TY  - JOUR
AU  - Pislar, Anja
AU  - Nedeljković, Biljana Bozic
AU  - Perić, Mina
AU  - Jakos, Tanja
AU  - Zidar, Nace
AU  - Kos, Janko
PY  - 2022
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1535
AB  - Microglia are resident macrophages in the central nervous system that are involved in immune responses driven by Toll-like receptors (TLRs). Microglia-mediated inflammation can lead to central nervous system disorders, and more than one TLR might be involved in these pathological processes. The cysteine peptidase cathepsin X has been recognized as a pathogenic factor for inflammation-induced neurodegeneration. Here, we hypothesized that simultaneous TLR3 and TLR4 activation induces synergized microglia responses and that these phenotype changes affect cathepsin X expression and activity. Murine microglia BV2 cells and primary murine microglia were exposed to the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) and the TLR4 ligand lipopolysaccharide (LPS), individually and simultaneously. TLR3 and TLR4 co-activation resulted in increased inflammatory responses compared to individual TLR activation, where poly(I:C) and LPS induced distinct patterns of proinflammatory factors together with different patterns of cathepsin X expression and activity. TLR co-activation decreased intracellular cathepsin X activity and increased cathepsin X localization at the plasma membrane with concomitant increased extracellular cathepsin X protein levels and activity. Inhibition of cathepsin X in BV2 cells by AMS36, cathepsin X inhibitor, significantly reduced the poly(I:C)- and LPS-induced production of proinflammatory cytokines as well as apoptosis. Additionally, inhibiting the TLR3 and TLR4 common signaling pathway, PI3K, with LY294002 reduced the inflammatory responses of the poly(I:C)- and LPS-activated microglia and recovered cathepsin X activity. We here provide evidence that microglial cathepsin X strengthens microglia activation and leads to subsequent inflammation-induced neurodegeneration. As such, cathepsin X represents a therapeutic target for treating neurodegenerative diseases related to excess inflammation.
PB  - Springer, New York
T2  - Molecular Neurobiology
T1  - Cysteine Peptidase Cathepsin X as a Therapeutic Target for Simultaneous TLR3/4-mediated Microglia Activation
EP  - 2276
IS  - 4
SP  - 2258
VL  - 59
DO  - 10.1007/s12035-021-02694-2
ER  - 

@article{
author = "Pislar, Anja and Nedeljković, Biljana Bozic and Perić, Mina and Jakos, Tanja and Zidar, Nace and Kos, Janko",
year = "2022",
abstract = "Microglia are resident macrophages in the central nervous system that are involved in immune responses driven by Toll-like receptors (TLRs). Microglia-mediated inflammation can lead to central nervous system disorders, and more than one TLR might be involved in these pathological processes. The cysteine peptidase cathepsin X has been recognized as a pathogenic factor for inflammation-induced neurodegeneration. Here, we hypothesized that simultaneous TLR3 and TLR4 activation induces synergized microglia responses and that these phenotype changes affect cathepsin X expression and activity. Murine microglia BV2 cells and primary murine microglia were exposed to the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) and the TLR4 ligand lipopolysaccharide (LPS), individually and simultaneously. TLR3 and TLR4 co-activation resulted in increased inflammatory responses compared to individual TLR activation, where poly(I:C) and LPS induced distinct patterns of proinflammatory factors together with different patterns of cathepsin X expression and activity. TLR co-activation decreased intracellular cathepsin X activity and increased cathepsin X localization at the plasma membrane with concomitant increased extracellular cathepsin X protein levels and activity. Inhibition of cathepsin X in BV2 cells by AMS36, cathepsin X inhibitor, significantly reduced the poly(I:C)- and LPS-induced production of proinflammatory cytokines as well as apoptosis. Additionally, inhibiting the TLR3 and TLR4 common signaling pathway, PI3K, with LY294002 reduced the inflammatory responses of the poly(I:C)- and LPS-activated microglia and recovered cathepsin X activity. We here provide evidence that microglial cathepsin X strengthens microglia activation and leads to subsequent inflammation-induced neurodegeneration. As such, cathepsin X represents a therapeutic target for treating neurodegenerative diseases related to excess inflammation.",
publisher = "Springer, New York",
journal = "Molecular Neurobiology",
title = "Cysteine Peptidase Cathepsin X as a Therapeutic Target for Simultaneous TLR3/4-mediated Microglia Activation",
pages = "2276-2258",
number = "4",
volume = "59",
doi = "10.1007/s12035-021-02694-2"
}

Pislar, A., Nedeljković, B. B., Perić, M., Jakos, T., Zidar, N.,& Kos, J.. (2022). Cysteine Peptidase Cathepsin X as a Therapeutic Target for Simultaneous TLR3/4-mediated Microglia Activation. in Molecular Neurobiology
Springer, New York., 59(4), 2258-2276.
https://doi.org/10.1007/s12035-021-02694-2

Pislar A, Nedeljković BB, Perić M, Jakos T, Zidar N, Kos J. Cysteine Peptidase Cathepsin X as a Therapeutic Target for Simultaneous TLR3/4-mediated Microglia Activation. in Molecular Neurobiology. 2022;59(4):2258-2276.
doi:10.1007/s12035-021-02694-2 .

