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      Gender Differences in the Pharmacological Actions of Pegylated Glucagon-Like Peptide-1 on Endothelial Progenitor Cells and Angiogenic Precursor Cells in a Combination of Metabolic Disorders and Lung Emphysema

      research-article
      1 , * , 1 , 2 , 1 , 3 , 1 , 1 , 4 , 1 , 1 , 1 , 5 , 5 , 1 , 5 , 1
      International Journal of Molecular Sciences
      MDPI
      gender differences, dyslipidemia, obesity, hyperglycemia, pulmonary emphysema, endothelial progenitor cells, angiogenic precursor cells, pegylated glucagon-like peptide 1, and endothelial regeneration

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          Abstract

          In clinical practice, the metabolic syndrome (MetS) is often associated with chronic obstructive pulmonary disease (COPD). Although gender differences in MetS are well documented, little is known about sex-specific differences in the pathogenesis of COPD, especially when combined with MetS. Consequently, it is not clear whether the same treatment regime has comparable efficacy in men and women diagnosed with MetS and COPD. In the present study, using sodium glutamate, lipopolysaccharide, and cigarette smoke extract, we simulated lipid metabolism disorders, obesity, hyperglycemia, and pulmonary emphysema (comorbidity) in male and female C57BL/6 mice. We assessed the gender-specific impact of lipid metabolism disorders and pulmonary emphysema on angiogenic precursor cells (endothelial progenitor cells (EPC), pericytes, vascular smooth muscle cells, cells of the lumen of the nascent vessel), as well as the biological effects of pegylated glucagon-like peptide 1 (pegGLP-1) in this experimental paradigm. Simulation of MetS/COPD comorbidity caused an accumulation of EPC (CD45 CD31 +CD34 +), pericytes, and vascular smooth muscle cells in the lungs of female mice. In contrast, the number of cells involved in the angiogenesis decreased in the lungs of male animals. PegGLP-1 had a positive effect on lipids and area under the curve (AUC), obesity, and prevented the development of pulmonary emphysema. The severity of these effects was stronger in males than in females. Furthermore, PegGLP-1 stimulated regeneration of pulmonary endothelium. At the same time, PegGLP-1 administration caused a mobilization of EPC (CD45 CD31 +CD34 +) into the bloodstream in females and migration of precursors of angiogenesis and vascular smooth muscle cells to the lungs in male animals. Gender differences in stimulatory action of pegGLP-1 on CD31 + endothelial lung cells in vitro were not observed. Based on these findings, we postulated that the cellular mechanism of in vivo regeneration of lung epithelium was at least partly gender-specific. Thus, we concluded that a pegGLP-1-based treatment regime for metabolic disorder and COPD should be further developed primarily for male patients.

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          Most cited references43

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          Haematopoietic stem cell activity and interactions with the niche

          The haematopoietic stem cell (HSC) microenvironment in the bone marrow, termed the niche, ensures haematopoietic homeostasis by controlling the proliferation, self-renewal, differentiation and migration of HSCs and progenitor cells at steady state and in response to emergencies and injury. Improved methods for HSC isolation, driven by advances in single-cell and molecular technologies, have led to a better understanding of their behaviour, heterogeneity and lineage fate, and of the niche cells and signals that regulate their function. Niche regulatory signals can be in the form of cell-bound or secreted factors and other local physical cues. A combination of technological advances in bone marrow imaging and genetic manipulation of crucial regulatory factors has enabled the identification of several candidate cell types regulating the niche, including both non-haematopoietic (e.g. perivascular mesenchymal stem and endothelial cells) and HSC-derived (e.g. megakaryocytes, macrophages and regulatory T cells), with better topographical understanding of HSC localization in the bone marrow. Here, we review advances in our understanding of HSC regulation by niches during homeostasis, ageing and malignancy, and discuss their implications for the development of therapies to rejuvenate aged HSCs or niches or to disrupt self-reinforcing malignant niches.
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            Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control

