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1
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Sudo K, Uno K, Tamahara T, Asano N, Kusano K, Tanabe M, Ogasawara K, Kanno T, Koike T, Shimizu R, Masamune A. Costimulation with high-fat diet and acidic bile salts may promote Warburg effect in gastric carcinogenesis around the squamocolumnar junction in Gan mice. Am J Physiol Gastrointest Liver Physiol 2025; 328:G645-G662. [PMID: 40246521 DOI: 10.1152/ajpgi.00305.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 01/05/2025] [Accepted: 03/23/2025] [Indexed: 04/19/2025]
Abstract
Epidemiological studies demonstrated relationships between gastric cardia adenocarcinoma (GCA) and metabolic syndrome (MetS). We aimed to clarify the mechanism underlying their relationship. To investigate whether systemic inflammation against high-fat diet (HFD)-related dysbiosis promotes the Warburg effect in tumors at the squamocolumnar junction (SCJ), we applied K19-Wnt1/C2mE (Gan) mice, fed either HFD or control diet ± acidic bile salts (ABS) with/without clodronate liposomes (CLs), and in vitro studies using MKN7 cells with/without THP1-derived macrophages. Then, we assessed the involvement of oxidative stress (OS) in the Warburg effect by comparing nuclear factor-erythroid 2-related factor 2 (Nrf2) knockout Gan mice with Gan mice. Tumors with macrophage infiltration in the HFD + ABS group were larger than in the control group. Gene Set Enrichment Analysis revealed enhancement of the OS signaling in tumor of the HFD + ABS group. The HFD + ABS group mice demonstrated induction of OS, Nqo1, tumor necrosis factor alpha (TNFα), and the Warburg effect in tumors and mucosal barrier dysfunction of dysbiotic gut. All of them were abolished with diminishing macrophage infiltration by additional CL treatment. Stimulation with TNFα, but not ABS nor lipopolysaccharide, on MKN7 cells activated the Warburg effect. In MKN7 cells cocultured with the macrophages whose TNFα expression was induced by the lipopolysaccharide pretreatment, the Warburg effect was enhanced in TNFα concentration-dependent manners. In Nrf2 knockout Gan mice, tumors shrank with reducing OS, TNFα, and Warburg effect, along with decreasing macrophage infiltration. Accordingly, MetS may develop GCA through the Nrf2-related Warburg effect under the TNFα stimulation from the macrophages activated by both local ABS exposure and systemic lipopolysaccharide exposure from leaky gut with HFD-related dysbiosis.NEW & NOTEWORTHY In K19-Wnt1/C2mE (Gan) mice, a high-fat diet accompanied by orally taking acidic bile salts (ABS) promoted inflammation-associated carcinogenesis at the squamocolumnar junction (SCJ), maybe due to transudates from dysbiotic gut into systemic circulation. Systemic lipopolysaccharide exposure and local ABS exposure at the SCJ activate macrophages to induce the expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2) and TNFα, which might promote Warburg effect in cancer cells. These phenomena were abolished in the Nrf2-knockout Gan mice.
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Affiliation(s)
- Koichiro Sudo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kaname Uno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Toru Tamahara
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Naoki Asano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keisuke Kusano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Mizuki Tanabe
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kouya Ogasawara
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeshi Kanno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoyuki Koike
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ritsuko Shimizu
- Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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2
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Mirchandani AS, Sanchez-Garcia MA, Walmsley SR. How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia. Nat Rev Immunol 2025; 25:161-177. [PMID: 39349943 DOI: 10.1038/s41577-024-01087-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/23/2024] [Indexed: 03/04/2025]
Abstract
Most eukaryotes require oxygen for their survival and, with increasing multicellular complexity, oxygen availability and delivery rates vary across the tissues of complex organisms. In humans, healthy tissues have markedly different oxygen gradients, ranging from the hypoxic environment of the bone marrow (where our haematopoietic stem cells reside) to the lungs and their alveoli, which are among the most oxygenated areas of the body. Immune cells are therefore required to adapt to varying oxygen availability as they move from the bone marrow to peripheral organs to mediate their effector functions. These changing oxygen gradients are exaggerated during inflammation, where oxygenation is often depleted owing to alterations in tissue perfusion and increased cellular activity. As such, it is important to consider the effects of oxygenation on shaping the immune response during tissue homeostasis and disease conditions. In this Review, we address the relevance of both physiological oxygenation (physioxia) and disease-associated hypoxia (where cellular oxygen demand outstrips supply) for immune cell functions, discussing the relevance of hypoxia for immune responses in the settings of tissue homeostasis, inflammation, infection, cancer and disease immunotherapy.
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Affiliation(s)
- Ananda Shanti Mirchandani
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
| | | | - Sarah Ruth Walmsley
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
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Rondeau JD, Lipari S, Mathieu B, Beckers C, Van de Velde JA, Mignion L, Da Silva Morais M, Kreuzer M, Colauzzi I, Capeloa T, Pruschy M, Gallez B, Sonveaux P. Mitochondria-targeted antioxidant MitoQ radiosensitizes tumors by decreasing mitochondrial oxygen consumption. Cell Death Discov 2024; 10:514. [PMID: 39730333 DOI: 10.1038/s41420-024-02277-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 12/10/2024] [Accepted: 12/17/2024] [Indexed: 12/29/2024] Open
Abstract
Hypoxic tumors are radioresistant stemming from the fact that oxygen promotes reactive oxygen species (ROS) propagation after water radiolysis and stabilizes irradiation-induced DNA damage. Therefore, an attractive strategy to radiosensitize solid tumors is to increase tumor oxygenation at the time of irradiation, ideally above a partial pressure of 10 mm-Hg at which full radiosensitization can be reached. Historically, the many attempts to increase vascular O2 delivery have had limited efficacy, but mathematical models predicted that inhibiting cancer cell respiration would be more effective. Here, we report that mitochondria-targeted antioxidant MitoQ can radiosensitize human breast tumors in mice. This was not a class effect, as neither MitoTEMPO nor SKQ1 shared this property. At clinically relevant nanomolar concentrations, MitoQ completely abrogated the oxygen consumption of several human cancer cell lines of different origins, which was associated with a glycolytic switch. Using orthotopic breast cancer models in mice, we observed that pretreating hypoxic MDA-MB-231 tumors with MitoQ delayed tumor growth with both single dose irradiation and clinically relevant fractionated radiotherapy. Oxygenated MCF7 tumors were not radiosensitized, suggesting an oxygen enhancement effect of MitoQ. Because MitoQ already successfully passed Phase I clinical trials, our findings foster its clinical evaluation in combination with radiotherapy.
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Affiliation(s)
- Justin D Rondeau
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Sara Lipari
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Barbara Mathieu
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute (LDRI), UCLouvain, Brussels, Belgium
| | - Claire Beckers
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Justine A Van de Velde
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Lionel Mignion
- Nuclear and Electron Spin Technologies (NEST) Platform, LDRI, UCLouvain, Brussels, Belgium
| | - Mauricio Da Silva Morais
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Marvin Kreuzer
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Ilaria Colauzzi
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Tania Capeloa
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Martin Pruschy
- Laboratory for Applied Radiobiology, Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Bernard Gallez
- Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute (LDRI), UCLouvain, Brussels, Belgium
| | - Pierre Sonveaux
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium.
- WEL Research Institute, WELBIO Department, Wavre, Belgium.
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4
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Solsona R, Sabater Pastor F, Normand-Gravier T, Borrani F, Sanchez AM. Sprint training in hypoxia and with blood flow restriction: Controversies and perspectives. J Sports Sci 2024:1-15. [PMID: 39422258 DOI: 10.1080/02640414.2024.2416839] [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: 06/28/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
This narrative review assesses the effects of repeated sprint training (RST) in hypoxia (RSH) and blood flow restriction (BFR) methods on skeletal muscle adaptations and performance. Current literature suggests that RSH promotes metabolic modifications in muscle cells, especially driven by reactive oxygen species production, HIF-1α stabilization, and changes in metabolism. Training with BFR promotes metabolite accumulation in working muscles due to limited blood flow, however, cellular mechanisms affected by BFR during RST are less explored. Data highlight that RSH improves repeated sprint ability (RSA) in several sport disciplines (e.g. rugby, tennis, soccer, cross-country skiing). However, recent studies showed that addition of hypoxia or BFR during RST did not promote supplementary benefits on aerobic performance, force-velocity power profile, and V ˙ O 2 max . Nonetheless, gains in V ˙ O 2 max were observed during sprint interval training protocols when BFR was applied during recovery between sets. Finally, recent studies highlighted that RSH can improve RSA in a short period. Thus, RSH and sprint training with BFR may be useful for sports disciplines requiring high glycolytic demand and can promote gains in RSA in a short window. Further studies must be encouraged to better understand the biological consequences of adding such stimuli to exercise, especially BFR, on long-term adaptation.
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Affiliation(s)
- Robert Solsona
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
- Faculty of Sports Sciences, Laboratoire Interdisciplinaire Performance Santé Environnement de Montagne (LIPSEM), University of Perpignan Via Domitia, Font-Romeu, France
| | - Frederic Sabater Pastor
- Faculty of Sports Sciences, Laboratoire Interdisciplinaire Performance Santé Environnement de Montagne (LIPSEM), University of Perpignan Via Domitia, Font-Romeu, France
| | - Tom Normand-Gravier
- Faculty of Sports Sciences, Laboratoire Interdisciplinaire Performance Santé Environnement de Montagne (LIPSEM), University of Perpignan Via Domitia, Font-Romeu, France
- Dynamique du Muscle et Métabolisme (DMeM), University of Montpellier, Montpellier, France
| | - Fabio Borrani
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
| | - Anthony Mj Sanchez
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland
- Faculty of Sports Sciences, Laboratoire Interdisciplinaire Performance Santé Environnement de Montagne (LIPSEM), University of Perpignan Via Domitia, Font-Romeu, France
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5
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Twigger SA, Dominguez B, Porto V, Hacker L, Chalmers AJ, Breckenridge R, Treder M, Sedgwick AC, Dominguez F, Hammond EM. The activity of therapeutic molecular cluster Ag5 is dependent on oxygen level and HIF-1 mediated signalling. Redox Biol 2024; 76:103326. [PMID: 39180984 PMCID: PMC11388176 DOI: 10.1016/j.redox.2024.103326] [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: 07/29/2024] [Revised: 08/17/2024] [Accepted: 08/21/2024] [Indexed: 08/27/2024] Open
Abstract
Regions of hypoxia occur in most solid tumours and are known to significantly impact therapy response and patient prognosis. Ag5 is a recently reported silver molecular cluster which inhibits both glutathione and thioredoxin signalling therefore limiting cellular antioxidant capacity. Ag5 treatment significantly reduces cell viability in a range of cancer cell lines with little to no impact on non-transformed cells. Characterisation of redox homeostasis in hypoxia demonstrated an increase in reactive oxygen species and glutathione albeit with different kinetics. Significant Ag5-mediated loss of viability was observed in a range of hypoxic conditions which mimic the tumour microenvironment however, this effect was reduced compared to normoxic conditions. Reduced sensitivity to Ag5 in hypoxia was attributed to HIF-1 mediated signalling to reduce PDH via PDK1/3 activity and changes in mitochondrial oxygen availability. Importantly, the addition of Ag5 significantly increased radiation-induced cell death in hypoxic conditions associated with radioresistance. Together, these data demonstrate Ag5 is a potent and cancer specific agent which could be used effectively in combination with radiotherapy.
