RESUMEN
BACKGROUND AND AIMS: The definitive treatment for pyrrolizidine alkaloids (PAs)-induced hepatic sinusoidal obstruction syndrome (HSOS) is not available. The effectiveness of anticoagulation therapy remains controversial. The efficacy of low molecular weight heparin (LMWH) should be investigated in patients and animal models, and the underlying mechanism should be explored. METHODS: The prognosis of patients with PAs-HSOS who received anticoagulation therapy was retrospectively analysed. The effect of enoxaparin on the liver injury was determined in animal models of monocrotaline (MCT)-induced HSOS was determined, and the underlying mechanism was investigated using a murine model. RESULTS: The cumulative survival rate of patients with PAs-induced HSOS was 60.00% and 90.90% in the non-anticoagulation group and anticoagulation group. Enoxaparin attenuated liver injury effectively in a rat model of MCT-induced HSOS. Additionally, the improvement of severe liver injury was observed in MCT-treated mice after the administration of enoxaparin (40 mg/kg). The alleviation of liver injury was observed in mice with hepatocyte-specific deletion of oncostatin M (Osmâ³Hep ). In MCT-treated mice administrated with enoxaparin, no significant differences in liver injury were observed between Osmâ³Hep mice and Osmflox/flox mice. Additionally, adenovirus-mediated overexpression of Osm resulted in severe liver injury in MCT-induced mice after the administration of enoxaparin. CONCLUSIONS: LMWH attenuated severe liver injury in patients with PAs-Induced HSOS and animal models of MCT-induced HSOS, which provides a rationale for the application of anticoagulation therapy.
Asunto(s)
Enfermedad Veno-Oclusiva Hepática , Alcaloides de Pirrolicidina , Ratas , Ratones , Animales , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Alcaloides de Pirrolicidina/efectos adversos , Enoxaparina , Estudios Retrospectivos , Heparina de Bajo-Peso-Molecular , Oncostatina M/efectos adversos , Monocrotalina/efectos adversos , Anticoagulantes/efectos adversosRESUMEN
Ulcerative colitis (UC) is a chronic and etiologically refractory inflammatory gut disorder. Although berberine, an isoquinoline alkaloid, has been revealed to exert protective effects on experimental colitis, the underlying molecular mechanism in chronic intestinal inflammation remains ill-defined. This study was designed to uncover the therapeutic efficacy and immunomodulatory role of berberine in chronic UC. Therapeutic effects of oral administration of berberine were investigated in dextran sodium sulfate (DSS)-induced murine chronic UC and the underlying mechanisms were further identified by si-OSMR transfection in human intestinal stromal cells. Berberine significantly attenuated the experimental symptoms and gut inflammation of chronic UC. Berberine treatment could also maintain the intestinal barrier function and rectify tissue fibrosis. In accordance with infiltrations of antigen-presenting cells (APCs), innate lymphoid cells (ILCs), and activated NK cells in colonic lamina propria, increased expression of OSM and OSMR were observed in the inflamed tissue of chronic UC, which were decreased following berberine treatment. Moreover, berberine inhibited the overactivation of human intestinal stromal cells through OSM-mediated JAK-STAT pathway, which was obviously blocked upon siRNA targeting OSMR. The research provided an infusive mechanism of berberine and illustrated that OSM and OSMR intervention might function as the potential target in chronic UC.
Asunto(s)
Berberina/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Inflamación/inducido químicamente , Mucosa Intestinal/efectos de los fármacos , Oncostatina M/efectos adversos , Animales , Berberina/farmacología , Enfermedad Crónica , Humanos , Masculino , Ratones , TransfecciónRESUMEN
BACKGROUND: Elevated levels of oncostatin M (OSM), an interleukin-6 cytokine family member, have been observed in HIV-1-associated neurocognitive disorders (HAND) and Alzheimer's disease. However, the function of OSM in these disease conditions is unclear. Since deficient glutamate uptake by astrocytes is instrumental in HAND-associated neurotoxicity, we hypothesized that OSM impairs glutamate uptake in astrocytes and thereby promotes neuronal excitotoxicity. METHODS: Primary cultures of mouse cortical astrocytes, neurons, microglia, and BV2 cell line were used. The expression of glutamate transporters (GLAST/EAAT1 and GLT-1/EAAT2) was investigated using real-time PCR and Western blot, and their activity was assessed by measuring (3)H-D-aspartate uptake. Neuronal toxicity was measured using the colorimetric MTT (3-(4,5-dimethylthiazol-2-yl-) 2,5-diphenyltetrazolium bromide) assay and immunocytochemistry. A chimeric HIV-1 that infects murine cells (EcoHIV/NL4-3-GFP virus (EcoHIV)) was used to investigate whether the virus induces OSM, OSM receptor (OSMR)-ß, glycoprotein 130 (gp130), GLT-1, GLAST (mRNA and protein), and OSM release (ELISA) in cultured BV2 cells, primary microglia, or astrocytes. Statistical analyses of the data were performed using one-way ANOVA (to allow multiple comparisons) and two-tailed Student's t test. RESULTS: OSM treatment (10 ng/mL) time-dependently reduced GLAST and GLT-1 expression and inhibited (3)H-D-aspartate uptake in cultured astrocytes in a concentration-dependent manner, an effect prevented by the Janus kinase (JAK)/signal transducers and activators of transcription (STAT)3 inhibitor AG490. Down-regulation of astrocytic glutamate transport by OSM resulted in NMDA receptor-dependent excitotoxicity in cortical neurons. Infection with EcoHIV induced OSM gene expression and protein release in BV2 cells and microglia, but not in astrocytes. Conversely, EcoHIV caused a fivefold increase in OSMR-ß mRNA (but not gp130) and protein in astrocytes, but not in microglia, which did not express OSMR-ß protein. Finally, astrocytic expression of GLAST gene was unaffected by EcoHIV, whereas GLT-1 mRNA was increased by twofold. CONCLUSIONS: We provide first evidence that activation of JAK/STAT3 signaling by OSM inhibits glutamate uptake in astrocytes, which results in neuronal excitotoxicity. Our findings with EcoHIV suggest that targeting OSMR-ß signaling in astrocytes might alleviate HIV-1-associated excitotoxicity.
