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Lee SH, Khoo ASB, Griffiths JR, Mat Lazim N. Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus. Int J Cancer 2025; 156:488-498. [PMID: 39291683 DOI: 10.1002/ijc.35192] [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: 07/15/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 09/19/2024]
Abstract
The Epstein-Barr virus (EBV), the first identified human tumour virus, infects over 95% of the individuals globally and has the potential to induce different types of cancers. It is increasingly recognised that EBV infection not only alters cellular metabolism, contributing to neoplastic transformation, but also utilises several non-cell autonomous mechanisms to shape the metabolic milieu in the tumour microenvironment (TME) and its constituent stromal and immune cells. In this review, we explore how EBV modulates metabolism to shape the interactions between cancer cells, stromal cells, and immune cells within a hypoxic and acidic TME. We highlight how metabolites resulting from EBV infection act as paracrine factors to regulate the TME, and how targeting them can disrupt barriers to immunotherapy.
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Affiliation(s)
- Shen-Han Lee
- Department of Otorhinolaryngology-Head & Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Alan Soo-Beng Khoo
- School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
- Department of Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - John R Griffiths
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Norhafiza Mat Lazim
- Department of Otorhinolaryngology-Head & Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
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2
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Ma N, Wang L, Meng M, Wang Y, Huo R, Chang G, Shen X. D-sodium lactate promotes the activation of NF-κB signaling pathway induced by lipopolysaccharide via histone lactylation in bovine mammary epithelial cells. Microb Pathog 2025; 199:107198. [PMID: 39662787 DOI: 10.1016/j.micpath.2024.107198] [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: 03/04/2024] [Revised: 11/28/2024] [Accepted: 12/02/2024] [Indexed: 12/13/2024]
Abstract
Lactate is a glycolytic end product that is further metabolized as an energy source. This end product has been associated with certain diseases, including sepsis and tumors, and it can regulate the transition of macrophages to an anti-inflammatory state. This study aimed to explore the effects of lactate on the inflammatory responses of mammary gland epithelial cells, which constitute the first line of defense against pathogens in mammary glands. Bovine mammary epithelial cells (BMECs) were challenged with lipopolysaccharide (LPS) in the presence or absence of D-sodium lactate (D-nala). LPS exposure increased the concentration of lactate both inside and outside the cells. Further, inhibiting glycolysis diminished the LPS-induced production of proinflammatory cytokines. Treatment with LPS, exogenous D-nala, and their combination upregulated the expression levels of MCT1, increased the intracellular levels of lactate and histone H3 lysine 18 lactylation (H3K18la), and activated the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway. The lactylation of H3K18 was mediated by p300/CBP. The p300/CBP inhibitor C646 decreased the level of H3K18la, reversing the activation of the NF-κB signaling pathway and release of proinflammatory cytokines. Therefore, LPS increased the intracellular level of lactate by upregulating MCT1 and glycolysis. D-nala exacerbated the LPS-induced inflammatory responses in BMECs. Moreover, intracellular lactate enhanced the activation of the NF-κB signaling pathway through the p300/CBP-mediated lactylation of H3K18. Thus, the findings of this study expand our understanding of lactate function in immune regulation.
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Affiliation(s)
- Nana Ma
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Lairong Wang
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Meijuan Meng
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Yan Wang
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Ran Huo
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Guangjun Chang
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Xiangzhen Shen
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China.
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3
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Chen T, Ashwood LM, Kondrashova O, Strasser A, Kelly G, Sutherland KD. Breathing new insights into the role of mutant p53 in lung cancer. Oncogene 2025; 44:115-129. [PMID: 39567755 PMCID: PMC11725503 DOI: 10.1038/s41388-024-03219-6] [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: 07/08/2024] [Revised: 10/25/2024] [Accepted: 11/01/2024] [Indexed: 11/22/2024]
Abstract
The tumour suppressor gene p53 is one of the most frequently mutated genes in lung cancer and these defects are associated with poor prognosis, albeit some debate exists in the lung cancer field. Despite extensive research, the exact mechanisms by which mutant p53 proteins promote the development and sustained expansion of cancer remain unclear. This review will discuss the cellular responses controlled by p53 that contribute to tumour suppression, p53 mutant lung cancer mouse models and characterisation of p53 mutant lung cancer. Furthermore, we discuss potential approaches of targeting mutant p53 for the treatment of lung cancer.
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Affiliation(s)
- Tianwei Chen
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Lauren M Ashwood
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- The University of Queensland, Brisbane, QLD, Australia
| | - Olga Kondrashova
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
- The University of Queensland, Brisbane, QLD, Australia
| | - Andreas Strasser
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
| | - Gemma Kelly
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
| | - Kate D Sutherland
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
- Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
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4
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Song C, Liu F, Wu X, Zhou D, Mei Y, Wei Z, Shi H, Zeng L, Chen F, Jiang F, Liu Z. ASIC1a mediated nucleus pulposus cells pyroptosis and glycolytic crosstalk as a molecular basis for intervertebral disc degeneration. Inflamm Res 2025; 74:29. [PMID: 39870819 DOI: 10.1007/s00011-025-02003-w] [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: 11/12/2024] [Revised: 01/16/2025] [Accepted: 01/23/2025] [Indexed: 01/29/2025] Open
Abstract
BACKGROUND One of the etiologic components of degenerative spinal illnesses is intervertebral disc degeneration (IVDD), and the accompanying lower back pain is progressively turning into a significant public health problem. Important pathologic characteristics of IVDD include inflammation and acidic microenvironment, albeit it is unclear how these factors contribute to the disease. PURPOSE To clarify the functions of inflammation and the acidic environment in IVDD, identify the critical connections facilitating glycolytic crosstalk and nucleus pulposus cells (NPCs) pyroptosis, and offer novel approaches to IVDD prevention and therapy. METHODS By developing keywords search strategy, literature was found and screened using databases such as PUBMED, Google Scholar, Web of Science, China National Knowledge Infrastructure, and others. Hub genes, protein interaction networks, clinical transcriptome data validation, and enrichment analysis were used to further validate relevant biological pathways. RESULTS It is clear that disc degeneration is associated with apoptosis or pyroptosis, inflammation, and an acidic environment based on literature review. The process of IVDD is intimately associated with pyroptosis, inflammation, and an acidic environment. The precise mechanism may entail the regulation of key genes such NLRP3, ASIC1a, IL1β, TNF-a, and GSDMD. While the acidic environment exacerbated extracellular matrix degradation and promoted cellular senescence and inflammatory factor expression, it was found to be unfavorable for NPCs survival and proliferation. Moreover, NPCs pyroptosis in an acidic environment, the molecular mechanism behind this phenomenon may be connected to ASIC1a mediated Ca + influx. On the other hand, IVDD can be constantly promoted by the interaction between the degenerating disc's acidic and inflammatory environments through "crosstalk" between anaerobic glycolysis and positive feedback. CONCLUSION In summary, the inflammatory process in NPCs is made worse by the buildup of glucose brought on by metabolic problems, such as anaerobic glycolytic processes, and pyroptosis caused by excessive glucose may be mitigated by inhibiting endoplasmic reticulum stress. A new therapeutic approach for IVDD will involve using ASIC1a as a regulatory target to enhance the inflammatory environment and decrease the incidence of NPCs pyroptosis. Following this, anaerobic glycolysis will be regulated, lactic acid generation will be reduced, and the degenerative vicious loop will be blocked.
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Affiliation(s)
- Chao Song
- Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Department of Orthopedics, RuiKang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Fei Liu
- Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- Department of Orthopedics, RuiKang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Xiaofei Wu
- Department of Orthopedics, RuiKang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Daqian Zhou
- Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Yongliang Mei
- Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Zhangchao Wei
- Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Houyin Shi
- Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Lianlin Zeng
- Department of Rehabilitation Medicine, Suining Central Hospital, Suining, Sichuan Provience, China.
| | - Feng Chen
- Department of Orthopedics, RuiKang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China.
| | - Feng Jiang
- Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.
| | - Zongchao Liu
- Department of Orthopedics and Traumatology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.
- Luzhou Longmatan District People's Hospital, No.182 Chunhui Road, Longmatan District, Luzhou, Sichuan Province, China.
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Glaviano A, Lau HSH, Carter LM, Lee EHC, Lam HY, Okina E, Tan DJJ, Tan W, Ang HL, Carbone D, Yee MYH, Shanmugam MK, Huang XZ, Sethi G, Tan TZ, Lim LHK, Huang RYJ, Ungefroren H, Giovannetti E, Tang DG, Bruno TC, Luo P, Andersen MH, Qian BZ, Ishihara J, Radisky DC, Elias S, Yadav S, Kim M, Robert C, Diana P, Schalper KA, Shi T, Merghoub T, Krebs S, Kusumbe AP, Davids MS, Brown JR, Kumar AP. Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition. J Hematol Oncol 2025; 18:6. [PMID: 39806516 PMCID: PMC11733683 DOI: 10.1186/s13045-024-01634-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 11/11/2024] [Indexed: 01/16/2025] Open
Abstract
The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Hannah Si-Hui Lau
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore
| | - Lukas M Carter
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - E Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Hiu Yan Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Donavan Jia Jie Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Wency Tan
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
- School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, 139651, Singapore
| | - Hui Li Ang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Michelle Yi-Hui Yee
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Xiao Zi Huang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore
| | - Lina H K Lim
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, Singapore, 169610, Singapore
- Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore
| | - Ruby Yun-Ju Huang
- School of Medicine and Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
- Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, 23538, Lübeck, Germany
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, UMC, Vrije Universiteit, HV Amsterdam, 1081, Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Fondazione Pisana Per La Scienza, 56017, San Giuliano, Italy
| | - Dean G Tang
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
- Experimental Therapeutics (ET) Graduate Program, University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Tullia C Bruno
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy, Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Bin-Zhi Qian
- Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, The Human Phenome Institute, Zhangjiang-Fudan International Innovation Center, Fudan University, Shanghai, China
| | - Jun Ishihara
- Department of Bioengineering, Imperial College London, London, W12 0BZ, UK
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, 32224, USA
| | - Salem Elias
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Saurabh Yadav
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Minah Kim
- Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Caroline Robert
- Department of Cancer Medicine, Inserm U981, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France
- Faculty of Medicine, University Paris-Saclay, Kremlin Bicêtre, Paris, France
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kurt A Schalper
- Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Tao Shi
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
| | - Taha Merghoub
- Swim Across America and Ludwig Collaborative Laboratory, Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, Department of Medicine, Parker Institute for Cancer Immunotherapy, Weill Cornell Medicine, New York, NY, USA
| | - Simone Krebs
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anjali P Kusumbe
- Tissue and Tumor Microenvironment Group, MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228, Singapore.
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Griffin KV, Saunders MN, Lyssiotis CA, Shea LD. Engineering immunity using metabolically active polymeric nanoparticles. Trends Biotechnol 2024:S0167-7799(24)00345-7. [PMID: 39732608 DOI: 10.1016/j.tibtech.2024.11.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 11/12/2024] [Accepted: 11/19/2024] [Indexed: 12/30/2024]
Abstract
Immune system functions play crucial roles in both health and disease, and these functions are regulated by their metabolic programming. The field of immune engineering has emerged to develop therapeutic strategies, including polymeric nanoparticles (NPs), that can direct immune cell phenotype and function by directing immunometabolic changes. Precise control of bioenergetic processes may offer the opportunity to prevent undesired immune activity and improve disease-specific outcomes. In this review we discuss the role that polymeric NPs can play in shaping immunometabolism and subsequent immune system activity through particle-mediated delivery of metabolically active agents as either structural components or cargo.
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Affiliation(s)
- Kate V Griffin
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Michael N Saunders
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.
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7
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Brummer C, Singer K, Henrich F, Peter K, Strobl C, Neueder B, Bruss C, Renner K, Pukrop T, Herr W, Aigner M, Kreutz M. The Tumor Metabolite 5'-Deoxy-5'Methylthioadenosine (MTA) Inhibits Maturation and T Cell-Stimulating Capacity of Dendritic Cells. Cells 2024; 13:2114. [PMID: 39768204 PMCID: PMC11727219 DOI: 10.3390/cells13242114] [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: 10/29/2024] [Revised: 12/16/2024] [Accepted: 12/18/2024] [Indexed: 01/16/2025] Open
Abstract
Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5'-deoxy-5'methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it is known to inhibit tumor-infiltrating T cells and NK cells. However, the impact of MTA on other intra-tumoral immune cells has not yet been fully elucidated. To study the effects of MTA on dendritic cells (DCs), human monocytes were maturated into DCs with (MTA-DC) or without MTA (co-DC) and analyzed for activation, differentiation, and T cell-stimulating capacity. MTA altered the cytokine secretion profile of monocytes and impaired their maturation into dendritic cells. MTA-DCs produced less IL-12 and showed a more immature-like phenotype characterized by decreased expression of the co-stimulatory molecules CD80, CD83, and CD86 and increased expression of the monocyte markers CD14 and CD16. Consequently, MTA reduced the capability of DCs to stimulate T cells. Mechanistically, the MTA-induced effects on monocytes and DCs were mediated by a mechanism beyond adenosine receptor signaling. These results provide new insights into how altered polyamine metabolism impairs the maturation of monocyte-derived DCs and impacts the crosstalk between T and dendritic cells.
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Affiliation(s)
- Christina Brummer
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Katrin Singer
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Frederik Henrich
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
- Department of Internal Medicine 5, University Hospital Erlangen, 91054 Erlangen, Germany
| | - Katrin Peter
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Carolin Strobl
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
- Department of Internal Medicine 5, University Hospital Erlangen, 91054 Erlangen, Germany
| | - Bernadette Neueder
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Christina Bruss
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Kathrin Renner
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
- Department of Otorhinolaryngology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Tobias Pukrop
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
- Comprehensive Cancer Center Eastern Bavaria (CCCO), 93053 Regensburg, Germany
- Center of Translational Oncology (CTO), 93053 Regensburg, Germany
| | - Wolfgang Herr
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Michael Aigner
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
- Department of Internal Medicine 5, University Hospital Erlangen, 91054 Erlangen, Germany
| | - Marina Kreutz
- Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
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8
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Liu H, Pan M, Liu M, Zeng L, Li Y, Huang Z, Guo C, Wang H. Lactate: a rising star in tumors and inflammation. Front Immunol 2024; 15:1496390. [PMID: 39660139 PMCID: PMC11628389 DOI: 10.3389/fimmu.2024.1496390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 11/04/2024] [Indexed: 12/12/2024] Open
Abstract
Lactate has been traditionally regarded as a mere byproduct of glycolysis or metabolic waste. However, an increasing body of literature suggests its critical role in regulating various physiological and pathological processes. Lactate is generally associated with hypoxia, inflammation, viral infections, and tumors. It performs complex physiological roles by activating monocarboxylate transporter (MCT) or the G protein-coupled receptor GPR81 across the cell membrane. Lactate exerts immunosuppressive effects by regulating the functions of various immune cells (such as natural killer cells, T cells, dendritic cells, and monocytes) and its role in macrophage polarization and myeloid-derived suppressor cell (MDSC) differentiation in the tumor microenvironment. Lactic acid has also recently been found to increase the density of CD8+ T cells, thereby enhancing the antitumor immune response. Acute or chronic inflammatory diseases have opposite immune states in the inflammatory disease microenvironment. Factors such as cell types, transcriptional regulators, ionic mediators, and the microenvironment all contribute to the diverse functions lactate exhibits. Herein, we reviewed the pleiotropic effects of lactate on the regulation of various functions of immune cells in the tumor microenvironment and under inflammatory conditions, which may help to provide new insights and potential targets for the diagnosis and treatment of inflammatory diseases and malignancies.
