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Peng A, Li J, Xing J, Yao Y, Niu X, Zhang K. The function of nicotinamide phosphoribosyl transferase (NAMPT) and its role in diseases. Front Mol Biosci 2024; 11:1480617. [PMID: 39513038 PMCID: PMC11540786 DOI: 10.3389/fmolb.2024.1480617] [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: 08/14/2024] [Accepted: 10/11/2024] [Indexed: 11/15/2024] Open
Abstract
Nicotinamide phosphoribosyl transferase (NAMPT) is a rate-limiting enzyme in the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway, and plays a vital role in the regulation of cell metabolic activity, reprogramming, aging and apoptosis. NAMPT synthesizes nicotinamide mononucleotide (NMN) through enzymatic action, which is a key protein involved in host defense mechanism and plays an important role in metabolic homeostasis and cell survival. NAMPT is involved in NAD metabolism and maintains intracellular NAD levels. Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases (HDACs), the members are capable of sensing cellular NAD+ levels. NAMPT-NAD and SIRT constitute a powerful anti-stress defense system. In this paper, the structure, biological function and correlation with diseases of NAMPT are introduced, aiming to provide new ideas for the targeted therapy of related diseases.
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Affiliation(s)
| | | | | | | | | | - Kaiming Zhang
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, State Key Breeding Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Center Hospital, Taiyuan, China
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Ismail H, Pathak AK, Lal N, Rastogi P, Ahmad K, Khan MA. Effect of non-surgical periodontal therapy on salivary and gingival crevicular fluid concentration of visfatin in periodontal health and disease. J Oral Biol Craniofac Res 2024; 14:430-434. [PMID: 38832289 PMCID: PMC11144723 DOI: 10.1016/j.jobcr.2024.04.010] [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: 02/13/2024] [Revised: 04/22/2024] [Accepted: 04/24/2024] [Indexed: 06/05/2024] Open
Abstract
Background and objective Visfatin, a pleotropic mediator mostly produced by visceral fat, is crucial in controlling the immunological and defensive systems. It serves the roles of a cytokine, an enzyme involved in energy metabolism, and a growth factor. The objective of the present study was to assess the impact of non-surgical periodontal therapy (scaling and root planing) on visfatin concentrations in saliva and gingival crevicular fluid in individuals with Periodontitis (stage-II grade-A). Materials and methods 54 individuals were divided into Group A (Periodontally Healthy) and Group B1(Periodontitis baseline) based on periodontal parameters including plaque index (PI), gingival index (GI), probing pocket depth (PPD), clinical attachment level (CAL), and radiographic parameters. After NSPT (SRP), Group B1 patients were recalled after 4 weeks, constituting Group B2 (post NSPT group B1). At baseline and 4 weeks after non-surgical periodontal therapy (SRP), all clinical parameters, salivary and GCF samples were recorded. An ELISA kit was used to measure the levels of visfatin. Using the paired t-test, unpaired t-test, and Pearson's correlation coefficient, data were analysed using SPSS 15. Results After non-surgical periodontal treatment (SRP), the mean salivary and gingival crevicular fluid concentration of visfatin considerably decreased to a level comparable to periodontal health. In all groups, GCF visfatin concentration was higher than salivary concentration of visfatin. In periodontitis patients, visfatin concentration in GCF was 1.5 times higher than in saliva. Conclusion The results of this investigation suggest a direct correlation between salivary and gingival crevicular fluid visfatin concentration and periodontal tissue inflammation and disease activity.
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Affiliation(s)
- Hira Ismail
- Department of Periodontology, Faculty of Dental Sciences, King George's Medical University, Uttar Pradesh, Lucknow, India
| | - Anjani Kumar Pathak
- Department of Periodontology, Faculty of Dental Sciences, King George's Medical University, Uttar Pradesh, Lucknow, India
| | - Nand Lal
- Department of Periodontology, Faculty of Dental Sciences, King George's Medical University, Uttar Pradesh, Lucknow, India
| | - Pavitra Rastogi
- Department of Periodontology, Faculty of Dental Sciences, King George's Medical University, Uttar Pradesh, Lucknow, India
| | - Kaleem Ahmad
- Department of Biochemistry, King George's Medical University, Uttar Pradesh, Lucknow, India
| | - Mohd. Aamir Khan
- Department of Periodontology, Faculty of Dental Sciences, King George's Medical University, Uttar Pradesh, Lucknow, India
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Semerena E, Nencioni A, Masternak K. Extracellular nicotinamide phosphoribosyltransferase: role in disease pathophysiology and as a biomarker. Front Immunol 2023; 14:1268756. [PMID: 37915565 PMCID: PMC10616597 DOI: 10.3389/fimmu.2023.1268756] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/03/2023] [Indexed: 11/03/2023] Open
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) plays a central role in mammalian cell metabolism by contributing to nicotinamide adenine dinucleotide biosynthesis. However, NAMPT activity is not limited to the intracellular compartment, as once secreted, the protein accomplishes diverse functions in the extracellular space. Extracellular NAMPT (eNAMPT, also called visfatin or pre-B-cell colony enhancing factor) has been shown to possess adipocytokine, pro-inflammatory, and pro-angiogenic activities. Numerous studies have reported the association between elevated levels of circulating eNAMPT and various inflammatory and metabolic disorders such as obesity, diabetes, atherosclerosis, arthritis, inflammatory bowel disease, lung injury and cancer. In this review, we summarize the current state of knowledge on eNAMPT biology, proposed roles in disease pathogenesis, and its potential as a disease biomarker. We also briefly discuss the emerging therapeutic approaches for eNAMPT inhibition.
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Affiliation(s)
- Elise Semerena
- Light Chain Bioscience - Novimmune SA, Plan-les-Ouates, Switzerland
| | - Alessio Nencioni
- Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
- Ospedale Policlinico San Martino IRCCS, Genoa, Italy
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Jiang Y, Zhou L. The Value of Visfatin in the Prediction of Metabolic Syndrome: A Systematic Review and Meta-Analysis. Horm Metab Res 2023; 55:610-616. [PMID: 36894154 DOI: 10.1055/a-2051-6776] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
Various studies have shown that visfatin may be connected to metabolic syndrome (MS). However, epidemiological studies yielded conflicting outcomes. The purpose of this article was to highlight the relationship between the plasma visfatin level and MS risk by conducting a meta-analysis of available literature. A comprehensive literature search of eligible studies was done up to January 2023. Data were presented as standard mean difference (SMD). Observational methodological meta-analysis was conducted to assess the relationships between visfatin levels and MS. The visfatin levels between patients with MS or not were calculated by SMD and 95% confidence interval (CI) using the random-effects model. Funnel plot (visually inspect publication bias), Egger's linear regression test and Begger's linear regression test were applied to describe the risk of publication bias. A sensitivity analysis was performed via sequentially omitting each of the study one by one. In total, 16 eligible studies comprising 1016 cases and 1414 healthy controls finally enrolled in the current meta-analysis for pooling meta-analysis. Overall, the meta-analysis results revealed that visfatin levels in MS patients were significantly greater than that of controls group (SMD: 0.60, 95% CI=0.18-1.03, I2=95%, p<0.001). The results of the subgroup analysis showed that gender did not affect the results of meta-analysis. This meta-analysis shed light on the fact that circulating visfatin levels were significantly higher in patients with MS than in the controls group. Visfatin may a chance to predict the occurrence of MS.
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Affiliation(s)
- Yingling Jiang
- Zhuzhou Hospital Affiliated to Central South University, Zhuzhou, China
| | - Lihua Zhou
- Zhuzhou Hospital Affiliated to Central South University, Zhuzhou, China
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Luo J, He Z, Li Q, Lv M, Cai Y, Ke W, Niu X, Zhang Z. Adipokines in atherosclerosis: unraveling complex roles. Front Cardiovasc Med 2023; 10:1235953. [PMID: 37645520 PMCID: PMC10461402 DOI: 10.3389/fcvm.2023.1235953] [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: 06/07/2023] [Accepted: 08/02/2023] [Indexed: 08/31/2023] Open
Abstract
Adipokines are biologically active factors secreted by adipose tissue that act on local and distant tissues through autocrine, paracrine, and endocrine mechanisms. However, adipokines are believed to be involved in an increased risk of atherosclerosis. Classical adipokines include leptin, adiponectin, and ceramide, while newly identified adipokines include visceral adipose tissue-derived serpin, omentin, and asprosin. New evidence suggests that adipokines can play an essential role in atherosclerosis progression and regression. Here, we summarize the complex roles of various adipokines in atherosclerosis lesions. Representative protective adipokines include adiponectin and neuregulin 4; deteriorating adipokines include leptin, resistin, thrombospondin-1, and C1q/tumor necrosis factor-related protein 5; and adipokines with dual protective and deteriorating effects include C1q/tumor necrosis factor-related protein 1 and C1q/tumor necrosis factor-related protein 3; and adipose tissue-derived bioactive materials include sphingosine-1-phosphate, ceramide, and adipose tissue-derived exosomes. However, the role of a newly discovered adipokine, asprosin, in atherosclerosis remains unclear. This article reviews progress in the research on the effects of adipokines in atherosclerosis and how they may be regulated to halt its progression.
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Affiliation(s)
- Jiaying Luo
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhiwei He
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qingwen Li
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Mengna Lv
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuli Cai
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Ke
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xuan Niu
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhaohui Zhang
- Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China
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Chen TH, Hsu HC, You JF, Lai CC, Tsou YK, Hsu CL, Fann CSJ, Chien RN, Chang ML. Extracellular Nicotinamide Phosphoribosyltransferase as a Surrogate Marker of Prominent Malignant Potential in Colonic Polyps: A 2-Year Prospective Study. Cancers (Basel) 2023; 15:1702. [PMID: 36980589 PMCID: PMC10046025 DOI: 10.3390/cancers15061702] [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: 01/06/2023] [Revised: 03/03/2023] [Accepted: 03/08/2023] [Indexed: 03/14/2023] Open
Abstract
BACKGROUND/AIMS The implications of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a cancer metabokine, in colonic polyps remain uncertain. METHODS A 2-year prospective cohort study of patients who underwent colonoscopy was conducted. Biochemical parameters and serum eNAMPT levels were analyzed at baseline and every 24 weeks postpolypectomy. NAMPT-associated single-nucleotide polymorphisms (SNPs), including rs61330082, rs2302559, rs10953502, and rs23058539, were assayed. RESULTS Of 532 patients, 80 (15%) had prominent malignant potential (PMP) in colonic polyps, including villous adenomas (n = 18, 3.3%), adenomas with high-grade dysplasia (n = 33, 6.2%), and adenocarcinomas (n = 29, 5.5%). Baseline associations were as follows: colonic polyp pathology (p < 0.001), total cholesterol (p = 0.019), and neutrophil-to-lymphocyte ratio (p = 0.023) with eNAMPT levels; and age (p < 0.001), polyp size (p < 0.001), and eNAMPT levels (p < 0.001) with polyp pathology. Higher baseline eNAMPT levels were noted in patients harboring polyps with PMP than in patients without PMP (p < 0.001), and baseline eNAMPT levels significantly predicted PMP (cutoff: >4.238 ng/mL, p < 0.001). Proportions of eNAMPT-positive glandular and stromal cells were higher in polyps with PMP than in polyps without PMP (64.55 ± 11.94 vs. 14.82 ± 11.45%, p = 0.025). eNAMPT levels decreased within 48 weeks postpolypectomy (p = 0.01) and remained stable afterward regardless of PMP until 96 weeks postpolypectomy. However, those with PMP had a higher degree of eNAMPT decline within 24 weeks (p = 0.046). All investigated SNPs were in linkage disequilibrium with each other but were not associated with eNAMPT levels. CONCLUSION With a link to inflammation and lipid metabolism, along with its decreasing trend after polypectomy, serum eNAMPT may serve as a surrogate marker of PMP in colonic polyps. In situ probing of the NAMPT-associated pathway holds promise in attenuating PMP, as much of the eNAMPT likely originates from colonic polyps.
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Affiliation(s)
- Tsung-Hsing Chen
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
| | - Hung-Chih Hsu
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
- Division of Hematology-Oncology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Jeng-Fu You
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Cheng-Chou Lai
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Yung-Kuan Tsou
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
| | - Chia-Lin Hsu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Cathy S. J. Fann
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
| | - Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
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Skelly PJ, Nation CS, Da'Dara AA. Schistosoma mansoni and the purinergic halo. Trends Parasitol 2022; 38:1080-1088. [PMID: 36182536 PMCID: PMC9669209 DOI: 10.1016/j.pt.2022.09.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/25/2022] [Accepted: 09/02/2022] [Indexed: 01/13/2023]
Abstract
Intravascular schistosomes may control immune and hemostatic responses by regulating the nature and amount of selected host purinergic signaling molecules - such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), and nicotinamide adenine dinucleotide (NAD) - surrounding them. Such metabolites are collectively known as the worm's 'purinergic halo'. Host-interactive, membrane-bound, tegumental ectonucleotidases, notably SmATPDase1, SmNPP5, SmAP and SmNACE, can degrade proinflammatory, prothrombotic and immunomodulatory purinergic metabolites like those listed. A common catabolic product is the anti-inflammatory metabolite adenosine that can additionally be taken in by the worms as food. We envision the tegumental ectonucleotidases as having a twofold role at the worm surface: first, they degrade potentially harmful host signaling molecules, and second, they generate vital nutrients around the worms from where these can be conveniently imported.
