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OBJECTIVE: Ischemic stroke is a leading cause of human mortality and long-term disability worldwide. As one of the main forms of regulator of calcineurin 1 (RCAN1), the contribution of RCAN1.4 in diverse biological and pathological conditions has been implicated. But the role of RCAN1.4 in ischemic stroke progression remains elusive. This study is to explore the expression changes and roles of RCAN1.4 in ischemic stroke as well as the underlying mechanisms for these changes and effects of RCAN1.4 in ischemic stroke. METHODS: Middle cerebral artery occlusion model in C57BL/6J mice and oxygen-glucose deprivation (OGD) model in primary astrocytes were performed to induce the cerebral ischemic stroke. The expression pattern of RCAN1.4 was assessed using real-time quantitative PCR and western blotting in vivo and in vitro. Mechanistically, the underlying mechanism for the elevation of RCAN1.4 in the upstream was investigated. Lentiviruses were administrated, and the effect of RCAN1.4 in postischemic inflammation was clearly clarified. RESULTS: Here we uncovered that RCAN1.4 was dramatically increased in mouse ischemic brains and OGD-induced primary astrocytes. HIF1α, activated upon OGD, significantly upregulated RCAN1.4 gene expression through specifically binding to the RCAN1.4 promoter region and activating its promoter activity. The functional hypoxia-responsive element (HRE) was located between -254 and -245 bp in the RCAN1.4 promoter region. Moreover, elevated RCAN1.4 alleviated the release of pro-inflammatory cytokines TNFα, IL1ß, IL6 and reduced expression of iNOS, COX2 in primary astrocytes upon OGD, whereas RCAN1.4 silencing has the opposite effect. Of note, RCAN1.4 overexpression inhibited OGD-induced NF-κB activation in primary astrocytes, leading to decreased degradation of IκBα and reduced nuclear translocation of NF-κB/p65. INTERPRETATION: Our results reveal a novel mechanism underscoring the upregulation of RCAN1.4 by HIF1α and the protective effect of RCAN1.4 against postischemic inflammation, suggesting its significance as a promising therapeutic target for ischemic stroke treatment.
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Astrocitos/metabolismo , Proteínas de Unión al Calcio/metabolismo , Accidente Cerebrovascular Isquémico , Proteínas Musculares/metabolismo , Accidente Cerebrovascular , Animales , Calcineurina/metabolismo , Calcineurina/farmacología , Calcineurina/uso terapéutico , Proteínas de Unión al ADN/metabolismo , Glucosa/metabolismo , Humanos , Inflamación/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Ratones , Ratones Endogámicos C57BL , FN-kappa B , Oxígeno/metabolismo , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Regulación hacia ArribaRESUMEN
BACKGROUND: Lipophagy is an autophagic process, which delivers the intracellular lipid droplets to the lysosomes for degradation. Recent studies revealed that the impairment of lysosomal biogenesis and autophagic flux led to dysregulation of lipophagy in hepatocytes, which exacerbated the development of nonalcoholic fatty liver disease (NAFLD). Therefore, agents restoring autophagic flux and lipophagy in hepatocytes may have therapeutic potential against this increasingly prevalent disease. Phillygenin (PHI), a lignin extracted from Forsythia suspense, exerts hepatoprotective and anti-inflammatory effects. However, the effect of PHI on NAFLD remains unknown. PURPOSE: This study aimed to investigate the protective effect of PHI on NAFLD and elucidate the underlying mechanism. METHODS: The effects of PHI were examined in palmitate (PA)-stimulated AML12 cells and primary hepatocytes, as well as in NAFLD mice induced by a high-fat diet (HFD). We also used transcription factor EB (TFEB) knockdown hepatocytes and hepatocyte-specific TFEB knockout (TFEBΔhep) mice for mechanistic studies. In vivo and in vitro studies were performed using western blots, immunofluorescence techniques, and transmission electron microscopy. RESULTS: Our results indicated that autophagic flux and lysosome biogenesis in PA-stimulated hepatocytes were impaired. PHI alleviated lipid deposition by increasing lysosomal biogenesis and autophagic flux. It also stimulated the release of endoplasmic reticulum Ca2+ to activate calcineurin, which regulated TFEB dephosphorylation and nuclear translocation, and promoted lysosomal biogenesis. In addition, PHI blocked the NLRP3 inflammasome