RESUMEN
Periodontitis is associated with numerous systemic diseases, and it has been shown that these associations are partly causal in nature. It is assumed that such interactions between periodontal and systemic diseases are also medi- ated via adipokines. Apelin, an adipokine about which there is little research in the dental field, is also produced together with its receptor in periodontal cells. The aim of this review was to summarize the currently available literature on the apelin-APJ system to better understand the pathomechanistic relationship between periodontitis and obesity and to de- termine the potential clinical relevance of apelin for diagnostics and therapy. In vitro studies suggest that apelin can en- hance bacterial-induced synthesis of proinflammatory and proteolytic molecules, indicating a significant etiopathogenic role of this adipokine. Since serum levels of apelin are elevated in diabetes and/or obesity, it is possible that such sys- temic diseases promote the development and progression of periodontitis via apelin. On the other hand, it is also conceivable that apelin from the periodontium influences such systemic diseases. Further research is needed to better understand the role of apelin in the periodontium and the entire oral cavity, but also in the interactions between periodontal and sys- temic diseases. In particular, clinical intervention studies are needed to further decipher the etiopathogenic role of apelin in periodontitis.
Asunto(s)
Apelina , Péptidos y Proteínas de Señalización Intercelular , Obesidad , Periodontitis , Humanos , Apelina/metabolismo , Obesidad/complicaciones , Receptores de Apelina/metabolismoRESUMEN
Cancer is the leading cause of death worldwide, and the number of cancer-related deaths is expected to increase. Common types of cancer include skin, breast, lung, prostate, and colorectal cancers. While clinical research has improved cancer therapies, these treatments often come with significant side effects such as chronic fatigue, hair loss, and nausea. In addition, cancer treatments can cause long-term cardiovascular complications. Doxorubicin (DOX) therapy is one example, which can lead to decreased left ventricle (LV) echocardiography (ECHO) parameters, increased oxidative stress in cellular level, and even cardiac fibrosis. The apelinergic system, specifically apelin and its receptor, together, has shown properties that could potentially protect the heart and mitigate the damages caused by DOX anti-cancer treatment. Studies have suggested that stimulating the apelinergic system may have therapeutic benefits for heart damage induced by DOX. Further research in chronic preclinical models is needed to confirm this hypothesis and understand the mechanism of action for the apelinergic system. This review aims to collect and present data on the effects of the apelinergic system on doxorubicin-induced cardiotoxicity.
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Antibióticos Antineoplásicos , Apelina , Cardiotoxicidad , Doxorrubicina , Humanos , Doxorrubicina/efectos adversos , Cardiotoxicidad/etiología , Antibióticos Antineoplásicos/efectos adversos , Apelina/metabolismo , Animales , Estrés Oxidativo/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Receptores de Apelina/metabolismoRESUMEN
Demyelination due to autoreactive T cells and inflammation in the central nervous system are principal features of multiple sclerosis (MS), a chronic and highly disabling human disease affecting brain and spinal cord. Here, we show that treatment with apelin, a secreted peptide ligand for the G protein-coupled receptor APJ/Aplnr, is protective in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Apelin reduces immune cell entry into the brain, delays the onset and reduces the severity of EAE. Apelin affects the trafficking of leukocytes through the lung by modulating the expression of cell adhesion molecules that mediate leukocyte recruitment. In addition, apelin induces the internalization and desensitization of its receptor in endothelial cells (ECs). Accordingly, protection against EAE major outcomes of apelin treatment are phenocopied by loss of APJ/Aplnr function, achieved by EC-specific gene inactivation in mice or knockdown experiments in cultured primary endothelial cells. Our findings highlight the importance of the lung-brain axis in neuroinflammation and indicate that apelin targets the transendothelial migration of immune cells into the lung during acute inflammation.
