RESUMEN
Progressive diabetic nephropathy (DN) in diabetes leads to major morbidity and mortality. The major pathological alterations of DN include mesangial expansion, extracellular matrix alterations, tubulointerstitial fibrosis, and glomerular sclerosis. Polygoni avicularis is widely used in traditional oriental medicine and has long been used as a diuretic, astringent, insecticide and antihypertensive. However, to the best of the authors' knowledge, the effects of the ethanolic extract from rhizome of Polygoni avicularis (ER-PA) on DN have not yet been assessed. The present study aimed to identify the effect of ER-PA on renal dysfunction, which has been implicated in DN in human renal mesangial cells and db/db mice and investigate its mechanism of action. The in vivo experiment was performed using Polygoni avicularis-ethanol soluble fraction (ER-PA) and was administrated to db/db mice at 10 and 50 mg/kg dose. For the in vitro experiments, the human renal mesangial cells were induced by high glucose (HG, 25 mM). The ER-PA group showed significant amelioration in oral glucose tolerance, and insulin resistance index. ER-PA significantly improved the albumin excretion and markedly reduced plasma creatinine, kidney injury molecule-1 and C-reactive protein. In addition, ER-PA significantly suppressed inflammatory cytokines. Histopathologically, ER-PA attenuated glomerular expansion and tubular fibrosis in db/db mice. Furthermore, ER-PA suppressed the expression of renal fibrosis biomarkers (TGF and Collagen IV). ER-PA also reduced the NLR family pyrin domain containing 3 inflammatory factor level. These results suggest that ER-PA has a protective effect against renal dysfunction through improved insulin resistance as well as the inhibition of nephritis and fibrosis in DN.
Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Fitoterapia , Polygonum/química , Animales , Células Cultivadas , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Fibrosis , Glucosa/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Resistencia a la Insulina , Masculino , Proteínas de la Membrana/metabolismo , Células Mesangiales/efectos de los fármacos , Células Mesangiales/metabolismo , Células Mesangiales/patología , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/química , Extractos Vegetales/farmacología , Rizoma/químicaRESUMEN
Abnormal and excessive growth of mesangial cells is important in the pathophysiologic processes of diabetes-associated interstitial fibrosis and glomerulosclerosis, leading to diabetic nephropathy, which eventually turns into end-stage renal disease. Sauchinone, a biologically-active lignan isolated from aerial parts of Saururus chinensis, has anti-inflammatory and anti-viral activities effects on various cell types. However, there are no studies reporting the effects of sauchinone on diabetic nephropathy. The present study aims to investigate the role of sauchinone in mesangial cell proliferation and fibrosis induced by angiotensin II, as well as the underlying mechanisms of these processes. Human renal mesangial cells were induced by angiotensin II (AngII, 10⯵M) in the presence or absence of sauchinone (0.1-1⯵M) and incubated for 48â¯h. In this study, we found that AngII induced mesangial cell proliferation, while treatment with sauchinone inhibited the cell proliferation in a dose-dependent manner. Pre-treatment with sauchinone induced down-regulation of cyclins/CDKs and up-regulation of CDK inhibitor, p21, and p27kip1 expression. In addition, AngII-enhanced expression of fibrosis biomarkers such as fibronectin, collagen IV, and connective tissue growth factor (CTGF), which was markedly attenuated by sauchinone. Sauchinone also decreased AngII-induced TGF-ß1 and Smad-2, Smad-3, and Smad-4 expression. This study further revealed that sauchinone ameliorated AngII-induced mesangial inflammation through disturbing activation of inflammatory factors, and NLRP3 inflammasome, which is composed of the NLRP3 protein, procaspase-1, and apoptosis-associated speck-like protein containing a CARD (ASC). Moreover, pretreatment of sauchinone inhibited NF-κB translocation and ROS production in AngII-exposed mesangial cells. These data suggest that sauchinone has a protective effect on renal proliferation, fibrosis and inflammation. Therefore, sauchinone might be a potential pharmacological agent in prevention of AngII-induced renal damage leading to diabetic nephropathy.
