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Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, Gao Z, Liu D, He W, Yang LL. Energy metabolism in health and diseases. Signal Transduct Target Ther 2025; 10:69. [PMID: 39966374 PMCID: PMC11836267 DOI: 10.1038/s41392-025-02141-x] [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: 08/12/2024] [Revised: 11/08/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Abstract
Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Hui Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuo Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhua Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Guo
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujing Song
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Fu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenjie Gao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Wei He
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Lei-Lei Yang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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Mocholi E, Corrigan E, Chalkiadakis T, Gulersonmez C, Stigter E, Vastert B, van Loosdregt J, Prekovic S, Coffer PJ. Glycolytic reprogramming shapes the histone acetylation profile of activated CD4 + T cells in juvenile idiopathic arthritis. Cell Rep 2025; 44:115287. [PMID: 40009514 DOI: 10.1016/j.celrep.2025.115287] [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: 02/27/2024] [Revised: 11/11/2024] [Accepted: 01/17/2025] [Indexed: 02/28/2025] Open
Abstract
Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by accumulation of activated CD4+ T cells in the synovial fluid (SF) of affected joints. JIA CD4+ T cells exhibit a unique inflammation-associated epigenomic signature, but the underlying mechanisms remain unclear. We demonstrate that CD4+ T cells from JIA SF display heightened glycolysis upon activation and JIA-specific H3K27 acetylation, driving transcriptional reprogramming. Pharmacological inhibition of glycolysis altered the expression of genes associated with these acetylated regions. Healthy CD4+ T cells exposed to JIA SF exhibited increased glycolytic activity and transcriptomic changes marked by heightened histone 3 lysine 27 acetylation (H3K27ac) at JIA-specific genes. Elevated H3K27ac was dependent on glycolytic flux, while inhibiting glycolysis or pyruvate dehydrogenase (PDH) impaired transcription of SF-driven genes. These findings demonstrate a key role of glycolysis in JIA-specific gene expression, offering potential therapeutic targets for modulating inflammation in JIA.
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Affiliation(s)
- Enric Mocholi
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands.
| | - Edward Corrigan
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Theo Chalkiadakis
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Can Gulersonmez
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Edwin Stigter
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Bas Vastert
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; Division of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Jorg van Loosdregt
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Stefan Prekovic
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Paul J Coffer
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands.
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3
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Zambrano Zambrano A, Del Río Zanatta H, González Espinoza A, Bernal Alferes B, Zambrano Zambrano K, Martinez Salazar J, Ixcamparij Rosales CH. Heart Failure in Rheumatoid Arthritis: Clinical Implications. Curr Heart Fail Rep 2024; 21:530-540. [PMID: 39287753 DOI: 10.1007/s11897-024-00682-w] [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] [Accepted: 09/04/2024] [Indexed: 09/19/2024]
Abstract
PURPOSE OF REVIEW This review focuses on the association between RA and heart failure, highlighting the role of inflammation and the prevalence of heart failure with preserved ejection fraction (HFpEF) in this population. RECENT FINDINGS The incidence of heart failure in RA patients is two to three times higher than in the general population, with inflammation playing a significant role independent of traditional cardiovascular risk factors. HFpEF accounts for about half of heart failure cases and is increasingly recognized in RA patients, although it remains underdiagnosed. Atypical presentations and non-specific symptoms further complicate diagnosis. Early control of inflammation has been shown to reduce the risk of heart failure development and progression, improving both morbidity and mortality outcomes. Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting approximately 1% of the population, with cardiovascular disease being the leading cause of premature death in these patients.
