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Woźnicki P, Bartusik-Aebisher D, Przygórzewska A, Aebisher D. Molecular mechanisms of the effects of photodynamic therapy on the brain: A review of the literature. Photodiagnosis Photodyn Ther 2025; 52:104536. [PMID: 40023269 DOI: 10.1016/j.pdpdt.2025.104536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 02/07/2025] [Accepted: 02/26/2025] [Indexed: 03/04/2025]
Abstract
Malignant gliomas are the most common primary brain tumors in adults. These tumors have a diverse molecular origin and a very poor prognosis. There is a lack of effective treatment at WHO grade IV glioma, and all glioblastomas progress or recur. Current treatments including surgical intervention, radiation therapy, and chemotherapy are insufficient and can cause damage to healthy brain tissue and neurological deficits. The preservation of healthy brain tissue during therapeutic intervention is made extremely difficult by the ability of malignant gliomas to diffusely infiltrate the surrounding brain parenchyma. Photodynamic therapy (PDT) is a treatment modality for glioma that can possibly overcome the inherent shortcommings of traditional therapies. Photodynamic therapy involves the use of a photosensitizer (PS) which, upon absorption of light by photosensitized tissue, triggers photochemical reactions generating reactive oxygen species (ROS) leading to the killing of tumor cells. Research focusing on the effective use of PDT in the treatment of glioma is already underway with promising results. Clinical studies on PDT for the treatment of gliomas have shown it to be a safe therapeutic modality with acceptable levels of side effects. However, some adverse sequelae have been observed during PDT of these tumours, such as increased photosensitivity, increased intracranial pressure or transient aphasia and worsening of pre-existing neurological deficits. Although the clinical sequelae of PDT are well described, the molecular mechanisms of PDT's effects on the healthy brain have not yet been thoroughly characterized. In our work, we attempt to summarize the molecular mechanisms of the effects of photosensitization on neural tissue, brain vasculature and the blood-brain barrier (BBB). We also point to findings presenting molecular approaches to protect the healthy brain from the adverse effects of photodynamic damage.
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Affiliation(s)
- Paweł Woźnicki
- Doctoral School, Medical College of the University of Rzeszów, Rzeszów 35-310, Poland
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College of The Rzeszów University, Rzeszów 35-310, Poland
| | - Agnieszka Przygórzewska
- English Division Science Club, Medical College of The Rzeszów University, Rzeszów 35-310, Poland
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College of The Rzeszów University, Rzeszów 35-310, Poland.
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2
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Korbelik M, Heger M, Girotti AW. Participation of lipids in the tumor response to photodynamic therapy and its exploitation for therapeutic gain. J Lipid Res 2025; 66:100729. [PMID: 39675508 PMCID: PMC11911859 DOI: 10.1016/j.jlr.2024.100729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 11/19/2024] [Accepted: 12/06/2024] [Indexed: 12/17/2024] Open
Abstract
Hydroperoxides of unsaturated membrane lipids (LOOHs) are the most abundant non-radical intermediates generated by photodynamic therapy (PDT) of soft tissues such as tumors and have far longer average lifetimes than singlet oxygen or oxygen radicals formed during initial photodynamic action. LOOH-initiated post-irradiation damage to remaining membrane lipids (chain peroxidation) or to membrane-associated proteins remains largely unrecognized. Such after-light processes could occur during clinical oncological PDT, but this is not well-perceived by practitioners of this therapy. In general, the pivotal influence of lipids in tumor responses to PDT needs to be better appreciated. Of related importance is the fact that most malignant tumors have dramatically different lipid metabolism compared with healthy tissues, and this too is often ignored. The response of tumors to PDT appears especially vulnerable to manipulations within the tumor lipid microenvironment. This can be exploited for therapeutic gain with PDT, as exemplified here by the combined treatment with the antitumor lipid edelfosine.