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Affiliation(s)
| | | | | | | | | | | | - Chunlei Guo
- Henan Key Laboratory of Immunology and Targeted Drug, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Hui Wang
- Henan Key Laboratory of Immunology and Targeted Drug, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
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9
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Gonzales-Huerta LE, Williams TJ, Aljohani R, Robertson BD, Evans CA, Armstrong-James D. Precision-cut lung slices in air-liquid interface (PCLS-ALI): A novel ex-vivo model for the study of Pulmonary Aspergillosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.15.615211. [PMID: 39605594 PMCID: PMC11601337 DOI: 10.1101/2024.11.15.615211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Pulmonary Aspergillosis is a respiratory infection with a high mortality rate, which affects patients with immunosuppression or structural lung defects. Antifungal treatment options are few and many have narrow therapeutic margins and potentially serious side effects. In recent years, there are growing numbers of reports of antifungal resistance. Thus, there is an urgent need for effective models to study fungal pathogenesis and test antifungal therapies in the respiratory system. Here, we present a novel ex-vivo model using precision-cut lung slices in an air-liquid interface platform to evaluate lung tissue responses to fungal infection and antifungal treatment. Readouts assessed were lactate dehydrogenase for tissue damage, release of inflammatory cytokines (TNF-α, IL-1β, CXCL1), and histology for confirmation of hyphal invasion. Overall, the PCLS-ALI model is a promising approach for understanding lung tissue responses to fungal infections, which fulfils the reduction and refinement components of the 3Rs guiding principles for ethical use of experimental animals.
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Affiliation(s)
- L E Gonzales-Huerta
- Department of Infectious Disease, Imperial College London, SW7 2AZ, UK
- Carrera de Medicina Humana, Facultad de Ciencias de la Salud, Universidad San Ignacio de Loyola, Lima 15024 Peru
| | - T J Williams
- Department of Infectious Disease, Imperial College London, SW7 2AZ, UK
| | - R Aljohani
- Department of Infectious Disease, Imperial College London, SW7 2AZ, UK
| | - B D Robertson
- Department of Infectious Disease, Imperial College London, SW7 2AZ, UK
| | - C A Evans
- Department of Infectious Disease, Imperial College London, SW7 2AZ, UK
- Innovación Por la Salud Y Desarrollo (IPSYD), Asociación Benéfica PRISMA, Lima, 15073, Peru4 IFHAD: Innovation for Health and Development, Laboratorio de Investigación y Desarrollo, Universidad Peruana Cayetano Heredia, Lima 150135 Peru
- IFHAD: Innovation For Health And Development, Laboratorio de Investigación y Desarrollo, Universidad Peruana Cayetano Heredia, Lima 150135 Peru
- IFHAD: Innovation For Health And Development, Department of infectious disease, Imperial College London, London, UK
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10
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Matos ID, Borges AD, Trindade LM, Andrade MER, Cavalcante GG, Leocádio PCL, Alvarez-Leite JI, Cassali GD, Costa BG, Martins FDS, Cardoso VN, Generoso SDV. Mitigation of chemotherapy-induced experimental intestinal mucositis through postbiotic lactate. Lett Appl Microbiol 2024; 77:ovae103. [PMID: 39496521 DOI: 10.1093/lambio/ovae103] [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: 05/16/2024] [Revised: 10/14/2024] [Accepted: 10/31/2024] [Indexed: 11/06/2024]
Abstract
Postbiotic lactate modulates the immune system in inflammatory bowel diseases. However, its role in experimental intestinal mucositis (IM) has not been elucidated. This study aimed to evaluate the effects of lactate supplementation (1 and 2 × 10-1 mol/l) in a 5-fluorouracil (5-FU)-induced IM model. Male BALB/c mice (6-8 weeks old) were randomly divided into four groups: control (CTL), mucositis (MUC), mucositis with 1 × 10-1 mol/l lactate solution (MUC10), and mucositis with 2 × 10-1 mol/l lactate solution (MUC200). Lactate was administered via oral gavage for 10 days. Following the treatment period, the animals were subjected to an intraperitoneal injection of 300 mg/kg 5-FU to induce IM and were euthanized 72 h later for analysis. The MUC group presented intestinal damage with a poor histological score and decreased morphometric parameters as well as decreased mucus production and increased inflammatory infiltration and intestinal permeability compared to those of the CTL group (P < .05). However, the MUC200 group exhibited better results for the evaluated parameters than the MUC group (P < .05). Notably, the results in the MUC10 group were similar to those in the MUC group (P > .05). In conclusion, lactate supplementation attenuates mucositis-induced damage in a dose-dependent manner.
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Affiliation(s)
- Isabel David Matos
- Food Department, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Amanda Dias Borges
- Food Department, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Luísa Martins Trindade
- Food Department, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Maria Emília Rabelo Andrade
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Gregório Grama Cavalcante
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Paola Caroline Lacerda Leocádio
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Jacqueline Isaura Alvarez-Leite
- Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Geovanni Dantas Cassali
- Department of Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Bruno Galotti Costa
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Flaviano Dos Santos Martins
- Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Valbert Nascimento Cardoso
- Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
| | - Simone de Vasconcelos Generoso
- Department of Nutrition, School of Nursing, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil
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11
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Liu AB, Tan B, Yang P, Tian N, Li JK, Wang SC, Yang LS, Ma L, Zhang JF. The role of inflammatory response and metabolic reprogramming in sepsis-associated acute kidney injury: mechanistic insights and therapeutic potential. Front Immunol 2024; 15:1487576. [PMID: 39544947 PMCID: PMC11560457 DOI: 10.3389/fimmu.2024.1487576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 10/11/2024] [Indexed: 11/17/2024] Open
Abstract
Sepsis represents a severe condition characterized by organ dysfunction resulting from a dysregulated host response to infection. Among the organs affected, the kidneys are particularly vulnerable, with significant functional impairment that markedly elevates mortality rates. Previous researches have highlighted that both inflammatory response dysregulation and metabolic reprogramming are crucial in the onset and progression of sepsis associated acute kidney injury (SA-AKI), making these processes potential targets for innovative therapies. This study aims to elucidate the pathophysiological mechanisms of renal injury in sepsis by perspective of inflammatory response dysregulation, with particular emphasis on pyroptosis, necroptosis, autophagy, and ferroptosis. Furthermore, it will incorporate insights into metabolic reprogramming to provide a detailed analysis of the mechanisms driving SA-AKI and explore potential targeted therapeutic strategies, providing solid theoretical framework for the development of targeted therapies for SA-AKI.
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Affiliation(s)
- An-Bu Liu
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Bin Tan
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Ping Yang
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Na Tian
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Jin-Kui Li
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Si-Cong Wang
- Department of Emergency Medical, Yanchi County People’s Hospital, Wuzhong, Ningxia, China
| | - Li-Shan Yang
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Lei Ma
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Jun-Fei Zhang
- Department of Emergency Medical, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, China
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12
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Zhou Y, Lou J, Tian Y, Ding J, Wang X, Tang B. How lactate affects immune strategies in lymphoma. Front Mol Biosci 2024; 11:1480884. [PMID: 39464313 PMCID: PMC11502318 DOI: 10.3389/fmolb.2024.1480884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 09/30/2024] [Indexed: 10/29/2024] Open
Abstract
Tumor cells undergo metabolic reprogramming through shared pathways, resulting in a hypoxic, acidic, and highly permeable internal tumor microenvironment (TME). Lactate, once only regarded as a waste product of glycolysis, has an inseparable dual role with tumor immunity. It can not only provide a carbon source for immune cells to enhance immunity but also help the immune escape through a variety of ways. Lymphoma also depends on the proliferation signal of TME. This review focuses on the dynamic process of lactate metabolism and immune function changes in lymphoma and aims to comprehensively summarize and explore which genes, transcription factors, and pathways affect the biological changes and functions of immune cells. To deeply understand the complex and multifaceted role of lactate metabolism and immunity in lymphoma, the combination of lactate targeted therapy and classical immunotherapy will be a promising development direction in the future.
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Affiliation(s)
- Yuehan Zhou
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinzhan Lou
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuqin Tian
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinlei Ding
- Department of Thoracic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaobo Wang
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bo Tang
- Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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13
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Bae WH, Maraka S, Daher A. Challenges and advances in glioblastoma targeted therapy: the promise of drug repurposing and biomarker exploration. Front Oncol 2024; 14:1441460. [PMID: 39439947 PMCID: PMC11493774 DOI: 10.3389/fonc.2024.1441460] [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: 05/31/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
Glioblastoma remains the most prevalent and aggressive primary malignant brain tumor in adults, characterized by limited treatment options and a poor prognosis. Previous drug repurposing efforts have yielded only marginal survival benefits, particularly those involving inhibitors targeting receptor tyrosine kinase and cyclin-dependent kinase-retinoblastoma pathways. This limited efficacy is likely due to several critical challenges, including the tumor's molecular heterogeneity, the dynamic evolution of its genetic profile, and the restrictive nature of the blood-brain barrier that impedes effective drug delivery. Emerging diagnostic tools, such as circulating tumor DNA and extracellular vesicles, offer promising non-invasive methods for real-time tumor monitoring, potentially enabling the application of targeted therapies to more selected patient populations. Moreover, innovative drug delivery strategies, including focused ultrasound, implantable drug-delivery systems, and engineered nanoparticles, hold potential for enhancing the bioavailability and therapeutic efficacy of treatments.
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Affiliation(s)
- William Han Bae
- Division of Hematology/Oncology, Department of Internal Medicine, University of Illinois Chicago, Chicago, IL, United States
| | - Stefania Maraka
- Department of Neurology and Rehabilitation, University of Illinois Chicago, Chicago, IL, United States
| | - Ahmad Daher
- Department of Neurology and Rehabilitation, University of Illinois Chicago, Chicago, IL, United States
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14
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Ahrazoglu T, Kluczny JI, Kleimann P, Irschfeld LM, Nienhaus FT, Bönner F, Gerdes N, Temme S. Design of a Robust Flow Cytometric Approach for Phenotypical and Functional Analysis of Human Monocyte Subsets in Health and Disease. Biomolecules 2024; 14:1251. [PMID: 39456184 PMCID: PMC11506830 DOI: 10.3390/biom14101251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/18/2024] [Accepted: 09/26/2024] [Indexed: 10/28/2024] Open
Abstract
Human monocytes can be subdivided into phenotypically and functionally different classical, intermediate and non-classical monocytes according to the cell surface expression of CD14 and CD16. A precise identification and characterisation of monocyte subsets is necessary to unravel their role in inflammatory diseases. Here, we compared three different flow cytometric strategies (A-C) and found that strategy C, which included staining against CD11b, HLA-DR, CD14 and CD16, followed by several gating steps, most reliably identified monocyte subtypes in blood samples from healthy volunteers and from patients with stable coronary heart disease (CHD) or ST-elevation myocardial infarction (STEMI). Additionally, we established a fixation and permeabilisation protocol to enable the analysis of intracellular markers. We investigated the phagocytosis of lipid nanoparticles, the uptake of 2-NBD-glucose and the intracellular levels of CD74 and HLA-DM. This revealed that classical and intermediate monocytes from patients with STEMI showed the highest uptake of 2-NBD-glucose, whereas classical and intermediate monocytes from patients with CHD took up the largest amounts of lipid nanoparticles. Interestingly, intermediate monocytes had the highest expression level of HLA-DM. Taken together, we present a robust flow cytometric approach for the identification and functional characterisation of monocyte subtypes in healthy humans and patients with diseases.
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Affiliation(s)
- Talia Ahrazoglu
- Department of Anesthesiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (T.A.); (J.I.K.)
| | - Jennifer Isabel Kluczny
- Department of Anesthesiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (T.A.); (J.I.K.)
| | - Patricia Kleimann
- Institute of Molecular Cardiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
| | - Lisa-Marie Irschfeld
- Department of Radiation Oncology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
| | - Fabian Theodor Nienhaus
- Department of Cardiology, Pulmonology and Vascular Medicine, Faculty of Medicine, University Hospital, Heinrich-Heine University, 40225 Düsseldorf, Germany; (F.T.N.); (F.B.); (N.G.)
| | - Florian Bönner
- Department of Cardiology, Pulmonology and Vascular Medicine, Faculty of Medicine, University Hospital, Heinrich-Heine University, 40225 Düsseldorf, Germany; (F.T.N.); (F.B.); (N.G.)
| | - Norbert Gerdes
- Department of Cardiology, Pulmonology and Vascular Medicine, Faculty of Medicine, University Hospital, Heinrich-Heine University, 40225 Düsseldorf, Germany; (F.T.N.); (F.B.); (N.G.)
- Cardiovascular Research Institute Düsseldorf (CARID), Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany
| | - Sebastian Temme
- Department of Anesthesiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (T.A.); (J.I.K.)
- Cardiovascular Research Institute Düsseldorf (CARID), Medical Faculty, Heinrich-Heine University, 40225 Düsseldorf, Germany
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15
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Romero-Moreno R, Czowski BJ, Harris L, Kuehn JF, White KA. Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells. J Biol Chem 2024; 300:107658. [PMID: 39128712 PMCID: PMC11489351 DOI: 10.1016/j.jbc.2024.107658] [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: 07/10/2024] [Accepted: 07/31/2024] [Indexed: 08/13/2024] Open
Abstract
Intracellular pH (pHi) dynamics regulate normal cell function, and dysregulated pHi dynamics is an emerging hallmark of cancer (constitutively increased pHi) and neurodegeneration (constitutively decreased pHi). However, the molecular mechanisms by which pHi dynamics regulate cell biology are poorly understood. Here, we discovered that altering pHi in normal human breast epithelial cells triggers global transcriptional changes. We identified 176 genes differentially regulated by pHi, with pHi-dependent genes clustering in signaling and glycolytic pathways. Using various normal epithelial cell models, we showed pH-dependent Notch homolog 1 protein expression, with increased protein abundance at high pHi. This resulted in pH-dependent downstream signaling, with increased Notch homolog 1 signaling at high pHi. We also found that high pHi increased the expression of glycolytic enzymes and regulators of pyruvate fate, including lactate dehydrogenase and pyruvate dehydrogenase kinase. These transcriptional changes were sufficient to alter lactate production, with high pHi shifting these normal epithelial cells toward a glycolytic metabolism and increasing lactate production. Thus, pHi dynamics transcriptionally regulate signaling and metabolic pathways in normal epithelial cells. Our data reveal new molecular regulators of pHi-dependent biology and a role for increased pHi in driving the acquisition of cancer-associated signaling and metabolic changes in normal human epithelial cells.
