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1.
Front Pharmacol ; 12: 708575, 2021.
Article in English | MEDLINE | ID: mdl-34588982

ABSTRACT

Maslinic acid (MA), also named crategolic acid, is a pentacyclic triterpene extracted from fruits and vegetables. Although various beneficial pharmacological effects of MA have been revealed, its effect on renal fibrosis remains unclear. This study was designed to clarify whether MA could attenuate renal fibrosis and determine the putative underlying molecular mechanisms. We demonstrated that MA-treated mice with unilateral ureteral obstruction (UUO) developed a histological injury of low severity and exhibited downregulated expression of fibrotic markers, including α-smooth muscle actin (α-SMA), vimentin, and fibronectin by 38, 44 and 40%, and upregulated expression of E-cadherin by 70% as compared with untreated UUO mice. Moreover, MA treatment restored the expression levels of α-SMA, connective tissue growth factor, and vimentin to 10, 7.8 and 38% of those induced by transforming growth factor (TGF)-ß in NRK49F cells. MA decreased expression of Smad2/3 phosphorylation and Smad4 in UUO kidneys and TGF-ß treated NRK49F cells (p < 0.05, respectively). Notably, MA specifically interferes with MyD88, an adaptor protein, thereby mitigating Smad4 nuclear expression (p < 0.01 compared to TGF-ß treated group) and ameliorating renal fibrotic changes (p < 0.01 for each fibrotic markers compared to TGF-ß induced cells). In addition, in the UUO model and lipopolysaccharide-induced NRK49F cells, MA treatment decreased the expression of IL-1ß, TGF-α and MCP-1, ICAM-1, associated with the suppression of NF-κB signaling. These findings suggest that MA is a potential agent that can reduce renal interstitial fibrosis, to some extent, via targeting TGF-ß/Smad and MyD88 signaling.

2.
Biosci Biotechnol Biochem ; 84(9): 1861-1869, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32475338

ABSTRACT

Dendritic cells (DCs) are play critical roles in the priming and regulation of immune responses. DCs rapidly process and convey these antigens to prime antigen-specific T cells. Therefore, regulation of DCs functions is important for immunity and immunotherapies. Immune adjuvants for DCs activation are needed to improve the efficacy of vaccines against tumors and many infectious diseases. Therefore, we demonstrate that H. fusiformis extract can regulate DCs maturation and activation. H. fusiformis extract induced costimulatory molecules (CD 80 and CD86), antigen-presenting molecules (major histocompatibility complex (MHC) I and II), CCR7 expression, and interleukin (IL)-12 production in DCs. These effects are associated with upregulation of mitogen-activated protein kinase (MAPK) signaling pathway. In addition, H. fusiformis extract induces costimulatory molecules on splenic DCs and activated CD8+ T cells in vivo. Taken together, these findings suggest that H. fusiformis extract may be a potential efficient immune therapeutic compound in DCs-mediated immunotherapies. ABBREVIATIONS: CTL: cytotoxic T lymphocytes; DCs: dendritic cells; ERK: extracellular signal-regulated kinases; IL: interleukini; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MHC: major histocompatibility complex.


Subject(s)
Dendritic Cells/cytology , Dendritic Cells/drug effects , Plant Extracts/pharmacology , Sargassum/chemistry , Cell Differentiation/drug effects , Cell Line , Dendritic Cells/immunology , Dendritic Cells/metabolism , Gene Expression Regulation/drug effects , Humans , Interleukin-12/biosynthesis , Lymphocyte Activation/drug effects , MAP Kinase Signaling System/drug effects , Receptors, CCR7/metabolism
3.
Mol Cell Biochem ; 451(1-2): 145-153, 2019 Jan.
Article in English | MEDLINE | ID: mdl-29995265

