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 ; Calcineurin Inhibitors/pharmacology* ; Immunosuppressive Agents/therapeutic use* ; Tacrolimus/pharmacology* ; T-Lymphocytes ; Immune System Diseases ; Rheumatic Diseases/drug therapy*

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. At present, no definite ALS biomarkers are available. In this study, exosomes from the plasma of patients with ALS and healthy controls were extracted, and differentially expressed exosomal proteins were compared. Among them, the expression of exosomal coronin-1a (CORO1A) was 5.3-fold higher than that in the controls. CORO1A increased with disease progression at a certain proportion in the plasma of patients with ALS and in the spinal cord of ALS mice. CORO1A was also overexpressed in NSC-34 motor neuron-like cells, and apoptosis, oxidative stress, and autophagic protein expression were evaluated. CORO1A overexpression resulted in increased apoptosis and oxidative stress, overactivated autophagy, and hindered the formation of autolysosomes. Moreover, CORO1A activated Ca²⁺-dependent phosphatase calcineurin, thereby blocking the fusion of autophagosomes and lysosomes. The inhibition of calcineurin activation by cyclosporin A reversed the damaged autolysosomes. In conclusion, the role of CORO1A in ALS pathogenesis was discovered, potentially affecting the disease onset and progression by blocking autophagic flux. Therefore, CORO1A might be a potential biomarker and therapeutic target for ALS.
Mice ; Animals ; Amyotrophic Lateral Sclerosis/pathology* ; Calcineurin/metabolism* ; Motor Neurons/pathology* ; Microfilament Proteins/metabolism* ; Cytoskeletal Proteins/metabolism*

Regulator of calcineurin 1 (RCAN1) can be induced by an intracellular calcium increase and oxidative stress, which are characteristic features of temporal lobe epilepsy. Thus, we investigated the spatiotemporal expression and cellular localization of RCAN1 protein and mRNA in the mouse hippocampus after pilocarpine-induced status epilepticus (SE). Male C57BL/6 mice were given pilocarpine hydrochloride (280 mg/kg, i.p.) and allowed to develop 2 h of SE. Then the animals were given diazepam (10 mg/kg, i.p.) to stop the seizures and sacrificed at 1, 3, 7, 14, or 28 day after SE. Cresyl violet staining showed that pilocarpine-induced SE resulted in cell death in the CA1 and CA3 subfields of the hippocampus from 3 day after SE. RCAN1 immunoreactivity showed that RCAN1 was mainly expressed in neurons in the shammanipulated hippocampi. At 1 day after SE, RCAN1 expression became detected in hippocampal neuropils. However, RCAN1 signals were markedly enhanced in cells with stellate morphology at 3 and 7 day after SE, which were confirmed to be reactive astrocytes, but not microglia by double immunofluorescence. In addition, real-time reverse transcriptase–polymerase chain reaction showed a significant upregulation of RCAN1 isoform 4 (RCAN1-4) mRNA in the SE-induced hippocampi. Finally, in situ hybridization with immunohistochemistry revealed astrocytic expression of RCAN1-4 after SE. These results demonstrate astrocytic upregulation of RCAN1 and RCAN1-4 in the mouse hippocampus in the acute and subacute phases of epileptogenesis, providing foundational information for the potential role of RCAN1 in reactive astrocytes during epileptogenesis.
Animals ; Astrocytes ; Calcineurin ; Calcium ; Cell Death ; Diazepam ; Epilepsy ; Epilepsy, Temporal Lobe ; Fluorescent Antibody Technique ; Hippocampus ; Humans ; Immunohistochemistry ; In Situ Hybridization ; Male ; Mice ; Microglia ; Neurons ; Neuropil ; Oxidative Stress ; Pilocarpine ; RNA, Messenger ; Seizures ; Status Epilepticus ; Up-Regulation ; Viola

BACKGROUND AND OBJECTIVES: This second adult heart transplantation (HTx) report is based on Korean Organ Transplant Registry data submitted on 400 HTxs in recipients of all ages. METHODS: From March 2014 to December 2017, a total of 400 HTxs were performed at 4 major centers in Korea. We analyzed demographics and characteristics according to transplant years. Patterns of immunosuppression, allograft rejection, and survival after HTx were analyzed. Donor and recipient age were highlighted. RESULTS: Some distinct differences in HTx statistics were noted. Mean donor age increased significantly in the most recent years compared to 2014–2015, while mean recipient age did not change. The proportion of patients on pre-transplant extracorporeal membrane oxygenation (ECMO) increased over time. One-year and intermediate-term survival was significantly worse in patients on pre-transplant ECMO compared to those without mechanical support. Over the years, tacrolimus has increased to become the most frequently used calcineurin inhibitor over cyclosporine, while the number of patients using steroids both at discharge and 1-year follow-up has declined. Age did not affect 1-year survival, but significantly affected intermediate-term survival. CONCLUSIONS: From 2014 to 2017, centers were willing to accept older donors to address increasing organ shortages and more patients received transplant under ECMO care. Increasing age was a strong independent factor for intermediate-term survival, however, post-transplant comorbidities did not differ among age groups. Further studies with longer follow-up duration are needed to better understand age-related post-transplant prognosis.
Adult ; Allografts ; Calcineurin ; Comorbidity ; Cyclosporine ; Demography ; Extracorporeal Membrane Oxygenation ; Follow-Up Studies ; Heart Failure ; Heart Transplantation ; Heart ; Humans ; Immunosuppression ; Korea ; Prognosis ; Registries ; Steroids ; Tacrolimus ; Tissue Donors ; Transplants

