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Bayar I, Erzurumlu Y, Akkoc S, Bulut Z, Nizamlioglu M. Investigation of the sensitivity of human A549 cells to paclitaxel and sesquiterpene lactone alantolactone via apoptosis induction. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03947-w. [PMID: 40019527 DOI: 10.1007/s00210-025-03947-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 02/17/2025] [Indexed: 03/01/2025]
Abstract
Alantolactone (ALA), a sesquiterpene lactone compound obtained from Inula helenium root, is known to have anticancer activity in many types of cancer. Paclitaxel (PAX) is an effective first-line chemotherapeutic drug and is widely used in the treatment of lung cancer. The in vitro anticancer efficacy of combined treatment of ALA with PAX was investigated in the A549 human lung cancer cell line. The results show that ALA potentiated the effect of PAX-induced growth restriction and apoptosis in A549 cells. The combined administration more effectively decreased the Bcl-2 expression and increased Bax gene expression in cells compared to ALA or PAX alone. Also, co-treatment of ALA and PAX caused apoptotic nuclear formations. Additionally, coadministration increased the caspase-3 and caspase-9 levels more than PAX or ALA alone. The increase in NF-κB gene expression levels suggests that an NF-κB-independent apoptotic trigger mechanism operates in cells. Together, the present in vitro findings suggest that ALA may contribute as a potential therapeutic strategy in the treatment of lung cancer.
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Affiliation(s)
- Irem Bayar
- Department of Biochemistry, Faculty of Veterinary Medicine, Selcuk University, Konya, Turkey.
- Department of Pharmaceutical Research and Development, Institute of Health Sciences, Suleyman Demirel University, Isparta, Turkey.
| | - Yalcin Erzurumlu
- Department of Pharmaceutical Research and Development, Institute of Health Sciences, Suleyman Demirel University, Isparta, Turkey
- Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Suleyman Demirel University, Isparta, Turkey
| | - Senem Akkoc
- Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Suleyman Demirel University, Isparta, Turkey
- Faculty of Engineering and Natural Sciences, Bahcesehir University, Istanbul, Turkey
| | - Zafer Bulut
- Department of Biochemistry, Faculty of Veterinary Medicine, Selcuk University, Konya, Turkey
- Department of Biochemistry, Faculty of Veterinary Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Mehmet Nizamlioglu
- Department of Biochemistry, Faculty of Veterinary Medicine, Selcuk University, Konya, Turkey
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2
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Leib L, Juli J, Jurida L, Mayr-Buro C, Priester J, Weiser H, Wirth S, Hanel S, Heylmann D, Weber A, Schmitz ML, Papantonis A, Bartkuhn M, Wilhelm J, Linne U, Meier-Soelch J, Kracht M. The proximity-based protein interactome and regulatory logics of the transcription factor p65 NF-κB/RELA. EMBO Rep 2025; 26:1144-1183. [PMID: 39753783 PMCID: PMC11850942 DOI: 10.1038/s44319-024-00339-8] [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: 01/31/2024] [Revised: 11/06/2024] [Accepted: 11/14/2024] [Indexed: 02/26/2025] Open
Abstract
The protein interactome of p65/RELA, the most active subunit of the transcription factor (TF) NF-κB, has not been previously determined in living cells. Using p65-miniTurbo fusion proteins and biotin tagging, we identify >350 RELA interactors from untreated and IL-1α-stimulated cells, including many TFs (47% of all interactors) and >50 epigenetic regulators belonging to different classes of chromatin remodeling complexes. A comparison with the interactomes of two point mutants of p65 reveals that the interactions primarily require intact dimerization rather than DNA-binding properties. A targeted RNAi screen for 38 interactors and subsequent functional transcriptome and bioinformatics studies identify gene regulatory (sub)networks, each controlled by RELA in combination with one of the TFs ZBTB5, GLIS2, TFE3/TFEB, or S100A8/A9. The large, dynamic and versatile high-resolution interactome of RELA and its gene regulatory logics provides a rich resource and a new framework for explaining how RELA cooperativity determines gene expression patterns.
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Affiliation(s)
- Lisa Leib
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Jana Juli
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Liane Jurida
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Christin Mayr-Buro
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Jasmin Priester
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Hendrik Weiser
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Stefanie Wirth
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Simon Hanel
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Daniel Heylmann
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Axel Weber
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | | | - Argyris Papantonis
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Marek Bartkuhn
- Biomedical Informatics and Systems Medicine, Justus Liebig University Giessen, Giessen, Germany
- Institute for Lung Health, Justus Liebig University Giessen, Giessen, Germany
- Member of the Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany
| | - Jochen Wilhelm
- Institute for Lung Health, Justus Liebig University Giessen, Giessen, Germany
- Member of the Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany
- German Center for Lung Research (DZL) and Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
| | - Uwe Linne
- Mass Spectrometry Facility of the Department of Chemistry, Philipps University, Marburg, Germany
| | - Johanna Meier-Soelch
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany.
| | - Michael Kracht
- Rudolf Buchheim Institute of Pharmacology, Justus Liebig University, Giessen, Germany.
- Member of the Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany.
- German Center for Lung Research (DZL) and Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.
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Chen C, Chen H, Dingda D, Wang L, Gao F. The primary studies of epigallocatechin-3-gallate in improving brain injury induced by chronic high-altitude natural environment in rats by 7.0T high-field MR imaging. Arch Biochem Biophys 2025; 764:110224. [PMID: 39586562 DOI: 10.1016/j.abb.2024.110224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/29/2024] [Accepted: 11/21/2024] [Indexed: 11/27/2024]
Abstract
BACKGROUND Epigallocatechin-3-gallate (EGCG) is one of the most abundant and important bioactive polyphenolic compounds in green tea. However, despite its potent antioxidant effects, its neuroprotective effects on chronic high altitude (HA)-induced nerve damage have not been reported. The purpose of this study is to use quantitative susceptibility mapping (QSM) with pathology to dynamically evaluate the status of brain damage and the effect of EGCG. METHODS A model of HA environments-induced brain injury was established of Sprague-Dawley (SD) rats in a natural plateau environment for 4 weeks, 8 weeks, 12 weeks and 20 weeks. Behavioral alterations were then observed and assessed with the open field test (OFT) and Morris water maze (MWM) test. The microglial activation, nissl staining and neural degeneration by Fluoro Jade B in the hippocampus of the rats were observed by immunohistochemistry. In the rats, serum erythropoietin (EPO), hippocampal inflammatory cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]), ferritin, oxidative stress (superoxide dismutase [SOD], glutathione peroxidase [GSH-Px], catalase [CAT] and malondialdehyde [MDA]) were detected using ELISA kits and biochemical methods. Iron accumulation was observed by QSM and colorimetry. Iron metabolisms (ceruloplasmin [Cp], transferrin [Tf], divalent metal transport1 [DMT1] and hepcidin [Hep]) were detected using qPCR. Neural ultrastructural changes were evaluated with electron microscope. Salidroside treatment was chosen as the positive control group in ELISA, biochemical detection and electron microscopy. RESULTS The susceptibility values in the left and right hippocampus, the hippocampal ferritin, serum and hippocampal iron content increased significantly after HA exposure. The expression of hippocampal Cp and Hep decreased and the expression of Tf increased. Nissl staining revealed that the neurons of hippocampal CA1 region of h-20w group were small and irregular, atrophied, and nuclear shrinkage. Tissue oxidative stress and inflammatory indicators (MDA, TNF-α, IL-1β, IL-6) increased while antioxidant enzymes (SOD, CAT, GSH-Px) decreased. EGCG attenuated HA environments-induced cognitive impairment, iron accumulation, microglial activation and neural degeneration. The effects of EGCG in reducing EPO and the metal chelating property with respect to iron were dose-dependent, with effects of EGCG (50 mg/kg) being similar to those of salidroside (50 mg/kg). CONCLUSIONS EGCG can act as a neuroprotective agent against chronic HA environments-mediated neural injuries. QSM provides a potential complementary imaging technique to detect the effect of treating HA diseases.
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Affiliation(s)
- Chen Chen
- Department of Radiology, Henan Provincial People's Hospital and Zhengzhou University People's Hospital, Zhengzhou, Henan, PR China; Department of Radiology, West China Hospital, Sichuan University, Chengdu, PR China
| | - Haotian Chen
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, PR China; Department of Radiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, PR China
| | - Duojie Dingda
- Department of Radiology, Yushu People's Hospital, Yushu, Qinghai, PR China
| | - Lei Wang
- Molecular Imaging Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
| | - Fabao Gao
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, PR China; Molecular Imaging Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
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Bammigatti A, Ghosh SK, Bandyopadhyay S, Saha B. Messages in CD40L are encrypted for residue-specific functions. Cytokine 2025; 185:156824. [PMID: 39615244 DOI: 10.1016/j.cyto.2024.156824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024]
Abstract
CD40-CD40-ligand (CD40L) interaction plays crucial immunoregulatory roles, as CD40 signals through different signaling intermediates to convert the messages from CD40L to effector functions. Being a TNFα receptor family member, CD40 binds TNFα receptor-associated factors, assembles signalosome complexes and decrypts the messages from CD40L through different signaling modules to result in residue-specific effector functions. The evidence for such a residue-specific message encryption first came from the CD40L mutations resulting in X-linked hyper-IgM syndrome, as the extent of effects varied with the residue mutated. The structural studies on the CD40-CD40L interaction implied differential involvement of the interacting residues on CD40L in influencing the effector functions. Three lines of evidence indicate the previously implied residue-specific message encryption in CD40L: screening of a dodecameric peptide library for CD40 binders identified two peptides with different sequences resulting in counteractive effector functions in macrophages; a series of CD40L mutants identified that the mutations in these residues selectively affected CD40 signaling and macrophage effector functions; and, a panel of 40-mer peptides, representing the CD40-interacting domain of mouse CD40L, with single substitutions resulted in altered CD40 signaling through various signaling intermediates and effector functions in mouse macrophages. We therefore construct the first-ever message encryption-decryption in a biological receptor-ligand system wherein the CD40L residues that interact with CD40 residues have encrypted messages, which are decoded by CD40 signaling to result in residue-specific effector functions. This review presents a novel perspective of receptor-ligand interaction as a system of message transmission, message decoding by signaling, and its transcription to various read-outs. [250 words].
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Affiliation(s)
| | | | | | - Bhaskar Saha
- JSPS Government Homeopathic Medical College, Hyderabad 500013, India.
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Bahrami A, Khalaji A, Bahri Najafi M, Sadati S, Raisi A, Abolhassani A, Eshraghi R, Khaksary Mahabady M, Rahimian N, Mirzaei H. NF-κB pathway and angiogenesis: insights into colorectal cancer development and therapeutic targets. Eur J Med Res 2024; 29:610. [PMID: 39702532 DOI: 10.1186/s40001-024-02168-w] [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: 06/11/2024] [Accepted: 11/21/2024] [Indexed: 12/21/2024] Open
Abstract
Colorectal cancer (CRC) is currently ranked as the third most common type of cancer, contributing significantly to mortality and morbidity worldwide. Epigenetic and genetic changes occurred during CRC progression resulted in the cell proliferation, cancer progression, angiogenesis, and invasion. Angiogenesis is one of the crucial steps during cancer progression required for the delivery of essential nutrients to cancer cells and removes metabolic waste. During angiogenesis, different molecules are secreted from tumoral cells to trigger vascular formation including epidermal growth factor and the vascular endothelial growth factor (VEGF). The production and regulation of the secretion of these molecules are modulated by different subcellular pathways such as NF-κB. NF-κB is involved in regulation of different homeostatic pathways including apoptosis, cell proliferation, inflammation, differentiation, tumor migration, and angiogenesis. Investigation of different aspects of this pathway and its role in angiogenesis could provide a comprehensive overview about the underlying mechanisms and could be used for development of further therapeutic targets. In this review of literature, we comprehensively reviewed the current understanding and potential of NF-κB-related angiogenesis in CRC. Moreover, we explored the treatments that are based on the NF-κB pathway.
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Affiliation(s)
- Ashkan Bahrami
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majed Bahri Najafi
- Applied Physiology Research Center, Cardiovascular Research Institute, Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sina Sadati
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Arash Raisi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Reza Eshraghi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran.
| | - Mahmood Khaksary Mahabady
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Neda Rahimian
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran.
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Xu X, Wang P, Sun H, Xia D, Huang H, Zhang Q, Liu J. Genome-wide identification of the TRAF gene family in humpback grouper (Cromileptes altivelis) and analysis of their expression in response to Vibrio harveyi challenge. FISH & SHELLFISH IMMUNOLOGY 2024; 154:109959. [PMID: 39395597 DOI: 10.1016/j.fsi.2024.109959] [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: 08/15/2024] [Revised: 10/06/2024] [Accepted: 10/09/2024] [Indexed: 10/14/2024]
Abstract
TRAF (Tumor necrosis factor receptor-associated factor) proteins are key mediators of signal transduction in cell signaling and immune regulation within the toll-like receptor (TLR) and tumor necrosis factor (TNFR) superfamily. Despite the importance of TRAF genes in teleost innate immunity, study on their functions in C. altivelis is limited. This study utilized bioinformatics methods to identify and named eight TRAF genes (CaTRAF2a, CaTRAF2a-like, CaTRAF2b, CaTRAF3, CaTRAF4a, CaTRAF5, CaTRAF6 and CaTRAF7) in C. altivelis. Phylogenetic, syntenic and molecular evolution revealed that all CaTRAF members were evolutionarily conserved in teleost. Domain analysis indicated the presence of a conserved N-terminal RING finger domain in all CaTRAF proteins. Most CaTRAF proteins also featured a MATH domain at the C-terminal, with the exception of CaTRAF7 which contained seven repeat WD40 domains. In addition, qRT-PCR was used to detect the expression patterns of nine different tissues and eight different embryonic development stages of healthy fish, and it was found that there were spatial and tissue specificities among the members. HE staining revealed evident pathological lesions in the tissues post V. harveyi infection. Atrophy and significant bending of the gill lamellae were observed in the gills, while irregular cell shapes, increased fat vacuoles, and enlarged cell volume were noted in the liver. Intestinal tissues displayed thickening of the muscle layer, elongation of intestinal villi, and increased folds. Moreover, the expression of TRAF gene changed significantly after V. harveyi infection. These results would help to clarify the molecular role of CaTRAF gene in the regulation of immune and inflammatory responses in C. altivelis.
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Affiliation(s)
- Xiaona Xu
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences / Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Sanya, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, China.
| | - Peng Wang
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences / Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Sanya, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, China.
| | - Huibang Sun
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences / Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Sanya, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, China.
| | - Dongxue Xia
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences / Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Sanya, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, China.
| | - Hai Huang
- MOE Key Laboratory of Utilization and Conservation for Tropical Marine Bioresources, Hainan Tropical Ocean University, Sanya, China.
| | - Quanqi Zhang
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences / Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Sanya, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, China; Hainan Seed Industry Laboratory, Sanya, China.
| | - Jinxiang Liu
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences / Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Qingdao, Sanya, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao Marine Science and Technology Center, Qingdao, China; Hainan Seed Industry Laboratory, Sanya, China.
