RESUMO
Although the use of intra-articular polynucleotide (IA PN) injection as a viscosupplement for knee osteoarthritis (OA) treatment has been proposed, its efficacy and safety compared to high molecular weight hyaluronic acid (HMWHA) injection has not yet been established. The present double-blind, multicenter, randomized controlled trial aimed to investigate the efficacy and safety of IA PN injection compared to IA HMWHA injection. A total of 60 patients (15 men, 45 women, 64.5 ± 7.5 years) with knee OA (Kellgren-Lawrence grade 1-4) were randomly allocated to each group. All patients were given three IA injections of PN (n = 30) or HMWHA (n = 30) at intervals of 1 week. The primary endpoint was the change rate in weight-bearing pain (WBP) 16 weeks from the baseline. The secondary endpoint included multiple measurements: the change rate in WBP rate at 8 weeks; the change rate in pain level at rest and during walking at 8 and 16 weeks; the Korean-Western Ontario and McMaster University Osteoarthritis index; the Euro-Quality of Life-5 Dimension; Clinical Global Impression, Patient Global Impression at 8 and16 weeks, and total consumption of rescue medicine. The mean change rate in the WBP at 16 weeks from the baseline was - 54.0 ± 38.1% in the IA PN group and - 42.8 (± 35.8%) in the IA HMWHA group, and there was no significant difference between the two groups (p = 0.296). All secondary endpoints related with pain and functional outcome also showed no significant difference between the two groups. Pain at the injection site and swelling were reported as adverse events, and the incidence was similar between the two groups. IA PN showed comparable efficacy and safety to IA HMWHA at 3 times injection with an interval of 1 week. IA PN can be useful alternative to IA HMWHA for the treatment of knee OA.
Assuntos
Ácido Hialurônico , Osteoartrite do Joelho , Masculino , Humanos , Feminino , Ácido Hialurônico/efeitos adversos , Qualidade de Vida , Resultado do Tratamento , Dor/complicações , Injeções Intra-Articulares , Método Duplo-CegoRESUMO
In women, ovary cancer is already the fifth leading cause of mortality worldwide. The use of cancer therapies, such as surgery, radiotherapy, and chemotherapy, may be a powerful anti-cancer therapeutic strategy; however, these therapies still have many problems, including resistance, toxicity, and side effects. Therefore, natural herbal medicine has the potential to be used for cancer therapy because of its low toxicity, fewer side effects, and high success. This study aimed to investigate the anti-cancer effect of 6-shogaol in ovarian cancer cells. 6-shogaol induces ER stress and cell death via the reduction in cell viability, the increase in LDH cytotoxicity, caspase-3 activity, and Ca2+ release, and the upregulation of GRP78, p-PERK, p-eIF2α, ATF-4, CHOP, and DR5. Moreover, 6-shogaol treatment medicates endoplasmic reticulum (ER) stress and cell death by upregulating Nox4 and releasing ROS. The knockdown of Nox4 in ovarian cancer cells inhibits ER stress and cell death by blocking the reduction in cell viability and the enhancement of LDH cytotoxicity, caspase-3 activity, Ca2+, and ROS release. In gefitinib-resistant ovarian cancer cells, A2780R and OVCAR-3R, 6-shogaol/gefitinib overcomes gefitinib resistance by inhibiting EMT phenomena such as the reduction in E-cadherin, and the increase in N-cadherin, vimentin, Slug, and Snail. Therefore, our results suggest that 6-shogaol exerts a potential anti-cancer effect in ovarian cancer and combination treatment with 6-shogaol and gefitinib may provide a novel anti-tumor therapeutic strategy in gefitinib-resistant ovarian cancer.
