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1.
Biochem Biophys Rep ; 35: 101525, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37601455

RESUMO

Background: Sarcopenia and muscular dystrophy are two muscle diseases. In cancer patients, cancer cachexia induces continuous weight loss and muscle loss due to the disease itself or the use of anticancer drugs. Cachexia occurs in up to 80% of cancer patients. It is recognized as a direct cause of reduced quality of life, contributing to at least 20% of cancer-associated deaths and limiting therapeutic options for cancer patients. Cancer cachexia is associated with multiple chronic or end-stage conditions and develops similarly. There are various options for the treatment of cancer cachexia, but there are still many issues to be solved. Hence, to determine its potential to overcome the muscle wasting during cancer cachexia, we studied the effect of BST204, a refined dry ginseng extract, on muscle fiber regeneration. Experimental procedure: We checked the muscle regeneration efficacy of BST204. First, BaCl2 and freeze injury models were selected to investigate muscle regeneration after BST204 administration. In addition, after inducing muscle differentiation of C2C12 cells, the efficacy of BST204 was analyzed. In this model, we analyzed the expression of the signal pathway (PI3K-AKT signal) by Western blot and imaging methods. Results and conclusion: These results showed that BST204 induced muscle fiber regeneration in BaCl2 and freeze injury models. Also, we confirmed that BST204 could regulate the PI3K/AKT signaling pathway and regulate the differentiation of C2C12 cells. These results indicate that BST204 has the potential to facilitate the skeletal muscle regeneration during muscle wasting induced by various factors including cancer cachexia.

2.
J Microbiol Biotechnol ; 33(8): 1057-1065, 2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37280778

RESUMO

Inflammatory bowel disease (IBD), a chronic inflammatory disease, results from dysregulation of the immune responses. Some lactic acid bacteria (LAB), including Lactobacillus, alleviate IBD through immunomodulation. In this study, the anti-colitis effect of LAB isolated from human breast milk was investigated in a mouse model induced acute colitis with 2,4,6-trinitrobenzene sulfonic acid (TNBS). TNBS remarkably increased weight loss, colon shortening, and colonic mucosal proliferation, as well as the expression levels of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1ß. Oral administration of LAB isolated from human breast milk resulted in a reduction in TNBS-induced colon shortening, as well as induced cyclooxygenase (COX)-2, nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB). In addition, LAB suppressed inflammatory cytokines such as TNF-α, IL-6, and IL-1ß, and thus showed an effect of suppressing the level of inflammation induced by TNBS. Furthermore, LAB alleviated gut microbiota dysbiosis, and inhibited intestinal permeability by increasing the expression of intestinal tight junction protein including ZO-1. Collectively, these results suggest that LAB isolated from human breast milk can be used as a functional food for colitis treatment by regulating NF-κB signaling, gut microbiota and increasing expression of intestinal tight junction protein.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Lactobacillales , Feminino , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/metabolismo , Lactobacillales/metabolismo , Leite Humano , Colite/induzido quimicamente , Colite/patologia , Colo/patologia , Citocinas/metabolismo , Ciclo-Oxigenase 2/metabolismo , Proteínas de Junções Íntimas/metabolismo
3.
J Microbiol ; 59(11): 1056-1062, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34613605

RESUMO

The COVID-19 pandemic has caused unprecedented health, social, and economic crises worldwide. However, to date, there is an only a limited effective treatment for this disease. Human placenta hydrolysate (hPH) has previously been shown to be safe and to improve the health condition in patients with hyperferritinemia and COVID-19. In this study, we aimed to determine the antiviral effects of hPH against SARS-CoV-2 in vitro and in vivo models and compared with Remdesivir, an FDA-approved drug for COVID-19 treatment. To assess whether hPH inhibited SARS-CoV-2 replication, we determined the CC50, EC50, and selective index (SI) in Vero cells by infection with a SARS-CoV-2 at an MOI of 0.01. Further, groups of ferrets infected with 105.8 TCID50/ml of SARS-CoV-2 and treated with hPH at 2, 4, 6 dpi, and compared their clinical manifestation and virus titers in respiratory tracts with PBS control-treated group. The mRNA expression of immune-related cytokines was determined by qRT-PCR. hPH treatment attenuated virus replication in a dose-dependent manner in vitro. In a ferret infection study, treatment with hPH resulted in minimal bodyweight loss and attenuated virus replication in the nasal wash, turbinates, and lungs of infected ferrets. In addition, qRT-PCR results revealed that the hPH treatment remarkably upregulated the gene expression of type I (IFN-α and IFN-ß) and II (IFN-γ) IFNs in SARS-CoV-2 infected ferrets. Our data collectively suggest that hPH has antiviral efficacy against SARS-CoV-2 and might be a promising therapeutic agent for the treatment of SARS-CoV-2 infection.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Placenta/química , Hidrolisados de Proteína , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Chlorocebus aethiops , Feminino , Furões , Humanos , Masculino , Gravidez , Hidrolisados de Proteína/farmacologia , Hidrolisados de Proteína/uso terapêutico , Células Vero , Replicação Viral/efeitos dos fármacos
4.
Artigo em Inglês | MEDLINE | ID: mdl-33804338

