scholarly journals Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos

2016 ◽  
Vol 35 (6) ◽  
pp. 712-718 ◽  
Author(s):  
Ling-Ling Jiang ◽  
Mei-Hui Liu ◽  
Jian-Ying Li ◽  
Zhi-Heng He ◽  
Huan Li ◽  
...  
Keyword(s):  
Mycophenolic Acid ◽  
De Novo ◽  
Quantitative Polymerase Chain Reaction ◽  
Solid Organ Transplantation ◽  
Zebrafish Embryos ◽  
Solid Organ ◽  
Dependent Manner ◽  
Inosine Monophosphate Dehydrogenase ◽  
Developmental Defects

With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, some clinical studies indicate that it is also a human teratogen. However, it is unknown by which mechanism MPA acts as a teratogen. Mycophenolic acid was a selective blocker of de novo purine synthesis, and its immunosuppressive effect is mediated by the inhibition of inosine monophosphate dehydrogenase, which could be a target for MPA-induced toxicity as well. The aim of our study was to examine the direct influence of MPA exposure on zebrafish ( Danio rerio) embryos. Morphological defects including tail curvature and severe pericardial edema in zebrafish embryos caused by MPA (3.7-11.1 µmol/L) were found in a dose-dependent manner. The teratogenic index (25% lethal concentration value (LC25)/no observed adverse effect level ratio) was 16, which indicated MPA as a teratogen. Quantitative polymerase chain reaction analysis revealed that the expression level of impdh1b and impdh2 was significantly reduced by MPA treatment at 8 µmol/L (equals to LC25 level). All the toxic effects could be partially reversed by the addition of 33.3 µmol/L guanosine. Our results indicated that MPA impairs the development of zebrafish embryos via inhibition of impdh activity, which subsequently caused a guanosine nucleotide depletion in vivo.

Effects of exogenous interleukin-7 on human thymus function

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2851-2858 ◽  
Author(s):  
Yukari Okamoto ◽  
Daniel C. Douek ◽  
Richard D. McFarland ◽  
Richard A. Koup
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
De Novo ◽  
Quantitative Polymerase Chain Reaction ◽  
Cell Receptor ◽  
Cellular Division ◽  
Hematopoietic Stem ◽  
Human Thymus ◽  
Interleukin 7

Abstract Immune reconstitution is a critical component of recovery after treatment of human immunodeficiency virus (HIV) infection, cancer chemotherapy, and hematopoietic stem cell transplantation. The ability to enhance T-cell production would benefit such treatment. We examined the effects of exogenous interleukin-7 (IL-7) on apoptosis, proliferation, and the generation of T-cell receptor rearrangement excision circles (TRECs) in human thymus. Quantitative polymerase chain reaction demonstrated that the highest level of TRECs (14 692 copies/10 000 cells) was present in the CD1a+CD3−CD4+CD8+stage in native thymus, suggesting that TREC generation occurred following the cellular division in this subpopulation. In a thymic organ culture system, exogenous IL-7 increased the TREC frequency in fetal as well as infant thymus, indicating increased T-cell receptor (TCR) rearrangement. Although this increase could be due to the effect of IL-7 to increase thymocyte proliferation and decrease apoptosis of immature CD3− cells, the in vivo experiments using NOD/LtSz-scid mice given transplants of human fetal thymus and liver suggested that IL-7 can also directly enhance TREC generation. Our results provide compelling evidence that IL-7 has a direct effect on increasing TCR-αβ rearrangement and indicate the potential use of IL-7 for enhancing de novo naı̈ve T-cell generation in immunocompromised patients.

scholarly journals Beneficial effects of mycophenolate mofetil on cardiotoxicity induced by tacrolimus in wistar rats

2016 ◽  
Vol 242 (4) ◽  
pp. 448-455 ◽  
Author(s):  
Hanen Ferjani ◽  
Rim Timoumi ◽  
Ines Amara ◽  
Salwa Abid ◽  
Abedellatif Achour ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mycophenolate Mofetil ◽  
Oral Administration ◽  
Protective Effect ◽  
Cardiac Toxicity ◽  
De Novo ◽  
Antioxidant Activities ◽  
Solid Organ Transplantation ◽  
Protein Carbonyl ◽  
Solid Organ

The immunosuppressive drug tacrolimus (TAC) is used clinically to reduce the rejection rate in transplant patients. TAC has contributed to an increased prevalence of cardiovascular disease in patients receiving solid organ transplantation. Mycophenolate mofetil (MMF), a potent inhibitor of de novo purine synthesis, is known to prevent ongoing rejection in combination with TAC. In the present study, we investigated the antioxidant and antigenotoxic effect of MMF on TAC-induced cardiotoxicity in rats. Oral administration of TAC at 2.4, 24, and 60 mg/kg b.w. corresponding, respectively, to 1, 10, and 25% of LD50 for 24 h caused cardiac toxicity in a dose-dependant manner. TAC increased significantly DNA damage level in hearts of treated rats. Furthermore, it increased malondialdehyde (MDA) and protein carbonyl (PC) levels and decreased catalase (CAT) and superoxide dismutase (SOD) activities. The oral administration of MMF at 50 mg/kg b.w. simultaneously with TAC at 60 mg/kg b.w. proved a significant cardiac protection by decreasing DNA damage, MDA, and PC levels, and by increasing the antioxidant activities of CAT and SOD. Thus, our study showed, for the first time, the protective effect of MMF against cardiac toxicity induced by TAC. This protective effect was mediated via an antioxidant process.

