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Extracellular vesicles (EVs) have emerged as biocompatible nanocarriers for efficient delivery of various therapeutic agents, with intrinsic long-term blood circulatory capability and low immunogenicity. Here, indocyanine green (ICG)- and paclitaxel (PTX)-loaded EVs [EV(ICG/PTX)] were developed as a biocompatible nanoplatform for safe and efficient cancer treatment through near-infrared (NIR) light-triggered combination chemo/photothermal/photodynamic therapy. High dual drug encapsulation in EVs was achieved for both the hydrophilic ICG and hydrophobic PTX by simple incubation. The EVs substantially improved the photostability and cellular internalization of ICG, thereby augmenting the photothermal effects and reactive oxygen species production in breast cancer cells upon NIR light irradiation. Hence, ICG-loaded EVs activated by NIR light irradiation showed greater cytotoxic effects than free ICG. EV(ICG/PTX) showed the highest anticancer activity owing to the simultaneous chemo/photothermal/photodynamic therapy when compared with EV(ICG) and free ICG. In vivo study revealed that EV(ICG/PTX) had higher accumulation in tumors and improved pharmacokinetics compared to free ICG and PTX. In addition, a single intravenous administration of EV(ICG/PTX) exhibited a considerable inhibition of tumor proliferation with negligible systemic toxicity. Thus, this study demonstrates the potential of EV(ICG/PTX) for clinical translation of combination chemo-phototherapy.
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Vesículas Extracelulares , Hipertermia Inducida , Nanopartículas , Línea Celular Tumoral , Verde de Indocianina/química , Nanopartículas/química , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Preparaciones Farmacéuticas , FototerapiaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Because of the growing incidence of AD, psychosocial and economic burden of AD patients are often considerable. Steroid treatments are widely used, but long term use of this treatment can cause side effects. To reduce the burden of AD patients and find new efficient treatment, this study chose Soshiho-tang, a traditional medicine used in eastern Asia. AIM OF THE STUDY: Soshiho-tang (SSHT) is a traditional herbal medicine that has anti-inflammatory effects and improves immune function. This clinical trial evaluated the efficacy and safety of SSHT in atopic dermatitis (AD) patients with gastrointestinal disorders in comparison with placebo. MATERIALS AND METHODS: This study was a single-center, randomized, double-blinded, placebo-controlled, and investigator-initiated clinical trial. A total of 60 patients aged 3-18 years with gastrointestinal disorders and diagnosed with AD by Hanifin & Rajka criteria with a Scoring Atopic Dermatitis (SCORAD) index between 15 and 49 were enrolled. Participants were randomly assigned to the SSHT or placebo groups in a ratio of 1:1 and efficacy evaluation was conducted at week 4 and 8. The participants orally administered SSHT or placebo three times a day for 4 weeks. The primary outcome was measured based on a change of SCORAD index. The secondary outcome measurements included the following: survey questionnaires of gastrointestinal disorder, amount and frequency of ointment application for AD, dermatology quality of life index, and safety evaluation (diagnostic test, adverse reaction, and vital sign monitoring). RESULTS: During efficacy evaluation, the SCORAD score and digestive symptoms in the experimental and placebo groups were not statistically significant. However, the amount and frequency of ointment application in the experimental group were reduced compared to those in the placebo group at week 8. Also, In the Children's Dermatology Life Quality Index (CDLQI), statistically significant Quality of Life (QOL) improvement was observed in the SSHT experimental group compared to the placebo group. In safety evaluation, all participants were within the normal range during the study period. Blood sample testing indicated that the lymphocytes ratio decreased, and neutrophils ratio increased in the experimental group, whereas the placebo group showed the opposite immune response pattern. CONCLUSION: We concluded that SSHT administration can reduce steroid ointment dependence and improve the QOL in AD patients by regulating neutrophil-lymphocyte ratio.
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Dermatitis Atópica/tratamiento farmacológico , Enfermedades Gastrointestinales/tratamiento farmacológico , Extractos Vegetales/efectos adversos , Administración Oral , Administración Tópica , Adolescente , Niño , Preescolar , Correlación de Datos , Dermatitis Atópica/complicaciones , Método Doble Ciego , Femenino , Enfermedades Gastrointestinales/complicaciones , Humanos , Hidrocortisona/administración & dosificación , Hidrocortisona/análogos & derivados , Linfocitos/metabolismo , Masculino , Medicina Tradicional de Asia Oriental , Neutrófilos/metabolismo , Pomadas/administración & dosificación , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Calidad de Vida , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Atopic dermatitis is a chronic inflammatory skin disease that affects the growth and development of children. The prevalence of atopic dermatitis has been continually increasing, and this has also been accompanied by rising socioeconomic costs. Interest has been growing in alternative medicine as a means of alleviating the burden of atopic dermatitis. This was a single-center, double-blinded, randomized, placebo-controlled investigator-led clinical trial including 60 atopic dermatitis patients. The participants were classified into an experimental group (30 persons) and a control group (30 persons), who were administered, respectively, socheongryong-tang or a placebo for 4 weeks. After 4 weeks of treatment, the participants visited the trial center again and assess their efficacy and safety. The researchers performed statistical comparisons of the changes in the SCORAD Index, amount and frequency of ointment use, and height and weight to assess the efficacy. To assess the safety, diagnostic tests and vital sign checks were performed at each visit, and the presence or absence of adverse events was observed. As a result, the frequency and the amount of steroid ointment application in both groups increased, but the experimental group showed less tendency (p = 0.081). Results of analyzing the children in the experimental group in relation to growth showed a significantly greater height growth than the control group (p < 0.05). In addition, all study participants did not show any remarkable abnormal signs in the safety evaluation. In conclusion, compared to the control group, the experimental group, who took socheongryong-tang showed a tendency to be less dependent on steroid ointment and statistically significant increase in height.
