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Nature Sep 2023Disruption of the lung endothelial-epithelial cell barrier following respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises...
Disruption of the lung endothelial-epithelial cell barrier following respiratory virus infection causes cell and fluid accumulation in the air spaces and compromises vital gas exchange function. Endothelial dysfunction can exacerbate tissue damage, yet it is unclear whether the lung endothelium promotes host resistance against viral pathogens. Here we show that the environmental sensor aryl hydrocarbon receptor (AHR) is highly active in lung endothelial cells and protects against influenza-induced lung vascular leakage. Loss of AHR in endothelia exacerbates lung damage and promotes the infiltration of red blood cells and leukocytes into alveolar air spaces. Moreover, barrier protection is compromised and host susceptibility to secondary bacterial infections is increased when endothelial AHR is missing. AHR engages tissue-protective transcriptional networks in endothelia, including the vasoactive apelin-APJ peptide system, to prevent a dysplastic and apoptotic response in airway epithelial cells. Finally, we show that protective AHR signalling in lung endothelial cells is dampened by the infection itself. Maintenance of protective AHR function requires a diet enriched in naturally occurring AHR ligands, which activate disease tolerance pathways in lung endothelia to prevent tissue damage. Our findings demonstrate the importance of endothelial function in lung barrier immunity. We identify a gut-lung axis that affects lung damage following encounters with viral pathogens, linking dietary composition and intake to host fitness and inter-individual variations in disease outcome.
Topics: Animals; Humans; Mice; Apelin; Diet; Endothelial Cells; Endothelium; Epithelial Cells; Erythrocytes; Influenza, Human; Intestines; Leukocytes; Ligands; Lung; Orthomyxoviridae Infections; Pulmonary Alveoli; Receptors, Aryl Hydrocarbon
PubMed: 37587341
DOI: 10.1038/s41586-023-06287-y -
Nature Communications Nov 2022Type 2 diabetes mellitus is one of the most prevalent metabolic diseases presenting with systemic pathologies, including reproductive disorders in male diabetic...
Type 2 diabetes mellitus is one of the most prevalent metabolic diseases presenting with systemic pathologies, including reproductive disorders in male diabetic patients. However, the molecular mechanisms that contributing to spermatogenesis dysfunction in diabetic patients have not yet been fully elucidated. Here, we perform STRT-seq to examine the transcriptome of diabetic patients' testes at single-cell resolution including all major cell types of the testis. Intriguingly, whereas spermatogenesis appears largely preserved, the gene expression profiles of Sertoli cells and the blood-testis barrier (BTB) structure are dramatically impaired. Among these deregulate pathways, the Apelin (APLN) peptide/Apelin-receptor (APJ) axis is hyper-activated in diabetic patients' testes. Mechanistically, APLN is produced locally by Sertoli cells upon high glucose treatment, which subsequently suppress the production of carnitine and repress the expression of cell adhesion genes in Sertoli cells. Together, these effects culminate in BTB structural dysfunction. Finally, using the small molecule APLN receptor antagonist, ML221, we show that blocking APLN/APJ significantly ameliorate the BTB damage and, importantly, improve functional spermatogenesis in diabetic db/db mice. We also translate and validate these findings in cultured human testes. Our findings identify the APLN/APJ axis as a promising therapeutic target to improve reproduction capacity in male diabetic patients.
