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1
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Kang JW, Chan KWK, Vasudevan SG, Low JG. α-Glucosidase inhibitors as broad-spectrum antivirals: Current knowledge and future prospects. Antiviral Res 2025; 238:106147. [PMID: 40120858 DOI: 10.1016/j.antiviral.2025.106147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/17/2025] [Accepted: 03/19/2025] [Indexed: 03/25/2025]
Affiliation(s)
- James Wj Kang
- Department of Infectious Diseases, Singapore General Hospital, Singapore, 168753, Singapore
| | - Kitti Wing Ki Chan
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Subhash G Vasudevan
- Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore; Institute of Biomedicine and Glycomics, Griffith University, Queensland, Australia
| | - Jenny G Low
- Department of Infectious Diseases, Singapore General Hospital, Singapore, 168753, Singapore; Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, 169857, Singapore; Viral Research and Experimental Medicine Centre, SingHealth Duke-NUS Academic Medical Centre, Singapore, 169857, Singapore.
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2
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Aryal B, Kwakye J, Ariyo OW, Ghareeb AFA, Milfort MC, Fuller AL, Khatiwada S, Rekaya R, Aggrey SE. Major Oxidative and Antioxidant Mechanisms During Heat Stress-Induced Oxidative Stress in Chickens. Antioxidants (Basel) 2025; 14:471. [PMID: 40298812 PMCID: PMC12023971 DOI: 10.3390/antiox14040471] [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: 02/18/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 04/30/2025] Open
Abstract
Heat stress (HS) is one of the most important stressors in chickens, and its adverse effects are primarily caused by disturbing the redox homeostasis. An increase in electron leakage from the mitochondrial electron transport chain is the major source of free radical production under HS, which triggers other enzymatic systems to generate more radicals. As a defense mechanism, cells have enzymatic and non-enzymatic antioxidant systems that work cooperatively against free radicals. The generation of free radicals, particularly the reactive oxygen species (ROS) and reactive nitrogen species (RNS), under HS condition outweighs the cellular antioxidant capacity, resulting in oxidative damage to macromolecules, including lipids, carbohydrates, proteins, and DNA. Understanding these detrimental oxidative processes and protective defense mechanisms is important in developing mitigation strategies against HS. This review summarizes the current understanding of major oxidative and antioxidant systems and their molecular mechanisms in generating or neutralizing the ROS/RNS. Importantly, this review explores the potential mechanisms that lead to the development of oxidative stress in heat-stressed chickens, highlighting their unique behavioral and physiological responses against thermal stress. Further, we summarize the major findings associated with these oxidative and antioxidant mechanisms in chickens.
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Affiliation(s)
- Bikash Aryal
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691, USA;
| | - Josephine Kwakye
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
| | - Oluwatomide W. Ariyo
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
| | - Ahmed F. A. Ghareeb
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
- Boehringer Ingelheim Animal Health (BIAH), Gainesville, GA 30501, USA
| | - Marie C. Milfort
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
| | - Alberta L. Fuller
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
| | - Saroj Khatiwada
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691, USA;
| | - Romdhane Rekaya
- Department of Animal and Dairy Science, The University of Georgia, Athens, GA 30602, USA;
| | - Samuel E. Aggrey
- NutriGenomics Laboratory, Department of Poultry Science, The University of Georgia, Athens, GA 30602, USA or (B.A.); (J.K.); (O.W.A.); (A.F.A.G.); (M.C.M.); (A.L.F.)
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3
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Chang TD, Chen YJ, Luo JL, Zhang C, Chen SY, Lin ZQ, Zhang PD, Shen YX, Tang TX, Li H, Dong LM, Tang ZH, Chen D, Wang YM. Adaptation of Natural Killer Cells to Hypoxia: A Review of the Transcriptional, Translational, and Metabolic Processes. Immunotargets Ther 2025; 14:99-121. [PMID: 39990274 PMCID: PMC11846490 DOI: 10.2147/itt.s492334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 02/08/2025] [Indexed: 02/25/2025] Open
Abstract
As important innate immune cells, natural killer (NK) cells play an essential role in resisting pathogen invasion and eliminating transformed cells. However, the hypoxic microenvironment caused by disease conditions is an important physicochemical factor that impairs NK cell function. With the increasing prominence of NK cells in immunotherapy, there has been a surge of interest in developing biological means through which NK cells may overcome the inhibition caused by hypoxia in disease conditions. Although the effects of hypoxic conditions in shaping the functions of NK cells have been increasingly recognized and investigated, reviews have been scantly. A comprehensive understanding of how NK cells adapt to hypoxia can provide valuable insights into how the functional capacity of NK cells may be restored. This review focuses on the functional alterations of NK cells in response to hypoxia. It delineates the mechanisms by which NK cells adapt to hypoxia at the transcriptional, metabolic, translational levels. Furthermore, given the complexity of the hypoxic microenvironment, we also elucidated the effects of key hypoxic metabolites on NK cells. Finally, this review discusses the current clinical therapies derived from targeting hypoxic NK cells. The study of NK cell adaptation to hypoxia has yielded new insights into immunotherapy. These insights may lead to development of novel strategies to improve the treatment of infectious diseases and cancer.
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Affiliation(s)
- Te-Ding Chang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yu-Jie Chen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jia-Liu Luo
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Cong Zhang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Shun-Yao Chen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Zhi-Qiang Lin
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Pei-Dong Zhang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - You-Xie Shen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Ting-Xuan Tang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Hui Li
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Li-Ming Dong
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Zhao-Hui Tang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Deng Chen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Yu-Man Wang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
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4
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Ali M, Wollenhaupt-Aguiar B, Wang Y, Abu-Hijleh F, Rigg N, de Azevedo Cardoso T, Ahmed I, Gopalakrishnan R, Jansen K, de Mattos Souza LD, Azevedo da Silva R, Mondin TC, Kapczinski F, Moreira FP, Lofts A, Gwynne WD, Hoare T, Mishra R, Frey BN. Investigation of the mesencephalic astrocyte-derived neurotrophic factor-endoplasmic reticulum stress pathway in mood disorders. Int J Neuropsychopharmacol 2025; 28:pyaf004. [PMID: 39803900 PMCID: PMC11808195 DOI: 10.1093/ijnp/pyaf004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 01/10/2025] [Indexed: 02/11/2025] Open
Abstract
BACKGROUND Bipolar disorder (BD) has been associated with impaired cellular resilience. Recent studies have shown abnormalities in the unfolded protein response (UPR) in BD. The UPR is the cellular response to endoplasmic reticulum (ER) stress. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a trophic factor, decreases ER stress by modulating the UPR. The objective of this study is to investigate the MANF-ER stress pathway in BD and major depressive disorder (MDD) compared to healthy controls (HC). METHODS MANF protein concentration and MANF and GRP78 gene expression were assessed in peripheral blood from individuals with BD, MDD, and HC (protein: 40 BD, 55 MDD, 55 HC; gene expression: 52 BD, 61 MDD, 69 HC). MANF protein and gene expression along with GRP78 gene expression were also analyzed in postmortem brain tissue (20 BD, 20 MDD, 19 HC). MANF protein was quantified using an ELISA assay while quantitative polymerase chain reaction was used for MANF and GRP78 gene expression. RESULTS Peripheral MANF protein levels were reduced in individuals with BD in a depressive state compared to controls (P = .031) and euthymic BD participants (P = .013). No significant differences in MANF or GRP78 gene expression were observed in BD irrespective of mood state, or MDD compared to HC (all P > .05). No differences were observed regarding MANF/GRP78 protein or gene expression levels in postmortem tissue (P > .05). CONCLUSIONS Individuals with BD who were in an acute depressive phase were found to have reduced peripheral MANF levels potentially signifying abnormal UPR and supporting the notion that BD is associated with increased ER stress.
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Affiliation(s)
- Mohammad Ali
- MiNDS Neuroscience Graduate Program, McMaster University, Hamilton, Ontario, Canada
- Centre for Clinical Neurosciences, McMaster University, Hamilton, Ontario, Canada
| | - Bianca Wollenhaupt-Aguiar
- Centre for Clinical Neurosciences, McMaster University, Hamilton, Ontario, Canada
- Mood Disorders Treatment and Research Centre and Women’s Health Concerns Clinic, St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada
| | - Yifan Wang
- Centre for Clinical Neurosciences, McMaster University, Hamilton, Ontario, Canada
- University of Ottawa Medical School, Ottawa, Ontario, Canada
| | - Fahed Abu-Hijleh
- MiNDS Neuroscience Graduate Program, McMaster University, Hamilton, Ontario, Canada
| | - Nicolette Rigg
- MiNDS Neuroscience Graduate Program, McMaster University, Hamilton, Ontario, Canada
| | - Taiane de Azevedo Cardoso
- IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - Imran Ahmed
- Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
- Michael G. Degroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Ridhi Gopalakrishnan
- Centre for Clinical Neurosciences, McMaster University, Hamilton, Ontario, Canada
| | - Karen Jansen
- Department of Health and Behavior, Catholic University of Pelotas, Pelotas, Brazil
| | | | | | | | - Flavio Kapczinski
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
- Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
- Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
- Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Porto Alegre, Brazil
| | | | - Andrew Lofts
- School of Biomedical Engineering, McMaster University, West Hamilton, Ontario L8S 4L8, Canada
| | - William D Gwynne
- Department of Surgery, McMaster University, West Hamilton, Ontario L8S 4L8, Canada
- Center for Discovery in Cancer Research (CDCR), McMaster University, West Hamilton, Ontario L8S 4L8, Canada
| | - Todd Hoare
- School of Biomedical Engineering, McMaster University, West Hamilton, Ontario L8S 4L8, Canada
- Department of Chemical Engineering, McMaster University, West Hamilton, Ontario L8S 4L8, Canada
| | - Ram Mishra
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
| | - Benicio N Frey
- Centre for Clinical Neurosciences, McMaster University, Hamilton, Ontario, Canada
- Mood Disorders Treatment and Research Centre and Women’s Health Concerns Clinic, St. Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
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5
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Cerqua M, Foiani M, Boccaccio C, Comoglio PM, Altintas DM. The integrated stress response drives MET oncogene overexpression in cancers. EMBO J 2025; 44:1107-1130. [PMID: 39774381 PMCID: PMC11832788 DOI: 10.1038/s44318-024-00338-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 11/09/2024] [Accepted: 11/29/2024] [Indexed: 01/11/2025] Open
Abstract
Cancer cells rely on invasive growth to survive in a hostile microenvironment; this growth is characterised by interconnected processes such as epithelial-to-mesenchymal transition and migration. A master regulator of these events is the MET oncogene, which is overexpressed in the majority of cancers; however, since mutations in the MET oncogene are seen only rarely in cancers and are relatively infrequent, the mechanisms that cause this widespread MET overexpression remain obscure. Here, we show that the 5' untranslated region (5'UTR) of MET mRNA harbours two functional stress-responsive elements, conferring translational regulation by the integrated stress response (ISR), regulated by phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) at serine 52. ISR activation by serum starvation, leucine deprivation, hypoxia, irradiation, thapsigargin or gemcitabine is followed by MET protein overexpression. We mechanistically link MET translation to the ISR by (i) mutation of the two uORFs within the MET 5'UTR, (ii) CRISPR/Cas9-mediated mutation of eIF2α (S52A), or (iii) the application of ISR pathway inhibitors. All of these interventions reduce stress-induced MET overexpression. Finally, we show that blocking stress-induced MET translation blunts MET-dependent invasive growth. These findings indicate that upregulation of the MET oncogene is a functional requirement linking integrated stress response to cancer progression.
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Affiliation(s)
- Marina Cerqua
- IFOM ETS-The AIRC Institute of Molecular Oncology, 20139, Milano, Italy
| | - Marco Foiani
- IFOM ETS-The AIRC Institute of Molecular Oncology, 20139, Milano, Italy
| | - Carla Boccaccio
- Candiolo Cancer Institute, 10060 Candiolo, Torino, Italy
- Department of Oncology, University of Torino, 10100, Torino, Italy
| | - Paolo M Comoglio
- IFOM ETS-The AIRC Institute of Molecular Oncology, 20139, Milano, Italy.
| | - Dogus M Altintas
- IFOM ETS-The AIRC Institute of Molecular Oncology, 20139, Milano, Italy.
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Choi HJ, Wu Y, Mcdaniel Mims B, Pugel A, Tang CHA, Tian L, Hu CCA, Yu XZ. Endoplasmic Reticulum Stress Response Mediator IRE-1α Promotes Host Dendritic Cells in Graft-versus-Host Disease Development. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:384-393. [PMID: 38864663 PMCID: PMC11415232 DOI: 10.4049/jimmunol.2300616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 05/22/2024] [Indexed: 06/13/2024]
Abstract
Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.