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Affiliation(s)
- Sophie A Twigger
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
| | - Blanca Dominguez
- Department of physiology and CIMUS Universidade de Santiago de Compostela, Spain
| | - Vanesa Porto
- Department of physiology and CIMUS Universidade de Santiago de Compostela, Spain
| | - Lina Hacker
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
| | | | | | | | - Adam C Sedgwick
- Department of Chemistry, King's College London, London, SE1 1DB, UK
| | - Fernando Dominguez
- Department of physiology and CIMUS Universidade de Santiago de Compostela, Spain
| | - Ester M Hammond
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
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6
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Sun B, Li J, Hu C, Giesy JP, Lam PKS, Chen L. Toxicity of perfluorobutanesulfonate on gill functions of marine medaka (Oryzias melastigma): A time course and hypoxia co-exposure study. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 872:162297. [PMID: 36801345 DOI: 10.1016/j.scitotenv.2023.162297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 02/05/2023] [Accepted: 02/13/2023] [Indexed: 06/18/2023]
Abstract
Perfluorobutanesulfonate (PFBS) is found in hypoxia regions. Results of previous studies have shown that hypoxia was capable of altering the inherent toxicity of PFBS. However, regarding gill functions, hypoxic influences and time course progression of toxic effects of PFBS remain unclear. In this study, with the aim to reveal the interaction behavior between PFBS and hypoxia, adult marine medaka Oryzias melastigma were exposed for 7 days to 0 or 10 μg PFBS/L under normoxic or hypoxic conditions. Subsequently, to explore the time-course transition in gill toxicity, medaka were exposed to PFBS for 21 days. The results showed that hypoxia dramatically increased the respiratory rate of medaka gill, which was further enhanced by exposure to PFBS; although exposure to PFBS under normoxic conditions for 7 days did not alter respiration, exposure to PFBS for 21 days significantly accelerated the respiration rate of female medaka. Concurrently, both hypoxia and PFBS were potent to interrupt the gene transcriptions and Na+, K+-ATPase enzymatic activity that play pivotal roles in the osmoregulation in gills of marine medaka, consequently disrupting homeostasis of major ions in blood, such as Na+, Cl-, and Ca2+. In addition, composition and diversity of the microbiome residing on surfaces of the gill were profiled by using amplicon sequencing. Acute exposure to hypoxia for only 7 days caused a significant decrease in diversity of the bacterial community of gill whatever the presence of PFBS, while PFBS exposure for 21 days increased the diversity of gill microbial community. Principal component analysis revealed that, compared with PFBS, hypoxia was the predominant driver of gill microbiome dysbiosis. Depending on duration of exposure, a divergence was caused in the microbial community of gill. Overall, the current findings underline the interaction between hypoxia and PFBS on gill function and demonstrate the temporal variation in PFBS toxicity.
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Affiliation(s)
- Baili Sun
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jing Li
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chenyan Hu
- School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430072, China.
| | - John P Giesy
- Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan, 44 Campus Drive, Saskatoon, SK S7N 5B3, Canada
| | - Paul K S Lam
- Office of the President, Hong Kong Metropolitan University, 30 Good Shepherd Street, Kowloon, Hong Kong
| | - Lianguo Chen
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
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7
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Aschner M, Skalny AV, Lu R, Santamaria A, Zhou JC, Ke T, Karganov MY, Tsatsakis A, Golokhvast KS, Bowman AB, Tinkov AA. The role of hypoxia-inducible factor 1 alpha (HIF-1α) modulation in heavy metal toxicity. Arch Toxicol 2023; 97:1299-1318. [PMID: 36933023 DOI: 10.1007/s00204-023-03483-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 03/02/2023] [Indexed: 03/19/2023]
Abstract
Hypoxia-inducible factor 1 (HIF-1) is an oxygen-sensing transcriptional regulator orchestrating a complex of adaptive cellular responses to hypoxia. Several studies have demonstrated that toxic metal exposure may also modulate HIF-1α signal transduction pathway, although the existing data are scarce. Therefore, the present review aims to summarize the existing data on the effects of toxic metals on HIF-1 signaling and the potential underlying mechanisms with a special focus on prooxidant effect of the metals. The particular effect of metals was shown to be dependent on cell type, varying from down- to up-regulation of HIF-1 pathway. Inhibition of HIF-1 signaling may contribute to impaired hypoxic tolerance and adaptation, thus promoting hypoxic damage in the cells. In contrast, its metal-induced activation may result in increased tolerance to hypoxia through increased angiogenesis, thus promoting tumor growth and contributing to carcinogenic effect of heavy metals. Up-regulation of HIF-1 signaling is mainly observed upon Cr, As, and Ni exposure, whereas Cd and Hg may both stimulate and inhibit HIF-1 pathway. The mechanisms underlying the influence of toxic metal exposure on HIF-1 signaling involve modulation of prolyl hydroxylases (PHD2) activity, as well as interference with other tightly related pathways including Nrf2, PI3K/Akt, NF-κB, and MAPK signaling. These effects are at least partially mediated by metal-induced ROS generation. Hypothetically, maintenance of adequate HIF-1 signaling upon toxic metal exposure through direct (PHD2 modulation) or indirect (antioxidant) mechanisms may provide an additional strategy for prevention of adverse effects of metal toxicity.
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Affiliation(s)
- Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Anatoly V Skalny
- IM Sechenov First Moscow State Medical University (Sechenov University), 119435, Moscow, Russia
| | - Rongzhu Lu
- Department of Preventive Medicine and Public Health Laboratory Science, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Abel Santamaria
- Laboratorio de Aminoácidos Excitadores/Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, 14269, Mexico City, Mexico
| | - Ji-Chang Zhou
- School of Public Health (Shenzhen), Sun Yat-Sen University, Shenzhen, 518100, China
| | - Tao Ke
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | | | - Aristides Tsatsakis
- IM Sechenov First Moscow State Medical University (Sechenov University), 119435, Moscow, Russia.,Laboratory of Toxicology, Medical School, University of Crete, Voutes, 700 13, Heraklion, Crete, Greece
| | - Kirill S Golokhvast
- Siberian Federal Scientific Centre of Agrobiotechnologies of the Russian Academy of Sciences, Krasnoobsk, Russia
| | - Aaron B Bowman
- School of Health Sciences, Purdue University, West Lafayette, USA
| | - Alexey A Tinkov
- IM Sechenov First Moscow State Medical University (Sechenov University), 119435, Moscow, Russia. .,Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003, Yaroslavl, Russia.
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8
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Hypoxia-Inducible Factor 1 and Mitochondria: An Intimate Connection. Biomolecules 2022; 13:biom13010050. [PMID: 36671435 PMCID: PMC9855368 DOI: 10.3390/biom13010050] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/21/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022] Open
Abstract
The general objective of the review is to explain the interaction between HIF-1 and mitochondria. On the one hand, this review describes the effects of HIF-1 on mitochondrial structure, including quantity, distribution, and morphology, as well as on mitochondrial metabolism and respiratory function. On the other hand, various factors, including mitochondrial activation of enzymes, the respiratory chain, complex and decoupling proteins, affect the stability and activity of HIF-1. It is possible to develop future molecular therapeutic interventions by understanding the interrelationships between HIF-1 and mitochondria.
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9
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Iacobini C, Vitale M, Haxhi J, Pesce C, Pugliese G, Menini S. Mutual Regulation between Redox and Hypoxia-Inducible Factors in Cardiovascular and Renal Complications of Diabetes. Antioxidants (Basel) 2022; 11:2183. [PMID: 36358555 PMCID: PMC9686572 DOI: 10.3390/antiox11112183] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 08/30/2023] Open
Abstract
Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes.
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Affiliation(s)
- Carla Iacobini
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
| | - Martina Vitale
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
| | - Jonida Haxhi
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
| | - Carlo Pesce
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal Infantile Sciences (DINOGMI), Department of Excellence of MIUR, University of Genoa Medical School, 16132 Genoa, Italy
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
| | - Stefano Menini
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
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10
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Kumar R, Mishra A, Gautam P, Feroz Z, Vijayaraghavalu S, Likos EM, Shukla GC, Kumar M. Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy. Cancers (Basel) 2022; 14:5268. [PMID: 36358687 PMCID: PMC9656396 DOI: 10.3390/cancers14215268] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/09/2022] [Accepted: 10/19/2022] [Indexed: 07/30/2023] Open
Abstract
Metabolic reprogramming enables cancer cells to proliferate and produce tumor biomass under a nutrient-deficient microenvironment and the stress of metabolic waste. A cancer cell adeptly undergoes a variety of adaptations in metabolic pathways and differential expression of metabolic enzyme genes. Metabolic adaptation is mainly determined by the physiological demands of the cancer cell of origin and the host tissue. Numerous metabolic regulators that assist cancer cell proliferation include uncontrolled anabolism/catabolism of glucose metabolism, fatty acids, amino acids metabolism, nucleotide metabolism, tumor suppressor genes, microRNAs, and many regulatory enzymes and genes. Using this paradigm, we review the current understanding of metabolic reprogramming in tumors and discuss the new strategies of cancer metabolomics that can be tapped into for cancer therapeutics.
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Affiliation(s)
- Rishabh Kumar
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
| | - Anurag Mishra
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
| | - Priyanka Gautam
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
| | - Zainab Feroz
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
| | | | - Eviania M. Likos
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA
| | - Girish C. Shukla
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA
| | - Munish Kumar
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, UP, India
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11
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Huang J, Li Z, Hu Y, Li Z, Xie Y, Huang H, Chen Q, Chen G, Zhu W, Chen Y, Su W, Chen X, Liang D. Melatonin, an endogenous hormone, modulates Th17 cells via the reactive-oxygen species/TXNIP/HIF-1α axis to alleviate autoimmune uveitis. J Neuroinflammation 2022; 19:124. [PMID: 35624485 PMCID: PMC9145533 DOI: 10.1186/s12974-022-02477-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 05/15/2022] [Indexed: 11/25/2022] Open
Abstract
Background Melatonin, an indoleamine produced by the pineal gland, plays a pivotal role in maintaining circadian rhythm homeostasis. Recently, the strong antioxidant and anti-inflammatory properties of melatonin have attracted attention of researchers. We evaluated the therapeutic efficacy of melatonin in experimental autoimmune uveitis (EAU), which is a representative animal model of human autoimmune uveitis. Methods EAU was induced in mice via immunization with the peptide interphotoreceptor retinoid binding protein 1–20 (IRBP1–20). Melatonin was then administered via intraperitoneal injection to induce protection against EAU. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the disease progression. T lymphocytes accumulation and the expression of inflammatory cytokines in the retinas were assessed via flow cytometry and RT-PCR, respectively. T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cells were detected via flow cytometry for both in vivo and in vitro experiments. Reactive-oxygen species (ROS) from CD4 + T cells was tested via flow cytometry. The expression of thioredoxin-interacting protein (TXNIP) and hypoxia-inducible factor 1 alpha (HIF-1α) proteins were quantified via western blot. Results Melatonin treatment resulted in notable attenuation of ocular inflammation in EAU mice, evidenced by decreasing optic disc edema, few signs of retinal vasculitis, and minimal retinal and choroidal infiltrates. Mechanistic studies revealed that melatonin restricted the proliferation of peripheral Th1 and Th17 cells by suppressing their transcription factors and potentiated Treg cells. In vitro studies corroborated that melatonin restrained the polarization of retina-specific T cells towards Th17 and Th1 cells in addition to enhancing the proportion of Treg cells. Pretreatment of retina-specific T cells with melatonin failed to induce EAU in naïve recipients. Furthermore, the ROS/ TXNIP/ HIF-1α pathway was shown to mediate the therapeutic effect of melatonin in EAU. Conclusions Melatonin regulates autoimmune T cells by restraining effector T cells and facilitating Treg generation, indicating that melatonin could be a hopeful treatment alternative for autoimmune uveitis. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-022-02477-z.
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Affiliation(s)
- Jun Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Zhuang Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Yunwei Hu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Zuoyi Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Yanyan Xie
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Haixiang Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Qian Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Guanyu Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Wenjie Zhu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Yuxi Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Xiaoqing Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China.
| | - Dan Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratoryof Ophthalmologyand VisualScience, Sun Yat-Sen University, Guangzhou, 510060, China.
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12
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Ozlem Zurnaci F, Guzel M. The Effects of Increased Glucose Level and the Role of Glycolysis on SARS CoV-2 Infection. Mini Rev Med Chem 2022; 22:2344-2349. [DOI: 10.2174/1389557522666220318115350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/12/2021] [Accepted: 12/20/2021] [Indexed: 01/08/2023]
Abstract
Abstract:
Covid-19 has entered our lives for a long time as an infection with high mortality rates. Although the vaccination process has provided benefits, the death toll remains to be frightening worldwide. Therefore, drugs and combined therapies that can be used against Covid-19 infection are still being investigated. Most of these antiviral medications are investigational drug candidates which are still in clinical trials. In this context, holistic and different approaches for the treatment of Covid-19 including prophylactic use of natural medicines are under investigation and may offer potential treatment options due to the fact that this is still an unmet medical need in the world. Thus, inhibiting the increased glycolysis on Covid-19 infection with glycolysis inhibitors may be beneficial for patient survival. This short review highlights the potential benefits of glycolysis inhibition as well as controlling the elevated glucose levels in patients with the treatment of Covid-19.
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Affiliation(s)
- Fatma Ozlem Zurnaci
- Istanbul Medipol University, Research Institute for Health Sciences and Technologies (SABITA), Center of Drug Discovery and Development, Kavacik-Beykoz/Istanbul, 34810, Turkey.
