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Magkouta S, Markaki E, Evangelou K, Petty R, Verginis P, Gorgoulis V. Decoding T cell senescence in cancer: Is revisiting required? Semin Cancer Biol 2025; 108:33-47. [PMID: 39615809 DOI: 10.1016/j.semcancer.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 12/14/2024]
Abstract
Senescence is an inherent cellular mechanism triggered as a response to stressful insults. It associates with several aspects of cancer progression and therapy. Senescent cells constitute a highly heterogeneous cellular population and their identification can be very challenging. In fact, the term "senescence" has been often misused. This is also true in the case of immune cells. While several studies indicate the presence of senescent-like features (mainly in T cells), senescent immune cells are poorly described. Under this prism, we herein review the current literature on what has been characterized as T cell senescence and provide insights on how to accurately discriminate senescent cells against exhausted or anergic ones. We also summarize the major metabolic and epigenetic modifications associated with T cell senescence and underline the role of senescent T cells in the tumor microenvironment (TME). Moreover, we discuss how these cells associate with standard clinical therapeutic interventions and how they impact their efficacy. Finally, we underline the importance of precise identification and thorough characterization of "truly" senescent T cells in order to design successful therapeutic manipulations that would delay cancer incidence and maximize efficacy of immunotherapy.
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Affiliation(s)
- Sophia Magkouta
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece; Marianthi Simou and G.P. Livanos Labs, 1st Department of Critical Care and Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, "Evangelismos" Hospital, Athens 10676, Greece; Ninewells Hospital and Medical School, University of Dundee, Dundee DD19SY, UK
| | - Efrosyni Markaki
- Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, University of Crete Medical School, Heraklion 70013, Greece
| | - Konstantinos Evangelou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Russell Petty
- Ninewells Hospital and Medical School, University of Dundee, Dundee DD19SY, UK
| | - Panayotis Verginis
- Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, University of Crete Medical School, Heraklion 70013, Greece; Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion 70013, Greece
| | - Vassilis Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece; Ninewells Hospital and Medical School, University of Dundee, Dundee DD19SY, UK; Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece; Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M20 4GJ, UK.
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Liu N, Li J, Dai H, Liang X, Fan H. Involvement of SIRT1-mediated cellular immune response in cancer. Biomed Pharmacother 2024; 180:117482. [PMID: 39321514 DOI: 10.1016/j.biopha.2024.117482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 09/27/2024] Open
Abstract
The morbidity and mortality of cancer are rising rapidly worldwide and immunotherapy has become an effective means to curb the progress of cancer. Sirtuin-1(SIRT1) is a NAD+ -dependent deacetylase that plays a key role in cancer development and immune regulation through mediating a variety of signaling pathways. Targeting SIRT1 in immunotherapy could enhance or erod immune responses against cancer cells, while SIRT1 activator and inhibitors are being developed as potential antineoplastic agents with important implications in clinic. This review summarizes the impact of SIRT1 in different types of immune cells and mechanism of SIRT1-mediated immune responses in tumor progression as well as its therapeutic perspectives.
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Affiliation(s)
- Nan Liu
- Department of Anesthesiology, the First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Jiafang Li
- Department of Dermatology, the Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, China
| | - Hui Dai
- Department of Tumor and Blood Disease, the Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, China
| | - Xinyue Liang
- Departments of Hematology, the First Hospital of Jilin University, Changchun, Jilin 130021, China.
| | - Hongqiong Fan
- Departments of Hematology, the First Hospital of Jilin University, Changchun, Jilin 130021, China.
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Pant T, Uche N, Juric M, Zielonka J, Bai X. Regulation of immunomodulatory networks by Nrf2-activation in immune cells: Redox control and therapeutic potential in inflammatory diseases. Redox Biol 2024; 70:103077. [PMID: 38359749 PMCID: PMC10877431 DOI: 10.1016/j.redox.2024.103077] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/26/2024] [Accepted: 02/05/2024] [Indexed: 02/17/2024] Open
Abstract
Inflammatory diseases present a serious health challenge due to their widespread prevalence and the severe impact on patients' lives. In the quest to alleviate the burden of these diseases, nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a pivotal player. As a transcription factor intimately involved in cellular defense against metabolic and oxidative stress, Nrf2's role in modulating the inflammatory responses of immune cells has garnered significant attention. Recent findings suggest that Nrf2's ability to alter the redox status of cells underlies its regulatory effects on immune responses. Our review delves into preclinical and clinical evidence that underscores the complex influence of Nrf2 activators on immune cell phenotypes, particularly in the inflammatory milieu. By offering a detailed analysis of Nrf2's role in different immune cell populations, we cast light on the potential of Nrf2 activators in shaping the immune response towards a more regulated state, mitigating the adverse effects of inflammation through modeling redox status of immune cells. Furthermore, we explore the innovative use of nanoencapsulation techniques that enhance the delivery and efficacy of Nrf2 activators, potentially advancing the treatment strategies for inflammatory ailments. We hope this review will stimulate the development and expansion of Nrf2-targeted treatments that could substantially improve outcomes for patients suffering from a broad range of inflammatory diseases.
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Affiliation(s)
- Tarun Pant
- Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA; Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
| | - Nnamdi Uche
- Department of Pharmacology and Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Matea Juric
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Jacek Zielonka
- Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Xiaowen Bai
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
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Brockmueller A, Sajeev A, Koklesova L, Samuel SM, Kubatka P, Büsselberg D, Kunnumakkara AB, Shakibaei M. Resveratrol as sensitizer in colorectal cancer plasticity. Cancer Metastasis Rev 2024; 43:55-85. [PMID: 37507626 PMCID: PMC11016130 DOI: 10.1007/s10555-023-10126-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023]
Abstract
Despite tremendous medical treatment successes, colorectal cancer (CRC) remains a leading cause of cancer deaths worldwide. Chemotherapy as monotherapy can lead to significant side effects and chemoresistance that can be linked to several resistance-activating biological processes, including an increase in inflammation, cellular plasticity, multidrug resistance (MDR), inhibition of the sentinel gene p53, and apoptosis. As a consequence, tumor cells can escape the effectiveness of chemotherapeutic agents. This underscores the need for cross-target therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Resveratrol, a natural polyphenolic phytoalexin found in various fruits and vegetables such as peanuts, berries, and red grapes, is one of the most effective natural chemopreventive agents. Abundant in vitro and in vivo studies have shown that resveratrol, in interaction with standard drugs, is an effective chemosensitizer for CRC cells to chemotherapeutic agents and thus prevents drug resistance by modulating multiple pathways, including transcription factors, epithelial-to-mesenchymal transition-plasticity, proliferation, metastasis, angiogenesis, cell cycle, and apoptosis. The ability of resveratrol to modify multiple subcellular pathways that may suppress cancer cell plasticity and reversal of chemoresistance are critical parameters for understanding its anti-cancer effects. In this review, we focus on the chemosensitizing properties of resveratrol in CRC and, thus, its potential importance as an additive to ongoing treatments.
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Affiliation(s)
- Aranka Brockmueller
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Lenka Koklesova
- Clinic of Gynecology and Obstetrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, Kollarova 2, 03601, Martin, Slovakia
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4, 03601, Martin, Slovakia
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Education City, Qatar Foundation, 24144, Doha, Qatar
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati, Assam, 781039, India
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Pettenkoferstr. 11, D-80336, Munich, Germany.