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Affiliation(s)
- Alexis Zambrano Zambrano
- Department of Internal Medicine, National Medical Center 20 de Noviembre ISSSTEFelix Cuevas, 540, Del Valle, Benito Juárez, Mexico City, 03104, Mexico.
| | - Hector Del Río Zanatta
- Department of Internal Medicine, National Medical Center 20 de Noviembre ISSSTEFelix Cuevas, 540, Del Valle, Benito Juárez, Mexico City, 03104, Mexico
| | - Andrea González Espinoza
- Department of Ophthalmology, Regional Hospital Lic. Adolfo López Mateos ISSSTE, Mexico City, Mexico
| | - Brian Bernal Alferes
- Department of Internal Medicine, National Medical Center 20 de Noviembre ISSSTEFelix Cuevas, 540, Del Valle, Benito Juárez, Mexico City, 03104, Mexico
| | - Kevin Zambrano Zambrano
- Department of Internal Medicine, National Medical Center 20 de Noviembre ISSSTEFelix Cuevas, 540, Del Valle, Benito Juárez, Mexico City, 03104, Mexico
| | - Julio Martinez Salazar
- Department of Internal Medicine, National Medical Center 20 de Noviembre ISSSTEFelix Cuevas, 540, Del Valle, Benito Juárez, Mexico City, 03104, Mexico
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Gan PR, Wu H, Zhu YL, Shu Y, Wei Y. Glycolysis, a driving force of rheumatoid arthritis. Int Immunopharmacol 2024; 132:111913. [PMID: 38603855 DOI: 10.1016/j.intimp.2024.111913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/12/2024] [Accepted: 03/20/2024] [Indexed: 04/13/2024]
Abstract
Resident synoviocytes and synovial microvasculature, together with immune cells from circulation, contribute to pannus formation, the main pathological feature of rheumatoid arthritis (RA), leading to destruction of adjacent cartilage and bone. Seeds, fibroblast-like synoviocytes (FLSs), macrophages, dendritic cells (DCs), B cells, T cells and endothelial cells (ECs) seeds with high metabolic demands undergo metabolic reprogramming from oxidative phosphorylation to glycolysis in response to poor soil of RA synovium with hypoxia, nutrient deficiency and inflammatory stimuli. Glycolysis provides rapid energy supply and biosynthetic precursors to support pathogenic growth of these seeds. The metabolite lactate accumulated during this process in turn condition the soil microenvironment and affect seeds growth by modulating signalling pathways and directing lactylation modifications. This review explores in depth the survival mechanism of seeds with high metabolic demands in the poor soil of RA synovium, providing useful support for elucidating the etiology of RA. In addition, we discuss the role and major post-translational modifications of proteins and enzymes linked to glycolysis to inspire the discovery of novel anti-rheumatic targets.
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Affiliation(s)
- Pei-Rong Gan
- College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China
| | - Hong Wu
- College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China.
| | - Yu-Long Zhu
- College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China
| | - Yin Shu
- College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China
| | - Yi Wei
- College of Pharmacy, Anhui University of Chinese Medicine, Qian Jiang Road 1, Hefei 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei 230012, China; Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, 230012, China
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Luo TT, Wu YJ, Yin Q, Chen WG, Zuo J. The Involvement of Glucose and Lipid Metabolism Alteration in Rheumatoid Arthritis and Its Clinical Implication. J Inflamm Res 2023; 16:1837-1852. [PMID: 37131409 PMCID: PMC10149064 DOI: 10.2147/jir.s398291] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 04/19/2023] [Indexed: 05/04/2023] Open
Abstract
Obviously, immune cells like T cells and macrophages play a major role in rheumatoid arthritis (RA). On one hand, the breakdown of immune homeostasis directly induces systemic inflammation; on the other hand, these cells initiate and perpetuate synovitis and tissue damages through the interaction with fibroblast-like synoviocytes (FLS). In recent years, the pathological link between metabolic disorders and immune imbalance has received increasing attention. High energy demand of immune cells leads to the accumulation of metabolic byproducts and inflammatory mediators. They act on various metabolism-sensitive signal pathways as well as relevant transcription factors, such as HIF-1α, and STATs. These molecular events will impact RA-related effectors like circulating immune cells and joint-resident cells in return, allowing the continuous progression of systemic inflammation, arthritic manifestations, and life-threatening complications. In other words, metabolic complications are secondary pathological factors for the progression of RA. Therefore, the status of energy metabolism may be an important indicator to evaluate RA severity, and in-depth explorations of the mechanisms underlying the mystery of how RA-related metabolic disorders develop will provide useful clues to further clarify the etiology of RA, and inspire the discovery of new anti-rheumatic targets. This article reviews the latest research progress on the interactions between immune and metabolism systems in the context of RA. Great importance is attached to the changes in certain pathways controlling both immune and metabolism functions during RA progression.
