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Bai X, Zhang Z, Zhang M, Xu J, Dong K, Du Q, Chen L, Ma P, Yang J. α-Mangostin prevents diabetic cardiomyopathy by inhibiting oxidative damage and lipotoxicity through the AKT-FOXO1-CD36 pathway. Front Pharmacol 2025; 16:1566311. [PMID: 40313619 PMCID: PMC12043880 DOI: 10.3389/fphar.2025.1566311] [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: 01/24/2025] [Accepted: 03/28/2025] [Indexed: 05/03/2025] Open
Abstract
Introduction Diabetic cardiomyopathy (DCM), a cardiac complication of diabetes, is the main cause of the high prevalence of heart failure and associated mortality in diabetic patients. Oxidative stress and lipid metabolism disorder-induced myocardial cell damage are part of the pathogenesis of DCM. In this study, we investigated the effects of alpha-mangostin (A-MG), a natural antioxidant extracted from mangosteen peel, on in vitro and in vivo DCM models. Methods H9C2 rat cardiomyocytes were treated with high glucose (HG) and palmitic acid (PA) for 24 h to establish an in vitro DCM cell model. Cell viability and cytotoxicity were evaluated after treatment with varying concentrations of A-MG (0.3, 1, 3, 9, or 27 μM) using Cell Counting Kit-8 (CCK8) and lactate dehydrogenase (LDH) assays. Flow cytometry assessment was used to detect apoptosis. Molecular mechanisms were investigated through transcriptome analysis, quantitative PCR (RT-qPCR), and Western blotting. Type 2 diabetic (T2D) mice, induced by feeding a high-fat diet (HFD) combined with low-dose streptozotocin (STZ), received either vehicle, low-dose A-MG (100 mg/kg/d), or high-dose A-MG (200 mg/kg/d) for 6 weeks. Cardiac function was assessed by echocardiography. H&E and Masson's staining were used to evaluate cardiac tissue structure and fibrosis, and Western blotting was used to evaluate myocardial protein expression. Results In HG/F-induced H9C2 cells, A-MG (1 and 3 μM) significantly increased cell viability (p < 0.01) and reduced LDH release (p < 0.05). A-MG (3 μM) attenuated lipid accumulation (p < 0.05), normalized mitochondrial membrane potential (p < 0.01), and inhibited reactive oxygen species (ROS) generation (p < 0.05), malondialdehyde (MDA) production (p < 0.01), and apoptosis (p < 0.05). A-MG also inhibited the nuclear translocation of Forkhead box class O1 (FOXO1) (p < 0.05); reduced the expression of CD36 (p < 0.05), PPARα (p < 0.01), and CPT1β (p < 0.05) proteins; enhanced superoxide dismutase (SOD) activity (p < 0.05); and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) (p < 0.01), HO-1 (p < 0.05), and SOD2 (p < 0.05) protein expression levels. Further investigation in HG/F-induced H9C2 cells indicated that A-MG inhibits the uptake of fatty acids (FAs) by regulating the AKT/FOXO1/CD36 signaling pathway, reduces excessive β-oxidation of FAs mediated by PPARα/CPT1β through the inhibition of FOXO1 nuclear translocation, and stimulates the AKT/Nrf2/HO-1 signaling pathway to increase the cellular antioxidant capacity. In diabetic mice, low-dose A-MG treatment increased anti-oxidative stress capacity, decreased myocardial lipid accumulation, reduced fibrosis and cardiomyocyte apoptosis, and improved left ventricular contractile function. Conclusion Using both in vitro and in vivo DCM models, our study demonstrates that A-MG reduces lipid accumulation and excessive mitochondrial β-oxidation while enhancing antioxidant capacity. These results suggest that A-MG may be a novel therapeutic option for DCM.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Jianhong Yang
- Medical School, University of Chinese Academy of Sciences, Beijing, China
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2
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Howe J, Barbar EJ. Dynamic interactions of dimeric hub proteins underlie their diverse functions and structures: A comparative analysis of 14-3-3 and LC8. J Biol Chem 2025; 301:108416. [PMID: 40107617 PMCID: PMC12017986 DOI: 10.1016/j.jbc.2025.108416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 03/22/2025] Open
Abstract
Hub proteins interact with a host of client proteins and regulate multiple cellular functions. Dynamic hubs have a single binding interface for one client at a time resulting in competition among clients with the highest affinity. Dynamic dimeric hubs with two identical sites bind either two different client proteins or two chains of the same client to form homogenous complexes and could also form heterogeneous mixtures of interconverting complexes. Here, we review the interactions of the dimeric hubs 14-3-3 and LC8. 14-3-3 is a phosphoserine/threonine binding protein involved in structuring client proteins and regulating their phosphorylation. LC8 is involved in promoting the dimerization of client peptides and the rigidification of their disordered regions. Both 14-3-3 and LC8 are essential genes, with 14-3-3 playing a crucial role in apoptosis and cell cycle regulation, while LC8 is critical for the assembly of proteins involved in transport, DNA repair, and transcription. Interestingly, both protein dimers can dissociate by phosphorylation, which results in their interactome-wide changes. Their interactions are also regulated by the phosphorylation of their clients. Both form heterogeneous complexes with various functions including phase separation, signaling, and viral hijacking where they restrict the conformational heterogeneity of their dimeric clients that bind nucleic acids. This comparative analysis highlights the importance of dynamic protein-protein interactions in the diversity of functions of 14-3-3 and LC8 and how small differences in structures of interfaces explain why 14-3-3 is primarily involved in the regulation of phosphorylation states while LC8 is primarily involved in the regulation of assembly of large dynamic complexes.
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Affiliation(s)
- Jesse Howe
- Oregon State University, Department of Biochemistry and Biophysics, Corvallis, Oregon, USA
| | - Elisar J Barbar
- Oregon State University, Department of Biochemistry and Biophysics, Corvallis, Oregon, USA.
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3
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Annunziata G, Verde L, Zink A, Muscogiuri G, Albanesi C, Paganelli A, Barrea L, Scala E. Plant-Based Foods for Chronic Skin Diseases: A Focus on the Mediterranean Diet. Curr Nutr Rep 2025; 14:42. [PMID: 40048018 PMCID: PMC11885338 DOI: 10.1007/s13668-025-00632-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2025] [Indexed: 03/09/2025]
Abstract
PURPOSE OF REVIEW In this narrative review, we provide an overview of how adherence to a Mediterranean dietary pattern can complement traditional treatment strategies for psoriasis, acne, and hidradenitis suppurativa. We emphasize the importance of an integrated approach, with dietary interventions as a key component of holistic patient care. RECENT FINDINGS Psoriasis, acne, and hidradenitis suppurativa are immune-mediated chronic diseases marked by systemic inflammation, with genetic and environmental factors influencing their onset. The Mediterranean diet, rich in plant-based foods with antioxidant and anti-inflammatory properties-such as whole-grain cereals, extra-virgin olive oil, vegetables, legumes, fruits, and nuts-has been shown to reduce the clinical severity of these conditions. It also supports weight control and positively impacts metabolic and cardiovascular risk factors, which are closely linked to these diseases. Dietary education, particularly about the Mediterranean diet, plays a crucial role in the management of these skin diseases and serves as an important non-pharmacological treatment option that can influence patient prognosis. This review offers specific nutrition recommendations for prescribing the Mediterranean diet to patients with chronic inflammatory skin diseases.
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Affiliation(s)
- Giuseppe Annunziata
- Facoltà Di Scienze Umane, Della Formazione E Dello Sport, Università Telematica Pegaso, Via Porzio, Centro Direzionale, Isola F2, 80143, Naples, Italy
| | - Ludovica Verde
- Department of Public Health, University of Naples Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
| | - Alexander Zink
- Department of Dermatology and Allergy, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Giovanna Muscogiuri
- Diabetologia E Andrologia, Dipartimento Di Medicina Clinica E Chirurgia, Unità Di Endocrinologia, Università Degli Studi Di Napoli Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
- Dipartimento Di Medicina Clinica E Chirurgia, Centro Italiano Per La Cura E Il Benessere del Paziente Con Obesità (C.I.B.O), Università Degli Studi Di Napoli Federico II, Via Sergio Pansini 5, 80131, Naples, Italy
- Cattedra Unesco "Educazione Alla Salute E Allo Sviluppo Sostenibile", University Federico II, 80131, Naples, Italy
| | - Cristina Albanesi
- Laboratory of Experimental Immunology, IDI-IRCCS, Via Monti Di Creta, 104, 00167, Rome, Italy
| | | | - Luigi Barrea
- Dipartimento Di Psicologia E Scienze Della Salute, Università Telematica Pegaso, Centro Direzionale, Via Porzio, Isola F2, 80143, Naples, Italy
| | - Emanuele Scala
- Laboratory of Experimental Immunology, IDI-IRCCS, Via Monti Di Creta, 104, 00167, Rome, Italy.
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Tian Y, Li L, Wu L, Xu Q, Li Y, Pan H, Bing T, Bai X, Finko AV, Li Z, Bian J. Recent Developments in 14-3-3 Stabilizers for Regulating Protein-Protein Interactions: An Update. J Med Chem 2025; 68:2124-2146. [PMID: 39902774 DOI: 10.1021/acs.jmedchem.4c01936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
14-3-3 proteins play a crucial role in the regulation of protein-protein interactions, impacting various cellular processes and disease mechanisms. Recent advancements have led to the development of stabilizers that enhance the binding of 14-3-3 proteins to clients, presenting promising therapeutic potentials. This perspective provides an updated overview of the latest developments in the field of 14-3-3 stabilizers, with a focus on their design, synthesis, and biological evaluation. We discuss the structural basis for the interaction between 14-3-3 proteins and their ligands, highlighting key modifications that enhance binding affinity and selectivity. Additionally, we explore the therapeutic applications of 14-3-3 stabilizers across major therapeutic areas such as cancer, metabolic disorders, and neurodegenerative diseases. By summarizing recent research findings and technological advancements, this perspective aims to shed light on the current state of 14-3-3 stabilizer developments and outline future directions for optimizing these compounds as effective therapeutic agents.
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Affiliation(s)
- Yucheng Tian
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Longjing Li
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Liuyi Wu
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Qianqian Xu
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Yaojie Li
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Huawei Pan
- ICE Bioscience, Bldg 15, Yd 18, Kechuang 13th St, Etown, Tongzhou Dist, Beijing 100176, China
| | - Tiejun Bing
- ICE Bioscience, Bldg 15, Yd 18, Kechuang 13th St, Etown, Tongzhou Dist, Beijing 100176, China
| | - Xiumei Bai
- Department of Chemistry, Lomonosov Moscow State University (MSU), Moscow 119991, Russia
| | - Alexander V Finko
- Department of Chemistry, Lomonosov Moscow State University (MSU), Moscow 119991, Russia
| | - Zhiyu Li
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Jinlei Bian
- Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
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Akin S, Cekin N. Preeclampsia and STOX1 (storkhead-box protein 1): Molecular evaluation of STOX1 in preeclampsia. Gene 2024; 927:148742. [PMID: 38969244 DOI: 10.1016/j.gene.2024.148742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/13/2024] [Accepted: 07/01/2024] [Indexed: 07/07/2024]
Abstract
Preeclampsia (PE) is clinically defined as a part of pregnancy characterized by hypertension and multiple organ failure. PE is broadly categorized into two types: "placental" and "maternal". Placental PE is associated with fetal growth restriction and adverse maternal and neonatal outcomes. STOX1 (Storkhead box 1), a transcription factor, discovered through a complete transcript analysis of the PE susceptibility locus of 70,000 bp on chromosome 10q22.1. So far, studies investigating the relationship between STOX1 and PE have focused on STOX1 overexpression, STOX1 isoform imbalance, and STOX1 variations that could have clinical consequence. Initially, the Y153H variation of STOX was associated with the placental form of PE. Additionally, studies focusing on the maternal and fetal interface have shown that NODAL and STOX1 variations play a role together in the unsuccessful remodeling of the spiral arteries. Research specifically addressing the overexpression of STOX1 has shown that its disruption of cellular hemoastasis, leading to impaired hypoxia response, disruption of the cellular antioxidant system, and nitroso/redox imbalance. Furthermore, functional studies have been conducted showing that the imbalance between STOX1 isoforms contributes to the pathogenesis of placental PE. Research indicates that STOX1B competes with STOX1A and that the overexpression of STOX1B reverses cellular changes that STOX1A induces to the pathogenesis of PE. In this review, we aimed at elucidating the relationship between STOX1 and PE as well as function of STOX1. In conclusion, based on a comprehensive literature review, numerous studies support the role of STOX1 in the pathogenesis of PE.
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Affiliation(s)
- Seyda Akin
- Sivas Cumhuriyet University, Faculty of Medicine, Department of Medical Biology, 58140 Sivas, Turkey.
| | - Nilgun Cekin
- Sivas Cumhuriyet University, Faculty of Medicine, Department of Medical Biology, 58140 Sivas, Turkey.
