1.Evidence-based recommendations for the treatment of rheumatic and immunologic diseases with calcineurin inhibitors: a consensus statement.
Chinese Journal of Internal Medicine 2023;62(11):1266-1281
Calcineurin inhibitors (CNI), including oral cyclosporin A and tacrolimus, are intensive immunosuppressants that are extensively used in the treatment of rheumatic and immunologic diseases in China. CNI selectively inhibit the activation and proliferation of T lymphocytes and the transcription of cytokines [such as tumor necrosis factor-α, interleukin (IL)-6, and IL-17] through inhibiting the activation of calcineurin in cells and reducing the release of IL-2. To standardize the use of CNI in the field of rheumatic and immunologic diseases, this consensus statement was developed by the National Clinical Research Center for Dermatologic and Immunologic Diseases (Peking Union Medical College Hospital), in conjunction with the Chinese Association of Rheumatology and Immunology Physicians, the Chinese Research Hospital Association, the Rheumatology and Immunology Professional Committee, and the Chinese Association of Rehabilitation Medicine. The 2011 Oxford Centre for Evidence-Based Medicine Levels of Evidence was used to rate the quality of the evidence and the strength of the recommendations, and the RIGHT (Reporting Items for practice Guidelines in HealThcare) checklist was followed to report the consensus. The consensus offers recommendations addressing nine clinical challenges to Chinese clinicians. The primary objective of this consensus is to deliver scientific and detailed guidance on CNI for Chinese clinicians, and to improve the quality of patient-centered medical services.
Humans
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Calcineurin Inhibitors/pharmacology*
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Immunosuppressive Agents/therapeutic use*
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Tacrolimus/pharmacology*
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T-Lymphocytes
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Immune System Diseases
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Rheumatic Diseases/drug therapy*
2.Effect of genetic polymorphism on disposition of calcineurin inhibitors in solid organ transplantation.
Dingyun LI ; Lijun ZHU ; Qifa YE
Journal of Central South University(Medical Sciences) 2010;35(9):1018-1022
Calcineurin inhibitors, tacrolimus and cyclosporine, characterized by a narrow therapeutic index and a high variability in pharmacokinetic behaviors, are 2 basic immunosuppressive drugs widely used in solid organ transplantation. Tailoring of immunosuppressive drug therapy to the specific requirements of individual patients to optimize the efficacy and minimize the toxicity remains one of the biggest challenges for doctors in solid organ transplantation. Pharmacogenetic and pharmacogenomic researches, studying the effect of genetic polymorphism encoding drug metabolizing enzymes, drug transporters and pharmacological target molecules on drug disposition and action, hold promise to produce useful clinical tools for individualizing immunosuppressive therapy.
Animals
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Calcineurin Inhibitors
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Cyclosporine
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pharmacokinetics
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pharmacology
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Cytochrome P-450 CYP3A
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genetics
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Humans
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Immunosuppressive Agents
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pharmacokinetics
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pharmacology
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Organ Transplantation
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Polymorphism, Genetic
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Tacrolimus
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pharmacokinetics
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pharmacology
3.Role of calcineurin in down-regulation of left ventricular transmural voltage- dependent K(+) currents in mice with heart failure.
Chen-Xia SHI ; Fang DONG ; Yan-Chao CHANG ; Xiao-Feng WANG ; Yan-Fang XU
Acta Physiologica Sinica 2015;67(4):401-408
The aim of the present study was to investigate the role of calcineurin in the down-regulation of left ventricular transmural voltage-dependent K(+) currents in heart failure. Transverse aorta was banded by using microsurgical techniques to create mouse heart failure model. Sham-operated (Sham) or aorta banded (Band) mice were randomized to receive calcineurin inhibitor cyclosporine A (CsA) or vehicle. The densities and kinetic properties of voltage-dependent K(+) currents, as well as action potential (AP), of left ventricular subendocardial (Endo) and subepicardial (Epi) myocytes were determined by using whole-cell patch-clamp technique. The results showed that calcineurin activity was significant higher in Endo myocytes than that in Epi ones in all the groups. Compared with Sham group, Band mice showed significantly increased calcineurin activity both in Endo and Epi myocytes. CsA significantly reduced calcineurin activity in Band mice. CsA treatment in Band mice partially reversed the down-regulation of Ito density, completely reversed the down-regulation of IK,slow density both in Endo and Epi myocytes, and Iss density in Endo myocytes. In addition, CsA treatment in Band mice partially antagonized the prolongation of action potential duration (APD), and APD at 50% (APD50) and 90% repolarization (APD90) were significantly reduced. Because of non-parallel shortening of APD in Endo and Epi myocytes, the ratio of Endo/Epi APD90 was reduced from 4.8:1 in Band mice to 2.6:1 in CsA-treated mice, which was close to that in Sham mice. The results suggest that non-parallel activation of calcineurin in Endo and Epi myocytes contributes to the down-regulation of transmural voltage-dependent K(+) currents and the amplification of transmural dispersion of repolarization (TDR) in left ventricular failure hearts. Inhibition of calcineurin may be a potential new therapeutic strategy to prevent and cure arrhythmias and sudden death in heart failure.
