RESUMO
Atopic dermatitis (AD) is an allergic, inflammatory skin disease caused by immune dysregulation. In this study, we investigated anti-atopic and anti-inflammatory activities of Sanguisorba hakusanensis ethanol extract (SHE) both in vivo using NC/Nga mice and in vitro using human HaCaT keratinocytes. Oral administration of SHE suppressed several atopic symptoms associated with house dust mites (induced with Dermatophagoides farinae extract) in NC/Nga mice and decreased serum levels of inflammatory mediators such as immunoglobulin E, histamine, and inflammatory chemokines. Additionally, SHE treatment reduced the infiltration of immune cells such as mast cells and macrophages in AD skin lesions. In vitro, interferon-γ- and tumor necrosis factor-α-stimulated HaCaT cells exhibited increased expression of T helper 1 and 2 chemokines; their expression was inhibited by SHE treatment. The anti-inflammatory effects of SHE treatment involved blocking of the mitogen-activated protein kinase and signal transducer and activator of transcription 1 signaling pathways. In conclusion, SHE exerts potent anti-atopic and anti-inflammatory effects and should be considered for the clinical treatment of AD.
Assuntos
Dermatite Atópica , Sanguisorba , Humanos , Animais , Camundongos , Queratinócitos , Células HaCaT , EtanolRESUMO
BACKGROUND: Terminalia chebula (TC) is a traditional medicinal plant used for treating various diseases in humans. However, pharmacological mechanisms underlying the effects of TC in atopic treatment remain unelucidated. HYPOTHESIS/PURPOSE: We investigated the therapeutic effects of TC extract in a mouse model of atopic dermatitis (AD) in vivo and the anti-inflammatory mechanism in vitro. STUDY DESIGN/METHODS: For the in vivo study, AD was induced by Dermatophagoides farinae extract (Dfe) in NC/Nga mice. After 14 days of oral administration, the effects of TC concentrations of 30, 100, and 300 mg/kg were analyzed by assessing morphological changes visually; measuring serum levels of inflammatory chemokines/cytokines, IgE, histamine, MDC, TARC, RANTES, and TSLP using ELISA kits; and counting infiltrated mast cells. For in vitro analyses, we used IFNγ/TNF-α-stimulated human keratinocyte cell lines to study the mechanism of action. The production of chemokines/cytokines in the IFNγ/TNF-α-stimulated HaCaT cells was measured using ELISA and a bead array kit. The signaling pathways were analyzed by western blotting and the expression of the transcriptional factors using RT-PCR and luciferase assay. RESULTS: Administration of TC significantly alleviated AD-like symptoms in vivo and decreased the ear thickness, dermatitis score, keratinization, and mast cell infiltration. It also resulted in decreased serum levels of IgE, histamine, and inflammation-related mediators MDC, TARC, RANTES, and TSLP compared with those in the Dfe treatment group. Moreover, TC downregulated the expression of the inflammatory chemokines RANTES and MDC in IFNγ/TNF-α-stimulated HaCaT cells. TC inhibited phosphorylated STAT1/3 and NK-κB subunits and nuclear translocation of NF-κB. It also suppressed the transcription of IFNγ, IL-6, IL-8 and MCP-1 in the IFNγ/TNF-α-stimulated HaCaT cells. TC and its constituents, chebulic acid, gallic acid, corlagin, chebulanin, chbulagic acid, ellagic acid, and chebulinic acid, strongly inhibited the nuclear translocation of NF-κB, STAT1, and STAT3 and decreased the expression of inflammatory cytokines at the mRNA level. CONCLUSIONS: Overall, TC extract alleviated AD-like symptoms by regulating anti-inflammatory factors in vivo and suppressing STAT1/3 and NF-κB signaling in vitro. In addition, our results show the in vivo effect of partial improvements in AD, as well as the in vitro effect on inflammatory factors by the constituents of TC. This finding provides that TC extract and its components could be potential therapeutic drugs for AD.