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Affiliation(s)
- Ricardo Romero-Moreno
- Harper Cancer Research Institute, South Bend, Indiana, USA; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
| | - Brandon J Czowski
- Harper Cancer Research Institute, South Bend, Indiana, USA; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
| | - Lindsey Harris
- Harper Cancer Research Institute, South Bend, Indiana, USA; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
| | - Jessamine F Kuehn
- Harper Cancer Research Institute, South Bend, Indiana, USA; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
| | - Katharine A White
- Harper Cancer Research Institute, South Bend, Indiana, USA; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
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16
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Krenz B, Lee J, Kannan T, Eilers M. Immune evasion: An imperative and consequence of MYC deregulation. Mol Oncol 2024; 18:2338-2355. [PMID: 38957016 PMCID: PMC11459038 DOI: 10.1002/1878-0261.13695] [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: 02/07/2024] [Revised: 05/08/2024] [Accepted: 06/19/2024] [Indexed: 07/04/2024] Open
Abstract
MYC has been implicated in the pathogenesis of a wide range of human tumors and has been described for many years as a transcription factor that regulates genes with pleiotropic functions to promote tumorigenic growth. However, despite extensive efforts to identify specific target genes of MYC that alone could be responsible for promoting tumorigenesis, the field is yet to reach a consensus whether this is the crucial function of MYC. Recent work shifts the view on MYC's function from being a gene-specific transcription factor to an essential stress resilience factor. In highly proliferating cells, MYC preserves cell integrity by promoting DNA repair at core promoters, protecting stalled replication forks, and/or preventing transcription-replication conflicts. Furthermore, an increasing body of evidence demonstrates that MYC not only promotes tumorigenesis by driving cell-autonomous growth, but also enables tumors to evade the host's immune system. In this review, we summarize our current understanding of how MYC impairs antitumor immunity and why this function is evolutionarily hard-wired to the biology of the MYC protein family. We show why the cell-autonomous and immune evasive functions of MYC are mutually dependent and discuss ways to target MYC proteins in cancer therapy.
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Affiliation(s)
- Bastian Krenz
- Department of Biochemistry and Molecular BiologyTheodor Boveri Institute, Biocenter, University of WürzburgWürzburgGermany
- Mildred Scheel Early Career CenterWürzburgGermany
| | - Jongkuen Lee
- Department of Biochemistry and Molecular BiologyTheodor Boveri Institute, Biocenter, University of WürzburgWürzburgGermany
| | - Toshitha Kannan
- Department of Biochemistry and Molecular BiologyTheodor Boveri Institute, Biocenter, University of WürzburgWürzburgGermany
| | - Martin Eilers
- Department of Biochemistry and Molecular BiologyTheodor Boveri Institute, Biocenter, University of WürzburgWürzburgGermany
- Comprehensive Cancer Center MainfrankenWürzburgGermany
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17
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Bekhbat M. Glycolytic metabolism: Food for immune cells, fuel for depression? Brain Behav Immun Health 2024; 40:100843. [PMID: 39263313 PMCID: PMC11387811 DOI: 10.1016/j.bbih.2024.100843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 07/16/2024] [Accepted: 08/10/2024] [Indexed: 09/13/2024] Open
Abstract
Inflammation is one biological pathway thought to impact the brain to contribute to major depressive disorder (MDD) and is reliably associated with resistance to standard antidepressant treatments. While peripheral immune cells, particularly monocytes, have been associated with aspects of increased inflammation in MDD and symptom severity, significant gaps in knowledge exist regarding the mechanisms by which these cells are activated to contribute to behavioral symptoms in MDD. One concept that has gained recent appreciation is that metabolic rewiring to glycolysis in activated myeloid cells plays a crucial role in facilitating these cells' pro-inflammatory functions, which may underlie myeloid contribution to systemic inflammation and its effects on the brain. Given emerging evidence from translational studies of depression that peripheral monocytes exhibit signs of glycolytic activation, better understanding the immunometabolic phenotypes of monocytes which are known to be elevated in MDD with high inflammation is a critical step toward comprehending and treating the impact of inflammation on the brain. This narrative review examines the extant literature on glycolytic metabolism of circulating monocytes in depression and discusses the functional implications of immunometabolic shifts at both cellular and systemic levels. Additionally, it proposes potential therapeutic applications of existing immunomodulators that target glycolysis and related metabolic pathways in order to reverse the impact of elevated inflammation on the brain and depressive symptoms.
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Affiliation(s)
- Mandakh Bekhbat
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, 30322, USA
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18
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Zhang T, Chen L, Kueth G, Shao E, Wang X, Ha T, Williams DL, Li C, Fan M, Yang K. Lactate's impact on immune cells in sepsis: unraveling the complex interplay. Front Immunol 2024; 15:1483400. [PMID: 39372401 PMCID: PMC11449721 DOI: 10.3389/fimmu.2024.1483400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 09/05/2024] [Indexed: 10/08/2024] Open
Abstract
Lactate significantly impacts immune cell function in sepsis and septic shock, transcending its traditional view as just a metabolic byproduct. This review summarizes the role of lactate as a biomarker and its influence on immune cell dynamics, emphasizing its critical role in modulating immune responses during sepsis. Mechanistically, key lactate transporters like MCT1, MCT4, and the receptor GPR81 are crucial in mediating these effects. HIF-1α also plays a significant role in lactate-driven immune modulation. Additionally, lactate affects immune cell function through post-translational modifications such as lactylation, acetylation, and phosphorylation, which alter enzyme activities and protein functions. These interactions between lactate and immune cells are central to understanding sepsis-associated immune dysregulation, offering insights that can guide future research and improve therapeutic strategies to enhance patient outcomes.
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Affiliation(s)
- Tao Zhang
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Linjian Chen
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Gatkek Kueth
- James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Emily Shao
- Program in Neuroscience, College of Arts and Science, Vanderbilt University, Nashville, TN, United States
| | - Xiaohui Wang
- Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Tuanzhu Ha
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - David L. Williams
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Chuanfu Li
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Min Fan
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
| | - Kun Yang
- Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States
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19
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Leblanc PO, Bourgoin SG, Poubelle PE, Tessier PA, Pelletier M. Metabolic regulation of neutrophil functions in homeostasis and diseases. J Leukoc Biol 2024; 116:456-468. [PMID: 38452242 DOI: 10.1093/jleuko/qiae025] [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: 11/01/2023] [Revised: 01/11/2024] [Accepted: 01/18/2024] [Indexed: 03/09/2024] Open
Abstract
Neutrophils are the most abundant leukocytes in humans and play a role in the innate immune response by being the first cells attracted to the site of infection. While early studies presented neutrophils as almost exclusively glycolytic cells, recent advances show that these cells use several metabolic pathways other than glycolysis, such as the pentose phosphate pathway, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis, which they modulate to perform their functions. Metabolism shifts from fatty acid oxidation-mediated mitochondrial respiration in immature neutrophils to glycolysis in mature neutrophils. Tissue environments largely influence neutrophil metabolism according to nutrient sources, inflammatory mediators, and oxygen availability. Inhibition of metabolic pathways in neutrophils results in impairment of certain effector functions, such as NETosis, chemotaxis, degranulation, and reactive oxygen species generation. Alteration of these neutrophil functions is implicated in certain human diseases, such as antiphospholipid syndrome, coronavirus disease 2019, and bronchiectasis. Metabolic regulators such as AMPK, HIF-1α, mTOR, and Arf6 are linked to neutrophil metabolism and function and could potentially be targeted for the treatment of diseases associated with neutrophil dysfunction. This review details the effects of alterations in neutrophil metabolism on the effector functions of these cells.
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Affiliation(s)
- Pier-Olivier Leblanc
- Infectious and Immune Diseases Axis, CHU de Québec-Université Laval Research Center, 2705 Boul. Laurier, Québec City, Québec G1V 4G2, Canada
- ARThrite Research Center, Laval University, 2705 Boul. Laurier, Québec City, Québec G1V 4G2, Canada
| | - Sylvain G Bourgoin
- Infectious and Immune Diseases Axis, CHU de Québec-Université Laval Research Center, 2705 Boul. Laurier, Québec City, Québec G1V 4G2, Canada
- ARThrite Research Center, Laval University, 2705 Boul. Laurier, Québec City, Québec G1V 4G2, Canada
- Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, 1050 Av. de la Médecine, Québec City, Québec G1V 0A6, Canada
| | - Patrice E Poubelle
- Infectious and Immune Diseases Axis, CHU de Québec-Université Laval Research Center, 2705 Boul. Laurier, Québec City, Québec G1V 4G2, Canada
- Department of Medicine, Faculty of Medicine, Laval University, 1050 Av. de la Médecine, Québec City, Québec G1V 0A6, Canada
| | - Philippe A Tessier
- Infectious and Immune Diseases Axis, CHU de Québec-Université Laval Research Center, 2705 Boul. Laurier, Québec City, Québec G1V 4G2, Canada
- ARThrite Research Center, Laval University, 2705 Boul. Laurier, Québec City, Québec G1V 4G2, Canada
- Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, 1050 Av. de la Médecine, Québec City, Québec G1V 0A6, Canada
| | - Martin Pelletier
- Infectious and Immune Diseases Axis, CHU de Québec-Université Laval Research Center, 2705 Boul. Laurier, Québec City, Québec G1V 4G2, Canada
- ARThrite Research Center, Laval University, 2705 Boul. Laurier, Québec City, Québec G1V 4G2, Canada
- Department of Microbiology-Infectious Diseases and Immunology, Faculty of Medicine, Laval University, 1050 Av. de la Médecine, Québec City, Québec G1V 0A6, Canada
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20
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Romero M, Miller K, Gelsomini A, Garcia D, Li K, Suresh D, Frasca D. Immunometabolic effects of lactate on humoral immunity in healthy individuals of different ages. Nat Commun 2024; 15:7515. [PMID: 39209820 PMCID: PMC11362567 DOI: 10.1038/s41467-024-51207-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 07/31/2024] [Indexed: 09/04/2024] Open
Abstract
Aging is characterized by chronic systemic inflammation and metabolic changes. We compare the metabolic status of B cells from young and elderly donors and found that aging is associated with higher oxygen consumption rates, and especially higher extracellular acidification rates, measures of oxidative phosphorylation and of anaerobic glycolysis, respectively. Importantly, this higher metabolic status, which reflects age-associated expansion of pro-inflammatory B cells, is found associated with higher secretion of lactate and autoimmune antibodies after in vitro stimulation. B cells from elderly individuals induce in vitro polarization of CD4+ T cells from young individuals into pro-inflammatory CD4+ T cells through metabolic pathways mediated by lactate, which can be inhibited by targeting lactate enzymes and transporters, as well as signaling pathways supporting anaerobic glycolysis. Lactate also induces immunosenescent B cells that are glycolytic, express transcripts for multiple pro-inflammatory molecules, and are characterized by a higher metabolic status. These results altogether may have relevant clinical implications and suggest alternative targets for therapeutic interventions in the elderly and patients with inflammatory conditions and diseases.
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Affiliation(s)
- Maria Romero
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kate Miller
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Andrew Gelsomini
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Denisse Garcia
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kevin Li
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Dhananjay Suresh
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Daniela Frasca
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
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21
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Bechtold V, Smolen KK, Burny W, de Angelis SP, Delandre S, Essaghir A, Marchant A, Ndour C, Taton M, van der Most R, Willems F, Didierlaurent AM. Functional and epigenetic changes in monocytes from adults immunized with an AS01-adjuvanted vaccine. Sci Transl Med 2024; 16:eadl3381. [PMID: 39083587 DOI: 10.1126/scitranslmed.adl3381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 03/25/2024] [Accepted: 06/10/2024] [Indexed: 08/02/2024]
Abstract
The adjuvant AS01 plays a key role in the immunogenicity of several approved human vaccines with demonstrated high efficacy. Its adjuvant effect relies on activation of the innate immune system. However, specific effects of AS01-adjuvanted vaccines on innate cell function and epigenetic remodeling, as described for Bacille Calmette-Guérin (BCG) and influenza vaccines, are still unknown. We assessed the long-term functional and epigenetic changes in circulating monocytes and dendritic cells induced by a model vaccine containing hepatitis B surface antigen and AS01 in healthy adults (NCT01777295). The AS01-adjuvanted vaccine, but not an Alum-adjuvanted vaccine, increased the number of circulating monocytes and their expression of human leukocyte antigen (HLA)-DR, which correlated with the magnitude of the memory CD4+ T cell response. Single-cell analyses revealed epigenetic alterations in monocyte and dendritic cell subsets, affecting accessibility of transcription factors involved in cell functions including activator protein-1 (AP-1), GATA, C/EBP, and interferon regulatory factor. The functional changes were characterized by a reduced proinflammatory response to Toll-like receptor activation and an improved response to interferon-γ, a cytokine critical for the adjuvant's mode of action. Epigenetic changes were most evident shortly after the second vaccine dose in CD14+ monocytes, for which accessibility differences of some transcription factors could persist for up to 6 months postvaccination. Together, we show that reprogramming of monocyte subsets occurs after vaccination with an AS01-adjuvanted vaccine, an effect that may contribute to the impact of vaccination beyond antigen-specific protection.
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Affiliation(s)
| | - Kinga K Smolen
- GSK, Rixensart, 1330, Belgium
- Institute for Medical Immunology and ULB Center for Research in Immunology (U-CRI), Faculty of Medicine, Université libre de Bruxelles (ULB), Brussels, 1070, Belgium
| | | | | | | | | | - Arnaud Marchant
- Institute for Medical Immunology and ULB Center for Research in Immunology (U-CRI), Faculty of Medicine, Université libre de Bruxelles (ULB), Brussels, 1070, Belgium
| | - Cheikh Ndour
- Business and Decision Life Sciences c/o GSK, Rixensart, 1330, Belgium
| | - Martin Taton
- Institute for Medical Immunology and ULB Center for Research in Immunology (U-CRI), Faculty of Medicine, Université libre de Bruxelles (ULB), Brussels, 1070, Belgium
| | | | - Fabienne Willems
- Institute for Medical Immunology and ULB Center for Research in Immunology (U-CRI), Faculty of Medicine, Université libre de Bruxelles (ULB), Brussels, 1070, Belgium
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22
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Qiao Q, Hu S, Wang X. The regulatory roles and clinical significance of glycolysis in tumor. Cancer Commun (Lond) 2024; 44:761-786. [PMID: 38851859 PMCID: PMC11260772 DOI: 10.1002/cac2.12549] [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: 11/09/2023] [Revised: 05/05/2024] [Accepted: 05/12/2024] [Indexed: 06/10/2024] Open
Abstract
Metabolic reprogramming has been demonstrated to have a significant impact on the biological behaviors of tumor cells, among which glycolysis is an important form. Recent research has revealed that the heightened glycolysis levels, the abnormal expression of glycolytic enzymes, and the accumulation of glycolytic products could regulate the growth, proliferation, invasion, and metastasis of tumor cells and provide a favorable microenvironment for tumor development and progression. Based on the distinctive glycolytic characteristics of tumor cells, novel imaging tests have been developed to evaluate tumor proliferation and metastasis. In addition, glycolytic enzymes have been found to serve as promising biomarkers in tumor, which could provide assistance in the early diagnosis and prognostic assessment of tumor patients. Numerous glycolytic enzymes have been identified as potential therapeutic targets for tumor treatment, and various small molecule inhibitors targeting glycolytic enzymes have been developed to inhibit tumor development and some of them are already applied in the clinic. In this review, we systematically summarized recent advances of the regulatory roles of glycolysis in tumor progression and highlighted the potential clinical significance of glycolytic enzymes and products as novel biomarkers and therapeutic targets in tumor treatment.
