New, Potent, Small Molecule Agonists of Tyrosine Kinase Receptors Improve Dry Eye Disease
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PROVIDER: PRJNA835818 | ENA |
REPOSITORIES: ENA
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Project description:Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin3 (NT-3) bind to tyrosine kinase (Trk) receptors, TrkA, TrkB, and TrkC, respectively. This study investigated the efficacy of novel molecule agonists of Trk receptors in an in vivo model of dry eye disease. Compared to vehicle, mice subjected to desiccating stress and treated with agonists pan and C1 showed improved corneal barrier function, while C1 also increased GC densities. NanoString analyses revealed upregulation of specific mRNA transcripts (Ptger4, Tnfaip3, Il1a and Ptger4, Tlr3, Osal1) in pan and C1 treated corneas compared to vehicle-treated corneas. Western blots showed pan and C1 decreased vehicle-induced NFkB nuclear translocation after DS for one day and increased PTGER4 and TNFAIP3 protein levels after 5 days of DS in corneal epithelium lysates. These results were confirmed by immunostaining using antibodies for TNFAIP3 and PTGER4 in wholemount corneas. We conclude that small-molecule agonists of Trk receptors improve dry eye disease by decreasing NFkB activation and increasing protein expression of anti-inflammatory molecules TNFAIP3 and PTGER4. Surprisingly, the most efficacious small molecule agonists were not TrkA selective, but TrkC and panTrk, suggesting that wider exploration of TrkB and C and pan Trk agonists are warranted in efforts to treat dry eye disease.
2022-05-08 | GSE202378 | GEO
Project description:Amorfrutins are selective PPARγ agonists with potent antidiabetic properties
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Project description:Melanoma is the most lethal form of skin cancer. Clinical efforts to combat melanoma include immune therapies whose benefit depends on antitumor T-cells, to target and to clear melanoma. However, most tumors lack significant immune infiltration prior to therapy, and some immune therapies are hindered by a persistent lack of immune-cell infiltration. Chemokines can promote T-cell migration into tumors; therefore, agents that induce T-cell attracting chemokines in the tumor microenvironment could potentially improve the clinical activity of current immune therapies for melanoma. CXCL10 has been implicated as a critical chemokine supporting T-cell infiltration into the tumor microenvironment. Here we report that combination treatment of human melanoma cell lines with Toll-like receptor (TLR) 2/6 agonists MALP-2 or FSL-1 +IFNlambda synergize to induce production of immune-cell attracting chemokines CCL3 and CXCL10 by melanoma cells. We find that TLR2 and TLR6 are widely expressed on human melanoma cells, and that stimulation of fresh patient melanoma specimens with TLR2/6 agonists+IFNlambda induces CXCL10 production from melanoma cells, endothelial and immune-cells. Furthermore, ex vivo migration assays demonstrate that stimulation of melanoma cells with TLR2/6 agonists+IFNlambda increases CD4+ and CD8+ T-cell migration toward melanoma. Collectively, these data identify a novel synergy of TLR2/6 agonists+IFNlambda for inducing CXCL10 production by melanoma cells and suggest that intralesional administration of TLR2/6 agonists+IFNlambda may improve immune signatures in melanoma metastases and have value in combination with other immune therapies, by supporting better T-cell migration to melanoma.
2015-08-13 | GSE49632 | GEO
Project description:Clinical approaches to treat advanced melanoma include immune therapies, whose benefits depend on tumor-reactive T-cells to infiltrate metastases. However, most tumors lack significant immune infiltration prior to therapy, and some immune therapies are hindered by a persistent lack of immune cell infiltration. CXCL10 has been implicated as a critical chemokine supporting T-cell migration into tumors; thus agents that induce CXCL10 in tumors may improve patient responses to systemic immune therapy. We find that melanoma cells treated with TLR2/6 agonists (MALP-2 or FSL-1) and interferon-gamma (IFNgamma) upregulate CXCL10 production, when compared to IFNgamma treatment alone or no treatment. Gene profiling of melanoma cells lines treated with TLR2/6 agonists and IFNgamma demonstrate that a selective profile of genes are induced which may be favorable for promoting immune cell infiltration of tumors. TLR2 and TLR6 are widely expressed on human melanoma cells, and treatment of melanoma cells with TLR2/6 agonists and IFNgamma does not hinder melanoma cell apoptosis or promote proliferation. Furthermore, melanoma cells from surgically resected patient tumors upregulate CXCL10 production after treatment with TLR2/6 agonists and IFNgamma when compared to treatment with either agent alone. Collectively, these data identify TLR2/6 agonists and IFNgamma as a novel target for promoting CXCL10 production directly from melanoma cells. Samples from four human melanoma cell lines, VMM1 (n=6), DM13 (n=6), DM93 (n=6) and VMM39 (n=6), were treated with media alone, MALP-2 (TLR2/6 agonist), FSL-1 (TLR2/6 agonist), IFNgamma alone, MALP-2 and IFNgamma, or FSL-1 and IFNgamma.