- Istanbul Medipol University, Health Sciences Institute, Department of Molecular Medicine and Biotechnology, Kavacik Campus, Kavacik-Beykoz/ISTANBUL 34810, Turkey
| | - Mustafa Guzel
- Istanbul Medipol University, Research Institute for Health Sciences and Technologies (SABITA), Center of Drug Discovery and Development, Kavacik-Beykoz/Istanbul, 34810, Turkey.
- Istanbul Medipol University, Health Sciences Institute, Department of Molecular Medicine and Biotechnology, Kavacik Campus, Kavacik-Beykoz/ISTANBUL 34810, Turkey
- Istanbul Medipol University, International School of Medicine, Department of Medical Pharmacology, Kavacik Campus, Kavacik-Beykoz/ISTANBUL 34810, Turkey
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13
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Jasaputra DK, Lucretia T, Ray HRD, Kwee L, Gunawan D, Edwinanto L, Viona SI, Goenawan H, Lesmana R, Gunadi JW. Moringa oleifera Leaves Extract Alters Exercise-Induced Cardiac Hypertrophy Adaptation. Pak J Biol Sci 2022; 25:210-217. [PMID: 35234011 DOI: 10.3923/pjbs.2022.210.217] [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] [Indexed: 11/15/2022]
Abstract
<b>Background and Objective:</b> Cardiomyocyte adaptation to exercise might require ROS as a central regulator. There is a limited study regarding the importance of ROS for inducing exercise-induced adaptation and its correlations with changes in histological scoring of cardiac muscles. The study aimed to explore the importance of physiological ROS induced by exercise and its correlation with Cardiomyocyte' histological appearance that is altered by <i>Moringa oleifera</i> leaves extract in Wistar rats. <b>Materials and Methods:</b> This was an animal experimental study, which use 4 groups of 24 Wistar rats divided into Control (Co), <i>Moringa</i> leaves extract (Mo), Exercise (Ex) and a combination of <i>Moringa </i>leaves extract and Exercise (MoEx). The <i>Moringa</i> leaves extract were given orally, 5 days a week, for 4 consecutive weeks. The exercise was given in moderate intensity, 5 days a week, also for 4 consecutive weeks. <b>Results:</b> This study found significant differences in heart weight and heart weight/body weight ratio in Ex group compared to the control. As for histology scoring, found that MoEx group has 16.7% cardiac hypertrophy and myofiber disarray compared to 83.3% mild hypertrophy and 50% mild disarray in Ex group. <b>Conclusion:</b> In summary, the study showed that the potential central role of exercise-induced physiological ROS for cardiac hypertrophy adaptation is altered by <i>Moringa oleifera </i>leaves extract treatment.
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14
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Sinenko SA, Starkova TY, Kuzmin AA, Tomilin AN. Physiological Signaling Functions of Reactive Oxygen Species in Stem Cells: From Flies to Man. Front Cell Dev Biol 2021; 9:714370. [PMID: 34422833 PMCID: PMC8377544 DOI: 10.3389/fcell.2021.714370] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/01/2021] [Indexed: 12/14/2022] Open
Abstract
Reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, are generated as byproducts of oxidative phosphorylation in the mitochondria or via cell signaling-induced NADPH oxidases in the cytosol. In the recent two decades, a plethora of studies established that elevated ROS levels generated by oxidative eustress are crucial physiological mediators of many cellular and developmental processes. In this review, we discuss the mechanisms of ROS generation and regulation, current understanding of ROS functions in the maintenance of adult and embryonic stem cells, as well as in the process of cell reprogramming to a pluripotent state. Recently discovered cell-non-autonomous ROS functions mediated by growth factors are crucial for controlling cell differentiation and cellular immune response in Drosophila. Importantly, many physiological functions of ROS discovered in Drosophila may allow for deciphering and understanding analogous processes in human, which could potentially lead to the development of novel therapeutic approaches in ROS-associated diseases treatment.
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Affiliation(s)
- Sergey A Sinenko
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
| | | | - Andrey A Kuzmin
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
| | - Alexey N Tomilin
- Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia
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15
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Chávez MD, Tse HM. Targeting Mitochondrial-Derived Reactive Oxygen Species in T Cell-Mediated Autoimmune Diseases. Front Immunol 2021; 12:703972. [PMID: 34276700 PMCID: PMC8281042 DOI: 10.3389/fimmu.2021.703972] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Accepted: 06/18/2021] [Indexed: 12/15/2022] Open
Abstract
Mitochondrial dysfunction resulting in oxidative stress could be associated with tissue and cell damage common in many T cell-mediated autoimmune diseases. Autoreactive CD4 T cell effector subsets (Th1,Th17) driving these diseases require increased glycolytic metabolism to upregulate key transcription factors (TF) like T-bet and RORγt that drive differentiation and proinflammatory responses. However, research in immunometabolism has demonstrated that mitochondrial-derived reactive oxygen species (ROS) act as signaling molecules contributing to T cell fate and function. Eliminating autoreactive T cells by targeting glycolysis or ROS production is a potential strategy to inhibit autoreactive T cell activation without compromising systemic immune function. Additionally, increasing self-tolerance by promoting functional immunosuppressive CD4 T regulatory (Treg) cells is another alternative therapeutic for autoimmune disease. Tregs require increased ROS and oxidative phosphorylation (OxPhos) for Foxp3 TF expression, differentiation, and anti-inflammatory IL-10 cytokine synthesis. Decreasing glycolytic activity or increasing glutathione and superoxide dismutase antioxidant activity can also be beneficial in inhibiting cytotoxic CD8 T cell effector responses. Current treatment options for T cell-mediated autoimmune diseases such as Type 1 diabetes (T1D), multiple sclerosis (MS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) include global immunosuppression, antibodies to deplete immune cells, and anti-cytokine therapy. While effective in diminishing autoreactive T cells, they can also compromise other immune responses resulting in increased susceptibility to other diseases and complications. The impact of mitochondrial-derived ROS and immunometabolism reprogramming in autoreactive T cell differentiation could be a potential target for T cell-mediated autoimmune diseases. Exploiting these pathways may delay autoimmune responses in T1D.
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Affiliation(s)
| | - Hubert M. Tse
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, United States
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16
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Sun B, Yu L, Xu C, Li YM, Zhao YR, Cao MM, Yang LY. NAD(P)HX epimerase downregulation promotes tumor progression through ROS/HIF-1α signaling in hepatocellular carcinoma. Cancer Sci 2021; 112:2753-2769. [PMID: 33932069 PMCID: PMC8253267 DOI: 10.1111/cas.14925] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/31/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Reactive oxygen species (ROS) derived from aberrant tumor metabolism could contribute to tumor invasion and metastasis. NAD(P)HX Epimerase (NAXE), an epimerase that allows the repair of damaged forms of antioxidant NADPH, is a potential cellular ROS scavenger and its role in tumor development is still elusive. Here, we found that NAXE is significantly downregulated in hepatocellular carcinoma (HCC) tissues and cell lines. NAXE downregulation is associated with poor clinicopathological characteristics and is an independent risk factor for overall and disease‐free survival of HCC patients after liver resection. In addition, low NAXE expression could identify worse prognosis of HCC patients before vascular invasion or in early stages of disease. In particularly, low NAXE expression in HCC is markedly associated with microvascular invasion (MVI) and its combination with MVI predicts poorer prognosis of HCC patients after liver resection. Furthermore, in vitro and in vivo experiments both showed that knockdown of NAXE expression in HCC cells promoted migration, invasion, and metastasis by inducing epithelial‐mesenchymal transition (EMT), whereas NAXE overexpression causes the opposite effects. Mechanistically, low NAXE expression reduced NADPH levels and further caused ROS level increase and hypoxia‐inducible factor‐1α (HIF‐1α) activation, thereby promoting invasion and metastasis of HCC by facilitating EMT. What is more, the tumor‐promoting effect of NAXE knockdown in HCC xenograft can be abolished by giving mice N‐acetyl‐l‐cysteine (NAC) in drinking water. Taken together, our findings uncovered a tumor suppressor role for NAXE in HCC by scavenging excessive ROS and inhibiting tumor‐promoting signaling pathways, suggesting a new strategy for HCC therapy by targeting redox signaling.
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Affiliation(s)
- Bo Sun
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Lei Yu
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Cong Xu
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yi-Ming Li
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Yan-Rong Zhao
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Mo-Mo Cao
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Lian-Yue Yang
- Liver Cancer Laboratory, Department of Surgery, Xiangya Hospital, Central South University, Changsha, China
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17
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HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow. Sci Rep 2021; 11:1468. [PMID: 33446832 PMCID: PMC7809484 DOI: 10.1038/s41598-020-80882-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 12/29/2020] [Indexed: 01/29/2023] Open
Abstract
Normal growth and development of lymphatic structures depends on mechanical forces created by accumulating interstitial fluid. However, prolonged exposure to pathologic mechanical stimuli generated by chronically elevated lymph flow results in lymphatic dysfunction. The mechanisms that transduce these mechanical forces are not fully understood. Our objective was to investigate molecular mechanisms that alter the growth and metabolism of isolated lymphatic endothelial cells (LECs) exposed to prolonged pathologically elevated lymph flow in vivo within the anatomic and physiologic context of a large animal model of congenital heart disease with increased pulmonary blood flow using in vitro approaches. To this end, late gestation fetal lambs underwent in utero placement of an aortopulmonary graft (shunt). Four weeks after birth, LECs were isolated and cultured from control and shunt lambs. Redox status and proliferation were quantified, and transcriptional profiling and metabolomic analyses were performed. Shunt LECs exhibited hyperproliferative growth driven by increased levels of Hypoxia Inducible Factor 1α (HIF-1α), along with upregulated expression of known HIF-1α target genes in response to mechanical stimuli and shear stress. Compared to control LECs, shunt LECs exhibited abnormal metabolism including abnormalities of glycolysis, the TCA cycle and aerobic respiration. In conclusion, LECs from lambs exposed in vivo to chronically increased pulmonary lymph flow are hyperproliferative, have enhanced expression of HIF-1α and its target genes, and demonstrate altered central carbon metabolism in vitro. Importantly, these findings suggest provocative therapeutic targets for patients with lymphatic abnormalities.
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18
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The ATPase subunit of ATP6V1C1 inhibits autophagy and enhances radiotherapy resistance in esophageal squamous cell carcinoma. Gene 2020; 768:145261. [PMID: 33183740 DOI: 10.1016/j.gene.2020.145261] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 10/20/2020] [Indexed: 01/20/2023]
Abstract
Radiotherapy is one of the primary therapeutic modalities for patients diagnosed esophageal squamous cell carcinoma(ESCC). Previous studies have shown that chemotherapy resistance could be linked with the overexpression vascular ATPases(V-ATPase) subunits genes. However, it is unknown whether V-ATPase subunits genes play a role in radiotherapy resistance. The aim of this study was to investigate the effect of the ATP6V1C1 in radiotherapy resistance. siRNA and plasmids were used to transfect low expression of ATP6V1C1 in TE13 (human ESCC cell) and high expressed in ECA109 (human ESCC cell), respectively. To observe proliferation, radiosensitivity, apoptosis and DNA-damage response, colony formation assays, EDU assays, flow cytometry and γH2AX assay were used with or without radiation exposure, separately. The quantities of the autophagosomes and autolysosomes by immunofluorescence were calculated. Autophagic microstructure were discovered by transmission electron microscopy, and the study also repeated in vivo by nude mice. Western blot assay was applied to prove changes in relative proteins. We found that suppressing ATP6V1C1 increased the sensitivity of ESCC cells after RT. Silencing ATP6V1C1 with IR suppressed the tumor growth and promoted autophagy. Besides, the underlying mechanism of ATP6V1C1, which is not fatally disrupted, is that ATP6V1C1 with ionizing radiation (IR)decreased apoptosis and inhibited autophagy may by activating mTOR signaling to suppress radiosensitivity for ESCC cells. Thus, we first reported that the ATP6V1C1 may represent a potential radiotherapeutic target by effect on radiation sensitivity for ESCC.
