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1.
Biochem Biophys Res Commun ; 506(4): 927-931, 2018 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-30392907

RESUMO

Rubiadin-1-methyl ether (RBM) is a natural anthraquinone compound isolated from the root of Morinda officinalis How. In our previous study, RBM was found to have inhibitory effects on the TRAP activity of osteoclasts, which means that RBM may be a candidate for therapy of bone diseases characterized by enhanced bone resorption. However, the further effect of RBM on osteoclasts and the underlying mechanism remain unclear. In the present study, we investigated the effects of RBM isolated from Morinda officinalis How. on osteoclasts derived from bone marrow macrophages (BMMs) and the underlying mechanism in vitro. RBM at the dose that did not affect the viability of cells significantly inhibited RANKL-induced osteoclastogenesis and actin ring formation of osteoclast, while RBM performed a stronger effect at the early stage. In addition, RBM downregulated the expression of osteoclast-related proteins, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), cellular oncogene Fos (c-Fos), matrix metallopeptidase 9 (MMP-9) and cathepsin K (CtsK) as shown by Western blot. Furthermore, RBM inhibited the phosphorylation of NF-κB p65 and the degradation of IκBα as well as decreased the nuclear translocation of p65. Collectively, the results suggest that RBM inhibit osteoclastic bone resorption through blocking NF-κB pathway and may be a promising agent for the prevention and treatment of bone diseases characterized by excessive bone resorption.


Assuntos
Antraquinonas/farmacologia , Morinda/química , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Ligante RANK/farmacologia , Transdução de Sinais , Actinas/metabolismo , Animais , Antraquinonas/química , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fosfatase Ácida Resistente a Tartarato/metabolismo
2.
BMC Complement Altern Med ; 18(1): 288, 2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30355303

RESUMO

BACKGROUND: Iridoid glycosides (IGs), including monotropein (MON) and deacetyl asperulosidic acid (DA) as the main ingredients, are the major chemical components in Morinda officinalis How. (MO) root, possessing various pharmacological properties including anti-osteoporosis, anti-inflammation and anti-rheumatism activities.The aim of the present study was to further elucidate the pharmacological actions of MO by investigating the pharmacokinetics and tissue distribution of IGs in MO. METHODS: An ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) method was developed and validated for simultaneous determination of MON and DA levels in plasma and various tissues of Wistar rats. MON, DA and acetaminophen (ACE) as the internal standard (IS) were extracted from rat plasma and tissue samples by direct deproteinization with methanol. The rats were administered orally at 1650 mg/kg MO and 25, 50 and 100 mg/kg MO iridoid glycosides (MOIGs) or intravenously at MOIG 25 mg/kg for pharmacokinetic study of MON and DA. In addition, 100 mg/kg MOIG was administered orally for tissue distribution study of MON and DA. Non-compartmental pharmacokinetic profiles were constructed. Tissue distributions were calculated according to the validated methods. RESULTS: Significant differences in the pharmacokinetic parameters were observed in male and female rats. The AUC0-t, Cmax and bioavailability of MON and DA in female rats were higher than those in male rats. MON and DA mainly distributed in the intestine and stomach after oral administration, and noteworthily high concentrations of MON and DA were detected in the rat hypothalamus. CONCLUSION: The results of the present study may shed new lights on the biological behavior of MOIGs in vivo, help explain their pharmacological actions, and provide experimental clues for rational clinical use of these IGs extracted from the MO root.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Glicosídeos/farmacocinética , Iridoides/farmacocinética , Morinda/química , Administração Oral , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Feminino , Glicosídeos/administração & dosagem , Glicosídeos/química , Glicosídeos Iridoides/administração & dosagem , Glicosídeos Iridoides/química , Glicosídeos Iridoides/farmacocinética , Iridoides/administração & dosagem , Iridoides/química , Masculino , Estrutura Molecular , Raízes de Plantas/química , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem , Distribuição Tecidual
3.
Int J Cancer ; 140(11): 2596-2607, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28198003

