scholarly journals Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors

2020 ◽  
Vol 21 (19) ◽  
pp. 7002
Author(s):  
Christiana Magkrioti ◽  
Eleanna Kaffe ◽  
Elli-Anna Stylianaki ◽  
Camelia Sidahmet ◽  
Georgia Melagraki ◽  
...  
Keyword(s):  
In Silico ◽  
Rational Design ◽  
Inflammatory Diseases ◽  
Molecular Model ◽  
Biological Fluids ◽  
Cell Types ◽  
Phase Iii ◽  
Priority List ◽  
Model Docking ◽  
Almost All

Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids, largely responsible for extracellular lysophosphatidic acid (LPA) production. LPA is a bioactive growth-factor-like lysophospholipid that exerts pleiotropic effects in almost all cell types, exerted through at least six G-protein-coupled receptors (LPAR1-6). Increased ATX expression has been detected in different chronic inflammatory diseases, while genetic or pharmacological studies have established ATX as a promising therapeutic target, exemplified by the ongoing phase III clinical trial for idiopathic pulmonary fibrosis. In this report, we employed an in silico drug discovery workflow, aiming at the identification of structurally novel series of ATX inhibitors that would be amenable to further optimization. Towards this end, a virtual screening protocol was applied involving the search into molecular databases for new small molecules potentially binding to ATX. The crystal structure of ATX in complex with a known inhibitor (HA-155) was used as a molecular model docking reference, yielding a priority list of 30 small molecule ATX inhibitors, validated by a well-established enzymatic assay of ATX activity. The two most potent, novel and structurally different compounds were further structurally optimized by deploying further in silico tools, resulting to the overall identification of six new ATX inhibitors that belong to distinct chemical classes than existing inhibitors, expanding the arsenal of chemical scaffolds and allowing further rational design.

Exosomes and cardiovascular cell–cell communication

2018 ◽  
Vol 62 (2) ◽  
pp. 193-204 ◽  
Author(s):  
Adam J. Poe ◽  
Anne A. Knowlton
Keyword(s):  
Biological Fluids ◽  
Cell Communication ◽  
Cell Types ◽  
Cardiac Cells ◽  
The Body ◽  
Biologically Active ◽  
Surrounding Tissue ◽  
Intercellular Signaling ◽  
Cardiac Damage ◽  
Almost All

Exosomes have become an important player in intercellular signaling. These lipid microvesicles can stably transfer miRNA, protein, and other molecules between cells and circulate throughout the body. Exosomes are released by almost all cell types and are present in most if not all biological fluids. The biologically active cargo carried by exosomes can alter the phenotype of recipient cells. Exosomes increasingly are recognized as having an important role in the progression and treatment of cardiac disease states. Injured cardiac cells can release exosomes with important pathological effects on surrounding tissue, in addition to effecting other organs. But of equal interest is the possible benefit(s) conferred by exosomes released from stem cells for use in treatment and possible repair of cardiac damage.

scholarly journals Microvesicles in bronchoalveolar lavage as a potential biomarker of COPD.

2020 ◽  
Author(s):  
Erica Bazzan ◽  
Claudia Maria Radu ◽  
Mariaenrica Tinè ◽  
Tommaso Neri ◽  
Davide Biondini ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Lung Function ◽  
Bronchoalveolar Lavage ◽  
Inflammatory Diseases ◽  
Biological Fluids ◽  
Cell Communication ◽  
Communication Tools ◽  
Inflammatory Signals ◽  
Potential Biomarker ◽  
Almost All

Background. Microvesicles (MVs) released from almost all cells are recognized as cell communication tools. MVs have been investigated in several inflammatory diseases but poorly in biological fluids like bronchoalveolar lavage (BAL) of smokers. Aims. The purpose of this study was to investigate the presence and source of MVs in BAL of smokers with and without COPD compared to non-smoking controls. Methods and Results. Using flow-cytometry in BAL we detected endothelial and Alveolar Macrophage (AM)-derived MVs, and found a higher number of AM-MVs in the BAL of smokers with COPD than in smokers without COPD and non-smokers, which correlated with the pack-years (r=0.46; p=0.05) and with the degree of airway obstruction measured by the FEV1 % predicted (r= -0.56; p=0.01). Conclusion. Endothelial and Alveolar Macrophages-derived MVs are present and measurable in human BAL fluid. In response to smoking and to the development of COPD, inflammatory signals in AM-derived MVs can be quantified, and their numbers are related to the pack-years and the decrease in lung function. These results open the opportunity for future investigation of these microvesicles as biomarkers and possible mechanistic guides in COPD.

