• Journal of Integrative Natural Science
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• v.8 no.3
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• pp.164-175
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• 2015

CXCR3 is a C-X-C chemokine receptor type 3 also known as GPR9 and CD183. CXCR3 is a G-Protein coupled chemokine receptor which interacts with three endogenous interferon inducible chemokine's (CXCL9, CXCL10 and CXCL11) and is proved to play a vital role in the Th1 inflammatory responses. CXCR3 has been implicated to be associated with various disease conditions like inflammatory diseases, autoimmune diseases, type I diabetes and acute cardiac allograft rejection. Therefore CXCR3 receptor is found to be an attractive therapeutic target for the treatment of inflammatory diseases. Inorder to decipher the biological function of a CXCR3, 3D structure is of much important but the crystal structure for CXCR3 has not yet been resolved. Hence, in the current study Homology modeling of CXCR3 was performed against various templates and validated using different parameters to suggest the best model for CXCR3. The reported best model can be used for further studies such as docking to identify the important binding site residues.

• The Journal of the Korean bone and joint tumor society
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• v.18 no.1
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• pp.20-27
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• 2012

Purpose: The chemokine receptor CXCR4 has been reported to be aberrantly expressed in human cancer and has been shown to participate in cancer metastasis. We compared the expression of CXCR4 in conventional high-grade and low-grade central osteosarcomas, and determined if an association between CXCR4 expression and prognosis could be made. Materials and Methods: We performed the immunohistochemistry for CXCR4 in a total of 63 patients with osteosarcoma and determined the relationships according to the clinicopathologic variables and overall survival rates. Results: CXCR4 was detected in 76.3% of conventional high-grade osteosarcoma patients and in 36% of low-grade central osteosarcomas. Diffuse expression was noted in 47.4% of the high-grade osteosarcomas and all low-grade cases were focal positive. CXCR4 expression was significantly correlated with histologic grade (p<0.0001). While overall survival rate was reduced significantly with increased CXCR4 expression (p=0.0058), higher histologic grade (p<0.0001), and younger age (p=0.0140), survival rate did not correlate with gender, tumor size, or AJCC stage. Conclusion: Our results suggest that CXCR4 expression is associated with higher-grade tumors and with poor prognosis for osteosarcoma patients.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7201-7205
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• 2014

Chemokine and chemokine receptor expression by tumor cells contributes to tumor growth and angiogenesis and thus these factors may be considered as tumor markers. Here we aimed to characterize cells directly extracted from glioma, meningioma, and secondary brain tumors as well as non-tumoral cells in vitro. Cells were isolated from brain tissues using 0.2% collagenase and characterized by flow cytometry. Expression of SDF-1, CXCR4, CXCR7, RANTES, CCR5, MCP-1 and IP-10 was defined using flow cytometry and qRT-PCR methods. Brain tissue isolated cells were observed as spindle-shaped cell populations. No significant differences were observed for expression of SDF-1, CXCR4, CXCR7, RANTES, CCR5, and IP-10 transcripts. However, the expression of CXCR4 was approximately 13-fold and 110-fold higher than its counterpart, CXCR7, in meningioma and glioma cells, respectively. CXCR7 was not detectable in secondary tumors but CXCR4 was expressed. In non tumoral cells, CXCR7 had 1.3-fold higher mRNA expression than CXCR4. Flow cytometry analyses of RANTES, MCP-1, IP-10, CCR5 and CXCR4 expression showed no significant difference between low and high grade gliomas. Differential expression of CXCR4 and CXCR7 in brain tumors derived cells compared to non-tumoral samples may have crucial impacts on therapeutic interventions targeting the SDF-1/CXCR4/CXCR7 axis.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.1073-1076
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• 2015

