APICALL: https://apimlqv2.tenwiseservice.nl/api/mlquery/refset/markup/?concept_ids=HGNC:4540,HGNC:10637&pmids=32324828,32324857,15590984,27165799&apikey=YOUR_APIKEY ====================================== RESULT: { "result": { "markup": { "15590984": { "abstract": "Chemokines have been implicated in tumor growth, angiogenesis, metastasis and the host immune response to malignant cells. Infection and autoimmune disorders can reduce androgen production by Leydig cells and adversely affect spermatogenesis. Cytokine-responsive gene-2 (crg-2) (systematic name CXCL10, also known as interferon-gamma-inducible protein 10 (IP-10)) is a potent chemokine expressed predominantly by macrophages and Leydig cells in the testis. CXCL10 binds to CXCR3 receptor (a G-protein-coupled receptor) and acts via Gialpha protein. We have shown previously that CXCL10 is differentially expressed in normal Leydig cells, inhibited by human chorionic gonadotropin and induced by interferon-gamma, interleukin-1alpha and tumor necrosis factor-alpha. The purpose of the present study was to determine the effects of overexpression of CXCL10 by transfection experiments in MA-10 cells on cell growth, CXCR3 expression, progesterone synthesis and steroidogenic acute regulatory protein (StAR D1, a key regulatory factor in steroidogenesis) gene expression. We cloned the complete CXCL10 cDNA in a mammalian expression vector with the CMV promoter, pcDNA3.1D/V5-His-TOPO, and confirmed its expression with rat CXCL10 antibody and V5 antibody. Results showed large amounts of CXCL10 protein secreted in the medium in the CXCL10 transfectants by Western blotting. The production of CXCL10 mRNA ranged from 30-50-fold more (n=6) in the transfected cells than the control cells, as determined by semiquantitative and real-time RT-PCR. 8-Br-cAMP downregulated CXCL10 mRNA expression and stimulated CXCR3 mRNA expression. Transfection of MA-10 cells with CXCL10 decreased cAMP-induced progesterone synthesis from 38.5+/-1.7 ng/ml (1.5 x 10(5) cells/ml) in control cells to 23.2+/-1.5 ng in transfected cells (P<0.01). 8-Br-cAMP (0.2 mM)-induced StAR D1 mRNA was decreased 30-40% by transfection with CXCL10. Interestingly, overexpression of CXCL10 induced the expression of its receptor CXCR3 gene, as determined by RT-PCR and fluorescence-activated cell sorter (FACS) analysis. Transfection of CXCL10 also significantly decreased insulin-like growth factor-I (IGF-I, 100 ng/ ml)-induced [3H]thymidine incorporation into DNA. These data suggest that CXCL10 also inhibits MA-10 tumor cell proliferation. In conclusion, CXCL10 inhibits StAR D1 expression, decreases progesterone synthesis and inhibits cell proliferation. CXCL10 has the potential to be used in gene therapy for prostate cancer due to its antiangiogenic effect and its inhibitory effect on steroidogenesis.", "refscore": 24, "sentences": [ { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "Effects of overexpression of CXCL10 (cytokine-responsive gene-2) on MA-10 mouse Leydig tumor cell steroidogenesis and proliferation." }, { "concepts": [ "HGNC:10637" ], "score": 3, "sentence": "Cytokine-responsive gene-2 (crg-2) (systematic name CXCL10, also known as interferon-gamma-inducible protein 10 (IP-10)) is a potent chemokine expressed predominantly by macrophages and Leydig cells in the testis. " }, { "concepts": [ "HGNC:10637", "HGNC:4540" ], "score": 2, "sentence": "CXCL10 binds to CXCR3 receptor (a G-protein-coupled receptor) and acts via Gialpha protein. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "We have shown previously that CXCL10 is differentially expressed in normal Leydig cells, inhibited by human chorionic gonadotropin and induced by interferon-gamma, interleukin-1alpha and tumor necrosis factor-alpha. " }, { "concepts": [ "HGNC:10637", "HGNC:4540" ], "score": 2, "sentence": "The purpose of the present study was to determine the effects of overexpression of CXCL10 by transfection experiments in MA-10 cells on cell growth, CXCR3 expression, progesterone synthesis and steroidogenic acute regulatory protein (StAR D1, a key regulatory factor in steroidogenesis) gene expression. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "We cloned the complete CXCL10 cDNA in a mammalian expression vector with the CMV promoter, pcDNA3." }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "V5-His-TOPO, and confirmed its expression with rat CXCL10 antibody and V5 antibody. " }, { "concepts": [ "HGNC:10637" ], "score": 2, "sentence": "Results showed large amounts of CXCL10 protein secreted in the medium in the CXCL10 transfectants by Western blotting. " }, { "concepts": [ "HGNC:10637", "HGNC:4540" ], "score": 2, "sentence": "Br-cAMP downregulated CXCL10 mRNA expression and stimulated CXCR3 mRNA expression. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "Transfection of MA-10 cells with CXCL10 decreased cAMP-induced progesterone synthesis from 38." }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "StAR D1 mRNA was decreased 30-40% by transfection with CXCL10. " }, { "concepts": [ "HGNC:10637", "HGNC:4540" ], "score": 2, "sentence": "Interestingly, overexpression of CXCL10 induced the expression of its receptor CXCR3 gene, as determined by RT-PCR and fluorescence-activated cell sorter (FACS) analysis. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "These data suggest that CXCL10 also inhibits MA-10 tumor cell proliferation. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "In conclusion, CXCL10 inhibits StAR D1 expression, decreases progesterone synthesis and inhibits cell proliferation. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "CXCL10 has the potential to be used in gene therapy for prostate cancer due to its antiangiogenic effect and its inhibitory effect on steroidogenesis." } ], "title": "Effects of overexpression of CXCL10 (cytokine-responsive gene-2) on MA-10 mouse Leydig tumor cell steroidogenesis and proliferation." }, "27165799": { "abstract": "UNLABELLED: Bacillus anthracis is killed by the interferon-inducible, ELR(-) CXC chemokine CXCL10. Previous studies showed that disruption of the gene encoding FtsX, a conserved membrane component of the ATP-binding cassette transporter-like complex FtsE/X, resulted in resistance to CXCL10. FtsX exhibits some sequence similarity to the mammalian CXCL10 receptor, CXCR3, suggesting that the CXCL10 N-terminal region that interacts with CXCR3 may also interact with FtsX. A C-terminal truncated CXCL10 was tested to determine if the FtsX-dependent antimicrobial activity is associated with the CXCR3-interacting N terminus. The truncated CXCL10 exhibited antimicrobial activity against the B.\u00a0anthracis parent strain but not the \u0394ftsX mutant, which supports a key role for the CXCL10 N terminus. Mutations in FtsE, the conserved ATP-binding protein of the FtsE/X complex, resulted in resistance to both CXCL10 and truncated CXCL10, indicating that both FtsX and FtsE are important. Higher concentrations of CXCL10 overcame the resistance of the \u0394ftsX mutant to CXCL10, suggesting an FtsX-independent killing mechanism, likely involving its C-terminal \u03b1-helix, which resembles a cationic antimicrobial peptide. Membrane depolarization studies revealed that CXCL10 disrupted membranes of the B.\u00a0anthracis parent strain and the \u0394ftsX mutant, but only the parent strain underwent depolarization with truncated CXCL10. These findings suggest that CXCL10 is a bifunctional molecule that kills B.\u00a0anthracis by two mechanisms. FtsE/X-dependent killing is mediated through an N-terminal portion of CXCL10 and is not reliant upon the C-terminal \u03b1-helix. The FtsE/X-independent mechanism involves membrane depolarization by CXCL10, likely because of its \u03b1-helix. These findings present a new paradigm for understanding mechanisms by which CXCL10 and related chemokines kill bacteria. IMPORTANCE: Chemokines are a class of molecules known for their chemoattractant properties but more recently have been shown to possess antimicrobial activity against a wide range of Gram-positive and Gram-negative bacterial pathogens. The mechanism(s) by which these chemokines kill bacteria is not well understood, but it is generally thought to be due to the conserved amphipathic C-terminal \u03b1-helix that resembles cationic antimicrobial peptides in charge and secondary structure. Our present study indicates that the interferon-inducible, ELR(-) chemokine CXCL10 kills the Gram-positive pathogen Bacillus anthracis through multiple molecular mechanisms. One mechanism is mediated by interaction of CXCL10 with the bacterial FtsE/X complex and does not require the presence of the CXCL10 C-terminal \u03b1-helix. The second mechanism is FtsE/X receptor independent and kills through membrane disruption due to the C-terminal \u03b1-helix. This study represents a new paradigm for understanding how chemokines exert an antimicrobial effect that may prove applicable to other bacterial species.", "refscore": 24, "sentences": [ { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "CXCL10 Acts as a Bifunctional Antimicrobial Molecule against Bacillus anthracis." }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "UNLABELLED: Bacillus anthracis is killed by the interferon-inducible, ELR(-) CXC chemokine CXCL10. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "Previous studies showed that disruption of the gene encoding FtsX, a conserved membrane component of the ATP-binding cassette transporter-like complex FtsE/X, resulted in resistance to CXCL10. " }, { "concepts": [ "HGNC:10637", "HGNC:4540" ], "score": 2, "sentence": "CXCL10 was tested to determine if the FtsX-dependent antimicrobial activity is associated with the CXCR3-interacting N terminus. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "CXCL10 N terminus. " }, { "concepts": [ "HGNC:10637" ], "score": 2, "sentence": "Mutations in FtsE, the conserved ATP-binding protein of the FtsE/X complex, resulted in resistance to both CXCL10 and truncated CXCL10, indicating that both FtsX and FtsE are important. " }, { "concepts": [ "HGNC:10637" ], "score": 2, "sentence": "Higher concentrations of CXCL10 overcame the resistance of the \u0394ftsX mutant to CXCL10, suggesting an FtsX-independent killing mechanism, likely involving its C-terminal \u03b1-helix, which resembles a cationic antimicrobial peptide. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "CXCL10. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "FtsE/X-dependent killing is mediated through an N-terminal portion of CXCL10 and is not reliant upon the C-terminal \u03b1-helix. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "The FtsE/X-independent mechanism involves membrane depolarization by CXCL10, likely because of its \u03b1-helix. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "These findings present a new paradigm for understanding mechanisms by which CXCL10 and related chemokines kill bacteria. " }, { "concepts": [ "HGNC:10637" ], "score": 1, "sentence": "Our present study indicates that the interferon-inducible, ELR(-) chemokine CXCL10 kills the Gram-positive pathogen Bacillus anthracis through multiple molecular mechanisms. " }, { "concepts": [ "HGNC:10637" ], "score": 2, "sentence": "One mechanism is mediated by interaction of CXCL10 with the bacterial FtsE/X complex and does not require the presence of the CXCL10 C-terminal \u03b1-helix. " } ], "title": "CXCL10 Acts as a Bifunctional Antimicrobial Molecule against Bacillus anthracis." }, "32324828": { "abstract": "Vascular deficits are a fundamental contributing factor of diabetes-associated diseases. Although previous studies have demonstrated that the pro-angiogenic phase of wound healing is blunted in diabetes, a comprehensive understanding of the mechanisms that regulate skin revascularization and capillary stabilization in diabetic wounds is lacking. Using a mouse model of diabetic wound healing, we performed microCT analysis of the 3-dimensional architecture of the capillary bed. As compared to wild type, vessel surface area, branch junction number, total vessel length, and total branch number were significantly decreased in wounds of diabetic mice as compared to WT mice. Diabetic mouse wounds also had significantly increased capillary permeability and decreased pericyte coverage of capillaries. Diabetic wounds exhibited significant perturbations in the expression of factors that affect vascular regrowth, maturation and stability. Specifically, the expression of VEGF-A, Sprouty2, PEDF, LRP6, Thrombospondin 1, CXCL10, CXCR3, PDGFR-\u03b2, HB-EGF, EGFR, TGF-\u03b21, Semaphorin3a, Neuropilin 1, angiopoietin 2, NG2, and RGS5 were down-regulated in diabetic wounds. Together, these studies provide novel information about the complexity of the perturbation of angiogenesis in diabetic wounds. Targeting factors responsible for wound resolution and vascular pruning, as well those that affect pericyte recruitment, maturation, and stability may have the potential to improve diabetic skin wound healing.", "refscore": 2, "sentences": [ { "concepts": [ "HGNC:10637", "HGNC:4540" ], "score": 2, "sentence": "Specifically, the expression of VEGF-A, Sprouty2, PEDF, LRP6, Thrombospondin 1, CXCL10, CXCR3, PDGFR-\u03b2, HB-EGF, EGFR, TGF-\u03b21, Semaphorin3a, Neuropilin 1, angiopoietin 2, NG2, and RGS5 were down-regulated in diabetic wounds. " } ], "title": "Compromised angiogenesis and vascular Integrity in impaired diabetic wound healing." }, "32324857": { "abstract": "Purpose: Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is a progressive disease with no treatment option. Previous studies show chemokine-mediated recruitment of immune cells in the retina, and therefore we investigated systemic levels of chemokines and chemokine receptors in patients with GA. Methods: This observational prospective study was conducted at a single center. We included 122 participants with no immune disease: 41 participants with GA and no choroidal neovascularization, 51 patients with neovascular AMD, and 30 healthy control individuals. Flow cytometric analysis was used to detect expression level of C-C chemokine receptor (CCR)1, CCR2, CCR3, CCR5, and C-X-C motif chemokine receptor (CXCR)3 on peripheral blood mononuclear cells (CD14+ monocytes, CD4+ T cells, CD8+ T cells). Plasma levels of C-C motif ligand (CCL)11, C-X-C motif chemokine (CXCL)10, and CCL5 were measured by specific immunoassays. Enlargement rate of GA lesion was measured from autofluorescence images. Results: Participants with GA have a specific chemokine profile with a higher expression of CCR5 than healthy controls in peripheral blood mononuclear cells, and a higher plasma levels of CCL-5. Further, GA was associated with higher monocytic expression of CCR2 than in neovascular AMD. We found that a high expression level of CCR5 on CD8+ T cells was associated with slower enlargement rate of atrophic lesion. Conclusions: The study showed an association between systemic chemokine profile and GA formation. Further studies are needed to fully elucidate the possible role of systemic chemokine regulation in mediating pathogenesis of GA.", "refscore": 4, "sentences": [ { "concepts": [ "HGNC:10637", "HGNC:4540" ], "score": 2, "sentence": "Plasma levels of C-C motif ligand (CCL)11, C-X-C motif chemokine (CXCL)10, and CCL5 were measured by specific immunoassays. " } ], "title": "Chemokine Profile and the Alterations in CCR5-CCL5 Axis in Geographic Atrophy Secondary to Age-Related Macular Degeneration." } } }, "status": "Success" }