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In this study, we aimed to determine the synergistic effects of a formula consisting of dried pomegranate concentrate powder, Eucommiae Cortex, and Achyranthis Radix 5:4:1 (g/g) (PCP:EC:AR) in a surgically induced osteoarthritis (OA) rabbit model. PCP:EC:AR was orally administered once per day. Knee thickness, maximum extension of the knee joint, gross articular defect area, and the histopathological appearance of the cartilage were monitored, along with serum collagen type II C-telopeptide (CTX-II), cartilage oligomeric matrix protein (COMP), matrix metalloproteinase (MMP)-3, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and subchondral IL-1ß and TNF-α levels. Roentgenographic images were also evaluated. PCP:EC:AR significantly inhibited the surgically induced increase in knee thickness, maximum extension of both knees, knee thickness after capsule exposure, gross femoral and tibial articular defect areas, loss of the knee joint area, serum and synovial COMP, CTX-II, and MMP expression, and synovial IL-1ß, and TNF-α expression. In addition, surgically induced narrowing of the knee bones, loss of the joint area, cartilage damage, and osteophyte formation were reduced. PCP:EC:AR suppressed the surgically induced increases in the Mankin score, and subchondral IL-1ß and TNF-α immunolabeled cell numbers. PCP:EC:AR exerted potent OA protective effects in a surgically induced OA rabbit model.
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Achyranthes , Medicamentos Herbarios Chinos/administración & dosificación , Eucommiaceae , Osteoartritis/tratamiento farmacológico , Fitoterapia , Granada (Fruta) , Administración Oral , Animales , Biomarcadores/sangre , Cartílago Articular/patología , Colágeno Tipo II/sangre , Citocinas/sangre , Modelos Animales de Enfermedad , Masculino , Metaloproteinasa 3 de la Matriz/sangre , Osteoartritis/diagnóstico , Osteoartritis/patología , Fragmentos de Péptidos/sangre , Polvos , Conejos , Resultado del TratamientoRESUMEN
BACKGROUND: Atopic dermatitis (AD, atopic eczema) is a pruritic, inflammatory, chronic skin disease. Since there is limitation of conventional treatment of AD, traditional herbal medicine can be an attractive therapeutic option in patients having AD for a long time. So-Cheong-Ryong-Tang (SCRT) has been found to inhibit histamine release and degranulation of mast cells, differentiation of basophils, and proliferation of eosinophils. We designed this clinical trial to evaluate the efficacy and safety of SCRT as compared to placebo in patients with AD and respiratory disorders. METHODS/DESIGN: This study is a single-center, randomized, double-blind, placebo-controlled, and investigator-initiated clinical trial. A total of 60 patients between 7 and 65 years of age with AD and respiratory disorders who received a diagnosis of AD by Hanifin and Rajka criteria who scored 15 to 50 in a scoring atopic dermatitis (SCORAD) will be enrolled. Participants will be randomly assigned to the SCRT or placebo group in a ratio of 1:1 and they will have a visit schedule comprising 4 visits including a screening visit during 8 to 10 weeks. The participants will be administered SCRT or placebo 3 times a day for 4 weeks. The primary outcome will be measured by a change of the SCORAD index. The secondary outcomes will be measured by changes in the dose and frequency of usage of the AD ointment, dermatology life quality index scores, pruritus and sleep disorder in visual analog scale, skin moisture content, skin surface temperature, Hamilton anxiety rating scale scores, depression rating scale scores, stress/autonomic nervous function test, and attention deficit hyperactivity disorder survey scores at week 4 as compared to those at the baseline. DISCUSSION: To the best of our knowledge, SCRT has rarely been reported for dermatologic diseases. This will be the first clinical trial to assess the efficacy and safety of SCRT in patients with AD and respiratory disorders. We hope that the results of this trial will provide evidence for the use of SCRT as a new treatment for AD with respiratory disorders. TRIAL REGISTRATION: Korean National Clinical Trial Registry, Clinical Research Information Service. (KCT0004148) (https://cris.nih.go.kr/cris/search/search_result_st01_en.jsp?seq=14981<ype=&rtype=).