pathway and improved hepatocyte inflammation in an autophagy-dependent manner. Consistent with the in vitro results, PHI improved hepatic steatosis and inflammation in HFD mice, but these beneficial effects were eliminated in hepatocyte-specific TFEB knockout mice. CONCLUSION: Despite PHI has been reported to have anti-hepatic fibrosis effects, whether it has a hepatoprotective effects against NAFLD and the underlying molecular mechanism remain unclear. Herein, we found that PHI restored lipophagy and suppressed lipid accumulation and inflammation by regulating the Ca2+-calcineurin-TFEB axis in hepatocytes. Thus, PHI represents a therapeutic candidate for the treatment of NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Calcineurina/metabolismo , Calcineurina/farmacología , Calcineurina/uso terapéutico , Hepatocitos , Inflamación/metabolismo , Lignanos , Lípidos , Lisosomas , Ratones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
INTRODUCTION: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus. Standard-of-care immunosuppressive therapies achieve poor complete renal response (CRR) rates, with considerable toxicity. This article reviews voclosporin, a novel oral calcineurin inhibitor (CNI) approved for treatment in adults with active LN by the US Food and Drug Administration (the FDA) in January 2021. AREAS COVERED: This review summarizes the chemical properties, pharmacokinetics, and pharmacodynamics of voclosporin, and its efficacy and safety in LN, based on literature review covering PubMed searches, manufacturers' websites, and documents produced by the FDA. EXPERT OPINION: Voclosporin is a CNI with a consistent pharmacokinetic-pharmacodynamic relationship resulting from enhanced calcineurin binding and reduced drug and metabolite load. This profile permits therapeutic efficacy in LN at a dose associated with relatively low calcineurin inhibition, and therefore a potentially improved safety profile. Pivotal trials demonstrated a significant benefit of adding voclosporin to standard therapy, with rapid reduction in proteinuria, and a clinically meaningful and significantly higher CRR rate at 1 year. At approved doses for LN, potential advantages of voclosporin versus historical experience with CNIs include lack of need for therapeutic drug monitoring, benign metabolic, lipid and electrolyte profile, and no impact on mycophenolate mofetil levels.
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Inhibidores de la Calcineurina , Nefritis Lúpica , Adulto , Calcineurina/uso terapéutico , Inhibidores de la Calcineurina/efectos adversos , Ciclosporina , Humanos , Inmunosupresores/efectos adversos , Nefritis Lúpica/tratamiento farmacológicoRESUMEN
A hypoxic tumor microenvironment (TME) promotes cancer progression, yet its value as a therapeutic target remains underexploited. Tripartite motif-containing 72 (TRIM72) may protect cells against various stresses including hypoxia. Recently, low TRIM72 expression has been implicated in cancer progression. However, the biological role and molecular mechanism of TRIM72 in breast cancer (BC) remain unclear. Herein, we analyzed the TRIM72 expression in BC tissue and cell lines by western blot (WB) and quantitative reverse transcription-PCR. We established the overexpression of TRIM72 using plasmids and lentiviral-mediated upregulation, as well as downregulation of protein phosphatase 3 catalytic subunit alpha (PPP3CA) by siRNA. The tumor-suppressive roles of TRIM72 were assessed on BT549 and MDA-MB-231 cells by MTS, Transwell, and flow cytometry assays in vitro and in xenografted tumors in vivo. The molecular mechanism of TRIM72 was investigated by luciferase reporter and co-immunoprecipitation (Co-IP) assay. Lactate production was measured by ELISA under hypoxic environments induced by CoCl2. Moreover, the expression of PI3K/Akt/mTOR pathway-associated proteins was detected by WB in BC cells. Results showed that TRIM72 was downregulated in BC. Overexpression of TRIM72 inhibited tumor proliferation and invasion in vitro and in a xenograft tumor model. Mechanistically, PPP3CA altered the inhibitory effects of TRIM72 on hypoxia-induced lactate production and monocarboxylate transporter 4-promoter activity, as well as the effect of the PI3K/Akt/mTOR signaling pathway. Our study suggests that TRIM72 modulates the TME and plays tumor-suppressive roles in BC progression. Therefore, TRIM72 may serve as a potential therapeutic target in BC.