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Affiliation(s)
- Hee-Jin Choi
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yongxia Wu
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Brianyell Mcdaniel Mims
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Allison Pugel
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Chih-Hang Anthony Tang
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, United States
| | - Linlu Tian
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Chih-Chi Andrew Hu
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, United States
| | - Xue-Zhong Yu
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
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7
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Gong Y, Chen S, Wang Z, Li W, Xie R, Zhang H, Huang X, Chen N, Li S. Dietary lipid sources affect growth performance, lipid deposition, antioxidant capacity and inflammatory response of largemouth bass (Micropterus salmoides). FISH & SHELLFISH IMMUNOLOGY 2024; 150:109635. [PMID: 38754648 DOI: 10.1016/j.fsi.2024.109635] [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: 03/04/2024] [Revised: 05/13/2024] [Accepted: 05/13/2024] [Indexed: 05/18/2024]
Abstract
The present study explored the effects of different lipid sources on growth performance, lipid deposition, antioxidant capacity, inflammatory response and disease resistance of largemouth bass (Micropterus salmoides). Four isonitrogenous (crude protein 50.46 %) and isolipidic (crude lipid 11.12 %) diets were formulated to contain 7 % of different oil sources including fish oil (FO) (control), soybean oil (SO), linseed oil (LO) and coconut oil (CO). Largemouth bass with initial body weight of 36.0 ± 0.2 g were randomly distributed into 12 tanks, with 30 fish per tank and 3 tanks per treatment. The fish were fed with the experiment diets twice daily for 8 weeks. The results indicated that the weight gain of largemouth bass fed the FO diet was significantly higher than that of fish fed the LO and CO diets. The liver crude lipid content in FO group was significantly higher than other groups, while the highest liver triglyceride content was showed in SO group and the lowest was detected in LO group. At transcriptional level, expression of lipogenesis related genes (pparγ, srebp1, fas, acc, dgat1 and dgat2) in the SO and CO group were significantly higher than the FO group. However, the expression of lipolysis and fatty acids oxidation related genes (pparα, cpt1, and aco) in vegetable oils groups were significantly higher than the FO group. As to the antioxidant capacity, vegetable oils significantly reduced the malondialdehyde content of largemouth bass. Total antioxidant capacity in the SO and LO groups were significantly increased compared with the FO group. Catalase in the LO group was significantly increased compared with the FO group. Furthermore, the ER stress related genes, such as grp78, atf6α, atf6β, chop and xbp1 were significantly enhanced in the vegetable oil groups compared with the FO group. The activity of serum lysozyme in vegetable oil groups were significantly higher than in FO group. Additionally, the relative expression of non-specific immune related genes, including tlr2, mapk11, mapk13, mapk14, rela, tgf-β1, tnfα, 5lox, il-1β and il10, were all significantly increased in SO and CO groups compared to the other groups. In conclusion, based on the indexes including growth performance, lipid deposition, antioxidant capacity and inflammatory response, SO and LO could be alternative oil sources for largemouth bass.
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Affiliation(s)
- Ye Gong
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, 201306, China
| | - Shiwen Chen
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, 201306, China
| | - Zhenjie Wang
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, 201306, China
| | - Wenfei Li
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, 201306, China
| | - Ruitao Xie
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture and Rural Affairs, Zhanjiang, 524000, China
| | - Haitao Zhang
- Key Laboratory of Aquatic, Livestock and Poultry Feed Science and Technology in South China, Ministry of Agriculture and Rural Affairs, Zhanjiang, 524000, China
| | - Xuxiong Huang
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, 201306, China; National Demonstration Center on Experiment Teaching of Fisheries Science, Shanghai Ocean University, Shanghai, 201306, China.
| | - Naisong Chen
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, 201306, China
| | - Songlin Li
- Research Centre of the Ministry of Agriculture and Rural Affairs on Environmental Ecology and Fish Nutrition, Shanghai Ocean University, Shanghai, 201306, China; National Demonstration Center on Experiment Teaching of Fisheries Science, Shanghai Ocean University, Shanghai, 201306, China.
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8
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Kanata E, Duffié R, Schulz EG. Establishment and maintenance of random monoallelic expression. Development 2024; 151:dev201741. [PMID: 38813842 PMCID: PMC11166465 DOI: 10.1242/dev.201741] [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] [Indexed: 05/31/2024]
Abstract
This Review elucidates the regulatory principles of random monoallelic expression by focusing on two well-studied examples: the X-chromosome inactivation regulator Xist and the olfactory receptor gene family. Although the choice of a single X chromosome or olfactory receptor occurs in different developmental contexts, common gene regulatory principles guide monoallelic expression in both systems. In both cases, an event breaks the symmetry between genetically and epigenetically identical copies of the gene, leading to the expression of one single random allele, stabilized through negative feedback control. Although many regulatory steps that govern the establishment and maintenance of monoallelic expression have been identified, key pieces of the puzzle are still missing. We provide an overview of the current knowledge and models for the monoallelic expression of Xist and olfactory receptors. We discuss their similarities and differences, and highlight open questions and approaches that could guide the study of other monoallelically expressed genes.
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Affiliation(s)
- Eleni Kanata
- Systems Epigenetics, Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
| | - Rachel Duffié
- Department of Biochemistry and Molecular Biophysics, Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
| | - Edda G. Schulz
- Systems Epigenetics, Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
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Qiu L, Liu H, Chen S, Wu Y, Yan J. Inhibition of the endoplasmic reticulum stress-associated IRE-1 pathway alleviates preterm birth. Am J Reprod Immunol 2024; 91:e13826. [PMID: 38531818 DOI: 10.1111/aji.13826] [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: 10/15/2023] [Revised: 01/16/2024] [Accepted: 02/05/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Premature birth (PTB) remains a major global health concern due to its association with neonatal morbidity and mortality. The unfolded protein response (UPR) within the endoplasmic reticulum (ER) is tightly regulated by Inositol-requiring enzyme type 1 (IRE-1), a pivotal cellular modulator. This study seeks to elucidate the role of the ER stress (ERS)-related IRE-1 pathway in PTB. METHODS Human placental trophoblast cells HTR8/Svneo were exposed to the ER-stress inducer tunicamycin (TM). The expression of IRE-1 and ERS-associated proteins ATF6, GRP78, and XBP-1 was assessed in placental tissues and TM-treated cells. Cellular viability, migration, invasion, and apoptosis were evaluated through a series of experimental assays. Additionally, various methods were employed to assess and verify the activation of autophagy, using the autophagy marker, microtubule-associated protein 1A/1B-light chain 3 (LC3). Additionally, TUDCA (an ERS inhibitor) was used to assess its potential to counteract the TM-induced cell effects. RESULTS Elevated levels of ATF6, GRP78, and XBP-1 were observed in PTB tissues and cells. TM treatment substantially reduced cell viability, migration, and invasion while promoting apoptosis. Treatment with TUDCA (an ERS inhibitor) counteracted the effects of TM on the cells. Furthermore, we identified an overexpression of IRE-1 in PTB tissues and cells and its knockdown enhanced cell viability, migration, and invasion while suppressed apoptosis and autophagy under TM stimulation. Notably, IRE-1 was found to modulate the activity of the IRE-1/XBP1/CHOP signaling pathway in TM-treated cells. CONCLUSION The upregulation of IRE-1 in PTB placental tissues is implicated in the pathogenesis of PTB. Importantly, inhibiting the ERS-associated IRE-1/XBP1/CHOP pathway may be a good strategy in mitigating PTB.
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Affiliation(s)
- Liyin Qiu
- Department of Obstetrics, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Hui Liu
- Department of Histology and Embryology, Fujian Medical University, Fuzhou, Fujian, China
| | - Shali Chen
- Department of Obstetrics, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Yiting Wu
- Department of Obstetrics, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
| | - Jianying Yan
- Department of Obstetrics, Fujian Maternity and Child Health Hospital College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, China
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Koushki M, Amiri-Dashatan N, Rezaei-Tavirani M, Robati RM, Fateminasab F, Rahimi S, Razzaghi Z, Farahani M. Screening the critical protein subnetwork to delineate potential mechanisms and protective agents associated with arsenic-induced cutaneous squamous cell carcinoma: A toxicogenomic study. Food Chem Toxicol 2024; 185:114451. [PMID: 38219847 DOI: 10.1016/j.fct.2024.114451] [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: 12/06/2023] [Revised: 01/01/2024] [Accepted: 01/11/2024] [Indexed: 01/16/2024]
Abstract
Recent studies show that complex mechanisms are involved in arsenic-induced malignant transformation of cells. This study aimed to decipher molecular mechanisms associated with arsenic-induced cutaneous squamous cell carcinoma (cSCC) and suggest potential protective factors. RNA-seq-based differentially expressed genes between arsenic-exposed human keratinocytes (HaCaT) and controls were used to construct a protein-protein interaction (PPI) network and discover critical subnetwork-based mechanisms. Protective compounds against arsenic toxicity were determined and their target interactions in the core sub-network were identified by the comparative toxicogenomic database (CTD). The binding affinity between the effective factor and target was calculated by molecular docking. A total of 15 key proteins were screened out as critical arsenic-responsive subnetwork (FN1, IL-1A, CCN2, PECAM1, FGF5, EDN1, FGF1, PXDN, DNAJB9, XBP1, ERN1, PDIA4, DNAJB11, FOS, PDIA6) and 7 effective protective agents were identified (folic acid, quercetin, zinc, acetylcysteine, methionine, catechin, selenium). The GeneMANIA predicted detailed interactions of the subnetwork and revealed terms related to unfolded protein response as the main processes. FN1, IL1A and CCN2, as top significant genes, had good docking affinity with folic acid and quercetin, as selected key compounds. Integration of gene expression and protein-protein interaction related to arsenic exposure in cSCC explored the potential mechanisms and protective agents.
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Affiliation(s)
- Mehdi Koushki
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Nasrin Amiri-Dashatan
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza M Robati
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Dermatology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Fateminasab
- Department of Physical Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar, 47416-95447, Iran
| | - Shadi Rahimi
- Division of Systems and Synthetic Biology, Department of Life Sciences, Chalmers University of Technology, SE-41296, Gothenburg, Sweden
| | - Zahra Razzaghi
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoumeh Farahani
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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11
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Banerjee S, Ansari AA, Upadhyay SP, Mettman DJ, Hibdon JR, Quadir M, Ghosh P, Kambhampati A, Banerjee SK. Benefits and Pitfalls of a Glycosylation Inhibitor Tunicamycin in the Therapeutic Implication of Cancers. Cells 2024; 13:395. [PMID: 38474359 PMCID: PMC10930662 DOI: 10.3390/cells13050395] [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: 01/25/2024] [Revised: 02/12/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
The aberrant glycosylation is a hallmark of cancer progression and chemoresistance. It is also an immune therapeutic target for various cancers. Tunicamycin (TM) is one of the potent nucleoside antibiotics and an inhibitor of aberrant glycosylation in various cancer cells, including breast cancer, gastric cancer, and pancreatic cancer, parallel with the inhibition of cancer cell growth and progression of tumors. Like chemotherapies such as doxorubicin (DOX), 5'fluorouracil, etoposide, and cisplatin, TM induces the unfolded protein response (UPR) by blocking aberrant glycosylation. Consequently, stress is induced in the endoplasmic reticulum (ER) that promotes apoptosis. TM can thus be considered a potent antitumor drug in various cancers and may promote chemosensitivity. However, its lack of cell-type-specific cytotoxicity impedes its anticancer efficacy. In this review, we focus on recent advances in our understanding of the benefits and pitfalls of TM therapies in various cancers, including breast, colon, and pancreatic cancers, and discuss the mechanisms identified by which TM functions. Finally, we discuss the potential use of nano-based drug delivery systems to overcome non-specific toxicity and enhance the therapeutic efficacy of TM as a targeted therapy.
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Affiliation(s)
- Snigdha Banerjee
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Affan A. Ansari
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
| | - Sunil P. Upadhyay
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
| | - Daniel J. Mettman
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Pathology Department, City VA Medical Center, Kansas City, MO 64128, USA
| | - Jamie R. Hibdon
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
| | - Mohiuddin Quadir
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58108, USA; (M.Q.); (P.G.)
| | - Pratyusha Ghosh
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58108, USA; (M.Q.); (P.G.)
| | - Anjali Kambhampati
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
| | - Sushanta K. Banerjee
- Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA; (A.A.A.); (S.P.U.); (D.J.M.); (J.R.H.); (A.K.)
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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12
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Liu Z, Wang G, Sheng C, Zheng Y, Tang D, Zhang Y, Hou X, Yao M, Zong Q, Zhou Z. Intracellular Protein Adsorption Behavior and Biological Effects of Polystyrene Nanoplastics in THP-1 Cells. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2024; 58:2652-2661. [PMID: 38294362 DOI: 10.1021/acs.est.3c05493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2024]
Abstract
Micro(nano)plastics (MNPs) are emerging pollutants that can adsorb pollutants in the environment and biological molecules and ultimately affect human health. However, the aspects of adsorption of intracellular proteins onto MNPs and its biological effects in cells have not been investigated to date. The present study revealed that 100 nm polystyrene nanoplastics (NPs) could be internalized by THP-1 cells and specifically adsorbed intracellular proteins. In total, 773 proteins adsorbed onto NPs with high reliability were identified using the proteomics approach and analyzed via bioinformatics to predict the route and distribution of NPs following cellular internalization. The representative proteins identified via the Kyoto Encyclopedia of Genes and Genomes pathway analysis were further investigated to characterize protein adsorption onto NPs and its biological effects. The analysis revealed that NPs affect glycolysis through pyruvate kinase M (PKM) adsorption, trigger the unfolded protein response through the adsorption of ribophorin 1 (RPN1) and heat shock 70 protein 8 (HSPA8), and are chiefly internalized into cells through clathrin-mediated endocytosis with concomitant clathrin heavy chain (CLTC) adsorption. Therefore, this work provides new insights and research strategies for the study of the biological effects caused by NPs.
