Targeted and reversible disruption of the blood‐testis barrier by an ΔFSH mutant‐occludin peptide conjugate
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| Titel: | Targeted and reversible disruption of the blood‐testis barrier by an ΔFSH mutant‐occludin peptide conjugate |
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| Autoren: | Lee, WM, Cheng, CY, Wong, CH, Mruk, DD |
| Quelle: | The FASEB Journal. 21:438-448 |
| Verlagsinformationen: | Wiley, 2006. |
| Publikationsjahr: | 2006 |
| Schlagwörter: | Follicle Stimulating Hormone - Chemistry - Metabolism - Pharmacology, Male, 0301 basic medicine, Immunoblotting, Cyclic Amp - Metabolism, Epithelium - Drug Effects - Metabolism, Electron, Fluorescence, Antibodies, Epithelium, Injections, Rats, Sprague-Dawley, 03 medical and health sciences, Microscopy, Electron, Transmission, Occludin, Receptors, Cell Adhesion, Cyclic AMP, Transmission, Animals, Intraperitoneal, Membrane Proteins - Chemistry - Genetics - Pharmacology, Antibodies - Blood, Spermatogenesis, Blood-Testis Barrier, Microscopy, 0303 health sciences, Testis - Cytology - Metabolism - Ultrastructure, Molecular Structure, Membrane Proteins, Cell Adhesion - Drug Effects, Germ Cells - Cytology - Drug Effects - Immunology, Receptors, Fsh - Metabolism, Rats, 3. Good health, Fsh - Metabolism, Germ Cells, Mutant Proteins - Chemistry - Metabolism - Pharmacology, Microscopy, Fluorescence, Mutant Proteins, Sprague-Dawley, Follicle Stimulating Hormone, Blood-Testis Barrier - Drug Effects - Metabolism, Injections, Intraperitoneal, Protein Binding |
| Beschreibung: | The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in mammals. As such, it poses a challenge to deliver any drugs to the seminiferous epithelium of the testis, such as a nonhormonal male contraceptive. To circumvent this problem, a genetically engineered follicle-stimulating hormone (FSH) mutant protein was produced in Spodoptera furgiperda (Sf)-9 insect cells to serve as a testis-specific carrier. Subsequently, a 22-amino acid peptide corresponding to the second extracellular loop of occludin, which was known to disrupt BTB integrity in vivo, was inserted to the FSH mutant by polymerase chain reaction (PCR), as well as chemical cross-linking. This molecule was found to have negligible hormonal activity but was still capable of binding to FSH receptors, which are restricted to Sertoli cells in mammals. When this FSH mutant-occludin peptide conjugate was administered to adult rats at 40 microg/adult rat (approximately 300 gm b.w.) via intraperitoneally (i.p.) injection, it induced transient and reversible disruption of the BTB, while at 150 microg/rat, it induced partial germ cell loss from the testis, particularly elongating/elongate spermatids. Most importantly, this effect was limited to the BTB without compromising the TJ-barrier integrity or cell adhesion in epithelia of other organs, such as kidney, liver, and small intestine. In summary, the use of an FSH mutant-occludin peptide conjugate is a feasible nanodevice to transiently compromise the BTB. |
| Publikationsart: | Article |
| Sprache: | English |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.05-4144com |
| Zugangs-URL: | https://europepmc.org/articles/pmc2806095?pdf=render https://pubmed.ncbi.nlm.nih.gov/17167075 https://core.ac.uk/display/38013463 http://hub.hku.hk/handle/10722/178980 http://europepmc.org/articles/PMC2806095 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806095/ https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.05-4144com https://jglobal.jst.go.jp/en/detail?JGLOBAL_ID=200902283551079507 http://hdl.handle.net/10722/178980 |
| Rights: | Wiley Online Library User Agreement |
| Dokumentencode: | edsair.doi.dedup.....5bdf12c0f979e52a11d1edd8adb8a5a0 |
| Datenbank: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstract: | The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in mammals. As such, it poses a challenge to deliver any drugs to the seminiferous epithelium of the testis, such as a nonhormonal male contraceptive. To circumvent this problem, a genetically engineered follicle-stimulating hormone (FSH) mutant protein was produced in Spodoptera furgiperda (Sf)-9 insect cells to serve as a testis-specific carrier. Subsequently, a 22-amino acid peptide corresponding to the second extracellular loop of occludin, which was known to disrupt BTB integrity in vivo, was inserted to the FSH mutant by polymerase chain reaction (PCR), as well as chemical cross-linking. This molecule was found to have negligible hormonal activity but was still capable of binding to FSH receptors, which are restricted to Sertoli cells in mammals. When this FSH mutant-occludin peptide conjugate was administered to adult rats at 40 microg/adult rat (approximately 300 gm b.w.) via intraperitoneally (i.p.) injection, it induced transient and reversible disruption of the BTB, while at 150 microg/rat, it induced partial germ cell loss from the testis, particularly elongating/elongate spermatids. Most importantly, this effect was limited to the BTB without compromising the TJ-barrier integrity or cell adhesion in epithelia of other organs, such as kidney, liver, and small intestine. In summary, the use of an FSH mutant-occludin peptide conjugate is a feasible nanodevice to transiently compromise the BTB. |
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| ISSN: | 15306860 08926638 |
| DOI: | 10.1096/fj.05-4144com |