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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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Cure E, Cumhur Cure M. Insulin may increase disease severity and mortality of COVID-19 through Na +/H + exchanger in patients with type 1 and type 2 diabetes mellitus. J Endocrinol Invest 2023; 46:845-847. [PMID: 36318448 PMCID: PMC9628438 DOI: 10.1007/s40618-022-01951-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 10/22/2022] [Indexed: 11/21/2022]
Affiliation(s)
- E. Cure
- Department of Internal Medicine, Bagcilar Medilife Hospital, Fevzicakmak Mh, Osmangazi Cd, Istanbul, Turkey
| | - M. Cumhur Cure
- Department of Biochemistry, Private Tanfer Hospital, Istanbul, Turkey
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Cumhur Cure M, Cure E. Severe acute respiratory syndrome coronavirus 2 may cause liver injury via Na +/H + exchanger. World J Virol 2023; 12:12-21. [PMID: 36743661 PMCID: PMC9896593 DOI: 10.5501/wjv.v12.i1.12] [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: 08/27/2022] [Revised: 10/03/2022] [Accepted: 11/22/2022] [Indexed: 01/18/2023] Open
Abstract
The liver has many significant functions, such as detoxification, the urea cycle, gluconeogenesis, and protein synthesis. Systemic diseases, hypoxia, infections, drugs, and toxins can easily affect the liver, which is extremely sensitive to injury. Systemic infection of severe acute respiratory syndrome coronavirus 2 can cause liver damage. The primary regulator of intracellular pH in the liver is the Na+/H+ exchanger (NHE). Physiologically, NHE protects hepatocytes from apoptosis by making the intracellular pH alkaline. Severe acute respiratory syndrome coronavirus 2 increases local angiotensin II levels by binding to angiotensin-converting enzyme 2. In severe cases of coronavirus disease 2019, high angi-otensin II levels may cause NHE overstimulation and lipid accumulation in the liver. NHE overstimulation can lead to hepatocyte death. NHE overstimulation may trigger a cytokine storm by increasing proinflammatory cytokines in the liver. Since the release of proinflammatory cytokines such as interleukin-6 increases with NHE activation, the virus may indirectly cause an increase in fibrinogen and D-dimer levels. NHE overstimulation may cause thrombotic events and systemic damage by increasing fibrinogen levels and cytokine release. Also, NHE overstimulation causes an increase in the urea cycle while inhibiting vitamin D synthesis and gluconeogenesis in the liver. Increasing NHE3 activity leads to Na+ loading, which impairs the containment and fluidity of bile acid. NHE overstimulation can change the gut microbiota composition by disrupting the structure and fluidity of bile acid, thus triggering systemic damage. Unlike other tissues, tumor necrosis factor-alpha and angiotensin II decrease NHE3 activity in the intestine. Thus, increased luminal Na+ leads to diarrhea and cytokine release. Severe acute respiratory syndrome coronavirus 2-induced local and systemic damage can be improved by preventing virus-induced NHE overstimulation in the liver.
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Affiliation(s)
- Medine Cumhur Cure
- Department of Biochemistry, Private Tanfer Hospital, Istanbul 34394, Turkey
| | - Erkan Cure
- Department of Internal Medicine, Bagcilar Medilife Hospital, Istanbul 34200, Turkey
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Significance of Catecholamine Biosynthetic/Metabolic Pathway in SARS-CoV-2 Infection and COVID-19 Severity. Cells 2022; 12:cells12010012. [PMID: 36611805 PMCID: PMC9818320 DOI: 10.3390/cells12010012] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/11/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
The SARS-CoV-2 infection was previously associated with the expression of the dopamine biosynthetic enzyme L-Dopa decarboxylase (DDC). Specifically, a negative correlation was detected between DDC mRNA and SARS-CoV-2 RNA levels in in vitro infected epithelial cells and the nasopharyngeal tissue of COVID-19 patients with mild/no symptoms. However, DDC, among other genes related to both DDC expression and SARS-CoV-2-infection (ACE2, dACE2, EPO), was upregulated in these patients, possibly attributed to an orchestrated host antiviral response. Herein, by comparing DDC expression in the nasopharyngeal swab samples of severe/critical to mild COVID-19 cases, we showed a 20 mean-fold reduction, highlighting the importance of the expression of this gene as a potential marker of COVID-19 severity. Moreover, we identified an association of SARS-CoV-2 infection with the expression of key catecholamine biosynthesis/metabolism-related genes, in whole blood samples from hospitalized patients and in cultured cells. Specifically, viral infection downregulated the biosynthetic part of the dopamine pathway (reduction in DDC expression up to 7.5 mean-fold), while enhanced the