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Ricci A, Cataldi A, Gallorini M, di Giacomo V, Rapino M, Di Pietro N, Mantarro M, Piattelli A, Zara S. Angiogenic Events Positively Modulated by Complex Magnetic Fields in an In Vitro Endothelial Cell Model. Cells 2025; 14:332. [PMID: 40072061 PMCID: PMC11898498 DOI: 10.3390/cells14050332] [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: 11/28/2024] [Revised: 02/19/2025] [Accepted: 02/20/2025] [Indexed: 03/15/2025] Open
Abstract
The vascular system is primarily responsible for orchestrating the underlying healing processes to achieve tissue regeneration, thus the promotion of angiogenic events could be a useful strategy to repair injured tissues. Among several approaches to stimulate tissue regeneration, non-invasive devices are currently widely diffused. Complex Magnetic Fields (CMFs) are innovative pulsed multifrequency electromagnetic fields used for their promising results in clinical applications, such as diabetic foot treatment or edema resorption. Nevertheless, few papers are available demonstrating the biological mechanisms involved. In this paper, in order to understand CMFs' capability to promote angiogenic events, Regenerative Tissue Program (RTP) was applied to an in vitro Endothelial Cells (ECs) model. ECs were stimulated with (I) 2 RTP consecutive cycles, (II) with an interval of 8 h (T0 + T8), or (III) 24 h (T0 + T24) from one cycle to another. Results demonstrate that (I) extracellular matrix degradation is promoted through matrix metalloproteinases 2 and 9 modulation, leading to an increased cell migratory capability; (II) CMFs support EC growth, activating Integrin β1-Erk-Cdk2 pathway and sustaining G1/S transition; (III) vessel morphogenesis is promoted when CMFs are applied. In conclusion, the promising clinical results are supported by in vitro analyses which evidence that main angiogenic events are stimulated by CMFs.
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Affiliation(s)
- Alessia Ricci
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.C.); (M.G.); (V.d.G.); (S.Z.)
| | - Amelia Cataldi
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.C.); (M.G.); (V.d.G.); (S.Z.)
- Ud’A Techlab, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | - Marialucia Gallorini
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.C.); (M.G.); (V.d.G.); (S.Z.)
| | - Viviana di Giacomo
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.C.); (M.G.); (V.d.G.); (S.Z.)
| | - Monica Rapino
- Unit of Chieti, Genetic Molecular Institute of CNR, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
| | - Natalia Di Pietro
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy;
- Center for Advanced Studies and Technologies (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy
| | | | - Adriano Piattelli
- School of Dentistry, UniCamillus-Saint Camillus International University of Health and Medical Sciences, 00131 Rome, Italy;
| | - Susi Zara
- Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, 66100 Chieti, Italy; (A.C.); (M.G.); (V.d.G.); (S.Z.)
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Buncha V, Lang L, Fopiano KA, Ilatovskaya DV, Kapuku G, Verin AD, Bagi Z. Endothelial cell-selective adhesion molecule deficiency exhibits increased pulmonary vascular resistance due to impaired endothelial nitric oxide signaling. Am J Physiol Heart Circ Physiol 2025; 328:H283-H293. [PMID: 39740345 DOI: 10.1152/ajpheart.00593.2024] [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: 08/29/2024] [Revised: 12/02/2024] [Accepted: 12/19/2024] [Indexed: 01/02/2025]
Abstract
Endothelial cell-selective adhesion molecule (ESAM) is a member of tight junction molecules, highly abundant in the heart and the lung, and plays a role in regulating endothelial cell permeability. We previously reported that mice with genetic ESAM deficiency (ESAM-/-) exhibit coronary microvascular dysfunction leading to the development of left ventricular diastolic dysfunction. Here, we hypothesize that ESAM-/- mice display impairments in the pulmonary vasculature, affecting the overall pulmonary vascular resistance (PVR). We utilized ESAM-/- mice and employed isolated, ventilated, and perfused whole lung preparation to assess PVR independently of cardiac function. PVR was assessed in response to stepwise increases in flow, and also in response to perfusion of the endothelium-dependent agonist, bradykinin, the thromboxane analog, U46619, and the nitric oxide (NO) donor sodium nitroprusside (SNP). We found that PVR, at every applied flow rate, is significantly elevated in ESAM-/- mice compared with WT mice. Bradykinin-induced reduction in PVR and U46619-induced increase in PVR were both diminished in ESAM-/- mice, whereas SNP-induced responses were similar in wild-type (WT) and ESAM-/- mice. Inhibition of NO synthase with N(ω)-nitro-l-arginine methyl ester increased agonist-induced PVR in WT but not in ESAM-/- mice. Pulmonary arteries isolated from ESAM-/- mice exhibited a reduced level of phospho-Ser473-Akt and phospho-Ser1177-eNOS. Furthermore, in human lung microvascular endothelial cells cultured under flow conditions, we found that siRNA-mediated knockdown of ESAM impaired fluid shear stress-induced endothelial cell alignment. Thus, we suggest that ESAM plays an important role in the endothelium-dependent, flow/shear stress- and vasoactive agonist-stimulated, and NO-mediated maintenance of PVR in mice.NEW & NOTEWORTHY Our study reveals a novel role for ESAM in contributing to the maintenance of pulmonary vascular resistance under normal physiological conditions. Employing mice with global genetic deficiency of ESAM and using isolated whole lung preparation, we show significant impairments in nitric oxide-mediated pulmonary artery function. In vitro cell culture studies demonstrate impaired fluid shear stress-induced cell alignment in human lung endothelial cells after siRNA-mediated ESAM knockdown.
