Y, Zhao M, and Zhang J
- Subjects
- Analgesics chemistry, Animals, Humans, Pain metabolism, Protein Isoforms, Scorpion Venoms chemistry, Scorpions, Voltage-Gated Sodium Channel Blockers chemistry, Voltage-Gated Sodium Channels genetics, Analgesics pharmacology, Ion Channel Gating drug effects, Pain drug therapy, Scorpion Venoms pharmacology, Voltage-Gated Sodium Channel Blockers pharmacology, Voltage-Gated Sodium Channels metabolism
- Abstract
Pain affects approximately 30% of people and places a large economic and social burden on society. Despite the availability of a range of analgesics, complete alleviation of symptoms still rarely occurred. Effective and safe drugs for the treatment of pain are still an unmet clinical need. In recent years, the voltage-gated sodium channels (VGSCs) have been recognized as potential targets for analgesic development. VGSCs are major players in generating and propagating action potentials. They represent an appealing target for the development of new and safer drugs in the treatment of pain. The majority of the research has been focused on Nav1.7 in particular, other VGSC subtypes, such as Nav1.1, Nav1.3, Nav1.6, Nav1.8 and Nav1.9 have recently come to the forefront of analgesic research. Peptides from scorpion have been proved to be a valuable tool in neuroscience, playing a significant role in the identification and characterization of VGSC subtypes and many of them resulting in analgesia in pain. This review assesses the potential of scorpion toxin targeting VGSCs for analgesic development., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2018
- Full Text
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31. Cloning and characterization of an insect apolipoprotein (apolipophorin-II/I) involved in the host immune response of Antheraea pernyi.
- Author
-
Wen D, Luo H, Li T, Wu C, Zhang J, Wang X, and Zhang R
- Subjects
- Animals, Apolipoproteins metabolism, Cloning, Molecular, Host-Pathogen Interactions, Immunity, Innate, Insect Proteins metabolism, Phylogeny, Protein Processing, Post-Translational, Sequence Alignment, Serine Endopeptidases metabolism, Transcriptome, Apolipoproteins genetics, Bacterial Infections immunology, Fat Body physiology, Insect Proteins genetics, Moths immunology
- Abstract
Apolipoproteins are protein components of lipoprotein particles, and are increasingly recognized to be functioning in the innate immune systems of both insects and mammals. Mammalian apolipoprotein B (apoB) is associated with a diverse range of innate immune defenses including suppression of bacterial pathogenesis, virus toxicity neutralization, and inhibition of cytokine releases from immune cells. However, little is known about apoB homologous insect apolipophorin-II/I (apoLp-II/I) in controlling of specific pathogen-host encounters such as microbial infections. In the present study, we describe cDNA cloning and characterization of an apoLp-II/I from Chinese oak silk worm, Antheraea pernyi. The apoLp-II/I cDNA is 10237bp in length, which possesses an open reading frame encoding 3305 amino acids. A consensus cleavage site RGRR presenting from Arg
710 to Arg713 implies posttranslational cleavage of this protein. Ap-apoLp-II/I shares high sequence identities with apoLp-II/I in lepidoptera and other insects. In addition, considerable similarities also exist between Ap-apoLp-II/I and human apoB, which basically positioned in first 1000 residues of the amino termini. Tissue distribution and time-course expression results demonstrate that Ap-apoLp-II/I transcripts were detected predominantly in the fat body, less in epidermis and rarely in midgut, while the synthetic apoLp-II/I protein was abundant in hemocytes and plasma instead of the fatbody. Expression of Ap-apoLp-II/I was stimulated in response to bacterial challenge. In addition, our preliminary studies established a novel role for Ap-apoLp-II/I in regulating prophenoloxidase activation system. Taken together, apoLp-II/I may play an essential role in innate responses of Antheraea pernyi., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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32. Investigation of Binding Modes and Functional Surface of Scorpion Toxins ANEP to Sodium Channels 1.7.
- Author
-
Song Y, Liu Z, Zhang Q, Li C, Jin W, Liu L, Zhang J, and Zhang J
- Subjects
- Binding Sites, Models, Molecular, NAV1.7 Voltage-Gated Sodium Channel chemistry, Scorpion Venoms chemistry
- Abstract
The depressant β toxin anti-neuroexcitation peptide (ANEP) from the Chinese scorpion Buthus martensii Karsch has analgesic activity by interacting with receptor site 4 of the voltage-gated sodium channels (VGSCs). Here, with molecular dynamics simulations, we examined the binding modes between ANEP and the site 4 of mice sodium channel 1.7 (mNa
v 1.7), a subtype of VGSCs related to peripheral pain. Homology modeling, molecular mechanics, and molecular dynamics in the biomembrane environment were adopted. The results suggested that ANEP bound to the resting site 4 mainly by amino acid residues in the β2-β3 loop and the 'NC' domains, and the activate site 4 mainly by amino acid residues in the hydrophobic domain of N-groove and residues in the 'pharmacophore'. Effects analysis of 14 mutants in the predicted functional domains of ANEP on mouse twisting models showed that the analgesic activity of mutants L15 and E24 of the 'pharmacophore', W36, T37, W38, and T39 forming the loop between the β2- and β3-strands and N8, V12, C60, and K64 in the NC domain increased distinctly after these residues were substituted for Ala, respectively. The binding modes and the active sites predicted were consistent with available mutagenesis data, and which is meaningful to understand the related mechanisms of ANEP for Nav 1.7., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
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33. A mutant of the Buthus martensii Karsch antitumor-analgesic peptide exhibits reduced inhibition to hNa v 1.4 and hNa v 1.5 channels while retaining analgesic activity.