Assuntos
Dermatite Atópica , Terminalia , Animais , Anti-Inflamatórios/uso terapêutico , Quimiocina CCL5/metabolismo , Quimiocina CCL5/farmacologia , Quimiocina CCL5/uso terapêutico , Quimiocinas/metabolismo , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/metabolismo , Histamina , Humanos , Imunoglobulina E , Queratinócitos , Camundongos , NF-kappa B/metabolismo , Extratos Vegetais/uso terapêutico , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3 , Fator de Necrose Tumoral alfa/metabolismoRESUMO
S. patholobus suberectus Dunn, a traditional Chinese herbal medicine, has various pharmacological activities, such as anti-inflammatory properties. However, to the best of our knowledge, its therapeutic effect on atopic dermatitis (AD) has not been investigated. In this study, we explored the effect of S. suberectus Dunn water extract (SSWex) on AD in vivo and in vitro. In Dermatophagoides farina extract (DfE)-treated NC/Nga mice, the oral administration of SSWex alleviated AD-like symptoms, such as ear thickness, dermatitis score, epidermal thickness, immune cell infiltration, and levels of AD-related serum parameters (immunoglobulin E, histamine, and proinflammatory chemokines). In HaCaT cells, the production of proinflammatory chemokines induced by interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) was inhibited by SSWex pretreatment. SSWex treatment inhibited the phosphorylation of mitogen-activated protein kinase and activation and translocation of transcriptional factors, such as signal transducer and activator of transcription 1 and nuclear factor kappa B in IFN-γ/TNF-α-stimulated HaCaT cells. These results indicate that SSWex may be developed as an efficient therapeutic agent for AD.
RESUMO
Alpinia officinarum (AO) has been traditionally used in Asia as an herbal medicine to treat inflammatory and internal diseases. However, the therapeutic effect of AO on atopic dermatitis (AD) is unclear. Therefore, we examined whether Alpinia officinarum water extract (AOWex) affects AD in vivo and in vitro. Oral administration of AOWex to NC/Nga mice with Dermatophagoies farina extract (DfE)-induced AD-like symptoms significantly reduced the severity of clinical dermatitis, epidermal thickness, and mast cell infiltration into the skin and ear tissue. Decreased total serum IgE, macrophage-derived chemokine (MDC), and regulated on activation, normal T-cell expressed and secreted (RANTES) levels were observed in DfE-induced NC/Nga mice in the AOWex-treated group. These effects were confirmed in vitro using HaCaT cells. Treatment with AOWex inhibited the expression of proinflammatory chemokines such as MDC, RANTES, IP-10 and I-TAC in interferon-γ and tumor necrosis factor-α-stimulated HaCaT cells. The anti-inflammatory effects of AOWex were due to its inhibitory action on MAPK phosphorylation (ERK and JNK), NF-κB, and STAT1. Furthermore, galangin, protocatechuic acid, and epicatechin from AOWex were identified as candidate anti-AD compounds. These results suggest that AOWex exerts therapeutic effects against AD by alleviating AD-like skin lesions, suppressing inflammatory mediators, and inhibiting major signaling molecules.
Assuntos
Alpinia , Anti-Inflamatórios/farmacologia , Quimiocinas/metabolismo , Dermatite Atópica/prevenção & controle , Queratinócitos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Pele/efeitos dos fármacos , Alpinia/química , Animais , Anti-Inflamatórios/isolamento & purificação , Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Catequina/isolamento & purificação , Catequina/farmacologia , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Dermatophagoides farinae/imunologia , Modelos Animais de Doenças , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Células HaCaT , Humanos , Hidroxibenzoatos/isolamento & purificação , Hidroxibenzoatos/farmacologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Masculino , Camundongos , Extratos Vegetais/isolamento & purificação , Transdução de Sinais , Pele/imunologia , Pele/metabolismo , Pele/patologia , Solventes/química , Água/químicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Akebia quinata Decaisne extract (AQE; Lardizabalaceae) is used in traditional herbal medicine for stress- and fatigue-related depression, improvement of fatigue, and mental relaxation. AIM OF THE STUDY: To clarify the effects of AQE on stress-induced fatigue, we investigated the neuroprotective pharmacological effects of A. quinata Decaisne in mice exposed to chronic restraint stress. MATERIALS AND METHODS: Seven-week old C57BL/6 mice chronically stressed by immobilization for 3â¯h daily for 15â¯d and non-stressed control mice underwent daily oral administration of AQE or distilled water. The open field, sucrose preference, and forced swimming behavioral tests were carried out once weekly, and immunohistochemical analyses of NeuN, brain-derived neurotrophic factor (BDNF), phosphorylated cAMP response element-binding (CREB) protein, and BDNF receptor tropomyosin receptor kinase B (TrkB) in striatum and hippocampus were performed at the end of the experimental period. Brain levels of serotonin, adrenaline, and noradrenaline as well as serum levels of corticosterone were measured. RESULTS: Behavioral tests showed that treatment with AQE improved all lethargic behaviors examined. AQE significantly attenuated the elevated levels of adrenaline, noradrenaline, and serotonin in the brain and corticosterone, alanine transaminase, and aspartate transaminase levels in the serum. Histopathological analysis showed that AQE reduced liver injury and lateral ventricle size in restraint-stress mice via inhibition of neuronal cell death. Immunohistochemical analysis showed increased phosphorylation of CREB and expression of BDNF and its receptor TrkB in striatum and hippocampus. Chlorogenic acid, isochlorogenic acid A, and isochlorogenic acid C were identified as the primary components of AQE. All three agents increased expression of BDNF in SH-SY5Y cells and PC12 cells with H2O2-induced neuronal cell damage. CONCLUSIONS: AQE may have a neuroprotective effect and ameliorate the effects of stress and fatigue-associated brain damage through mechanisms involving regulation of BDNF-TrkB signaling.