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Affiliation(s)
- Vadym Buncha
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States
| | - Liwei Lang
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States
| | - Katie Anne Fopiano
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States
| | - Daria V Ilatovskaya
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States
| | - Gaston Kapuku
- Department of Medicine, Georgia Prevention Institute, Medical College of Georgia, Augusta University, Augusta, Georgia, United States
| | - Alexander D Verin
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia, United States
| | - Zsolt Bagi
- Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, United States
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Chen X, Song Y, Hong Y, Zhang X, Li Q, Zhou H. "NO" controversy?: A controversial role in insulin signaling of diabetic encephalopathy. Mol Cell Endocrinol 2024; 593:112346. [PMID: 39151653 DOI: 10.1016/j.mce.2024.112346] [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] [Received: 03/22/2024] [Revised: 06/14/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
Insulin, a critical hormone in the human body, exerts its effects by binding to insulin receptors and regulating various cellular processes. While nitric oxide (NO) plays an important role in insulin secretion and acts as a mediator in the signal transduction pathway between upstream molecules and downstream effectors, holds a significant position in the downstream signal network of insulin. Researches have shown that the insulin-NO system exhibits a dual regulatory effect within the central nervous system, which is crucial in the regulation of diabetic encephalopathy (DE). Understanding this system holds immense practical importance in comprehending the targets of existing drugs and the development of potential therapeutic interventions. This review extensively examines the characterization of insulin, NO, Nitric oxide synthase (NOS), specific NO pathway, their interconnections, and the mechanisms underlying their regulatory effects in DE, providing a reference for new therapeutic targets of DE.
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Affiliation(s)
- Xi Chen
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Ying Song
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China; Hangzhou King's Bio-pharmaceutical Technology Co., Ltd, Hangzhou, Zhejiang, 310007, China.
| | - Ye Hong
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Xiaomin Zhang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Qisong Li
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
| | - Hongling Zhou
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China
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Tong KL, Mahmood Zuhdi AS, Wong PF. The role of miR-134-5p in 7-ketocholesterol-induced human aortic endothelial dysfunction. EXCLI JOURNAL 2024; 23:1073-1090. [PMID: 39391056 PMCID: PMC11464864 DOI: 10.17179/excli2024-7342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 08/22/2024] [Indexed: 10/12/2024]
Abstract
Atherosclerotic cardiovascular diseases are the leading causes of morbidity and mortality worldwide. In our previous study, a panel of miRNA including miR-134-5p was deregulated in young acute coronary syndrome (ACS) patients. However, the roles of these ACS-associated miRNAs in endothelial dysfunction, an early event preceding atherosclerosis, remain to be investigated. In the present study, human aortic endothelial cells (HAECs) were treated with 7-ketocholesterol (7-KC) to induce endothelial dysfunction. Following treatment with 20 μg/ml 7-KC, miR-134-5p was significantly up-regulated and endothelial nitric oxide synthase (eNOS) expression was suppressed. Endothelial barrier disruption was evidenced by the deregulation of adhesion molecules including the activation of focal adhesion kinase (FAK), down-regulation of VE-cadherin, up-regulation of adhesion molecules (E-selectin and ICAM-1), increased expression of inflammatory genes (IL1B, IL6 and COX2) and AKT activation. Knockdown of miR-134-5p in 7-KC-treated HAECs attenuated the suppression of eNOS, the activation of AKT, the down-regulation of VE-cadherin and the up-regulation of E-selectin. In addition, the interaction between miR-134-5p and FOXM1 mRNA was confirmed by the enrichment of FOXM1 transcripts in the pull-down miRNA-mRNA complex. Knockdown of miR-134-5p increased FOXM1 expression whereas transfection with mimic miR-134-5p decreased FOXM1 protein expression. In summary, the involvement of an ACS-associated miRNA, miR-134-5p in endothelial dysfunction was demonstrated. Findings from this study could pave future investigations into utilizing miRNAs as a supplementary tool in ACS diagnosis or as targets for the development of therapeutics.
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Affiliation(s)
- Kind-Leng Tong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
| | | | - Pooi-Fong Wong
- Department of Pharmacology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia
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Bozoni FT, Santos NCM, de Souza Paula Caetano E, Mariani NAP, da Rocha ALV, Silva EJR, Dias-Junior CA. Maternal pregnancy hypertension impairs nitric oxide formation and results in increased arterial blood pressure in first-generation offspring female rats. Pregnancy Hypertens 2024; 36:101130. [PMID: 38805888 DOI: 10.1016/j.preghy.2024.101130] [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: 01/29/2024] [Revised: 05/19/2024] [Accepted: 05/22/2024] [Indexed: 05/30/2024]
Abstract
OBJECTIVES Maternal endothelial dysfunction in pregnancy hypertension is related to impairment of nitric oxide (NO) formation. However, NO levels and hemodynamic repercussions on the female offspring remain unclear. Therefore, this study hypothesized that maternal pregnancy hypertension reduces circulating NO metabolites and increases arterial blood pressure in first-generation offspring female rats. STUDY DESIGN Descendant female rats were distributed in four groups as follows: virgin offspring of normotensive (VN) and hypertensive (VH) mothers and pregnant offspring of normotensive (PN) and hypertensive (PH) mothers. Hemodynamic and biochemical analyses were performed. MAIN OUTCOME MEASURES The systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR), and body weight were measured. NO metabolites in plasma, NO formation in human umbilical vein endothelial cells (HUVECs) incubated with plasma, and endothelial NO synthase (eNOS) expression in aortas were determined. RESULTS Increased SBP, DBP, and reduced HR were found on the 60 days of life in the VH group, whereas the PH group showed increased SBP and HR on pregnancy day 7. All groups showed no differences in body weight gain and eNOS expression. Plasma levels of NO metabolites were increased in the PN compared to the other groups. Increases in the NO formation were greater in HUVECs incubated with plasma from VN and PN groups compared to the VH and PH groups. CONCLUSIONS Female virgin and pregnant first-generation offspring rats from hypertensive pregnant mothers may have negative cardiovascular repercussions featured by increases in SBP, and possibly impaired NO formation is involved.
