|
1
|
Shantha Kumara HMC, Addison P, Yan XH, Sharma AR, Mitra N, Angammana HN, Hedjar Y, Chen YR, Cekic V, Richard WL. Plasma extracellular cold inducible RNA-binding protein levels are elevated for 1 month post-colectomy which may promote metastases. World J Gastrointest Oncol 2025; 17:100678. [DOI: 10.4251/wjgo.v17.i4.100678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 01/10/2025] [Accepted: 02/19/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Cold-inducible RNA-binding protein (CIRP) is related to a family of stress-induced RNA-binding proteins. It is primarily found in the nucleus, where it regulates transcription. Under stress, CIRP translocates to the cytoplasm where it modulates translation; a subset is secreted as extracellular CIRP (eCIRP) which is a damage-associated molecular pattern (DAMP) molecule that stimulates the production of inflammatory mediators. Elevated blood eCIRP levels may foster immune tolerance and facilitate tumor growth. Increased CIRP levels have been noted in various malignancies including colorectal cancer (CRC). This study’s objective was to determine plasma eCIRP levels before and after minimally invasive colorectal resection (MICR) for CRC.
AIM To assess plasma eCIRP levels prior to and following minimally invasive colorectal resection in the context of cancer pathology.
METHODS MICR patients from an IRB-approved data/tissue bank for whom plasma samples were available were eligible. Plasma specimens were obtained preoperatively (preop) and at least 3 time’s postop [between postoperative day (POD) 1-41]; late samples were grouped into 7-day blocks and were considered separate time points. eCIRP levels were assessed via enzyme-linked immunosorbent assay (pg/mL) and results presented as mean ± SD, analysis with Wilcoxon paired t-test).
RESULTS A total of 83 CRC patients who underwent MICR [colon 66%, rectal 34%; laparoscopic-assisted (LA), 70%; hand-assisted laparoscopic (HAL), 30%] were studied. The mean preop eCIRP level was 896.8 ± 757.0 pg/mL. Elevations in mean plasma levels (P = < 0.001) were noted on POD1 (2549 ± 2632 pg/mL, n = 83), POD3 (1871 ± 1362 pg/mL, n = 77), POD7-13 (1788 ± 1403 pg/mL, n = 57), POD14-20 (1473 ± 738.8 pg/mL, n = 30), and POD21-27 (1681 ± 1375 pg/mL, n = 21). No significant differences were noted at POD 28-41. Higher values were noted in the HAL’s (vs LA) group, however, there were more rectal cancers in the former.
CONCLUSION Elevated plasma eCIRP levels persist for a month post MICR for CRC (change from baseline, 77%-184%); highest values seen on POD1. The initial surge may be due to the acute inflammatory response while later elevations may be related to wound healing and remodeling. The higher levels noted in the HAL’s group (with greater IL and more rectal cases) suggest the extent of surgical trauma impacts eCIRP levels. Further investigations are needed.
Collapse
Affiliation(s)
- H M C Shantha Kumara
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Poppy Addison
- Division of Colon and Rectal Surgery, Department of Surgery, Staten Island University Hospital, Northwell Health, Staten Island, NY 10305, United States
| | - Xiao-Hong Yan
- Department of Pathology and Cell Biology, Columbia University Medical Center, Vanderbilt Clinic, New York, NY 10032, United States
| | - Anuj Raj Sharma
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Neil Mitra
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Hansani N Angammana
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Yanni Hedjar
- Department of Surgery, Brookdale Hospital and Medical Center, Brooklyn, NY 11212, United States
| | - Yi-Ru Chen
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Vesna Cekic
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
| | - Whelan L Richard
- Division of Colon and Rectal Surgery, Department of Surgery, Lenox Hill Hospital, Northwell Health, New York, NY 10028, United States
- Northwell, New Hyde Park, New York, NY 10042, United States
- Donald and Barbara Zucker School of Medicine, Hofstra/Northwell 500 Hofstra Blvd, Hempstead, NY 11549, United States
| |
Collapse
|
|
2
|
Liu T, Yang M, Feng X, Zou X, Xia Y, Chen L, Gao Z, Zhao L, Wang X. Unraveling the role of lncRNAs and their associated nearby coding genes in the pathogenesis of systemic lupus erythematosus. Arthritis Res Ther 2025; 27:44. [PMID: 40025620 PMCID: PMC11871770 DOI: 10.1186/s13075-025-03510-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 02/18/2025] [Indexed: 03/04/2025] Open
Abstract
