The Experts below are selected from a list of 137079 Experts worldwide ranked by ideXlab platform
Victor C. Yang - One of the best experts on this subject based on the ideXlab platform.
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15 years of attempts a macromolecular drug delivery system based on the cpp mediated intraCellular drug delivery and antibody targeting
Journal of Controlled Release, 2015Co-Authors: Meong Cheol Shin, Victor C. Yang, Qiuling LiangAbstract:Abstract Traditionally, any drug intended for combating the tumor would distribute profoundly to other organs and tissues as lack of targeting specificity, thus resulting in limited therapeutic effects toward the tumor but severe drug-induced toxic side effects. To prevail over this obstacle of drug-induced systemic toxicity, a novel approach termed “ATTEMPTS” (antibody targeted triggered electrically modified prodrug type strategy) was designed, which directly introduces both of the targeting and prodrug features onto the protein drugs. The ATTEMPTS system is composed of the antibody targeting component consisting of antibodies linked with heparin, and the Cell penetrating peptide (CPP) modified drug component. The two components mentioned above self-assembled into a tight complex via the charge to charge interaction between the anionic heparin and cationic CPP. Once accumulated at the targeting site, the CPP modified drug is released from the blockage by a second triggering agent, while remaining inactive in the circulation during tumor targeting thus aborting its effect on normal tissues. We utilized the heparin-induced inhibition on the Cell-penetrating activity of CPP to create the prodrug feature, and subsequently the protamine-induced reversal of heparin inhibition to resume Cell Transduction of the protein drug via the CPP function. Our approach is the first known system to overcome this selectivity issue, enabling CPP-mediated Cellular drug delivery to be practically applicable clinically. In this review, we thoroughly discussed the historical and novel progress of the “ATTEMPTS” system.
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recombinant tat gelonin fusion toxin synthesis and characterization of heparin protamine regulated Cell Transduction
Journal of Biomedical Materials Research Part A, 2015Co-Authors: Meong Cheol Shin, Jingwen Zhao, Jian Zhang, Yongzhuo Huang, Mei Wang, Kyoung Ah Min, Victor C. YangAbstract:Protein toxins, such as gelonin, are highly desirable anti-cancer drug candidates due to their unparalleled potency and repetitive reaction mechanism in inhibiting protein translation. However, for its potential application in cancer therapy, there remains the Cell membrane barrier that allows permeation of only small molecules, which must be overcome. To address this challenge, we conjugated gelonin with a protein Transduction domain (PTD), the TAT peptide, via genetic recombination. The chimeric TAT-gelonin fusion protein (TAT-Gel) retained equipotent N-glycosidase activity yet displayed greater Cell uptake than unmodified recombinant gelonin (rGel), thereby yielding a significantly augmented cytotoxic activity. Remarkably, TAT-Gel displayed up to 177-fold lower IC₅₀ (avg. 54.3 nM) than rGel (avg. IC₅₀ : 3640 nM) in tested Cell lines. This enhanced cytotoxicity, however, also raised potential toxicity concerns due to the non-selectivity of PTD in its mediated Cell Transduction. To solve this problem, we investigated the plausibility of regulating the Cell Transduction of TAT-Gel via a reversible masking using heparin and protamine. Here, we demonstrated, both in vitro and in vivo, that the Cell Transduction of TAT-Gel can be completely curbed with heparin and yet this heparin block can be efficiently reversed by the addition of protamine. This reversible tight regulation of the Cell Transduction of TAT-Gel by heparin and protamine sheds light of possible application of TAT-Gel in achieving a highly effective yet safe drug therapy for the treatment of tumors.
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nontoxic membrane translocation peptide from protamine low molecular weight protamine lmwp for enhanced intraCellular protein delivery in vitro and in vivo study
The FASEB Journal, 2005Co-Authors: Yoon Jeong Park, Lichien Chang, Jun Feng Liang, Cheol Moon, Chongpyoung Chung, Victor C. YangAbstract:SPECIFIC AIMThe aim of this study is to demonstrate the feasibility of naturally derived low molecular weight protamine as a potential translocational domain for the intraCellular delivery of molecular medicine including macromolecular drug (i.e., protein), therapeutic gene, or molecular diagnostic probes as well as nanoparticulates.PRINCIPAL FINDINGS1. Preparation of the low molecular weight protamine sequences and their translocational capacity through various types of Cells as well as biocompatibilityLMWP fragments were derived from native protamine by thermolysine digestion, which provided 5 different fractions, denoted TDSP (thermolysin-digested segmented protamine) 1 to 5 (PRRRR, PRRRRSSSRP, RPVRRRRRPR, VSRRRRRRGGRRR, VSRRRRRRGGRRRR) depending on their elution order from a heparin affinity chromatography. Except for TDSP1, which possessed less arginine residues than those required for Cell Transduction, the Cell internalization activity of TDSPs 2, 3, 4, and 5 were all examined. All of the studied L...
