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Kwon N, Weng H, Rajora MA, Zheng G. Activatable Photosensitizers: From Fundamental Principles to Advanced Designs. Angew Chem Int Ed Engl 2025; 64:e202423348. [PMID: 39899458 PMCID: PMC11976215 DOI: 10.1002/anie.202423348] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/23/2025] [Accepted: 01/28/2025] [Indexed: 02/05/2025]
Abstract
Photodynamic therapy (PDT) is a promising treatment that uses light to excite photosensitizers in target tissue, producing reactive oxygen species and localized cell death. It is recognized as a minimally invasive, clinically approved cancer therapy with additional preclinical applications in arthritis, atherosclerosis, and infection control. A hallmark of ideal PDT is delivering disease-specific cytotoxicity while sparing healthy tissue. However, conventional photosensitizers often suffer from non-specific photoactivation, causing off-target toxicity. Activatable photosensitizers (aPS) have emerged as more precise alternatives, offering controlled activation. Unlike traditional photosensitizers, they remain inert and photoinactive during circulation and off-target accumulation, minimizing collateral damage. These photosensitizers are designed to "turn on" in response to disease-specific biostimuli, enhancing therapeutic selectivity and reducing off-target effects. This review explores the principles of aPS, including quenching mechanisms stemming from activatable fluorescent probes and applied to activatable photosensitizers (RET, PeT, ICT, ACQ, AIE), as well as pathological biostimuli (pH, enzymes, redox conditions, cellular internalization), and bioresponsive constructs enabling quenching and activation. We also provide a critical assessment of unresolved challenges in aPS development, including limitations in targeting precision, selectivity under real-world conditions, and potential solutions to persistent issues (dual-lock, targeting moieties, biorthogonal chemistry and artificial receptors). Additionally, it provides an in-depth discussion of essential research design considerations needed to develop translationally relevant aPS with improved therapeutic outcomes and specificity.
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Affiliation(s)
- Nahyun Kwon
- Princess Margaret Cancer CentreUniversity Health Network101 College Street, PMCRT 5–354Toronto, ONM5G1L7Canada
| | - Hanyi Weng
- Princess Margaret Cancer CentreUniversity Health Network101 College Street, PMCRT 5–354Toronto, ONM5G1L7Canada
- Department of Medical BiophysicsUniversity of TorontoToronto, ONCanada
| | - Maneesha A. Rajora
- Princess Margaret Cancer CentreUniversity Health Network101 College Street, PMCRT 5–354Toronto, ONM5G1L7Canada
- Department of MedicineUniversity of TorontoToronto, ONCanada
| | - Gang Zheng
- Princess Margaret Cancer CentreUniversity Health Network101 College Street, PMCRT 5–354Toronto, ONM5G1L7Canada
- Department of Medical BiophysicsUniversity of TorontoToronto, ONCanada
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Lim J, Park S, Ryu S, Park S, Kim MS. Different Inactivation Mechanisms of Staphylococcus aureus and Escherichia coli in Water by Reactive Oxygen and Nitrogen Species Generated from an Argon Plasma Jet. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2025; 59:3276-3285. [PMID: 39907054 DOI: 10.1021/acs.est.4c10363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
The atmospheric pressure plasma jet (APPJ) is a promising technology for inactivating waterborne pathogens by generating diverse reactive species under ambient conditions. However, uncertainties regarding the bacterial inactivation mechanisms persist due to varying findings in prior research. This study aimed to clarify the inactivation mechanisms of two representative bacteria, Staphylococcus aureus (S. aureus, Gram-positive) and Escherichia coli (E. coli, Gram-negative), using an argon-based APPJ (Ar-APPJ) system in a controlled medium, primarily deionized water. We identified several reactive oxygen and nitrogen species (RONS), including hydrogen peroxide, peroxynitrous acid/peroxynitrite (ONOOH/ONOO-), hydroxyl radical (•OH), and hydroperoxyl radical/superoxide radical, and evaluated their roles in bacterial inactivation. Inactivation experiments and quantification of suspected RONS revealed that ONOOH was the primary lethal agent for S. aureus, while •OH predominantly inactivated E. coli. Assessment of cell membrane integrity and intracellular RONS levels showed that E. coli, with its thinner cell wall, was more vulnerable to surface damage caused by •OH. In contrast, for S. aureus, with its thicker cell wall, intracellular attack by penetrated ONOOH, being significantly more diffusive than •OH, was more effective, as •OH alone could not induce sufficient surface damage. These findings advance our understanding of bacterial inactivation by the Ar-APPJ and provide valuable insights for designing effective water disinfection strategies utilizing this technology.
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Affiliation(s)
- Junghyun Lim
- Department of Environmental & Energy, Soil Environment Research Center, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeonbuk State 54896, Republic of Korea
- Institute of Plasma Technology, Korea Institute of Fusion Energy, Gunsan-si, Jeonbuk State 54004, Republic of Korea
| | - Seungil Park
- Institute of Plasma Technology, Korea Institute of Fusion Energy, Gunsan-si, Jeonbuk State 54004, Republic of Korea
| | - Seungmin Ryu
- Institute of Plasma Technology, Korea Institute of Fusion Energy, Gunsan-si, Jeonbuk State 54004, Republic of Korea
| | - Sanghoo Park
- Department of Nuclear and Quantum Engineering, Korea Advanced Institute of Science and Technology (KAIST), Yuseong-gu, Daejeon-si 34141, Republic of Korea
| | - Min Sik Kim
- Department of Environmental & Energy, Soil Environment Research Center, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeonbuk State 54896, Republic of Korea
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Xu T, Liu F, He J, Xu P, Qu J, Wang H, Yue J, Yang Q, Wu W, Zeng G, Sun D, Chen X. Leveraging zebrafish models for advancing radiobiology: Mechanisms, applications, and future prospects in radiation exposure research. ENVIRONMENTAL RESEARCH 2025; 266:120504. [PMID: 39638026 DOI: 10.1016/j.envres.2024.120504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 11/12/2024] [Accepted: 12/01/2024] [Indexed: 12/07/2024]
Abstract
Ionizing radiation (IR) represents a significant risk to human health and societal stability. To effectively analyze the mechanisms of IR and enhance protective strategies, the development of more sophisticated animal models is imperative. The zebrafish, with its high degree of genomic homology to humans and the capacity for whole-body optical visualization and high-throughput screening, represents an invaluable model for the study of IR. This review examines the benefits of utilizing zebrafish as a model organism for research on IR, emphasizing recent advancements and applications. It presents a comprehensive overview of the methodologies for establishing IR models in zebrafish, addresses current challenges, and discusses future development trends. This paper provide theoretical support for elucidating the mechanisms of IR injury and developing effective treatment strategies.
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Affiliation(s)
- Ting Xu
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China; Department of Endocrinology, Yiwu Central Hospital, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu, 322000, China
| | - Fan Liu
- State and Local Joint Engineering Research Center for Ecological Treatment Technology of Urban Water Pollution, School of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Jiaxuan He
- State and Local Joint Engineering Research Center for Ecological Treatment Technology of Urban Water Pollution, School of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Peiye Xu
- State and Local Joint Engineering Research Center for Ecological Treatment Technology of Urban Water Pollution, School of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Junying Qu
- State and Local Joint Engineering Research Center for Ecological Treatment Technology of Urban Water Pollution, School of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China; Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, School of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Hanbing Wang
- Department of Biotechnology, The University of Hong Kong, Hong Kong SAR, 999077, China
| | - Jinghui Yue
- Nuclear Power Institute of China, Chengdu, 610200, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Wei Wu
- Bioengineering College, Chongqing University, Chongqing, 400044, China
| | - Guoming Zeng
- Intelligent Construction Technology Application Service Center, School of Architecture and Engineering, Chongqing City Vocational College, Chongqing, 402160, China
| | - Da Sun
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China; Department of Endocrinology, Yiwu Central Hospital, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu, 322000, China; Zhejiang Provincial Key Laboratory for Water Environment and Marine Biological Resources Protection, School of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China.
| | - Xia Chen
- Department of Endocrinology, Yiwu Central Hospital, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu, 322000, China.
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Jahng JWS, Little MP, No HJ, Loo BW, Wu JC. Consequences of ionizing radiation exposure to the cardiovascular system. Nat Rev Cardiol 2024; 21:880-898. [PMID: 38987578 PMCID: PMC12037960 DOI: 10.1038/s41569-024-01056-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 07/12/2024]
Abstract
Ionizing radiation is widely used in various industrial and medical applications, resulting in increased exposure for certain populations. Lessons from radiation accidents and occupational exposure have highlighted the cardiovascular and cerebrovascular risks associated with radiation exposure. In addition, radiation therapy for cancer has been linked to numerous cardiovascular complications, depending on the distribution of the dose by volume in the heart and other relevant target tissues in the circulatory system. The manifestation of symptoms is influenced by numerous factors, and distinct cardiac complications have previously been observed in different groups of patients with cancer undergoing radiation therapy. However, in contemporary radiation therapy, advances in treatment planning with conformal radiation delivery have markedly reduced the mean heart dose and volume of exposure, and these variables are therefore no longer sole surrogates for predicting the risk of specific types of heart disease. Nevertheless, certain cardiac substructures remain vulnerable to radiation exposure, necessitating close monitoring. In this Review, we provide a comprehensive overview of the consequences of radiation exposure on the cardiovascular system, drawing insights from various cohorts exposed to uniform, whole-body radiation or to partial-body irradiation, and identify potential risk modifiers in the development of radiation-associated cardiovascular disease.
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Affiliation(s)
- James W S Jahng
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
| | - Mark P Little
- Radiation Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA
- Faculty of Health and Life Sciences, Oxford Brookes University, Headington Campus, Oxford, UK
| | - Hyunsoo J No
- Department of Radiation Oncology, Southern California Permanente Medical Group, Los Angeles, CA, USA
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
| | - Billy W Loo
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
- Greenstone Biosciences, Palo Alto, CA, USA.
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Zhu J, Li X, Huang M, Zhu H, Tan Y, He X, Sun Z, Cheng H, Li F, Jiang P, Lou H, Ke G, Cao X, Zhu L, Xie P, Yan J, Zhang F. Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multicenter, Randomized, Open-label, Prospective Trial. Int J Radiat Oncol Biol Phys 2024; 120:720-729. [PMID: 38705489 DOI: 10.1016/j.ijrobp.2024.04.070] [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: 12/13/2023] [Revised: 03/25/2024] [Accepted: 04/25/2024] [Indexed: 05/07/2024]
Abstract
PURPOSE The purpose of this study was to evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. METHODS AND MATERIALS In this phase 3, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiation therapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiation therapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiation therapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea, ≥G1 and ≥G2 diarrhea lasting at least 3 days, and damage to the rectal mucosa due to radiation therapy measured by endoscopy. RESULTS Two hundred and eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 142). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs 14.8 and 4.5 days, respectively; P < .001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs 55.7%, P < .001). Three patients felt intolerable or abdominal pain after rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P = .061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P < .001). CONCLUSIONS The results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.
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Affiliation(s)
- Jiawei Zhu
- Department of Radiation Oncology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xiaofan Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Manni Huang
- Department of Gynecological Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yan Tan
- Radiation Oncology Key Laboratory of Sichuan Province, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China
| | - Xia He
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Zhihua Sun
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Huijun Cheng
- Department of Gynecologic Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Fenghu Li
- Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ping Jiang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, China
| | - Hanmei Lou
- Department of Gynecological Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Guihao Ke
- Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xinping Cao
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lihong Zhu
- Radiotherapy Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China
| | - Peng Xie
- Department of Gynecologic Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Junfang Yan
- Department of Radiation Oncology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
| | - Fuquan Zhang
- Department of Radiation Oncology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
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Jaiswal L, Shankar S, Lacroix M. Dual effect of pH and X-ray irradiation on properties of gelatin/trans-cinnamaldehyde-based composite films for sustainable packaging. Int J Biol Macromol 2024; 280:135652. [PMID: 39278443 DOI: 10.1016/j.ijbiomac.2024.135652] [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: 07/30/2024] [Revised: 09/11/2024] [Accepted: 09/12/2024] [Indexed: 09/18/2024]
Abstract
Gelatin (Gel) based water-insoluble films with antimicrobial properties were developed by the green method using trans-cinnamaldehyde (TCA) and low-energy X-ray irradiation as dual crosslinkers. The Gel/TCA composite films (GTCF) were prepared at different pH (4, 6, 8, and 10) and crosslinked by incorporating 5 % (w/w, based on Gel) TCA and X-ray irradiation (350 kV and 11.4 mA) with doses of 0, 5, 10 and 15 kGy. The presence of TCA in GTCF forms dense, flexible, and strong films when exposed to X-ray irradiation. The GTCF at pH 6, incorporated with 5 wt% TCA and irradiated with 10 kGy X-ray, displayed the highest degree of crosslinking (DOC) (93.4 ± 3.4 %), tensile strength, excellent UV-barrier (> 99.9 %), antimicrobial (inhibitory capacity of >50 %), and water vapor permeability (4.1 ± 0.6 g.mm/m2.day. kPa), and low solubility in water (0.5 ± 0.3 %), and oxygen permeability. The GTCF, crosslinked with X-ray irradiation, has multifunctional properties and strong potential in the sustainable packaging industry to augment the shelf life of food and reduce food waste. To the best of our information, this is the first and novel report investigating the effects of pH on the properties of GTCF crosslinked with X-ray.