RESUMO

BST204 is a purified ginseng dry extract that has an inhibitory effect on lipopolysaccharide-induced inflammatory responses, but its effect on muscle atrophy is yet to be investigated. In this study, C2C12 myoblasts were induced to differentiate for three days followed by the treatment of dexamethasone (DEX), a corticosteroid drug, with vehicle or BST204 for one day and subjected to immunoblotting, immunocytochemistry, qRT-PCR and biochemical analysis for mitochondrial function. BST204 alleviates the myotube atrophic effect mediated by DEX via the activation of protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling. Through this pathway, BST204 suppresses the expression of muscle-specific E3 ubiquitin ligases contributing to the enhanced myotube formation and enlarged myotube diameter in DEX-treated myotubes. In addition, BST204 treatment significantly decreases the mitochondrial reactive oxygen species production in DEX-treated myotubes. Furthermore, BST204 improves mitochondrial function by upregulating the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in DEX-induced myotube atrophy. This study provides a mechanistic insight into the effect of BST204 on DEX-induced myotube atrophy, suggesting that BST204 has protective effects against the toxicity of a corticosteroid drug in muscle and promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.


Assuntos
Dexametasona , Fibras Musculares Esqueléticas , Dexametasona/toxicidade , Humanos , Mitocôndrias , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/prevenção & controle , Regulação para Cima
5.
Metabolomics ; 17(4): 36, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33738589

RESUMO

INTRODUCTION: Chemotherapy is a major etiology of cachexia. Ginseng products are known to have various anti-cachectic and health-promoting effects, such as inhibiting inflammation and promoting energy production. In particular, BST204, purified ginseng dry extract, contains multiple ginsenosides that can reduce chemotherapy-related fatigue and toxicity. OBJECTIVES: To investigate the effects of BST204 on the alleviation of chemotherapy-induced cachexia using a multimodal approach. METHODS: In a CT26 mouse syngeneic colon cancer model, cachexia was predominantly induced by chemotherapy with 5-fluorouracil (5-FU) than by tumor growth. BST204 at a dose of 100 or 200 mg/kg was administered to 5-FU-treated mice. RESULTS: BST204 significantly mitigated the decrease in tumor-excluded body weight (change in 5-FU group and BST204 groups: - 13% vs. - 6% on day 7; - 30% vs. - 20% on day 11), muscle volume (- 19% vs. - 11%), and fat volume (- 91% vs. - 56%). The anti-cachectic effect of BST204 was histologically demonstrated by an improved balance between muscle regeneration and degeneration and a decrease in muscle cross-sectional area reduction. CONCLUSION: Chemotherapy-induced cachexia was biochemically and metabolically characterized by activated inflammation, enhanced oxidative stress, increased protein degradation, decreased protein stabilization, reduced glucose-mediated energy production, and deactivated glucose-mediated biosynthesis. These adverse effects were significantly improved by BST204 treatment. Overall, our multimodal study demonstrated that BST204 could effectively alleviate chemotherapy-induced cachexia.


Assuntos
Caquexia/induzido quimicamente , Caquexia/tratamento farmacológico , Tratamento Farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Extratos Vegetais/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Glucose/metabolismo , Inflamação , Interleucina-6/sangue , Masculino , Metabolômica , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo
6.
Am J Chin Med ; 48(3): 631-650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32329640