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Affiliation(s)
- Qiqi Qiao
- Department of HematologyShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandongP. R. China
| | - Shunfeng Hu
- Department of HematologyShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandongP. R. China
- Department of HematologyShandong Provincial HospitalShandong UniversityJinanShandongP. R. China
| | - Xin Wang
- Department of HematologyShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandongP. R. China
- Department of HematologyShandong Provincial HospitalShandong UniversityJinanShandongP. R. China
- Taishan Scholars Program of Shandong ProvinceJinanShandongP. R. China
- Branch of National Clinical Research Center for Hematologic DiseasesJinanShandongP. R. China
- National Clinical Research Center for Hematologic Diseasesthe First Affiliated Hospital of Soochow UniversitySuzhouJiangsuP. R. China
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23
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Gu W, Li C, Shen T, Tong L, Yuan W, Zheng X, Wang T, Wang S, Zhu B, Zhang C, Zhang C. NAT1 inhibits liver metastasis of colorectal cancer by regulating EMT and glycolysis. Aging (Albany NY) 2024; 16:10546-10562. [PMID: 38916406 PMCID: PMC11236320 DOI: 10.18632/aging.205957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Accepted: 05/29/2024] [Indexed: 06/26/2024]
Abstract
Metastasis is the primary cause of cancer-related deaths, and colorectal cancer (CRC) liver metastasis is a major poor prognostic factor in CRC. NAT1 (N-acetyltransferase 1) plays a crucial role in the invasive and metastatic processes of colorectal cancer. The role and molecular mechanism of NAT1 on tumor cells were verified by establishing a cell model of overexpression and knockdown of NAT1, and further verified by establishing a liver metastasis model of colorectal cancer for animal experiments. In vivo and in vitro experiments have demonstrated that overexpression of NAT1 reduces the ability of metastasis and invasion of colorectal cancer cells. NAT1 overexpression inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing the EMT (epithelial-mesenchymal transition) process and glycolytic ability of tumor cells. Additionally, decreased glycolytic ability results in reduced VEGF (Vascular endothelial growth factor) expression in colorectal cancer cells. The decreased VEGF expression leads to decreased angiogenesis and vascular permeability in liver metastases, ultimately reducing the occurrence of liver metastasis. Our findings highlight that overexpression of NAT1 significantly inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing EMT, glycolytic ability, and VEGF expression in colorectal cancer cells, collectively preventing the development of liver metastasis.
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Affiliation(s)
- Wang Gu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Chen Li
- Department of Biology, Chemistry, Pharmacy, Free University of Berlin, Berlin 14195, Germany
| | - Tingting Shen
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Li Tong
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Wenkang Yuan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Xiaofei Zheng
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Tianqi Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Siyu Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Benshuai Zhu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Chong Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
| | - Chao Zhang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China
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24
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Valle-Mendiola A, Rocha-Zavaleta L, Maldonado-Lagunas V, Morelos-Laguna D, Gutiérrez-Hoya A, Weiss-Steider B, Soto-Cruz I. STAT5 Is Necessary for the Metabolic Switch Induced by IL-2 in Cervical Cancer Cell Line SiHa. Int J Mol Sci 2024; 25:6835. [PMID: 38999946 PMCID: PMC11241652 DOI: 10.3390/ijms25136835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 05/07/2024] [Accepted: 06/10/2024] [Indexed: 07/14/2024] Open
Abstract
The tumor cells reprogram their metabolism to cover their high bioenergetic demands for maintaining uncontrolled growth. This response can be mediated by cytokines such as IL-2, which binds to its receptor and activates the JAK/STAT pathway. Some reports show a correlation between the JAK/STAT pathway and cellular metabolism, since the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of genes related to energetic metabolism. However, the role of STAT proteins in the metabolic switch induced by cytokines in cervical cancer remains poorly understood. In this study, we analyzed the effect of IL-2 on the metabolic switch and the role of STAT5 in this response. Our results show that IL-2 induces cervical cancer cell proliferation and the tyrosine phosphorylation of STAT5. Also, it induces an increase in lactate secretion and the ratio of NAD+/NADH, which suggest a metabolic reprogramming of their metabolism. When STAT5 was silenced, the lactate secretion and the NAD+/NADH ratio decreased. Also, the expression of HIF1α and GLUT1 decreased. These results indicate that STAT5 regulates IL-2-induced cell proliferation and the metabolic shift to aerobic glycolysis by regulating genes related to energy metabolism. Our results suggest that STAT proteins modulate the metabolic switch in cervical cancer cells to attend to their high demand of energy required for cell growth and proliferation.
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Affiliation(s)
- Arturo Valle-Mendiola
- Laboratorio de Oncología Molecular, Unidad de Investigación en Diferenciación Celular y Cáncer, FES Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Col. Ejército de Oriente, Mexico City 09230, Mexico; (A.V.-M.); (D.M.-L.); (A.G.-H.); (B.W.-S.)
| | - Leticia Rocha-Zavaleta
- Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
| | - Vilma Maldonado-Lagunas
- Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica (INMEGEN), Periférico Sur no. 4809, Col. Arenal Tepepan, Tlalpan, Mexico City 14610, Mexico;
| | - Diego Morelos-Laguna
- Laboratorio de Oncología Molecular, Unidad de Investigación en Diferenciación Celular y Cáncer, FES Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Col. Ejército de Oriente, Mexico City 09230, Mexico; (A.V.-M.); (D.M.-L.); (A.G.-H.); (B.W.-S.)
| | - Adriana Gutiérrez-Hoya
- Laboratorio de Oncología Molecular, Unidad de Investigación en Diferenciación Celular y Cáncer, FES Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Col. Ejército de Oriente, Mexico City 09230, Mexico; (A.V.-M.); (D.M.-L.); (A.G.-H.); (B.W.-S.)
- Cátedra CONAHCYT, FES Zaragoza, Universidad Nacional Autónoma de México, Mexico City 68020, Mexico
| | - Benny Weiss-Steider
- Laboratorio de Oncología Molecular, Unidad de Investigación en Diferenciación Celular y Cáncer, FES Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Col. Ejército de Oriente, Mexico City 09230, Mexico; (A.V.-M.); (D.M.-L.); (A.G.-H.); (B.W.-S.)
| | - Isabel Soto-Cruz
- Laboratorio de Oncología Molecular, Unidad de Investigación en Diferenciación Celular y Cáncer, FES Zaragoza, Universidad Nacional Autónoma de México, Batalla 5 de Mayo s/n Col. Ejército de Oriente, Mexico City 09230, Mexico; (A.V.-M.); (D.M.-L.); (A.G.-H.); (B.W.-S.)
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25
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Shi Z, Hu C, Zheng X, Sun C, Li Q. Feedback loop between hypoxia and energy metabolic reprogramming aggravates the radioresistance of cancer cells. Exp Hematol Oncol 2024; 13:55. [PMID: 38778409 PMCID: PMC11110349 DOI: 10.1186/s40164-024-00519-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Radiotherapy is one of the mainstream approaches for cancer treatment, although the clinical outcomes are limited due to the radioresistance of tumor cells. Hypoxia and metabolic reprogramming are the hallmarks of tumor initiation and progression and are closely linked to radioresistance. Inside a tumor, the rate of angiogenesis lags behind cell proliferation, and the underdevelopment and abnormal functions of blood vessels in some loci result in oxygen deficiency in cancer cells, i.e., hypoxia. This prevents radiation from effectively eliminating the hypoxic cancer cells. Cancer cells switch to glycolysis as the main source of energy, a phenomenon known as the Warburg effect, to sustain their rapid proliferation rates. Therefore, pathways involved in metabolic reprogramming and hypoxia-induced radioresistance are promising intervention targets for cancer treatment. In this review, we discussed the mechanisms and pathways underlying radioresistance due to hypoxia and metabolic reprogramming in detail, including DNA repair, role of cancer stem cells, oxidative stress relief, autophagy regulation, angiogenesis and immune escape. In addition, we proposed the existence of a feedback loop between energy metabolic reprogramming and hypoxia, which is associated with the development and exacerbation of radioresistance in tumors. Simultaneous blockade of this feedback loop and other tumor-specific targets can be an effective approach to overcome radioresistance of cancer cells. This comprehensive overview provides new insights into the mechanisms underlying tumor radiosensitivity and progression.
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Affiliation(s)
- Zheng Shi
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Cuilan Hu
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Xiaogang Zheng
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Chao Sun
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Qiang Li
- Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, China.
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Lanzhou, China.
- University of Chinese Academy of Sciences, Beijing, China.
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26
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Xu H, Li Y, Song J, Zhou L, Wu K, Lu X, Zhai X, Wan Z, Gao J. Highly active probiotic hydrogels matrixed on bacterial EPS accelerate wound healing via maintaining stable skin microbiota and reducing inflammation. Bioact Mater 2024; 35:31-44. [PMID: 38304916 PMCID: PMC10831122 DOI: 10.1016/j.bioactmat.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 12/13/2023] [Accepted: 01/12/2024] [Indexed: 02/03/2024] Open
Abstract
Skin microbiota plays an important role in wound healing, but skin injuries are highly susceptible to wound infections, leading to disruption of the skin microbiota. However, conventional antibacterial hydrogels eliminate both probiotics and pathogenic bacteria, disrupting the balance of the skin microbiota. Therefore, it is important to develop a wound dressing that can fend off foreign pathogenic bacteria while preserving skin microbiota stability. Inspired by live bacteria therapy, we designed a probiotic hydrogel (HAEPS@L.sei gel) with high viability for promoting wound healing. Lactobacillus paracasei TYM202 encapsulated in the hydrogel has the activity of promoting wound healing, and the hydrogel matrix EPS-M76 has the prebiotic activity that promotes the proliferation and metabolism of Lactobacillus paracasei TYM202. During the wound healing process, HAEPS@L.sei gel releases lactic acid and acetic acid to resist the growth of pathogenic bacteria while maintaining Firmicutes and Proteobacteria balance at the phylum level, thus preserving skin microbiota stability. Our results showed that live probiotic hydrogels reduce the incidence of inflammation during wound healing while promoting angiogenesis and increasing collagen deposition. This study provides new ideas for developing wound dressings predicated on live bacterial hydrogels.
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Affiliation(s)
- Hongtao Xu
- School of Light Industry and Food Engineering, Guangxi University, Nanning, 530004, China
| | - Yaqian Li
- School of Light Industry and Food Engineering, Guangxi University, Nanning, 530004, China
| | - Jiangping Song
- School of Light Industry and Food Engineering, Guangxi University, Nanning, 530004, China
| | - Liuyang Zhou
- School of Light Industry and Food Engineering, Guangxi University, Nanning, 530004, China
| | - Kaizhang Wu
- School of Light Industry and Food Engineering, Guangxi University, Nanning, 530004, China
| | - Xingyu Lu
- School of Light Industry and Food Engineering, Guangxi University, Nanning, 530004, China
| | - XiaoNing Zhai
- School of Light Industry and Food Engineering, Guangxi University, Nanning, 530004, China
| | - Zhili Wan
- Laboratory of Food Proteins and Colloids, School of Food Science and Engineering, South China University of Technology, Guangzhou, 510640, China
| | - Jie Gao
- School of Light Industry and Food Engineering, Guangxi University, Nanning, 530004, China
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27
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Feng X, Shang J, Gu Z, Luo X, Chen Y, Liu Y. Lactic Acid Chemical Peeling in Skin Disorders. Clin Cosmet Investig Dermatol 2024; 17:901-909. [PMID: 38682041 PMCID: PMC11055559 DOI: 10.2147/ccid.s455700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 04/13/2024] [Indexed: 05/01/2024]
Abstract
Lactic acid is the most widely occurring natural organic acid in nature. It not only exhibits mild and safe properties but also possesses multiple physiological activities, such as antibacterial effects, immune regulation, and promotion of wound healing, making it one of the most popular chemical peeling agents. Chemical peels are commonly used in the field of aesthetic dermatology as a non-invasive therapeutic approach. This research aims to provide valuable references for clinical dermatologists by summarizing the characteristics of lactic acid, elucidating its mechanism of action in peeling, and investigating the clinical applications of this compound. Furthermore, it anticipates the potential for lactic acid to be the most suitable chemical peeling agent for Chinese skin.
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Affiliation(s)
- Xiaoyue Feng
- Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, People’s Republic of China
| | - Jianli Shang
- Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, People’s Republic of China
| | - Zhengping Gu
- Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, People’s Republic of China
| | - Xingyi Luo
- Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, People’s Republic of China
| | - Yong Chen
- Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, People’s Republic of China
| | - Youting Liu
- Product Research & Development Center, Beijing Underproved Medical Technology Co., LTD, Beijing, People’s Republic of China
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28
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Cui G, Sun Y, Zou Y, Sun R, Gao Y, Liu X, Zhou Y, Zhang D, Wang X, Li Y, Liu L, Zhang G, Rao B, Yu Z, Ren Z. Dynamic changes of Bacterial Microbiomes in Oropharynx during Infection and Recovery of COVID-19 Omicron Variant. PLoS Pathog 2024; 20:e1012075. [PMID: 38568937 PMCID: PMC10990182 DOI: 10.1371/journal.ppat.1012075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 02/26/2024] [Indexed: 04/05/2024] Open
Abstract
Oropharyngeal microbiomes play a significant role in the susceptibility and severity of COVID-19, yet the role of these microbiomes play for the development of COVID-19 Omicron variant have not been reported. A total of 791 pharyngeal swab samples were prospectively included in this study, including 297 confirmed cases of Omicron variant (CCO), 222 confirmed case of Omicron who recovered (CCOR), 73 confirmed cases of original strain (CCOS) and 199 healthy controls (HC). All samples completed MiSeq sequencing. The results showed that compared with HC, conditional pathogens increased in CCO, while acid-producing bacteria decreased. Based on six optimal oropharyngeal operational taxonomy units (OTUs), we constructed a marker microbial classifier to distinguish between patients with Omicron variant and healthy people, and achieved high diagnostic efficiency in both the discovery queue and the verification queue. At same time, we introduced a group of cross-age infection verification cohort and Omicron variant subtype XBB.1.5 branch, which can be accurately distinguished by this diagnostic model. We also analyzed the characteristics of oropharyngeal microbiomes in two subgroups of Omicron disease group-severity of infection and vaccination times, and found that the change of oropharyngeal microbiomes may affect the severity of the disease and the efficacy of the vaccine. In addition, we found that some genera with significant differences gradually increased or decreased with the recovery of Omicron variant infection. The results of Spearman analysis showed that 27 oropharyngeal OTUs were closely related to 6 clinical indexes in CCO and HC. Finally, we found that the Omicron variant had different characterization of oropharyngeal microbiomes from the original strain. Our research characterizes oropharyngeal microbiomes of Omicron variant cases and rehabilitation cases, successfully constructed and verified the non-invasive diagnostic model of Omicron variant, described the correlation between microbial OTUs and clinical indexes. It was found that the infection of Omicron variant and the infection of original strain have different characteristics of oropharyngeal microbiomes.