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Neoplasias de la Mama , Neoplasias de la Mama/tratamiento farmacológico , Calcineurina/farmacología , Calcineurina/uso terapéutico , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Hipoxia , Ácido Láctico/farmacología , Ácido Láctico/uso terapéutico , Transportadores de Ácidos Monocarboxílicos , Proteínas Musculares , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas de Motivos Tripartitos , Microambiente TumoralRESUMEN
Intrapatient variability (IPV) in tacrolimus has been increasingly acknowledged as a risk factor for poor graft survival after kidney transplantation. Although past studies have mainly accounted for IPV in acute or chronic rejection states as due to underimmunosuppression, this is not yet clear. So far, tacrolimus IPV for BK virus-associated nephropathy (BKVN) and chronic calcineurin inhibitor toxicity (CNIT) has not been investigated. Here, we evaluated IPV in tacrolimus for BKVN and chronic CNIT, which are mainly considered as overimmunosuppression states. In this case-control study, kidney allograft biopsies conducted between 1998 and 2018 were included, with patients grouped by biopsy results as BKVN alone group, CNIT alone group, and normal graft function (control group). IPV was estimated as mean absolute deviation. Our study groups included 25 kidney transplant recipients with BKVN alone, 91 patients with CNIT alone, and 60 patients with normal 5-year graft survival (control group). In analyses of IPV in tacrolimus six months before graft biopsy, IPV was highest in the BKVN group (P = 0.001). The BKVN group also had the highest IPV in tacrolimus at 12 months after biopsy (P = 0.001), with all pairwise comparisons statistically different between groups. At 12 months after biopsy, five patients (20%) in the BKVN group and 10 patients (10.9%) in the CNIT group had graft loss. Among other risk factors, BKVN and chronic CNIT are consequences related to high IPV. Quantification of IVP for tacrolimus in clinical practice would help to optimize kidney transplant outcomes.
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Virus BK/aislamiento & purificación , Calcineurina/efectos adversos , Inmunosupresores/efectos adversos , Enfermedades Renales/inducido químicamente , Trasplante de Riñón , Infecciones por Polyomavirus/complicaciones , Tacrolimus/efectos adversos , Infecciones Tumorales por Virus/complicaciones , Infecciones Tumorales por Virus/epidemiología , Adulto , Anciano , Calcineurina/uso terapéutico , Estudios de Casos y Controles , Femenino , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Humanos , Inmunosupresores/uso terapéutico , Riñón/patología , Enfermedades Renales/diagnóstico , Enfermedades Renales/epidemiología , Enfermedades Renales/cirugía , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Nefritis Intersticial , Complicaciones Posoperatorias/virología , Estudios Retrospectivos , Factores de Riesgo , Tacrolimus/uso terapéutico , Resultado del Tratamiento , Infecciones Tumorales por Virus/virologíaRESUMEN
OBJECTIVES: To analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations. METHODS: According to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012. RESULTS: We identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500-700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b). CONCLUSIONS: There is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression.
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Nefritis Lúpica/terapia , Biomarcadores , Biopsia , Calcineurina/administración & dosificación , Calcineurina/efectos adversos , Calcineurina/uso terapéutico , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Resistencia a Medicamentos , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Fallo Renal Crónico/terapia , Nefritis Lúpica/complicaciones , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/etiología , Terapia Molecular Dirigida , Guías de Práctica Clínica como Asunto , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
The PIRCHE (Predicted Indirectly ReCognizable HLA Epitopes) score is an HLA epitope matching algorithm. PIRCHE algorithm estimates the level of presence of T-cell epitopes in mismatched HLA. The PIRCHE-II numbers associate with de novo donor-specific antibody (dnDSA) formation following liver transplantation and kidney allograft survival following renal transplantation. The aim of our study was to assess the PIRCHE-II score in calcineurin inhibitor (CNI)-free maintenance immunosuppression recipients. This was a retrospective study of forty-one liver transplant recipients on CNI-free immunosuppression and with available liver allograft biopsies. Donors and recipients were HLA typed. The HLA-derived mismatched peptide epitopes that could be presented by the recipient's HLA-DRB1 molecules were calculated using PIRCHE-II algorithm. The associations between PIRCHE-II scores and graft immune-mediated events were assessed using receiver operating characteristics curves and subsequent univariate and multivariate analyses. CNI-free patients with cellular rejection, humoral rejection, or severe portal inflammation had higher mean PIRCHE-II scores compared to patients with normal liver allografts. PIRCHE-II score and donor age were independent risk factors for liver graft survival in CNI-free patients (HR: 8.0, 95% CI: 1.3-49, p = .02; and HR: 0.88, 95% CI: 0.00-0.96, p = .007, respectively). PIRCHE-II scores could be predictive of liver allograft survival in CNI-free patients following liver transplantation. Larger studies are needed to confirm these results.
