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1.
Cell Biol Toxicol ; 39(4): 1471-1487, 2023 08.
Article in English | MEDLINE | ID: mdl-35687267

ABSTRACT

B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common childhood cancer, originates from lymphoid precursor cells in bone marrow committed to the B-cell lineage. Environmental factors and genetic abnormalities disturb the normal maturation of these precursor cells, promoting the formation of leukemia cells and suppressing normal hematopoiesis. The underlying mechanisms of progression are unclear, but BCP-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. This study hypothesized that air pollution and haze are risk factors for BCP-ALL progression. The current study revealed that indeno(1,2,3-cd)pyrene (IP), a major component of polycyclic aromatic hydrocarbons (PAHs) in air, promotes oncogenic activities (proliferation, transformation, and disease relapse) in vitro and in vivo. Mechanistically, IP treatment activated the aryl hydrocarbon receptor (AHR)-indoleamine-2,3-dioxygenase (IDOs) axis, thereby enhancing tryptophan metabolism and kynurenine (KYN) level and consequent promoting the KYN-AHR feedback loop. IP treatment decreased the time to disease relapse and increased the BCP-ALL cell count in an orthotopic xenograft mouse model. Additionally, in 50 clinical BCP-ALL samples, AHR and IDO were co-expressed in a disease-specific manner at mRNA and protein levels, while their mRNA levels showed a significant correlation with disease-free survival duration. These results indicated that PAH/IP exposure promotes BCP-ALL disease progression.


Subject(s)
Neoplasms , Polycyclic Aromatic Hydrocarbons , Humans , Mice , Animals , Kynurenine/metabolism , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism
2.
Curr Issues Mol Biol ; 44(10): 4616-4625, 2022 Oct 03.
Article in English | MEDLINE | ID: mdl-36286030

ABSTRACT

The 4-(phenylsulfanyl) butan-2-one (4-PSB-2), a marine-derived compound from soft coral, was proven to have multiple biological activities including neuroprotection and potent anti-inflammatory effects. CC chemokine ligand (CCL)-1 belongs to T helper (Th)2-related chemokines that are involved in the recruitment of Th2 inflammatory cells. Histone acetylation has been recognized as a critical mechanism underlying the regulated cytokine and chemokine production. Our study tried to investigate the anti-inflammatory effect of 4-PSB-2 on CCL-1 production in human monocytes and explore possible underlying intracellular processes, including epigenetic regulation. To confirm our hypothesis, human monocyte THP-1 cell line and primary CD14+ cells were pretreated with various concentrations of 4-PSB-2 and then were stimulated with lipopolysaccharide (LPS). The CCL-1 concentration was measured by enzyme-linked immunosorbent assays, and the intracellular signaling pathways and epigenetic regulation of 4-PSB-2 were investigated by using Western blotting and chromatin immunoprecipitation analysis. In this study, we found that 4-PSB-2 had a suppressive effect on LPS-induced CCL-1 production. Moreover, this suppressive effect of 4-PSB-2 was mediated via intracellular signaling such as the mitogen-activated protein kinase and nuclear factor-κB pathways. In addition, 4-PSB-2 could suppress CCL-1 production by epigenetic regulation through downregulating histone H3 and H4 acetylation. In short, our study demonstrated that 4-PSB-2 may have a potential role in the treatment of allergic inflammation.

3.
J Gastroenterol Hepatol ; 37(10): 1928-1934, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35816187

ABSTRACT

BACKGROUND AND AIM: Most consensuses recommend culture-guided therapy as third-line Helicobacter pylori treatment. This study aimed to investigate the efficacies of culture-guided therapy and empirical therapy with high-dose proton pump inhibitor (PPI) in the H. pylori third-line treatment. METHODS: Between August 2012 and October 2021, H. pylori-infected patients with at least two failed eradication attempts received anti-H. pylori therapy according to the results of antimicrobial sensitivity tests plus high-dose rabeprazole and/or bismuth. They were categorized into three groups: patients who had positive results of culture with equal to or more than three susceptible antibiotics were treated by culture-guided non-bismuth quadruple therapy, patients who had positive results of culture with one or two susceptible antibiotics were treated by culture-guided bismuth-containing therapy, and patients who had a negative result of culture were treated by an empirical therapy with high-dose rabeprazole plus amoxicillin, tetracycline and levofloxacin. A post-treatment assessment was conducted at week 8. RESULTS: We recruited 126 patients. The eradication rates of culture-guided non-bismuth quadruple therapy (n = 50), culture-guided bismuth-containing therapy (n = 46) and empirical therapy (n = 30) were 84.0%, 87.0%, and 66.7% (95% confidence interval: 73.8-94.2%, 77.3-96.7%, and 49.8-83.6%), respectively. Overall, culture-guided therapy achieved a higher eradication rate than empirical therapy (85.4% vs 66.7%; 95% confidence interval, 0.4% to 37.0%, P = 0.022). CONCLUSIONS: Culture-guided therapy with high-dose PPI achieves a higher eradication rate than empirical therapy with high-dose PPI in the third-line treatment of H. pylori infection. The eradication rate of rescue therapy with bismuth plus two susceptible antibiotics is not inferior to that with three susceptible antibiotics.


