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Molecular Medicine Reports Jun 2024Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co‑morbidities, including type‑2 diabetes mellitus (T2DM),... (Review)
Review
Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options (Review).
Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co‑morbidities, including type‑2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non‑alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro‑inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro‑inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low‑grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low‑grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti‑inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein‑1, and/or the blockade of pro‑inflammatory mediators, such as IL‑1β, TNF‑α, visfatin, and plasminogen activator inhibitor‑1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity‑associated metabolic dysfunction.
Topics: Humans; Obesity; Metabolic Syndrome; Inflammation; Insulin Resistance; Adipokines; Adipose Tissue; Diabetes Mellitus, Type 2; Inflammation Mediators
PubMed: 38606791
DOI: 10.3892/mmr.2024.13219 -
Arteriosclerosis, Thrombosis, and... Jun 2024CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary...
BACKGROUND
CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of expression in endothelial cells.
METHODS
To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene , we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells.
RESULTS
We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a decrease in cell proliferation, tube formation, and NO production.
CONCLUSIONS
Overall, our results demonstrate the existence of an endothelial-specific HSF (heat shock factor)-regulated transcriptional enhancer that mediates expression. A better understanding of gene regulation and the role of single-nucleotide polymorphisms in the modulation of expression could provide important steps toward understanding the genetic regulation of shear stress signaling responses.
Topics: Humans; Polymorphism, Single Nucleotide; Endothelial Cells; Coronary Artery Disease; Stress, Mechanical; Calcitonin Receptor-Like Protein; Enhancer Elements, Genetic; Heat Shock Transcription Factors; Mechanotransduction, Cellular; Cells, Cultured; Gene Expression Regulation; Protein Binding; Genetic Predisposition to Disease; Binding Sites
PubMed: 38602103
DOI: 10.1161/ATVBAHA.123.318964 -
Nature Communications Apr 2024Formation of organo-typical vascular networks requires cross-talk between differentiating parenchymal cells and developing blood vessels. Here we identify a Vegfa driven...
Formation of organo-typical vascular networks requires cross-talk between differentiating parenchymal cells and developing blood vessels. Here we identify a Vegfa driven venous sprouting process involving parenchymal to vein cross-talk regulating venous endothelial Vegfa signaling strength and subsequent formation of a specialized angiogenic cell, prefabricated with an intact lumen and pericyte coverage, termed L-Tip cell. L-Tip cell selection in the venous domain requires genetic interaction between vascular Aplnra and Kdrl in a subset of venous endothelial cells and exposure to parenchymal derived Vegfa and Apelin. Parenchymal Esm1 controls the spatial positioning of venous sprouting by fine-tuning local Vegfa availability. These findings may provide a conceptual framework for understanding how Vegfa generates organo-typical vascular networks based on the selection of competent endothelial cells, induced via spatio-temporal control of endothelial Kdrl signaling strength involving multiple parenchymal derived cues generated in a tissue dependent metabolic context.
Topics: Angiogenesis; Endothelial Cells; Neovascularization, Physiologic; Veins
PubMed: 38600061
DOI: 10.1038/s41467-024-47434-x -
Experimental and Therapeutic Medicine May 2024The complex manifestation of diabetic hearing loss and the relative inaccessibility of the inner ear contribute to the lack of research. The present study aimed to...
The complex manifestation of diabetic hearing loss and the relative inaccessibility of the inner ear contribute to the lack of research. The present study aimed to reveal the role of Apelin-13, a critical regulator of lipid metabolism, in diabetes-induced hearing loss. Cochlear hair cells treated with high glucose (HG) were adopted as an research model, and the impacts of Apelin-13 on cellular oxidative stress, apoptosis, mitochondrial dysfunction and endoplasmic reticulum (ER) stress were determined. In addition, cells were treated with the ER stress agonist tunicamycin to further explore its potential role in the regulatory effects of Apelin-13. Apelin-13 inhibited oxidative stress and apoptosis in the HG-induced cells. Additionally, Apelin-13 elevated mitochondrial membrane potential and ATP production, whereas it reduced mitochondrial reactive oxygen species levels. The levels of ER stress-related proteins exhibited a downward trend in response to Apelin-13. By contrast, tunicamycin reversed the effects of Apelin-13 on the aforementioned aspects, suggesting the role of ER stress in the regulatory effects of Apelin-13. In conclusion, the present study elucidated the protective role of Apelin-13 in ameliorating HG-induced mitochondrial functional impairment in cochlear hair cells by inhibiting ER stress.
PubMed: 38596659
DOI: 10.3892/etm.2024.12515 -
Heliyon Apr 2024This study aimed to assess the diagnostic, risk stratification, and prognostic capabilities of apelin-13 and APJ in comparison to procalcitonin (PCT) for septic patients...
OBJECTIVES
This study aimed to assess the diagnostic, risk stratification, and prognostic capabilities of apelin-13 and APJ in comparison to procalcitonin (PCT) for septic patients presenting to the emergency department (ED).