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Apelina , Encefalomielitis Autoinmune Experimental , Células Endoteliales , Leucocitos , Ratones Endogámicos C57BL , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Animales , Apelina/metabolismo , Ratones , Células Endoteliales/metabolismo , Células Endoteliales/inmunología , Leucocitos/inmunología , Leucocitos/metabolismo , Femenino , Pulmón/inmunología , Pulmón/patología , Inflamación/metabolismo , Inflamación/inmunología , Receptores de Apelina/metabolismo , Receptores de Apelina/genética , Humanos , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/inmunología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Migración Transendotelial y Transepitelial/efectos de los fármacos , Ratones Noqueados , Modelos Animales de EnfermedadRESUMEN
Apelin receptor (APJ), a member of the class A family of G protein-coupled receptor (GPCR), plays a crucial role in regulating cardiovascular and central nervous systems function. APJ influences the onset and progression of various diseases such as hypertension, atherosclerosis, and cerebral stroke, making it an important target for drug development. Our preliminary findings indicate that APJ can form homodimers, heterodimers, or even higher-order oligomers, which participate in different signaling pathways and have distinct functions compared with monomers. APJ homodimers can serve as neuroprotectors against, and provide new pharmaceutical targets for vascular dementia (VD). This review article aims to summarize the structural characteristics of APJ dimers and their roles in physiology and pathology, as well as explore their potential pharmacological applications.
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Receptores de Apelina , Multimerización de Proteína , Humanos , Receptores de Apelina/metabolismo , Receptores de Apelina/genética , Receptores de Apelina/química , Animales , Transducción de Señal , Aterosclerosis/metabolismo , Demencia Vascular/metabolismo , Demencia Vascular/patología , Hipertensión/metabolismo , Hipertensión/patologíaRESUMEN
AIMS: Polycystic ovarian syndrome (PCOS) is one of the most common (about 5-20%) reproductive disorders in women of reproductive age; it is characterized by polycystic ovaries, hyperandrogenism, and oligo/ anovulation. The levels and expression of ovarian adipokines are deregulated in the PCOS. Apelin is an adipokine that acts through its receptor (APJ) and is known to express in the various tissues including the ovary. It has also been suggested that apelin and APJ could be targeted as therapeutic adjuncts for the management of PCOS. However, no study has been conducted on the management of PCOS by targeting the apelin system. Thus, we aimed to evaluate its impact on combating PCOS-associated ovarian pathogenesis. METHODS: The current work employed a letrozole-induced-hyperandrogenism PCOS-like mice model to investigate the effects of apelin13 and APJ, antagonist ML221. The PCOS model was induced by oral administration of letrozole (1 mg/kg) for 21 days. A total of four experimental groups were made, control, PCOS control, PCOS + aplein13, and PCOS + ML221. The treatment of apelin13 and ML221 was given from day 22 for two weeks. KEY FINDINGS: The letrozole-induced PCOS-like features such as hyperandrogenism, cystic follicle, decreased corpus luteum, elevated levels of LH/FSH ratio, and up-regulation of ovarian AR expression were ameliorated by apelin13 and ML221 treatment. However, the PCOS-augmented oxidative stress and apoptosis were suppressed by apelin 13 treatments only. ML221 treatment still showed elevated oxidative stress and stimulated apoptosis as reflected by decreased antioxidant enzymes and increased active caspase3 and Bax expression. The expression of ERs was elevated in all groups except control. Furthermore, the PCOS model showed elevated expression of APJ and apelin13 treatment down-regulated its own receptor. Overall, observing the ovarian histology, corpus luteum formation, and decreased androgen levels by both apelin13 and ML221 showed ameliorative effects on the cystic ovary. SIGNIFICANCE: Despite the similar morphological observation of ovarian histology, apelin13 and ML221 exhibited opposite effects on oxidative stress and apoptosis. Therefore, apelin13 (which down-regulates APJ) and ML221 (an APJ antagonist) may have suppressed APJ signalling, which would account for our findings on the mitigation of polycystic ovarian syndrome. In conclusion, both apelin13 and ML221 mediated mitigation have different mechanisms, which need further investigation.