- Author
-
Xu Y, Meng X, Hou X, Sun J, Kong X, Sun Y, Liu Z, Ma Y, Niu Y, Song Y, Cui Y, Zhao M, and Zhang J
- Subjects
- Amino Acid Substitution, Analgesics, Non-Narcotic administration & dosage, Analgesics, Non-Narcotic pharmacology, Analgesics, Non-Narcotic therapeutic use, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Arthropod Proteins genetics, Arthropod Proteins pharmacology, Arthropod Proteins therapeutic use, CHO Cells, Cricetulus, Dose-Response Relationship, Drug, Female, Humans, Male, Mice, NAV1.4 Voltage-Gated Sodium Channel chemistry, NAV1.4 Voltage-Gated Sodium Channel genetics, NAV1.4 Voltage-Gated Sodium Channel metabolism, NAV1.5 Voltage-Gated Sodium Channel chemistry, NAV1.5 Voltage-Gated Sodium Channel genetics, NAV1.5 Voltage-Gated Sodium Channel metabolism, Peptides genetics, Peptides pharmacology, Peptides therapeutic use, Random Allocation, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Scorpion Venoms genetics, Scorpion Venoms pharmacology, Scorpion Venoms therapeutic use, Scorpions, Toxicity Tests, Acute, Toxicity Tests, Subacute, Voltage-Gated Sodium Channel Blockers administration & dosage, Voltage-Gated Sodium Channel Blockers pharmacology, Voltage-Gated Sodium Channel Blockers therapeutic use, Analgesics, Non-Narcotic adverse effects, Antineoplastic Agents adverse effects, Arthropod Proteins adverse effects, Mutation, Peptides adverse effects, Scorpion Venoms adverse effects, Voltage-Gated Sodium Channel Blockers adverse effects
- Abstract
Scorpion toxins can kill other animals by inducing paralysis and arrhythmia, which limits the potential applications of these agents in the clinical management of diseases. Antitumor-analgesic peptide (AGAP), purified from Buthus martensii Karsch, has been proved to possess analgesic and antitumor activities. Trp
38 , a conserved aromatic residue of AGAP, might play an important role in mediating AGAP activities according to the sequence and homology-modeling analyses. Therefore, an AGAP mutant, W38G, was generated, and effects of both AGAP and the mutant W38G were examined by whole-cell patch clamp techniques on the sodium channels hNav 1.4 and hNav 1.5, which were closely associated with the biotoxicity of skeletal and cardiac muscles, respectively. The data showed that both W38G and AGAP inhibited the peak currents of hNav 1.4 and hNav 1.5; however, W38G induced a much weaker inhibition of both channels than AGAP. Accordingly, W38G exhibited much less toxic effect on both skeletal and cardiac muscles than AGAP in vivo The analgesic activity of W38G and AGAP were verified in vivo as well, and W38G retained analgesic activity similar to AGAP. Inhibition to both Nav 1.7 and Nav 1.8 was involved in the analgesic mechanism of AGAP and W38G. These findings indicated that Trp38 was a key amino acid involved in the biotoxicity of AGAP, and the AGAP mutant W38G might be a safer alternative for clinical application because it retains the analgesic efficacy with less toxicity to skeletal and cardiac muscles., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)- Published
- 2017
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34. Staphylococcal enterotoxin C2 mutant drives T lymphocyte activation through PI3K/mTOR and NF-ĸB signaling pathways.
- Author
-
Fu X, Xu M, Yao S, Zhang H, Zhang C, and Zhang J
- Subjects
- Animals, Cells, Cultured, Female, Interleukin-2 immunology, Mice, Inbred BALB C, Mutation, Signal Transduction, Spleen cytology, Enterotoxins genetics, Lymphocyte Activation immunology, NF-kappa B immunology, Phosphatidylinositol 3-Kinases immunology, T-Lymphocytes immunology, TOR Serine-Threonine Kinases immunology
- Abstract
Staphylococcal enterotoxin C2 (SEC2), a superantigen, causes rapid clonal expansion of lymphocytes and secretion of T cell growth factors, leading to a severe inflammatory response within tissues. Although previous studies have shown that ST-4, a SEC2 mutant with enhanced recognition of Vβ regions of T-cell receptors (TCRVβ), can activate an increased number of T cells and produce more cytokines than SEC2. However, the signaling mechanisms of SEC2/ST-4-mediated immune activation have not been addressed. In this study, we showed that the phosphatidylinositide-3-kinase (PI-3K) inhibitor LY294002, mammalian target of rapamycin (mTOR) inhibitor rapamycin, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inhibitor Bay11-7085 could suppress SEC2/ST-4-induced proliferation, CD69/CD25 expression, cell-cycle progression, and IL-2 production in BALB/c mouse splenocytes. In addition, we observed significantly upregulated expression of p70S6K, cyclin E, cyclin D3, and NF-ĸB/p65, but downregulated expression of p27kip during SEC2/ST-4-driven T cells activation. However, SEC2/ST-4-induced changes in cell cycle and PI3K/mTOR signaling were significantly relieved by either LY294002 or rapamycin, and the induction of NF-ĸB/p65 induced was significantly downregulated by Bay11-7085. Moreover, we found that IL-2 secretion was positively associated with p65 expression in a time- and dose-dependent manner. Taken together, our findings demonstrate the involvement of PI3K/mTOR and NF-κB signaling pathways in SEC2/ST-4-induced T cell activation. ST-4 intensifies PI3K/mTOR and NF-ĸB signaling transduction, ultimately leading to enhance T cell activation. These results provide a theoretical mechanism for future immunotherapy using ST-4., (Copyright © 2017. Published by Elsevier Inc.)