METHODS
Two hundred and thirty-eight patients meeting the Third International Consensus Definition (Sepsis-3) criteria were enrolled from Beijing Chaoyang Hospital's ED, along with a control group of forty healthy individuals. Patients were categorized into two groups based on disease severity: those with sepsis or septic shock. Plasma levels of apelin-13, CD4 Th cells, and PCT were measured. The expression levels of plasma APJ mRNA were quantified using real-time fluorescence quantitative PCR (RT-qPCR) methodology. The Sequential Organ Failure Assessment (SOFA) score was determined at the time of enrollment. The prognostic values of apelin-13 and APJ was evaluated in comparison to that of PCT and the SOFA score. All patients were followed up for a duration of 28 days.
RESULTS
The plasma concentrations of apelin-13 and APJ exhibited a positive correlation with the severity of sepsis, while the number of CD4 T cells decreased in septic patients. The areas under the receiver operating characteristic (AUC) curves for apelin-13 and APJ in the diagnosis and prediction of 28-day mortality were greater than that of PCT. In non-survivors at the 28-day follow-up, the plasma levels of apelin-13 and APJ were significantly higher compared to survivors. Furthermore, apelin-13 levels were notably higher in cases of sepsis-induced cardiomyopathy (SICM) than in those without SICM. Apelin-13 and APJ emerged as independent predictors of 28-day mortality among septic patients.
CONCLUSIONS
Apelin-13 and APJ demonstrate value in the assessment of risk stratification, early diagnosis, and prognosis of sepsis in the ED. Apelin-13 also proves to be an effective biomarker for assessing the prognosis of SICM in the ED. Sepsis may lead to immune function suppression.
PubMed: 38590887
DOI: 10.1016/j.heliyon.2024.e28620 -
Acta Neurobiologiae Experimentalis Mar 2024Neuroinflammation is a process associated with degeneration and loss of neurons in different parts of the brain. The most important damage mechanisms in its formation...
Neuroinflammation is a process associated with degeneration and loss of neurons in different parts of the brain. The most important damage mechanisms in its formation are oxidative stress and inflammation. This study aimed to investigate the protective effects of cannabidiol (CBD) against neuroinflammation through various mechanisms. Thirty‑two female rats were randomly divided into 4 groups as control, lipopolysaccharide (LPS), LPS + CBD and CBD groups. After six hours following LPS administration, rats were sacrificed, brain and cerebellum tissues were obtained. Tissues were stained with hematoxylin‑eosin for histopathological analysis. Apelin and tyrosine hydroxylase synthesis were determined immunohistochemically. Total oxidant status and total antioxidant status levels were measured, and an oxidative stress index was calculated. Protein kinase B (AKT), brain-derived neurotrophic factor (BDNF), cyclic‑AMP response element‑binding protein (CREB) and nuclear factor erythroid 2‑related factor 2 (NRF2) mRNA expression levels were also determined. In the LPS group, hyperemia, degeneration, loss of neurons and gliosis were seen in all three tissues. Additionally, Purkinje cell loss in the cerebellum, as well as neuronal loss in the cerebral cortex and hippocampus, were found throughout the LPS group. The expressions of AKT, BDNF, CREB and NRF2, apelin and tyrosine hydroxylase synthesis all decreased significantly. CBD treatment reversed these changes and ameliorated oxidative stress parameters. CBD showed protective effects against neuroinflammation via regulating AKT, CREB, BDNF expressions, NRF2 signaling, apelin and tyrosine hydroxylase synthesis.
Topics: Female; Rats; Animals; Proto-Oncogene Proteins c-akt; Cannabidiol; Neuroprotective Agents; NF-E2-Related Factor 2; Dopamine; Apelin; Cyclic AMP Response Element-Binding Protein; Brain-Derived Neurotrophic Factor; Neuroinflammatory Diseases; Lipopolysaccharides; Tyrosine 3-Monooxygenase; Hippocampus; Gene Expression
PubMed: 38587319
DOI: 10.55782/ane-2024-2546 -
Brazilian Journal of Anesthesiology... 2024Cardiac arrest or arrhythmia caused by bupivacaine may be refractory to treatment. Apelin has been reported to directly increase the frequency of spontaneous activation...
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.min, and serial doses of apelin-13 (50, 150 and 450 μg.kg) 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.
Topics: Animals; Bupivacaine; Rats; Male; Intercellular Signaling Peptides and Proteins; Rats, Sprague-Dawley; Cardiotoxicity; Protein Kinase C; Dose-Response Relationship, Drug; Anesthetics, Local; Disease Models, Animal; NAV1.5 Voltage-Gated Sodium Channel; Receptors, G-Protein-Coupled; Apelin Receptors; Benzophenanthridines
PubMed: 38583586
DOI: 10.1016/j.bjane.2024.844501 -
International Journal of Emergency... Apr 2024Given the limited specificity of D-dimer, there is a perceived need to discover a more precise marker for diagnosing individuals who are suspected of having pulmonary...