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Affiliation(s)
- Ting-Ting Luo
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
- Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Yi-Jin Wu
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
- Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Qin Yin
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Wen-Gang Chen
- Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
| | - Jian Zuo
- Xin’an Medical Research Center, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241000, People’s Republic of China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, 241000, People’s Republic of China
- Correspondence: Jian Zuo, Email
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Tsaltskan V, Firestein GS. Targeting fibroblast-like synoviocytes in rheumatoid arthritis. Curr Opin Pharmacol 2022; 67:102304. [PMID: 36228471 PMCID: PMC9942784 DOI: 10.1016/j.coph.2022.102304] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 09/07/2022] [Indexed: 01/30/2023]
Abstract
Fibroblast-like synoviocytes (FLS) are mesenchymal-derived cells that play an important role in the physiology of the synovium by producing certain components of the synovial fluid and articular cartilage. In rheumatoid arthritis (RA), however, fibroblasts become a key driver of synovial inflammation and joint damage. Because of this, there has been recent interest in FLS as a therapeutic target in RA to avoid side effects such as systemic immune suppression associated with many existing RA treatments. In this review, we describe how approved treatments for RA affect FLS signaling and function and discuss the effects of investigational FLS-targeted drugs for RA.
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Affiliation(s)
- Vladislav Tsaltskan
- Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA, USA
| | - Gary S Firestein
- Division of Rheumatology, Allergy and Immunology, University of California, San Diego School of Medicine, La Jolla, CA, USA.
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7
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Song B, Shen S, Fu S, Fu J. HSPA6 and its role in cancers and other diseases. Mol Biol Rep 2022; 49:10565-10577. [PMID: 35666422 DOI: 10.1007/s11033-022-07641-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/25/2022] [Indexed: 12/13/2022]
Abstract
Heat Shock Protein Family A (Hsp70) Member 6 (HSPA6) (Online Mendelian Inheritance in Man: 140555) belongs to the HSP70 family and is a partially conserved inducible protein in mammals. The HSPA6 gene locates on the human chromosome 1q23.3 and encodes a protein containing two important structural domains: The N-terminal nucleotide-binding domain and the C-terminal substrate-binding domain. Currently, studies have found that HSPA6 not only plays a role in the tumorigenesis and tumor progresses but also causes non-tumor-related diseases. Furthermore, HSPA6 exhibits to inhibit tumorigenesis and tumor progression in some types of cancers but promotes in others. Even though HSPA6 research has increased, its exact roles and mechanisms are still unclear. This article reviews the structure, expression, function, research progress, possible mechanism, and perspective of HSPA6 in cancers and other diseases, highlighting its potential role as a targeted therapeutic and prognostic marker.
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Affiliation(s)
- Binghui Song
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Shiyi Shen
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Shangyi Fu
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
- School of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Junjiang Fu
- Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, 646000, Sichuan, China.
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8
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Dorgau B, Georgiou M, Chaudhary A, Moya-Molina M, Collin J, Queen R, Hilgen G, Davey T, Hewitt P, Schmitt M, Kustermann S, Pognan F, Steel DH, Sernagor E, Armstrong L, Lako M. Human Retinal Organoids Provide a Suitable Tool for Toxicological Investigations: A Comprehensive Validation Using Drugs and Compounds Affecting the Retina. Stem Cells Transl Med 2022; 11:159-177. [PMID: 35298655 PMCID: PMC8929478 DOI: 10.1093/stcltm/szab010] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/13/2021] [Indexed: 12/04/2022] Open
Abstract
Retinal drug toxicity screening is essential for the development of safe treatment strategies for a large number of diseases. To this end, retinal organoids derived from human pluripotent stem cells (hPSCs) provide a suitable screening platform due to their similarity to the human retina and the ease of generation in large-scale formats. In this study, two hPSC cell lines were differentiated to retinal organoids, which comprised all key retinal cell types in multiple nuclear and synaptic layers. Single-cell RNA-Seq of retinal organoids indicated the maintenance of retinal ganglion cells and development of bipolar cells: both cell types segregated into several subtypes. Ketorolac, digoxin, thioridazine, sildenafil, ethanol, and methanol were selected as key compounds to screen on retinal organoids because of their well-known retinal toxicity profile described in the literature. Exposure of the hPSC-derived retinal organoids to digoxin, thioridazine, and sildenafil resulted in photoreceptor cell death, while digoxin and thioridazine additionally affected all other cell types, including Müller glia cells. All drug treatments caused activation of astrocytes, indicated by dendrites sprouting into neuroepithelium. The ability to respond to light was preserved in organoids although the number of responsive retinal ganglion cells decreased after drug exposure. These data indicate similar drug effects in organoids to those reported in in vivo models and/or in humans, thus providing the first robust experimental evidence of their suitability for toxicological studies.
