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OBJECTIVES: PsA is characterized by enthesitis, synovitis and osseous involvement in the peripheral and axial joints. Few studies have examined axial involvement in PsA using imaging techniques. Here we examined axial involvement in PsA patients using MRI. In addition, we determined the efficacy of 24 week adalimumab treatment in improving the MRI findings of spondylitis and sacroiliitis. METHODS: This was a prospective, open-label, single-arm study in patients with PsA. Adalimumab was administered to patients for a total of 24 weeks. MRI examinations were conducted at baseline and at week 24 of adalimumab treatment. RESULTS: Thirty-seven patients with PsA were included in this study. Spondylitis was observed in at least one site of the positive scan in 91% (n = 31) of patients with PsA. The number of arthritic sites in the cervical, thoracic and lumbar regions of the spine was 48, 67 and 53, respectively. All patients had MRI-determined sacroiliitis of grade ≥1 severity while 28 patients (82%) had grade ≥2 sacroiliitis in at least one sacroiliac region. Sacroiliac arthritis was statistically more severe on the right side than on the left side (P < 0.05). In 34 patients with PsA, the thoracic spine was the most common site of spondylitis. In addition, 24 week adalimumab treatment led to an improvement in the mean number of spondylitis sites and the mean grade of sacroiliitis. CONCLUSION: Treatment with adalimumab for 24 weeks resulted in improvement in spondylitis and sacroiliitis.
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Adalimumab/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Adulto , Anciano , Artritis Psoriásica/diagnóstico por imagen , Artritis Psoriásica/fisiopatología , Femenino , Humanos , Japón , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sacroileítis/diagnóstico por imagen , Sacroileítis/fisiopatología , Espondilitis/diagnóstico por imagen , Espondilitis/fisiopatología , Vértebras Torácicas/diagnóstico por imagenRESUMEN
Chemokine systems modulate inflammatory and immune responses in inflammatory bowel disease (IBD). The colons of IBD patients show increased levels of fractalkine (FKN) and high numbers of FKN receptor-positive (CX3CR1+) cells; however, the FKN-CX3CR1 axis's role in intestinal inflammation, especially in intravascular leukocyte behaviors, still remains unclear. Here, we show that interruption of the FKN-CX3CR1 axis by anti-FKN monoclonal antibody (mAb) ameliorates murine colitis through regulation of intravascular monocyte behaviors in murine colitis models. FKN expression was detectable in vascular endothelium and CX3CR1+ macrophages accumulated in the mucosal lamina propria and submucosa of the inflamed colons. CD115+ monocytes tethered to the venous endothelium and expressed pro-inflammatory mediators. The anti-FKN mAb improved colitis symptoms, markedly reduced pro-inflammatory factors in the colon, maintained blood vessel integrity and reduced tethered monocytes in the inflamed veins. Intravital imaging revealed that CD115+Gr-1low/- monocytes crawled on the apical surfaces of venous endothelium, and anti-FKN mAb rapidly dislodged the crawling monocytes and inhibited their patrolling behavior. These findings suggest that the FKN-CX3CR1 axis triggers the patrolling behavior of crawling monocytes on the venous endothelium of inflamed colons, and accelerates the subsequent leukocyte activation and infiltration by locally producing inflammatory cytokines and chemokines. The mAb also ameliorated symptoms in another IBD model, T-cell-transferred colitis. Blocking the FKN-CX3CR1 axis with an anti-FKN mAb considerably inhibits the colitis-triggered inflammatory cascades, which may be an alternative strategy to treat IBD.