ABSTRACT

Neuroinflammation resulting from microglial activation is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's diseases. Microglial activation plays an important role in neuroinflammation and contributes to several neurological disorders. Hence, inhibition of both microglial activation and the generation of pro-inflammatory cytokines may lead to an effective treatment for neurodegenerative diseases. In the present study, the anti-neuroinflammatory effects of galangin were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Galangin significantly decreased the generation of nitric oxide, interleukin-1ß, and inducible nitric oxide synthase in LPS-stimulated BV-2 microglial cells. In addition, galangin inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase 1/2. Furthermore, it was observed that activation of both IκB-α and nuclear factor kappa B (NF-κB) was significantly increased following LPS stimulation, and this effect was suppressed by galangin treatment. In conclusion, galangin displayed an anti-neuroinflammatory activity in LPS-stimulated BV-2 microglial cells. Galangin inhibited LPS-induced neuroinflammation via the MAPK and NF-κB signaling pathways and might act as a natural therapeutic agent for the treatment of various neuroinflammatory conditions.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Flavonoids/pharmacology , Inflammation/drug therapy , Interleukin-1beta/metabolism , Lipopolysaccharides/pharmacology , Microglia/drug effects , NF-KappaB Inhibitor alpha/metabolism , Animals , Cytokines/metabolism , Gene Expression Regulation/drug effects , Inflammation/immunology , Inflammation/metabolism , Mice , Microglia/immunology , Microglia/metabolism , Mutagens/pharmacology , Nitric Oxide/metabolism , Phosphorylation , Signal Transduction
4.
Molecules ; 23(12)2018 Dec 04.
Article in English | MEDLINE | ID: mdl-30518111

ABSTRACT

We previously isolated pseudane-VII from the secondary metabolites of Pseudoalteromonas sp. M2 in marine water, and demonstrated its anti-inflammatory efficacy on macrophages. However, the molecular mechanism by which pseudane-VII suppresses neuroinflammation has not yet been elucidated in brain microglia. Microglia is activated by immunological stimulation or brain injury. Activated microglia secrete proinflammatory mediators which damage neurons. Neuroinflammation appears to be associated with certain neurological diseases, including Parkinson's disease and Alzheimer's disease. Natural compounds that suppress microglial inflammatory responses could potentially be used to prevent neurodegenerative diseases or slow their progression. In the present study, we found that pseudane-VII suppresses neuroinflammation in lipopolysaccaride (LPS)-stimulated BV-2 microglial cells and brain. Pseudane-VII was shown to inhibit the LPS-stimulated NO, ROS production and the expression of iNOS and COX-2. To identify the signaling pathway targeted by pseudane-VII, we used western blot analysis to assess the LPS-induced phosphorylation state of p38, ERK1/2, JNK1/2, and nuclear factor-kappaB (NF-κB). We found that pseudane-VII attenuated LPS-induced phosphorylation of MAPK and NF-κB. Moreover, administration of pseudane-VII in mice significantly reduced LPS-induced iNOS expression and microglia activation in brain. Taken together, our findings suggest that pseudane-VII may represent a potential novel target for treatment for neurodegenerative diseases.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Microglia/drug effects , Nitric Oxide Synthase Type II/antagonists & inhibitors , Quinolines/pharmacology , Animals , Cell Line , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides/toxicity , Macrophage Activation/drug effects , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Microglia/metabolism , Microglia/pathology , Neurodegenerative Diseases/drug therapy , Protein Kinase Inhibitors/pharmacology
5.
Mar Drugs ; 15(11)2017 Nov 01.
Article in English | MEDLINE | ID: mdl-29104209