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Affiliation(s)
- Birthe Dorgau
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
- Newcells Biotech, Biosphere, Newcastle Helix, Newcastle upon Tyne, UK
| | - Maria Georgiou
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
| | - Alexander Chaudhary
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
| | - Marina Moya-Molina
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
- Newcells Biotech, Biosphere, Newcastle Helix, Newcastle upon Tyne, UK
| | - Joseph Collin
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
| | - Rachel Queen
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
| | - Gerrit Hilgen
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
- Northumbria University, Applied Sciences, Faculty of Health and Life Science, Newcastle upon Tyne, UK
| | - Tracey Davey
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
- Electron Microscopy Research Services, Newcastle University, Newcastle upon Tyne, UK
| | | | | | - Stefan Kustermann
- Pharmaceutical Sciences, F. Hoffmann-La Roche, Pharma Research and Early Development, Roche Innovation Center Basel, Switzerland
| | | | - David H Steel
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
| | - Evelyne Sernagor
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
| | - Lyle Armstrong
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
- Newcells Biotech, Biosphere, Newcastle Helix, Newcastle upon Tyne, UK
| | - Majlinda Lako
- Newcastle University, Biosciences Institute, Faculty of Medical Sciences, Newcastle upon Tyne, UK
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Umar S, Palasiewicz K, Volin MV, Romay B, Rahat R, Tetali C, Arami S, Guma M, Ascoli C, Sweiss N, Zomorrodi RK, O'Neill LAJ, Shahrara S. Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types. Cell Mol Life Sci 2021; 78:7693-7707. [PMID: 34705053 PMCID: PMC8739866 DOI: 10.1007/s00018-021-03978-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 09/10/2021] [Accepted: 10/13/2021] [Indexed: 11/29/2022]
Abstract
Recent studies have shown the significance of metabolic reprogramming in immune and stromal cell function. Yet, the metabolic reconfiguration of RA macrophages (MΦs) is incompletely understood during active disease and in crosstalk with other cell types in experimental arthritis. This study elucidates a distinct regulation of glycolysis and oxidative phosphorylation in RA MΦs compared to fibroblast (FLS), although PPP (Pentose Phosphate pathway) is similarly reconfigured in both cell types. 2-DG treatment showed a more robust impact on impairing the RA M1 MΦ-mediated inflammatory phenotype than IACS-010759 (IACS, complexli), by reversing ERK, AKT and STAT1 signaling, IRF8/3 transcription and CCL2 or CCL5 secretion. This broader inhibitory effect of 2-DG therapy on RA M1 MΦs was linked to dysregulation of glycolysis (GLUT1, PFKFB3, LDHA, lactate) and oxidative PPP (NADP conversion to NADPH), while both compounds were ineffective on oxidative phosphorylation. Distinctly, in RA FLS, 2-DG and IACS therapies constrained LPS/IFNγ-induced AKT and JNK signaling, IRF5/7 and fibrokine expression. Disruption of RA FLS metabolic rewiring by 2-DG or IACS therapy was accompanied by a reduction of glycolysis (HIF1α, PFKFB3) and suppression of citrate or succinate buildup. We found that 2-DG therapy mitigated CIA pathology by intercepting joint F480+iNOS+MΦ, Vimentin+ fibroblast and CD3+T cell trafficking along with downregulation of IRFs and glycolytic intermediates. Surprisingly, IACS treatment was inconsequential on CIA swelling, cell infiltration, M1 and Th1/Th17 cytokines (IFN-γ/IL-17) and joint glycolytic mediators. Collectively, our results indicate that blockade of glycolysis is more effective than inhibition of complex 1 in CIA, in part due to its effectiveness on the MΦ inflammatory phenotype.
