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1.
Diabetes Obes Metab ; 24(3): 465-472, 2022 03.
Article in English | MEDLINE | ID: mdl-34726318

ABSTRACT

AIM: To investigate the relationship between nonalcoholic fatty liver disease (NAFLD) and cardiovascular events among a nationally representative sample of young adults in Korea. METHODS AND RESULTS: This population-based cohort study from the Korean National Health Insurance Service included adults who were aged 20 to 39 years when they underwent a health examination between 2009 and 2012. NAFLD was defined as a fatty liver index (FLI) ≥60, and participants were divided into three groups according to FLI (<30, 30-59 and ≥60) to investigate the dose-dependent effect of FLI score. Among 5 324 410 participants, 9.8% had an FLI ≥60. There were 13 051 myocardial infarctions (MIs; 0.39%) and 8573 strokes (0.26%) during a median follow-up of 8.4 years. In multivariable analysis, NAFLD was associated with a higher risk of MI and stroke (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.61-1.77 and HR  1.73, 95% CI 1.63-1.84, respectively). MI and stroke had dose-dependent relationships with FLI (HR 1.28 in participants with FLI 30-59 and 1.73 in those with FLI ≥60 for MI and HR 1.18 in participants with FLI 30-59 and 1.41 in those with FLI ≥60 for stroke, respectively). CONCLUSIONS: Nonalcholic fatty liver disease was an independent predictor of MI and stroke in young adults. These results suggest that primary prevention of cardiovascular disease should be emphasized in young adults with NAFLD.


Subject(s)
Myocardial Infarction , Non-alcoholic Fatty Liver Disease , Stroke , Adult , Cohort Studies , Humans , Myocardial Infarction/complications , Myocardial Infarction/etiology , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/epidemiology , Risk Factors , Stroke/complications , Stroke/etiology , Young Adult
2.
Immunopharmacol Immunotoxicol ; 43(6): 799-805, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34708672

ABSTRACT

BACKGROUND: Many people are troubled by allergic inflammation including ocular allergic diseases, anaphylaxis, allergic rhinitis, atopic dermatitis, and eczema. Consequently, finding medications for use in allergic inflammation therapy is crucial in human health. Manoalide, a marine natural product isolated as an anti-bacterial metabolite from Luffariella variabilis, is a calcium channel blocker. However, its latent ability as an anti-allergic inflammatory agent has not yet been reported. Our research aimed to elucidate whether manoalide exerts an anti-allergic inflammatory effect in the human mast cell line, HMC-1. METHODS: Herein, we investigated the immunoregulatory effects and molecular mechanisms of manoalide in HMC-1 cells. RESULTS: Manoalide significantly alleviated secretion of the inflammatory cytokines interleukin (IL)-1ß, thymic stromal lymphopoietin, tumor necrosis factor-α, IL-6, and IL-8 via blockage of caspase-1 without cytotoxicity in activated HMC-1 cells. Activation of nuclear factor-κB increased by mast cell stimulation was attenuated by treatment with manoalide. In addition, we demonstrated that manoalide treatment remarkably attenuated the activation of mitogen-activated protein kinases in activated-HMC-1 cells. CONCLUSIONS: Taken together, our findings indicate manoalide has an anti-allergic inflammatory role, and we propose that manoalide might have potential as a novel anti-allergic inflammatory agent.


Subject(s)
Anti-Allergic Agents/pharmacology , Calcium Channel Blockers/pharmacology , Mast Cells/drug effects , NF-kappa B/antagonists & inhibitors , Terpenes/pharmacology , Cell Line , Cell Survival/drug effects , Cell Survival/physiology , Dose-Response Relationship, Drug , Humans , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Mast Cells/immunology , Mast Cells/metabolism , NF-kappa B/immunology , NF-kappa B/metabolism
3.
J Clin Gastroenterol ; 54(4): 370-377, 2020 04.
Article in English | MEDLINE | ID: mdl-30439763