ABSTRACT

The ocean is a rich resource of flora, fauna, food, and biological products. We found a wild-type bacterial strain, Pseudoalteromonas sp. M2, from marine water and isolated various secondary metabolites. Pseudane-VII is a compound isolated from the Pseudoalteromonas sp. M2 metabolite that possesses anti-melanogenic activity. Inflammation is a response of the innate immune system to microbial infections. Macrophages have a critical role in fighting microbial infections and inflammation. Recent studies reported that various compounds derived from natural products can regulate immune responses including inflammation. However, the anti-inflammatory effects and mechanism of pseudane-VII in macrophages are still unknown. In this study, we investigated the anti-inflammatory effects of pseudane-VII. In present study, lipopolysaccharide (LPS)-induced nitric oxide (NO) production was significantly decreased by pseudane-VII treatment at 6 µM. Moreover, pseudane-VII treatment dose-dependently reduced mRNA levels of pro-inflammatory cytokines including inos, cox-2, il-1ß, tnf-α, and il-6 in LPS-stimulated macrophages. Pseudane-VII also diminished iNOS protein levels and IL-1ß secretion. In addition, Pseudane-VII elicited anti-inflammatory effects by inhibiting ERK, JNK, p38, and nuclear factor (NF)-κB-p65 phosphorylation. Consistently, pseudane-VII was also shown to inhibit the LPS-stimulated release of IL-1ß and expression of iNOS in mice. These results suggest that pseudane-VII exerted anti-inflammatory effects on LPS-stimulated macrophage activation via inhibition of ERK, JNK, p38 MAPK phosphorylation, and pro-inflammatory gene expression. These findings may provide new approaches in the effort to develop anti-inflammatory therapeutics.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Aquatic Organisms , Macrophages/drug effects , Pseudoalteromonas/chemistry , Quinolines/pharmacology , Water Microbiology , Animals , Inflammation/chemically induced , Inflammation/drug therapy , Lipopolysaccharides , Mass Spectrometry
6.
Biomed Pharmacother ; 91: 378-384, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28463801

ABSTRACT

Thyroid cancer is the most common endocrine malignancy and can range in severity from relatively slow-growing occult differentiated thyroid cancer to uniformly aggressive and fatal anaplastic thyroid cancer. A subset of patients with papillary thyroid cancer present with aggressive disease that is refractory to conventional treatment. Myricetin is a flavonol compound found in a variety of berries as well as walnuts and herbs. Previous studies have demonstrated that myricetin exhibits anti-cancer activity against several tumor types. However, an anti-cancer effect of myricetin against human papillary thyroid cancer (HPTC) cells has not been established. The present investigation was undertaken to gain insights into the molecular mechanism of the anti-cancer activity of myricetin against HPTC cells. We examined the cytotoxicity, DNA damaging, and cell cycle arresting activities of myricetin using SNU-790 HPTC cells. We found that myricetin exhibited cytotoxicity and induced DNA condensation in SNU-790 HPTC cells in a dose-dependent manner. Moreover, myricetin up-regulated the activation of caspase cascades and the Bax:Bcl-2 expression ratio. In addition, myricetin induced the release of apoptosis-inducing factor (AIF) and altered the mitochondrial membrane potential. Our results suggest that myricetin induces the death of SNU-790 HPTC cells and thus may prove useful in the development of therapeutic agents for human thyroid cancers.


Subject(s)
Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Carcinoma, Papillary/drug therapy , Carcinoma, Papillary/pathology , Flavonoids/therapeutic use , Mitochondria/metabolism , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/pathology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis Inducing Factor/metabolism , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Flavonoids/chemistry , Flavonoids/pharmacology , Humans , Mitochondria/drug effects , Thyroid Cancer, Papillary , bcl-2-Associated X Protein/metabolism
7.
Anticancer Res ; 37(4): 1705-1710, 2017 04.
Article in English | MEDLINE | ID: mdl-28373432