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Affiliation(s)
- Sadiq Umar
- Jesse Brown VA Medical Center, Chicago, IL, USA
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, 840 S Wood Street, CSB suite 1114, Chicago, IL, 60612, USA
| | - Karol Palasiewicz
- Jesse Brown VA Medical Center, Chicago, IL, USA
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, 840 S Wood Street, CSB suite 1114, Chicago, IL, 60612, USA
| | - Michael V Volin
- Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL, USA
| | - Bianca Romay
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, 840 S Wood Street, CSB suite 1114, Chicago, IL, 60612, USA
| | - Rani Rahat
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, 840 S Wood Street, CSB suite 1114, Chicago, IL, 60612, USA
| | - Chandana Tetali
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, 840 S Wood Street, CSB suite 1114, Chicago, IL, 60612, USA
| | - Shiva Arami
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, 840 S Wood Street, CSB suite 1114, Chicago, IL, 60612, USA
| | - Monica Guma
- Division of Rheumatology, Allergy and Immunology, San Diego, School of Medicine, University of California, La Jolla, CA, USA
- VA Medical Center, San Diego, CA, USA
| | - Christian Ascoli
- Division of Pulmonary, Critical Care, Sleep, and Allergy, The University of Illinois at Chicago, Chicago, IL, USA
| | - Nadera Sweiss
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, 840 S Wood Street, CSB suite 1114, Chicago, IL, 60612, USA
| | - Ryan K Zomorrodi
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, 840 S Wood Street, CSB suite 1114, Chicago, IL, 60612, USA
| | - Luke A J O'Neill
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Shiva Shahrara
- Jesse Brown VA Medical Center, Chicago, IL, USA.
- Department of Medicine, Division of Rheumatology, The University of Illinois at Chicago, 840 S Wood Street, CSB suite 1114, Chicago, IL, 60612, USA.
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10
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Li J, Zhang Y, Kang YJ, Ma N. Effect of family caregiver nursing education on patients with rheumatoid arthritis and its impact factors: A randomized controlled trial. World J Clin Cases 2021; 9:8413-8424. [PMID: 34754850 PMCID: PMC8554439 DOI: 10.12998/wjcc.v9.i28.8413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/12/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is a common autoimmune disease. Nursing education for family caregivers is considered a workable and effective intervention, but the validity of this intervention in RA has not been reported.
AIM To explore whether family caregiver nursing education (FCNE) works on patients with RA and the factors that influence FCNE.
METHODS In this randomized controlled study, a sample of 158 pairs was included in the study with 80 in the intervention group and 78 in the control group. Baseline data of patients and caregivers was collected. The FCNE intervention was administered to caregivers, and inflammation level indicators, disease activity indicators and mood disorder indicators of patients were followed up and analyzed.
RESULTS Baseline characteristics of the intervention and the control groups had no significant difference. Indicators were significantly reduced in the intervention group compared to the control group. The intervention group showed significant differences in stratification of relationship, education duration and age.
CONCLUSION The effect of FCNE on RA is multifaceted, weakening inflammation level, alleviating disease activity and relieving mood disorder. Relationship between caregiver and patient, caregiver’s education level and patient’s age may act as impact factors of FCNE.