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Affiliation(s)
- Zijia Liu
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Guozhen Wang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
- Clinical Laboratory, China-Japan Friendship Hospital, Beijing 100124, China
| | - Chao Sheng
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Yuchen Zheng
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Duo Tang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Yuchen Zhang
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Xiaonan Hou
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Mengfei Yao
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Qi Zong
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Zhixiang Zhou
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
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13
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Tawfik A, Kawaguchi T, Takahashi M, Setoh K, Yamaguchi I, Tabara Y, Van Steen K, Sakuntabhai A, Matsuda F. Transcriptomic Analysis Reveals Sixteen Potential Genes Associated with the Successful Differentiation of Antibody-Secreting Cells through the Utilization of Unfolded Protein Response Mechanisms in Robust Responders to the Influenza Vaccine. Vaccines (Basel) 2024; 12:136. [PMID: 38400120 PMCID: PMC10892001 DOI: 10.3390/vaccines12020136] [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: 12/29/2023] [Revised: 01/23/2024] [Accepted: 01/26/2024] [Indexed: 02/25/2024] Open
Abstract
The seasonal influenza vaccine remains one of the vital recommended infection control measures for the elderly with chronic illnesses. We investigated the immunogenicity of a single dose of influenza vaccine in 123 seronegative participants and classified them into four distinct groups, determined by the promptness of vaccine response, the longevity of humoral immunity, and the likelihood of exhibiting cross-reactivity. Subsequently, we used transcriptional profiling and differential gene expression analysis to identify potential genes directly associated with the robust response to the vaccine. The group of exemplary vaccine responders differentially expressed 16 genes, namely: MZB1, MYDGF, TXNDC5, TXNDC11, HSP90B1, FKBP11, PDIA5, PRDX4, CD38, SDC1, TNFRSF17, TNFRSF13B, PAX5, POU2AF1, IRF4, and XBP1. Our findings point out a list of expressed proteins that are related to B cell proliferation, unfolded protein response, and cellular haemostasis, as well as a linkage of these expressions to the survival of long-lived plasma cells.
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Affiliation(s)
- Ahmed Tawfik
- Functional Genetics of Infectious Diseases Unit, Institut Pasteur, CNRS UMR2000, 75015 Paris, France;
- Pasteur International Unit at Center for Genomic Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Takahisa Kawaguchi
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan (I.Y.)
| | - Meiko Takahashi
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan (I.Y.)
| | - Kazuya Setoh
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan (I.Y.)
| | - Izumi Yamaguchi
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan (I.Y.)
| | - Yasuharu Tabara
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan (I.Y.)
| | - Kristel Van Steen
- BIO3—Laboratory for Systems Genetics, GIGA-R Medical Genomics, University of Liège, 4000 Liège, Belgium
- BIO3—Laboratory for Systems Genetics, GIGA-R Medical Genomics, University of Leuven, 3000 Leuven, Belgium
| | - Anavaj Sakuntabhai
- Pasteur International Unit at Center for Genomic Medicine, Kyoto University, Kyoto 606-8507, Japan
- Ecology and Emergence of Arthropod-Borne Pathogens Unit, Institut Pasteur, CNRS UMR2000, 75015 Paris, France
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan (I.Y.)
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14
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Teixeira LF, Prauchner GRK, Gusso D, Wyse ATS. Classical Hereditary galactosemia: findings in patients and animal models. Metab Brain Dis 2024; 39:239-248. [PMID: 37702899 DOI: 10.1007/s11011-023-01281-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/21/2023] [Indexed: 09/14/2023]
Abstract
Classic galactosemia is a rare inborn error of metabolism that affects the metabolism of galactose, a sugar derived from milk and derivates. Classic galactosemia is caused by variants of the GALT gene, which lead to absent or misfolded forms of the ubiquitously present galactose-1-phosphate uridylyltransferase enzyme (GALT) driving galactose metabolites to accumulate, damaging cells from neurons to hepatocytes. The disease has different prevalence around the world due to different allele frequencies among populations and its symptoms range from cognitive and psychomotor impairment to hepatic, ophthalmological, and bone structural damage. The practice of newborn screening still varies among countries, dairy restriction treatment is a consensus despite advances in preclinical treatment strategies. Recent clinical studies in Duarte variant suggest dairy restriction could be reconsidered in these cases. Despite noteworthy advances in the classic galactosemia understanding, preclinical trials are still crucial to fully understand the pathophysiology of the disease and help propose new treatments. This review aims to report a comprehensive analysis of past studies and state of art research on galactosemia screening, its clinical and preclinical trials, and treatments with the goal of shedding light on this complex and multisystemic innate error of the metabolism.
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Affiliation(s)
- Lucas Ferreira Teixeira
- Laboratory of Neuroprotection and Neurometabolic Diseases, Department of Biochemistry - Wyse's Lab - ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Gustavo R Krupp Prauchner
- Laboratory of Neuroprotection and Neurometabolic Diseases, Department of Biochemistry - Wyse's Lab - ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Darlan Gusso
- Laboratory of Neuroprotection and Neurometabolic Diseases, Department of Biochemistry - Wyse's Lab - ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Angela T S Wyse
- Laboratory of Neuroprotection and Neurometabolic Diseases, Department of Biochemistry - Wyse's Lab - ICBS, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, CEP 90035-003, Brazil.
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15
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Shen Y, Zhao W, Bao Y, Zhu J, Jiao L, Duan X, Pan T, Monroig Ó, Zhou Q, Jin M. Molecular cloning and characterization of endoplasmic reticulum stress related genes grp78 and atf6α from black seabream (Acanthopagrus schlegelii) and their expressions in response to nutritional regulation. FISH PHYSIOLOGY AND BIOCHEMISTRY 2023; 49:1115-1128. [PMID: 37855969 DOI: 10.1007/s10695-023-01242-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 09/16/2023] [Indexed: 10/20/2023]
Abstract
Glucose-regulated protein 78 (grp78) and activating transcription factor 6α (atf6α) are considered vital endoplasmic reticulum (ER) molecular chaperones and ER stress (ERS) sensors, respectively. In the present study, the full cDNA sequences of these two ERS-related genes were first cloned and characterized from black seabream (Acanthopagrus schlegelii). The grp78 cDNA sequence is 2606 base pair (bp) encoding a protein of 654 amino acids (aa). The atf6α cDNA sequence is 2168 base pair (bp) encoding a protein of 645 aa. The predicted aa sequences of A. schlegelii grp78 and atf6α indicated that the proteins contain all the structural features, which were characteristic of the two genes in other species. Tissues transcript abundance analysis revealed that the mRNAs of grp78 and atf6α were expressed in all measured tissues, but the highest expression of these two genes was all recorded in the gill followed by liver/ brain. Moreover, in vivo experiment found that fish intake of a high lipid diet (HLD) can trigger ERS by activating grp78/Grp78 and atf6α/Atf6α. However, it can be alleviated by dietary betaine supplementation, similar results were also obtained by in vitro experiment using primary hepatocytes of A. schlegelii. These findings will be beneficial for us to evaluate the regulator effects of HLD supplemented with betaine on ERS at the molecular level, and thus provide some novel insights into the functions of betaine in marine fish fed with an HLD.
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Affiliation(s)
- Yuedong Shen
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Wenli Zhao
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Yangguang Bao
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Jiayun Zhu
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Lefei Jiao
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Xuemei Duan
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Tingting Pan
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, 315211, China
| | - Óscar Monroig
- Instituto de Acuicultura Torre de la Sal (IATS), CSIC, Ribera de Cabanes, 12595, Castellón, Spain
| | - Qicun Zhou
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, 315211, China.
| | - Min Jin
- Laboratory of Fish and Shellfish Nutrition, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
- Key Laboratory of Aquacultural Biotechnology Ministry of Education, Ningbo University, Ningbo, 315211, China.
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16
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Stokes ME, Calvo V, Fujisawa S, Dudgeon C, Huang S, Ballal N, Shen L, Gasparek J, Betzenhauser M, Taylor SJ, Staschke KA, Rigby AC, Mulvihill MJ, Bose N, Lightcap ES, Surguladze D. PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors. Clin Cancer Res 2023; 29:4870-4882. [PMID: 37733811 PMCID: PMC10690095 DOI: 10.1158/1078-0432.ccr-23-1182] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 07/28/2023] [Accepted: 09/19/2023] [Indexed: 09/23/2023]
Abstract
PURPOSE Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI). EXPERIMENTAL DESIGN HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC. RESULTS VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group. CONCLUSIONS By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.
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Affiliation(s)
| | | | | | | | | | | | - Leyi Shen
- HiberCell, Inc., New York City, New York
| | | | | | - Simon J. Taylor
- Drug Discovery, Pharmaron UK Ltd., Hoddesdon, Herts, United Kingdom
| | - Kirk A. Staschke
- Indiana University School of Medicine, Indianapolis, Indiana
- Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana
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17
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Kirimoto Y, Yamano-Adachi N, Koga Y, Omasa T. Effect of co-overexpression of the cargo receptor ERGIC-53/MCFD2 on antibody production and intracellular IgG secretion in recombinant Chinese hamster ovary cells. J Biosci Bioeng 2023; 136:400-406. [PMID: 35963666 DOI: 10.1016/j.jbiosc.2022.07.002] [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: 04/19/2022] [Revised: 06/30/2022] [Accepted: 07/04/2022] [Indexed: 11/26/2022]
Abstract
Therapeutic antibodies are attractive biopharmaceuticals because of their high therapeutic effects, fewer side effects, and prolonged half-life in the blood. Chinese hamster ovary (CHO) cells are the most widely used host cell lines to produce therapeutic antibodies in industries. High-producing recombinant CHO cells can be established via overexpression of endogenous proteins. In this study, we focused on the intracellular traffic of an antibody-producing CHO cell line, CHO-HcD6. Assembled antibodies were accumulated in the endoplasmic reticulum (ER) in the cell. We hypothesized that the accumulation was due to the insufficient number of cargo receptors in the cell and focused on a cargo receptor, the ERGIC-53-MCFD2 complex, which transports expressed proteins from the ER to the Golgi apparatus. Overexpression of the cargo receptor transport was expected to improve antibody production. Exogenous ERGIC-53 and MCFD2 were transfected into CHO-HcD6 cells, and overexpressing CHO-HcD6 cells were constructed. As a result of overexpression, antibody productivity increased in batch cultivation. However, the chase assay results and immunofluorescence microscopic observations revealed intracellular IgG accumulation in the overexpressing cells. These results suggest that overexpression of cargo receptors not only promoted extracellular secretion but also enhanced the retention of intracellular antibodies.
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Affiliation(s)
- Yutaka Kirimoto
- Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Noriko Yamano-Adachi
- Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Manufacturing Technology Association of Biologics, 7-1-49 Minatojima-minami, Kobe, Hyogo 650-0047, Japan; Industrial Biotechnology Initiative Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Yuichi Koga
- Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Industrial Biotechnology Initiative Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takeshi Omasa
- Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan; Manufacturing Technology Association of Biologics, 7-1-49 Minatojima-minami, Kobe, Hyogo 650-0047, Japan; Industrial Biotechnology Initiative Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
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18
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Gao Q, Lu W, Fan S, Xie W, Zhang H, Han Y, Weng Q. Seasonal changes in endoplasmic reticulum stress and steroidogenesis in the ovary of the wild ground squirrels (Citellus dauricus Brandt). Gen Comp Endocrinol 2023; 343:114368. [PMID: 37604348 DOI: 10.1016/j.ygcen.2023.114368] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/12/2023] [Accepted: 08/18/2023] [Indexed: 08/23/2023]
Abstract
The development of the follicle is accompanied by steroidogenesis and secretion, the endoplasmic reticulum (ER) requires significant synthesis of relevant proteins to support changes in the follicular microenvironment. The aim of this study was to investigate whether seasonal changes in gonadotropins and ovarian steroid hormones in the wild ground squirrels induce endoplasmic reticulum stress (ERS) and changes in ERS-mediated unfolded protein response (UPR) signaling. There were significant seasonal differences in ovarian mass, with values higher in the breeding season and relatively low in the non-breeding season. Histological observations revealed that ovaries in the breeding season had germ cells including primordial follicles, primary follicles, secondary follicles, tertiary follicles, and the corpus luteal, whereas ovaries consisted mainly of primary and secondary follicles in the non-breeding season. Analysis of ovarian transcriptome data showed that 1298 genes were up-regulated in expression and 1432 genes were down-regulated in expression during both periods. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that these genes were mainly enriched in estrogen signaling pathways, ovarian steroidogenesis and endoplasmic reticulum protein processing pathways. The expression levels of steroidogenic enzymes (P450scc, P450c17, 3β-HSD, and P450arom) and gonadotropin receptor (FSHR and LHR) were significantly increased during the breeding season compared to the non-breeding season. GRP78 and UPR signaling factors (ATF4, ATF6, XBP1s) associated with ERS were expressed in both seasons. The mRNA expressions of Atf6 and Xbp1s were higher in the breeding season than those of the non-breeding season. Conversely, Atf4 and its downstream homologous protein (Chop) exhibited higher expression during the non-breeding season. In addition, follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol-17β, and progesterone of serum were significantly higher in the breeding season than those of the non-breeding season. These results suggested that UPR signaling, associated with seasonal changes in ovarian steroidogenesis, was activated during the breeding season and that ERS might be involved in regulating seasonal changes in ovarian steroidogenesis in the wild ground squirrels.
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Affiliation(s)
- Qingjing Gao
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Wenjing Lu
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Sijie Fan
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Wenqiang Xie
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Haolin Zhang
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Yingying Han
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China
| | - Qiang Weng
- Laboratory of Animal Physiology, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China.
