The Experts below are selected from a list of 17118 Experts worldwide ranked by ideXlab platform
Cong Zhang - One of the best experts on this subject based on the ideXlab platform.
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new insights of subfertility among transplanted women Immunosuppressive Drug fk506 leads to calcium leak and oocyte activation before fertilization
Journal of Cellular Biochemistry, 2018Co-Authors: Linli Liu, Ma Yang, Naiqiang Wang, Zijiang Che, Cong ZhangAbstract:FKBP12, known as FK506 binding protein, binds to Immunosuppressive Drug FK506, which must be taken by patients who received organ transplant. The side effect of FK506 is that women have difficulties in bearing a baby, so it is important to find the reason of their subfertility. This research explored the expression of FKBP12 in pre-implantation embryos and investigated its potential effect on reproduction. The results demonstrate that FKBP12 had good co-localization with endoplasmic reticulum and inositol-1, 4, 5- trisphosphate receptor in pre-implantation stages. Inhibiting FKBP12 by FK506 significantly increased the rate of 1-cell and fragmented embryos, greatly reduced the rate of 2-cell embryos during in vitro fertilization. When the mice received FK506 by gavage for 21 days, the calcium intensity of oocytes was decreased, these mice were subfertile and gave birth to significantly less pups during 6-month breeding period. QPCR demonstrated that Fbxo43 and P27kip, which are related to the release of MII oocyte arrest, and calcium channel partner protein Orai1 were downregulated, while Cdc2 and Ca2+ sensor at ER, stromal interaction molecule 1 (Stim1) were upregulated for a short time after adding FK506. Further exploration discovered that FK506 treatment increased Ca2+ concentration in the cytoplasm and caused pronucleus formation, however, the rate of parthenogenetic activation was lower compared to SrCl2 group. These findings identify the previously unknown role of FKBP12 in female reproduction which contributes to the release of calcium via IP3R channel and might open up new strategies for women who want to bear a baby after transplantation. This article is protected by copyright. All rights reserved
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new insights of subfertility among transplanted women Immunosuppressive Drug fk506 leads to calcium leak and oocyte activation before fertilization
Journal of Cellular Biochemistry, 2018Co-Authors: Naiqiang Wang, Cong Zhang, Linlin Liu, Man Yang, Zijiang ChenAbstract:FKBP12, known as FK506 binding protein, binds to Immunosuppressive Drug FK506, which must be taken by patients who received organ transplant. The side effect of FK506 is that women have difficulties in bearing a baby, so it is important to find the reason of their subfertility. This research explored the expression of FKBP12 in pre-implantation embryos and investigated its potential effect on reproduction. The results demonstrate that FKBP12 had good co-localization with endoplasmic reticulum and inositol-1, 4, 5- trisphosphate receptor in pre-implantation stages. Inhibiting FKBP12 by FK506 significantly increased the rate of 1-cell and fragmented embryos, greatly reduced the rate of 2-cell embryos during in vitro fertilization. When the mice received FK506 by gavage for 21 days, the calcium intensity of oocytes was decreased, these mice were subfertile and gave birth to significantly less pups during 6-month breeding period. QPCR demonstrated that Fbxo43 and P27kip, which are related to the release of MII oocyte arrest, and calcium channel partner protein Orai1 were downregulated, while Cdc2 and Ca2+ sensor at ER, stromal interaction molecule 1 (Stim1) were upregulated for a short time after adding FK506. Further exploration discovered that FK506 treatment increased Ca2+ concentration in the cytoplasm and caused pronucleus formation, however, the rate of parthenogenetic activation was lower compared to SrCl2 group. These findings identify the previously unknown role of FKBP12 in female reproduction which contributes to the release of calcium via IP3 R channel and might open up new strategies for women who want to bear a baby after transplantation.
Dirk Kuypers - One of the best experts on this subject based on the ideXlab platform.
