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Fonseca PADS, Suarez-Vega A, Esteban-Blanco C, Marina H, Pelayo R, Gutiérrez-Gil B, Arranz JJ. Integration of epigenomic and genomic data to predict residual feed intake and the feed conversion ratio in dairy sheep via machine learning algorithms. BMC Genomics 2025; 26:313. [PMID: 40165084 PMCID: PMC11956460 DOI: 10.1186/s12864-025-11520-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 03/24/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Feed efficiency (FE) is an essential trait in livestock species because of the constant demand to increase the productivity and sustainability of livestock production systems. A better understanding of the biological mechanisms associated with FEs might help improve the estimation and selection of superior animals. In this work, differentially methylated regions (DMRs) were identified via genome-wide bisulfite sequencing (GWBS) by comparing the DNA methylation profiles of milk somatic cells from dairy ewes that were divergent in terms of residual feed intake. The DMRs were identified by comparing divergent groups for residual feed intake (RFI), the feed conversion ratio (FCR), and the consensus between both metrics (Cons). Additionally, the predictive performance of these DMRs and genetic variants mapped within these regions was evaluated via three machine learning (ML) models (xgboost, random forest (RF), and multilayer feedforward artificial neural network (deeplearning)). The average performance of each model was based on the root mean squared error (RMSE) and squared Spearman correlation (rho2). Finally, the best model for each scenario was selected on the basis of the highest ratio between rho2 and RMSE. RESULTS In total, 12,257, 9,328, and 6,723 genes were annotated for DMRs detected in the RFI, FCR, and Cons groups, respectively. These genes are associated with important pathways for regulating FE in dairy sheep, such as protein digestion and absorption, hormone synthesis and secretion, control of energy availability, cellular signaling, and feed behavior pathways. With respect to the ML predictions, the smallest mean RMSE (0.17) was obtained using RF, which was used to predict RFI. The highest mean rho2 (0.20) was obtained when the RFI was predicted via the mean methylation within the DMRs identified, the consensus groups were compared, and the genetic variants mapped within these DMRs were included. The best overall models were obtained for the prediction of RFI using the DMRs obtained in the comparison of RFI groups (RMSE = 0.10, rho2 = 0.86) using xgboost and the DMRs plus the genetic variants identified via the Cons groups (RMSE = 0.07, rho2 = 0.62) using RF. CONCLUSIONS The results provide new insights into the biological mechanisms associated with FE and the control of these processes through epigenetic mechanisms. Additionally, the potential use of epigenetic information as a biomarker for the prediction of FE can be suggested based on the obtained results.
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Affiliation(s)
| | - Aroa Suarez-Vega
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana, Leon, 24007, Spain
| | - Cristina Esteban-Blanco
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana, Leon, 24007, Spain
| | - Héctor Marina
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana, Leon, 24007, Spain
| | - Rocío Pelayo
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana, Leon, 24007, Spain
| | - Beatriz Gutiérrez-Gil
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana, Leon, 24007, Spain
| | - Juan-José Arranz
- Departamento de Producción Animal, Facultad de Veterinaria, Universidad de León, Campus de Vegazana, Leon, 24007, Spain.
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Wagenaar GTM, Moll GN. Advances in the therapeutic potentials of ligands of the apelin receptor APJ. Eur J Pharmacol 2025; 991:177302. [PMID: 39870231 DOI: 10.1016/j.ejphar.2025.177302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 01/08/2025] [Accepted: 01/22/2025] [Indexed: 01/29/2025]
Abstract
Angiotensin II protein J receptor, APJ, is a type A G protein coupled receptor. Endogenous apelin and elabela peptides stimulate APJ via distinct signalling profiles. A complex signalling map of elabela-stimulated APJ was published in 2022. Dimerization or oligomerization of APJ with itself or other receptor(s) can affect APJ signalling. Apelin has been shown to tolerate mutations and/or modifications at multiple sites without abolishing activity. This offers a great opportunity to design and engineer variants with desired signalling profiles and enhanced resistance to breakdown by peptidases. Several biased agonists with enhanced therapeutic potential have been generated. APJ agonists have therapeutic potential in multiple diseases including cardiovascular, renal, pulmonary and metabolic diseases, and viral infections. APJ antagonists may have therapeutic potential in cancer and retinopathy, and in related diseases in which unwanted angiogenesis is to be halted. A growing understanding of APJ signalling pathways and the robust therapeutic potential of associated ligands for many serious diseases will stimulate the clinical development of APJ ligands.
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Affiliation(s)
- Gerry T M Wagenaar
- Division of VitalTissue, Multi Tissue Center ETB-BISLIFE, Jan van Krimpenweg 17, 2031 CG, Haarlem, the Netherlands
| | - Gert N Moll
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747 AG, Groningen, the Netherlands.
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Hashemi M, Mohandesi Khosroshahi E, Asadi S, Tanha M, Ghatei Mohseni F, Abdolmohammad Sagha R, Taheri E, Vazayefi P, Shekarriz H, Habibi F, Mortazi S, Khorrami R, Nabavi N, Rashidi M, Taheriazam A, Rahimzadeh P, Entezari M. Emerging roles of non-coding RNAs in modulating the PI3K/Akt pathway in cancer. Noncoding RNA Res 2025; 10:1-15. [PMID: 39296640 PMCID: PMC11406677 DOI: 10.1016/j.ncrna.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 07/25/2024] [Accepted: 08/08/2024] [Indexed: 09/21/2024] Open
Abstract
Cancer progression results from the dysregulation of molecular pathways, each with unique features that can either promote or inhibit tumor growth. The complexity of carcinogenesis makes it challenging for researchers to target all pathways in cancer therapy, emphasizing the importance of focusing on specific pathways for targeted treatment. One such pathway is the PI3K/Akt pathway, which is often overexpressed in cancer. As tumor cells progress, the expression of PI3K/Akt increases, further driving cancer advancement. This study aims to explore how ncRNAs regulate the expression of PI3K/Akt. NcRNAs are found in both the cytoplasm and nucleus, and their functions vary depending on their location. They can bind to the promoters of PI3K or Akt, either reducing or increasing their expression, thus influencing tumorigenesis. The ncRNA/PI3K/Akt axis plays a crucial role in determining cell proliferation, metastasis, epithelial-mesenchymal transition (EMT), and even chemoresistance and radioresistance in human cancers. Anti-tumor compounds can target ncRNAs to modulate the PI3K/Akt axis. Moreover, ncRNAs can regulate the PI3K/Akt pathway both directly and indirectly.
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Affiliation(s)
- Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahsa Tanha
- Department of Biological Sciences, University of Alabama, Tuscaloosa, AL, United States
| | - Forough Ghatei Mohseni
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramina Abdolmohammad Sagha
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elham Taheri
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Paria Vazayefi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Helya Shekarriz
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Habibi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shaghayegh Mortazi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ramin Khorrami
- Department of Food Hygiene and Quality Control, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Noushin Nabavi
- Independent Researchers, Victoria, British Columbia, V8V 1P7, Canada
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Payman Rahimzadeh
- Surgical Research Society (SRS), Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maliheh Entezari
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
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JUMAAH YK, FATHI ZH, MOHAMMAD JA. Comparative Effects of Candesartan Versus Enalapril on Apelin, Visfatin, and Lipid Levels in Non-obese Hypertensive Patients. Medeni Med J 2024; 39:204-210. [PMID: 39350559 PMCID: PMC11572212 DOI: 10.4274/mmj.galenos.2024.16098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/26/2024] [Indexed: 11/20/2024] Open
Abstract
Objective Apelin and visfatin are adipokines secreted from adipose tissue that play important roles in regulating blood pressure. Therefore, the current study aimed to investigate the effects of candesartan versus enalapril on apelin, visfatin, and lipid profiles in hypertensive patients. Methods In this case-control study, 120 participants were enrolled in four groups; Healthy people, newly diagnosed hypertensive patients, and enalapril- and candesartan-treated patients. Results Serum apelin levels were significantly lower and visfatin levels were significantly higher in newly diagnosed hypertensive patients compared with the control group (p=0.0015, p=0.0175 respectively). Moreover, apelin levels were higher and visfatin levels were lower in the candesartan-treated patients compared with the newly diagnosed group (p=0.0487, p<0.0001 respectively). Interestingly, apelin levels were non-significantly higher and visfatin levels were significantly lower in enalapril-treated patients compared with the newly diagnosed group (p<0.0001). Conclusions Lower apelin and higher visfatin levels are associated with newly diagnosed patients with hypertension. Interestingly, the findings suggest that ACE inhibition and angiotensin receptor blockade by enalapril and candesartan, respectively, positively regulate apelin and visfatin levels in hypertension. Specifically, candesartan regulates these adipokine to a greater extent than enalapril.
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Affiliation(s)
- Yaseen K. JUMAAH
- University of Mosul, College of Pharmacy, Department of Pharmacognosy and Medicinal Plants, Mosul, Iraq
| | - Zainab H. FATHI
- University of Mosul, College of Pharmacy, Department of Pharmacognosy and Medicinal Plants, Mosul, Iraq
| | - Jehan A. MOHAMMAD
- University of Mosul, College of Pharmacy, Department of Pharmacognosy and Medicinal Plants, Mosul, Iraq
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van Rosmalen L, Zhu J, Maier G, Gacasan EG, Lin T, Zhemchuzhnikova E, Rothenberg V, Razu S, Deota S, Ramasamy RK, Sah RL, McCulloch AD, Hut RA, Panda S. Multi-organ transcriptome atlas of a mouse model of relative energy deficiency in sport. Cell Metab 2024; 36:2015-2037.e6. [PMID: 39232281 PMCID: PMC11378950 DOI: 10.1016/j.cmet.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 04/23/2024] [Accepted: 08/06/2024] [Indexed: 09/06/2024]
Abstract
Insufficient energy intake to meet energy expenditure demands of physical activity can result in systemic neuroendocrine and metabolic abnormalities in activity-dependent anorexia and relative energy deficiency in sport (REDs). REDs affects >40% of athletes, yet the lack of underlying molecular changes has been a hurdle to have a better understanding of REDs and its treatment. To assess the molecular changes in response to energy deficiency, we implemented the "exercise-for-food" paradigm, in which food reward size is determined by wheel-running activity. By using this paradigm, we replicated several aspects of REDs in female and male mice with high physical activity and gradually reduced food intake, which results in weight loss, compromised bone health, organ-specific mass changes, and altered rest-activity patterns. By integrating transcriptomics of 19 different organs, we provide a comprehensive dataset that will guide future understanding of REDs and may provide important implications for metabolic health and (athletic) performance.
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Affiliation(s)
- Laura van Rosmalen
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Jiaoyue Zhu
- Chronobiology unit, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen 9747 AG, the Netherlands
| | - Geraldine Maier
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Erica G Gacasan
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Terry Lin
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Elena Zhemchuzhnikova
- Chronobiology unit, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen 9747 AG, the Netherlands
| | - Vince Rothenberg
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Swithin Razu
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Shaunak Deota
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Ramesh K Ramasamy
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Robert L Sah
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Andrew D McCulloch
- Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Roelof A Hut
- Chronobiology unit, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen 9747 AG, the Netherlands
| | - Satchidananda Panda
- Regulatory Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
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Ziskoven PC, Nogueira AVB, Yoldaş O, Buduneli N, Wild PS, Koeck T, Deschner J. Apelin - A New Kid on the Block in Periodontology. ORAL HEALTH & PREVENTIVE DENTISTRY 2024; 22:417-424. [PMID: 39189510 PMCID: PMC11619819 DOI: 10.3290/j.ohpd.b5695264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 07/08/2024] [Indexed: 08/28/2024]
Abstract
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.
