RESUMEN
Apoptotic cells are rapidly engulfed and removed by phagocytes after displaying cell surface eat-me signals. Among many phospholipids, only phosphatidylserine (PS) is known to act as an eat-me signal on apoptotic cells. Using unbiased proteomics, we identified externalized phosphatidylinositides (PIPs) as apoptotic eat-me signals recognized by CD14+ phagocytes. Exofacial PIPs on the surfaces of early and late-apoptotic cells were observed in patches and blebs using anti-PI(3,4,5)P3 antibody, AKT- and PLCδ PH-domains, and CD14 protein. Phagocytosis of apoptotic cells was blocked either by masking exofacial PIPs or by CD14 knockout in phagocytes. We further confirmed that exofacial PIP+ thymocytes increased dramatically after in vivo irradiation and that exofacial PIP+ cells represented more significant populations in tissues of Cd14-/- than WT mice, especially after induction of apoptosis. Our findings reveal exofacial PIPs to be previously unknown cell death signals recognized by CD14+ phagocytes.
Asunto(s)
Fagocitosis , Transducción de Señal , Animales , Apoptosis/fisiología , Ratones , Fagocitos/metabolismo , Fagocitosis/fisiología , Fosfatidilserinas/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Angiotensin receptor neprilysin inhibitor (ARNI) treatment reduces functional mitral regurgitation (MR) to a greater extent than angiotensin receptor blocker (ARB) treatment alone, but the mechanism is unclear. We evaluated the mechanisms of how ARNI has an effect on functional MR. After inducing functional MR by left circumflex coronary artery occlusion, male Sprague Dawley rats (n = 31) were randomly assigned to receive the ARNI LCZ696, the ARB valsartan, or corn oil only (MR control). Excised mitral leaflets and left ventricle (LV) were analyzed, and valvular endothelial cells were evaluated focusing on molecular changes. LCZ696 significantly attenuated LV dilatation after 6 weeks when compared with the control group (LV end-diastolic volume, 461.3 ± 13.8 µL versus 525.1 ± 23.6 µL; p < 0.05), while valsartan did not (471.2 ± 8.9 µL; p > 0.05 to control). Histopathological analysis of mitral leaflets showed that LCZ696 strongly reduced fibrotic thickness compared to the control group (28.2 ± 2.7 µm vs. 48.8 ± 7.5 µm; p < 0.05). Transforming growth factor-ß and downstream phosphorylated extracellular-signal regulated kinase were also significantly lower in the LCZ696 group. Consequently, excessive endothelial-to-mesenchymal transition (EndoMT) was mitigated in the LCZ696 group compared to the control group and leaflet area was higher (11%) in the LCZ696 group than in the valsartan group. Finally, the MR extent was significantly lower in the LCZ696 group and functional improvement was observed. In conclusion, neprilysin inhibitor has positive effects on LV reverse remodeling and also attenuates fibrosis in MV leaflets and restores adaptive growth by directly modulating EndoMT.
Asunto(s)
Aminobutiratos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Insuficiencia de la Válvula Mitral/tratamiento farmacológico , Infarto del Miocardio/tratamiento farmacológico , Valsartán/uso terapéutico , Aminobutiratos/farmacología , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Animales , Compuestos de Bifenilo/farmacología , Células Cultivadas , Combinación de Medicamentos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Válvula Mitral/efectos de los fármacos , Válvula Mitral/patología , Válvula Mitral/fisiología , Insuficiencia de la Válvula Mitral/diagnóstico , Insuficiencia de la Válvula Mitral/etiología , Insuficiencia de la Válvula Mitral/fisiopatología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/complicaciones , Daño por Reperfusión Miocárdica/diagnóstico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/fisiopatología , Neprilisina/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Valsartán/farmacología , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency. METHODS: En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)-/- and ApoE-/-FXR-/- mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice. RESULTS: Compared with ApoE-/- mice, ApoE-/-FXR-/- mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE-/-FXR-/- mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver). CONCLUSION: Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, ß-oxidation, and triglyceride hydrolysis.
Asunto(s)
Aterosclerosis , Enfermedad del Hígado Graso no Alcohólico , Animales , Apolipoproteínas E/genética , Ratones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Receptores Activados del Proliferador del PeroxisomaRESUMEN
Atherosclerosis is a chronic inflammatory disease caused by lipids and calcareous accumulations in the vascular wall due to an inflammatory reaction. Recent reports have demonstrated that regulatory T (Treg) cells have an important role as a new treatment for atherosclerosis. This study suggests that bee venom phospholipase A2 (bvPLA2) may be a potential therapeutic agent in atherosclerosis by inducing Treg cells. We examined the effects of bvPLA2 on atherosclerosis using ApoE-/- and ApoE-/-/Foxp3DTR mice. In this study, bvPLA2 increased Treg cells, followed by a decrease in lipid accumulation in the aorta and aortic valve and the formation of foam cells. Importantly, the effect of bvPLA2 was found to depend on Treg cells. This study suggests that bvPLA2 can be a potential therapeutic agent for atherosclerosis.