BACKGROUND The role of long non-coding RNAs (lncRNAs) and their nearby messenger RNAs (mRNAs) in systemic lupus erythematosus (SLE) pathogenesis is not well understood. METHOD High-throughput sequencing was utilized to analyze PBMCs obtained from SLE patients. Subsequently, we conducted differential analysis, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and verification through quantitative real-time PCR (qRT-PCR). Additionally, qRT-PCR was used to analyze the levels of lncRNAs or mRNAs in transfected Raji cells. RESULTS We identified 419 differentially expressed (DE) lncRNAs and their 337 nearby DE mRNAs in SLE patients. More than 67% of the DE lncRNAs were lincRNAs and intronic_lncRNAs. The most significantly regulated nearby mRNAs in SLE patients were LTF and CIRBP, potentially involved in recurrent infection and photosensitivity. GO analysis revealed upregulation of the immune effector process term, with genes such as C1qA, C1qC, C1qB, NLRP3, and CXCL6 participating in this term and the upregulated pertussis signaling pathway. Analysis of the nearby coding genes of 88 lincRNAs indicated that XLOC_185773 had the highest number of nearby encoding genes and was negatively correlated with peripheral blood lymphocyte counts, potentially regulating HARS. Furthermore, LNC_005556, an antisense DE lncRNA, was negatively correlated with lupus nephritis occurrence and may regulate the upregulated IGLL5 in patients. CONCLUSIONS The current study provides insights into the dysregulation of lncRNAs and nearby mRNAs in SLE, highlighting potential key players in the pathogenesis of the disease.
Collapse
Affiliation(s)
- Tao Liu
- Department of Rheumatology and Immunology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Mingyue Yang
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China
| | - Xiunan Feng
- Department of Rheumatology and Immunology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Xiaojuan Zou
- Department of Rheumatology and Immunology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Ying Xia
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China
| | - Lu Chen
- Department of Rheumatology and Immunology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Zixin Gao
- Department of Rheumatology and Immunology, The First Hospital of Jilin University, Changchun, 130021, China
| | - Ling Zhao
- Department of Rheumatology and Immunology, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Xiaosong Wang
- Department of Translational Medicine, The First Hospital of Jilin University, Changchun, 130021, China.
| |
Collapse
|
|
3
|
Wang T, Wang M, Liu W, Zhang L, Zhang J, Zhao J, Wu Z, Lyu Y, Wu R. Intracellular CIRP promotes liver regeneration via STAT3 signaling pathway activation after partial hepatectomy in mice. Int J Mol Med 2025; 55:42. [PMID: 39791211 PMCID: PMC11758893 DOI: 10.3892/ijmm.2025.5483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 12/12/2024] [Indexed: 01/12/2025] Open
Abstract
Cold‑inducible RNA‑binding protein (CIRP) is a cold shock protein implicated in the regulation of multiple biological processes depending on its cellular localization. However, to the best of our knowledge, the role of CIRP in liver regeneration and injury after hepatectomy has not been investigated. The present study was therefore designed to explore whether CIRP is involved in liver regeneration after hepatectomy and its specific role and underlying molecular mechanism. The overall involvement of CIRP in liver regeneration and injury after hepatectomy was evaluated in CIRP‑deficient mice. C23, an antagonist of extracellular CIRP, was used to assess the effect of extracellular CIRP on liver regeneration and injury after hepatectomy. CIRP overexpression and short hairpin RNA plasmids were transfected into HepG2 cells to study the effect of intracellular CIRP on cell proliferation. The effects of extracellular CIRP on cell proliferation and injury were determined via the use of recombinant CIRP protein to stimulate HepG2 cells in vitro. The results indicated that both hepatic and serum CIRP levels significantly increased after partial hepatectomy. Additionally, CIRP deficiency impaired liver regeneration but alleviated liver injury after partial hepatectomy in mice. C23 administration attenuated liver injury and suppressed endoplasmic reticulum (ER) stress and oxidative stress. Loss‑ and gain‑of‑function analyses in HepG2 cells indicated that an increase in intracellular CIRP promoted cell proliferation via signal transducers and activation of transcription 3 (STAT3) signaling pathway activation. Moreover, recombinant CIRP had no effect on cell proliferation or STAT3 phosphorylation but induced ER stress, which was blocked by TAK242, an inhibitor of Toll‑like receptor 4 (TLR4), in HepG2 cells. Taken together, the results of the present study demonstrated that intracellular CIRP promotes liver regeneration by activating the STAT3 pathway, whereas extracellular CIRP induces ER stress possibly via the TLR4 signaling pathway after hepatectomy.