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Affiliation(s)
- Pablo Cores Ziskoven
- Dentist, Department of Periodontology and Operative Dentistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. Study conception and design, literature search, data analysis and interpretation, prepared the original draft, edited the manuscript, visualisation, reviewed and approved the final version of the manuscript
| | - Andressa V. B. Nogueira
- Dentist, Department of Periodontology and Operative Dentistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. Study conception and design, literature search, data analysis and interpretation, prepared the original draft, edited the manuscript, visualisation, supervision, reviewed and approved the final version of the manuscript
| | - Onur Yoldaş
- Dentist, Department of Periodontology, School of Dentistry, Ege University, İzmir, Turkey. Study conception and design, literature search, prepared the original draft, edited and reviewed the manuscript, reviewed and approved the final version of the manuscript
| | - Nurcan Buduneli
- Professor, Department of Periodontology, School of Dentistry, Ege University, İzmir, Turkey. Study conception and design, literature search, prepared the original draft, edited and reviewed the manuscript, reviewed and approved the final version of the manuscript
| | - Philipp S. Wild
- Professor, Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Institute of Molecular Biology (IMB), Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany. Study conception and design, literature search, prepared the original draft, edited and reviewed the manuscript, supervision, reviewed and approved the final version of the manuscript
| | - Thomas Koeck
- Head of Targeted Proteomic Biomarker Laboratory, Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Study conception and design, literature search, prepared the original draft, edited and reviewed the manuscript, visualisation, supervision, reviewed and approved the final version of the manuscript
| | - James Deschner
- Professor, Department of Periodontology and Operative Dentistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.Study conception and design, literature search, data analysis and interpretation, prepared the original draft, edited and reviewed the manuscript, visualisation, supervision, reviewed and approved the final version of the manuscript
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Albericio G, Higuera M, Araque P, Sánchez C, Herrero D, García-Brenes MA, Formentini L, Torán JL, Mora C, Bernad A. Development of a Bmi1+ Cardiac Mouse Progenitor Immortalized Model to Unravel the Relationship with Its Protective Vascular Endothelial Niche. Int J Mol Sci 2024; 25:8815. [PMID: 39201501 PMCID: PMC11354400 DOI: 10.3390/ijms25168815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 09/02/2024] Open
Abstract
The adult mammalian heart has been demonstrated to be endowed with low but real turnover capacity, especially for cardiomyocytes, the key functional cell type. The source, however, of that turnover capacity remains controversial. In this regard, we have defined and characterized a resident multipotent cardiac mouse progenitor population, Bmi1+DR (for Bmi1+ Damage-Responsive cells). Bmi1+DR is one of the cell types with the lowest ROS (Reactive Oxygen Species) levels in the adult heart, being particularly characterized by their close relationship with cardiac vessels, most probably involved in the regulation of proliferation/maintenance of Bmi1+DR. This was proposed to work as their endothelial niche. Due to the scarcity of Bmi1+DR cells in the adult mouse heart, we have generated an immortalization/dis-immortalization model using Simian Vacuolating Virus 40-Large Antigen T (SV40-T) to facilitate their in vitro characterization. We have obtained a heterogeneous population of immortalized Bmi1+DR cells (Bmi1+DRIMM) that was validated attending to different criteria, also showing a comparable sensitivity to strong oxidative damage. Then, we concluded that the Bmi1-DRIMM population is an appropriate model for primary Bmi1+DR in vitro studies. The co-culture of Bmi1+DRIMM cells with endothelial cells protects them against oxidative damage, showing a moderate depletion in non-canonical autophagy and also contributing with a modest metabolic regulation.
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Affiliation(s)
- Guillermo Albericio
- Cardiac Stem Cells Lab, Immunology and Oncology Department, National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain; (G.A.); (M.H.); (P.A.); (J.L.T.)
- Molecular Biology Department, National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Marina Higuera
- Cardiac Stem Cells Lab, Immunology and Oncology Department, National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain; (G.A.); (M.H.); (P.A.); (J.L.T.)
| | - Paula Araque
- Cardiac Stem Cells Lab, Immunology and Oncology Department, National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain; (G.A.); (M.H.); (P.A.); (J.L.T.)
| | - Cristina Sánchez
- Molecular Biology Department, Molecular Biology Center Severo Ochoa (CBMSO), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - Diego Herrero
- Cardiac Stem Cells Lab, Immunology and Oncology Department, National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain; (G.A.); (M.H.); (P.A.); (J.L.T.)
| | - Miguel A. García-Brenes
- Cardiac Stem Cells Lab, Immunology and Oncology Department, National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain; (G.A.); (M.H.); (P.A.); (J.L.T.)
| | - Laura Formentini
- Molecular Biology Department, Molecular Biology Center Severo Ochoa (CBMSO), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain
| | - José Luis Torán
- Cardiac Stem Cells Lab, Immunology and Oncology Department, National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain; (G.A.); (M.H.); (P.A.); (J.L.T.)
| | - Carmen Mora
- Cardiac Stem Cells Lab, Immunology and Oncology Department, National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain; (G.A.); (M.H.); (P.A.); (J.L.T.)
| | - Antonio Bernad
- Cardiac Stem Cells Lab, Immunology and Oncology Department, National Center for Biotechnology (CNB-CSIC), Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain; (G.A.); (M.H.); (P.A.); (J.L.T.)
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Kilpiö T, Skarp S, Perjés Á, Swan J, Kaikkonen L, Saarimäki S, Szokodi I, Penninger JM, Szabó Z, Magga J, Kerkelä R. Apelin regulates skeletal muscle adaptation to exercise in a high-intensity interval training model. Am J Physiol Cell Physiol 2024; 326:C1437-C1450. [PMID: 38525542 DOI: 10.1152/ajpcell.00427.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 03/18/2024] [Accepted: 03/18/2024] [Indexed: 03/26/2024]
Abstract
Plasma apelin levels are reduced in aging and muscle wasting conditions. We aimed to investigate the significance of apelin signaling in cardiac and skeletal muscle responses to physiological stress. Apelin knockout (KO) and wild-type (WT) mice were subjected to high-intensity interval training (HIIT) by treadmill running. The effects of apelin on energy metabolism were studied in primary mouse skeletal muscle myotubes and cardiomyocytes. Apelin increased mitochondrial ATP production and mitochondrial coupling efficiency in myotubes and promoted the expression of mitochondrial genes both in primary myotubes and cardiomyocytes. HIIT induced mild concentric cardiac hypertrophy in WT mice, whereas eccentric growth was observed in the left ventricles of apelin KO mice. HIIT did not affect myofiber size in skeletal muscles of WT mice but decreased the myofiber size in apelin KO mice. The decrease in myofiber size resulted from a fiber type switch toward smaller slow-twitch type I fibers. The increased proportion of slow-twitch type I fibers in apelin KO mice was associated with upregulation of myosin heavy chain slow isoform expression, accompanied with upregulated expression of genes related to fatty acid transport and downregulated expression of genes related to glucose metabolism. Mechanistically, skeletal muscles of apelin KO mice showed defective induction of insulin-like growth factor-1 signaling in response to HIIT. In conclusion, apelin is required for proper skeletal and cardiac muscle adaptation to high-intensity exercise. Promoting apelinergic signaling may have benefits in aging- or disease-related muscle wasting conditions.NEW & NOTEWORTHY Apelin levels decline with age. This study demonstrates that in trained mice, apelin deficiency results in a switch from fast type II myofibers to slow oxidative type I myofibers. This is associated with a concomitant change in gene expression profile toward fatty acid utilization, indicating an aged-muscle phenotype in exercised apelin-deficient mice. These data are of importance in the design of exercise programs for aging individuals and could offer therapeutic target to maintain muscle mass.
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Affiliation(s)
- Teemu Kilpiö
- Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Sini Skarp
- Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Ábel Perjés
- Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Julia Swan
- Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Leena Kaikkonen
- Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Samu Saarimäki
- Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - István Szokodi
- Heart Institute, Medical School, and Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Josef M Penninger
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada
| | - Zoltán Szabó
- Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
| | - Johanna Magga
- Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Risto Kerkelä
- Research Unit of Biomedicine and Internal Medicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
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9
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Zhou N, Gong L, Zhang E, Wang X. Exploring exercise-driven exerkines: unraveling the regulation of metabolism and inflammation. PeerJ 2024; 12:e17267. [PMID: 38699186 PMCID: PMC11064867 DOI: 10.7717/peerj.17267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 03/28/2024] [Indexed: 05/05/2024] Open
Abstract
Exercise has many beneficial effects that provide health and metabolic benefits. Signaling molecules are released from organs and tissues in response to exercise stimuli and are widely termed exerkines, which exert influence on a multitude of intricate multi-tissue processes, such as muscle, adipose tissue, pancreas, liver, cardiovascular tissue, kidney, and bone. For the metabolic effect, exerkines regulate the metabolic homeostasis of organisms by increasing glucose uptake and improving fat synthesis. For the anti-inflammatory effect, exerkines positively influence various chronic inflammation-related diseases, such as type 2 diabetes and atherosclerosis. This review highlights the prospective contribution of exerkines in regulating metabolism, augmenting the anti-inflammatory effects, and providing additional advantages associated with exercise. Moreover, a comprehensive overview and analysis of recent advancements are provided in this review, in addition to predicting future applications used as a potential biomarker or therapeutic target to benefit patients with chronic diseases.
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Affiliation(s)
- Nihong Zhou
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing, China
- School of Sport Science, Beijing Sport University, Beijing, China
| | - Lijing Gong
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing, China
- Key Laboratory for Performance Training & Recovery of General Administration of Sport, Beijing Sport University, Beijing, China
| | - Enming Zhang
- Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Lund University, Malmö, Sweden
- NanoLund Center for NanoScience, Lund University, Lund, Sweden
| | - Xintang Wang
- Key Laboratory for Performance Training & Recovery of General Administration of Sport, Beijing Sport University, Beijing, China
- China Institute of Sport and Health Science, Beijing Sport University, Beijing, China
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10
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Wu Z, Wang Z, Wang P, Cheng L, Li J, Luo Y, Yang L, Li L, Zeng J, Hu B. Integrative analysis of proteomics and lipidomic profiles reveal the fat deposition and meat quality in Duroc × Guangdong small spotted pig. Front Vet Sci 2024; 11:1361441. [PMID: 38659450 PMCID: PMC11041638 DOI: 10.3389/fvets.2024.1361441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 02/26/2024] [Indexed: 04/26/2024] Open
Abstract
Introduction This study aims to explore the important factors affecting the characteristics of different parts of pork. Methods Lipidomics and proteomics methods were used to analyze DAL (differential lipids) and DAPs (differential proteins) in five different parts (longissimus dorsi, belly meat, loin, forelegs and buttocks) of Duhua pig (Duroc × Guangdong small spotted pig), to identify potential pathways affecting meat quality, investigating fat deposition in pork and its lipid-protein interactions. Results The results show that TG (triglyceride) is the lipid subclass with the highest proportion in muscle, and the pathway with the most significantly enriched lipids is GP. DAP clustered on several GO terms closely related to lipid metabolism and lipogenesis (lipid binding, lipid metabolism, lipid transport, and lipid regulation). In KEGG analysis, there are two main DAP aggregation pathways related to lipid metabolism, namely Fatty acid degradation and oxidative phosphorylation. In PPI analysis, we screened out 31 core proteins, among which NDUFA6, NDUFA9 and ACO2 are the most critical. Discussion PC (phosphatidylcholine) is regulated by SNX5, THBS1, ANXA7, TPP1, CAVIN2, and VDAC2 in the phospholipid binding pathway. TG is regulated by AUH/HADH/ACADM/ACADL/HADHA in the lipid oxidation and lipid modification pathways. Potential biomarkers are rich in SFA, MUFA and PUFA respectively, the amounts of SFA, MUFA and PUFA in the lipid measurement results are consistent with the up- and down-regulation of potential biomarker lipids. This study clarified the differences in protein and lipid compositions in different parts of Duhua pigs and provided data support for revealing the interactions between pork lipids and proteins. These findings provide contributions to the study of intramuscular fat deposition in pork from a genetic and nutritional perspective.