Asunto(s)
Benzopiranos/farmacología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Dioxoles/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Células Mesangiales/metabolismo , Angiotensina II/efectos adversos , Angiotensina II/farmacología , Línea Celular , Nefropatías Diabéticas/patología , Fibrosis , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Células Mesangiales/patologíaRESUMEN
Heme oxygenase (HO)-1 is a detoxifying phase II enzyme that plays a role in both inflammatory and oxidative stress responses. Curdrania tricuspidata is widespread throughout East Asia and is used as a therapeutic agent in traditional medicine. We investigated whether treatment with sixteen flavonoid or xanthone compounds from C. tricuspidata could induce HO-1 expression in HT22 hippocampal cells, RAW264.7 macrophage, and BV2 microglia. In these compounds, kuwanon C showed the most remarkable HO-1 expression effects. In addition, treatment with kuwanon C reduced cytoplasmic nuclear erythroid 2-related factor (Nrf2) expression and increased Nrf2 expression in the nucleus. Significant inhibition of glutamate-induced oxidative injury and induction of reactive oxygen species (ROS) occurred when HT22 hippocampal cells were pretreated with kuwanon C. The levels of inflammatory mediator and cytokine, which increased following lipopolysaccharide (LPS) stimulation, were suppressed in RAW264.7 macrophage and BV2 microglia after kuwanon C pretreatment. Kuwanon C also attenuated p65 DNA binding and translocation into the nucleus in LPS-induced RAW264.7 and BV2 cells. The anti-inflammatory, anti-neuroinflammatory, and neuroprotective effects of kuwanon C were reversed when co-treatment with HO-1 inhibitor of tin protoporphyrin-IX (SnPP). These results suggest that the neuroprotective and anti-inflammatory effects of kuwanon C are regulated by HO-1 expression.
Asunto(s)
Antiinflamatorios/farmacología , Derivados del Benceno/farmacología , Hemo-Oxigenasa 1/metabolismo , Hipocampo/efectos de los fármacos , Macrófagos/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Microglía/efectos de los fármacos , Moraceae/química , Fármacos Neuroprotectores/farmacología , Animales , Línea Celular , Citocinas/metabolismo , Flavonoides/farmacología , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/metabolismo , Ratones , Microglía/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neuroprotección/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Xantonas/farmacologíaRESUMEN
Cardiac hypertrophy is a major risk factor for heart failure and leads to cardiovascular morbidity and mortality. Doxorubicin (DOX) is regarded as one of the most potent anthracycline antibiotic agents; however, its clinical usage has some limitations because it has serious cardiotoxic side effects such as dilated cardiomyopathy and congestive heart failure. Betulinic acid (BA) is a pentacyclic-cyclic lupane-type triterpene that has been reported to have anti-bacterial, anti-inflammatory, anti-vascular neogenesis, and anti-fibrotic effects. However, there is no study about its direct effect on DOX induced cardiac hypertrophy and apoptosis. The present study aims to investigate the effect of BA on DOX-induced cardiomyocyte hypertrophy and apoptosis in vitro in H9c2 cells. The H9c2 cells were stimulated with DOX (1 µM) in the presence or absence of BA (0.1-1 µM) and incubated for 24 h. The results of the present study indicated that DOX induces the increase cell surface area and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (ß-MHC), and Myosin Light Chain-2 (MLC2) in H9c2 cells. However, the pathological hypertrophic responses were downregulated after BA treatment. Moreover, phosphorylation of JNK, ERK, and p38 in DOX treated H9c2 cells was blocked by BA. As a result of measuring the change in ROS generation using DCF-DA, BA significantly inhibited DOX-induced the production of intracellular reactive oxygen species (ROS) when BA was treated at a concentration of over 0.1 µM. DOX-induced activation of GATA-4 and calcineurin/NFAT-3 signaling pathway were remarkably improved by pre-treating of BA to H9c2 cells. In addition, BA treatment significantly reduced DOX-induced cell apoptosis and protein expression levels of Bax and cleaved caspase-3/-9, while the expression of Bcl-2 was increased by BA. Therefore, BA can be a potential treatment for cardiomyocyte hypertrophy and apoptosis that lead to sudden heart failure.
Asunto(s)
Calcineurina/metabolismo , Cardiomegalia/etiología , Cardiomegalia/metabolismo , Cardiotónicos/farmacología , Factor de Transcripción GATA4/metabolismo , Factores de Transcripción NFATC/metabolismo , Triterpenos Pentacíclicos/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Cardiomegalia/patología , Cardiomegalia/prevención & control , Cardiotónicos/uso terapéutico , Línea Celular , Doxorrubicina/efectos adversos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Triterpenos Pentacíclicos/uso terapéutico , Ratas , Especies Reactivas de Oxígeno/metabolismo , Ácido BetulínicoRESUMEN
Objective: The isochroman-type fungal metabolite 3,7-dimethyl-1,8-hydroxy-6-methoxyisochroman (DMHM) was isolated from the extracts of a marine-derived fungal strain of Penicillium sp. SF-6013. In this study, we investigated the effect of DMHM on inflammatory response. Materials and methods: Anti-inflammatory effects of DMHM were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells. We observed their anti-inflammatory effects by ELISA, qRT-PCR, and western blot analysis. Results: DMHM revealed that it suppressed the production of prostaglandin E2 (PGE2), nitric oxide (NO), cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS) in LPS-stimulated RAW264.7 and BV2 cells. Furthermore, DMHM decreased the mRNA expression of pro-inflammatory cytokines including interleukin (IL)-1ß and IL-6. Therefore, DMHM was further investigated to elucidate the mechanisms of its anti-inflammatory properties; the results indicated that its effect was mediated by the suppression of the nuclear factor (NF)-κB and c-Jun N-terminal kinase (JNK) MAPK pathways. Furthermore, the anti-inflammatory activity of DMHM correlated with its induction of heme oxygenase-1 (HO)-1 expression via activation of the nuclear factor erythroid 2-like 2 (Nrf2) pathway. Discussion and conclusions: Collectively, the results of this study suggest that DMHM inhibited several inflammatory pathways including the NF-κB and MAPK pathways, and induced Nrf2-mediated HO-1 expression, demonstrating its potential usefulness for treating inflammatory and neuroinflammatory diseases.