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Affiliation(s)
- Lily Jaiswal
- INRS-Armand-Frappier Health Biotechnology Research Centre, Research Laboratories in Sciences, Applied to Food (RESALA), MAPAQ Research Chair in food safety and quality, Canadian Irradiation Center (CIC), Institute of Nutrition and Functional Foods (INAF), 531 des Prairies Blvd, Laval, QC H7V 1B7, Canada
| | - Shiv Shankar
- INRS-Armand-Frappier Health Biotechnology Research Centre, Research Laboratories in Sciences, Applied to Food (RESALA), MAPAQ Research Chair in food safety and quality, Canadian Irradiation Center (CIC), Institute of Nutrition and Functional Foods (INAF), 531 des Prairies Blvd, Laval, QC H7V 1B7, Canada
| | - Monique Lacroix
- INRS-Armand-Frappier Health Biotechnology Research Centre, Research Laboratories in Sciences, Applied to Food (RESALA), MAPAQ Research Chair in food safety and quality, Canadian Irradiation Center (CIC), Institute of Nutrition and Functional Foods (INAF), 531 des Prairies Blvd, Laval, QC H7V 1B7, Canada.
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Ren C, Wang L, Li X, Tang Y, Zhi X, Zhuang M, Chen Q, Gao X, Lv X, Wang C, Wu X, Liu K, Zhao X, Li Y. Elucidating the mechanism of action of Radix Angelica sinensis (Oliv.) Diels and Radix Astragalus mongholicus Bunge ultrafiltration extract on radiation-induced myocardial fibrosis based on network pharmacology and experimental research. Eur J Pharm Sci 2024; 199:106794. [PMID: 38788908 DOI: 10.1016/j.ejps.2024.106794] [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: 01/19/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024]
Abstract
Myocardial fibrosis can induce cardiac dysfunction and remodeling. Great attention has been paid to traditional chinese medicine (TCM) 's effectiveness in treating MF. Radix Angelica sinensis (Oliv.) Diels and Radix Astragalus mongholicus Bunge ultrafiltration extract (RAS-RA), which is a key TCM compound preparation, have high efficacy in regulating inflammation. However, studies on its therapeutic effect on radiation-induced myocardial fibrosis (RIMF) are rare. In this study, RAS-RA had therapeutic efficacy in RIMF and elucidated its mechanism of action. First, we formulated the prediction network that described the relation of RAS-RA with RIMF according to data obtained in different databases. Then, we conducted functional enrichment to investigate the functions and pathways associated with potential RIMF targets for RAS-RA. In vivo experiments were also performed to verify these functions and pathways. Second, small animal ultrasound examinations, H&E staining, Masson staining, transmission electron microscopy, Enzyme-linked immunosorbent assay (ELISA), Western-blotting, Immunohistochemical method and biochemical assays were conducted to investigate the possible key anti-RIMF pathway in RAS-RA. In total, 440 targets were detected in those 21 effective components of RAS-RA; meanwhile, 1,646 RIMF-related disease targets were also discovered. After that, PPI network analysis was conducted to identify 20 key targets based on 215 overlap gene targets. As indicated by the gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis results, inflammation and PI3K/AKT/mTOR pathways might have important effects on the therapeutic effects on RIMF. Molecular docking analysis revealed high binding of effective components to targets (affinity < -6 kcal/mol). Based on experimental verification results, RAS-RA greatly mitigated myocardial fibrosis while recovering the cardiac activity of rats caused by X-rays. According to relevant protein expression profiles, the PI3K/AKT/mTOR pathway was important for anti-fibrosis effect of RAS-RA. Experimental studies showed that RAS-RA improved cardiac function, decreased pathological damage and collagen fiber deposition in cardiac tissues, and improved the mitochondrial structure of the heart of rats. RAS-RA also downregulated TNF-α, IL-6, and IL-1β levels. Additionally, RAS-RA improved the liver and kidney functions and pathological injury of rat kidney and liver tissues, enhanced liver and kidney functions, and protected the liver and kidneys. RAS-RA also increased PI3K, AKT and mTOR protein levels within cardiac tissues and downregulated α-SMA, Collagen I, and Collagen III. The findings of this study suggested that RAS-RA decreased RIMF by suppressing collagen deposition and inflammatory response by inhibiting the PI3K/AKT/mTOR pathway. Thus, RAS-RA was the potential therapeutic agent used to alleviate RIMF.
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Affiliation(s)
- Chunzhen Ren
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China
| | - Lirong Wang
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China
| | - Xiaojing Li
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China
| | - Yan Tang
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China
| | - Xiaodong Zhi
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China; Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou 730000 PR China
| | - Mengjie Zhuang
- Xinjiang Medical University School of Basic Medicine, Urumqi 830000 PR China
| | - Qilin Chen
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China
| | - Xiang Gao
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China; Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou 730000 PR China
| | - Xinfang Lv
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China; Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou 730000 PR China
| | - Chunling Wang
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China
| | - Xue Wu
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China
| | - Kai Liu
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China
| | - Xinke Zhao
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China; Affiliated Hospital of Gansu University of Chinese Medicine, Lanzhou 730000 PR China.
| | - Yingdong Li
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000 PR China; Gansu Province Key Laboratory of Chinese Medicine for the Prevention and Treatment of Chronic Diseases, Lanzhou 730000 PR China; Key clinical specialty of the National Health Commission of the People's Republic of China, Key Specialized Cardiovascular Laboratory National Administration of Traditional Chinese Medicine, Lanzhou 730000 PR China.
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Boothe PF, Kumar VP, Kong Y, Wang K, Levinson H, Mu D, Brown ML. Radiation Induced Skin Fibrosis (RISF): Opportunity for Angiotensin II-Dependent Intervention. Int J Mol Sci 2024; 25:8261. [PMID: 39125831 PMCID: PMC11312688 DOI: 10.3390/ijms25158261] [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: 07/04/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Medical procedures, such as radiation therapy, are a vital element in treating many cancers, significantly contributing to improved survival rates. However, a common long-term complication of such exposure is radiation-induced skin fibrosis (RISF), a complex condition that poses substantial physical and psychological challenges. Notably, about 50% of patients undergoing radiation therapy may achieve long-term remission, resulting in a significant number of survivors managing the aftereffects of their treatment. This article delves into the intricate relationship between RISF, reactive oxygen species (ROS), and angiotensin II (Ang II) signaling. It proposes the underlying mechanisms and examines potential treatments for mitigating skin fibrosis. The primary goal is to offer essential insights in order to better care for and improve the quality of life of cancer survivors who face the risk of developing RISF.
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Affiliation(s)
- Patricia F. Boothe
- Department of Internal Medicine, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA
| | - Vidya P. Kumar
- Armed Forces Radiobiology Research Institute, The Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA
| | - Yali Kong
- Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA; (Y.K.); (D.M.)
| | - Kan Wang
- Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA; (Y.K.); (D.M.)
| | - Howard Levinson
- The Center for Plastic Surgery at Sentara, 301 Riverview Ave. #400, Norfolk, VA 23510, USA;
| | - David Mu
- Department of Biomedical and Translational Sciences, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA; (Y.K.); (D.M.)
- Leroy T. Canoles Jr. Cancer Research Center, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA
| | - Milton L. Brown
- Department of Internal Medicine, Macon & Joan Brock Virginia Health Sciences at Old Dominion University, Norfolk, VA 23507, USA
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9
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Duché G, Sanderson JM. The Chemical Reactivity of Membrane Lipids. Chem Rev 2024; 124:3284-3330. [PMID: 38498932 PMCID: PMC10979411 DOI: 10.1021/acs.chemrev.3c00608] [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: 09/04/2023] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 03/20/2024]
Abstract
It is well-known that aqueous dispersions of phospholipids spontaneously assemble into bilayer structures. These structures have numerous applications across chemistry and materials science and form the fundamental structural unit of the biological membrane. The particular environment of the lipid bilayer, with a water-poor low dielectric core surrounded by a more polar and better hydrated interfacial region, gives the membrane particular biophysical and physicochemical properties and presents a unique environment for chemical reactions to occur. Many different types of molecule spanning a range of sizes, from dissolved gases through small organics to proteins, are able to interact with membranes and promote chemical changes to lipids that subsequently affect the physicochemical properties of the bilayer. This Review describes the chemical reactivity exhibited by lipids in their membrane form, with an emphasis on conditions where the lipids are well hydrated in the form of bilayers. Key topics include the following: lytic reactions of glyceryl esters, including hydrolysis, aminolysis, and transesterification; oxidation reactions of alkenes in unsaturated fatty acids and sterols, including autoxidation and oxidation by singlet oxygen; reactivity of headgroups, particularly with reactive carbonyl species; and E/Z isomerization of alkenes. The consequences of reactivity for biological activity and biophysical properties are also discussed.
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Affiliation(s)
- Genevieve Duché
- Génie
Enzimatique et Cellulaire, Université
Technologique de Compiègne, Compiègne 60200, France
| | - John M Sanderson
- Chemistry
Department, Durham University, Durham DH1 3LE, United Kingdom
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10
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Clark GC, Lai A, Agarwal A, Liu Z, Wang XY. Biopterin metabolism and nitric oxide recoupling in cancer. Front Oncol 2024; 13:1321326. [PMID: 38469569 PMCID: PMC10925643 DOI: 10.3389/fonc.2023.1321326] [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: 10/13/2023] [Accepted: 12/26/2023] [Indexed: 03/13/2024] Open
Abstract
Tetrahydrobiopterin is a cofactor necessary for the activity of several enzymes, the most studied of which is nitric oxide synthase. The role of this cofactor-enzyme relationship in vascular biology is well established. Recently, tetrahydrobiopterin metabolism has received increasing attention in the field of cancer immunology and immunotherapy due to its involvement in the cytotoxic T cell response. Past research has demonstrated that when the availability of BH4 is low, as it is in chronic inflammatory conditions and tumors, electron transfer in the active site of nitric oxide synthase becomes uncoupled from the oxidation of arginine. This results in the production of radical species that are capable of a direct attack on tetrahydrobiopterin, further depleting its local availability. This feedforward loop may act like a molecular switch, reinforcing low tetrahydrobiopterin levels leading to altered NO signaling, restrained immune effector activity, and perpetual vascular inflammation within the tumor microenvironment. In this review, we discuss the evidence for this underappreciated mechanism in different aspects of tumor progression and therapeutic responses. Furthermore, we discuss the preclinical evidence supporting a clinical role for tetrahydrobiopterin supplementation to enhance immunotherapy and radiotherapy for solid tumors and the potential safety concerns.
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Affiliation(s)
- Gene Chatman Clark
- Department of Biochemistry, Virginia Commonwealth University, Richmond, VA, United States
- School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Alan Lai
- School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | | | - Zheng Liu
- Department of Human Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
| | - Xiang-Yang Wang
- Department of Human Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
- Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, United States
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11
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Wu J, Ran X, Wang T, Xiong K, Long S, Hao Y, Wang P, Wang A. Enteric α-Defensin Contributes to Recovery of Radiation-Induced Intestinal Injury by Modulating Gut Microbiota and Fecal Metabolites. Radiat Res 2024; 201:160-173. [PMID: 38124379 DOI: 10.1667/rade-23-00071.1] [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: 04/24/2023] [Accepted: 12/12/2023] [Indexed: 12/23/2023]
Abstract
The effect of ionizing radiation on the gastrointestinal tract is a common complication of abdominal and pelvic radiotherapy. However, the pathological features of radiation enteropathy and its effective medical intervention regimen is still a global challenge. Here, we explored the role and mechanism of enteric alpha-defensins (EαDs) in protecting against radiation enteropathy. To address this, we utilized EαDs-deficiency mice, in which the matrix metallopeptidase 7 to activate Paneth cell α-defensins was knockout (KO) mice, and the complementary wild-type (WT) control mice for this study. Remarkably, the KO mice were more susceptible to 5.0 Gy total-body irradiation, resulting in worse clinic scores and lower survival rate, compared with the wild-type mice. Histological examination indicated that the KO mice were subjected to slow recovery of intestinal villus and mucosa function, characterized by the reduced expression of TFF3, Glut1 and Muc2. In addition, compared with the wild-type controls, the KO mice experienced serious inflammation response in intestinal tissue, indicated by the remarkably increased expression level of IL-1β, IL-6 and IL-12. Using high-throughput sequencing analysis, we found that the intestinal bacterial community of the KO mice was more prone to dysbiosis than that of the WT mice, with significantly increased abundance of opportunistic pathogenic bacteria, such as Streptococcus sp. and Escherichia-Shigella sp., whereas remarkably decreased probiotics harboring Lactobacillus sp., Desulfovibrio sp. etc. Fecal metabolomics analysis indicated that the relative abundance of 31 metabolites arose significantly different between WT and KO mice on day 10 after radiation exposure. A subset of differential metabolites to regulate host metabolism and immunity, such as acetic acid, acetate, butanoic acid, was negatively correlated with the alteration of gut microbiota in the irradiated KO mice. This study provides new insight into EαDs contribution to the recovery of radiation-induced intestinal damage, and suggests a potential novel target to prevent the adverse effects of radiotherapy.