Assuntos
Apoptose , Neoplasias Ovarianas , Feminino , Humanos , Gefitinibe/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Caspase 3 , Estresse do Retículo Endoplasmático , Neoplasias Ovarianas/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Chemotherapy is a powerful anti-tumor therapeutic strategy; however, resistance to treatment remains a serious concern. To overcome chemoresistance, combination therapy with anticancer drugs is a potential strategy. We developed a novel herbal extract, JI017, with lower toxicity and lesser side effects. JI017 induced programmed cell death and excessive unfolded protein response through the release of intracellular reactive oxygen species (ROS) and calcium in breast cancer cells. JI017 treatment increased the expression of endoplasmic reticulum (ER) stress markers, including p-PERK, p-eIF2α, ATF4, and CHOP, via the activation of both exosomal GRP78 and cell lysate GRP78. The ROS inhibitors diphenyleneiodonium and N-acetyl cysteine suppressed apoptosis and excessive ER stress by inhibiting Nox4 in JI017-treated breast cancer cells. Furthermore, in paclitaxel-resistant breast cancer cell lines, MCF-7R and MDA-MB-231R, a combination of JI017 and paclitaxel overcame paclitaxel resistance by blocking epithelial-mesenchymal transition (EMT) processes, such as the downregulation of E-cadherin expression and the upregulation of HIF-1α, vimentin, Snail, and Slug expression. These findings suggested that JI017 exerts a powerful anti-cancer effect in breast cancer and a combination therapy of JI017 and paclitaxel may be a potential cancer therapy for paclitaxel resistant breast cancer.
RESUMO
Hypoxia is a major obstacle to gastric cancer (GC) therapy and leads to chemoresistance as GC cells are frequently exposed to the hypoxia environment. Apigenin, a flavonoid found in traditional medicine, fruits, and vegetables and an HDAC inhibitor, is a powerful anti-cancer agent against various cancer cell lines. However, detailed mechanisms involved in the treatment of GC using APG are not fully understood. In this study, we investigated the biological activity of and molecular mechanisms involved in APG-mediated treatment of GC under hypoxia. APG promoted autophagic cell death by increasing ATG5, LC3-II, and phosphorylation of AMPK and ULK1 and down-regulating p-mTOR and p62 in GC. Furthermore, our results show that APG induces autophagic cell death via the activation of the PERK signaling, indicating an endoplasmic reticulum (ER) stress response. The inhibition of ER stress suppressed APG-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further show that APG induces ER stress- and autophagy-related cell death through the inhibition of HIF-1α and Ezh2 under normoxia and hypoxia. Taken together, our findings indicate that APG activates autophagic cell death by inhibiting HIF-1α and Ezh2 under hypoxia conditions in GC cells.
Assuntos
Apigenina/metabolismo , Neoplasias Gástricas/metabolismo , Adenilato Quinase/metabolismo , Apigenina/farmacologia , Apoptose , Morte Celular Autofágica/efeitos dos fármacos , Autofagia , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Morte Celular , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Estresse do Retículo Endoplasmático , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais , Neoplasias Gástricas/fisiopatologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
Acute liver failure (ALF) refers to the sudden loss of liver function and is accompanied by several complications. In a previous study, we revealed the protective effect of Centella asiatica 50% ethanol extract (CA-HE50) on acetaminophen-induced liver injury. In the present study, we investigate the hepatoprotective effect of CA-HE50 in a lipopolysaccharide/galactosamine (LPS-D-Gal)-induced ALF animal model and compare it to existing therapeutic silymarin, Lentinus edodes mycelia (LEM) extracts, ursodeoxycholic acid (UDCA) and dimethyl diphenyl bicarboxylate (DDB). Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were decreased in the CA-HE50, silymarin, LEM, UDCA and DDB groups compared to the vehicle control group. In particular, AST and ALT levels of the 200 mg/kg CA-HE50 group were significantly decreased compared to positive control groups. Lactate dehydrogenase (LDH) levels were significantly decreased in the CA-HE50, silymarin, LEM, UDCA and DDB groups compared to the vehicle control group and LDH levels of the 200 mg/kg CA-HE50 group were similar to those of the positive control groups. Superoxide dismutase (SOD) activity was significantly increased in the 100 mg/kg CA-HE50, LEM and UDCA groups compared to the vehicle control group and, in particular, the 100 mg/kg CA-HE50 group increased significantly compared to positive control groups. In addition, the histopathological lesion score was significantly decreased in the CA-HE50 and positive control groups compared with the vehicle control group and the histopathological lesion score of the 200 mg/kg CA-HE50 group was similar to that of the positive control groups. These results show that CA-HE50 has antioxidant and hepatoprotective effects at a level similar to that of silymarin, LEM, UDCA and DDB, which are known to have hepatoprotective effects; further, CA-HE50 has potential as a prophylactic and therapeutic agent in ALF.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Falência Hepática Aguda/tratamento farmacológico , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Triterpenos/farmacologia , Alanina Transaminase/sangue , Animais , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Centella , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Dioxóis/farmacologia , Modelos Animais de Doenças , Proteínas Fúngicas/farmacologia , Galactosamina , Lipopolissacarídeos , Falência Hepática Aguda/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/farmacologia , Silimarina/farmacologia , Ácido Ursodesoxicólico/farmacologiaRESUMO
The objective of this study was to examine the therapeutic effect of ruxolitinib, an orally administered selective Janus kinase (JAK) 1/2 inhibitor, on chronic graft-versus-host disease (cGVHD) using a murine model of sclerodermatous GVHD (scl-GVHD). Compared with scl-GVHD controls, ruxolitinib-treated recipients had scl-GVHD of significantly attenuated clinical and pathological severity in the skin and decreased frequencies of effector cells, CD4+ T cells, and CD11b+ macrophage/monocytes. Regulatory CD4+ Foxp3+ T cells were expanded whereas interferon-γ (IFN-γ)-producing CD4+ T cells were significantly decreased in ruxolitinib-treated recipients. Ruxolitinib suppressed not only the production of IFN-γ from CD4+ T cells and monocyte chemoattractant protein 1 (MCP-1) from CD11b+ macrophage/monocytes, but also the proliferation of these cells in vitro. Levels of both cytokines (IFN-γ and MCP-1) were also reduced in the spleen and skin of ruxolitinib-treated recipients in vivo. IFN-γ-induced MCP-1 production and migration of RAW 264.7 cells, a macrophage cell line, were inhibited by ruxolitinib. However, supplementation with MCP-1 restored this effect of ruxolitinib. In addition, blocking JAK-STAT signaling using ruxolitinib reduced the activation of STAT1 in stimulated immune effector cells. Taken together, these results suggest that ruxolitinib can prevent scl-GVHD by suppressing IFN-γ produced by T cells and MCP-1 expression in macrophage/monocytes via inhibition of JAK-STAT signaling.
Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Pirazóis/farmacologia , Animais , Doença Crônica , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Doença Enxerto-Hospedeiro/enzimologia , Janus Quinase 1/metabolismo , Janus Quinase 2/genética , Camundongos , Camundongos Endogâmicos BALB C , Nitrilas , PirimidinasRESUMO
In gastric cancer (GC), hypoxia is one of the greatest obstacles to cancer therapy. In this present study, we report that SH003, an herbal formulation, induces ER stress via PERK-ATF4-CHOP signaling in GC. SH003-mediated ER stress inhibits G9a, a histone methyltransferase, by reducing STAT3 phosphorylation and activates autophagy, indicating to the dissociation of Beclin-1 and autophagy initiation from Bcl-2/Beclin-1 complex. However, the inhibition of PERK and CHOP inhibited SH003-induced cell death and autophagy activation. Moreover, targeting autophagy using specific siRNAs of LC3B or p62 or the autophagy inhibitor 3-MA also inhibited SH003-induced cell death in GC. Interestingly, SH003 induces BNIP3-mediated autophagic cell death under hypoxia than normoxia in GC. These findings reveal that SH003-induced ER stress regulates BNIP3-induced autophagic cell death via inhibition of STAT3-G9a axis under hypoxia in GC. Therefore, SH003 may an important tumor therapeutic strategy under hypoxia-mediated chemo-resistance.