scholarly journals Exosomes and Micro-RNAs in Aging Process

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 968
Author(s):  
Yousra Hamdan ◽  
Loubna Mazini ◽  
Gabriel Malka
Keyword(s):  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Biological Fluids ◽  
Cell Types ◽  
Exosome Biogenesis ◽  
Age Related ◽  
Micro Rnas ◽  
Underlying Mechanisms ◽  
Almost All

Exosomes are the main actors of intercellular communications and have gained great interest in the new cell-free regenerative medicine. These nanoparticles are secreted by almost all cell types and contain lipids, cytokines, growth factors, messenger RNA, and different non-coding RNA, especially micro-RNAs (mi-RNAs). Exosomes’ cargo is released in the neighboring microenvironment but is also expected to act on distant tissues or organs. Different biological processes such as cell development, growth and repair, senescence, migration, immunomodulation, and aging, among others, are mediated by exosomes and principally exosome-derived mi-RNAs. Moreover, their therapeutic potential has been proved and reinforced by their use as biomarkers for disease diagnostics and progression. Evidence has increasingly shown that exosome-derived mi-RNAs are key regulators of age-related diseases, and their involvement in longevity is becoming a promising issue. For instance, mi-RNAs such as mi-RNA-21, mi-RNA-29, and mi-RNA-34 modulate tissue functionality and regeneration by targeting different tissues and involving different pathways but might also interfere with long life expectancy. Human mi-RNAs profiling is effectively related to the biological fluids that are reported differently between young and old individuals. However, their underlying mechanisms modulating cell senescence and aging are still not fully understood, and little was reported on the involvement of mi-RNAs in cell or tissue longevity. In this review, we summarize exosome biogenesis and mi-RNA synthesis and loading mechanism into exosomes’ cargo. Additionally, we highlight the molecular mechanisms of exosomes and exosome-derived mi-RNA regulation in the different aging processes.

scholarly journals sICAM-1 intrathecal synthesis and release during the acute phase in children suffering from Coxsackie A9 and S. pneumoniae meningoencephalitis

2008 ◽  
Vol 66 (3a) ◽  
pp. 504-508 ◽  
Author(s):  
Alberto J. Dorta-Contreras ◽  
Piotr Lewczuk ◽  
Bárbara Padilla-Docal ◽  
Elena Noris-García ◽  
Raisa Bu Coifiu-Fanego ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Inflammatory Diseases ◽  
Biological Fluids ◽  
Cell Types ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Immunoglobulin Superfamily ◽  
Intercellular Adhesion Molecule 1 ◽  
Cns Inflammation ◽  
Subarachnoidal Space

The intercellular adhesion molecule is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. Serum and cerebrospinal fluid (CSF) soluble intercellular adhesion molecule 1 (sICAM-1) from normal control children as well as from children with Guillain-Barré syndrome (GBS), with Coxsackie A9 virus meningoencephalitis and with Streptococcus pneumoniae meningoencephalitis were studied. sICAM-1 was quantified using an immunoenzimatic assay and albumin using the immunodiffusion technique in both biological fluids. Increased sICAM-1 values in CSF in patients with GBS correspond to an increase of the albumin CSF/serum quotient. In contrast, in inflammatory diseases like S. pneumoniae and Coxsackie A9 virus meningoencephalitis an increased brain-derived fraction was observed. In particular cases these values are 60-65% and 70-75% respectively. The results indicate an additional synthesis of sICAM-1 in subarachnoidal space during central nervous system (CNS) inflammatory process. An important role of sICAM-1 in the transmigration of different cell types into CSF during CNS inflammation in children with S. pneumoniae and Coxsackie A9 meningoencephalitis may be suggested.