BACKGROUND: Management of atopic dermatitis (AD) involves the regular use of emollients together with topical steroids or calcineurin inhibitors for acute flares. However, the long-term use of oral medications in young children may have certain limitations. Wet wrap dressing (WWD) is an interesting alternative therapy for the short-term control of severe or refractory flares, thus avoiding the use of systemic treatments. OBJECTIVE: This study aimed to compare the efficacy between WWD and topical steroid agents and to control and estimate the utility of WWD in pediatric AD. METHODS: A total of 40 patients with mild-to-severe AD (eczema area and severity index of ≥3) aged <13 years were included in this study. Twenty patients were treated with WWD using two layers of cotton bandages or garments (Tubifast™), and the remaining were applied with topical steroid agents without cotton bandages. Improvement in severity of atopic dermatitis was evaluated using the eczema area and severity index (EASI). Improvement in skin barrier dysfunction was evaluated by measuring the transepidermal water loss (TEWL). We compared the two groups after 1 week of treatment using analysis of covariance and t-test. Furthermore, we surveyed the study groups using a questionnaire to estimate the utility of WWD and its adverse effects as well as to evaluate subjective outcomes of WWD. RESULTS: There were significant reductions in the mean EASI (−6.3, 95% confidence interval [CI]: −7.5 to −5.1, p=0.013) and TEWL (−26.7, 95% CI: −31.2 to −22.3, p=0.002) after 1 week of WWD treatment compared with the mean EASI (−4.0, 95% CI: −5.2 to −2.9) and TEWL (−15.4, 95% CI: −19.8 to −10.9) of the control group. Results of patient self-assessment and scores in the visual analogue scale (VAS) for pruritus were improved in both groups, but the differences were not statistically significant. Usefulness of WWD as an alternative therapy for the conventional therapy was satisfactory. CONCLUSION: This study is meaningful in that it estimates both the subjective and objective efficacy of WWD. In view of these findings, WWD showed superior therapeutic effects than conventional steroid application in the treatment of AD in children, with good compliance of patients and parent-caregivers.
Bandages ; Calcineurin Inhibitors ; Child ; Clothing ; Compliance ; Dermatitis, Atopic ; Eczema ; Emollients ; Humans ; Pruritus ; Self-Assessment ; Skin ; Steroids ; Therapeutic Uses ; Water

No abstract available.
Calcineurin ; Lichens

BACKGROUND: Optimal tacrolimus (TAC) trough levels for different periods after kidney transplantation (KT) has not been definitely established. This study aimed to investigate transplant outcomes of low-level (LL) and standard-level (SL) TAC according to post-transplant period. METHODS: A total of 278 consecutive kidney transplant recipients (KTRs) receiving TAC-based immunosuppression were divided into LL and SL-TAC groups (4–7 and 7–12 ng/mL for 0–2 months, 3–6 and 6–10 ng/mL for 3–6 months, 2–5 and 5–8 ng/mL for 7–12 months, respectively) according to TAC trough level at each period. We compared estimated glomerular filtration rate (eGFR), biopsy-proven acute rejection (BPAR), de novo donor-specific antibody (dnDSA), calcineurin inhibitor (CNI) toxicity, opportunistic infection, and allograft survival. RESULTS: SL-TAC group showed significantly higher mean eGFR at 0–2 months than LL-TAC group (72.1 ± 20.3 vs. 64.2 ± 22.7 mL/min/1.73m2; P = 0.003). Incidence of BPAR at 7–12 months was significantly lower in SL-TAC group than in LL-TAC group (0.0% vs. 3.9%; P = 0.039). Patients with persistent SL-TAC lasting 12 months showed higher eGFR at 7–12 months than those with persistent LL-TAC (65.5 ± 13.0 vs. 57.9 ± 13.9 mL/min/1.73m2; P = 0.007). No significant differences in dnDSA, CNI toxicity, serious infections, or allograft survival were observed. CONCLUSIONS: Maintenance of proper TAC trough level after 6 months could reduce BPAR without adverse drug toxicities in KTRs. Moreover, persistent SL-TAC during the first year after KT might have a beneficial effect on a trend for a lower incidence of dnDSA and better renal allograft function.
Allografts ; Calcineurin ; Drug-Related Side Effects and Adverse Reactions ; Glomerular Filtration Rate ; Humans ; Immunosuppression ; Incidence ; Kidney Transplantation ; Kidney ; Opportunistic Infections ; Tacrolimus ; Transplant Recipients

