RESUMO
BACKGROUND: Inflammation is an underlying mechanism for the development of obesity-related health complications. Yogurt consumption inhibits obesity-associated inflammation, but the tissue-specific mechanisms have not been adequately described. OBJECTIVES: We aimed to determine the tissue-specific responses by which yogurt supplementation inhibits inflammation. METHODS: C57BL/6 male mice (5 wk old) were fed a Teklad Global 14% Protein Rodent Maintenance diet as a control or a high-fat diet (60% calories from fat) to induce obesity for 11 wk, followed by feeding a Western diet (WD; 43% carbohydrate and 42% fat) or WD supplemented with 5.6% lyophilized yogurt powder for 3 wk to test for the impact of yogurt supplementation. Markers of metabolic endotoxemia and inflammation were assessed in plasma and tissues. Cecal and fecal microbiota were profiled by 16S rRNA sequencing. RESULTS: In obese mice, relative to the WD control group, yogurt supplementation attenuated HOMA-IR by 57% (P = 0.020), plasma TNF-α by 31% (P < 0.05) and colonic IFN-γ by 46% (P = 0.0034), which were accompanied by a 40% reduction in plasma LPS binding protein (LBP) (P = 0.0019) and 45% less colonic Lbp expression (P = 0.037), as well as alteration in the beta diversity of cecal microbiota (P = 0.0090) and relative abundance of certain cecal microbes (e.g., Lachnospiraceae Dorea longicatena with P = 0.049). There were no differences in the LBP, Lbp, and Cd14 levels in the liver and small intestine between obese mice with and without yogurt supplementation (P > 0.05). CONCLUSIONS: Yogurt consumption inhibits obesity-induced inflammation in mice by modulating colonic endotoxin detoxification, changing the gut microbiota, and improving glucose metabolism. This work helps to establish the underlying mechanisms by which yogurt consumption affects markers of metabolic and immune health.
Assuntos
Endotoxemia , Resistência à Insulina , Masculino , Camundongos , Animais , Endotoxemia/prevenção & controle , Camundongos Obesos , Iogurte , RNA Ribossômico 16S , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Inflamação , Dieta Hiperlipídica , Suplementos NutricionaisRESUMO
BACKGROUND: Sphingosine kinase (SphK) 1 has been reported as an important signaling node in anti-apoptotic signaling. Heparin is a pleiotropic drug that antagonizes many pathophysiological mechanisms. In this study, we evaluated if heparin prevents early brain injury (EBI) after subarachnoid hemorrhage (SAH) by anti-apoptotic mechanisms including SphK1. METHODS: SAH was induced by endovascular perforation in mice, which were randomly assigned to sham-operated (n = 23), SAH + vehicle (n = 36), SAH + 10U heparin pretreatment (n = 13), SAH + 30U heparin pretreatment (n = 15), SAH + 10U heparin posttreatment (n = 31), and SAH + 30U heparin posttreatment (n = 23). At 24 hours post-SAH, neurological scores, brain water content and Evans blue extravasation were evaluated. Also, the expression of SphK, phosphorylated Akt, and cleaved caspase-3 was determined by Western blotting, and cell death was examined by terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling staining. RESULTS: Low-dose heparin posttreatment improved neurobehavioral function, brain edema, blood-brain barrier disruption and cell death in the cortex, associated with an increase in SphK1 and phosphorylated Akt, and a decrease in cleaved caspase-3. High-dose heparin had a tendency for increased SAH severity, which obscured the neuroprotective effects by heparin. CONCLUSIONS: Low-dose heparin posttreatment may decrease the development of post-SAH EBI through anti-apoptotic mechanisms including sphingosine-related pathway activation.