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Affiliation(s)
- Jie Wu
- Department of Frigid Zone Medicine, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China
- Department of Radiation Medicine, College of Preventive Medicine, Army Medical University, Chongqing 400038, China
| | - Xi Ran
- Department of Clinical Laboratory, the Second Affiliated Hospital of Army Medical University, Chongqing 400037, China
| | - Tao Wang
- Department of Radiation Medicine, College of Preventive Medicine, Army Medical University, Chongqing 400038, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing 400038, China
| | - Kun Xiong
- Department of Frigid Zone Medicine, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China
| | - Shuang Long
- Department of Radiation Medicine, College of Preventive Medicine, Army Medical University, Chongqing 400038, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing 400038, China
| | - Yuhui Hao
- Department of Radiation Medicine, College of Preventive Medicine, Army Medical University, Chongqing 400038, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing 400038, China
| | - Peng Wang
- Department of Oncology, Southwest Hospital, Army Medical University
| | - Aiping Wang
- Department of Frigid Zone Medicine, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing 400038, China
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12
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Büttner T, Maerevoet MKE, Giordano FA, Veldwijk MR, Herskind C, Ruder AM. Combining a noble gas with radiotherapy: glutamate receptor antagonist xenon may act as a radiosensitizer in glioblastoma. Radiat Oncol 2024; 19:16. [PMID: 38291439 PMCID: PMC10826195 DOI: 10.1186/s13014-023-02395-1] [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: 05/28/2023] [Accepted: 12/21/2023] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Ionotropic glutamate receptors α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as a radiosensitizer in GB. METHODS We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine. RESULTS The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Indications for the presence of glutamate receptor subunits were present in glioblastoma-derived and HeLa cells. Significantly reduced clonogenic survival by xenon was shown in U87 and U251 at irradiation doses of 4-8 Gy and 2, 6 and 8 Gy, respectively (p < 0.05). Clonogenic survival was further reduced by the addition of memantine, showing a significant effect at 2-8 Gy for both glioblastoma cell lines (p < 0.05). Xenon did not significantly reduce the surviving fraction of HeLa cells until a radiation dose of 8 Gy. CONCLUSION The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled indications of radiosensitizing properties of xenon gas in glioblastoma.
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Affiliation(s)
- Thomas Büttner
- Department of Radiation Oncology, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany.
- Clinic for Urology and Paediatric Urology, University Hospital Bonn, Venusberg Campus 1, 53127, Bonn, Germany.
| | - Marielena K E Maerevoet
- Department of Radiation Oncology, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Frank A Giordano
- Department of Radiation Oncology, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Marlon R Veldwijk
- Department of Radiation Oncology, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Carsten Herskind
- Department of Radiation Oncology, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
| | - Arne Mathias Ruder
- Department of Radiation Oncology, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany
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13
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Liu J, Zhu L, Bao Y, Du Z, Shi L, Hong X, Zou Z, Peng G. Injectable dexamethasone-loaded peptide hydrogel for therapy of radiation-induced ototoxicity by regulating the mTOR signaling pathway. J Control Release 2024; 365:729-743. [PMID: 38065412 DOI: 10.1016/j.jconrel.2023.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 11/19/2023] [Accepted: 12/02/2023] [Indexed: 12/17/2023]
Abstract
Radiation-induced ototoxicity is associated with inflammation response and excessive reactive oxygen species in the cochlea. However, the effectiveness of many drugs in clinical settings is limited due to anatomical barriers in the inner ear and pharmacokinetic instability. To address this issue, we developed an injectable hydrogel called RADA32-HRN-dexamethasone (RHD). The RHD hydrogel possesses self-anti-inflammatory properties and can self-assemble into nanofibrous structures, ensuring controlled and sustained release of dexamethasone in the local region. Flow cytometry analysis revealed that the uptake of FITC-conjugated RHD gel by hair cells increased in a time-dependent manner. Compared to free dexamethasone solutions, dexamethasone-loaded RHD gel achieved a longer and more controlled release profile of dexamethasone. Additionally, RHD gel effectively protected against the inflammatory response, reduced excessive reactive oxygen species production, and reversed the decline in mitochondrial membrane potentials induced by ionizing radiation, leading to attenuation of apoptosis and DNA damage. Moreover, RHD gel promoted the recovery of outer hair cells and partially restored auditory function in mice exposed to ionizing radiation. These findings validated the protective effects of RHD gel against radiation-induced ototoxicity in both cell cultures and animal models. Furthermore, RHD gel enhanced the activity of the mammalian target of rapamycin (mTOR) signaling pathway, which was inhibited by ionizing radiation, thereby promoting the survival of hair cells. Importantly, intratympanic injections of RHD gel exhibited excellent biosafety and do not interfere with the anti-tumor effects of radiotherapy. In summary, our study demonstrates the therapeutic potential of injectable dexamethasone-loaded RHD hydrogel for the treatment of radiation-induced hearing loss by regulating the mTOR signaling pathway.
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Affiliation(s)
- Jingyu Liu
- Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430022, China
| | - Lisheng Zhu
- The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Yuqing Bao
- Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430022, China
| | - Zhouyuan Du
- Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430022, China
| | - Liangliang Shi
- Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430022, China
| | - Xiaohua Hong
- Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430022, China
| | - Zhenwei Zou
- Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430022, China.
| | - Gang Peng
- Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430022, China.
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14
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Arp NL, Seim GL, Votava JA, Josephson J, Fan J. Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism. J Biol Chem 2023; 299:105333. [PMID: 37827290 PMCID: PMC10656228 DOI: 10.1016/j.jbc.2023.105333] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/03/2023] [Accepted: 10/05/2023] [Indexed: 10/14/2023] Open
Abstract
Branched chain α-ketoacid dehydrogenase complex (BCKDC) is the rate-limiting enzyme in branched chain amino acid (BCAA) catabolism, a metabolic pathway with great importance for human health. BCKDC belongs to the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex. Here, we revealed that BCKDC can be substantially inhibited by reactive nitrogen species (RNS) via a mechanism similar to what we recently discovered with pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex-RNS can cause inactivating covalent modifications of the lipoic arm on its E2 subunit. In addition, we showed that such reaction between RNS and the lipoic arm of the E2 subunit can further promote inhibition of the E3 subunits of α-ketoacid dehydrogenase complexes. We examined the impacts of this RNS-mediated BCKDC inhibition in muscle cells, an important site of BCAA metabolism, and demonstrated that the nitric oxide production induced by cytokine stimulation leads to a strong inhibition of BCKDC activity and BCAA oxidation in myotubes and myoblasts. More broadly, nitric oxide production reduced the level of functional lipoic arms across the multiple α-ketoacid dehydrogenases and led to intracellular accumulation of their substrates (α-ketoacids), decrease of their products (acyl-CoAs), and a lower cellular energy charge. In sum, this work revealed a new mechanism for BCKDC regulation, demonstrated that RNS can generally inhibit all α-ketoacid dehydrogenases, which has broad physiological implications across multiple cell types, and elucidated the mechanistic connection between RNS-driven inhibitory modifications on the E2 and E3 subunits of α-ketoacid dehydrogenases.
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Affiliation(s)
- Nicholas L Arp
- Morgridge Institute for Research, Madison, Wisconsin, USA; Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; University of Wisconsin Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Gretchen L Seim
- Morgridge Institute for Research, Madison, Wisconsin, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - James A Votava
- Morgridge Institute for Research, Madison, Wisconsin, USA
| | | | - Jing Fan
- Morgridge Institute for Research, Madison, Wisconsin, USA; Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; University of Wisconsin Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
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15
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Andrabi SM, Sharma NS, Karan A, Shahriar SMS, Cordon B, Ma B, Xie J. Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2303259. [PMID: 37632708 PMCID: PMC10602574 DOI: 10.1002/advs.202303259] [Citation(s) in RCA: 163] [Impact Index Per Article: 81.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Indexed: 08/28/2023]
Abstract
Nitric oxide (NO) is a gaseous molecule that has a central role in signaling pathways involved in numerous physiological processes (e.g., vasodilation, neurotransmission, inflammation, apoptosis, and tumor growth). Due to its gaseous form, NO has a short half-life, and its physiology role is concentration dependent, often restricting its function to a target site. Providing NO from an external source is beneficial in promoting cellular functions and treatment of different pathological conditions. Hence, the multifaceted role of NO in physiology and pathology has garnered massive interest in developing strategies to deliver exogenous NO for the treatment of various regenerative and biomedical complexities. NO-releasing platforms or donors capable of delivering NO in a controlled and sustained manner to target tissues or organs have advanced in the past few decades. This review article discusses in detail the generation of NO via the enzymatic functions of NO synthase as well as from NO donors and the multiple biological and pathological processes that NO modulates. The methods for incorporating of NO donors into diverse biomaterials including physical, chemical, or supramolecular techniques are summarized. Then, these NO-releasing platforms are highlighted in terms of advancing treatment strategies for various medical problems.
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Affiliation(s)
- Syed Muntazir Andrabi
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Navatha Shree Sharma
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Anik Karan
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - S. M. Shatil Shahriar
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Brent Cordon
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Bing Ma
- Cell Therapy Manufacturing FacilityMedStar Georgetown University HospitalWashington, DC2007USA
| | - Jingwei Xie
- Department of Surgery‐Transplant and Mary & Dick Holland Regenerative Medicine ProgramCollege of MedicineUniversity of Nebraska Medical CenterOmahaNE68198USA
- Department of Mechanical and Materials EngineeringCollege of EngineeringUniversity of Nebraska LincolnLincolnNE68588USA
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16
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Koren SA, Ahmed Selim N, De la Rosa L, Horn J, Farooqi MA, Wei AY, Müller-Eigner A, Emerson J, Johnson GVW, Wojtovich AP. All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ. Nat Commun 2023; 14:6036. [PMID: 37758713 PMCID: PMC10533892 DOI: 10.1038/s41467-023-41682-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H2O2 biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H2O2 demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. This transient hyperfusion phenotype required mitochondrial fusion but not fission machinery. Measurement of microdomain-specific H2O2 diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H2O2 between mitochondrial compartments provide a map of mitochondrial H2O2 diffusion dynamics in situ as a framework to understand the role of ROS in health and disease.
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Affiliation(s)
- Shon A Koren
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Nada Ahmed Selim
- University of Rochester Medical Center, Department of Pharmacology and Physiology, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Lizbeth De la Rosa
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Jacob Horn
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - M Arsalan Farooqi
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Alicia Y Wei
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Annika Müller-Eigner
- Research Group Epigenetics, Metabolism and Longevity, Research Institute for Farm Animal Biology (FBN), Dummerstorf, 18196, Germany
| | - Jacen Emerson
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Gail V W Johnson
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA
| | - Andrew P Wojtovich
- University of Rochester Medical Center, Department of Anesthesiology and Perioperative Medicine, 575 Elmwood Ave., Rochester, NY, 14642, Box 711/604, USA.
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17
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Pokharel MD, Marciano DP, Fu P, Franco MC, Unwalla H, Tieu K, Fineman JR, Wang T, Black SM. Metabolic reprogramming, oxidative stress, and pulmonary hypertension. Redox Biol 2023; 64:102797. [PMID: 37392518 PMCID: PMC10363484 DOI: 10.1016/j.redox.2023.102797] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 06/15/2023] [Accepted: 06/23/2023] [Indexed: 07/03/2023] Open
Abstract
Mitochondria are highly dynamic organelles essential for cell metabolism, growth, and function. It is becoming increasingly clear that endothelial cell dysfunction significantly contributes to the pathogenesis and vascular remodeling of various lung diseases, including pulmonary arterial hypertension (PAH), and that mitochondria are at the center of this dysfunction. The more we uncover the role mitochondria play in pulmonary vascular disease, the more apparent it becomes that multiple pathways are involved. To achieve effective treatments, we must understand how these pathways are dysregulated to be able to intervene therapeutically. We know that nitric oxide signaling, glucose metabolism, fatty acid oxidation, and the TCA cycle are abnormal in PAH, along with alterations in the mitochondrial membrane potential, proliferation, and apoptosis. However, these pathways are incompletely characterized in PAH, especially in endothelial cells, highlighting the urgent need for further research. This review summarizes what is currently known about how mitochondrial metabolism facilitates a metabolic shift in endothelial cells that induces vascular remodeling during PAH.