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Affiliation(s)
- Filipe Trindade Bozoni
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil
| | - Natália Calixto Miranda Santos
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil
| | - Ediléia de Souza Paula Caetano
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil
| | - Noemia Aparecida Partelli Mariani
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil
| | - Ananda Lini Vieira da Rocha
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil
| | - Erick José Ramo Silva
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil
| | - Carlos Alan Dias-Junior
- Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil.
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Zhou B, Sh G, Xie D, Zhao X, Hao B, Liu D, Wang M, Wu L, Lin L, Qian X. Ginsenoside Rb1 prevents age-related endothelial senescence by modulating SIRT1/caveolin-1/enos signaling pathway. Heliyon 2024; 10:e24586. [PMID: 38322899 PMCID: PMC10844051 DOI: 10.1016/j.heliyon.2024.e24586] [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: 08/15/2023] [Revised: 01/09/2024] [Accepted: 01/10/2024] [Indexed: 02/08/2024] Open
Abstract
Background Advancing age is one of the independent risk factors for cardiovascular disorders. The Compendium of Materia Medica, a classic book on traditional Chinese medicine, states that ginseng "harmonizes the five internal organs, calming the spirit and prolonging the years of life." Considered one of the primary bioactive compounds derived from Panax ginseng, ginsenoside Rb1 (g-Rb1) has been scientifically suggested to possess anti-senescence efficacy. More research is needed to explore the vascular pharmacological activity and potential clinical application value of g-Rb1. Aims of the study Our previous study demonstrated that g-Rb1 could mitigate cellular senescence via the SIRT1/eNOS pathway. This study was performed to explore the exact mechanisms by which g-Rb1 modulates the SIRT1/eNOS pathway. Materials and methods We used human primary umbilical vein endothelial cells (HUVECs) to establish a replicative ageing model. Real-time (RT‒PCR), western blotting, small interfering RNA (siRNA), and immunoprecipitation were conducted to detect the effect of g-Rb1 on the SIRT1/caveolin-1/eNOS axis. Results G-Rb1 increased NO production and alleviated replicative senescence of HUVECs. The application of g-Rb1 elevated the mRNA and protein abundance of both SIRT1 and eNOS while concomitantly suppressing the expression of caveolin-1. Inhibition of SIRT1 and eNOS by siRNAs suppressed the anti-senescence function of g-Rb1, while caveolin-1 siRNA could enhance it. G-Rb1 decreased the acetylation level of caveolin-1 and increased NO production, which was suppressed by SIRT1 siRNA. Both g-Rb1 and caveolin-1 siRNA could reduce the acetylation level of eNOS and increase NO production. Conclusion G-Rb1 prevents age-related endothelial senescence by modulating the SIRT1/caveolin-1/eNOS signaling pathway.
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Affiliation(s)
| | | | | | | | - Baoshun Hao
- The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Dinhui Liu
- The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Min Wang
- The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Lin Wu
- The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Liangying Lin
- The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoxian Qian
- The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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González I, Lindner C, Schneider I, Diaz E, Morales MA, Rojas A. Emerging and multifaceted potential contributions of polyphenols in the management of type 2 diabetes mellitus. World J Diabetes 2024; 15:154-169. [PMID: 38464365 PMCID: PMC10921170 DOI: 10.4239/wjd.v15.i2.154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/16/2023] [Accepted: 01/19/2024] [Indexed: 02/04/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with a considerable impact on human life, long-term health expenditures, and substantial health losses. In this context, the use of dietary polyphenols to prevent and manage T2DM is widely documented. These dietary compounds exert their beneficial effects through several actions, including the protection of pancreatic islet β-cell, the antioxidant capacities of these molecules, their effects on insulin secretion and actions, the regulation of intestinal microbiota, and their contribution to ameliorate diabetic complications, particularly those of vascular origin. In the present review, we intend to highlight these multifaceted actions and the molecular mechanisms by which these plant-derived secondary metabolites exert their beneficial effects on type 2 diabetes patients.