Topics: Animals; Humans; Male; Mice; Apelin; Apelin Receptors; Blood-Testis Barrier; Diabetes Mellitus, Type 2; Spermatogenesis; Testis
PubMed: 36443325
DOI: 10.1038/s41467-022-34990-3 -
International Immunopharmacology Aug 2022Apelin, an endogenous ligand for the G protein-coupled receptor (APJ), is widely distributed within the central nervous system and diverse organs in human and animals.... (Review)
Review
Apelin, an endogenous ligand for the G protein-coupled receptor (APJ), is widely distributed within the central nervous system and diverse organs in human and animals. Recent studies indicate that the apelin/APJ system plays an important role in physiological and pathophysiological situations. Apelin/APJ could inhibit inflammatory response by down-regulation of the nuclear factor-κB (NF-κB) pathway and by up-regulation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway etc. Basic and preliminary research demonstrated that apelin/APJ system was involved in multiple diseases such as cardiovascular system diseases, liver and kidney diseases, neurological diseases, inflammatory intestinal diseases, pancreatitis, lung injury, aging, and obesity. Further, deficiency or overabundance of apelin can aggravate disease states in that inflammation is not only an important physiologic defense mechanism but also a potential mediator of organ damage. In this review, we summarize recent apelin/APJ system research progress with emphasis on the influence of the system on inflammation. Further, the mechanistic basis by which apelin regulates various inflammation-related diseases is analyzed. Finally, apelin and APJ might be presented as potential therapeutic targets for treatment of diseases mediated or exacerbated by inflammation.
Topics: Animals; Apelin; Apelin Receptors; Inflammation; Ligands; Receptors, G-Protein-Coupled
PubMed: 35605524
DOI: 10.1016/j.intimp.2022.108822 -
Cell Stem Cell Dec 2019Radiotherapy and chemotherapy disrupt bone vasculature, but the underlying causes and mechanisms enabling vessel regeneration after bone marrow (BM) transplantation...
Radiotherapy and chemotherapy disrupt bone vasculature, but the underlying causes and mechanisms enabling vessel regeneration after bone marrow (BM) transplantation remain poorly understood. Here, we show that loss of hematopoietic cells per se, in response to irradiation and other treatments, triggers vessel dilation, permeability, and endothelial cell (EC) proliferation. We further identify a small subpopulation of Apelin-expressing (Apln) ECs, representing 0.003% of BM cells, that is critical for physiological homeostasis and transplant-induced BM regeneration. Genetic ablation of Apln ECs or Apln-CreER-mediated deletion of Kitl and Vegfr2 disrupt hematopoietic stem cell (HSC) maintenance and contributions to regeneration. Consistently, the fraction of Apln ECs increases substantially after irradiation and promotes normalization of the bone vasculature in response to VEGF-A, which is provided by transplanted hematopoietic stem and progenitor cells (HSPCs). Together, these findings reveal critical functional roles for HSPCs in maintaining vascular integrity and for Apln ECs in hematopoiesis, suggesting potential targets for improving BM transplantation.
Topics: Animals; Apelin; Bone Marrow Cells; Bone Marrow Transplantation; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Hematopoiesis; Hematopoietic Stem Cells; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Microscopy, Confocal; Proteoglycans; Stem Cell Niche; Vascular Endothelial Growth Factor A
PubMed: 31761723
DOI: 10.1016/j.stem.2019.10.006 -
International Journal of Molecular... Apr 2023The apelinergic system is a highly conserved pleiotropic system. It comprises the apelin receptor apelin peptide jejunum (APJ) and its two peptide ligands,... (Review)
Review
The apelinergic system is a highly conserved pleiotropic system. It comprises the apelin receptor apelin peptide jejunum (APJ) and its two peptide ligands, Elabela/Toddler (ELA) and apelin, which have different spatiotemporal localizations. This system has been implicated in the regulation of the adipoinsular axis, in cardiovascular and central nervous systems, in carcinogenesis, and in pregnancy in humans. During pregnancy, the apelinergic system is essential for embryo cardiogenesis and vasculogenesis and for placental development and function. It may also play a role in the initiation of labor. The apelinergic system seems to be involved in the development of placenta-related pregnancy complications, such as preeclampsia (PE) and intrauterine growth restriction, but an improvement in PE-like symptoms and birth weight has been described in murine models after the exogenous administration of apelin or ELA. Although the expression of ELA, apelin, and APJ is altered in human PE placenta, data related to their circulating levels are inconsistent. This article reviews current knowledge about the roles of the apelinergic system in pregnancy and its pathophysiological roles in placenta-related complications in pregnancy. We also discuss the challenges in translating the actors of the apelinergic system into a marker or target for therapeutic interventions in obstetrics.