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Anticuerpos Monoclonales/farmacología , Receptor 1 de Quimiocinas CX3C/antagonistas & inhibidores , Quimiocina CX3CL1/antagonistas & inhibidores , Colitis/tratamiento farmacológico , Monocitos/efectos de los fármacos , Administración Rectal , Animales , Anticuerpos Monoclonales/inmunología , Receptor 1 de Quimiocinas CX3C/inmunología , Quimiocina CX3CL1/inmunología , Colitis/inducido químicamente , Colitis/inmunología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Monocitos/inmunología , OxazolesRESUMEN
Objectives: To evaluate the efficacy and safety of adalimumab in psoriatic arthritis (PsA) patients in Japan.Methods: In this open-label, single-arm study conducted at six sites from October 2014 to June 2016 (UMIN000016543), PsA patients (≥20 years old) with inadequate response to nonsteroidal anti-inflammatory drugs received adalimumab subcutaneously (80 mg initially, then 40 mg every other week; 24 weeks total). Primary endpoint was American College of Rheumatology 20% improvement (ACR20) response rate at week 12.Results: Of 42 enrolled patients, 37 were treated (mean (SD) age, 56.2 (13.0) years; male, 27 (73.0%)). ACR20, ACR50, and ACR70 response rates were 40.5%, 24.3%, and 16.2% at week 12 and increased to 45.9%, 37.8%, and 21.6% at week 24, respectively. Psoriasis Area and Severity Index (PASI) 50 response rates were unchanged at weeks 12 and 24 (73%), but PASI75 and PASI90 increased from 40.5% and 21.6% to 59.5% and 40.5%, respectively. Other indices such as Physician's Global Assessment score, C-reactive protein-based disease activity score in 28 joints, Bath Ankylosing Spondylitis Disease Activity Index, and serum biomarker levels were significantly improved. No unexpected adverse events were reported.Conclusion: Similar to the global population, adalimumab was efficacious and well tolerated in Japanese treatment-experienced PsA patients.
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Adalimumab/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Antirreumáticos/uso terapéutico , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Resultado del TratamientoRESUMEN
STUDY OBJECTIVES: Patients with chronic insomnia may respond differently to therapeutic modalities. This study examined differences in response of individuals with 2 insomnia phenotypes-short sleep duration (I-SSD; < 6 hours) and normal sleep duration (I-NSD; ≥ 6 hours) determined by polysomnography-to treatment with lemborexant and zolpidem tartrate extended-release 6.25 mg (zolpidem ER), compared with placebo. METHODS: Study E2006-G000-304 (Study 304; SUNRISE-1; NCT02783729) was a global, randomized, double-blind, placebo, and active comparator-controlled, parallel-group study comparing lemborexant 5 and 10 mg in individuals aged ≥ 55 years with insomnia disorder. In this analysis, changes in subjective (self-reported) variables based on sleep diaries and objective variables based on polysomnographs were assessed after 1-month administration of study drugs. Data from participants with I-SSD and I-NSD were compared. RESULTS: In the I-SSD subgroup, both lemborexant doses provided significant benefit for sleep-onset latency (SOL), total sleep time (TST), and wake after sleep onset (WASO) vs placebo; zolpidem ER also provided significant benefit for TST and WASO, but not SOL, on both measures vs placebo. In the I-NSD subgroup, lemborexant and zolpidem ER provided significant benefit for TST and WASO vs placebo objectively but not subjectively; both doses of lemborexant provided significant benefit for SOL vs placebo subjectively, but not objectively. CONCLUSIONS: Both drugs, but lemborexant more consistently, showed subjective and objective benefits compared with placebo in participants with insomnia with objective short sleep duration. However, neither lemborexant nor zolpidem provided consistent benefits for participants with normal sleep duration on sleep-onset and sleep maintenance variables. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1); URL: https://clinicaltrials.gov/ct2/show/record/NCT02783729; Identifier: NCT02783729. CITATION: Inoue Y, Nishida M, Kubota N, et al. Comparison of the treatment effectiveness between lemborexant and zolpidem tartrate extended-release for insomnia disorder subtypes defined based on polysomnographic findings. J Clin Sleep Med. 2023;19(3):519-528.