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Affiliation(s)
- Ileana González
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile
| | - Cristian Lindner
- Department of Radiology, Faculty of Medicine, University of Concepción, Concepción 4030000, Chile
| | - Ivan Schneider
- Centre of Primary Attention, South Metropolitan Health Service, Santiago 3830000, Chile
| | - Erik Diaz
- Faculty of Medicine, Catholic University of Maule, Talca 3460000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
| | - Armando Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile
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8
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Yan BH, Xu QX, Ge X, Gao MT, Li Y, Guo L, Hu P, Pan Y. Molecular mechanisms of Chengshi Beixie Fenqing Decoction based on network pharmacology: pivotal roles of relaxin signaling pathway and its associated target proteins against Benign prostatic hyperplasia. J Biomol Struct Dyn 2024; 42:2075-2093. [PMID: 37102991 DOI: 10.1080/07391102.2023.2203237] [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: 01/13/2023] [Accepted: 04/10/2023] [Indexed: 04/28/2023]
Abstract
Benign prostatic hyperplasia (BPH) is a common disease that affects the quality of life of middle-aged and older men. We investigated the therapeutical effects of Chengshi Beixie Fenqing Decoction (CBFD), a classic traditional Chinese medicine prescription, on BPH through in vivo model and network pharmacology. Bioactives in CBFD were detected through UPLC-Q-Tof-MS/MS and GC-MS, and filtered by the modified Lipinski's rule. Target proteins associated with the filtered compounds and BPH are selected from public databases. Venn diagram identified the overlapping target proteins between the bioactives-interacted target proteins and the BPH-targeted proteins. The bioactive-protein interactive networking of BPH was analyzed through the KEGG pathway on STRING to identify potential ligand-target and visualized the rich factors on the R packet. After that, the molecular docking test (MDT) was performed between bioactives and target proteins. It showed that the mechanism of CBFD against BPH was related to 104 signaling pathways of 42 compounds. AKT1, 6-demethyl-4'-methyl-N-methylcoclaurine and relaxin signaling pathways were selected as a hub target, key bioactivitie and hub signaling pathway, respectively. In addition, three major compounds, 6-demethyl-4'-methyl-N-methylcoclaurine, isoliensinine and liensinine, had the highest affinity on MDT for the three crucial target proteins, AKT1, JUN and MAPK1. These proteins were associated with the relaxin signaling pathway, which regulated the level of nitric oxide and is implicated in both BPH development and CBFD. We concluded that the three key bioactivities found in Plumula nelumbinis of CBFD may contribute to improving BPH condition by activating the relaxin signaling pathways.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Bing-Hui Yan
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Qi-Xuan Xu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xiao Ge
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, China
| | - Ming-Tong Gao
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yun Li
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Liang Guo
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Po Hu
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yang Pan
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
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AlZaim I, de Rooij LPMH, Sheikh BN, Börgeson E, Kalucka J. The evolving functions of the vasculature in regulating adipose tissue biology in health and obesity. Nat Rev Endocrinol 2023; 19:691-707. [PMID: 37749386 DOI: 10.1038/s41574-023-00893-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/17/2023] [Indexed: 09/27/2023]
Abstract
Adipose tissue is an endocrine organ and a crucial regulator of energy storage and systemic metabolic homeostasis. Additionally, adipose tissue is a pivotal regulator of cardiovascular health and disease, mediated in part by the endocrine and paracrine secretion of several bioactive products, such as adipokines. Adipose vasculature has an instrumental role in the modulation of adipose tissue expansion, homeostasis and metabolism. The role of the adipose vasculature has been extensively explored in the context of obesity, which is recognized as a global health problem. Obesity-induced accumulation of fat, in combination with vascular rarefaction, promotes adipocyte dysfunction and induces oxidative stress, hypoxia and inflammation. It is now recognized that obesity-associated endothelial dysfunction often precedes the development of cardiovascular diseases. Investigations have revealed heterogeneity within the vascular niche and dynamic reciprocity between vascular and adipose cells, which can become dysregulated in obesity. Here we provide a comprehensive overview of the evolving functions of the vasculature in regulating adipose tissue biology in health and obesity.
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Affiliation(s)
- Ibrahim AlZaim
- Department of Biomedicine, Aarhus University, Aarhus C, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Laura P M H de Rooij
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Bilal N Sheikh
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich, Leipzig, Germany
- Medical Faculty, University of Leipzig, Leipzig, Germany
| | - Emma Börgeson
- Department of Biomedicine, Aarhus University, Aarhus C, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Joanna Kalucka
- Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
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10
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Trejo-Moreno C, Alvarado-Ojeda ZA, Méndez-Martínez M, Cruz-Muñoz ME, Castro-Martínez G, Arrellín-Rosas G, Zamilpa A, Jimenez-Ferrer JE, Baez Reyes JC, Fragoso G, Salgado GR. Aqueous Fraction from Cucumis sativus Aerial Parts Attenuates Angiotensin II-Induced Endothelial Dysfunction In Vivo by Activating Akt. Nutrients 2023; 15:4680. [PMID: 37960332 PMCID: PMC10649625 DOI: 10.3390/nu15214680] [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: 10/12/2023] [Revised: 10/27/2023] [Accepted: 11/02/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Endothelial dysfunction (ED) is a marker of vascular damage and a precursor of cardiovascular diseases such as hypertension, which involve inflammation and organ damage. Nitric oxide (NO), produced by eNOS, which is induced by pAKT, plays a crucial role in the function of a healthy endothelium. METHODS A combination of subfractions SF1 and SF3 (C4) of the aqueous fraction from Cucumis sativus (Cs-Aq) was evaluated to control endothelial dysfunction in vivo and on HMEC-1 cells to assess the involvement of pAkt in vitro. C57BL/6J mice were injected daily with angiotensin II (Ang-II) for 10 weeks. Once hypertension was established, either Cs-AqC4 or losartan was orally administered along with Ang-II for a further 10 weeks. Blood pressure (BP) was measured at weeks 0, 5, 10, 15, and 20. In addition, serum creatinine, inflammatory status (in the kidney), tissue damage, and vascular remodeling (in the liver and aorta) were evaluated. Cs-AqC4 was also tested in vitro on HMEC-1 cells stimulated by Ang-II to assess the involvement of Akt phosphorylation. RESULTS Cs-AqC4 decreased systolic and diastolic BP, reversed vascular remodeling, decreased IL-1β and TGF-β, increased IL-10, and decreased kidney and liver damage. In HMEC-1 cells, AKT phosphorylation and NO production were increased. CONCLUSIONS Cs-AqC4 controlled inflammation and vascular remodeling, alleviating hypertension; it also improved tissue damage associated with ED, probably via Akt activation.