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19
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Choi HJ, Yu XZ. ER stress: an emerging regulator in GVHD development. Front Immunol 2023; 14:1212215. [PMID: 37744326 PMCID: PMC10511645 DOI: 10.3389/fimmu.2023.1212215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/21/2023] [Indexed: 09/26/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematologic malignancies. However, the clinical benefits of allo-HCT are limited by the development of complications including graft-versus-host disease (GVHD). Conditioning regimens, such as chemotherapy and irradiation, which are administered to the patients prior to allo-HCT, can disrupt the endoplasmic reticulum (ER) homeostasis, and induce ER stress in the recipient's cells. The conditioning regimen activates antigen-presenting cells (APCs), which, in turn, activate donor cells, leading to ER stress in the transplanted cells. The unfolded protein response (UPR) is an evolutionarily conserved signaling pathway that manages ER stress in response to cellular stress. UPR has been identified as a significant regulatory player that influences the function of various immune cells, including T cells, B cells, macrophages, and dendritic cells (DCs), in various disease progressions. Therefore, targeting the UPR pathway has garnered significant attention as a promising approach for the treatment of numerous diseases, such as cancer, neurodegeneration, diabetes, and inflammatory diseases. In this review, we summarize the current literature regarding the contribution of ER stress response to the development of GVHD in both hematopoietic and non-hematopoietic cells. Additionally, we explore the potential therapeutic implications of targeting UPR to enhance the effectiveness of allo-HCT for patients with hematopoietic malignancies.
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Affiliation(s)
| | - Xue-Zhong Yu
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, United States
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20
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Tuğrul B, Balcan E, Öztel Z, Çöllü F, Gürcü B. Prion protein-dependent regulation of p53-MDM2 crosstalk during endoplasmic reticulum stress and doxorubicin treatments might be essential for cell fate in human breast cancer cell line, MCF-7. Exp Cell Res 2023:113656. [PMID: 37245583 DOI: 10.1016/j.yexcr.2023.113656] [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: 03/01/2023] [Revised: 05/09/2023] [Accepted: 05/21/2023] [Indexed: 05/30/2023]
Abstract
In this study, we investigated the effect of doxorubicin and tunicamycin treatment alone or in combination on MDM-, Cul9-and prion protein (PrP)-mediated subcellular regulation of p53 in the context of apoptosis and autophagy. MTT analysis was performed to determine the cytotoxic effect of the agents. Apoptosis was monitorized by ELISA, flow cytometry and JC-1 assay. Monodansylcadaverine assay was performed for autophagy. Western blotting and immunofluorescence were performed to determine p53, MDM2, CUL9 and PrP levels. Doxorubicin increased p53, MDM2 and CUL9 levels in a dose-dependent manner. Expression of p53 and MDM2 was higher at the 0.25 μM concentration of tunicamycin compared to the control, but it decreased at 0.5 μM and 1 μM concentrations. CUL9 expression was significantly decreased only after treatment of tunicamycin at 0.25 μM. According to its glycosylation status, the upper band of PrP increased only in combination treatment. In combination treatment, p53 expression was higher than control, whereas MDM2 and CUL9 expressions were decreased. Combination treatments may make MCF-7 cells more susceptible to apoptosis rather than autophagy. In conclusion, PrP may be important in determining the fate of cell death through crosstalk between proteins such as p53 and MDM2 under endoplasmic reticulum (ER) stress conditions. Further studies are needed to obtain in-depth information on these potential molecular networks.
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Affiliation(s)
- Berrin Tuğrul
- Manisa Celal Bayar University, Faculty of Science and Letters, Department of Biology, Molecular Biology Section, 45140, Yunusemre, Manisa, Turkey.
| | - Erdal Balcan
- Manisa Celal Bayar University, Faculty of Science and Letters, Department of Biology, Molecular Biology Section, 45140, Yunusemre, Manisa, Turkey.
| | - Zübeyde Öztel
- Manisa Celal Bayar University, Faculty of Science and Letters, Department of Biology, Molecular Biology Section, 45140, Yunusemre, Manisa, Turkey.
| | - Fatih Çöllü
- Manisa Celal Bayar University, Faculty of Science and Letters, Department of Biology, Zoology Section, 45140, Yunusemre, Manisa, Turkey.
| | - Beyhan Gürcü
- Manisa Celal Bayar University, Faculty of Science and Letters, Department of Biology, Zoology Section, 45140, Yunusemre, Manisa, Turkey.
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21
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Li Q, Lan P. Activation of immune signals during organ transplantation. Signal Transduct Target Ther 2023; 8:110. [PMID: 36906586 PMCID: PMC10008588 DOI: 10.1038/s41392-023-01377-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 03/13/2023] Open
Abstract
The activation of host's innate and adaptive immune systems can lead to acute and chronic graft rejection, which seriously impacts graft survival. Thus, it is particularly significant to clarify the immune signals, which are critical to the initiation and maintenance of rejection generated after transplantation. The initiation of response to graft is dependent on sensing of danger and stranger molecules. The ischemia and reperfusion of grafts lead to cell stress or death, followed by releasing a variety of damage-associated molecular patterns (DAMPs), which are recognized by pattern recognition receptors (PRRs) of host immune cells to activate intracellular immune signals and induce sterile inflammation. In addition to DAMPs, the graft exposed to 'non-self' antigens (stranger molecules) are recognized by the host immune system, stimulating a more intense immune response and further aggravating the graft damage. The polymorphism of MHC genes between different individuals is the key for host or donor immune cells to identify heterologous 'non-self' components in allogeneic and xenogeneic organ transplantation. The recognition of 'non-self' antigen by immune cells mediates the activation of immune signals between donor and host, resulting in adaptive memory immunity and innate trained immunity to the graft, which poses a challenge to the long-term survival of the graft. This review focuses on innate and adaptive immune cells receptor recognition of damage-associated molecular patterns, alloantigens and xenoantigens, which is described as danger model and stranger model. In this review, we also discuss the innate trained immunity in organ transplantation.
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Affiliation(s)
- Qingwen Li
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Peixiang Lan
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China.
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22
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Greene ES, Maynard C, Mullenix G, Bedford M, Dridi S. Potential role of endoplasmic reticulum stress in broiler woody breast myopathy. Am J Physiol Cell Physiol 2023; 324:C679-C693. [PMID: 36717103 DOI: 10.1152/ajpcell.00275.2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Although broiler (meat-type) chickens are one of the most efficient protein sources that supports the livelihoods and food security of billions of people worldwide, they are facing several challenges. Due to its unknown etiology and heavy economic impact, woody breast (WB) myopathy is one of the most challenging problems facing the poultry industry, and for which there is no effective solution. Here, using a primary chicken myotube culture model, we show that hypoxia and endoplasmic reticulum (ER) stress are an integral component of the etiology of the myopathy. Multiple components of the ER stress response are significantly upregulated in WB as compared with normal muscle, and this response was mimicked by hypoxic conditions in chicken primary myotube culture. In addition, apoptotic pathways were activated as indicated by increases in active caspase 3 protein levels in both WB-affected tissues and hypoxic myotube culture, and caspase 3 activity and apoptosis in hypoxic myotube culture. Finally, as a phenotypic hallmark of WB is enhanced fibrosis and increased collagen aggregation, here, we show that hypoxic conditions increase collagen 1A1 and 1A2 gene expression, as well as collagen 1 protein levels in primary myotubes. These effects were partially reversed by tauroursodeoxycholic acid (TUDCA), an ER-stress inhibitor, in myotube culture. Taken together, these findings indicate that hypoxia and ER stress are present in WB, hypoxia can upregulate the cell death arm of the unfolded protein response (UPR) and lead to collagen production in a culture model of WB. This opens new vistas for potential mechanistic targets for future effective interventions to mitigate this myopathy.
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Affiliation(s)
- Elizabeth S Greene
- Center of Excellence for Poultry Science, Division of Agriculture, University of Arkansas, Fayetteville, Arkansas, United States
| | - Clay Maynard
- Center of Excellence for Poultry Science, Division of Agriculture, University of Arkansas, Fayetteville, Arkansas, United States
| | - Garrett Mullenix
- Center of Excellence for Poultry Science, Division of Agriculture, University of Arkansas, Fayetteville, Arkansas, United States
| | | | - Sami Dridi
- Center of Excellence for Poultry Science, Division of Agriculture, University of Arkansas, Fayetteville, Arkansas, United States
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23
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Jabarpour M, Aleyasin A, Nashtaei MS, Lotfi S, Amidi F. Astaxanthin treatment ameliorates ER stress in polycystic ovary syndrome patients: a randomized clinical trial. Sci Rep 2023; 13:3376. [PMID: 36854788 PMCID: PMC9974957 DOI: 10.1038/s41598-023-28956-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 01/27/2023] [Indexed: 03/02/2023] Open
Abstract
Astaxanthin (ASX), as a natural carotenoid compound, exists in various types of seafood and microorganisms. It has several possible beneficial therapeutic effects for patients with polycystic ovary syndrome (PCOS). Patients with PCOS also suffer from endoplasmic reticulum (ER) stress. In the present work, it was hypothesized that ER stress could be improved by ASX in PCOS patients. Granulosa cells (GCs) were obtained from 58 PCOS patients. The patients were classified into ASX treatment (receiving 12 mg/day for 60 days) and placebo groups. The expression levels of ER stress pathway genes and proteins were explored using Western blotting and quantitative polymerase chain reaction. To assess oxidative stress markers, follicular fluid (FF) was gained from all patients. The Student's t test was used to perform statistical analysis. After the intervention, ASX led to a considerable reduction in the expression levels of 78-kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and X-box-binding protein 1 compared to the placebo group, though the reduction in the messenger RNA (mRNA) expression level of activating transcription factor 6 was not statistically significant. However, ASX significantly increased the ATF4 expression level. GRP78 and CHOP protein levels represented a considerable decrease in the treatment group after the intervention. In addition, a statistically significant increase was found in the FF level of total antioxidant capacity in the treatment group. Based on clinical outcomes, no significant differences were found between the groups in terms of the oocyte number, fertilization rate, and fertility rate, but the ASX group had higher rates of high-quality oocytes, high-quality embryo, and oocyte maturity compared to the placebo group. Our findings demonstrated that ER stress in the GCs of PCOS patients could be modulated by ASX by changing the expression of genes and proteins included in the unfolding protein response.Trial registration This study was retrospectively registered on the Iranian Registry of Clinical Trials website ( www.irct.ir ; IRCT-ID: IRCT20201029049183N, 2020-11-27).
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Affiliation(s)
- Masoome Jabarpour
- grid.411705.60000 0001 0166 0922Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Pour Sina St, Tehran, 1416753955 Iran
| | - Ashraf Aleyasin
- grid.415646.40000 0004 0612 6034Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Shabani Nashtaei
- grid.411705.60000 0001 0166 0922Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Pour Sina St, Tehran, 1416753955 Iran ,grid.415646.40000 0004 0612 6034Department of Infertility, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Lotfi
- grid.411705.60000 0001 0166 0922Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Pour Sina St, Tehran, 1416753955 Iran
| | - Fardin Amidi
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Pour Sina St, Tehran, 1416753955, Iran. .,Department of Infertility, Yas Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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24
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Zhou X, Jin S, Pan J, Lin Q, Yang S, Lu Y, Qiu M, Ambe PC, Basharat Z, Zimmer V, Wang W, Hong W. Relationship between Cholesterol-Related Lipids and Severe Acute Pancreatitis: From Bench to Bedside. J Clin Med 2023; 12:jcm12051729. [PMID: 36902516 PMCID: PMC10003000 DOI: 10.3390/jcm12051729] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/29/2023] [Accepted: 02/07/2023] [Indexed: 02/24/2023] Open
Abstract
It is well known that hypercholesterolemia in the body has pro-inflammatory effects through the formation of inflammasomes and augmentation of TLR (Toll-like receptor) signaling, which gives rise to cardiovascular disease and neurodegenerative diseases. However, the interaction between cholesterol-related lipids and acute pancreatitis (AP) has not yet been summarized before. This hinders the consensus on the existence and clinical importance of cholesterol-associated AP. This review focuses on the possible interaction between AP and cholesterol-related lipids, which include total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (Apo) A1, from the bench to the bedside. With a higher serum level of total cholesterol, LDL-C is associated with the severity of AP, while the persistent inflammation of AP is allied with a decrease in serum levels of cholesterol-related lipids. Therefore, an interaction between cholesterol-related lipids and AP is postulated. Cholesterol-related lipids should be recommended as risk factors and early predictors for measuring the severity of AP. Cholesterol-lowering drugs may play a role in the treatment and prevention of AP with hypercholesterolemia.
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Affiliation(s)
- Xiaoying Zhou
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Shengchun Jin
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Jingyi Pan
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Qingyi Lin
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Shaopeng Yang
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Yajing Lu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Minhao Qiu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Peter C. Ambe
- Department of General Surgery, Visceral Surgery and Coloproctology, Vinzenz-Pallotti-Hospital Bensberg, Vinzenz-Pallotti-Str. 20–24, 51429 Bensberg, Germany
| | - Zarrin Basharat
- Jamil-ur-Rahman Center for Genome Research, Dr. Panjwani Centre for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Vincent Zimmer
- Department of Medicine, Marienhausklinik St. Josef Kohlhof, 66539 Neunkirchen, Germany
- Department of Medicine II, Saarland University Medical Center, Saarland University, 66421 Homburg, Germany
| | - Wei Wang
- School of Mental Health, Wenzhou Medical University, Wenzhou 325035, China
| | - Wandong Hong
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- Correspondence: ; Tel./Fax: +86-0577-55579122
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25
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Wang SY, Zhang LJ, Chen GJ, Ni QQ, Huang Y, Zhang D, Han FY, He WF, He LL, Ding YQ, Jiao HL, Ye YP. COPA A-to-I RNA editing hijacks endoplasmic reticulum stress to promote metastasis in colorectal cancer. Cancer Lett 2023; 553:215995. [PMID: 36336148 DOI: 10.1016/j.canlet.2022.215995] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/29/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022]
Abstract
RNA editing is among the most common RNA level modifications for generating amino acid changes. We identified a COPA A-to-I RNA editing event in CRC metastasis. Our results showed that the COPA A-to-I RNA editing rate was significantly increased in metastatic CRC tissues and was closely associated with aggressive tumors in the T and N stages. The COPA I164V protein damaged the Golgi-ER reverse transport function, induced ER stress, promoted the translocation of the transcription factors ATF6, XBP1 and ATF4 into the nucleus, and activated the expression of MALAT1, MET, ZEB1, and lead to CRC cell invasion and metastasis. Moreover, the COPA A-to-I RNA editing rate was positively correlated with the immune infiltration score. Collectively, the COPA I164V protein hijacked ER stress to promote the metastasis of CRC, and the COPA A-to-I RNA editing rate may be a potential predictor for patient response to immune checkpoint inhibitor (ICIs) treatment.