- Published
- 2017
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35. The roles of conserved aromatic residues (Tyr5 and Tyr42) in interaction of scorpion toxin BmK AGP-SYPU1 with human Na v 1.7.
- Author
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Meng X, Xu Y, Wang F, Zhao M, Hou X, Ma Y, Jin Y, Liu Y, Song Y, and Zhang J
- Subjects
- Animals, CHO Cells, Cricetinae, Cricetulus, Humans, Kinetics, Models, Molecular, Mutation, Protein Binding, Protein Domains, Scorpion Venoms genetics, Structure-Activity Relationship, Conserved Sequence, NAV1.7 Voltage-Gated Sodium Channel metabolism, Scorpion Venoms chemistry, Scorpion Venoms metabolism, Scorpions, Tyrosine
- Abstract
Scorpion toxins are invaluable source of therapeutic leads and pharmacological tools which produce influence on the voltage gated sodium channels. In the previous study, our group has reported BmK AGP-SYPU1 (64 amino acids), one scorpion toxin with both potential α-type and β-type scorpion characteristics and analgesic activity in vivo, act as an activator to hNa
v 1.4 and hNav 1.5. Additionally, conserved aromatic amino acids Tyr5 and Tyr42 played important roles in bioactivity of BmK AGP-SYPU1 on hNav 1.4 and hNav 1.5. However, the anti-nonceptitor mechanisms of BmK AGP-SYPU1 referred in vivo have not been clarified yet. The roles of Tyr5 and Tyr42 have still kept unclear in the interaction of BmK AGP-SYPU1 with other VGSCs. In this study, in order to give a deep insight into the relationship of structure and function, the effects of BmK AGP-SYPU1 and its two mutants (Y5F and Y42F) on hNav 1.7, which has emerged as a key molecule involved in pain processing, were examined by using Na+ -specialized fluorescent dye and the whole-cell patch clamp. The data showed that BmK AGP-SYPU1 also displayed as an activator to hNav 1.7 with the potential characteristic of α-type and β-type scorpion toxin. Both Tyr5 and Tyr42 were the key amino acids to the functional properties of BmK AGP-SYPU1 when interacting with hNav 1.7, and the Tyr42 was involved in the preferences of the toxin to distinct action sites of hNav 1.7. On the whole, these data provided more information about the structure of BmK AGP-SYPU1 related to its function upon hNav 1.7, and may bring some clues for engineering scorpion toxins to achieve high bioactivity with lower side effects., (Copyright © 2017. Published by Elsevier B.V.)- Published
- 2017
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36. The functions of serpin-3, a negative-regulator involved in prophenoloxidase activation and antimicrobial peptides expression of Chinese oak silkworm, Antheraea pernyi.
- Author
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Wang X, Wang K, He Y, Lu X, Wen D, Wu C, Zhang J, and Zhang R
- Subjects
- Animals, Antimicrobial Cationic Peptides genetics, Cloning, Molecular, Enzyme Activation, Gene Expression Regulation, Hemolymph metabolism, Humans, Immunity, Humoral, Insect Proteins genetics, RNA, Small Interfering genetics, Sequence Alignment, Serpins genetics, Antimicrobial Cationic Peptides metabolism, Catechol Oxidase metabolism, Enzyme Precursors metabolism, Fat Body metabolism, Hemocytes metabolism, Insect Proteins metabolism, Moths immunology, Serpins metabolism
- Abstract
Serpins are a superfamily of proteins engaged in various physiological processes in all kingdoms of life. To date, many striking results have demonstrated serpins are involved in the invertebrate immune system by regulating the proteolytic cascades. However, in most insect species, the immune functions of serpins in response against pathogen invasion remain obscure. In this study, we identified a full-length cDNA sequence of serpin, named serpin-3, from the Chinese oak silkworm Antheraea pernyi. Sequence alignments have indicated that Apserpin-3 might regulate the melanization reaction via inhibiting prophenoloxidases-activating protease(s) in plasma. Furthermore, it was detected to be primarily transcribed within the fat body, epidermis and hemocytes with significant induction following immune-challenge. Further studies have shown that the knockdown of serpin-3 up-regulated the prophenoloxidases cascade stimulated by pathogen in hemolymph, while the addition of recombinant serpin-3 along with the same elicitor led to the suppressed activation of prophenoloxidase. Besides, the injection of dsRNA of serpin-3 caused the elevated expression of antimicrobial peptides. Altogether, we arrived at a conclusion that serpin-3 might act as a negative-regulator in prophenoloxidases activation and inhibit the production of antimicrobial peptides in Antheraea pernyi larvae., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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37. Recombinant Expression, Functional Characterization of Two Scorpion Venom Toxins with Three Disulfide Bridges from the Chinese Scorpion Buthus martensii Karsch.