scholarly journals Exosomal MiRNAs in Pediatric Cancers

2019 ◽  
Vol 20 (18) ◽  
pp. 4600 ◽  
Author(s):  
Angela Galardi ◽  
Marta Colletti ◽  
Virginia Di Paolo ◽  
Patrizia Vitullo ◽  
Loretta Antonetti ◽  
...  
Keyword(s):  
Biological Fluids ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Aberrant Expression ◽  
Pediatric Cancers ◽  
Exosomal Mirnas ◽  
Rhabdoid Tumors ◽  
Almost All ◽  
Invasive Techniques ◽  
Different Cell Types

MicroRNAs (miRNAs) have generated great attention in oncology as they play a fundamental role in the regulation of gene expression and their aberrant expression is present in almost all types of tumors including pediatric ones. The discovery that miRNAs can be transported by exosomes, which are vesicles of 40–120 nm involved in cellular communication, that are produced by different cell types, and that are present in different biological fluids, has opened the possibility of using exosomal miRNAs as biomarkers. The possibility to diagnose and monitor the progression and response to drugs through molecules that can be easily isolated from biological fluids represents a particularly important aspect in the pediatric context where invasive techniques are often used. In recent years, the idea of liquid biopsy as well as studies on the possible role of exosomal miRNAs as biomarkers have developed greatly. In this review, we report an overview of all the evidences acquired in recent years on the identification of exosomal microRNAs with biomarker potential in pediatric cancers. We discuss the following herein: neuroblastoma, hepatoblastoma, sarcomas (osteosarcoma, Ewing’s sarcoma and rhabdoid tumors, and non-rhabdomyosarcoma soft tissue sarcoma), brain tumors, lymphomas, and leukemias.

scholarly journals Therapeutic Uses of Exosomes

2013 ◽  
Vol 1 (1) ◽  
Author(s):  
Zacharias E. Suntres ◽  
Milton G. Smith ◽  
Fatemeh Momen-Heravi ◽  
Jie Hu ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Biological Fluids ◽  
Membrane Vesicles ◽  
Cell Types ◽  
Practical Applications ◽  
Extracellular Milieu ◽  
Therapeutic Uses ◽  
Malignant Effusions ◽  
Culture Supernatants

Exosomes are membrane vesicles with a diameter of 40–100 nm that are secreted by many cell types into the extracellular milieu. Exosomes are found in cell culture supernatants and in different biological fluids and are known to be secreted by most cell types under normal and pathological conditions. Considerable research is focusing on the exploitation of exosomes in biological fluids for biomarkers in the diagnosis of disease. More recently, exosomes are being exploited for their therapeutic potential. Exosomes derived from dendritic cells, tumor cells, and malignant effusions demonstrate immunomodulatory functions and are able to present antigens to T-cells and stimulate antigen-specific T-cell responses. Exosomes have also been examined for their therapeutic potential in the treatment of infections such as toxoplasmosis, diphtheria, tuberculosis and atypical severe acute respiratory syndrome as well as autoimmune diseases. Attempts to find practical applications for exosomes continue to expand with the role of exosomes as a drug delivery system for the treatment of autoimmune/inflammatory diseases and cancers.

scholarly journals ATX expression from GFAP+ cells is essential for embryonic development

2020 ◽  
Author(s):  
Ioanna Sevastou ◽  
Ioanna Ninou ◽  
Vassilis Aidinis
Keyword(s):  
Embryonic Development ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Cellular Functions ◽  
Autoimmune Encephalomyelitis ◽  
Health And Disease ◽  
Genetic Deletion ◽  
Almost All ◽  
G Protein Coupled ◽  
Experimental Autoimmune

