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1.
PLoS One ; 6(9): e25338, 2011.
Article in English | MEDLINE | ID: mdl-21966503

ABSTRACT

Adipocyte and ß-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM), which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of γ-aminobutyric acid (GABA) receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD)-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4(+)Foxp3(+) Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic.


Subject(s)
Diet, High-Fat/adverse effects , Glucose Intolerance/drug therapy , Inflammation/drug therapy , Insulin Resistance/physiology , gamma-Aminobutyric Acid/therapeutic use , Administration, Oral , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Flow Cytometry , Forkhead Transcription Factors/metabolism , Glucose Intolerance/metabolism , Inflammation/chemically induced , Inflammation/metabolism , Intra-Abdominal Fat/metabolism , Mice , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolism , gamma-Aminobutyric Acid/administration & dosage
2.
Int J Antimicrob Agents ; 28(4): 352-60, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16963233

ABSTRACT

Transduction of salivary glands with antimicrobial peptide genes has great potential for oral infection control. Our ultimate goal is to introduce antimicrobial peptide genes into salivary glands that secrete these peptides into saliva to control bacterial/fungal infection in the oral cavity. However, an animal study model to test this potential has not been established. Therefore, we determined to test (i) whether the potent antimicrobial peptide human beta-defensin-2 (hBD-2) can be overexpressed in saliva after transduction of salivary glands and (ii) whether oral fungal infection can be developed in a NOD/SCID murine model. Lentiviral vector SIN18cPPTRhMLV bearing hBD-2 cDNA was introduced into SCID mouse submandibular glands via cannulation. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry or enzyme-linked immunosorbent assay (ELISA) were performed to detect hBD-2 expression in glands or in saliva. Candida albicans 613p was inoculated orally into SCID mice to establish oral candidiasis. Whilst expression of hBD-2 was detected in mouse salivary glands by RT-PCR and immunohistochemistry 1 day or 1 week following delivery of lentivirus, hBD-2 was not detected in saliva. There was recoverable C. albicans from the oral cavity and gastrointestinal tract 4 days to 4 weeks after infection, but there was no establishment of observable oral candidiasis in SCID mice under a stereomicroscope. Our data indicate that lentiviral vectors transduce mouse salivary glands, but not at a sufficient level to allow hBD-2 detection in saliva. Other vectors for gene transduction and additional treatment of SCID mice to establish oral candidiasis are needed in order to utilise mouse salivary glands to test antimicrobial gene therapy.


Subject(s)
Anti-Infective Agents/pharmacology , Candida albicans/drug effects , Retroviridae/drug effects , Saliva/metabolism , Salivary Ducts/metabolism , beta-Defensins/pharmacology , Animals , Anti-Infective Agents/therapeutic use , Enzyme-Linked Immunosorbent Assay , Gene Expression Regulation/physiology , Genetic Therapy , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Mouth Mucosa/metabolism , Retroviridae/genetics , Saliva/chemistry , Salivary Ducts/chemistry , Salivary Ducts/immunology , Salivary Ducts/pathology , beta-Defensins/genetics , beta-Defensins/therapeutic use
3.
Biochem Biophys Res Commun ; 339(1): 344-54, 2006 Jan 06.
Article in English | MEDLINE | ID: mdl-16298338

ABSTRACT

The purpose of this study was to determine the capacity of cells transduced with human beta-defensins (HBDs) to express antimicrobial peptides, since sufficient expression level is required for effective antimicrobial activity. Retroviral vector pBabeNeo and lentiviral vector SIN18cPPTRhMLV (SIN18) carrying HBDs were utilized to transduce non-HBD-expressing cells such as fibroblasts or HBD-producing oral epithelial cells. We found that HBD-3 gene transfer to fibroblasts was possible not via retrovirus but by direct vector transfection. SIN18 had high transduction efficiencies (80.9-99.9%) and transduced cells expressed higher amounts of HBD-2 than those by pBabeNeo. Primary human gingival epithelial cells (HGECs) expressed greater amounts of HBD-2 than primary fibroblasts after lentiviral transduction. Additionally, HBD-2 secretion from transduced HGECs cells was further increased when stimulated with IL-1 or TNFalpha. Our data indicate that while HBD-2 expression is limited in primary fibroblasts, its expression in HGECs may be maximized by gene transduction plus cytokine induction.