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Receptores de Apelina , Apelina , Letrozol , Ovario , Síndrome del Ovario Poliquístico , Letrozol/farmacología , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Animales , Femenino , Receptores de Apelina/metabolismo , Ratones , Apelina/metabolismo , Ovario/metabolismo , Ovario/patología , Ovario/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Hiperandrogenismo/metabolismo , Hiperandrogenismo/inducido químicamente , Apoptosis/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Infantile hemangiomas (IHs) are common benign vascular tumors in infants. Apelin, an endogenous cytokine, is implicated in the angiogenesis of neoplastic diseases. We aimed to explore the association between apelin and IHs, providing a foundation for clinical applications. METHODS: We identified differential expression of apelin in proliferative IHs compared to healthy controls (HCs) through bioinformatics analysis of publicly available databases and verified by Immunofluorescence. Enzyme-linked immunosorbent assay was used to quantify the serum levels of apelin and vascular endothelial growth factor (VEGF) in a cohort of 116 cases of proliferative IHs, 65 cases of capillary malformations (CMs), and 70 HCs. RESULTS: Apelin and APJ (APLNR, apelin receptor) were identified as the significantly upregulated differentially expressed genes (DEGs) in proliferative IHs. Immunofluorescence staining indicated high expression of apelin in proliferative IHs, while minimal expression in non-IH lesions. Apelin in IHs was reduced following 6 months of propranolol treatment. Serum apelin levels were significantly higher in the IH group compared to both the CM and HC groups. Moreover, apelin exhibited excellent discriminatory ability in distinguishing IHs from HCs, with an area under the curve (AUC) exceeding 0.90. A positive correlation was observed between the levels of apelin and the size of superficial IHs. The expression profiles of VEGF and apelin in IHs were found to be consistent. CONCLUSIONS: Apelin shows promise as a potential biomarker for IHs. The association between apelin and IH size, as well as its responsiveness to propranolol treatment, indicates its possible utility as a valuable indicator for the therapeutic evaluation of IHs.
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Apelina , Biomarcadores de Tumor , Humanos , Apelina/sangre , Lactante , Masculino , Femenino , Biomarcadores de Tumor/sangre , Hemangioma/sangre , Hemangioma/patología , Receptores de Apelina/sangre , Receptores de Apelina/metabolismo , Factor A de Crecimiento Endotelial Vascular/sangre , Estudios de Casos y Controles , Propranolol/uso terapéutico , Pronóstico , Recién NacidoRESUMEN
Neurodegenerative diseases, which occur when neurons begin to deteriorate, affect millions of people worldwide. These age-related disorders are becoming more common partly because the elderly population has increased in recent years. While no treatments are accessible, every year an increasing number of therapeutic and supportive options become available. Various substances that may have neuroprotective effects are currently being researched. One of them is apelin. This review aims to illustrate the results of research on the neuroprotective effect of apelin amino acid oligopeptide which binds to the apelin receptor and exhibits neuroprotective effects in the central nervous system. The collected data indicate that apelin can protect the central nervous system against injury by several mechanisms. More studies are needed to thoroughly investigate the potential neuroprotective effects of this peptide in neurodegenerative diseases and various other types of brain damage.
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Apelina , Péptidos y Proteínas de Señalización Intercelular , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Humanos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Animales , Apelina/farmacología , Apelina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/farmacología , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Receptores de Apelina/metabolismoRESUMEN
INTRODUCTION: Cardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation and the propagation of action potentials, ultimately promoting cardiac contractility. This study aimed to investigate the effects of apelin-13 in reversing cardiac suppression induced by bupivacaine in rats. METHODS: A rat model of cardiac suppression was established by a 3-min continuous intravenous infusion of bupivacaine at the rate of 5 mg.kg-1.min-1, and serial doses of apelin-13 (50, 150 and 450 µg.kg-1) were administered to rescue cardiac suppression to identify its dose-response relationship. We used F13A, an inhibitor of Angiotensin Receptor-Like 1 (APJ), and Protein Kinase C (PKC) inhibitor chelerythrine to reverse the effects of apelin-13. Moreover, the protein expressions of PKC, Nav1.5, and APJ in ventricular tissues were measured using Western blotting and immunofluorescence assay. RESULTS: Compared to the control rats, the rats subjected to continuous intravenous administration of bupivacaine had impaired hemodynamic stability. Administration of apelin-13, in a dose-dependent manner, significantly improved hemodynamic parameters in rats with bupivacaine-induced cardiac suppression (p < 0.05), and apelin-13 treatment also significantly upregulated the protein expressions of p-PKC and Nav1.5 (p < 0.05), these effects were abrogated by F13A or chelerythrine (p < 0.05). CONCLUSION: Exogenous apelin-13, at least in part, activates the PKC signaling pathway through the apelin/APJ system to improve cardiac function in a rat model of bupivacaine-induced cardiac suppression.