catabolizing part (increase in monoamine oxidases A and B expression up to 15 and 10 mean-fold, respectively) in vivo, irrespectively of the presence of comorbidities. In accordance, dopamine levels in the sera of severe cases were reduced (up to 3.8 mean-fold). Additionally, a moderate positive correlation between DDC and MAOA mRNA levels (r = 0.527, p < 00001) in the blood was identified upon SARS-CoV-2-infection. These observations were consistent to the gene expression data from SARS-CoV-2-infected Vero E6 and A549 epithelial cells. Furthermore, L-Dopa or dopamine treatment of infected cells attenuated the virus-derived cytopathic effect by 55% and 59%, respectively. The SARS-CoV-2 mediated suppression of dopamine biosynthesis in cell culture was, at least in part, attributed to hypoxia-like conditions triggered by viral infection. These findings suggest that L-Dopa/dopamine intake may have a preventive or therapeutic value for COVID-19 patients.
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Ren Y, Liu Y, Zhang Z, Liu Y, Li K, Zhang L. SNX27-mediated endocytic recycling of GLUT1 is suppressed by SARS-CoV-2 spike, possibly explaining neuromuscular disorders in patients with COVID-19. J Infect 2022; 85:e116-e118. [PMID: 35768050 PMCID: PMC9233752 DOI: 10.1016/j.jinf.2022.06.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Yongwen Ren
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yihan Liu
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhiwen Zhang
- Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuwen Liu
- Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Kangxin Li
- Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Leiliang Zhang
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Department of Pathogen Biology, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
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Grudlewska-Buda K, Wiktorczyk-Kapischke N, Budzyńska A, Kwiecińska-Piróg J, Przekwas J, Kijewska A, Sabiniarz D, Gospodarek-Komkowska E, Skowron K. The Variable Nature of Vitamin C—Does It Help When Dealing with Coronavirus? Antioxidants (Basel) 2022; 11:antiox11071247. [PMID: 35883738 PMCID: PMC9312329 DOI: 10.3390/antiox11071247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 02/06/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still spreading worldwide. For this reason, new treatment methods are constantly being researched. Consequently, new and already-known preparations are being investigated to potentially reduce the severe course of coronavirus disease 2019 (COVID-19). SARS-CoV-2 infection induces the production of pro-inflammatory cytokines and acute serum biomarkers in the host organism. In addition to antiviral drugs, there are other substances being used in the treatment of COVID-19, e.g., those with antioxidant properties, such as vitamin C (VC). Exciting aspects of the use of VC in antiviral therapy are its antioxidant and pro-oxidative abilities. In this review, we summarized both the positive effects of using VC in treating infections caused by SARS-CoV-2 in the light of the available research. We have tried to answer the question as to whether the use of high doses of VC brings the expected benefits in the treatment of COVID-19 and whether such treatment is the correct therapeutic choice. Each case requires individual assessment to determine whether the positives outweigh the negatives, especially in the light of populational studies concerning the genetic differentiation of genes encoding the solute carriers responsible forVC adsorption. Few data are available on the influence of VC on the course of SARS-CoV-2 infection. Deducing from already-published data, high-dose intravenous vitamin C (HDIVC) does not significantly lower the mortality or length of hospitalization. However, some data prove, among other things, its impact on the serum levels of inflammatory markers. Finally, the non-positive effect of VC administration is mainly neutral, but the negative effect is that it can result in urinary stones or nephropathies.
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Affiliation(s)
- Katarzyna Grudlewska-Buda
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Natalia Wiktorczyk-Kapischke
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Anna Budzyńska
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Joanna Kwiecińska-Piróg
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Jana Przekwas
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Agnieszka Kijewska
- Department of Immunobiology and Environmental Biology, Institute of Maritime and Tropical Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland;
| | | | - Eugenia Gospodarek-Komkowska
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
| | - Krzysztof Skowron
- Department of Microbiology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland; (K.G.-B.); (N.W.-K.); (A.B.); (J.K.-P.); (J.P.); (E.G.-K.)