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Affiliation(s)
- Patrick J Skelly
- Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA.
| | - Catherine S Nation
- Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA
| | - Akram A Da'Dara
- Molecular Helminthology Laboratory, Department of Infectious Disease and Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA
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Zhang Z, Xiao K, Wang S, Ansari AR, Niu X, Yang W, Lu M, Yang Z, Rehman ZU, Zou W, Bei W, Song H. Visfatin is a multifaceted molecule that exerts regulation effects on inflammation and apoptosis in RAW264.7 cells and mice immune organs. Front Immunol 2022; 13:1018973. [PMID: 36532047 PMCID: PMC9753570 DOI: 10.3389/fimmu.2022.1018973] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 11/15/2022] [Indexed: 12/03/2022] Open
Abstract
Visfatin, a multifunctional adipocytokine, is particularly important in the regulation of apoptosis and inflammation through an unidentified mechanism. Clarifying the control mechanisms of visfatin on inflammation and apoptosis in RAW264.7 cells and mice immunological organs was the goal of the current investigation. In order to create a pathophysiological model, the RAW264.7 cells were stimulated with 200 ng/mL visfatin and 20 μg/mL lipopolysaccharide (LPS), either separately or combined. The effects of exogenous visfatin on inflammation and apoptosis in RAW264.7 cells were investigated by flow cytometry assay, RNA-seq analysis and fluorescence quantitative PCR. According to the findings, exogenous visfatin exhibits dual effects on inflammation by modulating the expression of IL-1α, TNFRSF1B, and LIF as well as taking part in various signaling pathways, including the MAPK and Rap1 signaling pathways. By controlling the expression levels of Bcl2l1, Bcl2a1a, and Fas and primarily participating in the PI3K/AKT signaling pathway and Hippo signaling pathway, exogenous visfatin can inhibit apoptosis in RAW264.7 cells. The visfatin inhibitor FK866 was used to further confirm the effects of visfatin on inflammation and apoptosis in mice immune organs. Subsequently, mice spleen and thymus were collected. It is interesting to note that in LPS-treated mice, suppression of endogenous visfatin might worsen the immune system's inflammatory response and even result in rapid mortality. Additionally, endogenous visfatin promotes the apoptosis in mice immune organs by regulating the expression levels of Bcl2l1, Fas, Caspase 3, Bcl2a1a, and Bax. Together, these results imply that visfatin is a multifaceted molecule that regulates inflammation and apoptosis in RAW264.7 cells and mice immunological organs by taking part in a variety of biological processes and regulating the amounts of associated cytokines expression. Our findings offer additional understandings of how visfatin affects apoptosis and inflammation.
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Affiliation(s)
- Zhewei Zhang
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Ke Xiao
- The Brain Cognition and Brain Disease Institute of Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Sheng Wang
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Abdur Rahman Ansari
- Section of Anatomy and Histology, Department of Basic Sciences, College of Veterinary & Animal Sciences, Jhang University of Veterinary and Animal Sciences, Lahore, Pakistan
| | - Xiaoyu Niu
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Wenjie Yang
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Mengqi Lu
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Zhi Yang
- Animal Health Supervision Institute of Taihe County, Fuyang, China
| | - Zia ur Rehman
- College of Veterinary Sciences, Faculty of Animal Husbandry and Veterinary Sciences, University of Agriculture, Peshawar, Pakistan
| | - Weihua Zou
- Wuhan Keqian Biology Company Limited, Wuhan, China
| | - Weicheng Bei
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China
| | - Hui Song
- College of Animal Science and Veterinary Medicine, Huazhong Agricultural University, Wuhan, China,*Correspondence: Hui Song,
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Regulatory Networks, Management Approaches, and Emerging Treatments of Nonalcoholic Fatty Liver Disease. Can J Gastroenterol Hepatol 2022; 2022:6799414. [PMID: 36397950 PMCID: PMC9666027 DOI: 10.1155/2022/6799414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/05/2022] [Indexed: 11/09/2022] Open
Abstract
The pathogenesis of NAFLD is complex and diverse, involving multiple signaling pathways and cytokines from various organs. Hepatokines, stellakines, adipokines, and myokines secreted by hepatocytes, hepatic stellate cells, adipose tissue, and myocytes play an important role in the occurrence and development of nonalcoholic fatty liver disease (NAFLD). The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) contributes to the progression of NAFLD by mediating liver inflammation, immune response, hepatocyte death, and later compensatory proliferation. In this review, we first discuss the crosstalk and interaction between hepatokines, stellakines, adipokines, and myokines and NF-κB in NAFLD. The characterization of the crosstalk of NF-κB with these factors will provide a better understanding of the molecular mechanisms involved in the progression of NAFLD. In addition, we examine new expert management opinions for NAFLD and explore the therapeutic potential of silymarin in NAFLD/NASH.
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Bayram Z, Akcabag E, Ozbey G, Golbasi I, Ozdem SS. The Functional Effects of Visfatin on Human Left Internal Mammary Artery. J Cardiovasc Pharmacol 2022; 80:725-731. [PMID: 35881894 DOI: 10.1097/fjc.0000000000001327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/17/2022] [Indexed: 11/26/2022]
Abstract
ABSTRACT Visfatin may play a role in vascular dysfunction in metabolic disorders. Apart from its insulin-mimetic actions, it has divergent actions in the cardiovascular system with discordant results in the literature. Thus, we aimed to study the effects of visfatin on vascular responses of the human left internal mammary artery. Sections of redundant human left internal mammary artery were cut into 3-mm wide rings and hung in 20-mL organ baths containing physiologic salt solution and attached to an isometric force transducer connected to a computer-based data acquisition system. Removing endothelium caused an increase in pD2 values for visfatin-induced relaxation responses (10 -12 -10 -7 M) (9.06 ± 0.21 and 11.08 ± 0.92, respectively). Nicotinamide phosphoribosyltransferase inhibitor FK866 (10 µM) reversed the visfatin-induced relaxations (10 -12 -10 -7 M) ( P = 0.024). Incubations with nitric oxide synthase inhibitor nitro- l -arginine methylester and guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) caused significant reductions in relaxation responses of visfatin ( P = 0.011 and 0.008, respectively). Visfatin incubations decreased relaxation responses to acetylcholine but not to sodium nitroprusside. Incubations with visfatin did not change contractile responses to angiotensin II, endothelin-1, noradrenalin, and phenylephrine. In this study, visfatin caused endothelium-dependent relaxations mediated by nitric oxide-cyclic guanosine monophosphate pathway and nicotinamide phosphoribosyltransferase activity. Furthermore, visfatin-induced decreases in relaxation responses were also related to endothelium-derived nitric oxide.
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Affiliation(s)
- Zeliha Bayram
- Turkish Medicines and Medical Devices Agency, Ankara, Turkey
| | - Esra Akcabag
- Department of Medical Pharmacology, Akdeniz University Medical Faculty, Antalya, Turkey; and
| | - Gul Ozbey
- Department of Medical Pharmacology, Akdeniz University Medical Faculty, Antalya, Turkey; and
| | - Ilhan Golbasi
- Department of Cardiovascular Surgery, Akdeniz University Medical Faculty, Antalya, Turkey
| | - Sadi S Ozdem
- Department of Medical Pharmacology, Akdeniz University Medical Faculty, Antalya, Turkey; and
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Abdalla MMI. Role of visfatin in obesity-induced insulin resistance. World J Clin Cases 2022; 10:10840-10851. [PMID: 36338223 PMCID: PMC9631142 DOI: 10.12998/wjcc.v10.i30.10840] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/13/2022] [Accepted: 09/23/2022] [Indexed: 02/05/2023] Open
Abstract
The growing worldwide burden of insulin resistance (IR) emphasizes the importance of early identification for improved management. Obesity, particularly visceral obesity, has been a key contributing factor in the development of IR. The obesity-associated chronic inflammatory state contributes to the development of obesity-related comorbidities, including IR. Adipocytokines, which are released by adipose tissue, have been investigated as possible indicators of IR. Visfatin was one of the adipocytokines that attracted attention due to its insulin-mimetic activity. It is released from a variety of sources, including visceral fat and macrophages, and it influences glucose metabolism and increases inflammation. The relationship between visfatin and IR in obesity is debatable. As a result, the purpose of this review was to better understand the role of visfatin in glucose homeostasis and to review the literature on the association between visfatin levels and IR, cardiovascular diseases, and renal diseases in obesity.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Physiology Department, Human Biology Division, School of Medicine, International Medical University, Kuala Lumpur 57000, Bukit Jalil, Malaysia
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12
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Li H, Konja D, Wang L, Wang Y. Sex Differences in Adiposity and Cardiovascular Diseases. Int J Mol Sci 2022; 23:ijms23169338. [PMID: 36012601 PMCID: PMC9409326 DOI: 10.3390/ijms23169338] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 11/16/2022] Open
Abstract
Body fat distribution is a well-established predictor of adverse medical outcomes, independent of overall adiposity. Studying body fat distribution sheds insights into the causes of obesity and provides valuable information about the development of various comorbidities. Compared to total adiposity, body fat distribution is more closely associated with risks of cardiovascular diseases. The present review specifically focuses on the sexual dimorphism in body fat distribution, the biological clues, as well as the genetic traits that are distinct from overall obesity. Understanding the sex determinations on body fat distribution and adiposity will aid in the improvement of the prevention and treatment of cardiovascular diseases (CVD).
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13
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NAD-catabolizing ectoenzymes of Schistosoma mansoni. Biochem J 2022; 479:1165-1180. [PMID: 35593185 DOI: 10.1042/bcj20210784] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 05/18/2022] [Accepted: 05/20/2022] [Indexed: 11/17/2022]
Abstract
Infection with schistosomes (blood flukes) can result in the debilitating disease schistosomiasis. These parasites survive in their host for many years, and we hypothesize that proteins on their tegumental surface, interacting with the host microenvironment, facilitate longevity. One such ectoenzyme - the nucleotide pyrophosphatase/phosphodiesterase SmNPP5 can cleave ADP (to prevent platelet aggregation) and NAD (likely preventing Treg apoptosis). A second tegumental ectoenzyme, the glycohydrolase SmNACE, also catabolizes NAD. Here, we undertake a comparative biochemical characterization of these parasite ectoenzymes. Both are GPI-linked and exhibit different optimal pH ranges. While SmNPP5 requires divalent cations, SmNACE does not. The Km values of the two enzymes for NAD at physiological pH differ: SmNPP5, Km=340µM±44; SmNACE, Km=49µM±4. NAD cleavage by each enzyme yields different products. SmNPP5 cleaves NAD to form nicotinamide mononucleotide (NMN) and AMP, whereas SmNACE cleaves NAD to generate nicotinamide (NAM) and adenosine diphosphate ribose (ADPR). Each enzyme can process the other's reaction product. Thus, SmNACE cleaves NMN (to yield NAM and ribose phosphate) and SmNPP5 cleaves ADPR (yielding AMP and ribose phosphate). Metabolomic analysis of plasma containing adult worms supports the idea that these cleavage pathways are active in vivo. We hypothesize that a primary function of SmNPP5 is to cleave NAD to control host immune cell function and a primary function of SmNACE is to cleave NMN to generate the vital nutrient nicotinamide (vitamin B3) for convenient uptake by the worms. Chemical inhibition of one or both ectoenzymes could upset worm metabolism and control schistosome infection.
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Al-Jabory M, Ameen N. Serum visfatin level in sickle/β thalassemia in correlation with frequency of vaso occlusion crises: A comparative study. MEDICAL JOURNAL OF BABYLON 2022. [DOI: 10.4103/mjbl.mjbl_83_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Puspasari A, Hastuti P, Sadewa AH, Mus R, Maharani C, Setyawati I. A genetic variant of the NAMPT gene rs4730153 as a risk factor for the metabolic syndrome in younger age: a single-centre pilot study in Yogyakarta, Indonesia. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2021. [DOI: 10.1186/s43042-021-00187-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The genetic variation of nicotinamide phosphoribosyl transferase (NAMPT) gene rs4730153 is reported to be associated with cardiometabolic risk, but the results are inconsistent between populations. Ethnicity, metabolic risk and lifestyle play a role in the association of the genetic variant and the metabolic syndrome (MetS). To the best of our knowledge, no research has yet been published concerning the Javanese population, so this study aimed to investigate the association of rs4730153 with MetS and its interaction with metabolic risk and lifestyle.
Results
The GG genotype (p = 0.031; OR 95% CI 3.88 [1.13–13.33]), GA+GG genotype (p = 0.048; OR 95% CI 10.52 [1.02–108.01]) and G allele carrier (p = 0.006; OR 95% CI 4.19 [1.51–11.64]) of rs4730153 had a higher risk of the MetS after adjusting for obesity, hypercholesterolemia, smoking and food intake. The risk was statistically significant for the younger age group ≤ 45 years old.
Conclusion
The GG, GA+GG genotype and G allele carrier of rs4730153 have a higher risk of the MetS, especially those who are obese, hypercholesterolemic and smokers and have a higher food intake in those aged ≤ 45 years old. Further larger, multicentre studies are required to confirm these pilot results.