RESUMO

Activating mutation of epidermal growth factor receptor (EGFR) is correlated with malignant lung tumor. In our study, we demonstrated that recombinant LZ-8 (rLZ-8), a medicinal mushroom Ganoderma lucidum protein, induced cell cycle arrest and apoptosis by downregulating the expression of wild-type and mutated EGFR and inhibiting EGFR downstream effectors, AKT and ERK1/2 in lung cancer cells. We showed that rLZ-8 effectively inhibited lung cancer progression and suppressed EGFR expression of lung tumor lesions in mouse model. Functional studies revealed that rLZ-8 reduced the amount of EGFR in cell membranes by altering EGFR localization to enhance the EGF-induced degradation of EGFR. Mechanistically, we demonstrated that rLZ-8 bound to EGFR to induce EGFR autophosphorylation at tyrosine1045 and trigger ubiquitination by inducing the formation of EGFR/Cbl complexes, resulting in the degradation of EGFR; however, Cbl-shRNA abolished rLZ-8-induced EGFR degradation. We provide the first evidence showing that rLZ-8 inhibits growth and induces apoptosis of lung cancer cells by promoting EGFR degradation. The current findings therefore suggest a novel anti-cancer function of rLZ-8 that targeting EGFR overexpression or mutation as well as EGFR-dependent processes in cancer cells.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/genética , Proteínas Fúngicas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteína Oncogênica v-cbl/genética , Proteínas Recombinantes/farmacologia , Células A549 , Agaricales/genética , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Proteínas Fúngicas/economia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação/efeitos dos fármacos , Mutação/genética , Reishi/genética , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacos
4.
Proc Natl Acad Sci U S A ; 110(34): 13809-14, 2013 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-23908400

RESUMO

Carbohydrate-based vaccines have shown therapeutic efficacy for infectious disease and cancer. The mushroom Ganoderma lucidum (Reishi) containing complex polysaccharides has been used as antitumor supplement, but the mechanism of immune response has rarely been studied. Here, we show that the mice immunized with a l-fucose (Fuc)-enriched Reishi polysaccharide fraction (designated as FMS) induce antibodies against murine Lewis lung carcinoma cells, with increased antibody-mediated cytotoxicity and reduced production of tumor-associated inflammatory mediators (in particular, monocyte chemoattractant protein-1). The mice showed a significant increase in the peritoneal B1 B-cell population, suggesting FMS-mediated anti-glycan IgM production. Furthermore, the glycan microarray analysis of FMS-induced antisera displayed a high specificity toward tumor-associated glycans, with the antigenic structure located in the nonreducing termini (i.e., Fucα1-2Galß1-3GalNAc-R, where Gal, GalNAc, and R represent, respectively, D-galactose, D-N-acetyl galactosamine, and reducing end), typically found in Globo H and related tumor antigens. The composition of FMS contains mainly the backbone of 1,4-mannan and 1,6-α-galactan and through the Fucα1-2Gal, Fucα1-3/4Man, Fucα1-4Xyl, and Fucα1-2Fuc linkages (where Man and Xyl represent d-mannose and d-xylose, respectively), underlying the molecular basis of the FMS-induced IgM antibodies against tumor-specific glycans.


Assuntos
Anticorpos Antineoplásicos/imunologia , Antígenos Glicosídicos Associados a Tumores/imunologia , Carcinoma Pulmonar de Lewis/imunologia , Fucose/imunologia , Polissacarídeos Fúngicos/imunologia , Reishi/química , Animais , Linfócitos B/imunologia , Quimiocina CCL2/metabolismo , Polissacarídeos Fúngicos/metabolismo , Imunização , Imunoglobulina M/sangue , Imunoglobulina M/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries
5.
Carcinogenesis ; 34(4): 874-84, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23275155

