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Nature Medicine Sep 2018Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the... (Randomized Controlled Trial)
Randomized Controlled Trial
Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.
Topics: Adenylate Kinase; Adolescent; Adult; Aged; Aged, 80 and over; Aging; Animals; Apelin; Apelin Receptors; Body Weight; Exercise; Humans; Kinetics; Mice, Inbred C57BL; Muscle Cells; Muscle Weakness; Muscle, Skeletal; Organelle Biogenesis; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; Regeneration; Ribosomal Protein S6 Kinases, 70-kDa; Sarcopenia; Satellite Cells, Skeletal Muscle
PubMed: 30061698
DOI: 10.1038/s41591-018-0131-6 -
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 -
Clinica Chimica Acta; International... Aug 2018Apelin, a regulatory peptide, is a ligand of the APJ receptor that belongs to the G protein-coupled receptor family. Apelin and APJ are widely distributed in the body... (Review)
Review
Apelin, a regulatory peptide, is a ligand of the APJ receptor that belongs to the G protein-coupled receptor family. Apelin and APJ are widely distributed in the body and play potential physiological roles in the cytoprotection of many internal organs. This review article summarizes information about the roles of the apelin/APJ system in neurological, metabolic, hypertension, respiratory, gastrointestinal, hepatic, kidney and cancerous diseases. It is suggested that apelin positively affects the treatment of non-cancerous diseases and may be considered as a therapeutic drug in many illnesses. However, in cancers, apelin appears as a tumour growth stimulator, and its suggested role is as a marker in the diagnosis of tumour cancers in tissues. In summary, apelin has certain therapeutic abilities and can be useful in the treatment of, e.g., insulin resistance, hypertension, etc., but it also can sometimes serve as a negative factor.
Topics: Animals; Apelin; Diagnosis; Disease; Humans; Neoplasms; Therapeutics
PubMed: 29750964
DOI: 10.1016/j.cca.2018.05.012 -
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 -
Clinica Chimica Acta; International... Jun 2016Apelin is an endogenous ligand of the apelin receptor (APJ), a seven-transmembrane G protein-coupled receptor. Apelin/APJ system has a wide tissue distribution in the... (Review)
Review
Apelin is an endogenous ligand of the apelin receptor (APJ), a seven-transmembrane G protein-coupled receptor. Apelin/APJ system has a wide tissue distribution in the brain as well as in peripheral organs including heart, lung, vessels, and adipose tissue. Apelin/APJ was involved in regulating cardiac and vascular function, heart development, and vascular smooth muscle cell proliferation. In this article, we summarize the role of apelin/APJ system on lung cancer, gastroesophageal and colonic cancer, hepatocellular carcinoma, prostate cancer, endometrial cancer, oral squamous cell carcinoma, brain cancer, and tumor neoangiogenesis. Apelin/APJ may be a potential anticancer therapeutic target.
Topics: Apelin; Apelin Receptors; Humans; Intercellular Signaling Peptides and Proteins; Neoplasms; Neovascularization, Pathologic; Receptors, G-Protein-Coupled
PubMed: 27083318
DOI: 10.1016/j.cca.2016.04.001 -
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 -
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