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Affiliation(s)
- Guangying Cui
- Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ying Sun
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Disease, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yawen Zou
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China
| | - Ranran Sun
- Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanxia Gao
- Emergency Department, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaorui Liu
- Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yongjian Zhou
- Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Donghua Zhang
- Anyang City Fifth People’s Hospital, Long An District, Anyang, China
| | - Xueqing Wang
- Reproductive Medicine Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yonghong Li
- Anyang City Fifth People’s Hospital, Long An District, Anyang, China
| | - Liwen Liu
- Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guizhen Zhang
- Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Benchen Rao
- Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Zhang LN, Tan JT, Ng HY, Liao YS, Zhang RQ, Chan KH, Hung IFN, Lam TTY, Cheung KS. Association between Gut Microbiota Composition and Long-Term Vaccine Immunogenicity following Three Doses of CoronaVac. Vaccines (Basel) 2024; 12:365. [PMID: 38675747 PMCID: PMC11055114 DOI: 10.3390/vaccines12040365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 03/15/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Neutralizing antibody level wanes with time after COVID-19 vaccination. We aimed to study the relationship between baseline gut microbiota and immunogenicity after three doses of CoronaVac. METHODS This was a prospective cohort study recruiting three-dose CoronaVac recipients from two centers in Hong Kong. Blood samples were collected at baseline and one year post-first dose for virus microneutralization (vMN) assays to determine neutralization titers. The primary outcome was high immune response (defined as with vMN titer ≥ 40). Shotgun DNA metagenomic sequencing of baseline fecal samples identified potential bacterial species and metabolic pathways using Linear Discriminant Analysis Effect Size (LEfSe) analysis. Univariate and multivariable logistic regression models were used to identify high response predictors. RESULTS In total, 36 subjects were recruited (median age: 52.7 years [IQR: 47.9-56.4]; male: 14 [38.9%]), and 18 had low immune response at one year post-first dose vaccination. Eubacterium rectale (log10LDA score = 4.15, p = 0.001; relative abundance of 1.4% vs. 0, p = 0.002), Collinsella aerofaciens (log10LDA score = 3.31, p = 0.037; 0.39% vs. 0.18%, p = 0.038), and Streptococcus salivarius (log10LDA score = 2.79, p = 0.021; 0.05% vs. 0.02%, p = 0.022) were enriched in low responders. The aOR of high immune response with E. rectale, C. aerofaciens, and S. salivarius was 0.03 (95% CI: 9.56 × 10-4-0.32), 0.03 (95% CI: 4.47 × 10-4-0.59), and 10.19 (95% CI: 0.81-323.88), respectively. S. salivarius had a positive correlation with pathways enriched in high responders like incomplete reductive TCA cycle (log10LDA score = 2.23). C. aerofaciens similarly correlated with amino acid biosynthesis-related pathways. These pathways all showed anti-inflammation functions. CONCLUSION E. rectale,C. aerofaciens, and S. salivarius correlated with poorer long-term immunogenicity following three doses of CoronaVac.
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Affiliation(s)
- Li-Na Zhang
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Jing-Tong Tan
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Ho-Yu Ng
- School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Yun-Shi Liao
- State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong
- Centre for Immunology & Infection Limited, 17W Hong Kong Science & Technology Parks, Hong Kong
| | - Rui-Qi Zhang
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Kwok-Hung Chan
- Centre for Immunology & Infection Limited, 17W Hong Kong Science & Technology Parks, Hong Kong
| | - Ivan Fan-Ngai Hung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Tommy Tsan-Yuk Lam
- State Key Laboratory of Emerging Infectious Diseases, School of Public Health, The University of Hong Kong, Hong Kong
| | - Ka-Shing Cheung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
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30
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Shi W, Cassmann TJ, Bhagwate AV, Hitosugi T, Ip WKE. Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation. Cell Rep 2024; 43:113746. [PMID: 38329873 PMCID: PMC10957222 DOI: 10.1016/j.celrep.2024.113746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 12/09/2023] [Accepted: 01/22/2024] [Indexed: 02/10/2024] Open
Abstract
Lactic acid has emerged as an important modulator of immune cell function. It can be produced by both gut microbiota and the host metabolism at homeostasis and during disease states. The production of lactic acid in the gut microenvironment is vital for tissue homeostasis. In the present study, we examined how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory response. We found that lactic acid serves as a primary fuel source to promote histone H3K27 acetylation, which allows the expression of immunosuppressive gene program including Nr4a1. Consequently, macrophage pro-inflammatory function was transcriptionally repressed. Furthermore, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression ("trained immunosuppression"). Pre-exposure to lactic acid induces lipopolysaccharide tolerance. These findings thus indicate that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment.
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Affiliation(s)
- Weiwei Shi
- Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Tiffany J Cassmann
- Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Aditya Vijay Bhagwate
- Departments of Health Science Research, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - Taro Hitosugi
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA
| | - W K Eddie Ip
- Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA; Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
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31
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Jiang G, Hong J, Sun L, Wei H, Gong W, Wang S, Zhu J. Glycolysis regulation in tumor-associated macrophages: Its role in tumor development and cancer treatment. Int J Cancer 2024; 154:412-424. [PMID: 37688376 DOI: 10.1002/ijc.34711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 07/27/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023]
Abstract
Tumor-associated macrophages constitute the main cell population in the tumor microenvironment and play a crucial role in regulating the microenvironment composition. Emerging evidence has revealed that the metabolic profile determines the tumor-associated macrophage phenotype. Tumor-associated macrophage function is highly dependent on glucose metabolism, with glycolysis being the major metabolic pathway. Recent reports have demonstrated diversity in glucose flux of tumor-associated macrophages and complex substance communication with cancer cells. However, how the glucose flux in tumor-associated macrophages connects with glycolysis to influence tumor progression and the tumor microenvironment is still obscure. Moreover, while the development of single-cell sequencing technology allows a clearer and more accurate classification of tumor-associated macrophages, the metabolic profiles of tumor-associated macrophages from the perspective of single-cell omics has not been well summarized. Here, we review the current state of knowledge on glucose metabolism in tumor-associated macrophages and summarize the metabolic profiles of different tumor-associated macrophage subtypes from the perspective of single-cell omics. Additionally, we describe the current strategies targeting glycolysis in tumor-associated macrophages for cancer therapy.
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Affiliation(s)
- Guangyi Jiang
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Junjie Hong
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Lu Sun
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Haibin Wei
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Wangang Gong
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
| | - Shu Wang
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
- Department of Biological Sciences, National University of Singapore, Singapore, Singapore
| | - Jianqing Zhu
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang, Hangzhou, China
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Zhou R, Wang J. Identification of Metabolism-Related Prognostic Biomarkers and Immune Features of Head and Neck Squamous Cell Carcinoma. Crit Rev Immunol 2024; 44:61-78. [PMID: 38505922 DOI: 10.1615/critrevimmunol.2024050754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024]
Abstract
We aimed to identify an effective metabolic subtype and risk score to predict survival and immunotherapy response in head and neck squamous cell carcinoma (HNSCC). Data were obtained from an online database. We screened significant prognostic metabolism-related genes between the normal and tumor groups using a series of bioinformatics methods. Based on the selected prognostic genes, we conducted a subtype analysis to identify significantly different subtypes in HNSCC. We then investigated survival, immune features, and hallmark differences among different subtypes. LASSO was utilized to identify optimal genes for the risk score model construction. Finally, distribution of the risk score samples was analyzed for different subtypes. A total of 32 significantly prognostic metabolism-related genes were screened, and all samples were grouped into two subtypes: cluster 1 and cluster 2. Cluster 1 had worse survival. Different immune cell infiltration (CD8 T cells, macrophages, and regulatory T cells) and immune checkpoint gene expression (PD-1 and CLAT-4) were observed between the two clusters. Twelve optimal genes were involved in risk score model, and high-risk group had poorer survival. Cluster 1 contained more high-risk samples (60%). Finally, four genes CAV1, GGT6, PYGL, and HS3ST1 were identified as significantly related to immune cells, and these genes were differentially expressed in the normal oral epithelial cells and HNSCC cells. The subtypes and risk score model in the study provide a promising biomarker for prognosis and immunotherapy response.
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Affiliation(s)
- Rongjin Zhou
- Department of Ophthalmology and Otorhinolaryngology, Dongtai People's Hospital, Yancheng 224200, China
| | - Junguo Wang
- Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory)
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Truong N, Cottingham AL, Dharmaraj S, Shaw JR, Lasola JJM, Goodis CC, Fletcher S, Pearson RM. Multimodal nanoparticle-containing modified suberoylanilide hydroxamic acid polymer conjugates to mitigate immune dysfunction in severe inflammation. Bioeng Transl Med 2024; 9:e10611. [PMID: 38193117 PMCID: PMC10771562 DOI: 10.1002/btm2.10611] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 09/04/2023] [Accepted: 10/01/2023] [Indexed: 01/10/2024] Open
Abstract
Excessive immune activation and immunosuppression are opposing factors that contribute to the dysregulated innate and adaptive immune responses seen in severe inflammation and sepsis. Here, a novel analog of the histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA-OH), was incorporated into immunomodulatory poly(lactic acid)-based nanoparticles (iNP-SAHA) by employing a prodrug approach through the covalent modification of poly(lactic-co-glycolic acid) (PLGA) with SAHA-OH. iNP-SAHA formulation allowed for controlled incorporation and delivery of SAHA-OH from iNP-SAHA and treatment led to multimodal biological responses including significant reductions in proinflammatory cytokine secretions and gene expression, while increasing the survival of primary macrophages under lipopolysaccharide (LPS) challenge. Using a lethal LPS-induced endotoxemia mouse model of sepsis, iNP-SAHA administration improved the survival of mice in a dose-dependent manner and tended to improve survival at the lowest doses compared to iNP control. Further, iNP-SAHA reduced the levels of plasma proinflammatory cytokines and chemokines associated with sepsis more significantly than iNP and similarly improved inflammation-induced spleen and liver toxicity as iNP, supporting its potential polypharmacological activity. Collectively, iNP-SAHA offers a potential drug delivery approach to modulate the multifaceted inflammatory responses observed in diseases such as sepsis.
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Affiliation(s)
- Nhu Truong
- Department of Pharmaceutical SciencesUniversity of Maryland School of PharmacyBaltimoreMarylandUSA
| | - Andrea L. Cottingham
- Department of Pharmaceutical SciencesUniversity of Maryland School of PharmacyBaltimoreMarylandUSA
| | - Shruti Dharmaraj
- Department of Pharmaceutical SciencesUniversity of Maryland School of PharmacyBaltimoreMarylandUSA
| | - Jacob R. Shaw
- Department of Microbiology and ImmunologyUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | | | - Christopher C. Goodis
- Department of Pharmaceutical SciencesUniversity of Maryland School of PharmacyBaltimoreMarylandUSA
| | - Steven Fletcher
- Department of Pharmaceutical SciencesUniversity of Maryland School of PharmacyBaltimoreMarylandUSA
| | - Ryan M. Pearson
- Department of Pharmaceutical SciencesUniversity of Maryland School of PharmacyBaltimoreMarylandUSA
- Department of Microbiology and ImmunologyUniversity of Maryland School of MedicineBaltimoreMarylandUSA
- Marlene and Stewart Greenebaum Comprehensive Cancer CenterUniversity of Maryland School of MedicineBaltimoreMarylandUSA
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34
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Knopf P, Stowbur D, Hoffmann SHL, Hermann N, Maurer A, Bucher V, Poxleitner M, Tako B, Sonanini D, Krishnamachary B, Sinharay S, Fehrenbacher B, Gonzalez-Menendez I, Reckmann F, Bomze D, Flatz L, Kramer D, Schaller M, Forchhammer S, Bhujwalla ZM, Quintanilla-Martinez L, Schulze-Osthoff K, Pagel MD, Fransen MF, Röcken M, Martins AF, Pichler BJ, Ghoreschi K, Kneilling M. Acidosis-mediated increase in IFN-γ-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors. Mol Cancer 2023; 22:207. [PMID: 38102680 PMCID: PMC10722725 DOI: 10.1186/s12943-023-01900-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 11/12/2023] [Indexed: 12/17/2023] Open
Abstract
Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ-/- mice validated the dependency on immune cell-derived IFN-γ for acidosis-mediated cancer cell PD-L1 induction and tumor immune escape. Thus, acidosis and IFN-γ-induced elevation of PD-L1 expression on cancer cells represent a previously unknown immune escape mechanism that may serve as a novel biomarker for anti-PD-L1/PD-1 treatment response. These findings have important implications for the development of new strategies to enhance the efficacy of immunotherapy in cancer patients.
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Affiliation(s)
- Philipp Knopf
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
| | - Dimitri Stowbur
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany
| | - Sabrina H L Hoffmann
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
| | - Natalie Hermann
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
| | - Andreas Maurer
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany
| | - Valentina Bucher
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
| | - Marilena Poxleitner
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
| | - Bredi Tako
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
| | - Dominik Sonanini
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany
| | - Balaji Krishnamachary
- Division of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sanhita Sinharay
- Department of Cancer Systems Imaging, MD Anderson Cancer Center, 1881 East Rd, Houston, TX, 77054, USA
| | | | - Irene Gonzalez-Menendez
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany
- Institute of Pathology and Neuropathology, Department of Pathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany
| | - Felix Reckmann
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
| | - David Bomze
- Department of Dermatology, Tel-Aviv Medical Center, Tel-Aviv, Israel
| | - Lukas Flatz
- Department of Dermatology, Eberhard Karls University, Tübingen, Germany
| | - Daniela Kramer
- Interfaculty Institute of Biochemistry, Eberhard Karls University, Tübingen, Germany
| | - Martin Schaller
- Department of Dermatology, Eberhard Karls University, Tübingen, Germany
| | | | - Zaver M Bhujwalla
- Division of Cancer Imaging Research, The Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA
- Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA
| | - Leticia Quintanilla-Martinez
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany
- Institute of Pathology and Neuropathology, Department of Pathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany
| | - Klaus Schulze-Osthoff
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany
- Interfaculty Institute of Biochemistry, Eberhard Karls University, Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Mark D Pagel
- Department of Cancer Systems Imaging, MD Anderson Cancer Center, 1881 East Rd, Houston, TX, 77054, USA
| | - Marieke F Fransen
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Martin Röcken
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany
- Department of Dermatology, Eberhard Karls University, Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - André F Martins
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Bernd J Pichler
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Kamran Ghoreschi
- Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, 10117, Berlin, Germany
| | - Manfred Kneilling
- Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany.