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Vijayan Y, Sandhu JS, Harikumar KB. Modulatory Role of Phytochemicals/Natural Products in Cancer Immunotherapy. Curr Med Chem 2024; 31:5165-5177. [PMID: 38549529 DOI: 10.2174/0109298673274796240116105555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 12/27/2023] [Accepted: 01/08/2024] [Indexed: 09/06/2024]
Abstract
Immunotherapy is a newly emerging and effective approach to treating cancer. However, there are many challenges associated with using checkpoint inhibitors in this treatment strategy. The component of the tumor microenvironment plays a crucial role in antitumor immune response, regulating tumor immune surveillance and immunological evasion. Natural products/phytochemicals can modulate the tumor microenvironment and function as immunomodulatory agents. In clinical settings, there is a strong need to develop synergistic combination regimens using natural products that can effectively enhance the therapeutic benefits of immune checkpoint inhibitors relative to their effectiveness as single therapies. The review discusses immunotherapy, its side effects, and a summary of evidence suggesting the use of natural products to modulate immune checkpoint pathways.
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Affiliation(s)
- Yadu Vijayan
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, 695014, India
- Manipal Academy of Higher Education (MAHE), Manipal, 576104, India
| | - Jaskirat Singh Sandhu
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, 695014, India
| | - Kuzhuvelil B Harikumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, 695014, India
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Focaccetti C, Palumbo C, Benvenuto M, Carrano R, Melaiu O, Nardozi D, Angiolini V, Lucarini V, Kërpi B, Masuelli L, Cifaldi L, Bei R. The Combination of Bioavailable Concentrations of Curcumin and Resveratrol Shapes Immune Responses While Retaining the Ability to Reduce Cancer Cell Survival. Int J Mol Sci 2023; 25:232. [PMID: 38203402 PMCID: PMC10779126 DOI: 10.3390/ijms25010232] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 12/15/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
The polyphenols Curcumin (CUR) and Resveratrol (RES) are widely described for their antitumoral effects. However, their low bioavailability is a drawback for their use in therapy. The aim of this study was to explore whether CUR and RES, used at a bioavailable concentration, could modulate immune responses while retaining antitumor activity and to determine whether CUR and RES effects on the immune responses of peripheral blood mononuclear cells (PBMCs) and tumor growth inhibition could be improved by their combination. We demonstrate that the low-dose combination of CUR and RES reduced the survival of cancer cell lines but had no effect on the viability of PBMCs. Although following CUR + RES treatment T lymphocytes showed an enhanced activated state, RES counteracted the increased IFN-γ expression induced by CUR in T cells and the polyphenol combination increased IL-10 production by T regulatory cells. On the other hand, the combined treatment enhanced NK cell activity through the up- and downregulation of activating and inhibitory receptors and increased CD68 expression levels on monocytes/macrophages. Overall, our results indicate that the combination of CUR and RES at low doses differentially shapes immune cells while retaining antitumor activity, support the use of this polyphenol combinations in anticancer therapy and suggest its possible application as adjuvant for NK cell-based immunotherapies.
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Affiliation(s)
- Chiara Focaccetti
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.F.); (C.P.); (M.B.); (R.C.); (O.M.); (D.N.); (L.C.)
| | - Camilla Palumbo
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.F.); (C.P.); (M.B.); (R.C.); (O.M.); (D.N.); (L.C.)
| | - Monica Benvenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.F.); (C.P.); (M.B.); (R.C.); (O.M.); (D.N.); (L.C.)
- Departmental Faculty of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences, 00131 Rome, Italy
| | - Raffaele Carrano
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.F.); (C.P.); (M.B.); (R.C.); (O.M.); (D.N.); (L.C.)
| | - Ombretta Melaiu
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.F.); (C.P.); (M.B.); (R.C.); (O.M.); (D.N.); (L.C.)
| | - Daniela Nardozi
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.F.); (C.P.); (M.B.); (R.C.); (O.M.); (D.N.); (L.C.)
| | - Valentina Angiolini
- Department of Experimental Medicine, University of Rome “Sapienza”, 00161 Rome, Italy; (V.A.); (V.L.); (L.M.)
| | - Valeria Lucarini
- Department of Experimental Medicine, University of Rome “Sapienza”, 00161 Rome, Italy; (V.A.); (V.L.); (L.M.)
| | - Bora Kërpi
- Department of Biomedicine, Catholic University ‘Our Lady of Good Counsel’, 1000 Tirana, Albania;
| | - Laura Masuelli
- Department of Experimental Medicine, University of Rome “Sapienza”, 00161 Rome, Italy; (V.A.); (V.L.); (L.M.)
| | - Loredana Cifaldi
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.F.); (C.P.); (M.B.); (R.C.); (O.M.); (D.N.); (L.C.)
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy; (C.F.); (C.P.); (M.B.); (R.C.); (O.M.); (D.N.); (L.C.)
- Faculty of Medicine and Surgery, Catholic University ‘Our Lady of Good Counsel’, 1000 Tirana, Albania
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Vrânceanu M, Hegheş SC, Cozma-Petruţ A, Banc R, Stroia CM, Raischi V, Miere D, Popa DS, Filip L. Plant-Derived Nutraceuticals Involved in Body Weight Control by Modulating Gene Expression. PLANTS (BASEL, SWITZERLAND) 2023; 12:2273. [PMID: 37375898 DOI: 10.3390/plants12122273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/09/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023]
Abstract
Obesity is the most prevalent health problem in the Western world, with pathological body weight gain associated with numerous co-morbidities that can be the main cause of death. There are several factors that can contribute to the development of obesity, such as diet, sedentary lifestyle, and genetic make-up. Genetic predispositions play an important role in obesity, but genetic variations alone cannot fully explain the explosion of obesity, which is why studies have turned to epigenetics. The latest scientific evidence suggests that both genetics and environmental factors contribute to the rise in obesity. Certain variables, such as diet and exercise, have the ability to alter gene expression without affecting the DNA sequence, a phenomenon known as epigenetics. Epigenetic changes are reversible, and reversibility makes these changes attractive targets for therapeutic interventions. While anti-obesity drugs have been proposed to this end in recent decades, their numerous side effects make them not very attractive. On the other hand, the use of nutraceuticals for weight loss is increasing, and studies have shown that some of these products, such as resveratrol, curcumin, epigallocatechin-3-gallate, ginger, capsaicin, and caffeine, can alter gene expression, restoring the normal epigenetic profile and aiding weight loss.