Assuntos
Autofagia/efeitos dos fármacos , Extratos Vegetais/farmacologia , Neoplasias Gástricas/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Angelica , Astrágalo , Morte Celular Autofágica/efeitos dos fármacos , Proteína Beclina-1 , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Extratos Vegetais/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , TrichosanthesRESUMO
INTRODUCTION/PURPOSE: The purpose of this systematic review was to evaluate the effect of iron supplementation during total knee arthroplasty (TKA): (1) Is the iron supplementation necessary during TKA? (2) When is the optimal timing of iron supplementation? (3) Which is better, between orally and intravenously administered iron supplementation? And (4) What is the optimal dose of iron supplementation? MATERIALS AND METHODS: A rigorous and systematic approach was used and each of the selected studies was evaluated for methodological quality. Data about study design, total number of cases enrolled, iron administration method, timing, and dose were extracted. Change in hemoglobin and transfusion rates were extracted to evaluate the effectiveness of iron supplementation. RESULTS: Eleven studies were included in the final analysis. Most of studies reported that hemoglobin change between iron and control group did not show any difference. Only one study reported that iron supplementation could reduce the decrease in hemoglobin. However, transfusion rate showed a decrease in the iron supplementation group compared with the control group. There was no clear consensus on the optimum timing and dose of iron supplementation and intravenously administered iron was more effective than orally administered iron, especially in anemic patients. CONCLUSION: Iron supplementation is not clear as a way to raise hemoglobin levels after TKA, but an effective treatment for lowering transfusion rate, especially in patients with anemia. We could not determine the optimal timing and dose of the iron. Intravenously administered iron was similar to, or better than, orally administered iron for improving hemoglobin levels and transfusion rate.
RESUMO
Hepatic protective effects of Ligularia fischeri (LF) and Aronia melanocarpa (AM) against alcohol were investigated in vitro and in vivo test. LF, AM, and those composed mixing material (LF+AM) were treated in HepG2 cell. Alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) activities were significantly increased in each singleness extract and mixed composite. The protective effect on alcoholic liver damage was investigated by animal models. Serum alcohol level and acetaldehyde level were significantly decreased by LF+AM treatment in acute experimental model. In the chronic mouse model study, we had found that the increased plasma liver damage index (alkaline phosphatase) by alcohol treatment was declined by oral administration of LF+AM extraction composite. As well as, it was identified that the protection effect was induced by increasing catalase activity and suppressing COX-2, TNF-α, MCP-1, and IL-6 mRNA expressions. CYP2E1 mRNA expression was also increased. These results suggest that oral ingestion of LF and AM mixed composite is able to protect liver against alcohol-induced injury by increasing alcohol metabolism activity and antioxidant system along with decreasing inflammatory responses.
Assuntos
Ligularia/química , Hepatopatias Alcoólicas/prevenção & controle , Fígado/metabolismo , Photinia/química , Extratos Vegetais/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Citocinas/metabolismo , Células Hep G2 , Humanos , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Masculino , Extratos Vegetais/química , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Despite the significant disease burden, there is a paucity of data addressing the population-based incidence of acute angle closure glaucoma (AACG). Therefore, we estimated the nationwide, population-based standardized incidence rate of AACG in Korea. METHODS: We conducted a nationwide, population-based, retrospective study using the database of National Health Insurance (NHI) system, which includes the entire Korean population (approximately 50 million people) from 2009 to 2015. We identified patients with incident AACG during the 5-year study period from 2011 to 2015 based on their diagnosis and AACG-related treatments (laser iridotomy and cataract surgery), and estimated age- and gender-standardized incidence rate of AACG during the study period. RESULTS: We identified 11,049 patients (8,022 women, 72.6%) with incident AACG during the 5-year study period. Of these, after excluding 6 patients under 20 years old, 11,043 patients (8,020 women, 72.6%) aged ≥ 20 years were included in the analysis. The average standardized incidence rate during the 5-year study period was 59.95 (95% confidence interval [CI], 58.87-61.03) per 1,000,000 person-years. The incidence rates increased sharply with age and peaked at individuals aged 75-79 years; in men, those peaked at the same age group, however, in women, those peaked at individuals aged 70-74 years. Women has a 2.56 folds higher incidence rate (85.84 [95% CI, 84.03-87.66] per 1,000,000 person-years) than men (33.48 [95% CI, 32.33-34.62] per 1,000,000 person-years). CONCLUSION: The present study provides detailed estimates for AACG incidence according to all age groups and gender through the 5-year study period.