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Chen S, Sun D, Zhang S, Xu L, Wang N, Li H, Xu X, Wei F. TIN2 modulates FOXO1 mitochondrial shuttling to enhance oxidative stress-induced apoptosis in retinal pigment epithelium under hyperglycemia. Cell Death Differ 2024; 31:1487-1505. [PMID: 39080375 PMCID: PMC11519896 DOI: 10.1038/s41418-024-01349-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 07/12/2024] [Accepted: 07/18/2024] [Indexed: 10/30/2024] Open
Abstract
Progressive dysfunction of the retinal pigment epithelium (RPE) and the adjacent photoreceptor cells in the outer retina plays a pivotal role in the pathogenesis of diabetic retinopathy (DR). Here, we observed a marked increase in oxidative stress-induced apoptosis in parallel with higher expression of telomeric protein TIN2 in RPE cells under hyperglycemia in vivo and in vitro. Delving deeper, we confirm that high glucose-induced elevation of mitochondria-localized TIN2 compromises mitochondrial activity and weakens the intrinsic antioxidant defense, thereby leading to the activation of mitochondria-dependent apoptotic pathways. Mechanistically, mitochondrial TIN2 promotes the phosphorylation of FOXO1 and its relocation to the mitochondria. Such translocation of transcription factor FOXO1 not only promotes its binding to the D-loop region of mitochondrial DNA-resulting in the inhibition of mitochondrial respiration-but also hampers its availability to nuclear target DNA, thereby undermining the intrinsic antioxidant defense. Moreover, TIN2 knockdown effectively mitigates oxidative-induced apoptosis in diabetic mouse RPE by preserving mitochondrial homeostasis, which concurrently prevents secondary photoreceptor damage. Our study proposes the potential of TIN2 as a promising molecular target for therapeutic interventions for diabetic retinopathy, which emphasizes the potential significance of telomeric proteins in the regulation of metabolism and mitochondrial function. Created with BioRender ( https://www.biorender.com/ ).
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Affiliation(s)
- Shimei Chen
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Disease; Shanghai Engineering Center for Visual Science and Photo Medicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Dandan Sun
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Disease; Shanghai Engineering Center for Visual Science and Photo Medicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Shuchang Zhang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Disease; Shanghai Engineering Center for Visual Science and Photo Medicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Li Xu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Disease; Shanghai Engineering Center for Visual Science and Photo Medicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Ning Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Disease; Shanghai Engineering Center for Visual Science and Photo Medicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China
| | - Huiming Li
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xun Xu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Disease; Shanghai Engineering Center for Visual Science and Photo Medicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China.
| | - Fang Wei
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Disease; Shanghai Engineering Center for Visual Science and Photo Medicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China.
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Phuagkhaopong S, Janpattanapichai J, Sirirak N, Khemawoot P, Vivithanaporn P, Suknuntha K. Transcriptome analysis reveals a role of FOXO3 in antileukemia/lymphoma properties of panduratin A. Sci Rep 2024; 14:24795. [PMID: 39433897 PMCID: PMC11494127 DOI: 10.1038/s41598-024-75630-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 10/07/2024] [Indexed: 10/23/2024] Open
Abstract
Boesenbergia rotunda, commonly known as fingerroot, is a medicinal and culinary plant native to the Indochina Peninsula. We found that panduratin A (Pan-A), one of the compounds present in the rhizome extract of fingerroot, inhibited cell proliferation, induced apoptosis, and promoted cell cycle arrest at G0/G1 phase in multiple hematologic malignant cell lines including leukemia and lymphoma lines. Pan-A inhibited these activities in leukemia and lymphoma cells in a concentration-dependent manner. High-throughput transcriptome analysis indicated that Pan-A is involved in the cell cycle, cellular senescence, apoptosis, and multiple canonical signaling pathways in lymphoma cells. The Forkhead box O (FOXO) transcription factor family was identified as a potential target of Pan-A. Western blot showed elevated caspase 7 and cPARP/PARP in the B-cell lymphoma cells after treatment with Pan-A. The inhibitory effects were accompanied by stimulation of Akt signaling and phosphorylation of FOXO3. Immunohistochemistry of tissues from patients with B-cell lymphoma revealed detectable levels of FOXO3 protein specifically in neoplastic B cells. Overall, our results highlight FOXO3 as a player underlying antileukemia/lymphoma effects of Pan-A.
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Affiliation(s)
- Suttinee Phuagkhaopong
- Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Jiranan Janpattanapichai
- Interdisciplinary Program in Pharmacology, Graduate School, Chulalongkorn University, Bangkok, Thailand
| | - Noppavut Sirirak
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand
| | - Phisit Khemawoot
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand
| | - Pornpun Vivithanaporn
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand
| | - Kran Suknuntha
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand.
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Vural S, Baskurt D, Yıldırıcı Ş, Rasulova G, Danacı S, Botsalı A. Evaluating dietary considerations in hidradenitis suppurativa: a critical examination of existing knowledge. Int J Dermatol 2024; 63:987-998. [PMID: 38406977 DOI: 10.1111/ijd.17101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 01/15/2024] [Accepted: 02/07/2024] [Indexed: 02/27/2024]
Abstract
Hidradenitis suppurativa (HS) is a chronic condition that can overwhelm patients, and the effectiveness of supplementary dietary treatments remains uncertain. The primary aim of this review is to explore the connection between diet and HS progression. However, it is imperative to note that the evidence supporting a substantial role of the diet in HS remains weak. Dietary alterations alone should not be considered independent solutions for managing HS. Medical therapy continues to be indispensable for adequate treatment. Research indicates that the Mediterranean lifestyle and diet may provide cost-effective and beneficial adjustments when combined with traditional therapies. Conversely, foods with a high glycemic index and dairy could worsen HS symptoms, conceivably through mechanisms linked to insulin resistance and inflammation. Zinc, known for its antioxidant properties, shows promise as an adjunct therapy. Moreover, evidence suggests a connection between vitamin D deficiency and HS severity, although the findings are inconclusive. Brewer's yeast-free diet, B12 supplementation, intermittent fasting, and reducing the intake of refined sugar and dairy merit further investigation. In conclusion, this review highlights the need for additional research because of the lack of standardized reporting of clinical effects in the studies under scrutiny. A deeper exploration of the pathophysiology focusing on dietary modifications and their potential associations with HS severity is essential. Furthermore, it is crucial to recognize that patients' willingness to experiment with new diets makes them vulnerable to fraudulent interventions, highlighting the importance of evidence-based dietary guidance.
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Affiliation(s)
- Seçil Vural
- Department of Dermatology and Venereology, Koç University School of Medicine, Istanbul, Turkey
| | - Defne Baskurt
- School of Medicine, Koç University, Istanbul, Turkey
| | | | - Gunel Rasulova
- Department of Dermatology and Venereology, Koç University School of Medicine, Istanbul, Turkey
| | - Senem Danacı
- Department of Medical Pharmacology, Istanbul Cerrahpasa University, Istanbul, Turkey
| | - Aysenur Botsalı
- Department of Dermatology and Venereology, University of Health Sciences, Gülhane Training and Research Hospital, Ankara, Turkey
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9
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Ojaghi M, Pamenter ME. Hypoxia impairs blood glucose homeostasis in naked mole-rat adult subordinates but not queens. J Exp Biol 2024; 227:jeb247537. [PMID: 38680085 PMCID: PMC11166464 DOI: 10.1242/jeb.247537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 04/12/2024] [Indexed: 05/01/2024]
Abstract
Naked mole-rats (NMRs) are among the most hypoxia-tolerant mammals and metabolize only carbohydrates in hypoxia. Glucose is the primary building block of dietary carbohydrates, but how blood glucose is regulated during hypoxia has not been explored in NMRs. We hypothesized that NMRs mobilize glucose stores to support anaerobic energy metabolism in hypoxia. To test this, we treated newborn, juvenile and adult (subordinate and queen) NMRs in normoxia (21% O2) or hypoxia (7, 5 or 3% O2), while measuring metabolic rate, body temperature and blood [glucose]. We also challenged animals with glucose, insulin or insulin-like growth factor-1 (IGF-1) injections and measured the rate of glucose clearance in normoxia and hypoxia. We found that: (1) blood [glucose] increases in moderate hypoxia in queens and pups, but only in severe hypoxia in adult subordinates and juveniles; (2) glucose tolerance is similar between developmental stages in normoxia, but glucose clearance times are 2- to 3-fold longer in juveniles and subordinates than in queens or pups in hypoxia; and (3) reoxygenation accelerates glucose clearance in hypoxic subordinate adults. Mechanistically, (4) insulin and IGF-1 reduce blood [glucose] in subordinates in both normoxia but only IGF-1 impacts blood [glucose] in hypoxic queens. Our results indicate that insulin signaling is impaired by hypoxia in NMRs, but that queens utilize IGF-1 to overcome this limitation and effectively regulate blood glucose in hypoxia. This suggests that sexual maturation impacts blood glucose handling in hypoxic NMR queens, which may allow queens to spend longer periods of time in hypoxic nest chambers.
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Affiliation(s)
- Mohammad Ojaghi
- Department of Biology, University of Ottawa, Ottawa, ON, Canada, K1N 9A7
| | - Matthew E. Pamenter
- Department of Biology, University of Ottawa, Ottawa, ON, Canada, K1N 9A7
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada, K1H 8M5
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10
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Stallings CE, Das P, Athul SW, Ukagwu AE, Jensik PJ, Ellsworth BS. FOXO1 regulates expression of Neurod4 in the pituitary gland. Mol Cell Endocrinol 2024; 583:112128. [PMID: 38142853 PMCID: PMC10922409 DOI: 10.1016/j.mce.2023.112128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 12/26/2023]
Abstract
Pituitary gland function is regulated by the activity of various transcription factors that control cell fate decisions leading to cellular differentiation and hormone production. FOXO1 is necessary for normal somatotrope differentiation and function. Recent in vivo data implicate FOXO1 in the regulation of genes important for somatotrope differentiation including Gh1, Neurod4, and Pou1f1. In the current study, the somatotrope-like cell line GH3 was treated with a FOXO1 inhibitor, resulting in significant reduction in Neurod4 and Gh1 expression. Consistent with these findings, CRISPR/Cas9-mediated deletion of Foxo1 in GH3 cells significantly reduced expression of Gh1 and Neurod4. Chromatin immunoprecipitation sequencing identifies novel FOXO1 binding sites associated with the Neurod4, Gh1, and Pou1f1 genes. The FOXO1 binding site in the Neurod4 gene exhibits enhancer activity in somatotrope-like cells but not in gonadotrope-like cells. These data strongly suggest FOXO1 directly contributes to the transcriptional control of genes important for somatotrope differentiation.
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Affiliation(s)
| | - Pratyusa Das
- Department of Physiology, Southern Illinois University, Carbondale, IL, USA
| | - Sandria W Athul
- Department of Physiology, Southern Illinois University, Carbondale, IL, USA
| | - Arnold E Ukagwu
- Department of Physiology, Southern Illinois University, Carbondale, IL, USA
| | - Philip J Jensik
- Department of Physiology, Southern Illinois University, Carbondale, IL, USA
| | - Buffy S Ellsworth
- Department of Physiology, Southern Illinois University, Carbondale, IL, USA.
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Miyamura Y, Kamei S, Matsuo M, Yamazaki M, Usuki S, Yasunaga K, Uemura A, Satou Y, Ohguchi H, Minami T. FOXO1 stimulates tip cell-enriched gene expression in endothelial cells. iScience 2024; 27:109161. [PMID: 38444610 PMCID: PMC10914484 DOI: 10.1016/j.isci.2024.109161] [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: 01/05/2023] [Revised: 11/29/2023] [Accepted: 02/05/2024] [Indexed: 03/07/2024] Open
Abstract
Forkhead box O (FOXO) family proteins are expressed in various cells, and play crucial roles in cellular metabolism, apoptosis, and aging. FOXO1-null mice exhibit embryonic lethality due to impaired endothelial cell (EC) maturation and vascular remodeling. However, FOXO1-mediated genome-wide regulation in ECs remains unclear. Here, we demonstrate that VEGF dynamically regulates FOXO1 cytosol-nucleus translocation. FOXO1 re-localizes to the nucleus via PP2A phosphatase. RNA-seq combined with FOXO1 overexpression/knockdown in ECs demonstrated that FOXO1 governs the VEGF-responsive tip cell-enriched genes, and further inhibits DLL4-NOTCH signaling. Endogenous FOXO1 ChIP-seq revealed that FOXO1 binds to the EC-unique tip-enriched genes with co-enrichment of EC master regulators, and the condensed chromatin region as a pioneer factor. We identified new promoter/enhancer regions of the VEGF-responsive tip cell genes regulated by FOXO1: ESM1 and ANGPT2. This is the first study to identify cell type-specific FOXO1 functions, including VEGF-mediated tip cell definition in primary cultured ECs.