ABSTRACT

BACKGROUND/AIMS: Transarterial chemoembolization (TACE) is a major therapeutic modality for patients with unresectable hepatocellular carcinoma, which needs repeated treatments. Model to Estimate Survival in Ambulatory Hepatocellular carcinoma patients (MESIAH) was recently developed as a model for predicting survival. We aimed to develop a novel index for TACE retreatment using MESIAH scores. PATIENTS AND METHODS: From 2005 to 2008, 783 patients with hepatocellular carcinoma who had undergone 1 previous TACE procedure were enrolled. We calculated their pre-TACE and post-TACE-MESIAH and calculated the MESIAH ratio by dividing the post-TACE by pre-TACE score. The discriminatory abilities of the MESIAH ratio and post-TACE-MESIAH were compared with ART and ABCR scores. RESULTS: Among 783 patients, 355 (45.3%) received a second TACE (test set), and 195 (24.9%) patients received a third TACE treatment (validation set). In the test set, patients with a MESIAH ratio <0.9 obtained longer overall survival than patients with a MESIAH ratio ≥0.9 [26.0 vs. 9.0 mo, respectively; hazard ratio 1.66 (1.29-2.14)], and patients with a post-TACE-MESIAH<4.5 showed longer overall survival than patients with a post-TACE-MESIAH≥4.5 [38.0 vs. 7.0 mo, respectively; hazard ratio, 3.17 (2.45-4.09)]. The post-TACE-MESIAH [C-index 0.663 (0.628-0.697)] was better than the ART [C-index 0.596 (0.554-0.638)] and ABCR scores [C-index 0.576 (0.536-0.617)] at estimating prognosis. Our results were confirmed by the validation set. CONCLUSIONS: A MESIAH score ≥4.5 after TACE identifies patients with a poor prognosis. Randomized studies are needed to establish whether additional TACE may affect survival.


Subject(s)
Carcinoma, Hepatocellular , Chemoembolization, Therapeutic , Liver Neoplasms , Carcinoma, Hepatocellular/therapy , Humans , Liver Neoplasms/therapy , Prognosis , Retreatment , Retrospective Studies , Treatment Outcome
4.
Inflamm Res ; 68(7): 569-579, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31055607

ABSTRACT

OBJECTIVE: Natural products are well known as the source of drugs in the treatment of allergic inflammation. Chrysophanol, an anthraquinone from the AST2017-01 extract, showed a beneficial anti-inflammatory effect on activated human mast cells in our previous study. However, a regulatory effect of AST2017-01 and chrysophanol on mast cell proliferation induced by thymic stromal lymphopoietin (TSLP) remains unclear. The present study determined the anti-proliferative effect and the fundamental mechanism of AST2017-01 and chrysophanol in mast cells. METHODS: We evaluated an anti-proliferative effect of AST2017-01 and chrysophanol in TSLP-stimulated human mast cell line, HMC-1. RESULTS: Without cytotoxicity, AST2017-01 and chrysophanol decreased mast cells growth and Ki67 mRNA expression increased by TSLP. AST2017-01 and chrysophanol enhanced expressions of p53 and Bax, whereas inhibited expression of Bcl-2. AST2017-01 and chrysophanol restored caspase-3 activity which was decreased by TSLP. AST2017-01 and chrysophanol suppressed expressions of murine double minute-2 protein and phosphorylated-signal transducer and activator of transcription six which are associated with the regulation of p53 protein. AST2017-01 and chrysophanol decreased levels of interleukin (IL)-13, IL-6, and tumor necrosis factor-α. Moreover, AST2017-01 and chrysophanol reduced mRNA expressions of TSLP receptor and IL-7 receptor α. CONCLUSIONS: Therefore, this study proposes that AST2017-01 and chrysophanol may be promising candidates for the development of potent anti-inflammatory or health functional foods.


Subject(s)
Anthraquinones/pharmacology , Anti-Inflammatory Agents/pharmacology , Complex Mixtures/pharmacology , Cordyceps/chemistry , Mast Cells/drug effects , Rumex/chemistry , Tumor Suppressor Protein p53/metabolism , Caspase 3/metabolism , Cell Line , Cell Proliferation/drug effects , Cytokines , Humans , Mast Cells/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , STAT6 Transcription Factor/metabolism , Thymic Stromal Lymphopoietin
5.
Inflamm Res ; 66(10): 871-879, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28616734