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Rechazo de Injerto/inmunología , Inmunosupresores/uso terapéutico , Trasplante de Hígado , Adulto , Calcineurina/uso terapéutico , Epítopos/inmunología , Femenino , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , Antígenos HLA/inmunología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Receptores de TrasplantesRESUMEN
BACKGROUND: Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012. OBJECTIVES: Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens? SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included. DATA COLLECTION AND ANALYSIS: Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE. MAIN RESULTS: In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age.Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference.Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD.MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence.Maintenance therapyNine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates. AUTHORS' CONCLUSIONS: In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.
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Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Ácido Micofenólico/análogos & derivados , Adulto , Azatioprina/efectos adversos , Azatioprina/uso terapéutico , Calcineurina/uso terapéutico , Niño , Ciclofosfamida/efectos adversos , Femenino , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/efectos adversos , Quimioterapia de Inducción/métodos , Quimioterapia de Mantención/métodos , Masculino , Ácido Micofenólico/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Tacrolimus/efectos adversos , Tacrolimus/uso terapéuticoRESUMEN
Preventing conversion of donor-specific anti-HLA antibodies (DSAs) from an IgM-to-IgG could a way to prevent chronic rejection. We evaluated whether belatacept-treated patients (belatacept less-intensive [LI] or more-intensive [MI] regimens) have a lower rate of conversion than do cyclosporine A (CsA)-treated patients. We included 330 HLA-mismatched patients from 2 phase 3 trials with either (a) complete donor/recipient HLA-A, -B, -DR, and -DQ loci typing or (b) incomplete HLA typing with IgG DSAs detected pretransplant or posttransplant. IgM and IgG DSAs were tested with single antigen beads at 0, 6, 12, 24, and 36 months posttransplant. The overall (preexisting or de novo) rates of IgM- and IgG-positive DSAs were 29% and 34%, respectively. The pretransplant IgM and IgG DSA-positive frequencies were similar between treatment groups. The IgG-positive dnDSA rate was significantly higher in the CsA-treated group (34%) compared with the belatacept-LI (8%) and belatacept-MI (11%) (P < .001) groups. In IgM-positive dnDSA patients, the IgG-positive dnDSA rate of conversion was 2.8 times higher in the CsA group than in the combined belatacept groups (P = .006). However, the observed association between belatacept treatment and more limited conversion of IgM-to-IgG dnDSAs was based on a limited number of patients and requires further validation.
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Rechazo de Injerto/etiología , Antígenos HLA/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina M/inmunología , Inmunosupresores/uso terapéutico , Isoanticuerpos/efectos adversos , Trasplante de Riñón/efectos adversos , Abatacept/uso terapéutico , Calcineurina/uso terapéutico , Femenino , Estudios de Seguimiento , Rechazo de Injerto/tratamiento farmacológico , Rechazo de Injerto/patología , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Prueba de Histocompatibilidad , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/inmunología , Fallo Renal Crónico/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Donantes de TejidosRESUMEN
BACKGROUND: In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria. OBJECTIVES: The authors aimed to determine the role of the calcineurin splicing variant CnAß1 in the context of cardiac hypertrophy and its mechanism of action. METHODS: Transgenic mice overexpressing CnAß1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnAß1 (CnAß1Δi12 mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses. RESULTS: In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnAß1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAß1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnAß1. CnAß1Δi12 mice show increased cardiac hypertrophy and declined contractility. CONCLUSIONS: The metabolic reprogramming induced by CnAß1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one-carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approaches.