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19
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Faivre A, Scholz CC, de Seigneux S. Hypoxia in chronic kidney disease: towards a paradigm shift? Nephrol Dial Transplant 2020; 36:1782-1790. [PMID: 33895835 DOI: 10.1093/ndt/gfaa091] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Indexed: 11/15/2022] Open
Abstract
Chronic kidney disease (CKD) is defined as an alteration of kidney structure and/or function lasting for >3 months [1]. CKD affects 10% of the general adult population and is responsible for large healthcare costs [2]. Since the end of the last century, the role of hypoxia in CKD progression has controversially been discussed. To date, there is evidence of the presence of hypoxia in late-stage renal disease, but we lack time-course evidence, stage correlation and also spatial co-localization with fibrotic lesions to ensure its causative role. The classical view of hypoxia in CKD progression is that it is caused by peritubular capillary alterations, renal anaemia and increased oxygen consumption regardless of the primary injury. In this classical view, hypoxia is assumed to further induce pro-fibrotic and pro-inflammatory responses, as well as oxidative stress, leading to CKD worsening as part of a vicious circle. However, recent investigations tend to question this paradigm, and both the presence of hypoxia and its role in CKD progression are still not clearly demonstrated. Hypoxia-inducible factor (HIF) is the main transcriptional regulator of the hypoxia response. Genetic HIF modulation leads to variable effects on CKD progression in different murine models. In contrast, pharmacological modulation of the HIF pathway [i.e. by HIF hydroxylase inhibitors (HIs)] appears to be generally protective against fibrosis progression experimentally. We here review the existing literature on the role of hypoxia, the HIF pathway and HIF HIs in CKD progression and summarize the evidence that supports or rejects the hypoxia hypothesis, respectively.
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Affiliation(s)
- Anna Faivre
- Department of Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Carsten C Scholz
- Institute of Physiology, University of Zurich, Zurich, Switzerland.,National Centre of Competence in Research "Kidney.CH", Zurich, Switzerland
| | - Sophie de Seigneux
- Department of Cell physiology and Metabolism, University of Geneva, Geneva, Switzerland.,National Centre of Competence in Research "Kidney.CH", Zurich, Switzerland.,Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland
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20
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Kračun D, Klop M, Knirsch A, Petry A, Kanchev I, Chalupsky K, Wolf CM, Görlach A. NADPH oxidases and HIF1 promote cardiac dysfunction and pulmonary hypertension in response to glucocorticoid excess. Redox Biol 2020; 34:101536. [PMID: 32413743 PMCID: PMC7226895 DOI: 10.1016/j.redox.2020.101536] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 03/31/2020] [Accepted: 04/04/2020] [Indexed: 12/22/2022] Open
Abstract
Cardiovascular side effects are frequent problems accompanying systemic glucocorticoid therapy, although the underlying mechanisms are not fully resolved. Reactive oxygen species (ROS) have been shown to promote various cardiovascular diseases although the link between glucocorticoid and ROS signaling has been controversial. As the family of NADPH oxidases has been identified as important source of ROS in the cardiovascular system we investigated the role of NADPH oxidases in response to the synthetic glucocorticoid dexamethasone in the cardiovascular system in vitro and in vivo in mice lacking functional NADPH oxidases due to a mutation in the gene coding for the essential NADPH oxidase subunit p22phox. We show that dexamethasone induced NADPH oxidase-dependent ROS generation, leading to vascular proliferation and angiogenesis due to activation of the transcription factor hypoxia-inducible factor-1 (HIF1). Chronic treatment of mice with low doses of dexamethasone resulted in the development of systemic hypertension, cardiac hypertrophy and left ventricular dysfunction, as well as in pulmonary hypertension and pulmonary vascular remodeling. In contrast, mice deficient in p22phox-dependent NADPH oxidases were protected against these cardiovascular side effects. Mechanistically, dexamethasone failed to upregulate HIF1α levels in these mice, while vascular HIF1α deficiency prevented pulmonary vascular remodeling. Thus, p22phox-dependent NADPH oxidases and activation of the HIF pathway are critical elements in dexamethasone-induced cardiovascular pathologies and might provide interesting targets to limit cardiovascular side effects in patients on chronic glucocorticoid therapy.
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Affiliation(s)
- Damir Kračun
- Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich at the Technical University Munich, Munich, 80636, Germany
| | - Mathieu Klop
- Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich at the Technical University Munich, Munich, 80636, Germany
| | - Anna Knirsch
- Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich at the Technical University Munich, Munich, 80636, Germany
| | - Andreas Petry
- Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich at the Technical University Munich, Munich, 80636, Germany
| | - Ivan Kanchev
- Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich at the Technical University Munich, Munich, 80636, Germany
| | - Karel Chalupsky
- Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich at the Technical University Munich, Munich, 80636, Germany; Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v. v. i., Prague, Czech Republic
| | - Cordula M Wolf
- Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich at the Technical University Munich, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Agnes Görlach
- Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich at the Technical University Munich, Munich, 80636, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
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21
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Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 2020; 21:363-383. [PMID: 32231263 DOI: 10.1038/s41580-020-0230-3] [Citation(s) in RCA: 2727] [Impact Index Per Article: 545.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2020] [Indexed: 02/07/2023]
Abstract
'Reactive oxygen species' (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as 'oxidative distress'. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (H2O2) and the superoxide anion radical (O2·-), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H2O2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).
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Affiliation(s)
- Helmut Sies
- Institute for Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. .,Leibniz Research Institute for Environmental Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Dean P Jones
- Department of Medicine, Emory University, Atlanta, GA, USA.
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Han G, Wei P, He M, Teng H. Glucose Metabolic Characterization of Human Aqueous Humor in Relation to Wet Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2020; 61:49. [PMID: 32232346 PMCID: PMC7401462 DOI: 10.1167/iovs.61.3.49] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose Energy compromise underpins wet age-related macular degeneration (wAMD) pathogenesis, but the relationship between glucose metabolism and the disease remains unclear. Here, we characterized aqueous humor (AH) to elucidate glucose-related metabolic signatures in patients with wAMD. Methods In total, 25 eyes of 25 patients with wAMD were divided into phakic (15 eyes), pseudophakic (10 eyes), and intravitreal injections of ranibizumab (13 eyes) wAMD groups. Twenty patients with cataract (21 eyes) served as controls. Ultrahigh-performance liquid chromatography tandem mass spectrometry was used to quantitatively characterize AH. Results Twenty-one metabolites related to glucose metabolism were identified in AH from 45 patients. Tricarboxylic acid (TCA)-related metabolic substrates, including citrate, were detected in AH and were significantly increased in AMD (P < 0.01) and AMD pseudophakic groups (P < 0.05). In contrast, α-ketoglutarate levels were decreased in the AMD group (P < 0.05). The α-ketoglutarate/citrate ratio was significantly decreased, corresponding to 71.71% and 93.6% decreases in the AMD (phakic and pseudophakic) groups as compared with controls (P < 0.001), revealing a significant positive correlation with glutamine. A lower mean glutamine and higher glutamate level were detected in AMD cases compared with controls. No significant differences were observed for lactic acid or other Krebs cycle metabolites. Intravitreal injection significantly alleviated mean central foveal thickness but did not significantly alter metabolites. Conclusions Compromised glucose TCA cycle and altered glutamine metabolism are implicated in the AH metabolism in wAMD. These findings highlight potential treatments for alleviating wAMD from a metabolic perspective.
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Sadaghianloo N, Contenti J, Dardik A, Mazure NM. Role of Hypoxia and Metabolism in the Development of Neointimal Hyperplasia in Arteriovenous Fistulas. Int J Mol Sci 2019; 20:ijms20215387. [PMID: 31671790 PMCID: PMC6862436 DOI: 10.3390/ijms20215387] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 10/24/2019] [Accepted: 10/25/2019] [Indexed: 12/11/2022] Open
Abstract
For patients with end-stage renal disease requiring hemodialysis, their vascular access is both their lifeline and their Achilles heel. Despite being recommended as primary vascular access, the arteriovenous fistula (AVF) shows sub-optimal results, with about 50% of patients needing a revision during the year following creation. After the AVF is created, the venous wall must adapt to new environment. While hemodynamic changes are responsible for the adaptation of the extracellular matrix and activation of the endothelium, surgical dissection and mobilization of the vein disrupt the vasa vasorum, causing wall ischemia and oxidative stress. As a consequence, migration and proliferation of vascular cells participate in venous wall thickening by a mechanism of neointimal hyperplasia (NH). When aggressive, NH causes stenosis and AVF dysfunction. In this review we show how hypoxia, metabolism, and flow parameters are intricate mechanisms responsible for the development of NH and stenosis during AVF maturation.
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Affiliation(s)
- Nirvana Sadaghianloo
- Centre de Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, INSERM U1065, 151 Route de St Antoine de Ginestière, BP2 3194, 06204 Nice CEDEX 03, France.
- Department of Vascular Surgery, Centre Hospitalier Universitaire de Nice, 06000 Nice, France.
| | - Julie Contenti
- Centre de Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, INSERM U1065, 151 Route de St Antoine de Ginestière, BP2 3194, 06204 Nice CEDEX 03, France.
- Department of Emergency Medicine, Centre Hospitalier Universitaire de Nice, 06000 Nice, France.
| | - Alan Dardik
- Department of Surgery and the Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA.
- Department of Surgery, VA Connecticut Healthcare Systems, West Haven, CT 06516, USA.
| | - Nathalie M Mazure
- Centre de Méditerranéen de Médecine Moléculaire (C3M), Université Côte d'Azur, INSERM U1065, 151 Route de St Antoine de Ginestière, BP2 3194, 06204 Nice CEDEX 03, France.
- Department of Vascular Surgery, Centre Hospitalier Universitaire de Nice, 06000 Nice, France.
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Chan JYH, Chan SHH. Differential impacts of brain stem oxidative stress and nitrosative stress on sympathetic vasomotor tone. Pharmacol Ther 2019; 201:120-136. [PMID: 31153955 DOI: 10.1016/j.pharmthera.2019.05.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 05/24/2019] [Indexed: 02/07/2023]
Abstract
Based on work-done in the rostral ventrolateral medulla (RVLM), this review presents four lessons learnt from studying the differential impacts of oxidative stress and nitrosative stress on sympathetic vasomotor tone and their clinical and therapeutic implications. The first lesson is that an increase in sympathetic vasomotor tone because of augmented oxidative stress in the RVLM is responsible for the generation of neurogenic hypertension. On the other hand, a shift from oxidative stress to nitrosative stress in the RVLM underpins the succession of increase to decrease in sympathetic vasomotor tone during the progression towards brain stem death. The second lesson is that, by having different cellular sources, regulatory mechanisms on synthesis and degradation, kinetics of chemical reactions, and downstream signaling pathways, reactive oxygen species and reactive nitrogen species should not be regarded as a singular moiety. The third lesson is that well-defined differential roles of oxidative stress and nitrosative stress with distinct regulatory mechanisms in the RVLM during neurogenic hypertension and brain stem death clearly denote that they are not interchangeable phenomena with unified cellular actions. Special attention must be paid to their beneficial or detrimental roles under a specific disease or a particular time-window of that disease. The fourth lesson is that, to be successful, future antioxidant therapies against neurogenic hypertension must take into consideration the much more complicated picture than that presented in this review on the generation, maintenance, regulation or modulation of the sympathetic vasomotor tone. The identification that the progression towards brain stem death entails a shift from oxidative stress to nitrosative stress in the RVLM may open a new vista for therapeutic intervention to slow down this transition.
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Affiliation(s)
- Julie Y H Chan
- Institute for Translational Research in Biomedicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China
| | - Samuel H H Chan
- Institute for Translational Research in Biomedicine, Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Republic of China.
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25
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Jo YY, Kim DW, Choi JY, Kim SG. 4-Hexylresorcinol and silk sericin increase the expression of vascular endothelial growth factor via different pathways. Sci Rep 2019; 9:3448. [PMID: 30837602 PMCID: PMC6400942 DOI: 10.1038/s41598-019-40027-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 02/07/2019] [Indexed: 12/17/2022] Open
Abstract
Angiogenesis plays an important role in active inflammation and wound healing. Our results showed that silk sericin and 4-hexylresorcinol (4HR) increased vascular endothelial growth factor (VEGF) expression in a dose-dependent manner in RAW264.7 cells. Unlike 4HR, silk sericin increased the expression of hypoxia inducible factor-1α (HIF-1α) and HIF-2α. Pretreatment with an HIF inhibitor decreased the sericin-induced increase in VEGF expression. However, the HIF inhibitor did not affect the 4HR-induced increase in VEGF expression. An inhibitor of matrix metalloproteinase (MMP) declined the 4HR-induced increase in VEGF expression. Silk sericin increased production of reactive oxygen species (ROS), whereas 4HR decreased ROS. M1 markers were increased by silk sericin treatment, and M2 markers were increased by 4HR treatment. VEGF and angiogenin expression were higher in rats treated with a 4HR-incorporated silk mat than in rats treated with a silk mat alone. In conclusion, silk sericin and 4HR increased VEGF expression in RAW264.7 cells via HIF-mediated and MMP-mediated pathways, respectively. Silk sericin exerted like pro-oxidant effects and 4HR exerted anti-oxidant effects. Rats treated with a 4HR-incorporated silk mat showed higher levels of VEGF and angiogenin than those treated with a silk mat alone.