scholarly journals PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors

2018 ◽  
Vol 115 (15) ◽  
pp. 3930-3935 ◽  
Author(s):  
Dongshi Chen ◽  
Jingshan Tong ◽  
Liheng Yang ◽  
Liang Wei ◽  
Donna B. Stolz ◽  
...  
Keyword(s):  
Feedback Loop ◽  
Dependent Manner ◽  
Dna Sensors ◽  
Necrotic Cell ◽  
Developmental Defects ◽  
Tnf Α ◽  
Amplification Mechanism ◽  
Signaling Process

Necroptosis, a form of regulated necrotic cell death, is governed by RIP1/RIP3-mediated activation of MLKL. However, the signaling process leading to necroptotic death remains to be elucidated. In this study, we found that PUMA, a proapoptotic BH3-only Bcl-2 family member, is transcriptionally activated in an RIP3/MLKL-dependent manner following induction of necroptosis. The induction of PUMA, which is mediated by autocrine TNF-α and enhanced NF-κB activity, contributes to necroptotic death in RIP3-expressing cells with caspases inhibited. On induction, PUMA promotes the cytosolic release of mitochondrial DNA and activation of the DNA sensors DAI/Zbp1 and STING, leading to enhanced RIP3 and MLKL phosphorylation in a positive feedback loop. Furthermore, deletion of PUMA partially rescues necroptosis-mediated developmental defects in FADD-deficient embryos. Collectively, our results reveal a signal amplification mechanism mediated by PUMA and cytosolic DNA sensors that is involved in TNF-driven necroptotic death in vitro and in vivo.

scholarly journals Correlation of Cytomegalovirus (CMV) Disease Severity and Mortality With CMV Viral Burden in CMV-Seropositive Donor and CMV-Seronegative Solid Organ Transplant Recipients

2019 ◽  
Vol 6 (2) ◽  
Author(s):  
Jacqueline M McBride ◽  
Daniel Sheinson ◽  
Jenny Jiang ◽  
Nicholas Lewin-Koh ◽  
Barbara G Werner ◽  
...  
Keyword(s):  
Viral Load ◽  
Disease Severity ◽  
Quantitative Polymerase Chain Reaction ◽  
Solid Organ Transplantation ◽  
Area Under The Curve ◽  
World Health ◽  
Solid Organ ◽  
Transplant Recipients ◽  
Viral Burden ◽  
Cmv Disease

Abstract Background The rate of cytomegalovirus (CMV) viral load increase and peak viral loads are associated with CMV disease in kidney and liver transplant recipients, but relationships to disease severity or mortality have not been shown. Methods Using stored serial serum specimens from renal (n = 59) and liver (n = 35) transplant recipients (D+R-; CMV-seropositive donors, CMV-seronegative recipients) from 2 prospective, randomized, controlled, interventional prophylaxis trials of CMV immune globulin (CMVIG), CMV viral load was measured using the COBAS quantitative polymerase chain reaction assay and the World Health Organization CMV standard. Patients with severe CMV-associated disease were classified according to trial definitions. Pairwise comparisons of mean viral load among deceased, surviving diseased, and nondiseased patients were analyzed by 2-way analysis of variance. To determine if viral load could predict mortality, receiver operating characteristic (ROC) curves were constructed using area under the curve (AUC) of the viral load and peak viral concentration (Vmax). Results Viral load (mean log10 [AUC], peak viral load [Vmax]) for patients with severe CMV disease was significantly higher compared with nondiseased patients (P < .001). Similarly, higher viral burden was significantly associated with mortality (P < .001). Viral load AUC and Vmax AUROCs for predicting mortality were 0.796 and 0.824, respectively, for renal patients, and 0.769 and 0.807, respectively, for liver patients. Conclusions Using specimens from studies preceding the antiviral prophylaxis era, CMV viral load was associated with severe CMV disease and death, supporting CMV viral load quantification as a proxy for CMV disease severity and disease-associated mortality end points in solid organ transplantation.