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new insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid possible consequences for therapeutic Drug monitoring in solid organ transplantation
Therapeutic Drug Monitoring, 2009Co-Authors: Hylke De Jonge, Maarten Naesens, Dirk KuypersAbstract:Abstract:Although therapeutic Drug monitoring (TDM) of Immunosuppressive Drugs has been an integral part of routine clinical practice in solid organ transplantation for many years, ongoing research in the field of Immunosuppressive Drug metabolism, pharmacokinetics, pharmacogenetics, pharmacodynamic
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Immunosuppressive Drug therapy and subclinical acute renal allograft rejection impact and effect
Transplantation, 2008Co-Authors: Dirk KuypersAbstract:The incidence of subclinical acute rejection (SCAR) varies between 5% and 15% with current maintenance Immunosuppressive Drug regimens. Despite many similarities between SCAR and clinical acute rejection exist, the inflammatory activated cell infiltrates are not completely identical while graft cytokine profiles and counteractive immune responses are characterized by subtle differences that could explain why SCAR is not accompanied by immediate graft dysfunction. Evidence that SCAR contributes to chronic allograft damage (interstitial fibrosis and tubular atrophy) and negatively affects graft outcome is counterbalanced by the scarcity of controlled data proving the beneficial effect of SCAR treatment. The development of sensitive and specific noninvasive methods to monitor the immune status of the graft by using mRNA determinations, gene expression analysis (microarrays), proteomic analysis, and magnetic resonance spectroscopy, can help to ultimately replace protocol biopsies and also contribute to the further unraveling of the complex underlying immunological mechanisms responsible for SCAR. The latter would enable clinicians to preemptively make strategic adjustments to Immunosuppressive therapy in an attempt to further improve renal allograft survival and clinical care of the transplant patient.
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Immunosuppressive Drug monitoring what to use in clinical practice today to improve renal graft outcome
Transplant International, 2005Co-Authors: Dirk KuypersAbstract:Therapeutic Drug monitoring (TDM) of Immunosuppressive therapy is becoming an increasingly complex matter as the number of compounds and their respective combinations are continuously expanding. Unfortunately, in clinical practice, monitoring predose trough blood concentrations is often not sufficient for guiding optimal long-term dosing of these Drugs. The excellent short-term results obtained nowadays in renal transplantation confer a misleading feeling of safety despite the fact that long-term results have not substantially improved, definitely not to a point where longer graft survival could counteract the increasing need for transplant organs and less toxicity and side-effects could ameliorate patient survival. It is therefore a challenging task to try to tailor Immunosuppressive Drug therapy to the individual patient profile and this in a time-dependent manner. For the majority of currently used Immunosuppressive Drugs, measurement of total Drug exposure by determination of the dose-interval area under the concentration curve (AUC) seems to provide more useful information for clinicians in terms of concentration-exposure and exposure-response as well as reproducibility. To simplify this laborious way of measuring Drug exposure, several validated abbreviated AUC profiles, accurately predicting the dose-interval AUC, have been put forward. Together with an increasing knowledge of the time-related pharmacokinetic behaviour of Immunosuppressive Drug and their metabolites, studies are focusing on how to apply abbreviated AUC sampling methods in clinical transplantation, taking into account the numerous factors affecting Drug pharmacokinetics. Eventually, TDM using abbreviated AUC profiles has to be prospectively tested against classic methods of Drug monitoring in terms of cost-effectiveness, feasibility and clinical relevance with the ultimate goal of improving patient and graft survival.
Jean Paul Soulillou - One of the best experts on this subject based on the ideXlab platform.
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spontaneous operational tolerance after Immunosuppressive Drug withdrawal in clinical renal allotransplantation
Transplantation, 2007Co-Authors: Joanna Ashtonchess, Magali Giral, Sophie Brouard, Jean Paul SoulillouAbstract:Tolerance is the so-called "Holy Grail" of transplantation, but achieving this state is proving a major challenge, particularly in the clinical setting. Even in rodents, the definition of true transplant tolerance is not applicable to many models, with late graft damage often occurring despite long-term graft survival. Hence the term "operational tolerance," based more on graft function and absence of exogenous immunosuppression, is being adopted. Although the most sought-after goal in this field is to intentionally induce this state in a controlled manner, translating protocols across species from rodents to the clinic, the current literature demonstrates that this is proving a formidable task. A complementary approach is to address transplant tolerance from a different angle, by studying tolerance-like phenomena that occur "unintentionally" in transplant patients after Immunosuppressive Drug weaning. Such spontaneous operational tolerance, which can take place after years of immunosuppression, is rare in kidney transplant recipients. However, determining exactly how this state arises and how it can be detected may make it possible to induce it in a greater number of patients and then to return to the drawing board to rationally design protocols that have a greater chance of clinical success. Moreover, the study of such patients should help in the identification of biomarkers of low immunological risk that could be used to select patients for potential weaning. Collaborative efforts through international networks, together with the application of newer and more powerful technologies to diagnostic, prognostic, and mechanistic research, may help transplanters to achieve this goal.