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7
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Rodriguez BN, Huang H, Chia JJ, Hoffmann A. The noncanonical NFκB pathway: Regulatory mechanisms in health and disease. WIREs Mech Dis 2024; 16:e1646. [PMID: 38634218 PMCID: PMC11486840 DOI: 10.1002/wsbm.1646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/29/2024] [Accepted: 04/01/2024] [Indexed: 04/19/2024]
Abstract
The noncanonical NFκB signaling pathway mediates the biological functions of diverse cell survival, growth, maturation, and differentiation factors that are important for the development and maintenance of hematopoietic cells and immune organs. Its dysregulation is associated with a number of immune pathologies and malignancies. Originally described as the signaling pathway that controls the NFκB family member RelB, we now know that noncanonical signaling also controls NFκB RelA and cRel. Here, we aim to clarify our understanding of the molecular network that mediates noncanonical NFκB signaling and review the human diseases that result from a deficient or hyper-active noncanonical NFκB pathway. It turns out that dysregulation of RelA and cRel, not RelB, is often implicated in mediating the resulting pathology. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Cancer > Molecular and Cellular Physiology Immune System Diseases > Stem Cells and Development.
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Affiliation(s)
- Benancio N. Rodriguez
- Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA; Molecular Biology Institute, Los Angeles, CA
| | - Helen Huang
- Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA; Institute for Quantitative and Computational Biosciences, Los Angeles, CA
| | - Jennifer J. Chia
- Department of Microbiology, Immunology, and Molecular Genetics, Los Angeles, CA; Molecular Biology Institute, Los Angeles, Calif; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA
| | - Alexander Hoffmann
- Department of Microbiology, Immunology, and Molecular Genetics; Molecular Biology Institute; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA
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Tang GX, Li ML, Zhou C, Huang ZS, Chen SB, Chen XC, Tan JH. Mitochondrial RelA empowers mtDNA G-quadruplex formation for hypoxia adaptation in cancer cells. Cell Chem Biol 2024; 31:1800-1814.e7. [PMID: 38821064 DOI: 10.1016/j.chembiol.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 03/04/2024] [Accepted: 05/07/2024] [Indexed: 06/02/2024]
Abstract
Mitochondrial DNA (mtDNA) G-quadruplexes (G4s) have important regulatory roles in energy metabolism, yet their specific functions and underlying regulatory mechanisms have not been delineated. Using a chemical-genetic screening strategy, we demonstrated that the JAK/STAT3 pathway is the primary regulatory mechanism governing mtDNA G4 dynamics in hypoxic cancer cells. Further proteomic analysis showed that activation of the JAK/STAT3 pathway facilitates the translocation of RelA, a member of the NF-κB family, to the mitochondria, where RelA binds to mtDNA G4s and promotes their folding, resulting in increased mtDNA instability, inhibited mtDNA transcription, and subsequent mitochondrial dysfunction. This binding event disrupts the equilibrium of energy metabolism, catalyzing a metabolic shift favoring glycolysis. Collectively, the results provide insights into a strategy employed by cancer cells to adapt to hypoxia through metabolic reprogramming.
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Affiliation(s)
- Gui-Xue Tang
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Mao-Lin Li
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Cui Zhou
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Shu Huang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Shuo-Bin Chen
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xiu-Cai Chen
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China.
| | - Jia-Heng Tan
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
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9
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Yang CY, Tseng YC, Tu YF, Kuo BJ, Hsu LC, Lien CI, Lin YS, Wang YT, Lu YC, Su TW, Lo YC, Lin SC. Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes. Nat Commun 2024; 15:8974. [PMID: 39419969 PMCID: PMC11487272 DOI: 10.1038/s41467-024-53306-1] [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: 06/07/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024] Open
Abstract
cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions.
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Affiliation(s)
- Chao-Yu Yang
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Yi-Chun Tseng
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yi-Fan Tu
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Bai-Jiun Kuo
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Li-Chung Hsu
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
- Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
| | - Chia-I Lien
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
| | - You-Sheng Lin
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
| | - Yin-Ting Wang
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Yen-Chen Lu
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Tsung-Wei Su
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Yu-Chih Lo
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan.
| | - Su-Chang Lin
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
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10
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Fogarasi M, Dima S. Immunomodulatory Functions of TNF-Related Apoptosis-Inducing Ligand in Type 1 Diabetes. Cells 2024; 13:1676. [PMID: 39451194 PMCID: PMC11506310 DOI: 10.3390/cells13201676] [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: 09/02/2024] [Revised: 10/01/2024] [Accepted: 10/09/2024] [Indexed: 10/26/2024] Open
Abstract
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF protein superfamily and was initially identified as a protein capable of inducing apoptosis in cancer cells. In addition, TRAIL can promote pro-survival and proliferation signaling in various cell types. Subsequent studies have demonstrated that TRAIL plays several important roles in immunoregulation, immunosuppression, and immune effector functions. Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia due to the loss of insulin-producing β-cells, primarily driven by T-cell-mediated pancreatic islet inflammation. Various genetic, epigenetic, and environmental factors, in conjunction with the immune system, contribute to the initiation, development, and progression of T1D. Recent reports have highlighted TRAIL as an important immunomodulatory molecule with protective effects on pancreatic islets. Experimental data suggest that TRAIL protects against T1D by reducing the proliferation of diabetogenic T cells and pancreatic islet inflammation and restoring normoglycemia in animal models. In this review, we aimed to summarize the consequences of TRAIL action in T1D, focusing on and discussing its signaling mechanisms, role in the immune system, and protective effects in T1D.
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Affiliation(s)
- Marton Fogarasi
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Simona Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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11
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Tebbi CK, Yan J, Sahakian E, Mediavilla-Varela M, Pinilla-Ibarz J, Patel S, Rottinghaus GE, Liu RY, Dennison C. Mycovirus-Containing Aspergillus flavus Alters Transcription Factors in Normal and Acute Lymphoblastic Leukemia Cells. Int J Mol Sci 2024; 25:10361. [PMID: 39408690 PMCID: PMC11476453 DOI: 10.3390/ijms251910361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 09/08/2024] [Accepted: 09/12/2024] [Indexed: 10/20/2024] Open
Abstract
Transcription factors control genes to maintain normal hemopoiesis, and dysregulation of some factors can lead to acute lymphoblastic leukemia (ALL). Mycoviruses are known to alter the genetics of their fungal host. The present study evaluates the effects of the products of a mycovirus-containing Aspergillus flavus (MCAF), isolated from the home of a patient with ALL, on certain transcription factors of normal and ALL cell lines. Our published studies have shown that ALL patients have antibodies to MCAF, and that exposure of the mononuclear leukocytes of patients in complete remission to its products, unlike controls, results in the re-development of genetic and cell surface phenotypes characteristic of ALL. For the present study, normal, pre-B, and B-cell leukemia cell lines were exposed to the culture of MCAF. Pre- and post-exposure levels of PAX5, Ikaros, and NF-κB were assessed. Exposure to MCAF resulted in apoptosis, cell cycle changes, and complete downregulation of all transcription factors in normal cell lines. In acute leukemia cell lines, cellular apoptosis and alterations in the cell cycle were also noted; however, while there was downregulation of all tested transcription factors, residual levels were retained. The noted alterations in the transcription factors caused by MCAF are novel findings. The possible role of MCAF in leukemogenesis needs to be further investigated. Mycovirus-containing Aspergillus flavus was initially isolated from a leukemia patient's home. Our prior published studies have illuminated intriguing associations of this organism with leukemia. Unlike controls, patients diagnosed with acute lymphoblastic leukemia (ALL) harbor antibodies to this organism. Furthermore, the exposure of mononuclear cells from patients with ALL in complete remission to the products of this organism reproduced genetic and cell phenotypes characteristic of ALL. These findings underscore the potential role of environmental factors in leukemogenesis and hint at novel avenues for therapeutic intervention and preventive strategies.
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Affiliation(s)
- Cameron K. Tebbi
- Children’s Cancer Research Group Laboratory, Tampa, FL 33613, USA; (J.Y.); (R.Y.L.)
| | - Jiyu Yan
- Children’s Cancer Research Group Laboratory, Tampa, FL 33613, USA; (J.Y.); (R.Y.L.)
| | - Eva Sahakian
- Moffitt Cancer Center, Tampa, FL 33612, USA; (E.S.); (M.M.-V.); (J.P.-I.)
| | | | | | | | | | - Rachel Y. Liu
- Children’s Cancer Research Group Laboratory, Tampa, FL 33613, USA; (J.Y.); (R.Y.L.)
| | - Clare Dennison
- Diagnostic Laboratories, College of Veterinary Medicine, University of South Florida, Tampa, FL 33620, USA;
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12
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Sun ND, Carr AR, Krogman EN, Chawla Y, Zhong J, Guttormson MC, Chan M, Hsu MA, Dong H, Bogunovic D, Pandey A, Rogers LM, Ting AT. TBK1 and IKKε protect target cells from IFNγ-mediated T cell killing via an inflammatory apoptotic mechanism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.06.606693. [PMID: 39149268 PMCID: PMC11326184 DOI: 10.1101/2024.08.06.606693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Cytotoxic T cells produce interferon gamma (IFNγ), which plays a critical role in anti-microbial and anti-tumor responses. However, it is not clear whether T cell-derived IFNγ directly kills infected and tumor target cells, and how this may be regulated. Here, we report that target cell expression of the kinases TBK1 and IKKε regulate IFNγ cytotoxicity by suppressing the ability of T cell-derived IFNγ to kill target cells. In tumor targets lacking TBK1 and IKKε, IFNγ induces expression of TNFR1 and the Z-nucleic acid sensor, ZBP1, to trigger RIPK1-dependent apoptosis, largely in a target cell-autonomous manner. Unexpectedly, IFNγ, which is not known to signal to NFκB, induces hyperactivation of NFκB in TBK1 and IKKε double-deficient cells. TBK1 and IKKε suppress IKKα/β activity and in their absence, IFNγ induces elevated NFκB-dependent expression of inflammatory chemokines and cytokines. Apoptosis is thought to be non-inflammatory, but our observations demonstrate that IFNγ can induce an inflammatory form of apoptosis, and this is suppressed by TBK1 and IKKε. The two kinases provide a critical connection between innate and adaptive immunological responses by regulating three key responses: (1) phosphorylation of IRF3/7 to induce type I IFN; (2) inhibition of RIPK1-dependent death; and (3) inhibition of NFκB-dependent inflammation. We propose that these kinases evolved these functions such that their inhibition by pathogens attempting to block type I IFN expression would enable IFNγ to trigger apoptosis accompanied by an alternative inflammatory response. Our findings show that loss of TBK1 and IKKε in target cells sensitizes them to inflammatory apoptosis induced by T cell-derived IFNγ.
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Affiliation(s)
- Nicholas D. Sun
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Allison R. Carr
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Yogesh Chawla
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Jun Zhong
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Mark Chan
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Michelle A. Hsu
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Haidong Dong
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
- Department of Urology, Mayo Clinic, Rochester, MN 55905, USA
| | - Dusan Bogunovic
- Columbia Center for Genetic Errors of Immunity, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Laura M. Rogers
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
| | - Adrian T. Ting
- Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA
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13
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Wang Y, Chen Z, Zhu Q, Chen Z, Fu G, Ma B, Zhang W. Aiming at early-stage vulnerable plaques: A nanoplatform with dual-mode imaging and lipid-inflammation integrated regulation for atherosclerotic theranostics. Bioact Mater 2024; 37:94-105. [PMID: 38523705 PMCID: PMC10957523 DOI: 10.1016/j.bioactmat.2024.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 02/19/2024] [Accepted: 03/13/2024] [Indexed: 03/26/2024] Open
Abstract
The vulnerable plaques in atherosclerosis can cause severe outcome with great danger of acute cardiovascular events. Thus, timely diagnosis and treatment of vulnerable plaques in early stage can effectively benefit the clinical management of atherosclerosis. In this work, a targeting theranostic strategy on early-stage vulnerable plaques in atherosclerosis is realized by a LAID nanoplatform with X-CT and fluorescent dual-mode imaging and lipid-inflammation integrated regulation abilities. The iodinated contrast agents (ICA), phenylboronic acid modified astaxanthin and oxidized-dextran (oxDEX) jointly construct the nanoparticles loaded with the lipid-specific probe LFP. LAID indicates an active targeting to plaques along with the dual-responsive disassembly in oxidative stress and acidic microenvironment of atherosclerosis. The X-CT signals of ICA execute the location of early-stage plaques, while the LFP combines with lipid cores and realizes the recognition of vulnerable plaques. Meanwhile, the treatment based on astaxanthin is performed for restraining the progression of plaques. Transcriptome sequencing suggests that LAID can inhibit the lipid uptake and block NF-κB pathway, which synergistically demonstrates a lipid-inflammation integrated regulation to suppression the plaques growing. The in vivo investigations suggest that LAID delivers a favorable theranostics to the early-stage vulnerable plaques, which provides an impressive prospect for reducing the adverse prognosis of atherosclerosis.
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Affiliation(s)
- Yao Wang
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Zhebin Chen
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Qiongjun Zhu
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Zhezhe Chen
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Guosheng Fu
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Boxuan Ma
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China
| | - Wenbin Zhang
- Department of Cardiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, China
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14
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Sahu D, Gupta C, Yennamalli RM, Sharma S, Roy S, Hasan S, Gupta P, Sharma VK, Kashyap S, Kumar S, Dwivedi VP, Zhao X, Panda AK, Das HR, Liu CJ. Novel peptide inhibitor of human tumor necrosis factor-α has antiarthritic activity. Sci Rep 2024; 14:12935. [PMID: 38839973 PMCID: PMC11153517 DOI: 10.1038/s41598-024-63790-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 06/03/2024] [Indexed: 06/07/2024] Open
Abstract
The inhibition of tumor necrosis factor (TNF)-α trimer formation renders it inactive for binding to its receptors, thus mitigating the vicious cycle of inflammation. We designed a peptide (PIYLGGVFQ) that simulates a sequence strand of human TNFα monomer using a series of in silico methods, such as active site finding (Acsite), protein-protein interaction (PPI), docking studies (GOLD and Flex-X) followed by molecular dynamics (MD) simulation studies. The MD studies confirmed the intermolecular interaction of the peptide with the TNFα. Fluorescence-activated cell sorting and fluorescence microscopy revealed that the peptide effectively inhibited the binding of TNF to the cell surface receptors. The cell culture assays showed that the peptide significantly inhibited the TNFα-mediated cell death. In addition, the nuclear translocation of the nuclear factor kappa B (NFκB) was significantly suppressed in the peptide-treated A549 cells, as observed in immunofluorescence and gel mobility-shift assays. Furthermore, the peptide protected against joint damage in the collagen-induced arthritis (CIA) mouse model, as revealed in the micro focal-CT scans. In conclusion, this TNFα antagonist would be helpful for the prevention and repair of inflammatory bone destruction and subsequent loss in the mouse model of CIA as well as human rheumatoid arthritis (RA) patients. This calls upon further clinical investigation to utilize its potential effect as an antiarthritic drug.