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Affiliation(s)
- Shu-Yang Wang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Ling-Jie Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Guo-Jun Chen
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Qi-Qi Ni
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Yuan Huang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Dan Zhang
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Fang-Yi Han
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Wen-Feng He
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Li-Ling He
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China
| | - Yan-Qing Ding
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China.
| | - Hong-Li Jiao
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China.
| | - Ya-Ping Ye
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Molecular Tumor Pathology, China.
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26
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Ruchika FNU, Shah S, Neupane D, Vijay R, Mehkri Y, Lucke-Wold B. Understanding the Molecular Progression of Chronic Traumatic Encephalopathy in Traumatic Brain Injury, Aging and Neurodegenerative Disease. Int J Mol Sci 2023; 24:1847. [PMID: 36768171 PMCID: PMC9915198 DOI: 10.3390/ijms24031847] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/11/2023] [Accepted: 01/12/2023] [Indexed: 01/19/2023] Open
Abstract
Traumatic brain injury (TBI) is one of the leading causes of death and disability among children and adults in America. In addition, the acute morbidity caused by TBI is implicated in the development of devastating neuropsychiatric and neurodegenerative sequela. TBI is associated with the development of a neurodegenerative condition termed 'Punch Drunk syndrome' or 'dementia pugilistica', and the more recently renamed 'chronic traumatic encephalopathy'. Chronic traumatic encephalopathy (CTE) is a slowly progressive neurodegenerative condition caused by a single or repetitive blow to the head. CTE was first described in boxers and was later found to be associated with other contact sports and military combat. It is defined by a constellation of symptoms consisting of mood disorders, cognitive impairment, and memory loss with or without sensorimotor changes. It is also a Tauopathy characterized by the deposition of hyperphosphorylated Tau protein in the form of neurofibrillary tangles, astrocytoma tangles, and abnormal neurites found in clusters around small vessels, typically at the sulcal depths. Oxidative stress, neuroinflammation, and glutaminergic toxicity caused due to the insult play a role in developing this pathology. Additionally, the changes in the brain due to aging also plays an important role in the development of this condition. In this review, we discuss the molecular mechanisms behind the development of CTE, as well as genetic and environmental influences on its pathophysiology.
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Affiliation(s)
| | | | | | | | | | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32611, USA
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27
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DHA Induces Cell Death through the Production of ROS and the Upregulation of CHOP in Fibroblast-like Synovial Cells from Human Rheumatoid Arthritis Patients. Int J Mol Sci 2023; 24:ijms24021734. [PMID: 36675245 PMCID: PMC9865349 DOI: 10.3390/ijms24021734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 12/29/2022] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
Rheumatoid arthritis (RA) is an inflammatory disease marked by a massive proliferation of synovial cells in the joints. In this study, we investigated the pro-apoptotic effects of docosahexaenoic acid (DHA) in human fibroblast-like synovial cells from RA patients (RA-FLS). An in vitro study using MH7A cells showed that DHA treatment induced caspase-8-dependent apoptosis in a dose-dependent manner and reduced the TNF-α-mediated induction of MMP-9 and IL-1β. DHA also induced the phosphorylation of eIF2α, the expression of the ER stress markers ATF4 and C/EBP homologous protein (CHOP), and death receptor 5 (DR5). The knockdown of CHOP or DR5 increased cell viability and reduced apoptosis in DHA-treated cells. Furthermore, the knockdown of CHOP reduced DHA-mediated DR5 expression, while the overexpression of CHOP increased DR5 expression. We also found that DHA treatment induced the accumulation of reactive oxygen species (ROS), and pretreatment with the anti-oxidant Tiron effectively abrogated not only the expression of CHOP and DR5, but also DHA-induced apoptosis. Under this condition, cell viability was increased, while PARP-1 cleavage and caspase-8 activation were reduced. All the findings were reproduced in human primary synovial cells obtained from RA patients. These results suggest that the DHA-mediated induction of ROS and CHOP induced apoptosis through the upregulation of DR5 in RA-FLSs, and that CHOP could be used as a therapy for RA.
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Zhao H, Fu X, Zhang Y, Yang Y, Wang H. Hydrogen sulfide plays an important role by regulating endoplasmic reticulum stress in myocardial diseases. Front Pharmacol 2023; 14:1172147. [PMID: 37124222 PMCID: PMC10133551 DOI: 10.3389/fphar.2023.1172147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 04/04/2023] [Indexed: 05/02/2023] Open
Abstract
Endoplasmic reticulum (ER) is an important organelle for protein translation, folding and translocation, as well as the post-translational modification and assembly of newly synthesized secreted proteins. When the excessive accumulation of misfolded and/or unfolded proteins exceeds the processing capacity of ER, ER stress is triggered. The integrated intracellular signal cascade, namely the unfolded protein response, is induced to avoid ER stress. ER stress is involved in many pathological and physiological processes including myocardial diseases. For a long time, hydrogen sulfide (H2S) has been considered as a toxic gas with the smell of rotten eggs. However, more and more evidences indicate that H2S is an important gas signal molecule after nitric oxide and carbon monoxide, and regulates a variety of physiological and pathological processes in mammals. In recent years, increasing studies have focused on the regulatory effects of H2S on ER stress in myocardial diseases, however, the mechanism is not very clear. Therefore, this review focuses on the role of H2S regulation of ER stress in myocardial diseases, and deeply analyzes the relevant mechanisms so as to lay the foundation for the future researches.
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Affiliation(s)
- Huijie Zhao
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Xiaodi Fu
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China
| | - Yanting Zhang
- School of Clinical Medicine, Henan University, Kaifeng, Henan, China
| | - Yihan Yang
- School of Clinical Medicine, Henan University, Kaifeng, Henan, China
| | - Honggang Wang
- School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China
- *Correspondence: Honggang Wang,
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Wu Y, Fan X, Chen S, Deng L, Jiang L, Yang S, Dong Z. Geraniol-Mediated Suppression of Endoplasmic Reticulum Stress Protects against Cerebral Ischemia-Reperfusion Injury via the PERK-ATF4-CHOP Pathway. Int J Mol Sci 2022; 24:ijms24010544. [PMID: 36613992 PMCID: PMC9820715 DOI: 10.3390/ijms24010544] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/19/2022] [Accepted: 09/28/2022] [Indexed: 12/31/2022] Open
Abstract
Endoplasmic reticulum (ER) stress plays an important role in cerebral ischemia-reperfusion injury (CIRI). Geraniol has antioxidant, antibacterial, and anti-inflammatory activities. Studies have shown that geraniol has a protective effect against CIRI in rats, but the exact mechanism is unclear. Purpose: The aim of this study was to investigate the protective mechanism of geraniol against CIRI. We established a middle cerebral artery occlusion reperfusion model in rats and a PC12 cell oxygen-glucose deprivation/reoxygenation (OGD/R) model to observe the neuroprotective effects of geraniol. Neurological scoring, 2,3,5-triphenyltetrazolium chloride staining, and hematoxylin and eosin staining were used to evaluate the neuroprotective effects of geraniol against CIRI. ER-stress-related and apoptosis-related protein expression was detected via Western blotting and immunofluorescence. Apoptosis was also detected via TUNEL assays and flow cytometry. The fluorescent detection of intracellular calcium was achieved using fluorescent calcium-binding dyes, and transmission electron microscopy was used to assess the neuronal ultrastructure. Geraniol effectively attenuated cerebral infarction and pathological injury after CIRI, had a protective effect against CIRI, significantly reduced the expression of the ER-stress-related proteins P-PERK, ATF4, CHOP, and GRP78 and the pro-apoptotic protein BAX, increased the expression of the anti-apoptotic protein BCL-2, and reduced the occurrence of apoptosis. In the OGD/R model in PC12 cells, the protective effect of geraniol was the same as that in vivo. Our results suggest that geraniol has a protective effect against ischemic stroke by a mechanism possibly related to ER stress via the PERK-ATF4-CHOP pathway.
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Affiliation(s)
| | | | | | | | | | | | - Zhi Dong
- Correspondence: ; Tel.: +86-135-0839-3231
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Zhang T, Liu X, Gu X, Li D, Yin J, Jiang Q, Zhang W. Changes in life-history traits, antioxidant defense, energy metabolism and molecular outcomes in the cladoceran Daphnia pulex after exposure to polystyrene microplastics. CHEMOSPHERE 2022; 308:136066. [PMID: 35987273 DOI: 10.1016/j.chemosphere.2022.136066] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/14/2022] [Accepted: 08/10/2022] [Indexed: 06/15/2023]
Abstract
Ubiquitous plastic pollution is a threat to the organisms' survival and ecosystem functions, especially in aquatic environments. Although there is increasing concern about the toxicity of microplastics, knowledge about the effects of microplastics of diverse sizes and adverse impacts on freshwater organisms is still limited. In the present study, the alteration in life-history traits, antioxidant defense and energy metabolism of the model freshwater zooplankton Daphnia pulex were assessed after chronic exposure to gradient concentrations (0.5, 1, 2 and 4 mg/L) of 500-nm polystyrene microplastics (PS-MPs). Changes in protein abundance were analyzed using proteomics after exposure to 1 mg/L of PS-MPs for 14 days. The results showed that ingested PS-MPs accumulated in the digestive tract of D. pulex. 2 and 4 mg/L of PS-MPs inhibited the survival function and 4 mg/L of PS-MPs reduced the body length of D. pulex after 14 or 21 days of exposure. The exposure did not decrease the fecundity of D. pulex. After 14 days of exposure, PS-MPs changed the antioxidant capacity in a dose-dependent way and all concentrations of PS-MPs induced lipid oxidative damage. Exposure to 500-nm PS-MPs for 14 days decreased glucose and fructose contents and disturbed the lipid transport and utilization in D. pulex. Meanwhile, PS-MPs activated DNA repair and transcription regulation but inhibited lipid metabolism and response to unfolded or misfolded proteins. These results indicated that chronic exposure to 500-nm PS-MPs negatively affected D. pulex and showed similar toxic mechanisms to smaller nano-sized microplastics. Exposure to 500-nm PS-MPs resulted in restricted resources such as inhibited antioxidant capacity or energy metabolisms and D. pulex showed a potential trade-off among life-history traits to maintain fecundity at the cost of self-maintenance. The present study offers perspectives for understanding the differences in ecological effects caused by microplastics of different sizes.
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Affiliation(s)
- Tongqing Zhang
- Freshwater Fisheries Research Institute of Jiangsu Province, 79 Chating East Street, Nanjing, 210017, China
| | - Xiaowei Liu
- Freshwater Fisheries Research Institute of Jiangsu Province, 79 Chating East Street, Nanjing, 210017, China
| | - Xiankun Gu
- Freshwater Fisheries Research Institute of Jiangsu Province, 79 Chating East Street, Nanjing, 210017, China
| | - Daming Li
- Freshwater Fisheries Research Institute of Jiangsu Province, 79 Chating East Street, Nanjing, 210017, China
| | - Jiawen Yin
- Freshwater Fisheries Research Institute of Jiangsu Province, 79 Chating East Street, Nanjing, 210017, China
| | - Qichen Jiang
- Freshwater Fisheries Research Institute of Jiangsu Province, 79 Chating East Street, Nanjing, 210017, China.
| | - Wenyi Zhang
- Institute of Animal Genetic Resource, Nanjing Normal University, 1 Wenyuan Street, Nanjing, 210046, China.
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Guo J, Nie J, Chen Z, Wang X, Hu H, Xu J, Lu J, Ma L, Ji H, Yuan J, Xu B. Cold exposure-induced endoplasmic reticulum stress regulates autophagy through the SIRT2/FoxO1 signaling pathway. J Cell Physiol 2022; 237:3960-3970. [PMID: 35938526 DOI: 10.1002/jcp.30856] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/21/2022] [Accepted: 07/27/2022] [Indexed: 01/14/2023]
Abstract
Cold is a factor affecting health in humans and animals. The liver, a major metabolic center, is highly susceptible to ambient air temperature. Recent studies have shown that endoplasmic reticulum (ER) stress is associated with the liver, and regulates the occurrence and development of liver injury and autophagy. However, the mechanism underlying the relationship between cold exposure and ER stress in the liver is not well understood. In this study, we investigated the effect of ER stress on liver autophagy and its mechanism under cold exposure. AML12 cells were treated with Tg to construct an ER stress model, and the level of autophagy increased. To further explore the mechanism through which ER stress regulates autophagy, we knocked down SIRT2 with shRNA in Tg-treated AML12 cells. Knockdown of SIRT2 significantly increased ER stress and autophagy, increased FoxO1 acetylation, and promoted its entry into the nucleus. To further verify the results of in vitro experiments, we exposed mice to 4°C for 3 h per day for 3 weeks to exacerbate the burden on the liver after cold exposure. Cold exposure damaged the structure and function of the liver and promoted the inflammatory response. It also activated ER stress and promoted autophagy. In addition, cold exposure inhibited the expression of SIRT2, promoted FoxO1 acetylation, and enhanced the interaction with autophagy. Our findings indicated that cold exposure induces liver damage, ER stress, and autophagy through the SIRT2/FoxO1 pathway. These findings suggest that SIRT2 may be a potential target for regulating health under cold exposure.