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Affiliation(s)
- You-Young Jo
- Sericultural and Apicultural Division, National Institute of Agricultural Science, RDA, Wanju, 55365, Republic of Korea
| | - Dae-Won Kim
- Department of Oral Biochemistry, College of Dentistry, Gangneung-Wonju National University, Gangneung, 28644, Republic of Korea
| | - Je-Yong Choi
- School of Biochemistry and Cell Biology, BK21 Plus KNU Biomedical Convergence Program, Skeletal Diseases Analysis Center, Korea Mouse Phenotyping Center (KMPC), Kyungpook National University, Daegu, 41944, Republic of Korea
| | - Seong-Gon Kim
- Department of Oral and Maxillofacial Surgery, College of Dentistry, Gangneung-Wonju National University, Gangneung, 28644, Republic of Korea.
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Laurent V, Toulet A, Attané C, Milhas D, Dauvillier S, Zaidi F, Clement E, Cinato M, Le Gonidec S, Guérard A, Lehuédé C, Garandeau D, Nieto L, Renaud-Gabardos E, Prats AC, Valet P, Malavaud B, Muller C. Periprostatic Adipose Tissue Favors Prostate Cancer Cell Invasion in an Obesity-Dependent Manner: Role of Oxidative Stress. Mol Cancer Res 2019; 17:821-835. [PMID: 30606769 DOI: 10.1158/1541-7786.mcr-18-0748] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/02/2018] [Accepted: 12/19/2018] [Indexed: 11/16/2022]
Abstract
Prostate gland is surrounded by periprostatic adipose tissue (PPAT), which is increasingly believed to play a paracrine role in prostate cancer progression. Our previous work demonstrates that adipocytes promote homing of prostate cancer cells to PPAT and that this effect is upregulated by obesity. Here, we show that once tumor cells have invaded PPAT (mimicked by an in vitro model of coculture), they establish a bidirectional crosstalk with adipocytes, which promotes tumor cell invasion. Indeed, tumor cells induce adipocyte lipolysis and the free fatty acids (FFA) released are taken up and stored by tumor cells. Incubation with exogenous lipids also stimulates tumor cell invasion, underlining the importance of lipid transfer in prostate cancer aggressiveness. Transferred FFAs (after coculture or exogenous lipid treatment) stimulate the expression of one isoform of the pro-oxidant enzyme NADPH oxidase, NOX5. NOX5 increases intracellular reactive oxygen species (ROS) that, in turn, activate a HIF1/MMP14 pathway, which is responsible for the increased tumor cell invasion. In obesity, tumor-surrounding adipocytes are more prone to activate the depicted signaling pathway and to induce tumor invasion. Finally, the expression of NOX5 and MMP14 is upregulated at the invasive front of human tumors where cancer cells are in close proximity to adipocytes and this process is amplified in obese patients, underlining the clinical relevance of our results. IMPLICATIONS: Our work emphasizes the key role of adjacent PPAT in prostate cancer dissemination and proposes new molecular targets for the treatment of obese patients exhibiting aggressive diseases.
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Affiliation(s)
- Victor Laurent
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Aurélie Toulet
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Camille Attané
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Delphine Milhas
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Stéphanie Dauvillier
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Falek Zaidi
- Service d'Anatomo-Pathologie, Institut Universitaire du Cancer, Toulouse, France
| | - Emily Clement
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Mathieu Cinato
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, Inserm UMR 1048, UPS, Toulouse, France
| | - Sophie Le Gonidec
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, Inserm UMR 1048, UPS, Toulouse, France
| | - Adrien Guérard
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Camille Lehuédé
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - David Garandeau
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Laurence Nieto
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Edith Renaud-Gabardos
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, Inserm UMR 1048, UPS, Toulouse, France
| | - Anne-Catherine Prats
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, Inserm UMR 1048, UPS, Toulouse, France
| | - Philippe Valet
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université de Toulouse, Inserm UMR 1048, UPS, Toulouse, France
| | - Bernard Malavaud
- Département d'Urologie, Institut Universitaire du Cancer, Toulouse, France
| | - Catherine Muller
- Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, UPS, Toulouse, France.
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27
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Fu SC, Yeung MY, Rolf CG, Yung PSH, Chan KM, Hung LK. Hydrogen peroxide induced tendinopathic changes in a rat model of patellar tendon injury. J Orthop Res 2018; 36:3268-3274. [PMID: 30066401 DOI: 10.1002/jor.24119] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 07/26/2018] [Indexed: 02/04/2023]
Abstract
Tendinopathy includes cases with chronic tendon pain and spontaneous tendon ruptures, which is putatively resulted from failed tendon healing. Overuse is a major risk factor of tendinopathy, which can impose mechanical and oxidative stress to tendons. Previous studies investigated the influences of mechanical stress, but the direct impact of oxidative stress on tendon healing remains unclear. We hypothesized that imposed oxidative stress can impair tendon healing and lead to tendinopathic changes. Thirty-nine rats were operated for patellar tendon window injury. From weeks 3-5 post-operation, the rats received three weekly subcutaneous injections of saline, 50 or 500 μM H2 O2 (n = 13) over patellar tendon. Gait analysis for pain assessment and 3D ultrasound imaging for detection of tendinopathic changes were performed at pre-injury and 6-week post-operation. At week 6, knee specimens were harvested for histology or tensile mechanical test. Elastic modulus of the healing patellar tendons was significantly lower in 50 μM but not 500 μM H2 O2 group, while ultimate mechanical stress was not significantly different across groups. Similarly, only the 50 μM H2 O2 group exhibited pain-associated gait asymmetry. Significant tendon swelling with increased tendon volume was observed in the 50 μM H2 O2 group. There were hypoechogenic changes in the tendon wound, but there was no significant difference in percentage vascularity. H2 O2 impaired tendon healing and elicited tendinopathic changes, with respect to pain and structural abnormalities. Oxidative stress plays a role in the failed tendon healing of tendinopathies, and H2 O2 -induced failed tendon healing may serve as a good animal model to study tendinopathy. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:3268-3274, 2018.
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Affiliation(s)
- Sai-Chuen Fu
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.,Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Man-Yi Yeung
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.,Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Christer G Rolf
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.,Department of Orthopaedic Surgery, Huddinge University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Patrick Shu-Hang Yung
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.,Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Kai-Ming Chan
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.,Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Leung-Kim Hung
- Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.,Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
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28
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Tyeb S, Kumar N, Kumar A, Verma V. Flexible agar-sericin hydrogel film dressing for chronic wounds. Carbohydr Polym 2018; 200:572-582. [DOI: 10.1016/j.carbpol.2018.08.030] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 07/26/2018] [Accepted: 08/08/2018] [Indexed: 12/13/2022]
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29
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Böttcher M, Renner K, Berger R, Mentz K, Thomas S, Cardenas-Conejo ZE, Dettmer K, Oefner PJ, Mackensen A, Kreutz M, Mougiakakos D. D-2-hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing Th17 polarization. Oncoimmunology 2018; 7:e1445454. [PMID: 29900057 PMCID: PMC5993507 DOI: 10.1080/2162402x.2018.1445454] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 02/20/2018] [Accepted: 02/21/2018] [Indexed: 12/13/2022] Open
Abstract
D-2-hydroxyglutarate (D-2HG) is released by various types of malignant cells including acute myeloid leukemia (AML) blasts carrying isocitrate dehydrogenase (IDH) gain-of-function mutations. D-2HG acting as an oncometabolite promotes proliferation, anoikis, and differentiation block of hematopoietic cells in an autocrine fashion. However, prognostic impact of IDH mutations and high D-2HG levels remains controversial and might depend on the overall mutational context. An increasing number of studies focus on the permissive environment created by AML blasts to promote immune evasion. Impact of D-2HG on immune cells remains incompletely understood. Here, we sought out to investigate the effects of D-2HG on T-cells as key mediators of anti-AML immunity. D-2HG was efficiently taken up by T-cells in vitro, which is in line with high 2-HG levels measured in T-cells isolated from AML patients carrying IDH mutations. T-cell activation was slightly impacted by D-2HG. However, D-2HG triggered HIF-1a protein destabilization resulting in metabolic skewing towards oxidative phosphorylation, increased regulatory T-cell (Treg) frequency, and reduced T helper 17 (Th17) polarization. Our data suggest for the first time that D-2HG might contribute to fine tuning of immune responses.
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Affiliation(s)
- Martin Böttcher
- Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Kathrin Renner
- Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Raffaela Berger
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Kristin Mentz
- Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Simone Thomas
- Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
| | | | - Katja Dettmer
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Peter J Oefner
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Andreas Mackensen
- Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Marina Kreutz
- Internal Medicine III, Hematology and Oncology, University Hospital Regensburg, Regensburg, Germany
| | - Dimitrios Mougiakakos
- Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany
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30
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Edaravone Improves Septic Cardiac Function by Inducing an HIF-1 α/HO-1 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:5216383. [PMID: 29765498 PMCID: PMC5885492 DOI: 10.1155/2018/5216383] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2017] [Revised: 12/20/2017] [Accepted: 02/06/2018] [Indexed: 01/21/2023]
Abstract
Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia-inducible factor- (HIF-) 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO-) 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP) with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp.) before CLP and intraperitoneal injection of the HIF-1α antagonist, ME (15 mg/kg), after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1α, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1α by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1α/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction.
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31
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Santi A, Kugeratski FG, Zanivan S. Cancer Associated Fibroblasts: The Architects of Stroma Remodeling. Proteomics 2018; 18:e1700167. [PMID: 29280568 PMCID: PMC5900985 DOI: 10.1002/pmic.201700167] [Citation(s) in RCA: 166] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 12/15/2017] [Indexed: 12/24/2022]
Abstract
Fibroblasts have exceptional phenotypic plasticity and capability to secrete vast amount of soluble factors, extracellular matrix components and extracellular vesicles. While in physiological conditions this makes fibroblasts master regulators of tissue homeostasis and healing of injured tissues, in solid tumors cancer associated fibroblasts (CAFs) co-evolve with the disease, and alter the biochemical and physical structure of the tumor microenvironment, as well as the behavior of the surrounding stromal and cancer cells. Thus CAFs are fundamental regulators of tumor progression and influence response to therapeutic treatments. Increasing efforts are devoted to better understand the biology of CAFs to bring insights to develop complementary strategies to target this cell type in cancer. Here we highlight components of the tumor microenvironment that play key roles in cancer progression and invasion, and provide an extensive overview of past and emerging understanding of CAF biology as well as the contribution that MS-based proteomics has made to this field.
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Affiliation(s)
- Alice Santi
- Cancer Research UK Beatson InstituteGlasgowUK
| | | | - Sara Zanivan
- Cancer Research UK Beatson InstituteGlasgowUK
- Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
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32
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Iommarini L, Porcelli AM, Gasparre G, Kurelac I. Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer. Front Oncol 2017; 7:286. [PMID: 29230384 PMCID: PMC5711814 DOI: 10.3389/fonc.2017.00286] [Citation(s) in RCA: 171] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 11/13/2017] [Indexed: 12/21/2022] Open
Abstract
Hypoxia-inducible factor 1 alpha (HIF-1α) orchestrates cellular adaptation to low oxygen and nutrient-deprived environment and drives progression to malignancy in human solid cancers. Its canonical regulation involves prolyl hydroxylases (PHDs), which in normoxia induce degradation, whereas in hypoxia allow stabilization of HIF-1α. However, in certain circumstances, HIF-1α regulation goes beyond the actual external oxygen levels and involves PHD-independent mechanisms. Here, we gather and discuss the evidence on the non-canonical HIF-1α regulation, focusing in particular on the consequences of mitochondrial respiratory complexes damage on stabilization of this pleiotropic transcription factor.