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Dermatitis Atópica/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Trastornos Respiratorios/tratamiento farmacológico , Trastornos Respiratorios/epidemiología , Adolescente , Adulto , Anciano , Niño , Depresión/epidemiología , Dermatitis Atópica/epidemiología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prurito/epidemiología , Calidad de Vida , Piel/fisiopatología , Trastornos del Sueño-Vigilia/epidemiología , Estrés Psicológico/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease that affects the quality of life in patients with AD. Since there is limitation of conventional treatment of AD, complementary treatment is required to treat AD symptoms more effectively and safely Soshiho-tang (SSHT) is a traditional herbal medicine that exhibits anti-inflammatory and anti-ulcer effects and improves the immune function. In this clinical trial, we will evaluate the efficacy and safety of SSHT in patients with AD and gastrointestinal disorders in comparison with placebo. METHODS/DESIGN: This study is a single-center, randomized, double-blind, placebo-controlled, and investigator-initiated clinical trial. A total of 60 patients aged 3 to 18 years with AD and gastrointestinal disorders and who received a diagnosis of AD by Hanifin & Rajka criteria with a Scoring Atopic Dermatitis (SCORAD) index between 15 and 49 will be enrolled. Participants will be randomly assigned to the SSHT or placebo group in a ratio of 1:1. Additionally, they will have a visit schedule comprising 4 visits including a screening visit during 8 to 10 weeks. The participants will be administered SSHT or placebo 3 times a day for 4 weeks. The primary outcome will be measured by a change of the SCORAD index. The secondary outcome measures include the following: survey questionnaires for the perception of gastrointestinal disorders, amount and frequency of ointment usage for AD, dermatology quality of life index, itchiness and sleep disability score in visual analog scale, percutaneous water loss, skin surface temperature, Hamilton anxiety rating scale, and children's depression inventory. DISCUSSION: In our knowledge, this will be the first clinical trial to assess the efficacy and safety of SSHT in patients with AD and gastrointestinal disorders. The findings of this study will provide new treatment options for patients with AD and gastrointestinal disorders. TRIAL REGISTRATION: Korean National Clinical Trial Registry, Clinical Research Information Service. (KCT0003713) https://cris.nih.go.kr/cris/search/search_result_st01_en.jsp?seq=13489<ype=&rtype=.
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Dermatitis Atópica/tratamiento farmacológico , Enfermedades Gastrointestinales/tratamiento farmacológico , Pomadas/uso terapéutico , Extractos Vegetales/uso terapéutico , Adolescente , Niño , Preescolar , Dermatitis Atópica/complicaciones , Método Doble Ciego , Femenino , Enfermedades Gastrointestinales/complicaciones , Humanos , Masculino , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Wild ginseng is known to contain additional physiologically and pharmacologically active substances than common ginseng. The utilization of this herb can be maximized by altering its composition via tissue culture generating adventitious roots. We enriched the content of specific ginsenosides and investigated their role in ameliorating memory impairment. Cultured wild ginseng root was subjected to extraction, steaming, and fermentation using Pediococcus pentosaceus HLJG0702 to enhance the levels of ginsenosides Rg5 /Rk1. The analysis of product, HLJG0701, confirmed target ginsenosides. We analyzed the inhibitory effect of ginsenoside Rg5/Rk1, HLJG0701 and the raw material on acetylcholinesterase. Further, we performed Morris water maze, Y-maze, and passive avoidance tasks with mice exhibiting memory deficit induced by scopolamine, and we analyzed the concentrations of acetylcholinesterase and acetylcholine in their brains. Studies showed that the levels of ginsenosides Rg5 /Rk1, not found in the raw material, were enhanced in HLJG0701. Ginsenosides and HLJG0701 significantly inhibited acetylcholinesterase unlike the raw material. In all behavioral tasks, HLJG0701 showed memory improvement. It reduced acetylcholinesterase, whereas, it preserved acetylcholine in brain. In conclusion, cultured wild ginseng root extract fermented by P. pentosaceus HLJG0702 contains the distinctive ginsenosides Rg5/Rk1, which may ameliorate memory impairment via inhibition of acetylcholinesterase resulting in increased acetylcholine levels in the brain.