- Author
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Lin S, Wang X, Hu X, Zhao Y, Zhao M, Zhang J, and Cui Y
- Subjects
- Action Potentials drug effects, Amino Acid Sequence, Analgesics isolation & purification, Analgesics metabolism, Analgesics pharmacology, Animals, CHO Cells, China, Cloning, Molecular, Cricetulus, Disulfides chemistry, Escherichia coli genetics, Escherichia coli metabolism, Female, Gene Expression, Humans, Male, Mice, NAV1.7 Voltage-Gated Sodium Channel metabolism, Patch-Clamp Techniques, Plasmids chemistry, Plasmids metabolism, Recombinant Proteins genetics, Recombinant Proteins isolation & purification, Recombinant Proteins metabolism, Recombinant Proteins pharmacology, Scorpion Venoms genetics, Scorpion Venoms isolation & purification, Scorpion Venoms metabolism, Scorpion Venoms pharmacology, Scorpions chemistry, Scorpions physiology, Sequence Alignment, Sequence Homology, Amino Acid, Analgesics chemistry, NAV1.7 Voltage-Gated Sodium Channel genetics, Scorpion Venoms chemistry
- Abstract
Scorpion venom contains a large variety of biologically active peptides. However, most of these peptides have not been identified and characterized. Peptides with three disulfide bridges, existing in the scorpion venom, have not been studied in detail and have been poorly characterized until now. Here, we report the recombinant expression and functional characterization of two kinds of venom peptides (BmKBTx and BmNaL-3SS2) with three disulfide bridges. This study adopted an effective Escherichia coli system. The genes for BmKBTx and BmNaL-3SS2 were obtained by polymerase chain reaction and cloned to the pSYPU-1b vector. After expression and purification, the two recombinant proteins were subjected to an analgesic activity assay in mice and whole-cell patchclamp recording of hNav1.7-CHO cell lines. Functional tests showed that BmKBTx and BmNaL- 3SS2 have analgesic activity in mice and can interact with the hNav1.7 subtype of the voltage-gated sodium channel (VGSC). Scorpion venom is rich in bioactive proteins, but most of their functions are unknown to us. This study has increased our knowledge of these novel disulfide-bridged peptides (DBPs) and their biological activities., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)
- Published
- 2017
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38. A novel expression vector for the improved solubility of recombinant scorpion venom in Escherichia coli.
- Author
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Han T, Ming H, Deng L, Zhu H, Liu Z, Zhang J, and Song Y
- Subjects
- Affinity Labels, Escherichia coli genetics, Genetic Enhancement, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Scorpion Venoms chemistry, Solubility, Escherichia coli chemistry, Escherichia coli physiology, Genetic Vectors genetics, Protein Engineering methods, Scorpion Venoms biosynthesis, Scorpion Venoms genetics
- Abstract
Recombinant scorpion anti-excitation peptide (rANEP) has previously been expressed using the pET32a system and purified via affinity chromatography. However, rANEP is expressed in BL21(DE3) cells as an inclusion body, and the affinity tag can not be removed. To overcome this problem, we used a variety of protein, DsbA, MBP, TrxA, intein, and affinity tags in fusion and co-expression to achieve soluble and functional rANEP without any affinity tag. In the pCIT-ANEP expression vector, the highest soluble expression level was approximately 90% of the total cellular proteins in E. coli, and the rANEP was cleaved by the intein protein and subsequently purified to obtain rANEP, which had the same activity as the natural ANEP. The purity of rANEP obtained using this method was over 95%, with a quantity of 5.1 mg from of purified rANEP from 1 L of culture. This method could expand the application of the soluble expression of disulfide-rich peptides in E. coli., (Copyright © 2016. Published by Elsevier Inc.)
- Published
- 2017
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39. Involvement of a versatile pattern recognition receptor, apolipophorin-III in prophenoloxidase activation and antibacterial defense of the Chinese oak silkworm, Antheraea pernyi.
- Author
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Wen D, Wang X, Shang L, Huang Y, Li T, Wu C, Zhang R, and Zhang J
- Subjects
- Animals, Enzyme Activation, Gene Expression Regulation, Hemolymph metabolism, Immunity, Innate, Lipid Metabolism, Pathogen-Associated Molecular Pattern Molecules metabolism, RNA, Small Interfering genetics, Anti-Bacterial Agents metabolism, Apolipoproteins metabolism, Catechol Oxidase metabolism, Enzyme Precursors metabolism, Moths immunology, Receptors, Pattern Recognition metabolism, Staphylococcal Infections immunology, Staphylococcus aureus immunology
- Abstract
Apolipophorin-III (apoLp-III) is an exchangeable apolipoprotein found in many insect species and functions as a lipid transport vehicle. Recent studies have shown that apoLp-III is a multifunctional molecule involved in not only lipid transportation but also innate immune responses. In the present study, the pattern recognition properties of Antheraea pernyi apoLp-III were investigated. Recombinant Ap-apoLp-III was bound to different species of microbes and further study showed the rAp-apoLp-III is capable of interacting with pathogen associated molecular patterns (PAMPs) on the microbial cell surface. In addition, an Ap-apoLp-III/PAMP mixture stimulated the prophenoloxidase (PPO) activation of A. pernyi hemolymph in vitro, to a greater extent than PAMP alone while Ap-apoLp-III itself failed to activate the PPO system, indicating that Ap-apoLp-III up-regulates PPO activation by combining with PAMP. After pathogen invasion following an injection of Staphylococcus aureus, RNAi-mediated silencing of apoLp-III decreased the transcriptional abundance of three antimicrobial peptide genes. These data suggest that apoLp-III is a versatile pattern recognition receptor and may play important roles in the innate immune responses of Antheraea pernyi., (Copyright © 2016. Published by Elsevier Ltd.)
- Published
- 2016
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40. Analgesic-antitumor peptide inhibits the migration and invasion of HepG2 cells by an upregulated VGSC β1 subunit.