Asunto(s)
Antiinflamatorios/farmacología , Cromanos/farmacología , Hemo-Oxigenasa 1/inmunología , Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas de la Membrana/inmunología , Factor 2 Relacionado con NF-E2/inmunología , Animales , Antiinflamatorios/química , Cromanos/química , Ciclooxigenasa 2/inmunología , Dinoprostona/inmunología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Óxido Nítrico/inmunología , Penicillium/química , Células RAW 264.7RESUMEN
In the present study, the change in secretion of atrial natriuretic peptide (ANP) from the atria was defined in hypertension accompanied by ventricular hypertrophy and increased synthesis of ANP. To identify the change of the secretion and mechanisms involved, experiments were performed in isolated perfused beating atria from sham-operated normotensive and renovascular hypertensive rats. Expression of ANP, natriuretic peptide receptor (NPR)-C, components of the renin-angiotensin system, and muscarinic signaling pathway was measured in cardiac tissues. Basal levels of ANP secretion and acetylcholine (ACh)- and stretch-induced activation of ANP secretion were suppressed in the atria from hypertensive compared with normotensive rats. ACh increased ANP secretion via M2 muscarinic ACh receptor-ACh-sensitive K+ channel signaling. In hypertensive rats, ANP concentration increased in the left ventricle but decreased in the right ventricle. The atrial concentration of ANP was not changed in hypertensive compared with normotensive rats. ANP mRNA expression was accentuated in the left ventricle but suppressed in the other cardiac chambers in the hearts of hypertensive rats. NPR-C expression was inversely related to ANP mRNA levels. Angiotensin II type 1 receptor (AT1R) expression was accentuated in the cardiac chambers from hypertensive rats compared with normotensive rats, whereas angiotensin II type 2 receptor, M2 muscarinic receptor, and Kir3.4 channels were suppressed. AT1R blockade with losartan reversed the change observed in hypertensive rats. The present findings indicate that renovascular hypertension shifts the major site of ANP secretion and synthesis from the atria to the left ventricle through modulation of the expression of ANP, NPR-C, AT1R, and the M2 muscarinic signaling pathway. NEW & NOTEWORTHY Renovascular hypertension suppresses the atrial secretion of ANP and shifts the major site of the regulation of ANP secretion and synthesis from atria to the hypertrophied left ventricle possibly via modulation of the expression of ANP, natriuretic peptide receptor-C, angiotensin II subtype 1 receptor, and M2 muscarinic signaling pathway.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Atrios Cardíacos/metabolismo , Ventrículos Cardíacos/metabolismo , Hipertensión Renovascular/metabolismo , Animales , Factor Natriurético Atrial/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , Receptores Muscarínicos/genética , Receptores Muscarínicos/metabolismoRESUMEN
BACKGROUND: Metabolic syndrome such as dyslipidemia, hypertension, obesity, impaired glucose tolerance and fatty liver, can be caused by modification of diet by means of overconsumption of high fructose diet. This study was designed to investigate whether combination with Red ginseng and Polygoni Multiflori Radix (RGPM), widely used traditional herbal medicine, ameliorates on highfructose (HF) diet-induced metabolic syndrome. METHODS: SD rats were fed the 60% HF diet with/without rosiglitazone, and RGPM 100, 300 mg/kg/day, respectively. All groups received regular diet or HF diet, respectively, for 8 weeks. The last three groups treatment of rosiglitazone and RPGM orally for a period of 6 weeks. RESULTS: Chronic treatment with RGPM significantly decreased body weight, fat weight and adipocyte size. RGPM significantly prevented the development of the metabolic disturbances such as hypertension, hyperlipidemia and impaired glucose tolerance. RGPM also led to increase in high density lipoprotein level in the HF group. RGPM suppressed high-fructose diet induced vascular inflammation marker expression such as adhesion molecules and ET-1 in aorta as well as increasing of C-reactive protein (CRP) levels in plasma. Similarly, RGPM attenuated hepatic lipid accumulation by inhibition of monocyte chemoattractant protein-1 (MCP-1) expression. CONCLUSION: An administration of RGPM may be a beneficial therapy for the treatment of metabolic syndrome through the improvement of hypertension, obesity, hyperlipidemia, vascular inflammation and insulin resistance.
Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Fructosa/administración & dosificación , Síndrome Metabólico/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Panax , Fitoterapia , Polygonum , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Presión Sanguínea , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Proteína C-Reactiva/metabolismo , Quimiocina CCL2/sangre , Dieta/efectos adversos , Quimioterapia Combinada , Medicamentos Herbarios Chinos/farmacología , Fructosa/efectos adversos , Mediadores de Inflamación/metabolismo , Lipoproteínas HDL/sangre , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Ratas Sprague-DawleyRESUMEN
Cudrania tricuspidata Bureau (Moraceae) is an important source of traditional Korean and Chinese medicines used to treat neuritis and inflammation. Cudratricusxanthone A (1), a prenylated xanthone, isolated from C. tricuspidata, has a variety of biological and therapeutic activities. The goal of this study was to examine the effects of compound 1 on neuroinflammation and characterize its mechanism of action in lipopolysaccharide (LPS)-stimulated BV2 microglia. Cudratricusxanthone A (1) suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 enzymes and decreased the production of iNOS-derived nitric oxide and COX-2-derived prostaglandin E2 in LPS-stimulated mouse BV2 microglia. The compound also decreased tumor necrosis factor-α, interleukin (IL)-1ß, and IL-12 production; inhibited the phosphorylation and degradation of IκB-α; and blocked the nuclear translocation of p50 and p65 in mouse BV2 microglia induced by LPS. Cudratricusxanthone A (1) had inhibitory effects on nuclear factor kappa B DNA-binding activity. Additionally, it inhibited the p38 mitogen-activated protein kinase signaling pathway. Our data suggests that cudratricusxanthone A (1) may be a useful therapeutic agent in the treatment of neurodegenerative diseases caused by neuroinflammation.
Asunto(s)
Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Microglía/metabolismo , Moraceae/química , Subunidad p50 de NF-kappa B/metabolismo , Factor de Transcripción ReIA/metabolismo , Xantonas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Ratones , Microglía/patología , Xantonas/química , Xantonas/aislamiento & purificaciónRESUMEN
BACKGROUND: The pathological change of kidney in diabetic nephropathy is represented hypertrophy, inflammation, and renal fibrosis. Oryeongsan, traditional oriental herbal formula, is widely used for the treatment of nephrosis, dropsy, and uremia. This study was examined whether Oryeongsan attenuate high-glucose (HG)-promoted rat mesangial cell fibrosis and matrix accumulation, major features of diabetic glomerulosclerosis. METHODS: Oryeongsan was mixed traditional herbal medicine, Alisma orientale Juz, Polyporus umbellatus Fries, Atractylodes macrocephala Koidez, Poria cocos Wolf and Cinnamomum Cassia Presl (5:3:3:1). Renoprotective role in diabetic nephropathy of Oryeongsan was evaluated by [(3)H]-thymidine incorporation, Western blot, RT-qPCR and immunofluorescence microscopy assay. RESULTS: Rat mesangial cell proliferation induced by HG was significantly accelerated, which was inhibited by Oryeongsan in a dose dependent manner. HG enhanced expression of fibrosis biomarkers such as collagen IV and connective tissue growth factor (CTGF), which was markedly attenuated by Oryeongsan. Oryeongsan increased HG-inhibited membrane type-1 matrix metalloproteinase expression (MT1-MMP) and MMP-2 promotor activity, whereas suppressed HG-induced tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) expression. Moreover, Oryeongsan promoted extracellular matrix degradation through disturbing transforming growth factor ß (TGF-ß)-Smad signaling. This study further revealed that Oryeongsan ameliorated HG-induced mesangial inflammation accompanying induction of intracellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). Moreover, pretreatment of Oryeongsan inhibited NF-κB translocation in HG-exposed mesangial cell. CONCLUSION: These results demonstrate that Oryeongsan has protective effect against renal proliferation, fibrosis, and inflammation. Therefore Oryeongsan may be specific therapies targeting renal dysfunction leading to diabetic nephropathy.