RESUMO

Fucoidan, a polysaccharide extracted from brown seaweeds, reduces tumor cell proliferation. Fucoidan inhibits the growth of breast cancer cells such as 4T1 and MDA-MB-231 and decreases their cell colony formation. Moreover, fucoidan reduces metastatic lung nodules in 4T1 xenograft female Balb/c mice. The molecular network of transforming growth factor ß (TGFß) receptors (TGFRs) plays an important role in the regulation of the epithelial to mesenchymal transition (EMT) in cancer cells. Using 4T1 and MDA-MB-231 cells, we found that fucoidan effectively reverses TGFR-induced EMT morphological changes, upregulates epithelial markers, downregulates mesenchymal markers and decreases the expression of transcriptional repressors Snail, Slug and Twist. Moreover, fucoidan inhibits migration and invasion during the EMT, suggesting the involvement of TGFR-mediated signaling in breast cancer cells. Fucoidan decreases TGFRI and TGFRII proteins and affects downstream signaling molecules, including Smad2/3 phosphorylation and Smad4 expression. In order to elucidate how fucoidan decreases TGFRI and TGFRII proteins in MDA-MB-231 cells, we investigated ubiquitination activity downregulation of TGFRs. It was found that fucoidan enhances proteasome-mediated degradation/ubiquitination of TGFR. This study is the first to identify a novel mechanism for fucoidan antitumor activity, namely regulation of the EMT via modulation of TGFR/Smad-dependent signaling, which leads to an inhibition of breast cancer cell growth in vitro and in vivo. Our current findings indicate that fucoidan is a potential therapeutic agent for breast cancer and acts via an ubiquitin-dependent degradation pathway that affects the TGFR/Smad/Snail, Slug, Twist and EMT axes.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Metástase Neoplásica/tratamento farmacológico , Polissacarídeos/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Transplante de Neoplasias , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/biossíntese , Transplante Heterólogo , Proteína 1 Relacionada a Twist/biossíntese , Ubiquitina/metabolismo , Ubiquitinação/efeitos dos fármacos
6.
Int J Biol Macromol ; 227: 1-9, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36528139

RESUMO

Polysaccharide from Laminaria japonica (LJPS) exhibits multiple biological functions. However, we found that crude LJPS doesn't show good anti-lung cancer activity in this study. We therefore used tangential flow filtration (TFF) system to optimize the anticancer activity of LJPS. We divided the crude LJPS into two fractions by TFF system with a 10 kDa filter and denoted as retentate (10K-R) and filtration (10K-F). The chemical assay revealed that the main molecular mass of 10K-R and 10K-F is about 985 and 3 kDa, respectively. The main components of 10K-R include fucose (19.3 %), and glucose (59.5 %); while glucose (88.6 %) is a major component of 10K-F. Biological functions showed that 10K-R but not 10K-F inhibited the viability and mobility of cancer cells. 10K-R downregulated expressions of transforming growth factor ß receptor and Slug, and inhibited intracellular signaling molecules, including FAK, AKT, ERK1/2, and Smad2. This study is the first concept to purify the polysaccharide by TFF system and showed the potential mechanism of 10K-R inhibited cancer cells.


Assuntos
Laminaria , Neoplasias , Humanos , Laminaria/química , Polissacarídeos/química , Transdução de Sinais , Glucose
7.
J Cell Physiol ; 227(8): 3063-71, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22021110

RESUMO

Ganoderma lucidum is used in traditional Chinese medicine to prevent or treat a variety of diseases, including cardiovascular disorders. We previously demonstrated that a glucan-containing extract of Reishi polysaccharides (EORP) has the potent anti-inflammatory action of reducing ICAM-1 expression in lipopolysaccharide (LPS)-treated human aortic smooth muscle cells (HASMCs) and LPS-treated mice. In the present study, we examined whether EORP inhibited platelet-derived growth factor-BB (PDGF)-stimulated HASMC proliferation and the mechanism involved. EORP dose-dependently reduced cell numbers and DNA synthesis of PDGF-treated HASMCs in vitro. EORP also arrested cell cycle progression in the G0/G1 phase, and this was associated with decreased expression of cyclin D1, cyclin E, CDK2, CDK4, and p21(Cip1) and upregulation of the cyclin-dependent kinase inhibitor p27(Kip1). The anti-proliferative effect of EORP was partly mediated by downregulation of PDGF-induced JNK phosphorylation. In in vivo studies, the femoral artery of C57BL/6 mice was endothelial-denuded and the mice were fed a diet containing 100 mg/kg/day of EORP. On day 14, both cell proliferation (proliferating cell nuclear antigen-positive cells) in the neointima and the neointima/media area ratio (0.67 ± 0.03 vs. 1.46 ± 0.30) were significantly reduced. Our data show that EORP interferes with the mitogenic activation of JNK, preventing entry of HASMCs into the cell cycle in vitro and reducing cell proliferation in the neointima and decreasing the neointimal area in vivo. Thus, EORP may represent a safe and effective novel approach to the prevention and treatment of vascular proliferative diseases.