- Author
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Guo G, Cui Y, Chen H, Zhang L, Zhao M, Chen B, Zhang J, and Liu Y
- Subjects
- Cell Movement drug effects, Hep G2 Cells, Humans, Neoplasm Invasiveness, Recombinant Proteins pharmacology, Voltage-Gated Sodium Channel beta-1 Subunit analysis, Antineoplastic Agents pharmacology, Peptides pharmacology, Scorpion Venoms pharmacology, Voltage-Gated Sodium Channel beta-1 Subunit physiology
- Abstract
Analgesic-antitumor peptide (AGAP), one of the scorpion toxin polypeptides, has been shown to have an antitumor activity. Recombinant AGAP (rAGAP) was shown to affect the migration and invasion of HepG2 cells via a voltage-gated sodium channel (VGSC) β1 subunit. The VGSC β1 subunit was validated as a cell adhesion molecule (CAM) in human hepatocellular carcinoma (HCC) cell lines. rAGAP suppresses the migration and invasion of HepG2 cells but has no significant effect of human liver HL7702 cells without β1 subunit expression. rAGAP inhibits the migration and invasion of the cells when the VGSC β1 subunit is overexpressed in HL7702 cells. To explain these findings, VGSC β1 subunit messenger RNA (mRNA) and protein levels were measured. The β1 subunit protein level was upregulated in a dose-dependent manner following treatment with rAGAP while there was no significant change in the mRNA level, so rAGAP might be an active component of the VGSC β1 subunit.
- Published
- 2016
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41. Ganglioside GD1a suppresses LPS-induced pro-inflammatory cytokines in RAW264.7 macrophages by reducing MAPKs and NF-κB signaling pathways through TLR4.
- Author
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Wang Y, Cui Y, Cao F, Qin Y, Li W, and Zhang J
- Subjects
- Animals, Cell Survival drug effects, Cyclooxygenase 2 biosynthesis, Dinoprostone biosynthesis, Macrophages drug effects, Mice, Nitric Oxide biosynthesis, Nitric Oxide Synthase Type II biosynthesis, Phosphorylation, RAW 264.7 Cells, Signal Transduction drug effects, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cytokines biosynthesis, Gangliosides pharmacology, Lipopolysaccharides antagonists & inhibitors, Macrophages metabolism, Mitogen-Activated Protein Kinases antagonists & inhibitors, NF-kappa B drug effects, Toll-Like Receptor 4 drug effects
- Abstract
Gangliosides, sialic acid-containing glycosphingolipids, have been considered to be involved in the development, differentiation, and function of nervous systems in vertebrates. However, the mechanisms for anti-inflammation caused by gangliosides are not clear. In this paper, we investigated the anti-inflammation effects of ganglioside GD1a by using RAW264.7 macrophages. Our data demonstrated that treatment of macrophages with lipopolysaccharide significantly increased the production of NO and pro-inflammatory cytokines. GD1a suppressed the induction of iNOS and COX-2 mRNA and protein expression and secretory pro-inflammatory cytokines in culture medium, such as TNFα, IL-1α and IL-1β. In addition, LPS-induced phosphorylation of mitogen-activating protein kinases and IκBα degradation followed by translocation of the NF-κB from the cytoplasm to the nucleus were attenuated after GD1a treatment. Furthermore, GD1a probably inhibited LPS binding to macrophages and LPS-induced accumulation between TLR4 and MyD88. Taken together, the results demonstrated that ganglioside GD1a inhibited LPS-induced inflammation in RAW 264.7 macrophages by suppressing phosphorylation of mitogen-activating protein kinases and activation of NF-κB through repressing the Toll-like receptor 4 signaling pathway., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
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42. Polyion complex micelles composed of pegylated polyasparthydrazide derivatives for siRNA delivery to the brain.
- Author
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Huo H, Gao Y, Wang Y, Zhang J, Wang ZY, Jiang T, and Wang S
- Subjects
- Animals, Humans, Ions, Magnetic Resonance Spectroscopy, Mice, Tumor Cells, Cultured, Brain metabolism, Drug Delivery Systems methods, Glycoproteins chemistry, Hydrazines chemistry, Micelles, Neuroblastoma metabolism, Peptide Fragments chemistry, Polyethylene Glycols chemistry, Polymers chemistry, RNA, Small Interfering administration & dosage, Viral Proteins chemistry
- Abstract
In order to achieve efficient siRNA delivery to the brain, we designed a novel polyion complex (PIC) micelles composed of rabies virus glycoprotein (RVG) peptide tagged PEGylated polyasparthydrazide (PAHy) derivatives. The synthesized derivatives were characterized using (1)H NMR. The PIC micelles were formed by electrostatic attraction between the polymer and siRNA. Then the micelles were decorated with RVG using PEG as a linker. The physiochemical properties of micelles, such as gel retardation assay, zeta potential, particle size, morphology and serum stability, were investigated. Moreover, the cytotoxicity, cellular uptake, gene silencing efficiency and in vivo distribution of micelles were also evaluated systematically. Compared with unmodified micelles, RVG-modified micelles can be more easily internalized by the neuro2a cells and efficiently silence gene expression. In vivo animal experiments further confirmed that RVG modified micelles had brain targeting ability. These results demonstrated that RVG-modified micelles were promising carriers for siRNA delivery to the brain., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
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43. The Functional Property Changes of Muscular Na(v)1.4 and Cardiac Na(v)1.5 Induced by Scorpion Toxin BmK AGP-SYPU1 Mutants Y42F and Y5F.
