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1.
Leuk Lymphoma ; 60(4): 1062-1070, 2019 04.
Article in English | MEDLINE | ID: mdl-30277117

ABSTRACT

The interaction between CD40, and its ligand, CD154, is essential for the development of humoral and cellular immune responses. The selective inhibition or activation of this pathway forms the basis for the development of new therapeutics against immunologically based diseases and malignancies. We are developing a gene fusion of Salmonella typhi OmpC protein expressing the CD154 Tyr140-Ser-149 amino acid strand. This OmpC-CD154 binds CD40 and activates B cells. In this study, we demonstrate that OmpC-CD154p treatment inhibits cell growth, proliferation and induced apoptosis in the B-NHL cell lines Raji and Ramos. The Bcl-2 family proteins were regulated and the Bcl-6 and YY1 oncoproteins were inhibited. p38 MAPK activation is an important mechanism underlying the effect on proliferation and apoptosis mediated by this fusion protein. This study establishes a basis for the possible use of fusion protein OmpC-CD154 as an alternative treatment for B-NHL.


Subject(s)
Caspases/metabolism , Peptides/pharmacology , Proto-Oncogene Proteins c-bcl-6/metabolism , YY1 Transcription Factor/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , CD40 Antigens/metabolism , CD40 Ligand/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Humans , Molecular Mimicry , Peptides/chemistry , Porins/chemistry
2.
Tuberculosis (Edinb) ; 96: 87-95, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26786659

ABSTRACT

Mycobacterium tuberculosis (M. tb) is the etiological agent of pulmonary tuberculosis (TB); this disease remains a worldwide health problem. Yin-Yang-1 (YY1) plays a major role in the maintenance and progression of some pulmonary diseases, including pulmonary fibrosis. However, the role of YY1 in TB remains unknown. The aim of this study was to elucidate the role of YY1 in the regulation of CCL4 and its implication in TB. We determined whether YY1 regulates CCL4 using reporter plasmids, ChIP and siRNA assays. Immunohistochemistry and digital pathology were used to measure the expression of YY1 and CCL4 in a mouse model of TB. A retrospective comparison of patients with TB and control subjects was used to measure the expression of YY1 and CCL4 using tissue microarrays. Our results showed that YY1 regulates the transcription of CCL4; moreover, YY1, CCL4 and TGF-ß were overexpressed in the lung tissues of mice with TB during the late stages of the disease and the tissues of TB patients. The expression of CCL4 and TGF-ß correlated with YY1 expression. In conclusion, YY1 regulates CCL4 transcription; moreover, YY1 is overexpressed in experimental and human TB and is positively correlated with CCL4 and TGF-ß expression. Therefore, treatments that decrease YY1 expression may be a new therapeutic strategy against TB.


Subject(s)
Chemokine CCL4/metabolism , Lung/microbiology , Tuberculosis, Pulmonary/metabolism , YY1 Transcription Factor/metabolism , Animals , Cell Line , Chemokine CCL4/genetics , Chromatin Immunoprecipitation , Disease Models, Animal , Disease Progression , Gene Expression Regulation , Host-Pathogen Interactions , Humans , Immunohistochemistry , Lung/immunology , Male , Mice, Inbred BALB C , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/pathogenicity , RNA Interference , Retrospective Studies , Signal Transduction , Time Factors , Tissue Array Analysis , Transcription, Genetic , Transfection , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Tuberculosis, Pulmonary/genetics , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/microbiology , YY1 Transcription Factor/genetics
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