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Affiliation(s)
- Celeste Trejo-Moreno
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca 62350, Morelos, Mexico; (C.T.-M.); (Z.A.A.-O.); (M.E.C.-M.); (G.A.-R.)
| | - Zimri Aziel Alvarado-Ojeda
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca 62350, Morelos, Mexico; (C.T.-M.); (Z.A.A.-O.); (M.E.C.-M.); (G.A.-R.)
| | - Marisol Méndez-Martínez
- Departamento de Sistemas Biológicos, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Xochimilco, Ciudad de México 04960, Mexico;
| | - Mario Ernesto Cruz-Muñoz
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca 62350, Morelos, Mexico; (C.T.-M.); (Z.A.A.-O.); (M.E.C.-M.); (G.A.-R.)
| | - Gabriela Castro-Martínez
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico;
| | - Gerardo Arrellín-Rosas
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca 62350, Morelos, Mexico; (C.T.-M.); (Z.A.A.-O.); (M.E.C.-M.); (G.A.-R.)
- Facultad de Ciencias de la Salud, Universidad Panamericana, Ciudad de México 03920, Mexico
| | - Alejandro Zamilpa
- Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Xochitepec 62790, Morelos, Mexico; (A.Z.); (J.E.J.-F.)
| | - Jesús Enrique Jimenez-Ferrer
- Centro de Investigación Biomédica del Sur, Instituto Mexicano del Seguro Social, Xochitepec 62790, Morelos, Mexico; (A.Z.); (J.E.J.-F.)
| | - Juan Carlos Baez Reyes
- Escuela Nacional Preparatoria No. 1, Universidad Nacional Autónoma de México, Ciudad de México 16030, Mexico;
| | - Gladis Fragoso
- Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico
| | - Gabriela Rosas Salgado
- Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca 62350, Morelos, Mexico; (C.T.-M.); (Z.A.A.-O.); (M.E.C.-M.); (G.A.-R.)
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11
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Rodrigues SD, da Silva MLS, Martins LZ, Gomes SEB, Mariani NAP, Silva EJR, Kushima H, Mattos BR, Rizzi E, Dias-Junior CA. Pregnancy hypertension-associated endothelial dysfunction is attenuated by isoflurane anesthesia: Evidence of protective effect related to increases in nitric oxide. Life Sci 2023; 331:122039. [PMID: 37648198 DOI: 10.1016/j.lfs.2023.122039] [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: 07/10/2023] [Revised: 08/14/2023] [Accepted: 08/21/2023] [Indexed: 09/01/2023]
Abstract
AIMS Pregnancy hypertension-induced endothelial dysfunction associated with impairment of nitric oxide (NO) bioavailability and hemodynamic derangements is a challenging for urgent procedures requiring maternal anesthesia. The volatile anesthetic isoflurane has demonstrated NO-associated protective effects. However, this isoflurane-induced effect is still unclear in pregnancy hypertension. Therefore, the present study examined the potential protective effects of isoflurane anesthesia on endothelial dysfunction and hemodynamic changes induced by hypertensive pregnancy associated with fetal and placental growth restrictions. MATERIALS AND METHODS Animals were distributed into four groups: normotensive pregnant rats (Preg), anesthetized pregnant rats (Preg+Iso), hypertensive pregnant rats (HTN-Preg), and anesthetized hypertensive pregnant rats (HTN-Preg+Iso). Systolic and diastolic pressures, mean arterial pressure (MAP), heart rate, fetal and placental weights, vascular contraction, endothelium-derived NO-dependent vasodilation, and NO levels were assessed. The vascular endothelial growth factor (VEGF) levels and endothelial NO synthase (eNOS) Serine (1177) phosphorylation (p-eNOS) expression were also examined. KEY FINDINGS Isoflurane produced more expressive hypotensive effects in the HTN-Preg+Iso versus Preg+Iso group, with respective reductions in MAP by 50 ± 13 versus 25 ± 4 mmHg (P < 0.05). Also, HTN-Preg+Iso compared to the HTN-Preg group showed (respectively) preventions against the weight loss of the fetuses (4.0 ± 0.6 versus 2.8 ± 0.6 g, P < 0.05) and placentas (0.37 ± 0.06 versus 0.30 ± 0.06 mg, P < 0.05), hyper-reactive vasocontraction response (1.8 ± 0.4 versus 2.8 ± 0.6 g, P < 0.05), impaired endothelium-derived NO-dependent vasodilation (84 ± 8 versus 50 ± 17 %, P < 0.05), reduced VEGF levels (147 ± 46 versus 25 ± 13 pg/mL, P < 0.05), and decreased p-eNOS expression (0.24 ± 0.07 versus 0.09 ± 0.05 arbitrary units, P < 0.05). SIGNIFICANCE Isoflurane anesthesia protects maternal endothelial function in pregnancy hypertension, and possibly endothelium-derived NO is involved.