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Affiliation(s)
- Mladen Korbelik
- Department of Integrative Oncology, BC Cancer, Vancouver, BC, Canada
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, P. R. China; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
| | - Albert W Girotti
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA
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Wang Y, Chen L, Lai S, Liu Y, Yi B, Zhu S, Hu X, Zhang Q, Zhang C. Connexin 43 contributes to the sensitization of colorectal cancer cells to photodynamic therapy through Akt inhibition. Photodiagnosis Photodyn Ther 2022; 39:103040. [PMID: 35907621 DOI: 10.1016/j.pdpdt.2022.103040] [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: 05/06/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 10/16/2022]
Abstract
BACKGROUND Photodynamic therapy could be one approach to treat colorectal cancer though resistance leads to failure of therapy. Akt activation is a cellular survival response to photodynamic therapy and is also a reason for resistance. Thus, inhibition of Akt is a strategy to decrease resistance. Akt interacts with connexin 43, another protein involved in photodynamic therapy resistance. Connexin 43 is widely expressed in different human tissues and has a complex role in tumor development. However, the mechanism of inhibition of Akt by connexin 43 that sensitizes colorectal cancer cells to photodynamic therapy needs further investigation. METHODS In this study, two colorectal cancer cells with low phosphorylated connexin 43 level were used to explore this mechanism. LY294002 was used as an Akt inhibitor, and connexin 43-pCMV3 was transfected into cells to increase connexin 43 expression. RESULTS Akt and connexin 43 inhibit each other in both colorectal cancer cell lines. In vitro and in vivo experiments showed that LY294002 and connexin 43 transfection sensitized cells to hematoporphyrin-Photodynamic therapy. LY294002 increased the sensitivity of cells to photodynamic therapy with a pronounced effect in cells with high expression levels of connexin 43. CONCLUSIONS Connexin 43 should be considered an important factor in increasing the phototoxicity of photodynamic therapy in colorectal cancer through Akt inhibition.
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Affiliation(s)
- Yijia Wang
- Laboratory of Oncologic molecular medicine, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Lankai Chen
- Nankai University School of Medicine, Nankai University, Tianjin, 300121, China
| | - Sizhen Lai
- Tianjin University of Traditional Chinese Medicine, Tianjin, 300121, China
| | - Yanfei Liu
- Tianjin University of Traditional Chinese Medicine, Tianjin, 300121, China
| | - Ben Yi
- Tianjin University of Traditional Chinese Medicine, Tianjin, 300121, China
| | - Siwei Zhu
- Laboratory of Oncologic molecular medicine, Tianjin Union Medical Center, Tianjin, 300121, China
| | - Xia Hu
- Department of Agriculture Insect, Institute of Plant Protection, Tianjin Academy of Agricultural Sciences, Tianjin, 300381, China
| | - Qinghuai Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
| | - Chunze Zhang
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China.
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4
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de Klerk DJ, de Keijzer MJ, Dias LM, Heemskerk J, de Haan LR, Kleijn TG, Franchi LP, Heger M. Strategies for Improving Photodynamic Therapy Through Pharmacological Modulation of the Immediate Early Stress Response. Methods Mol Biol 2022; 2451:405-480. [PMID: 35505025 DOI: 10.1007/978-1-0716-2099-1_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Photodynamic therapy (PDT) is a minimally to noninvasive treatment modality that has emerged as a promising alternative to conventional cancer treatments. PDT induces hyperoxidative stress and disrupts cellular homeostasis in photosensitized cancer cells, resulting in cell death and ultimately removal of the tumor. However, various survival pathways can be activated in sublethally afflicted cancer cells following PDT. The acute stress response is one of the known survival pathways in PDT, which is activated by reactive oxygen species and signals via ASK-1 (directly) or via TNFR (indirectly). The acute stress response can activate various other survival pathways that may entail antioxidant, pro-inflammatory, angiogenic, and proteotoxic stress responses that culminate in the cancer cell's ability to cope with redox stress and oxidative damage. This review provides an overview of the immediate early stress response in the context of PDT, mechanisms of activation by PDT, and molecular intervention strategies aimed at inhibiting survival signaling and improving PDT outcome.
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Affiliation(s)
- Daniel J de Klerk
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Mark J de Keijzer
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Lionel M Dias
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Faculdade de Ciências da Saúde (FCS-UBI), Universidade da Beira Interior, Covilhã, Portugal
| | - Jordi Heemskerk
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Tony G Kleijn
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands
| | - Leonardo P Franchi
- Departamento de Bioquímica e Biologia Molecular, Instituto de Ciências Biológicas (ICB) 2, Universidade Federal de Goiás (UFG), Goiânia, GO, Brazil
- Faculty of Philosophy, Department of Chemistry, Center of Nanotechnology and Tissue Engineering-Photobiology and Photomedicine Research Group, Sciences, and Letters of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, People's Republic of China.