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Álvarez-Vásquez JL, Bravo-Guapisaca MI, Gavidia-Pazmiño JF, Intriago-Morales RV. Adipokines in dental pulp: physiological, pathological, and potential therapeutic roles. J Oral Biosci 2021; 64:59-70. [PMID: 34808362 DOI: 10.1016/j.job.2021.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/12/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hundreds of adipokines have been identified, and their extensive range of endocrine functions-regulating distant organs such as oral tissues-and local autocrine/paracrine roles have been studied. In dentistry, however, adipokines are poorly known proteins in the dental pulp; few of them have been studied despite their large number. This study reviews recent advances in the investigation of dental-pulp adipokines, with an emphasis on their roles in inflammatory processes and their potential therapeutic applications. HIGHLIGHTS The most recently identified adipokines in dental pulp include leptin, adiponectin, resistin, ghrelin, oncostatin, chemerin, and visfatin. They have numerous physiological and pathological functions in the pulp tissue: they are closely related to pulp inflammatory mechanisms and actively participate in cell differentiation, mineralization, angiogenesis, and immune-system modulation. CONCLUSION Adipokines have potential clinical applications in regenerative endodontics and as biomarkers or targets for the pharmacological management of inflammatory and degenerative processes in dental pulp. A promising direction for the development of new therapies may be the use of agonists/antagonists to modulate the expression of the most studied adipokines.
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Akcabag E, Bayram Z, Kucukcetin IO, Uzun G, Ozdem S, Ozdem SS. Functional effects of visfatin in isolated rat mesenteric small resistance arteries. Eur J Pharmacol 2021; 908:174333. [PMID: 34280396 DOI: 10.1016/j.ejphar.2021.174333] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/27/2021] [Accepted: 07/11/2021] [Indexed: 01/22/2023]
Abstract
A new adipocytokine, visfatin is expressed in perivascular adipose tissue (PVAT) and exerts effects on vascular system in addition to its relationship with various pathological conditions. The present study aimed to investigate the functional effects of visfatin and the possible underlying mechanism(s) of the effects of visfatin in isolated rat mesenteric small resistance arteries. The study was conducted in small resistance arterial rings isolated from rat mesenteric vascular beds. While visfatin incubation did not produce significant alterations in contractile responses of mesenteric arterial rings to noradrenaline, relaxation responses to acetylcholine but not to sodium nitroprusside (SNP) were significantly reduced in endothelium-intact rings. The inhibitory effect of visfatin on responses to acetylcholine was not observed in endothelium-denuded preparations. Incubation of tissues with nicotinamide phosphoribosyl transferase (NAMPT) inhibitor FK866 or superoxide dismutase (SOD) reversed the inhibitory effects of visfatin on relaxation responses to acetylcholine. Co-incubation of visfatin with Nω-nitro-L-arginine methylester (L-NAME) did not produce a significant alteration in vascular responses to acetylcholine compared to L-NAME incubation alone. Mesenteric PVAT visfatin levels were significantly higher than and correlated positively with plasma visfatin levels. The results of our study indicated that visfatin-induced reductions in endothelium-dependent relaxations of rat isolated small resistance arteries are mediated by oxygen free radicals and a reduction in nitric oxide (NO) bioavailability. It was suggested that increment in systemic and/or local visfatin levels due to various pathologies including obesity and excessive weight gain may play a substantial role in initiation and/or propagation of vascular dysfunctions.
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Affiliation(s)
- Esra Akcabag
- Akdeniz University, Medical Faculty, Department of Medical Pharmacology, Antalya, Turkey.
| | - Zeliha Bayram
- Akdeniz University, Medical Faculty, Department of Medical Pharmacology, Antalya, Turkey
| | - Ikbal Ozen Kucukcetin
- Akdeniz University, Medical Faculty, Department of Medical Biochemistry, Antalya, Turkey
| | - Gulbahar Uzun
- Akdeniz University, Medical Faculty, Department of Medical Biochemistry, Antalya, Turkey
| | - Sebahat Ozdem
- Akdeniz University, Medical Faculty, Department of Medical Biochemistry, Antalya, Turkey
| | - Sadi S Ozdem
- Akdeniz University, Medical Faculty, Department of Medical Pharmacology, Antalya, Turkey
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Erten M. Visfatin as a Promising Marker of Cardiometabolic Risk. ACTA CARDIOLOGICA SINICA 2021; 37:464-472. [PMID: 34584379 DOI: 10.6515/acs.202109_37(5).20210323b] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 03/23/2021] [Indexed: 12/11/2022]
Abstract
Adipose tissue is an endocrine organ that produces molecules with important functions in the human body called adipokines. Visfatin can be secreted from various sources, such as macrophages, chondrocytes and amniotic epithelial cells other than adipose tissue. The main effect of visfatin is to promote inflammatory processes. In addition, visfatin has pivotal effects on the entire cardiovascular system, such as endothelial dysfunction, atherosclerosis, plaque rupture and mobilization, myocardial damage, fibrosis and new vessel formation. Vascular pathologies in other tissues also mediate its effects. Visfatin changes in a similar manner to cardiac markers in acute myocardial infarction, and the most cited feature in research studies is that it may be a cardiovascular risk marker. Visfatin is therefore expected to be widely used in cardiovascular pathology in the near future. Visfatin has many target tissues and various effects that occur in relatively complex biological pathways, making it difficult to understand visfatin adequately. In this review, we provide comprehensive information about this promising molecule.
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Affiliation(s)
- Mehmet Erten
- Laboratory of Medical Biochemistry, Public Health Lab., Malatya, Turkey
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Heo YJ, Choi SE, Lee N, Jeon JY, Han SJ, Kim DJ, Kang Y, Lee KW, Kim HJ. Visfatin exacerbates hepatic inflammation and fibrosis in a methionine-choline-deficient diet mouse model. J Gastroenterol Hepatol 2021; 36:2592-2600. [PMID: 33600604 DOI: 10.1111/jgh.15465] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 12/14/2020] [Accepted: 02/11/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to non-alcoholic steatohepatitis, which is characterized by hepatic inflammation that can progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Visfatin, an adipocytokine, was reported to induce pro-inflammatory cytokines and can be associated with liver fibrosis. We investigated the role of visfatin on hepatic inflammation and fibrosis in a methionine-choline-deficient (MCD)-diet-induced steatohepatitis mouse model. METHODS Eight-week-old male C57BL/6 J mice were randomly assigned into one of three groups: (1) saline-injected control diet group; (2) saline-injected MCD diet group; and (3) visfatin-injected MCD diet group (n = 8 per group). Mice were administered intravenous saline or 10 μg/kg of recombinant murine visfatin for 2 weeks. Histologic assessment of liver and biochemical and molecular measurements of endoplasmic reticulum (ER) stress, reactive oxidative stress (ROS), inflammation, and fibrosis were performed in livers from these animals. RESULTS Visfatin injection aggravated hepatic steatosis and increased plasma alanine aminotransferase and aspartate aminotransferase concentrations. Visfatin increased inflammatory cell infiltration (as indicated by F4/80, CD68, ly6G, and CD3 mRNA expression) and expression of chemokines in the liver. Visfatin also increased the expression of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and activated fibrosis markers (CTGF, TIMP1, collagen 1α2, collagen 3α2, αSMA, fibronectin, and vimentin) in liver. Livers of visfatin-injected mice showed upregulation of ER stress and ROS and activation of JNK signaling. CONCLUSIONS These results suggest that visfatin aggravates hepatic inflammation together with induction of ER and oxidative stress and exacerbates fibrosis in an MCD-diet-fed mouse model of NAFLD.
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Affiliation(s)
- Yu Jung Heo
- Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Sung-E Choi
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Nami Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Ja Young Jeon
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Yup Kang
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
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Annie L, Gurusubramanian G, Roy VK. Inhibition of visfatin by FK866 mitigates pathogenesis of cystic ovary in letrozole-induced hyperandrogenised mice. Life Sci 2021; 276:119409. [PMID: 33781825 DOI: 10.1016/j.lfs.2021.119409] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/08/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023]
Abstract
Polycystic ovary syndrome is a common reproductive disorder in the female of reproductive age, which is characterized by hyperandrogenism, insulin resistance, cystic ovary and infertility. The level of pro-inflammatory adipokine, visfatin is elevated in PCOS conditions in human and animal. In this study, letrozole induced hyperandrogenised PCOS mice model have been used to unravel the effects of visfatin inhibition. The results showed that letrozole induced hyperandrogenisation significantly (p < 0.05) elevates ovarian visfatin concentration from 66.03 ± 1.77 to 112.08 ± 3.7 ng/ml, and visfatin expression to 2.5 fold (p < 0.05) compared to control. Visfatin inhibition in PCOS by FK866 has significantly (p < 0.05) suppressed the secretion of androgens, androstenedione (from 0.329 ± 0.07 to 0.097 ± 0.01 ng/ml) and testosterone levels (from 0.045 ± 0.003 to 0.014 ± 0.0009 ng/ml). Ovarian histology showed that visfatin inhibition suppressed cyst formation and promotes corpus luteum formation. Visfatin inhibition has suppressed apoptosis and increases the expression of BCL2 along with increase in the proliferation (GCNA expression elevated). Visfatin inhibition has increased ovarian glucose content (from 167.05 ± 8.5 to 210 ± 7 mg/dl), along with increase in ovarian GLUT8 expression. In vitro study has also supported the in vivo findings where FK866 treatment significantly (p < 0.05) suppressed testosterone (control-3.84 ± 0.44 ng/ml, 1 nM FK866-2.02 ± 0.048 ng/ml, 10 nM FK866-1.74 ± 0.20 ng/ml) and androstenedione (control-4.68 ± 0.91 ng/ml, 1 nM FK866-3.38 ± 0.27 ng/ml, 10 nM FK866-4.55 ± 0.83 ng/ml) production from PCOS ovary. In conclusion, this is first report, which showed that visfatin inhibition by FK866 in hyperandrogenised mice ameliorates pathogenesis of PCOS. Thus, it may be suggested that visfatin inhibition could have a therapeutic potential in PCOS management along with other intervention.
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Affiliation(s)
| | | | - Vikas Kumar Roy
- Department of Zoology, Mizoram University, Aizawl, Mizoram 796 004, India.
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Association between Tumor Prognosis Marker Visfatin and Proinflammatory Cytokines in Hypertensive Patients. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8568926. [PMID: 33816632 PMCID: PMC7990525 DOI: 10.1155/2021/8568926] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/22/2020] [Accepted: 02/19/2021] [Indexed: 12/03/2022]
Abstract
Visfatin has been reported as a risk factor and a potential diagnostic marker in cancer. It is an adipokine, secreted by visceral fat and associated with the pathogenesis of arterial hypertension. We investigated the circulatory levels of visfatin in hypertensive patients with hypertriglyceridemia, which are the risk factors for various cancers and its association with proinflammatory cytokines. A total of 81 (male/female: 33/48) subjects with or without hypertension were enrolled for this study. Group 1 was normotensive, Group 2 hypertensive, and Group 3 with hypertension with hypertriglyceridemia. Data on anthropometric and biochemical data were recorded. Plasma visfatin levels were measured using an ELISA kit. The plasma inflammatory cytokines were estimated using a multiplex bead-based assay. The results revealed that the hypertension with hypertriglyceridemia group has the highest levels of visfatin compared to the hypertension and control groups with a significant difference (p < 0.001). Besides, circulatory visfatin showed the strongest possible correlation with proinflammatory cytokines among hypertensive patients with hypertriglyceridemia. We found a positive correlation between visfatin and diastolic blood pressure as well as high-density lipoproteins. In conclusion, the outcomes of the present study demonstrate that plasma visfatin levels were found to be elevated in hypertensive patients with hypertriglyceridemia and associated with proinflammatory cytokines. Since hypertension has been documented as the most common comorbidity observed in cancer patients, visfatin may be a novel potential therapeutic target for hypertension in cancer patients and survivors.
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22
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Ji X. Visfatin and 25-Hydroxyvitamin D3 Levels Affect Coronary Collateral Circulation Development in Patients with Chronic Coronary Total Occlusion. CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2021. [DOI: 10.15212/cvia.2021.0032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Background: Coronary collateral circulation (CCC) plays a vital role in the myocardial blood supply, especially forischemic myocardium. Evidence suggests that the visfatin and 25-hydroxyvitamin D3 [25(OH)D3] levels are related to the degree and incidence of vascular stenosis associated with coronary artery disease; however, few studies have evaluated the effect of visfatin and 25(OH)D3 on CCC development in patients with chronic total occlusion (CTO).This study aimed to evaluate the relationship between the serum visfatin and 25(OH)D3 levels and CCC in patients with CTO.Methods: A total of 189 patients with CTO confirmed by coronary angiography were included. CCC was graded from 0 to 3 according to the Rentrop-Cohen classification. Patients with grade 0 or grade 1 collateral development were included in the poor CCC group (n = 82), whereas patients with grade 2 or grade 3 collateral development were included in the good CCC group (n = 107). The serum visfatin and 25(OH)D3 levels were measured by ELISA.Results: The visfatin level was significantly higher in the poor CCC group than in the good CCC group, and the 25(OH)D3 level was significantly lower in the poor CCC group than in the good CCC group (P = 0.000). Correlation analysis showed that the Rentrop grade was negatively correlated with the visfatin level (r = − 0.692, P = 0.000) but positively correlated with the 25(OH)D3 level (r = 0.635, P = 0.000). Logistic regression analysis showed that the visfatin and 25(OH)D3 levels were independent risk factors for CCC (odds ratio 1.597, 95% confidence interval 1.300–1.961, P = 0.000 and odds ratio 0.566, 95% confidence interval 0.444–0.722, P = 0.000, respectively). The visfatin and25(OH)D3 levels can effectively predict the CCC status.Conclusion: Serum visfatin and 25(OH)D3 levels are related to CCC development and are independent predictors of poor CCC.