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Calcineurina/metabolismo , Cardiomegalia/metabolismo , Transferasas del Grupo 1-Carbono/metabolismo , Serina/metabolismo , Función Ventricular/efectos de los fármacos , Animales , Calcineurina/farmacología , Calcineurina/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Humanos , Masculino , Ratones , Ratones Transgénicos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Función Ventricular/fisiologíaRESUMEN
No disponible
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Humanos , Femenino , Adulto , Queratoconjuntivitis Infecciosa/diagnóstico , Queratoconjuntivitis Infecciosa/tratamiento farmacológico , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/etiología , Anticuerpos Monoclonales/uso terapéutico , Queratoconjuntivitis Infecciosa/complicaciones , Corticoesteroides/uso terapéutico , Fototerapia , Ciclosporina/uso terapéutico , Metotrexato/uso terapéutico , Ustekinumab/uso terapéutico , Calcineurina/uso terapéutico , Vancomicina/uso terapéutico , Ceftazidima/uso terapéuticoRESUMEN
En la presente revisión sistemática se analizaron 55 artículos estructurados sobre la eficacia terapéutica frente al dolor y a los signos clínicos del liquen plano oral (LPO). La búsqueda bibliográfica se elaboró siguiendo los criterios del sistema PRISMA, seleccionando los ensayos realizados mediante alguno de los siguientes diseños metodológicos: entre fármaco (principio activo) vs. mismo fármaco en diferente excipiente o concentración, fármaco vs. diferente principio activo, fármaco vs. fitoterapia y fármaco vs. tratamiento con fototerapia. Basándonos en los resultados se propone un algoritmo que sirva de guía para establecer el tratamiento del LPO en sus formas clínicas atrófica y erosiva. Se destaca el empleo del propionato de clobetasol al 0,025-0,05% de aplicación tópica como primera alternativa terapéutica. En segundo lugar, el tacrolimús al 0,1% y pimecrolimús al 1% también formulado para su pauta tópica. Y, finalmente, se aborda el empleo de corticosteroide sistémico y la aplicación de láser de diodo (AU)
In this systematic review, 55 structured articles on the therapeutic efficacy against pain and clinical signs of oral lichen planus (OLP) were analysed. The literature search was developed according to the criteria of the PRISMA system, selecting the tests performed using one of the following methodological designs: drug (active ingredient) vs. drug in different excipient or concentration, drug vs. different active principle, drug vs. phytotherapy and drug vs. treatment with phototherapy. Based on the results, an algorithm is proposed to guide the treatment of OLP in its atrophic and erosive clinical forms. The use of clobetasol propionate at 0.025-0.05% of topical application as the first therapeutic alternative is highlighted. Secondly, 0.1% tacrolimus and 1% pimecrolimus also formulated for its topical regimen. And finally, we address the use of systemic corticosteroids and the application of diode lasers (AU)
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Humanos , Liquen Plano Oral/terapia , Clobetasol/uso terapéutico , Triamcinolona Acetonida/uso terapéutico , Calcineurina/uso terapéutico , Terapia por Láser , Protocolos Clínicos , Manejo del Dolor/métodos , Pautas de la Práctica en Odontología/tendencias , Resultado del Tratamiento , Miconazol/uso terapéutico , Dexametasona/uso terapéuticoRESUMEN
Graft-versus-host disease (GVHD) hampers the utility of allogeneic hematopoietic stem cell transplantation (AHSCT). The purpose of this study was to determine the feasibility, safety, and efficacy of a novel combination of post-transplantation cyclophosphamide (PTC) and bortezomib for the prevention of GVHD. Patients undergoing peripheral blood AHSCT for hematological malignancies after reduced-intensity conditioning with grafts from HLA-matched related or unrelated donors were enrolled in a phase I/II clinical trial. Patients received a fixed dose of PTC and an increasing dose of bortezomib in 3 cohorts, from .7 to 1 and then to 1.3 mg/m2, administered 6 hours after graft infusion and 72 hours thereafter, during phase I. The study was then extended at the higher dose in phase II for a total of 28 patients. No graft failure and no unexpected grade ≥3 nonhematologic toxicities were encountered. The median times to neutrophil and platelet engraftment were 16 and 27 days, respectively. Day +100 treatment-related mortality was 3.6% (95% confidence interval [CI], .2% to 15.7%). The cumulative incidences of grades II to IV and grades III and IV acute GVHD were 35.9% (95% CI, 18.6% to 53.6%) and 11.7% (95% CI, 2.8% to 27.5%), respectively. The incidence of chronic GVHD was 27% (95% CI, 11.4% to 45.3%). Progression-free survival, overall survival, and GVHD and relapse-free survival rates were 50% (95% CI, 30.6% to 66.6%), 50.8% (95% CI, 30.1% to 68.2%), and 37.7% (95% CI, 20.1% to 55.3%), respectively. Immune reconstitution, measured by CD3, CD4, and CD8 recovery, was prompt. The combination of PTC and bortezomib for the prevention of GVHD is feasible, safe, and yields promising results. The combination warrants further examination in a multi-institutional trial.