Assuntos
Glaucoma de Ângulo Fechado/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Feminino , Glaucoma de Ângulo Fechado/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde , República da Coreia/epidemiologia , Estudos Retrospectivos , Adulto JovemRESUMO
The current treatment options for inflammatory bowel disease (IBD) are unsatisfactory. Therefore, novel and safer therapies are needed. We previously reported that koreanaside A (KA) showed high radical scavenging activity and suppressed vascular cell adhesion molecule 1 (VCAM-1) expression in vascular smooth muscle cells. However, the molecular mechanisms involved in its anti-inflammatory effect have not been reported. KA inhibited pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), and prostaglandin E2 (PGE2). KA inhibited the production and mRNA expression of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) induced by LPS. KA downregulated the myeloid differentiation primary response 88 (MyD88)-dependent inflammatory gene expressions in the MyD88-overexpressed cells. KA suppressed the LPS-induced transcriptional and DNA-binding activities of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB). KA was found to inhibit the phosphorylation of Janus kinase 1/2 (JAK1/2) and signal transducers and activators of transcription 1/3 (STAT1/3). In DSS-induced colitis mice, KA relieved the symptoms of colitis by suppressing inflammatory cell infiltration, restoring tight junction (TJ)- and epithelial-mesenchymal transition (EMT)-related protein expression, and inactivating AP-1, NF-κB, and STAT1/3. Therefore, KA reduced inflammatory responses by downregulating AP-1, NF-κB, and JAK/STAT signaling in LPS-induced macrophages and DSS-induced colitis mice.
Assuntos
Anti-Inflamatórios/farmacologia , Colite/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/farmacologia , Lignanas/química , Lignanas/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Sulfato de Dextrana/toxicidade , Flores/química , Forsythia/química , Glicosídeos/isolamento & purificação , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Lignanas/isolamento & purificação , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Células RAW 264.7 , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismoRESUMO
A change in homeostasis between food intake and energy expenditure is the hallmark of obesity. Many plant-based weight-management products are available in dietary supplement markets with no direct efficacy comparison. In this in vivo acute feed intake study in rats, the appetite suppression efficacy of well-known natural ingredients in the weight-loss market were evaluated. We tested pure caffeine, potato skin extract, Cissus quadrangularis extract, Garcinia cambogia extract, Crocus sativus extract, raspberry ketone isolated from Rubus idaeus, one commercial product (Appetrex), and one novel composition (UP601). Rats treated with potato skin extract, Crocus sativus bulb extract, and Cissus quadrangularis extracts showed statistically significant reduction in food consumption only at the 2-hour timepoint with 44.9%, 34.1%, and 44.3% reductions, respectively, after food provision at an equivalent human dosage of 2 g, 10 g, and 10 g, respectively. Garcinia cambogia fruit extract and raspberry ketone from Rubus idaeus showed statistically significant reduction in food consumption only at the 1-hour timepoint with 33.7% and 79.4% reductions, respectively, after food provision at an equivalent human dosage of 8 g and 5 g, respectively. UP601 and Appetrex were compared at 230 mg/kg. While 88.5%, 73.8%, and 63.1% reductions in food intake were observed for the UP601 treatment group, 64.2%, 27.5%, and 34.7% reductions in food intake were observed for rats treated with Appetrex at 1 h, 2 h, and 4 h after food provision. The composition UP601 demonstrated superior activity in food intake compared to any of the dietary supplements marketed for appetite suppression tested in this study.