Asunto(s)
Antineoplásicos/efectos adversos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ácido Glutámico/metabolismo , Oncostatina M/efectos adversos , Sistema de Transporte de Aminoácidos X-AG/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Ácido Aspártico/metabolismo , Astrocitos/virología , Células Cultivadas , Corteza Cerebral/citología , Citocinas/genética , Citocinas/metabolismo , Embrión de Mamíferos , Agonistas de Aminoácidos Excitadores/toxicidad , Transportador 2 de Aminoácidos Excitadores/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones , Ratones Endogámicos C57BL , N-Metilaspartato/toxicidad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oncostatina M/farmacología , Subunidad beta del Receptor de Oncostatina M/metabolismo , Proteínas Oncogénicas de Retroviridae/toxicidad , Transducción de Señal/efectos de los fármacosRESUMEN
The aim of this study was to assess the anti-inflammatory efficacy of Boswellia frereana extracts in an in vitro model of cartilage degeneration and determine its potential as a therapy for treating osteoarthritis. Cartilage degradation was induced in vitro by treating explants with 5 ng/ml interleukin1alpha (IL-1alpha) and 10 ng/ml oncostatin M (OSM) over a 28-day period, in the presence or absence of 100 microg/ml B. frereana. Treatment of IL-1alpha/OSM stimulated cartilage explants with B. frereana inhibited the breakdown of the collagenous matrix. B. frereana reduced MMP9 and MMP13 mRNA levels, inhibited MMP9 expression and activation, and significantly reduced the production of nitrite (stable end product of nitric oxide), prostaglandin E2 and cycloxygenase-2. Epi-lupeol was identified as the principal constituent of B. frereana. This is the first report on the novel anti-inflammatory properties of Boswellia frereana in an in vitro model of cartilage degradation. We have demonstrated that B. frereana prevents collagen degradation, and inhibits the production of pro-inflammatory mediators and MMPs. Due to its efficacy we propose that B. frereana should be examined further as a potential therapeutic agent for treating inflammatory symptoms associated with arthritis.
Asunto(s)
Antiinflamatorios/farmacología , Boswellia/química , Cartílago Articular/metabolismo , Metaloproteinasa 13 de la Matriz/biosíntesis , Metaloproteinasa 9 de la Matriz/biosíntesis , Extractos Vegetales/farmacología , Animales , Bovinos , Supervivencia Celular , Condrocitos/citología , Ciclooxigenasa 2/biosíntesis , Dinoprostona/biosíntesis , Técnicas In Vitro , Interleucina-1alfa/efectos adversos , Nitritos/metabolismo , Oncostatina M/efectos adversos , Osteoartritis/tratamiento farmacológico , Triterpenos Pentacíclicos/farmacologíaRESUMEN
BACKGROUND: Vascular calcification is a clinically significant component of atherosclerosis and may be promoted by inflammatory stimuli. Phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is involved in the regulation of cell metabolism, survival, migration, and inflammatory responses in various cell types. METHODS: In this study, we investigated the roles of PI3K/Akt signaling pathway in human vascular smooth muscle cell (HVSMC) calcification induced by the inflammatory mediators (IM) including interferon-gamma, tumor necrosis factor-alpha, oncostatin M, and 1alpha,25-dihydroxyvitamin D3. RESULTS: Pharmacological inhibition of PI3K with wortmannin dose-dependently increased IM-induced HVSMC calcification. IM-induced expression of alkaline phosphatase (ALP) in HVSMC was also augmented by wortmannin, while wortmannin did not induce apoptosis of HVSMCs in the presence or absence of IM. Moreover, wortmannin inhibited Akt activation in HVSMC by shortterm exposure to IM. Overexpression of wild-type or dominant-negative forms of Akt significantly attenuated or enhanced IM-induced ALP expression in HVSMC, respectively. Furthermore, suppression of Akt with siRNA significantly intensified IM-induced ALP expression in HVSMC. CONCLUSIONS: These data suggest that PI3K/Akt pathway may play an inhibitory role in IM-induced HVSMC calcification through regulating ALP expression.