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Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Zolpidem , Hipnóticos y Sedantes , Resultado del Tratamiento , Método Doble CiegoRESUMEN
Orexin receptor antagonists have been approved for insomnia, and the insomnia pharmacotherapy is being greatly progressed. Orexin is a neuropeptide produced in the lateral hypothalamic area, and its physiological role has been suggested to be a key mediator controlling the sleep-wake state. Orexin receptor antagonists are thought to induce physiological sleep by acting specifically on the sleep-wake cycle. Lemborexant is a dual antagonist acting on both two orexin receptors, the orexin 1 (OX1R) and 2 receptor (OX2R), with stronger inhibitory effects on OX2R. Since it binds to and dissociates from orexin receptors rapidly, the pharmacokinetics of its blood concentration may have an impact on its pharmacological action. In rats, lemborexant exhibited a sleep-inducing effect without altering sleep architecture. In the phase III studies in patients with insomnia, lemborexant significantly improved difficulties in falling asleep and maintaining sleep. While somnolence occurred as treatment-related adverse events in a dose-dependent manner, lemborexant was generally well-tolerated. Also, the effects on body sway and driving skills 8-9 hours after administration did not differ from those in the placebo group, suggesting little next morning residual effects. Subgroup analysis has shown that efficacy and safety of lemborexant were similar in patients with insomnia with comorbidities, suggesting lemborexant may also be useful for those patients. Based on the above results and others, lemborexant has been approved for the indication of insomnia in January 2020 in Japan. Lemborexant will give a new treatment option for patients with insomnia.
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Antagonistas de los Receptores de Orexina , Trastornos del Inicio y del Mantenimiento del Sueño , Animales , Humanos , Japón , Antagonistas de los Receptores de Orexina/uso terapéutico , Receptores de Orexina , Piridinas , Pirimidinas , Ratas , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Clinical trial data of Carmustine implant (Gliadel Wafer) in Japanese patients with malignant glioma are limited; thus, we conducted a postmarketing surveillance study to evaluate the safety of Gliadel in real-world clinical practice in Japan. In this postmarketing surveillance study, all patients who received Gliadel placement for malignant glioma surgeries from its market launch (January 9, 2013) to July 10, 2013 were enrolled from 229 institutions using a central registration system. Up to eight wafers of Gliadel (containing 61.6 mg of carmustine) were used to cover the site of brain tumor resection intraoperatively according to the size and shape of the tumor resection cavity. The observation period lasted 3 months after Gliadel placement. Patients were followed up for 1 year postoperatively. Safety was assessed by the incidence of adverse events (AEs) and adverse drug reactions (ADRs). In total, 558 patients were included. Most patients (66.7%) received eight Gliadel wafers. The percentage of patients with ADRs was 35.7% (365 ADR episodes in 199 patients). Of the AEs of special interest, the most common were cerebral edema (22.2%, 124/558 patients), convulsion (9.9%, 55/558 patients), impaired healing (4.8%, 27/558 patients), and infection (3.4%, 19/558 patients). This first all-case postmarketing surveillance report of the safety of Gliadel in real-world clinical practice in Japan suggests that the risk of toxicity with Gliadel placement is relatively tolerable. The survival benefits of Gliadel placement should be evaluated and considered carefully by the clinician taking into account possible toxicities.
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Neoplasias Encefálicas , Glioma , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/cirugía , Carmustina/efectos adversos , Ácidos Decanoicos , Glioma/tratamiento farmacológico , Glioma/cirugía , Humanos , Japón , Poliésteres , Resultado del TratamientoRESUMEN
PURPOSE: Medication discontinuation for patients with Alzheimer's dementia (AD) influences treatment efficacy. This study aimed to evaluate the effect of psychoeducational intervention (PI) on donepezil retention rates and identify the factors associated with donepezil continuation in patients with AD. PATIENTS AND METHODS: One hundred and seventeen patients with AD were randomly allocated to the PI (n = 58) or standard care (SC; n = 59) groups. All patients were prescribed donepezil for 48 weeks. Primary endpoints were the 48-week donepezil retention rate and the reasons for donepezil discontinuation in the PI and SC groups. The secondary endpoint was the predictive factors, among the baseline clinical variables, for donepezil continuation in all patients. RESULTS: The donepezil retention rate was 62.1% (36/58) in the PI group and 66.1% (39/59) in the SC group. The most common reason for discontinuation in both groups was adverse events (PI, 12.1%; SC, 10.2%). Logistic regression analysis revealed that the results of the pentagon copying test in the Mini-Mental State Examination administered at baseline was a significant predictor of donepezil continuation for all patients in both the groups (odds ratio: 0.359; 95% confidence interval: 0.154-0.839). CONCLUSION: There was no significant difference between the PI and SC groups concerning donepezil retention rate in patients with AD. Our results demonstrate that the pentagon copying test can significantly predict donepezil continuation in patients with AD, indicating that impaired visuospatial and executive functions may reflect medication discontinuation. TRIAL REGISTRATION: UMIN-CTR:UMIN000012617.