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Affiliation(s)
- Zhuosui Wu
- Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Zhonggang Wang
- Guangdong Guanghong Agriculture and Animal Husbandry Development Co, Ltd., Huizhou, China
| | - Pan Wang
- Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Leiyan Cheng
- Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Jianhao Li
- Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Yanfeng Luo
- Guangdong Yihao Foodstuff Co, Ltd., Guangzhou, China
| | - Linfang Yang
- Guangdong Yihao Foodstuff Co, Ltd., Guangzhou, China
| | - Linfeng Li
- Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Jianhua Zeng
- Guangdong Yihao Foodstuff Co, Ltd., Guangzhou, China
| | - Bin Hu
- Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
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11
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Anima B, Gurusubramanian G, Roy VK. Possible role of apelin on the ovarian steroidogenesis and uterine apoptosis of infantile mice: An in vitro study. J Steroid Biochem Mol Biol 2024; 238:106463. [PMID: 38246202 DOI: 10.1016/j.jsbmb.2024.106463] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/04/2024] [Accepted: 01/17/2024] [Indexed: 01/23/2024]
Abstract
The expression of adipokines is well-known in the ovary and uterus. Recently we have shown that apelin and its receptor, APJ are developmentally regulated in the ovary and uterus of mice with elevation at postnatal day 14 (PND14). However, its role in the ovary and uterus of PND14 has not been investigated. Thus, we aimed to unravel the role of the apelin system (by APJ antagonist, ML221) on ovarian steroid secretion, proliferation, and apoptosis along with its role in uterine apoptosis in PND14 mice by in vitro approaches. The treatment of ML221 decreased estrogen, testosterone, and androstenedione secretion while increasing the progesterone secretion from the infantile ovary. These results suggest that apelin signaling would be important for ovarian estrogen synthesis in infantile mice (PND14). The abundance of 3β-HSD, 17β-HSD, aromatase, and active caspase3 increased in the infantile ovary after ML221 treatment. The expression of ERs and BCL2 were also down-regulated by ML221 treatment. The decreased BCL2 and increased active caspase3 by ML221 suggest the suppressive role of apelin on ovarian apoptosis. The APJ antagonist treatment also down-regulated the ER expression in the uterus along with increased active caspase3 and decreased BCL2 expression. In conclusion, apelin signaling inhibits the ovarian and uterine apoptosis via estrogen signaling in the ovary and uterus.
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Affiliation(s)
- Borgohain Anima
- Department of Zoology, Mizoram University, Aizawl 796004, Mizoram, India
| | | | - Vikas Kumar Roy
- Department of Zoology, Mizoram University, Aizawl 796004, Mizoram, India.
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12
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Song R, Yao X, Jing F, Yang W, Wu J, Zhang H, Zhang P, Xie Y, Pan X, Zhao L, Wu C. Effects of Five Lipid Sources on Growth, Hematological Parameters, Immunity and Muscle Quality in Juvenile Largemouth Bass ( Micropterus salmoides). Animals (Basel) 2024; 14:781. [PMID: 38473166 DOI: 10.3390/ani14050781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 02/25/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024] Open
Abstract
This study investigated the effects of fish oil (FO), soybean oil (SO), rapeseed oil (RO), peanut oil (PO) and lard oil (LO) on growth, immunity and muscle quality in juvenile largemouth bass. After 8 weeks, the results showed that FO and RO could increase weight gain and serum alkaline phosphatase and apelin values compared with LO (p < 0.05). Except lower crude lipid contents, higher amounts of n-3 polyunsaturated fatty acids (15.83% and 14.64%) were present in the dorsal muscle of the FO and RO groups. Meanwhile, FO and RO could heighten mRNA levels of immune defense molecules (lysozyme, hepcidin, and transforming growth factor β1) compared with PO (p < 0.05). While SO could increase potential inflammatory risk via rising counts of white blood cells, platelets, neutrophils and monocytes, and mRNA levels of interleukins (IL-1β, IL-8, IL-12 and IL-15), FO and RO could improve hardness, chewiness and springiness through increasing amounts of hydroxyproline, collagen and lysyl oxidase, and mRNA levels of collagen 1α2 and prolyl hydroxylase in the fish dorsal muscle. Moreover, FO and RO could improve firmness through increasing glycogen and glycogen synthase 1 levels when compared with LO (p < 0.05). Therefore, these results could provide dietary lipid source references during the feeding process of adult largemouth bass.
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Affiliation(s)
- Rui Song
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
| | - Xinfeng Yao
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
| | - Futao Jing
- Shandong Fisheries Development and Resources Conservation Center, 162 Jiefang Road, Jinan 250013, China
| | - Wenxue Yang
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
| | - Jiaojiao Wu
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
| | - Hao Zhang
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
| | - Penghui Zhang
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
| | - Yuanyuan Xie
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
| | - Xuewen Pan
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
| | - Long Zhao
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
| | - Chenglong Wu
- National-Local Joint Engineering Laboratory of Aquatic Animal Genetic Breeding and Nutrition (Zhejiang), Huzhou University, 759 East 2nd Road, Huzhou 313000, China
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13
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Zhu X, Ma S, Wong WH. Genetic effects of sequence-conserved enhancer-like elements on human complex traits. Genome Biol 2024; 25:1. [PMID: 38167462 PMCID: PMC10759394 DOI: 10.1186/s13059-023-03142-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/08/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND The vast majority of findings from human genome-wide association studies (GWAS) map to non-coding sequences, complicating their mechanistic interpretations and clinical translations. Non-coding sequences that are evolutionarily conserved and biochemically active could offer clues to the mechanisms underpinning GWAS discoveries. However, genetic effects of such sequences have not been systematically examined across a wide range of human tissues and traits, hampering progress to fully understand regulatory causes of human complex traits. RESULTS Here we develop a simple yet effective strategy to identify functional elements exhibiting high levels of human-mouse sequence conservation and enhancer-like biochemical activity, which scales well to 313 epigenomic datasets across 106 human tissues and cell types. Combined with 468 GWAS of European (EUR) and East Asian (EAS) ancestries, these elements show tissue-specific enrichments of heritability and causal variants for many traits, which are significantly stronger than enrichments based on enhancers without sequence conservation. These elements also help prioritize candidate genes that are functionally relevant to body mass index (BMI) and schizophrenia but were not reported in previous GWAS with large sample sizes. CONCLUSIONS Our findings provide a comprehensive assessment of how sequence-conserved enhancer-like elements affect complex traits in diverse tissues and demonstrate a generalizable strategy of integrating evolutionary and biochemical data to elucidate human disease genetics.
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Affiliation(s)
- Xiang Zhu
- Department of Statistics, The Pennsylvania State University, 326 Thomas Building, University Park, 16802, PA, USA.
- Huck Institutes of the Life Sciences, The Pennsylvania State University, 201 Huck Life Sciences Building, University Park, 16802, PA, USA.
- Department of Statistics, Stanford University, 390 Jane Stanford Way, Stanford, 94305, CA, USA.
| | - Shining Ma
- Department of Statistics, Stanford University, 390 Jane Stanford Way, Stanford, 94305, CA, USA
- Department of Biomedical Data Science, Stanford University School of Medicine, 1265 Welch Road MC5464, Stanford, 94305, CA, USA
| | - Wing Hung Wong
- Department of Statistics, Stanford University, 390 Jane Stanford Way, Stanford, 94305, CA, USA.
- Department of Biomedical Data Science, Stanford University School of Medicine, 1265 Welch Road MC5464, Stanford, 94305, CA, USA.
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Sierawska O, Sawczuk M. Interaction between Selected Adipokines and Musculoskeletal and Cardiovascular Systems: A Review of Current Knowledge. Int J Mol Sci 2023; 24:17287. [PMID: 38139115 PMCID: PMC10743430 DOI: 10.3390/ijms242417287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/04/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Adipokines are substances secreted by adipose tissue that are receiving increasing attention. The approach to adipose tissue has changed in recent years, and it is no longer looked at as just a storage organ but its secretion and how it influences systems in the human body are also looked at. The role of adipokine seems crucial in developing future therapies for pathologies of selected systems. In this study, we look at selected adipokines, leptin, adiponectin, chemerin, resistin, omentin-1, nesfatin, irisin-1, visfatin, apelin, vaspin, heparin-binding EGF-like growth factor (HB-EGF), and TGF-β2, and how they affect systems in the human body related to physical activity such as the musculoskeletal and cardiovascular systems.
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Affiliation(s)
- Olga Sierawska
- Institute of Physical Culture Sciences, University of Szczecin, 71-065 Szczecin, Poland;
- Doctoral School, University of Szczecin, 70-384 Szczecin, Poland
| | - Marek Sawczuk
- Institute of Physical Culture Sciences, University of Szczecin, 71-065 Szczecin, Poland;
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15
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Liu LQ, Zhang P, Qi YZ, Li H, Jiang YH, Yang CH. Quercetin Attenuates Atherosclerosis via Modulating Apelin Signaling Pathway Based on Plasma Metabolomics. Chin J Integr Med 2023; 29:1121-1132. [PMID: 37656412 DOI: 10.1007/s11655-023-3645-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2023] [Indexed: 09/02/2023]
Abstract
OBJECTIVE To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS). METHODS Fourteen apolipoprotein E-deficient (ApoE-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n=7). Quercetin [20 mg/(kg·d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin II receptor 1 (AT1R), were assayed by Western blot. RESULTS Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE-/- mice (all P<0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P<0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P<0.05). CONCLUSION Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.
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Affiliation(s)
- Li-Qun Liu
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Peng Zhang
- College of Integrated Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong Province, 264000, China
| | - Ying-Zi Qi
- Health College, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China
| | - Hui Li
- Department of Pharmacy, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200050, China
| | - Yue-Hua Jiang
- Central Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China
| | - Chuan-Hua Yang
- Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
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16
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Al Zein M, Zein O, Diab R, Dimachkie L, Sahebkar A, Al-Asmakh M, Kobeissy F, Eid AH. Intermittent fasting favorably modulates adipokines and potentially attenuates atherosclerosis. Biochem Pharmacol 2023; 218:115876. [PMID: 37871879 DOI: 10.1016/j.bcp.2023.115876] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 10/19/2023] [Accepted: 10/20/2023] [Indexed: 10/25/2023]
Abstract
Adipose tissue is now recognized as an endocrine organ that secretes bioactive molecules called adipokines. These biomolecules regulate key physiological functions, including insulin sensitivity, energy metabolism, appetite regulation, endothelial function and immunity. Dysregulated secretion of adipokines is intimately associated with obesity, and translates into increased risk of obesity-related cardiovasculo-metabolic diseases. In particular, emerging evidence suggests that adipokine imbalance contributes to the pathogenesis of atherosclerosis. One of the promising diet regimens that is beneficial in the fight against obesity and cardiometabolic disorders is intermittent fasting (IF). Indeed, IF robustly suppresses inflammation, meditates weight loss and mitigates many aspects of the cardiometabolic syndrome. In this paper, we review the main adipokines and their role in atherosclerosis, which remains a major contributor to cardiovascular-associated morbidity and mortality. We further discuss how IF can be employed as an effective management modality for obesity-associated atherosclerosis. By exploring a plethora of the beneficial effects of IF, particularly on inflammatory markers, we present IF as a possible intervention to help prevent atherosclerosis.
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Affiliation(s)
- Mohammad Al Zein
- Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | - Omar Zein
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Rawan Diab
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Lina Dimachkie
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maha Al-Asmakh
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar; Biomedical Research Center, Qatar University, Doha, Qatar
| | - Firas Kobeissy
- Department of Neurobiology and Neuroscience, Morehouse School of Medicine, Atlanta, GA, USA
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar.
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Pisarenko OI, Studneva IM. Apelin C-Terminal Fragments: Biological Properties and Therapeutic Potential. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:1874-1889. [PMID: 38105205 DOI: 10.1134/s0006297923110160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/10/2023] [Accepted: 09/11/2023] [Indexed: 12/19/2023]
Abstract
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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Affiliation(s)
- Oleg I Pisarenko
- Chazov National Medical Research Center of Cardiology, Moscow, 121552, Russia.
| | - Irina M Studneva
- Chazov National Medical Research Center of Cardiology, Moscow, 121552, Russia
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18
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Shokrollahi B, Zheng HY, Ma XY, Shang JH. The effects of apelin on IGF1/FSH-induced steroidogenesis, proliferation, Bax expression, and total antioxidant capacity in granulosa cells of buffalo ovarian follicles. Vet Res Commun 2023; 47:1523-1533. [PMID: 37036601 DOI: 10.1007/s11259-023-10107-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 03/15/2023] [Indexed: 04/11/2023]
Abstract
Apelin (APLN) was believed to be an adipokine secreted from adipose tissue. However, studies demonstrate that it is a pleiotropic peptide and has several effects on the female reproductive system. In this study, We examined the effects of different doses of IGF1 and FSH in the presence of APLN-13 on the production of progesterone in buffalo ovary granulosa cells. Furthermore, different doses of APLN isoforms (APLN-13 and APLN-17) were tested on proliferation, Bax protein expression, and antioxidant capacity in the same cells. Granulosa cells of buffalo ovaries were cultured in the presence of different doses of IGF1 and FSH with or without APLN-13 (10-9 M) to evaluate its effect on the secretion of progesterone tested by ELISA assay. The WST-1 method was used to survey the effect of APLN on granulosa cell proliferation and cytotoxicity. In addition, the antioxidant capacity of the cells in the presence of APLN was assessed using the FRAP method. mRNA and Bax protein levels were measured in granulosa cells treated with APLN using real-time PCR and western blot techniques. APLN-13 (10-9) stimulated the effect of IGF1 on the production of progesterone, and its levels were affected by APLN-13 dose-dependently. However, it did not significantly stimulate the effect of FSH on the secretion of progesterone. APLN-13 (all doses) and APLN-17 (10-8 and 10-9 M) improved the proliferation of granulosa cells. Moreover, preincubation of the cells for an hour by APLN receptor antagonist (ML221, 10 µM) did not significantly affect the proliferation of cells induced by APLN. Neither APLN-13 nor APLN-17 were not cytotoxic for the cells compared to the control treatment. APLN-13 at the doses of 10-6 and 10-8 M substantially up and down-regulated Bax protein expression; however, such effects were not observed when the cells were preincubated with ML221. In addition, APLN-17 did not influence the expression amount of Bax. Furthermore, both APLN-13 and -17 improved the total antioxidant capacity of the ovarian granulosa cells, but such effects were not seen when the cells were preincubated with ML221. According to these results, APLN enhanced the steroidogenesis induced by IGF1 but did not affect the steroidogenesis induced by FSH. APLN also enhanced the cell proliferation and antioxidant capacity of buffalo ovaries follicular granulosa cells; however, its effect on Bax expression was different.