Subject(s)
Cytokines/pharmacology , Epithelial Cells/metabolism , Transduction, Genetic , beta-Defensins/biosynthesis , Animals , Cells, Cultured , Fibroblasts/cytology , Fibroblasts/metabolism , Genetic Vectors , Gingiva/cytology , Gingiva/metabolism , Green Fluorescent Proteins/biosynthesis , Green Fluorescent Proteins/genetics , Humans , Interleukin-1/pharmacology , Mice , Retroviridae/genetics , Tumor Necrosis Factor-alpha/pharmacology , beta-Defensins/genetics
4.
Microb Pathog ; 37(6): 303-12, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15619426

ABSTRACT

IL-8 mRNA in human gingival epithelial cells (HGECs) is up-regulated by Fusobacterium nucleatum, and up-/down-regulated by Porphyromonas gingivalis in a complex interaction in the early stages (< or = 4 h) after infection. The mechanisms involved in this regulation in response to F. nucleatum and/or P. gingivalis infection, and identification of co-regulated cytokine genes, are the focus of this investigation. Heat, formalin or protease treatment of F. nucleatum cells attenuated the IL-8 mRNA up-regulation. NF-kappaB, mitogen-activated protein kinase (MAPK) p38 and MAPK kinase/extracellular signal-regulated kinase (MEK/ERK) pathways were involved in IL-8 mRNA induction by F. nucleatum. Pretreatment of P. gingivalis with heat, formalin or protease enhanced IL-8 mRNA induction. NF-kappaB, MARK p38, and MEK/ERK pathways were also involved in this induction. In contrast, down-regulation of IL-8 mRNA by P. gingivalis involved MEK/ERK, but not NF-kappaB or MAPK p38 pathways. cDNA arrays analysis revealed that mRNA down-regulation by P. gingivalis is a specific reaction that only a number of genes, e.g. IL-1beta, IL-8, macrophage inflammatory protein-2alpha, and migration inhibitory factor-related protein-14, are affected based on examination of 278 cytokine/receptor genes. These data indicate that F. nucleatum and P. gingivalis trigger specific and differential gene regulation pathways in HGECs.


Subject(s)
Cytokines/metabolism , Epithelial Cells/immunology , Fusobacterium nucleatum/pathogenicity , Gene Expression Regulation , Gingiva/immunology , Porphyromonas gingivalis/pathogenicity , Cell Line , Cytokines/genetics , Epithelial Cells/microbiology , Gingiva/cytology , Gingiva/microbiology , Humans , Interleukin-8/genetics , Interleukin-8/metabolism , MAP Kinase Signaling System , NF-kappa B/genetics , NF-kappa B/metabolism , Oligonucleotide Array Sequence Analysis , Proteins/genetics , Proteins/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction
5.
J Immunol ; 173(8): 5298-304, 2004 Oct 15.
Article in English | MEDLINE | ID: mdl-15470076

ABSTRACT

Gamma-aminobutyric acid (GABA) is both a major inhibitory neurotransmitter in the CNS and a product of beta cells of the peripheral islets. Our previous studies, and those of others, have shown that T cells express functional GABAA receptors. However, their subunit composition and physiological relevance are unknown. In this study, we show that a subset of GABAA receptor subunits are expressed by CD4+ T cells, including the delta subunit that confers high affinity for GABA and sensitivity to alcohol. GABA at relatively low concentrations down-regulated effector T cell responses to beta cell Ags ex vivo, and administration of GABA retarded the adoptive transfer of type 1 diabetes (T1D) in NOD/scid mice. Furthermore, treatment with low dose of GABA (600 microg daily) dramatically inhibited the development of proinflammatory T cell responses and disease progression in T1D-prone NOD mice that already had established autoimmunity. Finally, GABA inhibited TCR-mediated T cell cycle progression in vitro, which may underlie GABA's therapeutic effects. The immunoinhibitory effects of GABA on T cells may contribute to the long prodomal period preceding the development of T1D, the immunological privilege of the CNS, and the regulatory effects of alcohol on immune responses. Potentially, pharmacological modulation of GABAA receptors on T cells may provide a new class of therapies for human T1D as well as other inflammatory diseases.


Subject(s)
Autoimmunity/drug effects , Diabetes Mellitus, Type 1/prevention & control , Inflammation/prevention & control , T-Lymphocytes/drug effects , gamma-Aminobutyric Acid/pharmacology , Adoptive Transfer , Animals , CD4-Positive T-Lymphocytes/chemistry , Cell Cycle/drug effects , Female , Mice , Mice, Inbred NOD , Protein Subunits , Receptors, GABA-A/analysis , T-Lymphocytes/immunology
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