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Most conventional insomnia medications are gamma-aminobutylic acid receptor agonists. However, physical dependence is a concern and one of the major limiting factors for long-term treatment. The dual orexin receptor antagonists, suvorexant and lemborexant, were recently approved for treating chronic insomnia, giving a novel pharmacotherapeutic option. Because there are no comparative studies on these drugs, a network meta-analysis was conducted, which is suitable for comparing interventions. According to this analysis, 5- and 10-mg lemborexant were superior to 20-mg suvorexant because of the greater improvement in initiating sleep after 1-week administration. Furthermore, 5-mg lemborexant (not 10 mg) and suvorexant were similarly well tolerated, without requiring discontinuation due to adverse events. We also overviewed the pharmacological and pharmacokinetic properties of lemborexant and suvorexant that may support these clinical outcomes. When compared to suvorexant, lemborexant quickly binds to the orexin receptors. The time to reach the maximum concentration after multiple administrations is shorter for lemborexant than for suvorexant. Considering these results, we recommend 5-mg lemborexant as an initial treatment for insomnia, followed by 10-mg lemborexant or suvorexant.
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Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Metaanálisis en Red , Antagonistas de los Receptores de Orexina/efectos adversos , Receptores de Orexina/metabolismo , Orexinas , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológicoRESUMEN
BACKGROUND: It was reported that eribulin regulates the tumor microenvironment, including the immune system, by inducing vascular remodeling. Lymphocyte counts are a critical index of immune response in patients. The non-Asian, global EMBRACE study has suggested that baseline absolute lymphocyte count (ALC) may be a predictor of the survival benefit of eribulin in breast cancer patients. We examined whether the baseline ALC is a potential predictor of overall survival (OS) in Japanese patients with HER2-negative advanced breast cancer treated with eribulin. METHODS: This was a post hoc analysis of data from a post-marketing observational study of eribulin in Japan. The OS by baseline ALC was estimated using the Kaplan-Meier method, with the cut-off value of 1500/µL for ALC. The OS by baseline neutrophil-to-lymphocyte ratio (NLR), a general prognostic index in breast cancer patients, was also estimated, with the cut-off value of 3. RESULTS: The median OS was longer in patients with an ALC of ≥ 1500/µL than in those with an ALC of < 1500/µL (19.4 vs. 14.3 months; hazard ratio [HR]: 0.628; 95% confidence interval [CI]: 0.492, 0.801). Patients with an NLR of ≥ 3 showed shorter OS than those with an NLR of < 3 (13.2 vs. 18.8 months; HR: 1.552; 95% CI 1.254, 1.921), and NLR also separated OS in patients with an ALC of < 1500/µL. CONCLUSIONS: Consistent with the findings of a previous study involving a non-Asian, Western population, our study suggested that baseline ALC may be a predictive factor for the survival benefit of eribulin in Japanese patients.
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Neoplasias de la Mama/tratamiento farmacológico , Furanos/administración & dosificación , Cetonas/administración & dosificación , Moduladores de Tubulina/administración & dosificación , Administración Intravenosa , Adulto , Anciano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Japón/epidemiología , Recuento de Linfocitos , Persona de Mediana Edad , Neutrófilos , Modelos de Riesgos Proporcionales , Receptor ErbB-2RESUMEN
E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,10-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione)] is a novel anti-inflammatory agent that has potent inhibitory effects on the production of proinflammatory cytokines from leukocytes and antiproliferative activity on keratinocytes. To characterize the in vivo pharmacological activity of E6201, topically administered E6201 was evaluated in several different animal models of dermatitis. E6201 formulated as an ointment or cream showed dose-dependent inhibition of croton oil-induced acute edema formation and neutrophil infiltration into mouse skin. In addition, E6201 cream inhibited the 1-fluoro-2,4-dinitrobenzene-induced contact hypersensitivity reaction mediated by T cells in mice. In this model, E6201 cream also suppressed the migration of neutrophils and lymphocytes into the inflammatory site. Pretreatment with E6201 cream attenuated phorbol-12 myristate 13-acetate-induced ornithine decarboxylase activity, a marker of proliferation in epidermis. Furthermore, E6201 ointment showed inhibitory effects on both mezerein-induced and interleukin (IL)-23-induced epidermal hyperplasia. E6201 also suppressed T cell receptor-stimulated IL-17 production from human T cells. These results indicate that topically administered E6201 may be a useful agent for the prevention and treatment of cutaneous inflammatory and hyperproliferative diseases such as psoriasis.