- Cluster of Excellence iFIT (EXC 2180) "Image Guided and Functionally Instructed Tumor Therapies", Röntgenweg 13, 72076, Tübingen, Germany.
- Department of Dermatology, Eberhard Karls University, Tübingen, Germany.
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Bekhbat M, Drake J, Reed EC, Lauten TH, Natour T, Vladimirov VI, Case AJ. Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen. Brain Behav Immun Health 2023; 34:100690. [PMID: 37791319 PMCID: PMC10543777 DOI: 10.1016/j.bbih.2023.100690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 09/23/2023] [Indexed: 10/05/2023] Open
Abstract
Psychosocial stress has been shown to prime peripheral innate immune cells, which take on hyper-inflammatory phenotypes and are implicated in depressive-like behavior in mouse models. However, the impact of stress on cellular metabolic states that are thought to fuel inflammatory phenotypes in immune cells are unknown. Using single cell RNA-sequencing, we investigated mRNA enrichment of immunometabolic pathways in innate immune cells of the spleen in mice subjected to repeated social defeat stress (RSDS) or no stress (NS). RSDS mice displayed a significant increase in the number of splenic macrophages and granulocytes (p < 0.05) compared to NS littermates. RSDS-upregulated genes in macrophages, monocytes, and granulocytes significantly enriched immunometabolic pathways thought to play a role in myeloid-driven inflammation (glycolysis, HIF-1 signaling, MTORC1 signaling) as well as pathways related to oxidative phosphorylation (OXPHOS) and oxidative stress (p < 0.05 and FDR<0.1). These results suggest that the metabolic enhancement reflected by upregulation of glycolytic and OXPHOS pathways may be important for cellular proliferation of splenic macrophages and granulocytes following repeated stress exposure. A better understanding of these intracellular metabolic mechanisms may ultimately help develop novel strategies to reverse the impact of stress and associated peripheral immune changes on the brain and behavior.
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Affiliation(s)
- Mandakh Bekhbat
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, 30322, USA
| | - John Drake
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, 77807, USA
| | - Emily C. Reed
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, 77807, USA
- Department of Medical Physiology, Texas A&M University, Bryan, TX, 77807, USA
| | - Tatlock H. Lauten
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, 77807, USA
- Department of Medical Physiology, Texas A&M University, Bryan, TX, 77807, USA
| | - Tamara Natour
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, 77807, USA
- Department of Medical Physiology, Texas A&M University, Bryan, TX, 77807, USA
| | - Vladimir I. Vladimirov
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, 77807, USA
- Department of Psychiatry, University of Arizona, Phoenix, AZ, 85004, USA
- Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Adam J. Case
- Department of Psychiatry and Behavioral Sciences, Texas A&M University, Bryan, TX, 77807, USA
- Department of Medical Physiology, Texas A&M University, Bryan, TX, 77807, USA
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Roy RM, Allawzi A, Burns N, Sul C, Rubio V, Graham J, Stenmark K, Nozik ES, Tuder RM, Vohwinkel CU. Lactate produced by alveolar type II cells suppresses inflammatory alveolar macrophages in acute lung injury. FASEB J 2023; 37:e23316. [PMID: 37983890 PMCID: PMC10914122 DOI: 10.1096/fj.202301722r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/26/2023] [Accepted: 11/01/2023] [Indexed: 11/22/2023]
Abstract
Alveolar inflammation is a hallmark of acute lung injury (ALI), and its clinical correlate is acute respiratory distress syndrome-and it is as a result of interactions between alveolar type II cells (ATII) and alveolar macrophages (AM). In the setting of acute injury, the microenvironment of the intra-alveolar space is determined in part by metabolites and cytokines and is known to shape the AM phenotype. In response to ALI, increased glycolysis is observed in AT II cells, mediated by the transcription factor hypoxia-inducible factor (HIF) 1α, which has been shown to decrease inflammation. We hypothesized that in acute lung injury, lactate, the end product of glycolysis, produced by ATII cells shifts AMs toward an anti-inflammatory phenotype, thus mitigating ALI. We found that local intratracheal delivery of lactate improved ALI in two different mouse models. Lactate shifted cytokine expression of murine AMs toward increased IL-10, while decreasing IL-1 and IL-6 expression. Mice with ATII-specific deletion of Hif1a and mice treated with an inhibitor of lactate dehydrogenase displayed exacerbated ALI and increased inflammation with decreased levels of lactate in the bronchoalveolar lavage fluid; however, all those parameters improved with intratracheal lactate. When exposed to LPS (to recapitulate an inflammatory stimulus as it occurs in ALI), human primary AMs co-cultured with alveolar epithelial cells had reduced inflammatory responses. Taken together, these studies reveal an innate protective pathway, in which lactate produced by ATII cells shifts AMs toward an anti-inflammatory phenotype and dampens excessive inflammation in ALI.
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Affiliation(s)
- René M. Roy
- Children’s Hospital Colorado, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Ayed Allawzi
- Division of Pediatric Critical Care, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Nana Burns
- Division of Pediatric Critical Care, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Christina Sul
- Division of Pediatric Critical Care, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Victoria Rubio
- Children’s Hospital Colorado, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- Division of Pediatric Critical Care, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jessica Graham
- Children’s Hospital Colorado, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kurt Stenmark
- Division of Pediatric Critical Care, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Eva S. Nozik
- Division of Pediatric Critical Care, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Rubin M. Tuder
- Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- Division of Pulmonary Sciences and Critical Care Medicine, Program in Translational Lung Research, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Christine U. Vohwinkel
- Division of Pediatric Critical Care, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
- Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
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Ursu Ș, Ciocan A, Ursu CP, Gherman CD, Ciocan RA, Pop RS, Spârchez Z, Zaharie F, Al Hajjar N. Role of Metabolomics in Pathogenesis and Prompt Diagnosis of Gastric Cancer Metastasis-A Systematic Review. Diagnostics (Basel) 2023; 13:3401. [PMID: 37998537 PMCID: PMC10670422 DOI: 10.3390/diagnostics13223401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 11/05/2023] [Accepted: 11/06/2023] [Indexed: 11/25/2023] Open
Abstract
INTRODUCTION Gastric cancer is the fourth most frequently diagnosed form of cancer and the third leading cause of cancer-related mortality worldwide. The aim of this review is to identify individual metabolic biomarkers and their association with accurate diagnostic values, which can predict gastric cancer metastasis. MATERIALS AND METHODS After searching the keywords, 83 articles were found over a period of 13 years. One was eliminated because it was not written in English, and two were published outside the selected period. Seven scientific papers were qualified for this investigation after eliminating duplicates, non-related articles, systematic reviews, and restricted access studies. RESULTS New metabolic biomarkers with predictive value for gastric cancer metastasis and for elucidating metabolic pathways of the metastatic process have been found. The pathogenic processes can be outlined as follows: pro-oxidant capacity, T-cell inactivation, cell cycle arrest, energy production and mitochondrial enzyme impairment, cell viability and pro-apoptotic effect, enhanced degradation of collagen extracellular matrix, migration, invasion, structural protein synthesis, and tumoral angiogenesis. CONCLUSION Metabolic biomarkers have been recognized as independent risk factors in the molecular process of gastric cancer metastasis, with good diagnostic and prognostic value.
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Affiliation(s)
- Ștefan Ursu
- Department of Surgery, “Iuliu Hațieganu” University of Medicine and Pharmacy, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania; (Ș.U.); (C.-P.U.); (F.Z.); (N.A.H.)
- “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania
| | - Andra Ciocan
- Department of Surgery, “Iuliu Hațieganu” University of Medicine and Pharmacy, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania; (Ș.U.); (C.-P.U.); (F.Z.); (N.A.H.)
- “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania
| | - Cristina-Paula Ursu
- Department of Surgery, “Iuliu Hațieganu” University of Medicine and Pharmacy, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania; (Ș.U.); (C.-P.U.); (F.Z.); (N.A.H.)
- “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania
| | - Claudia Diana Gherman
- Department of Surgery-Practical Abilities, “Iuliu Hațieganu” University of Medicine and Pharmacy, Marinescu Street, No. 23, 400337 Cluj-Napoca, Romania; (C.D.G.); (R.A.C.)
| | - Răzvan Alexandru Ciocan
- Department of Surgery-Practical Abilities, “Iuliu Hațieganu” University of Medicine and Pharmacy, Marinescu Street, No. 23, 400337 Cluj-Napoca, Romania; (C.D.G.); (R.A.C.)
| | - Rodica Sorina Pop
- Department of Community Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Avram Iancu Street, No. 31, 400347 Cluj-Napoca, Romania;
| | - Zeno Spârchez
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania;
| | - Florin Zaharie
- Department of Surgery, “Iuliu Hațieganu” University of Medicine and Pharmacy, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania; (Ș.U.); (C.-P.U.); (F.Z.); (N.A.H.)
- “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania
| | - Nadim Al Hajjar
- Department of Surgery, “Iuliu Hațieganu” University of Medicine and Pharmacy, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania; (Ș.U.); (C.-P.U.); (F.Z.); (N.A.H.)
- “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, Croitorilor Street, No. 19–21, 400162 Cluj-Napoca, Romania
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Wei X, Michelakos T, He Q, Wang X, Chen Y, Kontos F, Wang H, Liu X, Liu H, Zheng W, Ferrone S, Zhang Y, Ferrone CR, Li X, Cai L. Association of Tumor Cell Metabolic Subtype and Immune Response With the Clinical Course of Hepatocellular Carcinoma. Oncologist 2023; 28:e1031-e1042. [PMID: 37159555 PMCID: PMC10628596 DOI: 10.1093/oncolo/oyad113] [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: 10/08/2022] [Accepted: 03/15/2023] [Indexed: 05/11/2023] Open
Abstract
AIM Tumor metabolism plays an important role in tumorigenesis and tumor progression. This study evaluated the potential association of tumor cell metabolism and immune cell tumor infiltration with the clinical course of hepatocellular carcinoma (HCC). METHODS Gene-wise normalization and principal component analysis were performed to evaluate the metabolic system. A tumor microenvironment score system of tumor immune cell infiltration was constructed to evaluate its association with metabolic subtypes. Finally, we analyzed the impact of metabolism and immune cell infiltration on the clinical course of HCC. RESULTS A total of 673 HCC patients were categorized into cholesterogenic (25.3%), glycolytic (14.6%), mixed (10.4%), and quiescent (49.8%) types based on glycolysis and cholesterol biosynthesis gene expression. The subgroups including the glycolytic genotyping expression (glycolytic and mixed types) showed a higher mortality rate. The glycolytic, cholesterogenic, and mixed types were positively correlated with M0 macrophage, resting mast cell, and naïve B-cell infiltration (P = .013, P = .019, and P = .006, respectively). In TCGA database, high CD8+ T cell and low M0 macrophage infiltration were associated with prolonged overall survival (OS, P = .0017 and P < .0001, respectively). Furthermore, in glycolytic and mixed types, patients with high M0 macrophage infiltration had a shorter OS (P = .03 and P = .013, respectively), and in quiescent type, patients with low naïve B-cell infiltration had a longer OS (P = .007). CONCLUSIONS Tumor metabolism plays a prognostic role and correlates with immune cell infiltration in HCC. M0 macrophage and CD8+ T cell appear to be promising prognostic biomarker for HCC. Finally, M0 macrophages may represent a useful immunotherapeutic target in patients with HCC.
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Affiliation(s)
- Xiaolin Wei
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital & Guangdong Provincial Key Laboratory of Regional Immunity and Diseases and Carson International Cancer Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Theodoros Michelakos
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Qian He
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital & Guangdong Provincial Key Laboratory of Regional Immunity and Diseases and Carson International Cancer Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Xianxing Wang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, People’s Republic of China
| | - Yu Chen
- Department of Digestive Diseases, Shanghai Fourth People’s Hospital Affiliated to Tongji University, Shanghai, People’s Republic of China
| | - Filippos Kontos
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Huaizhi Wang
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, People’s Republic of China
| | - Xiangde Liu
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital & Guangdong Provincial Key Laboratory of Regional Immunity and Diseases and Carson International Cancer Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Hui Liu
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital & Guangdong Provincial Key Laboratory of Regional Immunity and Diseases and Carson International Cancer Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Wenjing Zheng
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital & Guangdong Provincial Key Laboratory of Regional Immunity and Diseases and Carson International Cancer Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Soldano Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Yun Zhang
- Department of Foreign Languages, Army Medical University, Chongqing, People’s Republic of China
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Surgery, Cedar-Sinai Health System, Los Angeles, CA, USA
| | - Xiaowu Li
- Department of Hepatobiliary Surgery, Shenzhen University General Hospital & Guangdong Provincial Key Laboratory of Regional Immunity and Diseases and Carson International Cancer Shenzhen University General Hospital and Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Lei Cai
- Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, People’s Republic of China
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Hajjar S, Zhou X. pH sensing at the intersection of tissue homeostasis and inflammation. Trends Immunol 2023; 44:807-825. [PMID: 37714775 PMCID: PMC10543622 DOI: 10.1016/j.it.2023.08.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/13/2023] [Accepted: 08/13/2023] [Indexed: 09/17/2023]
Abstract
pH is tightly maintained at cellular, tissue, and systemic levels, and altered pH - particularly in the acidic range - is associated with infection, injury, solid tumors, and physiological and pathological inflammation. However, how pH is sensed and regulated and how it influences immune responses remain poorly understood at the tissue level. Applying conceptual frameworks of homeostatic and inflammatory circuitries, we categorize cellular and tissue components engaged in pH regulation, drawing parallels from established cases in physiology. By expressing various intracellular (pHi) and extracellular pH (pHe)-sensing receptors, the immune system may integrate information on tissue and cellular states into the regulation of homeostatic and inflammatory programs. We introduce the novel concept of resistance and adaptation responses to rationalize pH-dependent immunomodulation intertwined with homeostatic equilibrium and inflammatory control. We discuss emerging challenges and opportunities in understanding the immunological roles of pH sensing, which might reveal new strategies to combat inflammation and restore tissue homeostasis.