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Affiliation(s)
- Marissa D Pokharel
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - David P Marciano
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - Panfeng Fu
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA
| | - Maria Clara Franco
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - Hoshang Unwalla
- Department of Immunology and Nano-Medicine, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA
| | - Kim Tieu
- Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA
| | - Jeffrey R Fineman
- Department of Pediatrics, The University of California San Francisco, San Francisco, CA, 94143, USA; Cardiovascular Research Institute, The University of California San Francisco, San Francisco, CA, 94143, USA
| | - Ting Wang
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA
| | - Stephen M Black
- Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL, 34987-2352, USA; Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA; Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, 33199, USA.
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Arp NL, Seim G, Josephson J, Fan J. Reactive nitrogen species inhibit branched chain alpha-ketoacid dehydrogenase complex and impact muscle cell metabolism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.31.551364. [PMID: 37577551 PMCID: PMC10418113 DOI: 10.1101/2023.07.31.551364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Branched chain α-ketoacid dehydrogenase complex (BCKDC) is the rate limiting enzyme in branched chain amino acid (BCAA) catabolism, a metabolic pathway with great importance for human health. BCKDC belongs to the mitochondrial α-ketoacid dehydrogenase complex family, which also includes pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC). Here we revealed that BCKDC can be substantially inhibited by reactive nitrogen species (RNS) via a mechanism similar to what we recently discovered with PDHC and OGDC - modifying the lipoic arm on its E2 subunit. In addition, we showed that such reaction between RNS and the lipoic arm of the E2 subunit can further promote inhibition of the E3 subunits of α-ketoacid dehydrogenase complexes. We examined the impacts of this RNS-mediated BCKDC inhibition in muscle cells, an important site of BCAA metabolism, and demonstrated that the nitric oxide production induced by cytokine stimulation leads to a strong inhibition of BCKDC activity and BCAA oxidation in myotubes and myoblasts. More broadly, nitric oxide production reduced the level of functional lipoic arms across the multiple α-ketoacid dehydrogenases and led to intracellular accumulation of their substrates (α-ketoacids), reduction of their products (acyl-CoAs), and a lower cellular energy charge. This work revealed a new mechanism for BCKDC regulation, demonstrated its biological significance, and elucidated the mechanistic connection between RNS-driven inhibitory modifications on the E2 and E3 subunits of α-ketoacid dehydrogenases. Together with previous work, we revealed a general mechanism for RNS to inhibit all α-ketoacid dehydrogenases, which has numerous physiological implications across multiple cell types.
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Affiliation(s)
- Nicholas L. Arp
- Morgridge Institute for Research, Madison, WI 53715
- Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, 53715
- University of Wisconsin Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792
| | - Gretchen Seim
- Morgridge Institute for Research, Madison, WI 53715
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53715
| | | | - Jing Fan
- Morgridge Institute for Research, Madison, WI 53715
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53715
- Cellular and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, 53715
- University of Wisconsin Medical Scientist Training Program, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792
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Sahin M, Kaya A, Aytekin A, Akay E, Ozcan I. Tetramethylpyrazine Attenuates Radiation-Induced Ototoxicity in a Rat Model. Audiol Neurootol 2023; 28:427-435. [PMID: 37379818 DOI: 10.1159/000530685] [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: 12/26/2021] [Accepted: 04/10/2023] [Indexed: 06/30/2023] Open
Abstract
INTRODUCTION Tetramethylpyrazine (TMP) is a chemical compound, which has been shown to possess numerous biological features such as anticoagulation, inhibition of platelet aggregation, anti-inflammation, capillary dilatation, improvement in microcirculation, and protection against reactive oxygen radicals. The aim of the present study was to investigate the protective effect of TMP against radiation-induced ototoxicity. MATERIALS AND METHODS 40 rats were divided into four groups. The first group was irradiated for 5 days. The second group received a single dose of 140 mg/kg/day intraperitoneal TMP given to the rats 30 min before radiotherapy (RT) for 5 days. The third group received a single dose of 140 mg/kg/day i.p. TMP for 5 days, whereas the fourth group was administered saline. All rats underwent distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements before and after the application. The temporal bulla of animals was removed for immunohistopathological examination. RESULTS Signal-noise ratio values were significantly decreased in the RT group for the frequencies of 2-32 kHz after RT (p < 0.05), whereas the difference was not significant in terms of pre- and posttreatment values for the other groups. Also in the RT group, the ABR thresholds were significantly increased after treatment. In H&E staining, the mean scores for outer hair cells (OHCs), stria vascularis (SV), and spiral ganglion (SG) injuries were significantly higher in RT and RT + TMP groups than in the other groups. The mean OHCs and SV injury scores were also significantly higher in the RT group than in the RT + TMP group (p < 0.05). The number of cochleas that showed cytoplasmic caspase-3 immunoreactivity in the OHC, SV, and SG was significantly higher in RT and RT + TMP groups than in the other groups. CONCLUSION The findings of the present study suggest that TMP may have a therapeutic potential for preventing sensorineural hearing loss (SNHL) related to RT.
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Affiliation(s)
- Mustafa Sahin
- Department of Otorhinolaryngology and Head and Neck Surgery, Kayseri City Training and Research Hospital, Kayseri, Turkey
| | - Altan Kaya
- Department of Otorhinolaryngology and Head and Neck Surgery, Kayseri City Training and Research Hospital, Kayseri, Turkey
| | - Aynur Aytekin
- Department of Radiation Oncology, Kayseri City Training and Research Hospital, Kayseri, Turkey
| | - Ebru Akay
- Department of Pathology, Kayseri City Training and Research Hospital, Kayseri, Turkey
| | - Ibrahim Ozcan
- Department of Otorhinolaryngology and Head and Neck Surgery, Kayseri City Training and Research Hospital, Kayseri, Turkey
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Matsuu-Matsuyama M, Shichijo K, Tsuchiya T, Nakashima M. The effects of cystine and theanine mixture on the chronic survival rate and tumor incidence of rats after total body X-ray irradiation†. JOURNAL OF RADIATION RESEARCH 2023:rrad047. [PMID: 37336495 DOI: 10.1093/jrr/rrad047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/03/2023] [Indexed: 06/21/2023]
Abstract
Cystine and theanine (CT), an amino acid mixture, provides the substrates cysteine and glutamic acid that promote glutathione synthesis. We previously reported that CT pre-treatment significantly improved the acute survival rate and reduced acute radiation injury of the small intestine and bone marrow of rats after 5 Gy of total body X-ray irradiation. To examine the long-term effects of CT administration after irradiation, we investigated the effects of CT pre-treatment and pre- and post-treatment on the chronic survival rate and solid tumor (spleen, skin and subcutis, and thyroid) incidence after irradiation using 7-week-old male Wistar rats. CT pre-treatment of 280 mg/kg was administered orally for 5 days before 5 Gy irradiation, and CT pre- and post-treatment was administered 5 days before and 5 days after irradiation. A 0.5% carboxymethyl cellulose solution was administered as a control. The chronic survival rate of the pre-treated rats was higher than that of the control rats at 441 days after irradiation (40 vs 8.1%, P = 0.011). However, the survival rate did not significantly differ between the pre- and post-treatment and control rats at 467 days after irradiation (33.8 vs 30.2%, P = 0.792). In addition, more solid tumors, especially subcutis sarcomas, were observed in the pre-treatment rats (26.1%, 6/23) than in the control rats (4.5%, 1/22) after irradiation. Therefore, pre-administration of CT improves the chronic survival rate after irradiation; however, the occurrence of solid tumors was not suppressed.
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Affiliation(s)
- Mutsumi Matsuu-Matsuyama
- Division of Strategic Collaborative Research, Center for Promotion of Collaborative Research on Radiation and Environment Health Effects, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Nagasaki 852-8523, Japan
| | - Kazuko Shichijo
- Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Nagasaki 852-8523, Japan
| | - Takashi Tsuchiya
- Department of Surgery, Sendai City Medical Center, 5-22-1 Tsurugaya, Miyagino, Sendai, Miyagi 983-0824, Japan
| | - Masahiro Nakashima
- Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Nagasaki 852-8523, Japan
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Liu X, Wang Y, Li J, Wu B, Wang S, Guo Q, Liu Y. To study the protective effect of Huangqi Baihe Granules on Radiation brain injury based on network pharmacology and experiment. JOURNAL OF ETHNOPHARMACOLOGY 2023:116610. [PMID: 37150423 DOI: 10.1016/j.jep.2023.116610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 05/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Huangqi baihe Granules (HQBHG), which is a key Chinese medical prescription, has a remarkable efficacy in oxidative stress and inflammation. Nevertheless, the therapeutic effect on Radiation brain injury (RBI) has rarely been studied. AIM OF THE STUDY The study aimed to verify the effect of HQBHG against RBI and explore its potential mechanism. METHODS The potential targets and mechanisms of HQBHG against RBI were predicted by network pharmacology and verified by established rat model of RBI Firstly, the therapeutic effect of HQBHG in RBI was confirmed by water maze test, HE staining and Enzyme-linked immunosorbent assay (ELISA). Secondly, the potential critical anti-RBI pathway of HQBHG was further explored by water maze, HE staining, immunofluorescence assays, ELISA and western blot. RESULTS A total of 43 HQBHG anti-RBI targets were obtained. Gene Ontology (Go) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotations showed that the treatment of HQBHG in RBI might be mainly related to oxidative stress, inflammation and PI3K/AKT pathway. Experimental studies have indicated that HQBHG can improve spatial learning and memory ability, alleviate pathological damage of brain tissue in RBI of rats. HQBHG also can down-regulate the levels of IL-1β, TNF-α, ROS and MDA, meanwhile, GSH was significantly up-regulated. In addition, the HQBHG can increase the protein expression phosphorylations PI3K (p-PI3K), phosphorylations AKT(p-AKT) and Nrf2 in the brain tissue of RBI. CONCLUSION HQBHG may alleviated RBI by regulated oxidative stress and inflammatory response through PI3K/AKT/Nrf2 pathway.
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Affiliation(s)
- Xiuzhu Liu
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
| | - Yanru Wang
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
| | - Jiawei Li
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
| | - Bingbing Wu
- 940th Hospital of Chinese People 's Liberation Army Joint Support Force, Lanzhou, 730050, Gansu Province, China.
| | - Siyu Wang
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
| | - Qingyang Guo
- 940th Hospital of Chinese People 's Liberation Army Joint Support Force, Lanzhou, 730050, Gansu Province, China.
| | - Yongqi Liu
- Gansu University Key Laboratory for Molecular Medicine & Chinese Medicine Prevention and Treatment of Major Diseases, Gansu University of Chinese Medicine, Lanzhou, 730000, Gansu Province, China.
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Asgari A, Jurasz P. Role of Nitric Oxide in Megakaryocyte Function. Int J Mol Sci 2023; 24:ijms24098145. [PMID: 37175857 PMCID: PMC10179655 DOI: 10.3390/ijms24098145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/22/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Megakaryocytes are the main members of the hematopoietic system responsible for regulating vascular homeostasis through their progeny platelets, which are generally known for maintaining hemostasis. Megakaryocytes are characterized as large polyploid cells that reside in the bone marrow but may also circulate in the vasculature. They are generated directly or through a multi-lineage commitment step from the most primitive progenitor or Hematopoietic Stem Cells (HSCs) in a process called "megakaryopoiesis". Immature megakaryocytes enter a complicated development process defined as "thrombopoiesis" that ultimately results in the release of extended protrusions called proplatelets into bone marrow sinusoidal or lung microvessels. One of the main mediators that play an important modulatory role in hematopoiesis and hemostasis is nitric oxide (NO), a free radical gas produced by three isoforms of nitric oxide synthase within the mammalian cells. In this review, we summarize the effect of NO and its signaling on megakaryopoiesis and thrombopoiesis under both physiological and pathophysiological conditions.