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Affiliation(s)
- Maria Vrânceanu
- Department of Toxicology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Simona-Codruţa Hegheş
- Department of Drug Analysis, "Iuliu Haţieganu" University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Anamaria Cozma-Petruţ
- Department of Bromatology, Hygiene, Nutrition, "Iuliu Haţieganu" University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Roxana Banc
- Department of Bromatology, Hygiene, Nutrition, "Iuliu Haţieganu" University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Carmina Mariana Stroia
- Department of Pharmacy, Oradea University, 1 Universităţii Street, 410087 Oradea, Romania
| | - Viorica Raischi
- Laboratory of Physiology of Stress, Adaptation and General Sanocreatology, Institute of Physiology and Sanocreatology, 1 Academiei Street, 2028 Chișinău, Moldova
| | - Doina Miere
- Department of Bromatology, Hygiene, Nutrition, "Iuliu Haţieganu" University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Daniela-Saveta Popa
- Department of Toxicology, "Iuliu Haţieganu" University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
| | - Lorena Filip
- Department of Bromatology, Hygiene, Nutrition, "Iuliu Haţieganu" University of Medicine and Pharmacy, 6 Pasteur Street, 400349 Cluj-Napoca, Romania
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Jiang TT, Ji CL, Yu LJ, Song MK, Li Y, Liao Q, Wei T, Olatunji OJ, Zuo J, Han J. Resveratrol-induced SIRT1 activation inhibits glycolysis-fueled angiogenesis under rheumatoid arthritis conditions independent of HIF-1α. Inflamm Res 2023; 72:1021-1035. [PMID: 37016140 DOI: 10.1007/s00011-023-01728-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/22/2023] [Accepted: 03/28/2023] [Indexed: 04/06/2023] Open
Abstract
OBJECTIVE This study investigated the impacts of SIRT1 activation on rheumatoid arthritis (RA)-related angiogenesis. METHODS HUVECs were cultured by different human serum. Intracellular metabolites were quantified by UPLC-MS. Next, HUVECs and rat vascular epithelial cells under different inflammatory conditions were treated by a SIRT1 agonist resveratrol (RSV). Cytokines and biochemical indicators were detected by corresponding kits. Protein and mRNA expression levels were assessed by immunoblotting and PCR methods, respectively. Angiogenesis capabilities were evaluated by migration, wound-healing and tube-formation experiments. To down-regulate certain signals, gene-specific siRNA were applied. RESULTS Metabolomics study revealed the accelerated glycolysis in RA serum-treated HUVECs. It led to ATP accumulation, but did not affect GTP levels. RSV inhibited pro-angiogenesis cytokines production and glycolysis in both the cells, and impaired the angiogenesis potentials. These effects were mimicked by an energy metabolism interrupter bikini in lipopolysaccharide (LPS)-primed HUVECs, largely independent of HIF-1α. Both RSV and bikinin can inhibit the activation of the GTP-dependent pathway Rho/ROCK and reduce VEGF production. Abrogation of RhoA signaling reinforced HIF-1α silencing-brought changes in LPS-stimulated HUVECs, and overshadowed the anti-angiogenesis potentials of RSV. CONCLUSION Glycolysis provides additional energy to sustain Rho/ROCK activation in RA subjects, which promotes VEGF-driven angiogenesis and can be inhibited by SIRT1 activation.
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Affiliation(s)
- Tian-Tian Jiang
- Xin'an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
| | - Cong-Lan Ji
- School of Pharmacy, Anhui College of Traditional Chinese Medicine, Wuhu, 241000, China
| | - Li-Jun Yu
- Xin'an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, China
| | - Meng-Ke Song
- Xin'an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, China
| | - Yan Li
- Xin'an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
| | - Qiang Liao
- Xin'an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
- Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College, Wuhu, China
| | - Tuo Wei
- Xin'an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
| | | | - Jian Zuo
- Xin'an Medicine Research Center, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China.
- Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine, Institution of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230000, China.
- Anhui Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, 241000, China.
| | - Jun Han
- Anhui Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wuhu, 241000, China.
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China.
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Akbari B, Hosseini Z, Shahabinejad P, Ghassemi S, Mirzaei HR, O'Connor RS. Metabolic and epigenetic orchestration of (CAR) T cell fate and function. Cancer Lett 2022; 550:215948. [DOI: 10.1016/j.canlet.2022.215948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/20/2022] [Accepted: 10/04/2022] [Indexed: 11/16/2022]
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Toma G, Karapetian E, Massa C, Quandt D, Seliger B. Characterization of the effect of histone deacetylation inhibitors on CD8 + T cells in the context of aging. J Transl Med 2022; 20:539. [PMID: 36419167 PMCID: PMC9682763 DOI: 10.1186/s12967-022-03733-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 10/30/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Posttranslational protein modifications regulate essential cellular processes, including the immune cell activation. Despite known age-related alterations of the phenotype, composition and cytokine profiles of immune cells, the role of acetylation in the aging process of the immune system was not broadly investigated. Therefore, in the current study the effect of acetylation on the protein expression profiles and function of CD8+ T cells from donors of distinct age was analyzed using histone deacetylase inhibitors (HDACi). METHODS CD8+ T cells isolated from peripheral blood mononuclear cells of 30 young (< 30 years) and 30 old (> 60 years) healthy donors were activated with anti-CD3/anti-CD28 antibodies in the presence and absence of a cocktail of HDACi. The protein expression profiles of untreated and HDACi-treated CD8+ T cells were analyzed using two-dimensional gel electrophoresis. Proteins with a differential expression level (less than 0.66-fold decrease or more than 1.5-fold increase) between CD8+ T cells of young and old donors were identified by matrix-associated laser desorption ionization-time of flight mass spectrometry. Functional enrichment analysis of proteins identified was performed using the online tool STRING. The function of CD8+ T cells was assessed by analyses of cytokine secretion, surface expression of activation markers, proliferative capacity and apoptosis rate. RESULTS The HDACi treatment of CD8+ T cells increased in an age-independent manner the intracellular acetylation of proteins, in particular cytoskeleton components and chaperones. Despite a strong similarity between the protein expression profiles of both age groups, the functional activity of CD8+ T cells significantly differed with an age-dependent increase in cytokine secretion and expression of activation markers for CD8+ T cells from old donors, which was maintained after HDACi treatment. The proliferation and apoptosis rate of CD8+ T cells after HDACi treatment was equal between both age groups. CONCLUSIONS Despite a comparable effect of HDACi treatment on the protein signature of CD8+ T cells from donors of different ages, an initial higher functionality of CD8+ T cells from old donors when compared to CD8+ T cells from young donors was detected, which might have clinical relevance.
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Affiliation(s)
- Georgiana Toma
- grid.9018.00000 0001 0679 2801Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle, Germany
| | - Eliza Karapetian
- grid.9018.00000 0001 0679 2801Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle, Germany
| | - Chiara Massa
- grid.9018.00000 0001 0679 2801Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle, Germany
| | - Dagmar Quandt
- grid.9018.00000 0001 0679 2801Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle, Germany
| | - Barbara Seliger
- grid.9018.00000 0001 0679 2801Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle, Germany ,grid.418008.50000 0004 0494 3022Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany
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11
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Luís C, Maduro AT, Pereira P, Mendes JJ, Soares R, Ramalho R. Nutritional senolytics and senomorphics: Implications to immune cells metabolism and aging – from theory to practice. Front Nutr 2022; 9:958563. [PMID: 36159455 PMCID: PMC9493043 DOI: 10.3389/fnut.2022.958563] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/16/2022] [Indexed: 11/28/2022] Open
Abstract
Aging is a natural physiological process, but one that poses major challenges in an increasingly aging society prone to greater health risks such as diabetes, cardiovascular disease, cancer, frailty, increased susceptibility to infection, and reduced response to vaccine regimens. The loss of capacity for cell regeneration and the surrounding tissue microenvironment itself is conditioned by genetic, metabolic, and even environmental factors, such as nutrition. The senescence of the immune system (immunosenescence) represents a challenge, especially when associated with the presence of age-related chronic inflammation (inflammaging) and affecting the metabolic programming of immune cells (immunometabolism). These aspects are linked to poorer health outcomes and therefore present an opportunity for host-directed interventions aimed at both eliminating senescent cells and curbing the underlying inflammation. Senotherapeutics are a class of drugs and natural products that delay, prevent, or reverse the senescence process – senolytics; or inhibit senescence-associated secretory phenotype – senomorphics. Natural senotherapeutics from food sources – nutritional senotherapeutics – may constitute an interesting way to achieve better age-associated outcomes through personalized nutrition. In this sense, the authors present herein a framework of nutritional senotherapeutics as an intervention targeting immunosenescence and immunometabolism, identifying research gaps in this area, and gathering information on concluded and ongoing clinical trials on this subject. Also, we present future directions and ideation for future clinical possibilities in this field.