Assuntos
Apetite/efeitos dos fármacos , Suplementos Nutricionais , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Energia/efeitos dos fármacos , Magnoliopsida , Extratos Vegetais/farmacologia , Redução de Peso , Animais , Fármacos Antiobesidade/farmacologia , Produtos Biológicos/farmacologia , Cissus , Crocus , Frutas , Garcinia cambogia , Cetonas/farmacologia , Masculino , Obesidade/terapia , Ratos Sprague-Dawley , Rubus/químicaRESUMO
Kaempferol, a flavonoid, found in traditional medicine, fruits, and vegetables, and an HDAC inhibitor, is a powerful anti-cancer reagent against various cancer cell lines. However, detailed mechanisms involved in the treatment of gastric cancer (GC) using kaempferol are not fully understood. In our study, we investigated the biological activity and molecular mechanism involved in kaempferol-mediated treatment of GC. Kaempferol promoted autophagy and cell death, and increased LC3-I to LC3-II conversion and the downregulation of p62 in GC. Furthermore, our results showed that kaempferol induces autophagic cell death via the activation of the IRE1-JNK-CHOP signaling, indicating ER stress response. Indeed, the inhibition of ER stress suppressed kaempferol-induced autophagy and conferred prolonged cell survival, indicating autophagic cell death. We further showed that kaempferol mediates epigenetic change via the inhibition of G9a (HDAC/G9a axis) and also activates autophagic cell death. Taken together, our findings indicate that kaempferol activates the IRE1-JNK-CHOP signaling from cytosol to nucleus, and G9a inhibition activates autophagic cell death in GC cells.
Assuntos
Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Quempferóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/metabolismo , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Gástricas/metabolismo , Fator de Transcrição CHOP/metabolismoRESUMO
Radix Polygalae (RP) has been used to relieve psychological stress in traditional oriental medicine. Recently, cell protective, antiamnestic and antidepressant-like effects were disclosed but the possible application of RP to post-traumatic stress disorder, in which exaggerated fear memory persists, has not yet been explored. For this purpose, the effects of RP on fear behavior was examined in a mouse model of single prolonged stress and conditioned fear (SPS-CF), previously shown to mimic key symptoms of post-traumatic stress disorder. Male mice received daily oral dose of RP extract or vehicle during the SPS-CF procedure. Then fear-related memory (cohort 1, n=25), non-fear-related memory (cohort 2, n=38) and concentration-dependent effects of RP on fear memory (cohort 3, n=41) were measured in 3 separate cohort of animals. Also working memory and anxiety-like behaviors were measured in cohort 1. RP-treated SPS-CF mice exhibited attenuated contextual but not cued freezing and no impairments in the working memory and spatial reference memory performances relative to vehicle-treated SPS-CF controls. RP-treated SPS-CF and naive mice also demonstrated no difference in anxiety-like behavior levels relative to vehicle-treated SPS-CF and naive controls, respectively. In the hippocampus of SPS-CF mice, expression of BAG1, which regulates the activity of GR, was decreased, whereas RP increased expression of BAG1 in naïve and SPS-CF mice. These results suggest that RP exerts some symptomatic relief in a mouse with exaggerated fear response. RP and its molecular components may thus constitute valuable research targets in the development of novel therapeutics for stress-related psychological disorders.
RESUMO
Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang (DSGOST in Korean, Danggui-Sini-Jia-Wuzhuyu-Shengian-Tang in Chinese, and Tokishigyakukagoshuyushokyoto (TJ-38) in Japanese), a well-known traditional Korean/Chinese/Japanese medicine, has long been used to treat vascular diseases such as Raynaud's phenomenon (RP). However, anticancer effect of DSGOST remains elusive. In this study, we checked if DSGOST has an anticancer effect against gastric cancer cells, and investigated the mechanisms underlying DSGOST resistance. Moreover, DSGOST regulates chemoresistance in cisplatin-treated gastric cancer cells. Interestingly, DSGOST treatment induced the accumulation of GFP-LC3 puncta and increased the level of autophagy markers, such as LC3-II, ATG5, and Beclin-1, indicating activated autophagy. Furthermore, DSGOST could activate epithelial-to-mesenchymal transition (EMT) and exosomes via induction of autophagy. DSGOST in combination with TGFß also induced autophagy and EMT. However, autophagy inhibition induces DSGOST-mediated cell death in gastric cancer cells. In addition, autophagy inhibition blocks the activation of DSGOST-mediated EMT markers including N-cadherin, Snail, Slug, vimentin, ß-catenin, p-Smad2, and p-Smad3. Taken together, these findings indicated that prosurvival autophagy was one of the mechanisms involved in the resistance of gastric cancer to DSGOST. Targeting the inhibition of autophagy could be an effective therapeutic approach to overcome resistance to DSGOST in gastric cancer.
