Letteratura scientifica selezionata sul tema "Elr+cxcl"

Medulloblastoma (MB) is the most common and aggressive paediatric brain tumour. Although the cure rate can be as high as 70%, current treatments (surgery, radio- and chemotherapy) excessively affect the patients’ quality of life. Relapses cannot be controlled by conventional or targeted treatments and are usually fatal. The strong heterogeneity of the disease (four subgroups and several subtypes) is related to innate or acquired resistance to reference treatments. Therefore, more efficient and less-toxic therapies are needed. Here, we demonstrated the efficacy of a novel inhibitor (C29) of CXCR1/2 receptors for ELR+CXCL cytokines for the treatment of childhood MB. The correlation between ELR+CXCL/CXCR1/2 expression and patient survival was determined using the R2: Genomics Analysis and Visualization platform. In vitro efficacy of C29 was evaluated by its ability to inhibit proliferation, migration, invasion, and pseudo-vessel formation of MB cell lines sensitive or resistant to radiotherapy. The growth of experimental MB obtained by MB spheroids on organotypic mouse cerebellar slices was also assayed. ELR+CXCL/CXCR1/2 levels correlated with shorter survival. C29 inhibited proliferation, clone formation, CXCL8/CXCR1/2-dependent migration, invasion, and pseudo-vessel formation by sensitive and radioresistant MB cells. C29 reduced experimental growth of MB in the ex vivo organotypic mouse model and crossed the blood–brain barrier. Targeting CXCR1/2 represents a promising therapeutic strategy for the treatment of paediatric MB in first-line treatment or after relapse following conventional therapy.

Chemokines and their receptors play important roles in the pathophysiology of many diseases by regulating the cellular migration of major inflammatory and immune players. The CXC motif chemokine subfamily is the second largest family, and it is further subdivided into ELR motif CXC (ELR+) and non-ELR motif (ELR-) CXC chemokines, which are effective chemoattractants for neutrophils and lymphocytes/monocytes, respectively. These chemokines and their receptors are expected to have a significant impact on a wide range of lung diseases, many of which have inflammatory or immunological underpinnings. As a result, manipulations of this subfamily of chemokines and their receptors using small molecular agents and other means have been explored for potential therapeutic benefit in the setting of several lung pathologies. Furthermore, encouraging preclinical data has necessitated the progression of a few of these drugs into clinical trials in order to make the most effective use of interventions in the development of viable targeted therapeutics. The current review presents the understanding of the roles of CXC ligands (CXCLs) and their cognate receptors (CXCRs) in the pathogenesis of several lung diseases such as allergic rhinitis, COPD, lung fibrosis, lung cancer, pneumonia, and tuberculosis. The potential therapeutic benefits of pharmacological or other CXCL/CXCR axis manipulations are also discussed.

Abstract Background In clear cell renal cell carcinoma (ccRCC), first-line treatment combines nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4), yielding long-term remissions but with only a 40% success rate. Our study explored the potential of enhancing ccRCC treatment by concurrently using CXCR2 inhibitors alongside immunotherapies. Methods We analyzed ELR + CXCL levels and their correlation with patient survival during immunotherapy. RCT001, a unique CXCR2 inhibitor, was examined for its mechanism of action, particularly its effects on human primary macrophages. We tested the synergistic impact of RCT001 in combination with immunotherapies in both mouse models of ccRCC and human ccRCC in the presence of human PBMC. Resuts Elevated ELR + CXCL cytokine levels were found to correlate with reduced overall survival during immunotherapy. RCT001, our optimized compound, acted as an inverse agonist, effectively inhibiting angiogenesis and reducing viability of primary ccRCC cells. It redirected M2-like macrophages without affecting M1-like macrophage polarization directed against the tumor. In mouse models, RCT001 enhanced the efficacy of anti-CTLA4 + anti-PD1 by inhibiting tumor-associated M2 macrophages and tumor-associated neutrophils. It also impacted the activation of CD4 T lymphocytes, reducing immune-tolerant lymphocytes while increasing activated natural killer and dendritic cells. Similar effectiveness was observed in human RCC tumors when RCT001 was combined with anti-PD-1 treatment. Conclusions RCT001, by inhibiting CXCR2 through its unique mechanism, effectively suppresses ccRCC cell proliferation, angiogenesis, and M2 macrophage polarization. This optimization potentiates the efficacy of immunotherapy and holds promise for significantly improving the survival prospects of metastatic ccRCC patients.