Meong Cheol Shin - One of the best experts on this subject based on the ideXlab platform.
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15 years of attempts a macromolecular drug delivery system based on the cpp mediated intraCellular drug delivery and antibody targeting
Journal of Controlled Release, 2015Co-Authors: Meong Cheol Shin, Victor C. Yang, Qiuling LiangAbstract:Abstract Traditionally, any drug intended for combating the tumor would distribute profoundly to other organs and tissues as lack of targeting specificity, thus resulting in limited therapeutic effects toward the tumor but severe drug-induced toxic side effects. To prevail over this obstacle of drug-induced systemic toxicity, a novel approach termed “ATTEMPTS” (antibody targeted triggered electrically modified prodrug type strategy) was designed, which directly introduces both of the targeting and prodrug features onto the protein drugs. The ATTEMPTS system is composed of the antibody targeting component consisting of antibodies linked with heparin, and the Cell penetrating peptide (CPP) modified drug component. The two components mentioned above self-assembled into a tight complex via the charge to charge interaction between the anionic heparin and cationic CPP. Once accumulated at the targeting site, the CPP modified drug is released from the blockage by a second triggering agent, while remaining inactive in the circulation during tumor targeting thus aborting its effect on normal tissues. We utilized the heparin-induced inhibition on the Cell-penetrating activity of CPP to create the prodrug feature, and subsequently the protamine-induced reversal of heparin inhibition to resume Cell Transduction of the protein drug via the CPP function. Our approach is the first known system to overcome this selectivity issue, enabling CPP-mediated Cellular drug delivery to be practically applicable clinically. In this review, we thoroughly discussed the historical and novel progress of the “ATTEMPTS” system.
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recombinant tat gelonin fusion toxin synthesis and characterization of heparin protamine regulated Cell Transduction
Journal of Biomedical Materials Research Part A, 2015Co-Authors: Meong Cheol Shin, Jingwen Zhao, Jian Zhang, Yongzhuo Huang, Mei Wang, Kyoung Ah Min, Victor C. YangAbstract:Protein toxins, such as gelonin, are highly desirable anti-cancer drug candidates due to their unparalleled potency and repetitive reaction mechanism in inhibiting protein translation. However, for its potential application in cancer therapy, there remains the Cell membrane barrier that allows permeation of only small molecules, which must be overcome. To address this challenge, we conjugated gelonin with a protein Transduction domain (PTD), the TAT peptide, via genetic recombination. The chimeric TAT-gelonin fusion protein (TAT-Gel) retained equipotent N-glycosidase activity yet displayed greater Cell uptake than unmodified recombinant gelonin (rGel), thereby yielding a significantly augmented cytotoxic activity. Remarkably, TAT-Gel displayed up to 177-fold lower IC₅₀ (avg. 54.3 nM) than rGel (avg. IC₅₀ : 3640 nM) in tested Cell lines. This enhanced cytotoxicity, however, also raised potential toxicity concerns due to the non-selectivity of PTD in its mediated Cell Transduction. To solve this problem, we investigated the plausibility of regulating the Cell Transduction of TAT-Gel via a reversible masking using heparin and protamine. Here, we demonstrated, both in vitro and in vivo, that the Cell Transduction of TAT-Gel can be completely curbed with heparin and yet this heparin block can be efficiently reversed by the addition of protamine. This reversible tight regulation of the Cell Transduction of TAT-Gel by heparin and protamine sheds light of possible application of TAT-Gel in achieving a highly effective yet safe drug therapy for the treatment of tumors.
Wei Liu - One of the best experts on this subject based on the ideXlab platform.