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Affiliation(s)
- Stephanie Hajjar
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 300 Longwood Ave, Boston, MA 02115, USA
| | - Xu Zhou
- Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 300 Longwood Ave, Boston, MA 02115, USA.
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40
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Liu T, Han S, Yao Y, Zhang G. Role of Human Monocarboxylate Transporter 1 (hMCT1) and 4 (hMCT4) in Tumor Cells and the Tumor Microenvironment. Cancer Manag Res 2023; 15:957-975. [PMID: 37693221 PMCID: PMC10487743 DOI: 10.2147/cmar.s421771] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 08/30/2023] [Indexed: 09/12/2023] Open
Abstract
In recent years, the abnormal glucose metabolism of tumor cells has attracted increasing attention. Abnormal glucose metabolism is closely related to the occurrence and development of tumors. Monocarboxylate transporters (MCTs) transport the sugar metabolites lactic acid and pyruvate, which affect glucose metabolism and tumor progression in a variety of ways. Thus, research has recently focused on MCTs and their potential functions in cancer. The MCT superfamily consists of 14 members. MCT1 and MCT4 play a crucial role in the maintenance of intracellular pH in tumor cells by transporting monocarboxylic acids (such as lactate, pyruvate and butyrate). MCT1 and MCT4 are highly expressed in a variety of tumor cells and are involved the proliferation, invasion and migration of tumor cells, which are closely related to the prognosis of cancer. Because of their important functions in tumor cells, MCT1 and MCT4 have become potential targets for cancer treatment. In this review, we focus on the structure, function and regulation of MCT1 and MCT4 and discuss the developed inhibitors of MCT1 and MCT4 to provide more comprehensive information that might aid in the development of strategies targeting MCTs in cancer.
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Affiliation(s)
- Tian Liu
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Shangcong Han
- Department of Pharmaceutics, School of Pharmacy, Qingdao University, Qingdao, People’s Republic of China
| | - Yu Yao
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
| | - Guiming Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China
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Peng Y, Wu Q, Ding X, Wang L, Gong H, Feng C, Liu T, Zhu H. A hypoxia- and lactate metabolism-related gene signature to predict prognosis of sepsis: discovery and validation in independent cohorts. Eur J Med Res 2023; 28:320. [PMID: 37661250 PMCID: PMC10476321 DOI: 10.1186/s40001-023-01307-z] [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: 06/27/2023] [Accepted: 08/21/2023] [Indexed: 09/05/2023] Open
Abstract
BACKGROUND High throughput gene expression profiling is a valuable tool in providing insight into the molecular mechanism of human diseases. Hypoxia- and lactate metabolism-related genes (HLMRGs) are fundamentally dysregulated in sepsis and have great predictive potential. Therefore, we attempted to build an HLMRG signature to predict the prognosis of patients with sepsis. METHODS Three publicly available transcriptomic profiles of peripheral blood mononuclear cells from patients with sepsis (GSE65682, E-MTAB-4421 and E-MTAB-4451, total n = 850) were included in this study. An HLMRG signature was created by employing Cox regression and least absolute shrinkage and selection operator estimation. The CIBERSORT method was used to analyze the abundances of 22 immune cell subtypes based on transcriptomic data. Metascape was used to investigate pathways related to the HLMRG signature. RESULTS We developed a prognostic signature based on five HLMRGs (ERO1L, SIAH2, TGFA, TGFBI, and THBS1). This classifier successfully discriminated patients with disparate 28-day mortality in the discovery cohort (GSE65682, n = 479), and consistent results were observed in the validation cohort (E-MTAB-4421 plus E-MTAB-4451, n = 371). Estimation of immune infiltration revealed significant associations between the risk score and a subset of immune cells. Enrichment analysis revealed that pathways related to antimicrobial immune responses, leukocyte activation, and cell adhesion and migration were significantly associated with the HLMRG signature. CONCLUSIONS Identification of a prognostic signature suggests the critical role of hypoxia and lactate metabolism in the pathophysiology of sepsis. The HLMRG signature can be used as an efficient tool for the risk stratification of patients with sepsis.
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Affiliation(s)
- Yaojun Peng
- Medical School of Chinese PLA General Hospital, Beijing, China
- Department of Emergency, The First Medical Center, Chinese PLA General Hospital, 28th Fuxing Road, Beijing, China
| | - Qiyan Wu
- Institute of Oncology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Xinhuan Ding
- Medical School of Chinese PLA General Hospital, Beijing, China
- Department of Emergency, The First Medical Center, Chinese PLA General Hospital, 28th Fuxing Road, Beijing, China
| | - Lingxiong Wang
- Institute of Oncology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Hanpu Gong
- Department of Emergency, The First Medical Center, Chinese PLA General Hospital, 28th Fuxing Road, Beijing, China
| | - Cong Feng
- Department of Emergency, The First Medical Center, Chinese PLA General Hospital, 28th Fuxing Road, Beijing, China
| | - Tianyi Liu
- Institute of Oncology, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Haiyan Zhu
- Department of Emergency, The First Medical Center, Chinese PLA General Hospital, 28th Fuxing Road, Beijing, China.
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Rong Y, Dong F, Zhang G, Tang M, Zhao X, Zhang Y, Tao P, Cai H. The crosstalking of lactate-Histone lactylation and tumor. Proteomics Clin Appl 2023; 17:e2200102. [PMID: 36853081 DOI: 10.1002/prca.202200102] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/17/2023] [Accepted: 02/23/2023] [Indexed: 03/01/2023]
Abstract
Lactate was once considered to be a by-product of energy metabolism, but its unique biological value was only gradually explored with the advent of the Warburg effect. As an end product of glycolysis, lactate can act as a substrate for energy metabolism, a signal transduction molecule, a regulator of the tumor microenvironment and immune cells, and a regulator of the deubiquitination of specific enzymes, and is involved in various biological aspects of tumor regulation, including energy shuttling, growth and invasion, angiogenesis and immune escape. Furthermore, we describe a novel lactate-dependent epigenetic modification, namely histone lactylation modification, and review the progress of its study in tumors, mainly involving the reprogramming of tumor phenotypes, regulation of related gene expression, mediation of the glycolytic process in tumor stem cells (CSCs) and influence on the tumor immune microenvironment. The study of epigenetic regulation of tumor genes by histone modification is still in its infancy, and we expect that by summarizing the effects of lactate and histone modification on tumor and related gene regulation, we will clarify the scientific significance of future histone modification studies and the problems to be solved, and open up new fields for targeted tumor therapy.
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Affiliation(s)
- Yao Rong
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Gansu, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
| | - Fengyuan Dong
- Geriatrics Department, Lianyungang First People's Hospital, Lianyugang, China
| | - Guiqian Zhang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Gansu, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
| | - Mingzheng Tang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Gansu, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
| | - Xiashuang Zhao
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital), Lanzhou, China
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Gansu, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
| | - Yan Zhang
- Cadre Ward of General Surgery Department, Gansu Provincial Hospital, Lanzhou, China
| | - Pengxian Tao
- Cadre Ward of General Surgery Department, Gansu Provincial Hospital, Lanzhou, China
| | - Hui Cai
- General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Gansu, China
- NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China
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Shao J, Jin Y, Jin C. A new approach to overcoming resistance to immunotherapy: nanotechnology. Front Oncol 2023; 13:1210245. [PMID: 37637050 PMCID: PMC10457008 DOI: 10.3389/fonc.2023.1210245] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/27/2023] [Indexed: 08/29/2023] Open
Abstract
Immunotherapy for immune response has ushered in a new era of cancer treatment. In recent years, new immunotherapeutic agents have been introduced into clinical trials and even approved for marketing. However, the widespread use of immunotherapeutic agents faces an unavoidable challenge: immunotherapy does not work at all for some patients, or has good efficacy in the initial phase, but immunotherapy resistance develops within a short period of time, and immunotherapy can also cause serious adverse effects such as autoimmune inflammation and non-specific inflammation. How to enable patients to overcome drug resistance, reduce the toxic side effects of drugs, enhance patient compliance and improve patient survival has become a problem that clinicians have to face. The advent of nanotechnology provides an encouraging platform for immunotherapy. It can not only improve the bioavailability and stability of drugs and reduce toxic side effects, but also reduce resistance to immunotherapy. Here, we discuss these research advances and discuss potential challenges and future directions.
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Affiliation(s)
- Jiangbo Shao
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
| | - Ying Jin
- Department of Breast Surgery, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chunxiang Jin
- Department of Ultrasound, China-Japan Union Hospital of Jilin University, Changchun, Jilin, China
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Romero M, Miller K, Gelsomini A, Garcia D, Li K, Suresh D, Frasca D. Immunometabolic effects of lactate on B cell function in healthy individuals of different ages. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.08.07.23293760. [PMID: 37609164 PMCID: PMC10441492 DOI: 10.1101/2023.08.07.23293760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2023]
Abstract
Aging is characterized by chronic systemic inflammation and metabolic changes. When we compared B cells from young and elderly donors, we found that aging induces higher oxygen consumption rates, and especially higher extracellular acidification rates, measures of oxidative phosphorylation and of anaerobic glycolysis, respectively. Importantly, this higher metabolic status, which reflects the age-associated expansion of pro-inflammatory B cell subsets, was found associated with higher secretion of lactate and autoimmune antibodies after in vitro stimulation. B cells from elderly individuals, induce in vitro generation of pro-inflammatory CD4+ T cells from young individuals through metabolic pathways mediated by lactate secretion. Lactate also induces immunosenescent B cells that are glycolytic and express transcripts for multiple pro-inflammatory molecules. These results altogether may have relevant clinical implications and suggest novel targets for therapeutic interventions in patients with inflammatory conditions and diseases.
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Fang C, Ren P, Bian G, Wang J, Bai J, Huang J, Ding Y, Li X, Li M, Hou Z. Enhancing Spns2/S1P in macrophages alleviates hyperinflammation and prevents immunosuppression in sepsis. EMBO Rep 2023; 24:e56635. [PMID: 37358015 PMCID: PMC10398662 DOI: 10.15252/embr.202256635] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 05/29/2023] [Accepted: 06/13/2023] [Indexed: 06/27/2023] Open
Abstract
Sepsis is a leading cause of in-hospital mortality resulting from a dysregulated response to infection. Novel immunomodulatory therapies targeting macrophage metabolism have emerged as an important focus for current sepsis research. However, understanding the mechanisms underlying macrophage metabolic reprogramming and how they impact immune response requires further investigation. Here, we identify macrophage-expressed Spinster homolog 2 (Spns2), a major transporter of sphingosine-1-phosphate (S1P), as a crucial metabolic mediator that regulates inflammation through the lactate-reactive oxygen species (ROS) axis. Spns2 deficiency in macrophages significantly enhances glycolysis, thereby increasing intracellular lactate production. As a key effector, intracellular lactate promotes pro-inflammatory response by increasing ROS generation. The overactivity of the lactate-ROS axis drives lethal hyperinflammation during the early phase of sepsis. Furthermore, diminished Spns2/S1P signaling impairs the ability of macrophages to sustain an antibacterial response, leading to significant innate immunosuppression in the late stage of infection. Notably, reinforcing Spns2/S1P signaling contributes to balancing the immune response during sepsis, preventing both early hyperinflammation and later immunosuppression, making it a promising therapeutic target for sepsis.
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Affiliation(s)
- Chao Fang
- Department of Pharmacology, School of PharmacyFourth Military Medical UniversityXi'anChina
| | - Pan Ren
- Department of Burns and Plastic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
| | - Ganlan Bian
- Institute of Medical ResearchNorthwestern Polytechnical UniversityXi'anChina
| | - Jian Wang
- Department of Neurobiology, School of Basic MedicineFourth Military Medical UniversityXi'anChina
| | - Jiaxin Bai
- Department of Pharmacology, School of PharmacyFourth Military Medical UniversityXi'anChina
| | - Jiaxing Huang
- Department of Pharmacology, School of PharmacyFourth Military Medical UniversityXi'anChina
| | - Yixiao Ding
- Department of Pharmacology, School of PharmacyFourth Military Medical UniversityXi'anChina
| | - Xueyong Li
- Department of Burns and Plastic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
| | - Mingkai Li
- Department of Pharmacology, School of PharmacyFourth Military Medical UniversityXi'anChina
| | - Zheng Hou
- Department of Pharmacology, School of PharmacyFourth Military Medical UniversityXi'anChina
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Jiang H, Ren Y, Yu J, Hu S, Zhang J. Analysis of lactate metabolism-related genes and their association with immune infiltration in septic shock via bioinformatics method. Front Genet 2023; 14:1223243. [PMID: 37564869 PMCID: PMC10410269 DOI: 10.3389/fgene.2023.1223243] [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: 05/15/2023] [Accepted: 07/17/2023] [Indexed: 08/12/2023] Open
Abstract
Background: Lactate, as an essential clinical evaluation index of septic shock, is crucial in the incidence and progression of septic shock. This study aims to investigate the differential expression, regulatory relationship, clinical diagnostic efficacy, and immune infiltration of lactate metabolism-related genes (LMGs) in septic shock. Methods: Two sepsis shock datasets (GSE26440 and GSE131761) were screened from the GEO database, and the common differentially expressed genes (DEGs) of the two datasets were screened out. LMGs were selected from the GeneCards database, and lactate metabolism-related DEGs (LMDEGs) were determined by integrating DEGs and LMGs. Protein-protein interaction networks, mRNA-miRNA, mRNA-RBP, and mRNA-TF interaction networks were constructed using STRING, miRDB, ENCORI, and CHIPBase databases, respectively. Receiver operating characteristic (ROC) curves were constructed for each of the LMDEGs to evaluate the diagnostic efficacy of the expression changes in relation to septic shock. Finally, immune infiltration analysis was performed using ssGSEA and CIBERSORT. Results: This study identified 10 LMDEGs, including LDHB, STAT3, LDHA, GSR, FOXM1, PDP1, GCDH, GCKR, ABCC1, and CDKN3. Enrichment analysis revealed that DEGs were significantly enriched in pathways such as pyruvate metabolism, hypoxia pathway, and immune-inflammatory pathways. PPI networks based on LMDEGs, as well as 148 pairs of mRNA-miRNA interactions, 243 pairs of mRNA-RBP interactions, and 119 pairs of mRNA-TF interactions were established. ROC curves of eight LMDEGs (LDHA, GSR, STAT3, CDKN3, FOXM1, GCKR, PDP1, and LDHB) with consistent expression patterns in two datasets had an area under the curve (AUC) ranging from 0.662 to 0.889. The results of ssGSEA and CIBERSORT both showed significant differences in the infiltration of various immune cells, including CD8 T cells, T regulatory cells, and natural killer cells, and LMDEGs such as STAT3, LDHB, LDHA, PDP1, GSR, FOXM1, and CDKN3 were significantly associated with various immune cells. Conclusion: The LMDEGs are significantly associated with the immune-inflammatory response in septic shock and have a certain diagnostic accuracy for septic shock.