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spontaneous operational tolerance after Immunosuppressive Drug withdrawal in clinical renal allotransplantation
Transplantation, 2007Co-Authors: Joanna Ashtonchess, Magali Giral, Sophie Ouard, Jean Paul SoulillouAbstract:Tolerance is the so-called "Holy Grail" of transplantation, but achieving this state is proving a major challenge, particularly in the clinical setting. Even in rodents, the definition of true transplant tolerance is not applicable to many models, with late graft damage often occurring despite long-term graft survival. Hence the term "operational tolerance," based more on graft function and absence of exogenous immunosuppression, is being adopted. Although the most sought-after goal in this field is to intentionally induce this state in a controlled manner, translating protocols across species from rodents to the clinic, the current literature demonstrates that this is proving a formidable task. A complementary approach is to address transplant tolerance from a different angle, by studying tolerance-like phenomena that occur "unintentionally" in transplant patients after Immunosuppressive Drug weaning. Such spontaneous operational tolerance, which can take place after years of immunosuppression, is rare in kidney transplant recipients. However, determining exactly how this state arises and how it can be detected may make it possible to induce it in a greater number of patients and then to return to the drawing board to rationally design protocols that have a greater chance of clinical success. Moreover, the study of such patients should help in the identification of biomarkers of low immunological risk that could be used to select patients for potential weaning. Collaborative efforts through international networks, together with the application of newer and more powerful technologies to diagnostic, prognostic, and mechanistic research, may help transplanters to achieve this goal.
Franck Verrecchia - One of the best experts on this subject based on the ideXlab platform.
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vitro evidence for a direct antifibrotic role of the Immunosuppressive Drug mycophenolate mofetil
2016Co-Authors: Nina Roos, Dominique Farge, Isabelle Madelaine, Alai Mauviel, Nicolas Poulalhon, Franck VerrecchiaAbstract:The Immunosuppressive Drug mycophenolate mofetil (MMF) is used to prevent organ rejection after transplantation and has shown some efficacy to prevent the fibrotic complications that occur during autoimmune diseases such as systemic sclerosis or during graft-versus-host disease (GVHD). We tested the hypothesis that MMF may exert direct effects on fibroblast extracellular matrix remodeling. Incubation of human lung fi-broblast cultures with MMF led to dose- and time-dependent reduction in the synthesis and expression of type I collagen. Inhibition of COL1A1 and COL1A2 mRNA steady-state levels occurred at the level of transcription via repression of their promoters. In contrast, MMF significantly enhanced the expres-sion and the synthesis of interstitial collagenase (matrix metal-loproteinase-1). MMF was also found to diminish the capacit
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in vitro evidence for a direct antifibrotic role of the Immunosuppressive Drug mycophenolate mofetil
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Nina Roos, Nicolas Poulalho, Dominique Farge, Isabelle Madelaine, Alai Mauviel, Franck VerrecchiaAbstract:The Immunosuppressive Drug mycophenolate mofetil (MMF) is used to prevent organ rejection after transplantation and has shown some efficacy to prevent the fibrotic complications that occur during autoimmune diseases such as systemic sclerosis or during graft-versus-host disease (GVHD). We tested the hypothesis that MMF may exert direct effects on fibroblast extracellular matrix remodeling. Incubation of human lung fibroblast cultures with MMF led to dose- and time-dependent reduction in the synthesis and expression of type I collagen. Inhibition of COL1A1 and COL1A2 mRNA steady-state levels occurred at the level of transcription via repression of their promoters. In contrast, MMF significantly enhanced the expression and the synthesis of interstitial collagenase (matrix metalloproteinase-1). MMF was also found to diminish the capacity of fibroblast to contract mechanically unloaded collagen lattices and to reduce the synthesis of α-smooth muscle actin, a marker of the contractile myofibroblast phenotype. In addition, MMF diminished the fibroblasts motility. In conclusion, we provide novel mechanism by which MMF alters fibroblast functions important for wound healing and implicated in the development of tissue fibrosis, e.g., collagen production, extracellular matrix contraction, and cell migration. Such properties may contribute to the beneficial therapeutic effects of MMF against fibrotic lesions developing in systemic sclerosis or during GVHD.
