RESUMEN
The activation of microglia is an important cause of central nervous system (CNS) inflammatory cell infiltration and inflammatory demyelination in experimental autoimmune encephalomyelitis (EAE). Furthermore, the proinflammatory response induced by the NLR family pyrin domain containing 3 (NLRP3) inflammasome can be amplified in microglia after NLRP3 inflammasome activation. Autophagy is closely related to the inflammatory response. Caffeine exerts anti-inflammatory and autophagy-stimulating effects, but the specific mechanism remains unclear. This study examined the mechanism underlying the anti-inflammatory effect of caffeine on EAE. In this study, C57BL/6 mice were immunized to induce EAE and treated with caffeine to observe its effect on prognosis. The effects of caffeine on autophagy and inflammation were also analysed in mouse primary microglia (PM) and the BV2 cell line. The data demonstrated that caffeine reduced the clinical score, the infiltration of inflammatory cells, the demyelination level, and the activation of microglia in EAE mice. Furthermore, caffeine increased the LC3-II/LC3-I levels and decreased the NLRP3 and P62 levels in EAE mice, whereas the autophagy inhibitor 3-methylamine (3-MA) blocked these effects. In vitro, caffeine promoted autophagy by suppressing the mechanistic target of rapamycin (mTOR) pathway and inhibited activation of the NLRP3 inflammasome. However, autophagy-related gene 5 (ATG5)-specific siRNA abolished the anti-inflammatory effect of caffeine treatment in PM and BV2 cells. Taken together, these data suggest that caffeine exerts a newly discovered effect on EAE by reducing NLRP3 inflammasome activation via the induction of autophagy in microglia.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Inflamasomas , Animales , Autofagia , Cafeína/farmacología , Cafeína/uso terapéutico , Encefalomielitis Autoinmune Experimental/metabolismo , Inflamasomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedades NeuroinflamatoriasRESUMEN
Skeletal muscle atrophy is one of the clinical symptoms of myotonic dystrophy type 1 (DM1). A decline in skeletal muscle regeneration is an important contributor to muscle atrophy. Skeletal muscle satellite cells (SSCs) drive skeletal muscle regeneration. Increased autophagy can reduce the proliferative capacity of SSCs, which plays an important role in the early regeneration of damaged skeletal muscle in DM1. Discovering new ways to restore SSC proliferation may aid in the identification of new therapeutic targets for the treatment of skeletal muscle atrophy in DM1. In the pathogenesis of DM1, muscleblind-like 1 (MBNL1) protein is generally considered to form nuclear RNA foci and disturb the RNA-splicing function. However, the role of MBNL1 in SSC proliferation in DM1 has not been reported. In this study, we obtained SSCs differentiated from normal DM1-04-induced pluripotent stem cells (iPSCs), DM1-03 iPSCs, and DM1-13-3 iPSCs edited by transcription activator-like (TAL) effector nucleases (TALENs) targeting CTG repeats, and primary SSCs to study the pathogenesis of DM1. DM1 SSC lines and primary SSCs showed decreased MBNL1 expression and elevated autophagy levels. However, DM1 SSCs edited by TALENs showed increased cytoplasmic distribution of MBNL1, reduced levels of autophagy, increased levels of phosphorylated mammalian target of rapamycin (mTOR), and improved proliferation rates. In addition, we confirmed that after MBNL1 overexpression, the proliferative capability of DM1 SSCs and the level of phosphorylated mTOR were enhanced, while the autophagy levels were decreased. Our data also demonstrated that the proliferative capability of DM1 SSCs was enhanced after autophagy was inhibited by overexpressing mTOR. Finally, treatment with rapamycin (an mTOR inhibitor) was shown to abolish the increased proliferation capability of DM1 SSCs due to MBNL1 overexpression. Taken together, these data suggest that MBNL1 reverses the proliferation defect of SSCs in DM1 by inhibiting autophagy via the mTOR pathway.