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Affiliation(s)
- Borhan Shokrollahi
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China
- Department of Animal Science, Sanandaj Branch, Islamic Azad University, Sanandaj, Kurdistan, Iran
| | - Hai-Ying Zheng
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China
| | - Xiao-Ya Ma
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China
| | - Jiang-Hua Shang
- Key Laboratory of Buffalo Genetics, Breeding and Reproduction Technology, Guangxi Buffalo Research Institute, Chinese Academy of Agricultural Sciences, Nanning, 530001, China.
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Mehri K, Hamidian G, Zavvari Oskuye Z, Nayebirad S, Farajdokht F. The role of apelinergic system in metabolism and reproductive system in normal and pathological conditions: an overview. Front Endocrinol (Lausanne) 2023; 14:1193150. [PMID: 37424869 PMCID: PMC10324965 DOI: 10.3389/fendo.2023.1193150] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/06/2023] [Indexed: 07/11/2023] Open
Abstract
Lifestyle changes have made metabolic disorders as one of the major threats to life. Growing evidence demonstrates that obesity and diabetes disrupt the reproductive system by affecting the gonads and the hypothalamus-pituitary-gonadal (HPG) axis. Apelin, an adipocytokine, and its receptor (APJ) are broadly expressed in the hypothalamus nuclei, such as paraventricular and supraoptic, where gonadotropin-releasing hormone (GnRH) is released, and all three lobes of the pituitary, indicating that apelin is involved in the control of reproductive function. Moreover, apelin affects food intake, insulin sensitivity, fluid homeostasis, and glucose and lipid metabolisms. This review outlined the physiological effects of the apelinergic system, the relationship between apelin and metabolic disorders such as diabetes and obesity, as well as the effect of apelin on the reproductive system in both gender. The apelin-APJ system can be considered a potential therapeutic target in the management of obesity-associated metabolic dysfunction and reproductive disorders.
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Affiliation(s)
- Keyvan Mehri
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gholamreza Hamidian
- Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | | | - Sepehr Nayebirad
- Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Fereshteh Farajdokht
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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20
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Chae SA, Du M, Son JS, Zhu MJ. Exercise improves homeostasis of the intestinal epithelium by activation of apelin receptor-AMP-activated protein kinase signalling. J Physiol 2023; 601:2371-2389. [PMID: 37154385 PMCID: PMC10280693 DOI: 10.1113/jp284552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 05/05/2023] [Indexed: 05/10/2023] Open
Abstract
Intestinal remodelling is dynamically regulated by energy metabolism. Exercise is beneficial for gut health, but the specific mechanisms remain poorly understood. Intestine-specific apelin receptor (APJ) knockdown (KD) and wild-type male mice were randomly divided into two subgroups, with/without exercise, to obtain four groups: WT, WT with exercise, APJ KD and APJ KD with exercise. Animals in the exercise groups were subjected to daily treadmill exercise for 3 weeks. Duodenum was collected at 48 h after the last bout of exercise. AMP-activated protein kinase (AMPK) α1 KD and wild-type mice were also utilized for investigating the mediatory role of AMPK on exercise-induced duodenal epithelial development. AMPK and peroxisome proliferator-activated receptor γ coactivator-1 α were upregulated by exercise via APJ activation in the intestinal duodenum. Correspondingly, exercise induced permissive histone modifications in the PR domain containing 16 (PRDM16) promoter to activate its expression, which was dependent on APJ activation. In agreement, exercise elevated the expression of mitochondrial oxidative markers. The expression of intestinal epithelial markers was downregulated due to AMPK deficiency, and AMPK signalling facilitated epithelial renewal. These data demonstrate that exercise-induced activation of the APJ-AMPK axis facilitates the homeostasis of the intestinal duodenal epithelium. KEY POINTS: Apelin receptor (APJ) signalling is required for improved epithelial homeostasis of the small intestine in response to exercise. Exercise intervention activates PRDM16 through inducing histone modifications, enhanced mitochondrial biogenesis and fatty acid metabolism in duodenum. The morphological development of duodenal villus and crypt is enhanced by the muscle-derived exerkine apelin through the APJ-AMP-activated protein kinase axis.
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Affiliation(s)
- Song Ah Chae
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
| | - Min Du
- Nutrigenomics and Growth Biology Laboratory, Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
| | - Jun Seok Son
- Laboratory of Perinatal Kinesioepigenetics, Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA 99164, USA
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21
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Théroux L, Van Den Hauwe R, Trân K, Fournier J, Desgagné M, Meneboo N, Lavallée A, Fröhlich U, Côté J, Hollanders C, Longpré JM, Murza A, Marsault E, Sarret P, Boudreault PL, Ballet S. Signaling Modulation via Minimal C-Terminal Modifications of Apelin-13. ACS Pharmacol Transl Sci 2023; 6:290-305. [PMID: 36798478 PMCID: PMC9926529 DOI: 10.1021/acsptsci.2c00219] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Indexed: 01/27/2023]
Abstract
Apelin is an endogenous peptide that is involved in many diseases such as cardiovascular diseases, obesity, and cancer, which has made it an attractive target for drug discovery. Herein, we explore the penultimate and final sequence positions of [Pyr1]-apelin-13 (Ape13) via C-terminal N α-alkylated amide bonds and the introduction of positive charges, potentially targeting the allosteric sodium pocket, by assessing the binding affinity and signaling profiles at the apelin receptor (APJ). Synthetic analogues modified within this segment of Ape13 showed high affinity (K i 0.12-0.17 nM vs Ape13 K i 0.7 nM), potent Gαi1 activation (EC50 Gαi1 0.4-0.9 nM vs Ape13 EC50 1.1 nM), partial agonist behavior disfavoring β-arrestin 2 recruitment for positively charged ligands (e.g., 49 (SBL-AP-058), EC50 β-arr2 275 nM, E max 54%) and high plasma stability for N-alkyl ligands (t 1/2 > 7 h vs Ape13 t 1/2 0.5 h). Combining the benefits of the N α-alkylated amide bond with the guanidino substitution in a constrained ligand led to 63 (SBL-AP-049), which displayed increased plasma stability (t 1/2 5.3 h) and strong reduction of β-arrestin 2 signaling with partial maximal efficacy (EC50 β-arr 864 nM, E max 48%), significantly reducing the hypotensive effect in vivo.
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Affiliation(s)
- Léa Théroux
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Robin Van Den Hauwe
- Research
Group of Organic Chemistry, Departments of Chemistry and Bioengineering
Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium
| | - Kien Trân
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Justin Fournier
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Michael Desgagné
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Nathan Meneboo
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Alexis Lavallée
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Ulrike Fröhlich
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Jérôme Côté
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Charlie Hollanders
- Research
Group of Organic Chemistry, Departments of Chemistry and Bioengineering
Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium
| | - Jean-Michel Longpré
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Alexandre Murza
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Eric Marsault
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Philippe Sarret
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Pierre-Luc Boudreault
- Département
de Pharmacologie-Physiologie, Faculté de Médecine et
des Sciences de la Santé, Université
de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
- Institut
de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada
| | - Steven Ballet
- Research
Group of Organic Chemistry, Departments of Chemistry and Bioengineering
Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium
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22
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Gupta M, Korde JP, Bahiram KB, Sardar VM, Kurkure NV. Expression and localization of apelin and apelin receptor (APJ) in buffalo ovarian follicles and corpus luteum and the in-vitro effect of apelin on steroidogenesis and survival of granulosa cells. Theriogenology 2023; 197:240-251. [PMID: 36525863 DOI: 10.1016/j.theriogenology.2022.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/04/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
Apelin is an adipose tissue-derived hormone with many physiological functions, including the regulation of female reproduction. It acts through an orphan G protein-coupled receptor APJ/APLNR. The present study aimed to investigate the expression of apelin and its receptor APJ in the ovarian follicles and corpus luteum (CL) and the role of apelin on steroidogenesis and cell survival. Ovarian follicles were classified into four groups based on size and estradiol (E2) level in the follicular fluid as follows: (i) F1 (4-6 mm; <0.5 ng/mL) (ii) F2 (7-9 mm; 0.5-5 ng/mL) (iii) F3 (10-13 mm; 5-40 ng/mL) and (iv) F4 (dominant/pre-ovulatory follicle) (>13 mm; >180 ng/mL). The corpora lutea (CL) were categorized into early (CL1), mid (CL2), late luteal (CL3), and regressing (CL4) CL stages. Expression of apelin increased with follicle size, with significantly greatest in the dominant or pre-ovulatory follicle (P < 0.05). Expression of APJ was greater in large and dominant follicles than in small and medium follicles (P < 0.05). In CL, the mRNA and protein abundance of apelin and apelin receptor was greater during mid (CL2) and late luteal (CL3) stages as compared to early (CL1) and regressing (CL4) stages (P < 0.05). Both the factors were localized in granulosa and theca cells of follicles and small and large luteal cells of CL. The pattern of the intensity of immunofluorescence was similar to mRNA and protein expression. Granulosa cells were cultured in vitro and treated at 1, 10, and 10 ng/mL apelin-13 either alone or in the presence of the follicle-stimulating hormone (FSH) (30 ng/mL) or insulin-like growth factor-I (IGF-I) (10 ng/mL) for 48 h. The luteal cells were treated with apelin-13 at 1, 10, and 100 ng/mL doses for 48 h. Apelin treatment at 10 and 100 ng/ml significantly (P < 0.05) increased E2 secretion, cytochrome P450 aromatase or CYP19A1 expression in GC. In luteal cells, apelin at 10 ng/mL and 100 ng/mL significantly (P < 0.05) increased progesterone (P4) secretion and HSD3B1 expression. In GCs, apelin, either alone or in combination, increased PCNA expression and inhibited CASPASE3 expression suggesting its role in cell survival. In conclusion, this study provides novel evidence for the presence of apelin and receptor APJ in ovarian follicles and corpora lutea and the stimulatory effect on E2 and P4 production and promotes GC survival in buffalo, suggesting the role of apelin in follicular and luteal functions in buffalo.
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Affiliation(s)
- Mahesh Gupta
- Department of Veterinary Physiology, Nagpur Veterinary College, Nagpur, 440006, India.
| | - Jayant P Korde
- Department of Veterinary Physiology, Nagpur Veterinary College, Nagpur, 440006, India
| | - K B Bahiram
- Department of Veterinary Physiology, Nagpur Veterinary College, Nagpur, 440006, India
| | - V M Sardar
- Department of Veterinary Physiology, Nagpur Veterinary College, Nagpur, 440006, India
| | - Nitin V Kurkure
- Department of Veterinary Pathology, Nagpur Veterinary College, Nagpur, 440006, India
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23
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Trang NTN, Lai CY, Tsai HC, Huang YL, Liu SC, Tsai CH, Fong YC, Tzeng HE, Tang CH. Apelin promotes osteosarcoma metastasis by upregulating PLOD2 expression via the Hippo signaling pathway and hsa_circ_0000004/miR-1303 axis. Int J Biol Sci 2023; 19:412-425. [PMID: 36632453 PMCID: PMC9830518 DOI: 10.7150/ijbs.77688] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 11/02/2022] [Indexed: 12/23/2022] Open
Abstract
Osteosarcoma is a highly mortal bone tumor, with a high metastatic potential, promoted in part by the enzyme procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2). Increasing level of PLOD2 in osteosarcoma tissue correlates with lymphatic and distant metastasis. The adipokine apelin (APLN) is also found in different cancers and APLN upregulation promotes angiogenesis and metastasis, but its effects on osteosarcoma metastasis are uncertain. We explored APLN functioning in metastatic osteosarcoma. An analysis of records from the Gene Expression Omnibus (GEO) database showed higher levels of APLN expression in osteosarcoma tissue than in normal tissue. Similarly, levels of APLN and PLOD2 mRNA synthesis were upregulated in osteosarcoma tissue. Levels of APLN and PLOD2 protein correlated positively with osteosarcoma clinical stages. APLN increased PLOD2 expression in human osteosarcoma cell lines and cell migration via the mammalian Sterile 20-like kinase 1 (MST1), monopolar spindle-one-binder protein (MOB)1, and YAP cascades, and through hsa_circ_0000004 functioning as a sponge of miR-1303. We also found that knockdown of APLN antagonized lung metastasis in mice with osteosarcoma. APLN may be a therapeutic target in osteosarcoma metastasis.
