RESUMO
Obesity is the most common metabolic disease in developed countries and has become a global epidemic in recent years. Obesity is associated with various metabolic abnormalities, including glucose intolerance, insulin resistance, type 2 diabetes, dyslipidemia, and hypertension. Leaves from the plant Dendropanax morbiferus are beneficial to health as they contain high levels of vitamin C and tannin. There have been seminal studies on the anticancer, antimicrobial, antidiabetes, and antihyperglycemic effects of treatments with D. morbiferus trees. Herein, we investigated the toxicity of D. morbiferus water (DLW) extracts in vitro, and demonstrated no toxicity at 5-500 µg/mL in 24-72-h experiments with 3T3-L1 cells. The DLW increased cell viability at 48 h and inhibited adipogenesis in 3T3-L1 cells by reducing intracellular triglyceride levels and glucose uptake. In addition, mRNA and protein expression levels of adipogenesis-related genes were lowered by DLW, suggesting antiobesity effects in mouse 3T3-L1 cells. Because few studies have demonstrated cholesterol-lowering effects of D. morbiferus, we investigated the activities of adipogenic transcriptional factors following treatments of 3T3-L1 cells with D. morbiferus and observed increased CEBPα, CEBPß, PPARγ, and SREBP1 activities in the cells, indicating that DLW extracts inhibit adipogenesis.
Assuntos
Células 3T3-L1/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Araliaceae , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Células 3T3-L1/metabolismo , Animais , Fármacos Antiobesidade/uso terapêutico , Colesterol/metabolismo , Camundongos , Fitoterapia , Extratos Vegetais/uso terapêutico , Triglicerídeos/metabolismoRESUMO
Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors. Mechanistically, chondroitin sulfate glucuronyltransferase (CSGlcA-T) signals through its product CHSA to enhance casein kinase 2 (CK2)-PTEN binding and consequent phosphorylation and inhibition of PTEN, which requires CHSA chains and is essential to sustain AKT activation in BRAF V600E-expressing melanoma cells. However, this CHSA-dependent PTEN inhibition is dispensable in cancer cells expressing mutant NRAS or PI3KCA, which directly activate the PI3K-AKT pathway. These results suggest that dietary supplements may exhibit oncogene-dependent pro-tumor effects.
Assuntos
Carcinógenos/toxicidade , Transformação Celular Neoplásica/genética , Sulfatos de Condroitina/toxicidade , Suplementos Nutricionais/toxicidade , Melanoma/induzido quimicamente , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/induzido quimicamente , Animais , Antinematódeos/farmacologia , Caseína Quinase II/metabolismo , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , GTP Fosfo-Hidrolases/genética , Células HEK293 , Células HT29 , Humanos , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Melanoma/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos Transgênicos , Células NIH 3T3 , Proteínas Nucleares/genética , PTEN Fosfo-Hidrolase/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Porphyra tenera, also known as nori, is a red algal species of seaweed. It is cultivated in Asia for culinary purposes. We report that P. tenera extract (PTE) enhances the immune response in mouse macrophages. We found that P. tenera extract regulates the NF-κB IκB kinase (IKK) signaling pathway, and we assessed the expression and translocation of p65, a subunit of NF-κB, in RAW264.7 mouse macrophage cells after treatment with PTE. We also investigated the effects of 10% ethanol PTE (PTE10) in RAW264.7 cells. The production of IL-10, IL-6, TNF-α, and IFN-γ was induced by PTE treatment of the macrophages, and PTE also enhanced p-IκB and p-AKT. PTE10 showed no cytotoxicity at 10-20 µg/mL in RAW264.7 cells. PTE10, in fact, increased cell viability at 24 h, stimulated macrophage cells, and induced the phosphorylation of Akt. Akt stimulates IKK activity through the phosphorylation of IKKα and enhances immune activity through the activation of NF-κB. In this study, NF-κB activation was induced by increasing p-NF-κB and p-IKK. A subunit of NF-κB, p65, was located in the nucleus and increased the expression of various cytokines. PTE thus enhanced the immune response through IκB-α immunostimulation signaling in RAW264.7 cells. PTE10 has potential therefore for development of future treatments requiring immune system stimulation.
Assuntos
Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , NF-kappa B/imunologia , Extratos Vegetais/farmacologia , Porphyra/química , Alga Marinha/química , Animais , Quinase I-kappa B/genética , Quinase I-kappa B/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , NF-kappa B/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais/efeitos dos fármacosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Rosa rugosa Thunb. (Rosaceae) has been traditionally used for treatments of diabetes, chronic inflammatory diseases, pain, and anticancer in Korea. AIM OF STUDY: We investigate the inhibitory effect of histone acetyltransferase activity from the methanol extract of stems of Rosa rugosa on androgen receptor-mediated transcriptional regulation. MATERIALS AND METHODS: For the present study, Rosa rugosa methanol extract (RRME) was obtained from stem part of Rosa rugosa using methanol extraction. Histone acetyltransferase assay were performed to measure the inhibitory effect on acetylation, reporter assay, real-time PCR and ChIP assay were performed to measure androgen receptor-mediated transcriptional regulation, and MTT test were performed to measure cell viability. RESULTS: RRME inhibited both p300 and CBP (60-70% at 100 microg/ml) activity. We show RRME mediates agonist-dependent androgen receptor (AR) activation and suppresses antagonist-dependent inhibition. RRME treatment also decreased transcription of AR regulated genes and also reduced histone H3 and AR acetylation in the promoters of prostate-specific antigen (PSA) and beta-2-microglobulin (B2M). Finally, RRME treatment reduced the growth of LNCaP, a human prostate cancer cell line. CONCLUSION: These results demonstrate RRME is a potent HAT inhibitor, which reduced AR and histone acetylation leading to decreased AR-mediated transcription and reduced LNCaP cell growth.