Subject(s)
Anti-Infective Agents , Helicobacter Infections , Helicobacter pylori , Amoxicillin , Anti-Bacterial Agents , Bismuth , Drug Therapy, Combination , Helicobacter Infections/drug therapy , Humans , Levofloxacin , Proton Pump Inhibitors , Rabeprazole/therapeutic use , Tetracycline , Treatment Outcome
4.
Int J Mol Sci ; 20(7)2019 Mar 29.
Article in English | MEDLINE | ID: mdl-30934882

ABSTRACT

GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1.


Subject(s)
Central Nervous System/pathology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/immunology , Glucagon-Like Peptides/analogs & derivatives , Immunoglobulin Fc Fragments/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Th1 Cells/immunology , Th17 Cells/immunology , Animals , Chemotaxis/drug effects , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Disease Progression , Down-Regulation/drug effects , Encephalomyelitis, Autoimmune, Experimental/pathology , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptides/administration & dosage , Glucagon-Like Peptides/pharmacology , Glucagon-Like Peptides/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Immunization , Immunoglobulin Fc Fragments/administration & dosage , Immunoglobulin Fc Fragments/pharmacology , Lymphocyte Subsets/drug effects , Macrophages/drug effects , Macrophages/metabolism , Male , Mice, Inbred C57BL , Myelin-Oligodendrocyte Glycoprotein , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/pharmacology , Th1 Cells/drug effects , Th17 Cells/drug effects
5.
Chembiochem ; 19(8): 851-864, 2018 04 16.
Article in English | MEDLINE | ID: mdl-29369495

ABSTRACT

Pentachloropseudilin (PClP) is a chlorinated phenylpyrrole compound that was first isolated from Actinoplanes (ATCC33002), and its structure has been confirmed by chemical synthesis. PClP shows broad antimicrobial activity against Gram-negative and Gram-positive bacteria, protozoa, fungi, and yeast. In mammalian cells, PClP is known to act as a reversible and allosteric inhibitor of myosin 1c (Myo1c). Herein, we report that PCIP is a potent inhibitor of transforming growth factor-ß (TGF-ß)-stimulated signaling. PCIP inhibits TGF-ß-stimulated Smad2/3 phosphorylation and plasminogen activator inhibitor-1 (PAI-1) promoter activation with an IC50 of 0.1 µm in target cells (A549, HepG2, and Mv1Lu cells). In addition, PCIP attenuates TGF-ß-stimulated expression of vimentin, N-cadherin, and fibronectin and, thus, blocks TGF-ß-induced epithelial to mesenchymal transition (EMT) in these cells. Furthermore, cell-surface labeling and immunoblot analysis indicates that PCIP suppresses TGF-ß-stimulated cellular responses by attenuating cell-surface expression of the type II TGF-ß receptor through accelerating caveolae-mediated internalization followed by primarily lysosome-dependent degradation of the receptor, as demonstrated by sucrose density gradient analysis and immune fluorescence staining.


Subject(s)
Hydrocarbons, Chlorinated/pharmacology , Pyrroles/pharmacology , Receptor, Transforming Growth Factor-beta Type II/agonists , Transforming Growth Factor beta/drug effects , Animals , Cell Line , Epithelial-Mesenchymal Transition/drug effects , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Humans , Myosin Type I/genetics , Myosin Type I/metabolism , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolism
6.
Int J Med Sci ; 15(9): 875-882, 2018.
Article in English | MEDLINE | ID: mdl-30008599

ABSTRACT

Morphine is the most effective drugs for attenuating various types of severe pain, but morphine abuse carries a high risk of systemic fibrosis. Our previous have indicated that systemic administration of morphine hinders angiogenesis and delays wound healing. Here we have explained the pathological mechanism underlying the effect of morphine on wound healing. To determine how morphine affects wound healing, we first created a wound in mice treated them with a combination of a low doses (5 mg/kg/day) and high doses (20 or 30 mg/kg/day) of morphine. An In vivo study revealed that high-dose morphine-induced abnormal myofibroblasts persist after the end of wound healing because of connexin 43 (Cx43) upregulation. High-dose morphine-induced Cx43 increased the expression levels of focal adhesion molecules, namely fibronectin and alpha-smooth muscle actin (α-SMA) through the activation of transforming growth factor (TGF)-ß1 signaling. In addition, we found that Cx43 contributed to TGF-ßRII/ Smad2/3 signaling for regulating the differentiation of fibroblasts into myofibroblasts during high-dose morphine exposure. In conclusion, the abnormal regulation of Cx43 by morphine may induce systemic fibrosis because of abnormal myofibroblast function.