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Bupivacaína , Cardiotoxicidad , Péptidos y Proteínas de Señalización Intercelular , Ratas Sprague-Dawley , Animales , Bupivacaína/toxicidad , Ratas , Masculino , Péptidos y Proteínas de Señalización Intercelular/farmacología , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Cardiotoxicidad/etiología , Cardiotoxicidad/prevención & control , Proteína Quinasa C/metabolismo , Relación Dosis-Respuesta a Droga , Anestésicos Locales/farmacología , Modelos Animales de Enfermedad , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Canal de Sodio Activado por Voltaje NAV1.5/efectos de los fármacos , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Apelina , BenzofenantridinasRESUMEN
Abdominal aortic aneurysm (AAA) is a condition characterized by a pathological and progressive dilatation of the infrarenal abdominal aorta. The exploration of AAA feature genes is crucial for enhancing the prognosis of AAA patients. Microarray datasets of AAA were downloaded from the Gene Expression Omnibus database. A total of 43 upregulated differentially expressed genes (DEGs) and 32 downregulated DEGs were obtained. Function, pathway, disease, and gene set enrichment analyses were performed, in which enrichments were related to inflammation and immune response. AHR, APLNR, ITGA10 and NR2F6 were defined as feature genes via machine learning algorithms and a validation cohort, which indicated high diagnostic abilities by the receiver operating characteristic curves. The cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) method was used to quantify the proportions of immune infiltration in samples of AAA and normal tissues. We have predicted AHR, APLNR, ITGA10 and NR2F6 as feature genes of AAA. CD8 + T cells and M2 macrophages correlated with these genes may be involved in the development of AAA, which have the potential to be developed as risk predictors and immune interventions.
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Aneurisma de la Aorta Abdominal , Humanos , Receptores de Apelina , Aneurisma de la Aorta Abdominal/genética , Aorta Abdominal , Algoritmos , Aprendizaje Automático , Proteínas RepresorasRESUMEN
Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.
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Receptores de Apelina , Fármacos Cardiovasculares , Diseño de Fármacos , Receptores de Apelina/agonistas , Receptores de Apelina/química , Receptores de Apelina/ultraestructura , Microscopía por Crioelectrón , Proteínas de Unión al GTP/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Humanos , Fármacos Cardiovasculares/químicaRESUMEN
Scarring, a prevalent issue in clinical settings, is characterized by the excessive generation of extracellular matrix within the skin tissue. Among the numerous regulatory factors implicated in fibrosis across various organs, the apelin/APJ axis has emerged as a potential regulator of fibrosis. Given the shared attribute of heightened extracellular matrix production between organ fibrosis and scarring, we hypothesize that the apelin/APJ axis also plays a regulatory role in scar development. In this study, we examined the expression of apelin and APJ in scar tissue, normal skin, and fibroblasts derived from these tissues. We investigated the impact of the hypoxic microenvironment in scars on apelin/APJ expression to identify the transcription factors influencing apelin/APJ expression. Through overexpressing or knocking down apelin/APJ expression, we observed their effects on fibroblast secretion of extracellular matrix proteins. We further validated these effects in animal experiments while exploring the underlying mechanisms. Our findings demonstrated that the apelin/APJ axis is expressed in fibroblasts from keloid, hypertrophic scar, and normal skin. The regulation of apelin/APJ expression by the hypoxic environment in scars plays a significant role in hypertrophic scar and keloid development. This regulation promotes extracellular matrix secretion through upregulation of TGF-ß1 expression via the PI3K/Akt/CREB1 pathway.
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Cicatriz Hipertrófica , Queloide , Animales , Apelina/genética , Apelina/metabolismo , Receptores de Apelina/genética , Receptores de Apelina/metabolismo , Fibrosis , Queloide/metabolismo , Fosfatidilinositol 3-Quinasas , HumanosRESUMEN
In contrast to adult mammals, zebrafish display a high capacity to heal injuries and repair damage to various organs. One of the earliest responses to injury in adult zebrafish is revascularization, followed by tissue morphogenesis. Tissue vascularization entails the formation of a blood vessel plexus that remodels into arteries and veins. The mechanisms that coordinate these processes during vessel regeneration are poorly understood. Hence, investigating and identifying the factors that promote revascularization and vessel remodeling have great therapeutic potential. Here, we revealed that fin vessel remodeling critically depends on Apela peptide. We found that Apela selectively accumulated in newly formed zebrafish fin tissue and vessels. The temporal expression of Apela, Apln, and their receptor Aplnr is different during the regenerative process. While morpholino-mediated knockdown of Apela (Mo-Apela) prevented vessel remodeling, exogenous Apela peptide mediated plexus repression and the development of arteries in regenerated fins. In contrast, Apela enhanced subintestinal venous plexus formation (SIVP). The use of sunitinib completely inhibited vascular plexus formation in zebrafish, which was not prevented by exogenous application. Furthermore, Apela regulates the expression of vessel remolding-related genes including VWF, IGFPB3, ESM1, VEGFR2, Apln, and Aplnr, thereby linking Apela to the vascular plexus factor network as generated by the STRING online database. Together, our findings reveal a new role for Apela in vessel regeneration and remodeling in fin zebrafish and provide a framework for further understanding the cellular and molecular mechanisms involved in vessel regeneration.