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Affiliation(s)
- Nguyen Thi Nha Trang
- School of Medicine, China Medical University, Taichung, Taiwan.,Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
| | - Chao-Yang Lai
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
| | - Hsiao-Chi Tsai
- School of Medicine, China Medical University, Taichung, Taiwan
| | - Yuan-Li Huang
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Shan-Chi Liu
- Department of Medical Education and Research, China Medical University Beigang Hospital, Yunlin, Taiwan
| | - Chun-Hao Tsai
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.,Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
| | - Yi-Chin Fong
- Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.,Department of Orthopaedic Surgery, China Medical University Beigang Hospital, Yunlin, Taiwan
| | - Huey-En Tzeng
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.,Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, and Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,✉ Corresponding authors: Chih-Hsin Tang, PhD, Department of Pharmacology, School of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan. Tel: (886) 4-22052121 Ext. 7726; Fax: (886) 4-22333641; E-mail: . Huey-En Tzeng, MD, PhD, Department of Medical Research, Taichung Veterans General Hospital, Taichung 407219, Taiwan. Tel: (886) 4-2359-2525; E-mail:
| | - Chih-Hsin Tang
- School of Medicine, China Medical University, Taichung, Taiwan.,Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.,Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.,✉ Corresponding authors: Chih-Hsin Tang, PhD, Department of Pharmacology, School of Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 40402, Taiwan. Tel: (886) 4-22052121 Ext. 7726; Fax: (886) 4-22333641; E-mail: . Huey-En Tzeng, MD, PhD, Department of Medical Research, Taichung Veterans General Hospital, Taichung 407219, Taiwan. Tel: (886) 4-2359-2525; E-mail:
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24
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Mohseni R, Teimouri M, Safaei M, Arab Sadeghabadi Z. AMP-activated protein kinase is a key regulator of obesity-associated factors. Cell Biochem Funct 2023; 41:20-32. [PMID: 36468539 DOI: 10.1002/cbf.3767] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/29/2022] [Accepted: 11/19/2022] [Indexed: 12/12/2022]
Abstract
An imbalance between caloric intake and energy expenditure leads to obesity. Obesity is an important risk factor for the development of several metabolic diseases including insulin resistance, metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. So, controlling obesity could be effective in the improvement of obesity-related diseases. Various factors are involved in obesity, such as AMP-activated protein kinases (AMPK), silent information regulators, inflammatory mediators, oxidative stress parameters, gastrointestinal hormones, adipokines, angiopoietin-like proteins, and microRNAs. These factors play an important role in obesity by controlling fat metabolism, energy homeostasis, food intake, and insulin sensitivity. AMPK is a heterotrimeric serine/threonine protein kinase known as a fuel-sensing enzyme. The central role of AMPK in obesity makes it an attractive molecule to target obesity and related metabolic diseases. In this review, the critical role of AMPK in obesity and the interplay between AMPK and obesity-associated factors were elaborated.
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Affiliation(s)
- Roohollah Mohseni
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Department of Clinical Biochemistry & Nutrition, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Maryam Teimouri
- Department of Biochemistry, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Mohsen Safaei
- Department of Medical Biotechnology, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Zahra Arab Sadeghabadi
- Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.,Department of Clinical Biochemistry & Nutrition, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran
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25
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Sahu B, Bal NC. Adipokines from white adipose tissue in regulation of whole body energy homeostasis. Biochimie 2023; 204:92-107. [PMID: 36084909 DOI: 10.1016/j.biochi.2022.09.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 08/08/2022] [Accepted: 09/01/2022] [Indexed: 02/06/2023]
Abstract
Diseases originating from altered energy homeostasis including obesity, and type 2 diabetes are rapidly increasing worldwide. Research in the last few decades on animal models and humans demonstrates that the white adipose tissue (WAT) is critical for energy balance and more than just an energy storage site. WAT orchestrates the whole-body metabolism through inter-organ crosstalk primarily mediated by cytokines named "Adipokines". The adipokines influence metabolism and fuel selection of the skeletal muscle and liver thereby fine-tuning the load on WAT itself in physiological conditions like starvation, exercise and cold. In addition, adipokine secretion is influenced by various pathological conditions like obesity, inflammation and diabetes. In this review, we have surveyed the current state of knowledge on important adipokines and their significance in regulating energy balance and metabolic diseases. Furthermore, we have summarized the interplay of pro-inflammatory and anti-inflammatory adipokines in the modulation of pathological conditions.
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Affiliation(s)
- Bijayashree Sahu
- School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India.
| | - Naresh C Bal
- School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India.
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26
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Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models. Nat Commun 2022; 13:7335. [PMID: 36443325 PMCID: PMC9705293 DOI: 10.1038/s41467-022-34990-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/14/2022] [Indexed: 11/29/2022] Open
Abstract
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.
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27
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Presence and localization of apelin and its cognate receptor in canine testes using immunohistochemical and RT-PCR techniques. Vet Res Commun 2022; 47:929-935. [PMID: 36331787 DOI: 10.1007/s11259-022-10001-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 09/10/2022] [Indexed: 11/06/2022]
Abstract
Apelin, a member of the adipokine family, is a novel endogenous peptide which regulates the male reproductive system of mammals by interacting with a specific receptor. Recent studies have highlighted that apelin may play a role in the regulation of reproduction by reducing testosterone production and inhibiting LH secretion. To the best of our knowledge, there is no available data on the presence of the apelin and its receptor in canine testes. Therefore, the aim of this study was to reveal the presence of apelin and evaluate its distribution in the canine testes using immunohistochemical and RT-PCR techniques. For this purpose, five fertile and healthy male dogs were subjected to elective orchiectomy. The immunohistochemical reaction revealed the presence of apelin and its receptor in the canine testes. Apelin was localized in spermatids and spermatozoa with a positive signal in the "acrosomal bodies". As regards the apelin receptor, a positive immunoreaction was detected in the cytoplasm of the cells localized near to the basal membrane of the seminiferous tubules and in the cytoplasm of Leydig cells. The RT-PCR analysis showed the presence of transcripts for apelin and apelin receptor in all of the samples under study. A 35kDa band confirmed apelin receptor protein expression in all of the samples analysed. In conclusion, the paracrine and endocrine role of apelin and its cognate receptor on male reproduction reported in humans and laboratory animals could also be hypothesized in dogs.
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28
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Fuentes-Carrasco M, Ruíz-Román R, Savirón-Cornudella R, Pérez-Roncero G, López-Baena MT, Pérez-López FR. Systematic review and meta-analysis regarding maternal apelin in pregnant women with and without preeclampsia. Gynecol Endocrinol 2022; 38:918-927. [PMID: 36097365 DOI: 10.1080/09513590.2022.2122433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Aims: To investigate maternal circulating apelin levels in pregnancies with and without preeclampsia.Design and Method: Systematic review and meta-analysis of observational studies reporting circulating apelin in women who develop preeclampsia. We searched databases for appropriate studies published through December 2021, without language restriction. The quality of studies was evaluated using the Newcastle-Ottawa-Scale. Data were pooled as mean difference (MDs) or standardized MDs (SMDs) and 95% confidence interval (95% CI). A random-effects model enabled reporting of differences between groups, minimizing the effects of uncertainty associated with inter-study variability on the effects of different endpoints.Results: We identified a total of 122 studies, and ten of them reported circulating apelin in women with and without preeclampsia. Maternal apelin did not show a difference in preeclamptic compared to normotensive women (SMD: -0.38, 95%CI -0.91 to 0.15), although there was high heterogeneity between the included studies (I2 = 95%). Participants with preeclampsia had higher body mass index, lower gestational age at delivery, and birth weight. Preeclamptic pregnant women with higher BMI showed significantly lower apelin levels in the subgroup analysis. There was no significant apelin difference in the preeclampsia severity sub-analysis.Conclusion: There was no significant difference in apelin levels in pregnant women with and without preeclampsia.
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Affiliation(s)
- Marta Fuentes-Carrasco
- Department of Obstetrics and Gynecology, Facultad de Medicina, Hospital Clínico San Carlos, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Rebeca Ruíz-Román
- Department of Obstetrics and Gynecology, Facultad de Medicina, Hospital Clínico San Carlos, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Ricardo Savirón-Cornudella
- Department of Obstetrics and Gynecology, Facultad de Medicina, Hospital Clínico San Carlos, Universidad Complutense, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | | | | | - Faustino R Pérez-López
- Aragón Health Research Institute, Zaragoza, Spain
- Faculty of Medicine, University of Zaragoza, Zaragoza, Spain
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29
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Comparative analysis of microsatellites in coding regions provides insights into the adaptability of the giant panda, polar bear and brown bear. Genetica 2022; 150:355-366. [DOI: 10.1007/s10709-022-00173-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 09/13/2022] [Indexed: 11/27/2022]
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30
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Apelin Promotes Prostate Cancer Metastasis by Downregulating TIMP2 via Increases in miR-106a-5p Expression. Cells 2022; 11:cells11203285. [PMID: 36291151 PMCID: PMC9600532 DOI: 10.3390/cells11203285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 10/04/2022] [Accepted: 10/13/2022] [Indexed: 11/17/2022] Open
Abstract
Prostate cancer commonly affects the urinary tract of men and metastatic prostate cancer has a very low survival rate. Apelin belongs to the family of adipokines and is associated with cancer development and metastasis. However, the effects of apelin in prostate cancer metastasis is undetermined. Analysis of the database revealed a positive correlation between apelin level with the progression and metastasis of prostate cancer patients. Apelin treatment facilitates cell migration and invasion through inhibiting tissue inhibitor of metalloproteinase 2 (TIMP2) expression. The increasing miR-106a-5p synthesis via c-Src/PI3K/Akt signaling pathway is controlled in apelin-regulated TIMP2 production and cell motility. Importantly, apelin blockade inhibits prostate cancer metastasis in the orthotopic mouse model. Thus, apelin is a promising therapeutic target for curing metastatic prostate cancer.
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Abstract
Pregnancy complications affect millions of women each year. Some of these diseases have high morbidity and mortality such as preeclampsia. At present, there is no safe and effective treatment for pregnancy complications, so it is still a difficult clinical problem. As many pregnancy complications are closely related to placental dysplasia, placenta-specific therapy, as an important method, is expected to be a safe, effective, and specific therapeutic strategy. This review explains in detail the placenta physiological structure, characteristics, and action mechanism of some biomolecules and signaling pathways that play roles in normal development and disorders of the development of the placenta, and how to use these biomolecules as therapeutic targets when the placenta disorder causes disease, combining the latest progress in the field of nanodelivery systems, so as to lay a foundation for the development of placenta-specific therapy of pregnancy complications.