- Laboratory of Experimental Oncology, Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
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Tsai YJ, Ma MC, Wu PH, Wu WB. Novel involvement of PLD-PKCδ-CREB axis in regulating FGF-2-mediated pentraxin 3 production in human nasal fibroblast cells. J Cell Physiol 2021; 237:1871-1887. [PMID: 34897684 DOI: 10.1002/jcp.30657] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 11/26/2021] [Accepted: 11/29/2021] [Indexed: 01/27/2023]
Abstract
A higher expression level of mitogenic fibroblast growth factor-2 (FGF-2) has been reported in human nasal mucus of both chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). Meanwhile, we have shown that long pentraxin 3 (PTX3), an essential component of humoral innate immunity that is produced at sites of infection and inflammation, was overproduced in human nasal mucosae and secretions of CRSsNP. Therefore, this study was aimed to investigate how FGF-2 regulates PTX3 expression in human CRSsNP nasal mucosa-derived fibroblast cells (hNMDFs). The FGF-2 treatment caused ptx3 mRNA expression and PTX3 protein induction and secretion. In parallel, a differential expression of FGF receptor (FGFR)-1 to FGFR-4 was observed in hNMDFs and human nasal tissues. While conventionally known PI3K/Akt/mTOR and AP-1 pathways following FGFR activation were shown to be involved, the protein kinase Cδ (PKCδ) and cAMP response element-binding protein (CREB) were also found to be as critical signaling molecules in FGF-2-induced PTX3 induction. The PKCδ and CREB activation could be detected in total cells and in the cell nucleus. Accordingly, a novel CREB binding sequence was detected in the human ptx3 promoter region and could interact with activated CREB in cells challenged with FGF-2. Surprisingly, the phospholipase D (PLD), but not phosphoinositide- and phosphatidylcholine-phospholipase C, was necessarily required for PKCδ and CREB activation. Therefore, we demonstrated here for the first time that FGF-2 mediates PTX3 production not only through PI-3K/Akt/mTOR and AP-1 activation, but also through a novel FGFR-PLD-PKCδ-CREB cellular signaling pathway.
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Affiliation(s)
- Yih-Jeng Tsai
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.,Department of Otolaryngology Head and Neck Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Ming-Chieh Ma
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Pi-Hui Wu
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Wen-Bin Wu
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.,Graduate Institute of Biomedical and Pharmaceutical Science, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
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Ma H, Chen Y, Yu M, Chen X, Qi L, Wei S, Fan Q, Xu Q, Zhan M, Sha Z. Immune role of the complement component 6 gene and its associated novel miRNA, miR-727, in half-smooth tongue sole (Cynoglossus semilaevis). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 123:104156. [PMID: 34077766 DOI: 10.1016/j.dci.2021.104156] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/26/2021] [Accepted: 05/26/2021] [Indexed: 06/12/2023]
Abstract
The complement component 6 (C6) gene is a component of the membrane attack complex (MAC), which causes rapid lytic destruction of bacteria. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene stability, including that of immune genes. However, current research on the function of C6 and its regulation by miRNAs is lacking. In the present study, we identified and characterized C6 and a novel miRNA, miR-727 (designated CsC6 and Cse-miR-727, respectively), of the half-smooth tongue sole (Cynoglossus semilaevis) that responded to infection with Vibrio anguillarum, a Gram-negative pathogen of marine fish. The full-length cDNA of CsC6 contained a 256 bp 5' untranslated region (5'-UTR), a 2820 bp open reading frame (ORF) encoding 939 amino acids, and a 205 bp 3'-UTR. SMART analysis showed that CsC6 contains typical C6 domains, including three TSP1 domains, one LDLa domain, one MACPF domain, two CCP domains and two FIMAC domains. CsC6 and Cse-miR-727 are widely expressed in the 13 tissues of half-smooth tongue sole, and their expression in immune tissues is significantly changed after V. anguillarum infection, generally showing an inverse trend. We confirmed that CsC6 was the target gene of Cse-miR-727 using the dual luciferase reporter assay and that Cse-miR-727 regulated CsC6 at the protein level using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The hepatic expression levels of not only the MAC components C7, C8α, C8β, C8γ and C9 but also the MAPKs, NF-κβ, AP-1, IL1β, IL6 and TNFα, which are involved in many signaling pathways, changed significantly in half-smooth tongue sole following stimulation with the Cse-miR-727 agomir and inhibitor. This evidence suggested that CsC6 could be mediated by Cse-miR-727 to affect MAC assembly and immune signaling pathways in half-smooth tongue soles. To our best knowledge, this study is the first to investigate the regulatory mechanism and immune response of complement genes mediated by miRNAs in fish.