Assuntos
Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Miócitos de Músculo Liso , Neointima , Polissacarídeos/farmacologia , Reishi , Animais , Aorta/citologia , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Técnicas de Silenciamento de Genes , Humanos , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Fosforilação/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/farmacologia
8.
Carcinogenesis ; 32(12): 1890-6, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21983128

RESUMO

Ling Zhi-8 (LZ-8), an immunomodulatory protein, is derived from and has been cloned from the medicinal mushroom Ganoderma lucidum (Reishi or Ling Zhi); this protein exhibits immunomodulating and antitumor properties. We investigated the effects of recombinant LZ-8 protein (rLZ-8) on the proliferation of A549 human lung cancer cells. Here, we showed that rLZ-8 inhibits cell growth and that this is correlated with increased G(1) arrest. The treatment of A549 cells with rLZ-8 activated p53 and p21 expression, and both the G(1) arrest and the antigrowth effect were found to be p53 dependent. It was further demonstrated that rLZ-8 inhibited tumor growth in mice transplanted with Lewis lung carcinoma cells. Interestingly, rLZ-8 treatment was found to lead to nucleolar stress (or ribosomal stress) as evidenced by inhibition of precursor ribosomal RNA synthesis and reduced polysome formation in A549 cells. These changes resulted in an increasing binding of ribosomal protein S7 to MDM2 and a decreased interaction between MDM2 and p53. Taking these results together, we have identified a novel rLZ-8 antitumor function that positively modulates p53 via ribosomal stress and inhibits lung cancer cell growth in vitro and in vivo. Our current results suggest that rLZ-8 may have potential as a therapeutic intervention for the treatment of cancers that contain wild-type p53 and high expression of MDM2.


Assuntos
Proliferação de Células/efeitos dos fármacos , Proteínas Fúngicas/farmacologia , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Ribossômicas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Sequência de Bases , Primers do DNA , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Transplante de Neoplasias , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
9.
Int J Biol Macromol ; 153: 796-805, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32169452

RESUMO

Gefitinib is a first tyrosine kinase inhibitor (TKI) designed with an EGFR tyrosine kinase for lung cancer targeted therapy. However, some lung cancer patients with wild-type EGFR (wtEGFR) or acquired secondary EGFR mutation showed lower response rate of gefitinib. In this study, we examined the efficacy of fucoidan on altering gefitinib-sensitivity on TKI-resistant lung cancer A549 and H1975 cells. We found that the simultaneous administration of fucoidan and gefitinib synergistically inhibited lung cancer cell viability via activating apoptotic response. Moreover, we found that fucoidan effectively downregulated expressions of mesenchymal-like molecules. Mechanistically, we demonstrated that fucoidan altered the gefitinib-inhibitory rate may result from induction of proteasome-dependent Slug degradation. Abolishment of TGFß signaling enhanced gefitinib-inhibited cell viability and reduced N-cadherin, Twist and Slug levels. Moreover, knockdown of Slug contributed the increasing the gefitinib-sensitivity of H1975 cells. Our study is the first to find that fucoidan alters the gefitinib-sensitive of TKI-resistant cells by reduction of TGFß receptor-mediated expressions of mesenchymal-like molecules and induction of Slug degradation. Together, our current results indicate that combination of fucoidan and gefitinib may be a potential and effective therapeutic strategy in gefitinib non-sensitive lung cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares , Proteínas de Neoplasias/metabolismo , Polissacarídeos/farmacologia , Fatores de Transcrição da Família Snail/biossíntese , Fator de Crescimento Transformador beta/metabolismo , Células A549 , Animais , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos
10.
Int J Biol Macromol ; 165(Pt A): 1604-1613, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33011264