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Affiliation(s)
- Yang Liu
- School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Avenue, Zhengzhou, 450001, China
| | - Xingli Gao
- School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Avenue, Zhengzhou, 450001, China
| | - Songwei Gao
- School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Avenue, Zhengzhou, 450001, China.,Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yu Song
- School of Pharmacy, Xinxiang Medical University, Xinxiang, 453003, China
| | - Yongran Guo
- School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Kexue Avenue, Zhengzhou, 450001, China
| | - Jing Cao
- Department of Pathology, The Third Affiliated Hospital of Zhenzhou University, Zhengzhou, 450001, China
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High APLN Expression Predicts Poor Prognosis for Glioma Patients. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8393336. [PMID: 36193059 PMCID: PMC9526648 DOI: 10.1155/2022/8393336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/30/2022]
Abstract
Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN/APLNR system was involved in a variety of pathological and physiological functions, such as tumorigenesis and development. However, its prognostic roles in patients with central nervous system (CNS) cancers remain unknown. The present study was designed to explore the expression profile, prognostic significance, and interaction network of APLN/APLNR by integrating data from Oncomine, GEPIA, LOGpc, STRING, GeneMANIA, and immunohistochemical staining. The results demonstrated that APLN and APLNR mRNA expression were significantly increased in CNS cancers, including both low-grade glioma (LGG) and glioblastoma (GBM), when compared with normal CNS tissues. The high APLN, but not APLNR, expression was significantly correlated with overall survival (OS), recurrence free survival (RFS), and progression free survival (PFS) of LGG patients. However, neither APLN nor APLNR expression was significantly related to prognostic value in terms of OS, disease free interval (DFI), disease specific survival (DSS), or progression free interval (PFI) for GBM patients. Additionally, immunohistochemistry staining confirmed the increased APLN expression in tissues of LGG patients with grade II than grade I. These results showed that an elevated APLN level could predict poor OS, RFS, and PFS for LGG patients, and it could be a promising prognostic biomarker for LGG.
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Polat SHB, Dariyerli ND. A Physiological Approach to Inflammatory Markers in Obesity. Biomark Med 2022. [DOI: 10.2174/9789815040463122010028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Obesity is one of the most critical health problems all over the world; it is
associated with metabolic dysfunction and overnutrition. Changes in the physiological
function of adipose tissue, leading to altered secretion of adipocytokines, inflammatory
mediators release, and chronic low-grade inflammation, are seen in obesity.
Macrophages, neutrophils, CD4+ and CD8+ T cells, B cells, natural killer T (NKT)
cells, eosinophils, mast cells, and adipocytes are involved in the inflammatory response
that occurs during obesity. Various inflammatory markers are released from these cells.
In this chapter, we will mention inflammatory mechanisms and markers of obesity.
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Alizadeh Pahlavani H. Possible roles of exercise and apelin against pregnancy complications. Front Endocrinol (Lausanne) 2022; 13:965167. [PMID: 36093083 PMCID: PMC9452694 DOI: 10.3389/fendo.2022.965167] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/08/2022] [Indexed: 12/02/2022] Open
Abstract
The prevalence of maternal obesity during pregnancy is associated with the risk of gestational diabetes, preeclampsia, and cardiomyopathy. Environmental factors such as active lifestyles and apelin may lead to beneficial changes. In rats, apelin and exercise (45 to 65% VO2max for 6 to 9 weeks) during pregnancy increase brown adipose tissue (BAT) proteins such as Cidea, Elovl3, UCP1, PRDM16, and PGC-1α in males and females fetuses, while white adipose tissue (WAT) is reduced. In humans and animals, apelin and exercise stimulate the expression of the glucose transporters (GLUT1/2/4) in the muscle and adipose tissue through the PI3K/Akt and AMPK pathways. Hence, exercise and apelin may are known as regulators of energy metabolism and be anti-obesity and anti-diabetic properties. In mice, exercise also creates a short-term hypoxic environment in the pregnant mother, activating HIF-1, VEGF, and VEGFR, and increasing angiogenesis. Exercise and apelin also increase vasodilation, angiogenesis, and suppression of inflammation through the L-arginine/eNOS/NO pathway in humans. Exercise can stimulate the ACE2-Ang-(1-7)-Mas axis in parallel with inhibiting the ACE-Ang II-AT1 pathway. Exercise and apelin seem to prevent preeclampsia through these processes. In rats, moderate-intensity exercise (60 to 70% VO2max for 8 weeks) and apelin/APJ also may prevent pathological hypertrophy in pregnancy by activating the PI3K/Akt/mTOR/p70S6K pathway, PI3k-Akt-ERK1/2-p70S6K pathway, and the anti-inflammatory cytokine IL-10. Since pre-clinical studies have been more on animal models, future research with scientific guidelines should pay more attention to human specimens. In future research, time factors such as the first, second, and third trimesters of pregnancy and the intensity and duration of exercise are important variables that should be considered to determine the optimal intensity and duration of exercise.
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ID1 marks the tumorigenesis of pancreatic ductal adenocarcinoma in mouse and human. Sci Rep 2022; 12:13555. [PMID: 35941362 PMCID: PMC9359991 DOI: 10.1038/s41598-022-17827-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/01/2022] [Indexed: 11/26/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease that has an increasing death rate but no effective treatment to now. Although biological and immunological hallmarks of PDAC have been frequently reported recently, early detection and the particularly aggressive biological features are the major challenges remaining unclear. In the current study, we retrieved multiple scRNA-seq datasets and illustrated the genetic programs of PDAC development in genetically modified mouse models. Notably, the transcription levels of Id1 were elevated specifically along with the PDAC development. Pseudotime trajectory analysis revealed that Id1 was closely correlated with the malignancy of PDAC. The gene expression patterns of human PDAC cells were determined by the comparative analysis of the scRNA-seq data on human PDAC and normal pancreas tissues. ID1 levels in human PDAC cancer cells were dramatically increased compared to normal epithelial cells. ID1 deficiency in vitro significantly blunt the invasive tumor-formation related phenotypes. IPA analysis on the differentially expressed genes suggested that EIF2 signaling was the core pathway regulating the development of PDAC. Blocking EFI2 signaling remarkably decreased the expression of ID1 and attenuated the tumor-formation related phenotypes. These observations confirmed that ID1 was regulated by EIF2 signaling and was the critical determinator of PDAC development and progression. This study suggests that ID1 is a potential malignant biomarker of PDAC in both mouse models and human and detecting and targeting ID1 may be a promising strategy to treat or even rescue PDAC.
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Yang Y, Chen M, Qiu Y, Li X, Huang Y, Zhang W. The Apelin/APLNR system modulates tumor immune response by reshaping the tumor microenvironment. Gene X 2022; 834:146564. [PMID: 35598689 DOI: 10.1016/j.gene.2022.146564] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/12/2022] [Accepted: 05/06/2022] [Indexed: 11/04/2022] Open
Abstract
Apelin is an endogenous ligand of the Apelin receptor (APLNR), a seven-transmembrane G protein-coupled receptor, which is widely distributed in human tissue. The Apelin/APLNR system is involved in regulating several physiological and pathological processes. The Apelin expression is increased in a variety of cancer and the Apelin/APLNR system could regulate the development of tumors through mediating autophagy, apoptosis, pyroptosis, and other biological processes to regulate tumor cell proliferation, migration, and invasion. The Apelin/APLNR system also participates in immune response and immune regulation through PI3K-Akt, ERK-MAPK, and other signal pathways. The latest research points out that there is a negative regulatory relationship between APLNR and immune checkpoint PD-L1. In this review, we outline the significance of the Apelin/APLNR signaling pathway in tumorigenesis and its immune regulation. These endeavors provide new insights into the translational application of Apelin/APLNR in cancer and may contribute to the promotion of more effective treatments for cancers.
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Affiliation(s)
- Yuqin Yang
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province 410013, PR China
| | - Meilin Chen
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province 410013, PR China
| | - Yanbing Qiu
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province 410013, PR China
| | - Xiaoxu Li
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province 410013, PR China
| | - Yumei Huang
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province 410013, PR China
| | - Wenling Zhang
- Department of Medical Laboratory Science, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province 410013, PR China.
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Vints WAJ, Levin O, Fujiyama H, Verbunt J, Masiulis N. Exerkines and long-term synaptic potentiation: Mechanisms of exercise-induced neuroplasticity. Front Neuroendocrinol 2022; 66:100993. [PMID: 35283168 DOI: 10.1016/j.yfrne.2022.100993] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 03/03/2022] [Accepted: 03/06/2022] [Indexed: 01/30/2023]
Abstract
Physical exercise may improve cognitive function by modulating molecular and cellular mechanisms within the brain. We propose that the facilitation of long-term synaptic potentiation (LTP)-related pathways, by products induced by physical exercise (i.e., exerkines), is a crucial aspect of the exercise-effect on the brain. This review summarizes synaptic pathways that are activated by exerkines and may potentiate LTP. For a total of 16 exerkines, we indicated how blood and brain exerkine levels are altered depending on the type of physical exercise (i.e., cardiovascular or resistance exercise) and how they respond to a single bout (i.e., acute exercise) or multiple bouts of physical exercise (i.e., chronic exercise). This information may be used for designing individualized physical exercise programs. Finally, this review may serve to direct future research towards fundamental gaps in our current knowledge regarding the biophysical interactions between muscle activity and the brain at both cellular and system levels.
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Affiliation(s)
- Wouter A J Vints
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Sporto str. 6, LT-44221 Kaunas, Lithuania; Department of Rehabilitation Medicine Research School CAPHRI, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands; Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, P.O. Box 88, 6430 AB Hoensbroek, the Netherlands.
| | - Oron Levin
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Sporto str. 6, LT-44221 Kaunas, Lithuania; Movement Control & Neuroplasticity Research Group, Group Biomedical Sciences, Catholic University Leuven, Tervuursevest 101, 3001 Heverlee, Belgium.
| | - Hakuei Fujiyama
- Department of Psychology, Murdoch University, 90 South St., WA 6150 Perth, Australia; Centre for Healthy Ageing, Health Futures Institute, Murdoch University, 90 South St., WA 6150 Perth, Australia; Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, 90 South St., WA 6150 Perth, Australia.
| | - Jeanine Verbunt
- Department of Rehabilitation Medicine Research School CAPHRI, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands; Centre of Expertise in Rehabilitation and Audiology, Adelante Zorggroep, P.O. Box 88, 6430 AB Hoensbroek, the Netherlands.
| | - Nerijus Masiulis
- Department of Health Promotion and Rehabilitation, Lithuanian Sports University, Sporto str. 6, LT-44221 Kaunas, Lithuania; Department of Rehabilitation, Physical and Sports Medicine, Institute of Health Science, Faculty of Medicine, Vilnius University, M. K. Čiurlionio Str. 21, LT-03101 Vilnius, Lithuania.
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38
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Liu B, Chen B, Yi J, Long H, Wen H, Tian F, Liu Y, Xiao L, Li L. Liuwei Dihuang Decoction Alleviates Cognitive Dysfunction in Mice With D-Galactose-Induced Aging by Regulating Lipid Metabolism and Oxidative Stress via the Microbiota-Gut-Brain Axis. Front Neurosci 2022; 16:949298. [PMID: 35844229 PMCID: PMC9283918 DOI: 10.3389/fnins.2022.949298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 06/15/2022] [Indexed: 11/24/2022] Open
Abstract
Background Aging is an important cause of cognitive dysfunction. Liuwei Dihuang decoction (LW), a commonly applied Chinese medicine formula, is widely used for the treatment of aging-related diseases in China. Previously, LW was confirmed to be effective in prolonging life span and reducing oxidative stress in aged mice. Unfortunately, the underlying mechanism of LW remains unclear. The aim of this study was to interpret the mechanism by which LW alleviates cognitive dysfunction related to aging from the perspective of the microbiota-gut-brain axis. Method All C57BL/6 mice (n = 60) were randomly divided into five groups: the control, model, vitamin E (positive control group), low-dose LW and high-dose LW groups (n = 12 in each group). Except for those in the control group, D-galactose was subcutaneously injected into mice in the other groups to induce the aging model. The antiaging effect of LW was evaluated by the water maze test, electron microscopy, 16S rRNA sequencing, combined LC–MS and GC–MS metabolomics, and ELISA. Results Liuwei Dihuang decoction ameliorated cognitive dysfunction and hippocampal synaptic ultrastructure damage in aging mice. Moreover, LW decreased Proteobacteria abundance and increased gut microbiota diversity in aging mice. Metabolomic analysis showed that LW treatment was associated with the significantly differential abundance of 14 metabolites, which were mainly enriched in apelin signaling, sphingolipid metabolism, glycerophospholipid and other metabolic pathways. Additionally, LW affected lipid metabolism and oxidative stress in aging mice. Finally, we also found that LW-regulated microbial species such as Proteobacteria and Fibrobacterota had potential relationships with lipid metabolism, oxidative stress and hippocampal metabolites. Conclusion In brief, LW improved cognitive function in aging mice by regulating lipid metabolism and oxidative stress through restoration of the homeostasis of the microbiota-gut-brain axis.