2015-11-22 | E-GEOD-64506 | biostudies-arrayexpress
Project description:Clinical approaches to treat advanced melanoma include immune therapies, whose benefits depend on tumor-reactive T-cells to infiltrate metastases. However, most tumors lack significant immune infiltration prior to therapy, and some immune therapies are hindered by a persistent lack of immune cell infiltration. CXCL10 has been implicated as a critical chemokine supporting T-cell migration into tumors; thus agents that induce CXCL10 in tumors may improve patient responses to systemic immune therapy. We find that melanoma cells treated with TLR2/6 agonists (MALP-2 or FSL-1) and interferon-gamma (IFNgamma) upregulate CXCL10 production, when compared to IFNgamma treatment alone or no treatment. Gene profiling of melanoma cells lines treated with TLR2/6 agonists and IFNgamma demonstrate that a selective profile of genes are induced which may be favorable for promoting immune cell infiltration of tumors. TLR2 and TLR6 are widely expressed on human melanoma cells, and treatment of melanoma cells with TLR2/6 agonists and IFNgamma does not hinder melanoma cell apoptosis or promote proliferation. Furthermore, melanoma cells from surgically resected patient tumors upregulate CXCL10 production after treatment with TLR2/6 agonists and IFNgamma when compared to treatment with either agent alone. Collectively, these data identify TLR2/6 agonists and IFNgamma as a novel target for promoting CXCL10 production directly from melanoma cells.
2015-11-22 | GSE64506 | GEO
Project description:IP3 receptors are channels that mediate the release of Ca(2+) from the intracellular stores of cells stimulated by hormones or neurotransmitters. Adenophostin A (AdA) is the most potent agonist of IP3 receptors, with the ?-anomeric adenine contributing to the increased potency. The potency of AdA and its stability towards the enzymes that degrade IP3 have aroused interest in AdA analogs for biological studies. The complex structure of AdA poses problems that have necessitated optimization of synthetic conditions for each analog. Such lengthy one-at-a-time syntheses limit access to AdA analogs. We have addressed this problem by synthesizing a library of triazole-based AdA analogs, triazolophostins, by employing click chemistry. An advanced intermediate having all the necessary phosphates and a ?-azide at the anomeric position was reacted with various alkynes under Cu(i) catalysis to yield triazoles, which upon deprotection gave triazolophostins. All eleven triazolophostins synthesized are more potent than IP3 and some are equipotent with AdA in functional analyses of IP3 receptors. We show that a triazole ring can replace adenine without compromising the potency of AdA and provide facile routes to novel AdA analogs.