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Affiliation(s)
- Hui Ma
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Yadong Chen
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China; Key Laboratory for Sustainable Development of Marine Fisheries, Ministry of Agriculture, Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Qingdao, 266071, China
| | - Mengjun Yu
- College of Fisheries and Life Sciences, Dalian Ocean University, Dalian, 116023, China
| | - Xuejie Chen
- College of Fisheries and Life Sciences, Shanghai Ocean University, Shanghai, 200000, China
| | - Longjiang Qi
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Shu Wei
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Qingxin Fan
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Qian Xu
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Min Zhan
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Zhenxia Sha
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China.
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7
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Falk-Mahapatra R, Gollnick SO. Photodynamic Therapy and Immunity: An Update. Photochem Photobiol 2020; 96:550-559. [PMID: 32128821 DOI: 10.1111/php.13253] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 02/04/2020] [Indexed: 12/18/2022]
Abstract
Dr. Thomas Dougherty and his Oncology Foundation of Buffalo were the first to support my (S.O.G.) research into the effects of photodynamic therapy (PDT) on the host immune system. The small grant I was awarded in 2002 launched my career as an independent researcher; at the time, there were few studies on the importance of the immune response on the efficacy of PDT and no studies demonstrating the ability of PDT to enhance antitumor immunity. Over the last decades, the interest in PDT as an enhancer of antitumor immunity and our understanding of the mechanisms by which PDT enhances antitumor immunity have dramatically increased. In this review article, we look back on the studies that laid the foundation for our understanding and provide an update on current advances and therapies that take advantage of PDT enhancement of immunity.
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Affiliation(s)
| | - Sandra O Gollnick
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.,Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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Catarino SJ, Andrade FA, Boldt ABW, Guilherme L, Messias-Reason IJ. Sickening or Healing the Heart? The Association of Ficolin-1 and Rheumatic Fever. Front Immunol 2018; 9:3009. [PMID: 30619357 PMCID: PMC6305461 DOI: 10.3389/fimmu.2018.03009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 12/05/2018] [Indexed: 12/27/2022] Open
Abstract
Rheumatic fever (RF) and its subsequent progression to rheumatic heart disease (RHD) are chronic inflammatory disorders prevalent in children and adolescents in underdeveloped countries, and a contributing factor for high morbidity and mortality rates worldwide. Their primary cause is oropharynx infection by Streptococcus pyogenes, whose acetylated residues are recognized by ficolin-1. This is the only membrane-bound, as well as soluble activator molecule of the complement lectin pathway (LP). Although LP genetic polymorphisms are associated with RF, FCN1 gene's role remains unknown. To understand this role, we haplotyped five FCN1 promoter polymorphisms by sequence-specific amplification in 193 patients (138 with RHD and 55, RF only) and 193 controls, measuring ficolin-1 serum concentrations in 78 patients and 86 controls, using enzyme-linked immunosorbent assay (ELISA). Patients presented lower ficolin-1 serum levels (p < 0.0001), but did not differ according to cardiac commitment. Control's genotype distribution was in the Hardy-Weinberg equilibrium. Four alleles (rs2989727: c.-1981A, rs10120023: c.-542A, rs10117466: c.-144A, and rs10858293: c.33T), all associated with increased FCN1 gene expression in whole blood or adipose subcutaneous tissue (p = 0.000001), were also associated with increased protection against the disease. They occur within the *3C2 haplotype, associated with an increased protection against RF (OR = 0.41, p < 0.0001) and with higher ficolin-1 levels in patient serum (p = 0.03). In addition, major alleles of these same polymorphisms comprehend the most primitive *1 haplotype, associated with increased susceptibility to RF (OR = 1.76, p < 0.0001). Nevertheless, instead of having a clear-cut protective role, the minor c.-1981A and c.-144A alleles were also associated with additive susceptibility to valvar stenosis and mitral insufficiency (OR = 3.75, p = 0.009 and OR = 3.37, p = 0.027, respectively). All associations were independent of age, sex or ethnicity. Thus, minor FCN1 promoter variants may play a protective role against RF, by encouraging bacteria elimination as well as increasing gene expression and protein levels. On the other hand, they may also predispose the patients to RHD symptoms, by probably contributing to chronic inflammation and tissue injury, thus emphasizing the dual importance of ficolin-1 in both conditions.