RESUMO

The loss of skeletal muscle mass and function is a serious consequence of chronic diseases and aging. BST204 is a purified ginseng (the root of Panax ginseng) extract that has been processed using ginsenoside-ß-glucosidase and acid hydrolysis to enrich ginsenosides Rg3 and Rh2 from the crude ginseng. BST204 has a broad range of health benefits, but its effects and mechanism on muscle atrophy are currently unknown. In this study, we have examined the effects and underlying mechanisms of BST204 on myotube formation and myotube atrophy induced by tumor necrosis factor-α (TNF-α). BST204 promotes myogenic differentiation and multinucleated myotube formation through Akt activation. BST204 prevents myotube atrophy induced by TNF-α through the activation of Akt/mTOR signaling and down-regulation of muscle-specific ubiquitin ligases, MuRF1, and Atrogin-1. Furthermore, BST204 treatment in atrophic myotubes suppresses mitochondrial reactive oxygen species (ROS) production and regulates mitochondrial transcription factors such as NRF1 and Tfam, through enhancing the activity and expression of peroxisome proliferator-activated receptor-γ coactivator1α (PGC1α). Collectively, our findings indicate that BST204 improves myotube formation and PGC1α-mediated mitochondrial function, suggesting that BST204 is a potential therapeutic or neutraceutical remedy to intervene muscle weakness and atrophy.


Assuntos
Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Panax/química , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Atrofia/induzido quimicamente , Atrofia/tratamento farmacológico , Humanos , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/fisiologia , Fator 1 Nuclear Respiratório/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Extratos Vegetais/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estimulação Química , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa
7.
Int J Mol Med ; 44(5): 1641-1652, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432192

RESUMO

Conditioned media from various sources comprise numerous growth factors and cytokines and are known to promote the regeneration of damaged tissues. Among these, natural killer cell conditioned medium (NK­CdM) has been shown to stimulate collagen synthesis and the migration of fibroblasts during the wound healing process. With a long­term aim of developing a treatment for skin photoaging, the ability of NK­CdM to prevent ultraviolet­B (UV­B) damage was assessed in neonatal human dermal fibroblasts (NHDFs) and an in vitro reconstructed skin model. The factors present in NK­CdM were profiled using an antibody array analysis. Protein and mRNA levels in UV­B exposed NHDFs treated with NK­CdM were measured by western blotting and quantitative reverse transcription­PCR, respectively. The total antioxidant capacity of NK­CdM was determined to assess its ability to suppress reactive oxygen species. The anti­photoaging effect of NK­CdM was also assessed in a 3D reconstituted human full skin model. NK­CdM induced proliferation of UV­B­treated NHDFs, increased procollagen expression, and decreased matrix metalloproteinase (MMP)­1 expression. NK­CdM also exhibited a potent antioxidant activity as measured by the total antioxidant capacity. NK­CdM inhibited UV­B­induced collagen degradation by inactivating MAPK signaling. NK­CdM also elicited potential anti­wrinkle effects by inhibiting the UV­B­induced increase in MMP­1 expression levels in a 3D reconstituted human full skin model. Taken together, the suppression of both UV­B­induced MMP­1 expression and JNK activation by NK­CdM suggests NK­CdM as a possible candidate anti­skin aging agent.


Assuntos
Antioxidantes/metabolismo , Meios de Cultivo Condicionados/metabolismo , Fibroblastos/metabolismo , Células Matadoras Naturais/metabolismo , Envelhecimento da Pele/fisiologia , Pele/metabolismo , Adulto , Células Cultivadas , Colágeno Tipo I/metabolismo , Feminino , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Metaloproteinase 1 da Matriz/metabolismo , Pró-Colágeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Raios Ultravioleta/efeitos adversos
8.
Oncotarget ; 9(23): 16284-16296, 2018 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-29662645

RESUMO

Cachexia in cancer patients, characterized by marked involuntary weight loss and impaired physical function, is associated with a poor prognosis in response to conventional treatment and with an increase in cancer-related mortality. Prevention of skeletal muscle loss under cancer-induced cachexia via inhibition of pro-cachectic factors, as well as a reduction in tumor mass, has been considered reasonable pharmacological and nutritional interventions to treat cancer patients. In this study, we constructed a novel herbal formula, SGE, which contains Ginseng Radix alba, Atractylodis Rhizoma alba, and Hoelen, examined its anti-cancer and anti-cachexia efficacies. In in vitro experiments, SGE induced death of CT-26 murine colon carcinoma cells via endoplasmic reticulum stress, and suppressed the production of inflammatory cytokines in Raw 264.7 murine macrophage-like cells. In addition, SGE treatment attenuated CT-26-induced C2C12 skeletal muscle cell atrophy as well as CT-26-induced reduction in lipid accumulation in 3T3-L1 adipocyte. In CT-26 tumor-bearing mice, daily oral administration of 10 and 50 mg/kg SGE remarkably attenuated the cachexia-related symptoms, including body weight and muscle loss, compared with saline treatment, while food intake was not affected. These data collectively suggest that SGE is beneficial as an anti-cancer adjuvant to treat cancer patients with severe weight loss.