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Affiliation(s)
- Huimin Jiang
- Emergency Intensive Care Unit, Ningxiang People’s Hospital Affiliated to Hunan University of Chinese Medicine, Changsha, China
| | - Yun Ren
- Emergency Department, Ningxiang People’s Hospital Affiliated to Hunan University of Chinese Medicine, Changsha, China
| | - Jiale Yu
- Emergency Department, Ningxiang People’s Hospital Affiliated to Hunan University of Chinese Medicine, Changsha, China
| | - Sheng Hu
- Emergency Department, Ningxiang People’s Hospital Affiliated to Hunan University of Chinese Medicine, Changsha, China
| | - Jihui Zhang
- Emergency Intensive Care Unit, Ningxiang People’s Hospital Affiliated to Hunan University of Chinese Medicine, Changsha, China
- Emergency Department, Ningxiang People’s Hospital Affiliated to Hunan University of Chinese Medicine, Changsha, China
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Altaie AM, Mohammad MG, Madkour MI, AlSaegh MA, Jayakumar MN, K G AR, Samsudin AR, Halwani R, Hamoudi RA, Soliman SSM. Molecular pathogenicity of 1-nonadecene and L-lactic acid, unique metabolites in radicular cysts and periapical granulomas. Sci Rep 2023; 13:10722. [PMID: 37400519 DOI: 10.1038/s41598-023-37945-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 06/30/2023] [Indexed: 07/05/2023] Open
Abstract
Recently, 1-nonadecene and L-lactic acid were identified as unique metabolites in radicular cysts and periapical granuloma, respectively. However, the biological roles of these metabolites were unknown. Therefore, we aimed to investigate the inflammatory and mesenchymal-epithelial transition (MET) effects of 1-nonadecene, and the inflammatory and collagen precipitation effects of L-lactic acid on both periodontal ligament fibroblasts (PdLFs) and peripheral blood mononuclear cells (PBMCs). PdLFs and PBMCs were treated with 1-nonadecene and L-lactic acid. Cytokines' expression was measured using quantitative real-time polymerase chain reaction (qRT-PCR). E-cadherin, N-cadherin, and macrophage polarization markers were measured using flow cytometry. The collagen, matrix metalloproteinase (MMP)-1, and released cytokines were measured using collagen assay, western blot, and Luminex assay, respectively. In PdLFs, 1-nonadecene enhances inflammation through the upregulation of some inflammatory cytokines including IL-1β, IL-6, IL-12A, monocyte chemoattractant protein (MCP)-1, and platelet-derived growth factor (PDGF) α. 1-Nonadecene also induced MET through the upregulation of E-cadherin and the downregulation of N-cadherin in PdLFs. 1-Nonadecene polarized macrophages to a pro-inflammatory phenotype and suppressed their cytokines' release. L-lactic acid exerted a differential impact on the inflammation and proliferation markers. Intriguingly, L-lactic acid induced fibrosis-like effects by enhancing collagen synthesis, while inhibiting MMP-1 release in PdLFs. These results provide a deeper understanding of 1-nonadecene and L-lactic acid's roles in modulating the microenvironment of the periapical area. Consequently, further clinical investigation can be employed for target therapy.
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Affiliation(s)
- Alaa M Altaie
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
| | - Mohammad G Mohammad
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
| | - Mohamed I Madkour
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
| | - Mohammed Amjed AlSaegh
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
- Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
| | - Manju Nidagodu Jayakumar
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
| | - Aghila Rani K G
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
| | - A R Samsudin
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
- Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
| | - Rabih Halwani
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
- Department of Clinical Sciences, College of Medicine, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates
| | - Rifat A Hamoudi
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
- Department of Clinical Sciences, College of Medicine, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
- Division of Surgery and Interventional Science, University College London, London, United Kingdom.
- ASPIRE Precision Medicine Research Institute Abu Dhabi, University of Sharjah, Sharjah, United Arab Emirates.
| | - Sameh S M Soliman
- Research Institute for Medical and Health Sciences, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, P.O. Box 27272, Sharjah, United Arab Emirates.
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Semeniuk-Wojtaś A, Poddębniak-Strama K, Modzelewska M, Baryła M, Dziąg-Dudek E, Syryło T, Górnicka B, Jakieła A, Stec R. Tumour microenvironment as a predictive factor for immunotherapy in non-muscle-invasive bladder cancer. Cancer Immunol Immunother 2023; 72:1971-1989. [PMID: 36928373 PMCID: PMC10264486 DOI: 10.1007/s00262-023-03376-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 01/09/2023] [Indexed: 03/18/2023]
Abstract
Bladder cancer (BC) can be divided into two subgroups depending on invasion of the muscular layer: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Its aggressiveness is associated, inter alia, with genetic aberrations like losses of 1p, 6q, 9p, 9q and 13q; gain of 5p; or alterations in the p53 and p16 pathways. Moreover, there are reported metabolic disturbances connected with poor diagnosis-for example, enhanced aerobic glycolysis, gluconeogenesis or haem catabolism.Currently, the primary way of treatment method is transurethral resection of the bladder tumour (TURBT) with adjuvant Bacillus Calmette-Guérin (BCG) therapy for NMIBC or radical cystectomy for MIBC combined with chemotherapy or immunotherapy. However, intravesical BCG immunotherapy and immune checkpoint inhibitors are not efficient in every case, so appropriate biomarkers are needed in order to select the proper treatment options. It seems that the success of immunotherapy depends mainly on the tumour microenvironment (TME), which reflects the molecular disturbances in the tumour. TME consists of specific conditions like hypoxia or local acidosis and different populations of immune cells including tumour-infiltrating lymphocytes, natural killer cells, neutrophils and B lymphocytes, which are responsible for shaping the response against tumour neoantigens and crucial pathways like the PD-L1/PD-1 axis.In this review, we summarise holistically the impact of the immune system, genetic alterations and metabolic changes that are key factors in immunotherapy success. These findings should enable better understanding of the TME complexity in case of NMIBC and causes of failures of current therapies.
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Affiliation(s)
| | | | | | | | | | - Tomasz Syryło
- Department of General, Active and Oncological Urology, Military Institute of Medicine, Warsaw, Poland
| | - Barbara Górnicka
- Pathomorphology Department, Medical University of Warsaw, Warsaw, Poland
| | - Anna Jakieła
- Oncology Department, 4 Military Clinical Hospital with a Polyclinic, Wroclaw, Poland
| | - Rafał Stec
- Oncology Department, Medical University of Warsaw, Warsaw, Poland
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Brauer N, Maruta Y, Lisci M, Strege K, Oschlies I, Nakamura H, Böhm S, Lehmberg K, Brandhoff L, Ehl S, Parvaneh N, Klapper W, Fukuda M, Griffiths GM, Hennies HC, Niehues T, Ammann S. Immunodeficiency with susceptibility to lymphoma with complex genotype affecting energy metabolism ( FBP1, ACAD9) and vesicle trafficking (RAB27A). Front Immunol 2023; 14:1151166. [PMID: 37388727 PMCID: PMC10303925 DOI: 10.3389/fimmu.2023.1151166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 05/16/2023] [Indexed: 07/01/2023] Open
Abstract
Introduction Inborn errors of immunity (IEI) are characterized by a dysfunction of the immune system leading to increased susceptibility to infections, impaired immune regulation and cancer. We present a unique consanguineous family with a history of Hodgkin lymphoma, impaired EBV control and a late onset hemophagocytic lymphohistiocytosis (HLH). Methods and results Overall, family members presented with variable impairment of NK cell and cytotoxic T cell degranulation and cytotoxicity. Exome sequencing identified homozygous variants in RAB27A, FBP1 (Fructose-1,6-bisphosphatase 1) and ACAD9 (Acyl-CoA dehydrogenase family member 9). Variants in RAB27A lead to Griscelli syndrome type 2, hypopigmentation and HLH predisposition. Discussion Lymphoma is frequently seen in patients with hypomorphic mutations of genes predisposing to HLH. We hypothesize that the variants in FBP1 and ACAD9 might aggravate the clinical and immune phenotype, influence serial killing and lytic granule polarization by CD8 T cells. Understanding of the interplay between the multiple variants identified by whole exome sequencing (WES) is essential for correct interpretation of the immune phenotype and important for critical treatment decisions.
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Affiliation(s)
- Nina Brauer
- Department of Pediatrics, Helios Klinikum, Krefeld, Germany
| | - Yuto Maruta
- Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Miriam Lisci
- Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
- Department of Immunobiology, University of Lausanne, Epalinges, Switzerland
| | - Katharina Strege
- Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - Ilske Oschlies
- Department of Pathology, Haematopathology Section and Lymph Node Registry, University Hospitals Schleswig-Holstein, Christian-Albrecht University, Kiel, Germany
| | - Hikari Nakamura
- Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Svea Böhm
- Division of Pediatric Stem Cell Transplantation and Immunology, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Kai Lehmberg
- Division of Pediatric Stem Cell Transplantation and Immunology, Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Leon Brandhoff
- Cologne Center for Genomics, University Hospital Cologne, Cologne, Germany
| | - Stephan Ehl
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nima Parvaneh
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
| | - Wolfram Klapper
- Department of Pathology, Haematopathology Section and Lymph Node Registry, University Hospitals Schleswig-Holstein, Christian-Albrecht University, Kiel, Germany
| | - Mitsunori Fukuda
- Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Gillian M. Griffiths
- Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - Hans Christian Hennies
- Cologne Center for Genomics, University Hospital Cologne, Cologne, Germany
- Department of Biological and Geographical Sciences, University of Huddersfield, Huddersfield, United Kingdom
| | - Tim Niehues
- Department of Pediatrics, Helios Klinikum, Krefeld, Germany
| | - Sandra Ammann
- Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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50
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Muller Bark J, Karpe AV, Doecke JD, Leo P, Jeffree RL, Chua B, Day BW, Beale DJ, Punyadeera C. A pilot study: Metabolic profiling of plasma and saliva samples from newly diagnosed glioblastoma patients. Cancer Med 2023; 12:11427-11437. [PMID: 37031458 PMCID: PMC10242862 DOI: 10.1002/cam4.5857] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/04/2023] [Accepted: 03/14/2023] [Indexed: 04/11/2023] Open
Abstract
BACKGROUND Despite aggressive treatment, more than 90% of glioblastoma (GBM) patients experience recurrences. GBM response to therapy is currently assessed by imaging techniques and tissue biopsy. However, difficulties with these methods may cause misinterpretation of treatment outcomes. Currently, no validated therapy response biomarkers are available for monitoring GBM progression. Metabolomics holds potential as a complementary tool to improve the interpretation of therapy responses to help in clinical interventions for GBM patients. METHODS Saliva and blood from GBM patients were collected pre and postoperatively. Patients were stratified conforming their progression-free survival (PFS) into favourable or unfavourable clinical outcomes (>9 months or PFS ≤ 9 months, respectively). Analysis of saliva (whole-mouth and oral rinse) and plasma samples was conducted utilising LC-QqQ-MS and LC-QTOF-MS to determine the metabolomic and lipidomic profiles. The data were investigated using univariate and multivariate statistical analyses and graphical LASSO-based graphic network analyses. RESULTS Altogether, 151 metabolites and 197 lipids were detected within all saliva and plasma samples. Among the patients with unfavourable outcomes, metabolites such as cyclic-AMP, 3-hydroxy-kynurenine, dihydroorotate, UDP and cis-aconitate were elevated, compared to patients with favourable outcomes during pre-and post-surgery. These metabolites showed to impact the pentose phosphate and Warburg effect pathways. The lipid profile of patients who experienced unfavourable outcomes revealed a higher heterogeneity in the abundance of lipids and fewer associations between markers in contrast to the favourable outcome group. CONCLUSION Our findings indicate that changes in salivary and plasma metabolites in GBM patients can potentially be employed as less invasive prognostic biomarkers/biomarker panel but validation with larger cohorts is required.
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Affiliation(s)
- Juliana Muller Bark
- Faculty of Health, Centre for Biomedical TechnologiesSchool of Biomedical Sciences, Queensland University of TechnologyBrisbaneQueenslandAustralia
- Saliva and Liquid Biopsy Translational LaboratoryGriffith Institute for Drug Discovery – Griffith UniversityBrisbaneQueenslandAustralia
- Faculty of HealthSchool of Biomedical Sciences, Queensland University of TechnologyGardens PointQueenslandAustralia
| | - Avinash V. Karpe
- Environment, Commonwealth Scientific and Industrial Research Organization (CSIRO), Ecosciences PrecinctDutton ParkQueenslandAustralia
- Agriculture and FoodCommonwealth Scientific and Industrial Research Organization (CSIRO)ActonAustralian Capital TerritoryAustralia
| | - James D. Doecke
- Australian eHealth Research Centre, CSIRO. Level 7, Surgical Treatment and Rehabilitation Service – STARSRoyal Brisbane and Women's HospitalHerstonQueenslandAustralia
| | - Paul Leo
- Faculty of HealthSchool of Biomedical Sciences, Queensland University of TechnologyGardens PointQueenslandAustralia
- Faculty of Health, Translational Genomics GroupSchool of Biomedical Sciences, Queensland University of TechnologyWoolloongabbaAustralia
| | - Rosalind L. Jeffree
- QIMR Berghofer Medical Research InstituteHerstonQueenslandAustralia
- Faculty of MedicineUniversity of QueenslandHerstonQueenslandAustralia
- Kenneth G. Jamieson Department of NeurosurgeryRoyal Brisbane and Women's HospitalBrisbaneQueenslandAustralia
- Cell and Molecular Biology Department, Sid Faithfull Brain Cancer LaboratoryQIMR Berghofer MRIBrisbaneQueenslandAustralia
| | - Benjamin Chua
- Faculty of MedicineUniversity of QueenslandHerstonQueenslandAustralia
- Cancer Care ServicesRoyal Brisbane and Women's HospitalBrisbaneQueenslandAustralia
| | - Bryan W. Day
- Faculty of HealthSchool of Biomedical Sciences, Queensland University of TechnologyGardens PointQueenslandAustralia
- Faculty of MedicineUniversity of QueenslandHerstonQueenslandAustralia
- Cell and Molecular Biology Department, Sid Faithfull Brain Cancer LaboratoryQIMR Berghofer MRIBrisbaneQueenslandAustralia
| | - David J. Beale
- Environment, Commonwealth Scientific and Industrial Research Organization (CSIRO), Ecosciences PrecinctDutton ParkQueenslandAustralia
| | - Chamindie Punyadeera
- Saliva and Liquid Biopsy Translational LaboratoryGriffith Institute for Drug Discovery – Griffith UniversityBrisbaneQueenslandAustralia
- Menzies Health Institute, Griffith UniversitySouthportQueenslandAustralia
- Translational Research InstituteWoolloongabbaQueenslandAustralia
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