Subject(s)
Analgesics, Opioid/pharmacology , Connexin 43/metabolism , Fibroblasts/drug effects , Fibrosis/chemically induced , Morphine/pharmacology , Actins , Animals , Cell Differentiation , Cells, Cultured , Connexin 43/drug effects , Mice , Transforming Growth Factor beta1 , Up-Regulation , Wound Healing
7.
J Biol Chem ; 290(49): 29329-44, 2015 Dec 04.
Article in English | MEDLINE | ID: mdl-26468284

ABSTRACT

Glucosamine has immunomodulatory effects on autoimmune diseases. However, the mechanism(s) through which glucosamine modulates different T cell subsets and diseases remain unclear. We demonstrate that glucosamine impedes Th1, Th2, and iTreg but promotes Th17 differentiation through down-regulating N-linked glycosylation of CD25 and subsequently inhibiting its downstream Stat5 signaling in a dose-dependent manner. The effect of glucosamine on T helper cell differentiation was similar to that induced by anti-IL-2 treatment, further supporting an IL-2 signaling-dependent modulation. Interestingly, excess glucose rescued this glucosamine-mediated regulation, suggesting a functional competition between glucose and glucosamine. High-dose glucosamine significantly decreased Glut1 N-glycosylation in Th1-polarized cells. This finding suggests that both down-regulated IL-2 signaling and Glut1-dependent glycolytic metabolism contribute to the inhibition of Th1 differentiation by glucosamine. Finally, glucosamine treatment inhibited Th1 cells in vivo, prolonged the survival of islet grafts in diabetic recipients, and exacerbated the severity of EAE. Taken together, our results indicate that glucosamine interferes with N-glycosylation of CD25, and thereby attenuates IL-2 downstream signaling. These effects suggest that glucosamine may be an important modulator of T cell differentiation and immune homeostasis.


Subject(s)
CD4-Positive T-Lymphocytes/cytology , Cell Differentiation , Glucosamine/chemistry , Interleukin-2 Receptor alpha Subunit/metabolism , Animals , Autoimmune Diseases/metabolism , Down-Regulation , Female , Glucose Transporter Type 1/metabolism , Glycosylation , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Signal Transduction , Th1 Cells/cytology , Th17 Cells/cytology , Th2 Cells/cytology
8.
Gut ; 64(5): 765-75, 2015 May.
Article in English | MEDLINE | ID: mdl-25011937

ABSTRACT

OBJECTIVE: The soluble preligand assembly domain (PLAD) of tumour necrosis factor receptor 1 (TNFR1) interferes with receptor trimerisation to block downstream signalling, and mediates Th17 suppression. We explored the therapeutic potential of recombinant PLAD.Fc protein on a spontaneous experimental colitis. DESIGN: A T-cell-specific BLIMP-1 knockout mouse model with mixed Th1/Th17 responses, resembling human Crohn's disease (CD) was established, and its colitogenic phenotype was characterised. Mice, 9 weeks old, were treated with PLAD.Fc protein at 5 mg/kg of body weight twice per week for 16 weeks, and presence of colitis was monitored by the appearance of diarrhoea, weight loss, and by histological colonic scoring. Activation status, cytokine profiles, and transcription factors in T cells were further analysed. RESULTS: The colitogenic phenotype in BLIMP-1 knockout mice was alleviated when an interleukin (IL)-23 knockdown transgene was introduced, indicating a therapeutic potential by downregulating IL-23-Th17 axis in these knockout mice. In PLAD.Fc-treated group, the mouse body weight remained stable and only mild disease scores were revealed. The percentage of naive CD4 T cells was increased and that of effector/memory CD4 T cells was decreased after PLAD.Fc-treatment. Moreover, the levels of IFN-γ, IL-17, IL-21, IL-22, IL-23R, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α were diminished. Strikingly, Th2-associated cytokines (IL-4, IL-13 and IL-10) in sera, as well as percentages of Th2 cells, were increased in PLAD.Fc-treated mice. However, PLAD.Fc-mediated suppression of effector phenotypes in Th1/Th17 was abrogated after neutralising IL-10. CONCLUSIONS: The Th2 cytokine milieu induced by PLAD.Fc rebalanced T-helper cell subsets and conferred a protection against colitis in BLIMP-1 knockout mice.