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Hormonas Peptídicas , Pez Cebra , Animales , Aletas de Animales/metabolismo , Receptores de Apelina/metabolismo , Mamíferos/metabolismo , Hormonas Peptídicas/metabolismo , Regeneración , Remodelación Vascular , Pez Cebra/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
The apelin receptor (APJ) belongs to the member of the G protein-coupled receptor family, and expression of APJ has been reported in the different cell types of testis. The seminiferous tubules in the testis can be identified as different stages (I-XII). It has been also suggested that different factors could be expressed in stage and cell-specific manner in the seminiferous tubules. Recently, we also shown that expression of APJ is developmentally regulated in the testis from PND1 to PND42. Therefore, we analyzed the expression of APJ in the testis of adult mice by immunohistochemistry. Immunohistochemistry showed that the APJ was highly specific for the round and elongated spermatids with stage-dependent changes. The seminiferous tubules at stages I-VII showed APJ immunostaining in the spermatid steps 1-8, not steps of 13-16. The seminiferous tubules at stages IX-XII showed APJ immunostaining in the spermatid steps 9-12. These results suggested the possible role of APJ in the spermiogenesis process. The intratesticular administration of APJ antagonist, ML221 showed a few round spermatids in the seminiferous tubules and some of the tubules with complete absence of round spermatid. Overall, we present evidence that APJ expression in spermatid is dependent on the stages of the seminiferous epithelium cycle and APJ could be involved in the differentiation of round spermatid to elongated spermatid.
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Epitelio Seminífero , Testículo , Animales , Masculino , Ratones , Receptores de Apelina/metabolismo , Epitelio Seminífero/fisiología , Túbulos Seminíferos , Espermátides/metabolismoRESUMEN
Neuropathic cancer pain (NCP) is an important symptom in patients with cancer. However, significant analgesic tolerance and other side effects critically hamper the administration of morphine. Protein palmitoylation mediated by the DHHC family may be involved in the glial activation and inflammatory responses underlying organ failure. In this study, we investigated the key role of protein palmitoylation in cancer pain and sought to target palmitoylation to suppress morphine tolerance. We found that long-term use of morphine led to the accumulation of the morphine metabolite, morphine-3-glucuronide, in vivo and activated ERK1/2 and microglia to release inflammatory factors through the apelin receptor APLNR. Palmitoyltransferase ZDHHC9 was upregulated in NCP, and APLNR was palmitylated to protect it from lysosomal degradation and to maintain its stability. We also designed competitive inhibitors of APLNR palmitoylation to inhibit the development of NCP, release of inflammatory factors, and attenuation of morphine tolerance. Therefore, targeting APLNR palmitoylation in combination with morphine is a potent method for cancer pain treatment. Our data provide a basis for the future clinical use of related drugs combined with morphine for the treatment of cancer-related pain.