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Affiliation(s)
- Baiyan Liu
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, China
- Hunan Academy of Chinese Medicine, Changsha, China
- *Correspondence: Baiyan Liu,
| | - Bowei Chen
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, China
| | - Jian Yi
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, China
- Hunan Academy of Chinese Medicine, Changsha, China
| | - Hongping Long
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, China
| | - Huiqiao Wen
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, China
| | - Fengming Tian
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, China
| | - Yingfei Liu
- The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, China
| | - Lan Xiao
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Lisong Li
- College of Information Science and Engineering, Hunan University of Chinese Medicine, Changsha, China
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39
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Babaei P, Hoseini R. Exercise training modulates adipokine dysregulations in metabolic syndrome. SPORTS MEDICINE AND HEALTH SCIENCE 2022; 4:18-28. [PMID: 35782776 PMCID: PMC9219261 DOI: 10.1016/j.smhs.2022.01.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/01/2022] [Accepted: 01/07/2022] [Indexed: 12/16/2022] Open
Abstract
Metabolic syndrome (MetS) is a cluster of risk factors for various metabolic diseases, and it is characterized by central obesity, dyslipidemia, hypertension, and insulin resistance. The core component for MetS is adipose tissue, which releases adipokines and influences physical health. Adipokines consist of pro and anti-inflammatory cytokines and contribute to various physiological functions. Generally, a sedentary lifestyle promotes fat accumulation and secretion of pro-inflammatory adipokines. However, regular exercise has been known to exert various beneficial effects on metabolic and cognitive disorders. Although the mechanisms underlying exercise beneficial effects in MetS are not fully understood, changes in energy expenditure, fat accumulation, circulatory level of myokines, and adipokines might be involved. This review article focuses on some of the selected adipokines in MetS, and their responses to exercise training considering possible mechanisms.
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Affiliation(s)
- Parvin Babaei
- Cellular & Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Rastegar Hoseini
- Department of Sports Physiology, Faculty of Sport Sciences, Razi University, Kermanshah, Iran
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40
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Palmer ES, Irwin N, O’Harte FPM. Potential Therapeutic Role for Apelin and Related Peptides in Diabetes: An Update. Clin Med Insights Endocrinol Diabetes 2022; 15:11795514221074679. [PMID: 35177945 PMCID: PMC8844737 DOI: 10.1177/11795514221074679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 01/04/2022] [Indexed: 01/10/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is an epidemic with an ever-increasing global prevalence. Current treatment strategies, although plentiful and somewhat effective, often fail to achieve desired glycaemic goals in many people, leading ultimately to disease complications. The lack of sustained efficacy of clinically-approved drugs has led to a heightened interest in the development of novel alternative efficacious antidiabetic therapies. One potential option in this regard is the peptide apelin, an adipokine that acts as an endogenous ligand of the APJ receptor. Apelin exists in various molecular isoforms and was initially studied for its cardiovascular benefits, however recent research suggests that it also plays a key role in glycaemic control. As such, apelin peptides have been shown to improve insulin sensitivity, glucose tolerance and lower circulating blood glucose. Nevertheless, native apelin has a short biological half-life that limits its therapeutic potential. More recently, analogues of apelin, particularly apelin-13, have been developed that possess a significantly extended biological half-life. These analogues may represent a promising target for future development of therapies for metabolic disease including diabetes and obesity.
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Affiliation(s)
- Ethan S Palmer
- Ethan S Palmer, Diabetes Research Group, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK.
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Tran K, Sainsily X, Côté J, Coquerel D, Couvineau P, Saibi S, Haroune L, Besserer-Offroy É, Flynn-Robitaille J, Resua Rojas M, Murza A, Longpré JM, Auger-Messier M, Lesur O, Bouvier M, Marsault É, Boudreault PL, Sarret P. Size-Reduced Macrocyclic Analogues of [Pyr 1]-apelin-13 Showing Negative Gα 12 Bias Still Produce Prolonged Cardiac Effects. J Med Chem 2022; 65:531-551. [PMID: 34982553 DOI: 10.1021/acs.jmedchem.1c01708] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
We previously reported a series of macrocyclic analogues of [Pyr1]-apelin-13 (Ape13) with increased plasma stability and potent APJ agonist properties. Based on the most promising compound in this series, we synthesized and then evaluated novel macrocyclic compounds of Ape13 to identify agonists with specific pharmacological profiles. These efforts led to the development of analogues 39 and 40, which possess reduced molecular weight (MW 1020 Da vs Ape13, 1534 Da). Interestingly, compound 39 (Ki 0.6 nM), which does not activate the Gα12 signaling pathway while maintaining potency and efficacy similar to Ape13 to activate Gαi1 (EC50 0.8 nM) and β-arrestin2 recruitment (EC50 31 nM), still exerts cardiac actions. In addition, analogue 40 (Ki 5.6 nM), exhibiting a favorable Gα12-biased signaling and an increased in vivo half-life (t1/2 3.7 h vs <1 min of Ape13), produces a sustained cardiac response up to 6 h after a single subcutaneous bolus injection.
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Affiliation(s)
- Kien Tran
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Xavier Sainsily
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Jérôme Côté
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - David Coquerel
- Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Pierre Couvineau
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montreal H3T 1J4, Québec, Canada
| | - Sabrina Saibi
- Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Lounès Haroune
- Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Élie Besserer-Offroy
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California 90095, United States
| | | | - Martin Resua Rojas
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Alexandre Murza
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Jean-Michel Longpré
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Mannix Auger-Messier
- Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Olivier Lesur
- Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Département de Médecine, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Michel Bouvier
- Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal, Montreal H3T 1J4, Québec, Canada
| | - Éric Marsault
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Pierre-Luc Boudreault
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Philippe Sarret
- Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.,Institut de Pharmacologie de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
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Mancin E, Tuliozi B, Pegolo S, Sartori C, Mantovani R. Genome Wide Association Study of Beef Traits in Local Alpine Breed Reveals the Diversity of the Pathways Involved and the Role of Time Stratification. Front Genet 2022; 12:746665. [PMID: 35058966 PMCID: PMC8764395 DOI: 10.3389/fgene.2021.746665] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022] Open
Abstract
Knowledge of the genetic architecture of key growth and beef traits in livestock species has greatly improved worldwide thanks to genome-wide association studies (GWAS), which allow to link target phenotypes to Single Nucleotide Polymorphisms (SNPs) across the genome. Local dual-purpose breeds have rarely been the focus of such studies; recently, however, their value as a possible alternative to intensively farmed breeds has become clear, especially for their greater adaptability to environmental change and potential for survival in less productive areas. We performed single-step GWAS and post-GWAS analysis for body weight (BW), average daily gain (ADG), carcass fleshiness (CF) and dressing percentage (DP) in 1,690 individuals of local alpine cattle breed, Rendena. This breed is typical of alpine pastures, with a marked dual-purpose attitude and good genetic diversity. Moreover, we considered two of the target phenotypes (BW and ADG) at different times in the individuals' life, a potentially important aspect in the study of the traits' genetic architecture. We identified 8 significant and 47 suggestively associated SNPs, located in 14 autosomal chromosomes (BTA). Among the strongest signals, 3 significant and 16 suggestive SNPs were associated with ADG and were located on BTA10 (50-60 Mb), while the hotspot associated with CF and DP was on BTA18 (55-62 MB). Among the significant SNPs some were mapped within genes, such as SLC12A1, CGNL1, PRTG (ADG), LOC513941 (CF), NLRP2 (CF and DP), CDC155 (DP). Pathway analysis showed great diversity in the biological pathways linked to the different traits; several were associated with neurogenesis and synaptic transmission, but actin-related and transmembrane transport pathways were also represented. Time-stratification highlighted how the genetic architectures of the same traits were markedly different between different ages. The results from our GWAS of beef traits in Rendena led to the detection of a variety of genes both well-known and novel. We argue that our results show that expanding genomic research to local breeds can reveal hitherto undetected genetic architectures in livestock worldwide. This could greatly help efforts to map genomic complexity of the traits of interest and to make appropriate breeding decisions.
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Wang Y, Chen D, Pang Y, Xu X, Guan X, Liu L. Value of Immunohistochemical Expression of Apelin, Succinate Dehydrogenase B, Chromogranin B, Human Epidermal Growth Factor Receptor-2, Contactin 4, and Succinyl-CoA Synthetase Subunit Beta in Differentiating Metastatic From Non-Metastatic Pheochromocytoma and Paraganglioma. Front Endocrinol (Lausanne) 2022; 13:882906. [PMID: 35574028 PMCID: PMC9096168 DOI: 10.3389/fendo.2022.882906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 03/23/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE We aimed to retrospectively collect pathologically identified pheochromocytoma and paraganglioma (PPGL) tumor tissues from our center and investigate the expression of apelin and succinyl-CoA synthetase subunit beta (SUCLG2), human epidermal growth factor receptor-2 (HER2 or ERBB-2), contactin 4 (CNTN4), chromogranin B (CHGB), and succinate dehydrogenase B (SDHB) in metastatic and non-metastatic PPGLs, for exploring their roles in the diagnosis of metastatic PPGLs. METHODS A total of 369 patients with pathologically and surgically confirmed PPGLs at Xiangya Hospital, Central South University, between June 2010 and June 2020 were retrospectively included. Sixty patients-12 patients with metastatic PPGLs and 48 patients with non-metastatic PPGLs-were selected through propensity score matching (1:4) to reduce the effect of PPGL type, sex, and age. We observed and quantified the expression of apelin, SDHB, CHGB, ERBB-2, CNTN4, and SUCLG2 in paraffin-embedded samples using immunohistochemical staining. RESULTS No significant differences were observed between the metastatic group and non-metastatic group with respect to the expression of CNTN4 and SUCLG2. The expression of apelin, SDHB, CHGB, and ERBB-2 was significantly different between the two groups. The expression of apelin, SDHB, and CHGB was significantly lower in the metastatic group than that in the non-metastatic group (P < 0.001). ERBB-2 expression was significantly higher in the metastatic group than in the non-metastatic group (P = 0.042). Kaplan-Meier analysis revealed that patients with negative expression of apelin, SDHB, and CHGB showed significantly lower metastasis-free survival than those with positive expression. Multivariate Cox analysis revealed that SDHB and CHGB levels were independently associated with metastasis-free survival. CONCLUSION The expression levels of apelin, CHGB, SDHB, and ERBB-2 may be predictive biomarkers for the diagnosis of metastatic PPGLs. Patients with negative expression of apelin, CHGB, and SDHB should be subjected to frequent postoperative follow-up procedures.
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Affiliation(s)
- Yong Wang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Danlei Chen
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Yingxian Pang
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaowen Xu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Guan
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Xiao Guan, ; Longfei Liu,
| | - Longfei Liu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Xiao Guan, ; Longfei Liu,
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Marczewski K, Gospodarczyk N, Gospodarczyk A, Widuch M, Tkocz M. APELIN IN HEART FAILURE. WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2022; 75:2501-2506. [PMID: 36472288 DOI: 10.36740/wlek202210130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
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.
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Affiliation(s)
- Kamil Marczewski
- DEPARTMENT OF EMERGENCY MEDICINE, MEDICAL UNIVERSITY OF SILESIA, POLAND
| | | | | | - Michał Widuch
- DEPARTMENT OF BIOCHEMISTRY, MEDICAL UNIVERSITY OF SILESIA, POLAND
| | - Michał Tkocz
- UROLOGICAL DEPARTMENT OF MUNICIPAL HOSPITAL, MEDICAL UNIVERSITY OF SILESIA, POLAND
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Hao L, Bello NT. Reduced Body Fat and Epididymal Adipose Apelin Expression Associated With Raspberry Ketone [4-(4-Hydroxyphenyl)-2-Butanone] Weight Gain Prevention in High-Fat-Diet Fed Mice. Front Physiol 2021; 12:771816. [PMID: 34887778 PMCID: PMC8650585 DOI: 10.3389/fphys.2021.771816] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/19/2021] [Indexed: 11/18/2022] Open
Abstract
Raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] is a natural aromatic compound found in raspberries and other fruits. Raspberry ketone (RK) is synthetically produced for use as a commercial flavoring agent. In the United States and other markets, it is sold as a dietary supplement for weight control. The potential of RK to reduce or prevent excessive weight gain is unclear and could be a convergence of several different actions. This study sought to determine whether acute RK can immediately delay carbohydrate hyperglycemia and reduce gastrointestinal emptying. In addition, we explored the metabolic signature of chronic RK to prevent or remedy the metabolic effects of diet-induced weight gain. In high-fat diet (HFD; 45% fat)-fed male mice, acute oral gavage of RK (200 mg/kg) reduced hyperglycemia from oral sucrose load (4 g/kg) at 15 min. In HFD-fed female mice, acute oral RK resulted in an increase in blood glucose at 30 min. Chronic daily oral gavage of RK (200 mg/kg) commencing with HFD access (HFD_RK) for 11 weeks resulted in less body weight gain and reduced fat mass compared with vehicle treated (HFD_Veh) and chronic RK starting 4 weeks after HFD access (HFD_RKw4) groups. Compared with a control group fed a low-fat diet (LFD; 10% fat) and dosed with vehicle (LFD_Veh), glucose AUC of an oral glucose tolerance test was increased with HFD_Veh, but not in HFD_RK or HFD_RKw4. Apelin (Apln) gene expression in epididymal white adipose tissue was increased in HFD_Veh, but reduced to LFD_Veh levels in the HFD_RK group. Peroxisome proliferator activated receptor alpha (Ppara) gene expression was increased in the hepatic tissue of HFD_RK and HFD_RKw4 groups. Overall, our findings suggest that long term daily use of RK prevents diet-induced weight gain, normalizes high-fat diet-induced adipose Apln, and increases hepatic Ppara expression.