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Affiliation(s)
- Sandra Jeremias Catarino
- Molecular Immunopathology Laboratory, Department of Medical Pathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil
| | - Fabiana Antunes Andrade
- Molecular Immunopathology Laboratory, Department of Medical Pathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil
| | - Angelica Beate Winter Boldt
- Molecular Immunopathology Laboratory, Department of Medical Pathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil
- Human Molecular Genetics Laboratory, Department of Genetics, Federal University of Paraná, Curitiba, Brazil
| | - Luiza Guilherme
- Heart Institute (InCor), School of Medicine, University of São Paulo, São Paulo, Brazil
| | - Iara Jose Messias-Reason
- Molecular Immunopathology Laboratory, Department of Medical Pathology, Clinical Hospital, Federal University of Paraná, Curitiba, Brazil
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Yu NB. Therapeutic experience of the application of anisodamine on acute lung injury. JOURNAL OF ACUTE DISEASE 2016. [DOI: 10.1016/j.joad.2016.08.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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10
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Fornai F, Carrizzo A, Forte M, Ambrosio M, Damato A, Ferrucci M, Biagioni F, Busceti C, Puca AA, Vecchione C. The inflammatory protein Pentraxin 3 in cardiovascular disease. IMMUNITY & AGEING 2016; 13:25. [PMID: 27559355 PMCID: PMC4995820 DOI: 10.1186/s12979-016-0080-1] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 08/15/2016] [Indexed: 12/12/2022]
Abstract
The acute phase protein Pentraxin 3 (PTX3) plays a non-redundant role as a soluble pattern recognition receptor for selected pathogens and it represents a rapid biomarker for primary local activation of innate immunity and inflammation. Recent evidence indicates that PTX3 exerts an important role in modulating the cardiovascular system in humans and experimental models. In particular, there are conflicting points concerning the effects of PTX3 in cardiovascular diseases (CVD) since several observations indicate a cardiovascular protective effect of PTX3 while others speculate that the increased plasma levels of PTX3 in subjects with CVD correlate with disease severity and with poor prognosis in elderly patients. In the present review, we discuss the multifaceted effects of PTX3 on the cardiovascular system focusing on its involvement in atherosclerosis, endothelial function, hypertension, myocardial infarction and angiogenesis. This may help to explain how the specific modulation of PTX3 such as the use of different dosing, time, and target organs could help to contain different vascular diseases. These opposite actions of PTX3 will be emphasized concerning the modulation of cardiovascular system where potential therapeutic implications of PTX3 in humans are discussed.
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Affiliation(s)
- Francesco Fornai
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy ; I.R.C.C.S. Neuromed, Pozzilli, IS Italy
| | | | | | | | | | - Michela Ferrucci
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | | | | | - Annibale A Puca
- Vascular Physiopathology Unit, I.R.C.C.S. Multimedica, Milan, Italy ; Department of Medicine and Surgery, University of Salerno, Via S. Allende, Baronissi, SA 84081 Italy
| | - Carmine Vecchione
- I.R.C.C.S. Neuromed, Pozzilli, IS Italy ; Department of Medicine and Surgery, University of Salerno, Via S. Allende, Baronissi, SA 84081 Italy
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11
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Pizova K, Bajgar R, Fillerova R, Kriegova E, Cenklova V, Langova K, Konecny P, Kolarova H. C-MYC and C-FOS expression changes and cellular aspects of the photodynamic reaction with photosensitizers TMPyP and ClAlPcS2. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2014; 142:186-96. [PMID: 25545333 DOI: 10.1016/j.jphotobiol.2014.12.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 11/25/2014] [Accepted: 12/01/2014] [Indexed: 02/04/2023]
Abstract