ABSTRACT

OBJECTIVE: Inflammation has been closely associated with the development and progression of cancer. Previously, we reported that mast cells play a critical role in tumor growth. The purpose of this study is to investigate the anti-inflammatory effect of an anticancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), on an activated human mast cell line, in this case HMC-1 cells. METHODS: We evaluated the effect and specific molecular mechanism of Dp44mT on phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI) using HMC-1 cells. RESULTS: Here, we demonstrated that Dp44mT significantly decreased the protein levels of hypoxia-inducible factor-1α and vascular endothelial growth factor without exposing activated HMC-1 cells to any cytotoxicity. In activated mast cells, Dp44mT mitigated the strong production and mRNA expression of inflammatory cytokines, in this case, interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, and thymic stromal lymphopoietin, through a blockade of caspase-1 and nuclear factor-κB activities. Furthermore, phosphorylations of the mitogen-activated protein kinase family included in inflammatory signaling cascades were significantly inhibited by a Dp44mT treatment. CONCLUSIONS: Overall, our results indicate that the anticancer agent Dp44mT has an anti-inflammatory effect and may be of therapeutic importance for the treatment of mast cell-mediated inflammatory diseases.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Mast Cells/drug effects , Thiosemicarbazones/pharmacology , Calcimycin/pharmacology , Caspase Inhibitors/pharmacology , Cell Line , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Humans , Hypoxia-Inducible Factor 1/pharmacology , Ionophores/pharmacology , MAP Kinase Signaling System/drug effects , NF-kappa B/antagonists & inhibitors , RNA, Messenger/biosynthesis , Tetradecanoylphorbol Acetate/pharmacology , Vascular Endothelial Growth Factor A/biosynthesis , Thymic Stromal Lymphopoietin
6.
J Cell Sci ; 127(Pt 8): 1640-6, 2014 Apr 15.
Article in English | MEDLINE | ID: mdl-24522193

ABSTRACT

Son of sevenless 1 (SOS1) is a Ras-specific guanine-nucleotide-exchange factor (GEF) that mediates intracellular signaling processes induced by receptor tyrosine kinases. In this study, we show that CIIA (also known as VPS28) physically associates with SOS1 and thereby inhibits the GEF activity of SOS1 on Ras, which prevents the epidermal growth factor (EGF)-induced activation of the Ras-Erk1/2 pathway. Furthermore, CIIA inhibited cyclin D1 expression, as well as DNA, synthesis in response to EGF. Intriguingly, CIIA failed to inhibit the Ras-specific GEF activity of Noonan-syndrome-associated SOS1 mutants (M269R, R552G, W729L and E846K). Taken together, our results suggest that CIIA functions as a negative modulator of the SOS1-Ras signaling events initiated by peptide growth factors including EGF.


Subject(s)
Endosomal Sorting Complexes Required for Transport/physiology , MAP Kinase Signaling System , SOS1 Protein/physiology , ras Proteins/metabolism , Animals , Cyclin D1/genetics , Cyclin D1/metabolism , DNA Replication , Dogs , Epidermal Growth Factor/physiology , Extracellular Signal-Regulated MAP Kinases/metabolism , Guanine Nucleotide Exchange Factors/physiology , HEK293 Cells , HeLa Cells , Humans , Madin Darby Canine Kidney Cells , Mice , Mutation, Missense , NIH 3T3 Cells , Noonan Syndrome/genetics
7.
EMBO J ; 30(12): 2465-76, 2011 May 13.
Article in English | MEDLINE | ID: mdl-21572393