Collapse
Affiliation(s)
- Tao Wang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Mengzhou Wang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Wuming Liu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Lin Zhang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Junzhou Zhao
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yi Lyu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| |
Collapse
|
|
4
|
Jiao H, Huang S, Zhang M, Huang Q, Yan C, Qi J, Cheng J, Xu Y, Zhai X, Li X, Zhan S, Li W, Wu Z, Chan J, Chen L, Hu P. Uncovering the chromatin-mediated transcriptional regulatory network governing cold stress responses in fish immune cells. J Genet Genomics 2025:S1673-8527(25)00023-2. [PMID: 39848465 DOI: 10.1016/j.jgg.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/12/2025] [Accepted: 01/13/2025] [Indexed: 01/25/2025]
Abstract
Temperature fluctuations challenge ectothermic species, particularly tropical fish dependent on external temperatures for physiological regulation. However, the molecular mechanisms through which low-temperature stress impacts immune responses in these species, especially in relation to chromatin accessibility and epigenetic regulation, remain poorly understood. In this study, we investigate chromatin and transcriptional changes in the head kidney and thymus tissues of Nile tilapia (Oreochromis niloticus), a tropical fish of significant economic importance, under cold stress. By analyzing cis-regulatory elements in open chromatin regions and their associated transcription factors (TFs), we construct a comprehensive transcriptional regulatory network (TRN) governing immune responses, including DNA damage-induced apoptosis. Our analysis identifies 119 TFs within the TRN, with Stat1 emerging as a central hub exhibiting distinct binding dynamics under cold stress, as revealed by footprint analysis. Overexpression of Stat1 in immune cells leads to apoptosis and increases the expression of apoptosis-related genes, many of which contain Stat1 binding sites in their regulatory regions, emphasizing its critical role in immune cell survival during cold stress. These results provide insights into the transcriptional and epigenetic regulation of immune responses to cold stress in tilapia and highlight Stat1 as a promising target for enhancing cold tolerance in tropical fish species.
Collapse
Affiliation(s)
- He Jiao
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Songqian Huang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
| | - Minghao Zhang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Qiao Huang
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China; The Hunan Provincial Key Laboratory of the TCM Agricultural Biogenomics, Changsha Medical University, Changsha, Hunan 410219, China
| | - Chenyu Yan
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Jingting Qi
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Jiangbo Cheng
- The State Key Laboratory of Grassland Agro-ecosystems, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou, Gansu 730020, China
| | - Yuan Xu
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Xue Zhai
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Xinwen Li
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Siyao Zhan
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Wei Li
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Zhichao Wu
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Jiulin Chan
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China
| | - Liangbiao Chen
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
| | - Peng Hu
- Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources, Ministry of Education, Shanghai Ocean University, Shanghai 201306, China; International Research Center for Marine Biosciences, Ministry of Science and Technology, Shanghai Ocean University, Shanghai 201306, China; Marine Biomedical Science and Technology Innovation Platform of Lin-gang Special Area, Shanghai 201306, China.