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Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Ginsenósidos/farmacología , Trastornos de la Memoria/prevención & control , Memoria/efectos de los fármacos , Panax/metabolismo , Pediococcus pentosaceus/metabolismo , Extractos Vegetales/farmacología , Acetilcolinesterasa/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/fisiopatología , Inhibidores de la Colinesterasa/aislamiento & purificación , Modelos Animales de Enfermedad , Fermentación , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/metabolismo , Ginsenósidos/aislamiento & purificación , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/fisiopatología , Trastornos de la Memoria/psicología , Ratones Endogámicos C57BL , Panax/microbiología , Extractos Vegetales/aislamiento & purificación , Raíces de Plantas/metabolismo , Raíces de Plantas/microbiología , EscopolaminaRESUMEN
FoF1-ATP synthase catalyzes ATP hydrolysis/synthesis coupled with a transmembrane H+ translocation in membranes. The Fo c-subunit ring plays a major role in this reaction. We have developed an assignment strategy for solid-state 13C NMR (ssNMR) signals of the Fo c-subunit ring of thermophilic Bacillus PS3 (TFo c-ring, 72 residues), carrying one of the basic folds of membrane proteins. In a ssNMR spectrum of uniformly 13C-labeled sample, the signal overlap has been a major bottleneck because most amino acid residues are hydrophobic. To overcome signal overlapping, we developed a method designated as COmplementary Sequential assignment with MInimum Labeling Ensemble (COSMILE). According to this method, we generated three kinds of reverse-labeled samples to suppress signal overlapping. To assign the carbon signals sequentially, two-dimensional Cα(i+1)-C'Cα(i) correlation and dipolar assisted rotational resonance (DARR) experiments were performed under magic-angle sample spinning. On the basis of inter- and intra-residue 13C-13C chemical shift correlations, 97% of Cα, 97% of Cß and 92% of C' signals were assigned directly from the spectra. Secondary structure analysis predicted a hairpin fold of two helices with a central loop. The effects of saturated and unsaturated phosphatidylcholines on TFo c-ring structure were examined. The DARR spectra at 15 ms mixing time are essentially similar to each other in saturated and unsaturated lipid membranes, suggesting that TFo c-rings have similar structures under the different environments. The spectrum of the sample in saturated lipid membranes showed better resolution and structural stability in the gel state. The C-terminal helix was suggested to locate in the outer layer of the c-ring.
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Resonancia Magnética Nuclear Biomolecular/métodos , ATPasas de Translocación de Protón/química , Bacillus/química , Isótopos de Carbono , Lípidos de la Membrana/química , Fosfatidilcolinas/química , Subunidades de ProteínaRESUMEN
This study aimed to ascertain the optimal range of red clover dry extracts (RC) and dried pomegranate concentrate powder (PCP) to induce anti-climacteric effects. Thus, the dose ranges showing protective effect of mixed formulae consisting of RC and PCP were examined in ovariectomized mice. At 28 days after bilateral ovariectomy (OVX), mixed herbal compositions (RC:PCP = 1:1, 1:2, 1:4, 1:8, 2:1, 4:1, and 8:1) were administered orally, at 120 mg/kg once daily for 84 days. We evaluated that RC and PCP mixture attenuate OVX-caused obesity, hyperlipidemia, hepatic steatosis, and osteoporosis. Compared to OVX-induced control mice, body weight and abdominal fat weight in OVX-induced mice were significantly decreased, concomitantly with increase of uterus weight by RC:PCP mixture. Additionally, significant increases in serum estradiol levels were observed in all RC:PCP-treated mice. RC:PCP mixture also showed protective effect against OVX-induced hyperlipidemia, hepatic steatosis. Total body and femur mean bone mineral density (BMD), osteocalcin, bALP contents were effectively increased by RC:PCP mixture. Taken together, RC:PCP mixture (2:1, 1:1, and 4:1) has remarkable protective effects against the changes induced by OVX. In particular, RC:PCP mixture (2:1) shows the strongest effect and may be considered as a potential protective agent against climacteric symptoms.
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Suplementos Dietéticos , Modelos Animales de Enfermedad , Lythraceae/química , Osteoporosis Posmenopáusica/prevención & control , Fitoestrógenos/administración & dosificación , Extractos Vegetales/administración & dosificación , Trifolium/química , Animales , Animales no Consanguíneos , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/uso terapéutico , Biomarcadores/análisis , Biomarcadores/sangre , Conservadores de la Densidad Ósea/administración & dosificación , Conservadores de la Densidad Ósea/uso terapéutico , Hígado Graso/patología , Hígado Graso/prevención & control , Femenino , Frutas/química , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/patología , Hiperlipidemias/prevención & control , Reguladores del Metabolismo de Lípidos/administración & dosificación , Reguladores del Metabolismo de Lípidos/uso terapéutico , Ratones , Obesidad/sangre , Obesidad/patología , Obesidad/prevención & control , Osteoporosis Posmenopáusica/sangre , Osteoporosis Posmenopáusica/patología , Fitoestrógenos/uso terapéutico , Extractos Vegetales/uso terapéutico , Hojas de la Planta/química , Organismos Libres de Patógenos EspecíficosRESUMEN
Anti-diabetic effects on the metabolomic differences between green tea (GT) and Aquilariae lignum-fermented green tea (fGT) were investigated in the high fat-fed mouse. To prove the differences, hypoglycemic (blood glucose, insulin and glycated hemoglobin levels, pancreas weights and histopathological-immunohistochemistrical analysis of pancreas-insulin/glucagon cells), hepato- and nephron-protective (the changes in liver and kidney weight, histopathology of liver and kidney, serum aminotransferases (AST and ALT) levels, blood urea nitrogen, and serum creatinine levels), and hypolipidemic (the changes of serum total cholesterol, triglyceride, low- and high-density lipoprotein levels with fecal total cholesterol (TC) and triglyceride (TG) contents) effects were evaluated. In addition, liver lipid peroxidation, the glutathione contents, and catalase and superoxide dismutase activities were measured according to the hepatic glucose-regulating enzyme activities of glucokinase (GK), glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PEPCK) for action mechanisms. As a result, fGT showed a stronger hypoglycemic, hepato- and nephron-protective, hypolipidemic, and anti-oxidant effect than GT in high fat-fed mice. In addition, fGT-treated mice exerted more favorable inhibitory activities against GK, G6pase, PERCK activities as compared to GT-treated mice. Taken together, fGT fermented with Aquilariae lignum, 1:49 (2%; g/g) has a stronger effect compared with GT. Therefore, fGT has the potential to increase bioactivity against type 2 diabetics.