Assuntos
Autofagia/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Gástricas/patologia , Proteína Beclina-1/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the anti-arthritic and anti-inflammatory effects of the mixture of three herbal agents, Cinnamon Cortex, Persica Semen, and Natril Sulfas (CPN), the major ingredients of Taoren Chengqi Decoction (). METHODS: Collagen-induced arthritis (CIA) was induced by immunization with bovine type II collagen on day 1 and 21. DBA/1J mice were orally administered the water extract of CPN (100 and 500 mg/kg) and indomethacin (1 mg/kg) or vehicle (water) 3 times per week for 6 weeks. Arthritic symptoms were recorded on day 29, 31, 33, 36 and 38. On sacrififi ce, serum was obtained for inflammatory markers and anti-collagen antibodies as well as arthritic joints were obtained for histologic analysis. For the evaluation of in vitro anti-inflammatory mechanism of CPN, peritoneal macrophages were isolated from thioglycollate injected C57BL/6 mice and stimulated with lipopolysaccharides (LPS) for 15 min in the presence of CPN extract. Levels of inhibitor of NF-κB α isoform (IκBα), phospho-p38, phospho-C-Jun N-terminal kinases (JNK) and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) were detected by Western blot. RESULTS: Compared with mice in CIA group, oral administration of CPN signififi cantly reduced the clinical scores (P<0.05), histological analysis revealed the protective effect of CPN on inflamed joints. Serum levels of the pro-inflammatory markers tumor necrosis factor-α, interleukin-6 and prostaglandin E2, but not anti-collagen antibodies, were significantly reduced (P<0.05). CPN did not affect the activation of p38, JNK and ERK1/2 but inhibited LPS-induced IκBα degradation, a required event prior to the translocation of NF-κB to the nucleus. CONCLUSIONS: The ameliorating effect of CPN on arthritis progression seems to be mediated by its anti-inflammatory effect, without affecting antibody response. As a supplementary agent, CPN could be benefifi cial for treatment of CIA.
RESUMO
Background. Obesity and its comorbidities continue to challenge the world at an alarming rate. Although the long term solution lies on lifestyle changes in the form of dieting and exercising, drug, medical food, or dietary supplement interventions are required for those who are already obese. Here we describe a standardized blend composed of extracts from three medicinal plants: Morus alba, Yerba mate, and Magnolia officinalis for appetite suppression and metabolic disorders management. Method. Extracts were standardized to yield a composition designated as UP601. Appetite suppression activity was tested in acute feed intake rat model. Efficacy was evaluated in C57BL/6J mouse models treated with oral doses of 1.3 g/kg/day for 7 weeks. Orlistat at 40 mg/kg/day was used as a positive control. Body compositions of mice were assessed using a dual energy X-ray absorptiometry (DEXA). ELISA was done for insulin, leptin, and ghrelin level quantitation. Nonalcoholic steatohepatitis (NASH) scoring was conducted. Results. Marked acute hypophagia with 81.8, 75.3, 43.9, and 30.9% reductions in food intake at 2, 4, 6, and 24 hours were observed for UP601. Decreases in body weight gain (21.5% compared to the HFD at weeks 7 and 8.2% compared to baseline) and calorie intake (40.5% for the first week) were observed. 75.9% and 46.8% reductions in insulin and leptin, respectively, 4.2-fold increase in ghrelin level, and reductions of 18.6% in cholesterol and 59% in low-density lipoprotein were documented. A percentage body fat of 18.9%, 47.8%, 46.1%, and 30.4% was found for mice treated with normal control, HFD, Orlistat, and UP601, respectively. 59.3% less mesenteric fat pad and improved NASH scores were observed for UP601. Conclusion. UP601, a standardized botanical composition from Morus alba, Yerba mate, and Magnolia officinalis could be used as a natural alternative for appetite suppression, maintaining healthy body weight and metabolism management.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Extratos Vegetais/uso terapêutico , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Depressores do Apetite/administração & dosagem , Depressores do Apetite/uso terapêutico , Modelos Animais de Doenças , Ilex , Lactonas/administração & dosagem , Lactonas/uso terapêutico , Magnolia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morus , Orlistate , Fitoterapia , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Redução de PesoRESUMO