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Affiliation(s)
- Lihong Hao
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States
| | - Nicholas T Bello
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States
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Zouhal H, Zare-Kookandeh N, Haghighi MM, Daraei A, de Sousa M, Soltani M, Abderrahman AB, M Tijani J, Hackney AC, Laher I, Saeidi A. Physical activity and adipokine levels in individuals with type 2 diabetes: A literature review and practical applications. Rev Endocr Metab Disord 2021; 22:987-1011. [PMID: 33931803 DOI: 10.1007/s11154-021-09657-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2021] [Indexed: 12/13/2022]
Abstract
We review the effects of acute and long-term physical activity on adipokine levels in individuals with type 2 diabetes (T2D). Three electronic databases were searched. Studies made in animal models were excluded, while studies based on participants with and without T2D, and also studies with type 1 diabetes were included. Of the 2,450 citations, 63 trials, including randomised control trials, cross-sectional and longitudinal studies, met our inclusion criteria. Seventy and five percent of studies reported the effects of physical activity on tumor necrosis factor-alpha (TNFα), interleukin 6 (IL-6), adiponectin, visfatin, omentin-1, and leptin levels. There are no robust results due to variations in exercise modality, intensity, duration, and also differences in cohort characteristics in the literature. Only four studies described the effects of an acute session of physical activity on adipokine levels. Overall, physical activity improves diabetes status by regulating adipokine levels. However, long-term aerobic + resistance training combined with dietary modifications is likely to be a more effective strategy for improving adipokines profiles in patients with type 2 diabetes.
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Affiliation(s)
- Hassane Zouhal
- M2S (Laboratoire Mouvement, University of Rennes, 1274, F-35000, Sport, Santé), France.
| | | | | | - Ali Daraei
- Department of Biological Sciences in Sport, Faculty of Sports Sciences and Health, Shahid Beheshti University, Tehran, Iran
| | | | - Mohammad Soltani
- Department of Biological Sciences in Sport, Faculty of Sports Sciences and Health, Shahid Beheshti University, Tehran, Iran
| | | | | | - Anthony C Hackney
- Department of Exercise & Sport Science, Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA
| | - Ismail Laher
- Faculty of Medicine, Department of Anesthesiology, The University of British Columbia, Pharmacology & Therapeutics, Vancouver, Canada
| | - Ayoub Saeidi
- Department of Physical Education and Sport Sciences, University of Kurdistan, Sanandaj, Iran.
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Chapman FA, Nyimanu D, Maguire JJ, Davenport AP, Newby DE, Dhaun N. The therapeutic potential of apelin in kidney disease. Nat Rev Nephrol 2021; 17:840-853. [PMID: 34389827 PMCID: PMC8361827 DOI: 10.1038/s41581-021-00461-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2021] [Indexed: 02/07/2023]
Abstract
Chronic kidney disease (CKD) is a leading cause of global morbidity and mortality and is independently associated with cardiovascular disease. The mainstay of treatment for CKD is blockade of the renin-angiotensin-aldosterone system (RAAS), which reduces blood pressure and proteinuria and slows kidney function decline. Despite this treatment, many patients progress to kidney failure, which requires dialysis or kidney transplantation, and/or die as a result of cardiovascular disease. The apelin system is an endogenous physiological regulator that is emerging as a potential therapeutic target for many diseases. This system comprises the apelin receptor and its two families of endogenous ligands, apelin and elabela/toddler. Preclinical and clinical studies show that apelin receptor ligands are endothelium-dependent vasodilators and potent inotropes, and the apelin system has a reciprocal relationship with the RAAS. In preclinical studies, apelin regulates glomerular haemodynamics and acts on the tubule to promote aquaresis. In addition, apelin is protective in several kidney injury models. Although the apelin system has not yet been studied in patients with CKD, the available data suggest that apelin is a promising potential therapeutic target for kidney disease.
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Affiliation(s)
- Fiona A Chapman
- BHF/University Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh, UK
- Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Duuamene Nyimanu
- Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Centre for Clinical Investigation, University of Cambridge, Cambridge, UK
| | - Janet J Maguire
- Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Centre for Clinical Investigation, University of Cambridge, Cambridge, UK
| | - Anthony P Davenport
- Division of Experimental Medicine and Immunotherapeutics, Addenbrooke's Centre for Clinical Investigation, University of Cambridge, Cambridge, UK
| | - David E Newby
- BHF/University Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh, UK
| | - Neeraj Dhaun
- BHF/University Centre for Cardiovascular Science, The Queen's Medical Research Institute, Edinburgh, UK.
- Department of Renal Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK.
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Alipanah-Moghadam R, Mehri A, Manafi F, Malekzadeh V, Nemati A, Aghamohammadi V, Mazani M, Cain CTC, Mohammadzadeh-Vardin M. Andrographolide, a novel inducer of apelin gene expression. JOURNAL OF ETHNOPHARMACOLOGY 2021; 280:114487. [PMID: 34352330 DOI: 10.1016/j.jep.2021.114487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/17/2021] [Accepted: 08/02/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Andrographis paniculata (A. paniculata) has been used as a traditional medicine in Asia and Scandinavia for centuries to remedy several illnesses. It has since been shown to possess antibacterial, antifungal, antiviral, anti-neoplasm, hepatoprotective, hypoglycemic, hypocholesterolemic, and energetic effects. AIMS OF THE STUDY This study sought to investigate the effect of Andrographolide on apelin gene expression and serum levels of glucose. MATERIALS AND METHODS In this study, 18 male rats were used. They were divided into three groups of six, including i) negative control group, ii) 3.5 mg/kg Andrographolide group, and iii) 7 mg/kg Andrographolide group. Apelin gene expression was investigated by real-time PCR method. Serum levels of glucose were measured by the photometric method. RESULTS The results of this study revealed that 3.5 and 7 mg doses per kg of body weight of andrographolide, for six days, significantly increased hepatic expression of apelin gene in male Wistar rats, as compared with the control group (p < 0.05). Serum levels of glucose at doses of 3.5 and 7 mg/kg of andrographolide, and in the control group, were 71.5 ± 8.96, 51.5 ± 2.64, and 93.87 ± 14.27 mg/dl, respectively. Andrographolide induced a decrease in serum levels of HDL-c and an increase in LDL-c/HDL-c ratio. CONCLUSIONS Our results suggest that Andrographolide can elicit an increase of hepatic apelin gene expression and a decrease in serum levels of blood glucose.
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Affiliation(s)
- R Alipanah-Moghadam
- Ardabil University of Medical Sciences, Department of Clinical Biochemistry, Ardabil, Iran
| | - A Mehri
- Ardabil University of Medical Sciences, Department of Clinical Biochemistry, Ardabil, Iran
| | - F Manafi
- Ardabil University of Medical Sciences, Department of Clinical Biochemistry, Ardabil, Iran
| | - V Malekzadeh
- Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.
| | - A Nemati
- Ardabil University of Medical Sciences, Department of Clinical Biochemistry, Ardabil, Iran.
| | - V Aghamohammadi
- Department of Nutrition, Khalkhal University of Medical Sciences, Khalkhal, Iran.
| | - M Mazani
- Ardabil University of Medical Sciences, Department of Clinical Biochemistry, Ardabil, Iran
| | - C T Clark Cain
- Centre for Intelligent Healthcare, Coventry University, Coventry, CV1 4FB, UK
| | - M Mohammadzadeh-Vardin
- Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
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Apelin expression deficiency in mice contributes to vascular stiffening by extracellular matrix remodeling of the aortic wall. Sci Rep 2021; 11:22278. [PMID: 34782679 PMCID: PMC8593139 DOI: 10.1038/s41598-021-01735-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 10/25/2021] [Indexed: 01/15/2023] Open
Abstract
Numerous recent studies have shown that in the continuum of cardiovascular diseases, the measurement of arterial stiffness has powerful predictive value in cardiovascular risk and mortality and that this value is independent of other conventional risk factors, such as age, cholesterol levels, diabetes, smoking, or average blood pressure. Vascular stiffening is often the main cause of arterial hypertension (AHT), which is common in the presence of obesity. However, the mechanisms leading to vascular stiffening, as well as preventive factors, remain unclear. The aim of the present study was to investigate the consequences of apelin deficiency on the vascular stiffening and wall remodeling of aorta in mice. This factor freed by visceral adipose tissue, is known for its homeostasic role in lipid and vascular metabolisms, or again in inflammation. We compared the level of metabolic markers, inflammation of white adipose tissue (WAT), and aortic wall remodeling from functional and structural approaches in apelin-deficient and wild-type (WT) mice. Apelin-deficient mice were generated by knockout of the apelin gene (APL-KO). From 8 mice by groups, aortic stiffness was analyzed by pulse wave velocity measurements and by characterizations of collagen and elastic fibers. Mann-Whitney statistical test determined the significant data (p < 5%) between groups. The APL-KO mice developed inflammation, which was associated with significant remodeling of visceral WAT, such as neutrophil elastase and cathepsin S expressions. In vitro, cathepsin S activity was detected in conditioned medium prepared from adipose tissue of the APL-KO mice, and cathepsin S activity induced high fragmentations of elastic fiber of wild-type aorta, suggesting that the WAT secretome could play a major role in vascular stiffening. In vivo, remodeling of the extracellular matrix (ECM), such as collagen accumulation and elastolysis, was observed in the aortic walls of the APL-KO mice, with the latter associated with high cathepsin S activity. In addition, pulse wave velocity (PWV) and AHT were increased in the APL-KO mice. The latter could explain aortic wall remodeling in the APL-KO mice. The absence of apelin expression, particularly in WAT, modified the adipocyte secretome and facilitated remodeling of the ECM of the aortic wall. Thus, elastolysis of elastic fibers and collagen accumulation contributed to vascular stiffening and AHT. Therefore, apelin expression could be a major element to preserve vascular homeostasis.
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Apelin-13-Mediated AMPK ameliorates endothelial barrier dysfunction in acute lung injury mice via improvement of mitochondrial function and autophagy. Int Immunopharmacol 2021; 101:108230. [PMID: 34655850 DOI: 10.1016/j.intimp.2021.108230] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/02/2021] [Accepted: 10/04/2021] [Indexed: 01/04/2023]
Abstract
Maintaining the pulmonary endothelial barrier that prevents the exudation of inflammatory factors and proteins is the key to the treatment of acute lung injury (ALI). Apelin-13 plays an important role in vascular diseases; however, the protective effects of Apelin-13 on ALI with pulmonary endothelial barrier are unknown. Therefore, mice and human umbilical vein endothelial cells (HUVECs) were injured by LPS following Apelin-13 administration. ALI mice showed reduced pulmonary vascular permeability, adhesion junction, mitochondrial function, mitochondrial biogenesis, and autophagy compared to the control group. Apelin-13 administration in ALI mice ameliorated LPS-induced lung injury, pulmonary vascular permeability, mitochondrial function, and promoted autophagic flux in mice and HUVECs. However, the effect of Apelin-13 was reduced after AMPK inhibition using Compound C. These data suggest that Apelin-13 ameliorates pulmonary vascular permeability in mice with ALI induced by LPS, which may be related to enhanced phosphorylation of AMPK to regulate mitochondrial function and autophagy.
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