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Affiliation(s)
- Jingru Guo
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Junshu Nie
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Zhuo Chen
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Xian Wang
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Huijie Hu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Jing Xu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Jingjing Lu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Li Ma
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Hong Ji
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Jianbin Yuan
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Bin Xu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
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Barańska A, Bukowska B, Michałowicz J. Determination of Apoptotic Mechanism of Action of Tetrabromobisphenol A and Tetrabromobisphenol S in Human Peripheral Blood Mononuclear Cells: A Comparative Study. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27186052. [PMID: 36144785 PMCID: PMC9500834 DOI: 10.3390/molecules27186052] [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] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/10/2022] [Accepted: 09/12/2022] [Indexed: 11/16/2022]
Abstract
Background: Tetrabromobisphenol A (TBBPA) is the most commonly used brominated flame retardant (BFR) in the industry. TBBPA has been determined in environmental samples, food, tap water, dust as well as outdoor and indoor air and in the human body. Studies have also shown the toxic potential of this substance. In search of a better and less toxic BFR, tetrabromobisphenol S (TBBPS) has been developed in order to replace TBBPA in the industry. There is a lack of data on the toxic effects of TBBPS, while no study has explored apoptotic mechanism of action of TBBPA and TBBPS in human leukocytes. Methods: The cells were separated from leucocyte-platelet buffy coat and were incubated with studied compounds in concentrations ranging from 0.01 to 50 µg/mL for 24 h. In order to explore the apoptotic mechanism of action of tested BFRs, phosphatidylserine externalization at cellular membrane (the number of apoptotic cells), cytosolic calcium ion and transmembrane mitochondrial potential levels, caspase-8, -9 and -3 activation, as well as PARP-1 cleavage, DNA fragmentation and chromatin condensation in PBMCs were determined. Results: TBBPA and TBBPS triggered apoptosis in human PBMCs as they changed all tested parameters in the incubated cells. It was also observed that the mitochondrial pathway was mainly involved in the apoptotic action of studied compounds. Conclusions: It was found that TBBPS, and more strongly TBBPA, triggered apoptosis in human PBMCs. Generally, the mitochondrial pathway was involved in the apoptotic action of tested compounds; nevertheless, TBBPS more strongly than TBBPA caused intrinsic pathway activation.
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Apoptosis-Inducing Potential of Selected Bromophenolic Flame Retardants 2,4,6-Tribromophenol and Pentabromophenol in Human Peripheral Blood Mononuclear Cells. Molecules 2022; 27:molecules27165056. [PMID: 36014294 PMCID: PMC9413844 DOI: 10.3390/molecules27165056] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/01/2022] [Accepted: 08/07/2022] [Indexed: 01/06/2023] Open
Abstract
(1) Background: 2,4,6-Tribromophenol (2,4,6-TBP) and pentabromophenol (PBP) are utilized as brominated flame retardants (BFRs) in order to reduce the combustion of materials used in various utility products. The presence of 2,4,6-TBP and PBP has been reported in environmental samples as well as in inhaled air, dust, food, drinking water, and the human body. To date, there are limited data concerning the toxic action of 2,4,6-TBP and particularly PBP, and no study has been conducted to assess the apoptotic mechanism of action of these substances in human leukocytes. (2) Methods: PBMCs were isolated from leukocyte–platelet buffy coat and treated with tested substances in concentrations ranging from 0.01 to 50 µg/mL for 24 h. The apoptotic mechanism of action of the tested BFRs was assessed by the determination of phosphatidylserine exposure on the PBMCs surface, the evaluation of mitochondrial potential and cytosolic calcium ion levels, and the determination of caspase-8, -9, and -3 activation. Moreover, poly (ADP-ribose) polymerase-1 (PARP-1) cleavage, DNA fragmentation, and chromatin condensation were analyzed. (3) Results: 2,4,6-TBP and, more strongly, PBP induced apoptosis in PBMCs, changing all tested parameters. It was also found that the mitochondrial pathway was mainly involved in the apoptosis of PBMCs exposed to the studied compounds. (4) Conclusions: 2,4,6-TBP and PBP triggered apoptosis in human PBMCs, and some observed changes occurred at 2,4,6-TBP concentrations that were detected in humans occupationally exposed to this substance.
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De Masi R, Orlando S. GANAB and N-Glycans Substrates Are Relevant in Human Physiology, Polycystic Pathology and Multiple Sclerosis: A Review. Int J Mol Sci 2022; 23:7373. [PMID: 35806376 PMCID: PMC9266668 DOI: 10.3390/ijms23137373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022] Open
Abstract
Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc3Man9GlcNAc2 highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.
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Affiliation(s)
- Roberto De Masi
- Complex Operative Unit of Neurology, “F. Ferrari” Hospital, Casarano, 73042 Lecce, Italy;
- Laboratory of Neuroproteomics, Multiple Sclerosis Centre, “F. Ferrari” Hospital, Casarano, 73042 Lecce, Italy
| | - Stefania Orlando
- Laboratory of Neuroproteomics, Multiple Sclerosis Centre, “F. Ferrari” Hospital, Casarano, 73042 Lecce, Italy
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Liu Y, Zhou T, Hu J, Jin S, Wu J, Guan X, Wu Y, Cui J. Targeting Selective Autophagy as a Therapeutic Strategy for Viral Infectious Diseases. Front Microbiol 2022; 13:889835. [PMID: 35572624 PMCID: PMC9096610 DOI: 10.3389/fmicb.2022.889835] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 03/29/2022] [Indexed: 12/13/2022] Open
Abstract
Autophagy is an evolutionarily conserved lysosomal degradation system which can recycle multiple cytoplasmic components under both physiological and stressful conditions. Autophagy could be highly selective to deliver different cargoes or substrates, including protein aggregates, pathogenic proteins or superfluous organelles to lysosome using a series of cargo receptor proteins. During viral invasion, cargo receptors selectively target pathogenic components to autolysosome to defense against infection. However, viruses not only evolve different strategies to counteract and escape selective autophagy, but also utilize selective autophagy to restrict antiviral responses to expedite viral replication. Furthermore, several viruses could activate certain forms of selective autophagy, including mitophagy, lipophagy, aggrephagy, and ferritinophagy, for more effective infection and replication. The complicated relationship between selective autophagy and viral infection indicates that selective autophagy may provide potential therapeutic targets for human infectious diseases. In this review, we will summarize the recent progress on the interplay between selective autophagy and host antiviral defense, aiming to arouse the importance of modulating selective autophagy as future therapies toward viral infectious diseases.
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Affiliation(s)
- Yishan Liu
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tao Zhou
- Ministry of Education (MOE) Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jiajia Hu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shouheng Jin
- Ministry of Education (MOE) Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jianfeng Wu
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiangdong Guan
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yaoxing Wu
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jun Cui
- Ministry of Education (MOE) Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
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Cheng Y, Niu Z, Cai Y, Zhang W. Emerging role of UFMylation in secretory cells involved in the endocrine system by maintaining ER proteostasis. Front Endocrinol (Lausanne) 2022; 13:1085408. [PMID: 36743909 PMCID: PMC9894094 DOI: 10.3389/fendo.2022.1085408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/13/2022] [Indexed: 01/21/2023] Open
Abstract
Ubiquitin-fold modifier 1 (UFM1) is a ubiquitin-like molecule (UBL) discovered almost two decades ago, but our knowledge about the cellular and molecular mechanisms of this novel protein post-translational modification is still very fragmentary. In this review, we first summarize the core enzymes and factors involved in the UFMylation cascade, which, similar to ubiquitin, is consecutively catalyzed by UFM1-activating enzyme 5 (UBA5), UFM1-conjugating enzyme 1 (UFC1) and UFM1-specific ligase 1 (UFL1). Inspired by the substantial implications of UFM1 machinery in the secretory pathway, we next concentrate on the puzzling role of UFMylation in maintaining ER protein homeostasis, intending to illustrate the underlying mechanisms and future perspectives. At last, given a robust ER network is a hallmark of healthy endocrine secretory cells, we emphasize the function of UFM1 modification in physiology and pathology in the context of endocrine glands pancreas and female ovaries, aiming to provide precise insight into other internal glands of the endocrine system.
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Affiliation(s)
- Yun Cheng
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Zikang Niu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Yafei Cai
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Wei Zhang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
- *Correspondence: Wei Zhang,
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Ghareghomi S, Rahban M, Moosavi-Movahedi Z, Habibi-Rezaei M, Saso L, Moosavi-Movahedi AA. The Potential Role of Curcumin in Modulating the Master Antioxidant Pathway in Diabetic Hypoxia-Induced Complications. Molecules 2021; 26:molecules26247658. [PMID: 34946740 PMCID: PMC8706440 DOI: 10.3390/molecules26247658] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 12/13/2022] Open
Abstract
Oxidative stress is the leading player in the onset and development of various diseases. The Keap1-Nrf2 pathway is a pivotal antioxidant system that preserves the cells' redox balance. It decreases inflammation in which the nuclear trans-localization of Nrf2 as a transcription factor promotes various antioxidant responses in cells. Through some other directions and regulatory proteins, this pathway plays a fundamental role in preventing several diseases and reducing their complications. Regulation of the Nrf2 pathway occurs on transcriptional and post-transcriptional levels, and these regulations play a significant role in its activity. There is a subtle correlation between the Nrf2 pathway and the pivotal signaling pathways, including PI3 kinase/AKT/mTOR, NF-κB and HIF-1 factors. This demonstrates its role in the development of various diseases. Curcumin is a yellow polyphenolic compound from Curcuma longa with multiple bioactivities, including antioxidant, anti-inflammatory, anti-tumor, and anti-viral activities. Since hyperglycemia and increased reactive oxygen species (ROS) are the leading causes of common diabetic complications, reducing the generation of ROS can be a fundamental approach to dealing with these complications. Curcumin can be considered a potential treatment option by creating an efficient therapeutic to counteract ROS and reduce its detrimental effects. This review discusses Nrf2 pathway regulation at different levels and its correlation with other important pathways and proteins in the cell involved in the progression of diabetic complications and targeting these pathways by curcumin.
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Affiliation(s)
- Somayyeh Ghareghomi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417466191, Iran; (S.G.); (M.R.)
| | - Mahdie Rahban
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417466191, Iran; (S.G.); (M.R.)
| | | | - Mehran Habibi-Rezaei
- School of Biology, College of Science, University of Tehran, Tehran 1417466191, Iran
- Center of Excellence in NanoBiomedicine, University of Tehran, Tehran 1417466191, Iran
- Correspondence: (M.H.-R.); (A.A.M.-M.); Tel.: +98-21-6111-3214 (M.H.-R.); +98-21-6111-3381 (A.A.M.-M.); Fax: +98-21-6697-1941 (M.H.-R.); +98-21-6640-4680 (A.A.M.-M.)
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer,” Sapienza University of Rome, 00185 Rome, Italy;
| | - Ali Akbar Moosavi-Movahedi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran 1417466191, Iran; (S.G.); (M.R.)
- UNESCO Chair on Interdisciplinary Research in Diabetes, University of Tehran, Tehran 1417466191, Iran
- Correspondence: (M.H.-R.); (A.A.M.-M.); Tel.: +98-21-6111-3214 (M.H.-R.); +98-21-6111-3381 (A.A.M.-M.); Fax: +98-21-6697-1941 (M.H.-R.); +98-21-6640-4680 (A.A.M.-M.)
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Crouzier L, Richard EM, Sourbron J, Lagae L, Maurice T, Delprat B. Use of Zebrafish Models to Boost Research in Rare Genetic Diseases. Int J Mol Sci 2021; 22:13356. [PMID: 34948153 PMCID: PMC8706563 DOI: 10.3390/ijms222413356] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 12/09/2021] [Accepted: 12/10/2021] [Indexed: 02/06/2023] Open
Abstract
Rare genetic diseases are a group of pathologies with often unmet clinical needs. Even if rare by a single genetic disease (from 1/2000 to 1/more than 1,000,000), the total number of patients concerned account for approximatively 400 million peoples worldwide. Finding treatments remains challenging due to the complexity of these diseases, the small number of patients and the challenge in conducting clinical trials. Therefore, innovative preclinical research strategies are required. The zebrafish has emerged as a powerful animal model for investigating rare diseases. Zebrafish combines conserved vertebrate characteristics with high rate of breeding, limited housing requirements and low costs. More than 84% of human genes responsible for diseases present an orthologue, suggesting that the majority of genetic diseases could be modelized in zebrafish. In this review, we emphasize the unique advantages of zebrafish models over other in vivo models, particularly underlining the high throughput phenotypic capacity for therapeutic screening. We briefly introduce how the generation of zebrafish transgenic lines by gene-modulating technologies can be used to model rare genetic diseases. Then, we describe how zebrafish could be phenotyped using state-of-the-art technologies. Two prototypic examples of rare diseases illustrate how zebrafish models could play a critical role in deciphering the underlying mechanisms of rare genetic diseases and their use to identify innovative therapeutic solutions.