BACKGROUND: Although kidney transplantation outcomes have improved dramatically after using calcineurin inhibitors (CNIs), CNI toxicity continues to be reported and the mechanism remains uncertain. Here, we investigated the neurotoxicity of CNIs by focusing on the viability of glioma cells.METHODS: Glioma cells were treated with several concentrations of CNIs for 24 hours at 37℃ and their cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.RESULTS: Exposure to 0, 0.25, 0.5, 2.5, 5.0, and 10.0 mM concentrations respectively showed 100%, 64.3%, 61.3%, 68.1%, 62.4%, and 68.6% cell viability for cyclosporine and 100%, 38.6%, 40.8%, 43.7%, 37.8%, and 43.0% for tacrolimus. The direct toxic effect of tacrolimus on glioma cell viability was stronger than that of cyclosporine at the same concentration.CONCLUSION: CNIs can cause neurological side effects by directly exerting cytotoxic effects on brain cells. Therefore, we should carefully monitor the neurologic symptoms and level of CNIs in kidney transplant patients.
Animals ; Brain ; Calcineurin Inhibitors ; Calcineurin ; Cell Survival ; Cyclosporine ; Glioma ; Humans ; Kidney ; Kidney Transplantation ; Neurologic Manifestations ; Rats ; Tacrolimus

OBJECTIVETo investigate the effects of evodiamine (Evo), a component of Evodiaminedia rutaecarpa (Juss.) Benth, on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) and further explore the potential mechanisms.

METHODSCardiomyocytes from neonatal Sprague Dawley rats were isolated and characterized, and then the cadiomyocyte cultures were randomly divided into control, model (Ang II 0.1 μmol/L), and Evo (0.03, 0.3, 3 μmol/L) groups. The cardiomyocyte surface area, protein level, intracellular free calcium ([Ca]) concentration, activity of nitric oxide synthase (NOS) and content of nitric oxide (NO) were measured, respectively. The mRNA expressions of atrial natriuretic factor (ANF), calcineurin (CaN), extracellular signal-regulated kinase-2 (ERK-2), and endothelial nitric oxide synthase (eNOS) of cardiomyocytes were analyzed by real-time reverse transcriptionpolymerase chain reaction. The protein expressions of calcineurin catalytic subunit (CnA) and mitogen-activated protein kinase phosphatase-1 (MKP-1) were detected by Western blot analysis.

RESULTSCompared with the control group, Ang II induced cardiomyocytes hypertrophy, as evidenced by increased cardiomyocyte surface area, protein content, and ANF mRNA expression; increased intracellular free calcium ([Ca]) concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but decreased MKP-1 protein expression (P<0.05 or P<0.01). Compared with Ang II, Evo (0.3, 3 μmol/L) significantly attenuated Ang II-induced cardiomyocyte hypertrophy, decreased the [Ca] concentration and expressions of CaN mRNA, CnA protein, and ERK-2 mRNA, but increased MKP-1 protein expression (P<0.05 or P<0.01). Most interestingly, Evo increased the NOS activity and NO production, and upregulated the eNOS mRNA expression (P<0.05).

CONCLUSIONEvo signifificantly attenuated Ang II-induced cardiomyocyte hypertrophy, and this effect was partly due to promotion of NO production, reduction of [Ca]i concentration, and inhibition of CaN and ERK-2 signal transduction pathways.

Angiotensin II ; Animals ; Atrial Natriuretic Factor ; metabolism ; Calcineurin ; genetics ; metabolism ; Calcium ; metabolism ; Dual Specificity Phosphatase 1 ; genetics ; metabolism ; Extracellular Signal-Regulated MAP Kinases ; genetics ; metabolism ; Hypertrophy ; Myocytes, Cardiac ; drug effects ; metabolism ; pathology ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; Quinazolines ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Rats, Sprague-Dawley

Atopic dermatitis (AD) is a common, chronic, relapsing, inflammatory skin disease that affects both children and adults. AD is the cause of considerable morbidity including severe pruritus and impaired quality of life. Treatments for active disease include avoidance of triggering factors, barrier repair, topical medications including topical corticosteroids (TCs) and topical calcineurin inhibitors (TCIs), phototherapy, antibacterial agents, and systemic immunosuppressants including cyclosporine. Until recently, the only Food and Drug Administration (FDA)-approved systemic treatment options for patients with moderate-to-severe AD were steroids and cyclosporine. Systemic steroids are not recommended by current guidelines and are commonly associated with disease rebound. Instead, clinicians choose from several off-label immunosuppressants. In 2018, the Korean FDA approved dupilumab for adults with moderate-to-severe AD whose disease is not adequately controlled with topical therapies. The implementation of treatment guidelines for AD is challenging. Herein, we review the several treatment modalities for AD and recommend a treatment algorithm.
Adrenal Cortex Hormones ; Adult ; Anti-Bacterial Agents ; Calcineurin Inhibitors ; Child ; Cyclosporine ; Dermatitis, Atopic* ; Humans ; Immunosuppressive Agents ; Phototherapy ; Pruritus ; Quality of Life ; Skin Diseases ; Steroids ; United States Food and Drug Administration