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Affiliation(s)
- Luisa Iommarini
- Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Bologna, Italy
| | - Anna Maria Porcelli
- Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Bologna, Italy
| | - Giuseppe Gasparre
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
| | - Ivana Kurelac
- Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy
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Joyal JS, Gantner ML, Smith LEH. Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism. Prog Retin Eye Res 2017; 64:131-156. [PMID: 29175509 DOI: 10.1016/j.preteyeres.2017.11.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 11/11/2017] [Accepted: 11/15/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Jean-Sébastien Joyal
- Department of Pediatrics, Pharmacology and Ophthalmology, CHU Sainte-Justine Research Center, Université de Montréal, Montreal, Qc, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Qc, Canada.
| | - Marin L Gantner
- The Lowy Medical Research Institute, La Jolla, United States
| | - Lois E H Smith
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston MA 02115, United States.
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Ni G, Wang T, Yang L, Wang Y, Liu X, Wei MQ. Combining anaerobic bacterial oncolysis with vaccination that blocks interleukin-10 signaling may achieve better outcomes for late stage cancer management. Hum Vaccin Immunother 2017; 12:599-606. [PMID: 26367244 DOI: 10.1080/21645515.2015.1089008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Late stage solid tumors cause significant cancer mortality rates worldwide and effective therapy remains a big challenge. Cancer therapeutic vaccines elicit tumor specific T cells that kill tumor cells yet often fail to result in tumor destruction because of the limited T cell response and the local immune-suppressive environment. Blocking interleukin 10 (IL-10) signaling at the time of therapeutic vaccination elicits much stronger T cell responses than vaccination without IL-10 blocking. Anaerobic oncolytic bacteria target hypoxic regions of the late stage tumor tissues which not only stops tumor growth but also provides a pro-inflammatory environment that may increase the effectiveness of a therapeutic vaccine by recruiting more effector T cells to tumor site. In this review, we argue that combining both bacterial and vaccine therapies may improve the efficiency of late stage cancer management.
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Affiliation(s)
- Guoying Ni
- a School of Medical Science and Griffith Health Institute, Griffith University , Gold Coast , QLD , Australia.,d Tangshan Supervision Institute of Health , Tangshan , China
| | - Tianfang Wang
- c Genecology Research Center, University of the Sunshine Coast , Maroochydore DC , QLD , Australia
| | - Lin Yang
- f Department of Surgical Oncology , Tangshan Gongren Hospital , Tangshan , Hebei , China
| | - Yuejian Wang
- e Cancer Research Institute, Foshan First People's Hospital , Foshan, Guangdong , China
| | - Xiaosong Liu
- b Inflammation and Healing Research Cluster, University of the Sunshine Coast , Maroochydore DC , QLD , Australia.,e Cancer Research Institute, Foshan First People's Hospital , Foshan, Guangdong , China
| | - Ming Q Wei
- a School of Medical Science and Griffith Health Institute, Griffith University , Gold Coast , QLD , Australia
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Sadaghianloo N, Yamamoto K, Bai H, Tsuneki M, Protack CD, Hall MR, Declemy S, Hassen-Khodja R, Madri J, Dardik A. Increased Oxidative Stress and Hypoxia Inducible Factor-1 Expression during Arteriovenous Fistula Maturation. Ann Vasc Surg 2017; 41:225-234. [PMID: 28163173 PMCID: PMC5411319 DOI: 10.1016/j.avsg.2016.09.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 09/19/2016] [Accepted: 09/19/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND The poor clinical results that are frequently reported for arteriovenous fistulae (AVF) for hemodialysis are typically due to failure of AVF maturation. We hypothesized that early AVF maturation is associated with generation of reactive oxygen species and activation of the hypoxia-inducible factor-1 (HIF-1) pathway, potentially promoting neointimal hyperplasia. We tested this hypothesis using a previously reported mouse AVF model that recapitulates human AVF maturation. METHODS Aortocaval fistulae were created in C57Bl/6 mice and compared with sham-operated mice. AVFs or inferior vena cavas were analyzed using a microarray, Amplex Red for extracellular H2O2, quantitative polymerase chain reaction, immunohistochemistry, and immunoblotting for HIF-1α and immunofluorescence for NOX-2, nitrotyrosine, heme oxygenase-1 (HO-1), and vascular endothelial growth factor (VEGF)-A. RESULTS Oxidative stress was higher in AVF than that in control veins, with more H2O2 (P = 0.007) and enhanced nitrotyrosine immunostaining (P = 0.005). Immunohistochemistry and immunoblot showed increased HIF-1α immunoreactivity in the AVF endothelium; HIF-1 targets NOX-2, HO-1 and VEGF-A were overexpressed in the AVF (P < 0.01). AVF expressed increased numbers of HIF-1α (P < 0.0001) and HO-1 (P < 0.0001) messenger RNA transcripts. CONCLUSIONS Oxidative stress increases in mouse AVF during early maturation, with increased expression of HIF-1α and its target genes NOX-2, HO-1, and VEGF-A. These results suggest that clinical strategies to improve AVF maturation could target the HIF-1 pathway.
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Affiliation(s)
- Nirvana Sadaghianloo
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Vascular Surgery, University Hospital of Nice-Sophia Antipolis, Nice, France.
| | - Kota Yamamoto
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Surgery, Yale University School of Medicine, New Haven, CT; Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hualong Bai
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Vascular Surgery, First Affiliated Hospital of Zhengzhou University, Henan, China
| | - Masayuki Tsuneki
- National Cancer Center Research Institute, Tokyo, Japan; Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Clinton D Protack
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Surgery, Yale University School of Medicine, New Haven, CT
| | - Michael R Hall
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Surgery, Yale University School of Medicine, New Haven, CT
| | - Serge Declemy
- Department of Vascular Surgery, University Hospital of Nice-Sophia Antipolis, Nice, France
| | - Réda Hassen-Khodja
- Department of Vascular Surgery, University Hospital of Nice-Sophia Antipolis, Nice, France
| | - Joseph Madri
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Alan Dardik
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Surgery, Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare Systems, West Haven, CT
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Lee EK, Shin YJ, Park EY, Kim ND, Moon A, Kwack SJ, Son JY, Kacew S, Lee BM, Bae ON, Kim HS. Selenium-binding protein 1: a sensitive urinary biomarker to detect heavy metal-induced nephrotoxicity. Arch Toxicol 2017; 91:1635-1648. [PMID: 27578022 DOI: 10.1007/s00204-016-1832-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 08/24/2016] [Indexed: 11/24/2022]
Abstract
Identifying novel biomarkers to detect nephrotoxicity is clinically important. Here, we attempted to identify new biomarkers for mercury-induced nephrotoxicity and compared their sensitivity to that of traditional biomarkers in animal models. Comparative proteomics analysis was performed in kidney tissues of Sprague-Dawley rats after oral treatment with HgCl2 (0.1, 1, or 5 mg/kg/day) for 21 days. Kidney cortex tissues were analyzed by two-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization, and differentially expressed proteins were identified. The corresponding spots were quantitated by RT-PCR. Selenium-binding protein 1 (SBP1) was found to be the most markedly upregulated protein in the kidney cortex of rats after HgCl2 administration. However, blood urea nitrogen, serum creatinine, and glucose levels increased significantly only in the 1 or 5 mg/kg HgCl2-treated groups. A number of urinary excretion proteins, including kidney injury molecule-1, clusterin, monocyte chemoattractant protein-1, and β-microglobulin, increased dose-dependently. Histopathological examination revealed severe proximal tubular damage in high-dose (5 mg/kg) HgCl2-exposed groups. In addition, urinary excretion of SBP1 significantly increased in a dose-dependent manner. To confirm the critical role of SBP1 as a biomarker for nephrotoxicity, normal kidney proximal tubular cells were treated with HgCl2, CdCl2, or cisplatin for 24 h. SBP1 levels significantly increased in conditioned media exposed to nephrotoxicants, but decreased in cell lysates. Our investigations suggest that SBP1 may play a critical role in the pathological processes underlying chemical-induced nephrotoxicity. Thus, urinary excretion of SBP1 might be a sensitive and specific biomarker to detect early stages of kidney injury.
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Affiliation(s)
- Eui Kyung Lee
- College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea
| | - Young-Jun Shin
- College of Pharmacy, Hanyang University, Ansan, 426-791, Republic of Korea
| | - Eun Young Park
- College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea
| | - Nam Deuk Kim
- College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea
| | - Aree Moon
- College of Pharmacy, Duksung Women's University, Seoul, 132-714, Republic of Korea
| | - Seung Jun Kwack
- Department of Biochemistry and Health Science, Changwon National University, Gyeongnam, 641-773, Republic of Korea
| | - Ji Yeon Son
- School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea
| | - Sam Kacew
- McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, ON, Canada
| | - Byung Mu Lee
- School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea
| | - Ok-Nam Bae
- College of Pharmacy, Hanyang University, Ansan, 426-791, Republic of Korea.
| | - Hyung Sik Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Republic of Korea.
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Abstract
SIGNIFICANCE In the last years, metabolic reprogramming, fluctuations in bioenergetic fuels, and modulation of oxidative stress became new key hallmarks of tumor development. In cancer, elevated glucose uptake and high glycolytic rate, as a source of adenosine triphosphate, constitute a growth advantage for tumors. This represents the universally known Warburg effect, which gave rise to one major clinical application for detecting cancer cells using glucose analogs: the positron emission tomography scan imaging. Recent Advances: Glucose utilization and carbon sources in tumors are much more heterogeneous than initially thought. Indeed, new studies emerged and revealed a dual capacity of tumor cells for glycolytic and oxidative phosphorylation (OXPHOS) metabolism. OXPHOS metabolism, which relies predominantly on mitochondrial respiration, exhibits fine-tuned regulation of respiratory chain complexes and enhanced antioxidant response or detoxification capacity. CRITICAL ISSUES OXPHOS-dependent cancer cells use alternative oxidizable substrates, such as glutamine and fatty acids. The diversity of carbon substrates fueling neoplastic cells is indicative of metabolic heterogeneity, even within tumors sharing the same clinical diagnosis. Metabolic switch supports cancer cell stemness and their bioenergy-consuming functions, such as proliferation, survival, migration, and invasion. Moreover, reactive oxygen species-induced mitochondrial metabolism and nutrient availability are important for interaction with tumor microenvironment components. Carcinoma-associated fibroblasts and immune cells participate in the metabolic interplay with neoplastic cells. They collectively adapt in a dynamic manner to the metabolic needs of cancer cells, thus participating in tumorigenesis and resistance to treatments. FUTURE DIRECTIONS Characterizing the reciprocal metabolic interplay between stromal, immune, and neoplastic cells will provide a better understanding of treatment resistance. Antioxid. Redox Signal. 26, 462-485.
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Affiliation(s)
- Géraldine Gentric
- 1 Stress and Cancer Laboratory, Équipe Labelisée LNCC, Institut Curie , Paris, France .,2 Inserm , U830, Paris, France
| | - Virginie Mieulet
- 1 Stress and Cancer Laboratory, Équipe Labelisée LNCC, Institut Curie , Paris, France .,2 Inserm , U830, Paris, France
| | - Fatima Mechta-Grigoriou
- 1 Stress and Cancer Laboratory, Équipe Labelisée LNCC, Institut Curie , Paris, France .,2 Inserm , U830, Paris, France
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Ocaña GJ, Pérez L, Guindon L, Deffit SN, Evans-Molina C, Thurmond DC, Blum JS. Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90α. Immunology 2017; 151:198-210. [PMID: 28190264 DOI: 10.1111/imm.12723] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 01/19/2017] [Accepted: 02/05/2017] [Indexed: 12/26/2022] Open
Abstract
A major obstacle in predicting and preventing the development of autoimmune type 1 diabetes (T1D) in at-risk individuals is the lack of well-established early biomarkers indicative of ongoing beta cell stress during the pre-clinical phase of disease. Recently, serum levels of the α cytoplasmic isoform of heat-shock protein 90 (hsp90) were shown to be elevated in individuals with new-onset T1D. We therefore hypothesized that hsp90α could be released from beta cells in response to cellular stress and inflammation associated with the earliest stages of T1D. Here, human beta cell lines and cadaveric islets released hsp90α in response to stress induced by treatment with a combination of pro-inflammatory cytokines including interleukin-1β, tumour necrosis factor-α and interferon-γ. Mechanistically, hsp90α release was found to be driven by cytokine-induced endoplasmic reticulum stress mediated by c-Jun N-terminal kinase (JNK), a pathway that can eventually lead to beta cell apoptosis. Cytokine-induced beta cell hsp90α release and JNK activation were significantly reduced by pre-treating cells with the endoplasmic reticulum stress-mitigating chemical chaperone tauroursodeoxycholic acid. The hsp90α release by cells may therefore be a sensitive indicator of stress during inflammation and a useful tool in assessing therapeutic mitigation of cytokine-induced cell damage linked to autoimmunity.