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Affiliation(s)
- Carla Luís
- Department of Biomedicine, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Ana T. Maduro
- Department of Biomedicine, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Paula Pereira
- Nutritional Immunology – Clinical and Experimental Lab (NICE Lab), Clinical Research Unit, Centro de Investigação Interdisciplinar Egas Moniz (CiiEM, U4585 FCT), Egas Moniz Higher Education School, Monte de Caparica, Portugal
- Applied Nutrition Study Group (Grupo de Estudos em Nutrição Aplicada – G.E.N.A.-IUEM), Egas Moniz Higher Education School, Monte de Caparica, Portugal
- Instituto Universitário Egas Moniz, Egas Moniz Higher Education School, Monte de Caparica, Portugal
| | - José João Mendes
- Nutritional Immunology – Clinical and Experimental Lab (NICE Lab), Clinical Research Unit, Centro de Investigação Interdisciplinar Egas Moniz (CiiEM, U4585 FCT), Egas Moniz Higher Education School, Monte de Caparica, Portugal
- Instituto Universitário Egas Moniz, Egas Moniz Higher Education School, Monte de Caparica, Portugal
| | - Raquel Soares
- Department of Biomedicine, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Renata Ramalho
- Nutritional Immunology – Clinical and Experimental Lab (NICE Lab), Clinical Research Unit, Centro de Investigação Interdisciplinar Egas Moniz (CiiEM, U4585 FCT), Egas Moniz Higher Education School, Monte de Caparica, Portugal
- Applied Nutrition Study Group (Grupo de Estudos em Nutrição Aplicada – G.E.N.A.-IUEM), Egas Moniz Higher Education School, Monte de Caparica, Portugal
- Instituto Universitário Egas Moniz, Egas Moniz Higher Education School, Monte de Caparica, Portugal
- *Correspondence: Renata Ramalho,
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12
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Resveratrol for Weight Loss in Obesity: An Assessment of Randomized Control Trial Designs in ClinicalTrials.gov. Nutrients 2022; 14:nu14071424. [PMID: 35406038 PMCID: PMC9002514 DOI: 10.3390/nu14071424] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 12/13/2022] Open
Abstract
Resveratrol is a polyphenol that may improve weight loss outcomes in obese individuals. However, assessing the effectiveness of resveratrol supplementations as an appropriate intervention for weight loss in obesity across randomized control trials (RCTs) has been complicated by variability in their design. This study aims to evaluate design elements across RCTs of resveratrol interventions in obesity with weight loss as an end-point outcome, as recorded in ClinicalTrials.gov. We found discrepancies in participant inclusion criteria (sample size, age ranges, sex, BMI, medical conditions), interventional design (delivery modalities, dosages, duration) and primary outcomes measured (anthropomorphic, blood biomarkers). We identified a near three-fold variation in study sample size, two-fold variation in minimum inclusion age, five modalities of therapeutic resveratrol delivery with interventional durations ranging from two weeks to six months. Weight loss was only identified as a primary outcome in three of the seven studies evaluated. In conclusion, heterogeneity in trial design using resveratrol suggests that weight-loss-related outcomes are difficult to interpret and cross-validate. Indeed, conclusions drawn from human studies have been inconsistent, which may be attributed to study design heterogeneity including major differences in sample population, age, sex, BMI, underlying health conditions and end-point measures.
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13
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Holthaus L, Sharma V, Brandt D, Ziegler AG, Jastroch M, Bonifacio E. Functional and metabolic fitness of human CD4 + T lymphocytes during metabolic stress. Life Sci Alliance 2021; 4:4/12/e202101013. [PMID: 34580176 PMCID: PMC8500231 DOI: 10.26508/lsa.202101013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 09/11/2021] [Accepted: 09/13/2021] [Indexed: 12/12/2022] Open
Abstract
Human T-cell activation, expansion, and effector function is grossly impaired in conditions that combine glucose deprivation and mild mitochondrial stress. Human CD4+ T cells are essential mediators of immune responses. By altering the mitochondrial and metabolic states, we defined metabolic requirements of human CD4+ T cells for in vitro activation, expansion, and effector function. T-cell activation and proliferation were reduced by inhibiting oxidative phosphorylation, whereas early cytokine production was maintained by either OXPHOS or glycolytic activity. Glucose deprivation in the presence of mild mitochondrial stress markedly reduced all three T-cell functions, contrasting the exposure to resveratrol, an antioxidant and sirtuin-1 activator, which specifically inhibited cytokine production and T-cell proliferation, but not T-cell activation. Conditions that inhibited T-cell activation were associated with the down-regulation of 2′,5′-oligoadenylate synthetase genes via interferon response pathways. Our findings indicate that T-cell function is grossly impaired by stressors combined with nutrient deprivation, suggesting that correcting nutrient availability, metabolic stress, and/or the function of T cells in these conditions will improve the efficacy of T-cell–based therapies.
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Affiliation(s)
- Lisa Holthaus
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.,Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Virag Sharma
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.,Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany
| | - Daniel Brandt
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Anette-Gabriele Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Martin Jastroch
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.,Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Ezio Bonifacio
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany .,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.,Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.,Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany
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14
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Resveratrol, EGCG and Vitamins Modulate Activated T Lymphocytes. Molecules 2021; 26:molecules26185600. [PMID: 34577071 PMCID: PMC8470394 DOI: 10.3390/molecules26185600] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 11/23/2022] Open
Abstract
Vitamins and bioactives, which are constituents of the food chain, modulate T lymphocyte proliferation and differentiation, antibody production, and prevent inflammation and autoimmunity. We investigated the effects of vitamins (vitamin A (VA), D (VD), E (VE)) and bioactives (i.e., resveratrol (Res), epigallocatechin-3-gallate (EGCG)) on the adaptive immune response, as well as their synergistic or antagonistic interactions. Freshly isolated T lymphocytes from healthy individuals were activated with anti-CD3/CD28 antibodies for 4–5 days in the presence of bioactives and were analyzed by cytofluorometry. Interleukins, cytokines, and chemokines were measured by multiple ELISA. Gene expression was measured by quantitative RT-PCR. Res and EGCG increased CD4 surface intensity. EGCG led to an increased proportion of CD8+ lymphocytes. Anti-CD3/CD28 activation induced exuberant secretion of interleukins and cytokines by T lymphocyte subsets. VD strongly enhanced Th2 cytokines (e.g., IL-5, IL-13), whereas Res and EGCG favored secretion of Th1 cytokines (e.g., IL-2, INF-γ). Res and VD mutually influenced cytokine production, but VD dominated the cytokine secretion pattern. The substances changed gene expression of interleukins and cytokines in a similar way as they did secretion. Collectively, VD strongly modulated cytokine and interleukin production and favored Th2 functions. Resveratrol and EGCG promoted the Th1 response. VA and VE had only a marginal effect, but they altered both Th1 and Th2 response. In vivo, bioactives might therefore interact with vitamins and support the outcome and extent of the adaptive immune response.