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Erupciones por Medicamentos/patología , Lactonas/farmacología , Quinasa 1 de Quinasa de Quinasa MAP/antagonistas & inhibidores , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Administración Tópica , Animales , Antineoplásicos Fitogénicos , Aceite de Crotón , Dinitrofluorobenceno , Diterpenos , Hiperplasia/inducido químicamente , Hiperplasia/patología , Indicadores y Reactivos , Interleucina-17/biosíntesis , Interleucina-23/toxicidad , Lactonas/administración & dosificación , Masculino , Ratones , Ratones Endogámicos BALB C , Ornitina Descarboxilasa/biosíntesis , Ornitina Descarboxilasa/metabolismo , Peroxidasa/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Psoriasis/inducido químicamente , Psoriasis/patología , Piel/patología , Linfocitos T/fisiología , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
BACKGROUND: Eribulin, a nontaxane synthetic inhibitor of microtubule dynamics, is widely used to manage locally advanced or metastatic breast cancer (MBC). Eribulin has demonstrated immunomodulatory activity on the tumour microenvironment. Baseline neutrophil-to-lymphocyte ratio (NLR), a marker of immune status, may predict progression-free survival in eribulin treatment. This post hoc analysis assessed predictors for overall survival (OS). METHODS: The phase 3 open-label study (EMBRACE) of eribulin versus treatment of physician's choice (TPC) in patients with MBC provided source data. Baseline absolute lymphocyte counts (ALCs) and NLR were evaluable in 751 and 713 patients, respectively. RESULTS: Eribulin prolonged OS versus TPC in patients with baseline ALC ≥ 1500/µl (hazard ratio [HR] 0.586; 95% confidence interval [CI] 0.437-0.784; P < 0.001). There was no significant difference by treatment for ALC < 1500/µl (HR 1.002; 95% CI 0.800-1.253; P = 0.989). Univariate and multivariate analyses were performed and identified baseline ALC as a potential predictor of OS in eribulin-treated patients. Interaction analysis of OS supported 1500/µl as a potentially differential cutoff value. NLR at a cutoff value of 3 was associated with prolonged OS (eribulin group). However, similar results were also observed in the TPC group, without apparent interaction effect, suggesting that NLR may be a general prognostic marker rather than a specific predictor of OS for eribulin. DISCUSSION: This hypothesis-generating study speculates that baseline ALC may be an independent predictor for longer OS in eribulin-treated MBC patients and could be clinically impactful because it can be evaluated without the need for additional invasive procedures. TRIAL REGISTRATION: www.ClinicalTrials.gov code: NCT00388726.