Asunto(s)
Autofagia/efectos de los fármacos , Distrofia Miotónica/patología , Proteínas de Unión al ARN/metabolismo , Células Satélite del Músculo Esquelético/metabolismo , Células Satélite del Músculo Esquelético/patología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Línea Celular , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Femenino , Genoma , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Células Satélite del Músculo Esquelético/efectos de los fármacos , Sirolimus/farmacología , Nucleasas de los Efectores Tipo Activadores de la TranscripciónRESUMEN
BACKGROUND: Hospital mortality rates are higher among patients with sepsis-associated acute kidney injury (SA-AKI) than among patients with sepsis. However, the pathogenesis underlying SA-AKI remains unclear. We hypothesized that the source of infection affects development of SA-AKI. We aim to explore the relationship between the anatomical source of infection and outcome in patients with SA-AKI. METHODS: Between January 2013 and January 2018, 113 patients with SA-AKI admitted to our Emergency Center were identified and divided into two groups: those with pulmonary infections and those with other sources of infection. For each patient, we collected data from admission until either discharge or death. We also recorded the clinical outcome after 90 days for the discharged patients. RESULTS: The most common source of infection was the lung (52/113 cases, 46%), followed by gastrointestinal (GI) (25/113 cases, 22.1%) and urinary (22/113, 19.5%) sources. Our analysis showed that patients with SA-AKI had a significantly worse outcome (30/52 cases, P<0.001) and poorer kidney recovery (P=0.015) with pulmonary sources of infection than those infected by another source. Data also showed that patients not infected by a pulmonary source more likely experienced shock (28/61 cases, P=0.037). CONCLUSION: This study demonstrated that the source of infection influenced the outcome of SA-AKI patients in an independent manner. Lung injury may influence renal function in an as-yet undetermined manner as the recovery of kidney function was poorer in SA-AKI patients with a pulmonary source of infection.
RESUMEN
Background: Cerebral small vessel disease (SVD) is generally considered as a cause of stroke, disability, gait disturbances, vascular cognitive impairment, and dementia. The aim of this study was to investigate whether the total SVD burden can be used to predict functional outcome in patients with acute ischemic stroke. Methods: From April 2017 to January 2018, consecutive patients with acute ischemic stroke who underwent baseline MRI scan were evaluated. The functional outcome was assessed using the modified Rankin Scale (mRS) at 90 days and defined as i) excellent outcome (mRS ≤ 1) and ii) good outcome (mRS ≤ 2). Brain MRI was performed and assessed for lacunes, white matter hyperintensities (WMH), and enlarged perivascular spaces (EPVS). The total SVD burden was calculated based on lacunes, WMH, and EPVS and then summed up to generate an ordinal "total SVD burden" (range 0-3). Bivariate logistic regression models were used to identify the association between SVD and functional outcome. Results: A total of 416 patients were included in the final analysis; 44.0, 33.4, 19.2, and 3.4% of the patients had 0, 1, 2, and 3 features of SVD, respectively. In regard to individual SVD feature, lacunes (OR: 0.48, 95% CI: 0.32-0.71; OR: 0.49, 95% CI: 0.31-0.77) and WMH (OR: 0.53, 95% CI: 0.34-0.82; OR: 0.53, 95% CI: 0.33-0.85) were negatively associated with excellent outcome and good outcome. As to the total burden of SVD, three SVD features had strongest negative associations with functional outcomes (excellent outcome, OR: 0.13, 95% CI: 0.03-0.48; good outcome, OR: 0.18, 95% CI: 0.06-0.54). After adjustment for potential confounders, a high SVD burden (3 features, OR: 0.07, 95% CI: 0.01-0.41) and the score of total SVD burden (OR: 0.64, 95% CI: 0.44-0.93) remained negatively associated with excellent outcome. Conclusion: Total SVD burden negatively associated with functional outcome at 3 months in patients with acute ischemic stroke and is superior to individual SVD feature in prediction of functional outcome. MRI-based assessment of total SVD burden is highly valuable in clinical management of stroke victims and could help guide the allocation of resources to improve outcome.