| |
Collapse
|
|
5
|
Rashid N, Hu Z, Jacob A, Wang P. Extracellular Cold-Inducible RNA-Binding Protein and Hemorrhagic Shock: Mechanisms and Therapeutics. Biomedicines 2024; 13:12. [PMID: 39857596 PMCID: PMC11759867 DOI: 10.3390/biomedicines13010012] [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: 11/05/2024] [Revised: 12/12/2024] [Accepted: 12/19/2024] [Indexed: 01/27/2025] Open
Abstract
Hemorrhagic shock is a type of hypovolemic shock and a significant cause of trauma-related death worldwide. The innate immune system has been implicated as a key mediator in developing severe complications after shock. Inflammation from the innate immune system begins at the time of initial insult; however, its activation is exaggerated, resulting in early and late-stage complications. Hypoxia and hypoperfusion lead to the release of molecules that act as danger signals known as damage-associated molecular patterns (DAMPs). DAMPs continue to circulate after shock, resulting in excess inflammation and tissue damage. We recently discovered that cold-inducible RNA-binding protein released into the extracellular space acts as a DAMP. During hemorrhagic shock, hypoperfusion leads to cell necrosis and the release of CIRP into circulation, triggering both systemic inflammation and local tissue damage. In this review, we discuss extracellular cold-inducible RNA-binding protein (eCIRP)'s role in sterile inflammation, as well as its various mechanisms of action. We also share our more newly developed anti-eCIRP agents with the eventual goal of producing drug therapies to mitigate organ damage, reduce mortality, and improve patient outcomes related to hemorrhagic shock. Finally, we suggest that future preclinical studies are required to develop the listed therapeutics for hemorrhagic shock and related conditions. In addition, we emphasize on the challenges to the translational phase and caution that the therapy should allow the immune system to continue to function well against secondary infections during hospitalization.
Collapse
Affiliation(s)
- Naureen Rashid
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; (N.R.); (Z.H.)
| | - Zhijian Hu
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; (N.R.); (Z.H.)
| | - Asha Jacob
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; (N.R.); (Z.H.)
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| | - Ping Wang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA; (N.R.); (Z.H.)
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| |
Collapse
|
|
6
|
Yao Y, Jiang H, Xu D, Zhang B, Yao F, Guo W. The extracellular CIRP as a predictive marker for the endothelial dysfunction in chronic obstructive pulmonary disease combined with pulmonary hypertension. BMC Pulm Med 2024; 24:615. [PMID: 39695535 DOI: 10.1186/s12890-024-03416-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/25/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD), distinguished by pulmonary endothelial dysfunction. The extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern (DAMP) that triggers inflammation and causes vascular endothelial dysfunction in COPD-PH. METHODS The expression levels of CIRP were compared in peripheral lung tissues among 40 individuals. Moreover, A prospective analysis was conducted on serum levels of eCIRP, interleukin (IL) 1β, IL-33, endothelin-1 (ET-1), and nitric oxide (NO) in 150 COPD patients and 50 healthy control individuals at Jiangsu Taizhou Peoples Hospital. The study aimed to compare these serum levels and correlations among COPD-PH group, COPD non-PH group and the normal group. RESULTS We found higher CIRP levels in COPD-PH compared to COPD non-PH and the normal in lung tissue samples. A prospective analysis showed higher serum levels of eCIRP, IL-1β, IL-33, and ET 1 in COPD-PH, while a noticeable reduction in NO levels. There exists a correlation between the severity of COPD-PH and elevated levels of eCIRP, proinflammatory cytokines like IL-1β and IL-33, along with indicators of endothelial dysfunction like endothelin-1 ET-1 and NO. Moreover, the serum eCIRP level demonstrated a notable positive correlation with the levels of IL-1β, IL-33, PCT, and ET-1, while displaying a negative correlation with NO and Peripheral Oxygen Saturation (SpO2). Moreover, the serum eCIRP level demonstrated a notable positive correlation with the levels of IL-1β, IL-33, PCT, and ET-1, while displaying a negative correlation with NO and SpO2. Moreover, an assessment of independent risk factors for COPD-PH with ROC curve analysis, gauged the predictive value of serum eCIRP, IL-1β, IL-33, ET-1, and NO levels in diagnosing COPD-PH. Elevated eCIRP, IL-33, and ET-1 levels significantly correlated with COPD-PH, highlighting eCIRP's strong predictive value for this condition. CONCLUSION eCIRP levels could serve as a valuable biomarker for predicting endothelial dysfunction in COPD-PH.