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Project description:Tyrosine Kinase Inhibitor Cardiotoxicity
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Project description:Dry Eye Disease (DED) is part of several conditions, including Sjögren's syndrome (SS) and no single test to diagnosis DED. The present study intends to evaluate whether a set of signs and symptoms of DED can distinguish: a) SS from other non-overlapping systemic diseases related to DED; b) primary and secondary SS. 182 consecutive patients with DED were evaluated under five groups: SS, graft-versus-host disease (GVHD), Graves' orbitopathy (GO), diabetes mellitus (DM), glaucoma under treatment with benzalkonium chloride medications (BAK). Twenty-four healthy subjects were included as control group (CG). The evaluation consisted of Ocular Surface Disease Index (OSDI), Schirmer test (ST), corneal fluorescein staining (CFS) and tear film break up time (TFBUT). Indeed, a subset of DED patients (n = 130), classified as SS1, SS2 and nonSS (NSS) by the American-European Criteria were compared. Quadratic discriminant analysis (QDA) classified the individuals based on variables collected. The area under Receiver Operating Characteristics (ROC) curve evaluated the classification performance in both comparisons. Comparing SS with other diseases, QDA showed that the most important variable for classification was OSDI, followed by TFBUT and CFS. Combined, these variables were able to correctly classify 62.6% of subjects in their actual group. At the discretion of the area under the ROC curve, the group with better classification was the control (97.2%), followed by DM (95.5%) and SS (92.5%). DED tests were different among the NSS, SS1 and SS2 groups. The analysis revealed that the combined tests correctly classified 54.6% of the patients in their groups. The area under the ROC curve better classified NSS (79.5%), followed by SS2 (74.4%) and SS1 (69.4%). Diseases that causes DED, and also SS1, SS2 and NSS are distinguishable conditions, however a single ocular tools was not able to detect the differences among the respective groups.
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Project description:Background: Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer in the adult population. Late diagnosis, resistance to therapeutics and recurrence of metastatic lesions account for the highest mortality rate among kidney cancer patients. Identifying novel biomarkers for early cancer detection and elucidating the mechanisms underlying ccRCC growth and progression will provide clues to treat this aggressive malignant tumor. Method: Expression studies of RING ligase praja2 and tyrosine kinase receptors (RTKs) in renal cell carcinoma was evaluated by immunoblot and immunohistochemistry. Gene transcription profiling in RCC cells was evaluated by RNA sequencing and Ingenuity Pathway Analysis. Imunofluorescence assays were used to evaluate the intracellular distribution and clearance of membrane receptors in cells devoid of praja2. Ubiquitin modifications and protein-protein interaction networks were monitored by IP, western blot, mass spectrometry and proteomic analysis. Experiments in vitro and in vivo were performed to define the role of praja2 in RTKs turnover, metabolism, renal cell carcinoma growth and metastatic diffusion. Results: We report here that the ubiquitin ligase praja2 controls endocytosis and the signal strength of different types of receptors (EGFR, VEGFR, TfR). Praja2 forms a complex with- and ubiquitinates the adaptor protein AP2m required for the activity of ATPase and acidification of endosomes and lysosomes necessary for receptor endocytosis and clearance. Downregulation of praja2 blocks the endocytosis of several membrane receptors, including EGFR, VEGFR and TfR and amplifies mitogenic and proliferative signaling as shown in the clear cell renal cell carcinoma (ccRCC). Restoring praja2 expression in RCC cells reduces EGFR levels, rewires cancer cell metabolism and inhibits growth and metastatic diffusion. In vivo, praja2 knockout mice show upregulation of tyrosine kinase receptors (RTKs) and pronounced histopathological renal alterations. Conclusion: Our findings identify praja2 as an important regulator of tyrosine kinase receptor(s) turnover and can be considered a bona fide oncosuppressor because it finely regulates signaling of several types of receptors and its loss supports kidney cancer growth and diffusion.
2024-02-01 | E-MTAB-13105 | biostudies-arrayexpress
Project description:Dinucleoside polyphosphates act as agonists on purinergic P2Y receptors to mediate a variety of cellular processes. Symmetrical, naturally occurring purine dinucleotides are found in most living cells and their actions are generally known. Unsymmetrical purine dinucleotides and all pyrimidine containing dinucleotides, however, are not as common and therefore their actions are not well understood. To carry out a thorough examination of the activities and specificities of these dinucleotides, a robust method of synthesis was developed to allow manipulation of either nucleoside of the dinucleotide as well as the phosphate chain lengths. Adenosine containing dinucleotides exhibit some level of activity on P2Y(1) while uridine containing dinucleotides have some level of agonist response on P2Y(2) and P2Y(6). The length of the linking phosphate chain determines a different specificity; diphosphates are most accurately mimicked by dinucleoside triphosphates and triphosphates most resemble dinucleoside tetraphosphates. The pharmacological activities and relative metabolic stabilities of these dinucleotides are reported with their potential therapeutic applications being discussed.
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