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Affiliation(s)
- Xiaoling Ji
- China Aerospace Science and Industry Corporation 731 Hospital
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Wnuk A, Stangret A, Wątroba M, Płatek AE, Skoda M, Cendrowski K, Sawicki W, Szukiewicz D. Can adipokine visfatin be a novel marker of pregnancy-related disorders in women with obesity? Obes Rev 2020; 21:e13022. [PMID: 32220005 DOI: 10.1111/obr.13022] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 03/03/2020] [Accepted: 03/07/2020] [Indexed: 12/14/2022]
Abstract
Overweight and obesity have become a dangerous disease requiring multiple interventions, treatment and preventions. In women of reproductive age, obesity is one of the most common medical conditions. Among others, obese state is characterized by low-grade systemic inflammation and enhanced oxidative stress. Increased maternal body mass index might amplify inflammation and reactive oxygen species production, which is associated with unfavourable clinical outcomes that affect both mother and child. Intrauterine growth retardation, preeclampsia, or gestational diabetes mellitus are examples of the hampered maternal and foetoplacental unit interactions. Visfatin is the obesity-related adipokine produced mainly by the visceral adipose tissue. Visfatin affects glucose homeostasis, as well as the regulation of genes related to oxidative stress and inflammatory response. Here, we review visfatin interactions in pregnancy-related disorders linked to obesity. We highlight the possible predictive and prognostic value of visfatin in diagnostic strategies on gravidas with obesity.
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Affiliation(s)
- Anna Wnuk
- Chair and Department of Obstetrics, Gynecology and Oncology, Medical University of Warsaw, Warsaw, Poland
| | - Aleksandra Stangret
- Chair and Department of General and Experimental Pathology with Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Mateusz Wątroba
- Chair and Department of General and Experimental Pathology with Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Anna E Płatek
- Chair and Department of General and Experimental Pathology with Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland.,1st Department of Cardiology, Medical University of Warsaw, Warsaw, Poland
| | - Marta Skoda
- Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Cendrowski
- Chair and Department of Obstetrics, Gynecology and Oncology, Medical University of Warsaw, Warsaw, Poland
| | - Włodzimierz Sawicki
- Chair and Department of Obstetrics, Gynecology and Oncology, Medical University of Warsaw, Warsaw, Poland
| | - Dariusz Szukiewicz
- Chair and Department of General and Experimental Pathology with Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
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Visfatin/eNampt induces endothelial dysfunction in vivo: a role for Toll-Like Receptor 4 and NLRP3 inflammasome. Sci Rep 2020; 10:5386. [PMID: 32214150 PMCID: PMC7096459 DOI: 10.1038/s41598-020-62190-w] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
Visfatin/extracellular-nicotinamide-phosphoribosyltranferase-(eNampt) is a multifaceted adipokine enhanced in type-2-diabetes and obesity. Visfatin/eNampt cause in vitro endothelial dysfunction and vascular inflammation, although whether the same effects are achieved in vivo is unknown. Toll-like receptor-4 (TLR4), a main surface pattern recognition receptor of innate immune system is a potential target for visfatin/eNampt. We studied its capacity to generate vascular dysfunction in vivo, focusing on TLR4 role and downstream activation of nod-like-receptor-protein-3 (NLRP3)-inflammasome. 4 month-old C57BL/6 mice were exposed to 7 days infusion of visfatin/eNampt, alone or together with FK 866 (Nampt enzymatic inhibitor), CLI 095 (TLR4 blocker), MCC 950 (NLRP3-inflammasome inhibitor), or anakinra (interleukin(IL)-1-receptor antagonist). Endothelial dysfunction was tested in isolated microvessels. In human umbilical endothelial cells (HUVEC), proteins related to the NLRP3-inflammasome phosphorylated p-65, NLRP3, caspase-1, pro-IL-1β, and mature IL-1β were determined by Western blot, while the inflammasome related apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC-specks) was studied by immunofluorescence. Impaired endothelium-dependent relaxations were observed in isolated mesenteric microvessels from visfatin/eNampt-infused mice. This effect was attenuated by co-treatment with FK 866 or CLI 095, supporting a role for Nampt enzymatic activity and TLR4 activation. Moreover, cultured HUVEC exposed to visfatin/eNampt showed higher expression and activation of NLRP3-inflammasome. Again, this effect relied on Nampt enzymatic activity and TLR4 activation, and it was abrogated by the inflammasome assembly blockade with MCC 950. The endothelial dysfunction evoked by visfatin/eNampt infusion in vivo was also sensitive to both MCC 950 and anakinra treatments, suggesting that the NLRP3-inflammasome-driven tissular release of IL-1β is the final mediator of endothelial damage. We conclude that Visfatin/eNampt produces in vivo vascular dysfunction in mice by a Nampt-dependent TLR4-mediated pathway, involving NLRP3-inflammasome and paracrine IL-1β. Thus, those targets may become therapeutic strategies for attenuating the adipokine-mediated vascular dysfunction associated to obesity and/or type-2-diabetes.
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Audrito V, Messana VG, Deaglio S. NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation. Front Oncol 2020; 10:358. [PMID: 32266141 PMCID: PMC7096376 DOI: 10.3389/fonc.2020.00358] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 03/02/2020] [Indexed: 12/13/2022] Open
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPRT) are two intracellular enzymes that catalyze the first step in the biosynthesis of NAD from nicotinamide and nicotinic acid, respectively. By fine tuning intracellular NAD levels, they are involved in the regulation/reprogramming of cellular metabolism and in the control of the activity of NAD-dependent enzymes, including sirtuins, PARPs, and NADases. However, during evolution they both acquired novel functions as extracellular endogenous mediators of inflammation. It is well-known that cellular stress and/or damage induce release in the extracellular milieu of endogenous molecules, called alarmins or damage-associated molecular patterns (DAMPs), which modulate immune functions through binding pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), and activate inflammatory responses. Increasing evidence suggests that extracellular (e)NAMPT and eNAPRT are novel soluble factors with cytokine/adipokine/DAMP-like actions. Elevated eNAMPT were reported in several metabolic and inflammatory disorders, including obesity, diabetes, and cancer, while eNAPRT is emerging as a biomarker of sepsis and septic shock. This review will discuss available data concerning the dual role of this unique family of enzymes.
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Affiliation(s)
- Valentina Audrito
- Laboratory of Tumor Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Vincenzo Gianluca Messana
- Laboratory of Tumor Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Silvia Deaglio
- Laboratory of Tumor Immunogenetics, Department of Medical Sciences, University of Turin, Turin, Italy
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Ahmed HH, Shousha WG, El-mezayen HA, Emara IA, Hassan ME. New Biomarkers as Prognostic Factors for Cardiovascular Complications in Type 2 Diabetic Patients. Indian J Clin Biochem 2020; 35:54-62. [PMID: 32071496 PMCID: PMC6995459 DOI: 10.1007/s12291-018-0784-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 07/10/2018] [Indexed: 10/28/2022]
Abstract
This study was initiated to explore some novel biomarkers like pro-inflammatory markers (chemerin and visfatin) and anti-inflammatory marker (omentin-1) as prognostic factors for cardiovascular complications in type 2 diabetic patients. Forty diabetic patients without cardiovascular disease, 40 diabetic patients with cardiovascular disease and twenty healthy control counterparts were included in this study. Serum chemerin, omentin-1 and visfatin levels were quantified. Receiver operating characteristic curve analysis was done to identify the cut off value for each marker. The mean serum level of chemerin was 57.65 ± 15.69 ng/l in diabetic patients versus 93.97 ± 26.62 ng/l for the cardio-diabetic ones (P < 0.0001). The mean serum level of omentin-1 was 8.77 ± 1.53 ng/ml in diabetic patients versus 1.76 ± 0.96 ng/ml for the cardio-diabetic ones (P < 0.0001). The mean level of visfatin was 1.44 ± 0.71 ug/l in diabetic patients versus 3.92 ± 3.32 ug/l for the cardio-diabetic ones (P < 0.0001). Chemerin and Visfatin levels were significantly enhanced in the cardio-diabetic patients with increasing C-reactive protein (CRP), triglycerides (TG), fasting blood glucose (FBG), micro-albumin and cholesterol. Omentin-1 level was significantly reduced in the cardio-diabetic patients with increasing CRP, TG, FBG, and cholesterol. It was observed that the area under curve for chemerin, omentin-1and visfatin was 0.877, 0.998 and 0.735, respectively. In conclusion, this study evidences that the measuring serum levels of chemerin, omentin-1 and visfatin may help in the prognosis of cardiovascular complications in type 2 diabetic patients.
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Affiliation(s)
- Hanaa H. Ahmed
- Hormones Department, National Research Centre, Dokki, Giza, Egypt
| | - Wafaa Gh. Shousha
- Biochemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Hatem A. El-mezayen
- Biochemistry Department, Faculty of Science, Helwan University, Cairo, Egypt
| | - Ibrahim A. Emara
- Biochemistry Department, National Institute of Diabetes and Endocrinology, Cairo, Egypt
| | - Marwa E. Hassan
- Biochemistry Department, National Institute of Diabetes and Endocrinology, Cairo, Egypt
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Kulikova V, Shabalin K, Nerinovski K, Yakimov A, Svetlova M, Solovjeva L, Kropotov A, Khodorkovskiy M, Migaud ME, Ziegler M, Nikiforov A. Degradation of Extracellular NAD + Intermediates in Cultures of Human HEK293 Cells. Metabolites 2019; 9:E293. [PMID: 31795381 PMCID: PMC6950141 DOI: 10.3390/metabo9120293] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 11/22/2019] [Accepted: 11/27/2019] [Indexed: 01/06/2023] Open
Abstract
Nicotinamide adenine dinucleotide (NAD) is an essential redox carrier, whereas its degradation is a key element of important signaling pathways. Human cells replenish their NAD contents through NAD biosynthesis from extracellular precursors. These precursors encompass bases nicotinamide (Nam) and nicotinic acid and their corresponding nucleosides nicotinamide riboside (NR) and nicotinic acid riboside (NAR), now collectively referred to as vitamin B3. In addition, extracellular NAD+ and nicotinamide mononucleotide (NMN), and potentially their deamidated counterparts, nicotinic acid adenine dinucleotide (NAAD) and nicotinic acid mononucleotide (NAMN), may serve as precursors of intracellular NAD. However, it is still debated whether nucleotides enter cells directly or whether they are converted to nucleosides and bases prior to uptake into cells. Here, we studied the metabolism of extracellular NAD+ and its derivatives in human HEK293 cells using normal and serum-free culture medium. Using medium containing 10% fetal bovine serum (FBS), mono- and dinucleotides were degraded to the corresponding nucleosides. In turn, the nucleosides were cleaved to their corresponding bases. Degradation was also observed in culture medium alone, in the absence of cells, indicating that FBS contains enzymatic activities which degrade NAD+ intermediates. Surprisingly, NR was also rather efficiently hydrolyzed to Nam in the absence of FBS. When cultivated in serum-free medium, HEK293 cells efficiently cleaved NAD+ and NAAD to NMN and NAMN. NMN exhibited rather high stability in cell culture, but was partially metabolized to NR. Using pharmacological inhibitors of plasma membrane transporters, we also showed that extracellular cleavage of NAD+ and NMN to NR is a prerequisite for using these nucleotides to maintain intracellular NAD contents. We also present evidence that, besides spontaneous hydrolysis, NR is intensively metabolized in cell culture by intracellular conversion to Nam. Our results demonstrate that both the cultured cells and the culture medium mediate a rather active conversion of NAD+ intermediates. Consequently, in studies of precursor supplementation and uptake, the culture conditions need to be carefully defined.
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Affiliation(s)
- Veronika Kulikova
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (V.K.); (M.S.); (L.S.); (A.K.)
- Peter the Great St. Petersburg Polytechnic University, St. Petersburg 195251, Russia; (A.Y.); (M.K.)
- Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg 194223, Russia
| | - Konstantin Shabalin
- Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre “Kurchatov Institute”, Gatchina 188300, Russia;
| | - Kirill Nerinovski
- Department of Nuclear Physics Research Methods, St. Petersburg State University, St. Petersburg 199034, Russia;
| | - Alexander Yakimov
- Peter the Great St. Petersburg Polytechnic University, St. Petersburg 195251, Russia; (A.Y.); (M.K.)
- Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre “Kurchatov Institute”, Gatchina 188300, Russia;
| | - Maria Svetlova
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (V.K.); (M.S.); (L.S.); (A.K.)
| | - Ljudmila Solovjeva
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (V.K.); (M.S.); (L.S.); (A.K.)
| | - Andrey Kropotov
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (V.K.); (M.S.); (L.S.); (A.K.)
| | - Mikhail Khodorkovskiy
- Peter the Great St. Petersburg Polytechnic University, St. Petersburg 195251, Russia; (A.Y.); (M.K.)
| | - Marie E. Migaud
- Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA;
| | - Mathias Ziegler
- Department of Biomedicine, University of Bergen, 5020 Bergen, Norway;
| | - Andrey Nikiforov
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg 194064, Russia; (V.K.); (M.S.); (L.S.); (A.K.)
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Kong YY, Li GQ, Zhang WJ, Hua X, Zhou CC, Xu TY, Li ZY, Wang P, Miao CY. Nicotinamide phosphoribosyltransferase aggravates inflammation and promotes atherosclerosis in ApoE knockout mice. Acta Pharmacol Sin 2019; 40:1184-1192. [PMID: 30833708 PMCID: PMC6786310 DOI: 10.1038/s41401-018-0207-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 12/19/2018] [Accepted: 12/23/2018] [Indexed: 12/31/2022]
Abstract
Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme of nicotinamide adenine dinucleotide (NAD) salvage biosynthesis in mammals, and is involved in fundamental physiological processes and pathophysiology of many diseases. Thus far, however, the role of Nampt in atherosclerosis development is still in debate. In this study, we crossed global Nampt transgenic mice (Nampt-Tg) with a well-established atherosclerosis animal model (ApoE knockout mice, ApoE-/-) to generate ApoE-/-;Nampt-Tg mice and investigated the effects of Nampt overexpression on atherosclerosis development in ApoE-/- mice. Both ApoE-/- and ApoE-/-;Nampt-Tg mice were fed with a pro-atherosclerotic high-fat diet (HFD) for 16 weeks. Their serum lipid contents and atherosclerotic lesion were assessed. The results showed that there was no significant difference in body weight or serum levels of glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol between the two strains of mice, but ApoE-/-;Nampt-Tg mice had a significantly higher level of serum non-esterified fatty acid. Compared with ApoE-/- mice, ApoE-/-;Nampt-Tg mice displayed significantly increased atherosclerotic lesion area and thickness, lower collagen content, decreased collagen I/III ratio (collagen immaturation), increased number of apoptotic cells, and enhanced activities of caspase-3, caspase-8, and caspase-9. Moreover, macrophage infiltration (F4/80 staining), tumor necrosis factor signaling, and chemokines expression (ICAM-1 and CXCR-4) were all activated in aortic atherosclerotic plaque of ApoE-/-;Nampt-Tg mice compared with ApoE-/- mice. Our results provide in vivo evidence that Nampt transgene aggravates atherosclerotic inflammation and promotes atherosclerosis development in ApoE-/- mice.
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Affiliation(s)
- Yuan-Yuan Kong
- Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China
| | - Guo-Qiang Li
- Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China
| | - Wen-Jie Zhang
- Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China
| | - Xia Hua
- Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China
| | - Can-Can Zhou
- Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China
| | - Tian-Ying Xu
- Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China
| | - Zhi-Yong Li
- Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China
| | - Pei Wang
- Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China.
- School of Pharmacy, Yantai University, Yantai, 264000, China.
| | - Chao-Yu Miao
- Department of Pharmacology, Second Military Medical University, Shanghai, 200433, China.
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MicroRNA-34a and MicroRNA-181a Mediate Visfatin-Induced Apoptosis and Oxidative Stress via NF-κB Pathway in Human Osteoarthritic Chondrocytes. Cells 2019; 8:cells8080874. [PMID: 31405216 PMCID: PMC6721672 DOI: 10.3390/cells8080874] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 07/31/2019] [Accepted: 08/09/2019] [Indexed: 01/16/2023] Open
Abstract
Current evidence suggests a complex interaction between adipokines and microRNA (miRNA) in osteoarthritis (OA) pathogenesis. The present study explored the role of miR-34a and miR-181a in regulating apoptosis and oxidative stress induced by visfatin in human OA chondrocytes. Chondrocytes were transfected with miR-34a and miR-181a inhibitors and stimulated with visfatin for 24 h, in the presence of nuclear factor (NF)-κB inhibitor (BAY-11-7082, 2 h pre-incubation). Apoptosis and reactive oxygen species (ROS) production were detected by cytometry, miRNA, antioxidant enzymes, nuclear factor erythroid (NRF)2 and B-cell lymphoma (BCL)2 expressions by quantitative real time polymerase chain reaction (real time PCR) and western blot. P50 NF-κB subunit was measured by immunofluorescence. Visfatin significantly induced apoptosis and superoxide anion production, increased miR-34a, miR-181a, superoxide dismutase (SOD)-2, catalase (CAT), NRF2 and decreased BCL2 gene and protein expression in OA chondrocytes. All the visfatin-caused effects were suppressed by using miR-34a and miR-181a inhibitors. Pre-incubation with BAY-11-7082 counteracted visfatin-induced expression of miRNA, BCL2, SOD-2, CAT and NRF2. Inhibition of miR-34a and miR-181a significantly reduced the activation of p50 NF-κB. Visfatin confirms its ability to induce apoptosis and oxidative stress in human OA chondrocytes; these effects appeared mediated by miR-34a and miR-181a via NF-κB pathway. We highlight the relevance of visfatin as potential therapeutic target for OA treatment.
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Audrito V, Managò A, Gaudino F, Deaglio S. Targeting metabolic reprogramming in metastatic melanoma: The key role of nicotinamide phosphoribosyltransferase (NAMPT). Semin Cell Dev Biol 2019; 98:192-201. [PMID: 31059816 DOI: 10.1016/j.semcdb.2019.05.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/02/2019] [Accepted: 05/02/2019] [Indexed: 12/13/2022]
Abstract
Cancer cells rewire their metabolism to support proliferation, growth and survival. In metastatic melanoma the BRAF oncogenic pathway is a master regulator of this process, highlighting the importance of metabolic reprogramming in the pathogenesis of this tumor and offering potential therapeutic approaches. Metabolic adaptation of melanoma cells generally requires increased amounts of NAD+, an essential redox cofactor in cellular metabolism and a signaling molecule. Nicotinamide phosphoribosyltransferase (NAMPT) is the most important NAD+ biosynthetic enzyme in mammalian cells and a direct target of the BRAF oncogenic signaling pathway. These findings suggest that NAMPT is an attractive new therapeutic target, particularly in combination strategies with BRAF or MEK inhibitors. Here we review current knowledge on how oncogenic signaling reprograms metabolism in BRAF-mutated melanoma, and discuss how NAMPT/NAD+ axis contributes to these processes. Lastly, we present evidence supporting a role of NAMPT as a novel therapeutic target in metastatic melanoma.
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Affiliation(s)
- Valentina Audrito
- Department of Medical Sciences, University of Turin, Turin, Italy; Italian Institute for Genomic Medicine, Turin, Italy.
| | - Antonella Managò
- Department of Medical Sciences, University of Turin, Turin, Italy; Italian Institute for Genomic Medicine, Turin, Italy
| | - Federica Gaudino
- Department of Medical Sciences, University of Turin, Turin, Italy; Italian Institute for Genomic Medicine, Turin, Italy
| | - Silvia Deaglio
- Department of Medical Sciences, University of Turin, Turin, Italy; Italian Institute for Genomic Medicine, Turin, Italy.
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Zheng LY, Xu X, Wan RH, Xia S, Lu J, Huang Q. Association between serum visfatin levels and atherosclerotic plaque in patients with type 2 diabetes. Diabetol Metab Syndr 2019; 11:60. [PMID: 31367237 PMCID: PMC6657107 DOI: 10.1186/s13098-019-0455-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Accepted: 07/18/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Visfatin is a multifaceted protein that plays an important role in regulating a variety of physiological and pathological processes, including obesity, diabetes and cardiovascular disease. However, circulating visfatin levels in atherosclerosis plaque progression in patients with type 2 diabetes, or its association with the vascular territory affected remain unclear. METHODS We evaluated the relationship between visfatin levels and carotid or femoral artery atherosclerosis in Chinese patients with type 2 diabetes. Serum levels of visfatin were measured by enzyme-linked immunosorbent assay (ELISA) in 97 inpatients with type 2 diabetes. Carotid and/or femoral atherosclerotic plaques were detected by B-mode ultrasound. RESULTS Serum visfatin levels were elevated in the group with atherosclerotic plaques compared to the control group without plaques [0.68 (0.46-1.58) versus 0.45 (0.23-0.76) ng/mL, respectively, P = 0.0002]. Patients with carotid plaques showed higher visfatin levels than those with or without femoral plaques. Pearson's correlation analysis showed that serum visfatin levels were positively correlated with waist circumference (r = 0.226, P = 0.029), waist-hip ratio (r = 0.221, P = 0.032), TG (r = 0.222, P = 0.030) and number of plaques (r = 0.275, P = 0.009). Logistic regression analysis showed that a higher serum visfatin level was an independent predictor for the presence of atherosclerotic plaques. CONCLUSIONS In conclusion, among patients with T2DM, serum visfatin levels were elevated in those with atherosclerotic plaques, especially in patients with carotid atherosclerotic plaques. Serum visfatin may serve as a predictor of atherosclerotic plaques in patients with T2DM.
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Affiliation(s)
- Long-Yi Zheng
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433 China
| | - Xia Xu
- Department of Rheumatology and Immunology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433 China
| | - Ren-Hui Wan
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433 China
| | - Sheng Xia
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433 China
| | - Jin Lu
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433 China
| | - Qin Huang
- Department of Endocrinology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433 China
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Heo YJ, Choi SE, Jeon JY, Han SJ, Kim DJ, Kang Y, Lee KW, Kim HJ. Visfatin Induces Inflammation and Insulin Resistance via the NF- κB and STAT3 Signaling Pathways in Hepatocytes. J Diabetes Res 2019; 2019:4021623. [PMID: 31396538 PMCID: PMC6664505 DOI: 10.1155/2019/4021623] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 05/09/2019] [Accepted: 06/10/2019] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND It has been suggested that visfatin, which is an adipocytokine, exhibits proinflammatory properties and is associated with insulin resistance. Insulin resistance and inflammation are the principal pathogeneses of nonalcoholic fatty liver disease (NAFLD), but the relationship, if any, between visfatin and NAFLD remains unclear. Here, we evaluated the effects of visfatin on hepatic inflammation and insulin resistance in HepG2 cells and examined the molecular mechanisms involved. METHODS After treatment with visfatin, the inflammatory cytokines IL-6, TNF-α, and IL-1β were assessed by real-time polymerase chain reaction (RT-PCR) and immunocytochemical staining in HepG2 cells. To investigate the effects of visfatin on insulin resistance, we evaluated insulin-signaling pathways, such as IR, IRS-1, GSK, and AKT using immunoblotting. We assessed the intracellular signaling molecules including STAT3, NF-κB, IKK, p38, JNK, and ERK by western blotting. We treated HepG2 cells with both visfatin and either AG490 (a JAK2 inhibitor) or Bay 7082 (an NF-κB inhibitor); we examined proinflammatory cytokine mRNA levels using RT-PCR and insulin signaling using western blotting. RESULTS In HepG2 cells, visfatin significantly increased the levels of proinflammatory cytokines, reduced the levels of proteins (e.g., phospho-IR, phospho-IRS-1 (Tyr612), phospho-AKT, and phospho-GSK-3α/β) involved in insulin signaling, and increased IRS-1 S307 phosphorylation compared to controls. Interestingly, visfatin increased the activities of the JAK2/STAT3 and IKK/NF-κB signaling pathways but not those of the JNK, p38, and ERK pathways. Visfatin-induced inflammation and insulin resistance were regulated by JAK2/STAT3 and IKK/NF-κB signaling; together with AG490 or Bay 7082, visfatin significantly reduced mRNA levels of IL-6, TNF-α and IL-1β and rescued insulin signaling. CONCLUSION Visfatin induced proinflammatory cytokine production and inhibited insulin signaling via the STAT3 and NF-κB pathways in HepG2 cells.
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Affiliation(s)
- Yu Jung Heo
- Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Sung-E Choi
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Ja Young Jeon
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Seung Jin Han
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Dae Jung Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Yup Kang
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
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A Complex Relationship between Visfatin and Resistin and microRNA: An In Vitro Study on Human Chondrocyte Cultures. Int J Mol Sci 2018; 19:ijms19123909. [PMID: 30563239 PMCID: PMC6320832 DOI: 10.3390/ijms19123909] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 11/26/2018] [Accepted: 12/05/2018] [Indexed: 12/13/2022] Open
Abstract
Growing evidence indicates the important role of adipokines and microRNA (miRNA) in osteoarthritis (OA) pathogenesis. The purpose of the present study was to investigate the effect of visfatin and resistin on some miRNA (34a, 140, 146a, 155, 181a, let-7e), metalloproteinases (MMPs), and collagen type II alpha 1 chain (Col2a1) in human OA chondrocytes and in the T/C-28a2 cell line. The implication of nuclear factor (NF)-κB in response to adipokines was also assessed. Chondrocytes were stimulated with visfatin (5 or 10 μg/mL) and resistin (50 or 100 ng/mL) with or without NF-κB inhibitor (BAY-11-7082, 1 μM) for 24 h. Viability and apoptosis were detected by MMT and cytometry, miRNA, MMP-1, MMP-13, and Col2a1 by qRT-PCR and NF-κB activation by immunofluorescence. Visfatin and resistin significantly reduced viability, induced apoptosis, increased miR-34a, miR-155, miR-181a, and miR-let7e, and reduced miR-140 and miR-146a gene expression in OA chondrocytes. MMP-1, MMP-13, and Col2a1 were significantly modulated by treatment of OA chondrocytes with adipokines. Visfatin and resistin significantly increased NF-κB activation, while the co-treatment with BAY11-7082 did not change MMPs or Col2a1 levels beyond that caused by single treatment. Visfatin and resistin regulate the expression levels of some miRNA involved in OA pathogenesis and exert catabolic functions in chondrocytes via the NF-κB pathway. These data confirm the complex relationship between adipokines and miRNA.
