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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 -
Nature Aug 2017Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic...
Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR-Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8 T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8 T cells with the resistance or non-responsiveness of cancer to immunotherapies.
Topics: Adoptive Transfer; Animals; Antigen Presentation; Apelin; Apelin Receptors; CRISPR-Cas Systems; Cell Line, Tumor; Female; Genes, Essential; Genome; Histocompatibility Antigens Class I; Humans; Immunotherapy; Interferon-gamma; Janus Kinase 1; Knowledge Bases; Melanoma; Mice; Mutation; Neoplasms; Reproducibility of Results; T-Lymphocytes, Cytotoxic
PubMed: 28783722
DOI: 10.1038/nature23477 -
Frontiers in Endocrinology 2021Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. Experimental data performed in rodents... (Review)
Review
Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. Experimental data performed in rodents have shown that apelin has an aquaretic effect its central and renal actions. In the brain, apelin inhibits the phasic electrical activity of vasopressinergic neurons and the release of vasopressin from the posterior pituitary into the bloodstream and in the kidney, apelin regulates renal microcirculation and counteracts in the collecting duct, the antidiuretic effect of vasopressin occurring the vasopressin receptor type 2. In humans and rodents, if plasma osmolality is increased by hypertonic saline infusion/water deprivation or decreased by water loading, plasma vasopressin and apelin are conversely regulated to maintain body fluid homeostasis. In patients with the syndrome of inappropriate antidiuresis, in which vasopressin hypersecretion leads to hyponatremia, the balance between apelin and vasopressin is significantly altered. In order to re-establish the correct balance, a metabolically stable apelin-17 analog, LIT01-196, was developed, to overcome the problem of the very short half-life (in the minute range) of apelin In a rat experimental model of vasopressin-induced hyponatremia, subcutaneously (.) administered LIT01-196 blocks the antidiuretic effect of vasopressin and the vasopressin-induced increase in urinary osmolality, and induces a progressive improvement in hyponatremia, suggesting that apelin receptor activation constitutes an original approach for hyponatremia treatment.
Topics: Apelin; Apelin Receptors; Brain; Humans; Neurons; Vasopressins; Water-Electrolyte Balance
PubMed: 34880830
DOI: 10.3389/fendo.2021.735515 -
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 -
Frontiers in Endocrinology 2022Nowadays, diabetes and obesity are two main health-threatening metabolic disorders in the world, which increase the risk for many chronic diseases. Apelin, a peptide... (Review)
Review
Nowadays, diabetes and obesity are two main health-threatening metabolic disorders in the world, which increase the risk for many chronic diseases. Apelin, a peptide hormone, exerts its effect by binding with angiotensin II protein J receptor (APJ) and is considered to be linked with diabetes and obesity. Apelin and its receptor are widely present in the body and are involved in many physiological processes, such as glucose and lipid metabolism, homeostasis, endocrine response to stress, and angiogenesis. In this review, we summarize the literatures on the role of the Apelin-APJ system in diabetes and obesity for a better understanding of the mechanism and function of apelin and its receptor in the pathophysiology of diseases that may contribute to the development of new therapies.
Topics: Apelin; Apelin Receptors; Diabetes Mellitus, Type 2; Humans; Intercellular Signaling Peptides and Proteins; Obesity
PubMed: 35355561
DOI: 10.3389/fendo.2022.820002 -
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 -
Biomedicine & Pharmacotherapy =... Oct 2023Apelin and Elabela (Ela) are peptides encoded by APLN and APELA, respectively, which act on their receptor APJ and play crucial roles in the body. Recent research has... (Review)
Review
Apelin and Elabela (Ela) are peptides encoded by APLN and APELA, respectively, which act on their receptor APJ and play crucial roles in the body. Recent research has shown that they not only have important effects on the endocrine system, but also promote vascular development and maintain the homeostasis of myocardial cells. From a molecular biology perspective, we explored the roles of Ela and apelin in the cardiovascular system and summarized the mechanisms of apelin-APJ signaling in the progression of myocardial infarction, ischemia-reperfusion injury, atherosclerosis, pulmonary arterial hypertension, preeclampsia, and congenital heart disease. Evidences indicated that apelin and Ela play important roles in cardiovascular diseases, and there are many studies focused on developing apelin, Ela, and their analogues for clinical treatments. However, the literature on the therapeutic potential of apelin, Ela and their analogues and other APJ agonists in the cardiovascular system is still limited. This review summarized the regulatory pathways of apelin/ELA-APJ axis in cardiovascular function and cardiovascular-related diseases, and the therapeutic effects of their analogues in cardiovascular diseases were also included.
Topics: Female; Humans; Pregnancy; Apelin; Apelin Receptors; Cardiovascular Diseases; Cardiovascular System; Peptide Hormones; Signal Transduction
PubMed: 37562237
DOI: 10.1016/j.biopha.2023.115268 -
Comprehensive Physiology Dec 2017Apelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G-protein-coupled receptor named the apelin receptor (AR/APJ/APLNR). Ligand-AR interactions... (Review)
Review
Apelin and apela (ELABELA/ELA/Toddler) are two peptide ligands for a class A G-protein-coupled receptor named the apelin receptor (AR/APJ/APLNR). Ligand-AR interactions have been implicated in regulation of the adipoinsular axis, cardiovascular system, and central nervous system alongside pathological processes. Each ligand may be processed into a variety of bioactive isoforms endogenously, with apelin ranging from 13 to 55 amino acids and apela from 11 to 32, typically being cleaved C-terminal to dibasic proprotein convertase cleavage sites. The C-terminal region of the respective precursor protein is retained and is responsible for receptor binding and subsequent activation. Interestingly, both apelin and apela exhibit isoform-dependent variability in potency and efficacy under various physiological and pathological conditions, but most studies focus on a single isoform. Biophysical behavior and structural properties of apelin and apela isoforms show strong correlations with functional studies, with key motifs now well determined for apelin. Unlike its ligands, the AR has been relatively difficult to characterize by biophysical techniques, with most characterization to date being focused on effects of mutagenesis. This situation may improve following a recently reported AR crystal structure, but there are still barriers to overcome in terms of comprehensive biophysical study. In this review, we summarize the three components of the apelinergic system in terms of structure-function correlation, with a particular focus on isoform-dependent properties, underlining the potential for regulation of the system through multiple endogenous ligands and isoforms, isoform-dependent pharmacological properties, and biological membrane-mediated receptor interaction. © 2018 American Physiological Society. Compr Physiol 8:407-450, 2018.
Topics: Amino Acid Sequence; Apelin; Crystallization; Humans; Molecular Structure; Peptide Hormones; Structure-Activity Relationship
PubMed: 29357134
DOI: 10.1002/cphy.c170028 -
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