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Affiliation(s)
- Gail J Ocaña
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Liliana Pérez
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Lynette Guindon
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Sarah N Deffit
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Carmella Evans-Molina
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.,Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Debbie C Thurmond
- Department of Molecular and Cellular Endocrinology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Janice S Blum
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
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Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol 2017; 43:74-89. [PMID: 28267587 DOI: 10.1016/j.semcancer.2017.03.001] [Citation(s) in RCA: 405] [Impact Index Per Article: 50.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 02/22/2017] [Accepted: 03/01/2017] [Indexed: 12/21/2022]
Abstract
The link between cancer metabolism and immunosuppression, inflammation and immune escape has generated major interest in investigating the effects of low pH on tumor immunity. Indeed, microenvironmental acidity may differentially impact on diverse components of tumor immune surveillance, eventually contributing to immune escape and cancer progression. Although the molecular pathways underlying acidity-related immune dysfunctions are just emerging, initial evidence indicates that antitumor effectors such as T and NK cells tend to lose their function and undergo a state of mostly reversible anergy followed by apoptosis, when exposed to low pH environment. At opposite, immunosuppressive components such as myeloid cells and regulatory T cells are engaged by tumor acidity to sustain tumor growth while blocking antitumor immune responses. Local acidity could also profoundly influence bioactivity and distribution of antibodies, thus potentially interfering with the clinical efficacy of therapeutic antibodies including immune checkpoint inhibitors. Hence tumor acidity is a central regulator of cancer immunity that orchestrates both local and systemic immunosuppression and that may offer a broad panel of therapeutic targets. This review outlines the fundamental pathways of acidity-driven immune dysfunctions and sheds light on the potential strategies that could be envisaged to potentiate immune-mediated tumor control in cancer patients.
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Klumpen E, Hoffschröer N, Zeis B, Gigengack U, Dohmen E, Paul RJ. Reactive oxygen species (ROS) and the heat stress response of Daphnia pulex: ROS-mediated activation of hypoxia-inducible factor 1 (HIF-1) and heat shock factor 1 (HSF-1) and the clustered expression of stress genes. Biol Cell 2016; 109:39-64. [PMID: 27515976 DOI: 10.1111/boc.201600017] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 08/09/2016] [Indexed: 11/30/2022]
Abstract
BACKGROUND INFORMATION Heat stress in ectotherms involves direct (e.g. protein damage) and/or indirect effects (temperature-induced hypoxia and ROS formation), which cause activation of the transcription factors (TF) heat shock factor 1 (HSF-1) and/or hypoxia-inducible factor 1 (HIF-1). The present study focused on the links between stress (ROS) signals, nuclear (n) and cytoplasmic (c) HSF-1/HIF-1 levels, and stress gene expression on mRNA and protein levels (e.g. heat-shock protein 90, HSP90) upon acute heat and ROS (H2 O2 ) stress. RESULTS Acute heat stress (30°C) evoked fluctuations in ROS level. Different feeding regimens, which affected the glutathione (GSH) level, allowed altering the frequency of ROS fluctuations. Other data showed fluctuation frequency to depend also on ROS production rate. The heat-induced slow or fast ROS fluctuations (at high or low GSH levels) evoked slow or fast fluctuations in the levels of nHIF-1α, nHSF-1 and gene products (mRNAs and protein), albeit after different time delays. Time delays to ROS fluctuations were, for example,shorter for nHIF-1α than for nHSF-1 fluctuations, and nHIF-1α fluctuations preceded and nHSF-1 fluctuations followed fluctuations in HSP90 mRNA level. Cytoplasmic TF levels either changed little (cHIF-1α) or showed a steady increase (cHSF-1). Applying acute H2 O2 stress (at 20°C) revealed effects on nHIF-1α and mRNA levels, but no significant effects on nHSF-1 level. Transcriptome data additionally showed coordinated fluctuations of mRNA levels upon acute heat stress, involving mRNAs for HSPs and other stress proteins, with all corresponding genes carrying DNA binding motifs for HIF-1 and HSF-1. CONCLUSIONS This study provided evidence for promoting effects of ROS and HIF-1 on early haemoglobin, HIF-1α and HSP90 mRNA expressions upon heat or ROS stress. The increasing cHSF-1 level likely affected nHSF-1 level and later HSP90 mRNA expression. SIGNIFICANCE Heat stress evoked ROS fluctuations, with this stress signal forwarded via nHIF-1 and nHSF-1 fluctuations to stress gene expression. The frequency of ROS fluctuations seemed to integrate information about ROS productionrate and GSH antioxidant buffer capacity, resulting in stress protein expression of different speed. Results of this study suggest ROS as early (pre-damage) and protein defects as later (post-damage) stress signals to trigger heat stress responses.
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Affiliation(s)
- Eva Klumpen
- Institute of Zoophysiology, WWU Münster, Münster, Germany
| | | | - Bettina Zeis
- Institute of Zoophysiology, WWU Münster, Münster, Germany
| | | | - Elias Dohmen
- Institute of Zoophysiology, WWU Münster, Münster, Germany
| | - Rüdiger J Paul
- Institute of Zoophysiology, WWU Münster, Münster, Germany
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Mavrofrydi O, Mavroeidi P, Papazafiri P. Comparative assessment of HIF-1α and Akt responses in human lung and skin cells exposed to benzo[α]pyrene: Effect of conditioned medium from pre-exposed primary fibroblasts. ENVIRONMENTAL TOXICOLOGY 2016; 31:1103-1112. [PMID: 25728052 DOI: 10.1002/tox.22119] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 01/08/2015] [Accepted: 01/10/2015] [Indexed: 06/04/2023]
Abstract
Exposure to atmospheric pollutants has been accused for many adverse health effects. Benzo[α]pyrene (Β[α]Ρ) in particular, the most extensively studied member of pollutants, is implicated in both cancer initiation and promotion. In the present study, we compared the effects of noncytotoxic doses of Β[α]Ρ, between human skin and lung epithelial cells A431 and A549, respectively, focusing on Akt kinase and HIF-1α, as it is well known that these proteins are upregulated in various human cancers promoting survival, angiogenesis and metastasis of tumor cells. Also, taking into consideration that fibroblasts are involved in cancer progression, we tested the possible modulation of epithelial cell response by paracrine factors secreted by Β[α]Ρ-treated fibroblasts. Low doses of Β[α]Ρ were found to enhance epithelial cell proliferation and upregulate both Akt kinase and HIF-1α, with A549 cells exhibiting a more sustained profile of upregulation. It is to notice that, the response of HIF-1α was remarkably early, acting as a sensitive marker in response to airborne pollutants. Also, HIF-1α was induced by Β[α]Ρ in both lung and skin fibroblasts indicating that this effect may be conserved throughout different cell types and tissues. Interestingly however, the response of both proteins was differentially modified upon treatment with conditioned medium from Β[α]Ρ-exposed fibroblasts. This is particularly evident in A459 cells and confirms the critical role of intercellular and paracrine factors in the modulation of the final response to an extracellular signal. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1103-1112, 2016.
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Affiliation(s)
- Olga Mavrofrydi
- Division of Animal and Human Physiology, Department of Biology, University of Athens, 15784 Panepistimiopolis, Ilissia, Athens, Greece
| | - Panagiota Mavroeidi
- Division of Animal and Human Physiology, Department of Biology, University of Athens, 15784 Panepistimiopolis, Ilissia, Athens, Greece
| | - Panagiota Papazafiri
- Division of Animal and Human Physiology, Department of Biology, University of Athens, 15784 Panepistimiopolis, Ilissia, Athens, Greece
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Wilkins SE, Abboud MI, Hancock RL, Schofield CJ. Targeting Protein-Protein Interactions in the HIF System. ChemMedChem 2016; 11:773-86. [PMID: 26997519 PMCID: PMC4848768 DOI: 10.1002/cmdc.201600012] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 02/24/2016] [Indexed: 12/18/2022]
Abstract
Animals respond to chronic hypoxia by increasing the levels of a transcription factor known as the hypoxia-inducible factor (HIF). HIF upregulates multiple genes, the products of which work to ameliorate the effects of limited oxygen at cellular and systemic levels. Hypoxia sensing by the HIF system involves hydroxylase-catalysed post-translational modifications of the HIF α-subunits, which 1) signal for degradation of HIF-α and 2) limit binding of HIF to transcriptional coactivator proteins. Because the hypoxic response is relevant to multiple disease states, therapeutic manipulation of the HIF-mediated response has considerable medicinal potential. In addition to modulation of catalysis by the HIF hydroxylases, the HIF system manifests other possibilities for therapeutic intervention involving protein-protein and protein-nucleic acid interactions. Recent advances in our understanding of the structural biology and biochemistry of the HIF system are facilitating medicinal chemistry efforts. Herein we give an overview of the HIF system, focusing on structural knowledge of protein-protein interactions and how this might be used to modulate the hypoxic response for therapeutic benefit.
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Affiliation(s)
- Sarah E Wilkins
- Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
| | - Martine I Abboud
- Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
| | - Rebecca L Hancock
- Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK
| | - Christopher J Schofield
- Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
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Farías JG, Herrera EA, Carrasco-Pozo C, Sotomayor-Zárate R, Cruz G, Morales P, Castillo RL. Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress. Pharmacol Ther 2015; 158:1-23. [PMID: 26617218 DOI: 10.1016/j.pharmthera.2015.11.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hypoxia is the failure of oxygenation at the tissue level, where the reduced oxygen delivered is not enough to satisfy tissue demands. Metabolic depression is the physiological adaptation associated with reduced oxygen consumption, which evidently does not cause any harm to organs that are exposed to acute and short hypoxic insults. Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability of endogenous antioxidant systems to scavenge ROS, where ROS overwhelms the antioxidant capacity. Oxidative stress plays a crucial role in the pathogenesis of diseases related to hypoxia during intrauterine development and postnatal life. Thus, excessive ROS are implicated in the irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Here, we describe several pathophysiological conditions and in vivo and ex vivo models developed for the study of hypoxic and oxidative stress injury. We reviewed existing literature on the responses to hypoxia and oxidative stress of the cardiovascular, renal, reproductive, and central nervous systems, and discussed paradigms of chronic and intermittent hypobaric hypoxia. This systematic review is a critical analysis of the advantages in the application of some experimental strategies and their contributions leading to novel pharmacological therapies.
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Affiliation(s)
- Jorge G Farías
- Facultad de Ingeniería y Ciencias, Departamento de Ingeniería Química, Universidad de la Frontera, Casilla 54-D, Temuco, Chile
| | - Emilio A Herrera
- Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Chile; International Center for Andean Studies (INCAS), Universidad de Chile, Chile
| | | | - Ramón Sotomayor-Zárate
- Centro de Neurobiología y Plasticidad Cerebral (CNPC), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Chile
| | - Gonzalo Cruz
- Centro de Neurobiología y Plasticidad Cerebral (CNPC), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Chile
| | - Paola Morales
- Programa de Farmacología Molecular y Clínica, ICBM, Facultad de Medicina, Universidad de Chile, Chile
| | - Rodrigo L Castillo
- Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Chile.
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Braunschweig L, Meyer AK, Wagenführ L, Storch A. Oxygen regulates proliferation of neural stem cells through Wnt/β-catenin signalling. Mol Cell Neurosci 2015; 67:84-92. [PMID: 26079803 DOI: 10.1016/j.mcn.2015.06.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 06/10/2015] [Accepted: 06/12/2015] [Indexed: 11/25/2022] Open
Abstract
Reduced oxygen levels (1-5% O2, named herein 'physioxia') are beneficial for stem cell cultures leading to enhanced proliferation, better survival and higher differentiation potential, but the underlying molecular mechanisms remain elusive. A potential link between physioxia and the canonical Wnt pathway was found recently, but the differential involvement of this signalling pathway for the various stem cell properties such as proliferation, stem cell maintenance, and differentiation capacity remains enigmatic. We here demonstrate increased Wnt target gene transcription and stabilised active β-catenin upon physioxic cell culture in primary tissue-specific foetal mouse neural stem cells. Knock-out of the main oxygen sensing molecule, hypoxia-inducible factor-1α (Hif-1α), had no impact on Wnt activation assuming that physioxia induces the Wnt pathway independently of Hif-1α. To determine the physiological relevance of physioxia-induced Wnt/β-catenin signalling, we examined proliferation, cell cycle kinetics, survival and stem cell maintenance upon Wnt activation and inhibition. Whereas survival and stem cell maintenance seem to be independent of the Wnt pathway, our studies provide first evidence that Wnt/β-catenin signalling positively stimulates proliferation of physioxic cells by affecting cell cycle regulation. Together, our results provide mechanistic insight into oxygen-mediated regulation of the self-renewal activity of neural stem cells.