Topics: Pregnancy; Female; Humans; Mice; Animals; Apelin; Placenta; Peptide Hormones; Placentation; Pre-Eclampsia
PubMed: 37175743
DOI: 10.3390/ijms24098014 -
Journal of Sport and Health Science Mar 2023This study investigates the effects of exercise training on exerkines in patients with type 2 diabetes mellitus to determine the optimal exercise prescription. (Meta-Analysis)
Meta-Analysis Review
Exercise training-induced changes in exerkine concentrations may be relevant to the metabolic control of type 2 diabetes mellitus patients: A systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
This study investigates the effects of exercise training on exerkines in patients with type 2 diabetes mellitus to determine the optimal exercise prescription.
METHODS
A systematic search for relevant studies was performed in 3 databases. Randomized controlled trials investigating the effects of exercise training on at least one of the following exerkines were included: adiponectin, apelin, brain-derived neurotrophic factor, fetuin-A, fibroblast growth factor-21, follistatin, ghrelin, interleukin (IL)-6, IL-8, IL-10, IL-15, IL-18, leptin, myostatin, omentin, resistin, retinol-binding protein 4, tumor necrosis factor-α, and visfatin.
RESULTS
Forty randomized controlled trials were selected for data extraction (n = 2160). Exercise training induces changes in adiponectin, fetuin-A, fibroblast growth factor-21, IL-6, IL-10, leptin, resistin, and tumor necrosis factor-α levels but has no significant effects on apelin, IL-18, and ghrelin compared to controls. Physical exercise training favored large and positive changes in pooled exerkines (i.e., an overall effect size calculated from several exerkines) (Hedge's g = 1.02, 95% confidence interval (95%CI): 0.76-1.28), which in turn were related to changes in glycated hemoglobin (mean difference (MD) = -0.81%, 95%CI: -0.95% to -0.67%), fasting glucose (MD = -23.43 mg/dL, 95%CI: -30.07 mg/dL to -16.80 mg/dL), waist circumference (MD = -3.04 cm, 95%CI: -4.02 cm to -2.07 cm), and body mass (MD = -1.93 kg, 95%CI: -2.00 kg to -1.86 kg). Slightly stronger effects were observed with aerobic, resistance, or high-intensity interval protocols at moderate- to vigorous-intensity and with programs longer than 24 weeks that comprise at least 3 sessions per week and more than 60 min per session.
CONCLUSION
Exercise training represents an anti-inflammatory therapy and metabolism-improving strategy with minimal side effects for patients with type 2 diabetes mellitus.
Topics: Humans; Diabetes Mellitus, Type 2; Resistin; Apelin; Leptin; Ghrelin; Interleukin-10; Interleukin-18; Adiponectin; alpha-2-HS-Glycoprotein; Tumor Necrosis Factor-alpha; Randomized Controlled Trials as Topic; Exercise; Fibroblast Growth Factors
PubMed: 36351545
DOI: 10.1016/j.jshs.2022.11.003 -
Neuropeptides Jun 2021Apelin is an endogenous ligand of G protein-coupled receptor APJ. In recent years, many studies have shown that the apelin/APJ system has neuroprotective properties,... (Review)
Review
Apelin is an endogenous ligand of G protein-coupled receptor APJ. In recent years, many studies have shown that the apelin/APJ system has neuroprotective properties, such as anti-inflammatory, anti-oxidative stress, anti-apoptosis, and regulating autophagy, blocking excitatory toxicity. Apelin/APJ system has been proven to play a role in various neurological diseases and may be a promising therapeutic target for nervous system diseases. In this paper, the neuroprotective properties of the apelin/APJ system and its role in neurologic disorders are reviewed. Further understanding of the pathophysiological effect and mechanism of the apelin/APJ system in the nervous system will help develop new therapeutic interventions for various neurological diseases.