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Affiliation(s)
- Debasis Sahu
- Product Development Cell, National Institute of Immunology, New Delhi, India.
- Department of Orthopedics Surgery, New York University School of Medicine, New York, NY, USA.
- Science Habitat, Ubioquitos Inc, London, ON, Canada.
| | - Charu Gupta
- School of Biomedical Sciences, Galgotias University, Greater Noida, UP, India
- CSIR-Institute of Genomics and Integrative Biology, Delhi, India
| | - Ragothaman M Yennamalli
- Department of Bioinformatics, School of Chemical and Biotechnology, SASTRA Deemed to Be University, Thanjavur, Tamil Nadu, India
| | - Shikha Sharma
- Amity Institute of Forensic Sciences, Amity University, Noida, Uttar Pradesh, India
- Science Habitat, Ubioquitos Inc, London, ON, Canada
| | - Saugata Roy
- CSIR-Institute of Genomics and Integrative Biology, Delhi, India
| | - Sadaf Hasan
- Department of Orthopedics Surgery, New York University School of Medicine, New York, NY, USA
| | - Pawan Gupta
- Department of Pharmaceutical Chemistry, Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule, Maharashtra, India
| | - Vishnu Kumar Sharma
- Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Mohali, Punjab, India
| | - Sujit Kashyap
- Division of Pediatric Rheumatology, University of California San Francisco, San Francisco, CA, USA
- Department of Genetics, University of Delhi, Delhi, India
| | - Santosh Kumar
- Immunobiology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Ved Prakash Dwivedi
- Immunobiology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India
| | - Xiangli Zhao
- Department of Orthopedics Surgery, New York University School of Medicine, New York, NY, USA
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
| | - Amulya Kumar Panda
- Product Development Cell, National Institute of Immunology, New Delhi, India
| | - Hasi Rani Das
- CSIR-Institute of Genomics and Integrative Biology, Delhi, India
| | - Chuan-Ju Liu
- Department of Orthopedics Surgery, New York University School of Medicine, New York, NY, USA
- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
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15
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Yang CY, Lien CI, Tseng YC, Tu YF, Kulczyk AW, Lu YC, Wang YT, Su TW, Hsu LC, Lo YC, Lin SC. Deciphering DED assembly mechanisms in FADD-procaspase-8-cFLIP complexes regulating apoptosis. Nat Commun 2024; 15:3791. [PMID: 38710704 PMCID: PMC11074299 DOI: 10.1038/s41467-024-47990-2] [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: 02/04/2024] [Accepted: 04/17/2024] [Indexed: 05/08/2024] Open
Abstract
Fas-associated protein with death domain (FADD), procaspase-8, and cellular FLICE-inhibitory proteins (cFLIP) assemble through death-effector domains (DEDs), directing death receptor signaling towards cell survival or apoptosis. Understanding their three-dimensional regulatory mechanism has been limited by the absence of atomic coordinates for their ternary DED complex. By employing X-ray crystallography and cryogenic electron microscopy (cryo-EM), we present the atomic coordinates of human FADD-procaspase-8-cFLIP complexes, revealing structural insights into these critical interactions. These structures illustrate how FADD and cFLIP orchestrate the assembly of caspase-8-containing complexes and offer mechanistic explanations for their role in promoting or inhibiting apoptotic and necroptotic signaling. A helical procaspase-8-cFLIP hetero-double layer in the complex appears to promote limited caspase-8 activation for cell survival. Our structure-guided mutagenesis supports the role of the triple-FADD complex in caspase-8 activation and in regulating receptor-interacting protein kinase 1 (RIPK1). These results propose a unified mechanism for DED assembly and procaspase-8 activation in the regulation of apoptotic and necroptotic signaling across various cellular pathways involved in development, innate immunity, and disease.
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Grants
- AS-TP-107-L16, AS-TP-107-L16-1, AS-102-TP-B14 and AS-102-TP-B14-2 Academia Sinica
- AS-TP-107-L16-2 and AS-102-TP-B14-1 Academia Sinica
- AS-TP-107-L16-3 Academia Sinica
- MoST 107-2320-B-001-018-, 108-2311-B-001-018-, 109-2311-B-001-016-, and 110-2311-B-001-015- Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- MoST 107-2320-B-006-062-MY3, and 111-2311-B-006-005-MY3 Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
- MoST 108-2320-B-002-020-MY3, 111-2320-B-002-048-MY3, and 112-2326-B-002-007- Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)
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Affiliation(s)
- Chao-Yu Yang
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Chia-I Lien
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan
| | - Yi-Chun Tseng
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yi-Fan Tu
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Arkadiusz W Kulczyk
- Institute for Quantitative Biomedicine, Rutgers University, Department of Biochemistry and Microbiology, Rutgers University, Piscataway, NJ, 08854, USA
| | - Yen-Chen Lu
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan
| | - Yin-Ting Wang
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Tsung-Wei Su
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan
| | - Li-Chung Hsu
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan.
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 10002, Taiwan.
| | - Yu-Chih Lo
- Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan.
| | - Su-Chang Lin
- Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
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16
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Yarahmadi A, Zare M, Aghayari M, Afkhami H, Jafari GA. Therapeutic bacteria and viruses to combat cancer: double-edged sword in cancer therapy: new insights for future. Cell Commun Signal 2024; 22:239. [PMID: 38654309 PMCID: PMC11040964 DOI: 10.1186/s12964-024-01622-w] [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: 12/04/2023] [Accepted: 04/17/2024] [Indexed: 04/25/2024] Open
Abstract
Cancer, ranked as the second leading cause of mortality worldwide, leads to the death of approximately seven million people annually, establishing itself as one of the most significant health challenges globally. The discovery and identification of new anti-cancer drugs that kill or inactivate cancer cells without harming normal and healthy cells and reduce adverse effects on the immune system is a potential challenge in medicine and a fundamental goal in Many studies. Therapeutic bacteria and viruses have become a dual-faceted instrument in cancer therapy. They provide a promising avenue for cancer treatment, but at the same time, they also create significant obstacles and complications that contribute to cancer growth and development. This review article explores the role of bacteria and viruses in cancer treatment, examining their potential benefits and drawbacks. By amalgamating established knowledge and perspectives, this review offers an in-depth examination of the present research landscape within this domain and identifies avenues for future investigation.
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Affiliation(s)
- Aref Yarahmadi
- Department of Biology, Khorramabad Branch, Islamic Azad University, Khorramabad, Iran
| | - Mitra Zare
- Department of Microbiology, Faculty of Sciences, Kerman Branch, Islamic Azad University, Kerman, Iran
| | - Masoomeh Aghayari
- Department of Microbiology, Faculty of Sciences, Urmia Branch, Islamic Azad University, Urmia, Iran
| | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran.
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran.
| | - Gholam Ali Jafari
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
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17
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Rahman SMT, Singh A, Lowe S, Aqdas M, Jiang K, Vaidehi Narayanan H, Hoffmann A, Sung MH. Co-imaging of RelA and c-Rel reveals features of NF-κB signaling for ligand discrimination. Cell Rep 2024; 43:113940. [PMID: 38483906 PMCID: PMC11015162 DOI: 10.1016/j.celrep.2024.113940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 12/11/2023] [Accepted: 02/23/2024] [Indexed: 04/02/2024] Open
Abstract
Individual cell sensing of external cues has evolved through the temporal patterns in signaling. Since nuclear factor κB (NF-κB) signaling dynamics have been examined using a single subunit, RelA, it remains unclear whether more information might be transmitted via other subunits. Using NF-κB double-knockin reporter mice, we monitored both canonical NF-κB subunits, RelA and c-Rel, simultaneously in single macrophages by quantitative live-cell imaging. We show that signaling features of RelA and c-Rel convey more information about the stimuli than those of either subunit alone. Machine learning is used to predict the ligand identity accurately based on RelA and c-Rel signaling features without considering the co-activated factors. Ligand discrimination is achieved through selective non-redundancy of RelA and c-Rel signaling dynamics, as well as their temporal coordination. These results suggest a potential role of c-Rel in fine-tuning immune responses and highlight the need for approaches that will elucidate the mechanisms regulating NF-κB subunit specificity.
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Affiliation(s)
- Shah Md Toufiqur Rahman
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Apeksha Singh
- Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Sarina Lowe
- Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Mohammad Aqdas
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Kevin Jiang
- Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Haripriya Vaidehi Narayanan
- Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Alexander Hoffmann
- Institute for Quantitative and Computational Biosciences and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA
| | - Myong-Hee Sung
- Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
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18
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Preedy MK, White MRH, Tergaonkar V. Cellular heterogeneity in TNF/TNFR1 signalling: live cell imaging of cell fate decisions in single cells. Cell Death Dis 2024; 15:202. [PMID: 38467621 PMCID: PMC10928192 DOI: 10.1038/s41419-024-06559-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 03/13/2024]
Abstract
Cellular responses to TNF are inherently heterogeneous within an isogenic cell population and across different cell types. TNF promotes cell survival by activating pro-inflammatory NF-κB and MAPK signalling pathways but may also trigger apoptosis and necroptosis. Following TNF stimulation, the fate of individual cells is governed by the balance of pro-survival and pro-apoptotic signalling pathways. To elucidate the molecular mechanisms driving heterogenous responses to TNF, quantifying TNF/TNFR1 signalling at the single-cell level is crucial. Fluorescence live-cell imaging techniques offer real-time, dynamic insights into molecular processes in single cells, allowing for detection of rapid and transient changes, as well as identification of subpopulations, that are likely to be missed with traditional endpoint assays. Whilst fluorescence live-cell imaging has been employed extensively to investigate TNF-induced inflammation and TNF-induced cell death, it has been underutilised in studying the role of TNF/TNFR1 signalling pathway crosstalk in guiding cell-fate decisions in single cells. Here, we outline the various opportunities for pathway crosstalk during TNF/TNFR1 signalling and how these interactions may govern heterogenous responses to TNF. We also advocate for the use of live-cell imaging techniques to elucidate the molecular processes driving cell-to-cell variability in single cells. Understanding and overcoming cellular heterogeneity in response to TNF and modulators of the TNF/TNFR1 signalling pathway could lead to the development of targeted therapies for various diseases associated with aberrant TNF/TNFR1 signalling, such as rheumatoid arthritis, metabolic syndrome, and cancer.
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Affiliation(s)
- Marcus K Preedy
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
- Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Michael Smith Building, D3308, Dover Street, Manchester, M13 9PT, England, UK
| | - Michael R H White
- Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Michael Smith Building, D3308, Dover Street, Manchester, M13 9PT, England, UK.
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore.
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 8 Medical Drive, MD7, Singapore, 117596, Singapore.
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19
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Gao Q, Feng Y, Gong T, Wu D, Zheng X, Luo Y, Yang Y, Song Z, Gong L, Zhang G. Porcine enteric alphacoronavirus infection increases lipid droplet accumulation to facilitate the virus replication. JOURNAL OF INTEGRATIVE AGRICULTURE 2024; 23:988-1005. [DOI: 10.1016/j.jia.2023.10.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Cooper E, Oyagawa CRM, Johnson R, Choi PJ, Foliaki JM, Correia J, Schweder P, Heppner P, Mee E, Turner C, Faull R, Denny WA, Dragunow M, Jose J, Park TIH. Involvement of the tumour necrosis factor receptor system in glioblastoma cell death induced by palbociclib-heptamethine cyanine dye conjugate. Cell Commun Signal 2024; 22:30. [PMID: 38212807 PMCID: PMC10782607 DOI: 10.1186/s12964-023-01277-z] [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: 05/31/2023] [Accepted: 08/14/2023] [Indexed: 01/13/2024] Open
Abstract
Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-brain cancer agents are challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery. We conjugated palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, to an HMCD, MHI-148, and conducted drug activity analysis on primary patient-derived glioblastoma cell lines. In addition to the expected cytostatic activity, our in vitro studies revealed that palbociclib-MHI-148 conjugate resulted in an almost 100-fold increase in cytotoxicity compared to palbociclib alone. This shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI-148 was due to increased DNA damage, as indicated by an increase in γH2AX foci, followed by an increased expression of key extrinsic apoptosis genes, including TP53, TNFR1, TRAIL, FADD and caspase 8. In addition, we observed a time-dependent increase in the cell surface expression of TNFR1, consistent with an observed increase in the secretion TNFα, followed by TNFR1 endocytosis at 48 h. The treatment of patient GBM cells with the palbociclib-MHI-148 conjugate prevented TNFα-induced NFκB translocation, suggesting conjugate-induced TNFR1 signalling favoured the TNFR1-mediated apoptotic response rather than the pro-inflammatory response pathway. Notably, pharmacological inhibition of endocytosis of TNFR1, and siRNA-knockdown of TNFR1 reversed the palbociclib-MHI-148-induced cell death. These results show a novel susceptibility of glioblastoma cells to TNFR1-dependent apoptosis, dependent on inhibition of canonical NFκB signalling using our previously reported palbociclib-HMCD conjugate. Video Abstract.
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Affiliation(s)
- Elizabeth Cooper
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Caitlin R M Oyagawa
- Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Rebecca Johnson
- Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Peter J Choi
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Jena Macapagal Foliaki
- Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Jason Correia
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Department of Neurosurgery, Auckland City Hospital, Private Bag 92024, Auckland, 1142, New Zealand
| | - Patrick Schweder
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Department of Neurosurgery, Auckland City Hospital, Private Bag 92024, Auckland, 1142, New Zealand
| | - Peter Heppner
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Department of Neurosurgery, Auckland City Hospital, Private Bag 92024, Auckland, 1142, New Zealand
| | - Edward Mee
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Department of Neurosurgery, Auckland City Hospital, Private Bag 92024, Auckland, 1142, New Zealand
| | - Clinton Turner
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
- Department of Anatomical Pathology, Auckland City Hospital, 2 Park Road, LabPlus, Auckland, New Zealand
| | - Richard Faull
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - William A Denny
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
| | - Mike Dragunow
- Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
| | - Jiney Jose
- Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
| | - Thomas I-H Park
- Department of Pharmacology, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
- Neurosurgery Research Unit, The Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.