Asunto(s)
Aorta/efectos de los fármacos , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Venenos de Abeja/enzimología , Proteínas de Insectos/farmacología , Fosfolipasas A2/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Animales , Aorta/inmunología , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Citocinas/metabolismo , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteínas de Insectos/aislamiento & purificación , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Fosfolipasas A2/aislamiento & purificación , Placa Aterosclerótica , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
We present data showing that Iodotyrosine Deiodinase (IYD) is a dual-function enzyme acting as a catalyst in metabolism and a receptor for cooperative stem cell differentiation. IYD is present both in thyroid cells where it is critical for scavenging iodine from halogenated by-products of thyroid hormone production and on hematopoietic stem cells. To close the cooperative loop, the mono- and di-Iodotyrosine (MIT and DIT) substrates of IYD in the thyroid are also agonists for IYD now acting as a receptor on bone marrow stem cells. While studying intracellular combinatorial antibody libraries, we discovered an agonist antibody, H3 Ab, of which the target is the enzyme IYD. When agonized by H3 Ab, IYD expressed on stem cells induces differentiation of the cells into brown adipocyte-like cells, which selectively migrate to mouse heart tissue. H3 Ab also binds to IYD expressed on human myocardium. Thus, one has a single enzyme acting in different ways on different cells for the cooperative purpose of enhancing thermogenesis or of regenerating damaged heart tissue.
Asunto(s)
Adipocitos Marrones/citología , Anticuerpos/farmacología , Movimiento Celular , Miocardio/citología , Células Madre/citología , Adipocitos Marrones/efectos de los fármacos , Adipocitos Marrones/ultraestructura , Animales , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Miocardio/ultraestructura , Células Madre/efectos de los fármacosRESUMEN
Menopause is associated with a decrease in the level of sex hormones such as ovarian estradiol and progesterone and can cause various symptoms such as depression, hot flash, fatigue, heart palpitations, and headache. Furthermore, there is a risk of developing complications such as osteoporosis, cardiovascular diseases, Alzheimer's disease, and ovarian cancer. Schisandrae Fructus (SF) is widely used in Korean medicine as a cure for such complications. This study was conducted to evaluate the therapeutic effects of SF against menopause symptoms associated with follicle depletion caused by the industrial chemical 4-vinylcyclohexene diepoxide (VCD) in mice. VCD directly targets the preantral follicles. Mice were injected with VCD (160 mg/kg intraperitoneally) daily for 15 days and then with SF dosage 3 times/week for six weeks. To evaluate the effects of SF, body weight, tail skin temperature, uterine weight, lipid profile, and osteocalcin levels were measured. A decrease in body weight and tail skin temperature and an increase in uterine weight were observed upon SF treatment. Moreover, SF treatment significantly decreased total cholesterol, triglyceride, osteocalcin, and low-density lipoprotein levels and low-density/high-density lipoprotein ratio. These results suggest the potential use of SF in the treatment of menopausal symptoms in women.
RESUMEN
Alzheimer's disease patients display neuropathological lesions, including the accumulation of amyloid-beta (Aß) peptide and neurofibrillary tangles. Although the mechanisms causing the neurodegenerative process are largely unknown, increasing evidence highlights a critical role of immunity in the pathogenesis of Alzheimer's disease. In the present study, we investigated the role of regulatory T cells (Tregs) on Alzheimer's disease progression. First, we explored the effect of Tregs (CD4+CD25+ T cells) and Teffs (CD4+CD25- T cells) in an adoptive transfer model. Systemic transplantation of purified Tregs into 3xTg-AD mice improved cognitive function and reduced deposition of Aß plaques. In contrast, adoptive transfer of Teffs diminished behavioral function and cytokine production. Next, we transiently depleted Treg population using an anti-CD25 antibody (PC61). Depletion of Tregs for four months resulted in a marked aggravation of the spatial learning deficits of six-month-old 3xTg-AD mice. Additionally, it resulted in decreasing glucose metabolism, as assessed by positron emission tomography (PET) with 18F-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) neuroimaging. Importantly, the deposition of Aß plaques and microglia/macrophage was increased in the hippocampal CA1 and CA3 regions of the Treg depleted 3xTg-AD compared to the vehicle-treated 3xTg-AD group. Our finding suggested that systemic Treg administration ameliorates disease progression and could be an effective Alzheimer's disease treatment.