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modulation of collagen and mmp 1 gene expression in fibroblasts by the Immunosuppressive Drug rapamycin a direct role as an antifibrotic agent
Journal of Biological Chemistry, 2006Co-Authors: Nicolas Poulalho, Nina Roos, Dominique Farge, Alai Mauviel, Charlotte Tacheau, Cindy Neuzille, Laurence Michel, Franck VerrecchiaAbstract:We have examined whether rapamycin, an Immunosuppressive Drug, may exert part of its antifibrotic activity by directly targeting fibroblast extracellular matrix deposition. Incubation of human lung fibroblast (WI-26) cultures with rapamycin led to dose- and time-dependent reduction in the expression of types I and III collagens, both at the protein and mRNA levels. Rapamycin had no effect on collagen promoter activity but accelerated mRNA decay, indicating post-transcriptional control of collagen gene expression. In contrast, rapamycin significantly enhanced the expression of interstitial collagenase (MMP-1) at the protein and mRNA levels and transcriptionally. We determined that rapamycin efficiently activates AP-1-driven transcription by rapidly inducing c-jun/AP-1 phosphorylation with activation of the c-Jun N-terminal kinase (JNK) cascade, resulting in enhanced binding of AP-1.DNA complex formation and AP-1-dependent gene transactivation. Conversely, the JNK inhibitor SP600125 inhibited rapamycin-induced MMP-1 gene transactivation and AP-1/DNA interactions. A c-jun antisense expression vector efficiently prevented rapamycin-induced MMP-1 gene transcription. Pharmacological inhibition of either ERK or p38 MAPK pathways was without effect on rapamycin-induced MMP-1 gene expression. It thus appears that rapamycin may exert direct antifibrotic activities independent from its Immunosuppressive action.
Joanna Ashtonchess - One of the best experts on this subject based on the ideXlab platform.
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spontaneous operational tolerance after Immunosuppressive Drug withdrawal in clinical renal allotransplantation
Transplantation, 2007Co-Authors: Joanna Ashtonchess, Magali Giral, Sophie Brouard, Jean Paul SoulillouAbstract:Tolerance is the so-called "Holy Grail" of transplantation, but achieving this state is proving a major challenge, particularly in the clinical setting. Even in rodents, the definition of true transplant tolerance is not applicable to many models, with late graft damage often occurring despite long-term graft survival. Hence the term "operational tolerance," based more on graft function and absence of exogenous immunosuppression, is being adopted. Although the most sought-after goal in this field is to intentionally induce this state in a controlled manner, translating protocols across species from rodents to the clinic, the current literature demonstrates that this is proving a formidable task. A complementary approach is to address transplant tolerance from a different angle, by studying tolerance-like phenomena that occur "unintentionally" in transplant patients after Immunosuppressive Drug weaning. Such spontaneous operational tolerance, which can take place after years of immunosuppression, is rare in kidney transplant recipients. However, determining exactly how this state arises and how it can be detected may make it possible to induce it in a greater number of patients and then to return to the drawing board to rationally design protocols that have a greater chance of clinical success. Moreover, the study of such patients should help in the identification of biomarkers of low immunological risk that could be used to select patients for potential weaning. Collaborative efforts through international networks, together with the application of newer and more powerful technologies to diagnostic, prognostic, and mechanistic research, may help transplanters to achieve this goal.
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spontaneous operational tolerance after Immunosuppressive Drug withdrawal in clinical renal allotransplantation
Transplantation, 2007Co-Authors: Joanna Ashtonchess, Magali Giral, Sophie Ouard, Jean Paul SoulillouAbstract:Tolerance is the so-called "Holy Grail" of transplantation, but achieving this state is proving a major challenge, particularly in the clinical setting. Even in rodents, the definition of true transplant tolerance is not applicable to many models, with late graft damage often occurring despite long-term graft survival. Hence the term "operational tolerance," based more on graft function and absence of exogenous immunosuppression, is being adopted. Although the most sought-after goal in this field is to intentionally induce this state in a controlled manner, translating protocols across species from rodents to the clinic, the current literature demonstrates that this is proving a formidable task. A complementary approach is to address transplant tolerance from a different angle, by studying tolerance-like phenomena that occur "unintentionally" in transplant patients after Immunosuppressive Drug weaning. Such spontaneous operational tolerance, which can take place after years of immunosuppression, is rare in kidney transplant recipients. However, determining exactly how this state arises and how it can be detected may make it possible to induce it in a greater number of patients and then to return to the drawing board to rationally design protocols that have a greater chance of clinical success. Moreover, the study of such patients should help in the identification of biomarkers of low immunological risk that could be used to select patients for potential weaning. Collaborative efforts through international networks, together with the application of newer and more powerful technologies to diagnostic, prognostic, and mechanistic research, may help transplanters to achieve this goal.