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1.
Nat Commun ; 13(1): 4220, 2022 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-35864098

RESUMEN

Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration.


Asunto(s)
Autofagia Mediada por Chaperones , Degeneración Retiniana , Retinitis Pigmentosa , Animales , Autofagia , Proteínas Co-Represoras , Ratones , Receptor alfa de Ácido Retinoico/genética
2.
Arthritis Rheumatol ; 74(11): 1796-1807, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35637551

RESUMEN

OBJECTIVE: T cells are critical in the pathogenesis of systemic lupus erythematosus (SLE) in that they secrete inflammatory cytokines, help autoantibody production, and form autoreactive memory T cells. Although the contribution of T cells to several forms of organ-mediated damage in SLE has been previously demonstrated, the role of T cells in neuropsychiatric SLE (NPSLE), which involves diffuse central nervous system manifestations and is observed in 20-40% of SLE patients, is not known. Therefore, we conducted this study to evaluate how behavioral deficits are altered after depletion or transfer of T cells, to directly assess the role of T cells in NPSLE. METHODS: MRL/lpr mice, an NPSLE mouse model, were either systemically depleted of CD4+ T cells or intracerebroventricularly injected with choroid plexus (CP)-infiltrating T cells and subsequently evaluated for alterations in neuropsychiatric manifestations. Our study end points included evaluation of systemic disease and assessment of central nervous system changes. RESULTS: Systemic depletion of CD4+ T cells ameliorated systemic disease and cognitive deficits. Intracerebroventricular injection of CP-infiltrating T cells exacerbated depressive-like behavior and worsened cognition in recipient mice compared with mice who received injection of splenic lupus T cells or phosphate buffered saline. Moreover, we observed enhanced activation in CP-infiltrating T cells when cocultured with brain lysate-pulsed dendritic cells in comparison to the activation levels observed in cocultures with splenic T cells. CONCLUSION: T cells, and more specifically CP-infiltrating antigen-specific T cells, contributed to the pathogenesis of NPSLE in mice, indicating that, in the development of more targeted treatments for NPSLE, modulation of T cells may represent a potential therapeutic strategy.


Asunto(s)
Lupus Eritematoso Sistémico , Vasculitis por Lupus del Sistema Nervioso Central , Animales , Ratones , Ratones Endogámicos MRL lpr , Plexo Coroideo/patología , Modelos Animales de Enfermedad
3.
Autophagy ; 16(2): 223-238, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-30982401

RESUMEN

Obesity is associated with changes in the immune system that significantly hinder its ability to mount efficient immune responses. Previous studies have reported a dysregulation of immune responses caused by lipid challenge; however, the mechanisms underlying that dysregulation are still not completely understood. Autophagy is an essential catabolic process through which cellular components are degraded by the lysosomal machinery. In T cells, autophagy is an actively regulated process necessary to sustain homeostasis and activation. Here, we report that CD4+ T cell responses are inhibited when cells are challenged with increasing concentrations of fatty acids. Furthermore, analysis of T cells from diet-induced obese mice confirms that high lipid load inhibits activation-induced responses in T cells. We have found that autophagy is inhibited in CD4+ T cells exposed in vitro or in vivo to lipid stress, which causes decreased autophagosome formation and degradation. Supporting that inhibition of autophagy caused by high lipid load is a key mechanism that accounts for the effects on T cell function of lipid stress, we found that ATG7 (autophagy-related 7)-deficient T cells, unable to activate autophagy, did not show additional inhibitory effects on their responses to activation when subjected to lipid challenge. Our results indicate, thus, that increased lipid load can dysregulate autophagy and cause defective T cell responses, and suggest that inhibition of autophagy may underlie some of the characteristic obesity-associated defects in the T cell compartment.Abbreviations: ACTB: actin, beta; ATG: autophagy-related; CDKN1B: cyclin-dependent kinase inhibitor 1B; HFD: high-fat diet; IFNG: interferon gamma; IL: interleukin; MAPK1/ERK2: mitogen-activated protein kinase 1; MAPK3/ERK1: mitogen-activated protein kinase 3; MAPK8/JNK: mitogen-activated protein kinase 8; LC3-I: non-conjugated form of MAP1LC3B; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3B; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MS: mass spectrometry; MTOR: mechanistic target of rapamycin kinase; NFATC2: nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2; NLRP3: NLR family, pyrin domain containing 3; OA: oleic acid; PI: propidium iodide; ROS: reactive oxygen species; STAT5A: signal transducer and activator of transcription 5A; TCR: T cell receptor; TH1: T helper cell type 1.


Asunto(s)
Autofagia/efectos de los fármacos , Lípidos/farmacología , Linfocitos T/inmunología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/ultraestructura , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , Dieta Alta en Grasa , Regulación hacia Abajo/efectos de los fármacos , Femenino , Homeostasis/efectos de los fármacos , Humanos , Activación de Linfocitos/efectos de los fármacos , Ratones Endogámicos C57BL , Obesidad/inmunología , Ácido Oléico/farmacología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/efectos de los fármacos
5.
Am J Med Qual ; 25(4): 261-7, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20460560

RESUMEN

The objective was to study the impact of a practice-based quality improvement program on practice teams' care for patients who have increased risk of cardiovascular disease. A total of 54 team members from 18 internal medicine practices participated in an educational program that used a pre-post intervention study design and focused on measures related to cardiovascular risk factors. The program involved live instruction, faculty-led conference calls, practice data collection, and progress reports detailing practices' improvement strategies. Data on 817 patients were reported. Practices showed significant improvement in counseling for diet (70% to 78%), exercise (67% to 74%), and weight loss (64% to 72%). Use of aspirin (53% to 64%) and statins (83% to 89%) also showed significant improvement. Administration of flu vaccine increased significantly from 51% to 54%. Improvements in patient counseling and medication management, if sustained, should lead to fewer cardiovascular events. However, program duration did not allow the capture of outcomes measures improvement.


Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Prevención Primaria/métodos , Garantía de la Calidad de Atención de Salud , Sociedades Médicas , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevención Primaria/normas , Conducta de Reducción del Riesgo
6.
Am J Med Qual ; 23(3): 176-83, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18539978

RESUMEN

OBJECTIVE: The American College of Physicians (ACP) developed a quality improvement (QI) program to address deficiencies in immunization rates, primarily for influenza, and determine the program's impact on adult immunization. DESIGN: An interventional study using a pre-post design. Three cohorts of physician practices were invited from a random sample of 2000 to attend 1-day training sessions in 2004, 2005, and 2006 in Philadelphia, Pennsylvania. Participants performed data abstractions and developed QI plans. Baseline data were compared with follow-up. RESULTS: Fifty-five practices received training, 39 practices provided baseline data, and 11 practices provided follow-up data, reporting on 4208 patients. Baseline rates for influenza were 51% for cohort 1, 42% for cohort 2, and 59% for cohort 3. Follow-up data collection is ongoing. CONCLUSION: Rates increased for patients with private insurance and patients aged 50 to 64 years, suggesting that many providers attending the training were unaware of the need to vaccinate these patients.


Asunto(s)
Promoción de la Salud/organización & administración , Vacunas contra la Influenza/administración & dosificación , Calidad de la Atención de Salud/organización & administración , Vacunación/estadística & datos numéricos , Anciano , Estudios de Cohortes , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Persona de Mediana Edad
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