ABSTRACT

Microglia, the resident macrophages of the mammalian central nervous system, migrate to sites of tissue damage or infection and become activated. Although the persistent secretion of inflammatory mediators by the activated cells contributes to the pathogenesis of various neurological disorders, most activated microglia eventually undergo apoptosis through the process of activation-induced cell death (AICD). The molecular mechanism of AICD, however, has remained unclear. Here, we show that Daxx and mammalian Ste20-like kinase-1 (MST1) mediate apoptosis elicited by interferon-γ (IFN-γ) in microglia. IFN-γ upregulated the expression of Daxx, which in turn mediated the homodimerization, activation, and nuclear translocation of MST1 and apoptosis in microglial cells. Depletion of Daxx or MST1 by RNA interference also attenuated IFN-γ-induced cell death in primary rat microglia. Furthermore, the extent of IFN-γ-induced death of microglia in the brain of MST1-null mice was significantly reduced compared with that apparent in wild-type mice. Our results thus highlight new functions of Daxx and MST1 that they are the key mediators of microglial cell death initiated by the proinflammatory cytokine IFN-γ.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Carrier Proteins/physiology , Hepatocyte Growth Factor/physiology , Intracellular Signaling Peptides and Proteins/physiology , Microglia/cytology , Microglia/physiology , Nuclear Proteins/physiology , Proto-Oncogene Proteins/physiology , Signal Transduction , Animals , Apoptosis/genetics , COS Cells , Carrier Proteins/genetics , Cell Death/genetics , Cell Survival/genetics , Cells, Cultured , Chlorocebus aethiops , Co-Repressor Proteins , Fibroblasts/cytology , Fibroblasts/physiology , HEK293 Cells , HeLa Cells , Hepatocyte Growth Factor/deficiency , Hepatocyte Growth Factor/genetics , Humans , Inflammation Mediators , Interferon-gamma/administration & dosage , Interferon-gamma/physiology , Intracellular Signaling Peptides and Proteins/deficiency , Intracellular Signaling Peptides and Proteins/genetics , Mice , Mice, Knockout , Molecular Chaperones , Nuclear Proteins/deficiency , Nuclear Proteins/genetics , Proto-Oncogene Proteins/deficiency , Proto-Oncogene Proteins/genetics , Rats , Rats, Sprague-Dawley , Signal Transduction/genetics
8.
Adv Sci (Weinh) ; 10(17): e2204378, 2023 06.
Article in English | MEDLINE | ID: mdl-37097643

ABSTRACT

Immune checkpoint inhibitor (ICI) clinically benefits cancer treatment. However, the ICI responses are only achieved in a subset of patients, and the underlying mechanisms of the limited response remain unclear. 160 patients with non-small cell lung cancer treated with anti-programmed cell death protein-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) are analyzed to understand the early determinants of response to ICI. It is observed that high levels of intracellular adhesion molecule-1 (ICAM-1) in tumors and plasma of patients are associated with prolonged survival. Further reverse translational studies using murine syngeneic tumor models reveal that soluble ICAM-1 (sICAM-1) is a key molecule that increases the efficacy of anti-PD-1 via activation of cytotoxic T cells. Moreover, chemokine (CXC motif) ligand 13 (CXCL13) in tumors and plasma is correlated with the level of ICAM-1 and ICI efficacy, suggesting that CXCL13 might be involved in the ICAM-1-mediated anti-tumor pathway. Using sICAM-1 alone and in combination with anti-PD-1 enhances anti-tumor efficacy in anti-PD-1-responsive tumors in murine models. Notably, combinatorial therapy with sICAM-1 and anti-PD-1 converts anti-PD-1-resistant tumors to responsive ones in a preclinical study. These findings provide a new immunotherapeutic strategy for treating cancers using ICAM-1.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Mice , Animals , CD8-Positive T-Lymphocytes , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Intercellular Adhesion Molecule-1
9.
Proc Natl Acad Sci U S A ; 106(41): 17389-94, 2009 Oct 13.
Article in English | MEDLINE | ID: mdl-19805025

ABSTRACT

Calcium and integrin binding protein 1 (CIB1) is a Ca(2+)-binding protein of 22 kDa that was initially identified as a protein that interacts with integrin alpha(IIb). Although it interacts with various proteins and has been implicated in diverse cellular functions, the molecular mechanism by which CIB1 regulates intracellular signaling networks has remained unclear. We now show that, by targeting apoptosis signal-regulating kinase 1 (ASK1), CIB1 negatively regulates stress-activated MAPK signaling pathways. CIB1 was thus shown to bind to ASK1, to interfere with the recruitment of TRAF2 to ASK1, and to inhibit the autophosphorylation of ASK1 on threonine-838, thereby blocking ASK1 activation. Furthermore, CIB1 mitigated apoptotic cell death initiated either by TNF-alpha in breast cancer MCF7 cells or by 6-hydroxydopamine (6-OHDA) in dopaminergic cells. Ca(2+) influx induced by membrane depolarization reversed the inhibitory effect of CIB1 on 6-OHDA-induced ASK1 activation and cell death in dopaminergic neurons. These observations thus suggest that CIB1 functions as a Ca(2+)-sensitive negative regulator of ASK1-mediated signaling events.