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15
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Yang L, Yin J, Wu J, Qiao L, Zhao EM, Cai F, Ye H. Engineering genetic devices for in vivo control of therapeutic T cell activity triggered by the dietary molecule resveratrol. Proc Natl Acad Sci U S A 2021; 118:e2106612118. [PMID: 34404729 PMCID: PMC8403971 DOI: 10.1073/pnas.2106612118] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Chimeric antigen receptor (CAR)-engineered T cell therapies have been recognized as powerful strategies in cancer immunotherapy; however, the clinical application of CAR-T is currently constrained by severe adverse effects in patients, caused by excessive cytotoxic activity and poor T cell control. Herein, we harnessed a dietary molecule resveratrol (RES)-responsive transactivator and a transrepressor to develop a repressible transgene expression (RESrep) device and an inducible transgene expression (RESind) device, respectively. After optimization, these tools enabled the control of CAR expression and CAR-mediated antitumor function in engineered human cells. We demonstrated that a resveratrol-repressible CAR expression (RESrep-CAR) device can effectively inhibit T cell activation upon resveratrol administration in primary T cells and a xenograft tumor mouse model. Additionally, we exhibit how a resveratrol-inducible CAR expression (RESind-CAR) device can achieve fine-tuned and reversible control over T cell activation via a resveratrol-titratable mechanism. Furthermore, our results revealed that the presence of RES can activate RESind-CAR T cells with strong anticancer cytotoxicity against cells in vitro and in vivo. Our study demonstrates the utility of RESrep and RESind devices as effective tools for transgene expression and illustrates the potential of RESrep-CAR and RESind-CAR devices to enhance patient safety in precision cancer immunotherapies.
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MESH Headings
- Animals
- Apoptosis
- Cell Proliferation
- Cytotoxicity, Immunologic/immunology
- Disease Models, Animal
- Female
- Humans
- Immunotherapy, Adoptive/methods
- Leukemia, Erythroblastic, Acute/genetics
- Leukemia, Erythroblastic, Acute/immunology
- Leukemia, Erythroblastic, Acute/metabolism
- Leukemia, Erythroblastic, Acute/therapy
- Lymphocyte Activation/immunology
- Mice
- Mice, Inbred NOD
- Mice, SCID
- Receptors, Antigen, T-Cell/immunology
- Receptors, Chimeric Antigen/immunology
- T-Lymphocytes/immunology
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Linfeng Yang
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jianli Yin
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jiali Wu
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Longliang Qiao
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Evan M Zhao
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02215
| | - Fengfeng Cai
- Department of Breast Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China
| | - Haifeng Ye
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China;
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16
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Resveratrol attenuates TNBC lung metastasis by down-regulating PD-1 expression on pulmonary T cells and converting macrophages to M1 phenotype in a murine tumor model. Cell Immunol 2021; 368:104423. [PMID: 34399171 DOI: 10.1016/j.cellimm.2021.104423] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 08/01/2021] [Accepted: 08/06/2021] [Indexed: 01/12/2023]
Abstract
Triple-negative breast cancer (TNBC) is an invasive breast cancer with the characteristics of easy to develop distant metastasis. Immune escape is one of the main reasons for TNBC growth and metastasis. Enhancement of T cell-mediated anti-tumor activity may benefit to inhibit tumor metastasis and improve the efficacy of cancer therapy. As a natural bioactive substance, resveratrol shows potential capability to prevent or suppress the development of a variety of cancers through direct or indirect effects, including immunoregulatory effect. However, whether resveratrol might affect lung metastasis of TNBC, and whether the effect of resveratrol might be associated with resveratrol-regulated immune responses in tumor microenvironment is still unknown. In this study, by using an experimental metastatic mouse 4 T1 tumor model, we identified that resveratrol may suppress TNBC lung metastasis by elevating local anti-tumor immunity. Indeed, an increase in the cytotoxic activity of CD8+T cells as well as the levels of type 1 cytokine IFN-γ and IL-2 in the lungs of resveratrol-treated tumor bearing mice were observed. The enhanced CD8+T cell activity and Th1 immune responses by resveratrol administration might be related to the down-regulated PD-1 expression on pulmonary CD8+T cells and CD4+T cells. Resveratrol may also convert macrophages to M1 phenotype in the lungs of tumor bearing mice. However, it seems likely resveratrol has no effect on pulmonary myeloid-derived suppressor cell activation. Our results provide an evidence that resveratrol might be a promising candidate agent for adjuvant therapy in the process of TNBC metastasis.
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17
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Mu Q, Najafi M. Resveratrol for targeting the tumor microenvironment and its interactions with cancer cells. Int Immunopharmacol 2021; 98:107895. [PMID: 34171623 DOI: 10.1016/j.intimp.2021.107895] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/09/2021] [Accepted: 06/13/2021] [Indexed: 12/17/2022]
Abstract
Tumor resistance to therapy modalities is one of the major challenges to the eradication of cancer cells and complete treatment. Tumor includes a wide range of cancer and non-cancer cells that play key roles in the proliferation of cancer cells and suppression of anti-tumor immunity. For overcoming tumor resistance to therapy, it is important to have in-depth knowledge relating to intercellular communications within the tumor microenvironment (TME). TME includes various types of immune cells such as CD4 + T lymphocytes, cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, macrophages, and T regulatory cells (Tregs). Furthermore, some non-immune cells like cancer stem cells (CSCs), mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs) are involved in the promotion of tumor growth. The interactions between these cells with cancer cells play a key role in tumor growth or inhibition. Resveratrol as a natural agent has shown the ability to modulate the immune system to potentiate anti-tumor immunity and also help to attenuate cancer cells and CSCs resistance. Thus, this review explains how resveratrol can modulate interactions within TME.
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Affiliation(s)
- Qi Mu
- College of Nursing, Inner Mongolia University for Nationalities, Tongliao 028000, China.
| | - Masoud Najafi
- Medical Technology Research Center, Institute of Health Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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18
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Chen L, Musa AE. Boosting immune system against cancer by resveratrol. Phytother Res 2021; 35:5514-5526. [PMID: 34101276 DOI: 10.1002/ptr.7189] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/03/2021] [Accepted: 05/26/2021] [Indexed: 01/16/2023]
Abstract
Modulation of the immune system is a critical part of anticancer therapies including immunotherapy, chemotherapy, and radiotherapy. The aim of immunomodulation in cancer therapy is boosting immune system cells including CD8+ T lymphocytes and natural killer (NK) cells, as well as suppression of immunosuppressive responses by macrophages and regulatory T cells (Tregs). Usually, using single or dual modality can induce immune system responses against cancer. However, immunosuppressive responses attenuate antitumor immunity following cancer therapy. Using some agents to boost immune system's function against cancer can increase therapeutic efficiency of anticancer therapy. Resveratrol, as a natural agent, has shown ability to modulate the immune system to potentiate antitumor immunity. Resveratrol has been shown to induce the release of anticancer cytokines such as IFN-γ and TNF-α and also inhibits the release of TGF-β. It also can stimulate the polarization of CD4+ T cells and macrophages toward anticancer cells and reduce infiltration and polarization of immunosuppressive cells. Furthermore, resveratrol can sensitize cancer cells to the released dead signals by anticancer immune cells. This review explains how resveratrol can boost the immune system against cancer via modulation of immune cell responses within tumor.