            Glucagon-like peptide-1 (GLP-1) is an incretin hormone mainly secreted from intestinal L cells in response to nutrient ingestion. GLP-1 has beneficial effects for glucose homeostasis by stimulating insulin secretion from pancreatic beta-cells, delaying gastric emptying, decreasing plasma glucagon, reducing food intake, and stimulating glucose disposal. Therefore, GLP-1-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4, which is a GLP-1 inactivating enzyme, have been developed for treatment of type 2 diabetes. In addition to glucose-lowering effects, emerging data suggests that GLP-1-based therapies also show anti-inflammatory effects in chronic inflammatory diseases including type 1 and 2 diabetes, atherosclerosis, neurodegenerative disorders, nonalcoholic steatohepatitis, diabetic nephropathy, asthma, and psoriasis. This review outlines the anti-inflammatory actions of GLP-1-based therapies on diseases associated with chronic inflammation in vivo and in vitro, and their molecular mechanisms of anti-inflammatory action.
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              Mechanisms of stem cell self-renewal.

              Self-renewal is the process by which stem cells divide to make more stem cells, perpetuating the stem cell pool throughout life. Self-renewal is division with maintenance of the undifferentiated state. This requires cell cycle control and often maintenance of multipotency or pluripotency, depending on the stem cell. Self-renewal programs involve networks that balance proto-oncogenes (promoting self-renewal), gate-keeping tumor suppressors (limiting self-renewal), and care-taking tumor suppressors (maintaining genomic integrity). These cell-intrinsic mechanisms are regulated by cell-extrinsic signals from the niche, the microenvironment that maintains stem cells and regulates their function in tissues. In response to changing tissue demands, stem cells undergo changes in cell cycle status and developmental potential over time, requiring different self-renewal programs at different stages of life. Reduced stem cell function and tissue regenerative capacity during aging are caused by changes in self-renewal programs that augment tumor suppression. Cancer arises from mutations that inappropriately activate self-renewal programs.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                30 October 2019
                November 2019
                : 20
                : 21
                : 5414
                Affiliations
                [1 ]Laboratory of Regenerative Pharmacology, Goldberg ED Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Centre of the Russian Academy of Sciences, 634028 Tomsk, Russia; angelinapakhomova2011@ 123456gmail.com (A.V.P.); nejela@ 123456mail.ru (N.N.E.); artifexpan@ 123456gmail.com (E.S.P.); vakrupin88@ 123456gmail.com (V.A.K.); olesya.putrova@ 123456mail.ru (O.D.P.); ermolaeva_la@ 123456mail.ru (L.A.S.); irinakuro4kina93@ 123456yandex.ru (I.V.K.); amdygay@ 123456gmail.com (A.M.D.); eskurihin@ 123456inbox.ru (E.G.S.)
                [2 ]Stem Cell Biology and Regenerative Medicine Group, School of Pharmacy, University of Reading, Whiteknights campus, Reading RG6 6AP, UK; d.widera@ 123456reading.ac.uk
                [3 ]Branch Federal State Unitary Enterprise “Scientific and Production Association for Immunological Preparations “Microgen” of Ministry of Health of the Russian Federation “SIC “Virion” in Tomsk, 634040 Tomsk, Russia; a.a.epanchintsev@ 123456gmail.com
                [4 ]Department of Pharmacology, Siberian State Medical University, 634050 Tomsk, Russia; vaizova@ 123456mail.ru
                [5 ]Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia; biopharm@ 123456list.ru (S.G.M.); niiopp@ 123456mail.ru (A.A.K.)
                Author notes
                [* ]Correspondence: ovpershina@ 123456gmail.com ; Tel.: +7-3822-418-375
                Author information
                https://orcid.org/0000-0002-0468-0272
                https://orcid.org/0000-0003-0725-1323
                https://orcid.org/0000-0003-1686-130X
                https://orcid.org/0000-0003-4083-976X
                Article
                ijms-20-05414
                10.3390/ijms20215414
                6862381
                31671663
                d88fa460-dd42-470e-af1f-22f0339a6318
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 23 September 2019
                : 27 October 2019
                Categories
                Article

                Molecular biology
                gender differences,dyslipidemia,obesity,hyperglycemia,pulmonary emphysema,endothelial progenitor cells,angiogenic precursor cells,pegylated glucagon-like peptide 1,and endothelial regeneration

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