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Affiliation(s)
- Yuri Miyamura
- Divison of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, Japan
| | - Shunsuke Kamei
- Divison of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, Japan
| | - Misaki Matsuo
- Division of Genomics and Transcriptomics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-8556, Japan
| | - Masaya Yamazaki
- Division of Medical Biochemistry, Graduate School of Medical Science, Kumamoto University, Kumamoto 860-8556, Japan
| | - Shingo Usuki
- Liaison Laboratory Research Promotion Center, IMEG, Kumamoto University, Kumamoto 860-8556, Japan
| | - Keiichiro Yasunaga
- Liaison Laboratory Research Promotion Center, IMEG, Kumamoto University, Kumamoto 860-8556, Japan
| | - Akiyoshi Uemura
- Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
| | - Yorifumi Satou
- Division of Genomics and Transcriptomics, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hiroto Ohguchi
- Division of Disease Epigenetics, IRDA, Kumamoto University, Kumamoto 860-0811, Japan
| | - Takashi Minami
- Divison of Molecular and Vascular Biology, IRDA, Kumamoto University, Kumamoto 860-0811, Japan
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12
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Lee J, Hong SW, Kim MJ, Lim YM, Moon SJ, Kwon H, Park SE, Rhee EJ, Lee WY. Inhibition of Sodium-Glucose Cotransporter-2 during Serum Deprivation Increases Hepatic Gluconeogenesis via the AMPK/AKT/FOXO Signaling Pathway. Endocrinol Metab (Seoul) 2024; 39:98-108. [PMID: 38171209 PMCID: PMC10901661 DOI: 10.3803/enm.2023.1786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/25/2023] [Accepted: 10/17/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGRUOUND Sodium-dependent glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in the renal proximal tubules, and SGLT2 inhibitors are used as therapeutic agents for treating type 2 diabetes mellitus. This study aimed to elucidate the effects and mechanisms of SGLT2 inhibition on hepatic glucose metabolism in both serum deprivation and serum supplementation states. METHODS Huh7 cells were treated with the SGLT2 inhibitors empagliflozin and dapagliflozin to examine the effect of SGLT2 on hepatic glucose uptake. To examine the modulation of glucose metabolism by SGLT2 inhibition under serum deprivation and serum supplementation conditions, HepG2 cells were transfected with SGLT2 small interfering RNA (siRNA), cultured in serum-free Dulbecco's modified Eagle's medium for 16 hours, and then cultured in media supplemented with or without 10% fetal bovine serum for 8 hours. RESULTS SGLT2 inhibitors dose-dependently decreased hepatic glucose uptake. Serum deprivation increased the expression levels of the gluconeogenesis genes peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), glucose 6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (PEPCK), and their expression levels during serum deprivation were further increased in cells transfected with SGLT2 siRNA. SGLT2 inhibition by siRNA during serum deprivation induces nuclear localization of the transcription factor forkhead box class O 1 (FOXO1), decreases nuclear phosphorylated-AKT (p-AKT), and p-FOXO1 protein expression, and increases phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK) protein expression. However, treatment with the AMPK inhibitor, compound C, reversed the reduction in the protein expression levels of nuclear p- AKT and p-FOXO1 and decreased the protein expression levels of p-AMPK and PEPCK in cells transfected with SGLT2 siRNA during serum deprivation. CONCLUSION These data show that SGLT2 mediates glucose uptake in hepatocytes and that SGLT2 inhibition during serum deprivation increases gluconeogenesis via the AMPK/AKT/FOXO1 signaling pathway.
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Affiliation(s)
- Jinmi Lee
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seok-Woo Hong
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min-Jeong Kim
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yu-Mi Lim
- Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sun Joon Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyemi Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Eun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun-Jung Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won-Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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13
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Asadi Y, Wang H. Regulation of mitochondrial function by FOXOs in ischemic stroke and Alzheimer's disease. ORGANELLE (TUCSON, ARIZ.) 2024; 1:2. [PMID: 40255585 PMCID: PMC12007694 DOI: 10.61747/0ifp.202403001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/22/2025]
Abstract
Transcriptional control is a pivotal mechanism governing various cellular processes. FOXO proteins, a subgroup of the forkhead family of transcription factors, play a key role in determining cell fate. The localization and function of FOXO proteins are regulated by post-translational modifications to control target gene expression, with a pronounced impact on various aspects of mitochondrial function, including mitochondrial dynamics, biogenesis, and quality control. Mitochondria stand out as the primary target of FOXO transcription factors, which recruit downstream signaling factors to govern mitochondrial processes. Essential signaling pathways are modulated by FOXOs, exemplified by their regulation of mitochondrial biogenesis through SIRT1-Pgc1α and NRF1-TFAM, as well as their influence on mitochondrial dynamics involving Mfn1, Mfn2, Drp1, and Fis1. Furthermore, FOXOs demonstrate the ability to upregulate and downregulate genes that serve as regulators in oxidative and apoptosis cascades. The functional role of FOXO proteins is highly context-dependent, varying with cell type, organ, and specific FOXO isoform. Notably, FOXOs emerge as prominent players in various pathological conditions, including ischemic conditions, neurodegenerative diseases, cancer, and metabolic disorders. Unraveling the intricate role of FOXOs in mammalian cell pathology positions them as promising therapeutic targets amenable to pharmacological intervention. This review aims to provide insights into the intricate roles of FOXOs in mitochondria, illuminating their potential as therapeutic targets amenable to pharmacological intervention in diverse pathological contexts, particularly in ischemic stroke and Alzheimer's disease.
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Affiliation(s)
| | - Hongmin Wang
- Department of Pharmacology and Neuroscience, Garrison Institute on Aging, Texas Tech University Health Science Center, School of Medicine, Lubbock, TX 79430, USA
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14
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Park E, Jeon H, Lee N, Yu J, Park H, Satoh T, Akira S, Furuyama T, Lee C, Choi J, Rho J. TDAG51 promotes transcription factor FoxO1 activity during LPS-induced inflammatory responses. EMBO J 2023; 42:e111867. [PMID: 37203866 PMCID: PMC10308371 DOI: 10.15252/embj.2022111867] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 04/28/2023] [Accepted: 05/03/2023] [Indexed: 05/20/2023] Open
Abstract
Tight regulation of Toll-like receptor (TLR)-mediated inflammatory responses is important for innate immunity. Here, we show that T-cell death-associated gene 51 (TDAG51/PHLDA1) is a novel regulator of the transcription factor FoxO1, regulating inflammatory mediator production in the lipopolysaccharide (LPS)-induced inflammatory response. TDAG51 induction by LPS stimulation was mediated by the TLR2/4 signaling pathway in bone marrow-derived macrophages (BMMs). LPS-induced inflammatory mediator production was significantly decreased in TDAG51-deficient BMMs. In TDAG51-deficient mice, LPS- or pathogenic Escherichia coli infection-induced lethal shock was reduced by decreasing serum proinflammatory cytokine levels. The recruitment of 14-3-3ζ to FoxO1 was competitively inhibited by the TDAG51-FoxO1 interaction, leading to blockade of FoxO1 cytoplasmic translocation and thereby strengthening FoxO1 nuclear accumulation. TDAG51/FoxO1 double-deficient BMMs showed significantly reduced inflammatory mediator production compared with TDAG51- or FoxO1-deficient BMMs. TDAG51/FoxO1 double deficiency protected mice against LPS- or pathogenic E. coli infection-induced lethal shock by weakening the systemic inflammatory response. Thus, these results indicate that TDAG51 acts as a regulator of the transcription factor FoxO1, leading to strengthened FoxO1 activity in the LPS-induced inflammatory response.
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Affiliation(s)
- Eui‐Soon Park
- Department of Microbiology and Molecular BiologyChungnam National UniversityDaejeonKorea
| | - Hyoeun Jeon
- Department of Microbiology and Molecular BiologyChungnam National UniversityDaejeonKorea
| | - Nari Lee
- Department of Microbiology and Molecular BiologyChungnam National UniversityDaejeonKorea
| | - Jiyeon Yu
- Department of Microbiology and Molecular BiologyChungnam National UniversityDaejeonKorea
| | - Hye‐Won Park
- Department of Microbiology and Molecular BiologyChungnam National UniversityDaejeonKorea
| | - Takashi Satoh
- Department of Immune Regulation, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Shizuo Akira
- Laboratory of Host Defense, WPI Immunology Frontier Research CenterOsaka UniversityOsakaJapan
| | - Tatsuo Furuyama
- Department of Clinical ExaminationKagawa Prefectural University of Health SciencesKagawaJapan
| | - Chul‐Ho Lee
- Laboratory Animal CenterKorea Research Institute of Bioscience & Biotechnology (KRIBB)DaejeonKorea
| | - Jong‐Soon Choi
- Division of Life ScienceKorea Basic Science Institute (KBSI)DaejeonKorea
| | - Jaerang Rho
- Department of Microbiology and Molecular BiologyChungnam National UniversityDaejeonKorea
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15
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Wu M, Li T, Li G, Niu B, Wu T, Yan L, Wang S, He S, Huang C, Tong W, Li N, Jiang J. LncRNA DANCR deficiency promotes high glucose-induced endothelial to mesenchymal transition in cardiac microvascular cells via the FoxO1/DDAH1/ADMA signaling pathway. Eur J Pharmacol 2023; 950:175732. [PMID: 37116560 DOI: 10.1016/j.ejphar.2023.175732] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 03/31/2023] [Accepted: 04/17/2023] [Indexed: 04/30/2023]
Abstract
Cardiac fibrosis is the main pathological basis of diabetic cardiomyopathy (DCM), and endothelial-to-meschenymal transition (EndMT) is a key driver to cardiac fibrosis and plays an important role in the pathogenesis of DCM. Asymmetric dimethylarginine (ADMA), a crucial pathologic factor in diabetes mellitus, is involved in organ fibrosis. This study aims to evaluate underlying mechanisms of ADMA in DCM especially for EndMT under diabetic conditions. A diabetic rat model was induced by streptozotocin (STZ) injection, and human cardiac microvascular endothelial cells (HCMECs) were stimulated with high glucose to induce EndMT. Subsequently, the role of ADMA in EndMT was detected either by exogenous ADMA or by over-expressing dimethylarginine dimethylaminohydrolase 1 (DDAH1, degradation enzyme for ADMA) before high glucose stimulation. Furthermore, the relationships among forkhead box protein O1 (FoxO1), DDAH1 and ADMA were evaluated by FoxO1 over-expression or FoxO1 siRNA. Finally, we examined the roles of LncRNA DANCR in FoxO1/DDAH1/ADMA pathway and EndMT of HCMECs. Here, we found that EndMT in HCMECs was induced by high glucose, as evidenced by down-regulated expression of CD31 and up-regulated expression of FSP-1 and collagen Ⅰ. Importantly, ADMA induced EndMT in HCMECs, and over-expressing DDAH1 protected from developing EndMT by high glucose. Furthermore, we demonstrated that over-expression of FoxO1-ADA with mutant phosphorylation sites of T24A, S256D, and S316A induced EndMT of HCMECs by down-regulating of DDAH1 and elevating ADMA, and that EndMT of HCMECs induced by high glucose was reversed by FoxO1 siRNA. We also found that LncRNA DANCR siRNA induced EndMT of HCMECs, activated FoxO1, and inhibited DDAH1 expression. Moreover, over-expression of LncRNA DANCR could markedly attenuated high glucose-mediated EndMT of HCMECs by inhibiting the activation of FoxO1 and increasing the expression of DDAH1. Collectively, our results indicate that LncRNA DANCR deficiency promotes high glucose-induced EndMT in HCMECs by regulating FoxO1/DDAH1/ADMA pathway.
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Affiliation(s)
- Meiting Wu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, 570100, China
| | - Ting Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Ge Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Department of Basic Medicine, Zhaoqing Medical College, Zhaoqing, 526020, China
| | - Bingxuan Niu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Collage of Pharmacy, Xinxiang Medical University, Xinxiang, 453002, China
| | - Tian Wu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Li Yan
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Shiming Wang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Shuangyi He
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Chuyi Huang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Weiqiang Tong
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Niansheng Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China
| | - Junlin Jiang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410078, China; Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, 410078, China.
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16
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De Sousa-Coelho AL, Gacias M, O'Neill BT, Relat J, Link W, Haro D, Marrero PF. FOXO1 represses PPARα-Mediated induction of FGF21 gene expression. Biochem Biophys Res Commun 2023; 644:122-129. [PMID: 36640666 DOI: 10.1016/j.bbrc.2023.01.012] [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: 12/26/2022] [Accepted: 01/05/2023] [Indexed: 01/07/2023]
Abstract
Fibroblast growth factor 21 (FGF21) has emerged as a metabolic regulator that exerts potent anti-diabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes, showing a protective role in fatty liver disease and hepatocellular carcinoma progression. Hepatic expression of FGF21 is regulated by PPARα and is induced by fasting. Ablation of FoxO1 in liver has been shown to increase FGF21 expression in hyperglycemia. To better understand the role of FOXO1 in the regulation of FGF21 expression we have modified HepG2 human hepatoma cells to overexpress FoxO1 and PPARα. Here we show that FoxO1 represses PPARα-mediated FGF21 induction, and that the repression acts on the FGF21 gene promoter without affecting other PPARα target genes. Additionally, we demonstrate that FoxO1 physically interacts with PPARα and that FoxO1/3/4 depletion in skeletal muscle contributes to increased Fgf21 tissue levels. Taken together, these data indicate that FOXO1 is a PPARα-interacting protein that antagonizes PPARα activity on the FGF21 promoter. Because other PPARα target genes remained unaffected, these results suggest a highly specific mechanism implicated in FGF21 regulation. We conclude that FGF21 can be specifically modulated by FOXO1 in a PPARα-dependent manner.
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Affiliation(s)
- Ana Luísa De Sousa-Coelho
- Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, Campus de Gambelas, Edifício 2, 8005-139, Faro, Portugal; Algarve Biomedical Center (ABC), Campus de Gambelas, Edifício 2, 8005-139, Faro, Portugal; Escola Superior de Saúde, Universidade do Algarve, Campus de Gambelas, Edifício 1, 8005-139, Faro, Portugal.
| | - Mar Gacias
- Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences, Food Torribera Campus, University of Barcelona, E-08921, Santa Coloma de Gramenet, Spain
| | - Brian T O'Neill
- Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, 52242, Iowa, USA
| | - Joana Relat
- Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences, Food Torribera Campus, University of Barcelona, E-08921, Santa Coloma de Gramenet, Spain; Institute of Nutrition and Food Safety of the University of Barcelona (INSA-UB), E-08921, Santa Coloma de Gramenet, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBER-OBN), Instituto de Salud Carlos III, E-28029, Madrid, Spain
| | - Wolfgang Link
- Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
| | - Diego Haro
- Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences, Food Torribera Campus, University of Barcelona, E-08921, Santa Coloma de Gramenet, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBER-OBN), Instituto de Salud Carlos III, E-28029, Madrid, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), E-08028 Barcelona, Spain
| | - Pedro F Marrero
- Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences, Food Torribera Campus, University of Barcelona, E-08921, Santa Coloma de Gramenet, Spain; CIBER Physiopathology of Obesity and Nutrition (CIBER-OBN), Instituto de Salud Carlos III, E-28029, Madrid, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), E-08028 Barcelona, Spain.