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Affiliation(s)
- Lucie Crouzier
- MMDN, University of Montpellier, EPHE, INSERM, 34095 Montpellier, France; (L.C.); (E.M.R.); (T.M.)
| | - Elodie M. Richard
- MMDN, University of Montpellier, EPHE, INSERM, 34095 Montpellier, France; (L.C.); (E.M.R.); (T.M.)
| | - Jo Sourbron
- Department of Development and Regeneration, Section Pediatric Neurology, University Hospital KU Leuven, 3000 Leuven, Belgium; (J.S.); (L.L.)
| | - Lieven Lagae
- Department of Development and Regeneration, Section Pediatric Neurology, University Hospital KU Leuven, 3000 Leuven, Belgium; (J.S.); (L.L.)
| | - Tangui Maurice
- MMDN, University of Montpellier, EPHE, INSERM, 34095 Montpellier, France; (L.C.); (E.M.R.); (T.M.)
| | - Benjamin Delprat
- MMDN, University of Montpellier, EPHE, INSERM, 34095 Montpellier, France; (L.C.); (E.M.R.); (T.M.)
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635 nm LED irradiation may prevent endoplasmic reticulum stress in MC3T3-E1 cells. J Mol Histol 2021; 53:75-83. [PMID: 34676487 DOI: 10.1007/s10735-021-10034-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/18/2021] [Indexed: 10/20/2022]
Abstract
Although endoplasmic reticulum (ER) stress is thought to be involved in various diseases such as cancer, metabolic, and inflammatory disorders, the relationship between ER stress and bone diseases, are remains unclear. Tunicamycin-treated MC3T3-E1 osteoblasts were used as the ER stress model in this study. 635 nm light-emitting diode irradiation (635 nm-IR) was carried out for 1 h before and after inducing ER stress. To investigate the effects of 635 nm-IR on ER stress-induced MC3T3-E1 osteoblasts and the underlying mechanism, western blot, reverse transcription polymerase chain reaction, alkaline phosphatase and Alizarin red staining, 2',7'-dichlorodyhydrofluorescein diacetate assay, Fluo-3AM and immunocytochemistry were performed. Pretreatment with 635 nm-IR effectively prevented intracellular reactive oxygen species production and alleviated ER stress through the pancreatic ER kinase (PERK)-eukaryotic initiation factor 2 (eIF2)-activating transcription factor 4 (ATF4)-nuclear factor-like 2 (Nrf2) signaling pathway. Hence, 635 nm-IR may serve a protective role in the treatment of ER stress-related bone diseases.
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Srisapoome P, Ju-Ngam T, Wongpanya R. Characterization, Stress Response and Functional Analyses of Giant River Prawn ( Macrobrachium rosenbergii) Glucose-Regulated Protein 78 (Mr-grp78) under Temperature Stress and during Aeromonas hydrophila Infection. Animals (Basel) 2021; 11:ani11103004. [PMID: 34680024 PMCID: PMC8532774 DOI: 10.3390/ani11103004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 10/01/2021] [Accepted: 10/15/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Glucose-regulated protein 78 (grp78) is classified as a member of the Hsp70 subfamily. This protein functions as a key factor in signal transduction associated with the unfolded protein response (UPR) in the endoplasmic reticulum (ER) during cellular stress and protects against cell damage caused by toxic chemicals, oxidative stress, Ca2+ depletion, programmed cell death and various infectious conditions. To investigate this crucial mechanism in giant river prawn (Macrobrachium rosenbergii), we analyzed the biological function of prawn grp78 at the molecular level in this study. The regulation of this gene was intensively analyzed under normal bacterial infection and heat/cold-shock inductions. A functional analysis of this gene under heat and infectious stress conditions was performed by gene knockdown. The information obtained in the current study clearly indicates the crucially significant roles of grp78 in the cellular stress responses of the target experimental animal under various stress conditions. Abstract The endoplasmic reticulum (ER) is an organelle important for several functions of cellular physiology. This study identified the giant river prawn’s glucose-regulated protein 78 (Mr-grp78), which is important for ER stress mechanisms. Nucleotide and amino acid analyses of Mr-grp78, as compared with other species, revealed the highest similarity scores with the grp78 genes of crustaceans. An expression analysis by quantitative RT-PCR indicated that Mr-grp78 was expressed in all tissues and presented its highest expression in the ovary (57.64 ± 2.39-fold), followed by the gills (42.25 ± 1.12), hindgut (37.15 ± 2.47), thoracic ganglia (28.55 ± 2.45) and hemocytes (28.45 ± 2.26). Expression analysis of Mr-grp78 mRNA levels under Aeromonas hydrophila induction and heat/cold-shock exposure was conducted in the gills, hepatopancreas and hemocytes. The expression levels of Mr-grp78 in these tissues were highly upregulated 12 h after bacterial infection. In contrast, under heat- and cold-shock conditions, the expression of Mr-grp78 was significantly suppressed in the gills at 24–96 h and in the hepatopancreas at 12 h (p < 0.05). A functional analysis via Mr-grp78 gene knockdown showed that Mr-grp78 transcription in the gills, hepatopancreas and muscle strongly decreased from 6 to 96 h. Furthermore, the silencing of this gene effectively increased the sensitivity of the tested prawns to heat- and pathogenic-bacterium-induced stress. The results of this study clearly demonstrate the significant functional roles of Mr-grp78 in response to both temperature and pathogen treatments.
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Affiliation(s)
- Prapansak Srisapoome
- Laboratory of Aquatic Animal Health Management, Department of Aquaculture, Faculty of Fisheries, Kasetsart University, Chatuchak, Bangkok 10900, Thailand;
- Center of Advanced Studies for Agriculture and Food, Kasetsart University Institute for Advanced Studies, Kasetsart University, Bangkok 10900, Thailand
- Center of Excellence in Aquatic Animal Health Management, Faculty of Fisheries, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
- Correspondence: ; Tel.: +66-2579-2924
| | - Tanya Ju-Ngam
- Laboratory of Aquatic Animal Health Management, Department of Aquaculture, Faculty of Fisheries, Kasetsart University, Chatuchak, Bangkok 10900, Thailand;
- Center of Advanced Studies for Agriculture and Food, Kasetsart University Institute for Advanced Studies, Kasetsart University, Bangkok 10900, Thailand
- Center of Excellence in Aquatic Animal Health Management, Faculty of Fisheries, Kasetsart University, Chatuchak, Bangkok 10900, Thailand
| | - Ratree Wongpanya
- Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand;
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Danyukova T, Schöneck K, Pohl S. Site-1 and site-2 proteases: A team of two in regulated proteolysis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119138. [PMID: 34619164 DOI: 10.1016/j.bbamcr.2021.119138] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/12/2021] [Accepted: 09/06/2021] [Indexed: 12/19/2022]
Abstract
The site-1 and site-2 proteases (S1P and S2P) were identified over 20 years ago, and the functions of both have been addressed in numerous studies ever since. Whereas S1P processes a set of substrates independently of S2P, the latter acts in concert with S1P in a mechanism, called regulated intramembrane proteolysis, that controls lipid metabolism and response to unfolded proteins. This review summarizes the molecular roles that S1P and S2P jointly play in these processes. As S1P and S2P deficiencies mainly affect connective tissues, yet with varying phenotypes, we discuss the segregated functions of S1P and S2P in terms of cell homeostasis and maintenance of the connective tissues. In addition, we provide experimental data that point at S2P, but not S1P, as a critical regulator of cell adaptation to proteotoxicity or lipid imbalance. Therefore, we hypothesize that S2P can also function independently of S1P activity.
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Affiliation(s)
- Tatyana Danyukova
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
| | - Kenneth Schöneck
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - Sandra Pohl
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
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Suliman M, Schmidtke MW, Greenberg ML. The Role of the UPR Pathway in the Pathophysiology and Treatment of Bipolar Disorder. Front Cell Neurosci 2021; 15:735622. [PMID: 34531727 PMCID: PMC8439382 DOI: 10.3389/fncel.2021.735622] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/09/2021] [Indexed: 11/13/2022] Open
Abstract
Bipolar disorder (BD) is a mood disorder that affects millions worldwide and is associated with severe mood swings between mania and depression. The mood stabilizers valproate (VPA) and lithium (Li) are among the main drugs that are used to treat BD patients. However, these drugs are not effective for all patients and cause serious side effects. Therefore, better drugs are needed to treat BD patients. The main barrier to developing new drugs is the lack of knowledge about the therapeutic mechanism of currently available drugs. Several hypotheses have been proposed for the mechanism of action of mood stabilizers. However, it is still not known how they act to alleviate both mania and depression. The pathology of BD is characterized by mitochondrial dysfunction, oxidative stress, and abnormalities in calcium signaling. A deficiency in the unfolded protein response (UPR) pathway may be a shared mechanism that leads to these cellular dysfunctions. This is supported by reported abnormalities in the UPR pathway in lymphoblasts from BD patients. Additionally, studies have demonstrated that mood stabilizers alter the expression of several UPR target genes in mouse and human neuronal cells. In this review, we outline a new perspective wherein mood stabilizers exert their therapeutic mechanism by activating the UPR. Furthermore, we discuss UPR abnormalities in BD patients and suggest future research directions to resolve discrepancies in the literature.
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Affiliation(s)
- Mahmoud Suliman
- Department of Biological Sciences, Wayne State University, Detroit, MI, United States
| | - Michael W Schmidtke
- Department of Biological Sciences, Wayne State University, Detroit, MI, United States
| | - Miriam L Greenberg
- Department of Biological Sciences, Wayne State University, Detroit, MI, United States
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Park JM, Han YM, Oh JY, Lee DY, Choi SH, Kim SJ, Hahm KB. Fermented kimchi rejuvenated precancerous atrophic gastritis via mitigating Helicobacter pylori-associated endoplasmic reticulum and oxidative stress. J Clin Biochem Nutr 2021; 69:158-170. [PMID: 34616108 PMCID: PMC8482386 DOI: 10.3164/jcbn.20-180] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/25/2020] [Indexed: 12/12/2022] Open
Abstract
Dietary intervention to prevent Helicobacter pylori (H. pylori)-gastric cancer might be ideal by long-term intervention, rejuvenating action, and no risk of bacterial resistance. Stimulated with finding that kimchi prevented H. pylori-gastric cancer, we compared the efficacy of cancer preventive kimchi (cpkimchi) and standard recipe kimchi (skimchi) and the efficacy between fermented kimchi and non-fermented kimchi (kimuchi) in H. pylori-initiated gastric cancer model and explored novel mechanisms hinted from RNAseq transcriptome analysis. Animal models assessing gastric pathology on 24 and 36 weeks after H. pylori initiated, salt diet-promoted gastric mutagenesis model showed fermented cpkimchi afforded the best outcome of either rejuvenating atrophic gastritis or inhibiting tumorigenesis compared to skimchi and kimuchi. Highest inhibition of atrophic gastritis was achieved with cpkimchi, while significantly lower in kimuchi. Transcriptomic analysis showed ameliorated-endoplasmic reticulum (ER) stress, -oxidative stress, and -apoptosis as major rejuvenating action of cpkimchi. Homogenates from animal model showed that elevated expressions of p-PERK, IRE, ATF6, p-elf, and XBP1 in control group, while significantly decreased with dietary intake of only cpkimchi. Significantly increased expressions of HO-1 and γ-GCS were only noted with cpkimchi. Conclusively, long-term dietary intervention of fermented cpkimchi can be potential way preventing H. pylori-associated carcinogenesis via rejuvenation of atrophic gastritis.
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Affiliation(s)
- Jong Min Park
- Daejeon University School of Oriental Medicine, Daehak-ro 62, Dong-gu, Daejeon 34520, Korea
| | - Young Min Han
- Western Seoul Center, Korea Basic Science Institute, University-Industry Cooperate Building, 150 Bugahyeon-ro, Seodaemun-gu, Seoul 03759, Korea
| | - Ji Young Oh
- CJ Food Research, CJ Blossom Park, Gwanggyo-ro, Yeongtong-gu, Suwon 16471, Korea
| | - Dong Yoon Lee
- CJ Food Research, CJ Blossom Park, Gwanggyo-ro, Yeongtong-gu, Suwon 16471, Korea
| | - Seung Hye Choi
- CJ Food Research, CJ Blossom Park, Gwanggyo-ro, Yeongtong-gu, Suwon 16471, Korea
| | - Seong Jin Kim
- Medpacto Research Institute, Medpacto Inc., 92, Myeongdal-ro, Sheocho-gu, Seoul 06668, Korea
| | - Ki Baik Hahm
- Medpacto Research Institute, Medpacto Inc., 92, Myeongdal-ro, Sheocho-gu, Seoul 06668, Korea
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Cai B, Yuan X, Li X, Xu J, Du J. Urinary Congophilia Confirmed With the CapCord Test Is Associated With Pregnancy Outcomes in Women With Early-Onset Pre-eclampsia. Front Med (Lausanne) 2021; 8:700157. [PMID: 34409051 PMCID: PMC8365157 DOI: 10.3389/fmed.2021.700157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 07/12/2021] [Indexed: 11/13/2022] Open
Abstract
Background: The association between misfolded proteins presented in the urine of pregnant women and pregnancy outcomes associated with early-onset pre-eclampsia (PE) remains unclear. This study aimed to investigate this association to examine the predictive value of urinary congophilia in the prognostication of pregnancy outcomes in this patient group in the Chinese population. Materials and Methods: This study included 1,397 patients, of which 46, 147, and 8 patients had gestational hypertension, PE, and chronic hypertension, respectively, and 1,196 were healthy controls undergoing the CapCord test for urinary congophilia. Patients with PE were divided into early- and late-onset groups. Patients with early-onset PE were further divided into iatrogenic prematurity and full-term delivery groups, the rates of urinary congophilia were compared between the groups; additionally, this patient group was divided into positive and negative urinary congophilia groups, clinical characteristics and pregnancy outcomes were compared between the groups. Univariate and multivariate logistic regression analyses were performed. Results: A total of 113 (76.9%) of 147 patients in the PE group had urinary congophilia; this rate was higher than that observed in the other three groups (χ2 = 780.892, p < 0.001). Gestational age in the early-onset PE group at both onset and delivery was lower than that in the late-onset PE group (p < 0.001). The rates of iatrogenic prematurity and hemolysis, elevated liver enzymes, and low platelet count syndrome were both higher in the early-onset PE group than in the late-onset PE group (p < 0.001, p < 0.05). In addition, the rate of urinary congophilia in the early-onset PE group was higher than that in the late-onset PE group (χ2 = 13.297, p < 0.001). Urinary congophilia was an independent risk factor for iatrogenic prematurity among patients with early-onset PE in both univariate [odds ratio (OR) 17.143, 95% confidence interval (CI): 4.719–62.271; p < 0.001] and multivariate (OR 18.174; 95% CI: 4.460–74.063; p < 0.001) analyses. Patients with early-onset PE and urinary congophilia were more likely than their counterparts without urinary congophilia to deliver at a lower gestational age, present with iatrogenic prematurity, and have a shorter latency period between onset and delivery. Conclusion: Urinary congophilia confirmed with the CapCord test may help predict pregnancy outcomes in patients with early-onset PE.
