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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.
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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 OxidativoRESUMO
To evaluate the efficacy of human placenta hydrolysate (HPH) in a mice model of CFA-induced inflammatory pain. TNF-α, IL-1ß, and IL-6 are key pro-inflammatory cytokine factors for relieving inflammatory pain. Therefore, this study investigates whether HPH suppresses CFA-induced pain and attenuates the inflammatory process by regulating cytokines. In addition, the relationship between neuropathic pain and HPH was established by staining GFAP and Iba-1 in mice spinal cord tissues. This study was conducted for a total of day 28, and inflammatory pain was induced in mice by injecting CFA into the right paw at day 0 and day 14, respectively. 100 µL of 20% glucose and polydeoxyribonucleotide (PDRN) and 100, 200, and 300 µL of HPH were administered intraperitoneally twice a week. In the CFA-induced group, cold and mechanical allodynia and pro-inflammatory cytokine factors in the spinal cord and plantar tissue were significantly increased. The five groups of drugs evenly reduced pain and gene expression of inflammatory factors, and particularly excellent effects were confirmed in the HPH 200 and 300 groups. Meanwhile, the expression of GFAP and Iba-1 in the spinal cord was increased by CFA administration but decreased by HPH administration, which was confirmed to suppress damage to peripheral ganglia. The present study suggests that HPH attenuates CFA-induced inflammatory pain through inhibition of pro-inflammatory cytokine factors and protection of peripheral nerves.
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Atopic dermatitis (AD), a chronic inflammatory disease, severely interferes with patient life. Human placenta extract (HPH; also known as human placenta hydrolysate) is a rich source of various bioactive substances and has widely been used to dampen inflammation, improve fatigue, exert anti-aging effects, and promote wound healing. However, information regarding HPH's incorporation in AD therapies is limited. Therefore, this study aimed to evaluate HPH's effective potential in treating AD using tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated human keratinocytes (HaCaT), immunized splenocytes, and a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. In TNF-α /IFN-γ-stimulated HaCaT cells, HPH markedly reduced the production of reactive oxygen species (ROS) and restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 1(SOD1), catalase, and filaggrin (FLG). HPH reduced interleukin (IL)-6; thymus- and activation-regulated chemokine (TARC); thymic stromal lymphopoietin (TSLP); and regulated upon activation, normal T cell expressed and presumably secreted (RANTES) levels and inhibited nuclear factor kappa B phosphorylation. Additionally, HPH suppressed the T helper 2 (Th2) immune response in immunized splenocytes. In the AD-like mouse model, it significantly mitigated the DNCB-induced elevation in infiltrating mast cells and macrophages, epidermal thickness, and AD symptoms. HPH also reduced TSLP levels and prevented FLG downregulation. Furthermore, it decreased the expression levels of IL-4, IL-5, IL-13, TARC, RANTES, and immunoglobulin E (IgE) in serum and AD-like skin lesion. Overall, our findings demonstrate that HPH effectively inhibits AD development and is a potentially useful therapeutic agent for AD-like skin disease.
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Citocinas , Dermatite Atópica , Dinitroclorobenzeno , Modelos Animais de Doenças , Proteínas Filagrinas , Células HaCaT , Interferon gama , Queratinócitos , Extratos Placentários , Fator de Necrose Tumoral alfa , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Animais , Humanos , Camundongos , Feminino , Fator de Necrose Tumoral alfa/metabolismo , Interferon gama/metabolismo , Citocinas/metabolismo , Extratos Placentários/farmacologia , Queratinócitos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos BALB C , Anti-Inflamatórios/farmacologia , Gravidez , Imunoglobulina E/sangue , Baço/efeitos dos fármacos , Inflamação/tratamento farmacológico , Placenta/metabolismo , Placenta/efeitos dos fármacosRESUMO
BACKGROUND: Ssanghwa-tang (SHT) is a widely used medication for the treatment of fatigue, pain, inflammation, hypothermia, erectile dysfunction, cancer, and osteoporosis in Asia, however, role of SHT on the melanin synthesis has not been checked previously. Thus, the present study was designed to determine the effect of SHT on α-melanocyte stimulating hormone (α-MSH)-induced melanogensis and its mechanisms of action in murine B16F10 melanoma cells. METHOD: Cellular melanin content and tyrosinase activity in murine B16F10 melanoma cells were determined after α-MSH stimulation with or without pre-treatment of SHT at the concentration of 250 and 500 µg/ml. Expression level of tyrosinase, tyrosinase-related protein 1 (TRP-1), TRP-2, microphthalmia-associated transcription factor (MITF), and activation of c-AMP-dependent protein kinase (PKA), c-AMP-related element binding protein (CREB), and mitogen-activated protein kinases (MAPKs) were examined by Western blot analysis. RESULTS: SHT significantly inhibited α-MSH-induced melanin synthesis and tyrosinase activity, and also decreased α-MSH-induced expression of MITF, tyrosinase, and TRP-1. In addition, SHT remarkably suppressed tyrosinase, CRE, and MITF luciferase reporter activity in a resting state as well as in α-MSH-stimulating condition. Phosphorylation of p38 MAPK by α-MSH stimulation was efficiently blocked by SHT pre-treatment. Moreover, SHT as an herbal cocktail showed synergistic anti-melanogenic effect compared with that of each single constituent herb. CONCLUSION: SHT efficiently inhibited c-AMP-induced melanin synthesis in B16F10 cells via suppression of PKA and p38 MAPK signaling pathways and subsequently decreased the level of CREB phosphorylation, MITF, and melanogenic enzymes. These results indicate that SHT may be useful as herbal medicine for treating hyperpigmentation and cosmetics as a skin-whitening agent.