Asunto(s)
Nefropatías Diabéticas/tratamiento farmacológico , Mesangio Glomerular/efectos de los fármacos , Glucosa/efectos adversos , Magnoliopsida , Células Mesangiales/efectos de los fármacos , Extractos Vegetales/uso terapéutico , Polyporaceae , Animales , Quimiocina CCL2/metabolismo , Nefropatías Diabéticas/inducido químicamente , Nefropatías Diabéticas/metabolismo , Fibrosis , Mesangio Glomerular/patología , Glucosa/administración & dosificación , Glucosa/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Metaloproteinasa 14 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Células Mesangiales/patología , FN-kappa B/metabolismo , Fitoterapia , Extractos Vegetales/farmacología , Ratas , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
A chemical investigation of the methanol extract from the roots of Cudrania tricuspidata resulted in the isolation of 16 compounds, including prenylated xanthones 1-9 and flavonoids 10-16. Their structures were identified by NMR spectroscopy and mass spectrometry and comparisons with published data. Compounds 1-9 and 13-16 significantly inhibited PTP1B activity in a dose dependent manner, with IC50 values ranging from 1.9-13.6 µM. Prenylated xanthones showed stronger PTP1B inhibitory effects than the flavonoids, suggesting that they may be promising targets for the future discovery of novel PTP1B inhibitors. Furthermore, kinetic analyses indicated that compounds 1 and 13 inhibited PTP1B in a noncompetitive manner; therefore, they may be potential lead compounds in the development of anti-obesity and -diabetic agents.
Asunto(s)
Moraceae/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Raíces de Plantas/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Catálisis/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Hidrólisis/efectos de los fármacos , Concentración 50 InhibidoraRESUMEN
BACKGROUND: Gal-geun-dang-gwi-tang (GGDGT), an herbal medicine, is used to treat hypertension, stroke, and other inflammatory disorders in the clinical setting. Recently, GGDGT was recognized by the Korea Institute of Oriental Medicine. This study aimed to evaluate the effects of GGDGT in a diabetic atherosclerosis model using apolipoprotein E knockout (ApoE-/-) mice fed a Western diet. METHODS: The mice were divided into four groups: control group, C57BL6J mice receiving a regular diet (RD); ApoE-/- group, ApoE-/- mice receiving a Western diet (WD); rosiglitazone group, ApoE-/- mice receiving rosiglitazone (WD + 10 mg · kg(-1) · day(-1)); GGDGT group, ApoE-/- mice receiving GGDGT (WD + 200 mg · kg(-1) · day(-1)). RESULTS: Treatment with GGDGT significantly improved glucose tolerance and plasma lipid levels. In addition, GGDGT ameliorated acetylcholine-induced vascular relaxation of the aortic rings. Immunohistochemical staining showed that GGDGT suppressed intercellular adhesion molecule (ICAM)-1 expression; however, expression of endothelial nitric oxide synthase (eNOS) and insulin receptor substrate (IRS)-1 were restored in the thoracic aorta and skeletal muscle, respectively. CONCLUSIONS: These findings suggest that GGDGT attenuates endothelial dysfunction via improvement of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling pathway and improves insulin sensitivity in diabetic atherosclerosis.
Asunto(s)
Apolipoproteínas E , Aterosclerosis/tratamiento farmacológico , Angiopatías Diabéticas/tratamiento farmacológico , Dieta Occidental , Endotelio Vascular/efectos de los fármacos , Fitoterapia , Extractos Vegetales/uso terapéutico , Animales , Aorta Torácica , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Glucemia/metabolismo , GMP Cíclico/metabolismo , Angiopatías Diabéticas/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Insulina/sangre , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina , Lípidos/sangre , Masculino , Medicina Tradicional Coreana , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Extractos Vegetales/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
Background: Herbal medicine Oryeongsan (ORS), also known as Wulingsan in Chinesehas been used for the treatment of impaired body fluid balance. However, the mechanisms involved are not clearly defined. The purpose of the present study was to identify the actions of ORS on the renal excretory function and blood pressure (BP) and to define the mechanisms involved in association with renin-angiotensin system (RAS) and natriuretic peptide system (NPS) in spontaneously hypertensive rats (SHR), an animal model of human essential hypertension. Methods: Changes in urine volume (UV), excretion of electrolytes including Na+ (urinary excretion of Na+ (UNaV)) were measured. RT-PCR was performed to trace the changes in expression of RAS, NPS and sodium (Na+)-hydrogen (H+) exchanger 3 (NHE3) in the renal cortex. Results: In the SHR treated with vehicle (SHR-V) group, UV and UNaV were suppressed and the Na+ balance was maintained at the higher levels leading to an increase in BP compared to WKY-V group. These were accompanied by an increase in NHE3 expression with an accentuation of angiotensin I converting enzyme-angiotensin II type 1 (ACE-AT1) receptor and concurrent suppression of angiotensin II type 2 (AT2) receptor/ACE2-Mas receptor expression in the renal cortex. Chronic treatment with ORS increased UV and UNaV, and decreased the Na+ and water balance with a decrease in BP in the ORS-treated SHR-ORS group compared to SHR-V. These were accompanied by a decrease in NHE3 expression with a suppression of ACE-AT1 receptor and concurrent accentuation of AT2/ACE2-Mas receptor. Conclusion: The present study shows that ORS reduced BP with a decrease in Na+ and water retention by a suppression of NHE3 expression via modulation of RAS and NPS in SHR. The present study provides pharmacological rationale for the treatment of hypertension with ORS in SHR.