BACKGROUND
Given the limited specificity of D-dimer, there is a perceived need to discover a more precise marker for diagnosing individuals who are suspected of having pulmonary embolism (PE). In this study, by evaluating the increase in the serum level of Apelin-13 and D-dimer, we found valuable findings about Apelin-13, which can be suggested as an auxiliary and non-invasive diagnostic biomarker in individuals with suspected PE, based on the obtained results.
METHODS
In this case-control study, 52 Iranian individuals were included, all of whom were suspected to have PE. These individuals were then divided into two groups based on the results of CT angiography, which is considered the gold standard imaging method for diagnosing PE. The two groups were patients with PE and patients without PE. Finally, the levels of certain markers in the serum were compared between the two groups.
RESULTS
The mean serum D-dimer levels in patients with PE were significantly elevated (p < 0.001) in comparison to those without PE (1102.47 to 456.2 ng/ml). Furthermore, the mean level of Apelin-13 was significantly higher in patients with PE (49.8 to 73.11 ng/L) (p < 0.001). The cutoff point of Apelin-13 has been calculated at 58.50 ng/ml, with 90.9% sensitivity and 90% specificity. The D-dimer cutoff point was 500 ng/ml, with 95.5% sensitivity and 43.3% specificity.
CONCLUSIONS
Based on the results of this study, the serum level of Apelin-13 can be used as a novel diagnostic and screening biomarker in patients with pulmonary thromboembolism.
PubMed: 38565984
DOI: 10.1186/s12245-024-00619-z -
Archives of Biochemistry and Biophysics May 2024Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN has been implicated in the development of multiple tumours. Herein, we...
Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN has been implicated in the development of multiple tumours. Herein, we determined the effect of APLN on the biological behaviour and underlying mechanisms of cervical cancer. The expression and survival curves of APLN were determined using Gene Expression Profiling Interactive Analysis. The cellular functions of APLN were detected using CCK-8, clone formation, EdU, Transwell assays, flow cytometry, and seahorse metabolic analysis. The underlying mechanisms were elucidated using gene set enrichment analysis and Western blotting. APLN was upregulated in the samples of patients with cervical cancer and is associated with poor prognosis. APLN knockdown decreased the proliferation, migration, and glycolysis of cervical cancer cells. The opposite results were observed when APLN was overexpressed. Mechanistically, we determined that APLN was critical for activating the PI3K/AKT/mTOR pathway via APLNR. APLN receptor inhibitor ML221 reversed the effect of APLN overexpression on cervical cancer cells. Treatment with LY294002, the PI3K inhibitor, drastically reversed the oncological behaviour of APLN-overexpressing C-33A cells. APLN promoted the proliferation, migration, and glycolysis of cervical cancer cells via the PI3K/AKT/mTOR pathway.
PubMed: 38561035
DOI: 10.1016/j.abb.2024.109983 -
Frontiers in Endocrinology 2024The prevalence of osteoporosis has been on the rise globally. With ageing populations, research has sought therapeutic solutions in novel areas. One such area is that of... (Review)
Review
The prevalence of osteoporosis has been on the rise globally. With ageing populations, research has sought therapeutic solutions in novel areas. One such area is that of the adipokines. Current literature points to an important role for these chemical mediators in relation to bone metabolism. Well-established adipokines have been broadly reported upon. These include adiponectin and leptin. However, other novel adipokines such as visfatin, nesfatin-1, meteorin-like protein (Metrnl), apelin and lipocalin-2 are starting to be addressed pre-clinically and clinically. Adipokines hold pro-inflammatory and anti-inflammatory properties that influence the pathophysiology of various bone diseases. Omentin-1 and vaspin, two novel adipokines, share cardioprotective effects and play essential roles in bone metabolism. Studies have reported bone-protective effects of omentin-1, whilst others report negative associations between omentin-1 and bone mineral density. Lipocalin-2 is linked to poor bone microarchitecture in mice and is even suggested to mediate osteoporosis development from prolonged disuse. Nesfatin-1, an anorexigenic adipokine, has been known to preserve bone density. Animal studies have demonstrated that nesfatin-1 treatment limits bone loss and increases bone strength, suggesting exogenous use as a potential treatment for osteopenic disorders. Pre-clinical studies have shown adipokine apelin to have a role in bone metabolism, mediated by the enhancement of osteoblast genesis and the inhibition of programmed cell death. Although many investigations have reported conflicting findings, sufficient literature supports the notion that adipokines have a significant influence on the metabolism of bone. This review aims at highlighting the role of novel adipokines in osteoporosis while also discussing their potential for treating osteoporosis.
Topics: Animals; Mice; Adipokines; Apelin; Lipocalin-2; Adiponectin; Osteoporosis; Serpins
PubMed: 38516409
DOI: 10.3389/fendo.2024.1336543