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Dolor en Cáncer , Neoplasias , Neuralgia , Humanos , Morfina/farmacología , Morfina/uso terapéutico , Receptores de Apelina , Dolor en Cáncer/tratamiento farmacológico , Lipoilación , Neuralgia/tratamiento farmacológico , Neoplasias/tratamiento farmacológicoRESUMEN
INTRODUCTION: Apelin is an endogenous peptide, whose expression has been shown in the hypothalamus, pituitary, and ovary; furthermore, it is also called a neuropeptide, binding to apelin receptor (APJ) for various functions. It has been suggested that the hypothalamus, pituitary, and ovarian (HPO) axis is tightly regulated and factors and functions of the HPO axis can be modulated during the estrous cycle to influence reproductive status. To the best of our knowledge, the status of apelin and its receptor, APJ has not been investigated in the HPO axis during the estrous cycle. METHODS: To explore the expression of apelin and APJ in the HPO axis of mice during the estrous cycle, mice were divided into four groups: proestrus (Pro), estrus (Est), metestrus (Met), and diestrus (Di), and apelin and APJ were checked. Further, to explore the role of apelin in gonadotropin secretion, an in vitro study of the pituitary was performed at the Pro and Est stages. RESULT: The expression apelin and APJ in the hypothalamus showed elevation during the estrous cycle of postovulatory phases, Met, and Di. The immunolocalization of apelin and APJ in the anterior pituitary showed more abundance in the Est and Di. Our in vitro results showed that gonadotropin-releasing hormone agonist stimulated luteinizing hormone secretion was suppressed by the apelin 13 peptide from the pituitary of Pro and Est phases. This suggests an inhibitory role of apelin on gonadotropin secretion. The ovary also showed conspicuous changes in the presence of apelin and APJ during the estrous cycle. The expression of apelin and APJ coincides with folliculogenesis and corpus luteum formation and the expression of the apelin system in the different cell types of the ovary suggests its cell-specific role. Previous studies also showed that apelin has a stimulatory role in ovarian steroid secretion, proliferation, and corpus luteum. CONCLUSION: Overall our results showed that the apelin system changes along the HPO axis during the estrous cycle and might have an inhibitory at level of hypothalamus and pituitary and a stimulatory role at ovarian level.
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Ovario , Enfermedades de la Hipófisis , Animales , Femenino , Ratones , Apelina/metabolismo , Receptores de Apelina/metabolismo , Ciclo Estral , Gonadotropinas/metabolismo , Ovario/metabolismoRESUMEN
Apelin, a novel endogenous ligand of the G-protein-coupled receptor APJ, is encoded by the APLN gene and can be hydrolyzed into multiple subtypes, with Apelin-13 being one of the most active subtypes of the Apelin family. Recent studies have revealed that Apelin-13 functions as an adipokine that participates in the regulation of different biological processes, such as oxidative stress, inflammation, apoptosis, and energy metabolism, thereby playing an important role in the prevention and treatment of various metabolic diseases. However, the results of recent studies on the association between Apelin-13 and various metabolic states remain controversial. Furthermore, Apelin-13 is regulated or influenced by various forms of exercise and could therefore be categorized as a new type of exercise-sensitive factor that attenuates metabolic diseases. Thus, in this review, our purpose was to focus on the relationship between Apelin-13 and related metabolic diseases and the regulation of response movements, with particular reference to the establishment of a theoretical basis for improving and treating metabolic diseases.
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Péptidos y Proteínas de Señalización Intercelular , Enfermedades Metabólicas , Humanos , Apelina/metabolismo , Receptores de Apelina/metabolismo , Enfermedades Metabólicas/tratamiento farmacológicoRESUMEN
Creation of bioactive molecules for treatment of cardiovascular diseases based on natural peptides is the focus of intensive experimental research. In the recent years, it has been established that C-terminal fragments of apelin, an endogenous ligand of the APJ receptor, reduce metabolic and functional disorders in experimental heart damage. The review presents literature data and generalized results of our own experiments on the effect of apelin-13, [Pyr]apelin-13, apelin-12, and their chemically modified analogues on the heart under normal and pathophysiological conditions in vitro and in vivo. It has been shown that the spectrum of action of apelin peptides on the damaged myocardium includes decrease in the death of cardiomyocytes from necrosis, reduction of damage to cardiomyocyte membranes, improvement in myocardial metabolic state, and decrease in formation of reactive oxygen species and lipid peroxidation products. The mechanisms of protective action of these peptides associated with activation of the APJ receptor and manifestation of antioxidant properties are discussed. The data presented in the review show promise of the molecular design of APJ receptor peptide agonists, which can serve as the basis for the development of cardioprotectors that affect the processes of free radical oxidation and metabolic adaptation.