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21
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Davidovich P, Higgins CA, Najda Z, Longley DB, Martin SJ. cFLIP L acts as a suppressor of TRAIL- and Fas-initiated inflammation by inhibiting assembly of caspase-8/FADD/RIPK1 NF-κB-activating complexes. Cell Rep 2023; 42:113476. [PMID: 37988267 DOI: 10.1016/j.celrep.2023.113476] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 08/16/2023] [Accepted: 11/03/2023] [Indexed: 11/23/2023] Open
Abstract
TRAIL and FasL are potent inducers of apoptosis but can also promote inflammation through assembly of cytoplasmic caspase-8/FADD/RIPK1 (FADDosome) complexes, wherein caspase-8 acts as a scaffold to drive FADD/RIPK1-mediated nuclear factor κB (NF-κB) activation. cFLIP is also recruited to FADDosomes and restricts caspase-8 activity and apoptosis, but whether cFLIP also regulates death receptor-initiated inflammation is unclear. Here, we show that silencing or deletion of cFLIP leads to robustly enhanced Fas-, TRAIL-, or TLR3-induced inflammatory cytokine production, which can be uncoupled from the effects of cFLIP on caspase-8 activation and apoptosis. Mechanistically, cFLIPL suppresses Fas- or TRAIL-initiated NF-κB activation through inhibiting the assembly of caspase-8/FADD/RIPK1 FADDosome complexes, due to the low affinity of cFLIPL for FADD. Consequently, increased cFLIPL occupancy of FADDosomes diminishes recruitment of FADD/RIPK1 to caspase-8, thereby suppressing NF-κB activation and inflammatory cytokine production downstream. Thus, cFLIP acts as a dual suppressor of apoptosis and inflammation via distinct modes of action.
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Affiliation(s)
- Pavel Davidovich
- Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Catherine A Higgins
- Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK
| | - Zaneta Najda
- Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland
| | - Daniel B Longley
- Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK
| | - Seamus J Martin
- Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
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22
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Kizilirmak C, Monteleone E, García-Manteiga JM, Brambilla F, Agresti A, Bianchi ME, Zambrano S. Small transcriptional differences among cell clones lead to distinct NF-κB dynamics. iScience 2023; 26:108573. [PMID: 38144455 PMCID: PMC10746373 DOI: 10.1016/j.isci.2023.108573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 10/06/2023] [Accepted: 11/21/2023] [Indexed: 12/26/2023] Open
Abstract
Transcription factor dynamics is fundamental to determine the activation of accurate transcriptional programs and yet is heterogeneous at a single-cell level, even within homogeneous populations. We asked how such heterogeneity emerges for the nuclear factor κB (NF-κB). We found that clonal populations of immortalized fibroblasts derived from a single mouse embryo display robustly distinct NF-κB dynamics upon tumor necrosis factor ɑ (TNF-ɑ) stimulation including persistent, oscillatory, and weak activation, giving rise to differences in the transcription of its targets. By combining transcriptomics and simulations we show how less than two-fold differences in the expression levels of genes coding for key proteins of the signaling cascade and feedback system are predictive of the differences of the NF-κB dynamic response of the clones to TNF-ɑ and IL-1β. We propose that small transcriptional differences in the regulatory circuit of a transcription factor can lead to distinct signaling dynamics in cells within homogeneous cell populations and among different cell types.
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Affiliation(s)
- Cise Kizilirmak
- School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
- Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Emanuele Monteleone
- School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
- Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | | | - Francesca Brambilla
- Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Alessandra Agresti
- Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Marco E. Bianchi
- School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
- Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Samuel Zambrano
- School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
- Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
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23
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Sarıekiz FG, Tomatır AG, Tokgün PE, Bir LS. Evaluation of Long Non-coding RNA Expression Profiles in Peripheral Blood Mononuclear Cells of Patients with Parkinson's Disease. Mol Neurobiol 2023; 60:6201-6211. [PMID: 37436601 DOI: 10.1007/s12035-023-03470-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 06/29/2023] [Indexed: 07/13/2023]
Abstract
As in many biological processes, the long non-coding RNAs (lncRNA) are currently known to have important roles in Parkinson's disease (PD). The aim of the study is to evaluate differentiated expressions of lncRNAs and their target mRNAs in the peripheral blood cells of individuals with Parkinson's disease. The peripheral blood samples were taken from 10 Parkinson's diagnosed people aging 50 years and more and from 10 healthy people as for the control group. Total RNA was isolated from peripheral blood mononuclear cells (PBMC), and a total of 5 samples were selected and evaluated by microarray analysis. lncRNAs with high fold change (fc < 1.5/fc > 1.5) were determined as a result of the analysis. Following this, the expression changes of some lncRNAs and their target mRNAs were examined by quantitative simultaneous polymerase chain reaction (qRT-PCR) in all individuals in the patient and control groups. Also, in order to determine the molecular level basic activities of lncRNAs determined by microarray analysis and which biological process and biochemical pathway they were in, Gene Ontology (GO) analysis ( http://geneontology.org/ ) database was used. Thirteen upregulated and 31 downregulated lncRNAs whose expression changes were determined by microarray analysis and confirmed by qRT-PCR method were found in Parkinson's patients. As they were evaluated by GO analysis, lncRNAs were expressed differently in patient and control groups and they are found to be related with the processes such as macromolecule metabolic processes, immune system, gene expression, cell activation, ATPase activity, DNA packaging complex, signal receptor activity, immune receptor activity, and protein binding were found to be significant.
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Affiliation(s)
- Fatma Gizem Sarıekiz
- Department of Medical Biology, Faculty of Medicine, Pamukkale University, Kınıklı/Denizli, Turkey.
| | - Ayşe Gaye Tomatır
- Department of Medical Biology, Faculty of Medicine, Pamukkale University, Kınıklı/Denizli, Turkey
| | - Pervin Elvan Tokgün
- Department of Medical Genetics, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Levent Sinan Bir
- Department of Neurology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
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24
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Han N, Jiang W, Li G, Lu L, Shan J, Feng L, Jin L. Low-intensity pulsed ultrasound at ST36 improves the gastric motility by TNF-α/IKKβ/NF-κB signaling pathway in diabetic rats. J Gastroenterol Hepatol 2023; 38:2018-2026. [PMID: 37581362 DOI: 10.1111/jgh.16321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/17/2023] [Accepted: 07/25/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND AND AIM Low-intensity pulsed ultrasound (LIPUS) can effectively regulate the central and peripheral nervous system. However, whether LIPUS could act on acupuncture points to modulate the activity of peripheral nervous has rarely been studied. Our study aimed to investigate whether LIPUS at ST36 could improve gastric emptying in diabetic gastroparesis rats. METHODS Sprague-Dawley male rats were divided into three groups: control group (CON), diabetic gastroparesis group (DM), and diabetic gastroparesis LIPUS treated group (LIPUS). The body weight and blood glucose were recorded every week. Glucose tolerance, gastric emptying rate, and gastric motility were measured before and after treatment. Gastric motility was assessed by ultrasonic examination and Muscle strip experiment. The expression level of c-Kit was assessed by immunohistochemistry staining. Levels of TNF-α, p-NF-κB p-65, NF-κB p-65, and p-IKKβ, IKKβ were measured by western blot. RESULTS We reported LIPUS at an intensity of 0.88 W/cm2 exhibited significant differences in functional recovery of gastric delayed emptying in diabetic rats. Through ultrasound gastric motility functional testing and analysis of gastric antral smooth muscle strips indirectly and directly proved the effectiveness of LIPUS for the recovery of gastric delayed emptying. Pathological analysis and western blot indicated that the mechanism by which LIPUS applied to ST36 improved gastric motility may be partially attributed to the inhibition of the TNF-α/IKKβ/NF-κB signaling pathway, thereby rescuing the damaged interstitial cells of Cajal network. CONCLUSION LIPUS at ST36 improved the gastric motility and rescued the damaged networks of interstitial cells of Cajal. LIPUS may have a promising therapeutic potential for diabetic gastroparesis.
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Affiliation(s)
- Nie Han
- Department of Ultrasound, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- School of Exercise and Health, Shanghai University of Sport, Shanghai, China
| | - Weijun Jiang
- Department of Gastroenterology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guanheng Li
- Department of Ultrasound, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lingling Lu
- Department of Ultrasound, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiali Shan
- Department of Ultrasound, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Lan Feng
- Department of Ultrasound, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Lin Jin
- Department of Ultrasound, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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25
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Alhazzani K, Almangour A, Alsalem A, Alqinyah M, Alhamed AS, Alhamami HN, Alanazi AZ. Examining the Effects of Dasatinib, Sorafenib, and Nilotinib on Vascular Smooth Muscle Cells: Insights into Proliferation, Migration, and Gene Expression Dynamics. Diseases 2023; 11:147. [PMID: 37873791 PMCID: PMC10594443 DOI: 10.3390/diseases11040147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/17/2023] [Accepted: 10/21/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND Dasatinib, nilotinib, and sorafenib are clinically proven tyrosine kinase inhibitors (TKIs) used for the treatment of leukemia and hepatocellular carcinoma. However, there is a growing concern regarding cardiotoxicity associated with their use. The impact of these TKIs on vascular smooth muscle cells (VSMCs) remains unexplored. This study aims to investigate the effects of TKIs on VSMC proliferation and migration, as well as to elucidate the underlying mechanisms involving inflammatory and apoptotic pathways. METHODS VSMCs were extracted from albino rats and cultured in vitro. The cells were divided into four experimental groups: control, dasatinib, sorafenib, and nilotinib. The MTT assay was employed to assess the cytotoxic effects of TKIs on VSMCs. A scratch assay was conducted to evaluate the inhibitory potential of TKIs on VSMC migration. Flow cytometry analysis was used to detect apoptotic cells. Real-Time PCR expression was utilized to determine the differential gene expression of apoptotic and inflammatory markers. RESULTS Dasatinib, nilotinib, and sorafenib demonstrated significant inhibitory effects on VSMC viability and migration at low concentrations (<1 µmol/L, p < 0.05). Furthermore, gene expression analysis revealed up-regulation of inflammatory biomarkers (TNF-α, IL-6, and IL-1β) and apoptotic markers (P53, BAX), along with down-regulation of the anti-apoptotic biomarker BCL-2 in response to all TKIs. CONCLUSIONS This study demonstrates that dasatinib, nilotinib, and sorafenib inhibit VSMC proliferation and migration, suggesting their potential to induce vascular injury and remodeling by activating inflammation and apoptosis pathways. These findings highlight the need for further investigation into the cardiotoxic effects of these TKIs and the development of strategies to mitigate their adverse vascular effects.
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Affiliation(s)
- Khalid Alhazzani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
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26
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Wu X, Sun L, Xu F. NF-κB in Cell Deaths, Therapeutic Resistance and Nanotherapy of Tumors: Recent Advances. Pharmaceuticals (Basel) 2023; 16:783. [PMID: 37375731 DOI: 10.3390/ph16060783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
The transcription factor nuclear factor-κB (NF-κB) plays a complicated role in multiple tumors. Mounting evidence demonstrates that NF-κB activation supports tumorigenesis and development by enhancing cell proliferation, invasion, and metastasis, preventing cell death, facilitating angiogenesis, regulating tumor immune microenvironment and metabolism, and inducing therapeutic resistance. Notably, NF-κB functions as a double-edged sword exerting positive or negative influences on cancers. In this review, we summarize and discuss recent research on the regulation of NF-κB in cancer cell deaths, therapy resistance, and NF-κB-based nano delivery systems.
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Affiliation(s)
- Xuesong Wu
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Liang Sun
- Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University, Hangzhou 310058, China
| | - Fangying Xu
- Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University, Hangzhou 310058, China
- Department of Pathology and Pathophysiology, and Department of Hepatobiliary and Pancreatic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310005, China
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27
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Ciapała K, Rojewska E, Pawlik K, Ciechanowska A, Mika J. Analgesic Effects of Fisetin, Peimine, Astaxanthin, Artemisinin, Bardoxolone Methyl and 740 Y-P and Their Influence on Opioid Analgesia in a Mouse Model of Neuropathic Pain. Int J Mol Sci 2023; 24:ijms24109000. [PMID: 37240346 DOI: 10.3390/ijms24109000] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Treatment of neuropathic pain remains a challenge for modern medicine due to the insufficiently understood molecular mechanisms of its development and maintenance. One of the most important cascades that modulate the nociceptive response is the family of mitogen-activated protein (MAP) kinases and phosphatidylinositol-3-kinase (PI3K), as well as nuclear factor erythroid 2-related factor 2 (Nrf2). The aim of this study was to determine the effect of nonselective modulators of MAP kinases-fisetin (ERK1/2 and NFκB inhibitor, PI3K activator), peimine (MAPK inhibitor), astaxanthin (MAPK inhibitor, Nrf2 activator) and artemisinin (MAPK inhibitor, NFκB activator), as well as bardoxolone methyl (selective activator of Nrf2) and 740 Y-P (selective activator of PI3K)-in mice with peripheral neuropathy and to compare their antinociceptive potency and examine their effect on analgesia induced by opioids. The study was performed using albino Swiss male mice that were exposed to chronic constriction injury of the sciatic nerve (CCI model). Tactile and thermal hypersensitivity was measured using von Frey and cold plate tests, respectively. Single doses of substances were administered intrathecally on day 7 after CCI. Among the tested substances, fisetin, peimine, and astaxanthin effectively diminished tactile and thermal hypersensitivity in mice after CCI, while artemisinin did not exhibit analgesic potency in this model of neuropathic pain. Additionally, both of the activators tested, bardoxolone methyl and 740 Y-P, also showed analgesic effects after intrathecal administration in mice exposed to CCI. In the case of astaxanthin and bardoxolone methyl, an increase in analgesia after combined administration with morphine, buprenorphine, and/or oxycodone was observed. Fisetin and peimine induced a similar effect on tactile hypersensitivity, where analgesia was enhanced after administration of morphine or oxycodone. In the case of 740 Y-P, the effects of combined administration with each opioid were observed only in the case of thermal hypersensitivity. The results of our research clearly indicate that substances that inhibit all three MAPKs provide pain relief and improve opioid effectiveness, especially if they additionally block NF-κB, such as peimine, inhibit NF-κB and activate PI3K, such as fisetin, or activate Nrf2, such as astaxanthin. In light of our research, Nrf2 activation appears to be particularly beneficial. The abovementioned substances bring promising results, and further research on them will broaden our knowledge regarding the mechanisms of neuropathy and perhaps contribute to the development of more effective therapy in the future.