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Affiliation(s)
- Serginara David Rodrigues
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, 18618-689, SP, Brazil
| | - Maria Luiza Santos da Silva
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, 18618-689, SP, Brazil
| | - Laisla Zanetoni Martins
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, 18618-689, SP, Brazil
| | - Sáskia Estela Biasotti Gomes
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, 18618-689, SP, Brazil
| | - Noemia A P Mariani
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, 18618-689, SP, Brazil
| | - Erick J R Silva
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, 18618-689, SP, Brazil
| | - Hélio Kushima
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, 18618-689, SP, Brazil
| | - Bruna Rahal Mattos
- Unit of Biotechnology, University of Ribeirao Preto (UNAERP), Ribeirao Preto 14096-900, SP, Brazil
| | - Elen Rizzi
- Unit of Biotechnology, University of Ribeirao Preto (UNAERP), Ribeirao Preto 14096-900, SP, Brazil
| | - Carlos Alan Dias-Junior
- Department of Biophysics and Pharmacology, Institute of Biosciences, Sao Paulo State University (UNESP), Botucatu, 18618-689, SP, Brazil.
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12
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Guo Y, Wen J, He A, Qu C, Peng Y, Luo S, Wang X. iNOS contributes to heart failure with preserved ejection fraction through mitochondrial dysfunction and Akt S-nitrosylation. J Adv Res 2023; 43:175-186. [PMID: 36585107 PMCID: PMC9811328 DOI: 10.1016/j.jare.2022.03.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 03/02/2022] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION Despite the high morbidity and mortality of heart failure with preserved fraction (HFpEF), there are currently no effective therapies for this condition. Moreover, the pathophysiological basis of HFpEF remains poorly understood. OBJECTIVE The aim of the present study was to investigate the role of inducible nitric oxide synthase (iNOS) and its underlying mechanism in a high-fat diet and Nω-nitro-L-arginine methyl ester-induced HFpEF mouse model. METHODS The selective iNOS inhibitor L-NIL was used to examine the effects of short-term iNOS inhibition, whereas the long-term effects of iNOS deficiency were evaluated using iNOS-null mice. Cardiac and mitochondrial function, oxidative stress and Akt S-nitrosylation were then measured. RESULTS The results demonstrated that both pharmacological inhibition and iNOS knockout mitigated mitochondrial dysfunction, oxidative stress and Akt S-nitrosylation, leading to an ameliorated HFpEF phenotype in mice. In vitro, iNOS directly induced Akt S-nitrosylation at cysteine 224 residues , leading to oxidative stress, while inhibiting insulin-mediated glucose uptake in myocytes. CONCLUSION Altogether, the present findings suggested an important role for iNOS in the pathophysiological development of HFpEF, indicating that iNOS inhibition may represent a potential therapeutic strategy for HFpEF.
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Affiliation(s)
- Yongzheng Guo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Junjie Wen
- Division of Cardiology, West China Guang'an Hospital of Sichan University, Guang'an 638500, China
| | - An He
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Can Qu
- Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yuce Peng
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Suxin Luo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
| | - Xiaowen Wang
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
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13
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Dhar A, Venkadakrishnan J, Roy U, Vedam S, Lalwani N, Ramos KS, Pandita TK, Bhat A. A comprehensive review of the novel therapeutic targets for the treatment of diabetic cardiomyopathy. Ther Adv Cardiovasc Dis 2023; 17:17539447231210170. [PMID: 38069578 PMCID: PMC10710750 DOI: 10.1177/17539447231210170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 10/09/2023] [Indexed: 12/18/2023] Open
Abstract
Diabetic cardiomyopathy (DCM) is characterized by structural and functional abnormalities in the myocardium affecting people with diabetes. Treatment of DCM focuses on glucose control, blood pressure management, lipid-lowering, and lifestyle changes. Due to limited therapeutic options, DCM remains a significant cause of morbidity and mortality in patients with diabetes, thus emphasizing the need to develop new therapeutic strategies. Ongoing research is aimed at understanding the underlying molecular mechanism(s) involved in the development and progression of DCM, including oxidative stress, inflammation, and metabolic dysregulation. The goal is to develope innovative pharmaceutical therapeutics, offering significant improvements in the clinical management of DCM. Some of these approaches include the effective targeting of impaired insulin signaling, cardiac stiffness, glucotoxicity, lipotoxicity, inflammation, oxidative stress, cardiac hypertrophy, and fibrosis. This review focuses on the latest developments in understanding the underlying causes of DCM and the therapeutic landscape of DCM treatment.