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the human cochlear battery claudin 11 barrier and ion transport proteins in the lateral wall of the cochlea
Frontiers in Molecular Neuroscience, 2017Co-Authors: Wei Liu, Rudolf Glueckert, Heval Benav, Annelies Schrottfischer, Helge RaskandersenAbstract:Background: The cochlea produces an electric field potential essential for hair Cell Transduction and hearing. This biological "battery" is situated in the lateral wall of the cochlea and contains ...
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The Human “Cochlear Battery” – Claudin-11 Barrier and Ion Transport Proteins in the Lateral Wall of the Cochlea
Frontiers Media S.A., 2017Co-Authors: Wei Liu, Annelies Schrott-fischer, Rudolf Glueckert, Heval Benav, Helge Rask-andersenAbstract:Background: The cochlea produces an electric field potential essential for hair Cell Transduction and hearing. This biological “battery” is situated in the lateral wall of the cochlea and contains molecular machinery that secretes and recycles K+ ions. Its functioning depends on junctional proteins that restrict the para-Cellular escape of ions. The tight junction protein Claudin-11 has been found to be one of the major constituents of this barrier that maintains ion gradients (Gow et al., 2004; Kitajiri et al., 2004a). We are the first to elucidate the human Claudin-11 framework and the associated ion transport machinery using super-resolution fluorescence illumination microscopy (SR-SIM).Methods: Archival cochleae obtained during meningioma surgery were used for SR-SIM together with transmission electron microscopy after ethical consent.Results: Claudin-11-expressing Cells formed parallel tight junction lamellae that insulated the epithelial syncytium of the stria vascularis and extended to the suprastrial region. InterCellular gap junctions were found between the barrier Cells and fibrocytes.Conclusion: Transmission electron microscopy, confocal microscopy and SR-SIM revealed exclusive Cell specialization in the various subdomains of the lateral wall of the human cochlea. The Claudin-11-expressing Cells exhibited both conductor and isolator characteristics, and these micro-porous separators may selectively mediate the movement of charged units to the intrastrial space in a manner that is analogous to a conventional electrochemical “battery.” The function and relevance of this battery for the development of inner ear disease are discussed
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Molecular organization and fine structure of the human tectorial membrane: is it replenished?
Cell and Tissue Research, 2015Co-Authors: Hisamitsu Hayashi, Wei Liu, Annelies Schrott-fischer, Rudolf Glueckert, Willi Salvenmoser, Peter Santi, Helge Rask-andersenAbstract:Auditory sensitivity and frequency resolution depend on the physical properties of the basilar membrane in combination with outer hair Cell-based amplification in the cochlea. The physiological role of the tectorial membrane (TM) in hair Cell Transduction has been controversial for decades. New insights into the TM structure and function have been gained from studies of targeted gene disruption. Several missense mutations in genes regulating the human TM structure have been described with phenotypic expressions. Here, we portray the remarkable gradient structure and molecular organization of the human TM. Ultrastructural analysis and confocal immunohistochemistry were performed in freshly fixed human cochleae obtained during surgery. Based on these findings and recent literature, we discuss the role of human TMs in hair Cell activation. Moreover, the outcome proposes that the α-tectorin-positive amorphous layer of the human TM is replenished and partly undergoes regeneration during life.
Anthony J Ricci - One of the best experts on this subject based on the ideXlab platform.
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trpv6 trpm6 and trpm7 do not contribute to hair Cell mechanoTransduction
Frontiers in Cellular Neuroscience, 2018Co-Authors: Clive P Morgan, Meredith Lemasurier, Matthew R Avenarius, Michael Bateschell, Ruby Larisch, Piotr Kazmierczak, Hongyu Zhao, Wei Xiong, Anthony J RicciAbstract:The hair-Cell mechanoTransduction channel remains unidentified. We tested whether three transient receptor channel (TRP) family members, TRPV6, TRPM6, and TRPM7, were necessary for Transduction. TRPV6 interacted with USH1C (harmonin), a scaffolding protein that participates in Transduction. Using a cysteine-substitution knock-in mouse line and methanethiosulfonate reagents selective for this allele, we found that inhibition of TRPV6 had no effect on Transduction in mouse cochlear hair Cells. TRPM6 and TRPM7 each interacted with the tip-link component PCDH15 in cultured eukaryotic Cells, which suggested they might be part of the Transduction complex. Cochlear hair Cell Transduction was not affected by manipulations of Mg2+, however, which normally perturbs TRPM6 and TRPM7. To definitively examine the role of these two channels in Transduction, we showed that deletion of either or both of their genes selectively in hair Cells had no effect on auditory function. We suggest that TRPV6, TRPM6, and TRPM7 are unlikely to be the pore-forming subunit of the hair-Cell Transduction channel.