AbstractTo investigate the differential expression of tear cytokine levels among chronic Stevens–Johnson syndrome (SJS) patients to better understand the role of significantly altered cytokines in disease development. Tear samples were collected using Schirmer strips in 24 eyes of chronic SJS, 24 eyes of age and gender-matched controls, and 14 eyes of aqueous deficiency dry eye disease (DED) patients. The cytokine analysis was performed among 18 analytes which include pro-inflammatory, anti-inflammatory factors, and ELR-negative CXC chemokines. String analysis was performed for the significantly altered cytokines to understand their co-expression and role in the disease development. Additionally, a literature review was conducted to identify the signature cytokines present in chronic SJS tears. The differential expression of IL-6 (p ≤ 0.029), CXCL8/IL-8 (p ≤ 0.009), IL-1β (p ≤ 0.041), IL-2 (p ≤ 0.025), IL-10 (p ≤ 0.053), and CXCL-10 (p ≤ 0.044) were observed in chronic SJS patients and healthy controls. Whereas, IL-6 (p ≤ 0.029), CXCL8/IL-8 (p ≤ 0.058), CCL4 (p ≤ 0.056), GM-CSF (p ≤ 0.0001) IL-10 (p ≤ 0.025), and CXCL-10 (p ≤ 0.010), were differentially expressed in SJS as compared to severe DED patients. String analysis of the significantly altered cytokines revealed the involvement of several biological processes including the chronic inflammatory response, nitric oxide synthesis, angiogenesis, and cellular response to drugs. Among all the cytokines evaluated, the expression of CXCL8/IL-8 and CXCL10 levels were consistently reported in the literature. There was a differential expression of tear cytokines in SJS when compared to DED and healthy controls. The differential expression of CXCL8/IL-8 and CXCL10 was in line with existing literature and their role in chronic SJS pathogenesis merits further evaluation.

Advanced age is associated with higher risk for cardiovascular disease and poor prognosis in patients with established cardiovascular disease. Moreover, the pathophysiology underlying CAD in older individuals may be distinct from that in younger individuals. Therefore, we utilized candidate biomarker and systems biology approaches to improve our understanding of the pathogenesis and progression of CAD in older adults. We enrolled individuals who were at least 65 years of age and undergoing diagnostic cardiac catheterization. Coronary artery disease (CAD) severity was quantified in each subject via coronary angiography by calculating a CAD score. Circulating biomarkers of inflammation and mRNA expression levels in peripheral blood mononuclear cells were quantified. We identified 553 genes (FDR<7%) that correlated with CAD severity and consisted of clusters of inflammatory genes, p38 MAPK signaling genes, and leukocyte activation, consistent with a heightened inflammatory state. The enriched expression of genes related to leukocyte activation suggested that inflammation mediated by the mobilization of leukocytes impacts the CAD gene expression signature and perhaps the extent of disease. We used the functional gene expression analysis to identify candidate circulating molecules that could propagate the CAD‐associated inflammatory response through recruitment of leukocytes to the area of injury. One class of molecules known to recruit leukocytes is the ELR+‐CXCL chemokine family. One chemokine of interest was the leukocyte‐derived CXCL5 (initially described as ENA‐78) in particular due to its ability to activate p38 and its proposed role as a key mediator in the formation of a inflammatory microenvironment in cancer and tuberculosis. Therefore, we hypothesized that the CXCL5 levels would be higher in patients with obstructive CAD and with increased CAD severity. We performed the analyses on CXCL5 plasma levels and surprisingly we observed a negative association of CXCL5 levels with CAD at an odds ratio (OR) of 0.46 (95% confidence interval: 0.27 − 0.75). Controlling for known covariates including gender and statin use, the OR was not significantly affected, 0.54 (0.30 − 0.91), consistent with a protective role for CXCL5 in coronary atherosclerosis. Our data are consistent with a recent study in a mouse model of atherosclerosis that demonstrated that CXCL5 is protective in atherosclerosis by limiting foam cell accumulation at the site of injury (doi:10.1172/JCI66580). It is unclear if CXCL5 limits foam cell formation in humans, however our clinical findings are consistent with the emerging link between chemokines and foam cell formation and represents a new therapeutic target for CAD.Support or Funding Information5R01HL065619‐13 National Heart, Lung, and Blood Institute