AbstractAutotaxin (ATX) is secreted by various type of cells in health and disease and catalyzes the extracellular production of lysophosphatidic acid (LPA). In turn, LPA is a bioactive lysophospholipid promoting a wide array of cellular functions through its multiple G-protein coupled receptors, differentially expressed in almost all cell types. ATX expression has been shown necessary for embryonic development and has been suggested to participate in the pathogenesis of different chronic inflammatory diseases and cancer. Deregulated ATX and LPA levels have been reported in multiple sclerosis (MS) and its experimental model, experimental autoimmune encephalomyelitis (EAE). ATX genetic deletion from macrophages and microglia (CD11b+ cells) attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in MS/EAE. In this report, increased ATX staining was localized to glial fibrillary acidic protein positive (GFAP+) cells, mostly astrocytes, in spinal cord sections from EAE mice at the peak of the disease. However, genetic deletion of ATX from GFAP+ cells resulted in embryonic lethality, suggesting a major role for ΑΤΧ expression from GFAP+ cells in embryonic development, that urges further dissection. Moreover, the re-expression of ATX from GFAP+ cells during the pathogenesis of EAE, reinforces the concept that ATX/LPA is a developmental program aberrantly reactivated upon chronic inflammation.

In the Quest for a Stable Triplet State in Small Polyaromatic Hydrocarbons : An In-Silico Tool for Rational Design and Prediction

2019 ◽  
Author(s):  
Madhumita Rano ◽  
Sumanta K Ghosh ◽  
Debashree Ghosh
Keyword(s):  
Triplet State ◽  
Small Molecules ◽  
In Silico ◽  
Qualitative Agreement ◽  
Rational Design ◽  
Polyaromatic Hydrocarbons ◽  
Spin Hamiltonian ◽  
Spin Frustration ◽  
Computationally Efficient ◽  
High Level

<div>Combining the roles of spin frustration and geometry of odd and even numbered rings in polyaromatic hydrocarbons (PAHs), we design small molecules that show exceedingly small singlet-triplet gaps and stable triplet ground states. Furthermore, a computationally efficient protocol with a model spin Hamiltonian is shown to be capable of qualitative agreement with respect to high level multireference calculations and therefore, can be used for fast molecular discovery and screening.</div>

Salivary mir-27b Expression in Oral Lichen Planus Patients: A Series of Cases and a Narrative Review of Literature

2020 ◽  
Vol 19 (31) ◽  
pp. 2816-2823 ◽  
Author(s):  
Dario Di Stasio ◽  
Laura Mosca ◽  
Alberta Lucchese ◽  
Donatella Delle Cave ◽  
Hiromichi Kawasaki ◽  
...  
Keyword(s):  
Lichen Planus ◽  
Oral Lichen Planus ◽  
Inflammatory Diseases ◽  
Biological Fluids ◽  
Critical Role ◽  
Invasive Procedure ◽  
Control Group ◽  
Study Group ◽  
Immune Functions ◽  
Oral Lichen

Background: microRNAs play a critical role in auto-immunity, cell proliferation, differentiation and cell death. miRNAs are present in all biological fluids, and their expression is essential in maintaining regular immune functions and preventing autoimmunity, whereas miRNA dysregulation may be associated with the pathogenesis of autoimmune and inflammatory diseases. Oral lichen planus (OLP) is an inflammatory disease mediated by cytotoxic T cells attack against epithelial cells. The present study aims to perform a specific microRNA expression profile through the analysis of saliva in this disease. Methods: The study group was formed by five patients (mean age 62.8±1.98 years; 3 females/2 males) affected by oral lichen planus and control group by five healthy subjects (mean age 59.8 years±2.3; 3 females/ 2 males); using a low-density microarray analysis, we recorded a total of 98 differentially expressed miRNAs in the saliva of patients with oral lichen planus compared to the control group. The validation was performed for miR-27b with qRT-PCR in all saliva samples of oral lichen planus group. Results: 89 miRNAs were up-regulated and nine down-regulated. In details, levels of miR-21, miR- 125b, miR-203 and miR15b were increased (p<0.001) in study group while levels of miR-27b were about 3.0-fold decreased compared to controls (p<0.001) of miR-27b expression in OLP saliva. QRTPCR validation confirmed the down regulation of miR-27b in all saliva samples. Conclusions: Collecting saliva samples is a non-invasive procedure and is well accepted by all patients. microRNAs can be readily isolated and identified and can represent useful biomarkers of OLP.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

Sign in / Sign up

Export Citation Format

Share Document