9.
Sci Rep ; 7(1): 12756, 2017 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-29038437

RESUMO

When cells lose adhesion, they undergo detachment-induced apoptosis, known as anoikis. In contrast, tumor cells acquire resistance to anoikis, enabling them to survive, even after separating from neighboring cells or the ECM. Therefore, agents that restore anoikis sensitivity may serve as anti-cancer candidates. In this study, we constructed a novel herbal formula, SRVF, which contains Scrophulariae Radix (SR) and Viticis Fructus (VF). SRVF rapidly decreased cell adhesion, altered the cell morphology to round, and induced cell death; however, SR, VF, or their co-treatment did not. SRVF arrested HT1080 cells in G2/M phase, increased the levels of pro-apoptotic proteins, and decreased the levels of anti-apoptotic proteins. Furthermore, SRVF efficiently reduced cell-cell and cell-ECM interactions by disrupting the F-actin cytoskeleton and down-regulating the levels of focal adhesion-related proteins, suggesting that SRVF efficiently triggers detachment-induced apoptosis (i.e., anoikis) in malignant cancer cells. In xenograft mouse models, daily oral administration of 50 or 100 mg/kg SRVF retarded tumor growth in vivo, and repeated administration of SRVF did not cause systemic toxicity in normal mice. These data collectively indicate that SRVF induces cancer cell death by restoring anoikis sensitivity via disrupting focal adhesion. Therefore, SRVF may be a safe and potent anti-cancer herbal decoction.


Assuntos
Antineoplásicos/uso terapêutico , Adesões Focais/metabolismo , Neoplasias/tratamento farmacológico , Scrophularia/química , Actinas/metabolismo , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Feminino , Adesões Focais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias/genética , Neoplasias/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Sci Rep ; 6: 36277, 2016 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-27808120

RESUMO

Lophatheri Herba (LH), dried leaf of Lophatherum gracile Brongn, has long been used to reduce thirst and treat fever and inflammation in Chinese medicine. Recent studies have shown that LH has anti-viral, anti-bacterial, anti-cancer, anti-oxidant, diuretic, and hyperglycemic properties. However, the effects of an ethanol extract of L. herba (ELH), at non-cytotoxic doses, on the metastatic and angiogenic abilities of malignant tumor cells have not been reported. We found that ELH significantly suppressed p38, JNK, and NF-κB activation and proteolytic activities under phorbol 12-myristate 13-acetate (PMA) stimulation, thus leading to a decrease in metastatic potential, including migration and invasion. In addition, ELH suppressed tumor-induced angiogenesis, including migration and tube formation in human umbilical vein endothelial cells (HUVECs) and microvessel sprouting from aortic rings via decreasing the pro-angiogenic factors in tumors. Interestingly, in ovo xenografts ELH-treated HT1080 cells did not increase in volume and eventually disappeared, owing to a lack of angiogenesis. Daily oral administration of ELH at 50 and 100 mg/kg markedly inhibited metastatic colonization of B16F10 cells in the lungs of C57BL/6J mice and caused no apparent side effects. These data collectively indicate that ELH is safe and may be useful for managing metastasis and growth of malignant cancers.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Poaceae/química , Inibidores da Angiogênese/química , Animais , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Etanol/química , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Metástase Neoplásica , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Extratos Vegetais/química , Ratos Sprague-Dawley
11.
Int J Oncol ; 49(6): 2377-2386, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27779658

RESUMO

Gardeniae Fructus (GF, Zhi Zi in China), a fruit of Gardenia jasminoides Ellis, has been used in traditional medicine to reduce inflammation and headache and to treat hepatic disorders, hypertension, and icterus. In recent studies, extract of raw or stir-baked GF was shown to have pharmacological activities for viral infection, thrombosis, hyperlipidemia, convulsion, inflammation, oxidative stress, and others. In addition, baked GF extract suppressed the proteolytic activities and altered the cellular morphology of tumor cells. However, the effects of ethanol extract of baked GF (EBGF) on the metastatic and angiogenic capacities of malignant tumor cells and its detailed mechanism of action have not been reported. In this study, we found that EBGF significantly inhibited phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 and -13 and uPA expression via suppression of PMA-induced nuclear translocation of NF-κBp65. Metastatic potential, including migration, invasion, and colonization, was substantially reduced by EBGF with no cytotoxicity. In addition, EBGF attenuated tumor-induced angiogenesis, including microvessel sprouting, migration of endothelial cells (ECs), and tube formation of ECs, by inhibiting the release of pro-angiogenic factors from tumor cells. In C57BL/6 mice, we observed that daily administration of EBGF at 50 and 100 mg/kg suppressed metastatic colonization of B16F10 melanoma cells in the lungs. Furthermore, EBGF administration did not cause adverse effects, suggesting that EBGF is safe and may be a potential herbal medicine capable of controlling metastatic malignant cancers.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Gardenia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Melanoma Experimental/patologia , Extratos Vegetais/farmacologia , Fator de Transcrição RelA/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Metaloproteinase 13 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Metástase Neoplásica/patologia , Neovascularização Patológica/prevenção & controle , Acetato de Tetradecanoilforbol/toxicidade
12.
Sci Rep ; 6: 24214, 2016 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-27064118