Asunto(s)
Quimioterapia Combinada/métodos , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre de Sangre Periférica/métodos , Adulto , Anciano , Aloinjertos , Bortezomib/uso terapéutico , Calcineurina/uso terapéutico , Ciclofosfamida/uso terapéutico , Femenino , Neoplasias Hematológicas/terapia , Humanos , Reconstitución Inmune , Masculino , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica/efectos adversosRESUMEN
La alopecia frontal fibrosante (AFF) es un tipo de alopecia cicatricial primaria adquirida, descrita por Kossard en 1994, cuya incidencia ha aumentado en los últimos años. Se caracteriza clínicamente por una recesión de la línea de implantación frontotemporal del cabello, acompañada frecuentemente por alopecia de las cejas. La AFF fue inicialmente descrita en mujeres posmenopáusicas y premenopáusicas con antecedentes personales de histerectomía o menopausia precoz, por lo que se propuso un origen hormonal de la enfermedad. Sin embargo, en los últimos años se han publicado estudios en varones, así como en mujeres premenopáusicas que cuestionan dicha etiología. A pesar de que las manifestaciones clínicas de la AFF son muy características, desde el punto de vista histopatológico los hallazgos son similares al liquen plano pilaris, por lo que actualmente es considerada como una variante clínica de este último. Hasta el momento no se han realizado ensayos clínicos sobre las diferentes alternativas de tratamiento en pacientes con AFF. En los estudios observacionales publicados se valora el uso de múltiples fármacos, siendo los inhibidores de la 5-alfa-reductasa y los corticoides intralesionales los que mejor resultado han obtenido hasta el momento, seguidos por los antipalúdicos y los inhibidores de la calcineurina. Esta revisión analiza de forma exhaustiva la información más recientemente publicada sobre la etiopatogenia, la clínica, el diagnóstico y el tratamiento de los pacientes con AFF (AU)
Frontal fibrosing alopecia (FFA) is an increasingly common acquired primary scarring alopecia, first described by Kossard in 1994. Clinically it is characterized by frontotemporal hairline recession, frequently accompanied by eyebrow loss. FFA was initially thought to have a hormonal origin as it was first described in postmenopausal women and premenopausal women with a history of hysterectomy or early menopause. This origin, however, has been questioned in recent years due to the publication of cases in men and premenopausal women. Although FFA has a highly characteristic clincal pattern, it is histologically similar to lichen planopilaris, and is currently believed to be a clinical variant of this condition. No clinical trials to date have investigated the efficacy of treatments for FFA. Numerous drugs, however, have been assessed in observational studies, and the best results to date have been reported for 5-αreductase inhibitors and intralesional corticosteroids, followed by antimalarials and calcineurin inhibitors. In this article, we review the latest data on the etiology, pathogenesis, clinical presentation, diagnosis, and treatment of FFA (AU)
Asunto(s)
Humanos , Alopecia/terapia , Liquen Plano/tratamiento farmacológico , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Corticoesteroides/uso terapéutico , Antimaláricos/uso terapéutico , Calcineurina/uso terapéuticoRESUMEN
The purpose of this review is to summarize current data on the role of immunosuppressants in the pathogenesis of hypertension and the efficacy and tolerability of major antihypertensive classes in kidney transplant recipients. Arterial hypertension is a common complication after kidney transplantation and a major risk factor for adverse outcome and graft rejection due to blood pressure elevation by immunosuppressive medications. Calcineurin inhibitors induce hypertension by a mechanism related to the imbalance of vasoactive substances endothelin and nitric oxide, and probably by causing overactivity of thiazide-sensitive sodium-chloride-cotransporter. Corticosteroids are well known for their hypertensive effects. The interactions of calcineurin inhibitors and mammalian target of rapamycin inhibitor sirolimus also promote hypertension. Management of arterial hypertension is a complex problem in the care of kidney transplant recipients. Target blood