- Author
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Meng X, Xu Y, Zhao M, Wang F, Ma Y, Jin Y, Liu Y, Song Y, and Zhang J
- Subjects
- Animals, Biological Transport drug effects, CHO Cells, Cricetulus, Patch-Clamp Techniques, Protein Structure, Secondary, Scorpion Venoms genetics, Sodium metabolism, Structure-Activity Relationship, NAV1.4 Voltage-Gated Sodium Channel metabolism, NAV1.5 Voltage-Gated Sodium Channel metabolism, Scorpion Venoms chemistry, Scorpion Venoms pharmacology
- Abstract
Scorpion toxins are invaluable therapeutic leads and pharmacological tools which influence the voltage-gated sodium channels. However, the details were still unclear about the structure-function relationship of scorpion toxins on VGSC subtypes. In the previous study, we reported one α-type scorpion toxin Bmk AGP-SYPU1 and its two mutants (Y5F and Y42F) which had been demonstrated to ease pain in mice acetic acid writhing test. However, the function of Bmk AGP-SYPU1 on VGSCs is still unknown. In this study, we examined the effects of BmK AGP-SYPU1 and its two mutants (Y5F and Y42F) on hNa(v)1.4 and hNa(v)1.5 heterologously expressed CHO cell lines by using Na⁺-specialized fluorescent dye and whole-cell patch clamp. The data showed that BmK AGP-SYPU1 displayed as an activator of hNa(v)1.4 and hNa(v)1.5, which might indeed contribute to its biotoxicity to muscular and cardiac system and exhibited the functional properties of both the α-type and β-type scorpion toxin. Notably, Y5F mutant exhibited lower activatory effects on hNa(v)1.4 and hNa(v)1.5 compared with BmK AGP-SYPU1. Y42F was an enhanced activator and confirmed that the conserved Tyr42 was the key amino acid involved in bioactivity or biotoxicity. These data provided a deep insight into the structure-function relationship of BmK AGP-SYPU1, which may be the guidance for engineering α-toxin with high selectivity on VGSC subtypes.
- Published
- 2015
- Full Text
- View/download PDF
44. Mechanism study on pH-responsive cyclodextrin capped mesoporous silica: effect of different stalk densities and the type of cyclodextrin.
- Author
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Bai L, Zhao Q, Wang J, Gao Y, Sha Z, Di D, Han N, Wang Y, Zhang J, and Wang S
- Subjects
- Hydrogen-Ion Concentration, Models, Molecular, Cyclodextrins chemistry, Drug Carriers chemistry, Nanoparticles chemistry, Silicon Dioxide chemistry
- Abstract
Cyclodextrin (CD)-capped mesoporous silica nanoparticles (MSN) with pH-responsive properties were synthesized, but little research has been carried out to evaluate the impact of critical factors such as the stalk density and the type of CD on the pH-responsive release behavior. Here, the effect of different stalk densities on the pH-responsive release behavior was investigated. Either too low or too high density of the grafted p-anisidine stalk could result in poor cargo release, and the optimum stalk density for MSN was measured by thermal analysis, and found to be approximately 8.7 stalks nm(-2). To achieve effective release control, the CD capes, α-CD and β-CD, were also investigated. Isothermal titration calorimetry (ITC) analysis was employed to determine the formation constants (Kf) of the two CD with p-anisidine at different pH values. The results obtained showed that the complex of β-CD with p-anisidine had excellent pH-responsive behavior as it exhibited the largest changed formation constant (ΔKf) in different pH media. Furthermore, the pH-responsive mechanism between CD and p-anisidine molecules was investigated through ITC and a molecular modeling study. The release of antitumor drug DOX presents a significant prospect toward the development of pH-responsive nanoparticles as a drug delivery vehicle.
- Published
- 2015
- Full Text
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45. NSK-01105 inhibits proliferation and induces apoptosis of prostate cancer cells by blocking the Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways.
- Author
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Yu P, Ye L, Wang H, Du G, Zhang J, Zhang J, and Tian J
- Subjects
- Cell Cycle drug effects, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Extracellular Signal-Regulated MAP Kinases metabolism, HCT116 Cells, HT29 Cells, Hep G2 Cells, Humans, MAP Kinase Kinase Kinases metabolism, MCF-7 Cells, Male, Niacinamide pharmacology, Phosphatidylinositol 3-Kinases metabolism, Prostatic Neoplasms metabolism, Proto-Oncogene Proteins c-akt metabolism, Proto-Oncogene Proteins c-raf metabolism, Sorafenib, TOR Serine-Threonine Kinases metabolism, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Proliferation drug effects, Niacinamide analogs & derivatives, Phenylurea Compounds pharmacology, Prostatic Neoplasms drug therapy, Quinazolines pharmacology, Signal Transduction drug effects
- Abstract
The purposes of this study are to investigate the antitumor activities of NSK-01105, a novel sorafenib derivative, in in vitro and in vivo models, and explore the potential mechanisms. The effects of NSK-01105 on proliferation and apoptosis of prostate cancer cells were established by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blot analysis. Two xenograft tumor models were used to verify the therapeutic effect of NSK-01105 in vivo. NSK-01105 exhibited broad-spectrum antitumor activity, particularly in prostate cancer cells. Characterization of apoptosis morphology was observed, and the percentage of apoptosis-positive cells significantly increased after NSK-01105 treatment for 24 h. Furthermore, a significant increase of the "sub-G1" population in LNCaP and PC-3 cells after NSK-01105 treatment was determined by cell cycle analysis. Tumor growth was significantly suppressed by once daily oral 30 mg/kg dose of NSK-01105 with the inhibition rates of 63.82% in LNCaP models and 64.29% in PC-3 models, respectively. The activation of Raf-1 kinase and epidermal growth factor receptor was downregulated by NSK-01105 at 10 μmol/L. Consequently, the dual inhibitions of Raf/MEK/ERK and PI3K/Akt/mTOR signal pathways were observed by Western blot analysis. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors by inhibiting cell proliferation and inducing apoptosis. NSK-01105 appears to be a promising orally active anticancer drug and deserves further investigation.
- Published
- 2015
- Full Text
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46. Hybrid lipid-capped mesoporous silica for stimuli-responsive drug release and overcoming multidrug resistance.