- Correspondence: ; Tel.: +48-(52)-585-38-38
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One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome. Biomedicines 2022; 10:biomedicines10061249. [PMID: 35740271 PMCID: PMC9219734 DOI: 10.3390/biomedicines10061249] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/17/2022] [Accepted: 05/23/2022] [Indexed: 01/27/2023] Open
Abstract
Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive glucose transport across the blood–brain barrier. All age groups, from infants to adults, may be affected, with age-specific symptoms. In its classic form, the syndrome presents as an early-onset drug-resistant metabolic epileptic encephalopathy with a complex movement disorder and developmental delay. In later-onset forms, complex motor disorder predominates, with dystonia, ataxia, chorea or spasticity, often triggered by fasting. Diagnosis is confirmed by hypoglycorrhachia (below 45 mg/dL) with normal blood glucose, 18F-fluorodeoxyglucose positron emission tomography, and genetic analysis showing pathogenic SLC2A1 variants. There are also ongoing positive studies on erythrocytes’ Glut1 surface expression using flow cytometry. The standard treatment still consists of ketogenic therapies supplying ketones as alternative brain fuel. Anaplerotic substances may provide alternative energy sources. Understanding the complex interactions of Glut1 with other tissues, its signaling function for brain angiogenesis and gliosis, and the complex regulation of glucose transportation, including compensatory mechanisms in different tissues, will hopefully advance therapy. Ongoing research for future interventions is focusing on small molecules to restore Glut1, metabolic stimulation, and SLC2A1 transfer strategies. Newborn screening, early identification and treatment could minimize the neurodevelopmental disease consequences. Furthermore, understanding Glut1 relative deficiency or inhibition in inflammation, neurodegenerative disorders, and viral infections including COVID-19 and other settings could provide clues for future therapeutic approaches.
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Sardu C, Marfella R, Prattichizzo F, La Grotta R, Paolisso G, Ceriello A. Effect of Hyperglycemia on COVID-19 Outcomes: Vaccination Efficacy, Disease Severity, and Molecular Mechanisms. J Clin Med 2022; 11:jcm11061564. [PMID: 35329890 PMCID: PMC8955791 DOI: 10.3390/jcm11061564] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/03/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023] Open
Abstract
Background/Aims: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-stranded single-stranded RNA virus, a member of the subgenus Sarbecovirus (beta-CoV lineage B) and responsible for the coronavirus disease 2019 (COVID-19). COVID-19 encompasses a large range of disease severity, from mild symptoms to severe forms with Intensive Care Unit admission and eventually death. The severe forms of COVID-19 are usually observed in high-risk patients, such as those with type two diabetes mellitus. Here, we review the available evidence linking acute and chronic hyperglycemia to COVID-19 outcomes, describing also the putative mediators of such interactions. Findings/Conclusions: Acute hyperglycemia at hospital admission represents a risk factor for poor COVID-19 prognosis in patients with and without diabetes. Acute and chronic glycemic control are both emerging as major determinants of vaccination efficacy, disease severity and mortality rate in COVID-19 patients. Mechanistically, it has been proposed that hyperglycemia might be a disease-modifier for COVID-19 through multiple mechanisms: (a) induction of glycation and oligomerization of ACE2, the main receptor of SARS-CoV-2; (b) increased expression of the serine protease TMPRSS2, responsible for S protein priming; (c) impairment of the function of innate and adaptive immunity despite the induction of higher pro-inflammatory responses, both local and systemic. Consistently, managing acute hyperglycemia through insulin infusion has been suggested to improve clinical outcomes, while implementing chronic glycemic control positively affects immune response following vaccination. Although more research is warranted to better disentangle the relationship between hyperglycemia and COVID-19, it might be worth considering glycemic control as a potential route to optimize disease prevention and management.
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Affiliation(s)
- Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (R.M.); (G.P.)
- Correspondence: (C.S.); (F.P.)
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (R.M.); (G.P.)
- Mediterranea Cardiocentro, 80122 Naples, Italy
| | - Francesco Prattichizzo
- IRCCS MultiMedica, Via Fantoli 16/15, 20138 Milan, Italy; (R.L.G.); (A.C.)