Subject(s)
Crohn Disease/prevention & control , Molecular Targeted Therapy/methods , Recombinant Fusion Proteins/therapeutic use , Th17 Cells/immunology , Th2 Cells/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , Crohn Disease/immunology , Disease Models, Animal , Disease Progression , Down-Regulation/immunology , Drug Evaluation, Preclinical/methods , Gene Deletion , Interleukin-23/immunology , Mice, Knockout , Positive Regulatory Domain I-Binding Factor 1 , Transcription Factors/deficiency , Transcription Factors/genetics
9.
Mol Med ; 20: 684-96, 2015 Mar 24.
Article in English | MEDLINE | ID: mdl-25535034

ABSTRACT

Glycine N-methyltransferase (GNMT) is known for its function as a tumor suppressor gene. Since 100% of female Gnmt(-/-) mice developed hepatocellular carcinoma, we hypothesized that Gnmt(-/-) mice may have defective immune surveillance. In this study, we examined the immune modulation of GNMT in T-cell responses using experimental autoimmune encephalomyelitis (EAE). The results showed that EAE severity was reduced significantly in Gnmt(-/-) mice. Pathological examination of the spinal cords revealed that Gnmt(-/-) mice had significantly lower levels of mononuclear cell infiltration and demyelination than the wild-type mice. In addition, quantitative real-time PCR showed that expression levels of proinflammatory cytokines, including interferon (IFN)-γ and interleukin (IL)-17A, were much lower in the spinal cord of Gnmt(-/-) than in that of wild-type mice. Accordingly, myelin oligodendrocyte glycoprotein (MOG)-specific T-cell proliferation and induction of T-helper (Th)1 and Th17 cells were markedly suppressed in MOG(35-55)-induced Gnmt(-/-) mice. Moreover, the number of regulatory T (Treg) cells was increased significantly in these mice. When the T-cell receptor was stimulated, the proliferative capacity and the activation status of mTOR-associated downstream signaling were decreased significantly in Gnmt(-/-) CD4(+) T cells via an IL-2- and CD25-independent manner. Moreover, GNMT deficiency enhanced the differentiation of Treg cells without affecting the differentiation of Th1 and Th17 cells. Furthermore, the severity of EAE in mice adoptive transferred with GNMT-deficient CD4(+) T cells was much milder than in those with wild-type CD4(+) T cells. In summary, our findings suggest that GNMT is involved in the pathogenesis of EAE and plays a crucial role in the regulation of CD4(+) T-cell functions.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , Glycine N-Methyltransferase/immunology , T-Lymphocytes/immunology , Animals , Cytokines/immunology , Female , Mice, Inbred C57BL , Mice, Knockout , TOR Serine-Threonine Kinases/immunology
10.
J Immunol ; 191(2): 594-607, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23752610

ABSTRACT

Ptpn22 encodes PEST domain-enriched tyrosine phosphatase (Pep), which negatively regulates TCR proximal signaling and is strongly associated with a variety of autoimmune diseases in humans. The net effect of Pep on the balance of immunity and tolerance is uncertain because of the simultaneous inhibition of TCR-mediated signaling of effector and regulatory T cells (T(regs)). In this study, we generated transgenic NOD mice that overexpressed Pep in T cells. The transgenic mice had a significantly lower incidence of spontaneous autoimmune diabetes, which was accompanied by fewer IFN-γ-producing T cells, and an increased ratio of CD4(+)Foxp3(+) T(regs)to CD4(+)IFN-γ(+) or to CD8(+)IFN-γ(+) T cells, respectively, in pancreatic islets. Transgenic T cells showed markedly decreased TCR-mediated effector cell responses such as proliferation and Th1 differentiation. By contrast, the inhibitory effect of transgenic Pep on TCR signaling did not affect the differentiation of T(regs) or their suppressive activity. Adoptive transfer experiments showed that transgenic splenocytes exhibited attenuated diabetogenic ability. To examine further the pathogenic features of transgenic T cells, we generated Ptpn22/BDC2.5 doubly transgenic mice and found reduced proliferation and Th1 differentiation in CD4(+) T lymphocytes with additional Pep in pancreatic lymph nodes but not in inguinal lymph nodes of NOD/SCID recipients. This finding indicates that transgenic Pep attenuates T cell functions in an islet Ag-driven manner. Taken together, our results demonstrate that Pep overexpression in T cells attenuates autoimmune diabetes in NOD mice by preferentially modulating TCR signaling-mediated functions in diabetogenic T cells but not in T(regs).


Subject(s)
Diabetes Mellitus, Type 1/immunology , Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes, Regulatory/immunology , Animals , CD4 Antigens/biosynthesis , CD8 Antigens/biosynthesis , Cell Differentiation , Cell Proliferation , Cells, Cultured , Diabetes Mellitus, Type 1/epidemiology , Female , Forkhead Transcription Factors/biosynthesis , Genotype , Incidence , Interferon-gamma/biosynthesis , Male , Mice , Mice, Inbred NOD , Mice, Transgenic , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Signal Transduction , T-Lymphocytes, Regulatory/metabolism
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