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Affiliation(s)
- Jing Li
- Department of Immunology and Rheumatology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
| | - Ying Zhang
- Department of Immunology and Rheumatology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
| | - Ya-Juan Kang
- Department of Immunology and Rheumatology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
| | - Nan Ma
- Department of Immunology and Rheumatology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
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Puentes-Osorio Y, Amariles P, Calleja MÁ, Merino V, Díaz-Coronado JC, Taborda D. Potential clinical biomarkers in rheumatoid arthritis with an omic approach. AUTOIMMUNITY HIGHLIGHTS 2021; 12:9. [PMID: 34059137 PMCID: PMC8165788 DOI: 10.1186/s13317-021-00152-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/18/2021] [Indexed: 12/29/2022]
Abstract
Objective To aid in the selection of the most suitable therapeutic option in patients with diagnosis of rheumatoid arthritis according to the phase of disease, through the review of articles that identify omics biological markers. Methods A systematic review in PubMed/Medline databases was performed. We searched articles from August 2014 to September 2019, in English and Spanish, filtered by title and full text; and using the terms "Biomarkers" AND “Rheumatoid arthritis". Results This article supplies an exhaustive review from research of objective measurement, omics biomarkers and how disease activity appraise decrease unpredictability in treatment determinations, and finally, economic, and clinical outcomes of treatment options by biomarkers’ potential influence. A total of 122 articles were included. Only 92 met the established criteria for review purposes and 17 relevant references about the topic were included as well. Therefore, it was possible to identify 196 potential clinical biomarkers: 22 non-omics, 20 epigenomics, 33 genomics, 21 transcriptomics, 78 proteomics, 4 glycomics, 1 lipidomics and 17 metabolomics. Conclusion A biomarker is a measurable indicator of some, biochemical, physiological, or morphological condition; evaluable at a molecular, biochemical, or cellular level. Biomarkers work as indicators of physiological or pathological processes, or as a result of a therapeutic management. In the last five years, new biomarkers have been identified, especially the omics, which are those that proceed from the investigation of genes (genomics), metabolites (metabolomics), and proteins (proteomics). These biomarkers contribute to the physician choosing the best therapeutic option in patients with rheumatoid arthritis.
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12
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Wang S, Xu J, Guo Y, Cai Y, Ren X, Zhu W, Geng M, Meng L, Jiang C, Lu S. MicroRNA-497 Reduction and Increase of Its Family Member MicroRNA-424 Lead to Dysregulation of Multiple Inflammation Related Genes in Synovial Fibroblasts With Rheumatoid Arthritis. Front Immunol 2021; 12:619392. [PMID: 33841401 PMCID: PMC8034293 DOI: 10.3389/fimmu.2021.619392] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/10/2021] [Indexed: 01/26/2023] Open
Abstract
Objectives Mounting evidence has demonstrated that microRNAs (miRNAs) participate in rheumatoid arthritis (RA). The role of highly conserved miR-15/107 family in RA has not been clarified yet, and hence investigated in this study. Methods Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression of miRNAs and genes. Cell counting kit 8 (CCK-8) and FACS were used to detect proliferation and apoptosis. Protein expression was detected by using Western blotting. mRNA deep sequencing and cytokine antibody array were used to analyze differentially expressed genes, signaling pathways and cytokines. Results The expression of miR-15a, miR-103, miR-497, and miR-646 was found decreased, while miR-424 increased in RA patients. MiR-424 and miR-497 were further investigated and the results showed that they could regulate the expression of multiple genes in rheumatoid arthritis synovial fibroblast (RASF) and affect signaling pathways. At the protein level, miR-497 mimic altered all the selected inflammation-related genes while miR-424 inhibitor only affected part of genes. MiR-497 mimic, rather than miR-424 inhibitor, had significant effects on proliferation and apoptosis of RASF. DICER1 was found to positively regulate the expression of miR-424 and miR-497, while DICER1 was also negatively regulated by miR-424. The increase of miR-424 could reduce miR-497 expression, thus forming a loop, which facilitated explaining the dysregulated miR-424 and miR-497 in RA. Conclusion The miR-424 and miR-497 of miR-15/107 family affect cell proliferation and apoptosis in RA, and the proposed miR-424-DICER1-miR-497 feedback loop provides a novel insight into regulating miRNA expression and a candidate target for controlling RA.