Assuntos
Fadiga/tratamento farmacológico , Magnoliopsida , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Estresse Psicológico/tratamento farmacológico , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ácido Clorogênico/análogos & derivados , Ácido Clorogênico/análise , Ácido Clorogênico/uso terapêutico , Corticosterona/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas de Ligação a DNA , Fadiga/sangue , Humanos , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Fármacos Neuroprotetores/análise , Proteínas Nucleares/metabolismo , Extratos Vegetais/análise , Proteínas Tirosina Quinases/metabolismo , Ratos , Restrição Física , Estresse Psicológico/sangueRESUMO
Atherosclerosis was previously thought to be a disease that primarily involves lipid accumulation in the arterial wall. In this report, we investigated the effect of Viola mandshurica W. Becker (V. mandshurica) water extract on atherosclerosis in apolipoprotein E deficient (ApoE[Formula: see text]) mice. The administration of V. mandshurica to high-fat diet-fed mice reduced body weight, liver weight, and serum levels of lipids (total cholesterol, low-density lipoprotein-cholesterol, triglycerides), glucose, alanine transaminase, and aspartate transaminase. Histopathologic analyses of the aorta and liver revealed that V. mandshurica attenuated atherosclerotic lesions and reduced lipid accumulation, inflammatory responses and fatty acid synthesis. V. mandshurica also increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), thereby reducing acetyl-CoA carboxylase (ACC) in liver tissue and inhibiting sterol regulatory element-binding protein 1c (SREBP-1c). V. mandshurica reduced protein expression levels of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin) as well as ACC, fatty acid synthase, and SREBP-1c. In addition, quantitative analysis of V. mandshurica by high-performance liquid chromatography revealed the presence of esculetin and scopoletin. Esculetin and scopoletin reduced adhesion molecules in human aortic smooth muscle cells. Our results indicate that the anti-atherosclerotic effects of V. mandshurica may be associated with activation of the AMPK pathway. Therefore, AMPK-dependent phosphorylation of SREBP-1c by V. mandshurica may be an effective therapeutic strategy for combatting atherosclerosis and hepatic steatosis.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/etiologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Terapia de Alvo Molecular , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Viola/química , Acetil-CoA Carboxilase/metabolismo , Animais , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular/metabolismo , Modelos Animais de Doenças , Imunoglobulinas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Escopoletina/isolamento & purificação , Escopoletina/farmacologia , Escopoletina/uso terapêutico , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Umbeliferonas/isolamento & purificação , Umbeliferonas/farmacologia , Umbeliferonas/uso terapêuticoRESUMO
BACKGROUND: Do In Seung Gi-Tang (DISGT) is an herbal mixture of traditional Korean medicine that is composed of Rheum undulatum Linne, Prunus Persica (L.) Batsch, Conyza canadensis L., Cinnamomum Cassia Presl, and Glycytthiza uralensis Fischer (8: 6: 4: 4: 4 ratio). We investigated the effect of DISGT on vascular inflammation and lipid accumulation in apolipoprotein E-deficient (ApoE(-/-)) mice. METHODS: ApoE(-/-) mice that were fed a high-fat diet (HFD) were treated with DISGT (300 mg/kg/day) or statin (10 mg/kg/day) for 16 weeks. Serum lipid levels were analyzed. Oil Red O staining was used to evaluate atherosclerotic lesions and lipid accumulation in the aorta and liver, respectively. The expression of adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1], and E-selectin), fatty acid synthase (FAS), adenosine monophosphate-activated protein kinase (AMPK), and acetyl-coA carboxylase (ACC) in the aorta or liver tissues was measured by western blot analysis. Lipid synthesis and inflammatory responses were assessed by immunohistochemistry and hematoxylin & eosin staining, respectively. RESULTS: Treatment of HFD-fed mice with DISGT significantly lowered body weight, liver weight, and the levels of