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Affiliation(s)
- Katarzyna Ciapała
- Department of Pain Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Str., 31-343 Krakow, Poland
| | - Ewelina Rojewska
- Department of Pain Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Str., 31-343 Krakow, Poland
| | - Katarzyna Pawlik
- Department of Pain Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Str., 31-343 Krakow, Poland
| | - Agata Ciechanowska
- Department of Pain Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Str., 31-343 Krakow, Poland
| | - Joanna Mika
- Department of Pain Pharmacology, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Str., 31-343 Krakow, Poland
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28
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Rogers NM, Zammit N, Nguyen-Ngo D, Souilmi Y, Minhas N, Meijles DN, Self E, Walters SN, Warren J, Cultrone D, El-Rashid M, Li J, Chtanova T, O'Connell PJ, Grey ST. The impact of the cytoplasmic ubiquitin ligase TNFAIP3 gene variation on transcription factor NF-κB activation in acute kidney injury. Kidney Int 2023; 103:1105-1119. [PMID: 37097268 DOI: 10.1016/j.kint.2023.02.030] [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: 08/23/2021] [Revised: 02/08/2023] [Accepted: 02/23/2023] [Indexed: 04/26/2023]
Abstract
Nuclear factor κB (NF-κB) activation is a deleterious molecular mechanism that drives acute kidney injury (AKI) and manifests in transplanted kidneys as delayed graft function. The TNFAIP3 gene encodes A20, a cytoplasmic ubiquitin ligase and a master negative regulator of the NF- κB signaling pathway. Common population-specific TNFAIP3 coding variants that reduce A20's enzyme function and increase NF- κB activation have been linked to heightened protective immunity and autoimmune disease, but have not been investigated in AKI. Here, we functionally identified a series of unique human TNFAIP3 coding variants linked to the autoimmune genome-wide association studies single nucleotide polymorphisms of F127C; namely F127C;R22Q, F127C;G281E, F127C;W448C and F127C;N449K that reduce A20's anti-inflammatory function in an NF- κB reporter assay. To investigate the impact of TNFAIP3 hypomorphic coding variants in AKI we tested a mouse Tnfaip3 hypomorph in a model of ischemia reperfusion injury (IRI). The mouse Tnfaip3 coding variant I325N increases NF- κB activation without overt inflammatory disease, providing an immune boost as I325N mice exhibit enhanced innate immunity to a bacterial challenge. Surprisingly, despite exhibiting increased intra-kidney NF- κB activation with inflammation in IRI, the kidney of I325N mice was protected. The I325N variant influenced the outcome of IRI by changing the dynamic expression of multiple cytoprotective mechanisms, particularly by increasing NF- κB-dependent anti-apoptotic factors BCL-2, BCL-XL, c-FLIP and A20, altering the active redox state of the kidney with a reduction of superoxide levels and the enzyme super oxide dismutase-1, and enhancing cellular protective mechanisms including increased Foxp3+ T cells. Thus, TNFAIP3 gene variants represent a kidney and population-specific molecular factor that can dictate the course of IRI.
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Affiliation(s)
- Natasha M Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia; Renal and Transplant Medicine Unit, Westmead Hospital, Westmead, New South Wales, Australia; Westmead Clinical School, University of Sydney, New South Wales, Australia
| | - Nathan Zammit
- Transplantation Immunology Laboratory, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; Translational Research Pillar, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Danny Nguyen-Ngo
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Yassine Souilmi
- Australian Centre for Ancient DNA, School of Biological Sciences, University of Adelaide, South Australia, Australia; Environment Institute, Faculty of Sciences, University of Adelaide, South Australia, Australia
| | - Nikita Minhas
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Daniel N Meijles
- Molecular and Clinical Sciences Research Institute, St George's University of London, London, UK
| | - Eleanor Self
- Transplantation Immunology Laboratory, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; Translational Research Pillar, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Stacey N Walters
- Transplantation Immunology Laboratory, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; Translational Research Pillar, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Joanna Warren
- Transplantation Immunology Laboratory, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; Translational Research Pillar, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Daniele Cultrone
- Transplantation Immunology Laboratory, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; Translational Research Pillar, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
| | - Maryam El-Rashid
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Jennifer Li
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Tatyana Chtanova
- Translational Research Pillar, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; Innate and Tumour Immunology Laboratory, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia
| | - Philip J O'Connell
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia; Renal and Transplant Medicine Unit, Westmead Hospital, Westmead, New South Wales, Australia; Westmead Clinical School, University of Sydney, New South Wales, Australia
| | - Shane T Grey
- Transplantation Immunology Laboratory, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; Translational Research Pillar, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales, Australia.
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Wu B, Xu Y, Ban Y, Zhang M, Sun Z, Cai Y, Li J, Hao Y, Ouyang Q, Hu L, Tian X, Liu D. Correlation between the intestinal microflora and peripheral blood Th1/Th2 balance in hypothyroidism during the first half of pregnancy. Front Cell Infect Microbiol 2023; 13:1159238. [PMID: 37051293 PMCID: PMC10083372 DOI: 10.3389/fcimb.2023.1159238] [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: 02/05/2023] [Accepted: 03/14/2023] [Indexed: 03/28/2023] Open
Abstract
ObjectiveThis study aimed to investigate the relationship between intestinal microflora characteristics and the peripheral blood T helper cell (Th)1/Th2 balance in patients with hypothyroidism during the first half of pregnancy.MethodsThe Th1/Th2 ratios in the peripheral blood of pregnant women in the hypothyroidism and control groups were determined using flow cytometry. The cytometric bead array assay was used to determine the serum levels of interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. Moreover, 16S rRNA amplicon sequencing was used to determine the intestinal microbial composition in the two groups. Finally, the relationships between intestinal microflora, Th1/Th2 cells, cytokines, and clinical indicators were analyzed.ResultsC-reactive protein levels were higher in the hypothyroidism group than in the control group. In contrast to the control group, the hypothyroidism group showed an increase in Th1 cells and the Th1/Th2 ratio, and a decrease in Th2 cells. The hypothyroidism group had higher serum IL-2, TNF-α, and IFN-γ levels, and lower IL-10 levels, than the control group. The richness of the intestinal microflora in the hypothyroidism group increased whereas the diversity decreased. The linear discriminant analysis effect size revealed that the hypothyroidism group had a higher abundance of Prevotella and Faecalibacterium, but a lower abundance of Bacteroides, compared to the control group. Prevotella was positively correlated with Th1 cells, the Th1/2 ratio, and TNF-α. Bacteroides was positively correlated with Th2 cells and IL-10, but negatively correlated with Th1 cells, the Th1/2 ratio, TNF-α, and IFN-γ. The thyroid peroxidase antibody level was directly proportional to TNF-α.ConclusionA Th1/Th2 imbalance occurs in patients with hypothyroidism during the first half of pregnancy. Disorders of the intestinal microflora may lead to hypothyroidism during pregnancy by affecting the Th1/Th2 balance.
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Khadrawy SM, Mohamed DS, Hassan RM, Abdelgawad MA, Ghoneim MM, Alshehri S, Shaban NS. Royal Jelly and Chlorella vulgaris Mitigate Gibberellic Acid-Induced Cytogenotoxicity and Hepatotoxicity in Rats via Modulation of the PPARα/AP-1 Signaling Pathway and Suppression of Oxidative Stress and Inflammation. Foods 2023; 12:foods12061223. [PMID: 36981150 PMCID: PMC10048508 DOI: 10.3390/foods12061223] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/21/2023] [Accepted: 03/01/2023] [Indexed: 03/14/2023] Open
Abstract
Gibberellic acid (GA3) is a well-known plant growth regulator used in several countries, but its widespread use has negative effects on both animal and human health. The current study assesses the protective effect of royal jelly (RJ) and Chlorella vulgaris (CV) on the genotoxicity and hepatic injury induced by GA3 in rats. Daily oral administration of 55 mg/kg GA3 to rats for 6 constitutive weeks induced biochemical and histopathological changes in the liver via oxidative stress and inflammation. Co-administration of 300 mg/kg RJ or 500 mg/kg CV with GA3 considerably ameliorated the serum levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), ALP (alkaline phosphatase), γGT (gamma-glutamyl transferase), total bilirubin, and albumin. Lowered malondialdehyde, tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) levels along with elevated SOD (superoxide dismutase), CAT (catalase), and GPx (glutathione peroxidase) enzyme activities indicated the antioxidant and anti-inflammatory properties of both RJ and CV. Also, they improved the histological structure and reduced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions along with up-regulating peroxisome proliferator activated receptor α (PPARα) and down-regulating activator protein 1 (AP-1) gene expression. Additionally, chromosomal abnormalities and mitotic index were nearly normalized after treatment with RJ and CV. In conclusion, RJ and CV can protect against GA3-induced genotoxicity and liver toxicity by diminishing oxidative stress and inflammation, and modulating the PPARα/AP-1 signaling pathway.
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Affiliation(s)
- Sally M. Khadrawy
- Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62511, Egypt
- Correspondence: (S.M.K.); (M.A.A.)
| | - Doaa Sh. Mohamed
- Department of Biochemistry and Chemistry of Nutrition, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt
| | - Randa M. Hassan
- Cytology and Histology Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt
| | - Mohamed A. Abdelgawad
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Saudi Arabia
- Correspondence: (S.M.K.); (M.A.A.)
| | - Mohammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Nema S. Shaban
- Department of Pharmacology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt
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Deka K, Li Y. Transcriptional Regulation during Aberrant Activation of NF-κB Signalling in Cancer. Cells 2023; 12:788. [PMID: 36899924 PMCID: PMC10001244 DOI: 10.3390/cells12050788] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/16/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
The NF-κB signalling pathway is a major signalling cascade involved in the regulation of inflammation and innate immunity. It is also increasingly recognised as a crucial player in many steps of cancer initiation and progression. The five members of the NF-κB family of transcription factors are activated through two major signalling pathways, the canonical and non-canonical pathways. The canonical NF-κB pathway is prevalently activated in various human malignancies as well as inflammation-related disease conditions. Meanwhile, the significance of non-canonical NF-κB pathway in disease pathogenesis is also increasingly recognized in recent studies. In this review, we discuss the double-edged role of the NF-κB pathway in inflammation and cancer, which depends on the severity and extent of the inflammatory response. We also discuss the intrinsic factors, including selected driver mutations, and extrinsic factors, such as tumour microenvironment and epigenetic modifiers, driving aberrant activation of NF-κB in multiple cancer types. We further provide insights into the importance of the interaction of NF-κB pathway components with various macromolecules to its role in transcriptional regulation in cancer. Finally, we provide a perspective on the potential role of aberrant NF-κB activation in altering the chromatin landscape to support oncogenic development.
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Affiliation(s)
- Kamalakshi Deka
- School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore 637551, Singapore
| | - Yinghui Li
- School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore 637551, Singapore
- Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore 138673, Singapore
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Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα. Cancers (Basel) 2023; 15:cancers15051495. [PMID: 36900285 PMCID: PMC10000776 DOI: 10.3390/cancers15051495] [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: 11/22/2022] [Accepted: 02/23/2023] [Indexed: 03/06/2023] Open
Abstract
Tumour necrosis factor alpha (TNFα) is a multifunctional cytokine that plays a pivotal role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNFα also has tumour-promoting properties. TNFα is often present in large quantities in tumours, and cancer cells frequently acquire resistance to this cytokine. Consequently, TNFα may increase the proliferation and metastatic potential of cancer cells. Furthermore, the TNFα-driven increase in metastasis is a result of the ability of this cytokine to induce the epithelial-to-mesenchymal transition (EMT). Overcoming the resistance of cancer cells to TNFα may have a potential therapeutic benefit. NF-κB is a crucial transcription factor mediating inflammatory signals and has a wide-ranging role in tumour progression. NF-κB is strongly activated in response to TNFα and contributes to cell survival and proliferation. The pro-inflammatory and pro-survival function of NF-κB can be disrupted by blocking macromolecule synthesis (transcription, translation). Consistently, inhibition of transcription or translation strongly sensitises cells to TNFα-induced cell death. RNA polymerase III (Pol III) synthesises several essential components of the protein biosynthetic machinery, such as tRNA, 5S rRNA, and 7SL RNA. No studies, however, directly explored the possibility that specific inhibition of Pol III activity sensitises cancer cells to TNFα. Here we show that in colorectal cancer cells, Pol III inhibition augments the cytotoxic and cytostatic effects of TNFα. Pol III inhibition enhances TNFα-induced apoptosis and also blocks TNFα-induced EMT. Concomitantly, we observe alterations in the levels of proteins related to proliferation, migration, and EMT. Finally, our data show that Pol III inhibition is associated with lower NF-κB activation upon TNFα treatment, thus potentially suggesting the mechanism of Pol III inhibition-driven sensitisation of cancer cells to this cytokine.
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Jin K, Qiu S, Chen B, Zhang Z, Zhang C, Zhou X, Yang L, Ai J, Wei Q. DOK3 promotes proliferation and inhibits apoptosis of prostate cancer via the NF-κB signaling pathway. Chin Med J (Engl) 2023; 136:423-432. [PMID: 36867541 PMCID: PMC10106266 DOI: 10.1097/cm9.0000000000002251] [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: 05/05/2022] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND DOK3 (Downstream of kinase 3) is involved primarily with immune cell infiltration. Recent research reported the role of DOK3 in tumor progression, with opposite effects in lung cancer and gliomas; however, its role in prostate cancer (PCa) remains elusive. This study aimed to explore the role of DOK3 in PCa and to determine the mechanisms involved. METHODS To investigate the functions and mechanisms of DOK3 in PCa, we performed bioinformatic and biofunctional analyses. Samples from patients with PCa were collected from West China Hospital, and 46 were selected for the final correlation analysis. A lentivirus-based short hairpin ribonucleic acid (shRNA) carrier was established for silencing DOK3. A series of experiments involving the cell counting kit-8, bromodeoxyuridine, and flow cytometry assays were performed to identify cell proliferation and apoptosis. Changes in biomarkers from the nuclear factor kappa B (NF-κB) signaling pathway were detected to verify the relationship between DOK3 and the NF-κB pathway. A subcutaneous xenograft mouse model was performed to examine phenotypes after knocking down DOK3 in vivo . Rescue experiments with DOK3 knockdown and NF-κB pathway activation were designed to verify regulating effects. RESULTS DOK3 was up-regulated in PCa cell lines and tissues. In addition, a high level of DOK3 was predictive of higher pathological stages and worse prognoses. Similar results were observed with PCa patient samples. After silencing DOK3 in PCa cell lines 22RV1 and PC3, cell proliferation was significantly inhibited while apoptosis was promoted. Gene set enrichment analysis revealed that DOK3 function was enriched in the NF-κB pathway. Mechanism experiments determined that knockdown of DOK3 suppressed activation of the NF-κB pathway, increased the expressions of B-cell lymphoma-2 like 11 (BIM) and B-cell lymphoma-2 associated X (BAX), and decreased the expression of phosphorylated-P65 and X-linked inhibitor of apoptosis (XIAP). In the rescue experiments, pharmacological activation of NF-κB by tumor necrosis factor-α (TNF-α) partially recovered cell proliferation after the knockdown of DOK3. CONCLUSION Our findings suggest that overexpression of DOK3 promotes PCa progression by activating the NF-κB signaling pathway.