RESUMEN
Exogenous acetylcholine (ACh) is known to stimulate atrial natriuretic peptide (ANP) secretion concomitantly with a decrease in atrial pulse pressure. However, the role of intrinsic ACh in the regulation of ANP secretion remains unknown. Recently, it was shown that nonneuronal and neuronal ACh is present in the cardiac atria. From this finding we hypothesize that endogenously released ACh is involved in the regulation of ANP secretion in an autocrine or paracrine manner in the atria. Experiments were performed in isolated beating rat atria. ANP was measured using radioimmunoassay. To increase the availability of the ACh in the extracellular space of the atrium, its degradation was inhibited with an inhibitor of acetylcholinesterase. Acetylcholinesterase inhibition with physostigmine increased ANP secretion concomitantly with a decrease in atrial dynamics in a concentration-dependent manner. Inhibitors of M2 muscarinic ACh receptor (mAChR), methoctramine, and ACh-activated K(+) (KACh(+)) channels, tertiapin-Q, abolished the physostigmine-induced changes. The effects were not observed in the atria from rats treated with pertussis toxin. Furthermore, the physostigmine-induced effects were attenuated by an inhibitor of high-affinity choline transporter, hemicholinium-3, which is a rate-limiting step of ACh synthesis. Inhibitors of the mAChR signaling pathway and ACh synthesis also attenuated the basal levels of ANP secretion and accentuated atrial dynamics. These findings suggest that endogenously released ACh tonically stimulates ANP secretion from atrial cardiomyocytes via activation of M2 mAChR-Gi/o-KACh(+) channel signaling. It is also suggested that the ACh-ANP signaling is implicated in cardiac physiology and pathophysiology.
Asunto(s)
Acetilcolina/metabolismo , Factor Natriurético Atrial/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Función Atrial , Inhibidores de la Colinesterasa/farmacología , Relación Dosis-Respuesta a Droga , Atrios Cardíacos/metabolismo , Hemodinámica , Masculino , Antagonistas Muscarínicos/farmacología , Miocitos Cardíacos/efectos de los fármacos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/efectos de los fármacos , Canales de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Cardiac hypertrophy is developed by various diseases such as myocardial infarction, valve diseases, hypertension, and aortic stenosis. Sibjotang (, Shizaotang, SJT), a classic formula in Korean traditional medicine, has been shown to modulate the equilibrium of body fluids and blood pressure. This research study sought to explore the impact and underlying process of Sibjotang on cardiotoxicity induced by DOX in H9c2 cells. In vitro, H9c2 cells were induced by DOX (1 µM) in the presence or absence of SJT (1-5 µg/mL) and incubated for 24 h. In vivo, SJT was administrated to isoproterenol (ISO)-induced cardiac hypertrophy mice (n = 8) at 100 mg/kg/day concentrations. Immunofluorescence staining revealed that SJT mitigated the enlargement of H9c2 cells caused by DOX in a dose-dependent way. Using SJT as a pretreatment notably suppressed the rise in cardiac hypertrophic marker levels induced by DOX. SJT inhibited the DOX-induced ERK1/2 and p38 MAPK signaling pathways. In addition, SJT significantly decreased the expression of the hypertrophy-associated transcription factor GATA binding factor 4 (GATA 4) induced by DOX. SJT also decreased hypertrophy-associated calcineurin and NFAT protein levels. Pretreatment with SJT significantly attenuated DOX-induced apoptosis-associated proteins such as Bax, caspase-3, and caspase-9 without affecting cell viability. In addition, the results of the in vivo study indicated that SJT significantly reduced the left ventricle/body weight ratio level. Administration of SJT reduced the expression of hypertrophy markers, such as ANP and BNP. These results suggest that SJT attenuates cardiac hypertrophy and heart failure induced by DOX or ISO through the inhibition of the calcineurin/NFAT/GATA4 pathway. Therefore, SJT may be a potential treatment for the prevention and treatment of cardiac hypertrophy that leads to heart failure.