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Affiliation(s)
- Benshuo Cai
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
| | | | - Xingmin Li
- Shuwen Biotech Company Ltd., Deqing, China
| | - Jun Xu
- Shuwen Biotech Company Ltd., Deqing, China
| | - Juan Du
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
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Tang H, Cui M, Han M. Fatty acids impact sarcomere integrity through myristoylation and ER homeostasis. Cell Rep 2021; 36:109539. [PMID: 34407398 PMCID: PMC8404530 DOI: 10.1016/j.celrep.2021.109539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 06/04/2021] [Accepted: 07/26/2021] [Indexed: 01/01/2023] Open
Abstract
Decreased ability to maintain tissue integrity is critically involved in aging and degenerative diseases. Fatty acid (FA) metabolism has a profound impact on animal development and tissue maintenance, but our understanding of the underlying mechanisms is limited. We investigated whether and how FA abundance affects muscle integrity using Caenorhabditis elegans. We show that reducing the overall FA level by blocking FA biosynthesis or inhibiting protein myristoylation leads to disorganization of sarcomere structure and adult-onset paralysis. Further analysis indicates that myristoylation of two ARF guanosine triphosphatases (GTPases) critically mediates the effect of FA deficiency on sarcomere integrity through inducing endoplasmic reticulum (ER) stress and ER unfolded protein response (UPRER), which in turn leads to reduction of the level of sarcomere component PINCH and myosin disorganization. We thus present a mechanism that links FA signal, protein myristoylation, and ER homeostasis with muscle integrity, which provides valuable insights into the regulatory role of nutrients and ER homeostasis in muscle maintenance.
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Affiliation(s)
- Hongyun Tang
- Department of MCDB, University of Colorado Boulder, Boulder, CO 80309, USA; Key Laboratory of Growth Regulation and Transformation Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang Province, China; Institute of Biology, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou 310024, Zhejiang Province, China
| | - Mingxue Cui
- Department of MCDB, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Min Han
- Department of MCDB, University of Colorado Boulder, Boulder, CO 80309, USA.
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Swift CL, Malinov NG, Mondo SJ, Salamov A, Grigoriev IV, O'Malley MA. A Genomic Catalog of Stress Response Genes in Anaerobic Fungi for Applications in Bioproduction. FRONTIERS IN FUNGAL BIOLOGY 2021; 2:708358. [PMID: 37744151 PMCID: PMC10512342 DOI: 10.3389/ffunb.2021.708358] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/07/2021] [Indexed: 09/26/2023]
Abstract
Anaerobic fungi are a potential biotechnology platform to produce biomass-degrading enzymes. Unlike model fungi such as yeasts, stress responses that are relevant during bioprocessing have not yet been established for anaerobic fungi. In this work, we characterize both the heat shock and unfolded protein responses of four strains of anaerobic fungi (Anaeromyces robustus, Caecomyces churrovis, Neocallimastix californiae, and Piromyces finnis). The inositol-requiring 1 (Ire1) stress sensor, which typically initiates the fungal UPR, was conserved in all four genomes. However, these genomes also encode putative transmembrane kinases with catalytic domains that are similar to the metazoan stress-sensing enzyme PKR-like endoplasmic reticulum kinase (PERK), although whether they function in the UPR of anaerobic fungi remains unclear. Furthermore, we characterized the global transcriptional responses of Anaeromyces robustus and Neocallimastix californiae to a transient heat shock. Both fungi exhibited the hallmarks of ER stress, including upregulation of genes with functions in protein folding, ER-associated degradation, and intracellular protein trafficking. Relative to other fungi, the genomes of Neocallimastigomycetes contained the greatest gene percentage of HSP20 and HSP70 chaperones, which may serve to stabilize their asparagine-rich genomes. Taken together, these results delineate the unique stress response of anaerobic fungi, which is an important step toward their development as a biotechnology platform to produce enzymes and valuable biomolecules.
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Affiliation(s)
- Candice L. Swift
- Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, CA, United States
| | - Nikola G. Malinov
- Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, CA, United States
| | - Stephen J. Mondo
- U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, United States
- Department of Agricultural Biology, Colorado State University, Fort Collins, CO, United States
| | - Asaf Salamov
- U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, United States
| | - Igor V. Grigoriev
- U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA, United States
- Lawrence Berkeley National Laboratory, Environmental Genomics and Systems Biology Division, Berkeley, CA, United States
- Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, CA, United States
| | - Michelle A. O'Malley
- Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, CA, United States
- Joint BioEnergy Institute, Emeryville, CA, United States
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Bouwman AC, van Daalen KR, Crnko S, Ten Broeke T, Bovenschen N. Intracellular and Extracellular Roles of Granzyme K. Front Immunol 2021; 12:677707. [PMID: 34017346 PMCID: PMC8129556 DOI: 10.3389/fimmu.2021.677707] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 04/21/2021] [Indexed: 12/30/2022] Open
Abstract
Granzymes are a family of serine proteases stored in granules inside cytotoxic cells of the immune system. Granzyme K (GrK) has been only limitedly characterized and knowledge on its molecular functions is emerging. Traditionally GrK is described as a granule-secreted, pro-apoptotic serine protease. However, accumulating evidence is redefining the functions of GrK by the discovery of novel intracellular (e.g. cytotoxicity, inhibition of viral replication) and extracellular roles (e.g. endothelial activation and modulation of a pro-inflammatory immune cytokine response). Moreover, elevated GrK levels are associated with disease, including viral and bacterial infections, airway inflammation and thermal injury. This review aims to summarize and discuss the current knowledge of i) intracellular and extracellular GrK activity, ii) cytotoxic and non-cytotoxic GrK functioning, iii) the role of GrK in disease, and iv) GrK as a potential therapeutic target.
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Affiliation(s)
- Annemieke C Bouwman
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Kim R van Daalen
- Cardiovascular Epidemiology Unit, Department of Public Health & Primary Care, University of Cambridge, Cambridge, United Kingdom
| | - Sandra Crnko
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Toine Ten Broeke
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Niels Bovenschen
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
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The Unfolded Protein Response: An Overview. BIOLOGY 2021; 10:biology10050384. [PMID: 33946669 PMCID: PMC8146082 DOI: 10.3390/biology10050384] [Citation(s) in RCA: 220] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/23/2021] [Accepted: 04/27/2021] [Indexed: 12/11/2022]
Abstract
Simple Summary The unfolded protein response (UPR) is the cells’ way of maintaining the balance of protein folding in the endoplasmic reticulum, which is the section of the cell designated for folding proteins with specific destinations such as other organelles or to be secreted by the cell. The UPR is activated when unfolded proteins accumulate in the endoplasmic reticulum. This accumulation puts a greater load on the molecules in charge of folding the proteins, and therefore the UPR works to balance this by lowering the number of unfolded proteins present in the cell. This is done in multiple ways, such as lowering the number of proteins that need to be folded; increasing the folding ability of the endoplasmic reticulum and by removing some of the unfolded proteins which take longer to fold. If the UPR is successful at reducing the number of unfolded proteins, the UPR is inactivated and the cells protein folding balance is returned to normal. However, if the UPR is unsuccessful, then this can lead to cell death. Abstract The unfolded protein response is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. Under normal conditions, the UPR is not activated; however, under certain stresses, such as hypoxia or altered glycosylation, the UPR can be activated due to an accumulation of unfolded proteins. The activation of the UPR involves three signaling pathways, IRE1, PERK and ATF6, which all play vital roles in returning protein homeostasis to levels seen in non-stressed cells. IRE1 is the best studied of the three pathways, as it is the only pathway present in Saccharomyces cerevisiae. This pathway involves spliceosome independent splicing of HAC1 or XBP1 in yeast and mammalians cells, respectively. PERK limits protein synthesis, therefore reducing the number of new proteins requiring folding. ATF6 is translocated and proteolytically cleaved, releasing a NH2 domain fragment which is transported to the nucleus and which affects gene expression. If the UPR is unsuccessful at reducing the load of unfolded proteins in the ER and the UPR signals remain activated, this can lead to programmed cell death.
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Maturation conditions, post-ovulatory age, medium pH, and ER stress affect [Ca 2+]i oscillation patterns in mouse oocytes. J Assist Reprod Genet 2021; 38:1373-1385. [PMID: 33914207 DOI: 10.1007/s10815-021-02100-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 02/03/2021] [Indexed: 02/05/2023] Open
Abstract
Insufficiency of oocyte activation impairs the subsequent embryo development in assisted reproductive technology (ART). Intracellular Ca2+ concentration ([Ca2+]i) oscillations switch the oocytes to resume the second meiosis and initiate embryonic development. However, the [Ca2+]i oscillation patterns in oocytes are poorly characterized. In this study, we investigated the effects of various factors, such as the oocytes age, pH, cumulus cells, in vitro or in vivo maturation, and ER stress on [Ca2+]i oscillation patterns and pronuclear formation after parthenogenetic activation of mouse oocytes. Our results showed that the oocytes released to the oviduct at 17 h post-human chorionic gonadotrophin (hCG) displayed a significantly stronger [Ca2+]i oscillation, including higher frequency, shorter cycle, and higher peak, compared with oocytes collected at earlier or later time points. [Ca2+]i oscillations in acidic conditions (pH 6.4 and 6.6) were significantly weaker than those in neutral and mildly alkaline conditions (pH from 6.8 to 7.6). In vitro-matured oocytes showed reduced frequency and peak of [Ca2+]i oscillations compared with those matured in vivo. In vitro-matured oocytes from the cumulus-oocyte complexes (COCs) showed a significantly higher frequency, shorter cycle, and higher peak compared with the denuded oocytes (DOs). Finally, endoplasmic reticulum stress (ER stress) severely affected the parameters of [Ca2+]i oscillations, including elongated cycles and lower frequency. The pronuclear (PN) rate of oocytes after parthenogenetic activation was correlated with [Ca2+]i oscillation pattern, decreasing with oocyte aging, cumulus removal, acidic pH, and increasing ER stress. These results provide fundamental but critical information for the mechanism of how these factors affect oocyte activation.
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Zare ME, Kansestani AN, Hemmati S, Mansouri K, Vaisi-Raygani A. The rate of aerobic glycolysis is a pivotal regulator of tumor progression. J Diabetes Metab Disord 2021; 20:523-531. [PMID: 34178852 DOI: 10.1007/s40200-021-00774-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/18/2021] [Indexed: 12/30/2022]
Abstract
Purpose Cancer cells depend on glucose metabolism via exclusive glycolysis pathway is named Aerobic glycolysis or Warburg effect. The aim of this study was investigation of different glucose accessibility conditions on the rate of Warburg effect and its impact on Hypoxia inducible factors-1 α (HIF-1 α)/vascular endothelium growth factor (VEGF) pathway in breast cancer cells lines. Methods MDA-MB-231 (Warburg phenomenon) and MCF-7 (oxidative) cell lines were cultured in DMEM and exposed to three different glucose accessibility medium for 48 h (5.5 mM as normal glucose (NG), 25 mM as high glucose (HG) and 2-Deoxyglucose (2-DG) as restricted glucose accessibility). Glucose uptake, intra/extracellular lactate and pyruvate, HIF-1α accumulation and vascular endothelium growth factor (VEGF) expression were evaluated by standard methods. Results Our results showed in NG condition both of cell lines produce lactate, but it was higher in MDA-MB-231. HG condition increased extracellular lactate in both cell lines especially in MCF-7 cells whereas intracellular lactate and pyruvate raised only in MCF-7. 2-DG decreased extracellular and intracellular lactate and pyruvate in both cell lines especially in MDA-MB-231. HIF-1α accumulation was detectable in NG condition in both cell lines. HG condition increased HIF-1α accumulation in MCF-7 cells but not in MDA-MB-231 and 2-DG decreased it in both call lines, especially in MDA-MB-231. Expression of VEGF had similar pattern with HIF-1α in different conditions. Conclusions Our findings revealed the rate of Warburg effect is an important indicator for tumor promotion and invasion due to its impacts on important transcription factors like HIF-1α.
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Affiliation(s)
- Mohammad Erfan Zare
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Clinical Biochemistry, Medical School, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Atefeh Nasir Kansestani
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Shahrooz Hemmati
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Asad Vaisi-Raygani
- Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Daneshgah Avenue, Kermanshah, 67148-69914 Iran
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