Background: To explore the relationship between CXCR4, CD133 co-expression and clinicopathological features as well as prognosis of patients with phase II~III colon cancer. Materials and Methods: Forty-nine paraffin-embedded samples of tumor tissue and epithelial tissue adjacent to cancer were collected from patients with colon cancer undergoing radical surgery in Baotou Cancer Hospital from January, 2010 to June, 2011. CXCR4 and CD133 expression was detected using immunohistochemistry and its relationship with clinicopathological features and the 3-year survival rate was analyzed. Results: In the tumor tissue and colonic epithelial tissue adjacent to cancer, the positive expression rates of CXCR4 were respectively 61.2% (30/49) and 8.16% (4/49), while those of CD133 being 36.7% (18/49) and 6.12% (3/49). CXCR4 and CD133 expression in tumor tissue was not related to patient age, gender, primary focal sites, tumor size, TNM staging, histological type, tumor infiltration depth and presence or absence of lymphatic metastasis, but CXCR4 and CD133 co-expression was associated with TNM staging and lymphatic metastasis. The 3-year survival rate of patients with CXCR4 and CD133 co-expression was 27.3% (3/11), and that of the remainderwas 76.3% (29/38), the difference being significant ($X^2=7.0206$, p=0.0081). Conclusions: CXCR4 and CD133 co-expression may be a risk factor for poor prognosis of patients with stage II~III colon cancer.

• Biomolecules & Therapeutics
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• v.25 no.2
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• pp.130-139
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• 2017

$CXCR5^+$ T follicular helper (Tfh) cells are associated with aberrant autoantibody production in patients with antibody-mediated autoimmune diseases including lupus. Follicular regulatory T (Tfr) cells expressing CXCR5 and Bcl6 have been recently identified as a specialized subset of $Foxp3^+$ regulatory T (Treg) cells that control germinal center reactions. In this study, we show that retroviral transduction of CXCR5 gene in $Foxp3^+$ Treg cells induced a stable expression of functional CXCR5 on their surface. The Cxcr5-transduced Treg cells maintained the expression of Treg cell signature genes and the suppressive activity. The expression of CXCR5 as well as Foxp3 in the transduced Treg cells appeared to be stable in vivo in an adoptive transfer experiment. Moreover, Cxcr5-transduced Treg cells preferentially migrated toward the CXCL13 gradient, leading to an effective suppression of antibody production from B cells stimulated with Tfh cells. Therefore, our results demonstrate that enforced expression of CXCR5 onto Treg cells efficiently induces Tfr cell-like properties, which might be a promising cellular therapeutic approach for the treatment of antibody-mediated autoimmune diseases.

• Journal of Integrative Natural Science
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• v.9 no.3
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• pp.177-184
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• 2016

CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils and it regulates the neutrophilic inflammation in the lung diseases. CXCR2 antagonist may reduce the neutrophil chemotaxis and alter the inflammatory response. Hence, in the present study, ligand based Comparative Molecular Similar Indices Analysis (CoMSIA) was performed on a series of CXCR2 antagonist named pyrimidine-5-carbonitrile-6-alkyl derivatives. The optimum CoMSIA model was obtained with statistically significant cross-validated coefficients ($q^2$) of 0.582 and conventional coefficients ($r^2$) of 0.987 with steric, electrostatic, hydrophobic, donor and acceptor fields. The contour maps suggest the important structural modifications and this study can be used to guide the development of potent CXCR2 antagonist.

• Journal of Integrative Natural Science
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• v.11 no.2
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• pp.121-129
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• 2018

CXCR6 is a major target in drug design as it is a determinant receptor in many diseases like AIDS, Type I Diabetes, some cancer types, atherosclerosis, tumor formation, liver disease and steatohepatitis. In this study, we propose the active site residues of CXCR6 molecule. We employed homology modelling and molecular docking approach to generate the 3D structure for CXCR6 and to explore its interaction between the antagonists and agonists. 3D models were generated using 14 different templates having high sequence identity with CXCR6. Surflex docking studies using pyridine and pyrimidine derivatives enabled the analysis of the binding site and finding of the important residues involved in binding. 3D structure of CXCL16, a natural ligand for CXCR6, was modelled using PHYRE and protein - protein docking was performed using ClusPro. The residues which were found to be crucial in interaction with the ligand are THR110, PHE113, TYR114, GLN160, GLN195, CYS251 and SER255. This study can be used as a guide for therapeutic studies of human CXCR6.