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Camellia sinensis , Diabetes Mellitus Tipo 2/prevención & control , Fermentación , Hipoglucemiantes/uso terapéutico , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Thymelaeaceae , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Dieta Alta en Grasa , Femenino , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Hipolipemiantes/uso terapéutico , Riñón/efectos de los fármacos , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Ratones , Páncreas/efectos de los fármacos , Páncreas/patología , Preparaciones de Plantas/metabolismo , Preparaciones de Plantas/farmacologíaRESUMEN
Plants rich in antioxidant substances may be useful for preventing skin aging. Pomegranates, containing flavonoids and other polyphenolic compounds, are widely consumed due to their beneficial properties. We examined the underlying mechanisms of dried pomegranate concentrate powder (PCP) on melanin synthesis in B16F10 melanoma cells. The antioxidant effects of PCP were determined by measuring free radical scavenging capacity and transcript levels of antioxidant enzymes. To explore the inhibitory effects of PCP on melanin synthesis, we measured tyrosinase activity and melanin content in α-melanocyte stimulating hormone (α-MSH)-stimulated B16F10 cells. In addition, the levels of tyrosinase-related protein-1 (TRP-1), TRP-2, tyrosinase, and microphthalmia-associated transcription factor (MITF) expression were determined by Western blotting. Changes in the phosphorylation status of protein kinase A (PKA), cAMP response element-binding protein (CREB), mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K), serine/threonine kinase Akt, and glycogen kinase 3ß (GSK3ß) were also examined. The free radical scavenging activity of PCP increased in a dose-dependent manner. In PCP-treated B16F10 cells, transcript levels of glutathione peroxidase-1 (GPx-1) were increased compared with α-MSH-stimulated cells. In addition, PCP led to the down-regulation of phospho-p38, phospho-PKA, phospho-CREB, phospho-GSK3ß, MITF, and TRP-1 compared with α-MSH-stimulated B16F10 cells. We believe this effect may be associated with PCP activity, which leads to the inhibition of melanin production and tyrosinase activity. These results suggest that PCP decreases tyrosinase activity and melanin production via inactivation of the p38 and PKA signaling pathways, and subsequently decreases phosphorylation of CREB, MITF, and melanogenic enzymes. These observations provided new insights on the molecular mechanisms of the skin-whitening property of PCP.
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Lythraceae/metabolismo , Melaninas/biosíntesis , Melanoma Experimental/tratamiento farmacológico , Monofenol Monooxigenasa/metabolismo , Preparaciones de Plantas/farmacología , Animales , Antioxidantes/farmacología , Proteína de Unión a CREB/metabolismo , Línea Celular Tumoral , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Depuradores de Radicales Libres/farmacología , Liofilización , Glutatión Peroxidasa/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Ratones , Factor de Transcripción Asociado a Microftalmía/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , alfa-MSH/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Glutatión Peroxidasa GPX1RESUMEN
Ionizing radiation has different biological effects according to dose and dose rate. In particular, the biological effect of low-dose radiation is unclear. Low-dose whole-body gamma irradiation activates immune responses in several ways. However, the effects and mechanism of low-dose radiation on allergic responses remain poorly understood. Previously, we reported that low-dose ionizing radiation inhibits mediator release in IgE-mediated RBL-2H3 mast cell activation. In this study, to have any physiological relevance, we investigated whether low-dose radiation inhibits allergic responses in activated human mast cells (HMC-1(5C6) and LAD2 cells), mouse models of passive cutaneous anaphylaxis and the late-phase cutaneous response. High-dose radiation induced cell death, but low-dose ionizing radiation of <0.5 Gy did not induce mast cell death. Low-dose ionizing radiation that did not induce cell death significantly suppressed mediator release from human mast cells (HMC-1(5C6) and LAD2 cells) that were activated by antigen-antibody reaction. To determine the inhibitory mechanism of mediator released by low-dose ionizing radiation, we examined the phosphorylation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cγ, and protein kinase C, as well as the intracellular free Ca2+ concentration ([Ca2+]i). The phosphorylation of signaling molecules and [Ca2+]i following stimulation of FcεRI receptors was inhibited by low dose ionizing radiation. In agreement with its in vitro effect, ionizing radiation also significantly inhibited inflammatory cells infiltration, cytokine mRNA expression (TNF-α, IL-4, IL-13), and symptoms of passive cutaneous anaphylaxis reaction and the late-phase cutaneous response in anti-dinitrophenyl IgE-sensitized mice. These results indicate that ionizing radiation inhibits both mast cell-mediated immediate- and delayed-type allergic reactions in vivo and in vitro.