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Affiliation(s)
- Amir Asgari
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G-2E1, Canada
| | - Paul Jurasz
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G-2E1, Canada
- Department of Pharmacology, University of Alberta, Edmonton, AB T6G-2H7, Canada
- Cardiovascular Research Institute, University of Alberta, Edmonton, AB T6G-2S2, Canada
- Mazankowski Alberta Heart Institute, Edmonton, AB T6G-2R7, Canada
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Ribeiro YM, Moreira DP, Weber AA, Miranda TGR, Bazzoli N, Rizzo E. Chronic estrone exposure affects spermatogenesis and sperm quality in zebrafish (Danio rerio). ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2023; 98:104058. [PMID: 36596390 DOI: 10.1016/j.etap.2022.104058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 12/21/2022] [Accepted: 12/29/2022] [Indexed: 06/17/2023]
Abstract
Estrone (E1) is a common environmental contaminant found in rivers and streams due to the farming of animals, such as swine and cattle. Our study evaluated the effects of chronic E1 exposure at environmentally relevant concentrations on spermatogenesis and the semen quality of zebrafish (Danio rerio). We exposed the fish to E1 at concentrations of 20, 200, and 2000 ng/L diluted in 0.001% ethanol (v/v) for 49 days. There were two control groups: one was exposed to water only and the other to ethanol at the same concentration used in the E1 groups. Following exposure, we analyzed the proportion of testicular cell types and other components (%), rate of cell proliferation and death, and sex steroid concentrations. Furthermore, we analyzed the expression of insulin-like growth factor 1 (IGF1), IGF2, IGF1 receptor (IGF1R), and inducible nitric oxide synthase and assessed the semen quality. E1 exposure increased spermatogonia, spermatids, Sertoli cells, Leydig cells, and the proportion of inflammatory infiltrate but decreased the spermatozoa amount. These changes were reflected by reductions in the gonadosomatic index and levels of 11-ketotestosterone in the testes. On the other hand, E1 exposure increased testicular estradiol, IGF1R expression, and nitric oxide production. After an evaluation using a computer-assisted sperm analysis (CASA) system, we observed reduced progressive motility, curvilinear velocity, and beat cross frequency of 20 and 2000 ng/L E1 groups. Our findings support that E1 causes deleterious effects on the testicular function and semen quality of D. rerio even at environmental concentrations. Thus, E1 concentrations should be monitored in surface waters for the purposes of fish conservation.
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Affiliation(s)
- Yves Moreira Ribeiro
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Davidson Peruci Moreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | | | | | - Nilo Bazzoli
- Programa de Pós-Graduação em Biologia de Vertebrados, Pontifícia Universidade Católica de Minas Gerais, PUC Minas, Belo Horizonte, Minas Gerais, Brazil
| | - Elizete Rizzo
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil.
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24
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Dhawan U, Tseng CL, Wu PH, Liao MY, Wang HY, Wu KCW, Chung RJ. Theranostic doxorubicin encapsulated FeAu alloy@metal-organic framework nanostructures enable magnetic hyperthermia and medical imaging in oral carcinoma. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2023; 48:102652. [PMID: 36623714 DOI: 10.1016/j.nano.2023.102652] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/23/2022] [Accepted: 12/27/2022] [Indexed: 01/08/2023]
Abstract
Metal-organic frameworks (MOFs) have emerged as attractive candidates in cancer theranostics due to their ability to envelop magnetic nanoparticles, resulting in reduced cytotoxicity and high porosity, enabling chemodrug encapsulation. Here, FeAu alloy nanoparticles (FeAu NPs) are synthesized and coated with MIL-100(Fe) MOFs to fabricate FeAu@MOF nanostructures. We encapsulated Doxorubicin within the nanostructures and evaluated the suitability of this platform for medical imaging and cancer theranostics. FeAu@MOF nanostructures (FeAu@MIL-100(Fe)) exhibited superparamagnetism, magnetic hyperthermia behavior and displayed DOX encapsulation and release efficiency of 69.95 % and 97.19 %, respectively, when stimulated with alternating magnetic field (AMF). In-vitro experiments showed that AMF-induced hyperthermia resulted in 90 % HSC-3 oral squamous carcinoma cell death, indicating application in cancer theranostics. Finally, in an in-vivo mouse model, FeAu@MOF nanostructures improved image contrast, reduced tumor volume by 30-fold and tumor weight by 10-fold, which translated to enhancement in cumulative survival, highlighting the prospect of this platform for oral cancer treatment.
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Affiliation(s)
- Udesh Dhawan
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow G12 8LT, UK
| | - Ching-Li Tseng
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City 110, Taiwan; International Ph. D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City 110, Taiwan; Research Center of Biomedical Device, College of Biomedical Engineering, Taipei Medical University, Taipei City 110, Taiwan; International Ph. D. Program in Cell Therapy and Regenerative Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan
| | - Ping-Hsuan Wu
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology (Taipei Tech), Taipei 106344, Taiwan
| | - Mei-Yi Liao
- Department of Applied Chemistry, National Pingtung University, Pingtung 90003, Taiwan
| | - Huey-Yuan Wang
- Department of Stomatology, MacKay Memorial Hospital, Taipei 104217, Taiwan.
| | - Kevin C-W Wu
- Department of Chemical Engineering, National Taiwan University, Taipei 10617, Taiwan; Institute of Biomedical Engineering & Nanomedicine, National Health Research Institute, Keyan Road, Zhunan, Miaoli City 350, Taiwan; Center of Atomic Initiative for New Materials (Al-MAT), National Taiwan University, Taipei 106216, Taiwan.
| | - Ren-Jei Chung
- Department of Chemical Engineering and Biotechnology, National Taipei University of Technology (Taipei Tech), Taipei 106344, Taiwan.
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Mitra S, Dash R, Sohel M, Chowdhury A, Munni YA, Ali C, Hannan MA, Islam T, Moon IS. Targeting Estrogen Signaling in the Radiation-induced Neurodegeneration: A Possible Role of Phytoestrogens. Curr Neuropharmacol 2023; 21:353-379. [PMID: 35272592 PMCID: PMC10190149 DOI: 10.2174/1570159x20666220310115004] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/01/2022] [Accepted: 03/06/2022] [Indexed: 11/22/2022] Open
Abstract
Radiation for medical use is a well-established therapeutic method with an excellent prognosis rate for various cancer treatments. Unfortunately, a high dose of radiation therapy comes with its own share of side effects, causing radiation-induced non-specific cellular toxicity; consequently, a large percentage of treated patients suffer from chronic effects during the treatment and even after the post-treatment. Accumulating data evidenced that radiation exposure to the brain can alter the diverse cognitive-related signaling and cause progressive neurodegeneration in patients because of elevated oxidative stress, neuroinflammation, and loss of neurogenesis. Epidemiological studies suggested the beneficial effect of hormonal therapy using estrogen in slowing down the progression of various neuropathologies. Despite its primary function as a sex hormone, estrogen is also renowned for its neuroprotective activity and could manage radiation-induced side effects as it regulates many hallmarks of neurodegenerations. Thus, treatment with estrogen and estrogen-like molecules or modulators, including phytoestrogens, might be a potential approach capable of neuroprotection in radiation-induced brain degeneration. This review summarized the molecular mechanisms of radiation effects and estrogen signaling in the manifestation of neurodegeneration and highlighted the current evidence on the phytoestrogen mediated protective effect against radiationinduced brain injury. This existing knowledge points towards a new area to expand to identify the possible alternative therapy that can be taken with radiation therapy as adjuvants to improve patients' quality of life with compromised cognitive function.
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Affiliation(s)
- Sarmistha Mitra
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju38066, Republic of Korea
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju38066, Republic of Korea
| | - Md. Sohel
- Department of Biochemistry and Molecular Biology, Mawlana Bhashani Science and Technology University, Santosh, Tangail-1902, Bangladesh
| | - Apusi Chowdhury
- Department of Pharmaceutical Science, North-South University, Dhaka-12 29, Bangladesh
| | - Yeasmin Akter Munni
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju38066, Republic of Korea
| | - Chayan Ali
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala SE-751 08, Sweden
| | - Md. Abdul Hannan
- Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh
| | - Tofazzal Islam
- Institute of Biotechnology and Genetic Engineering (IBGE), Bangabandhu Sheikh Mujibur Rahman Agricultural University (BSMRAU), Gazipur, Bangladesh
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju38066, Republic of Korea
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Ralston NVC. Concomitant selenoenzyme inhibitor exposures as etiologic contributors to disease: Implications for preventative medicine. Arch Biochem Biophys 2023; 733:109469. [PMID: 36423662 DOI: 10.1016/j.abb.2022.109469] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/16/2022] [Accepted: 11/16/2022] [Indexed: 11/23/2022]
Abstract
The physiological activities of selenium (Se) occur through enzymes that incorporate selenocysteine (Sec), a rare but important amino acid. The human genome includes 25 genes coding for Sec that employ it to catalyze challenging reactions. Selenoenzymes control thyroid hormones, calcium activities, immune responses, and perform other vital roles, but most are devoted to preventing and reversing oxidative damage. As the most potent intracellular nucleophile (pKa 5.2), Sec is vulnerable to binding by metallic and organic soft electrophiles (E*). These electron poor reactants initially form covalent bonds with nucleophiles such as cysteine (Cys) whose thiol (pKa 8.3) forms adducts which function as suicide substrates for selenoenzymes. These adducts orient E* to interact with Sec and since Se has a higher affinity for E* than sulfur, the E* transfers to Sec and irreversibly inhibits the enzyme's activity. Organic electrophiles have lower Se-binding affinities than metallic E*, but exposure sources are more abundant. Individuals with poor Se status are more vulnerable to the toxic effects of high E* exposures. The relative E*:Se stoichiometries remain undefined, but the aggregate effects of multiple E* exposures are predicted to be additive and possibly synergistic under certain conditions. The potential for the combined Se-binding effects of common pharmaceutical, dietary, or environmental E* require study, but even temporary loss of selenoenzyme activities would accentuate oxidative damage to tissues. As various degenerative diseases are associated with accumulating DNA damage, defining the effects of complementary E* exposures on selenoenzyme activities may enhance the ability of preventative medicine to support healthy aging.
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Affiliation(s)
- Nicholas V C Ralston
- Earth System Science and Policy, University of North Dakota, Grand Forks, ND, USA.
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Zhu L, Luo M, Zhang Y, Fang F, Li M, An F, Zhao D, Zhang J. Free radical as a double-edged sword in disease: Deriving strategic opportunities for nanotherapeutics. Coord Chem Rev 2023. [DOI: 10.1016/j.ccr.2022.214875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Qian X, Wang Y, Xie H, Wang C, Li J, Lei Y, Liu H, Wu Y, Li Y, Zhang Z. Bioinspired nanovehicle of furoxans-oxaliplatin improves tumoral distribution for chemo-radiotherapy. J Control Release 2023; 353:447-461. [PMID: 36470332 DOI: 10.1016/j.jconrel.2022.11.044] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/13/2022] [Accepted: 11/26/2022] [Indexed: 12/12/2022]
Abstract
The spatiotemporal distribution of therapeutic agents in tumors remains an essential challenge of radiation-mediated therapy. Herein, we rationally designed a macrophage microvesicle-inspired nanovehicle of nitric oxide donor-oxaliplatin (FO) conjugate (M-PFO), aiming to promote intratumor permeation and distribution profiles for chemo-radiotherapy. FO was responsively released from M-PFO in intracellular acidic environments, and then be activated by glutathione (GSH) into active oxaliplatin and NO molecules in a programmed manner. M-PFO exhibited notable accumulation, permeation and cancer cell accessibility in tumor tissues. Upon radiation, the reactive peroxynitrite species (ONOO-) were largely produced, which could diffuse into regions over 400 μm away from the tumor vessels and be detectable after 24 h of radiation, thereby exhibiting superior efficacy in improving the spatiotemporal distribution in tumors versus common reactive oxygen species (ROS). Moreover, M-PFO mediated chemo-radiotherapy caused notable inhibition of tumor growth, with an 89.45% inhibition in HT-29 tumor models and a 92.69% suppression in CT-26 tumor models. Therefore, this bioinspired design provides an encouraging platform to improve intratumor spatiotemporal distribution to synergize chemo-radiotherapy.
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Affiliation(s)
- Xindi Qian
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuqi Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Honglei Xie
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China
| | - Chen Wang
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China
| | - Jie Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Ying Lei
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai 201203, China
| | - Huanzhen Liu
- Shanghai Institute for Advanced Immunochemical Studies (SIAIS), ShanghaiTech University, Shanghai 201203, China
| | - Yao Wu
- School of Pharmacy& Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai 201203, China
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
| | - Zhiwen Zhang
- School of Pharmacy& Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai 201203, China; Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China.
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The Normal, the Radiosensitive, and the Ataxic in the Era of Precision Radiotherapy: A Narrative Review. Cancers (Basel) 2022; 14:cancers14246252. [PMID: 36551737 PMCID: PMC9776433 DOI: 10.3390/cancers14246252] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/06/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
(1) Background: radiotherapy is a cornerstone of cancer treatment. When delivering a tumoricidal dose, the risk of severe late toxicities is usually kept below 5% using dose-volume constraints. However, individual radiation sensitivity (iRS) is responsible (with other technical factors) for unexpected toxicities after exposure to a dose that induces no toxicity in the general population. Diagnosing iRS before radiotherapy could avoid unnecessary toxicities in patients with a grossly normal phenotype. Thus, we reviewed iRS diagnostic data and their impact on decision-making processes and the RT workflow; (2) Methods: following a description of radiation toxicities, we conducted a critical review of the current state of the knowledge on individual determinants of cellular/tissue radiation; (3) Results: tremendous advances in technology now allow minimally-invasive genomic, epigenetic and functional testing and a better understanding of iRS. Ongoing large translational studies implement various tests and enriched NTCP models designed to improve the prediction of toxicities. iRS testing could better support informed radiotherapy decisions for individuals with a normal phenotype who experience unusual toxicities. Ethics of medical decisions with an accurate prediction of personalized radiotherapy's risk/benefits and its health economics impact are at stake; (4) Conclusions: iRS testing represents a critical unmet need to design personalized radiotherapy protocols relying on extended NTCP models integrating iRS.