• Journal of Integrative Natural Science
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• v.9 no.2
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• pp.121-127
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• 2016

CXC chemokine receptor 2 (CXCR2) is a prominent chemokine receptor on neutrophils. The neutrophilic inflammation in the lung diseases is found to be largely regulated through CXCR2 receptor. Antagonist of CXCR2 may reduce the neutrophil chemotaxis and alter the inflammatory response. Hence, in the present study, ligand based Comparative molecular field analysis (CoMFA) was performed on a series of CXCR2 antagonist named pyrimidine-5-carbonitrile-6-alkyl derivatives. The optimum CoMFA model was obtained with statistically significant cross-validated coefficients ($q^2$) of 0.568 and conventional coefficients ($r^2$) of 0.975. The contour maps suggest the important structural modifications and this study can be used to guide the development of potent CXCR2 antagonist.

• Biomolecules & Therapeutics
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• v.31 no.2
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• pp.210-218
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• 2023

Prostate cancer is the fifth leading cause of cancer-related mortality in men, primarily because of treatment resistance, recurrence, and metastasis. In the present study, we investigated the role of paracrine interleukin-8 (IL-8) in the antagonistic expression of IL-8 and androgen receptor (AR), and the contribution of IL-8 to prostate cancer aggressiveness. In hormone-responsive LNCaP cells that do not express IL-8, recombinant IL-8 treatment significantly increased expressions of IL-8, CXC chemokine receptor 2 (CXCR2), matrix metalloproteinase (MMP)-2/9, Snail, and vimentin. IL-8 treatment significantly decreased AR and E-cadherin expression. IL-8-induced gene expression changes were suppressed by navarixin, a CXCR1/2 inhibitor, and gallein, a Gβγ inhibitor. In PC-3 androgen-refractory prostate cancer cells, IL-8 knockdown reduced expressions of CXCR2, MMP-2/9, Snail, and vimentin, and increased AR and E-cadherin expressions at the mRNA and protein levels. Co-culture with MEG-01 human megakaryocytic cells secreting high levels of IL-8 induced gene expression changes in both LNCaP and PC-3 cells, similar to those induced by IL-8 treatment. The altered gene expressions were accompanied by significant activation of transcription factor Snail in LNCaP and PC-3 cells. Treatment with the CXCR blocker navarixin inhibited the invasion of PC-3 cells but not LNCaP cells. However, invasion induced by MEG-01 was inhibited by navarixin in both LNCaP and PC-3 cells. The collective findings demonstrate that IL-8 enhances CXCR2 expression, which antagonistically regulates AR expression. More importantly, through changes in IL-8/CXCR2-regulated gene expression, IL-8 induces antiandrogen therapy resistance and epithelial-mesenchymal transition in prostate cancer.

• Clinical and Experimental Pediatrics
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• v.64 no.1
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• pp.37-43
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• 2021

Background: Animal studies have shown that a leukocyte influx precedes the development of bronchopulmonary dysplasia (BPD) in premature sheep. The CXC chemokine receptor 2 (CXCR2) pathway has been implicated in the pathogenesis of BPD because of the predominance of CXCR2 ligands in tracheal aspirates of preterm infants who later developed BPD. Purpose: To test the effect of CXCR2 antagonist on postnatal systemic and pulmonary inflammation and alveolarization in a newborn Sprague-Dawley rat model of BPD. Methods: Lipopolysaccharide (LPS) was injected intraperitoneally (i.p.) into the newborn rats on postnatal day 1 (P1), P3, and P5 to induce systemic inflammation and inhibit alveolarization. In the same time with LPS administration, CXCR2 antagonist (SB-265610) or vehicle was injected i.p. to investigate whether CXCR2 antagonist can alleviate the detrimental effect of LPS on alveolarization by attenuating inflammation. On P7 and P14, bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) were collected from the pups. To assess alveolarization, mean cord length and alveolar surface area were measured on 4 random nonoverlapping fields per animal in 2 distal lung sections at ×100 magnification. Results: Early postnatal LPS administration significantly increased neutrophil counts in BALF and PB and inhibited alveolarization, which was indicated by a greater mean cord length and lesser alveolar surface area. CXCR2 antagonist significantly attenuated the increase of neutrophil counts in BALF and PB and restored alveolarization as indicated by a decreased mean cord length and increased alveolar surface area in rat pups exposed to early postnatal systemic LPS. Conclusion: CXCR2 antagonist preserved alveolarization by alleviating pulmonary and systemic inflammation induced by early postnatal systemic LPS administration. These results suggest that CXCR2 antagonist can be considered a potential therapeutic agent for BPD that results from disrupted alveolarization induced by inflammation.