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1.
Nature ; 632(8023): 157-165, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39020175

RESUMEN

For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.


Asunto(s)
Envejecimiento , Interleucina-11 , Longevidad , Transducción de Señal , Animales , Femenino , Masculino , Ratones , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Proteínas Quinasas Activadas por AMP/metabolismo , Fragilidad/genética , Fragilidad/metabolismo , Fragilidad/prevención & control , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Interleucina-11/antagonistas & inhibidores , Interleucina-11/deficiencia , Interleucina-11/genética , Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11/deficiencia , Longevidad/efectos de los fármacos , Longevidad/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Humanos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología
2.
Int J Mol Sci ; 23(16)2022 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-36012165

RESUMEN

Interleukin 11 (IL11) is upregulated in inflammatory conditions, where it is mostly believed to have anti-inflammatory activity. However, recent studies suggest instead that IL11 promotes inflammation by activating fibroblasts. Here, we assessed whether IL11 is pro- or anti-inflammatory in fibroblasts. Primary cultures of human kidney, lung or skin fibroblasts were stimulated with IL11 that resulted in the transient phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the sustained activation of extracellular signal-regulated protein kinases (ERK). RNA sequencing over a time course of IL11 stimulation revealed a robust but short-lived transcriptional response that was enriched for gene set hallmarks of inflammation and characterized by the upregulation of SERPINB2, TNFRSF18, Interleukin 33 (IL33), CCL20, IL1RL1, CXCL3/5/8, ICAM1 and IL11 itself. IL33 was the most upregulated signaling factor (38-fold, p = 9.8 × 10-5), and IL1RL1, its cognate receptor, was similarly increased (18-fold, p = 1.1 × 10-34). In proteomic studies, IL11 triggered a proinflammatory secretome with the notable upregulation of IL8, IL6, MCP1, CCL20 and CXCL1/5/6, which are important chemotaxins for neutrophils, monocytes, and lymphocytes. IL11 induced IL33 expression across fibroblast types, and the inhibition of STAT3 but not of MEK/ERK prevented this. These data establish IL11 as pro-inflammatory with specific importance for priming the IL33 alarmin response in inflammatory fibroblasts across tissues.


Asunto(s)
Interleucina-11 , Interleucina-33 , Fibroblastos/metabolismo , Humanos , Inflamación/genética , Inflamación/metabolismo , Interleucina-11/genética , Interleucina-11/metabolismo , Interleucina-33/metabolismo , Proteómica
3.
Int J Mol Sci ; 23(13)2022 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-35806094

RESUMEN

N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1ß, and Tnfα expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.


Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Acetaminofén/toxicidad , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/metabolismo , Hepatocitos/metabolismo , Interleucina-11/genética , Interleucina-11/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Necrosis/metabolismo
4.
Int J Mol Sci ; 23(7)2022 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-35408908

RESUMEN

Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFß, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1ß) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis.


Asunto(s)
Interleucina-11 , Pancreatitis Crónica , Animales , Atrofia/patología , Modelos Animales de Enfermedad , Fibrosis , Inflamación/patología , Interleucina-6 , Ratones , Páncreas/patología , Células Estrelladas Pancreáticas/patología , Pancreatitis Crónica/patología
5.
Nat Commun ; 13(1): 7497, 2022 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-36470928

RESUMEN

The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3ß inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGFß reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney.


Asunto(s)
Lesión Renal Aguda , Anticuerpos Neutralizantes , Interleucina-11 , Túbulos Renales , Nefritis , Regeneración , Insuficiencia Renal Crónica , Animales , Ratones , Lesión Renal Aguda/terapia , Fibrosis , Subunidad alfa del Receptor de Interleucina-11/genética , Túbulos Renales/fisiología , Nefritis/terapia , Interleucina-11/antagonistas & inhibidores , Interleucina-11/fisiología , Eliminación de Gen , Anticuerpos Neutralizantes/uso terapéutico , Insuficiencia Renal Crónica/terapia , Modelos Animales de Enfermedad
6.
BMJ Open ; 11(10): e048764, 2021 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-34635517

RESUMEN

INTRODUCTION: Perinatal depression is common and can often lead to adverse health outcomes for mother and child. Multiple pharmacological and non-pharmacological treatments have been evaluated against usual care or placebo controls in meta-analyses for preventing and treating perinatal depression compared. It is not yet established which of these candidate treatments might be the optimal approach for prevention or treatment. METHODS AND ANALYSIS: A systematic review and Bayesian network meta-analyses will be conducted. Eight electronic databases shall be searched for randomised controlled trials that have evaluated the effectiveness of treatments for prevention and/or treatment of perinatal depression. Screening of articles shall be conducted by two reviewers independently. One network meta-analysis shall evaluate the effectiveness of interventions in preventing depression during the perinatal period. A second network meta-analysis shall compare the effectiveness of treatments for depression symptoms in women with perinatal depression. Bayesian 95% credible intervals shall be used to estimate the pooled mean effect size of each treatment, and surface under cumulative ranking area will be used to rank the treatments' effectiveness. ETHICS AND DISSEMINATION: We shall report our findings so that healthcare providers can make informed decisions on what might be the optimal approach for addressing perinatal depression to prevent cases and improve outcomes in those suffering from depression through knowledge exchange workshops, international conference presentations and journal article publications. PROSPERO REGISTRATION NUMBER: CRD42020200081.