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Youden B, Jiang R, Carrier AJ, Servos MR, Zhang X. A Nanomedicine Structure-Activity Framework for Research, Development, and Regulation of Future Cancer Therapies. ACS NANO 2022; 16:17497-17551. [PMID: 36322785 DOI: 10.1021/acsnano.2c06337] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Despite their clinical success in drug delivery applications, the potential of theranostic nanomedicines is hampered by mechanistic uncertainty and a lack of science-informed regulatory guidance. Both the therapeutic efficacy and the toxicity of nanoformulations are tightly controlled by the complex interplay of the nanoparticle's physicochemical properties and the individual patient/tumor biology; however, it can be difficult to correlate such information with observed outcomes. Additionally, as nanomedicine research attempts to gradually move away from large-scale animal testing, the need for computer-assisted solutions for evaluation will increase. Such models will depend on a clear understanding of structure-activity relationships. This review provides a comprehensive overview of the field of cancer nanomedicine and provides a knowledge framework and foundational interaction maps that can facilitate future research, assessments, and regulation. By forming three complementary maps profiling nanobio interactions and pathways at different levels of biological complexity, a clear picture of a nanoparticle's journey through the body and the therapeutic and adverse consequences of each potential interaction are presented.
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Affiliation(s)
- Brian Youden
- Department of Biology, University of Waterloo, 200 University Ave. W, Waterloo, Ontario N2L 3G1, Canada
| | - Runqing Jiang
- Department of Biology, University of Waterloo, 200 University Ave. W, Waterloo, Ontario N2L 3G1, Canada
- Department of Medical Physics, Grand River Regional Cancer Centre, Kitchener, Ontario N2G 1G3, Canada
| | - Andrew J Carrier
- Department of Chemistry, Cape Breton University, 1250 Grand Lake Road, Sydney, Nova Scotia B1P 6L2, Canada
| | - Mark R Servos
- Department of Biology, University of Waterloo, 200 University Ave. W, Waterloo, Ontario N2L 3G1, Canada
| | - Xu Zhang
- Department of Biology, University of Waterloo, 200 University Ave. W, Waterloo, Ontario N2L 3G1, Canada
- Department of Chemistry, Cape Breton University, 1250 Grand Lake Road, Sydney, Nova Scotia B1P 6L2, Canada
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Paradoxical Radiosensitizing Effect of Carnosic Acid on B16F10 Metastatic Melanoma Cells: A New Treatment Strategy. Antioxidants (Basel) 2022; 11:antiox11112166. [PMID: 36358539 PMCID: PMC9686564 DOI: 10.3390/antiox11112166] [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: 09/23/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Carnosic acid (CA) is a phenolic diterpene characterized by its high antioxidant activity; it is used in industrial, cosmetic, and nutritional applications. We evaluated the radioprotective capacity of CA on cells directly exposed to X-rays and non-irradiated cells that received signals from X-ray treated cells (radiation induced bystander effect, RIBE). The genoprotective capacity was studied by in vivo and in vitro micronucleus assays. Radioprotective capacity was evaluated by clonogenic cell survival, MTT, apoptosis and intracellular glutathione assays comparing radiosensitive cells (human prostate epithelium, PNT2) with radioresistant cells (murine metastatic melanoma, B16F10). CA was found to exhibit a genoprotective capacity in cells exposed to radiation (p < 0.001) and in RIBE (p < 0.01). In PNT2 cells, considered as normal cells in our study, CA achieved 97% cell survival after exposure to 20 Gy of X-rays, eliminating 67% of radiation-induced cell death (p < 0.001), decreasing apoptosis (p < 0.001), and increasing the GSH/GSSH ratio (p < 0.01). However, the administration of CA to B16F10 cells decreased cell survival by 32%, increased cell death by 200% (p < 0.001) compared to irradiated cells, and increased cell death by 100% (p < 0.001) in RIBE bystander cells (p < 0.01). Furthermore, it increased apoptosis (p < 0.001) and decreased the GSH/GSSG ratio (p < 0.01), expressing a paradoxical radiosensitizing effect in these cells. Knowing the potential mechanisms of action of substances such as CA could help to create new applications that would protect healthy cells and exclusively damage neoplastic cells, thus presenting a new desirable strategy for cancer patients in need of radiotherapy.
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Rajh T, Koritarov T, Blaiszik B, Rizvi SFZ, Konda V, Bissonnette M. Triggering cell death in cancers using self-illuminating nanocomposites. Front Chem 2022; 10:962161. [PMID: 36186597 PMCID: PMC9521829 DOI: 10.3389/fchem.2022.962161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 08/22/2022] [Indexed: 11/21/2022] Open
Abstract
Bioinspired photocatalysis has resulted in efficient solutions for many areas of science and technology spanning from solar cells to medicine. Here we show a new bioinspired semiconductor nanocomposite (nanoTiO2-DOPA-luciferase, TiDoL) capable of converting light energy within cancerous tissues into chemical species that are highly disruptive to cell metabolism and lead to cell death. This localized activity of semiconductor nanocomposites is triggered by cancer-generated activators. Adenosine triphosphate (ATP) is produced in excess in cancer tissues only and activates nearby immobilized TiDoL composites, thereby eliminating its off-target toxicity. The interaction of TiDoL with cancerous cells was probed in situ and in real-time to establish a detailed mechanism of nanoparticle activation, triggering of the apoptotic signaling cascade, and finally, cancer cell death. Activation of TiDoL with non-cancerous cells did not result in cell toxicity. Exploring the activation of antibody-targeted semiconductor conjugates using ATP is a step toward a universal approach to single-cell-targeted medical therapies with more precision, efficacy, and potentially fewer side effects.
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Affiliation(s)
- Tijana Rajh
- Center for Nanoscale Materials, Argonne National Laboratory, Argonne, IL, United States
- School of Molecular Sciences, Arizona State University, Tempe, AZ, United States
- *Correspondence: Tijana Rajh,
| | - Tamara Koritarov
- Center for Nanoscale Materials, Argonne National Laboratory, Argonne, IL, United States
| | - Ben Blaiszik
- Center for Nanoscale Materials, Argonne National Laboratory, Argonne, IL, United States
| | - Syeda Fatima Z. Rizvi
- Center for Nanoscale Materials, Argonne National Laboratory, Argonne, IL, United States
| | - Vani Konda
- Department of Medicine, The University of Chicago Medicine, Chicago, IL, United States
| | - Marc Bissonnette
- Department of Medicine, The University of Chicago Medicine, Chicago, IL, United States
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Randolph JT, Pak ES, McMains JC, Koontz BF, Hannan JL. Cocultured Schwann Cells Rescue Irradiated Pelvic Neuron Outgrowth and Increase Survival. J Sex Med 2022; 19:1333-1342. [DOI: 10.1016/j.jsxm.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/13/2022] [Accepted: 06/11/2022] [Indexed: 10/17/2022]
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Phytochemical Screening, Antioxidant and Antibacterial Properties of Extracts of Viscum continuum E. Mey. Ex Sprague, a South African Mistletoe. PLANTS 2022; 11:plants11162094. [PMID: 36015398 PMCID: PMC9412615 DOI: 10.3390/plants11162094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 11/24/2022]
Abstract
Viscum continuum E. Mey. Ex Sprague is a woody evergreen semi-parasitic shrub that grows on the branches of other trees. It is used by African traditional healers for post-stroke management. This study reports on the qualitative phytochemical screening and the antioxidant and antimicrobial activities of Viscum continuum’s acetone, methanol, hexane and dichloromethane extracts. Standard protocols for the phytochemical screening of extracts were employed. TLC bio-autography was used for qualitative antioxidants analysis. Assays: 2,2-diphenyl-1-picrylhydrazyl, H2O2 free-radical scavenging and ferric chloride reducing power were carried out for quantitative antioxidant analysis. The antimicrobial potential of extracts was screened using disc diffusion, bio-autography and broth micro-dilution. The results indicate the presence of alkaloids, phenolics and tannins in all extracts. Acetone and methanol revealed significant amount of saponins, phenolics, tannins and terpenoids. The extracts exhibited significant antioxidant potential on TLC with positive compound bands at an Rf range of 0.05–0.89. DPPH, H2O2 and the reduction of Fe3+ to Fe2+ assays indicated that methanol extract has a strong antioxidant potential, followed by acetone, DCM and lastly hexane. The extracts of Viscum continuum show the potential to be antibacterial agents. It can be concluded that Viscum continuum extracts contain phytochemicals which are capable of mitigating against chronic health conditions such as cancer, stroke and stress-related and infectious diseases.
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35
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Mukherjee S, Dutta A, Chakraborty A. The interaction of oxidative stress with MAPK, PI3/AKT, NF-κB, and DNA damage kinases influences the fate of γ-radiation-induced bystander cells. Arch Biochem Biophys 2022; 725:109302. [DOI: 10.1016/j.abb.2022.109302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/27/2022] [Accepted: 05/22/2022] [Indexed: 11/02/2022]
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36
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Uppalapati SR, Vazquez-Torres A. Manganese Utilization in Salmonella Pathogenesis: Beyond the Canonical Antioxidant Response. Front Cell Dev Biol 2022; 10:924925. [PMID: 35903545 PMCID: PMC9315381 DOI: 10.3389/fcell.2022.924925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/22/2022] [Indexed: 11/16/2022] Open
Abstract
The metal ion manganese (Mn2+) is equally coveted by hosts and bacterial pathogens. The host restricts Mn2+ in the gastrointestinal tract and Salmonella-containing vacuoles, as part of a process generally known as nutritional immunity. Salmonella enterica serovar Typhimurium counteract Mn2+ limitation using a plethora of metal importers, whose expression is under elaborate transcriptional and posttranscriptional control. Mn2+ serves as cofactor for a variety of enzymes involved in antioxidant defense or central metabolism. Because of its thermodynamic stability and low reactivity, bacterial pathogens may favor Mn2+-cofactored metalloenzymes during periods of oxidative stress. This divalent metal catalyzes metabolic flow through lower glycolysis, reductive tricarboxylic acid and the pentose phosphate pathway, thereby providing energetic, redox and biosynthetic outputs associated with the resistance of Salmonella to reactive oxygen species generated in the respiratory burst of professional phagocytic cells. Combined, the oxyradical-detoxifying properties of Mn2+ together with the ability of this divalent metal cation to support central metabolism help Salmonella colonize the mammalian gut and establish systemic infections.
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Affiliation(s)
- Siva R. Uppalapati
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO, United States,*Correspondence: Siva R. Uppalapati, ; Andres Vazquez-Torres,
| | - Andres Vazquez-Torres
- Department of Immunology & Microbiology, University of Colorado School of Medicine, Aurora, CO, United States,Veterans Affairs Eastern Colorado Health Care System, Denver, CO, United States,*Correspondence: Siva R. Uppalapati, ; Andres Vazquez-Torres,
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37
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Kundu S. TemporalGSSA: a numerically robust R-wrapper to facilitate computation of a metabolite-specific and simulation time-dependent trajectory from stochastic simulation algorithm (SSA)-generated datasets. J Bioinform Comput Biol 2022; 20:2250018. [DOI: 10.1142/s0219720022500184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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38
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Obrador E, Salvador-Palmer R, Villaescusa JI, Gallego E, Pellicer B, Estrela JM, Montoro A. Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry. Antioxidants (Basel) 2022; 11:1098. [PMID: 35739995 PMCID: PMC9219873 DOI: 10.3390/antiox11061098] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 11/17/2022] Open
Abstract
Atomic and radiological crises can be caused by accidents, military activities, terrorist assaults involving atomic installations, the explosion of nuclear devices, or the utilization of concealed radiation exposure devices. Direct damage is caused when radiation interacts directly with cellular components. Indirect effects are mainly caused by the generation of reactive oxygen species due to radiolysis of water molecules. Acute and persistent oxidative stress associates to radiation-induced biological damages. Biological impacts of atomic radiation exposure can be deterministic (in a period range a posteriori of the event and because of destructive tissue/organ harm) or stochastic (irregular, for example cell mutation related pathologies and heritable infections). Potential countermeasures according to a specific scenario require considering basic issues, e.g., the type of radiation, people directly affected and first responders, range of doses received and whether the exposure or contamination has affected the total body or is partial. This review focuses on available medical countermeasures (radioprotectors, radiomitigators, radionuclide scavengers), biodosimetry (biological and biophysical techniques that can be quantitatively correlated with the magnitude of the radiation dose received), and strategies to implement the response to an accidental radiation exposure. In the case of large-scale atomic or radiological events, the most ideal choice for triage, dose assessment and victim classification, is the utilization of global biodosimetry networks, in combination with the automation of strategies based on modular platforms.