Photodynamic therapy (PDT) is based on the tumor-selective accumulation of photosensitizer followed by irradiation with light of an appropriate wavelength. After irradiation and in the presence of oxygen, photosensitizer induces cellular damage. The aim of this study was to evaluate effects of two photosensitizers TMPyP and ClAlPcS2 on cell lines to obtain better insight into their mechanisms of action. We determined cell viability, reactive oxygen species (ROS) generation and changes in expression levels of two important early response genes, C-MYC and C-FOS, on tumor MCF7 (human breast adenocarcinoma) and G361 (human melanoma) cell lines and non-tumor BJ cell line (human fibroblast) after photodynamic reaction with TMPyP and ClAlPcS2 as photosensitizers. In addition TMPyP and ClAlPcS2 cellular uptake and clearance and antioxidant capacity of the mentioned cell lines were investigated. We found appropriate therapeutic doses and confirmed that both tested photosensitizers are photodynamically efficient in treatment used cells in vitro. TMPyP is more efficient; it had higher ROS production and toxicity after irradiation by intermediate therapeutic doses than ClAlPcS2. We revealed that both TMPyP and ClAlPcS2-PDT increased C-FOS expression on tumor cell lines (G361 and MCF7), but not on non-tumor BJ cell line. Conversely, both TMPyP and ClAlPcS2-PDT decreased C-MYC expression on non-tumor BJ cell line but not on tumor cell lines. As first we tested these photosensitizers in such extent and we believe that it can help to better understand mechanisms of PDT and increase its efficiency and applicability.
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Affiliation(s)
- Klara Pizova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, 77900 Olomouc, Czech Republic.
| | - Robert Bajgar
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, 77900 Olomouc, Czech Republic
| | - Regina Fillerova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic
| | - Eva Kriegova
- Department of Immunology, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic
| | - Vera Cenklova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, 77900 Olomouc, Czech Republic
| | - Katerina Langova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic
| | - Petr Konecny
- Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, 77900 Olomouc, Czech Republic
| | - Hana Kolarova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, 77900 Olomouc, Czech Republic
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Reginato E, Wolf P, Hamblin MR. Immune response after photodynamic therapy increases anti-cancer and anti-bacterial effects. World J Immunol 2014; 4:1-11. [PMID: 25364655 PMCID: PMC4214901 DOI: 10.5411/wji.v4.i1.1] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 12/20/2013] [Accepted: 02/18/2014] [Indexed: 02/05/2023] Open
Abstract
Photodynamic therapy (PDT) is a clinically approved procedure for treatment of cancer and infections. PDT involves systemic or topical administration of a photosensitizer (PS), followed by irradiation of the diseased area with light of a wavelength corresponding to an absorbance band of the PS. In the presence of oxygen, a photochemical reaction is initiated, leading to the generation of reactive oxygen species and cell death. Besides causing direct cytotoxic effects on illuminated tumor cells, PDT is known to cause damage to the tumor vasculature and induce the release of pro-inflammatory molecules. Pre-clinical and clinical studies have demonstrated that PDT is capable of affecting both the innate and adaptive arms of the immune system. Immune stimulatory properties of PDT may increase its beneficial effects giving the therapy wider potential to become more extensively used in clinical practice. Be sides stimulating tumor-specific cytotoxic T-cells capable to destroy distant untreated tumor cells, PDT leads to development of anti-tumor memory immunity that can potentially prevent the recurrence of cancer. The immunological effects of PDT make the therapy more effective also when used for treatment of bacterial infections, due to an augmented infiltration of neutrophils into the infected regions that seems to potentiate the outcome of the treatment.