L’angiogenèse et l’inflammation sont deux acteurs primordiaux dans le développement et la progression de nombreux cancers. Une meilleure connaissance des mécanismes cellulaires a permis l’essor des thérapies ciblées anti-angiogéniques. L’intérêt de ces thérapies ciblées anti-angiogéniques, est limité du fait de l’apparition de résistances. En parallèle de la voie du VEGF, il existe un second axe pro-angiogénique et pro-inflammatoire : la voie des CXCL-ELR+/CXCR, qui est particulièrement sollicitée dans le cancer et notamment dans le cancer du rein métastatique. Le but de cette thèse a été de développer de petites molécules originales capables d’inhiber l’interaction ligands/récepteurs (CXCL/CXCR1-2) afin d’avoir une action duale : à la fois anti-inflammatoire et anti-angiogénique. Le motif 2-aminobenzothiazinone a été choisi pour la préparation de trois familles d’inhibiteurs. Des stratégies de synthèse divergentes permettent d’obtenir les composés des deux premières familles, bien que les conditions opératoires aient nécessité une adaptation en fonction de la réactivité de chaque substrat. La dernière famille de molécules, est accessible selon une stratégie de synthèse linéaire qui comporte cependant des limitations lors de la dernière étape de cyclisation. Les évaluations biologiques des molécules obtenues ont mis en évidence un composé prometteur possédant une IC50 de 0.6 μM sur la lignée 786-O et inhibant la chimiotaxie des cellules exprimant les récepteurs CXCR1-2. Des études supplémentaires vont être effectuée pour confirmer ces résultats préliminaires encourageants afin d’envisager par la suite une campagne in vivo sur des poissons-zèbres, avec ce composé afin d’étudier sa capacité à entraver l’angiogenèse
Cancer is one of the main causes of death in the world. Angiogenesis and inflammation represent two essential hallmarks in the development and progression of tumors and are essential for the survival of the cancer cells. Better knowledge of cellular mechanisms has enabled the development of targeted anti-angiogenic therapies. However, the emergence of resistance constitutes the main limitation of these current anti-angiogenics targeted therapies, as you may know the anti-VEGF therapies. But in parallel to the VEGF pathway, another crucial pro-angiogenic and pro-inflammatory axis in cancers is required: the CXCL-ELR+/CXCR pathway, particularly in metastatic kidney cancer. The aim of this work was to develop original small organic molecules able to inhibit the ligand/receptor interaction (CXCL-ELR+ / CXCR1-2) in order to have both anti-inflammatory and anti-angiogenic activities. The 2-aminobenzothiazinone pattern was chosen for the preparation of 3 new classes of inhibitors. Divergent synthesis strategies were used to obtain the members of families 1 & 2, although the conditions have been adapted according to the reactivity of each substrate. The last family of molecules was prepared according to a linear synthesis. However, this latter strategy displayed some limitations during the cyclisation step. Thereafter, biological evaluations revealed a promising compound exhibiting an IC50 of 0.6 μM on the 786-O cell line compared with our reference molecule (IC50 = 2 μM). Other result highlighted that this compound also exerted an inhibition of the chemotaxis of cells expressing CXCR1-2 receptors. Further studies on zebrafish are planned with this compound in order to study its ability to interfere with the angiogenesis phenomenon in vivo