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Affiliation(s)
- Libo Chen
- School of Pharmaceutical and Environmental Technology, Jilin Vocational College of Industry and Technology, Jilin, China
| | - Ahmed Eleojo Musa
- Department of Medical Physics, Tehran University of Medical Sciences, Tehran, Iran
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19
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Dias AS, Helguero L, Almeida CR, Duarte IF. Natural Compounds as Metabolic Modulators of the Tumor Microenvironment. Molecules 2021; 26:molecules26123494. [PMID: 34201298 PMCID: PMC8228554 DOI: 10.3390/molecules26123494] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/03/2021] [Accepted: 06/04/2021] [Indexed: 02/07/2023] Open
Abstract
The tumor microenvironment (TME) is a heterogenous assemblage of malignant and non-malignant cells, including infiltrating immune cells and other stromal cells, together with extracellular matrix and a variety of soluble factors. This complex and dynamic milieu strongly affects tumor differentiation, progression, immune evasion, and response to therapy, thus being an important therapeutic target. The phenotypic and functional features of the various cell types present in the TME are largely dependent on their ability to adopt different metabolic programs. Hence, modulating the metabolism of the cells in the TME, and their metabolic crosstalk, has emerged as a promising strategy in the context of anticancer therapies. Natural compounds offer an attractive tool in this respect as their multiple biological activities can potentially be harnessed to ‘(re)-educate’ TME cells towards antitumoral roles. The present review discusses how natural compounds shape the metabolism of stromal cells in the TME and how this may impact tumor development and progression.
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Affiliation(s)
- Ana S. Dias
- Department of Chemistry, CICECO—Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal;
- Department of Medical Sciences, iBiMED—Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, Portugal; (L.H.); (C.R.A.)
| | - Luisa Helguero
- Department of Medical Sciences, iBiMED—Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, Portugal; (L.H.); (C.R.A.)
| | - Catarina R. Almeida
- Department of Medical Sciences, iBiMED—Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, Portugal; (L.H.); (C.R.A.)
| | - Iola F. Duarte
- Department of Chemistry, CICECO—Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal;
- Correspondence: ; Tel.: +351-234-401-418
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20
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Zhang M, Chen X, Radacsi N. New tricks of old drugs: Repurposing non-chemo drugs and dietary phytochemicals as adjuvants in anti-tumor therapies. J Control Release 2020; 329:96-120. [PMID: 33259852 DOI: 10.1016/j.jconrel.2020.11.047] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/22/2020] [Accepted: 11/24/2020] [Indexed: 12/14/2022]
Abstract
Combination therapy has long been applied to enhance therapeutic effect and deal with the occurrence of multi-drug resistance in cancer treatment. However, the overlapping toxicity of multiple anticancer drugs to healthy tissues and increasing financial burden on patients emerged as major concerns. As promising alternatives to chemo agents, repurposed non-chemo drugs and dietary phytochemicals have been investigated as adjuvants to conventional anti-tumor therapeutics, offering a safe and economic strategy for combination therapy. In this review, we aim to highlight the advances in research about combination therapy using conventional therapeutics and repurposed drugs or phytochemicals for an enhanced anti-tumor efficacy, along with the mechanisms involved in the synergism. Beyond these, we outlined the potential challenges and solutions for clinical translation of the proposed combination therapy, providing a safe and affordable strategy to improve the reach of cancer therapy to low income regions with such new tricks of old drugs.
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Affiliation(s)
- Mei Zhang
- School of Engineering, Institute for Materials and Processes, University of Edinburgh, Robert Stevenson Road, Edinburgh EH9 3FB, United Kingdom; School of Engineering, Institute for Bioengineering, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JL, United Kingdom.
| | - Xianfeng Chen
- School of Engineering, Institute for Bioengineering, University of Edinburgh, The King's Buildings, Edinburgh EH9 3JL, United Kingdom.
| | - Norbert Radacsi
- School of Engineering, Institute for Materials and Processes, University of Edinburgh, Robert Stevenson Road, Edinburgh EH9 3FB, United Kingdom.
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21
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Hogenkamp A, Ehlers A, Garssen J, Willemsen LEM. Allergy Modulation by N-3 Long Chain Polyunsaturated Fatty Acids and Fat Soluble Nutrients of the Mediterranean Diet. Front Pharmacol 2020; 11:1244. [PMID: 32973501 PMCID: PMC7472571 DOI: 10.3389/fphar.2020.01244] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
The Mediterranean diet, containing valuable nutrients such as n-3 long chain poly-unsaturated fatty acids (LCPUFAs) and other fat-soluble micronutrients, is known for its health promoting and anti-inflammatory effects. Its valuable elements might help in the battle against the rising prevalence of non-communicable diseases (NCD), including the development of allergic diseases and other (chronic) inflammatory diseases. The fat fraction of the Mediterranean diet contains bioactive fatty acids but can also serve as a matrix to dissolve and increase the uptake of fat-soluble vitamins and phytochemicals, such as luteolin, quercetin, resveratrol and lycopene with known immunomodulatory and anti-inflammatory capacities. Especially n-3 LCPUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derived from marine oils can target specific receptors or signaling cascades, act as eicosanoid precursors and/or alter membrane fluidity and lipid raft formation, hereby exhibiting anti-inflammatory properties. Beyond n-3 LCPUFAs, fat-soluble vitamins A, D, E, and K1/2 have the potential to affect pro-inflammatory signaling cascades by interacting with receptors or activating/inhibiting signaling proteins or phosphorylation in immune cells (DCs, T-cells, mast cells) involved in allergic sensitization or the elicitation/effector phase of allergic reactions. Moreover, fat-soluble plant-derived phytochemicals can manipulate signaling cascades, mostly by interacting with other receptors or signaling proteins compared to those modified by fat-soluble vitamins, suggesting potential additive or synergistic actions by applying a combination of these nutrients which are all part of the regular Mediterranean diet. Research concerning the effects of phytochemicals such as polyphenols has been hampered due to their poor bio-availability. However, their solubility and uptake are improved by applying them within the dietary fat matrix. Alternatively, they can be prepared for targeted delivery by means of pharmaceutical approaches such as encapsulation within liposomes or even unique nanoparticles. This review illuminates the molecular mechanisms of action and possible immunomodulatory effects of n-3 LCPUFAs and fat-soluble micronutrients from the Mediterranean diet in allergic disease development and allergic inflammation. This will enable us to further appreciate how to make use of the beneficial effects of n-3 LCPUFAs, fat-soluble vitamins and a selection of phytochemicals as active biological components in allergy prevention and/or symptom reduction.