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Affiliation(s)
- Elena Obrador
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (R.S.-P.); (B.P.); (J.M.E.)
| | - Rosario Salvador-Palmer
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (R.S.-P.); (B.P.); (J.M.E.)
| | - Juan I. Villaescusa
- Service of Radiological Protection, Clinical Area of Medical Image, La Fe University Hospital, 46026 Valencia, Spain; (J.I.V.); (A.M.)
- Biomedical Imaging Research Group GIBI230, Health Research Institute (IISLaFe), La Fe University Hospital, 46026 Valencia, Spain
| | - Eduardo Gallego
- Energy Engineering Department, School of Industrial Engineering, Polytechnic University of Madrid, 28040 Madrid, Spain;
| | - Blanca Pellicer
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (R.S.-P.); (B.P.); (J.M.E.)
| | - José M. Estrela
- Department of Physiology, Faculty of Medicine and Odontology, University of Valencia, 46010 Valencia, Spain; (R.S.-P.); (B.P.); (J.M.E.)
| | - Alegría Montoro
- Service of Radiological Protection, Clinical Area of Medical Image, La Fe University Hospital, 46026 Valencia, Spain; (J.I.V.); (A.M.)
- Biomedical Imaging Research Group GIBI230, Health Research Institute (IISLaFe), La Fe University Hospital, 46026 Valencia, Spain
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Peter MCS, Gayathry R, Peter VS. Inducible Nitric Oxide Synthase/Nitric Oxide System as a Biomarker for Stress and Ease Response in Fish: Implication on Na+ Homeostasis During Hypoxia. Front Physiol 2022; 13:821300. [PMID: 35655956 PMCID: PMC9152262 DOI: 10.3389/fphys.2022.821300] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 04/06/2022] [Indexed: 11/22/2022] Open
Abstract
The cellular and organismal response to stressor-driven stimuli evokes stress response in vertebrates including fishes. Fishes have evolved varied patterns of stress response, including ionosmotic stress response, due to their sensitivity to both intrinsic and extrinsic stimuli. Fishes that experience hypoxia, a detrimental stressor that imposes systemic and cellular stress response, can evoke disturbed ion homeostasis. In addition, like other vertebrates, fishes have also developed mechanisms to recover from the impact of stress by way of shifting stress response into ease response that could reduce the magnitude of stress response with the aid of certain neuroendocrine signals. Nitric oxide (NO) has been identified as a potent molecule that attenuates the impact of ionosmotic stress response in fish, particularly during hypoxia stress. Limited information is, however, available on this important aspect of ion transport physiology that contributes to the mechanistic understanding of survival during environmental challenges. The present review, thus, discusses the role of NO in Na+ homeostasis in fish particularly in stressed conditions. Isoforms of nitric oxide synthase (NOS) are essential for the synthesis and availability of NO at the cellular level. The NOS/NO system, thus, appears as a unique molecular drive that performs both regulatory and integrative mechanisms of control within and across varied fish ionocytes. The activation of the inducible NOS (iNOS)/NO system during hypoxia stress and its action on the dynamics of Na+/K+-ATPase, an active Na+ transporter in fish ionocytes, reveal that the iNOS/NO system controls cellular and systemic Na+ transport in stressed fish. In addition, the higher sensitivity of iNOS to varied physical stressors in fishes and the ability of NO to lower the magnitude of ionosmotic stress in hypoxemic fish clearly put forth NO as an ease-promoting signal molecule in fishes. This further points to the signature role of the iNOS/NO system as a biomarker for stress and ease response in the cycle of adaptive response in fish.
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Affiliation(s)
- M. C. Subhash Peter
- Inter-University Centre for Evolutionary and Integrative Biology iCEIB, School of Life Science, University of Kerala, Kariavattom, Thiruvananthapuram, India
- Department of Zoology, University of Kerala, Kariavattom, Thiruvananthapuram, India
- *Correspondence: M. C. Subhash Peter,
| | - R. Gayathry
- Inter-University Centre for Evolutionary and Integrative Biology iCEIB, School of Life Science, University of Kerala, Kariavattom, Thiruvananthapuram, India
| | - Valsa S. Peter
- Inter-University Centre for Evolutionary and Integrative Biology iCEIB, School of Life Science, University of Kerala, Kariavattom, Thiruvananthapuram, India
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40
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Chugh RM, Bhanja P, Olea XD, Tao F, Schroeder K, Zitter R, Arora T, Pathak H, Kimler BF, Godwin AK, Perry JM, Saha S. Human Peripheral Blood Mononucleocyte Derived Myeloid Committed Progenitor Cells Mitigate H-ARS by Exosomal Paracrine Signal. Int J Mol Sci 2022; 23:5498. [PMID: 35628308 PMCID: PMC9142131 DOI: 10.3390/ijms23105498] [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: 04/01/2022] [Revised: 04/28/2022] [Accepted: 05/11/2022] [Indexed: 01/27/2023] Open
Abstract
Radiation-induced loss of the hematopoietic stem cell progenitor population compromises bone marrow regeneration and development of mature blood cells. Failure to rescue bone marrow functions results in fatal consequences from hematopoietic injury, systemic infections, and sepsis. So far, bone marrow transplant is the only effective option, which partially minimizes radiation-induced hematopoietic toxicities. However, a bone marrow transplant will require HLA matching, which will not be feasible in large casualty settings such as a nuclear accident or an act of terrorism. In this study we demonstrated that human peripheral blood mononuclear cell-derived myeloid committed progenitor cells can mitigate radiation-induced bone marrow toxicity and improve survival in mice. These cells can rescue the recipient's hematopoietic stem cells from radiation toxicity even when administered up to 24 h after radiation exposure and can be subjected to allogenic transplant without GVHD development. Transplanted cells deliver sEVs enriched with regenerative and immune-modulatory paracrine signals to mitigate radiation-induced hematopoietic toxicity. This provides a natural polypharmacy solution against a complex injury process. In summary, myeloid committed progenitor cells can be prepared from blood cells as an off-the-shelf alternative to invasive bone marrow harvesting and can be administered in an allogenic setting to mitigate hematopoietic acute radiation syndrome.
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Affiliation(s)
- Rishi Man Chugh
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Payel Bhanja
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Ximena Diaz Olea
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Fang Tao
- Departments of Pediatrics, Children’s Mercy Kansas City, Kansas City, MO 64108, USA; (F.T.); (K.S.); (J.M.P.)
| | - Kealan Schroeder
- Departments of Pediatrics, Children’s Mercy Kansas City, Kansas City, MO 64108, USA; (F.T.); (K.S.); (J.M.P.)
| | - Ryan Zitter
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Tanu Arora
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Harsh Pathak
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (H.P.); (A.K.G.)
| | - Bruce F. Kimler
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
| | - Andrew K. Godwin
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (H.P.); (A.K.G.)
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, MO 66160, USA
| | - John M. Perry
- Departments of Pediatrics, Children’s Mercy Kansas City, Kansas City, MO 64108, USA; (F.T.); (K.S.); (J.M.P.)
- Department of Pediatrics, University of Kansas Medical Center, Kansas City, MO 66160, USA
- Departments of Pediatrics, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Subhrajit Saha
- Departments of Radiation Oncology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (R.M.C.); (P.B.); (X.D.O.); (R.Z.); (T.A.); (B.F.K.)
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, MO 66160, USA; (H.P.); (A.K.G.)
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Hudkova O, Krysiuk I, Drobot L, Latyshko N. Rhabdomyolysis attenuates activity of semicarbazide sensitive amine oxidase as the marker of nephropathy in diabetic rats. UKRAINIAN BIOCHEMICAL JOURNAL 2022. [DOI: 10.15407/ubj94.01.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
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Tandl D, Sponagel T, Alansary D, Fuck S, Smit T, Hehlgans S, Jakob B, Fournier C, Niemeyer BA, Rödel F, Roth B, Moroni A, Thiel G. X-ray irradiation triggers immune response in human T-lymphocytes via store-operated Ca2+ entry and NFAT activation. J Gen Physiol 2022; 154:213138. [PMID: 35416945 PMCID: PMC9011325 DOI: 10.1085/jgp.202112865] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 09/25/2021] [Accepted: 02/11/2022] [Indexed: 12/30/2022] Open
Abstract
Radiation therapy efficiently eliminates cancer cells and reduces tumor growth. To understand collateral agonistic and antagonistic effects of this treatment on the immune system, we examined the impact of x-ray irradiation on human T cells. We find that, in a major population of leukemic Jurkat T cells and peripheral blood mononuclear cells, clinically relevant radiation doses trigger delayed oscillations of the cytosolic Ca2+ concentration. They are generated by store-operated Ca2+ entry (SOCE) following x-ray–induced clustering of Orai1 and STIM1 and formation of a Ca2+ release–activated Ca2+ (CRAC) channel. A consequence of the x-ray–triggered Ca2+ signaling cascade is translocation of the transcription factor nuclear factor of activated T cells (NFAT) from the cytosol into the nucleus, where it elicits the expression of genes required for immune activation. The data imply activation of blood immune cells by ionizing irradiation, with consequences for toxicity and therapeutic effects of radiation therapy.
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Affiliation(s)
- Dominique Tandl
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
| | - Tim Sponagel
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
| | - Dalia Alansary
- Molecular Biophysics, University of Saarland, Center for Integrative Physiology and Molecular Medicine, Homburg/Saar, Germany
| | - Sebastian Fuck
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
| | - Timo Smit
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
| | - Stephanie Hehlgans
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany
| | - Burkhard Jakob
- Department of Biophysics, GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany
| | - Claudia Fournier
- Department of Biophysics, GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany
| | - Barbara A Niemeyer
- Molecular Biophysics, University of Saarland, Center for Integrative Physiology and Molecular Medicine, Homburg/Saar, Germany
| | - Franz Rödel
- Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany
| | - Bastian Roth
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
| | - Anna Moroni
- Department of Biosciences and CNR IBF-Mi, Università degli Studi di Milano, Milano, Italy
| | - Gerhard Thiel
- Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany
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Halilagić A, Selimović E, Stanković JSK, Srećković N, Virijević K, Živanović MN, Šmit B, Soldatović TV. Novel heterometallic Zn(II)-L-Cu(II) complexes: studies of the nucleophilic substitution reactions, antimicrobial, redox and cytotoxic activity. J COORD CHEM 2022. [DOI: 10.1080/00958972.2022.2048376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Asija Halilagić
- Department of Natural-Mathematical Sciences, State University of Novi Pazar, Novi Pazar, Serbia
- Faculty of Science, Department of Chemistry, University of Kragujevac, Kragujevac, Serbia
| | - Enisa Selimović
- Department of Natural-Mathematical Sciences, State University of Novi Pazar, Novi Pazar, Serbia
| | - Jelena S. Katanić Stanković
- Institute for Information Technologies Kragujevac, Department of Science, University of Kragujevac, Kragujevac, Serbia
| | - Nikola Srećković
- Faculty of Science, Department of Chemistry, University of Kragujevac, Kragujevac, Serbia
| | - Katarina Virijević
- Institute for Information Technologies Kragujevac, Department of Science, University of Kragujevac, Kragujevac, Serbia
| | - Marko N. Živanović
- Institute for Information Technologies Kragujevac, Department of Science, University of Kragujevac, Kragujevac, Serbia
| | - Biljana Šmit
- Institute for Information Technologies Kragujevac, Department of Science, University of Kragujevac, Kragujevac, Serbia
| | - Tanja V. Soldatović
- Department of Natural-Mathematical Sciences, State University of Novi Pazar, Novi Pazar, Serbia
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Ouellette MM, Zhou S, Yan Y. Cell Signaling Pathways That Promote Radioresistance of Cancer Cells. Diagnostics (Basel) 2022; 12:diagnostics12030656. [PMID: 35328212 PMCID: PMC8947583 DOI: 10.3390/diagnostics12030656] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/26/2022] [Accepted: 03/02/2022] [Indexed: 12/20/2022] Open
Abstract
Radiation therapy (RT) is a standard treatment for solid tumors and about 50% of patients with cancer, including pediatric cancer, receive RT. While RT has significantly improved the overall survival and quality of life of cancer patients, its efficacy has still been markedly limited by radioresistance in a significant number of cancer patients (intrinsic or acquired), resulting in failure of the RT control of the disease. Radiation eradicates cancer cells mainly by causing DNA damage. However, radiation also concomitantly activates multiple prosurvival signaling pathways, which include those mediated by ATM, ATR, AKT, ERK, and NF-κB that promote DNA damage checkpoint activation/DNA repair, autophagy induction, and/or inhibition of apoptosis. Furthermore, emerging data support the role of YAP signaling in promoting the intrinsic radioresistance of cancer cells, which occurs through its activation of the transcription of many essential genes that support cell survival, DNA repair, proliferation, and the stemness of cancer stem cells. Together, these signaling pathways protect cancer cells by reducing the magnitude of radiation-induced cytotoxicity and promoting radioresistance. Thus, targeting these prosurvival signaling pathways could potentially improve the radiosensitivity of cancer cells. In this review, we summarize the contribution of these pathways to the radioresistance of cancer cells.