Topics: Animals; Apelin; Apelin Receptors; Apoptosis; Autophagy; Brain Injuries, Traumatic; Epilepsy; Humans; Inflammation; Ischemic Stroke; Mental Disorders; Mice; Models, Neurological; Nervous System Diseases; Neurodegenerative Diseases; Neuroprotective Agents; Neurotoxins; Oxidative Stress; Pain Management; Peptide Fragments; Rats; Signal Transduction
PubMed: 33640616
DOI: 10.1016/j.npep.2021.102131 -
Cardiovascular Research Dec 2023Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as... (Review)
Review
Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as chronic kidney disease, obesity, and diabetes that are associated with elevated cardiovascular risk. Despite currently available treatments, there remains a huge burden of cardiovascular disease-associated morbidity for patients and healthcare systems, and newer treatments are needed. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is a broad regulator of physiology that opposes the actions of the renin-angiotensin and vasopressin systems. Activation of the apelin receptor promotes endothelium-dependent vasodilatation and inotropy, lowers blood pressure, and promotes angiogenesis. The apelin system appears to protect against arrhythmias, inhibits thrombosis, and has broad anti-inflammatory and anti-fibrotic actions. It also promotes aqueous diuresis through direct and indirect (central) effects in the kidney. Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney, and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism.
Topics: Humans; Apelin; Apelin Receptors; Cardiovascular Diseases; Cardiovascular System; Heart
PubMed: 37956047
DOI: 10.1093/cvr/cvad171 -
Northern Clinics of Istanbul 2022Apelin is a G protein-linked receptor endogenous ligand, synthesized as a 77-amino acid pre-propeptide. Increased expression of apelin is present in many cardiovascular... (Review)
Review
Apelin is a G protein-linked receptor endogenous ligand, synthesized as a 77-amino acid pre-propeptide. Increased expression of apelin is present in many cardiovascular (CV) tissues, including cardiomyocytes. It is a peripheral vasodilator and one of the most potent stimulants of ventricular contraction. Apelin may be a valuable therapeutic for both blood pressure regulation and myocardial performance. More information is needed for the CV pathophysiology of apelin. We will discuss the importance of apelin level in CV diseases in this review.
PubMed: 36199867
DOI: 10.14744/nci.2021.33427 -
Wiadomosci Lekarskie (Warsaw, Poland :... 2022Apelin is a biologically active protein encoded by the APLN gene. It was first isolated in 1998 as a ligand for the APJ receptor. It exists in several isoforms differing...
Apelin is a biologically active protein encoded by the APLN gene. It was first isolated in 1998 as a ligand for the APJ receptor. It exists in several isoforms differing in polypeptide chain length and biological activity. It is secreted by white adipose tissue, and its expression has been identified in many body tissues, including the cardiovascular system, kidneys, lungs, CNS (especially the hypothalamus, suprachiasmatic and ventricular nuclei), skeletal muscle, mammary glands, adrenal glands, ovaries, stomach, liver cells, placenta, and breast milk. However, the highest concentrations were observed in the endocardium and endothelium of vascular smooth muscle cells. In myocardial tissue, apelin has a positive inotropic effect and exerts an opposing effect to the RAA (renin-angiotensin-aldosterone) system, lowering blood pressure. Therefore, its positive role in early stages of heart failure, in patients with hypertension and ischemic heart disease is emphasized. The synthesis and secretion of apelin by adipocytes makes it possible to classify this peptide as an adipokine. Therefore, its production in adipose tissue is enhanced in obesity. Furthermore, apelin has been shown to increase cellular sensitivity to insulin and improve glucose tolerance in the onset of type 2 diabetes, and therefore appears to play a significant role in the pathogenesis of metabolic disease. An accurate assessment of the importance of apelin in cardiovascular disease requires further studies, which may contribute to the use of apelin in the treatment of heart failure.
Topics: Female; Humans; Apelin; Diabetes Mellitus, Type 2; Intercellular Signaling Peptides and Proteins; Receptors, G-Protein-Coupled; Heart Failure
PubMed: 36472288
DOI: 10.36740/WLek202210130