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17
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Kohoutova K, Dočekal V, Ausserlechner MJ, Kaiser N, Tekel A, Mandal R, Horvath M, Obsilova V, Vesely J, Hagenbuchner J, Obsil T. Lengthening the Guanidine-Aryl Linker of Phenylpyrimidinylguanidines Increases Their Potency as Inhibitors of FOXO3-Induced Gene Transcription. ACS OMEGA 2022; 7:34632-34646. [PMID: 36188303 PMCID: PMC9521028 DOI: 10.1021/acsomega.2c04613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/07/2022] [Indexed: 06/16/2023]
Abstract
Increased FOXO3 nuclear localization is involved in neuroblastoma chemoresistance and tumor angiogenesis. Accordingly, FOXO3 inhibition is a promising strategy for boosting antitumor immune responses and suppressing FOXO3-mediated therapy resistance in cancer cells. However, no FOXO3 inhibitors are currently available for clinical use. Nevertheless, we have recently identified (4-propoxy)phenylpyrimidinylguanidine as a FOXO3 inhibitor in cancer cells in the low micromolar range. Here, we report the synthesis and structure-activity relationship study of a small library of its derivatives, some of which inhibit FOXO3-induced gene transcription in cancer cells in a submicromolar range and are thus 1 order of magnitude more potent than their parent compound. By NMR and molecular docking, we showed that these compounds differ in their interactions with the DNA-binding domain of FOXO3. These results may provide a foundation for further optimizing (4-propoxy)phenylpyrimidinylguanidine and developing therapeutics for inhibiting the activity of forkhead box (FOX) transcription factors and their interactions with other binding partners.
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Affiliation(s)
- Klara Kohoutova
- Department
of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Albertov 6, Prague 12843, Czech Republic
- Institute
of Physiology of the Czech Academy of Sciences, Laboratory of Structural
Biology of Signaling Proteins, Division
BIOCEV, Prumyslova 595, Vestec 25250, Czech Republic
| | - Vojtěch Dočekal
- Department
of Organic Chemistry, Faculty of Science, Charles University, Albertov 6, Prague 12843, Czech Republic
| | | | - Nora Kaiser
- Department
of Pediatrics I, Medical University Innsbruck, Innrain 66, Innsbruck 6020, Austria
| | - Andrej Tekel
- Department
of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Albertov 6, Prague 12843, Czech Republic
| | - Raju Mandal
- Department
of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Albertov 6, Prague 12843, Czech Republic
| | - Matej Horvath
- Department
of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Albertov 6, Prague 12843, Czech Republic
| | - Veronika Obsilova
- Institute
of Physiology of the Czech Academy of Sciences, Laboratory of Structural
Biology of Signaling Proteins, Division
BIOCEV, Prumyslova 595, Vestec 25250, Czech Republic
| | - Jan Vesely
- Department
of Organic Chemistry, Faculty of Science, Charles University, Albertov 6, Prague 12843, Czech Republic
| | - Judith Hagenbuchner
- Department
of Pediatrics II, Medical University Innsbruck, Innrain 66, Innsbruck 6020, Austria
| | - Tomas Obsil
- Department
of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Albertov 6, Prague 12843, Czech Republic
- Institute
of Physiology of the Czech Academy of Sciences, Laboratory of Structural
Biology of Signaling Proteins, Division
BIOCEV, Prumyslova 595, Vestec 25250, Czech Republic
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18
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Obsilova V, Obsil T. Structural insights into the functional roles of 14-3-3 proteins. Front Mol Biosci 2022; 9:1016071. [PMID: 36188227 PMCID: PMC9523730 DOI: 10.3389/fmolb.2022.1016071] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 09/02/2022] [Indexed: 12/02/2022] Open
Abstract
Signal transduction cascades efficiently transmit chemical and/or physical signals from the extracellular environment to intracellular compartments, thereby eliciting an appropriate cellular response. Most often, these signaling processes are mediated by specific protein-protein interactions involving hundreds of different receptors, enzymes, transcription factors, and signaling, adaptor and scaffolding proteins. Among them, 14-3-3 proteins are a family of highly conserved scaffolding molecules expressed in all eukaryotes, where they modulate the function of other proteins, primarily in a phosphorylation-dependent manner. Through these binding interactions, 14-3-3 proteins participate in key cellular processes, such as cell-cycle control, apoptosis, signal transduction, energy metabolism, and protein trafficking. To date, several hundreds of 14-3-3 binding partners have been identified, including protein kinases, phosphatases, receptors and transcription factors, which have been implicated in the onset of various diseases. As such, 14-3-3 proteins are promising targets for pharmaceutical interventions. However, despite intensive research into their protein-protein interactions, our understanding of the molecular mechanisms whereby 14-3-3 proteins regulate the functions of their binding partners remains insufficient. This review article provides an overview of the current state of the art of the molecular mechanisms whereby 14-3-3 proteins regulate their binding partners, focusing on recent structural studies of 14-3-3 protein complexes.
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Affiliation(s)
- Veronika Obsilova
- Institute of Physiology of the Czech Academy of Sciences, Laboratory of Structural Biology of Signaling Proteins, Division BIOCEV, Vestec, Czechia
- *Correspondence: Veronika Obsilova, ; Tomas Obsil,
| | - Tomas Obsil
- Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czechia
- *Correspondence: Veronika Obsilova, ; Tomas Obsil,
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19
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Huang L, Ma Y, Guo H, Tang N, Ouyang S, Nuro-Gyina P, Tao L, Liu Y, O'Brien MC, Langdon WY, Zhang J. Akt-2 Is a Potential Therapeutic Target for Disseminated Candidiasis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:991-1000. [PMID: 36130126 PMCID: PMC11141526 DOI: 10.4049/jimmunol.2101003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 06/30/2022] [Indexed: 05/22/2024]
Abstract
Akt-1 and Akt-2 are the major isoforms of the serine/threonine Akt family that play a key role in controlling immune responses. However, the involvement of Akt-1 and Akt-2 isoforms in antifungal innate immunity is completely unknown. In this study, we show that Akt2 -/-, but not Akt1 -/-, mice are protected from lethal Candida albicans infection. Loss of Akt-2 facilitates the recruitment of neutrophils and macrophages to the spleen and increases reactive oxygen species expression in these cells. Treating C57BL/6 mice with a specific inhibitor for Akt-2, but not Akt-1, provides protection from lethal C. albicans infection. Our data demonstrate that Akt-2 inhibits antifungal innate immunity by hampering neutrophil and macrophage recruitment to spleens and suppressing oxidative burst, myeloperoxidase activity, and NETosis. We thus describe a novel role for Akt-2 in the regulation of antifungal innate immunity and unveil Akt-2 as a potential target for the treatment of fungal sepsis.
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Affiliation(s)
- Ling Huang
- Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Yilei Ma
- Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA
| | - Hui Guo
- Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA
| | - Na Tang
- Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA
| | - Song Ouyang
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH
- Department of Neurology, The First Hospital of Changsha City, South China University, Changsha, Hunan, People's Republic of China
| | - Patrick Nuro-Gyina
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH
| | - Lijian Tao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Yusen Liu
- Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH; and
| | - Matthew C O'Brien
- Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA
| | - Wallace Y Langdon
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Jian Zhang
- Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA;
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH
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Li L, Wang H, Zhao S, Zhao Y, Chen Y, Zhang J, Wang C, Sun N, Fan H. Paeoniflorin ameliorates lipopolysaccharide-induced acute liver injury by inhibiting oxidative stress and inflammation via SIRT1/FOXO1a/SOD2 signaling in rats. Phytother Res 2022; 36:2558-2571. [PMID: 35570830 DOI: 10.1002/ptr.7471] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 03/18/2022] [Accepted: 04/03/2022] [Indexed: 12/13/2022]
Abstract
Acute liver injury (ALI) is a poor prognosis and high mortality complication of sepsis. Paeoniflorin (PF) has remarkable anti-inflammatory effects in different disease models. Here, we explored the protective effect and underlying molecular mechanisms of PF against lipopolysaccharide (LPS)-induced ALI. Sprague-Dawley rats received intraperitoneal (i.p.) injection of PF for 7 days, 1 h after the last administration, and rats were injected i.p. 10 mg/kg LPS. PF improved liver structure and function, reduced hepatic reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) levels, and increased superoxide dismutase (SOD) activity. Western blot analysis suggested that PF significantly inhibited expression of inflammatory cytokines (TNF-α, IL-1β, and IL-18) and inhibited activation of the NLRP3 inflammasome. PF or mitochondrial ROS scavenger (mito-TEMPO) significantly improved liver mitochondrial function by scavenging mitochondrial ROS (mROS), restoring mitochondrial membrane potential loss and increasing level of ATP and enzyme activity of complex I and III. In addition, PF increased expression of sirtuin-1 (SIRT1), forkhead box O1 (FOXO1a) and manganese superoxide dismutase (SOD2), and increased FOXO1a nuclear retention. However, the inhibitor of SIRT1 (EX527) abolished the protective effect of PF. Taken together, PF promotes mROS clearance to inhibit mitochondrial damage and activation of the NLRP3 inflammasome via SIRT1/FOXO1a/SOD2 signaling.
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Affiliation(s)
- Lin Li
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Hui Wang
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Shuping Zhao
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Yuan Zhao
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Yongping Chen
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Jiuyan Zhang
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Chuqiao Wang
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Ning Sun
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Honggang Fan
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
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21
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Signaling pathways of Periplaneta americana peptide resist H2O2-induced apoptosis in pig-ovary granulosa cells through FoxO1. Theriogenology 2022; 183:108-119. [DOI: 10.1016/j.theriogenology.2022.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 01/30/2022] [Accepted: 02/04/2022] [Indexed: 01/12/2023]
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22
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Lorite-Fuentes I, Montero-Vilchez T, Arias-Santiago S, Molina-Leyva A. Potential Benefits of the Mediterranean Diet and Physical Activity in Patients with Hidradenitis Suppurativa: A Cross-Sectional Study in a Spanish Population. Nutrients 2022; 14:nu14030551. [PMID: 35276909 PMCID: PMC8840522 DOI: 10.3390/nu14030551] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/01/2023] Open
Abstract
There is scarce scientific information regarding the potential benefits of healthy lifestyles in patients with hidradenitis suppurativa (HS). The objective of this study is to explore the potential association between the adherence to a Mediterranean diet (MD), physical activity and HS severity. A cross-sectional study that included patients with HS was conducted. Disease severity was evaluated by the International Hidradenitis Suppurativa Severity Score System (IHS4) and self-reported disease activity using a Numeric Rating Scale (NRS, 0−10). The adherence to a MD was assessed by the PREvención con DIeta MEDiterránea (PREDIMED) questionnaire and the level of physical activity by the International Physical Activity questionnaire. A total of 221 patients with HS were included in our study. The adherence to a MD was average for a Spanish population. A higher adherence to a MD was associated with lower disease activity, lower self-reported Hurley and lower IHS4. The use of extra virgin olive oil as the main culinary lipid was the dietary habit that implied a lower degree of disease activity (p < 0.05). Regarding physical activity, both the self-reported severity and IHS4 presented an inverse association with the intensity of physical activity. The adherence to a MD and the intensity of physical activity were positively associated. The Mediterranean dietary pattern may have an impact on HS. Greater adherence to a MD is related to lower HS severity and more physical activity also correlates to lower disease severity. The MD could be an appropriate dietary pattern for patients with HS due to its anti-inflammatory properties, and combining this with increased levels of physical activity could have additional benefits.
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Affiliation(s)
- Irene Lorite-Fuentes
- Dermatology Department, Hospital Universitario Virgen de las Nieves, Avenida de Madrid 15, 18014 Granada, Spain;
| | - Trinidad Montero-Vilchez
- Hidradenitis Suppurativa Clinic, Dermatology, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; (T.M.-V.); (A.M.-L.)
- Instituto de Investigación Biosanitaria Granada, 18014 Granada, Spain
| | - Salvador Arias-Santiago
- Dermatology Department, Hospital Universitario Virgen de las Nieves, Avenida de Madrid 15, 18014 Granada, Spain;
- Hidradenitis Suppurativa Clinic, Dermatology, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; (T.M.-V.); (A.M.-L.)
- Instituto de Investigación Biosanitaria Granada, 18014 Granada, Spain
- Correspondence: ; Tel.: +34-958023422
| | - Alejandro Molina-Leyva
- Hidradenitis Suppurativa Clinic, Dermatology, Hospital Universitario Virgen de las Nieves, 18014 Granada, Spain; (T.M.-V.); (A.M.-L.)