lipids, including total cholesterol, low-density lipoprotein-cholesterol, and triglycerides. Glucose levels were also lowered. In the aorta, DISGT attenuated atherosclerotic lesions and reduced the expression of ICAM-1, VCAM-1, and E-selectin. Moreover, DISGT decreased lipid accumulation, inflammatory responses, and FAS levels, and it activated AMPK and reduced ACC expression in liver tissues. CONCLUSIONS: The beneficial, anti-lipolytic, and anti-inflammatory effects of DISGT were mediated by the AMPK pathway. As a result, the expression of inflammatory factors was reduced. Our data provide evidence that DISGT may have strong therapeutic potential in treating vascular diseases, such as atherosclerosis.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Extratos Vegetais/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado/efeitos dos fármacos , Masculino , Medicina Tradicional Coreana , Camundongos , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacosRESUMO
Atherosclerosis, which manifests as acute coronary syndrome, stroke, and peripheral arterial diseases, is a chronic inflammatory disease of the arterial wall. Prunella vulgaris, a perennial herb with a worldwide distribution, has been used as a traditional medicine in inflammatory disease. Here, we investigated the effects of P. vulgaris ethanol extract on TNF-α-induced inflammatory responses in human aortic smooth muscle cells (HASMCs). We found that P. vulgaris ethanol extract inhibited adhesion of monocyte/macrophage-like THP-1 cells to activated HASMCs. It also decreased expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin and ROS, No production in TNF-α-induced HASMCs and reduced NF-kB activation. Furthermore, P. vulgaris extract suppressed TNF-α-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK). These results demonstrate that P. vulgaris possesses antiinflammatory properties and can regulate TNF-α-induced expression of adhesion molecules by inhibiting the p38 MAPK/ERK signaling pathway.
Assuntos
Anti-Inflamatórios/farmacologia , Extratos Vegetais/farmacologia , Prunella/química , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Anti-Inflamatórios/química , Aorta/citologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Selectina E/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Monócitos/citologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Alzheimer's disease (AD), which is characterized by progressive cognitive impairment, is the most common neurodegenerative disease. Here, we investigated the preventive effect of a phosphodiesterase III inhibitor, cilostazol against cognitive decline in AD mouse model. In vitro studies using N2a cells stably expressing human amyloid precursor protein Swedish mutation (N2aSwe) showed that cilostazol decreased the amyloid ß (Aß) levels in the conditioned medium and cell lysates. Cilostazol attenuated the expression of ApoE, which is responsible for Aß aggregation, in N2aSwe. Intracerebroventricular injection of Aß(25-35) in C57BL/6J mice resulted in increased immunoreactivity of Aß and p-Tau, and microglia activation in the brain. Oral administration of cilostazol for 2 weeks before Aß administration and once a day for 4 weeks post-surgery almost completely prevented the Aß-induced increases of Aß and p-Tau immunoreactivity, as well as CD11b immunoreactivity. However, post-treatment with cilostazol 4 weeks after Aß administration, when Aß was already accumulated, did not prevent the Aß-induced neuropathological responses. Furthermore, cilostazol did not affect the neprilysin and insulin degrading enzymes involved in the degradation of the Aß peptide, but decreased ApoE levels in Aß-injected brain. In addition, cilostazol significantly improved spatial learning and memory in Aß-injected mice. The findings suggest that a phosphodiesterase III inhibitor, cilostazol significantly decreased Aß accumulation and improved memory impairment induced by Aß(25-35). The beneficial effects of cilostazol might be explained by the reduction of Aß accumulation and tau phosphorylation, not through an increase in Aß degradation but via a significant decrease in ApoE-mediated Aß aggregation. Cilostazol may be the basis of a novel strategy for the therapy of AD.