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Inmunoglobulina E/inmunología , Anafilaxis Cutánea Pasiva/efectos de la radiación , Radiación Ionizante , Animales , Señalización del Calcio , Línea Celular , Citocinas/genética , Citocinas/metabolismo , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mastocitos/inmunología , Mastocitos/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Anafilaxis Cutánea Pasiva/inmunología , Fosfolipasa C gamma/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Receptores de IgE/inmunología , Quinasa Syk , Familia-src Quinasas/metabolismoRESUMEN
We evaluated the preventive effects of four types of seawater collected in Republic of Korea on hairless mice with 2,4-dinitrochlorobenzene- (DNCB-) induced allergic/atopic dermatitis (AD). The anti-inflammatory effects were evaluated by measuring tumor necrosis factor- (TNF-) α and interleukins (ILs). Glutathione (GSH), malondialdehyde (MDA), superoxide anion, and inducible nitric oxide synthase (iNOS) were measured to evaluate the antioxidant effects. Caspase-3 and poly (ADP-ribose) polymerase (PARP) were observed to measure the antiapoptotic effects; matrix metalloproteinase- (MMP-) 9 levels were also evaluated. Mice with AD had markedly higher clinical skin severity scores and scratching behaviors; higher TNF-α and ILs (1ß, 10, 4, 5, and 13) levels; higher MDA, superoxide anion, caspase-3, PARP, and MMP-9 levels; and greater iNOS activity. However, the severity of AD was significantly decreased by bathing in seawaters, but it did not influence the dermal collagen depositions and skin tissue antioxidant defense systems. These results suggest that bathing in all four seawaters has protective effects against DNCB-induced AD through their favorable systemic and local immunomodulatory effects, active cytoprotective antiapoptotic effects, inhibitory effects of MMP activity and anti-inflammatory and antioxidative effects.
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Red clover (RC) shows potential activity against menopausal symptoms and pomegranates have antioxidative and beneficial effects on postmenopausal symptoms; thus, we investigated whether the anti-climacteric activity of RC could be enhanced by the addition of dried pomegranate concentrate powder (PCP) extracts in ovariectomized (OVX) rats. Regarding the anti-osteoporotic effects, bone mineral density increased significantly in OVX induced rats treated with 60 and 120 mg/kg of an RC:PCP 2:1 mixture, respectively, compared with OVX control rats. Additionally, femoral, tibia, and L4 bone resorption was decreased in OVX induced control rats treated with the RC:PCP 2:1 mixture (60 and 120 mg/kg), respectively, compared with OVX control rats. Regarding anti-obesity effects, the OVX induced rats treated with 60 and 120 mg/kg of the RC:PCP 2:1 mixture showed a decrease in total fat pad thickness, the mean diameters of adipocytes and the body weights gain compared with OVX induced control rats. The estradiol and bone-specific alkaline phosphatase levels were significantly increased in OVX induced rats treated with the RC:PCP 2:1 mixture (120 mg/kg) compared with OVX induced control rats, also, the uterine atrophy was significantly inhibited in 60 and 120 mg/kg of the RC:PCP 2:1 mixture treatment compared with OVX control rats. In conclusion, our results indicate that PCP enhanced the anti-climacteric effects of RC in OVX rats. The RC:PCP 2:1 mixture used in this study may be a promising new potent and protective agent for relieving climacteric symptoms.
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Fármacos Antiobesidad/farmacología , Frutas , Lythraceae , Osteoporosis/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/farmacología , Trifolium/química , Fosfatasa Alcalina/sangre , Animales , Antioxidantes/farmacología , Densidad Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Desecación , Estradiol/sangre , Femenino , Fémur/efectos de los fármacos , Fémur/metabolismo , Osteocalcina/sangre , Ovariectomía , Preparaciones de Plantas/farmacología , Ratas , Ratas Sprague-Dawley , Tibia/efectos de los fármacos , Tibia/metabolismoRESUMEN
The major components of tea may be significantly influenced according to the type of fermentation, and consequently the effects of different teas will differ. We examined whether green tea fermented with Aquilariae Lignum (fGT) shows a stronger anti-diabetic effect than unfermented green tea (GT) on mice with type 2 diabetes. To evaluate the anti-obesity effect of fGT, we assessed body weight, fecal excretion, serum leptin levels, exocrine pancreatic zymogen granule contents, and periovarian fat weight and adiponectin contents. Blood glucose levels, pancreatic weight, and numbers of pancreatic islet insulin- and glucagon-producing cells were determined to evaluate anti-hypoglycemic effects, while total cholesterol, triglyceride, and low- and high-density lipoprotein levels were determined to evaluate anti-hyperlipidemic effects. The antioxidant effect of fGT was detected by measuring malondialdehyde and glutathione contents and the activities of catalase and superoxide dismutase. fGT showed anti-obesity, anti-hypoglycemic, anti-hyperlipidemia, and antioxidant effects. Additionally, fGT exerted stronger anti-diabetic effects compared with GT. Collectively, these results suggested that fGT fermented with the appropriate amounts of Aquilariae Lignum (49:1) has a stronger effect compared with GT. Thus, fGT is a promising and potent new therapeutic agent for type 2 diabetes.