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Affiliation(s)
- Kun Jin
- Department of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Shi Qiu
- Center of Biomedical Big Data, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Bo Chen
- Department of Urology and Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zilong Zhang
- Department of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Chichen Zhang
- Department of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xianghong Zhou
- Department of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lu Yang
- Department of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jianzhong Ai
- Department of Urology and Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Qiang Wei
- Department of Urology and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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Kaur K, Chen PC, Ko MW, Mei A, Huerta-Yepez S, Maharaj D, Malarkannan S, Jewett A. Successes and Challenges in Taming the Beast: Cytotoxic Immune Effectors in Amyotrophic Lateral Sclerosis. Crit Rev Immunol 2023; 43:1-11. [PMID: 37522557 DOI: 10.1615/critrevimmunol.2023047235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of motor neurons in the brain and spinal cord. No effective therapeutic strategies have been established thus far, and therefore there is a significant unmet need for effective therapeutics to arrest the disease and reverse the pathologies induced by it. Although the cause of ALS is not well-defined, it appears to be heterogenous. Currently over 20 genes have been found to be associated with ALS. Family history can only be found in 10% of ALS patients, but in the remaining 90% no association with family history is found. The most common genetic causes are expansion in the C9orf72 gene and mutations in superoxide dismutase 1, TDP-43, and FUS. In our recent study, we also found mutations in TDP43 and FUS in ALS patients. To understand the pathogenesis of the disease, we set ourselves the task of analyzing the phenotype and function of all key immune effectors in ALS patients, comparing them with either a genetically healthy twin or healthy individuals. Our study demonstrated a significant increase in functional activation of NK and CD8+ T cytotoxic immune effectors and release of significant IFN-γ not only by the effector cells but also in the serum of ALS patients. Longitudinal analysis of CD8+ T cell-mediated IFN-γ secretion from ALS patients demonstrated continued and sustained increase in IFN-γ secretion with periods of decrease which coincided with certain treatments; however, the effects were largely short-lived. N-acetyl cysteine (NAC), one of the treatments used, is known to block cell death; however, even though such treatment was able to block most of the proinflammatory cytokines, chemokines, and growth factor release, it was not able to block IFN-γ and TNF-α, the two cytokines we had demonstrated previously to induce differentiation of the cells. In this review, we discuss the contribution of cytotoxic effector cells, especially primary NK cells, supercharged NK cells (sNK), and the contribution of sNK cells in expansion and functional activation of CD8+ T cells to memory/effector T cells in the pathogenesis of ALS. Potential new targeted therapeutic strategies are also discussed.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Po-Chun Chen
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA
| | - Ao Mei
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226
| | - Sara Huerta-Yepez
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Los Angeles, CA 90095, USA
| | - Dipnarine Maharaj
- South Florida Bone Marrow Stem Cell Transplant Institute, DBA Maharaj Institute of Immune Regenerative Medicine, Boynton Beach, FL 33437
| | - Subramaniam Malarkannan
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee WI 53226; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; Department of Pediatrics, Medical College of Wisconsin, Milwaukee WI
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, CA, USA; The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, Los Angeles, CA, USA
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Specific S100 Proteins Bind Tumor Necrosis Factor and Inhibit Its Activity. Int J Mol Sci 2022; 23:ijms232415956. [PMID: 36555597 PMCID: PMC9783754 DOI: 10.3390/ijms232415956] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/05/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Tumor necrosis factor (TNF) inhibitors (anti-TNFs) represent a cornerstone of the treatment of various immune-mediated inflammatory diseases and are among the most commercially successful therapeutic agents. Knowledge of TNF binding partners is critical for identification of the factors able to affect clinical efficacy of the anti-TNFs. Here, we report that among eighteen representatives of the multifunctional S100 protein family, only S100A11, S100A12 and S100A13 interact with the soluble form of TNF (sTNF) in vitro. The lowest equilibrium dissociation constants (Kd) for the complexes with monomeric sTNF determined using surface plasmon resonance spectroscopy range from 2 nM to 28 nM. The apparent Kd values for the complexes of multimeric sTNF with S100A11/A12 estimated from fluorimetric titrations are 0.1-0.3 µM. S100A12/A13 suppress the cytotoxic activity of sTNF against Huh-7 cells, as evidenced by the MTT assay. Structural modeling indicates that the sTNF-S100 interactions may interfere with the sTNF recognition by the therapeutic anti-TNFs. Bioinformatics analysis reveals dysregulation of TNF and S100A11/A12/A13 in numerous disorders. Overall, we have shown a novel potential regulatory role of the extracellular forms of specific S100 proteins that may affect the efficacy of anti-TNF treatment in various diseases.
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Huang B, Lang X, Li X. The role of TIGAR in nervous system diseases. Front Aging Neurosci 2022; 14:1023161. [DOI: 10.3389/fnagi.2022.1023161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/05/2022] [Indexed: 11/10/2022] Open
Abstract
TP53-induced glycolysis and apoptosis regulator (TIGAR) mainly regulates pentose phosphate pathway by inhibiting glycolysis, so as to synthesize ribose required by DNA, promote DNA damage repair and cell proliferation, maintain cell homeostasis and avoid body injury. Its physiological functions include anti-oxidative stress, reducing inflammation, maintaining mitochondrial function, inhibiting apoptosis, reducing autophagy etc. This paper reviews the research of TIGAR in neurological diseases, including stroke, Parkinson’s disease (PD), Alzheimer’s disease (AD), seizures and brain tumors, aiming to provide reference for the development of new therapeutic targets.
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Kaur K, Chen PC, Ko MW, Mei A, Chovatiya N, Huerta-Yepez S, Ni W, Mackay S, Zhou J, Maharaj D, Malarkannan S, Jewett A. The Potential Role of Cytotoxic Immune Effectors in Induction, Progression and Pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Cells 2022; 11:3431. [PMID: 36359827 PMCID: PMC9656116 DOI: 10.3390/cells11213431] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/18/2022] [Accepted: 10/21/2022] [Indexed: 11/09/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neuron system. The causes of ALS are heterogeneous, and are only partially understood. We studied different aspects of immune pathogenesis in ALS and found several basic mechanisms which are potentially involved in the disease. Our findings demonstrated that ALS patients' peripheral blood contains higher proportions of NK and B cells in comparison to healthy individuals. Significantly increased IFN-γ secretion by anti-CD3/28 mAbs-treated peripheral blood mononuclear cells (PBMCs) were observed in ALS patients, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism for ALS progression. In addition, elevated granzyme B and perforin secretion at a single cell level, and increased cytotoxicity and secretion of IFN-γ by patients' NK cells under specific treatment conditions were also observed. Increased IFN-γ secretion by ALS patients' CD8+ T cells in the absence of IFN-γ receptor expression, and increased CD8+ T cell effector/memory phenotype as well as increased granzyme B at the single cell level points to the CD8+ T cells as potential cells in targeting motor neurons. Along with the hyper-responsiveness of cytotoxic immune cells, significantly higher levels of inflammatory cytokines including IFN-γ was observed in peripheral blood-derived serum of ALS patients. Supernatants obtained from ALS patients' CD8+ T cells induced augmented cell death and differentiation of the epithelial cells. Weekly N-acetyl cysteine (NAC) infusion in patients decreased the levels of many inflammatory cytokines in peripheral blood of ALS patient except IFN-γ, TNF-α, IL-17a and GMCSF which remained elevated. Findings of this study indicated that CD8+ T cells and NK cells are likely culprits in targeting motor neurons and therefore, strategies should be designed to decrease their function, and eliminate the aggressive nature of these cells. Analysis of genetic mutations in ALS patient in comparison to identical twin revealed a number of differences and similarities which may be important in the pathogenesis of the disease.
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Affiliation(s)
- Kawaljit Kaur
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA 90095, USA
| | - Po-Chun Chen
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA 90095, USA
| | - Meng-Wei Ko
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA 90095, USA
| | - Ao Mei
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Nishant Chovatiya
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA 90095, USA
| | - Sara Huerta-Yepez
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA 90095, USA
| | - Weiming Ni
- IsoPlexis, 35 North East Industrial Road, Branford, CT 06405, USA
| | - Sean Mackay
- IsoPlexis, 35 North East Industrial Road, Branford, CT 06405, USA
| | - Jing Zhou
- IsoPlexis, 35 North East Industrial Road, Branford, CT 06405, USA
| | - Dipanarine Maharaj
- South Florida Bone Marrow Stem Cell Transplant Institute, DBA Maharaj Institute of Immune Regenerative Medicine, 10301 Hagen Ranch Rd Ste. 600, Boynton Beach, FL 33437, USA
| | - Subramaniam Malarkannan
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA
| | - Anahid Jewett
- Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA 90095, USA
- The Jonsson Comprehensive Cancer Center, UCLA School of Dentistry and Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095, USA
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Dhingra R, Rabinovich-Nikitin I, Rothman S, Guberman M, Gang H, Margulets V, Jassal DS, Alagarsamy KN, Dhingra S, Ripoll CV, Billia F, Diwan A, Javaheri A, Kirshenbaum LA. Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy. Circulation 2022; 146:934-954. [PMID: 35983756 PMCID: PMC10043946 DOI: 10.1161/circulationaha.121.058411] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Cytokines such as tumor necrosis factor-α (TNFα) have been implicated in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although TNFα can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart remain cryptic. The E3 ubiquitin ligase TRAF2 (TNF receptor associated factor 2) provides a critical signaling platform for K63-linked polyubiquitination of RIPK1 (receptor interacting protein 1), crucial for nuclear factor-κB (NF-κB) activation by TNFα and survival. Here, we investigate alterations in TNFα-TRAF2-NF-κB signaling in the pathogenesis of DOX cardiotoxicity. METHODS Using a combination of in vivo (4 weekly injections of DOX 5 mg·kg-1·wk-1) in C57/BL6J mice and in vitro approaches (rat, mouse, and human inducible pluripotent stem cell-derived cardiac myocytes), we monitored TNFα levels, lactate dehydrogenase, cardiac ultrastructure and function, mitochondrial bioenergetics, and cardiac cell viability. RESULTS In contrast to vehicle-treated mice, ultrastructural defects, including cytoplasmic swelling, mitochondrial perturbations, and elevated TNFα levels, were observed in the hearts of mice treated with DOX. While investigating the involvement of TNFα in DOX cardiotoxicity, we discovered that NF-κB was readily activated by TNFα. However, TNFα-mediated NF-κB activation was impaired in cardiac myocytes treated with DOX. This coincided with loss of K63- linked polyubiquitination of RIPK1 from the proteasomal degradation of TRAF2. Furthermore, TRAF2 protein abundance was markedly reduced in hearts of patients with cancer treated with DOX. We further established that the reciprocal actions of the ubiquitinating and deubiquitinating enzymes cellular inhibitors of apoptosis 1 and USP19 (ubiquitin-specific peptidase 19), respectively, regulated the proteasomal degradation of TRAF2 in DOX-treated cardiac myocytes. An E3-ligase mutant of cellular inhibitors of apoptosis 1 (H588A) or gain of function of USP19 prevented proteasomal degradation of TRAF2 and DOX-induced cell death. Furthermore, wild-type TRAF2, but not a RING finger mutant defective for K63-linked polyubiquitination of RIPK1, restored NF-κB signaling and suppressed DOX-induced cardiac cell death. Last, cardiomyocyte-restricted expression of TRAF2 (cardiac troponin T-adeno-associated virus 9-TRAF2) in vivo protected against mitochondrial defects and cardiac dysfunction induced by DOX. CONCLUSIONS Our findings reveal a novel signaling axis that functionally connects the cardiotoxic effects of DOX to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by DOX sensitizes cardiac myocytes to TNFα-mediated necrotic cell death and DOX cardiotoxicity.
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Affiliation(s)
- Rimpy Dhingra
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
| | - Inna Rabinovich-Nikitin
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
| | - Sonny Rothman
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
| | - Matthew Guberman
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
| | - Hongying Gang
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
| | - Victoria Margulets
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
| | - Davinder S. Jassal
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
| | - Keshav N. Alagarsamy
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
- Regenerative Medicine Program, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
| | - Sanjiv Dhingra
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
- Regenerative Medicine Program, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
| | - Carla Valenzuela Ripoll
- Center for Cardiovascular Research and Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Filio Billia
- Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada, Peter Munk Cardiac Center, University Health Network, Toronto, Ontario, Canada
| | - Abhinav Diwan
- Center for Cardiovascular Research and Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Ali Javaheri
- Center for Cardiovascular Research and Cardiovascular Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO
| | - Lorrie A. Kirshenbaum
- Department of Physiology and Pathophysiology, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
- Department of Pharmacology and Therapeutics, The Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre
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Abu-Serie MM, Habashy NH. Suppressing crucial oncogenes of leukemia initiator cells by major royal jelly protein 2 for mediating apoptosis in myeloid and lymphoid leukemia cells. Food Funct 2022; 13:8951-8966. [PMID: 35929786 DOI: 10.1039/d2fo00999d] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Relapse of leukemia and drug resistance are still the major obstacles to therapy due to leukemia-initiating stem/progenitor cells (LICs); thus, targeting them using safe compounds is crucial. Here, we evaluated the anti-leukemic effect of royal jelly (RJ) components, which had a higher safe concentration (EC100 values) than the chemotherapeutic drug doxorubicin (DOX). The RJ-protein fraction 50 (PF50, precipitated at 40-50% ammonium sulfate saturation) and its constituents, major RJ protein (MRJP) 2 and its isoform X1, exhibited the highest growth inhibitory effect against myeloid NFS-60 and lymphoid Jurkat cell lines. MRJP2 has a nanosize, which may be the reason for its higher anti-leukemic activity than its isoform. These RJ proteins, particularly MRJP2, suppressed LIC-associated oncogenes (GATA2 and Evi-1) and eliminated CD34+ LICs, in contrast to the low anti-LIC efficacy of DOX. MRJP2 demonstrated higher apoptotic activity than its isoform by upregulating p53 and p21-mediated cell cycle arrest. This study also reported the potent inhibitory effect of RJ-proteins on matrix metallopeptidase 10 (metastatic marker) and histone deacetylase 8 (mediates LIC survival) activities. Thus, MRJP2 can be considered a promising novel therapeutic agent for both myeloid and lymphoid leukemia.
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Affiliation(s)
- Marwa M Abu-Serie
- Department of Medical Biotechnology, Genetic Engineering, and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), New Borg EL-Arab 21934, Alexandria, Egypt
| | - Noha H Habashy
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt.