Subject(s)
Calcium-Binding Proteins/metabolism , MAP Kinase Kinase Kinase 5/metabolism , Annexin A5/pharmacology , Basic Helix-Loop-Helix Transcription Factors/chemistry , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Calcium/metabolism , Calcium-Binding Proteins/chemistry , Calcium-Binding Proteins/genetics , Flow Cytometry , Fluorescein-5-isothiocyanate , Genetic Variation , MAP Kinase Kinase Kinase 5/genetics , Mesencephalon/embryology , Mesencephalon/physiology , Neurons/physiology , Oxidation-Reduction , Oxidopamine/pharmacology , Propidium/pharmacology , RNA Interference , Signal Transduction , TNF Receptor-Associated Factor 2/chemistry , TNF Receptor-Associated Factor 2/metabolism , TNF Receptor-Associated Factor 6/chemistry , TNF Receptor-Associated Factor 6/metabolism , Tumor Necrosis Factor-alpha/pharmacology
10.
Commun Biol ; 4(1): 231, 2021 02 19.
Article in English | MEDLINE | ID: mdl-33608630

ABSTRACT

An unbalanced microbial ecosystem on the human skin is closely related to skin diseases and has been associated with inflammation and immune responses. However, little is known about the role of the skin microbiome on skin aging. Here, we report that the Streptococcus species improved the skin structure and barrier function, thereby contributing to anti-aging. Metagenomic analyses showed the abundance of Streptococcus in younger individuals or those having more elastic skin. Particularly, we isolated Streptococcus pneumoniae, Streptococcus infantis, and Streptococcus thermophilus from face of young individuals. Treatment with secretions of S. pneumoniae and S. infantis induced the expression of genes associated with the formation of skin structure and the skin barrier function in human skin cells. The application of culture supernatant including Streptococcal secretions on human skin showed marked improvements on skin phenotypes such as elasticity, hydration, and desquamation. Gene Ontology analysis revealed overlaps in spermidine biosynthetic and glycogen biosynthetic processes. Streptococcus-secreted spermidine contributed to the recovery of skin structure and barrier function through the upregulation of collagen and lipid synthesis in aged cells. Overall, our data suggest the role of skin microbiome into anti-aging and clinical applications.


Subject(s)
Microbiota , Skin Aging , Skin/microbiology , Spermidine/metabolism , Streptococcus/metabolism , Adult , Collagen/metabolism , Dysbiosis , Elasticity , Female , Humans , Lipogenesis , Metagenome , Phenotype , Skin/metabolism , Streptococcus/genetics , Streptococcus/growth & development , Young Adult
11.
Nat Microbiol ; 6(3): 277-288, 2021 03.
Article in English | MEDLINE | ID: mdl-33432149

ABSTRACT

The gut microbiome can influence the development of tumours and the efficacy of cancer therapeutics1-5; however, the multi-omics characteristics of antitumour bacterial strains have not been fully elucidated. In this study, we integrated metagenomics, genomics and transcriptomics of bacteria, and analyses of mouse intestinal transcriptome and serum metabolome data to reveal an additional mechanism by which bacteria determine the efficacy of cancer therapeutics. In gut microbiome analyses of 96 samples from patients with non-small-cell lung cancer, Bifidobacterium bifidum was abundant in patients responsive to therapy. However, when we treated syngeneic mouse tumours with commercial strains of B. bifidum to establish relevance for potential therapeutic uses, only specific B. bifidum strains reduced tumour burden synergistically with PD-1 blockade or oxaliplatin treatment by eliciting an antitumour host immune response. In mice, these strains induced tuning of the immunological background by potentiating the production of interferon-γ, probably through the enhanced biosynthesis of immune-stimulating molecules and metabolites.