RESUMO

Skeletal muscle atrophy is a critical feature of cancer-induced cachexia, caused by pro-cachectic factors secreted by host cells and tumor cells. Therefore, blockade of these factors has considered a reasonable target for pharmacological and nutritional interventions to prevent skeletal muscle loss under cancer-induced cachexia. Citrus unshiu peel (CUP) has been used for treating the common cold, dyspepsia, and bronchial discomfort and reported to have pharmacological activities against inflammation, allergy, diabetes, and viral infection. In the present study, we observed that daily oral administration of water extract of CUP (WCUP) to male BALB/c mice bearing CT-26 adenocarcinoma remarkably reduced the losses in final body weight, carcass weight, gastrocnemius muscle, epididymal adipose tissue, and hemoglobin (Hb), compared with saline treatment. The levels of serum IL-6 and muscle-specific E3 ligases elevated by tumor burden were also considerably reduced by WCUP administration. In an in vitro experiment, WCUP efficiently suppressed the production of pro-cachectic cytokines in immune cells as well as cancer cells. In addition, WCUP treatment attenuated C2C12 skeletal muscle cell atrophy caused by cancer cells. These findings collectively suggest that WCUP is beneficial as a nutritional supplement for the management of cancer patients with severe weight loss.


Assuntos
Citrus/química , Extratos Vegetais/farmacologia , Redução de Peso/efeitos dos fármacos , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Linhagem Celular , Sobrevivência Celular , Citrus/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Hemoglobinas/análise , Humanos , Interleucina-6/sangue , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Transplante Heterólogo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
13.
Oncol Rep ; 35(3): 1841-50, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26718030

RESUMO

Cachexia accompanied by muscle wasting is a key determinant of poor prognosis in cancer patients and cancer­related death. Previous studies have demonstrated that inflammatory cytokines such as interleukin­6 (IL­6), tumor necrosis factor­α (TNF­α), IL­1 and interferon­Î³ (IFN­Î³) secreted from host cells and tumor cells participate in skeletal muscle wasting followed by severe loss of body weight. Therefore, blockade of the inflammatory response is thought to be a logical target for pharmacological and nutritional interventions to preserve skeletal muscle mass under cachectic conditions. Sosiho­tang (SO; Xiaocharihu­tang in Chinese and Sho­saiko­to in Japanese) is an Oriental herbal medicine that has been used to treat chronic hepatic diseases and to control fever. In recent studies, SO inhibited the production of inflammatory cytokines in lipopolysaccharide (LPS)­stimulated macrophages, prevented thrombus formation and suppressed cancer progression. However, the anti­cachectic activity of SO in tumor­bearing mice has not yet been examined. In the present study, we characterized the effect of SO administration on cancer­induced cachexia in CT­26­bearing mice, and elucidated the anti­cachectic mechanisms. Daily oral administration of SO at doses of 50 and 100 mg/kg to CT­26­bearing mice significantly retarded tumor growth and prevented the loss of final body weight, carcass weight, heart weight, gastrocnemius muscle, and epididymal fat, compared with saline­treated control mice. In addition, serum IL­6 levels elevated by cancer were decreased by SO administration. In the J774A.1 macrophage cell line, SO efficiently suppressed LPS­mediated increases in inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO), and procachectic inflammatory cytokine production through inhibition of nuclear factor­κB (NF­κB) and p38 activation. In addition, SO attenuated muscle atrophy caused by cancer cells by affecting myoblast proliferation and differentiation, and C2C12 myotube wasting. Taken together, these results suggest that SO is a safe and useful anti­cachectic therapy for cancer patients with severe weight loss.