ABSTRACT

AIM: Thyroid cancer is the most common endocrine malignancy, with an increasing incidence worldwide. Most thyroid cancers are well differentiated and have a favorable outcome. However, undifferentiated thyroid cancers are one of the most lethal human malignancies. Anaplastic thyroid cancer (ATC) accounts for 2% of all thyroid cancers, and its median survival rate is low. ATC is responsible for more than one-third of thyroid cancer-related deaths. Myricetin is a flavonol compound found in walnuts, herbs, and various berries and is known to induce apoptotic death of various types of cancer cells. However, an anticancer effect of myricetin against human anaplastic thyroid cancer (HATCs) cells has not been demonstrated. MATERIALS AND METHODS: In the present study, the anticancer effects and mechanism of action of myricetin were examined using SNU-80 HATC cells. SNU-80 HATC cells were treated with various concentrations of myricetin and compared with untreated controls. RESULTS: Myricetin significantly reduced HATC cell proliferation, by approximately 70%. A substantial proportion of dead cells exhibited arrest in the sub-G1 phase. Myricetin also exhibited cytotoxicity and induced DNA condensation in SNU-80 HATC cells in a dose-dependent manner. The mechanism of myricetin-induced cell death involved an increase in the activation of caspase cascades and the Bax:Bcl-2 ratio at a concentration of 100 µM. Myricetin also induced the release of apoptosis-inducing factor (AIF) from mitochondria into the cytosol and altered the mitochondrial membrane potential. CONCLUSION: Our results indicate that myricetin is a potent inducer of HATC cell death and may thus prove useful in the development of therapeutic agents for HATC.


Subject(s)
Apoptosis/drug effects , Flavonoids/pharmacology , Membrane Potential, Mitochondrial/drug effects , Mitochondria/pathology , Thyroid Carcinoma, Anaplastic/pathology , Thyroid Neoplasms/pathology , Caspases/metabolism , Cell Cycle/drug effects , Cell Proliferation/drug effects , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Thyroid Carcinoma, Anaplastic/drug therapy , Thyroid Carcinoma, Anaplastic/metabolism , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/metabolism , Tumor Cells, Cultured , bcl-2-Associated X Protein/metabolism
8.
Immunol Invest ; 44(2): 137-46, 2015.
Article in English | MEDLINE | ID: mdl-25140761

ABSTRACT

Inflammation is major symptom of the innate immune response by infection of microbes. Macrophages, one of immune response related cells, play a role in inflammatory response. Recent studies reported that various natural products can regulate the activation of immune cells such as macrophage. Sargassum horneri (Turner) C. Agardh is one of brown algae. Recently, various seaweeds including brown algae have antioxidant and anti-inflammatory effects. However, anti-inflammatory effects of Sargassum horneri (Turner) C. Agardh are still unknown. In this study, we investigated anti-inflammatory effects of ethanolic extract of Sargassum horneri (Turner) C. Agardh (ESH) on RAW 264.7 murine macrophage cell line. The ESH was extracted from dried Sargassum horneri (Turner) C. Agardh with 70% ethanol and then lyophilized at -40 °C. ESH was not cytotoxic to RAW 264.7, and nitric oxide (NO) production induced by LPS-stimulated macrophage activation was significantly decreased by the addition of 200 µg/mL of ESH. Moreover, ESH treatment reduced mRNA level of cytokines, including IL-1ß, and pro-inflammatory genes such as iNOS and COX-2 in LPS-stimulated macrophage activation in a dose-dependent manner. ESH was found to elicit anti-inflammatory effects by inhibiting ERK, p-p38 and NF-κB phosphorylation. In addition, ESH inhibited the release of IL-1ß in LPS-stimulated macrophages. These results suggest that ESH elicits anti-inflammatory effects on LPS-stimulated macrophage activation via the inhibition of ERK, p-p38, NF-κB, and pro-inflammatory gene expression.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Macrophage Activation/drug effects , Macrophage Activation/immunology , Macrophages/immunology , Macrophages/metabolism , NF-kappa B , Plant Extracts/pharmacology , Sargassum/chemistry , Signal Transduction , Animals , Cell Line , Cell Survival , Cytokines/genetics , Cytokines/metabolism , Enzyme Activation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation/drug effects , Inflammation Mediators/metabolism , Lipopolysaccharides/immunology , Macrophages/drug effects , Mice , NF-kappa B/metabolism , Nitric Oxide/metabolism
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