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Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Furanos/administración & dosificación , Cetonas/administración & dosificación , Linfocitos/inmunología , Anciano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Recuento de Linfocitos , Persona de Mediana Edad , Neutrófilos/inmunología , Pronóstico , Supervivencia sin Progresión , Microambiente TumoralRESUMEN
The goal of this study is to identify a novel inhibitor with anti-inflammatory and antiproliferative properties for the treatment of psoriasis. Compound f152A1 [(3S,5Z,8S,11E)-8,9,16-trihydroxy-14-methoxy-3-methyl-3,4,9,10-tetrahydro-1H-benzo[c][1]oxacyclotetradecine1,7(8H)-dione] was identified as the main active metabolite with strong inhibitory activity against tumor necrosis factor-alpha (TNFalpha) transcription in a fraction originated from the fermentation broth of the fungus Curvularia verruculosa. Although active in cell-based assays, f152A1 was unstable in plasma and liver microsome preparations, thus limiting its pharmaceutical utilization. To improve the metabolic properties of f152A1, a medicinal chemistry program was undertaken, resulting in the generation of over 400 analogs of f152A1. Eventually, E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] was identified as a promising analog in this series. In the present study, we characterized the in vitro activities of E6201 and discovered that the compound inhibits lipopolysaccharide-activated TNFalpha reporter activity in THP-1-33 cells with an IC(50) value of 50 nM and selectively inhibits mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1 and MEK kinase-1 in cell-free biochemical assays. In addition, E6201 showed inhibitory activity in several other cell-based systems: 1) phosphorylation of c-jun N-terminal kinase and p38 MAPKs; 2) nuclear factor-kappaB and activated protein-1 activation in various cell types; 3) interleukin (IL)-2 production from human lymphocytes; 4) hyperproliferation of human keratinocytes; 5) IL-8 production from human keratinocytes; and 6) proinflammatory cytokine production from human peripheral blood mononuclear cells. Based on the data presented here, E6201 may be beneficial for treatment of inflammatory and hyperproliferative diseases such as psoriasis through its anti-inflammatory activities on immune cells and antihyperproliferative activities on keratinocytes.
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Antiinflamatorios/farmacología , Proliferación Celular/efectos de los fármacos , Lactonas/farmacología , MAP Quinasa Quinasa 1/antagonistas & inhibidores , Quinasa 1 de Quinasa de Quinasa MAP/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Actinas/metabolismo , Línea Celular , Citocinas/biosíntesis , Humanos , Inmunidad Celular/efectos de los fármacos , Indicadores y Reactivos , Interleucina-2/biosíntesis , Interleucina-8/biosíntesis , Células Jurkat , Queratinocitos/efectos de los fármacos , Linfocitos/efectos de los fármacos , Fosforilación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced colitis mice reveals that the increased expression of pro-inflammatory genes is downregulated by ER-464195-01. Its prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases. We propose that leukocytes infiltration via the binding of CRT to ITGAs is necessary for the onset and development of the colitis and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD.
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Antiinflamatorios/farmacología , Calreticulina/inmunología , Colitis Ulcerosa/inmunología , Ciclohexanos/farmacología , Cadenas alfa de Integrinas/inmunología , Piperazinas/farmacología , Animales , Antiinflamatorios/uso terapéutico , Calreticulina/antagonistas & inhibidores , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colon/citología , Colon/inmunología , Colon/patología , Ciclohexanos/uso terapéutico , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Femenino , Voluntarios Sanos , Humanos , Cadenas alfa de Integrinas/metabolismo , Células Jurkat , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Infiltración Neutrófila/efectos de los fármacos , Infiltración Neutrófila/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Piperazinas/uso terapéutico , Unión Proteica , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Recent decades have witnessed a rapid worldwide increase in chronic inflammatory disorders such as asthma. CD4+ T helper 2 cells play critical roles in the pathogenesis of allergic airway inflammation, and CD69 expression on activated CD4 T cells is required to induce allergic inflammation in tissues. However, how CD69 mechanistically controls allergic inflammation remains poorly defined. In lymphoid tissues, CD69 regulates cellular retention through inhibition of S1P1 expression and requires no specific ligands to function. In contrast, we show herein that myosin light chain (Myl) 9 and Myl12 are new functional ligands for CD69. Blockade of CD69-Myl9/12 interaction ameliorates allergic airway inflammation in ovalbumin-induced and house dust mite-induced mouse models of asthma. Within the inflamed mouse airways, we found that the expression of Myl9/12 was increased and that platelet-derived Myl9/12 localized to the luminal surface of blood vessels and formed intravascular net-like structures. Analysis of nasal polyps of eosinophilic chronic rhinosinusitis patients revealed that Myl9/12 expression was increased in inflammatory lesions and was distributed within net-like structures in the intravascular space. In addition, we detected Myl9/12 in perivascular spaces where many CD69+ cells were positioned within Myl9/12 structures. Thus, CD69-Myl9/12 interaction is a key event in the recruitment of activated CD69+ T cells to inflamed tissues and could be a therapeutic target for intractable airway inflammatory diseases.