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trpv6 trpm6 and trpm7 do not contribute to hair Cell mechanoTransduction
Frontiers in Cellular Neuroscience, 2018Co-Authors: Clive P Morgan, Meredith Lemasurier, Matthew R Avenarius, Michael Bateschell, Ruby Larisch, Piotr Kazmierczak, Hongyu Zhao, Wei Xiong, Bifeng Pan, Anthony J RicciAbstract:Hair Cells of the inner ear transduce mechanical stimuli like sound or head movements into electrical signals, which are propagated to the central nervous system. The hair-Cell mechanoTransduction channel remains unidentified. We tested whether three transient receptor channel (TRP) family members, TRPV6, TRPM6 and TRPM7, were necessary for Transduction. TRPV6 interacted with USH1C (harmonin), a scaffolding protein that participates in Transduction. Using a cysteine-substitution knock-in mouse line and methanethiosulfonate (MTS) reagents selective for this allele, we found that inhibition of TRPV6 had no effect on Transduction in mouse cochlear hair Cells. TRPM6 and TRPM7 each interacted with the tip-link component PCDH15 in cultured eukaryotic Cells, which suggested they might be part of the Transduction complex. Cochlear hair Cell Transduction was not affected by manipulations of Mg2+, however, which normally perturbs TRPM6 and TRPM7. To definitively examine the role of these two channels in Transduction, we showed that deletion of either or both of their genes selectively in hair Cells had no effect on auditory function. We suggest that TRPV6, TRPM6 and TRPM7 are unlikely to be the pore-forming subunit of the hair-Cell Transduction channel.
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2018Co-Authors: Clive P Morgan, Meredith Lemasurier, Matthew R Avenarius, Michael Bateschell, Ruby Larisch, Piotr Kazmierczak, Hongyu Zhao, Wei Xiong, Bifeng Pan, Anthony J RicciAbstract:Hair Cells of the inner ear transduce mechanical stimuli like sound or head movements into electrical signals, which are propagated to the central nervous system. The hair-Cell mechanoTransduction channel remains unidentified. We tested whether three transient receptor channel (TRP) family members, TRPV6, TRPM6 and TRPM7, were necessary for Transduction. TRPV6 interacted with USH1C (harmonin), a scaffolding protein that participates in Transduction. Using a cysteine-substitution knock-in mouse line and methanethiosulfonate (MTS) reagents selective for this allele, we found that inhibition of TRPV6 had no effect on Transduction in mouse cochlear hair Cells. TRPM6 and TRPM7 each interacted with the tip-link component PCDH15 in cultured eukaryotic Cells, which suggested they might be part of the Transduction complex. Cochlear hair Cell Transduction was not affected by manipulations of Mg2+, however, which normally perturbs TRPM6 and TRPM7. To definitively examine the role of these two channels in Transduction, we showed that deletion of either or both of their genes selectively in hair Cells had no effect on auditory function. We suggest that TRPV6, TRPM6 and TRPM7 are unlikely to be the pore-forming subunit of the hair-Cell Transduction channel.
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trpv5 trpv6 trpm6 and trpm7 do not contribute to hair Cell mechanoTransduction
bioRxiv, 2017Co-Authors: Clive P Morgan, Meredith Lemasurier, Matthew R Avenarius, Michael Bateschell, Ruby Larisch, Ulrich Mueller, Hongyu Zhao, Anthony J Ricci, Wei Xiong, Peter G BarrgillespieAbstract:The hair-Cell mechanoTransduction channel remains unidentified. We tested whether four transient receptor channel (TRP) family members, TRPV5, TRPV6, TRPM6, and TRPM7, participated in Transduction. Using cysteine-substitution mouse knock-ins and methanethiosulfonate reagents selective for those alleles, we found that inhibition of TRPV5 or TRPV6 had no effect on Transduction in mouse cochlear hair Cells. TRPM6 and TRPM7 each interacted with the tip-link component PCDH15 in cultured eukaryotic Cells, which suggested they could participate in Transduction. Cochlear hair Cell Transduction was insensitive to shRNA knockdown of Trpm6 or Trpm7, however, and was not affected by manipulations of Mg2+, which normally perturbs TRPM6 and TRPM7. To definitively examine the role of these two channels in Transduction, we showed that deletion of either or both of their genes selectively in hair Cells had no effect on auditory function. We suggest that TRPV5, TRPV6, TRPM6, and TRPM7 are unlikely to be the pore-forming subunit of the hair-Cell Transduction channel.