Assuntos
Edema Encefálico/tratamento farmacológico , Lesões Encefálicas/tratamento farmacológico , Heparina/farmacologia , Esfingosina/farmacologia , Hemorragia Subaracnóidea/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Lesões Encefálicas/fisiopatologia , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
The poor prognosis of subarachnoid hemorrhage (SAH) might be associated with sympathetic nerve activation (catecholamine surge) initiated by hypothalamic injury. As renal denervation (RD) has been shown to exert protective effects on cardiovascular dysfunction by suppressing increased central sympathetic nerve activation, we examined whether RD improved the experimental SAH prognosis in this study. Two hundred thirty-eight male Sprague-Dawley rats were divided into sham-operated and SAH-operated groups, and then each rat was further separated into Sham-operated and RD-operated groups. Bilateral RD was performed approximately 45 min after SAH induction. We examined the effect of RD on early brain injury (EBI) and delayed cerebral ischemia (DCI) as a primary endpoint, and also explored the effect on cerebral vasospasm (CVS) as a secondary endpoint. Although RD did not exert significant effects on primary endpoint, RD significantly prevented CVS and reduced SAH-induced increases in the number of phosphorylated extracellular signal-regulated kinase (ERK)-positive endothelial cells, cyclooxygenase-2 expression, and macrophage infiltration in major cerebral arteries. Moreover, RD significantly decreased the areas displaying dopamine ß-hydroxylase and glial fibrillary acidic protein immunopositivity in the paraventricular nucleus of the hypothalamus and serum angiotensin II levels, all of which were increased by SAH. Although RD decreased systolic blood pressure, significant changes in cerebral blood flow were not observed compared with SAH + Sham group. Based on the findings, RD improved CVS by reducing endothelial cell damage and the effects were associated with the stabilization of central sympathetic nerve activation in a SAH model.
Assuntos
Rim/inervação , Hemorragia Subaracnóidea/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Vasoespasmo Intracraniano/fisiopatologia , Animais , Astrócitos/fisiologia , Denervação , Hipotálamo/fisiopatologia , Rim/irrigação sanguínea , Masculino , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/complicações , Vasoespasmo Intracraniano/etiologiaRESUMO
BACKGROUND: LCZ696, an angiotensin receptor-neprilysin inhibitor, has recently been demonstrated to exert more beneficial effects on hypertensive or heart failure patients than conventional renin-angiotensin system blockers. However, the mechanism underlying the benefit of LCZ696 remains to be understood. The present study was undertaken to examine the effect of LCZ696 compared with valsartan on hypertension and cardiovascular injury. METHODS: (i) Using telemetry, we compared the hypotensive effect of LCZ696 and valsartan in spontaneously hypertensive rats (SHR) that were fed a high-salt diet followed by a low-salt diet. (ii) We also examined the comparative effect of LCZ696 and valsartan on salt loaded SHRcp, a model of metabolic syndrome. RESULTS: (i) LCZ696 exerted a greater blood pressure (BP) lowering effect than valsartan in SHR regardless of high-salt or low-salt intake. Additive BP reduction by LCZ696 was associated with a significant increase in urinary sodium excretion and sympathetic activity suppression. (ii) LCZ696 significantly ameliorated cardiac hypertrophy and inflammation, coronary arterial remodeling, and vascular endothelial dysfunction in high-salt loaded SHRcp compared with valsartan. CONCLUSIONS: LCZ696 caused greater BP reduction than valsartan in SHR regardless of the degree of salt intake, which was associated with a significant enhancement in urinary sodium excretion and sympathetic activity suppression. Furthermore, an additive BP lowering effect of LCZ696 led to greater cardiovascular protection in hypertensive rats.
Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Tetrazóis/uso terapêutico , Valsartana/uso terapêutico , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Ritmo Circadiano/efeitos dos fármacos , GMP Cíclico/sangue , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Endotélio Vascular/efeitos dos fármacos , Fibrose/tratamento farmacológico , Coração/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/etiologia , Inflamação/tratamento farmacológico , Masculino , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Distribuição Aleatória , Ratos Endogâmicos SHR , Sódio na Dieta/efeitos adversos , Sódio na Dieta/urina , Tetrazóis/farmacologia , Valsartana/farmacologia , Remodelação Vascular/efeitos dos fármacosRESUMO
OBJECTIVE: Elderly hypertensive patients are characterized by blood pressure (BP) variability, impaired autonomic function, and vascular endothelial dysfunction and stiffness. However, the mechanisms causing these conditions are unclear. The present study examined the effect of angiotensin receptor blockers (ARBs) on aged spontaneously hypertensive rats (SHR). METHODS: We surgically implanted telemetry devices in SHR and WKY at the age of 15 weeks (Young) and 80 weeks (Aged). Aged SHR were orally administered either olmesartan or valsartan once daily at 19:00 h (at the beginning of the dark period (active phase)) for 4 weeks to examine the effects on BP variability, impaired autonomic function, and vascular senescence. RESULTS: Aging and hypertension in SHR additively caused the following: increased low frequency (LF) power of systolic BP, a decreased spontaneous baroreceptor reflex gain (sBRG), increased BP variability, increased urinary norepinephrine excretion, increased vascular senescence-related beta-galactosidase positive cells and oxidative stress. Treatment with olmesartan or valsartan significantly ameliorated these changes in aged SHR. However, olmesartan ameliorated these changes in aged SHR better than valsartan. The reductions in BP caused by olmesartan in aged SHR were sustained longer than reductions by valsartan. This result indicates longer-lasting inhibition of the AT1 receptor by olmesartan than by valsartan. CONCLUSION: ARBs ameliorated autonomic dysfunction, BP variability, and vascular senescence in aged SHR. Olmesartan ameliorated the aging-related disorders better than valsartan and was associated with longer-lasting AT1 receptor inhibition by olmesartan. Thus, the magnitude of improvement of these aging-related abnormalities differs for ARBs.