Assuntos
Caquexia/tratamento farmacológico , Neoplasias do Colo/tratamento farmacológico , Inflamação/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/fisiopatologia , Animais , Caquexia/genética , Caquexia/fisiopatologia , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/fisiopatologia , Humanos , Inflamação/genética , Inflamação/fisiopatologia , Interleucina-1/biossíntese , Interleucina-6/sangue , Lipopolissacarídeos/administração & dosagem , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , NF-kappa B/biossíntese , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/biossíntese , Redução de Peso/efeitos dos fármacos
14.
Oncol Rep ; 34(2): 900-12, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26035620

RESUMO

MA128, a novel herbal medicine, was previously identified and its effectiveness in the treatment of asthma and atopic dermatitis (AD) was demonstrated. In particular, post-inflammatory hyperpigmentation (PIH) in AD mice was improved by treatment with MA128. In addition, MA128 exhibited anti-melanogenic activity by inhibiting tyrosinase activity via the p38 MAPK and protein kinase A signaling pathways in B16F10 cells. In the present study, we examined whether oral administration of MA128 suppressed the in vivo tumor growth of HT1080 cells in athymic nude mice. The results showed that the daily oral administration of 75 and 150 mg/kg MA128 suppressed the tumorigenic growth of HT1080 cells efficiently. Since metastasis is a major cause of cancer-associated mortality and the greatest challenge during cancer treatment, we investigated the effect of non-toxic concentrations of MA128 on the metastatic potential of HT1080 cells. MA128 inhibited anchorage-independent colony formation, migration and invasion. Matrix metalloproteinase-9 (MMP-9) activity under resting and PMA-stimulated conditions was decreased in a dose-dependent manner by MA128 in HT1080 cells. In addition, the daily oral administration of MA128 at doses of 75 and 150 mg/kg efficiently blocked the lung metastasis of B16F10 cells that had been injected into the tail veins of C57BL/6 mice. In particular, none of the mice treated with MA128 exhibited systemic toxicity, such as body weight loss or liver and kidney dysfunction. MA128 also inhibited tumor­induced angiogenesis. Taken together, the results suggest that MA128 is a potential therapeutic agent and a safe herbal medicine for controlling malignant and metastatic cancer.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Fibrossarcoma/tratamento farmacológico , Melanoma/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Plantas Medicinais/química , Administração Oral , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fibrossarcoma/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melanoma/metabolismo , Camundongos , Metástase Neoplásica , Extratos Vegetais/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
PLoS One ; 10(5): e0127898, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26020238

RESUMO

Jaeumganghwa-tang (JGT, Zi-yin-jiang-huo-tang in Chinese and Jiin-koka-to in Japanese) is an oriental herbal formula that has long been used as a traditional medicine to treat respiratory and kidney diseases. Recent studies revealed that JGT exhibited potent inhibitory effects on allergies, inflammation, pain, convulsions, and prostate hyperplasia. Several constituent herbs in JGT induce apoptotic cancer cell death. However, the anti-cancer activity of JGT has not been examined. In this study, we investigated the anti-cancer effects of JGT using highly tumorigenic HT1080 human fibrosarcoma cells and elucidated the underlying mechanisms. In addition, we examined whether the Lactobacillus fermentation of JGT enhanced its anti-cancer activity using an in vivo xenograft model because fermentation of herbal extracts is thought to strengthen their therapeutic effects. Data revealed that JGT suppressed the growth of cancer cells efficiently by stimulating G1 cell cycle arrest and then inducing apoptotic cell death by causing mitochondrial damage and activating caspases. The phosphorylation of p38 and ERK also played a role in JGT-induced cell death. In vitro experiments demonstrated that JGT fermented with Lactobacillus acidophilus, designated fJGT162, elicited similar patterns of cell death as did non-fermented JGT. Meanwhile, the daily oral administration of 120 mg/kg fJGT162 to HT1080-bearing BALB/c nude mice suppressed tumor growth dramatically (up to 90%) compared with saline treatment, whereas the administration of non-fermented JGT suppressed tumor growth by ~70%. Collectively, these results suggest that JGT and fJGT162 are safe and useful complementary and alternative anti-cancer herbal therapies, and that Lactobacillus fermentation improves the in vivo anti-cancer efficacy of JGT significantly.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Fibrossarcoma/tratamento farmacológico , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Lactobacillus acidophilus , Animais , Caspases/metabolismo , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Fibrossarcoma/metabolismo , Fibrossarcoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas de Neoplasias/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Sci Rep ; 5: 8394, 2015 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-25670261