Subject(s)
Bifidobacterium bifidum/physiology , Immune Checkpoint Inhibitors/therapeutic use , Probiotics/therapeutic use , Tumor Burden/drug effects , Animals , Bifidobacterium bifidum/classification , Bifidobacterium bifidum/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/microbiology , Carcinoma, Non-Small-Cell Lung/pathology , Drug Therapy, Combination , Gastrointestinal Microbiome , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/microbiology , Lung Neoplasms/pathology , Metabolome/drug effects , Mice , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Probiotics/administration & dosage , Species Specificity , Transcriptome/drug effects , Tryptophan/metabolism
12.
J Cell Biol ; 163(1): 71-81, 2003 Oct 13.
Article in English | MEDLINE | ID: mdl-14557248

ABSTRACT

Diverse stimuli initiate the activation of apoptotic signaling pathways that often causes nuclear DNA fragmentation. Here, we report a new antiapoptotic protein, a caspase-activated DNase (CAD) inhibitor that interacts with ASK1 (CIIA). CIIA, by binding to apoptosis signal-regulating kinase 1 (ASK1), inhibits oligomerization-induced ASK1 activation. CIIA also associates with CAD and inhibits the nuclease activity of CAD without affecting caspase-3-mediated ICAD cleavage. Overexpressed CIIA reduces H2O2- and tumor necrosis factor-alpha-induced apoptosis. CIIA antisense oligonucleotides, which abolish expression of endogenous CIIA in murine L929 cells, block the inhibitory effect of CIIA on ASK1 activation, deoxyribonucleic acid fragmentation, and apoptosis. These findings suggest that CIIA is an endogenous antagonist of both ASK1- and CAD-mediated signaling.


Subject(s)
Apoptosis/physiology , Deoxyribonucleases/antagonists & inhibitors , MAP Kinase Kinase Kinases/antagonists & inhibitors , Animals , DNA Fragmentation/physiology , Hydrogen Peroxide/metabolism , MAP Kinase Kinase Kinase 5 , Mice , Oligonucleotides, Antisense/metabolism , Tumor Necrosis Factor-alpha/metabolism
13.
Fundam Clin Pharmacol ; 32(3): 279-287, 2018 Jun.
Article in English | MEDLINE | ID: mdl-29368407

ABSTRACT

HM0601 consists of Allium hookeri and Lycium chinense fruit and contains a lot of rutin. Here, we ascertained whether HM0601 and its major compound rutin reduce proliferation of human mast cell line, HMC-1, under thymic stromal lymphopoietin (TSLP) stimulation. Therapeutic rutin or HM0601 treatment considerably reduced proliferation of mast cells without exposing activated HMC-1 cells to any cytotoxicity. Reduced levels of mouse double minute 2 and phosphorylated signal transducers and activators of transcription 6 were accompanied by treatment with rutin or HM0601. In TSLP-stimulated cells, rutin or HM0601 treatment significantly impaired levels of interleukin (IL)-13 and Bcl2 expression. Notably, rutin or HM0601 treatment returned Bax and phosphorylated p53 protein levels and caspase-3 activities impaired by TSLP. In addition, levels of inflammatory cytokine were considerably reduced by treatment with rutin or HM0601 on TSLP-stimulated cells. In conclusion, these results indicate that HM0601 can be used as a new therapeutic herbal drug for prevention and therapeutic intervention of allergic inflammatory diseases.


Subject(s)
Anti-Allergic Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Cell Proliferation/drug effects , Mast Cells/drug effects , Plant Extracts/pharmacology , Rutin/pharmacology , Apoptosis Regulatory Proteins/metabolism , Cell Line , Cytokines/pharmacology , Dose-Response Relationship, Drug , Fruit , Humans , Interleukin-13/metabolism , Mast Cells/metabolism , Phosphorylation , Proto-Oncogene Proteins c-mdm2/metabolism , STAT6 Transcription Factor/metabolism , Signal Transduction/drug effects , Tumor Suppressor Protein p53/metabolism , Thymic Stromal Lymphopoietin
14.
BMB Rep ; 50(10): 496-503, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28768566

ABSTRACT

The human body loses several billions of cells daily. When cells die in vivo, the corpse of each dead cell is immediately cleared. Specifically, dead cells are efficiently recognized and cleared by multiple types of neighboring phagocytes. Early research on cell death focused more on molecular mechanisms of cell death regulation while the cellular corpses were merely considered cellular debris. However, it has come to light that various biological stimuli following cell death are important for immune regulation. Clearance of normal dead cells occurs silently in immune tolerance. Exogenous or mutated antigens of malignant or infected cells can initiate adaptive immunity, thereby inducing immunogenicity by adjuvant signals. Several pathogens and cancer cells have strategies to limit the adjuvant signals and escape immune surveillance. In this review, we present an overview of the mechanisms of dead cell clearance and its immune regulations. [BMB Reports 2017; 50(10): 496-503].