Assuntos
Envelhecimento/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Sistema Nervoso Autônomo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Imidazóis/uso terapêutico , Sistema Renina-Angiotensina/efeitos dos fármacos , Tetrazóis/uso terapêutico , Valina/análogos & derivados , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/química , Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Avaliação Pré-Clínica de Medicamentos , Endotélio Vascular/fisiopatologia , Hipertensão/genética , Hipertensão/fisiopatologia , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Miocárdio/patologia , NADPH Oxidases/análise , NG-Nitroarginina Metil Éster/farmacologia , Norepinefrina/urina , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Reflexo Anormal/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Tetrazóis/administração & dosagem , Tetrazóis/farmacologia , Valina/administração & dosagem , Valina/farmacologia , Valina/uso terapêutico , Valsartana , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , beta-Galactosidase/análiseRESUMO
T-lymphocytes promote cerebral inflammation, thus aggravating neuronal injury after stroke. Fingolimod, a sphingosine 1-phosphate receptor analog, prevents the egress of lymphocytes from primary and secondary lymphoid organs. Based on these findings, we hypothesized fingolimod treatment would reduce the number of T-lymphocytes migrating into the brain, thereby ameliorating cerebral inflammation following experimental intracerebral hemorrhage (ICH). We investigated the effects of fingolimod in two well-established murine models of ICH, implementing intrastriatal infusions of either bacterial collagenase (cICH) or autologous blood (bICH). Furthermore, we tested the long term neurological improvements by Fingolimod in a collagenase-induced rat model of ICH. Fingolimod, in contrast to vehicle administration alone, improved neurological functions and reduced brain edema at 24 and 72 h following experimental ICH in CD-1 mice (n=103; p<0.05). Significantly fewer lymphocytes were found in blood and brain samples of treated animals when compared to the vehicle group (p<0.05). Moreover, fingolimod treatment significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (INF-γ), and interleukin-17 (IL-17) in the mouse brain at 72 h post-cICH (p<0.05 compared to vehicle). Long-term neurocognitive performance and histopathological analysis were evaluated in Sprague-Dawley rats between 8 and 10 weeks post-cICH (n=28). Treated rats showed reduced spatial and motor learning deficits, along with significantly reduced brain atrophy and neuronal cell loss within the basal ganglia (p<0.05 compared to vehicle). We conclude that fingolimod treatment ameliorated cerebral inflammation, at least to some extent, by reducing the availability and subsequent brain infiltration of T-lymphocytes, which improved the short and long-term sequelae after experimental ICH in rodents.
Assuntos
Córtex Cerebral/patologia , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/patologia , Imunossupressores/uso terapêutico , Linfócitos/efeitos dos fármacos , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , Análise de Variância , Animais , Gânglios da Base/patologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Transfusão de Sangue Autóloga/efeitos adversos , Edema Encefálico/etiologia , Edema Encefálico/prevenção & controle , Complexo CD3/metabolismo , Contagem de Células , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/complicações , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/imunologia , Colagenases/toxicidade , Modelos Animais de Doenças , Cloridrato de Fingolimode , Membro Anterior/fisiopatologia , Lateralidade Funcional/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/metabolismo , Interferon gama/metabolismo , Interleucina-17/metabolismo , Leucócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/prevenção & controle , Propilenoglicóis/farmacologia , Transtornos Psicomotores/tratamento farmacológico , Transtornos Psicomotores/etiologia , Ratos , Ratos Sprague-Dawley , Percepção Espacial/efeitos dos fármacos , Esfingosina/farmacologia , Esfingosina/uso terapêutico , Fatores de TempoRESUMO
From Iris delavayi collected in the northwestern Yunnan Province of China, eight iridal-type triterpenoids were isolated, three of which were new. Both 2(7)Z- and 2(7)E-iridals were isolated in about equal amounts from the sample collected at Laojunshan, while only 2(7)Z-iridals were isolated from samples collected in Shangrila area, indicating the presence of chemical diversity in the species.