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Affiliation(s)
- Lena Braunschweig
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany
| | - Anne K Meyer
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany; Leibniz Institute for Solid State and Material Research, IFW Dresden, Institute for Integrative Nanosciences, Helmholtzstrasse 20, 01069 Dresden, Germany
| | - Lisa Wagenführ
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany
| | - Alexander Storch
- Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany; Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany; German Centre for Neurodegenerative Diseases (DZNE) Dresden, 01307 Dresden, Germany.
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Tan X, Yin R, Chen Y, Gao D, Zhang X. Postconditioning attenuates renal ischemia-reperfusion injury by mobilization of stem cells. J Nephrol 2015; 28:289-98. [PMID: 25663348 DOI: 10.1007/s40620-015-0171-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 01/08/2015] [Indexed: 11/29/2022]
Abstract
BACKGROUND We recently showed that reactive oxygen species (ROS) and mitochondrial DNA damage and deletions were attenuated by postconditioning (POC). It is not known, however, whether a population of progenitor cells is recruited by POC and is responsible for repair of renal tubular epithelial cells after ischemic injury. METHODS The model of renal POC was induced by 45 min clamping of the left renal artery and right nephrectomy followed by 7 min of short-time full reperfusion and 3 cycles of 30 s ischemia and 30 s reperfusion. The lymphocyte compartment of peripheral blood was evaluated by fluorescence-activated cell sorting (FACS) to determine expression of the bone marrow-derived progenitor cell markers CXC-chemokine receptor 4 (CXCR4), c-Kit, and CD34, at 12 h, 1 day and 3 days post-ischemia. Serum and kidney tissue were collected for analysis at 3 and 7 days post-ischemia. RESULTS Renal functional and structural recovery was markedly improved by POC, which increased the number of CXCR4(+) and CD34(+) stem cells in peripheral blood and kidney tissue. Inhibition of ROS burst by POC was likely associated with increased hypoxia-inducible factor-1 expression, which may further promote stromal cell-derived factor 1 (SDF-1) expression. CONCLUSIONS The mechanisms of stem cell recruitment to the injured foci mobilized by POC appear to be mediated by moderate oxidative stress, which may lead to increased SDF-1 expression.
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Affiliation(s)
- Xiaohua Tan
- Key Laboratory of Biotechnology and Pharmaceutical Engineering, Molecular Pharmacology Research Center, School of Pharmacy, Wenzhou Medical University, Wenzhou, China
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Cindrova-Davies T, van Patot MT, Gardner L, Jauniaux E, Burton GJ, Charnock-Jones DS. Energy status and HIF signalling in chorionic villi show no evidence of hypoxic stress during human early placental development. Mol Hum Reprod 2014; 21:296-308. [PMID: 25391298 PMCID: PMC4339857 DOI: 10.1093/molehr/gau105] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Early human placental and embryonic development occurs in a physiologically low oxygen environment supported by histiotrophic secretions from endometrial glands. In this study, we compare the placental metabolomic profile in the first, second and third trimesters to determine whether the energy demands are adequately met in the first trimester. We investigated whether hypoxia-inducible factors, HIF-1α and/or HIF-2α, might regulate transcription during the first trimester. First and second trimester tissue was collected using a chorionic villus sampling-like (CVS) technique. Part of each villus sample was frozen immediately and the remainder cultured under 2 or 21% O2 ± 1 mM H2O2, and ±the p38 MAPK pathway inhibitor, PD169316. Levels of HIF-1α were assessed by western blotting and VEGFA, PlGF and GLUT3 transcripts were quantified by RT-PCR. Term samples were collected from normal elective Caesarean deliveries. There were no significant differences in concentrations of ADP, NAD(+), lactate, and glucose, and in the ATP/ADP ratio, across gestational age. Neither HIF-1α nor HIF-2α could be detected in time-zero CVS samples. However, culture under any condition (2 or 21% O2 ± 1 mM H2O2) increased HIF-1α and HIF-2α. HIF-1α and HIF-2α were additionally detected in specimens retrieved after curettage. HIF-1α stabilization was accompanied by significant increases in VEGFA and GLUT3 and a decrease in PlGF mRNAs. These effects were suppressed by PD169316. In conclusion, our data suggest that first trimester placental tissues are not energetically compromised, and that HIF-1α is unlikely to play an appreciable role in regulating transcriptional activity under steady-state conditions in vivo. However, the pathway may be activated by stress conditions.
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Affiliation(s)
- T Cindrova-Davies
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - M Tissot van Patot
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - L Gardner
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - E Jauniaux
- Academic Department of Obstetrics and Gynaecology, Royal Free and University College, London, UK
| | - G J Burton
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK
| | - D S Charnock-Jones
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, UK National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge, UK
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Lei Q, Qiang F, Chao D, Di W, Guoqian Z, Bo Y, Lina Y. Amelioration of hypoxia and LPS-induced intestinal epithelial barrier dysfunction by emodin through the suppression of the NF-κB and HIF-1α signaling pathways. Int J Mol Med 2014; 34:1629-39. [PMID: 25318952 DOI: 10.3892/ijmm.2014.1965] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2014] [Accepted: 09/25/2014] [Indexed: 12/22/2022] Open
Abstract
Intestinal barrier dysfunction occurs in critical illnesses and involves the inflammatory and hypoxic injury of intestinal epithelial cells. Researchers are still defining the underlying mechanisms and evaluating therapeutic strategies for restoring intestinal barrier function. The anti-inflammatory drug, emodin, has been shown to exert a protective effect on intestinal barrier function; however, its mechanisms of action remain unknown. In this study, we investigated the protective effects of emodin on intestinal barrier function and the underlying mechanisms in intestinal epithelial cells challenged with lipopolysaccharide (LPS) and hypoxia/reoxygenation (HR). To induce barrier dysfunction, Caco-2 monolayers were subjected to HR with or without LPS treatment. Transepithelial electrical resistance and paracellular permeability were measured to evaluate barrier function. The expression of the tight junction (TJ) proteins, zonula occludens (ZO)-1, occludin, and claudin-1, as well as that of hypoxia-inducible factor (HIF)-1α, phosphor-IκB-α, phosphor-nuclear factor (NF)-κB p65 and cyclooxygenase (COX)-2 was determined by western blot analysis. The results revealed that emodin markedly attenuated the decrease in transepithelial electrical resistance and the increase in paracellular permeability in the Caco-2 monolayers treated with LPS and subjected to HR. Emodin also markedly alleviated the damage caused by LPS and HR (manifested by a decrease in the expression of the TJ protein, ZO-1), and inhibited the expression of HIF-1α, IκB-α, NF-κB and COX-2 in a dose-dependent manner. In conclusion, our data suggest that emodin attenuates LPS- and HR-induced intestinal epithelial barrier dysfunction by inhibiting the HIF-1α and NF-κB signaling pathways and preventing the damage caused to the TJ barrier (shown by the decrease in the expression of ZO-1).
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Affiliation(s)
- Qi Lei
- Department of ICU, Tianjin Huanhu Hospital, Tianjin, P.R. China
| | - Fu Qiang
- Department of ICU, Tianjin 4th Central Hospital, Tianjin, P.R. China
| | - Du Chao
- Department of ICU, Tianjin Medical University, Nankai Hospital, Tianjin, P.R. China
| | - Wu Di
- Department of ICU, Tianjin Huanhu Hospital, Tianjin, P.R. China
| | - Zhang Guoqian
- Clinical Laboratory, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Yuan Bo
- Graduate College, Tianjin Medical University, Tianjin, P.R. China
| | - Yan Lina
- Graduate College, Tianjin Medical University, Tianjin, P.R. China
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Song Y, Salbu B, Teien HC, Sørlie Heier L, Rosseland BO, Høgåsen T, Tollefsen KE. Hepatic transcriptomic profiling reveals early toxicological mechanisms of uranium in Atlantic salmon (Salmo salar). BMC Genomics 2014; 15:694. [PMID: 25145280 PMCID: PMC4148957 DOI: 10.1186/1471-2164-15-694] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Accepted: 08/11/2014] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Uranium (U) is a naturally occurring radionuclide that has been found in the aquatic environment due to anthropogenic activities. Exposure to U may pose risk to aquatic organisms due to its radiological and chemical toxicity. The present study aimed to characterize the chemical toxicity of U in Atlantic salmon (Salmo salar) using depleted uranium (DU) as a test model. The fish were exposed to three environmentally relevant concentrations of DU (0.25, 0.5 and 1.0 mg U/L) for 48 h. Hepatic transcriptional responses were studied using microarrays in combination with quantitative real-time reverse transcription polymerase chain reaction (qPCR). Plasma variables and chromosomal damages were also studied to link transcriptional responses to potential physiological changes at higher levels. RESULTS The microarray gene expression analysis identified 847, 891 and 766 differentially expressed genes (DEGs) in the liver of salmon after 48 h exposure to 0.25, 0.5 and 1.0 mg/L DU, respectively. These DEGs were associated with known gene ontology functions such as generation of precursor metabolites and energy, carbohydrate metabolic process and cellular homeostasis. The salmon DEGs were then mapped to mammalian orthologs and subjected to protein-protein network and pathway analysis. The results showed that various toxicity pathways involved in mitochondrial functions, oxidative stress, nuclear receptor signaling, organ damage were commonly affected by all DU concentrations. Eight genes representative of several key pathways were further verified using qPCR No significant formation of micronuclei in the red blood cells or alterations of plasma stress variables were identified. CONCLUSION The current study suggested that the mitochondrion may be a key target of U chemical toxicity in salmon. The induction of oxidative stress and uncoupling of oxidative phosphorylation may be two potential modes of action (MoA) of DU. These MoAs may subsequently lead to downstream events such as apoptosis, DNA repair, hypoxia signaling and immune response. The early toxicological mechanisms of U chemical toxicity in salmon has for the first time been systematically profiled. However, no other physiological changes were observed. Future efforts to link transcriptional responses to adverse effects have been outlined as important for understanding of potential risk to aquatic organisms.
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Affiliation(s)
- You Song
- Department of Environmental Sciences (IMV), Norwegian University of Life Sciences (NMBU), Faculty of Environmental Science and Technology, Centre for Environmental Radioactivity (CERAD), P,O, Box 5003, N-1432 Ås, Norway.
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Kulshrestha A, Jarouliya U, Prasad GBKS, Flora SJS, Bisen PS. Arsenic-induced abnormalities in glucose metabolism: Biochemical basis and potential therapeutic and nutritional interventions. World J Transl Med 2014; 3:96-111. [DOI: 10.5528/wjtm.v3.i2.96] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Revised: 06/21/2014] [Accepted: 07/17/2014] [Indexed: 02/05/2023] Open
Abstract
Health hazards due to the consumption of heavy metals such as arsenic have become a worldwide problem. Metabolism of arsenic produces various intermediates which are more toxic and cause toxicity. Arsenic exposure results in impairment of glucose metabolism, insulin secretion in pancreatic β-cells, altered gene expressions and signal transduction, and affects insulin-stimulated glucose uptake in adipocytes or skeletal muscle cells. Arsenic toxicity causes abnormalities in glucose metabolism through an increase in oxidative stress. Arsenic interferes with the sulfhydryl groups and phosphate groups present in various enzymes involved in glucose metabolism including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, and contributes to their impairment. Arsenic inhibits glucose transporters present in the cell membrane, alters expression of genes involved in glucose metabolism, transcription factors and inflammatory cytokines which stimulate oxidative stress. Some theories suggest that arsenic exposure under diabetic conditions inhibits hyperglycemia. However, the exact mechanism behind the behavior of arsenic as an antagonist or synergist on glucose homeostasis and insulin secretion is not yet fully understood. The present review delineates the relationship between arsenic and the biochemical basis of its relationship to glucose metabolism. This review also addresses potential therapeutic and nutritional interventions for attenuating arsenic toxicity. Several other potential nutritional supplements are highlighted in the review that could be used to combat arsenic toxicity.
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Sag CM, Santos CX, Shah AM. Redox regulation of cardiac hypertrophy. J Mol Cell Cardiol 2014; 73:103-11. [DOI: 10.1016/j.yjmcc.2014.02.002] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 01/31/2014] [Accepted: 02/03/2014] [Indexed: 02/07/2023]
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