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Affiliation(s)
- Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad, Telangana, India
| | | | - Utsa Roy
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad, Telangana, India
| | - Sahithi Vedam
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad, Telangana, India
| | - Nikita Lalwani
- Department of Pharmacy, Birla Institute of Technology and Science Pilani, Hyderabad, Telangana, India
| | - Kenneth S. Ramos
- Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX 77030, USA
| | - Tej K. Pandita
- Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX 77030, USA
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Samba, Jammu and Kashmir (UT) 184311, India
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14
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Alvariño R, Alfonso A, Pérez-Fuentes N, González-Jartín JM, Gegunde S, Vieytes MR, Botana LM. Extracellular cyclophilins A and C induce dysfunction of pancreatic microendothelial cells. Front Physiol 2022; 13:980232. [PMID: 36277217 PMCID: PMC9579281 DOI: 10.3389/fphys.2022.980232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Extracellular cyclophilins (eCyps) A and B are chemotactic mediators in several illnesses in which inflammation plays an important role such as diabetes and cardiovascular diseases. Recently, eCypC has been reported as a potential biomarker for coronary artery disease but its effect in endothelium has not been determined. Moreover, there is a lack of studies with all these proteins in the same model, which makes difficult a direct comparison of their effects. In this work, MS1 pancreatic microendothelial cells were treated with eCyps A, B and C and their impact on endothelial function was analysed. eCyps A and C stimulated the release of IL-6 and MCP-1 and increased the expression of the receptor CD147, but eCypB did not affect these pro-inflammatory markers. Moreover, eCypC activated the translocation of NFkB-p65 to the nucleus. All these effects were reversed by pre-treatment with cyclosporine A. eCyps also produced endothelial dysfunction, as evidenced by the decrease in eNOS activation. Finally, the crosstalk among eCyps addition and their protein and gene expression was evaluated. eCypA generated a depletion in its protein and gene levels, whilst eCyps B and C upregulated their own protein expression. Moreover, each eCyp altered the intracellular expression of other Cyps, including cyclophilin D. This work is the first report of eCyps influence on iCyps expression, as well as the first description of eCypC as an activator of CD147 receptor and a mediator of endothelial dysfunction, which points to a potential role of this protein in vascular complications associated to diabetes.
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Affiliation(s)
- Rebeca Alvariño
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain
- Grupo Investigación Biodiscovery, IDIS, Lugo, Spain
| | - Amparo Alfonso
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain
- Grupo Investigación Biodiscovery, IDIS, Lugo, Spain
- *Correspondence: Amparo Alfonso, ; Luis M. Botana,
| | - Nadia Pérez-Fuentes
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain
- Grupo Investigación Biodiscovery, IDIS, Lugo, Spain
| | - Jesús M. González-Jartín
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain
- Grupo Investigación Biodiscovery, IDIS, Lugo, Spain
| | - Sandra Gegunde
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain
- Grupo Investigación Biodiscovery, IDIS, Lugo, Spain
- Fundación Instituto de Investigación Sanitario Santiago de Compostela (FIDIS), Hospital Universitario Lucus Augusti, Lugo, Spain
| | - Mercedes R. Vieytes
- Grupo Investigación Biodiscovery, IDIS, Lugo, Spain
- Departamento de Fisiología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain
| | - Luis M. Botana
- Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain
- Grupo Investigación Biodiscovery, IDIS, Lugo, Spain
- *Correspondence: Amparo Alfonso, ; Luis M. Botana,
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15
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Spinelli S, Guida L, Vigliarolo T, Passalacqua M, Begani G, Magnone M, Sturla L, Benzi A, Ameri P, Lazzarini E, Bearzi C, Rizzi R, Zocchi E. The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism. Cells 2022; 11:cells11182888. [PMID: 36139463 PMCID: PMC9496903 DOI: 10.3390/cells11182888] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO. The effect of ABA and of the silencing or overexpression of LANCL1 and LANCL2 were investigated in H9c2 rat cardiomyoblasts under normoxia or hypoxia/reoxygenation. In H9c2, hypoxia induced ABA release, and ABA stimulated NO production. ABA increased the survival of H9c2 to hypoxia, and L-NAME, an inhibitor of NO synthase (NOS), abrogated this effect. ABA also increased glucose uptake and NADPH levels and increased phosphorylation of Akt, AMPK and eNOS. Overexpression or silencing of LANCL1/2 significantly increased or decreased, respectively, transcription, expression and phosphorylation of AMPK, Akt and eNOS; transcription of NAMPT, Sirt1 and the arginine transporter. The mitochondrial proton gradient and cell vitality increased in LANCL1/2-overexpressing vs. -silenced cells after hypoxia/reoxygenation, and L-NAME abrogated this difference. These results implicate the ABA-LANCL1/2 hormone-receptor system in NO-mediated cardiomyocyte protection against hypoxia.