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Audrito V, Managò A, La Vecchia S, Zamporlini F, Vitale N, Baroni G, Cignetto S, Serra S, Bologna C, Stingi A, Arruga F, Vaisitti T, Massi D, Mandalà M, Raffaelli N, Deaglio S. Nicotinamide Phosphoribosyltransferase (NAMPT) as a Therapeutic Target in BRAF-Mutated Metastatic Melanoma. J Natl Cancer Inst 2018; 110:290-303. [DOI: 10.1093/jnci/djx198] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Affiliation(s)
- Valentina Audrito
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
| | - Antonella Managò
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
| | - Sofia La Vecchia
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
| | - Federica Zamporlini
- Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Nicoletta Vitale
- Department of Molecular Biotechnologies and Health Science, University of Turin, Italy
| | - Gianna Baroni
- Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Italy
| | - Simona Cignetto
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
| | - Sara Serra
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
| | - Cinzia Bologna
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
| | - Aureliano Stingi
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
| | - Francesca Arruga
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
| | - Tiziana Vaisitti
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
| | - Daniela Massi
- Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Italy
| | - Mario Mandalà
- Unit of Medical Oncology, Department of Oncology and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Nadia Raffaelli
- Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Silvia Deaglio
- Department of Medical Sciences, University of Turin, Italy
- Italian Institute for Genomic Medicine, Turin, Italy
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Wang W, Jiang W, Hou L, Duan H, Wu Y, Xu C, Tan Q, Li S, Zhang D. Weighted gene co-expression network analysis of expression data of monozygotic twins identifies specific modules and hub genes related to BMI. BMC Genomics 2017; 18:872. [PMID: 29132311 PMCID: PMC5683603 DOI: 10.1186/s12864-017-4257-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 11/01/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The therapeutic management of obesity is challenging, hence further elucidating the underlying mechanisms of obesity development and identifying new diagnostic biomarkers and therapeutic targets are urgent and necessary. Here, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to identify significant genes and specific modules related to BMI based on gene expression profile data of 7 discordant monozygotic twins. RESULTS In the differential gene expression analysis, it appeared that 32 differentially expressed genes (DEGs) were with a trend of up-regulation in twins with higher BMI when compared to their siblings. Categories of positive regulation of nitric-oxide synthase biosynthetic process, positive regulation of NF-kappa B import into nucleus, and peroxidase activity were significantly enriched within GO database and NF-kappa B signaling pathway within KEGG database. DEGs of NAMPT, TLR9, PTGS2, HBD, and PCSK1N might be associated with obesity. In the WGCNA, among the total 20 distinct co-expression modules identified, coral1 module (68 genes) had the strongest positive correlation with BMI (r = 0.56, P = 0.04) and disease status (r = 0.56, P = 0.04). Categories of positive regulation of phospholipase activity, high-density lipoprotein particle clearance, chylomicron remnant clearance, reverse cholesterol transport, intermediate-density lipoprotein particle, chylomicron, low-density lipoprotein particle, very-low-density lipoprotein particle, voltage-gated potassium channel complex, cholesterol transporter activity, and neuropeptide hormone activity were significantly enriched within GO database for this module. And alcoholism and cell adhesion molecules pathways were significantly enriched within KEGG database. Several hub genes, such as GAL, ASB9, NPPB, TBX2, IL17C, APOE, ABCG4, and APOC2 were also identified. The module eigengene of saddlebrown module (212 genes) was also significantly correlated with BMI (r = 0.56, P = 0.04), and hub genes of KCNN1 and AQP10 were differentially expressed. CONCLUSION We identified significant genes and specific modules potentially related to BMI based on the gene expression profile data of monozygotic twins. The findings may help further elucidate the underlying mechanisms of obesity development and provide novel insights to research potential gene biomarkers and signaling pathways for obesity treatment. Further analysis and validation of the findings reported here are important and necessary when more sample size is acquired.
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Affiliation(s)
- Weijing Wang
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, No. 38 Dengzhou Road, Shibei District, Qingdao, 266021 Shandong Province People’s Republic of China
| | - Wenjie Jiang
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, No. 38 Dengzhou Road, Shibei District, Qingdao, 266021 Shandong Province People’s Republic of China
| | - Lin Hou
- Department of Biochemistry, Medical College, Qingdao University, No. 38 Dengzhou Road, Shibei District, Qingdao, 266021 Shandong Province People’s Republic of China
| | - Haiping Duan
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, No. 38 Dengzhou Road, Shibei District, Qingdao, 266021 Shandong Province People’s Republic of China
- Qingdao Municipal Center for Disease Control and Prevention, No. 175 Shandong Road, Shibei District, Qingdao, 266033 Shandong Province People’s Republic of China
| | - Yili Wu
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, No. 38 Dengzhou Road, Shibei District, Qingdao, 266021 Shandong Province People’s Republic of China
| | - Chunsheng Xu
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, No. 38 Dengzhou Road, Shibei District, Qingdao, 266021 Shandong Province People’s Republic of China
- Qingdao Municipal Center for Disease Control and Prevention, No. 175 Shandong Road, Shibei District, Qingdao, 266033 Shandong Province People’s Republic of China
- Qingdao Institute of Preventive Medicine, No. 175 Shandong Road, Shibei District, Qingdao, 266033 Shandong Province People’s Republic of China
| | - Qihua Tan
- Epidemiology, Biostatistics and Bio-demography, Institute of Public Health, University of Southern Denmark, DK-5000 Odense C, Denmark
- Human Genetics, Institute of Clinical Research, University of Southern Denmark, DK-5000 Odense C, Denmark
| | - Shuxia Li
- Human Genetics, Institute of Clinical Research, University of Southern Denmark, DK-5000 Odense C, Denmark
| | - Dongfeng Zhang
- Department of Epidemiology and Health Statistics, Public Health College, Qingdao University, No. 38 Dengzhou Road, Shibei District, Qingdao, 266021 Shandong Province People’s Republic of China
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Liu Z, Yu H, Guo Q. MicroRNA‑20a promotes inflammation via the nuclear factor‑κB signaling pathway in pediatric pneumonia. Mol Med Rep 2017; 17:612-617. [PMID: 29115456 DOI: 10.3892/mmr.2017.7899] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Accepted: 08/22/2017] [Indexed: 11/06/2022] Open
Abstract
Pneumonia is a common respiratory disease worldwide, which is preventable and treatable; however, it is recognized as a leading cause of mortality in children. The present study aimed to investigate the role and mechanism of microRNA (miR)‑20a in inflammation in pediatric pneumonia. Clinical serum samples were collected from children with pneumonia and healthy children. Initially, the serum expression levels of miR‑20a were detected by reverse transcription‑quantitative polymerase chain reaction. Subsequently, A549 cells were randomly divided into four groups: Control group; lipopolysaccharide (LPS; 1 µg/ml) group; LPS + miR‑20a group; and LPS + miR‑20a + pyrrolidine dithiocarbamate (PDTC; 100 mmol/l) group. The concentrations of interleukin‑6 (IL‑6), tumor necrosis factor (TNF)‑α and C‑reactive protein (CRP) in clinical serum samples and A549 cells were determined by ELISA. In addition, the protein expression levels of inhibitor of nuclear factor (NF)‑κB α (IκBα) and phosphorylated (p)‑NF‑κB were measured by western blotting. The results demonstrated that miR‑20a was upregulated in children with pneumonia and in lung cells with LPS‑induced inflammatory injury (P<0.01). In addition, compared with the LPS group, cells in the LPS + miR‑20a group exhibited increased expression levels of IL‑6, TNF‑α and CRP (P<0.05). Overexpression of miR‑20a also resulted in upregulation of the expression levels of IκBα and p‑NF‑κB compared with in the LPS group (P<0.05). Furthermore, treatment with the NF‑κB inhibitor PDTC inhibited the expression of inflammatory factors compared with in the LPS + miR‑20a group (P<0.05). In conclusion, the present study indicated that miR‑20a is upregulated in pediatric pneumonia, and overexpression of miR‑20a may promote inflammation through activation of the NF‑κB signaling pathway.
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Affiliation(s)
- Zhihong Liu
- Department of Emergency, Jinan Maternity and Child Care Hospital, Jinan, Shandong 250001, P.R. China
| | - Haiying Yu
- Department of Pediatrics, Weifang People's Hospital, Weifang, Shandong 261000, P.R. China
| | - Qiuye Guo
- Department of Respiratory Medicine, Hanzhong Central Hospital, Hanzhong, Shaanxi 723000, P.R. China
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Penke M, Schuster S, Gorski T, Gebhardt R, Kiess W, Garten A. Oleate ameliorates palmitate-induced reduction of NAMPT activity and NAD levels in primary human hepatocytes and hepatocarcinoma cells. Lipids Health Dis 2017; 16:191. [PMID: 28974242 PMCID: PMC5627432 DOI: 10.1186/s12944-017-0583-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 09/26/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide adenine dinucleotide (NAD) levels are crucial for liver function. The saturated fatty acid palmitate and the unsaturated fatty acid oleate are the main free fatty acids in adipose tissue and human diet. We asked how these fatty acids affect cell survival, NAMPT and NAD levels in HepG2 cells and primary human hepatocytes. METHODS HepG2 cells were stimulated with palmitate (0.5mM), oleate (1mM) or a combination of both (0.5mM/1mM) as well as nicotinamide mononucleotide (NMN) (0.5 mM) or the specific NAMPT inhibitor FK866 (10nM). Cell survival was measured by WST-1 assay and Annexin V/propidium iodide staining. NAD levels were determined by NAD/NADH Assay or HPLC. Protein and mRNA levels were analysed by Western blot analyses and qPCR, respectively. NAMPT enzyme activity was measured using radiolabelled 14C-nicotinamide. Lipids were stained by Oil red O staining. RESULTS Palmitate significantly reduced cell survival and induced apoptosis at physiological doses. NAMPT activity and NAD levels significantly declined after 48h of palmitate. In addition, NAMPT mRNA expression was enhanced which was associated with increased NAMPT release into the supernatant, while intracellular NAMPT protein levels remained stable. Oleate alone did not influence cell viability and NAMPT activity but ameliorated the negative impact of palmitate on cell survival, NAMPT activity and NAD levels, as well as the increased NAMPT mRNA expression and secretion. NMN was able to normalize intracellular NAD levels but did not ameliorate cell viability after co-stimulation with palmitate. FK866, a specific NAMPT inhibitor did not influence lipid accumulation after oleate-treatment. CONCLUSIONS Palmitate targets NAMPT activity with a consequent cellular depletion of NAD. Oleate protects from palmitate-induced apoptosis and variation of NAMPT and NAD levels. Palmitate-induced cell stress leads to an increase of NAMPT mRNA and accumulation in the supernatant. However, the proapoptotic action of palmitate seems not to be mediated by decreased NAD levels.
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Affiliation(s)
- Melanie Penke
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
| | - Susanne Schuster
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
| | - Theresa Gorski
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
| | - Rolf Gebhardt
- Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
| | - Wieland Kiess
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
| | - Antje Garten
- Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103 Leipzig, Germany
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Gan S, Qiu S, Feng Y, Zhang Y, Qian Q, Wan Z, Tang J. Identification of genes associated with the effect of inflammation on the neurotransmission of vascular smooth muscle cell. Exp Ther Med 2017; 13:1303-1312. [PMID: 28413470 PMCID: PMC5377265 DOI: 10.3892/etm.2017.4138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 12/09/2016] [Indexed: 01/23/2023] Open
Abstract
Vascular smooth muscle cell (VSMC) accumulation and hypertrophy are common in vascular disorders, and inflammation has a crucial role in the development of these diseases. To investigate the effect of inflammation on the neurotransmission of VSMC, bioinformatic analysis was performed, following next generation sequencing. Genes of lipopolysaccharide (LPS)-treated A7r5 cells and phosphate-buffered saline (PBS)-treated A7r5 cells were sequenced via next generation sequencing, and each assay was repeated three times. Differentially expressed genes (DEGs) were obtained using the NOISeq package in R. Subsequently, their potential functions were predicted by functional and pathway enrichment analyses using the Database for Annotation, Visualization and Integrated Discovery online tool. Interaction relationships of the proteins enriched in pathways associated with neurological diseases, the proteins which had interaction relationships with adrenoceptor α 1D (ADRA1D) or calcium voltage-gated channel subunit α1 S (CACNA1S), separately, were obtained from STRING, and protein-protein interaction (PPI) networks were constructed using Cytoscape software. A total of 2,038 DEGs, including 1,094 upregulated and 944 downregulated genes in the LPS treatment group were identified when compared with the control group. Enrichment analyses showed that NADH:Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2) was involved in several neurological diseases, including oxidative phosphorylation, Alzheimer's disease, Parkinson's disease and Huntington's disease. Furthermore, NDUFV2 (degree, 20) had a higher degree in the PPI network for DEGs enriched in pathways associated with neurological diseases. In the PPI network for ADRA1D, CACNA1S and the DEGs interacting with them, prohibitin (PHB), oxytocin receptor (OXTR), collapsin response mediator protein 1 (CRMP1) and dihydropyrimidinase like 2 (DPYSL2) had interaction relationships with both ADRA1D and CACNA1S. To conclude, the present study revealed that NDUFV2, PHB, OXTR, CRMP1 and DPYSL2 may have key roles in the effect of inflammation on neurotransmission of VSMC.