Subject(s)
Cytophagocytosis/immunology , Cytophagocytosis/physiology , Immunity, Innate/immunology , Phagocytosis/immunology , Animals , Apoptosis/immunology , Cell Death , Humans , Immune Tolerance , Phagocytes/physiology
15.
Eur J Pharmacol ; 802: 1-6, 2017 May 05.
Article in English | MEDLINE | ID: mdl-28219709

ABSTRACT

Atopic dermatitis (AD) is known to aggravate by thymic stromal lymphopoietin (TSLP) and TSLP is also known to up-regulate mast cell proliferation via production of interleukin (IL)-13. Thus, we investigated whether cordycepin could regulate mast cell proliferation induced by TSLP in human mast cell line, HMC-1 cell. Cordycepin significantly diminished the production and mRNA of IL-13 through the down-regulation of phosphorylated-signal transducer and activation of transcription 6 in the TSLP-stimulated HMC-1 cells. Cordycepin also significantly diminished the cell proliferation via down-regulating MDM2 and Bcl2 levels and up-regulating p53, caspase-3, and cleaved poly ADP-ribose polymerase levels in the TSLP-stimulated HMC-1 cells. Moreover, cordycepin significantly diminished the production of IL-6, tumor necrosis factor-α, and IL-1ß in the TSLP-stimulated HMC-1 cells. In conclusion, our study shows that cordycepin has potential effect for the treatment of allergic inflammatory diseases through the blockade of IL-13 and MDM2 exacerbated by TSLP.


Subject(s)
Anti-Allergic Agents/pharmacology , Cytokines/pharmacology , Deoxyadenosines/pharmacology , Interleukin-13/biosynthesis , Caspase 3/metabolism , Cell Line , Humans , Interleukin-13/metabolism , Mast Cells/drug effects , Mast Cells/metabolism , Phosphoproteins/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , STAT6 Transcription Factor/metabolism , Tumor Suppressor Protein p53/metabolism , Thymic Stromal Lymphopoietin
16.
Sci Rep ; 7(1): 12178, 2017 09 22.
Article in English | MEDLINE | ID: mdl-28939911

ABSTRACT

Calcium and integrin binding protein 1 (CIB1) is a calcium-binding protein that was initially identified as a binding partner of platelet integrin αIIb. Although CIB1 has been shown to interact with multiple proteins, its biological function in the brain remains unclear. Here, we show that CIB1 negatively regulates degeneration of dopaminergic neurons in a mouse model of Parkinson's disease using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Genetic deficiency of the CIB1 gene enhances MPTP-induced neurotoxicity in dopaminergic neurons in CIB1-/- mice. Furthermore, RNAi-mediated depletion of CIB1 in primary dopaminergic neurons potentiated 1-methyl-4-phenyl pyrinidium (MPP+)-induced neuronal death. CIB1 physically associated with apoptosis signal-regulating kinase 1 (ASK1) and thereby inhibited the MPP+-induced stimulation of the ASK1-mediated signaling cascade. These findings suggest that CIB1 plays a protective role in MPTP/MPP+-induced neurotoxicity by blocking ASK1-mediated signaling.


Subject(s)
Calcium-Binding Proteins/metabolism , MAP Kinase Kinase Kinase 5/metabolism , MPTP Poisoning/pathology , Parkinson Disease/pathology , 1-Methyl-4-phenylpyridinium/toxicity , Animals , Apoptosis/drug effects , Brain/cytology , Brain/drug effects , Brain/pathology , Calcium-Binding Proteins/genetics , Cell Line, Tumor , Disease Models, Animal , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Primary Cell Culture , RNA, Small Interfering/metabolism , Rats , Signal Transduction/drug effects
17.
Oncotarget ; 6(24): 19990-20001, 2015 Aug 21.
Article in English | MEDLINE | ID: mdl-26254280

ABSTRACT

Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1α and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1α degradation. Moreover, IRE1α inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1α/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53.