pressure values of <130/80 mm Hg are suggested by the National Kidney Foundation/ Kidney Disease Outcomes Quality Initiative. Calcium channel blockers may be useful in antagonizing the vasoconstrictive effects of calcineurin inhibitors. The renin-angiotensin system inhibitors seem a good option, especially in patients with proteinuria, however their effects on long-term graft and patient survival are controversial. ß-Blockers could be beneficial in patients with coronary heart disease, but caution is required due to metabolic adverse effects. Thiazide diuretics could be the reasonable option for patients with glomerular filtration rate ≥30 mL/min/1.73 m2, also with caution regarding hypokalemia and glycemia. Until more evidence is provided, the choice of optimal antihypertensive therapy in kidney transplant recipients should be based on previous individual antihypertensive tolerability and efficacy, comorbidities, concomitant medications and post-transplant kidney function.
Asunto(s)
Rechazo de Injerto/prevención & control , Hipertensión/etiología , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Corticoesteroides/efectos adversos , Corticoesteroides/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Calcineurina/efectos adversos , Calcineurina/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Diuréticos/uso terapéutico , Humanos , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Inmunosupresores/efectos adversos , Factores de RiesgoRESUMEN
El manejo del eczema de manos es complejo, ya que engloba eczemas de etiopatogenia, curso y pronóstico muy diferentes; la mayoría de tratamientos disponibles no cuentan con niveles de eficacia establecidos, y en sus formas graves la calidad de vida se afecta de forma importante. La educación del paciente, las medidas de protección y el uso de emolientes constituyen un pilar fundamental en el abordaje de estos pacientes. Los corticoides tópicos de alta potencia son el tratamiento de elección, seguidos de los inhibidores de la calcineurina para el mantenimiento de la enfermedad. En los casos refractarios a estos tratamientos deberíamos utilizar la fototerapia o tratamientos sistémicos, los cuales no deberían demorarse para evitar sensibilizaciones, bajas laborales y alteración en la calidad de vida. La alitretinoína es el único tratamiento oral disponible que ha sido aprobado para su utilización en el eczema crónico de manos
Management of hand eczema is complex because of the broad range of different pathogeneses, courses, and prognoses. Furthermore, the efficacy of most available treatments is not well established and the more severe forms can have a major impact on the patient's quality of life. Patient education, preventive measures, and the use of emollients are the mainstays in the management of hand eczema. High-potency topical corticosteroids are the treatment of choice, with calcineurin inhibitors used for maintenance. Phototherapy or systemic treatments are indicated in patients who do not respond to topical treatments. Switching from topical treatments should not be delayed to avoid sensitizations, time off work, and a negative impact on quality of life. Alitretinoin is the only oral treatment approved for use in chronic hand eczema
Asunto(s)
Femenino , Humanos , Masculino , Eccema/metabolismo , Eccema/patología , Mano/patología , /normas , Calcineurina/provisión & distribución , Terapéutica/métodos , Calidad de Vida/psicología , Prevención Primaria/métodos , Prevención Secundaria/educación , Prevención Terciaria/métodos , Eccema/diagnóstico , Mano/crecimiento & desarrollo , Calcineurina/uso terapéutico , Terapéutica/tendencias , Terapéutica , Calidad de Vida/legislación & jurisprudencia , Prevención Primaria , Prevención Secundaria/normas , Prevención Terciaria , Educación del Paciente como Asunto/clasificaciónRESUMEN