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Affiliation(s)
- Astrid Hogenkamp
- Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
| | - Anna Ehlers
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Dermatology/Allergology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Johan Garssen
- Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.,Global Centre of Excellence Immunology, Danone Nutricia Research B.V., Utrecht, Netherlands
| | - Linette E M Willemsen
- Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands
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22
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Endo K, Matsui R, Sugiyama M, Asami T, Inaba C, Kobayashi S, Makabe H, Tanaka S. Procyanidin B2 gallate regulates TNF-α production from T cells through inhibiting glycolytic activity via mTOR-HIF-1 pathway. Biochem Pharmacol 2020; 177:113952. [DOI: 10.1016/j.bcp.2020.113952] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 04/01/2020] [Indexed: 01/01/2023]
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Zhou L, Long J, Sun Y, Chen W, Qiu R, Yuan D. Resveratrol ameliorates atherosclerosis induced by high-fat diet and LPS in ApoE -/- mice and inhibits the activation of CD4 + T cells. Nutr Metab (Lond) 2020; 17:41. [PMID: 32508962 PMCID: PMC7251691 DOI: 10.1186/s12986-020-00461-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 05/15/2020] [Indexed: 02/06/2023] Open
Abstract
Background Atherosclerosis (AS), which characterized with the accumulation of lipids on the vessel wall, is the pathological basis of many cardiovascular diseases (CVD) and seriously threatens human health. Resveratrol (RES) has been reported to be benefit for AS treatment. This research aimed to observe the effects of RES on AS induced by high-fat diet (HFD) and LPS in ApoE-/- mice and investigate the underlying mechanism. Methods ApoE-/- mice were fed with HFD companied with LPS to induce AS and RES was administrated for 20 weeks. Splenic CD4+ T cells were cultured and treated with anti-CD3/CD28 together with LPS, and RES was added. Serum lipids and the atherosclerotic areas of aortas were detected. The activation of CD4+ T cells were investigated both in vivo and in vitro and the expression of DNA methyltransferases (Dnmt) in CD4+ T cells were measured. Results In vivo, administration of RES prevented HFD and LPS induced dysfunction of serum lipids including TC (total cholesterol), TG (triglyceride), LDL-C (low density lipoprotein cholesterol) and HDL-C (high density lipoprotein cholesterol), ameliorated the thickened coronary artery wall and decreased the areas of atherosclerotic lesion on aortas. Besides, RES decreased the number of CD4+ T cells in peripheral blood, decreased the expression of CD25 and CD44, but not affected the expression of L-selectin (CD62L). In vitro, RES decreased the expression of Ki67, CD25 and CD44 in CD4+ T cells. Moreover, RES increased the secretion of IL-2, IL-10 and TGF-β1, decreased IL-6. In addition, RES decreased both the mRNA and protein level of Dnmt1 and Dnmt3b in CD4+ T cells. Conclusion These results indicated that RES ameliorated AS induced by HFD companied with LPS in ApoE-/- mice, inhibited the proliferation and activation of CD4+ T cells and regulated the expression of Dnmt1 and Dnmt3b.
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Affiliation(s)
- Liyu Zhou
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023 Jiangsu People's Republic of China
| | - Jun Long
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023 Jiangsu People's Republic of China
| | - Yuting Sun
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023 Jiangsu People's Republic of China
| | - Weikai Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023 Jiangsu People's Republic of China
| | - Runze Qiu
- Department of Clinical Pharmacology Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006 People's Republic of China
| | - Dongping Yuan
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Xianlin Dadao 138, Nanjing, 210023 Jiangsu People's Republic of China
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Alrafas HR, Busbee PB, Nagarkatti M, Nagarkatti PS. Resveratrol Downregulates miR-31 to Promote T Regulatory Cells during Prevention of TNBS-Induced Colitis. Mol Nutr Food Res 2019; 64:e1900633. [PMID: 31730734 DOI: 10.1002/mnfr.201900633] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 10/21/2019] [Indexed: 12/11/2022]
Abstract
SCOPE Colitis, an inflammatory bowel disease, is associated with aberrant regulation of the colonic mucosal immune system. Resveratrol, a natural plant product, has been found to exert anti-inflammatory properties and attenuate the development of murine colitis. In the current study, the role of microRNA (miR) in the ability of resveratrol to suppress colonic inflammation is examined. METHODS AND RESULTS BALB/C mice with 2,4,6-Trinitrobenzenesulfonic acid solution (TNBS)-induced colitis, when treated with resveratrol, show improved clinical outcomes and reduce induction of inflammatory T cells (Th17 and Th1) while increasing CD4+Foxp3+ regulatory T cells (Tregs) and IL-10-producing CD4+ T cells. miR microarray analysis and polymerase chain reaction (PCR) validation from CD4+ T cells show treatment with resveratrol decreases the expression of several miRs (miR-31, Let7a, miR-132) that targets cytokines and transcription factors involved in anti-inflammatory T cell responses (Foxp3 and TGF-β). Transfection studies with miR-31 confirm that this miR directly regulates the expression of Foxp3. Lastly, analysis of public data from human patients with ulcerative colitis reveals that miR-31 expression is significantly increased when compared to controls. CONCLUSION Together, the current study demonstrates that resveratrol-mediated attenuation of colitis may be regulated by miR-31 through induction of Tregs and miR-31 may serve as a therapeutic target for human colitis.
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Affiliation(s)
- Haider Rasheed Alrafas
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA
| | - Philip B Busbee
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA
| | - Prakash S Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29208, USA
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Yerinde C, Siegmund B, Glauben R, Weidinger C. Metabolic Control of Epigenetics and Its Role in CD8 + T Cell Differentiation and Function. Front Immunol 2019; 10:2718. [PMID: 31849941 PMCID: PMC6901948 DOI: 10.3389/fimmu.2019.02718] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 11/05/2019] [Indexed: 12/19/2022] Open
Abstract
Epigenetic programs that control posttranslational modifications of histone proteins and DNA itself tightly regulate transcriptional networks determining the identity and function of CD8+ T cells. Chromatin-modifying enzymes such as histone acetyltransferases and deacetylases, represent key molecular determinants of the epigenetic imprinting of CD8+ T cells. The functions of these enzymes highly depend on the availability of key products of cellular metabolism pathways such as acetyl-CoA, NAD (Nicotinamide adenine dinucleotide) and SEM (S-adenosylmethionine), suggesting that there is a close crosstalk between the metabolic and the epigenetic regulation of CD8+ T cells. In this review, we will discuss the metabolic regulation of CD8+ T cell epigenetics during activation and differentiation. We will furthermore summarize how metabolic signals from the tumor microenvironment (TME) shape the epigenetic landscape of CD8+ T cells to better understand the mechanism underlying CD8+ T cell exhaustion in anti-tumor and anti-viral immunity, which might help to overcome limitations of current CD8+ T cell-based therapies.