Asunto(s)
Depresión , Trastorno Depresivo , Teorema de Bayes , Niño , Depresión/prevención & control , Trastorno Depresivo/prevención & control , Femenino , Humanos , Metaanálisis como Asunto , Metaanálisis en Red , Embarazo , Revisiones Sistemáticas como Asunto , Resultado del Tratamiento
7.
Sci Transl Med ; 13(597)2021 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-34108253

RESUMEN

Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)-dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 (Il11ra1) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.


Asunto(s)
Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Acetaminofén/toxicidad , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Hepatocitos , Interleucina-11 , Subunidad alfa del Receptor de Interleucina-11 , Hígado , Ratones , Ratones Endogámicos C57BL
8.
PLoS One ; 5(8): e11956, 2010 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-20694142

RESUMEN

BACKGROUND: Phosphatidic acid (PA) is a key regulated intermediate and precursor for de novo biosynthesis of all glycerophospholipids. PA can be synthesized through the acylation of lysophosphatidic acid (LPA) by 1-acyl-3-phosphate acyltransferase (also called lysophosphatidic acid acyltransferase, LPAAT). Recent findings have substantiated the essential roles of acyltransferases in various biological functions. METHODOLOGIES/PRINCIPAL FINDINGS: We used a flow-injection-based lipidomic approach with approximately 200 multiple reaction monitoring (MRM) transitions to pre-screen fatty acyl composition of phospholipids in the yeast Saccharomyces cerevisiae mutants. Dramatic changes were observed in fatty acyl composition in some yeast mutants including Slc1p, a well-characterized LPAAT, and Cst26p, a recently characterized phosphatidylinositol stearoyl incorporating 1 protein and putative LPAAT in S. cerevisiae. A comprehensive high-performance liquid chromatography-based multi-stage MRM approach (more than 500 MRM transitions) was developed and further applied to quantify individual phospholipids in both strains to confirm these changes. Our data suggest potential fatty acyl substrates as well as fatty acyls that compensate for defects in both Cst26p and Slc1p mutants. These results were consistent with those from a non-radioactive LPAAT enzymatic assay using C17-LPA and acyl-CoA donors as substrates. CONCLUSIONS: We found that Slc1p utilized fatty acid (FA) 18:1 and FA 14:0 as substrates to synthesize corresponding PAs; moreover, it was probably the only acyltransferase responsible for acylation of saturated short-chain fatty acyls (12:0 and 10:0) in S. cerevisiae. We also identified FA 18:0, FA 16:0, FA 14:0 and exogenous FA 17:0 as preferred substrates for Cst26p because transformation with a GFP-tagged CST26 restored the phospholipid profile of a CST26 mutant. Our current findings expand the enzymes and existing scope of acyl-CoA donors for glycerophospholipid biosynthesis.


Asunto(s)
Aciltransferasas/metabolismo , Biología Computacional/métodos , Pruebas de Enzimas/métodos , Metabolismo de los Lípidos , Proteínas de Saccharomyces cerevisiae/metabolismo , Aciltransferasas/genética , Bases de Datos de Proteínas , Dineínas , Ácidos Grasos/metabolismo , Espectrometría de Masas , Mutación , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Especificidad por Sustrato
9.
Mol Biosyst ; 6(6): 1008-17, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20485745

RESUMEN

Recent rapid growth of lipidomics is mainly attributed to technological advances in mass spectrometry. Development of soft ionization techniques, in combination with computational tools, has spurred subsequent development of various methods for lipid analysis. However, none of these existing approaches can cover major cellular lipids in a single run. Here we demonstrate that a single method of liquid chromatography coupled with mass spectrometry (LCMS) can be used for simultaneous profiling of major cellular lipids including glycerophospholipids (PLs), sphingolipids (SPLs), waxes, sterols (ST) and mono-, di- as well as triacylglycerides (MAG, DAG, TAG). We applied this approach to analyze these lipids in various organisms including Saccharomyces cerevisiae and Schizosaccharomyces pombe. While phospholipids and triacylglycerides of S. pombe mainly contain 18 : 1 fatty acyls, those of S. cerevisiae contain 16 : 1, 16 : 0 and 18 : 1 fatty acyls. S. cerevisiae and S. pombe contain distinct sphingolipid profiles. S. cerevisiae has abundant inositol phytoceramides (IPC), while S. pombe contains high levels of free phytoceramides as well as short chain phytoceramides (t18:1/20 : 0-B) and IPC (t18:1/20 : 0-B). In S. cerevisiae, our results demonstrated accumulation of ergosterol esters in tgl1Delta cells and accumulation of various TAG species in tgl3Delta cells, which are consistent with the function of the respective enzymes. Furthermore, we, for the first time, systematically characterized lipids in S. pombe and measured their dynamic changes in Deltaplh1Deltadga1 cells at different growth phases. We further discussed dynamic changes of phospholipids, sphingolipids and neutral lipids in the progress of programmed cell death in Deltaplh1Deltadga1 cells of S. pombe.