- Instituto de Investigación Biosanitaria Granada, 18014 Granada, Spain
- European Hidradenitis Suppurativa Foundation (EHSF), 06844 Dessau-Roßlau, Germany
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Hu H, Zhao M, Li Z, Nie H, He J, Chen Z, Yuan J, Guo H, Zhang X, Yang H, Wu T, He M. Plasma miR-193b-3p Is Elevated in Type 2 Diabetes and Could Impair Glucose Metabolism. Front Endocrinol (Lausanne) 2022; 13:814347. [PMID: 35712251 PMCID: PMC9197112 DOI: 10.3389/fendo.2022.814347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 04/12/2022] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE To explore differentially expressed miRNAs in type 2 diabetes and their potential cellular functions. METHODS We screened plasma miRNAs by miRNA array analysis and validated them by TaqMan real-time PCR in 113 newly diagnosed, untreated type 2 diabetes cases and 113 healthy controls. Low-abundance plasma proteins encoded by miR-193b-3p target genes were explored in this study population. We further investigated the potential cellular functions of the differentially expressed miRNAs in HepG2 cells. RESULTS miR-193b-3p was differentially expressed in type 2 diabetes cases compared to healthy controls (fold change = 2.01, P = 0.006). Plasma levels of triosephosphate isomerase (TPI1, a protein involved in the glycolytic pathway) decreased in type 2 diabetes cases (fold change = 1.37, P = 0.002). The effect of miR-193b-3p on TPI1 was verified by transfection of miR-193b-3p into HepG2 cells. miR-193b-3p inhibited the expression of YWHAZ/14-3-3ζ in the PI3K-AKT pathway, subsequently altering the expression of FOXO1 and PCK1. After transfection, cells were incubated in glucose-free medium for another 4 h. Glucose levels in medium from cells with elevated miR-193b-3p levels were significantly higher than those in medium from negative control cells (P = 0.016). In addition, elevated miR-193b-3p reduced glucose uptake by inhibiting insulin receptor (IR) and GLUT2 expression. CONCLUSION Plasma miR-193b-3p levels increased in type 2 diabetes cases, and TPI1 levels decreased in both plasma and HepG2 cells with increased miR-193b-3p levels, while extracellular lactate levels did not significantly changed. Moreover, miR-193b-3p may affect glucose metabolism by directly targeting YWHAZ/14-3-3ζ and upregulating the transcription factor FOXO1 downstream of the PI3K-AKT pathway.
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Affiliation(s)
- Hua Hu
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Meng Zhao
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaoyang Li
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Hongli Nie
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Jia He
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Zhuo Chen
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Yuan
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Guo
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaomin Zhang
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Handong Yang
- Dongfeng Central Hospital, Dongfeng Motor Corporation and Hubei University of Medicine, Shiyan, China
| | - Tangchun Wu
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
| | - Meian He
- Department of Occupational and Environmental Health and State Key Laboratory of Environmental Health for Incubating, School of Public Health, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Meian He,
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Fan D, Liu C, Guo Z, Huang K, Peng M, Li N, Luo H, Wang T, Cen Z, Cai W, Gu L, Chen S, Li Z. Resveratrol Promotes Angiogenesis in a FoxO1-Dependent Manner in Hind Limb Ischemia in Mice. Molecules 2021; 26:molecules26247528. [PMID: 34946610 PMCID: PMC8707225 DOI: 10.3390/molecules26247528] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/29/2021] [Accepted: 12/09/2021] [Indexed: 12/29/2022] Open
Abstract
Critical limb ischemia (CLI) is a severe form of peripheral artery diseases (PAD) and seriously endangers the health of people. Therapeutic angiogenesis represents an important treatment strategy for CLI; various methods have been applied to enhance collateral circulation. However, the current development drug therapy to promote angiogenesis is limited. Resveratrol (RSV), a polyphenol compound extracted from plants, has various properties such as anti-oxidative, anti-inflammatory and anti-cancer effects. Whether RSV exerts protective effects on CLI remains elusive. In the current study, we demonstrated that oral intake of RSV significantly improved hind limb ischemia in mice, and increased the expression of phosphorylated Forkhead box class-O1 (FoxO1). RSV treatment in human umbilical vein endothelial cells (HUVECs) could increase the phosphorylation of FoxO1 and its cytoplasmic re-localization to promote angiogenesis. Then we manipulated FoxO1 in HUVECs to further verify that the effect of RSV on angiogenesis is in a FoxO1-dependent manner. Furthermore, we performed metabolomics to screen the metabolic pathways altered upon RSV intervention. We found that the pathways of pyrimidine metabolism, purine metabolism, as well as alanine, aspartate and glutamate metabolism, were highly correlated with the beneficial effects of RSV on the ischemic muscle. This study provides a novel direction for the medical therapy to CLI.
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Affiliation(s)
- Dongxiao Fan
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; (D.F.); (C.L.); (K.H.); (N.L.)
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China;
| | - Chenshu Liu
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; (D.F.); (C.L.); (K.H.); (N.L.)
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China;
| | - Zeling Guo
- Department of Otolaryngology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China;
| | - Kan Huang
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; (D.F.); (C.L.); (K.H.); (N.L.)
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China;
| | - Meixiu Peng
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China;
| | - Na Li
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; (D.F.); (C.L.); (K.H.); (N.L.)
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China;
| | - Hengli Luo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (H.L.); (T.W.); (Z.C.)
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Tengyao Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (H.L.); (T.W.); (Z.C.)
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Zhipeng Cen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (H.L.); (T.W.); (Z.C.)
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Weikang Cai
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568, USA;
| | - Lei Gu
- Max Planck Institute for Heart and Lung Research and Cardiopulmonary Institute (CPI), 61231 Bad Nauheim, Germany;
| | - Sifan Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; (H.L.); (T.W.); (Z.C.)
- Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
- Correspondence: (S.C.); (Z.L.)
| | - Zilun Li
- Division of Vascular Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; (D.F.); (C.L.); (K.H.); (N.L.)
- National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China;
- Correspondence: (S.C.); (Z.L.)
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Enchéry F, Dumont C, Iampietro M, Pelissier R, Aurine N, Bloyet LM, Carbonnelle C, Mathieu C, Journo C, Gerlier D, Horvat B. Nipah virus W protein harnesses nuclear 14-3-3 to inhibit NF-κB-induced proinflammatory response. Commun Biol 2021; 4:1292. [PMID: 34785771 PMCID: PMC8595879 DOI: 10.1038/s42003-021-02797-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 10/08/2021] [Indexed: 12/15/2022] Open
Abstract
Nipah virus (NiV) is a highly pathogenic emerging bat-borne Henipavirus that has caused numerous outbreaks with public health concerns. It is able to inhibit the host innate immune response. Since the NF-κB pathway plays a crucial role in the innate antiviral response as a major transcriptional regulator of inflammation, we postulated its implication in the still poorly understood NiV immunopathogenesis. We report here that NiV inhibits the canonical NF-κB pathway via its nonstructural W protein. Translocation of the W protein into the nucleus causes nuclear accumulation of the cellular scaffold protein 14-3-3 in both African green monkey and human cells infected by NiV. Excess of 14-3-3 in the nucleus was associated with a reduction of NF-κB p65 subunit phosphorylation and of its nuclear accumulation. Importantly, W-S449A substitution impairs the binding of the W protein to 14-3-3 and the subsequent suppression of NF-κB signaling, thus restoring the production of proinflammatory cytokines. Our data suggest that the W protein increases the steady-state level of 14-3-3 in the nucleus and consequently enhances 14-3-3-mediated negative feedback on the NF-κB pathway. These findings provide a mechanistic model of W-mediated disruption of the host inflammatory response, which could contribute to the high severity of NiV infection.
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Affiliation(s)
- François Enchéry
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France
| | - Claire Dumont
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France
| | - Mathieu Iampietro
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France
| | - Rodolphe Pelissier
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France
| | - Noémie Aurine
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France
| | - Louis-Marie Bloyet
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France
| | - Caroline Carbonnelle
- INSERM- Laboratoire P4 Jean Mérieux, 21 Avenue Tony Garnier, 69365, Lyon, France
| | - Cyrille Mathieu
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France
| | - Chloé Journo
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France
| | - Denis Gerlier
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France
| | - Branka Horvat
- CIRI, Centre International de Recherche en Infectiologie, Inserm U1111, CNRS, UMR5308, Univ Lyon, Université Claude Bernard Lyon 1, École Normale Supérieure de Lyon, Lyon, France.
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26
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Pang H, Li J, Wang Y, Su X, Gao Y, Li SJ. Mice lacking the proton channel Hv1 exhibit sex-specific differences in glucose homeostasis. J Biol Chem 2021; 297:101212. [PMID: 34547291 PMCID: PMC8503595 DOI: 10.1016/j.jbc.2021.101212] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/07/2021] [Accepted: 09/16/2021] [Indexed: 02/07/2023] Open
Abstract
Sex as a physiologic factor has a strong association with the features of metabolic syndrome. Our previous study showed that loss of the voltage-gated proton channel Hv1 inhibits insulin secretion and leads to hyperglycemia and glucose intolerance in male mice. However, there are significant differences in blood glucose between male and female Hv1-knockout (KO) mice. Here, we investigated the differences in glucose metabolism and insulin sensitivity between male and female KO mice and how sex steroids contribute to these differences. We found that the fasting blood glucose in female KO mice was visibly lower than that in male KO mice, which was accompanied by hypotestosteronemia. KO mice in both sexes exhibited higher expression of gluconeogenesis-related genes in liver compared with WT mice. Also, the livers from KO males displayed a decrease in glycolysis-related gene expression and an increase in gluconeogenesis-related gene expression compared with KO females. Furthermore, exogenous testosterone supplementation decreased blood glucose levels in male KO mice, as well as enhancing insulin signaling. Taken together, our data demonstrate that knockout of Hv1 results in higher blood glucose levels in male than female mice, despite a decreased insulin secretion in both sexes. This sex-related difference in glucose homeostasis is associated with the glucose metabolism in liver tissue, likely due to the physiological levels of testosterone in KO male mice.
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Affiliation(s)
- Huimin Pang
- Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, PR China
| | - Jinzhi Li
- Biology Laboratory, Tianjin High School, Tianjin, PR China
| | - Yuzhou Wang
- Laboratory Animal Center, College of Life Sciences, Nankai University, Tianjin, PR China
| | - Xiaomin Su
- Laboratory Animal Center, College of Life Sciences, Nankai University, Tianjin, PR China
| | - Yingtang Gao
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Institute of Hepatobiliary Disease, Nankai University Affiliated Third Center Hospital, Tianjin, PR China.
| | - Shu Jie Li
- Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, PR China; Biomedical Research Center, Qilu Institute of Technology, Shandong, PR China.
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Liu D, Wan L, Gong H, Chen S, Kong Y, Xiao B. Sevoflurane promotes the apoptosis of laryngeal squamous cell carcinoma in-vitro and inhibits its malignant progression via miR-26a/FOXO1 axis. Bioengineered 2021; 12:6364-6376. [PMID: 34511023 PMCID: PMC8806578 DOI: 10.1080/21655979.2021.1962684] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Laryngeal squamous cell carcinoma (LSCC) is a laryngeal malignancy with a high mortality rates, and its treatment remains difficult. Sevoflurane is a surgical anesthesia which has anti-tumor effect. This investigation assessed the effects of LSCC cells treatment with Sevoflurane in vitro and in vivo. Hep-2 and Tu177 cells, human LSCC samples and BALB/C nude mice were used for result assessments. Cell viability, proliferation, migration and invasion were assessed via Cell Count Kit-8, wound healing assay and transwell invasion assay respectively. MiR-26a and FOXO1 expressions was examined by qRT-PCR. FOXO1, E-cadherin, N-cadherin and vimentin activities were examined by Western blotting. Moreover, animal experiments were performed to verify our findings in vitro. Lastly, miR-26a and FOXO1 expression levels in clinical samples were analyzed. According to the results, Sevoflurane decreased LSCC cells’ viability and even stimulated their apoptosis in vitro and in vivo. Moreover, it could reduce the migration, invasion and EMT. Mechanistically, sevoflurane could downregulate miR-26a expression and that miR-26a could negatively modulate FOXO1 activity. Thus, sevoflurane could increase FOXO1 activity. In the clinical samples, miR-26a expression was significantly upregulated, but FOXO1 was remarkably down-regulated and miR-26a expression in LSCC was linked with better prognosis. In conclusion, MiR-26a is increased and FOXO1 is reduced in human LSCC, Sevoflurane inhibits proliferation and mediates apoptosis of LSCC cells. Further, MiR-26a binds FOXO1 directly, and FOXO1 expression is down-regulated by Sevoflurane. Finally, Sevoflurane triggers LSCC cells apoptosis in vivo. Sevoflurane use to target miR-26a/FOXO1 may be a novel alternative for LSCC therapy.
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Affiliation(s)
- Dan Liu
- Department Of Otorhinolaryngology, Huangshi Central Hospital Of Edong Healthcare Group, Hubei Polytechnic University, Huangshi City, Hubei Province, China
| | - Lang Wan
- Department Of Otorhinolaryngology, Huangshi Central Hospital Of Edong Healthcare Group, Hubei Polytechnic University, Huangshi City, Hubei Province, China
| | - Hao Gong
- Department Of Anesthesiology, Huangshi Maternity And Children's Health Hospital, Huangshi City, Hubei Province, China
| | - Shiming Chen
- Department Of Otolaryngology Head And Neck Surgery, Renmin Hospital Of Wuhan University, Wuhan City, Hubei Province, China
| | - Yonggang Kong
- Department Of Otolaryngology Head And Neck Surgery, Renmin Hospital Of Wuhan University, Wuhan City, Hubei Province, China
| | - Bokui Xiao
- Otorhinolaryngology-Head And Neck Surgery Laboratory, Wuhan University School Of Medicine, Wuhan City, Hubei Province, China
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Moghbeli M, Zangouei AS, Nasrpour Navaii Z, Taghehchian N. Molecular mechanisms of the microRNA-132 during tumor progressions. Cancer Cell Int 2021; 21:439. [PMID: 34419060 PMCID: PMC8379808 DOI: 10.1186/s12935-021-02149-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 08/13/2021] [Indexed: 12/21/2022] Open
Abstract
Cancer as one of the leading causes of human deaths has always been one of the main health challenges in the world. Despite recent advances in therapeutic and diagnostic methods, there is still a high mortality rate among cancer patients. Late diagnosis is one of the main reasons for the high ratio of cancer related deaths. Therefore, it is required to introduce novel early detection methods. Various molecular mechanisms are associated with the tumor progression and metastasis. MicroRNAs (miRNAs) are a class of non-coding RNAs (ncRNAs) family that has important functions in regulation of the cellular processes such as cell proliferation, apoptosis, and tumor progression. Moreover, they have higher stability in body fluids compared with mRNAs which can be introduced as non-invasive diagnostic markers in cancer patients. MiR-132 has important functions as tumor suppressor or oncogene in different cancers. In the present review, we have summarized all of the studies which have been reported the role of miR-132 during tumor progressions. We categorized the miR-132 target genes based on their cell and molecular functions. Although, it has been reported that the miR-132 mainly functions as a tumor suppressor, it has also oncogenic functions especially in pancreatic tumors. MiR-132 mainly exerts its roles during tumor progressions by regulation of the transcription factors and signaling pathways. Present review clarifies the tumor specific molecular mechanisms of miR-132 to introduce that as an efficient non-invasive diagnostic marker in various cancers.