RESUMO

WSG is a water soluble polysaccharides isolated from Ganoderma lucidum. In this study, we showed that WSG, a glucose-rich polysaccharide with an average molecular mass of approximately 1000 kDa, effectively inhibited cell viability and mobility of lung cancer cells. Functional studies revealed that WSG reduced phosphorylation of ERK1/2 in cells upon either EGF or TGFß stimulation. WSG also inhibited phosphorylation of multiple intracellular signaling molecules such as FAK, AKT and Smad2. Mechanistically, we demonstrated that WSG induced degradation of TGFß and EGF receptors via proteasome and lysosome, respectively. Moreover, we found that WSG significantly suppressed lung tumor growth, reduced the size of metastatic nodules in the lungs and prolonged the survival of LLC1-bearing mice. Our findings suggested that WSG may have potential as a therapeutic intervention for treatment of lung cancer.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Polissacarídeos/química , Reishi/química , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Proteínas de Neoplasias/genética , Polissacarídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Clin Transl Med ; 8(1): 15, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31041568

RESUMO

The chemical composition of fucoidan, a kind of sulfated polysaccharide mainly derived from brown seaweed, includes a substantial percentage of L-fucose. Fucoidan has various biological and pharmacological activities, such as anti-cancer/anti-tumor, anti-proliferation, anti-inflammatory and immune-modulatory functions, and fucoidan-related dietary supplements and nutraceuticals have recently drawn considerable attention. In this review, we aim to provide a current view of different aspects of fucoidan biological activity, with a focus on the anti-cancer regulatory effects of fucoidan on growth signaling mechanisms. First, we discuss historical aspects of fucoidan and fucoidan products, as well as the anti-cancer effects of fucoidan on various cancer cells. Second, we discuss fucoidan's biological activities and induction of cell death in cancer cells, including multiple mechanisms and signal transduction pathways related to its anti-cancer effects. Next, we focus on fucoidan and fucoidan-derived products that have been marketed as dietary supplements or nutraceuticals for cancer, including anti-cancer effects of fucoidan when combined as an adjuvant with clinical drugs. Finally, case studies of fucoidan in complementary therapy and as an alternative medicine in animal and mouse models and human clinical trials to alleviate side effects of anti-cancer chemotherapy are discussed. Combining fucoidan with clinical therapeutic agents in the treatment of cancer patients, dissecting the related signal transduction pathways and investigating their dynamic interactions may reveal potential molecular targets in cancer prevention, therapies and key obstacles in the current development of anti-cancer strategies.

12.
J Cell Physiol ; 215(3): 603-12, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18357586

RESUMO

Curcumin, a polyphenolic compound derived from plant, regulates heme oxygenase (HO-1) expression within certain cell types; however, the Curcumin-mediated signal transduction in the regulation of HO-1 expression within human monocytes/macrophages is unclear. Herein, we show that Curcumin dose dependently induced HO-1 expression and HO-1 activity through the activation of PKCalpha, PKCdelta/ERK1/2, p38alpha, and PI3-kinase. In addition, H2O2 release is essential for Curcumin-mediated ERK1/2 and p38 phosphorylation and HO-1 expression. Further, Curcumin inhibited LPS-induced IL-1 and IL-6 secretion and blockage of HO-1 expression/activity by HO-1 siRNA or HO-1 inhibitor, SnPP reversed the inhibitory effects of Curcumin on cytokines secretion. HO-1 over-expression produced the same inhibitory effects of Curcumin on IL-1 secretion. Collectively, our results suggest that Curcumin inhibits cytokines secretion within LPS-stimulated monocytes through a mechanism that involves the action of HO-1.


Assuntos
Anti-Inflamatórios/farmacologia , Curcumina/farmacologia , Heme Oxigenase-1/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/enzimologia , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Modelos Biológicos , Monócitos/citologia , Monócitos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Quinase C-delta/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
J Cell Physiol ; 215(1): 15-26, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18189229