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Camellia sinensis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Fermentación , Hipoglucemiantes/uso terapéutico , Obesidad/tratamiento farmacológico , Fitoterapia , Thymelaeaceae , Tejido Adiposo/metabolismo , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/sangre , Femenino , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Hipolipemiantes/uso terapéutico , Lípidos/sangre , Ratones Endogámicos , Obesidad/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
BACKGROUND: This study aimed to determine whether calcium gluconate exerts protective effects on osteoarthritis (OA) induced by anterior cruciate ligament (ACL) transection and partial medial meniscectomy. METHODS: Calcium gluconate was administered by mouth daily for 84 days to male ACL transected and partial medial meniscectomized Sprague-Dawley rats 1 week after operation. RESULTS: Eighty-four days of treatment with 50 mg/kg calcium gluconate led to a lower degree of articular stiffness and cartilage damage compared to the OA control, possibly through inhibition of overexpressed cyclooxygenase (COX)-2 and related chondrocyte apoptosis. Similar favorable effects on stiffness and cartilage were detected in calcium gluconate-administered rats. Additionally, calcium gluconate increased 5-bromo-2'-deoxyuridine (BrdU) uptake based on observation of BrdU-immunoreactive cells on both the femur and tibia articular surface cartilages 84 days after intra-joint treatment with calcium gluconate. CONCLUSIONS: Taken together, our results demonstrate that calcium gluconate has a protective effect against OA through inhibition of COX-2 and related chondrocyte apoptosis.
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Gluconato de Calcio/farmacología , Osteoartritis/tratamiento farmacológico , Animales , Ligamento Cruzado Anterior/cirugía , Apoptosis/efectos de los fármacos , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Bromodesoxiuridina/metabolismo , Cartílago Articular/efectos de los fármacos , Cartílago Articular/metabolismo , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Ciclooxigenasa 2/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Masculino , Meniscos Tibiales/cirugía , Osteoartritis/metabolismo , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
High-dose rosuvastatin induces regression of coronary atherosclerosis, but it remains uncertain whether usual-dose statin has similar effects. We compared the effects of atorvastatin 20 mg/day versus rosuvastatin 10 mg/day on mild coronary atherosclerotic plaques (20% to 50% luminal narrowing and lesion length >10 mm) using intravascular ultrasound (IVUS). Three hundred fifty statin-naive patients with mild coronary atherosclerotic plaques were randomized to receive atorvastatin 20 mg/day or rosuvastatin 10 mg/day. IVUS examinations were performed at baseline and 6-month follow-up. Primary end point was percent change in total atheroma volume (TAV) defined as (TAV at 6 months - TAV at baseline)/(TAV at baseline) × 100. Evaluable IVUS was obtained for 271 patients (atorvastatin in 143, rosuvastatin in 128). Clinical characteristics, lipid levels, and IVUS measurements at baseline were similar between the 2 groups. At 6-month follow-up, percent change in TAV was significantly less in the atorvastatin group than in the rosuvastatin group (-3.9 ± 11.9% vs -7.4 ± 10.6%, respectively, p = 0.018). In contrast, change in percent atheroma volume was not different between the 2 groups (-0.3 ± 4.2 vs -1.1 ± 3.5, respectively, p = 0.157). Compared to baseline, TAV and TAV at the most diseased 10-mm subsegment were significantly decreased in the 2 groups (p <0.001). Changes in lipid profiles at 6-month follow-up were similar between the 2 groups. In conclusion, usual doses of atorvastatin and rosuvastatin induced significant regression of coronary atherosclerosis in statin-naive patients, with a greater decrease in favor of rosuvastatin.