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Affiliation(s)
- Michel M. Ouellette
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Sumin Zhou
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Ying Yan
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA;
- Correspondence:
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Bannow LI, Bonaterra GA, Bertoune M, Maus S, Schulz R, Weissmann N, Kraut S, Kinscherf R, Hildebrandt W. Effect of chronic intermittent hypoxia (CIH) on neuromuscular junctions and mitochondria in slow- and fast-twitch skeletal muscles of mice—the role of iNOS. Skelet Muscle 2022; 12:6. [PMID: 35151349 PMCID: PMC8841105 DOI: 10.1186/s13395-022-00288-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/10/2022] [Indexed: 01/17/2023] Open
Abstract
Background Obstructive sleep apnea (OSA) imposes vascular and metabolic risks through chronic intermittent hypoxia (CIH) and impairs skeletal muscle performance. As studies addressing limb muscles are rare, the reasons for the lower exercise capacity are unknown. We hypothesize that CIH-related morphological alterations in neuromuscular junctions (NMJ) and mitochondrial integrity might be the cause of functional disorders in skeletal muscles. Methods Mice were kept under 6 weeks of CIH (alternating 7% and 21% O2 fractions every 30 s, 8 h/day, 5 days/week) compared to normoxia (NOX). Analyses included neuromuscular junctions (NMJ) postsynaptic morphology and integrity, fiber cross-sectional area (CSA) and composition (ATPase), mitochondrial ultrastructure (transmission-electron-microscopy), and relevant transcripts (RT-qPCR). Besides wildtype (WT), we included inducible nitric oxide synthase knockout mice (iNOS−/−) to evaluate whether iNOS is protective or risk-mediating. Results In WT soleus muscle, CIH vs. NOX reduced NMJ size (− 37.0%, p < 0.001) and length (− 25.0%, p < 0.05) together with fiber CSA of type IIa fibers (− 14%, p < 0.05) and increased centronucleated fiber fraction (p < 0.001). Moreover, CIH vs. NOX increased the fraction of damaged mitochondria (1.8-fold, p < 0.001). Compared to WT, iNOS−/− similarly decreased NMJ area and length with NOX (− 55%, p < 0.001 and − 33%, p < 0.05, respectively) or with CIH (− 37%, p < 0.05 and − 29%, p < 0.05), however, prompted no fiber atrophy. Moreover, increased fractions of damaged (2.1-fold, p < 0.001) or swollen (> 6-fold, p < 0.001) mitochondria were observed with iNOS−/− vs. WT under NOX and similarly under CIH. Both, CIH- and iNOS−/− massively upregulated suppressor-of-cytokine-signaling-3 (SOCS3) > 10-fold without changes in IL6 mRNA expression. Furthermore, inflammatory markers like CD68 (macrophages) and IL1β were significantly lower in CIH vs. NOX. None of these morphological alterations with CIH- or iNOS−/− were detected in the gastrocnemius muscle. Notably, iNOS expression was undetectable in WT muscle, unlike the liver, where it was massively decreased with CIH. Conclusion CIH leads to NMJ and mitochondrial damage associated with fiber atrophy/centronucleation selectively in slow-twitch muscle of WT. This effect is largely mimicked by iNOS−/− at NOX (except for atrophy). Both conditions involve massive SOCS3 upregulation likely through denervation without Il6 upregulation but accompanied by a decrease of macrophage density especially next to denervated endplates. In the absence of muscular iNOS expression in WT, this damage may arise from extramuscular, e.g., motoneuronal iNOS deficiency (through CIH or knockout) awaiting functional evaluation. Supplementary Information The online version contains supplementary material available at 10.1186/s13395-022-00288-7.
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Wardman P. Approaches to modeling chemical reaction pathways in radiobiology. Int J Radiat Biol 2022; 98:1399-1413. [DOI: 10.1080/09553002.2022.2033342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Peter Wardman
- 20 Highover Park, Amersham, Buckinghamshire HP7 0BN, United Kingdom
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Mechanism and Protection of Radiotherapy Induced Sensorineural Hearing Loss for Head and Neck Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2021:3548706. [PMID: 34970625 PMCID: PMC8714384 DOI: 10.1155/2021/3548706] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 11/18/2021] [Accepted: 12/08/2021] [Indexed: 12/15/2022]
Abstract
Purpose Radiotherapy-induced sensorineural hearing loss (RISNHL) is a common adverse effect in patients with head and neck cancer. Given that there are few studies on the pathogenesis of RISNHL at present, we summarized the possible pathogenesis of RISNHL and possible protective measures found at present by referring to relevant literatures. Methods We performed a comprehensive literature search in the PubMed database, using keywords “sensorineural hearing loss,” “radiotherapy,” and “cancer,” among others. The literature was examined for the possible mechanism and preventive measures of sensorineural hearing loss induced by radiotherapy. Results We found that the incidence of RISNHL was closely related to the damage directly caused by ionizing radiation and the radiation-induced bystander effect. It also depends on the dose of radiation and the timing of chemotherapy. Studies confirmed that RISNHL is mainly involved in post-RT inflammatory response and changes in reactive oxygen species, mitogen-activated protein kinase, and p53 signaling pathways, leading to specific manners of cell death. We expect to reduce the incidence of hearing loss through advanced radiotherapy techniques, dose limitation of organs at risk, application of cell signaling inhibitors, use of antioxidants, induction of cochlear hair cell regeneration, and cochlear implantation. Conclusion RISNHL is associated with radiation damage to DNA, oxidative stress, and inflammation of cochlear cells, stria vascularis endothelial cells, vascular endothelial cells, spiral ganglion neurons, and other supporting cells. At present, the occurrence mechanism of RISNHL has not been clearly illustrated, and further studies are needed to better understand the underlying mechanism, which is crucial to promote the formulation of better strategies and prevent the occurrence of RISNHL.
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Lu CH, Yeh YC. Fabrication of Multiresponsive Magnetic Nanocomposite Double-Network Hydrogels for Controlled Release Applications. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2105997. [PMID: 34791796 DOI: 10.1002/smll.202105997] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/01/2021] [Indexed: 06/13/2023]
Abstract
Nanocomposite double-network hydrogels (ncDN hydrogels) have been demonstrated as promising biomaterials to present several desired properties (e.g., high mechanical strength, stimuli-responsiveness, and local therapy) for biomedicine. Here, a new type of ncDN hydrogels featuring definable microstructures and properties as well as multistimuli responsiveness for controlled release applications is developed. Amine-functionalized iron oxide nanoparticles (IOPs_NH2 ) are used as nanoparticle cross-linkers to simultaneously connect the dual networks of gelatin (Gel) and polydextran aldehyde (PDA) through hydrogen bonding, electrostatic interactions, and dynamic imine bonds. The pH- and temperature-responsive Gel/PDA/IOP_NH2 ncDN hydrogels present a fast release profile of proteins at acidic pH and high temperature. Besides, IOP_NH2 also contributes the magnetic-responsiveness to the ncDN hydrogels, allowing the use of magnetic field to generate heat to facilitate the structural change of hydrogels and the subsequent applications. Taken together, a versatile ncDN hydrogel platform capable of multistimuli responsiveness and local heating for controlled release is developed for advanced biomedical applications.
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Affiliation(s)
- Cheng-Hsun Lu
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, 10617, Taiwan
| | - Yi-Cheun Yeh
- Institute of Polymer Science and Engineering, National Taiwan University, Taipei, 10617, Taiwan
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Kim M, Jeon K, Shin S, Yoon S, Kim H, Kang HY, Ryu D, Park D, Jung E. Melanogenesis-promoting effect of Cirsium japonicum flower extract in vitro and ex vivo. Int J Cosmet Sci 2021; 43:703-714. [PMID: 34674286 DOI: 10.1111/ics.12746] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 09/30/2021] [Accepted: 10/11/2021] [Indexed: 01/02/2023]
Abstract
OBJECTIVE In this study, we examined the effect of C. japonicum flower extract (CFE) on melanogenesis and its mechanism in vitro and ex vivo. METHODS The effect of CFE on melanogenesis was investigated with lightly (HEMn-LP) and moderately (HEMn-MP) pigmented normal human melanocytes, reconstituted three-dimensional skin (3D skin) model and ex vivo human hair follicles. The melanogenesis-inducing effect of CFE was evaluated using melanin content and intracellular tyrosinase activity assay. The amount and type of eumelanin and pheomelanin were analysed by using HPLC method. The mechanism involved in the effect of CFE on hyperpigmentation was explored by cyclic adenosine monophosphate (cAMP) immunoassay and western blot analysis for tyrosinase, microphthalmia-associated transcription factor (MITF) and phosphorylated CRE-binding protein (pCREB) expression. The degree of pigmentation in 3D skin and L-values were measured using a CR-300 chroma meter. The amount of dissolved melanin was measured using a spectrophotometer. The content of melanin in the hair follicles was evaluated by Fontana Masson staining. RESULTS C. japonicum flower extract significantly increased the melanin content and cellular tyrosinase activity in both HEMn-LP and HEMn-MP cells. The markers of pheomelanin and eumelanin in HEMn-LP and HEMn-MP were also increased by CFE. We observed that CFE treatment on melanocytes increased intracellular cAMP with inducing pCREB and up-regulating the protein levels of TYR and MITF. Furthermore, CFE considerably increased the melanin content in a 3D skin model and ex vivo human hair follicles. CONCLUSIONS These results suggest that CFE exerts hyperpigmentation activity through cAMP signalling in human melanocytes that it can improve follicular depigmentation and vitiligo by stimulating the melanin synthesis.
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Affiliation(s)
- Minkyung Kim
- Biospectrum Life Science Institute, Yongin-si, Republic of Korea
| | - Kyungeun Jeon
- Biospectrum Life Science Institute, Yongin-si, Republic of Korea
| | - Seoungwoo Shin
- Biospectrum Life Science Institute, Yongin-si, Republic of Korea
| | - Sohyun Yoon
- Biospectrum Life Science Institute, Yongin-si, Republic of Korea
| | - Hayeon Kim
- Biospectrum Life Science Institute, Yongin-si, Republic of Korea
| | - Hee Young Kang
- Department of Dermatology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Dehun Ryu
- Biospectrum Life Science Institute, Yongin-si, Republic of Korea
| | - Deokhoon Park
- Biospectrum Life Science Institute, Yongin-si, Republic of Korea
| | - Eunsun Jung
- Biospectrum Life Science Institute, Yongin-si, Republic of Korea
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Liu Y, Cao X, Ge J. Antioxidative Composites Based on Multienzyme Systems Encapsulated in Metal-Organic Frameworks. ACS APPLIED MATERIALS & INTERFACES 2021; 13:46431-46439. [PMID: 34551515 DOI: 10.1021/acsami.1c15506] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Skin is exposed to ultraviolet radiation from the sun constantly, which may induce overproduction of reactive oxygen species (ROS) causing oxidative stress to cells and tissues. Enzymes and small molecules work together to maintain the redox homeostasis, among which superoxide dismutase (SOD) and catalase (CAT) are two kinds of most important antioxidants that suffer from the fragile nature of proteins. Moreover, the proportion of two enzymes used in products must be precisely controlled to reduce the damage caused by the toxic intermediate H2O2. Metal-organic frameworks (MOFs) are emerging as promising candidates for multiple enzyme encapsulation due to their high porosity, easy synthesis, and good biocompatibility. Herein, we developed enzyme-MOF composites, SC@ZIF-8, which exhibited an excellent antioxidative activity in vitro. Chemically protective cages formed by MOFs endow the encapsulated enzymes the long-term stability under unnatural conditions in cosmetic and biomedical materials. The pH-dependent protein release profile of SC@ZIF-8 facilitated the successful delivery of enzymes into the cytoplasm to scavenge toxic ROS. The nanocomposites protected human cells from paraquat-induced oxidative stress, paving a new path for the stable and efficient application of antioxidative enzymes in cosmetic and dermatological fields.
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Affiliation(s)
- Yu Liu
- Key Laboratory of Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
| | - Xun Cao
- Key Laboratory of Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
| | - Jun Ge
- Key Laboratory of Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, China
- Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518107, China
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