RESUMO

Remotiflori radix is the root of Mosidae, which has long been used as a traditional medicine to treat chills, fever, and phlegm discharge. The ethanol extract of Mosidae leaves (MLE) possesses strong antioxidant and chemopreventive activities. However, the anti-cancer effects of the Remotiflori radix have not been examined. We used the ethanol extract of Remotiflori radix (ERR) and the PC-3 and DU145 prostate cancer cell lines in this study. We found that > 100 µg/mL ERR caused dose- and time-dependent cell death. Autophagic and apoptotic cell numbers increased in a dose-dependent manner as incubation time was prolonged, and LC3 punctuation, YO-PRO-1 uptake, DNA fragmentation, activation of caspases, and PARP cleavage were induced. Phosphorylation of AMPK, ULK, and p38 was increased after ERR treatment, and the level of the ER stress marker CHOP was also elevated. AMPK knockdown dramatically blocked ERR-mediated CHOP expression and cell death, suggesting that AMPK activation and ER stress play a critical role in ERR-induced cell death. Furthermore, oral administration of ERR at 50 mg/kg efficiently suppressed tumorigenic growth of PC-3 cells with no adverse effects. These results suggest that the ERR can be used as a safe and potent alternative therapy for patients with prostate cancer.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Extratos Vegetais/farmacologia , Neoplasias da Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Sci Rep ; 4: 6994, 2014 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-25385232

RESUMO

Eupatorium fortunei has long been used to treat nausea and poor appetite, and has been prescribed as a diuretic and detoxifying drug in Chinese medicine. Recent studies have demonstrated that E. fortunei possesses anti-bacterial, anti-oxidant, and anti-diabetic activities, as well as cytotoxicity to human leukemia cells. However, at non-toxic concentrations, the effects of an aqueous extract of E. fortunei (WEF) on the metastatic and angiogenic potential of malignant tumor cells have not been reported. In this study, we found that WEF suppressed the metastatic properties, including anchorage-independent colony formation, migration, and invasion, by downregulating the proteolytic activity of MMP-9. NF-κB activation and the phosphorylation of p38 and JNK were reduced significantly by WEF. Additionally, WEF inhibited tumor-induced angiogenesis markedly, affecting HUVEC migration, tube formation by HUVECs, and microvessel sprouting from rat aortic rings via a reduction in VEGF in tumors. In a pulmonary metastasis model, daily administration of WEF at 50 mg/kg markedly decreased metastatic colonies of intravenously injected B16F10 cells on the lung surface in C57BL/6J mice. Further, none of the WEF-administered mice exhibited systemic toxicity. Taken together, our results indicate that WEF is a potential therapeutic herbal product that may be useful for controlling malignant metastatic cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Eupatorium/química , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinase 9 da Matriz/metabolismo , Melanoma Experimental/tratamento farmacológico , Extratos Vegetais/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Animais , Aorta/citologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Metaloproteinase 9 da Matriz/genética , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/secundário , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Invasividade Neoplásica/prevenção & controle , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle , Ratos , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Ensaio Tumoral de Célula-Tronco , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Int J Oncol ; 45(5): 1937-48, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25176510

RESUMO

Anisi stellati fructus (ASF), commonly known as star anise, has long been used as a traditional Chinese medicine to treat inflammation, nervousness, insomnia and pain. In recent studies, it has been demonstrated that ASF possesses anti-bacterial, anti-fungal and anti-oxidant activities, as well as exhibits inhibitory effects on capillary­like tube formation in human umbilical vein endothelial cells (HUVECs). However, the effects of ASF extract on the metastatic potential of malignant tumor cells have not been examined. In this study, we found that daily oral administration of ASF (50 mg/kg) remarkably reduced the number of pulmonary metastatic colonies of B16F10 cells in C57BL/6J mice with no observed systemic toxicity. In an in vitro system, ASF inhibited metastatic properties, including anchorage­independent colony formation, migration and invasion. Upon phorbol 12-myristate 13-acetate (PMA) stimulation, the mRNA levels of matrix metalloproteinases (MMPs) -9, -13, -14 and urokinase plasminogen activator (uPA) decreased in a dose-dependent manner with ASF treatment. Gelatinase, type I collagenase, and uPA activities were also suppressed efficiently by ASF treatment. In response to PMA, NF-κB and AP-1 activation as well as p38 phosphorylation, which are crucial for MMP activation, were significantly decreased by ASF. In particular, ASF considerably inhibited tumor-induced HUVEC migration and tube formation and suppressed in vivo tumor-induced angiogenesis via a reduction of pro-angiogenic factors in tumors. These results collectively indicate that ASF might be useful in the management of metastatic malignant tumors.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Inibidores da Angiogênese/química , Animais , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Illicium/química , Medicina Tradicional Chinesa , Camundongos , Metástase Neoplásica , Neoplasias/patologia , Neovascularização Patológica/patologia , Extratos Vegetais/química
19.
PLoS One ; 9(5): e98703, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24878898