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mechanosensitive hair Cell like Cells from embryonic and induced pluripotent stem Cells
Cell, 2010Co-Authors: Kazuo Oshima, Anthony J Ricci, Kunyoo Shin, Marc Diensthuber, Anthony W Peng, Stefan HellerAbstract:Mechanosensitive sensory hair Cells are the linchpin of our senses of hearing and balance. The inability of the mammalian inner ear to regenerate lost hair Cells is the major reason for the permanence of hearing loss and certain balance disorders. Here, we present a stepwise guidance protocol starting with mouse embryonic stem and induced pluripotent stem Cells, which were directed toward becoming ectoderm capable of responding to otic-inducing growth factors. The resulting otic progenitor Cells were subjected to varying differentiation conditions, one of which promoted the organization of the Cells into epithelial clusters displaying hair Cell-like Cells with stereociliary bundles. Bundle-bearing Cells in these clusters responded to mechanical stimulation with currents that were reminiscent of immature hair Cell Transduction currents.
Helge Rask-andersen - One of the best experts on this subject based on the ideXlab platform.
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The Human “Cochlear Battery” – Claudin-11 Barrier and Ion Transport Proteins in the Lateral Wall of the Cochlea
Frontiers Media S.A., 2017Co-Authors: Wei Liu, Annelies Schrott-fischer, Rudolf Glueckert, Heval Benav, Helge Rask-andersenAbstract:Background: The cochlea produces an electric field potential essential for hair Cell Transduction and hearing. This biological “battery” is situated in the lateral wall of the cochlea and contains molecular machinery that secretes and recycles K+ ions. Its functioning depends on junctional proteins that restrict the para-Cellular escape of ions. The tight junction protein Claudin-11 has been found to be one of the major constituents of this barrier that maintains ion gradients (Gow et al., 2004; Kitajiri et al., 2004a). We are the first to elucidate the human Claudin-11 framework and the associated ion transport machinery using super-resolution fluorescence illumination microscopy (SR-SIM).Methods: Archival cochleae obtained during meningioma surgery were used for SR-SIM together with transmission electron microscopy after ethical consent.Results: Claudin-11-expressing Cells formed parallel tight junction lamellae that insulated the epithelial syncytium of the stria vascularis and extended to the suprastrial region. InterCellular gap junctions were found between the barrier Cells and fibrocytes.Conclusion: Transmission electron microscopy, confocal microscopy and SR-SIM revealed exclusive Cell specialization in the various subdomains of the lateral wall of the human cochlea. The Claudin-11-expressing Cells exhibited both conductor and isolator characteristics, and these micro-porous separators may selectively mediate the movement of charged units to the intrastrial space in a manner that is analogous to a conventional electrochemical “battery.” The function and relevance of this battery for the development of inner ear disease are discussed
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Molecular organization and fine structure of the human tectorial membrane: is it replenished?
Cell and Tissue Research, 2015Co-Authors: Hisamitsu Hayashi, Wei Liu, Annelies Schrott-fischer, Rudolf Glueckert, Willi Salvenmoser, Peter Santi, Helge Rask-andersenAbstract:Auditory sensitivity and frequency resolution depend on the physical properties of the basilar membrane in combination with outer hair Cell-based amplification in the cochlea. The physiological role of the tectorial membrane (TM) in hair Cell Transduction has been controversial for decades. New insights into the TM structure and function have been gained from studies of targeted gene disruption. Several missense mutations in genes regulating the human TM structure have been described with phenotypic expressions. Here, we portray the remarkable gradient structure and molecular organization of the human TM. Ultrastructural analysis and confocal immunohistochemistry were performed in freshly fixed human cochleae obtained during surgery. Based on these findings and recent literature, we discuss the role of human TMs in hair Cell activation. Moreover, the outcome proposes that the α-tectorin-positive amorphous layer of the human TM is replenished and partly undergoes regeneration during life.