RESUMO

Ganoderma lucidum, a medicinal fungus is thought to possess and enhance a variety of human immune functions. An immuno-modulatory protein, Ling Zhi-8 (LZ-8) isolated from G. lucidum exhibited potent mitogenic effects upon human peripheral blood lymphocytes (PBL). However, LZ-8-mediated signal transduction in the regulation of interleukin-2 (IL-2) gene expression within human T cells is largely unknown. Here we cloned the LZ-8 gene of G. lucidum, and expressed the recombinant LZ-8 protein (rLZ-8) by means of a yeast Pichia pastoris protein expression system. We found that rLZ-8 induces IL-2 gene expression via the Src-family protein tyrosine kinase (PTK), via reactive oxygen species (ROS), and differential protein kinase-dependent pathways within human primary T cells and cultured Jurkat T cells. In essence, we have established the nature of the rLZ-8-mediated signal-transduction pathways, such as PTK/protein kinase C (PKC)/ROS, PTK/PLC/PKCalpha/ERK1/2, and PTK/PLC/PKCalpha/p38 pathways in the regulation of IL-2 gene expression within human T cells. Our current results of analyzing rLZ-8-mediated signal transduction in T cells might provide a potential application for rLZ-8 as a pharmacological immune-modulating agent.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Interleucina-2/genética , Proteína Quinase C/metabolismo , Reishi/imunologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Complexo CD3/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Proteínas Fúngicas/imunologia , Proteínas Fúngicas/farmacologia , Humanos , Fatores Imunológicos/imunologia , Interleucina-2/metabolismo , Isoenzimas/metabolismo , Células Jurkat , Ativação Linfocitária/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas Recombinantes/farmacologia , Reishi/química , Linfócitos T/enzimologia , Linfócitos T/metabolismo , Fatores de Tempo , Fosfolipases Tipo C/metabolismo , Quinases da Família src/metabolismo
14.
J Biomed Sci ; 15(3): 357-63, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18038269

RESUMO

Lysophosphatidic acid (LPA), a low-molecular-weight lysophospholipid enriched in platelets and mildly oxidized low-density lipoproteins, is known to regulate inflammation and atherosclerosis by binding to its cognate receptors. In this study, we reported that LPA upregulated interleukin-1 beta (IL-1 beta) expression in mouse J774A.1 macrophages. By using pharmacological inhibitors, it was suggested that G(i)/Rho activation and subsequent reactive oxygen species (ROS) production were involved in IL-1 beta induction. In addition, IL-1 beta induction by LPA was also observed in human primary macrophages. In summary, LPA is involved in the processes of inflammation by affecting macrophage behavior.


Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Interleucina-1beta/metabolismo , Lisofosfolipídeos/farmacologia , Macrófagos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Sequência de Bases , Western Blotting , Linhagem Celular , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Humanos , Macrófagos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica
15.
Prostaglandins Other Lipid Mediat ; 87(1-4): 20-5, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18585471

RESUMO

Lysophosphatidic acid (LPA) is a low-molecular-weight lysophospholipid enriched in platelets and mildly oxidized low-density lipoprotein (OxLDL). It is suggested that LPA is involved in atherosclerosis, and our previous studies showed that LPA regulates inflammation in multiple cell types. The main aim of this study was to investigate the effects of LPA on the uptake of OxLDL by mouse J774A.1 macrophages. We observed that LPA upregulated fluorescence-labeled DiI-OxLDL uptake in J774A.1 cells. Meanwhile, expression of the class A scavenger receptor (SR-A), a receptor for modified LDL, was also enhanced. Furthermore, pertussis toxin (PTx) or Ki16425 significantly abolished LPA's effects, indicating that G(i) and LPA(3) are involved in OxLDL uptake and SR-A expression. Of most importance, the LPA-induced OxLDL uptake could be inhibited when cells were incubated with a functional blocking antibody of SR-A. Our results suggest that LPA-enhanced OxLDL uptake is mediated via LPA(3)-G(i) activation and subsequent SR-A expression.


Assuntos
Lipoproteínas LDL/metabolismo , Lisofosfolipídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Receptores Depuradores/metabolismo , Animais , Anticorpos/imunologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores Depuradores Classe A/antagonistas & inibidores , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/imunologia , Transdução de Sinais/efeitos dos fármacos
16.
Food Chem Toxicol ; 46(1): 220-31, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17868967