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Affiliation(s)
- Cansu Yerinde
- Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany
| | - Britta Siegmund
- Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Rainer Glauben
- Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Carl Weidinger
- Division of Gastroenterology, Infectiology and Rheumatology, Medical Department, Charité - Universitätsmedizin Berlin, Berlin, Germany.,Clinician Scientist Program, Berlin Institute of Health (BIH), Berlin, Germany
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26
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Xu W, Ma F, Li R, Zhou Q, Yao W, Jiao Y, Zhang C, Zhang J, Wang X, Xu Y, Wang Y. VpSTS29/STS2 enhances fungal tolerance in grapevine through a positive feedback loop. PLANT, CELL & ENVIRONMENT 2019; 42:2979-2998. [PMID: 31309591 DOI: 10.1111/pce.13600] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 06/02/2019] [Accepted: 06/03/2019] [Indexed: 05/03/2023]
Abstract
Accumulation of stilbene phytoalexins stimulates resistance mechanisms against the grapevine fungus Uncinula necator. However, the defensive mechanisms triggered by stilbene synthase (STS) genes, remain largely unknown. Here, we report the function and molecular mechanism of the stilbene synthase gene VpSTS29/STS2 from Vitis pseudoreticulata in the regulation of plant responses to powdery mildew. Stilbene synthesis occurred mainly in root tips and mesophyll cells of transgenic grapevines via transport through the vascular bundles. Overexpression of VpSTS29/STS2 in Vitis vinifera increased the abundance of STSs in mesophyll tissue and resulted in the accumulation of biologically active resveratrol derivatives at the invasion site. Similarly, expression of VpSTS29/STS2 in Arabidopsis increased resistance to Golovinomyces cichoracearum. The VpSTS29/STS2-expressing Arabidopsis lines showed increased piceid accumulation together with more local hypersensitive reactions, inhibition of mycelial growth, and a reduced incidence of pathogens. Transcriptome profiling analyses demonstrated that VpSTS29/STS2-induced defences led to reprograming of global gene expression and activation of salicylic acid (SA) signalling, thus increasing expression of WRKY-MYB transcription factors and other defence response genes. We propose a model for resveratrol-mediated coordination of defence responses in which SA participates in a positive feedback loop.
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Affiliation(s)
- Weirong Xu
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Fuli Ma
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Ruimin Li
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Qi Zhou
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Wenkong Yao
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Yuntong Jiao
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Chaohong Zhang
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Jianxia Zhang
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Xiping Wang
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Yan Xu
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
| | - Yuejin Wang
- College of Horticulture, Northwest A&F University, Yangling, People's Republic of China
- Key Laboratory of Horticultural Plant Biology and Germplasm Innovation in Northwest China, Ministry of Agriculture, Northwest A&F University, Yangling, People's Republic of China
- State Key Laboratory of Crop Stress Biology in Arid Areas, Northwest A&F University, Yangling, People's Republic of China
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Qian M, Liu B. Pharmaceutical Intervention of Aging. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1086:235-254. [PMID: 30232763 DOI: 10.1007/978-981-13-1117-8_15] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The aging population represents a significant worldwide socioeconomic challenge. Aging is an inevitable and multifactorial biological process and primary risk factor for most age-related diseases, such as cardiovascular diseases, cancers, type 2 diabetes mellitus (T2DM), and neurodegenerative diseases. Pharmacological interventions targeting aging appear to be a more effective approach in preventing age-related disorders compared with the treatments targeted to specific disease. In this chapter, we focus on the latest findings on molecular compounds that mimic caloric restriction (CR), supplement nicotinamide adenine dinucleotide (NAD+) levels, and eliminate senescent cells, including metformin, resveratrol, spermidine, rapamycin, NAD+ boosters, as well as senolytics. All these interventions modulate the determinants and pathways responsible for aging/longevity, such as the kinase target of rapamycin (TOR), AMP-activated protein kinase (AMPK), sirtuins, and insulin-like growth factor (IGF-1) signaling (Fig. 15.1).
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Affiliation(s)
- Minxian Qian
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Medical Research Center, Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, China
| | - Baohua Liu
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Medical Research Center, Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, China.
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28
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Qian M, Liu B. Advances in pharmacological interventions of aging in mice. TRANSLATIONAL MEDICINE OF AGING 2019. [DOI: 10.1016/j.tma.2019.11.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Lucas J, Hsieh TC, Halicka HD, Darzynkiewicz Z, Wu JM. Upregulation of PD‑L1 expression by resveratrol and piceatannol in breast and colorectal cancer cells occurs via HDAC3/p300‑mediated NF‑κB signaling. Int J Oncol 2018; 53:1469-1480. [PMID: 30066852 PMCID: PMC6086626 DOI: 10.3892/ijo.2018.4512] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/05/2018] [Indexed: 12/24/2022] Open
Abstract
Programmed cell death ligand 1 (PD-L1) expressed in cancer cells interacting with its receptor programmed cell death 1 (PD-1) expressed in immune cells represents a regulatory axis linked to the suppression and evasion of host immune functions. The blockade of PD-1/PD-L1 interaction using monoclonal antibodies has emerged as an effective therapy for several solid tumors; however, durable response has been observed in a subset of patients with PD-L1-positive tumors. Thus, the understanding of the mechanisms responsible for the expression of PD-L1 in tumor cells may help to improve the response to PD-L1 blockade therapies. In this study, we investigated whether resveratrol, a grape-derived stilbenoid with immunoregulatory activity, modulates the expression of PD-L1 in breast and colorectal cancer cells. The surface expression of PD-L1 was determined by flow cytometry in cancer cells treated with resveratrol and/or piceatannol. Each stilbenoid alone induced PD-L1 and when used in combination, elicited a synergistic upregulation of PD-L1 in some cell lines. The induction of PD-L1 by the combined use of stilbenoids was most pronounced in the Cal51 triple-negative breast cancer (TNBC) and SW620 colon cancer cells. The observed induction of PD-L1 was transcriptionally mediated by nuclear factor (NF)-κB, as shown by NF-κB reporter assays, the nuclear accumulation of the p65 subunit of NF-κB, inhibition by the IKK inhibitor, BMS-345541, and histone the modification inhibitors, resminostat, entinostat or anacardic acid. Combined treatment with resveratrol and piceatannol also decreased tumor cell survival as indicated by the upregulation of the DNA damaging marker, γH2AX, the cleavage of caspase 3, the downregulation of the survival markers, p38-MAPK/c-Myc, and G1-to-S cell cycle arrest.
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Affiliation(s)
- Justin Lucas
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
| | - Tze-Chen Hsieh
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
| | - H Dorota Halicka
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY 10595, USA
| | - Zbigniew Darzynkiewicz
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY 10595, USA
| | - Joseph M Wu
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
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Yong CS, Abba Moussa D, Cretenet G, Kinet S, Dardalhon V, Taylor N. Metabolic orchestration of T lineage differentiation and function. FEBS Lett 2017; 591:3104-3118. [PMID: 28901530 DOI: 10.1002/1873-3468.12849] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Revised: 09/04/2017] [Accepted: 09/06/2017] [Indexed: 12/14/2022]
Abstract
T cells are stimulated by the engagement of antigen, cytokine, pathogen, and hormone receptors. While research performed over many years has focused on deciphering the molecular components of these pathways, recent data underscore the importance of the metabolic environment in conditioning responses to receptor engagement. The ability of T cells to undergo a massive proliferation and cytokine secretion in response to receptor signals requires alterations to their bioenergetic homeostasis, allowing them to meet new energetic and biosynthetic demands. The metabolic reprogramming of activated T cells is regulated not only by changes in intracellular nutrient uptake and utilization but also by nutrient and oxygen concentrations in the extracellular environment. Notably, the extracellular environment can be profoundly altered by pathological conditions such as infections and tumors, thereby perturbing the metabolism and function of antigen-specific T lymphocytes. This review highlights the interplay between diverse metabolic networks and the transcriptional/epigenetic states that condition T-cell differentiation, comparing the metabolic features of T lymphocytes with other immune cells. We further address recent discoveries in the metabolic pathways that govern T-cell function in physiological and pathological conditions.
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Affiliation(s)
- Carmen S Yong
- IGMM, CNRS, Univ. Montpellier, Montpellier, France
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Vic., Australia
| | | | | | | | | | - Naomi Taylor
- IGMM, CNRS, Univ. Montpellier, Montpellier, France
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