- Correspondence: (C.S.); (F.P.)
| | - Rosalba La Grotta
- IRCCS MultiMedica, Via Fantoli 16/15, 20138 Milan, Italy; (R.L.G.); (A.C.)
| | - Giuseppe Paolisso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy; (R.M.); (G.P.)
- Mediterranea Cardiocentro, 80122 Naples, Italy
| | - Antonio Ceriello
- IRCCS MultiMedica, Via Fantoli 16/15, 20138 Milan, Italy; (R.L.G.); (A.C.)
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Cure MC, Cure E. Prolonged NHE Activation may be both Cause and Outcome of Cytokine Release Syndrome in COVID-19. Curr Pharm Des 2022; 28:1815-1822. [PMID: 35838211 DOI: 10.2174/1381612828666220713121741] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023]
Abstract
The release of cytokines and chemokines such as IL-1β, IL-2, IL-6, IL-7, IL-10, TNF-α, IFN-γ, CCL2, CCL3, and CXCL10 is increased in critically ill patients with COVID-19. Excessive cytokine release during COVID-19 is related to increased morbidity and mortality. Several mechanisms are put forward for cytokine release syndrome during COVID-19. Here we have mentioned novel pathways. SARS-CoV-2 increases angiotensin II levels by rendering ACE2 nonfunctional. Angiotensin II causes cytokine release via AT1 and AT2 receptors. Moreover, angiotensin II potently stimulates the Na+/H+ exchanger (NHE). It is a pump found in the membranes of many cells that pumps Na+ inward and H+ outward. NHE has nine isoforms. NHE1 is the most common isoform found in endothelial cells and many cells. NHE is involved in keeping the intracellular pH within physiological limits. When the intracellular pH is acidic, NHE is activated, bringing the intracellular pH to physiological levels, ending its activity. Sustained NHE activity is highly pathological and causes many problems. Prolonged NHE activation in COVID-19 may cause a decrease in intracellular pH through H+ ion accumulation in the extracellular area and subsequent redox reactions. The activation reduces the intracellular K+ concentration and leads to Na+ and Ca2+ overload. Increased ROS can cause intense cytokine release by stimulating NF-κB and NLRP3 inflammasomes. Cytokines also cause overstimulation of NHE. As the intracellular pH decreases, SARS-CoV-2 rapidly infects new cells, increasing the viral load. This vicious circle increases morbidity and mortality in patients with COVID-19. On the other hand, SARS-CoV-2 interaction with NHE3 in intestinal tissue is different from other tissues. SARS-CoV-2 can trigger CRS via NHE3 inhibition by disrupting the intestinal microbiota. This review aimed to help develop new treatment models against SARS-CoV-2- induced CRS by revealing the possible effects of SARS-CoV-2 on the NHE.
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Affiliation(s)
| | - Erkan Cure
- Department of Internal Medicine, Bagcilar Medilife Hospital, Istanbul, Turkey
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Mustroph J, Hupf J, Baier MJ, Evert K, Brochhausen C, Broeker K, Meindl C, Seither B, Jungbauer C, Evert M, Maier LS, Wagner S. Cardiac Fibrosis Is a Risk Factor for Severe COVID-19. Front Immunol 2021; 12:740260. [PMID: 34745111 PMCID: PMC8569622 DOI: 10.3389/fimmu.2021.740260] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/07/2021] [Indexed: 12/20/2022] Open
Abstract
Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventricular myocardium of deceased COVID-19 patients, compared with matched controls. We also detected increased mRNA levels of soluble interleukin-1 receptor-like 1 (sIL1-RL1) and transforming growth factor β1 (TGF-β1) in the left ventricular myocardium of deceased COVID-19 patients. Biochemical analysis of blood sampled from patients admitted to the emergency department (ED) with COVID-19 revealed highly elevated levels of TGF-β1 mRNA in these patients compared to controls. Left ventricular strain measured by echocardiography as a marker of pre-existing cardiac fibrosis correlated strongly with blood TGF-β1 mRNA levels and predicted disease severity in COVID-19 patients. In the left ventricular myocardium and lungs of COVID-19 patients, we found increased neuropilin-1 (NRP-1) RNA levels, which correlated strongly with the prevalence of pulmonary SARS-CoV-2 nucleocapsid. Cardiac and pulmonary fibrosis may therefore predispose these patients to increased cellular viral entry in the lung, which may explain the worse clinical outcome observed in our cohort. Our study demonstrates that patients at risk of clinical deterioration can be identified early by echocardiographic strain analysis and quantification of blood TGF-β1 mRNA performed at the time of first medical contact.