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Respiratory exposure to Particulate matter (PM), including Diesel exhaust particulate (DEP), causes oxidative stress-induced lung inflammation. Especially, fine particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5) is a serious air pollutant associated with various health problems including cardiovascular diseases. The present study aimed to examine the inhibitory effect of Securiniga suffruticosa (S. suffruiticosa) on DEP and PM-induced lung and cardiovascular diseases. Mice inhaled DEP by using nebulizer chamber for two weeks. Treatment with S. suffruiticosa reduced the expression of C-X-C motif ligand 1/2 in bronchoalveolar lavage fluid and Muc5ac, ICAM-1, TNF-âº, IL-6 mRNA in lung were also attenuated by S. suffruiticosa. In thoracic aorta, DEP increased CAMs, TNF-⺠and inflammasome markers such as NLRP3, Caspase-1, and ASC. However, S. suffruiticosa suppressed these levels. S. suffruiticosa inhibited PM2.5 induced production of intracellular reactive oxygen species (ROS); and inhibited the translocation of NF-κB p65 to the nucleus in human umbilical vein endothelial cells. Taken together, this study proved that exposure to PM2.5 induced both lung and vascular inflammation, however, S. suffruiticosa attenuated this injury via the downregulation of the NLRP3 signaling pathway. These findings suggest that S. suffruiticosa may have potential therapeutic benefit against air pollution-mediated lung and cardiovascular diseases.
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Enfermedades Cardiovasculares , FN-kappa B , Humanos , Animales , Ratones , FN-kappa B/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células Endoteliales/metabolismo , Pulmón , Material Particulado/farmacologíaRESUMEN
Edema is a symptom that results from the abnormal accumulation of fluid in the body. The cause of edema is related to the level of aquaporin (AQP)2 protein expression, which regulates the reabsorption of water in the kidney. Edema is caused by overexpression of the AQP2 protein when the concentration of Na(+) in the blood increases. The rhizome of Atractylodes macrocephala has been used in traditional oriental medicine as a diuretic drug; however, the mechanism responsible for the diuretic effect of the aqueous extract from A. macrocephala rhizomes (AAMs) has not yet been identified. We examined the effect of the AAM on the regulation of water channels in the mouse inner medullary collecting duct (mIMCD)-3 cells under hypertonic stress. Pretreatment of AAM attenuates a hypertonicity-induced increase in AQP2 expression as well as the trafficking of AQP2 to the apical plasma membrane. Tonicity-responsive enhancer binding protein (TonEBP) is a transcription factor known to play a central role in cellular homeostasis by regulating the expression of some proteins, including AQP2. Western immunoblot analysis demonstrated that the protein and mRNA expression levels of TonEBP also decrease after AAM treatment. These results suggest that the AAM has a diuretic effect by suppressing water reabsorption via the downregulation of the TonEBP-AQP2 signaling pathway.
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Aims of study. The aim of the present study was to investigate whether an ethanol extract of Scutellaria baicalensis (ESB) relaxes penile corpus cavernosum muscle in organ bath experiments. Materials and methods. Changes in tension of cavernous smooth muscle strips were determined by penile strip chamber model and in penile perfusion model. Isolated endothelium-intact rabbit corpus cavernosum was precontracted with phenylephrine (PE) and then treated with ESB. Results. ESB relaxed penile smooth muscle in a dose-dependent manner, and this was inhibited by pre-treatment with N(G)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide (NO) synthase inhibitor, and 1H-[1, 2, 4]-oxadiazolo-[4,3-α]-quinoxalin-1-one (ODQ), a soluble guanylyl cyclase (sGC) inhibitor. ESB-induced relaxation was significantly attenuated by pretreatment with tetraethylammonium (TEA), a nonselective K(+) channel blocker, and charybdotoxin, a selective Ca(2+)-dependent K(+) channel inhibitor. ESB increased the cGMP levels of rabbit corpus cavernosum in a concentration-dependent manner without changes in cAMP levels. In a perfusion model of penile tissue, ESB also relaxed penile corpus cavernosum smooth muscle in a dose-dependent manner. Conclusion. Taken together, these results suggest that ESB relaxed rabbit cavernous smooth muscle via the NO/cGMP system and Ca(2+)-sensitive K(+) channels in the corpus cavernosum.