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Affiliation(s)
- Si Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Institute of Molecular and Translational Medicine (IMTM), Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Jing Xu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Institute of Molecular and Translational Medicine (IMTM), Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Yuanxu Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Institute of Molecular and Translational Medicine (IMTM), Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Yongsong Cai
- Department of Joint Surgery, Xi'an Hong Hui Hospital, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Xiaoyu Ren
- Department of Joint Surgery, Xi'an Hong Hui Hospital, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Wenhua Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Institute of Molecular and Translational Medicine (IMTM), Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Manman Geng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Institute of Molecular and Translational Medicine (IMTM), Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Liesu Meng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Institute of Molecular and Translational Medicine (IMTM), Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Congshan Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Institute of Molecular and Translational Medicine (IMTM), Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
| | - Shemin Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Institute of Molecular and Translational Medicine (IMTM), Xi'an Jiaotong University Health Science Center, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, China
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13
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Metabolic reprogramming as a key regulator in the pathogenesis of rheumatoid arthritis. Inflamm Res 2020; 69:1087-1101. [DOI: 10.1007/s00011-020-01391-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/02/2020] [Accepted: 08/05/2020] [Indexed: 02/07/2023] Open
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14
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de Oliveira PG, Farinon M, Sanchez-Lopez E, Miyamoto S, Guma M. Fibroblast-Like Synoviocytes Glucose Metabolism as a Therapeutic Target in Rheumatoid Arthritis. Front Immunol 2019; 10:1743. [PMID: 31428089 PMCID: PMC6688519 DOI: 10.3389/fimmu.2019.01743] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 07/10/2019] [Indexed: 12/29/2022] Open
Abstract
Metabolomic studies show that rheumatoid arthritis (RA) is associated with metabolic disruption that may be therapeutically targetable. Among them, glucose metabolism and glycolytic intermediaries seem to have an important role in fibroblast-like synoviocytes (FLS) phenotype and might contribute to early stage disease pathogenesis. RA FLS are transformed from quiescent to aggressive and metabolically active cells and several works have shown that glucose metabolism is increased in activated FLS. Glycolytic inhibitors reduce not only FLS aggressive phenotype in vitro but also decrease bone and cartilage damage in several murine models of arthritis. Essential glycolytic enzymes, including hexokinase 2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) enzymes, have important roles in FLS behavior. Of interest, HK2 is an inducible enzyme present only in the inflamed rheumatic tissues compared to osteoarthritis synovium. It is a contributor to glucose metabolism that could be selectively targeted without compromising systemic homeostasis as a novel approach for combination therapy independent of systemic immunosuppression. More information about metabolic targets that do not compromise global glucose metabolism in normal cells is needed.
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Affiliation(s)
| | - Mirian Farinon
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Elsa Sanchez-Lopez
- Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Shigeki Miyamoto
- Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Monica Guma
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, United States
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15
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Widdifield J. Preventing Rheumatoid Arthritis: A Global Challenge. Clin Ther 2019; 41:1355-1365. [DOI: 10.1016/j.clinthera.2019.04.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 03/08/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023]
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Can Metabolic Pathways Be Therapeutic Targets in Rheumatoid Arthritis? J Clin Med 2019; 8:jcm8050753. [PMID: 31137815 PMCID: PMC6572063 DOI: 10.3390/jcm8050753] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/05/2019] [Accepted: 05/20/2019] [Indexed: 12/18/2022] Open
Abstract
The metabolic rewiring of tumor cells and immune cells has been viewed as a promising source of novel drug targets. Many of the molecular pathways implicated in rheumatoid arthritis (RA) directly modify synovium metabolism and transform the resident cells, such as the fibroblast-like synoviocytes (FLS), and the synovial tissue macrophages (STM), toward an overproduction of enzymes, which degrade cartilage and bone, and cytokines, which promote immune cell infiltration. Recent studies have shown metabolic changes in stromal and immune cells from RA patients. Metabolic disruption in the synovium provide the opportunity to use in vivo metabolism-based imaging techniques for patient stratification and to monitor treatment response. In addition, these metabolic changes may be therapeutically targetable. Thus, resetting metabolism of the synovial membrane offers additional opportunities for disease modulation and restoration of homeostasis in RA. In fact, rheumatologists already use the antimetabolite methotrexate, a chemotherapy agent, for the treatment of patients with inflammatory arthritis. Metabolic targets that do not compromise systemic homeostasis or corresponding metabolic functions in normal cells could increase the drug armamentarium in rheumatic diseases for combination therapy independent of systemic immunosuppression. This article summarizes what is known about metabolism in synovial tissue cells and highlights chemotherapies that target metabolism as potential future therapeutic strategies for RA.
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