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Enfermedades Cardiovasculares , Miocardio , Humanos , Apelina/farmacología , Apelina/metabolismo , Receptores de Apelina/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos , Enfermedades Cardiovasculares/metabolismo , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Although preterm birth is among the preventable causes of maternal and infant death, its mechanism has not yet been clarified. When evaluated in terms of the results, the psycho-social burden of mother-infant losses and the costs of rehabilitation, care, and treatment for postpartum sequelae are high. When evaluated in terms of its causes, infection/inflammation has an important place. Therefore, it is essential to understand the role of pro- and anti-inflammatory proteins in the process. In our study, apelin and apelin receptor (APJ) expression in the cervix-uterus and placental axis were evaluated at tissue and protein levels in pregnant and non-pregnant control, sham, PBS, and LPS groups in the infection model in which LPS induction was performed by midline laparotomy, in CD-1 mice. The evaluation of this axis regarding apelin and apelin receptor in the preterm birth model is new in the literature. Apelin is expressed more intensely in uterine epithelial cells than in the cervix. In the placenta, expression is more intense in the junctional zone compared to other zones. Apelin protein levels decrease significantly in the cervix and placenta whereas it increases in the uterus. While no change was observed in the expression of the apelin receptor at the tissue and protein level in the cervix and uterus, it increased in both aspects in the placenta in the invasive procedure groups. We propose that the decrease in apelin protein due to LPS in the preterm delivery model may be related to the effort to compensate for the balance deteriorated in the pro-inflammatory direction with post-transitional modification at the tissue level. The tendency of apelin to increase with pregnancy has led to the conclusion that it is necessary for a healthy pregnancy. Although the apelin receptor does not change with inflammation, it is necessary to investigate the mechanisms associated with its stress and trauma-induced increase, since it increases in the invasive procedure group.
Asunto(s)
Trabajo de Parto Prematuro , Nacimiento Prematuro , Humanos , Femenino , Embarazo , Ratones , Animales , Placenta/metabolismo , Receptores de Apelina/metabolismo , Apelina/metabolismo , Cuello del Útero/metabolismo , Lipopolisacáridos/metabolismo , Nacimiento Prematuro/metabolismo , Útero/metabolismo , Trabajo de Parto Prematuro/metabolismo , InflamaciónRESUMEN
Cancerassociated fibroblasts (CAFs) are pivotal in tumor progression. TP53deficiency in cancer cells is associated with robust stromal activation. The apelinapelin receptor (APJ) system has been implicated in suppressing fibroblasttomyofibroblast transition in nonneoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelinAPJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53wild colon cancer, HCT116, and Caco2; TP53mutant colon cancer, SW480, and DLD1; and colon fibroblasts, CCD18Co), resected human tissue samples of colorectal cancers, and immunedeficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts cocultured with p53suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJsuppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblastlike properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma and Madrelated protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJsuppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cellderived exosomes induced CAFlike properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.
Asunto(s)
Fibroblastos Asociados al Cáncer , Neoplasias del Colon , MicroARNs , Ratones , Animales , Humanos , Receptores de Apelina/genética , Receptores de Apelina/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Células CACO-2 , Apelina/genética , Apelina/metabolismo , Fibroblastos/metabolismo , MicroARNs/genética , Neoplasias del Colon/patología , Transducción de Señal , Fibroblastos Asociados al Cáncer/metabolismo , Proliferación Celular , Microambiente TumoralRESUMEN
Acute cardiac dysfunction caused by stroke-heart syndrome (SHS) is the second leading cause of stroke-related death. The inflammatory response plays a significant role in the pathophysiological process of cardiac damage. However, the mechanisms underlying the brain-heart interaction are poorly understood. Therefore, we aimed to analysis the immunological characterization and identify inflammation therapeutic targets of SHS. We analyzed gene expression data of heart tissue 24 hours after induction of ischemia stoke by MCAO or sham surgery in a publicly available dataset (GSE102558) from Gene Expression Omnibus (GEO). Bioinformatics analysis revealed 138 differentially expressed genes (DEGs) in myocardium of MCAO-treated compared with sham-treated mice, among which, immune and inflammatory pathways were enriched. Analysis of the immune cells infiltration showed that the natural killer cell populations were significantly different between the two groups. We identified five DIREGs, Aplnr, Ccrl2, Cdkn1a, Irak2, and Serpine1 and found that their expression correlated with specific populations of infiltrating immune cells in the cardiac tissue. RT-qPCR and Western blot methods confirmed significant changes in the expression levels of Aplnr, Cdkn1a, Irak2, and Serpine1 after MCAO, which may serve as therapeutic targets to prevent cardiovascular complications after stroke.