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Type 2 diabetes is associated with significantly accelerated rates of micro- and macrovascular complications such as diabetic vascular inflammation and endothelial dysfunction. In the present study, we investigated the protective effect of the aqueous extract of Portulaca oleracea L. (AP), an edible plant used as a folk medicine, on diabetic vascular complications. The db/db mice were treated with AP (300 mg/kg/day, p.o.) for 10 weeks, and AP treatment markedly lowered blood glucose, plasma triglyceride, plasma level of LDL-cholesterol, and systolic blood pressure in diabetic db/db mice. Furthermore, AP significantly increased plasma level of HDL-cholesterol and insulin level. The impairment of ACh- and SNP-induced vascular relaxation of aortic rings were ameliorated by AP treatment in diabetic db/db mice. This study also showed that overexpression of VCAM-1, ICAM-1, E-selectin, MMP-2, and ET-1 were observed in aortic tissues of untreated db/db mice, which were significantly suppressed by treatment with AP. We also found that the insulin immunoreactivity of the pancreatic islets remarkably increased in AP treated db/db mice compared with untreated db/db mice. Taken together, AP suppresses hyperglycemia and diabetic vascular inflammation, and prevents the development of diabetic endothelial dysfunction for the development of diabetes and its vascular complications.
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BACKGROUND: Arctium lappa L. (Asteraceae), burdock, is a medicinal plant that is popularly used for treating hypertension, gout, hepatitis, and other inflammatory disorders. This study was performed to test the effect of ethanol extract of Arctium lappa L. (EAL) seeds on vascular reactivity and inflammatory factors in rats fed a high fat/cholesterol diet (HFCD). METHOD: EAL-I (100 mg·kg-1/day), EAL-II (200 mg·kg-1/day), and fluvastatin (3 mg·kg-1/day) groups initially received HFCD alone for 8 weeks, with EAL supplementation provided during the final 6 weeks. RESULTS: Treatment with low or high doses of EAL markedly attenuated plasma levels of triglycerides and augmented plasma levels of high-density lipoprotein (HDL) in HFCD-fed rats. Chronic treatment with EAL markedly reduced impairments of acetylcholine (ACh)-induced relaxation of aortic rings. Furthermore, chronic treatment with EAL significantly lowered systolic blood pressure (SBP) and maintained smooth and flexible intimal endothelial layers in HFCD-fed rats. Chronic treatment with EAL suppressed upregulation of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in the aorta. Chronic treatment with EAL also suppressed increases in matrix metalloproteinase (MMP)-2 expression. These results suggested that EAL can inhibit HFCD-induced vascular inflammation in the rat model. CONCLUSION: The present study provides evidence that EAL ameliorates HFCD-induced vascular dysfunction through protection of vascular relaxation and suppression of vascular inflammation.
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Arctium , Endotelio Vascular/efectos de los fármacos , Inflamación/prevención & control , Fitoterapia , Extractos Vegetales/uso terapéutico , Enfermedades Vasculares/prevención & control , Vasodilatación/efectos de los fármacos , Animales , Anticolesterolemiantes/farmacología , Anticolesterolemiantes/uso terapéutico , Aorta/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Moléculas de Adhesión Celular/metabolismo , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/efectos adversos , Grasas de la Dieta/sangre , Suplementos Dietéticos , Selectina E/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Lípidos/sangre , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-Dawley , Semillas , Regulación hacia Arriba , Enfermedades Vasculares/etiología , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/patologíaRESUMEN
Hypercholesterolemia increases the incidence of atherosclerosis and its pathologic complications. This study was performed to test the effect of an ethanol extract of Cynanchum wilfordii (ECW) on vascular dysfunction in rats fed with high fat/cholesterol diets (HFCD). Male rats were fed a HFCD consisting of 7.5% cocoa butter and 1.25% cholesterol, with or without 100, 200 mg/day/kg ECW. Rats fed with HFCD increased body weight associated with an increase in plasma low-density lipoprotein (LDL) cholesterol level. Chronic ECW treatment in HFCD-fed rats lessened LDL cholesterol and triglyceride levels as well as elevated high-density lipoprotein (HDL) cholesterol. Chronic ECW treatment recovered the HFCD-induced increase in systolic blood pressure, maintained smooth and soft intima endothelial layers by the decrease of intima-media thickness. ECW significantly recovered the diet-induced decrease in vasorelaxation to acetylcholine, high-dose ECW apparently increased vasorelaxation response to sodium nitroprusside in rats fed with HFCD. ECW clearly restored the HFCD-induced reduction in endothelial nitric oxide (NO) synthase expression and Akt expression levels in aortic tissue, leading to improve endothelial function through an increase in endothelium-derived NO production. Furthermore, treatment of ECW significantly recovered the HFCD-induced decrease in aortic cGMP levels in rats. These findings suggest that ECW ameliorates hypertension and endothelial dysfunction via improvement of NO/cGMP signaling pathway in aortic tissue of rats fed with HFCD, suggesting a vascular protective role for this herb in the treatment and prevention of atherosclerotic vascular disease.