RESUMO

We investigated the in vitro anti-inflammatory effects of Cinnamaldehyde, a cytokine production inhibitor isolated from an essential oil produced from the leaves of Cinnamomum osmophloeum Kaneh, and its mechanism of action. Although Cinnamaldehyde has been reported to have contact sensitizing properties at high concentration (mM), we found that low concentration of Cinnamaldehyde (muM) inhibited the secretion of interleukin-1beta and tumor necrosis factor alpha within lipopolysaccharide (LPS) or lipoteichoic acid (LTA) stimulated murine J774A.1 macrophages. Cinnamaldehyde also suppressed the production of these cytokines from LPS stimulated human blood monocytes derived primary macrophages and human THP-1 monocytes. Furthermore, Cinnamaldehyde also inhibited the production of prointerleukin-1beta within LPS or LTA stimulated human THP-1 monocytes. Reactive oxygen species release from LPS stimulated J774A.1 macrophages was reduced by Cinnamaldehyde. The phosphorylation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase 1/2 induced by LPS was also inhibited by Cinnamaldehyde; however, Cinnamaldehyde neither antagonize the binding of LPS to the cells nor alter the cell surface expression of toll-like receptor 4 and CD14. In addition, we also noted that Cinnamaldehyde appeared to elicit no cytotoxic effect upon J774A.1 macrophages under our experimental conditions, although Cinnamaldehyde reduced J774A.1 macrophages proliferation as analysed by MTT assay. Our current results have demonstrated the anti-oxidation and anti-inflammatory properties of Cinnamaldehyde that could provide the possibility for Cinnamaldehyde's future pharmaceutical application in the realm of immuno-modulation.


Assuntos
Acroleína/análogos & derivados , Cinnamomum/química , Citocinas/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Macrófagos/metabolismo , Monócitos/metabolismo , Acroleína/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Sequestradores de Radicais Livres/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Fatores Imunológicos/farmacologia , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/efeitos dos fármacos , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacologia , Oxidantes/metabolismo , Folhas de Planta/química , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/metabolismo
17.
Cancer Lett ; 432: 112-120, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-29746926

RESUMO

Cisplatin-based therapy is a traditional, clinical treatment for cancers, including lung cancer. In this study, we found that sequential therapy, i.e., cisplatin followed by fucoidan, reduced tumor volume in an LLC1-bearing C57BL/6 mouse model. Using a series of combined therapeutic experiments, we found that the inhibition rate of the sequential treatment (cisplatin→fucoidan) was 50-75%. However, the inhibition rate of the sequential treatment, with fucoidan pretreatment, was increased to 75-85%. Moreover, we found that the simultaneous administration of fucoidan and cisplatin synergistically inhibited lung cancer cell viability via inducing apoptotic responses, including upregulating cleaved caspase-3 and poly (ADP ribose) polymerase (PARP) expression. Mechanistically, we demonstrated that the fucoidan-induced, TLR4-mediated endoplasmic reticulum stress molecule CHOP promoted caspase-3 activation, which was further stimulated by the cisplatin-induced DNA damage responses, and CHOP shRNA eliminated fucoidan-induced caspase-3 cleavage but did not affect cisplatin-mediated apoptotic molecules. In addition, we observed an increasing number of clinical results that suggest combined cisplatin and fucoidan exerts a greater anti-tumorigenic effect in patients with lung cancer in Taiwan. Together, our current results support the potential of combined fucoidan and cisplatin treatment as an effective therapeutic strategy in lung cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Pulmonar de Lewis/patologia , Caspase 3/metabolismo , Neoplasias Pulmonares/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição CHOP/metabolismo , Animais , Apoptose , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/metabolismo , Caspase 3/genética , Ciclo Celular , Proliferação de Células , Cisplatino/administração & dosagem , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerase-1/genética , Polissacarídeos/administração & dosagem , Receptor 4 Toll-Like/genética , Fator de Transcrição CHOP/genética , Células Tumorais Cultivadas
18.
Chem Biol Interact ; 291: 128-136, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29908987