Asunto(s)
Traslado Adoptivo/métodos , Enfermedad de Alzheimer/terapia , Modelos Animales de Enfermedad , Linfocitos T Reguladores/trasplante , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Factores de Transcripción Forkhead/metabolismo , Glucosa/metabolismo , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Hipocampo/fisiopatología , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Discapacidades para el Aprendizaje/genética , Discapacidades para el Aprendizaje/metabolismo , Discapacidades para el Aprendizaje/terapia , Masculino , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/terapia , Ratones Endogámicos C57BL , Ratones Transgénicos , Tomografía de Emisión de Positrones/métodos , Linfocitos T Reguladores/metabolismoRESUMEN
Thyroid-stimulating hormone (TSH) receptor is expressed in extrathyroidal tissues such as hepatocytes, adipocytes, and skeletal muscle, which suggests a possible novel role of TSH in various metabolic processes in extrathyroidal tissues independent of thyroid hormones. We investigated whether TSH has any effects on glucose tolerance and insulin sensitivity in the skeletal muscle using diet-induced obesity (DIO) mouse models and rodent skeletal muscle cells. TSH improved glucose tolerance in DIO mice and this was associated with an improvement of skeletal muscle insulin sensitivity resulting from the increased expression of insulin receptor substrate (IRS)-1 protein and mRNA therein. TSH significantly increased both basal and insulin-stimulated glucose transport in rat L6 myotubes and increased the expression of IRS-1 protein and mRNA in these cells as well. TSH also stimulated Irs1 promoter activation; this stimulation was abolished by protein kinase A (PKA) inhibition using H89 or by mutation of the cAMP-response element site located at -1155 to -875 bp of the Irs1 promoter region, supporting a novel role of TSH activated-cAMP/PKA/CREB signaling in the regulation of Irs1 expression. In conclusion, TSH improves insulin sensitivity in skeletal muscle by increasing Irs1 gene expression. This regulatory effect is mediated by a PKA-CREB-dependent pathway.
Asunto(s)
Proteínas Sustrato del Receptor de Insulina/genética , Resistencia a la Insulina , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Transducción de Señal/efectos de los fármacos , Tirotropina/farmacología , Regulación hacia Arriba/efectos de los fármacos , Animales , Secuencia de Bases , Transporte Biológico/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Dieta Alta en Grasa , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/genética , RatasRESUMEN
Previously, we found that Foxp3-expressing CD4(+) regulatory T (Treg) cells attenuate cisplatin-induced acute kidney injury in mice and that bee venom and its constituent phospholipase A2 (PLA2) are capable of modulating Treg cells. Here we tested whether PLA2 could inhibit cisplatin-induced acute kidney injury. As a result of treatment with PLA2, the population of Treg cells was significantly increased, both in vivo and in vitro. PLA2-injected mice showed reduced levels of serum creatinine, blood urea nitrogen, renal tissue damage, and pro-inflammatory cytokine production upon cisplatin administration. These renoprotective effects were abolished by depletion of Treg cells. Furthermore, PLA2 bound to CD206 mannose receptors on dendritic cells, essential for the PLA2-mediated protective effects on renal dysfunction. Interestingly, PLA2 treatment increased the secretion of IL-10 in the kidney from normal mice. Foxp3(+)IL-10(+) cells and CD11c(+)IL-10(+) cells were increased by PLA2 treatment. The anticancer effects of repeated administrations of a low dose of cisplatin were not affected by PLA2 treatment in a tumor-bearing model. Thus, PLA2 may prevent inflammatory responses in cisplatin-induced acute kidney injury by modulating Treg cells and IL-10 through the CD206 mannose receptor.