Action Potentials
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Animals
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Calcineurin
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physiology
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Calcineurin Inhibitors
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pharmacology
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Cyclosporine
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pharmacology
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Disease Models, Animal
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Down-Regulation
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Heart
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physiopathology
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Heart Failure
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physiopathology
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Mice
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Patch-Clamp Techniques
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Potassium Channels, Voltage-Gated
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physiology
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Ventricular Function, Left
4.Induction of fibronectin gene expression by inhibitors of protein phosphatase type 2B in normal and transformed fibroblasts.
Jung Hwa RHEW ; Young Ah SHIN ; Byung Heon LEE ; Rang Woon PARK ; In San KIM
Experimental & Molecular Medicine 1999;31(2):71-75
Two intracellular signal pathways mediated by cAMP and protein kinase C (PKC) were involved in the regulation of FN gene expression (Lee et al., Exp. Mol. Med. 30: 240, 1998). In this study, a possible involvement of protein phosphatase-dependent pathways in the regulation of FN gene expression was investigated by using protein phosphatase type 2B (PP2B) inhibitors, cyclosporin A and ascomycin. Both cyclosporin A and ascomycin increased the levels of FN mRNA in WI-38 human lung fibroblasts and the SV40-transformed WI-38 cells but not in MC3T3-E1 osteoblasts. The expression of FN appears to increase from six hours up to 48 hours after treatment suggesting that it is not an immediate effect. In addition, this effect required a new protein synthesis. Neither cyclosporin A nor ascomycin affects the phorbol myristate acetate (PMA)-induced stimulation of FN gene expression and the same result occurred in vice versa suggesting the mechanism of PMA and cyclosporin A/ascomycin in the regulation of FN gene expression may share a common downstream pathway. Taken together, this study suggests that PP2B is involved in the regulation of FN gene expression in normal and transformed fibroblasts but not in osteoblasts.
Animal
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Calcineurin/antagonists & inhibitors*
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Cell Line, Transformed
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Cell Transformation, Viral
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Cyclosporine/pharmacology*
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Enzyme Inhibitors/pharmacology
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Fibroblasts
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Fibronectins/metabolism
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Fibronectins/genetics*
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Gene Expression Regulation*
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Human
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Lung/cytology
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Mice
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Osteoblasts
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Tacrolimus/pharmacology
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Tacrolimus/analogs & derivatives*
5.Down syndrome critical region 1 enhances the proteolytic cleavage of calcineurin.
Ji Eun LEE ; Hyonchol JANG ; Eun Jung CHO ; Hong Duk YOUN
Experimental & Molecular Medicine 2009;41(7):471-477
Down syndrome critical region 1 (DSCR1), an oxidative stress-response gene, interacts with calcineurin and represses its phosphatase activity. Recently it was shown that hydrogen peroxide inactivates calcineurin by proteolytic cleavage. Based on these facts, we investigated whether oxidative stress affects DSCR1-mediated inactivation of calcineurin. We determined that overexpression of DSCR1 leads to increased proteolytic cleavage of calcineurin. Convertsely, knockdown of DSCR1 abolished calcineurin cleavage upon treatment with hydrogen peroxide. The PXIIXT motif in the COOH-terminus of DSCR1 is responsible for both binding and cleavage of calcineurin. The knockdown of overexpressed DSCR1 in DS fibroblast cells also abrogated calcineurin proteolysis by hydrogen peroxide. These results suggest that DSCR1 has the ability to inactivate calcineurin by inducing proteolytic cleavage of calcineurin upon oxidative stress.
Adenoviridae/genetics
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Adult
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Animals
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Calcineurin/antagonists & inhibitors/*metabolism
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Cells, Cultured
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Chromatin Immunoprecipitation
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Down Syndrome/*metabolism/pathology
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Fibroblasts/metabolism/pathology
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Humans
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Hydrogen Peroxide/pharmacology
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Immunoglobulin G/immunology
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Intracellular Signaling Peptides and Proteins/*physiology
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Male
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Mice
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Mice, Inbred ICR
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Muscle Proteins/*physiology
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Neuroblastoma/genetics/metabolism/pathology
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Neurons/cytology/metabolism
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Oxidants/pharmacology
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Oxidative Stress
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Peptide Fragments/immunology
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RNA, Messenger/genetics/metabolism
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RNA, Small Interfering/pharmacology
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Rabbits
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Reverse Transcriptase Polymerase Chain Reaction
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Skin/pathology
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Young Adult