A comprehensive update of the metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation

Vidigal, Ana Cláudia; Lucena, Débora D. de; Beyerstedt, Stephany; Rangel, Érika Bevilaqua

doi:10.1080/17425255.2023.2243808

Cited by 2 publications

(1 citation statement)

References 161 publications

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“…Sirolimus (rapamycin) is approved by Food and Drug Administration and other regulatory authorities to prevent organ rejection in patients receiving renal transplantation [ 44 , 45 , 46 ]. Moreover, a high number of clinical studies have been published using sirolimus as bioactive molecules in the treatment of patients who underwent transplantation of the lung [ 47 ], heart [ 48 ], pancreas [ 49 ], liver [ 50 ], intestine [ 51 ], cornea [ 52 ], and bone marrow [ 53 ]. Consequently, sirolimus (rapamycin) is of great interest for several pathologies in which transplantation is a clinical option, including (but not restricted to) solid cancers (for instance liver transplantation in hepatocellular carcinoma, or kidney transplantation in renal cancers) [ 54 , 55 ], leukemia, lymphoma and other blood cancers (for instance bone marrow transplantation in leukemia) [ 56 ], cystic fibrosis (lung transplantation) [ 57 ], serine/threonine kinase 4 (STK4) deficiency, characterized by recurrent bacterial, viral, and fungal infections (allogeneic hematopoietic stem cell transplantation, HSCT) [ 58 ], and hematological diseases (bone marrow transplantation) [ 59 ].…”

Section: Rapamycin In Organ and Tissue Transplantationmentioning

confidence: 99%

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Gambari,

Zuccato,

Cosenza

et al. 2023

Biology

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In this review article, we present the fascinating story of rapamycin (sirolimus), a drug able to induce γ-globin gene expression and increased production of fetal hemoglobin (HbF) in erythroid cells, including primary erythroid precursor cells (ErPCs) isolated from β-thalassemia patients. For this reason, rapamycin is considered of great interest for the treatment of β-thalassemia. In fact, high levels of HbF are known to be highly beneficial for β-thalassemia patients. The story of rapamycin discovery began in 1964, with METEI, the Medical Expedition to Easter Island (Rapa Nui). During this expedition, samples of the soil from different parts of the island were collected and, from this material, an antibiotic-producing microorganism (Streptomyces hygroscopicus) was identified. Rapamycin was extracted from the mycelium with organic solvents, isolated, and demonstrated to be very active as an anti-bacterial and anti-fungal agent. Later, rapamycin was demonstrated to inhibit the in vitro cell growth of tumor cell lines. More importantly, rapamycin was found to be an immunosuppressive agent applicable to prevent kidney rejection after transplantation. More recently, rapamycin was found to be a potent inducer of HbF both in vitro using ErPCs isolated from β-thalassemia patients, in vivo using experimental mice, and in patients treated with this compound. These studies were the basis for proposing clinical trials on β-thalassemia patients.

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Section: Rapamycin In Organ and Tissue Transplantationmentioning

confidence: 99%

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Gambari,

Zuccato,

Cosenza

et al. 2023

Biology

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Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer’s phenotypes without blocking peripheral T cell IL-2 response

Stallings,

O’Neal,

et al. 2023

Alz Res Therapy

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Background Current treatments for Alzheimer’s disease (AD) have largely failed to yield significant therapeutic benefits. Novel approaches are desperately needed to help address this immense public health issue. Data suggests that early intervention at the first stages of mild cognitive impairment may have a greater chance for success. The calcineurin (CN)-Pin1 signaling cascade can be selectively targeted with tacrolimus (FK506), a highly specific, FDA-approved CN inhibitor used safely for > 20 years in solid organ transplant recipients. AD prevalence was significantly reduced in solid organ recipients treated with FK506. Methods Time release pellets were used to deliver constant FK506 dosage to APP/PS1 mice without deleterious manipulation or handling. Immunofluorescence, histology, molecular biology, and behavior were used to evaluate changes in AD pathology. Results FK506 can be safely and consistently delivered into juvenile APP/PS1 mice via time-release pellets to levels roughly seen in transplant patients, leading to the normalization of CN activity and reduction or elimination of AD pathologies including synapse loss, neuroinflammation, and cognitive impairment. Pin1 activity and function were rescued despite the continuing presence of high levels of transgenic Aβ42. Indicators of neuroinflammation including Iba1 positivity and IL-6 production were also reduced to normal levels. Peripheral blood mononuclear cells (PBMC) obtained during treatment or splenocytes isolated at euthanasia activated normally after mitogens. Conclusions Low-dose, constant FK506 can normalize CNS CN and Pin1 activity, suppress neuroinflammation, and attenuate AD-associated pathology without blocking peripheral IL-2 responses making repurposed FK506 a viable option for early, therapeutic intervention in AD.

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A comprehensive update of the metabolic and toxicological considerations for immunosuppressive drugs used during pancreas transplantation

Cited by 2 publications

References 161 publications

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer’s phenotypes without blocking peripheral T cell IL-2 response

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