RESUMO

KIOM-C was recently demonstrated to have anti-metastatic activity in highly malignant cancer cells via suppression of NF-κB-mediated MMP-9 activity. In addition, it was reported to be effective for clearance of the influenza virus by increasing production of anti-viral cytokines, such as TNF-α and IFN-γ, and efficacious in the treatment of pigs suffering from porcine circovirus-associated disease (PCVAD). In this study, we investigated whether KIOM-C induces cancer cell death and elucidated the underlying anti-cancer mechanisms. In addition, we examined whether KIOM-C oral administration suppresses in vivo tumor growth of HT1080 cells in athymic nude mice. We initially found that KIOM-C at concentrations of 500 and 1000 µg/ml caused dose- and time-dependent cell death in cancer cells, but not normal hepatocytes, to approximately 50% of control levels. At the early stage of KIOM-C treatment (12 h), cells were arrested in G1 phase, which was accompanied by up-regulation of p21 and p27, down-regulation of cyclin D1, and subsequent increases in apoptotic and autophagic cells. Following KIOM-C treatment, the extent of caspase-3 activation, PARP cleavage, Beclin-1 expression, and LC3-II conversion was remarkably up-regulated, but p62 expression was down-regulated. Phosphorylation of AMPK, ULK, JNK, c-jun, and p53 was increased significantly in response to KIOM-C treatment. The levels of intracellular ROS and CHOP expression were also increased. In particular, the JNK-specific inhibitor SP600125 blocked KIOM-C-induced ROS generation and CHOP expression almost completely, which consequently almost completely rescued cell death, indicating that JNK activation plays a critical role in KIOM-C-induced cell death. Furthermore, daily oral administration of 85 and 170 mg/kg KIOM-C efficiently suppressed the tumorigenic growth of HT1080 cells, without systemic toxicity. These results collectively suggest that KIOM-C efficiently induces cancer cell death by both autophagy and apoptosis via activation of JNK signaling pathways, and KIOM-C represents a safe and potent herbal therapy for treating malignancies.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Fibrossarcoma/tratamento farmacológico , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Feminino , Fibrossarcoma/metabolismo , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Medicina Herbária/métodos , Humanos , Camundongos , Camundongos Nus , Plantas Medicinais , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
Oncotarget ; 5(6): 1554-64, 2014 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-24721928

RESUMO

Rho GDP dissociation inhibitor 2 (RhoGDI2) expression correlates with tumor growth, metastasis, and chemoresistance in gastric cancer. Here, we show that RhoGDI2 functions in the epithelial-mesenchymal transition (EMT), which is responsible for invasiveness during tumor progression. This tumorigenic activity is associated with repression of E-cadherin by RhoGDI2 via upregulation of Snail. Overexpression of RhoGDI2 induced phenotypic changes consistent with EMT in gastric cancer cells, including abnormal epithelial cell morphology, fibroblast-like properties, and reduced intercellular adhesion. RhoGDI2 overexpression also resulted in decreased expression of the epithelial markers E-cadherin and ß-catenin and increased expression of the mesenchymal markers vimentin and fibronectin. Importantly, RhoGDI2 overexpression also stimulated the expression of Snail, a repressor of E-cadherin and inducer of EMT, but not other family members such as Slug or Twist. RNA interference-mediated knockdown of Snail expression suppressed RhoGDI2-induced EMT and invasion, confirming that the effect was Snail-specific. These results indicate that RhoGDI2 plays a critical role in tumor progression in gastric cancer through induction of EMT. Targeting RhoGDI2 may thus be a useful strategy to inhibit gastric cancer cell invasion and metastasis.


Assuntos
Caderinas/metabolismo , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Neoplasias Gástricas/patologia , Fatores de Transcrição/metabolismo , Inibidor beta de Dissociação do Nucleotídeo Guanina rho/metabolismo , Antineoplásicos/farmacologia , Apoptose , Western Blotting , Caderinas/genética , Resistencia a Medicamentos Antineoplásicos , Imunofluorescência , Humanos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição da Família Snail , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Inibidor beta de Dissociação do Nucleotídeo Guanina rho/genética
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