Panax sp., including Panax ginseng Meyer, Panax quiquifolius L., or Panax notoginseng (Burk.) FH Chen, have been used as functional foods or for traditional Chinese medicine for diabetes, inflammation, stress, aging, hepatic injury, and cancer. In recent decades, a number of both in vitro and in vivo experiments as well as human studies have been conducted to investigate the efficacy and safety of various types of ginseng samples and their components. Of these, the hepatoprotective and hepatotoxic effects of ginseng and their ginsenosides and polysaccharides are reviewed and summarized.
RESUMO
Osteoarthritis (OA) is a multifactorial disease primarily noted by cartilage degradation in association with inflammation that causes significant morbidity, joint pain, stiffness, and limited mobility. Present-day management of OA is inadequate due to the lack of principal therapies proven to be effective in hindering disease progression where symptomatic therapy focused approach masks the actual etiology leading to irreversible damage. Here, we describe the effect of UP3005, a composition containing a proprietary blend of two standardized extracts from the leaf of Uncaria gambir and the root bark of Morus alba, in maintaining joint structural integrity and alleviating OA associated symptoms in monosodium-iodoacetate- (MIA-) induced rat OA disease model. Pain sensitivity, micro-CT, histopathology, and glycosaminoglycans (GAGs) level analysis were conducted. Diclofenac at 10 mg/kg was used as a reference compound. UP3005 resulted in almost a complete inhibition in proteoglycans degradation, reductions of 16.6% (week 4), 40.5% (week 5), and 22.0% (week 6) in pain sensitivity, statistically significant improvements in articular cartilage matrix integrity, minimal visual subchondral bone damage, and statistically significant increase in bone mineral density when compared to the vehicle control with MIA. Therefore, UP3005 could potentially be considered as an alternative therapy from natural sources for the treatment of OA and/or its associated symptoms.
RESUMO
Vitamin E has been shown to have strong anticarcinogenic properties, including antioxidant characteristics, making it an ideal candidate for use in combination with immunotherapies that modify the tumor microenvironment. The tumor microenvironment contains immunosuppressive components, which can be diminished, and immunogenic components, which can be augmented by immunotherapies in order to generate a productive immune response. In the current study, we employ the α-tocopherol succinate isomer of vitamin E to reduce immunosuppression by myeloid derived suppressor cells (MDSCs) as well as adoptive transfer of antigen-specific CD8+ T cells to generate potent antitumor effects against the HPV16 E7-expressing TC-1 tumor model. We show that vitamin E alone induces necrosis of TC-1 cells and elicits antitumor effects in TC-1 tumor-bearing mice. We further demonstrate that vitamin E reverses the suppression of T cell activation by MDSCs and that this effect is mediated in part by a nitric oxide-dependent mechanism. Additionally, treatment with vitamin E reduces the percentage of MDSCs in tumor loci, and induces a higher percentage of T cells, following T cell adoptive transfer. Finally, we demonstrate that treatment with vitamin E followed by E7-specific T cell adoptive transfer experience elicits potent antitumor effects in tumor-bearing mice. Our data provide additional evidence that vitamin E has anticancer properties and that it has promise for use as an adjuvant in combination with a variety of cancer therapies.