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Affiliation(s)
- Julian Mustroph
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Julian Hupf
- Emergency Department, University Hospital Regensburg, Regensburg, Germany
| | - Maria J Baier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Katja Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | | | - Katharina Broeker
- Department of Physiology, University of Regensburg, Regensburg, Germany
| | - Christine Meindl
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Benedikt Seither
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Carsten Jungbauer
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Lars S Maier
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Stefan Wagner
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
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Krishnan S, Nordqvist H, Ambikan AT, Gupta S, Sperk M, Svensson-Akusjärvi S, Mikaeloff F, Benfeitas R, Saccon E, Ponnan SM, Rodriguez JE, Nikouyan N, Odeh A, Ahlén G, Asghar M, Sällberg M, Vesterbacka J, Nowak P, Végvári Á, Sönnerborg A, Treutiger CJ, Neogi U. Metabolic Perturbation Associated With COVID-19 Disease Severity and SARS-CoV-2 Replication. Mol Cell Proteomics 2021; 20:100159. [PMID: 34619366 PMCID: PMC8490130 DOI: 10.1016/j.mcpro.2021.100159] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 08/29/2021] [Accepted: 09/28/2021] [Indexed: 02/06/2023] Open
Abstract
Viruses hijack host metabolic pathways for their replicative advantage. In this study, using patient-derived multiomics data and in vitro infection assays, we aimed to understand the role of key metabolic pathways that can regulate severe acute respiratory syndrome coronavirus-2 reproduction and their association with disease severity. We used multiomics platforms (targeted and untargeted proteomics and untargeted metabolomics) on patient samples and cell-line models along with immune phenotyping of metabolite transporters in patient blood cells to understand viral-induced metabolic modulations. We also modulated key metabolic pathways that were identified using multiomics data to regulate the viral reproduction in vitro. Coronavirus disease 2019 disease severity was characterized by increased plasma glucose and mannose levels. Immune phenotyping identified altered expression patterns of carbohydrate transporter, glucose transporter 1, in CD8+ T cells, intermediate and nonclassical monocytes, and amino acid transporter, xCT, in classical, intermediate, and nonclassical monocytes. In in vitro lung epithelial cell (Calu-3) infection model, we found that glycolysis and glutaminolysis are essential for virus replication, and blocking these metabolic pathways caused significant reduction in virus production. Taken together, we therefore hypothesized that severe acute respiratory syndrome coronavirus-2 utilizes and rewires pathways governing central carbon metabolism leading to the efflux of toxic metabolites and associated with disease severity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.
COVID-19 disease severity was characterized by increased plasma glucose and mannose. Mannose is a strong biomarker of COVID-19 disease severity. Glycolysis and glutaminolysis are essential for virus replication. Blocking the metabolic pathways caused significant reduction in virus production.
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Affiliation(s)
- Shuba Krishnan
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | | | - Anoop T Ambikan
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Soham Gupta
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Maike Sperk
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Sara Svensson-Akusjärvi
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Flora Mikaeloff
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Rui Benfeitas
- National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Elisa Saccon
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | | | - Jimmy Esneider Rodriguez
- Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Negin Nikouyan
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Amani Odeh
- Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Gustaf Ahlén
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Muhammad Asghar
- Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Matti Sällberg
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Jan Vesterbacka
- Department of Medicine Huddinge, Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden
| | - Piotr Nowak
- Department of Medicine Huddinge, Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden; The Laboratory for Molecular Infection Medicine Sweden MIMS, Umeå University, Umea, Sweden
| | - Ákos Végvári
- Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Anders Sönnerborg
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden; Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Carl Johan Treutiger
- Södersjukhuset (The South General Hospital), Stockholm, Sweden; Department of Medicine Huddinge, Division of Infectious Diseases, Karolinska Institutet, Stockholm, Sweden
| | - Ujjwal Neogi
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, ANA Futura, Campus Flemingsberg, Stockholm, Sweden; Manipal Institute of Virology (MIV), Manipal Academy of Higher Education, Manipal, Karnataka, India.
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