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Huang R, Huang D, Wang S, Xian S, Liu Y, Jin M, Zhang X, Chen S, Yue X, Zhang W, Lu J, Liu H, Huang Z, Zhang H, Yin H. Repression of enhancer RNA PHLDA1 promotes tumorigenesis and progression of Ewing sarcoma via decreasing infiltrating T‐lymphocytes: A bioinformatic analysis. Front Genet 2022; 13:952162. [PMID: 36092920 PMCID: PMC9453160 DOI: 10.3389/fgene.2022.952162] [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: 05/24/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Background: The molecular mechanisms of EWS-FLI-mediating target genes and downstream pathways may provide a new way in the targeted therapy of Ewing sarcoma. Meanwhile, enhancers transcript non-coding RNAs, known as enhancer RNAs (eRNAs), which may serve as potential diagnosis markers and therapeutic targets in Ewing sarcoma. Materials and methods: Differentially expressed genes (DEGs) were identified between 85 Ewing sarcoma samples downloaded from the Treehouse database and 3 normal bone samples downloaded from the Sequence Read Archive database. Included in DEGs, differentially expressed eRNAs (DEeRNAs) and target genes corresponding to DEeRNAs (DETGs), as well as the differentially expressed TFs, were annotated. Then, cell type identification by estimating relative subsets of known RNA transcripts (CIBERSORT) was used to infer portions of infiltrating immune cells in Ewing sarcoma and normal bone samples. To evaluate the prognostic value of DEeRNAs and immune function, cross validation, independent prognosis analysis, and Kaplan–Meier survival analysis were implemented using sarcoma samples from the Cancer Genome Atlas database. Next, hallmarks of cancer by gene set variation analysis (GSVA) and immune gene sets by single-sample gene set enrichment analysis (ssGSEA) were identified to be significantly associated with Ewing sarcoma. After screening by co-expression analysis, most significant DEeRNAs, DETGs and DETFs, immune cells, immune gene sets, and hallmarks of cancer were merged to construct a co-expression regulatory network to eventually identify the key DEeRNAs in tumorigenesis of Ewing sarcoma. Moreover, Connectivity Map Analysis was utilized to identify small molecules targeting Ewing sarcoma. External validation based on multidimensional online databases and scRNA-seq analysis were used to verify our key findings. Results: A six-different-dimension regulatory network was constructed based on 17 DEeRNAs, 29 DETFs, 9 DETGs, 5 immune cells, 24 immune gene sets, and 8 hallmarks of cancer. Four key DEeRNAs (CCR1, CD3D, PHLDA1, and RASD1) showed significant co-expression relationships in the network. Connectivity Map Analysis screened two candidate compounds, MS-275 and pyrvinium, that might target Ewing sarcoma. PHLDA1 (key DEeRNA) was extensively expressed in cancer stem cells of Ewing sarcoma, which might play a critical role in the tumorigenesis of Ewing sarcoma. Conclusion: PHLDA1 is a key regulator in the tumorigenesis and progression of Ewing sarcoma. PHLDA1 is directly repressed by EWS/FLI1 protein and low expression of FOSL2, resulting in the deregulation of FOX proteins and CC chemokine receptors. The decrease of infiltrating T‐lymphocytes and TNFA signaling may promote tumorigenesis and progression of Ewing sarcoma.
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Affiliation(s)
- Runzhi Huang
- Department of Orthopedics, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Tongji University School of Medicine, Shanghai, China
| | - Dan Huang
- Tongji University School of Medicine, Shanghai, China
| | - Siqiao Wang
- Tongji University School of Medicine, Shanghai, China
| | - Shuyuan Xian
- Tongji University School of Medicine, Shanghai, China
| | - Yifan Liu
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minghao Jin
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinkun Zhang
- Tongji University School of Medicine, Shanghai, China
| | - Shaofeng Chen
- Department of Orthopedics, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Xi Yue
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wei Zhang
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jianyu Lu
- Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Huizhen Liu
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zongqiang Huang
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Tongji University School of Medicine, Shanghai, China
- *Correspondence: Zongqiang Huang, ; Hao Zhang, ; Huabin Yin,
| | - Hao Zhang
- Department of Orthopedics, Naval Medical Center of PLA, Second Military Medical University, Shanghai, China
- *Correspondence: Zongqiang Huang, ; Hao Zhang, ; Huabin Yin,
| | - Huabin Yin
- Department of Orthopedics, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
- *Correspondence: Zongqiang Huang, ; Hao Zhang, ; Huabin Yin,
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Ren Z, Chen S, Lv H, Peng L, Yang W, Chen J, Wu Z, Wan C. Effect of Bifidobacterium animalis subsp. lactis SF on enhancing the tumor suppression of irinotecan by regulating the intestinal flora. Pharmacol Res 2022; 184:106406. [PMID: 35987480 DOI: 10.1016/j.phrs.2022.106406] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/12/2022] [Accepted: 08/16/2022] [Indexed: 10/15/2022]
Abstract
The gut microbiota plays a role in tumor therapy by participating in immune regulation. Here, we demonstrated through 8-day probiotic supplementation experiments and fecal microbiota transplantation experiments that Bifidobacterium animalis subsp. lactis SF enhanced the antitumor effect of irinotecan and prevented the occurrence of intestinal damage by modulating the gut microbiota and reducing the relative abundance of pro-inflammatory microbiota. Therefore, the intestinal inflammation was inhibited, the TGF-β leakage was reduced, and the PI3K/AKT pathway activation was inhibited. Thus, the tumor apoptotic autophagy was finally promoted. Simultaneously, the reduction of TGF-β relieved the immunosuppression caused by CPT-11, promoted the differentiation of CD4+ and CD8+ T cells in tumor tissue, and consequently inhibited tumor growth and invasion. This study disclosed the mechanism of B. lactis SF assisting CPT-11 in antitumor activity and suggested that B. lactis SF plays a new role in anticancer effects as a nutritional intervention.
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Affiliation(s)
- Zhongyue Ren
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Shufang Chen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Huihui Lv
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Lingling Peng
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Wanyu Yang
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Jiahui Chen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, PR China
| | - Zhihua Wu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, PR China; Jiangxi-OAI Joint Research Institute, Nanchang University, Nanchang 330047, PR China.
| | - Cuixiang Wan
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, PR China; Jiangxi-OAI Joint Research Institute, Nanchang University, Nanchang 330047, PR China.
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Han M, Liu Y, Jin C, Wang X, Song W, Zhang Q. Genome-wide identification, characterization and expression profiling of TRAF family genes in Sebastes schlegelii. FISH & SHELLFISH IMMUNOLOGY 2022; 127:203-210. [PMID: 35724846 DOI: 10.1016/j.fsi.2022.06.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/14/2022] [Accepted: 06/15/2022] [Indexed: 06/15/2023]
Abstract
Tumor necrosis factor receptor-associated factors (TRAFs) are signaling mediators for Toll-like receptor (TLR) and tumor necrosis factor (TNFR) superfamily that play important roles in organism immune response. However, reports on systematic identification of TRAF gene family in teleost fish and the function of TRAFs in innate immunity of black rockfish (Sebastes schlegelii) are lacked. In our study, eight TRAF genes were identified and characterized, namely, SsTRAF2a, SsTRAF2a-like, SsTRAF2b, SsTRAF3, SsTRAF4, SsTRAF5, SsTRAF6 and SsTRAF7 in S. schegelii. Furthermore, we analyzed their sequences, conserved domains, gene structures, motif compositions, phylogeny, tissue expression patterns in healthy and Vibro. anguillarum challenged individuals. All the SsTRAFs contained typical conserved domain, including C-terminal MATH domain and N-terminal RING finger domain. Analyses of gene structures and motifs showed the distribution of exon-intron and conserved motifs in S. schegelii and serval other teleost fish. We also analyzed the expression file of SsTRAFs in five immune-relate organs, liver, spleen, kidney, gill and intestine in healthy and bacterial challenged fish. The results indicated that all SsTRAF member were widely involved in immune response after pathogenic bacteria infection. In summary, the analyses of TRAFs in S. schegelii will be helpful to better understand the diverse roles of TRAF genes in the innate immune response to bacterial challenge.
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Affiliation(s)
- Miao Han
- MOE Key Laboratory of Marine Genetics and Breeding, Ministry of Education, Ocean University of China, Qingdao, 266003, China.
| | - Yuxiang Liu
- MOE Key Laboratory of Marine Genetics and Breeding, Ministry of Education, Ocean University of China, Qingdao, 266003, China.
| | - Chaofan Jin
- MOE Key Laboratory of Marine Genetics and Breeding, Ministry of Education, Ocean University of China, Qingdao, 266003, China.
| | - Xuangang Wang
- MOE Key Laboratory of Marine Genetics and Breeding, Ministry of Education, Ocean University of China, Qingdao, 266003, China.
| | - Weihao Song
- MOE Key Laboratory of Marine Genetics and Breeding, Ministry of Education, Ocean University of China, Qingdao, 266003, China.
| | - Quanqi Zhang
- MOE Key Laboratory of Marine Genetics and Breeding, Ministry of Education, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, China; Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Sanya, China.
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Chen Y, Guan W, Zhang N, Wang Y, Tian Y, Sun H, Li X, Wang Y, Liu J. <em>Lactobacillus plantarum</em> Lp2 improved LPS-induced liver injury through the TLR-4/MAPK/NFκB and Nrf2-HO-1/CYP2E1 pathways in mice. Food Nutr Res 2022; 66:5459. [PMID: 35903291 PMCID: PMC9287763 DOI: 10.29219/fnr.v66.5459] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/24/2022] [Accepted: 01/28/2022] [Indexed: 11/20/2022] Open
Abstract
Background: Inflammatory liver diseases present a significant public health problem. Probiotics are a kind of living microorganisms, which can improve the balance of host intestinal flora, promote the proliferation of intestinal beneficial bacteria, inhibit the growth of harmful bacteria, improve immunity, reduce blood lipids and so on. Probiotics in fermented foods have attracted considerable attention lately as treatment options for liver injury.
Objective: The aim of this study was selected probiotic strain with well probiotic properties from naturally fermented foods and investigated the underlying mechanisms of screened probiotic strain on lipopolysaccharide (LPS)-induced liver injury, which provided the theoretical foundation for the development of probiotics functional food.
Design: The probiotic characteristics of Lactobacillus plantarum Lp2 isolated from Chinese traditional fermented food were evaluated. Male KM mice were randomly assigned into three groups: normal chow (Control), LPS and LPS with L. plantarum Lp2. L. plantarum Lp2 were orally administered for 4 weeks before exposure to LPS. The liver injury of LPS-induced mice was observed through the evaluation of biochemical indexes, protein expression level and liver histopathology.
Results and discussions: After treatment for 4 weeks, L. plantarum Lp2 administration significantly reduced the LPS-induced liver coefficient and the levels of serum or liver aspartate transaminase (AST), alanine aminotransferase (ALT), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and LPS, as well as decreasing the histological alterations and protein compared with the LPS group. Western-blotting results showed that L. plantarum Lp2 activated the signal pathway of TLR4/MAPK/NFκB/NRF2-HO-1/CYP2E1/Caspase-3 and regulated the expression of related proteins.
Conclusions: In summary, L. plantarum Lp2 suppressed the LPS-induced activation of inflammatory pathways, oxidative injury and apoptosis has the potential to be used to improve liver injury.
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Affiliation(s)
- Yiying Chen
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Wuyang Guan
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Nan Zhang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Yu Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Yuan Tian
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Haiyue Sun
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
| | - Xia Li
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
- Xia Li Tel: +86 0431 84533312; fax: +86 0431 84533312 E-mail:
| | - Yuhua Wang
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
- National Processing Laboratory for Soybean Industry and Technology, Changchun, China
- National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China
- Xia Li Tel: +86 0431 84533312; fax: +86 0431 84533312 E-mail:
| | - Jingsheng Liu
- College of Food Science and Engineering, Jilin Agricultural University, Changchun, China
- Jilin Province Innovation Center for Food Biological Manufacture, Jilin Agricultural University, Changchun, China
- National Engineering Laboratory for Wheat and Corn Deep Processing, Changchun, China
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Sorrentino A, Menevse AN, Michels T, Volpin V, Durst FC, Sax J, Xydia M, Hussein A, Stamova S, Spoerl S, Heuschneider N, Muehlbauer J, Jeltsch KM, Rathinasamy A, Werner-Klein M, Breinig M, Mikietyn D, Kohler C, Poschke I, Purr S, Reidell O, Martins Freire C, Offringa R, Gebhard C, Spang R, Rehli M, Boutros M, Schmidl C, Khandelwal N, Beckhove P. Salt-inducible kinase 3 protects tumor cells from cytotoxic T-cell attack by promoting TNF-induced NF-κB activation. J Immunother Cancer 2022; 10:jitc-2021-004258. [PMID: 35606086 PMCID: PMC9174898 DOI: 10.1136/jitc-2021-004258] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2022] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Cancer immunotherapeutic strategies showed unprecedented results in the clinic. However, many patients do not respond to immuno-oncological treatments due to the occurrence of a plethora of immunological obstacles, including tumor intrinsic mechanisms of resistance to cytotoxic T-cell (TC) attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies. METHODS To identify novel genes that protect tumor cells from effective TC-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with tumor-infiltrating lymphocytes and antigen-specific TCs. RESULTS The screening revealed 108 potential genes that protected tumor cells from TC attack. Among them, salt-inducible kinase 3 (SIK3) was one of the strongest hits identified in the screening. Both genetic and pharmacological inhibitions of SIK3 in tumor cells dramatically increased TC-mediated cytotoxicity in several in vitro coculture models, using different sources of tumor and TCs. Consistently, adoptive TC transfer of TILs led to tumor growth inhibition of SIK3-depleted cancer cells in vivo. Mechanistic analysis revealed that SIK3 rendered tumor cells susceptible to tumor necrosis factor (TNF) secreted by tumor-activated TCs. SIK3 promoted nuclear factor kappa B (NF-κB) nuclear translocation and inhibited caspase-8 and caspase-9 after TNF stimulation. Chromatin accessibility and transcriptome analyses showed that SIK3 knockdown profoundly impaired the expression of prosurvival genes under the TNF-NF-κB axis. TNF stimulation led to SIK3-dependent phosphorylation of the NF-κB upstream regulators inhibitory-κB kinase and NF-kappa-B inhibitor alpha on the one side, and to inhibition of histone deacetylase 4 on the other side, thus sustaining NF-κB activation and nuclear stabilization. A SIK3-dependent gene signature of TNF-mediated NF-κB activation was found in a majority of pancreatic cancers where it correlated with increased cytotoxic TC activity and poor prognosis. CONCLUSION Our data reveal an abundant molecular mechanism that protects tumor cells from cytotoxic TC attack and demonstrate that pharmacological inhibition of this pathway is feasible.