Asunto(s)
Cromatografía Liquida/métodos , Lípidos/análisis , Espectrometría de Masas/métodos , Saccharomyces cerevisiae/química , Schizosaccharomyces/química , Ceramidas/análisis , Lípidos/química , Esfingolípidos/análisis , Esfingolípidos/química
10.
Australas Psychiatry ; 14(2): 156-68, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16734644

RESUMEN

OBJECTIVE: To describe a framework for the initiation and ongoing monitoring of patients on clozapine, and detail support materials that can be used in clinical settings, including general practice, to support this process. CONCLUSIONS: A framework is described. Clozapine has a special place in the management of treatment-resistant schizophrenia. However, it has certain side-effects that require its use to be carefully evaluated on an individual patient basis, and encompass excellent documentation and discussion with all relevant parties. Comprehensive longitudinal monitoring is required.


Asunto(s)
Antipsicóticos/uso terapéutico , Clozapina/uso terapéutico , Monitoreo de Drogas , Monitoreo Fisiológico , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/efectos adversos , Clozapina/efectos adversos , Documentación/métodos , Interacciones Farmacológicas , Resistencia a Medicamentos , Humanos , Estudios Longitudinales , Registros Médicos Orientados a Problemas , Derivación y Consulta , Esquizofrenia/diagnóstico , Resultado del Tratamiento
11.
Australas Psychiatry ; 13(2): 111-5, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15948904

RESUMEN

OBJECTIVES: To demonstrate the use of the National Health Performance Framework as an evaluation framework for clinical interventions and service outcomes in mental health. CONCLUSIONS: Evaluation is not a complex process. What is required is a willingness to be accountable for outcomes of care. It does not require complex data systems but openness to scrutiny through reflective practices and a commitment to continue to explore the possibilities of making things better.


Asunto(s)
Servicios de Salud Mental/normas , Programas Nacionales de Salud/normas , Psiquiatría/métodos , Garantía de la Calidad de Atención de Salud/organización & administración , Australia , Investigación sobre Servicios de Salud/métodos , Encuestas Epidemiológicas , Humanos , Auditoría Administrativa/organización & administración , Auditoría Médica/métodos , Auditoría Médica/organización & administración , Servicios de Salud Mental/organización & administración , Evaluación de Procesos y Resultados en Atención de Salud , Garantía de la Calidad de Atención de Salud/métodos , Indicadores de Calidad de la Atención de Salud , Encuestas y Cuestionarios
12.
Australas Psychiatry ; 13(3): 247-52, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16174197

RESUMEN

OBJECTIVE: To describe the process underpinning the development of clinical guidelines for the management of behavioural disturbance in psychosis. METHOD: A structured process was followed, encompassing a literature review, focus groups with key staff, and pilot testing and monitoring of the guidelines in an acute psychiatric setting. RESULTS: The process was well accepted by staff and was found useful in monitoring outcomes in a naturalistic setting. The final guidelines proved safe and effective in the acute setting. CONCLUSIONS: The incorporation of a monitoring system for interventions for the management of behavioural disturbance in acute psychiatric settings is beneficial for staff and patients alike.


Asunto(s)
Agresión/efectos de los fármacos , Quimioterapia , Guías de Práctica Clínica como Asunto , Trastornos Psicóticos/psicología , Enfermedad Aguda , Agresión/psicología , Grupos Focales , Humanos , Monitoreo Fisiológico , Trastornos Psicóticos/complicaciones , Seguridad , Resultado del Tratamiento
13.
Australas Psychiatry ; 12(3): 220-4; discussion 225-6, 2004 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15715778

RESUMEN

OBJECTIVE: To examine the relationship between academic psychiatry and the pharmaceutical industry, focusing on a partnership between academics in Melbourne and Eli Lilly and Company (Lilly Melbourne Academic Psychiatry). CONCLUSIONS: Relationships between the pharmaceutical industry and the medical profession (including psychiatry) are under scrutiny as never before. Despite the complex nature of the relationship, the present paper argues that partnerships with external corporations such as pharmaceutical companies are of increasing importance for academic departments of psychiatry and research institutes, in environments in which core funding for tertiary institutes is being reduced. The partnership between Melbourne psychiatric academics and Eli Lilly and Company shows that benefits accrue to both parties, and suggests that there is a worthwhile place for other industry- academic collaborations of a similar nature in Australia.


Asunto(s)
Centros Médicos Académicos/organización & administración , Conducta Cooperativa , Industria Farmacéutica/organización & administración , Relaciones Interinstitucionales , Psiquiatría/educación , Australia , Humanos
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