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Affiliation(s)
- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amir Sadra Zangouei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Nasrpour Navaii
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negin Taghehchian
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
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Soh R, Hardy A, Zur Nieden NI. The FOXO signaling axis displays conjoined functions in redox homeostasis and stemness. Free Radic Biol Med 2021; 169:224-237. [PMID: 33878426 PMCID: PMC9910585 DOI: 10.1016/j.freeradbiomed.2021.04.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 02/07/2023]
Abstract
Previous views of reactive oxygen species (ROS) depicted them as harmful byproducts of metabolism as uncontrolled levels of ROS can lead to DNA damage and cell death. However, recent studies have shed light into the key role of ROS in the self-renewal or differentiation of the stem cell. The interplay between ROS levels, metabolism, and the downstream redox signaling pathways influence stem cell fate. In this review we will define ROS, explain how they are generated, and how ROS signaling can influence transcription factors, first and foremost forkhead box-O transcription factors, that shape not only the cellular redox state, but also stem cell fate. Now that studies have illustrated the importance of redox homeostasis and the role of redox signaling, understanding the mechanisms behind this interplay will further shed light into stem cell biology.
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Affiliation(s)
- Ruthia Soh
- Department of Molecular, Cell and Systems Biology, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, 92521, CA, USA
| | - Ariana Hardy
- Department of Molecular, Cell and Systems Biology, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, 92521, CA, USA
| | - Nicole I Zur Nieden
- Department of Molecular, Cell and Systems Biology, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, 92521, CA, USA; Stem Cell Center, College of Natural and Agricultural Sciences, University of California Riverside, Riverside, 92521, CA, USA.
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Zhang X, Jiang L, Liu H. Forkhead Box Protein O1: Functional Diversity and Post-Translational Modification, a New Therapeutic Target? DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:1851-1860. [PMID: 33976536 PMCID: PMC8106445 DOI: 10.2147/dddt.s305016] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 04/19/2021] [Indexed: 11/23/2022]
Abstract
Forkhead box protein O1 (FoXO1) is a transcription factor involved in the regulation of a wide variety of physiological process including glucose metabolism, lipogenesis, bone mass, apoptosis, and autophagy. FoXO1 dysfunction is involved in the pathophysiology of various diseases including metabolic diseases, atherosclerosis, and tumors. FoXO1 activity is regulated in response to different physiological or pathogenic conditions by changes in protein expression and post-translational modifications. Various modifications cooperate to regulate FoXO1 activity and FoXO1 target gene transcription. In this review, we summarize how different post-translational modifications regulate FoXO1 physiological function, which may provide new insights for drug design and development.
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Affiliation(s)
- Xiaojun Zhang
- Department of Cardiology, Shandong Rongjun General Hospital, Jinan, 250013, People's Republic of China
| | - Lusheng Jiang
- Department of Emergency, Shandong Rongjun General Hospital, Jinan, 250013, People's Republic of China
| | - Huimin Liu
- Blood Purification Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250011, People's Republic of China
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31
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Wang Y, He W. Improving the Dysregulation of FoxO1 Activity Is a Potential Therapy for Alleviating Diabetic Kidney Disease. Front Pharmacol 2021; 12:630617. [PMID: 33859563 PMCID: PMC8042272 DOI: 10.3389/fphar.2021.630617] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/02/2021] [Indexed: 02/06/2023] Open
Abstract
A substantial proportion of patients with diabetes will develop kidney disease. Diabetic kidney disease (DKD) is one of the most serious complications in diabetic patients and the leading cause of end-stage kidney disease worldwide. Although some mechanisms have been revealed to contribute to the understanding of the pathogenesis of DKD and some drugs currently in use have been shown to be beneficial, prevention and management of DKD remain tricky and challenging. FoxO1 transcriptional factor is a crucial regulator of cellular homeostasis and posttranslational modification is a major mechanism to alter FoxO1 activity. There is increasing evidence that FoxO1 is involved in the regulation of various cellular processes such as stress resistance, autophagy, cell cycle arrest, and apoptosis, thereby playing an important role in the pathogenesis of DKD. Improving the dysregulation of FoxO1 activity by natural compounds, synthetic drugs, or manipulation of gene expression may attenuate renal cell injury and kidney lesion in the cells cultured under a high-glucose environment and in diabetic animal models. The available data imply that FoxO1 may be a potential clinical target for the prevention and treatment of DKD.
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Affiliation(s)
- Yan Wang
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Weichun He
- Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
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32
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Xu R, Wang Z. Involvement of Transcription Factor FoxO1 in the Pathogenesis of Polycystic Ovary Syndrome. Front Physiol 2021; 12:649295. [PMID: 33746783 PMCID: PMC7973228 DOI: 10.3389/fphys.2021.649295] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/15/2021] [Indexed: 11/13/2022] Open
Abstract
FoxO1 is a member of the forkhead transcription factor family subgroup O (FoxO), which is expressed in many cell types, and participates in various pathophysiological processes, including cell proliferation, apoptosis, autophagy, metabolism, inflammatory response, cytokine expression, immune differentiation, and oxidative stress resistance. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in the women of childbearing age, which is regulated via a variety of signaling pathways. Currently, the specific mechanism underlying the pathogenesis of PCOS is still unclear. As an important transcription factor, FoxO1 activity might be involved in the pathophysiology of PCOS. PCOS has been associated with insulin resistance and low-grade inflammatory response. Therefore, the studies regarding the role of FoxO1 in the incidence and associated complications of PCOS will help provide novel ideas for establishing the treatment strategy of PCOS.
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Affiliation(s)
- Renfeng Xu
- Provincial Key Laboratory for Developmental Biology and Neurosciences, Provincial University Key Laboratory of Sport and Health Science, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Zhengchao Wang
- Provincial Key Laboratory for Developmental Biology and Neurosciences, Provincial University Key Laboratory of Sport and Health Science, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
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33
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Takemoto R, Kamiya T, Atobe T, Hara H, Adachi T. Regulation of lysyl oxidase expression in THP-1 cell-derived M2-like macrophages. J Cell Biochem 2021; 122:777-786. [PMID: 33644883 DOI: 10.1002/jcb.29911] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/27/2021] [Accepted: 02/08/2021] [Indexed: 01/16/2023]
Abstract
Lysyl oxidase (LOX) is a copper-containing enzyme and its overexpression in tumor tissues promote tumor metastasis through the crosslinking of extracellular matrix. Our previous report demonstrated that LOX expression is significantly increased in human leukemic THP-1 cell-derived M2-like macrophages, and histone modification plays a key role in its induction. However, the rigorous mechanism of LOX regulation remains unclear. In this study, we investigated the role of functional transcription factors, hypoxia-inducible factor 1α (HIF1α), signal transducer and activator of transcription 3 (STAT3) and forkhead box O1 (FOXO1) in LOX regulation in M2-like macrophages. HIF1α expression was significantly increased in M2-like macrophages, and HIF1α inhibitor, TX402, suppressed LOX induction. The significant STAT3 activation was also observed in M2-like macrophages. Additionally, LOX induction was canceled in the presence of STAT3 inhibitor, S3I-201, suggesting that HIF1α and STAT3 pathways play a critical role in LOX induction. On the other hand, our ChIP results clearly indicated that the enrichment of FOXO1 within the lox promoter region was dramatically decreased in M2-like macrophages. In this context, knockdown of FOXO1 further enhanced LOX induction. LOX induction and HIF1α binding to the lox promoter region were suppressed in FOXO1-overexpressed cells, suggesting that the FOXO1 binding to the lox promoter region counteracted HIF1α binding to that region. Overall, the present data suggested that both of HIF1α and STAT3 were required for LOX induction in M2-like macrophages, and loss of FOXO1 within the lox promoter region facilitated HIF1α binding to that region which promoted LOX induction.
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Affiliation(s)
- Ryuhei Takemoto
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Tetsuro Kamiya
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Taku Atobe
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Hirokazu Hara
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
| | - Tetsuo Adachi
- Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan
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34
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Zhong L, Liu Q, Liu Q, Zhang S, Cao Y, Yang D, Wang MW. W2476 represses TXNIP transcription via dephosphorylation of FOXO1 at Ser319. Chem Biol Drug Des 2021; 97:1089-1099. [PMID: 33560565 DOI: 10.1111/cbdd.13828] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/27/2021] [Accepted: 01/31/2021] [Indexed: 12/20/2022]
Abstract
Thioredoxin-interacting protein (TXNIP) overexpression is implicated in the pathogenesis of type 2 diabetes. Previous studies have shown that a small molecule compound (W2476) was able to improve β-cell dysfunction and exert therapeutic effects in diabetic mice via repression of TXNIP signaling pathway. The impact of W2476 on TXNIP transcription was thus investigated using the chromatin immunoprecipitation method. It was found that W2476 promotes competitive binding of forkhead box O1 transcription factor (FOXO1) to the carbohydrate response element (ChoRE) sequence associated with ChoRE-binding protein (ChREBP)/Mlx interacting protein-like(Mlx) complexes. This interaction hinders the attachment of histone acetyltransferase p300 and reduces histone H4 acetylation on the TXNIP promoter, leading to decreasing TXNIP transcription.
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Affiliation(s)
- Li Zhong
- The National Center for Drug Screening, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Qing Liu
- The National Center for Drug Screening, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Qiaofeng Liu
- School of Pharmacy, Fudan University, Shanghai, China
| | - Shikai Zhang
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yongbing Cao
- Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Dehua Yang
- The National Center for Drug Screening, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China
| | - Ming-Wei Wang
- The National Center for Drug Screening, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China.,School of Pharmacy, Fudan University, Shanghai, China
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35
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Calissi G, Lam EWF, Link W. Therapeutic strategies targeting FOXO transcription factors. Nat Rev Drug Discov 2021; 20:21-38. [PMID: 33173189 DOI: 10.1038/s41573-020-0088-2] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2020] [Indexed: 12/13/2022]
Abstract
FOXO proteins are transcription factors that are involved in numerous physiological processes and in various pathological conditions, including cardiovascular disease, cancer, diabetes and chronic neurological diseases. For example, FOXO proteins are context-dependent tumour suppressors that are frequently inactivated in human cancers, and FOXO3 is the second most replicated gene associated with extreme human longevity. Therefore, pharmacological manipulation of FOXO proteins is a promising approach to developing therapeutics for cancer and for healthy ageing. In this Review, we overview the role of FOXO proteins in health and disease and discuss the pharmacological approaches to modulate FOXO function.
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Affiliation(s)
- Giampaolo Calissi
- Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, UK
| | - Wolfgang Link
- Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
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36
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Zhu L, Duan W, Wu G, Zhang D, Wang L, Chen D, Chen Z, Yang B. Protective effect of hydrogen sulfide on endothelial cells through Sirt1-FoxO1-mediated autophagy. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1586. [PMID: 33437785 PMCID: PMC7791216 DOI: 10.21037/atm-20-3647] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background As a new member of the vasculoprotective gasotransmitter family, hydrogen sulfide (H2S) functions similar to nitric oxide (NO) and carbon monoxide (CO). Endothelial cell (EC) death and autophagy enable cells to cope with the progression of cardiovascular diseases. However, the impacts and underlying mechanisms of H2S in the autophagic process in ECs are not completely understood. Here, we investigated the effects of H2S on autophagy in human vascular ECs. Methods Human umbilical vein endothelial cells (HUVECs) were exposed to different concentrations (0, 50, 100, 200, 500 and 1,000 µmol/L) GYY4137 (H2S donor) for indicated times (0, 0.5, 1, 2, 4 and 8 h), with or without pre-treatment with the autophagy inhibitor 3-methyladenine (3-MA) or bafilomycin A1. HUVECs were transfected with sirtuin 1 (Sirt1) overexpression plasmids (PIRES-Sirt1), Sirt1-siRNAs or forkhead box O1 (FoxO1)-siRNA using Lipofectamine 2000. Cell autophagy was evaluated via Western blotting and fluorescence microscopy. Co-immunoprecipitation assay was used to measure acetylation level of FoxO1. The distribution of FoxO1 in the cytoplasm and nucleus was observed using Western blotting and immunofluorescence. Western blotting, flow cytometric analysis, and cell count kit-8 assay were conducted to evaluate the effect of H2S on the oxidized low-density lipoprotein (Ox-LDL) induced apoptosis of HUVECs. Results Using both gain- and loss-of-function experiments, we showed that Sirt1-dependent activation of FoxO1, including its nuclear translocation and deacetylation, was critical for mediating H2S-induced autophagy in ECs. Furthermore, H2S-induced autophagy protected ECs from Ox-LDL-induced apoptosis by activating Sirt1. Conclusions These results suggest that Sirt1-mediated autophagy in ECs is a novel mechanism by which H2S exerts vascular-protective actions.