Pislar, Anja, Nedeljković, Biljana Bozic, Perić, Mina, Jakos, Tanja, Zidar, Nace, Kos, Janko, "Cysteine Peptidase Cathepsin X as a Therapeutic Target for Simultaneous TLR3/4-mediated Microglia Activation" in Molecular Neurobiology, 59, no. 4 (2022):2258-2276,
https://doi.org/10.1007/s12035-021-02694-2 . .

TY  - JOUR
AU  - Cumbo, Marija
AU  - Tomić, Branko
AU  - Dunjić Manevski, Sofija
AU  - Jovanović, Tamara
AU  - Gvozdenov, Maja
AU  - Pruner, Iva
AU  - Aralica, Gorana
AU  - Kapitanović, Sanja
AU  - Cacev, Tamara
AU  - Đorđević, Valentina
PY  - 2019
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1219
AB  - Background/ Aim: Thrombin plays significant roles in various types of cancer. However, the expression levels of prothrombin, the thrombin precursor, in cancer remain unclear. Variants of the 3'end of the prothrombin gene lead to increased prothrombin expression. This study aimed to analyze prothrombin 3'end gene variants in colon tumor and adjacent normal tissue samples. Materials and Methods: The study group consisted of 93 patients suffering from colon adenocarcinoma. The 3'end of the prothrombin gene was analyzed by DNA sequencing. Results: Three variants, all previously associated with increased prothrombin expression were detected. Frequency of the FII 19911G allele was 46.77% and 47.85% in tumor and normal tissue, respectively. For the FII 20210A allele, the detected frequencies were 2.15% and 1.61%, respectively. The frequency of the FII c.1824T allele was 0.54% in both tissues. Four patients showed different genotypes in tumor and normal tissue. Conclusion: Prothrombin 3' end gene variants may play a role in colorectal cancer.
PB  - Int Inst Anticancer Research, Athens
T2  - Anticancer Research
T1  - Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma
EP  - 6071
IS  - 11
SP  - 6067
VL  - 39
DO  - 10.21873/anticanres.13814
ER  - 

@article{
author = "Cumbo, Marija and Tomić, Branko and Dunjić Manevski, Sofija and Jovanović, Tamara and Gvozdenov, Maja and Pruner, Iva and Aralica, Gorana and Kapitanović, Sanja and Cacev, Tamara and Đorđević, Valentina",
year = "2019",
abstract = "Background/ Aim: Thrombin plays significant roles in various types of cancer. However, the expression levels of prothrombin, the thrombin precursor, in cancer remain unclear. Variants of the 3'end of the prothrombin gene lead to increased prothrombin expression. This study aimed to analyze prothrombin 3'end gene variants in colon tumor and adjacent normal tissue samples. Materials and Methods: The study group consisted of 93 patients suffering from colon adenocarcinoma. The 3'end of the prothrombin gene was analyzed by DNA sequencing. Results: Three variants, all previously associated with increased prothrombin expression were detected. Frequency of the FII 19911G allele was 46.77% and 47.85% in tumor and normal tissue, respectively. For the FII 20210A allele, the detected frequencies were 2.15% and 1.61%, respectively. The frequency of the FII c.1824T allele was 0.54% in both tissues. Four patients showed different genotypes in tumor and normal tissue. Conclusion: Prothrombin 3' end gene variants may play a role in colorectal cancer.",
publisher = "Int Inst Anticancer Research, Athens",
journal = "Anticancer Research",
title = "Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma",
pages = "6071-6067",
number = "11",
volume = "39",
doi = "10.21873/anticanres.13814"
}

Cumbo, M., Tomić, B., Dunjić Manevski, S., Jovanović, T., Gvozdenov, M., Pruner, I., Aralica, G., Kapitanović, S., Cacev, T.,& Đorđević, V.. (2019). Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma. in Anticancer Research
Int Inst Anticancer Research, Athens., 39(11), 6067-6071.
https://doi.org/10.21873/anticanres.13814

Cumbo M, Tomić B, Dunjić Manevski S, Jovanović T, Gvozdenov M, Pruner I, Aralica G, Kapitanović S, Cacev T, Đorđević V. Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma. in Anticancer Research. 2019;39(11):6067-6071.
doi:10.21873/anticanres.13814 .

Cumbo, Marija, Tomić, Branko, Dunjić Manevski, Sofija, Jovanović, Tamara, Gvozdenov, Maja, Pruner, Iva, Aralica, Gorana, Kapitanović, Sanja, Cacev, Tamara, Đorđević, Valentina, "Prothrombin 3'end Gene Variants in Patients With Sporadic Colon Adenocarcinoma" in Anticancer Research, 39, no. 11 (2019):6067-6071,
https://doi.org/10.21873/anticanres.13814 . .