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Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.
Asunto(s)
Metilación de ADN , Exoma/genética , Genoma Humano/genética , Leucemia-Linfoma de Células T del Adulto/genética , Análisis de Secuencia de ADN/métodos , Transcriptoma/genética , Adulto , Secuencia de Aminoácidos , Variaciones en el Número de Copia de ADN , Productos del Gen tax/genética , Células HEK293 , Interacciones Huésped-Patógeno/genética , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/fisiología , Humanos , Células Jurkat , Leucemia-Linfoma de Células T del Adulto/virología , Datos de Secuencia Molecular , Mutación , Homología de Secuencia de Aminoácido , Transducción de Señal/genética , Análisis de Supervivencia , Linfocitos T/metabolismo , Linfocitos T/virologíaRESUMEN
INTRODUCTION: Chemerin is a chemotactic agonist identified as a ligand for ChemR23 that is expressed on macrophages and dendritic cells (DCs). In this study, we analyzed the expression of chemerin and ChemR23 in the synovium of rheumatoid arthritis (RA) patients and the stimulatory effects of chemerin on fibroblast-like synoviocytes (FLSs) from RA patients. METHODS: Chemerin and ChemR23 expression in the RA synovium was ascertained by immunohistochemistry and Western blot analysis. Chemerin expression on cultured FLSs was analyzed by ELISA. ChemR23 expression on FLSs was determined by immunocytochemistry and Western blot analysis. Cytokine production from FLSs was measured by ELISA. FLS cell motility was evaluated by utilizing a scrape motility assay. We also examined the stimulating effect of chemerin on the phosphorylation of mitogen-activated protein kinase (MAPK), p44/42 mitogen-activated protein kinase (ERK1/2), p38MAPK, c-Jun N-terminal kinase (JNK)1/2 and Akt, as well as on the degradation of regulator of NF-κB (IκBα) in FLSs, by Western blot analysis. RESULTS: Chemerin was expressed on endothelial cells and synovial lining and sublining cells. ChemR23 was expressed on macrophages, immature DCs and FLSs and a few mature DCs in the RA synovium. Chemerin and ChemR23 were highly expressed in the RA synovium compared with osteoarthritis. Chemerin and ChemR23 were expressed on unstimulated FLSs. TNF-α and IFN-γ upregulated chemerin production. Chemerin enhanced the production of IL-6, chemokine (C-C motif) ligand 2 and matrix metalloproteinase 3 by FLSs, as well as increasing FLS motility. The stimulatory effects of chemerin on FLSs were mediated by activation of ERK1/2, p38MAPK and Akt, but not by JNK1/2. Degradation of IκB in FLSs was not promoted by chemerin stimulation. Inhibition of the ERK1/2, p38MAPK and Akt signaling pathways significantly suppressed chemerin-induced IL-6 production. Moreover, blockade of the p38MAPK and Akt pathways, but not the ERK1/2 pathway, inhibited chemerin-enhanced cell motility. CONCLUSIONS: The interaction of chemerin and ChemR23 may play an important role in the pathogenesis of RA through the activation of FLSs.
Asunto(s)
Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Quimiocinas/fisiología , Fibroblastos/metabolismo , Membrana Sinovial/citología , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Anciano , Células Cultivadas , Quimiocinas/biosíntesis , Femenino , Fibroblastos/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular , Receptores de Quimiocina/biosíntesisRESUMEN
The inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are illness characterized by a chronic clinical course of relapse and remission associated with self-destructive inflammation of the gastrointestinal tract. In both UC and CD, leukocyte infiltration into the intestine is fundamental event in disease development and progression where the chemokines and their receptors are orchestrating the tissue-specific and the cell type-selective trafficking of leukocytes. In this review, we will discuss the homeostatic and inflammatory roles of the chemokines and their receptors with their potentials and promise as molecular targets for therapeutic interventions in human IBD, focusing on the recently identified role of the CX3CL1-CX3CR1 axis, as well as the CCL20-CCR6, CCL25-CCR9, and CXCL10-CXCR3 pathways.