- Author
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Han N, Zhao Q, Wan L, Wang Y, Gao Y, Wang P, Wang Z, Zhang J, Jiang T, and Wang S
- Subjects
- Antibiotics, Antineoplastic administration & dosage, Antibiotics, Antineoplastic chemistry, Cell Survival drug effects, Delayed-Action Preparations administration & dosage, Diffusion, Doxorubicin chemistry, Drug Resistance, Multiple, Humans, MCF-7 Cells, Nanocapsules ultrastructure, Neoplasms, Experimental pathology, Particle Size, Polyethylene Glycols chemistry, Porosity, Delayed-Action Preparations chemistry, Doxorubicin administration & dosage, Nanocapsules chemistry, Neoplasms, Experimental drug therapy, Silicon Dioxide chemistry, Tocopherols chemistry
- Abstract
Multidrug resistance (MDR) is known to be a great obstruction to successful chemotherapy, and considerable efforts have been devoted to reverse MDR including designing various functional drug delivery systems. In this study, hybrid lipid-capped mesoporous silica nanoparticles (LTMSNs), aimed toward achieving stimuli-responsive drug release to circumvent MDR, were specially designated for drug delivery. After modifying MSNs with hydrophobic chains through disulfide bond on the surface, lipid molecules composing polymer d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) with molar ratio of 5:1 were subsequently added to self-assemble into a surrounded lipid layer via hydrophobic interaction acting as smart valves to block the pore channels of carrier. The obtained LTMSNs had a narrow size distribution of ca. 190 nm and can be stably dispersed in body fluids, which may ensure a long circulating time and ideal enhanced permeability and retention effect. Doxorubicin (DOX) was chosen as a model drug to be encapsulated into LTMSNs. Results showed that this hybrid lipid-capped mesoporous silica drug delivery system can achieve redox and pH-responsive release of DOX, thereby avoiding the premature leakage of drug before reaching the specific site and releasing DOX within the cancerous cells. Owing to the presence of TPGS-containing lipid layer, LTMSNs-DOX exhibited higher uptake efficiency, cytotoxicity, and increased intracellular accumulation in resistant MCF-7/Adr cells compared with DOX solution, proving to be a promising vehicle to realize intracellular drug release and inhibit drug efflux.
- Published
- 2015
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47. NSK-01105, a novel sorafenib derivative, inhibits human prostate tumor growth via suppression of VEGFR2/EGFR-mediated angiogenesis.
- Author
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Yu P, Ye L, Wang H, Du G, Zhang J, Zuo Y, Zhang J, and Tian J
- Subjects
- Angiogenesis Inhibitors chemistry, Angiogenesis Inhibitors therapeutic use, Animals, Cell Line, Tumor, Cell Movement drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Drug Discovery, Human Umbilical Vein Endothelial Cells cytology, Human Umbilical Vein Endothelial Cells drug effects, Humans, Male, Mice, Niacinamide chemistry, Niacinamide pharmacology, Niacinamide therapeutic use, Phenylurea Compounds chemistry, Phenylurea Compounds therapeutic use, Prostatic Neoplasms pathology, Quinazolines chemistry, Quinazolines therapeutic use, Signal Transduction drug effects, Sorafenib, Xenograft Model Antitumor Assays, Angiogenesis Inhibitors pharmacology, Enzyme Activation drug effects, ErbB Receptors metabolism, Neovascularization, Pathologic drug therapy, Niacinamide analogs & derivatives, Phenylurea Compounds pharmacology, Prostatic Neoplasms blood supply, Quinazolines pharmacology, Vascular Endothelial Growth Factor Receptor-2 metabolism
- Abstract
The purpose of this study is to investigate the anti-angiogenic activities of NSK-01105, a novel sorafenib derivative, in in vitro, ex vivo and in vivo models, and explore the potential mechanisms. NSK-01105 significantly inhibited vascular endothelial growth factor (VEGF)-induced migration and tube formation of human umbilical vein endothelial cells at non-cytotoxic concentrations as shown by wound-healing, transwell migration and endothelial cell tube formation assays, respectively. Cell viability and invasion of LNCaP and PC-3 cells were significantly inhibited by cytotoxicity assay and matrigel invasion assay. Furthermore, NSK-01105 also inhibited ex vivo angiogenesis in matrigel plug assay. Western blot analysis showed that NSK-01105 down-regulated VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2) and the activation of epidermal growth factor receptor (EGFR). Tumor volumes were significantly reduced by NSK-01105 at 60 mg/kg/day in both xenograft models. Immunohistochemical staining demonstrated a close association between inhibition of tumor growth and neovascularization. Collectively, our results suggest a role of NSK-01105 in treatment for human prostate tumors, and one of the potential mechanisms may be attributed to anti-angiogenic activities.
- Published
- 2014
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48. Hyaluronic acid oligosaccharide modified redox-responsive mesoporous silica nanoparticles for targeted drug delivery.