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Cai Y, Yang Q, Tang Y, Zhang M, Liu H, Zhang G, Deng Q, Huang J, Gao Z, Zhou B, Feng CG, Chen X. Increased complement C1q level marks active disease in human tuberculosis. PLoS One 2014; 9:e92340. [PMID: 24647646 PMCID: PMC3960215 DOI: 10.1371/journal.pone.0092340] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 02/21/2014] [Indexed: 12/25/2022] Open
Abstract
Background Complement functions as an important host defense system and complement C5 and C7 have been implicated in immunopathology of tuberculosis. However, little is known about the role of other complement components in tuberculosis. Methods Complement gene expression in peripheral blood mononuclear cells of tuberculosis patients and controls were determined using whole genome transcriptional microarray assays. The mRNA and protein levels of three C1q components, C1qA, C1qB, and C1qC, were further validated by qRT-PCR and enzyme-linked immunosorbent assay, respectively. The percentages of C1q expression in CD14 positive cells were determined by flow cytometry. Finally, C1qC protein level was quantified in the pleural fluid of tuberculosis and non-tuberculosis pleurisy. Results C1q expression increases significantly in the peripheral blood of patients with active tuberculosis compared to healthy controls and individuals with latent TB infection. The percentage of C1q-expressing CD14 positive cells is significantly increased in active TB patients. C1q expression in the peripheral blood correlates with sputum smear positivity in tuberculosis patients and is reduced after anti-tuberculosis chemotherapy. Notably, receiver operating characteristic analysis showed that C1qC mRNA levels in peripheral blood efficiently discriminate active from latent tuberculosis infection and healthy controls. Additionally, C1qC protein level in pleural effusion shows improved power in discriminating tuberculosis from non-tuberculosis pleurisy when compared to other inflammatory markers, such as IL-6 and TNF-α. Conclusions C1q expression correlates with active disease in human tuberculosis. C1q could be a potential diagnostic marker to discriminate active tuberculosis from latent tuberculosis infection as well as tuberculosis pleurisy from non-tuberculosis pleurisy.
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Affiliation(s)
- Yi Cai
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China
| | - Qianting Yang
- Guangdong Key Laboratory for Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
- Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China
| | - Yueqiang Tang
- Guangdong Key Laboratory for Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
- Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China
| | - Mingxia Zhang
- Guangdong Key Laboratory for Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Haiying Liu
- Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Beijing, China
| | - Guoliang Zhang
- Guangdong Key Laboratory for Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Qunyi Deng
- Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China
| | - Jian Huang
- Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China
- Shanghai-MOST Key Laboratory of Disease and Health Genomics, National Engineering Center for Biochip at Shanghai, Shanghai, China
| | - Zhiliang Gao
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Boping Zhou
- Guangdong Key Laboratory for Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
| | - Carl G. Feng
- Department of Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney University, Australia
| | - Xinchun Chen
- Guangdong Key Laboratory for Emerging Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
- Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen, China
- * E-mail:
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Korbelik M, Zhang W, Saw KM, Szulc ZM, Bielawska A, Separovic D. Cationic ceramides and analogues, LCL30 and LCL85, as adjuvants to photodynamic therapy of tumors. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2013; 126:72-7. [PMID: 23911762 DOI: 10.1016/j.jphotobiol.2013.06.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Revised: 06/01/2013] [Accepted: 06/22/2013] [Indexed: 11/18/2022]
Abstract
Photodynamic therapy (PDT) is known to alter the expression of various genes in treated cells. This prompted us to examine the activity of genes encoding two important enzymes in sphingolipid (SL) metabolism, dihydroceramide desaturase (DES) and sphingosine kinase (SPHK), in mouse SCCVII tumor cells treated by PDT using either the porphyrin-based photosensitizer Photofrin or silicon phthalocyanine Pc4. The results revealed that PDT induced an upregulation in the expression of two major isoforms of both genes (DES1 and DES2 as well as SPHK1 and SPHK2). While the changes were generally moderate (2-3-fold gains), the increase in DES2 expression was more pronounced and it was much greater with Photofrin-PDT than with Pc4-PDT (over 23-fold vs. less than 5-fold). Combining either Photofrin-PDT or Pc4-PDT with the cationic C16-ceramide LCL30 (20mg/kg i.p.) for treatment of subcutaneously growing SCCVII tumors rendered important differences in the therapy outcome. Photofrin-PDT, used at a dose that attained good initial response but no tumor cures, produced 50% cures when combined with a single LCL30 treatment. In contrast, the same LCL30 treatment combined with Pc4-PDT had no significant effect on tumor response. The optimal timing of LCL30 injection was immediately after Photofrin-PDT. The therapeutic benefit was lost when LCL30 was given in two 20mg/kg injections encompassing intervals before and after PDT. LCL85, the cationic B13 ceramide analogue and SL-modulating agent, also increased cure rates of Photofrin-PDT treated tumors, but the therapeutic benefit was less pronounced than with LCL30. These results with LCL30 and LCL85, and our previous findings for LCL29 (another SL analogue), assert the potential of SLs for use as adjuvants to augment the efficacy of PDT-mediated tumor destruction.
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