Subject(s)
DNA-Binding Proteins/metabolism , Endoplasmic Reticulum/physiology , Endoribonucleases/metabolism , Protein Serine-Threonine Kinases/metabolism , Transcription Factors/metabolism , Tumor Suppressor Protein p53/deficiency , Animals , Cell Line, Tumor , DNA-Binding Proteins/genetics , Endoplasmic Reticulum/metabolism , Endoribonucleases/antagonists & inhibitors , Endoribonucleases/genetics , HCT116 Cells , Heterografts , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Proteasome Endopeptidase Complex/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Regulatory Factor X Transcription Factors , Signal Transduction , Sulfonamides/pharmacology , Thiophenes/pharmacology , Transcription Factors/genetics , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Protein Ligases/metabolism , X-Box Binding Protein 1
18.
Science ; 349(6247): 1261669, 2015 Jul 31.
Article in English | MEDLINE | ID: mdl-26228159

ABSTRACT

The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1α (DD1α), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1α appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1α-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1α thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses.


Subject(s)
Apoptosis/immunology , Membrane Proteins/metabolism , Phagocytosis/immunology , Phosphatidylserines/metabolism , Tumor Suppressor Protein p53/metabolism , Amino Acid Sequence , Animals , Apoptosis/genetics , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , B7 Antigens , Cell Line, Tumor , Female , Humans , Inflammation/genetics , Inflammation/immunology , Macrophages/immunology , Male , Membrane Proteins/genetics , Mice , Mice, Knockout , Molecular Sequence Data , Signal Transduction
19.
Chem Biol ; 22(9): 1206-16, 2015 Sep 17.
Article in English | MEDLINE | ID: mdl-26320861

ABSTRACT

TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transactivate target genes, restored MDM2 negative regulation, and selectively inhibited the growth of cancer cells harboring mutant p53 R175H in vitro and in vivo. We found that CTM binds to Hsp40 and increases the binding capacity of Hsp40 to the p53 R175H mutant protein, causing a potential conformational change to a wild-type-like p53. Thus, CTM acts as a specific reactivator of the p53 R175H mutant form through Hsp40. These results provide new insights into the mechanism of reactivation of this specific p53 mutant.


Subject(s)
Antineoplastic Agents/pharmacology , Disulfides/pharmacology , HSP40 Heat-Shock Proteins/metabolism , Indole Alkaloids/pharmacology , Small Molecule Libraries/pharmacology , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Disulfides/chemistry , Drug Screening Assays, Antitumor , HCT116 Cells , High-Throughput Screening Assays , Humans , Indole Alkaloids/chemistry , Mice , Mice, Nude , Mutation , Small Molecule Libraries/chemistry , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
20.
Cell Rep ; 5(2): 331-9, 2013 Oct 31.
Article in English | MEDLINE | ID: mdl-24139803

ABSTRACT

Resolved endoplasmic reticulum (ER) stress response is essential for intracellular homeostatic balance, but unsettled ER stress can lead to apoptosis. Here, we show that a proapoptotic p53 target, CDIP1, acts as a key signal transducer of ER-stress-mediated apoptosis. We identify B-cell-receptor-associated protein 31 (BAP31) as an interacting partner of CDIP1. Upon ER stress, CDIP1 is induced and enhances an association with BAP31 at the ER membrane. We also show that CDIP1 binding to BAP31 is required for BAP31 cleavage upon ER stress and for BAP31-Bcl-2 association. The recruitment of Bcl-2 to the BAP31-CDIP1 complex, as well as CDIP1-dependent truncated Bid (tBid) and caspase-8 activation, contributes to BAX oligomerization. Genetic knockout of CDIP1 in mice leads to impaired response to ER-stress-mediated apoptosis. Altogether, our data demonstrate that the CDIP1/BAP31-mediated regulation of mitochondrial apoptosis pathway represents a mechanism for establishing an ER-mitochondrial crosstalk for ER-stress-mediated apoptosis signaling.


Subject(s)
Apoptosis Regulatory Proteins/metabolism , Endoplasmic Reticulum Stress , Endoplasmic Reticulum/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Mitochondria/metabolism , Animals , Apoptosis , Apoptosis Regulatory Proteins/antagonists & inhibitors , Apoptosis Regulatory Proteins/genetics , BH3 Interacting Domain Death Agonist Protein/metabolism , Caspase 8/metabolism , Cell Line , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/chemistry , Mice , Mice, Knockout , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction , bcl-2-Associated X Protein/metabolism
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