RESUMO
The herbal extract Angelica gigas (AG) has been applied as a vasodilating agent for patients suffering from vascular diseases for many years; however, the underlying mechanism has not been fully elucidated. The present study hypothesized that the antivasoconstrictive effect of AG may be effective in the treatment of abnormal coldmediated vasospasms that occur in Raynaud's phenomenon (RP). The effect of AG on the activity of ras homolog gene family member A (RhoA) was investigated in coldexposed vascular cells. Vascular cells were pretreated to AG, followed by a warm (37ËC) or cold (25ËC) incubation for 30 min and investigated with western blotting, ELISA and confocal microscopy. Cold treatment induced the activation of RhoA in pericytes and vascular endothelial cells, however this was reduced by treatment with AG. Furthermore, AG treatment reduced the endothelin1 (ET1)mediated RhoA activation in pericytes; however, coldinduced ET1 production by vascular endothelial cells was not affected by treatment with AG. In addition, AG treatment suppressed the formation of stress fibers and focal adhesion complexes, and the coldinduced phosphorylation of focal adhesion kinase, protooncogene tyrosineprotein kinase Src and extracellular signalrelated kinase. Therefore, AG treatment demonstrated an ability to reduce coldinduced RhoA activation in pericytes and vascular endothelial cells, and attenuated ET1mediated RhoA activation in pericytes. In conclusion, the present study indicated that AG may be useful for the treatment of RP.
Assuntos
Angelica/química , Extratos Vegetais/química , Proteína rhoA de Ligação ao GTP/metabolismo , Angelica/metabolismo , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Endotelina-1/análise , Endotelina-1/metabolismo , Ensaio de Imunoadsorção Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Microscopia Confocal , Pericitos/citologia , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Temperatura , Vasodilatadores/química , Vasodilatadores/isolamento & purificação , Vasodilatadores/farmacologia , Quinases da Família src/metabolismoRESUMO
Danggui-Sayuk-Ga-Osuyu-Senggang-Tang (DSGOST), one of the traditional Chinese medicines, has long been prescribed for patients suffering from Raynaud phenomenon (RP) in Northeast Asian countries, including China, Japan and Korea. Although a previous in vitro study from our laboratory revealed that DSGOST prevents cold (25ËC)induced RhoA activation and endothelin1 (ET1) production in endothelial cells (ECs), the mechanisms by which DSGOST is able to alleviate the symptoms of RP have yet to be fully elucidated. The present study aimed to demonstrate that DSGOST regulates RhoAmediated pathways in coldexposed pericytes. In pericytes, DSGOST amplified coldinduced RhoA activation, while markedly reducing ET1induced RhoA activation. Additionally, DSGOSTmediated regulation of RhoA was closely associated with Rhoassociated, coiledcoilcontaining protein kinase 1 (ROCK1)/testisspecific kinase 1 (TESK1)/PDXP, but not with LIM domain kinase 1/2 (LIMK1/2), cofilin and myosin light chain (MLC). Thus, DSGOST activation of RhoA/ROCK1/TESK1/PDXP in coldexposed pericytes appeared to be crucial for treating vessel contraction. In addition, the DSGOST effect on the RhoAmediated pathway in coldinduced human umbilical vein endothelial cells or human dermal microvascular endothelial cells was similar to that in ET1treated pericytes, but not in coldinduced pericytes. The results of the present study further confirmed that DSGOST inhibits coldinduced contraction of the mouse tail vein in vivo. Furthermore, DSGOST treatment reduced coldinduced expression of the α2cadrenergic receptor in mouse tail vessels. Therefore, the data in the present study suggest that DSGOST may be useful for the treatment of RPlike disease.
Assuntos
Temperatura Baixa , Medicamentos de Ervas Chinesas/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Endotelina-1/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Cancer-associated anorexia and cachexia are a multifactorial condition described by a loss of body weight and muscle with anorexia, asthenia, and anemia. Moreover, they correlate with a high mortality rate, poor response to chemotherapy, poor performance status, and poor quality of life. Cancer cachexia is regulated by proinflammatory cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor- α (TNF- α). In addition, glucagon like peptide-1 (GIP-1), peptide YY (PYY), ghrelin, and leptin plays a crucial role in food intake. In this study, we investigated the therapeutic effects of one of the traditional herbal medicines, Sipjeondaebo-tang (Juzen-taiho-to in Japanese; SJDBT), on cancer anorexia and cachexia in a fundamental mouse cancer anorexia/cachexia model, CT-26 tumor-bearing mice. SJDBT was more significantly effective in a treatment model where it was treated after anorexia and cachexia than in a prevention model where it was treated before anorexia and cachexia on the basis of parameters such as weights of muscles and whole body and food intakes. Moreover, SJDBT inhibited a production of IL-6, MCP-1, PYY, and GLP-1 and ameliorated cancer-induced anemia. Therefore, our in vivo studies provide evidence on the role of SJDBT in cancer-associated anorexia and cachexia, thereby suggesting that SJDBT may be useful for treating cancer-associated anorexia and cachexia.
Assuntos
Anorexia/complicações , Caquexia/complicações , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias/complicações , Animais , Anorexia/tratamento farmacológico , Peso Corporal , Caquexia/tratamento farmacológico , Linhagem Celular Tumoral , Quimiocina CCL2/sangue , Grelina/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Inflamação , Interleucina-6/sangue , Mucosa Intestinal/metabolismo , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculos/patologia , Transplante de Neoplasias , Neoplasias/tratamento farmacológico , Peptídeo YY/sangue , Preparações de Plantas/farmacologia , Fator de Necrose Tumoral alfa/sangueRESUMO
Herbal prescription, Danggui-Sayuk-Ga-Osuyu-Saenggang-tang (DSGOST), has long been used to treat Raynaud's phenomenon (RP) in traditional Chinese medicine (TCM). However, a biological mechanism by which DSGOST ameliorates RP is yet deciphered. In this study, we demonstrate that DSGOST inhibits cold-induced activation of RhoA, in both vascular smooth muscle cells (VSMC) and endothelial cells (EC), and blocks endothelin-1-mediated paracrine path for cold response on vessels. While cold induced RhoA activity in both cell types, DSGOST pretreatment prevented cold-induced RhoA activation. DSGOST inhibition of cold-induced RhoA activation further blocked α 2c-adrenoreceptor translocation to the plasma membrane in VSMC. In addition, DSGOST inhibited endothelin-1-mediated RhoA activation and α 2c-adrenoreceptor translocation in VSMC. Meanwhile, DSGOST inhibited cold-induced or RhoA-dependent phosphorylation of FAK, SRC, and ERK. Consistently, DSGOST inhibited cold-induced endothelin-1 expression in EC. Therefore, DSGOST prevents cold-induced RhoA in EC and blocks endothelin-1-mediated paracrine path between EC and VSMC. In conclusion, our data suggest that DSGOST is beneficial for treating RP-like syndrome.