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Affiliation(s)
- Shujie Gan
- Department of Vascular Surgery, The First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Shenlong Qiu
- Department of Vascular Surgery, The First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Yiwen Feng
- Department of Vascular Surgery, The First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Yanping Zhang
- Department of Vascular Surgery, The First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Qin Qian
- Department of Vascular Surgery, The First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Zhong Wan
- Department of Vascular Surgery, The First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, P.R. China
| | - Jingdong Tang
- Department of Vascular Surgery, Shanghai Pudong Hospital, Fudan University, Pudong Medical Center, Shanghai 201399, P.R. China
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Bitto A, Arcoraci V, Alibrandi A, D'Anna R, Corrado F, Atteritano M, Minutoli L, Altavilla D, Squadrito F. Visfatin correlates with hot flashes in postmenopausal women with metabolic syndrome: effects of genistein. Endocrine 2017; 55:899-906. [PMID: 27126198 DOI: 10.1007/s12020-016-0968-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 04/20/2016] [Indexed: 01/08/2023]
Abstract
During menopause, an increased prevalence of metabolic syndrome (MetS) and central obesity seems to increase hot flashes (HFs). Visfatin is an inflammatory adipokine secreted by visceral fat. We investigated visfatin levels and its relationship with hot flash number and BMI, in postmenopausal women with MetS. We also evaluated the effect of genistein, an isoflavone effective in reducing HFs, on visfatin levels and HFs after 1 year of treatment. This was a randomized, double-blind, placebo-controlled trial. Postmenopausal women with MetS were randomly assigned to receive placebo (n = 60) or 54 mg genistein (n = 60), daily for 1 year. As main outcome measures, hot flashes number and circulating visfatin levels were evaluated. Visfatin significantly correlated with BMI and HFs number in women with MetS at basal. After 6 and 12 months, our results indicate a strong correlation and a significant effect of genistein in reducing both HFs and visfatin in women with MetS. The present study suggests that visfatin plays a role in the vasomotor symptoms, at least in postmenopausal women with metabolic syndrome. Genistein may reduce HFs decreasing the circulating levels of this inflammatory adipokine.
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Affiliation(s)
- Alessandra Bitto
- Department of Clinical and Experimental Medicine, University of Messina, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy.
| | - Vincenzo Arcoraci
- Department of Clinical and Experimental Medicine, University of Messina, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy
| | - Angela Alibrandi
- Department of Economical Business and Environmental Sciences and Quantitative Methods, University of Messina, Messina, Italy
| | - Rosario D'Anna
- Department of Paediatric Gynaecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy
| | - Francesco Corrado
- Department of Paediatric Gynaecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy
| | - Marco Atteritano
- Department of Clinical and Experimental Medicine, University of Messina, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy
| | - Letteria Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy
| | - Domenica Altavilla
- Department of Paediatric Gynaecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy
| | - Francesco Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy
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Chen J, Sysol JR, Singla S, Zhao S, Yamamura A, Valdez-Jasso D, Abbasi T, Shioura KM, Sahni S, Reddy V, Sridhar A, Gao H, Torres J, Camp SM, Tang H, Ye SQ, Comhair S, Dweik R, Hassoun P, Yuan JXJ, Garcia JGN, Machado RF. Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension. Circulation 2017; 135:1532-1546. [PMID: 28202489 DOI: 10.1161/circulationaha.116.024557] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 02/06/2017] [Indexed: 11/16/2022]
Abstract
BACKGROUND Pulmonary arterial hypertension is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT) is a cytozyme that regulates intracellular nicotinamide adenine dinucleotide levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation, and inhibits apoptosis. We hypothesized that NAMPT promotes pulmonary vascular remodeling and that inhibition of NAMPT could attenuate pulmonary hypertension. METHODS Plasma, mRNA, and protein levels of NAMPT were measured in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension and in the lungs of rodent models of pulmonary hypertension. Nampt+/- mice were exposed to 10% hypoxia and room air for 4 weeks, and the preventive and therapeutic effects of NAMPT inhibition were tested in the monocrotaline and Sugen hypoxia models of pulmonary hypertension. The effects of NAMPT activity on proliferation, migration, apoptosis, and calcium signaling were tested in human pulmonary artery smooth muscle cells. RESULTS Plasma and mRNA and protein levels of NAMPT were increased in the lungs and isolated pulmonary artery endothelial cells from patients with pulmonary arterial hypertension, as well as in lungs of rodent models of pulmonary hypertension. Nampt+/- mice were protected from hypoxia-mediated pulmonary hypertension. NAMPT activity promoted human pulmonary artery smooth muscle cell proliferation via a paracrine effect. In addition, recombinant NAMPT stimulated human pulmonary artery smooth muscle cell proliferation via enhancement of store-operated calcium entry by enhancing expression of Orai2 and STIM2. Last, inhibition of NAMPT activity attenuated monocrotaline and Sugen hypoxia-induced pulmonary hypertension in rats. CONCLUSIONS Our data provide evidence that NAMPT plays a role in pulmonary vascular remodeling and that its inhibition could be a potential therapeutic target for pulmonary arterial hypertension.
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Affiliation(s)
- Jiwang Chen
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Justin R Sysol
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Sunit Singla
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Shuangping Zhao
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Aya Yamamura
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Daniela Valdez-Jasso
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Taimur Abbasi
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Krystyna M Shioura
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Sakshi Sahni
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Vamsi Reddy
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Arvind Sridhar
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Hui Gao
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Jaime Torres
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Sara M Camp
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Haiyang Tang
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Shui Q Ye
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Suzy Comhair
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Raed Dweik
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Paul Hassoun
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Jason X-J Yuan
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.)
| | - Joe G N Garcia
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.).
| | - Roberto F Machado
- From Division of Pulmonary, Critical Care Medicine, Sleep and Allergy, Department of Medicine (J.C., J.R.S., S.S., S.Z., A.Y., T.A., K.M.S., S.S., V.R., A.S., H.G., J.T., R.F.M.), Department of Pharmacology (J.R.S., R.F.M.), and Department of Bioengineering (A.V.-J., T.A.), University of Illinois at Chicago; Institute of Precision Medicine, Jining Medical University, China (J.C.); Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, Nagoya, Japan (A.Y.); Department of Medicine, Mercy Hospital and Medical Center, Chicago, IL (T.A.); Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (H.G.); Department of Medicine, University of Arizona, Tucson (S.M.C., H.T., J.X.-J.Y., J.G.N.G.); Department of Biomedical and Health Informatics and Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City School of Medicine (S.Q.Y.); Department of Pathobiology, Lerner Research Institute, Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, OH (S.C., R.D.); and Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD (P.H.).
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Villalobos LA, San Hipólito-Luengo Á, Ramos-González M, Cercas E, Vallejo S, Romero A, Romacho T, Carraro R, Sánchez-Ferrer CF, Peiró C. The Angiotensin-(1-7)/Mas Axis Counteracts Angiotensin II-Dependent and -Independent Pro-inflammatory Signaling in Human Vascular Smooth Muscle Cells. Front Pharmacol 2016; 7:482. [PMID: 28018220 PMCID: PMC5156706 DOI: 10.3389/fphar.2016.00482] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 11/25/2016] [Indexed: 01/08/2023] Open
Abstract
Background and Aims: Targeting inflammation is nowadays considered as a challenging pharmacological strategy to prevent or delay the development of vascular diseases. Angiotensin-(1-7) is a member of the renin-angiotensin system (RAS) that binds Mas receptors and has gained growing attention in the last years as a regulator of vascular homeostasis. Here, we explored the capacity of Ang-(1-7) to counteract human aortic smooth muscle cell (HASMC) inflammation triggered by RAS-dependent and -independent stimuli, such as Ang II or interleukin (IL)-1β. Methods and Results: In cultured HASMC, the expression of inducible nitric oxide synthase (iNOS) and the release of nitric oxide were stimulated by both Ang II and IL-1β, as determined by Western blot and indirect immunofluorescence or the Griess method, respectively. iNOS induction was inhibited by Ang-(1-7) in a concentration-dependent manner. This effect was equally blocked by two different Mas receptor antagonists, A779 and D-Pro7-Ang-(1-7), suggesting the participation of a unique Mas receptor subtype. Using pharmacological inhibitors, the induction of iNOS was proven to rely on the consecutive upstream activation of NADPH oxidase and nuclear factor (NF)-κB. Indeed, Ang-(1-7) markedly inhibited the activation of the NADPH oxidase and subsequently of NF-κB, as determined by lucigenin-derived chemiluminescence and electromobility shift assay, respectively. Conclusion: Ang-(1-7) can act as a counter-regulator of the inflammation of vascular smooth muscle cells triggered by Ang II, but also by other stimuli beyond the RAS. Activating or mimicking the Ang-(1-7)/Mas axis may represent a pharmacological opportunity to attenuate the pro-inflammatory environment that promotes and sustains the development of vascular diseases.
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Affiliation(s)
- Laura A Villalobos
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain
| | | | - Mariella Ramos-González
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain
| | - Elena Cercas
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain
| | - Susana Vallejo
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain
| | - Alejandra Romero
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain
| | - Tania Romacho
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain
| | - Raffaele Carraro
- Service of Endocrinology, Hospital de La PrincesaMadrid, Spain; Department of Medicine, School of Medicine, Universidad Autónoma de MadridMadrid, Spain
| | - Carlos F Sánchez-Ferrer
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain
| | - Concepción Peiró
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain
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Wang Y, Gao C, Zhang Y, Gao J, Teng F, Tian W, Yang W, Yan Y, Xue F. Visfatin stimulates endometrial cancer cell proliferation via activation of PI3K/Akt and MAPK/ERK1/2 signalling pathways. Gynecol Oncol 2016; 143:168-178. [PMID: 27473926 DOI: 10.1016/j.ygyno.2016.07.109] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 07/18/2016] [Accepted: 07/21/2016] [Indexed: 01/24/2023]
Abstract
OBJECTIVE Endometrial carcinoma is one of the most common malignancies of the female reproductive system, but the aetiology and pathogenesis are not well understood, although adipokines such as visfatin may be involved. Our study provides insight into the mechanism underlying the tumorigenic effects of visfatin in endometrial carcinoma. METHODS We investigated the effect of visfatin on endometrial carcinoma cell proliferation, cell cycle, and apoptosis using well-differentiated Ishikawa cells and poorly differentiated KLE cells. We also assessed the effect of visfatin on tumour growth in vivo. RESULTS Visfatin stimulated the proliferation of both Ishikawa and KLE cells, and visfatin treatment promoted G1/S phase progression and inhibited endometrial carcinoma cell apoptosis. Visfatin promoted endometrial carcinoma tumour growth in BALB/c-nu mice. Transplanted tumour tissues from an endometrial carcinoma mouse model were analysed using immunohistochemical staining, which revealed much stronger positive signals for Ki-67 with over-abundant visfatin. Western blot analysis revealed that insulin receptor (IR), insulin receptor substrate (IRS)1/2 and key components of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 signalling pathways were highly expressed in endometrial carcinoma cells exposed to visfatin. Treated cells showed increased C-MYC and cyclin D1 and reduced caspase-3 expression. The effects of visfatin on proliferation and apoptosis were abrogated by treatment with the PI3K inhibitor LY294002 and MEK inhibitor U0126. CONCLUSIONS Visfatin promotes the malignant progression of endometrial carcinoma via activation of IR and PI3K/Akt and MAPK/ERK signalling. Visfatin may serve as a therapeutic target in the treatment of endometrial carcinoma.
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Affiliation(s)
- Yingmei Wang
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Chao Gao
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Yanfang Zhang
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Jinping Gao
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Fei Teng
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Wenyan Tian
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Wen Yang
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Ye Yan
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
| | - Fengxia Xue
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.