Asunto(s)
Lesión Renal Aguda/prevención & control , Antiinflamatorios/farmacología , Antineoplásicos , Cisplatino , Riñón/efectos de los fármacos , Lectinas Tipo C/metabolismo , Activación de Linfocitos/efectos de los fármacos , Lectinas de Unión a Manosa/metabolismo , Fosfolipasas A2/farmacología , Receptores de Superficie Celular/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/enzimología , Lesión Renal Aguda/genética , Lesión Renal Aguda/inmunología , Lesión Renal Aguda/patología , Animales , Células Cultivadas , Citoprotección , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Mediadores de Inflamación/metabolismo , Interleucina-10/deficiencia , Interleucina-10/genética , Riñón/enzimología , Riñón/inmunología , Riñón/patología , Lectinas Tipo C/deficiencia , Lectinas Tipo C/genética , Linfoma/tratamiento farmacológico , Linfoma/patología , Masculino , Receptor de Manosa , Lectinas de Unión a Manosa/deficiencia , Lectinas de Unión a Manosa/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Transducción de Señal/efectos de los fármacos , Linfocitos T Reguladores/enzimología , Linfocitos T Reguladores/inmunología , Factores de TiempoRESUMEN
Bee venom (BV) is one of the alternative medicines that have been widely used in the treatment of chronic inflammatory diseases. We previously demonstrated that BV induces immune tolerance by increasing the population of regulatory T cells (Tregs) in immune disorders. However, the major component and how it regulates the immune response have not been elucidated. We investigated whether bee venom phospholipase A2 (bvPLA2) exerts protective effects that are mediated via Tregs in OVA-induced asthma model. bvPLA2 was administered by intraperitoneal injection into control and OVA-challenged mice. The Treg population, total and differential bronchoalveolar lavage fluid (BALF) cell count, Th2 cytokines, and lung histological features were assessed. Treg depletion was used to determine the involvement of Treg migration and the reduction of asthmatic symptoms. The CD206-dependence of bvPLA2-treated suppression of airway inflammation was evaluated in OVA-challenged CD206(-/-) mice. The bvPLA2 treatment induced the Tregs and reduced the infiltration of inflammatory cells into the lung in the OVA-challenged mice. Th2 cytokines in the bronchoalveolar lavage fluid (BALF) were reduced in bvPLA2-treated mice. Although bvPLA2 suppressed the number of inflammatory cells after OVA challenge, these effects were not observed in Treg-depleted mice. In addition, we investigated the involvement of CD206 in bvPLA2-mediated immune tolerance in OVA-induced asthma model. We observed a significant reduction in the levels of Th2 cytokines and inflammatory cells in the BALF of bvPLA2-treated OVA-induced mice but not in bvPLA2-treated OVA-induced CD206(-/-) mice. These results demonstrated that bvPLA2 can mitigate airway inflammation by the induction of Tregs in an OVA-induced asthma model.
RESUMEN
In epidemiological studies, there is growing concern regarding the association between human exposure to bisphenol A (BPA) and an increased risk for cardiovascular disease. Therefore, we investigated whether BPA accelerates atherosclerosis in mouse model. Apolipoprotein E knockout (ApoE(-/-)) mice were fed a high-fat and high-cholesterol diet with or without 50 µg/kg body weight/day BPA for 12 weeks. Atherosclerotic lesions of the aorta and aortic sinus were evaluated by Oil red O staining. After the 12-week BPA treatment, BPA significantly increased atherosclerotic lesions in the aortas of ApoE(-/-) mice by 1.7-fold (p = 0.03). Non-high-density lipoprotein (HDL) cholesterol levels in the BPA group were significantly higher compared to those in the control group (1,035 ± 70 vs. 484 ± 48 mg/dL, p = 0.02) although body weight and blood glucose levels were not different between groups. Human umbilical vein endothelial cells (HUVECs) were treated with 0.1-10 nM BPA but BPA did not affect HUVEC proliferation or migration. BPA could accelerate atherosclerosis in ApoE(-/-) mice, which may have resulted from an increase in non-HDL cholesterol levels.
Asunto(s)
Aorta/efectos de los fármacos , Enfermedades de la Aorta/inducido químicamente , Apolipoproteínas E/deficiencia , Aterosclerosis/inducido químicamente , Compuestos de Bencidrilo/toxicidad , Colesterol en la Dieta , Dieta Alta en Grasa , Contaminantes Ambientales/toxicidad , Fenoles/toxicidad , Animales , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Apolipoproteínas E/genética , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Biomarcadores/sangre , Células Cultivadas , Colesterol en la Dieta/sangre , Modelos Animales de Enfermedad , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Masculino , Ratones Noqueados , Factores de Riesgo , Factores de Tiempo , Regulación hacia ArribaRESUMEN
The applicability of the in vivo proton magnetic resonance spectroscopy hepatic lipid profiling (MR-HLP) technique in nonalcoholic fatty liver disease was investigated. Using magnetic resonance spectroscopy, the relative fractions of diunsaturated (fdi), monounsaturated (fmono), and saturated (fsat) fatty acids as well as total hepatic lipid content were estimated in the livers of 8 control and 23 CCl4-treated rats at 9.4 T. The mean steatosis, necrosis, inflammation, and fibrosis scores of the treated group were all significantly higher than those of the control group (P < 0.01). There was a strong correlation between the histopathologic parameters and the MR-HLP parameters (r = 0.775, P < 0.01) where both steatosis and fibrosis are positively correlated with fmono and negatively correlated with fdi. Both necrosis and inflammation, however, were not correlated with any of the MR-HLP parameters. Hepatic lipid composition appears to be changed in association with the severity of steatosis and fibrosis in nonalcoholic fatty liver disease, and these changes can be depicted in vivo by using the MR-HLP method at 9.4 T. Thus, while it may not likely be that MR-HLP helps differentiate between steatohepatitis in its early stages and simple steatosis, these findings altogether are in support of potential applicability of in vivo MR-HLP at high field in nonalcoholic fatty liver disease.