De Novo Malignancy After Solid Organ Transplantation in Children

2009 ◽  
Vol 41 (2) ◽  
pp. 674-675 ◽  
Author(s):  
D. Debray ◽  
V. Baudouin ◽  
F. Lacaille ◽  
M. Charbit ◽  
C. Rivet ◽  
...  
Keyword(s):  
Organ Transplantation ◽  
De Novo ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
De Novo Malignancy

scholarly journals Consensus Report on Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplantation

2010 ◽  
Vol 5 (2) ◽  
pp. 341-358 ◽  
Author(s):  
Dirk R.J. Kuypers ◽  
Yannick Le Meur ◽  
Marcelo Cantarovich ◽  
Michael J. Tredger ◽  
Susan E. Tett ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Organ Transplantation ◽  
Mycophenolic Acid ◽  
Drug Monitoring ◽  
Solid Organ Transplantation ◽  
Therapeutic Drug ◽  
Solid Organ ◽  
Consensus Report

scholarly journals In VivoAssessment of Drug Efficacy against Mycobacterium abscessus Using the Embryonic Zebrafish Test System

2014 ◽  
Vol 58 (7) ◽  
pp. 4054-4063 ◽  
Author(s):  
Audrey Bernut ◽  
Vincent Le Moigne ◽  
Tiffany Lesne ◽  
Georges Lutfalla ◽  
Jean-Louis Herrmann ◽  
...  
Keyword(s):  
Drug Efficacy ◽  
Test System ◽  
Mycobacterium Abscessus ◽  
Zebrafish Embryos ◽  
Dependent Manner ◽  
Bacterial Killing ◽  
Content Type ◽  
Fluorescence Measurements ◽  
Drug Concentrations

ABSTRACTMycobacterium abscessusis responsible for a wide spectrum of clinical syndromes and is one of the most intrinsically drug-resistant mycobacterial species. Recent evaluation of thein vivotherapeutic efficacy of the few potentially active antibiotics againstM. abscessuswas essentially performed using immunocompromised mice. Herein, we assessed the feasibility and sensitivity of fluorescence imaging for monitoring thein vivoactivity of drugs against acuteM. abscessusinfection using zebrafish embryos. A protocol was developed where clarithromycin and imipenem were directly added to water containing fluorescentM. abscessus-infected embryos in a 96-well plate format. The status of the infection with increasing drug concentrations was visualized on a spatiotemporal level. Drug efficacy was assessed quantitatively by measuring the index of protection, the bacterial burden (CFU), and the number of abscesses through fluorescence measurements. Both drugs were active in infected embryos and were capable of significantly increasing embryo survival in a dose-dependent manner. Protection from bacterial killing correlated with restricted mycobacterial growth in the drug-treated larvae and with reduced pathophysiological symptoms, such as the number of abscesses within the brain. In conclusion, we present here a new and efficient method for testing and compare thein vivoactivity of two clinically relevant drugs based on a fluorescent reporter strain in zebrafish embryos. This approach could be used for rapid determination of thein vivodrug susceptibility profile of clinical isolates and to assess the preclinical efficacy of new compounds againstM. abscessus.

Epidemiology of de novo malignancies after solid-organ transplantation: Immunosuppression, infection and other risk factors

2014 ◽  
Vol 28 (8) ◽  
pp. 1251-1265 ◽  
Author(s):  
Pierluca Piselli ◽  
Diana Verdirosi ◽  
Claudia Cimaglia ◽  
Ghil Busnach ◽  
Lucia Fratino ◽  
...  
Keyword(s):  
Risk Factors ◽  
Organ Transplantation ◽  
De Novo ◽  
Solid Organ Transplantation ◽  
Solid Organ

scholarly journals P202 De novo Inflamatory Bowel Disease after solid organ transplantation

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S265-S266
Author(s):  
A M Luque Carmona ◽  
M Rojas Feria ◽  
M D De la Cruz Ramirez ◽  
C Trigo Salado ◽  
J M Herrera Justiniano ◽  
...  
Keyword(s):  
Organ Transplantation ◽  
Bowel Disease ◽  
Biological Therapy ◽  
De Novo ◽  
Solid Organ Transplantation ◽  
Perianal Disease ◽  
Control Group ◽  
Solid Organ ◽  
Extraintestinal Manifestations ◽  
Frequent Change

Abstract Background The aim of this study was to determine the disease phenotype, evolution and therapeutic needs of de novo inflammatory bowel disease (IBD) in transplanted patients. Methods A retrospective single center study that included all patients who developed IBD after solid organ transplantation in a tertiary hospital. Data collected included transplant-related variables, IBD phenotype, course of the disease and its treatment. A control group of non-transplanted IBD patients was randomly selected. Results We included 17 post-transplanted IBD patients and 57 non-transplanted IBD patients. Post-trasplanted patients were older at diagnosis, had greater colonic involvement, with an inflammatory behaviour, absence of perianal involvement and extraintestinal manifestations compared to control group (Table 1). The most common immunosuppression regimen was tacrolimus+mycophenolate mofetil (MMF)+prednisone and the most frequent change after diagnosis was the switch of MMF for azathioprine. De novo IBD patients required less biological therapy than the control group (11.8 vs 42.1% p 0.02) and none required surgical intervention compared to 35.1% in the control group (p 0.002). Multivariate analysis carried out on the total population showed that active smoking, perianal disease and extraintestinal manifestations were associated with a greater need for biologics, while the only factor that influenced surgical risk was stricturing and penetrating behaviour of Crohn′s disease. Conclusion De novo IBD after solid organ transplantation has a favorable course, predominating the inflammatory behaviour and requiring less biological therapy and surgical interventions. The absence of extraintestinal manifestations and perianal disease stands out.

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