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Chen H, Wang S, Zhang H, Nice EC, Huang C. Nicotinamide phosphoribosyltransferase (Nampt) in carcinogenesis: new clinical opportunities. Expert Rev Anticancer Ther 2016; 16:827-38. [PMID: 27186719 DOI: 10.1080/14737140.2016.1190649] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes the first step in the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway. Aberrant NAD metabolism was associated with oncogenic signal transduction, suggesting the critical roles of Nampt in tumorigenesis and metastasis. Additionally, Nampt can be secreted out of the cell, and this extracellular form of Nampt (eNampt) was shown to induce inflammation and angiogenesis due to its cytokine activity, which may also be involved in carcinogenesis. AREAS COVERED This article reviews recent advances in the studies of Nampt in carcinogenesis, with a special highlight on Nampt inhibitors and future clinical application, including cancer diagnosis, prognosis and therapy. Expert commentary: Nampt not only maintains the balance of cellular metabolism, but also has a profound influence on multiple aspects of carcinogenesis. Therefore, elucidation of these mechanisms opens the door for future clinical applications targeting this protein. Additional studies are needed to address important questions including the relationship between extracellular Nampt and carcinogenesis.
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Affiliation(s)
- Hang Chen
- a Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education & Department of Neurology , The Affiliated Hospital of Hainan Medical College , Haikou , China
| | - Shiyu Wang
- a Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education & Department of Neurology , The Affiliated Hospital of Hainan Medical College , Haikou , China
| | - Haiyuan Zhang
- a Key Laboratory of Tropical Diseases and Translational Medicine of Ministry of Education & Department of Neurology , The Affiliated Hospital of Hainan Medical College , Haikou , China
| | - Edouard C Nice
- b Department of Biochemistry and Molecular Biology , Monash University , Clayton , Australia
| | - Canhua Huang
- c State Key Laboratory for Biotherapy and Cancer Center, West China Hospital , Sichuan University, and Collaborative Innovation Center of Biotherapy , Chengdu , China
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Obesity and Cardiovascular Risk: Variations in Visfatin Gene Can Modify the Obesity Associated Cardiovascular Risk. Results from the Segovia Population Based-Study. Spain. PLoS One 2016; 11:e0153976. [PMID: 27166797 PMCID: PMC4864316 DOI: 10.1371/journal.pone.0153976] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 04/06/2016] [Indexed: 01/19/2023] Open
Abstract
Objectives Our aim was to investigate if genetic variations in the visfatin gene (SNPs rs7789066/ rs11977021/rs4730153) could modify the cardiovascular-risk (CV-risk) despite the metabolic phenotype (obesity and glucose tolerance). In addition, we investigated the relationship between insulin sensitivity and variations in visfatin gene. Material and Methods A population-based study in rural and urban areas of the Province of Segovia, Spain, was carried out in the period of 2001–2003 years. A total of 587 individuals were included, 25.4% subjects were defined as obese (BMI ≥30 Kg/m2). Results Plasma visfatin levels were significantly higher in obese subjects with DM2 than in other categories of glucose tolerance. The genotype AA of the rs4730153 SNP was significantly associated with fasting glucose, fasting insulin and HOMA-IR (Homeostasis model assessment-insulin resistance) after adjustment for gender, age, BMI and waist circumference. The obese individuals carrying the CC genotype of the rs11977021 SNP showed higher circulating levels of fasting proinsulin after adjustment for the same variables. The genotype AA of the rs4730153 SNP seems to be protective from CV-risk either estimated by Framingham or SCORE charts in general population; and in obese and non-obese individuals. No associations with CV-risk were observed for other studied SNPs (rs11977021/rs7789066). Conclusions In summary, this is the first study which concludes that the genotype AA of the rs4730153 SNP appear to protect against CV-risk in obese and non–obese individuals, estimated by Framingham and SCORE charts. Our results confirm that the different polymorphisms in the visfatin gene might be influencing the glucose homeostasis in obese individuals.
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Nagy K, Nagaraju SP, Rhee CM, Mathe Z, Molnar MZ. Adipocytokines in renal transplant recipients. Clin Kidney J 2016; 9:359-73. [PMID: 27274819 PMCID: PMC4886901 DOI: 10.1093/ckj/sfv156] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 12/18/2015] [Indexed: 02/07/2023] Open
Abstract
In the last two decades, perceptions about the role of body fat have changed. Adipocytes modulate endocrine and immune homeostasis by synthesizing hundreds of hormones, known as adipocytokines. Many studies have been investigating the influences and effects of these adipocytokines and suggest that they are modulated by the nutritional and immunologic milieu. Kidney transplant recipients (KTRs) are a unique and relevant population in which the function of adipocytokines can be examined, given their altered nutritional and immune status and subsequent dysregulation of adipocytokine metabolism. In this review, we summarize the recent findings about four specific adipocytokines and their respective roles in KTRs. We decided to evaluate the most widely described adipocytokines, including leptin, adiponectin, visfatin and resistin. Increasing evidence suggests that these adipocytokines may lead to cardiovascular events and metabolic changes in the general population and may also increase mortality and graft loss rate in KTRs. In addition, we present findings on the interrelationship between serum adipocytokine levels and nutritional and immunologic status, and mechanisms by which adipocytokines modulate morbidity and outcomes in KTRs.
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Affiliation(s)
- Kristof Nagy
- Department of Transplantation and Surgery , Semmelweis University , Budapest , Hungary
| | | | - Connie M Rhee
- Harold Simmons Center for Chronic Disease Research and Epidemiology, Division of Nephrology and Hypertension , University of California Irvine , Orange, CA , USA
| | - Zoltan Mathe
- Department of Transplantation and Surgery , Semmelweis University , Budapest , Hungary
| | - Miklos Z Molnar
- Division of Nephrology, Department of Medicine , University of Tennessee Health Science Center , Memphis, TN , USA
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Garatachea N, Pareja-Galeano H, Sanchis-Gomar F, Santos-Lozano A, Fiuza-Luces C, Morán M, Emanuele E, Joyner MJ, Lucia A. Exercise attenuates the major hallmarks of aging. Rejuvenation Res 2016; 18:57-89. [PMID: 25431878 DOI: 10.1089/rej.2014.1623] [Citation(s) in RCA: 276] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Regular exercise has multi-system anti-aging effects. Here we summarize how exercise impacts the major hallmarks of aging. We propose that, besides searching for novel pharmaceutical targets of the aging process, more research efforts should be devoted to gaining insights into the molecular mediators of the benefits of exercise and to implement effective exercise interventions for elderly people.
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Affiliation(s)
- Nuria Garatachea
- 1 Faculty of Health and Sport Science, University of Zaragoza , Huesca, Spain
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47
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Saad MI, Abdelkhalek TM, Saleh MM, Kamel MA, Youssef M, Tawfik SH, Dominguez H. Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells. Endocrine 2015; 50:537-67. [PMID: 26271514 DOI: 10.1007/s12020-015-0709-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 07/25/2015] [Indexed: 12/13/2022]
Abstract
Diabetes mellitus is a heterogeneous, multifactorial, chronic disease characterized by hyperglycemia owing to insulin insufficiency and insulin resistance (IR). Recent epidemiological studies showed that the diabetes epidemic affects 382 million people worldwide in 2013, and this figure is expected to be 600 million people by 2035. Diabetes is associated with microvascular and macrovascular complications resulting in accelerated endothelial dysfunction (ED), atherosclerosis, and cardiovascular disease (CVD). Unfortunately, the complex pathophysiology of diabetic cardiovascular damage is not fully understood. Therefore, there is a clear need to better understand the molecular pathophysiology of ED in diabetes, and consequently, better treatment options and novel efficacious therapies could be identified. In the light of recent extensive research, we re-investigate the association between diabetes-associated metabolic disturbances (IR, subclinical inflammation, dyslipidemia, hyperglycemia, dysregulated production of adipokines, defective incretin and gut hormones production/action, and oxidative stress) and ED, focusing on oxidative stress and endothelial progenitor cells (EPCs). In addition, we re-emphasize that oxidative stress is the final common pathway that transduces signals from other conditions-either directly or indirectly-leading to ED and CVD.
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Affiliation(s)
- Mohamed I Saad
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.
- Hudson Institute of Medical Research, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.
| | - Taha M Abdelkhalek
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Moustafa M Saleh
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Maher A Kamel
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Mina Youssef
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Shady H Tawfik
- Department of Molecular Medicine, University of Padova, Padua, Italy
| | - Helena Dominguez
- Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark
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48
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Grolla AA, Torretta S, Gnemmi I, Amoruso A, Orsomando G, Gatti M, Caldarelli A, Lim D, Penengo L, Brunelleschi S, Genazzani AA, Travelli C. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is a tumoural cytokine released from melanoma. Pigment Cell Melanoma Res 2015; 28:718-29. [DOI: 10.1111/pcmr.12420] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 09/08/2015] [Indexed: 12/20/2022]
Affiliation(s)
- Ambra A. Grolla
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Simone Torretta
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Ilaria Gnemmi
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Angela Amoruso
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Giuseppe Orsomando
- Section of Biochemistry; Department of Clinical Sciences; Polytechnic University of Marche; Ancona Italy
| | - Marco Gatti
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Antonio Caldarelli
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Dmitry Lim
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Lorenza Penengo
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
- Institute of Pharmacology and Toxicology; University of Zürich-Vetsuisse; Zürich Switzerland
| | - Sandra Brunelleschi
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Armando A. Genazzani
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
| | - Cristina Travelli
- Department of Pharmaceutical Sciences and Department of Medical Sciences; Università del Piemonte Orientale; Novara Italy
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49
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Garten A, Schuster S, Penke M, Gorski T, de Giorgis T, Kiess W. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat Rev Endocrinol 2015. [PMID: 26215259 DOI: 10.1038/nrendo.2015.117] [Citation(s) in RCA: 492] [Impact Index Per Article: 49.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is a regulator of the intracellular nicotinamide adenine dinucleotide (NAD) pool. NAD is an essential coenzyme involved in cellular redox reactions and is a substrate for NAD-dependent enzymes. In various metabolic disorders and during ageing, levels of NAD are decreased. Through its NAD-biosynthetic activity, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism. In addition to its enzymatic function, extracellular NAMPT (eNAMPT) has cytokine-like activity. Abnormal levels of eNAMPT are associated with various metabolic disorders. NAMPT is able to modulate processes involved in the pathogenesis of obesity and related disorders such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) by influencing the oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation and insulin resistance. NAMPT also has a crucial role in cancer cell metabolism, is often overexpressed in tumour tissues and is an experimental target for antitumour therapies. In this Review, we discuss current understanding of the functions of NAMPT and highlight progress made in identifying the physiological role of NAMPT and its relevance in various human diseases and conditions, such as obesity, NAFLD, T2DM, cancer and ageing.
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Affiliation(s)
- Antje Garten
- Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, University of Leipzig, Liebigstrasse 21, 04103 Leipzig, Germany
| | - Susanne Schuster
- Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, University of Leipzig, Liebigstrasse 21, 04103 Leipzig, Germany
| | - Melanie Penke
- Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, University of Leipzig, Liebigstrasse 21, 04103 Leipzig, Germany
| | - Theresa Gorski
- Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, University of Leipzig, Liebigstrasse 21, 04103 Leipzig, Germany
| | - Tommaso de Giorgis
- Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, University of Leipzig, Liebigstrasse 21, 04103 Leipzig, Germany
| | - Wieland Kiess
- Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, University of Leipzig, Liebigstrasse 21, 04103 Leipzig, Germany
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50
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Vazquez Prieto MA, Bettaieb A, Rodriguez Lanzi C, Soto VC, Perdicaro DJ, Galmarini CR, Haj FG, Miatello RM, Oteiza PI. Catechin and quercetin attenuate adipose inflammation in fructose-fed rats and 3T3-L1 adipocytes. Mol Nutr Food Res 2015; 59:622-33. [PMID: 25620282 DOI: 10.1002/mnfr.201400631] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 12/10/2014] [Accepted: 01/12/2015] [Indexed: 12/25/2022]
Abstract
SCOPE This study evaluated the capacity of dietary catechin (C), quercetin (Q), and the combination of both (CQ), to attenuate adipose inflammation triggered by high fructose (HFr) consumption in rats and by tumor necrosis factor alpha (TNF-α) in 3T3-L1 adipocytes. METHODS AND RESULTS In rats, HFr consumption for 6 wk caused dyslipidemia, insulin resistance, reduced plasma adiponectin, adiposity, and adipose tissue inflammation. Dietary supplementation with 20 mg/kg/day of C, Q, and CQ improved all these parameters. In 3T3-L1 adipocytes, C and Q attenuated TNF-α-induced elevated protein carbonyls, increased proinflammatory cytokine expression (MCP-1, resistin), and decreased adiponectin. The protective effects of C and Q on adipose inflammation are in part associated with their capacity to (i) decrease the activation of the mitogen-activated kinases (MAPKs) JNK and p38; and (ii) prevent the downregulation of PPAR-γ. In summary, C and Q, and to a larger extent the combination of both, attenuated adipose proinflammatory signaling cascades and regulated the balance of molecules that improve (adiponectin) or impair (TNF-α, MCP-1, resistin) insulin sensitivity. CONCLUSION Together, these findings suggest that dietary Q and C may have potential benefits in mitigating MetS-associated adipose inflammation, oxidative stress, and insulin resistance.
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Affiliation(s)
- Marcela A Vazquez Prieto
- Area de Fisiología Patológica, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, e Instituto de Medicina y Biología Experimental de Cuyo (IMBECU-CONICET), Mendoza, Argentina
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