RESUMO

Estrogen deficiency and inflammation are known to play important roles in bone metabolism and occurrence of osteoporosis. Monotropein as an iridoid glycoside is reported to decrease estrogen deficiency-induced bone loss and inhibit inflammatory response in LPS-induced RAW 264.7 macrophages. However, the effect of monotropein on bone loss in chronic inflammatory conditions remains unclear. It was found in the present study that monotropein significantly inhibited bone mass reduction and improved bone micro-architectures by enhancing bone formation and blocking increased secretion of inflammatory cytokines in osteoporotic mice induced by combined ovariectomy and LPS. Our in vitro experiment further demonstrated that monotropein was able to increase the proliferation and activity of alkaline phosphatase (ALP), bone matrix mineralization and the expression of bone matrix protein osteopontin (OPN) in osteoblastic MC3T3-E1 cells injured by LPS. In addition, monotropein significantly decreased the production of IL-6 and IL-1ß, inhibited the nuclear translocation of p65 and NF-κB P50, and down-regulated the phosphorylation of NF-κB p65 and IKK, indicating that monotropein could attenuate inflammatory impairment to MC3T3-E1 cells by suppressing the activation of NF-κB pathway. All these results suggest that monotropein may prove to be a promising candidate for the prevention and treatment of inflammatory bone loss.


Assuntos
Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/tratamento farmacológico , Inflamação/patologia , Iridoides/uso terapêutico , NF-kappa B/metabolismo , Osteoblastos/patologia , Ovariectomia , Transdução de Sinais/efeitos dos fármacos , Fosfatase Alcalina/sangue , Animais , Densidade Óssea/efeitos dos fármacos , Matriz Óssea/efeitos dos fármacos , Matriz Óssea/metabolismo , Reabsorção Óssea/sangue , Calcificação Fisiológica/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Inflamação/complicações , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Iridoides/química , Iridoides/farmacologia , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteoporose/sangue , Osteoporose/patologia , Microtomografia por Raio-X
19.
Opt Express ; 15(17): 11020-32, 2007 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-19547459

RESUMO

Lipopolysaccharide (LPS), one of the cell wall components of Gram-negative bacteria, is recognized by and interacted with receptors on macrophages. In this paper, we report the trapping of LPS-coated polystyrene particles via optical tweezers and measured its interaction with murine macrophages (J774A.1 cells) for cells pre-treated with extract of Reishi polysaccharides (EORP) vs. those without EORP treatment. Our experimental results indicate that the cellular affinity for LPS increases when the macrophage is pretreated with EORP. We demonstrate for the first time by conventional biological methods and by tracking the dynamics of optically-trapped LPS-coated particles interacting with J774A.1 cells, that EORP not only enhances J774A.1 cells surface expression of TLR4 and CD14, two receptors on macrophages, as well as LPS binding and phagocytosis internalization, but also reduces the adhesion time constant and increases the force constant of the binding interaction. The application of optical tweezers allows us to study the effect on a single cell quantitatively in real-time with a spatial resolution ~ 1 mum within a single cell.

20.
J Biomed Opt ; 12(2): 024025, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17477740

RESUMO

Application of a fiber optic biosensor (FOB) to the real-time investigation of the interaction kinetics between FITC-conjugated monoclonal sheep anti-human C-reactive protein (CRP) antibody and CRP isoforms on the surface of optical fiber is described. Recently, both the native pentameric CRP (pCRP), an acute phase protein belonging to pentraxin family, and an isoform of pCRP, modified CRP (mCRP), have been suggested to have proinflammation effects on vascular cells in acute myocardial infarction (AMI). In current studies, we generate mCRP from pCRP, and use several methods including fluorescence spectral properties, circular dichroism, analytical ultracentrifuge, and Western blotting to demonstrate their differences in physical and chemical properties as well as the purity of pCRP and mCRP. In addition, we design and implement an FOB to study the real-time qualitative and quantitative biomolecular recognition of CRP isoforms. Specifically, the association and dissociation rate constants of the reaction between FITC-conjugated monoclonal sheep anti-human CRP antibody and the pCRP and mCRP are determined. The feasibility of our current approach to measure the association and dissociation rate constants of the reaction between tested CRP isoforms was successfully demonstrated.


Assuntos
Anticorpos Monoclonais/imunologia , Proteína C-Reativa/análise , Proteína C-Reativa/imunologia , Tecnologia de Fibra Óptica/instrumentação , Imunoensaio/instrumentação , Técnicas Analíticas Microfluídicas/instrumentação , Desenho de Equipamento , Análise de Falha de Equipamento , Tecnologia de Fibra Óptica/métodos , Técnicas Analíticas Microfluídicas/métodos , Fibras Ópticas , Ligação Proteica , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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