Le médulloblastome (MB) est la tumeur pédiatrique cérébrale la plus fréquente et la plus agressive. Malgré un traitement multimodal agressif, entraînant des effets secondaires importants, 30% des patients développent une résistance et rechutent suite à l'apparition de métastases dans les 5 ans. Les récidives ne peuvent être contrôlées par des traitements conventionnels (radio et chimiothérapie) ou ciblés (anti-angiogénique, anti-inflammatoire, anti-point de contrôle immunitaire). L'objectif de ma thèse est donc de découvrir de nouvelles cibles et stratégies thérapeutiques pertinentes pour ces patients au diagnostic ou après une rechute.Les MB sont des tumeurs très vascularisées. Le phénomène de résistance est, en partie, lié au développement de vaisseaux sanguins (angiogenèse) et lymphatiques (lymphangiogenèse) dans la tumeur, qui constituent les principales voies de dissémination métastatique. Le facteur de croissance des vaisseaux lymphatiques, le VEGFC, et ses récepteurs/co-récepteurs sont les acteurs majeurs de la lymphangiogenèse. Dans la première partie de ma thèse, j'ai montré que le VEGFC est inversement corrélé à la croissance et l'agressivité cellulaire du MB. En effet, le VEGFC diminue de manière autocrine la prolifération et la migration des cellules MB, ainsi que leur capacité à former des pseudo-vaisseaux in vitro. Les cellules résistantes à la radiothérapie présentent des niveaux élevés de VEGFC et perdent leur capacité à migrer et à former des pseudo-vaisseaux. L'irradiation réduit l'agressivité des cellules de MB par un processus dépendant du VEGFC. Les cellules surexprimant le VEGFC et les cellules résistantes à l'irradiation forment des tumeurs expérimentales plus petites chez la souris Nude. Le VEGC semble être un régulateur négatif de la croissance des MB. Ces résultats ouvrent la voie au développement de thérapies pro-VEGFC dans ces cancers.Dans la seconde partie de ma thèse, j'ai corrélé l'expression de la voie de signalisation pro-angiogénique et pro-inflammatoire ELR+CXCL/CXCR1-2 à une survie plus courte chez des patients atteints de MB. J'ai montré qu'un nouvel inhibiteur pharmacologique (C29) des récepteurs CXCR1-2 inhibe la prolifération, la migration dépendante de CXCL8/CXCR1/2, l'invasion et la formation de pseudo-vaisseaux par des cellules de MB sensibles ou résistantes à la radiothérapie. C29 réduit la croissance de MB expérimentaux dans un modèle de souris organotypique ex vivo et traverse la barrière hémato-encéphalique. Ainsi, le ciblage de CXCR1-2 représente une stratégie prometteuse pour le traitement des MB pédiatriques, en première ligne ou à la suite de rechutes.Mots-clés : médulloblastome pédiatrique, VEGFC/VEGFR, CXCR1-2, cytokines ELR+CXCL, thérapie ciblée, lymphangiogenèse, angiogenèse
Medulloblastoma (MB) is the most common and aggressive pediatric brain tumor. Despite aggressive multimodal treatment, resulting in significant side effects, 30% of patients develop resistance and relapse following the appearance of metastases within 5 years. Recurrences cannot be controlled by conventional (radio- and chemotherapy) or targeted (anti-angiogenic, anti-inflammatory, anti-immune checkpoint) treatments. The objective of my thesis is therefore to discover new targets and relevant therapeutic strategies for these patients at diagnosis or after a relapse.MBs are highly vascularized tumors. The phenomenon of resistance is, in part, linked to the development of blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels in the tumor, which constitute the main routes of metastatic dissemination. The lymphatic growth factor, VEGFC, and its receptors/co-receptors are the major players in lymphangiogenesis. In the first part of my thesis, I showed that VEGFC is inversely correlated to MB cell growth and aggressiveness. Indeed, VEGFC decreases the proliferation and migration of MB cells, as well as their ability to form pseudo-vessels in vitro, by an autocrine signalization. Cells resistant to radiotherapy show elevated levels of VEGFC and lose their ability to migrate and form pseudo-vessels. Irradiation reduces the aggressiveness of MB cells by a VEGFC-dependent process. VEGFC-overexpressing cells and radiation-resistant cells form smaller experimental tumors in nude mice. Thus, VEGC appears to be a negative regulator of MB growth. These results pave the way for the development of pro-VEGFC therapies in these cancers.In the second part of my thesis, I correlated the expression of the ELR+CXCL/CXCR1-2 pro-angiogenic and pro-inflammatory signaling pathway to shorter survival in patients with MB. I showed that a novel pharmacological inhibitor (C29) of CXCR1-2 receptors inhibits proliferation, CXCL8/CXCR1-2-dependent migration, invasion and pseudo-vessel formation by susceptible or resistant MB cells to radiotherapy. C29 reduces the growth of experimental MBs in an ex vivo organotypic mouse model and crosses the blood-brain barrier. Thus, targeting CXCR1-2 represents a promising strategy for the treatment of pediatric MB, at first line or at relapse.Key words: pediatric medulloblastoma, VEGFC/VEGFR, CXCR1-2, ELR+CXCL cytokines, targeted therapy, lymphangiogenesis, angiogenesis