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Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Fluorobencenos/uso terapéutico , Ácidos Heptanoicos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Placa Aterosclerótica/tratamiento farmacológico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Sulfonamidas/uso terapéutico , Atorvastatina , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/sangre , Placa Aterosclerótica/diagnóstico por imagen , Estudios Prospectivos , República de Corea , Rosuvastatina Cálcica , Ultrasonografía IntervencionalRESUMEN
Despite the excellent chemotherapeutic effect of 5-fluorouracil, its cytotoxicity and genotoxicity in normal cells remain a major problem. We sought to assess whether Bupleuri Radix extract enhances 5-fluorouracil-induced cytotoxicity in HepG2 hepatoma cells, while protecting normal blood lymphocytes. Bupleuri Radix, used for treatment of liver disease in oriental medicine, possesses antitumour properties; it induces apoptosis through cell arrest in tumour cells, but does not affect normal lymphocytes. In this study, we evaluated the protective and enhancing effects of Bupleuri Radix on 5-fluorouracil-induced cytotoxicity in HepG2 cells and normal lymphocytes. Treatment with Bupleuri Radix increased the micronuclei frequency and DNA damage, resulting from 5-fluorouracil treatment. However, when human lymphocytes were cotreated with Bupleuri Radix and 5-fluorouracil, the frequency of 5-fluorouracil-induced micronuclei decreased. Although the extent of 5-fluorouracil-induced DNA damage, determined by single-cell gel electrophoresis, increased after treating HepG2 cells with Bupleuri Radix, it decreased in normal lymphocytes. When cells were treated with 20 microM 5-fluorouracil and 200 microg/ml Bupleuri Radix simultaneously, Bax protein increased in HepG2 cells at 24 hr; however, p21 and p53 proteins were up-regulated in normal human lymphocytes. Cotreatment with 200 microg/ml Bupleuri Radix and 20 microM 5-fluorouracil resulted in cell arrest at the late G(1)/early S phase in HepG2 cells (55.80 +/- 0.19%) and normal lymphocytes (97.19 +/- 0.27%). In addition, Bupleuri Radix and 5-fluorouracil treatment increased mitochondria membrane potential collapse only in HepG2 cells (19.02%), while it was not changed in lymphocytes. In conclusion, our findings suggest that Bupleuri Radix may be effective as a therapeutic agent to treat hepatomas.
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Antimetabolitos Antineoplásicos , Bupleurum/química , Fluorouracilo , Linfocitos/efectos de los fármacos , Sustancias Protectoras/farmacología , Antimetabolitos Antineoplásicos/farmacología , Antimetabolitos Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Apoptosis/genética , Western Blotting , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayo Cometa , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Fluorouracilo/farmacología , Fluorouracilo/toxicidad , Expresión Génica/efectos de los fármacos , Humanos , Linfocitos/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Micronúcleos con Defecto Cromosómico/inducido químicamente , Micronúcleos con Defecto Cromosómico/efectos de los fármacos , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Sustancias Protectoras/aislamiento & purificación , Factores de TiempoRESUMEN
Whole bee venom (BV) is used to treat inflammatory diseases in Korean traditional medicine. Various studies have demonstrated anti-inflammatory and anticancer effects of BV. The toxicity of individual components of BV has been widely studied, although few studies have reported on the toxicity of BV. We sought to evaluate the cytotoxicity of BV in normal human lymphocytes and HL-60 cells. When cells were treated with BV at concentrations of 1 or 5 microg/ml, BV induced cell death in a time-dependent manner until 24 h, but these cytotoxic effects ended thereafter. When cells were treated with BV at a concentration of 10 microg/ml, however, viability decreased until 72 h, which may have been due to the half-life of BV. Whole BV also inhibited proliferation in these cells. BV induced DNA fragmentation and micronuclei in HL-60 cells and DNA fragmentation in human lymphocytes. Phosphate and tensin homolog (PTEN) up-regulation in HL-60 cells may induce S-phase cell cycle arrest. Forkhead transcription factor (FKHR and FKHRL1) up-regulation in human lymphocytes by whole BV treatment may be involved in the repair of damaged DNA and reduce genotoxicity. Based on these results, whole BV may exert cytotoxicity in these two cells in a different fashion.
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Venenos de Abeja/toxicidad , Abejas/química , Linfocitos/citología , Linfocitos/efectos de los fármacos , Adulto , Animales , Forma de la Célula , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Femenino , Citometría de Flujo , Células HL-60 , Humanos , Cinética , Linfocitos/metabolismo , Transducción de SeñalRESUMEN
We have developed fluorescence polarization (FP) assays of human melanocortin 4 receptor (MC4R) in 384-well microtiter plates using TAMRA-NDP-MSH as a tracer. The rank order of potency of agonists and antagonists agrees well relative to the published assays: SHU9119>MTII>NDP alphaMSH>alphaMSH. We have screened libraries of Korean plant extracts and frog peptide analogues in search of MC4R ligands using FP assays and cell-based CRE luciferase reporter assays. We report that FLGFLFKVASK, FLGWLFKVASK, FLGALFKWASK, and FLGWLFKWASK are the peptide analogues, which bind to human MC4R receptor with good affinity in vitro. FLGWLFKVASK and FLGWLFKWASK stimulated CRE-driven reporter gene via MC4R. In luciferase reporter assays, they possess the pharmacological and functional profiles of full agonists. We demonstrate the interaction of MC4R with 11-residue antimicrobial peptides derived from the Korean frog, Rana rugosa. The results suggest that MC4R interacts promiscuously with bioactive analogues of antimicrobial peptide, gaegurin-5.