- Author
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Zhao Q, Geng H, Wang Y, Gao Y, Huang J, Wang Y, Zhang J, and Wang S
- Subjects
- Animals, Biocompatible Materials chemistry, Biocompatible Materials pharmacology, Cattle, Cell Survival drug effects, Drug Carriers pharmacology, Endocytosis drug effects, Glutathione chemistry, Glutathione metabolism, HCT116 Cells, Hemolysis drug effects, Humans, Hyaluronan Receptors metabolism, Hyaluronic Acid chemistry, Mercaptopurine chemistry, Mercaptopurine metabolism, Mice, NIH 3T3 Cells, Nanoparticles ultrastructure, Oxidation-Reduction, Porosity, Protein Binding, Serum Albumin, Bovine chemistry, Serum Albumin, Bovine metabolism, Drug Carriers chemistry, Nanoparticles chemistry, Oligosaccharides chemistry, Silicon Dioxide chemistry
- Abstract
A redox-responsive delivery system based on colloidal mesoporous silica (CMS) has been developed, in which 6-mercaptopurine (6-MP) was conjugated to vehicles by cleavable disulfide bonds. The oligosaccharide of hyaluronic acid (oHA) was modified on the surface of CMS by disulfide bonds as a targeting ligand and was able to increase the stability and biocompatibility of CMS under physiological conditions. In vitro release studies indicated that the cumulative release of 6-MP was less than 3% in the absence of glutathione (GSH), and reached nearly 80% within 2 h in the presence of 3 mM GSH. Confocal microscopy and fluorescence-activated cell sorter (FACS) methods were used to evaluate the cellular uptake performance of fluorescein isothiocyanate (FITC) labeled CMS, with and without oHA modification. The CMS-SS-oHA exhibited a higher cellular uptake performance via CD44 receptor-mediated endocytosis in HCT-116 (CD44 receptor-positive) cells than in NIH-3T3 (CD44 receptor-negative) cells. 6-MP loaded CMS-SS-oHA exhibited greater cytotoxicity against HCT-116 cells than NIH-3T3 cells due to the enhanced cell uptake behavior of CMS-SS-oHA. This study provides a novel strategy to covalently link bioactive drug and targeting ligand to the interiors and exteriors of mesoporous silica to construct a stimulus-responsive targeted drug delivery system.
- Published
- 2014
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49. AGAP, a new recombinant neurotoxic polypeptide, targets the voltage-gated calcium channels in rat small diameter DRG neurons.
- Author
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Liu X, Li C, Chen J, Du J, Zhang J, Li G, Jin X, and Wu C
- Subjects
- Animals, Calcium Channels, T-Type physiology, Ganglia, Spinal physiology, Rats, Calcium Channels, T-Type drug effects, Ganglia, Spinal drug effects, Ion Channel Gating drug effects, Scorpion Venoms toxicity
- Abstract
A previous study showed that antitumor-analgesic peptide (AGAP), a novel recombinant polypeptide, which had been expressed in Escherichia coli, exhibits analgesic and antitumor effects in mice. In the present study, we investigated the underlying analgesic mechanism of AGAP. The effect of AGAP on voltage-gated calcium channels (VGCCs) was assessed in acutely isolated rat dorsal root ganglia (DRG) neurons using the whole-cell patch clamp technique. The results showed that AGAP potently inhibited VGCCs, especially high-voltage activated (HVA) calcium channels. AGAP inhibited HVA and T-type calcium currents in a dose-dependent manner, but had no significant effect on their dynamic functions in rat small-diameter DRG neurons. AGAP inhibited N- and L-type calcium currents at 78.2% and 57.3%, respectively. Thus, the present study demonstrates that AGAP affects calcium currents through the inhibition of N-, L- and T-type channels in DRG neurons, explaining the potential mechanisms of antinociception., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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50. The investigation of MCM-48-type and MCM-41-type mesoporous silica as oral solid dispersion carriers for water insoluble cilostazol.
- Author
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Wang Y, Sun L, Jiang T, Zhang J, Zhang C, Sun C, Deng Y, Sun J, and Wang S
- Subjects
- Administration, Oral, Calorimetry, Differential Scanning, Cilostazol, Drug Compounding, Drug Liberation, Drug Stability, Microscopy, Electron, Scanning, Microscopy, Electron, Transmission, Particle Size, Porosity, Solubility, Spectrophotometry, Ultraviolet, Surface Properties, Tetrazoles chemistry, Thermogravimetry, Drug Carriers chemistry, Silicon Dioxide chemistry, Tetrazoles administration & dosage, Water chemistry
- Abstract
Objective: To explore the suitable application of MCM-41 (Mobil Composition of Matter number forty-one)-type and MCM-48-type mesoporous silica in the oral water insoluble drug delivery system., Methods: Cilostazol (CLT) as a model drug was loaded into synthesized MCM-48 (Mobil Composition of Matter number forty-eight) and commercial MCM-41 by three common methods. The obtained MCM-41, MCM-48 and CLT-loaded samples were characterized by means of nitrogen adsorption, thermogravimetric analysis, ultraviolet-visible spectrophotometry, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry and powder X-ray diffractometer., Results: It was found that solvent evaporation method was preferred according to the drug loading efficiency and the maximum percent cumulative drug dissolution. MCM-48 with 3D cubic pore structure and MCM-41 with 2D long tubular structure are nearly spherical particles in 300-500 nm. Nevertheless, the silica carriers with similar large specific surface areas and concentrating pore size distributions (978.66 m(2)/g, 3.8 nm for MCM-41 and 1108.04 m(2)/g, 3.6 nm for MCM-48) exhibited different adsorption behaviors for CLT. The maximum percent cumulative drug release of the two CLT/silica solid dispersion (CLT-MCM-48 and CLT-MCM-41) was 63.41% and 85.78% within 60 min, respectively; while in the subsequent 12 h release experiment, almost 100% cumulative drug release were both obtained. In the pharmacokinetics aspect, the maximum plasma concentrations of CLT-MCM-48 reached 3.63 mg/L by 0.92 h. The AUC0-∞ values of the CLT-MCM-41 and CLT-MCM-48 were 1.14-fold and 1.73-fold, respectively, compared with the commercial preparation., Conclusion: Our findings suggest that MCM-41-type and MCM-48-type mesoporous silica have great promise as solid dispersion carriers for sustained and immediate release separately.
- Published
- 2014
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