BACKGROUND: The therapeutic success of renal transplantation has been largely attributable to the development of effective and balanced immunosuppressive treatment regimens. This study provides a meta-analysis of a series of randomized controlled trials that compared the effects of tacrolimus and cyclosporine on metabolic syndrome (MetS) and cardiovascular risk factors after renal transplantation. METHODS: We searched various electronic databases and bibliographies, including MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE, for relevant studies published prior to October 2012. RESULTS: Our meta-analysis included five randomized controlled trials that examined a total of 923 patients. The tacrolimus group and the cyclosporine group exhibited no significant differences in MetS incidence after renal transplantation; risk ratio (RR): 1.06, 95% confidence interval (CI): 0.73-1.55, P = 0.76. Cyclosporine treatment was associated with a higher incidence of hyperlipidemia (RR: 0.50, 95% CI: 0.39-0.64, P < 0.01). Although there were no statistically significant differences, cyclosporine treatment was associated with a higher incidence of hypertension (RR: 0.91, 95% CI: 0.83-1.00, P = 0.06) after renal transplantation compared to tacrolimus treatment, and tacrolimus treatment was associated with a higher incidence of diabetes after renal transplantation (RR: 1.79, 95% CI: 0.98-3.27, P = 0.06) compared to cyclosporine treatment. CONCLUSIONS: Compared to tacrolimus treatment, cyclosporine treatment was associated with a higher incidence of hyperlipidemia. Future large-scale studies are expected to be conducted to further confirm our findings.
Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Ciclosporina/uso terapéutico , Trasplante de Riñón , Síndrome Metabólico/tratamiento farmacológico , Tacrolimus/uso terapéutico , Calcineurina/uso terapéutico , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
In a cross-sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T-regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg-specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty-eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =-0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =-0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long-term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.
Asunto(s)
Calcineurina/uso terapéutico , Rechazo de Injerto/inmunología , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Trasplante de Hígado/inmunología , Sirolimus/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Adolescente , Estudios de Casos y Controles , Niño , Estudios Transversales , Femenino , Estudios de Seguimiento , Factores de Transcripción Forkhead/metabolismo , Humanos , Leucocitos Mononucleares/inmunología , Masculino , Pronóstico , Linfocitos T Reguladores/inmunología , Trasplante HomólogoRESUMEN
OBJECTIVE: To provide an overview of the literature concerning the topical treatment of vulvar lichen sclerosus, a chronic inflammatory skin disease, with calcineurin inhibitors, such as pimecrolimus and tacrolimus. DESIGN: A literature review into the use of topical calcineurin inhibitors (TCIs) in the treatment of vulvar lichen sclerosus. METHOD: A literature search was performed using PubMed and EMBASE and the search terms 'tacrolimus', 'pimecrolimus' or 'calcineurin inhibitors' and 'lichen sclerosus et atrophicus', 'vulvar lichen sclerosus', 'vulvar dermatoses' or 'vulvar diseases'. RESULTS: The search produced 6 case reports, 5 patient series, 3 pilot studies, 2 open-label studies and 1 RCT concerning the use of TCIs for the treatment of vulvar lichen sclerosus. The literature shows that both medications are effective and well tolerated. However, glucocorticoids seem to be effective in more patients than TCIs. Tacrolimus has a stronger immunosuppressant effect than pimecrolimus and therefore seems to be more effective without having more observed side-effects. CONCLUSIONS: TCIs may represent a useful second-line therapeutic option for patients for whom treatment with glucocorticoids is not effective or who do not tolerate them well. Randomized clinical studies are required to determine the role of TCIs in the treatment of lichen sclerosus. CONFLICT OF INTEREST: none declared. Financial support: none declared.
Asunto(s)
Inhibidores de la Calcineurina , Inmunosupresores/uso terapéutico , Liquen Escleroso Vulvar/tratamiento farmacológico , Administración Cutánea , Administración Tópica , Calcineurina/efectos adversos , Calcineurina/uso terapéutico , Femenino , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality. METHODS AND RESULTS: Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002). CONCLUSIONS: Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.