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Affiliation(s)
- Antonio Sorrentino
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
- Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ayse Nur Menevse
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Tillmann Michels
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
- Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Valentina Volpin
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
- Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Julian Sax
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Maria Xydia
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Abir Hussein
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Slava Stamova
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Steffen Spoerl
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
- Department of Oral and Maxillofacial Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Nicole Heuschneider
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Jasmin Muehlbauer
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
| | | | - Anchana Rathinasamy
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Melanie Werner-Klein
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
- Experimental Medicine and Therapy Research, University of Regensburg, Regensburg, Germany
| | - Marco Breinig
- Signalling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Helmholtz-University Group 'Cell Plasticity and Epigenetic Remodeling', German Cancer Research Center (DKFZ), Heidelberg, Germany
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Damian Mikietyn
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Christian Kohler
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Isabel Poschke
- Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany
- DKTK CCU Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Immune Monitoring Unit, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Sabrina Purr
- Joint Immunotherapeutics Laboratory, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Olivia Reidell
- Research Department, iOmx Therapeutics, Munich/Martinsried, Germany
| | | | - Rienk Offringa
- Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Claudia Gebhard
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - Rainer Spang
- Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Michael Rehli
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - Michael Boutros
- Signalling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christian Schmidl
- Junior Group 'Epigenetic Immunooncology', Leibniz Institute for Immunotherapy, Regensburg, Germany
| | - Nisit Khandelwal
- Translational Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Research Department, iOmx Therapeutics, Munich/Martinsried, Germany
| | - Philipp Beckhove
- Division of Interventional Immunology, Leibniz Institute for Immunotherapy, Regensburg, Germany
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
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Bakshi HA, Quinn GA, Nasef MM, Mishra V, Aljabali AAA, El-Tanani M, Serrano-Aroca Á, Webba Da Silva M, McCarron PA, Tambuwala MM. Crocin Inhibits Angiogenesis and Metastasis in Colon Cancer via TNF-α/NF-kB/VEGF Pathways. Cells 2022; 11:1502. [PMID: 35563808 PMCID: PMC9104358 DOI: 10.3390/cells11091502] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/22/2022] [Accepted: 04/28/2022] [Indexed: 02/01/2023] Open
Abstract
Angiogenesis and metastasis play pivotal roles in the progression of cancer. We recently discovered that crocin, a dietary carotenoid derived from the Himalayan crocus, inhibited the growth of colon cancer cells. However, the exact role of crocin on the angiogenesis and metastasis in colorectal cancer remains unclear. In the present study, we demonstrated that crocin significantly reduces the viability of colon cancer cells (HT-29, Caco-2) and human umbilical vein endothelial cells (HUVEC), but was not toxic to human colon epithelial (HCEC) cells. Furthermore, pre-treatment of human carcinoma cells (HT-29 and Caco-2) with crocin inhibited cell migration, invasion, and angiogenesis in concentration -dependent manner. Further studies demonstrated that crocin inhibited TNF-α, NF-κB and VEGF pathways in colon carcinoma cell angiogenesis and metastasis. Crocin also inhibited cell migration, invasion, and tube formation in human umbilical vein endothelial cells (HUVEC) in a concentration -dependent manner. We also observed that crocin significantly reduced the secretion of VEGF and TNF-α induced activation of NF-kB by human colon carcinoma cells. In the absence of TNF-α, a concentration-dependent reduction in NF-kB was observed. Many of these observations were confirmed by in vivo angiogenesis models, which showed that crocin significantly reduced the progression of tumour growth. Collectively, these finding suggest that crocin inhibits angiogenesis and colorectal cancer cell metastasis by targeting NF-kB and blocking TNF-α/NF-κB/VEGF pathways.
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Affiliation(s)
- Hamid A. Bakshi
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine BT52 1SA, UK; (M.W.D.S.); (P.A.M.)
| | - Gerry A. Quinn
- School of Biomedical Sciences, Ulster University, Coleraine BT52 1SA, UK;
| | - Mohamed M. Nasef
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK;
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
| | - Alaa A. A. Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid 566, Jordan;
| | - Mohamed El-Tanani
- Pharmacological and Diagnostic Research Centre, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan;
| | - Ángel Serrano-Aroca
- Biomaterials and Bioengineering Lab, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain;
| | - Mateus Webba Da Silva
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine BT52 1SA, UK; (M.W.D.S.); (P.A.M.)
| | - Paul A. McCarron
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine BT52 1SA, UK; (M.W.D.S.); (P.A.M.)
| | - Murtaza M. Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine BT52 1SA, UK; (M.W.D.S.); (P.A.M.)
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Gissler MC, Stachon P, Wolf D, Marchini T. The Role of Tumor Necrosis Factor Associated Factors (TRAFs) in Vascular Inflammation and Atherosclerosis. Front Cardiovasc Med 2022; 9:826630. [PMID: 35252400 PMCID: PMC8891542 DOI: 10.3389/fcvm.2022.826630] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/27/2022] [Indexed: 12/20/2022] Open
Abstract
TNF receptor associated factors (TRAFs) represent a family of cytoplasmic signaling adaptor proteins that regulate, bundle, and transduce inflammatory signals downstream of TNF- (TNF-Rs), interleukin (IL)-1-, Toll-like- (TLRs), and IL-17 receptors. TRAFs play a pivotal role in regulating cell survival and immune cell function and are fundamental regulators of acute and chronic inflammation. Lately, the inhibition of inflammation by anti-cytokine therapy has emerged as novel treatment strategy in patients with atherosclerosis. Likewise, growing evidence from preclinical experiments proposes TRAFs as potent modulators of inflammation in atherosclerosis and vascular inflammation. Yet, TRAFs show a highly complex interplay between different TRAF-family members with partially opposing and overlapping functions that are determined by the level of cellular expression, concomitant signaling events, and the context of the disease. Therefore, inhibition of specific TRAFs may be beneficial in one condition and harmful in others. Here, we carefully discuss the cellular expression and signaling events of TRAFs and evaluate their role in vascular inflammation and atherosclerosis. We also highlight metabolic effects of TRAFs and discuss the development of TRAF-based therapeutics in the future.
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Affiliation(s)
- Mark Colin Gissler
- Cardiology and Angiology, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
- Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Peter Stachon
- Cardiology and Angiology, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
| | - Dennis Wolf
- Cardiology and Angiology, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
- Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- *Correspondence: Dennis Wolf
| | - Timoteo Marchini
- Cardiology and Angiology, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
- Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Universidad de Buenos Aires, CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina
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Gao Q, Yang Y, Feng Y, Quan W, Luo Y, Wang H, Zheng J, Chen X, Huang Z, Chen X, Xu R, Zhang G, Gong L. Effects of the NF-κB Signaling Pathway Inhibitor BAY11-7082 in the Replication of ASFV. Viruses 2022; 14:297. [PMID: 35215890 PMCID: PMC8877168 DOI: 10.3390/v14020297] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/20/2022] [Accepted: 01/28/2022] [Indexed: 02/01/2023] Open
Abstract
African swine fever virus (ASFV) mainly infects the monocyte/macrophage lineage of pigs and regulates the production of cytokines that influence host immune responses. Several studies have reported changes in cytokine production after infection with ASFV, but the regulatory mechanisms have not yet been elucidated. Therefore, the aim of this study was to examine the immune response mechanism of ASFV using transcriptomic and proteomic analyses. Through multi-omics joint analysis, it was found that ASFV infection regulates the expression of the host NF-B signal pathway and related cytokines. Additionally, changes in the NF-κB signaling pathway and IL-1β and IL-8 expression in porcine alveolar macrophages (PAMs) infected with ASFV were examined. Results show that ASFV infection activates the NF-κB signaling pathway and up-regulates the expression of IL-1β and IL-8. The NF-κB inhibitor BAY11-7082 inhibited the expression profiles of phospho-NF-κB p65, p-IκB, and MyD88 proteins, and inhibited ASFV-induced NF-κB signaling pathway activation. Additionally, the results show that the NF-κB inhibitor BAY11-7082 can inhibit the replication of ASFV and can inhibit IL-1β and, IL-8 expression. Overall, the findings of this study indicate that ASFV infection activates the NF-κB signaling pathway and up-regulates the expression of IL-1β and IL-8, and inhibits the replication of ASFV by inhibiting the NF-κB signaling pathway and interleukin-1 beta and interleukin-8 production. These findings not only provide new insights into the molecular mechanism of the association between the NF-κB signaling pathway and ASFV infection, but also indicate that the NF-κB signaling pathway is a potential immunomodulatory pathway that controls ASF.
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Affiliation(s)
- Qi Gao
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- Research Center for African Swine Fever Prevention and Control, South China Agricultural University, Guangzhou 510642, China
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China
| | - Yunlong Yang
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- Research Center for African Swine Fever Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Yongzhi Feng
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China
| | - Weipeng Quan
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- African Swine Fever Regional Laboratory of China (Guangzhou), Guangzhou 510642, China
| | - Yizhuo Luo
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- Research Center for African Swine Fever Prevention and Control, South China Agricultural University, Guangzhou 510642, China
| | - Heng Wang
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- Research Center for African Swine Fever Prevention and Control, South China Agricultural University, Guangzhou 510642, China
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China
| | - Jiachen Zheng
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- African Swine Fever Regional Laboratory of China (Guangzhou), Guangzhou 510642, China
| | - Xiongnan Chen
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- African Swine Fever Regional Laboratory of China (Guangzhou), Guangzhou 510642, China
| | - Zhao Huang
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- African Swine Fever Regional Laboratory of China (Guangzhou), Guangzhou 510642, China
| | - Xiaojun Chen
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- African Swine Fever Regional Laboratory of China (Guangzhou), Guangzhou 510642, China
| | - Runda Xu
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- African Swine Fever Regional Laboratory of China (Guangzhou), Guangzhou 510642, China
| | - Guihong Zhang
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- Research Center for African Swine Fever Prevention and Control, South China Agricultural University, Guangzhou 510642, China
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China
| | - Lang Gong
- Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510462, China; (Q.G.); (Y.Y.); (Y.F.); (W.Q.); (Y.L.); (H.W.); (J.Z.); (X.C.); (Z.H.); (X.C.); (R.X.)
- Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China
- African Swine Fever Regional Laboratory of China (Guangzhou), Guangzhou 510642, China
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Salvaras L, Kovacic T, Janega P, Liptak B, Sasvariova M, Michalikova D, Tyukos Kaprinay B, Bezek S, Sotnikova R, Knezl V, Sankovicova T, Gasparova Z. Synthetic Pyridoindole and Rutin Affect Upregulation of Endothelial Nitric Oxide Synthase and Heart Function in Rats Fed a High-Fat-Fructose Diet. Physiol Res 2021; 70:851-863. [PMID: 34717058 PMCID: PMC8815465 DOI: 10.33549/physiolres.934670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 08/10/2021] [Indexed: 11/25/2022] Open
Abstract
Metabolic syndrome (MetS) belongs to the serious health complications expanding in cardiovascular diseases, obesity, insulin resistance, and hyperglycemia. In this study, hypertriacylglycerolemic rats fed a high-fat-fructose diet (HFFD) were used as an experimental model of MetS to explore the effect of tested compounds. Effects of a new prospective pyridoindole derivative coded SMe1EC2 and the natural polyphenol rutin were tested. Endothelial nitric oxide synthase (NOS3) and nuclear factor kappa B (NF-?B) expression were assessed in the left ventricle immunohistochemically and left ventricle activity was monitored in isolated perfused rat hearts. NOS3 activity in the left ventricle decreased markedly as a result of a HFFD. NOS3 expression was upregulated by both substances. NF-?B expression was increased in the MetS group in comparison to control rats and the expression further increased in the SMe1EC2 treatment. This compound significantly improved the coronary flow in comparison to the control group during reperfusion of the heart followed after ischemia. Further, it tended to increase left ventricular systolic pressure, heart product, rate of maximal contraction and relaxation, and coronary flow during baseline assessment. Moreover, the compound SMe1EC2 decreased the sensitivity of hearts to electrically induced ventricular fibrillation. Contrary to this rutin decreased coronary flow in reperfusion. Present results suggest that despite upregulation of NOS3 by both substances tested, pyridoindole SMe1EC2 rather than rutin could be suitable in treatment strategies of cardiovascular disorders in MetS-like conditions.
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Affiliation(s)
- L Salvaras
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic
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Li H, Fang H, Chang L, Qiu S, Ren X, Cao L, Bian J, Wang Z, Guo Y, Lv J, Sun Z, Wang T, Li B. TC2N: A Novel Vital Oncogene or Tumor Suppressor Gene In Cancers. Front Immunol 2021; 12:764749. [PMID: 34925334 PMCID: PMC8674203 DOI: 10.3389/fimmu.2021.764749] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 10/29/2021] [Indexed: 12/12/2022] Open
Abstract
Several C2 domain-containing proteins play key roles in tumorigenesis, signal transduction, and mediating protein–protein interactions. Tandem C2 domains nuclear protein (TC2N) is a tandem C2 domain-containing protein that is differentially expressed in several types of cancers and is closely associated with tumorigenesis and tumor progression. Notably, TC2N has been identified as an oncogene in lung and gastric cancer but as a tumor suppressor gene in breast cancer. Recently, a large number of tumor-associated antigens (TAAs), such as heat shock proteins, alpha-fetoprotein, and carcinoembryonic antigen, have been identified in a variety of malignant tumors. Differences in the expression levels of TAAs between cancer cells and normal cells have led to these antigens being investigated as diagnostic and prognostic biomarkers and as novel targets in cancer treatment. In this review, we summarize the clinical characteristics of TC2N-positive cancers and potential mechanisms of action of TC2N in the occurrence and development of specific cancers. This article provides an exploration of TC2N as a potential target for the diagnosis and treatment of different types of cancers.
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Affiliation(s)
- Hanyang Li
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
- Department of Thyroid Surgery, The Second Hospital of Jilin University, Changchun, China
| | - He Fang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Li Chang
- Department of Pathology, The Second Hospital of Jilin University, Changchun, China
| | - Shuang Qiu
- Department of Biobank, The China-Japan Union Hospital of Jilin University, Changchun, China
| | - Xiaojun Ren
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Lidong Cao
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Jinda Bian
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Zhenxiao Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Yi Guo
- Department of Breast Surgery, The Affiliated Hospital Changchun University of Chinese Medicine, Changchun, China
| | - Jiayin Lv
- Department of Orthopedics, The China-Japan Union Hospital of Jilin University, Changchun, China
| | - Zhihui Sun
- Department of Pharmacy, The Second Hospital of Jilin University, Changchun, China
| | - Tiejun Wang
- Department of Radiotherapy, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Tiejun Wang, ; Bingjin Li,
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Tiejun Wang, ; Bingjin Li,
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50
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The African Swine Fever Virus with MGF360 and MGF505 Deleted Reduces the Apoptosis of Porcine Alveolar Macrophages by Inhibiting the NF-κB Signaling Pathway and Interleukin-1β. Vaccines (Basel) 2021; 9:vaccines9111371. [PMID: 34835302 PMCID: PMC8622997 DOI: 10.3390/vaccines9111371] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/11/2021] [Accepted: 11/13/2021] [Indexed: 12/19/2022] Open
Abstract
African swine fever virus (ASFV) poses serious threats to the swine industry. The mortality rate of African swine fever (ASF) is 100%, and there is no effective vaccine currently available. Complex immune escape strategies of ASFV are crucial factors affecting immune prevention and vaccine development. CD2v and MGF360-505R genes have been implicated in the modulation of the immune response. The molecular mechanisms contributing to innate immunity are poorly understood. In this study, we discover the cytopathic effect and apoptosis of ΔCD2v/ΔMGF360-505R-ASFV after infection in porcine alveolar macrophages (PAMs) was significantly less than wild-type ASFV. We demonstrated that CD2v- and MGF360-505R-deficient ASFV decrease the level of apoptosis by inhibiting the NF-κB signaling pathway and IL-1β mRNA transcription. Compared with wild-type ASFV infection, the levels of phospho-NF-κB p65 and p-IκB protein decreased in CD2v- and MGF360-505R-deficient ASFV. Moreover, CD2v- and MGF360-505R-deficient ASFV induced less IL-1β production than wild-type ASFV and was attenuated in replication compared with wild-type ASFV. We further found that MGF360-12L, MGF360-13L, and MGF-505-2R suppress the promoter activity of NF-κB by reporter assays, and CD2v activates the NF-κB signaling pathway. These findings suggested that CD2v- and MGF360-505R-deficient ASFV could reduce the level of ASFV p30 and the apoptosis of PAMs by inhibiting the NF-κB signaling pathway and IL-1β mRNA transcription, which might reveal a novel strategy for ASFV to maintain the replication of the virus in the host.
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