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Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Melaninas , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/química , Integrases/efeitos dos fármacos , Melaninas/análise , Melaninas/metabolismo , Camundongos , Fator de Transcrição Associado à Microftalmia/efeitos dos fármacos , Monofenol Mono-Oxigenase/efeitos dos fármacos , Fosforilação/efeitos dos fármacosRESUMO
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.
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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/metabolismoRESUMO
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.
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Rho GDP dissociation inhibitor 2 (RhoGDI2) was initially identified as a regulator of the Rho family of GTPases. Our recent works suggest that RhoGDI2 promotes tumor growth and malignant progression, as well as enhances chemoresistance in gastric cancer. Here, we delineate the mechanism by which RhoGDI2 promotes gastric cancer cell invasion and chemoresistance using two-dimensional gel electrophoresis (2-DE) on proteins derived from a RhoGDI2-overexpressing SNU-484 human gastric cancer cell line and control cells. Differentially expressed proteins were identified using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF-MS). In total, 47 differential protein spots were identified; 33 were upregulated, and 14 were downregulated by RhoGDI2 overexpression. Upregulation of SAE1, Cathepsin D, Cofilin1, CIAPIN1, and PAK2 proteins was validated by Western blot analysis. Loss-of-function analysis using small interference RNA (siRNA) directed against candidate genes reveals the need for CIAPIN1 and PAK2 in RhoGDI2-induced cancer cell invasion and Cathepsin D and PAK2 in RhoGDI2-mediated chemoresistance in gastric cancer cells. These data extend our understanding of the genes that act downstream of RhoGDI2 during the progression of gastric cancer and the acquisition of chemoresistance.
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Inibidores de Dissociação do Nucleotídeo Guanina/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Eletroforese em Gel Bidimensional , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/análise , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Metástase Neoplásica , Proteoma/análise , Proteoma/metabolismo , Proteômica/métodos , Reprodutibilidade dos Testes , Neoplasias Gástricas/tratamento farmacológico , Regulação para Cima , Quinases Ativadas por p21/análise , Quinases Ativadas por p21/metabolismo , Inibidor beta de Dissociação do Nucleotídeo Guanina rho , Inibidores da Dissociação do Nucleotídeo Guanina rho-EspecíficoRESUMO
PURPOSE: Transforming growth factor-ß (TGF-ß) plays a key role in transforming retinal pigment epithelial (RPE) cells into mesenchymal fibroblastic cells, which are implicated in proliferative vitreoretinopathy. Herein, we tested the effect of pirfenidone, a novel antifibrotic agent, on TGF-ß1-mediated fibrogenesis in the human RPE cell line ARPE-19. METHODS: The effect of pirfenidone on the TGF-ß1-induced phenotype in ARPE-19 cells was measured with immunocytochemistry as the change in F-actin. Fibronectin and collagen production was measured with enzyme-linked immunosorbent assay, and cell migration activity was investigated using a scratch assay. Immunoblot analyses of cofilin, sma and mad protein (smad) 2/3, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular signal-related kinase expression were conducted to elucidate the cell signaling networks that contribute to the antifibrotic effect of pirfenidone. RESULTS: Treatment with TGF-ß1 induced typical phenotypic changes such as formation of stress fiber running parallel to the long axis of cells and enhanced migration and production of extracellular matrix components such as collagen type I and fibronectin. This fibroblast-like phenotype induced by TGF-ß1 was significantly inhibited by pretreatment with pirfenidone in a dose-dependent manner. We also elucidated the TGF-ß signaling pathways as the target of the inhibitory effect of pirfenidone. Pirfenidone inhibited TGF-ß signaling by preventing nuclear accumulation of active Smad2/3 complexes rather than phosphorylation of Smad2/3. CONCLUSIONS: These results collectively provide a rational background for future evaluation of pirfenidone as a potential antifibrotic agent for treating proliferative vitreoretinopathy and other fibrotic retinal disorders.