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Affiliation(s)
- Sonia Spinelli
- Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
| | - Lucrezia Guida
- Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
| | - Tiziana Vigliarolo
- Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
| | - Mario Passalacqua
- Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
| | - Giulia Begani
- Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
| | - Mirko Magnone
- Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
| | - Laura Sturla
- Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
| | - Andrea Benzi
- Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
| | - Pietro Ameri
- Laboratory of Cardiovascular Biology, Department of Internal Medicine, University of Genova, Viale Benedetto XV 6, 16132 Genova, Italy
| | - Edoardo Lazzarini
- Cardiovascular Theranostics, Istituto Cardiocentro Ticino, Laboratories for Translational Research, Ente Ospedaliero Cantonale, Via Tesserete 48, 6500 Bellinzona, Switzerland
| | - Claudia Bearzi
- Institute of Biomedical Technologies, National Research Council of Italy (ITB-CNR), Via Fratelli Cervi 93, 20054 Milan, Italy
- Fondazione Istituto Nazionale di Genetica Molecolare, Via F. Sforza 35, 20122 Milan, Italy
| | - Roberto Rizzi
- Fondazione Istituto Nazionale di Genetica Molecolare, Via F. Sforza 35, 20122 Milan, Italy
- Department of Medical Surgical Sciences and Biotechnologies, Sapienza University of Rome, C.so della Repubblica 79, 04100 Latina, Italy
| | - Elena Zocchi
- Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova, Italy
- Correspondence:
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16
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Mao XQ, Cheng Y, Zhang RZ, Liu YB, Li Y, Ge K, Jin HL. RNA-seq and ATAC-seq analyses of multilineage differentiating stress enduring cells: Comparison with dermal fibroblasts. Cell Biol Int 2022; 46:1480-1494. [PMID: 35673985 DOI: 10.1002/cbin.11834] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 04/20/2022] [Accepted: 04/30/2022] [Indexed: 11/09/2022]
Abstract
The aim of this study is to characterize the molecular properties of multilineage differentiating stress-enduring (Muse) cells compared with dermal fibroblasts (FBs) and to characterize differences in their transcriptomes and open chromatin regions that are involved in cellular plasticity. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing (RNA-seq) analyses was then performed on FBs and Muse cells. Subsequently, cell type-selective gene regulatory regions were identified by coalition analysis. Expression patterns of transcription factors (TFs) and signaling pathways intermediates were verified using quantitative real-time polymerase chain reaction and Western blot analyses. RNA-seq identified 2355 significantly differentially expressed genes (DEGs) that regulate the transcriptome, including 1222 upregulated and 1133 downregulated DEGs. The general panorama of RNA-seq and ATAC-seq analyses confirmed the differences in TFs and open chromatin regions between FBs and Muse cells. ATAC-seq analysis showed that Muse cells had more reproducible and meaningful peaks than FBs, and the peak signals were concentrated near promoter-transcription start site areas. In genomic regions that can be preferentially accessed in FBs and Muse cells, more than 200 TFs had binding motif sequences. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and coalition analyses identified differences in factors involved in the cell cycle and the protein kinase B (AKT) signaling pathway of FBs and Muse cells. The results of RNA-seq and ATAC-seq analyses clarified the genetic basis of the different biological properties of Muse cells and FBs. These results suggest that the cell cycle transition and the AKT signaling pathway may affect the morphology and biological characteristics of Muse cells.
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Affiliation(s)
- Xiao-Qian Mao
- Department of Dermatology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Dermatology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Yan Cheng
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Ru-Zhi Zhang
- Department of Dermatology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yi-Bo Liu
- Department of Plastic Surgery, Affiliated Renmin Hospital of Jiangsu University, Zhenjiang, China
| | - Yue Li
- Department of Dermatology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Kang Ge
- Department of Dermatology, The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Dermatology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Hui-Ling Jin
- Department of Dermatology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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17
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Wang Y, Chen J, Huang Y, Yang S, Tan T, Wang N, Zhang J, Ye C, Wei M, Luo J, Luo X. Schisandrin B suppresses osteosarcoma lung metastasis in vivo by inhibiting the activation of the Wnt/β‑catenin and PI3K/Akt signaling pathways. Oncol Rep 2022; 47:50. [PMID: 35029287 PMCID: PMC8771162 DOI: 10.3892/or.2022.8261] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 12/16/2021] [Indexed: 02/07/2023] Open
Abstract
Osteosarcoma (OS) is the most common malignant bone tumor worldwide and is associated with a poor prognosis, often being accompanied by lung metastasis at an early stage. At present, there are several side-effects associated with the OS clinical treatment of OS, with the treatment effects often being unsatisfactory. Thus, there is an urgent need for the development of safe and effective novel drugs for the treatment of OS. Schisandrin B (Sch B) has been previously demonstrated to exhibit antitumor properties. The present study was focused on the effects of Sch B on OS cells (143B, MG63, Saos2 and U2OS) in vitro and in vivo, and also on its possible antitumor mechanisms. In cell experiments, it was revealed that Sch B inhibited OS cell proliferation, migration and invasion, and increased OS cell apoptosis. As regards its biosafety, no notable effects of Sch B on the vitality of normal cells were observed. Mechanistically, it was demonstrated that Sch B blocked OS cell proliferation in the G1 phase. Subsequently, by using established animal models, it was revealed that Sch B significantly inhibited OS growth and lung metastasis in vivo. In summary, the results of the present study revealed that Sch B inhibited OS cell proliferation, migration and invasion, and promoted apoptosis via the inhibition of the Wnt/β-catenin and PI3K/Akt signaling pathways, without causing any noticeable toxic effects on healthy cells at the therapeutic concentrations used. These findings suggest that Sch B has potential for use as a novel agent for the clinical treatment of OS.
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Affiliation(s)
- Yuping Wang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jin Chen
- Department of Dermatology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yanran Huang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Shengdong Yang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Tao Tan
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Nan Wang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jun Zhang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Caihong Ye
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Mengqi Wei
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jinyong Luo
- Key Laboratory of Clinical Diagnosis of Education Ministry, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Xiaoji Luo
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
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