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Affiliation(s)
- Lin Zhu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wu Duan
- Division of Endocrinology, Department of Internal Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Guangjie Wu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Di Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lan Wang
- Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhishui Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Yang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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37
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Luu BE, Zhang Y, Storey KB. The regulation of Akt and FoxO transcription factors during dehydration in the African clawed frog (Xenopus laevis). Cell Stress Chaperones 2020; 25:887-897. [PMID: 32451989 PMCID: PMC7591653 DOI: 10.1007/s12192-020-01123-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/12/2020] [Accepted: 05/15/2020] [Indexed: 12/11/2022] Open
Abstract
The African clawed frog (Xenopus laevis) naturally tolerates severe dehydration using biochemical adaptation, one of which is the elevation of antioxidant defenses during whole-body dehydration. The present study investigated the role and regulation of a pathway known to regulate oxidative stress response, the Akt-FoxO signaling pathway, in clawed frog skeletal muscle, responding to medium (15%) and high (30%) dehydration. Protein levels of total and phosphorylated Akt, FoxO1, and FoxO3 were assessed via immunoblotting, in addition to the levels of the E3 ubiquitin ligase known to be associated with muscle atrophy, MAFbx. Akt activity/phosphorylation in addition to its total protein levels were decreased in the skeletal muscle during dehydration, and this corresponded with decreases in the relative phosphorylation of FoxO1 and FoxO3 as well on several residues. Akt is an inhibitor of FoxO1 and FoxO3 activity via phosphorylation, suggesting that FoxO activities were increased during dehydration stress. Furthermore, MAFbx showed decreased protein expression during high dehydration as well, suggesting that the clawed frog may exhibit some natural resistance to skeletal muscle atrophy during severe dehydration conditions. In addition to identifying that the suppression of Akt could lead to an activation of FoxO transcription factors in X. laevis during dehydration, these investigations suggest that X. laevis dehydration may implicate FoxO1 and FoxO3 in controlling skeletal muscle atrophy in X. laevis exposed to dehydration. This study implicates the Akt signaling pathway, its regulation of FoxO transcription factors, and FoxO-controlled targets, in stress adaptation against dehydration.
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Affiliation(s)
- Bryan E Luu
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada
- Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Yichi Zhang
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada
- Department of Molecular Biology, Hamon Center for Regenerative Science and Medicine, Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA
| | - Kenneth B Storey
- Institute of Biochemistry and Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa, ON, K1S 5B6, Canada.
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Martin APJ, Camonis JH. The hippo kinase STK38 ensures functionality of XPO1. Cell Cycle 2020; 19:2982-2995. [PMID: 33017560 PMCID: PMC7714482 DOI: 10.1080/15384101.2020.1826619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 08/06/2020] [Accepted: 08/08/2020] [Indexed: 10/23/2022] Open
Abstract
The proper segregation of basic elements such as the compartmentalization of the genome and the shuttling of macromolecules between the nucleus and the cytoplasm is a crucial mechanism for homeostasis maintenance in eukaryotic cells. XPO1 (Exportin 1) is the major nuclear export receptor and is required for the export of proteins and RNAs out of the nucleus. STK38 (also known as NDR1) is a Hippo pathway serine/threonine kinase with multifarious functions in normal and cancer cells. In this review, we summarize the history of the discovery of the nucleo/cytoplasmic shuttling of proteins and focus on the major actor of nuclear export: XPO1. After describing the molecular events required for XPO1-mediated nuclear export of proteins, we introduce the Hippo pathway STK38 kinase, synthetize its regulation mechanisms as well as its biological functions in both normal and cancer cells, and finally its intersection with XPO1 biology. We discuss the recently identified mechanism of XPO1 activation by phosphorylation of XPO1_S1055 by STK38 and contextualize this finding according to the biological functions previously reported for both XPO1 and STK38, including the second identity of STK38 as an autophagy regulator. Finally, we phrase this newly identified activation mechanism into the general nuclear export machinery and examine the possible outcomes of nuclear export inhibition in cancer treatment.
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Affiliation(s)
- Alexandre PJ Martin
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, USA
| | - Jacques H Camonis
- Inserm U830, Institut Curie, Centre de Recherche, Paris Sciences et Lettres Research University, Paris, France
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Russell SJ, Schneider MF. Alternative signaling pathways from IGF1 or insulin to AKT activation and FOXO1 nuclear efflux in adult skeletal muscle fibers. J Biol Chem 2020; 295:15292-15306. [PMID: 32868454 DOI: 10.1074/jbc.ra120.013634] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 08/20/2020] [Indexed: 12/25/2022] Open
Abstract
Muscle atrophy is regulated by the balance between protein degradation and synthesis. FOXO1, a transcription factor, helps to determine this balance by activating pro-atrophic gene transcription when present in muscle fiber nuclei. Foxo1 nuclear efflux is promoted by AKT-mediated Foxo1 phosphorylation, eliminating FOXO1's atrophy-promoting effect. AKT activation can be promoted by insulin-like growth factor 1 (IGF1) or insulin via a pathway including IGF1 or insulin, phosphatidylinositol 3-kinase, and AKT. We used confocal fluorescence time-lapse imaging of FOXO1-GFP in adult isolated living muscle fibers maintained in culture to explore the effects of IGF1 and insulin on FOXO1-GFP nuclear efflux with and without pharmacological inhibitors. We observed that although AKT inhibitor blocks the IGF1- or insulin-induced effect on FOXO1 nuclear efflux, phosphatidylinositol 3-kinase inhibitors, which we show to be effective in these fibers, do not. We also found that inhibition of the protein kinase ACK1 or ATM contributes to the suppression of FOXO1 nuclear efflux after IGF1. These results indicate a novel pathway that has been unexplored in the IGF1- or insulin-induced regulation of FOXO1 and present information useful both for therapeutic interventions for muscle atrophy and for further investigative areas into insulin insensitivity and type 2 diabetes.
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Affiliation(s)
- Sarah J Russell
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Martin F Schneider
- Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
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40
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Fernandez JM, Marr KD, Hendricks AJ, Price KN, Ludwig CM, Maarouf M, Hsiao JL, Shi VY. Alleviating and exacerbating foods in hidradenitis suppurativa. Dermatol Ther 2020; 33:e14246. [PMID: 32860476 DOI: 10.1111/dth.14246] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/15/2020] [Accepted: 08/22/2020] [Indexed: 12/27/2022]
Abstract
While dietary triggers have been investigated in acne and other inflammatory follicular dermatoses, there is a paucity of data on diet and hidradenitis suppurativa (HS). We sought to identify exacerbating and alleviating foods in HS patients. An anonymous survey was distributed via HS Facebook support groups and in person at HS specialty clinics. Participants were asked to select all that apply from a list to indicate foods that worsen and make HS better including sweet foods, breads and pasta, red meat, chicken, fish, canned foods, fruits, vegetables, dairy, high-fat foods, I do not know, and no. Only 12.0% (n = 89/744) identified alleviating foods while 32.6% (n = 237/728) identified HS-symptom-exacerbating foods. The most commonly reported exacerbating foods were sweets (67.9%), bread/pasta/rice (51.1%), dairy (50.6%), and high-fat foods (44.2%). The most commonly reported alleviating foods included vegetables (78.7%), fruit (56.2%), chicken (51.7%), and fish (42.7%). Further studies are required to evaluate the mechanistic links between diet and HS. HS patients may benefit from receiving dietary counseling as part of a comprehensive HS management plan.
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Affiliation(s)
| | - Kendra D Marr
- University of Arizona, College of Medicine, Tucson, Arizona, USA
| | | | - Kyla N Price
- University of Illinois Chicago, College of Medicine, Chicago, Illinois, USA
| | - Catherine M Ludwig
- University of Illinois Chicago, College of Medicine, Chicago, Illinois, USA
| | - Melody Maarouf
- Division of Dermatology, Department of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Jennifer L Hsiao
- Division of Dermatology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Vivian Y Shi
- Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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Asmamaw MD, Liu Y, Zheng YC, Shi XJ, Liu HM. Skp2 in the ubiquitin-proteasome system: A comprehensive review. Med Res Rev 2020; 40:1920-1949. [PMID: 32391596 DOI: 10.1002/med.21675] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 03/26/2020] [Accepted: 04/27/2020] [Indexed: 12/19/2022]
Abstract
The ubiquitin-proteasome system (UPS) is a complex process that regulates protein stability and activity by the sequential actions of E1, E2 and E3 enzymes to influence diverse aspects of eukaryotic cells. However, due to the diversity of proteins in cells, substrate selection is a highly critical part of the process. As a key player in UPS, E3 ubiquitin ligases recruit substrates for ubiquitination specifically. Among them, RING E3 ubiquitin ligases which are the most abundant E3 ubiquitin ligases contribute to diverse cellular processes. The multisubunit cullin-RING ligases (CRLs) are the largest family of RING E3 ubiquitin ligases with tremendous plasticity in substrate specificity and regulate a vast array of cellular functions. The F-box protein Skp2 is a component of CRL1 (the prototype of CRLs) which is expressed in many tissues and participates in multiple cellular functions such as cell proliferation, metabolism, and tumorigenesis by contributing to the ubiquitination and subsequent degradation of several specific tumor suppressors. Most importantly, Skp2 plays a pivotal role in a plethora of cancer-associated signaling pathways. It enhances cell growth, accelerates cell cycle progression, promotes migration and invasion, and inhibits cell apoptosis among others. Hence, targeting Skp2 may represent a novel and attractive strategy for the treatment of different human cancers overexpressing this oncogene. In this review article, we summarized the known roles of Skp2 both in health and disease states in relation to the UPS.
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Affiliation(s)
- Moges Dessale Asmamaw
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Henan Key Laboratory of Drug Quality Control & Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan, China
| | - Ying Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Henan Key Laboratory of Drug Quality Control & Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan, China
| | - Yi-Chao Zheng
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Henan Key Laboratory of Drug Quality Control & Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan, China
| | - Xiao-Jing Shi
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Henan Key Laboratory of Drug Quality Control & Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan, China
| | - Hong-Min Liu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Henan Key Laboratory of Drug Quality Control & Evaluation, School of Pharmaceutical Sciences, Zhengzhou University, Ministry of Education of China, Zhengzhou, Henan, China
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42
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Fatty liver diseases, mechanisms, and potential therapeutic plant medicines. Chin J Nat Med 2020; 18:161-168. [PMID: 32245585 DOI: 10.1016/s1875-5364(20)30017-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Indexed: 02/07/2023]
Abstract
The liver is an important metabolic organ and controls lipid, glucose and energy metabolism. Dysruption of hepatic lipid metabolism is often associated with fatty liver diseases, including nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver diseases (AFLD) and hyperlipidemia. Recent studies have uncovered the contribution of hormones, transcription factors, and inflammatory cytokines to the pathogenesis of dyslipidemia and fatty liver diseases. Moreover, a significant amount of effort has been put to examine the mechanisms underlying the potential therapeutic effects of many natural plant products on fatty liver diseases and metabolic diseases. We review the current understanding of insulin, thyroid hormone and inflammatory cytokines in regulating hepatic lipid metabolism, focusing on several essential transcription regulators, such as Sirtuins (SIRTs), Forkhead box O (FoxO), Sterol-regulatory element-binding proteins (SREBPs). We also discuss a few representative natural products with promising thereapeutic effects on fatty liver disease and dyslipidemia.
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43
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Jin X, Hapsari ND, Lee S, Jo K. DNA binding fluorescent proteins as single-molecule probes. Analyst 2020; 145:4079-4095. [DOI: 10.1039/d0an00218f] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
DNA binding fluorescent proteins are useful probes for a broad range of biological applications.
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Affiliation(s)
- Xuelin Jin
- Department of Chemistry and Interdisciplinary Program of Integrated Biotechnology
- Sogang University
- Seoul
- Republic of Korea
| | - Natalia Diyah Hapsari
- Department of Chemistry and Interdisciplinary Program of Integrated Biotechnology
- Sogang University
- Seoul
- Republic of Korea
- Chemistry Education Program
| | - Seonghyun Lee
- Department of Chemistry and Interdisciplinary Program of Integrated Biotechnology
- Sogang University
- Seoul
- Republic of Korea
| | - Kyubong Jo
- Department of Chemistry and Interdisciplinary Program of Integrated Biotechnology
- Sogang University
- Seoul
- Republic of Korea
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44
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Amaya E, Alarcón L, Martín-Tapia D, Cuellar-Pérez F, Cano-Cortina M, Ortega-Olvera JM, Cisneros B, Rodriguez AJ, Gamba G, González-Mariscal L. Activation of the Ca 2+ sensing receptor and the PKC/WNK4 downstream signaling cascade induces incorporation of ZO-2 to tight junctions and its separation from 14-3-3. Mol Biol Cell 2019; 30:2377-2398. [PMID: 31318316 PMCID: PMC6741067 DOI: 10.1091/mbc.e18-09-0591] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Zonula occludens-2 (ZO-2) is a tight junction (TJ) cytoplasmic protein, whose localization varies according to cell density and Ca2+ in the media. In cells cultured in low calcium (LC), ZO-2 displays a diffuse cytoplasmic distribution, but activation of the Ca2+ sensing receptor (CaSR) with Gd3+ triggers the appearance of ZO-2 at the cell borders. CaSR downstream signaling involves activation of protein kinase C, which phosphorylates and activates with no lysine kinase-4 that phosphorylates ZO-2 inducing its concentration at TJs. In LC, ZO-2 is protected from degradation by association to 14-3-3 proteins. When monolayers are transferred to normal calcium, the complexes ZO-2/14-3-3ζ and ZO-2/14-3-3σ move to the cell borders and dissociate. The 14-3-3 proteins are then degraded in proteosomes, whereas ZO-2 integrates to TJs. From the plasma membrane residual ZO-2 is endocyted and degradaded in lysosomes. The unique region 2 of ZO-2, and S261 located within a nuclear localization signal, are critical for the interaction with 14-3-3 ζ and σ and for the efficient nuclear importation of ZO-2. These results explain the molecular mechanism through which extracellular Ca2+ triggers the appearance of ZO-2 at TJs in epithelial cells and reveal the novel interaction between ZO-2 and 14-3-3 proteins, which is critical for ZO-2 protection and intracellular traffic.