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Anti-Inflamatórios não Esteroides/farmacologia , Células Epiteliais/efeitos dos fármacos , Piridonas/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Actinas/genética , Actinas/metabolismo , Diferenciação Celular , Linhagem Celular , Movimento Celular , Colágeno/genética , Colágeno/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose/prevenção & controle , Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transporte Proteico/efeitos dos fármacos , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/farmacologia , Vitreorretinopatia Proliferativa/tratamento farmacológicoRESUMO
Gadd45b has been known as a positive mediator of apoptosis induced by certain cytokines and oncogenes. Here, we identified Gadd45b as an effector of Fas-induced apoptosis and found that p38-mediated Rb hyperphosphorylation is one of the mechanisms of Fas-induced apoptosis in murine hepatocyte AML12 cells. Gadd45b has been shown to activate p38 through its physical interaction with MTK1 and induce apoptosis. However, in this study, we have showed that the function of Gadd45b during Fas-induced apoptosis in AML12 cells is different from that reported in previous studies. Depletion of Gadd45b expression did not inhibit the phosphorylation of p38, but it suppressed p38-mediated Rb phosphorylation and apoptosis in response to Fas stimulation by reducing the interaction between p38 and Rb. Ectopic expression of Gadd45b was sufficient to enhance this interaction. These findings suggest that Gadd45b mediates p38-induced Rb phosphorylation by enhancing the interaction between p38 and Rb during Fas-induced apoptosis in murine hepatocytes.
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Antígenos de Diferenciação/metabolismo , Proteína do Retinoblastoma/metabolismo , Receptor fas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Células HeLa , Humanos , Imidazóis/farmacologia , Imunoprecipitação , Marcação In Situ das Extremidades Cortadas , Camundongos , Ligação Proteica/genética , Ligação Proteica/fisiologia , Piridinas/farmacologia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor fas/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
Rho GDP dissociation inhibitor 2 (RhoGDI2) is a regulator of the Rho family GTPases. Recent work from our laboratory suggests that RhoGDI2 expression potentially enhances resistance to cisplatin as well as promotes tumor growth and malignant progression in gastric cancer. In this study, we demonstrate that phospholipase C-gamma (PLCγ) is required for RhoGDI2-mediated cisplatin resistance and cancer cell invasion in gastric cancer. The levels of phosphorylated PLCγ are markedly enhanced in RhoGDI2-overexpressing SNU-484 cells and, by contrast, repressed in RhoGDI2-depleted MKN-28 cells. Depletion of PLCγ expression or inhibition of its activity not only significantly increases cisplatin-induced apoptosis but also suppresses the invasive ability of RhoGDI2-overexpressing SNU-484 cells. Taken together, our results suggest that PLCγ plays a key role in RhoGDI2-mediated cisplatin resistance and cell invasion in gastric cancer cells.
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Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Dissociação do Nucleotídeo Guanina/metabolismo , Fosfolipase C gama/fisiologia , Neoplasias Gástricas/tratamento farmacológico , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , Inibidores de Dissociação do Nucleotídeo Guanina/genética , Humanos , Invasividade Neoplásica , Fosfolipase C gama/genética , Fosforilação , Neoplasias Gástricas/patologia , Proteínas Supressoras de Tumor/genética , Inibidor beta de Dissociação do Nucleotídeo Guanina rho , Inibidores da Dissociação do Nucleotídeo Guanina rho-EspecíficoRESUMO
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.
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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 fármacosRESUMO
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.
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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 CimaRESUMO
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.
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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 alfaRESUMO
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.
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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 adversosRESUMO
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.
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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 fármacosRESUMO
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/toxicidadeRESUMO
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 interferonγ (IFNγ) 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 fármacosRESUMO
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-DawleyRESUMO
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.