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Affiliation(s)
- Elida Amaya
- Center for Research and Advanced Studies (Cinvestav), Department of Physiology, Biophysics and Neuroscience, Mexico City 07360, Mexico
| | - Lourdes Alarcón
- Center for Research and Advanced Studies (Cinvestav), Department of Physiology, Biophysics and Neuroscience, Mexico City 07360, Mexico
| | - Dolores Martín-Tapia
- Center for Research and Advanced Studies (Cinvestav), Department of Physiology, Biophysics and Neuroscience, Mexico City 07360, Mexico
| | - Francisco Cuellar-Pérez
- Center for Research and Advanced Studies (Cinvestav), Department of Physiology, Biophysics and Neuroscience, Mexico City 07360, Mexico
| | - Misael Cano-Cortina
- Center for Research and Advanced Studies (Cinvestav), Department of Physiology, Biophysics and Neuroscience, Mexico City 07360, Mexico
| | - Jose Mario Ortega-Olvera
- Center for Research and Advanced Studies (Cinvestav), Department of Physiology, Biophysics and Neuroscience, Mexico City 07360, Mexico
| | - Bulmaro Cisneros
- Department of Genetics and Molecular Biology, Mexico City 07360, Mexico
| | - Alexis J Rodriguez
- Department of Biological Science, Rutgers, The State University of New Jersey, Newark, NJ 07102
| | - Gerardo Gamba
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, México.,Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico.,Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, 64710 Monterrey, Nuevo Leon, México
| | - Lorenza González-Mariscal
- Center for Research and Advanced Studies (Cinvestav), Department of Physiology, Biophysics and Neuroscience, Mexico City 07360, Mexico
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Chen J, Lu Y, Tian M, Huang Q. Molecular mechanisms of FOXO1 in adipocyte differentiation. J Mol Endocrinol 2019; 62:R239-R253. [PMID: 30780132 DOI: 10.1530/jme-18-0178] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 02/05/2019] [Indexed: 12/14/2022]
Abstract
Forkhead box-O1 (FOXO1) is a downstream target of AKT and plays crucial roles in cell cycle control, apoptosis, metabolism and adipocyte differentiation. It is thought that FOXO1 affects adipocyte differentiation by regulating lipogenesis and cell cycle. With the deepening in the understanding of this field, it is currently believed that FOXO1 translocation between nuclei and cytoplasm is involved in the regulation of FOXO1 activity, thus affecting adipocyte differentiation. Translocation of FOXO1 depends on its post-translational modifications and interactions with 14-3-3. Based on these modifications and interactions, FOXO1 could regulate lipogenesis through PPARγ and the adipocyte cell cycle through p21 and p27. In this review, we aim to provide a comprehensive FOXO1 regulation network in adipocyte differentiation by linking together distinct functions mentioned above to explain their effects on adipocyte differentiation and to emphasize the regulatory role of FOXO1. In addition, we also focus on the novel findings such as the use of miRNAs in FOXO1 regulation and highlight the improvable issues, such as RNA modifications, for future research in the field.
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Affiliation(s)
- Junye Chen
- Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
- Nanchang Joint Programme, Queen Mary, University of London, London, UK
| | - Yi Lu
- Key Provincial Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
- Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
| | - Mengyuan Tian
- Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
- Nanchang Joint Programme, Queen Mary, University of London, London, UK
| | - Qiren Huang
- Key Provincial Laboratory of Basic Pharmacology, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
- Department of Pharmacology, School of Pharmacy, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
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Yan H, Yang W, Zhou F, Li X, Pan Q, Shen Z, Han G, Newell-Fugate A, Tian Y, Majeti R, Liu W, Xu Y, Wu C, Allred K, Allred C, Sun Y, Guo S. Estrogen Improves Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1. Diabetes 2019; 68:291-304. [PMID: 30487265 PMCID: PMC6341301 DOI: 10.2337/db18-0638] [Citation(s) in RCA: 171] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 11/03/2018] [Indexed: 12/18/2022]
Abstract
Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes (T2D) compared with age-matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17β-estradiol (E2). Fasting hyperglycemia is a hallmark of T2D derived largely from dysregulation of hepatic glucose production (HGP), in which Foxo1 plays a central role in the regulation of gluconeogenesis. Here, we investigated the action of E2 on glucose homeostasis in male and ovariectomized (OVX) female control and liver-specific Foxo1 knockout (L-F1KO) mice and sought to understand the mechanism by which E2 regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E2 implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E2 were abolished in L-F1KO mice of both sexes. In our use of mouse primary hepatocytes, E2 suppressed HGP and gluconeogenesis in hepatocytes from control mice but failed in hepatocytes from L-F1KO mice, suggesting that Foxo1 is required for E2 action on the suppression of gluconeogenesis. We further demonstrated that E2 suppresses hepatic gluconeogenesis through activation of estrogen receptor (ER)α-phosphoinositide 3-kinase-Akt-Foxo1 signaling, which can be independent of insulin receptor substrates 1 and 2 (Irs1 and Irs2), revealing an important mechanism for E2 in the regulation of glucose homeostasis. These results may help explain why premenopausal women have lower incidence of T2D than age-matched men and suggest that targeting ERα can be a potential approach to modulate glucose metabolism and prevent diabetes.
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Affiliation(s)
- Hui Yan
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Wangbao Yang
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Fenghua Zhou
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Xiaopeng Li
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Quan Pan
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Zheng Shen
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Guichun Han
- Department of Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX
| | - Annie Newell-Fugate
- Department of Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX
| | - Yanan Tian
- Department of Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX
| | - Ravikumar Majeti
- Department of Pharmaceutical Sciences, College of Pharmacy, Texas A&M University, College Station, TX
| | - Wenshe Liu
- Department of Chemistry, Texas A&M University, College Station, TX
| | - Yong Xu
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - Chaodong Wu
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Kimberly Allred
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Clinton Allred
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Yuxiang Sun
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
| | - Shaodong Guo
- Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX
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El Ouaamari A, O-Sullivan I, Shirakawa J, Basile G, Zhang W, Roger S, Thomou T, Xu S, Qiang G, Liew CW, Kulkarni RN, Unterman TG. Forkhead box protein O1 (FoxO1) regulates hepatic serine protease inhibitor B1 (serpinB1) expression in a non-cell-autonomous fashion. J Biol Chem 2018; 294:1059-1069. [PMID: 30459233 DOI: 10.1074/jbc.ra118.006031] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/15/2018] [Indexed: 12/13/2022] Open
Abstract
FoxO proteins are major targets of insulin action, and FoxO1 mediates the effects of insulin on hepatic glucose metabolism. We reported previously that serpinB1 is a liver-secreted factor (hepatokine) that promotes adaptive β-cell proliferation in response to insulin resistance in the liver-specific insulin receptor knockout (LIRKO) mouse. Here we report that FoxO1 plays a critical role in promoting serpinB1 expression in hepatic insulin resistance in a non-cell-autonomous manner. Mice lacking both the insulin receptor and FoxO1 (LIRFKO) exhibit reduced β-cell mass compared with LIRKO mice because of attenuation of β-cell proliferation. Although hepatic expression of serpinB1 mRNA and protein levels was increased in LIRKO mice, both the mRNA and protein levels returned to control levels in LIRFKO mice. Furthermore, liver-specific expression of constitutively active FoxO1 in transgenic mice induced an increase in hepatic serpinB1 mRNA and protein levels in refed mice. Conversely, serpinB1 mRNA and protein levels were reduced in mice lacking FoxO proteins in the liver. ChIP studies demonstrated that FoxO1 binds to three distinct sites located ∼9 kb upstream of the serpinb1 gene in primary mouse hepatocytes and that this binding is enhanced in hepatocytes from LIRKO mice. However, adenoviral expression of WT or constitutively active FoxO1 and insulin treatment are sufficient to regulate other FoxO1 target genes (IGFBP-1 and PEPCK) but not serpinB1 expression in mouse primary hepatocytes. These results indicate that liver FoxO1 promotes serpinB1 expression in hepatic insulin resistance and that non-cell-autonomous factors contribute to FoxO1-dependent effects on serpinB1 expression in the liver.
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Affiliation(s)
- Abdelfattah El Ouaamari
- From the Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02215
| | - InSug O-Sullivan
- the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois, Chicago, Illinois 60612.,the Medical Research Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
| | - Jun Shirakawa
- From the Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02215
| | - Giorgio Basile
- From the Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02215
| | - Wenwei Zhang
- the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois, Chicago, Illinois 60612.,the Medical Research Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
| | - Sandra Roger
- From the Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02215
| | - Thomas Thomou
- the Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, and
| | - Shanshan Xu
- the Department of Physiology and Biophysics, College of Medicine, University of Illinois, Chicago, Illinois 60612
| | - Guifen Qiang
- the Department of Physiology and Biophysics, College of Medicine, University of Illinois, Chicago, Illinois 60612
| | - Chong Wee Liew
- the Department of Physiology and Biophysics, College of Medicine, University of Illinois, Chicago, Illinois 60612
| | - Rohit N Kulkarni
- From the Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Harvard Stem Cell Institute, Boston, Massachusetts 02215,
| | - Terry G Unterman
- the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois, Chicago, Illinois 60612, .,the Medical Research Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
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48
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Mathematical Modeling of Nuclear Trafficking of FOXO Transcription Factors. Methods Mol Biol 2018. [PMID: 30414156 DOI: 10.1007/978-1-4939-8900-3_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023]
Abstract
Nuclear cytoplasmic flux of Foxo transcription factors is paramount in cellular gene regulation. For example, excluding Foxo from skeletal muscle nuclei is necessary to avoid muscle wasting through elevated protein breakdown. Constructing a mathematical model of the signaling process leading to alteration of Foxo nuclear cytoplasm ratio is useful in predicting and interpreting such ratio changes. In this chapter we derive a general mathematical model for nuclear cytoplasmic flux. We apply this model to Foxo flux and take advantage of rapid phosphorylation approximation and conservation conditions to reduce the Foxo flux model. We constrain our model with data from mouse skeletal muscle with applied IGF. This procedure provides an example of what might be called the central approach of mathematical modeling: The cycling of a biological question through mathematical formulation and back to biological interpretation.
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49
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Leptin Signaling in the Control of Metabolism and Appetite: Lessons from Animal Models. J Mol Neurosci 2018; 66:390-402. [PMID: 30284225 DOI: 10.1007/s12031-018-1185-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 09/24/2018] [Indexed: 12/15/2022]
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50
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Nuclear trapping of inactive FOXO1 by the Nrf2 activator diethyl maleate. Redox Biol 2018; 20:19-27. [PMID: 30261343 PMCID: PMC6156746 DOI: 10.1016/j.redox.2018.09.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 09/13/2018] [Indexed: 12/18/2022] Open
Abstract
Diethyl maleate (DEM), a thiol-reactive α,β-unsaturated carbonyl compound, depletes glutathione (GSH) in exposed cells and was previously shown by us to elicit a stress response in Caenorhabditis elegans that, at lower concentrations, results in enhanced stress resistance and longer lifespan. This hormetic response was mediated through both the Nrf2 ortholog, SKN-1, and the forkhead box O (FOXO) family transcription factor DAF-16. As FOXO signaling is evolutionarily conserved, we analyzed here the effects of DEM exposure on FOXO in cultured human cells (HepG2, HEK293). DEM elicited nuclear accumulation of GFP-coupled wild-type human FOXO1, as well as of a cysteine-deficient FOXO1 mutant. Despite the nuclear accumulation of FOXO1, neither FOXO1 DNA binding nor FOXO target gene expression were stimulated, suggesting that DEM causes nuclear accumulation but not activation of FOXO1. FOXO1 nuclear exclusion elicited by insulin or xenobiotics such as arsenite or copper ions was attenuated by DEM, suggesting that DEM interfered with nuclear export. In addition, insulin-induced FOXO1 phosphorylation at Thr-24, which is associated with FOXO1 nuclear exclusion, was attenuated upon exposure to DEM. Different from FOXO-dependent expression of genes, Nrf2 target gene mRNAs were elevated upon exposure to DEM. These data suggest that, different from C. elegans, DEM elicits opposing effects on the two stress-responsive transcription factors, Nrf2 and FOXO1, in cultured human cells.
Diethyl maleate (DEM) causes FOXO1 nuclear accumulation in HepG2 or HEK293 cells. DEM also elicits nuclear accumulation of the FOXO-ortholog, DAF-16, in C. elegans. Nevertheless, DEM does not elicit expression of FOXO, but of Nrf2 target genes. Insulin-induced FOXO1 phosphorylation and nuclear exclusion are attenuated by DEM. Nuclear accumulation of FOXO1 is due to interference with nuclear export machinery.
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