Collapse
Affiliation(s)
- Yun Yao
- Department of Respiratory and Critical Care Medicine, Anhui Provincial Lujiang County People's Hospital, Hefei, Anhui, P.R. China
| | - Haibo Jiang
- Department of Respiratory and Critical Care Medicine, Anhui Provincial Lujiang County People's Hospital, Hefei, Anhui, P.R. China
| | - Dalin Xu
- Department of Respiratory and Critical Care Medicine, Anhui Provincial Lujiang County People's Hospital, Hefei, Anhui, P.R. China
| | - Bing Zhang
- Department of Internal Medicine, Taizhou People's Hospital, Taizhou, Jiangsu, P.R. China
| | - Feng Yao
- Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, P.R. China.
| | - Wei Guo
- Department of Respiratory and Critical Care Medicine, Anhui Provincial Lujiang County People's Hospital, Hefei, Anhui, P.R. China.
| |
Collapse
|
|
7
|
Hu R, Zhang J, Jawdy S, Sreedasyam A, Lipzen A, Wang M, Ng V, Daum C, Keymanesh K, Liu D, Hu A, Chen JG, Tuskan GA, Schmutz J, Yang X. Transcriptomic Analysis of the CAM Species Kalanchoë fedtschenkoi Under Low- and High-Temperature Regimes. PLANTS (BASEL, SWITZERLAND) 2024; 13:3444. [PMID: 39683237 DOI: 10.3390/plants13233444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/25/2024] [Accepted: 12/05/2024] [Indexed: 12/18/2024]
Abstract
Temperature stress is one of the major limiting environmental factors that negatively impact global crop yields. Kalanchoë fedtschenkoi is an obligate crassulacean acid metabolism (CAM) plant species, exhibiting much higher water-use efficiency and tolerance to drought and heat stresses than C3 or C4 plant species. Previous studies on gene expression responses to low- or high-temperature stress have been focused on C3 and C4 plants. There is a lack of information about the regulation of gene expression by low and high temperatures in CAM plants. To address this knowledge gap, we performed transcriptome sequencing (RNA-Seq) of leaf and root tissues of K. fedtschenkoi under cold (8 °C), normal (25 °C), and heat (37 °C) conditions at dawn (i.e., 2 h before the light period) and dusk (i.e., 2 h before the dark period). Our analysis revealed differentially expressed genes (DEGs) under cold or heat treatment in comparison to normal conditions in leaf or root tissue at each of the two time points. In particular, DEGs exhibiting either the same or opposite direction of expression change (either up-regulated or down-regulated) under cold and heat treatments were identified. In addition, we analyzed gene co-expression modules regulated by cold or heat treatment, and we performed in-depth analyses of expression regulation by temperature stresses for selected gene categories, including CAM-related genes, genes encoding heat shock factors and heat shock proteins, circadian rhythm genes, and stomatal movement genes. Our study highlights both the common and distinct molecular strategies employed by CAM and C3/C4 plants in adapting to extreme temperatures, providing new insights into the molecular mechanisms underlying temperature stress responses in CAM species.
Collapse
Affiliation(s)
- Rongbin Hu
- Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
| | - Jin Zhang
- Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
- The Center for Bioenergy Innovation, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
- State Key Laboratory of Subtropical Silviculture, School of Forestry and Biotechnology, Zhejiang A&F University, Hangzhou 311300, China
| | - Sara Jawdy
- Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
| | - Avinash Sreedasyam
- HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35801, USA
| | - Anna Lipzen
- Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94589, USA
| | - Mei Wang
- Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94589, USA
| | - Vivian Ng
- Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94589, USA
| | - Christopher Daum
- Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94589, USA
| | - Keykhosrow Keymanesh
- Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94589, USA
| | - Degao Liu
- Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
- Institute of Genomics for Crop Abiotic Stress Tolerance, Department of Plant and Soil Science, Texas Tech University, Lubbock, TX 79409, USA
| | - Alex Hu
- Department of Chemical and Environmental Engineering, University of California-Riverside, Riverside, CA 92521, USA
| | - Jin-Gui Chen
- Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
- The Center for Bioenergy Innovation, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
| | - Gerald A Tuskan
- Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
- The Center for Bioenergy Innovation, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
| | - Jeremy Schmutz
- HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, AL 35801, USA
- Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94589, USA
| | - Xiaohan Yang
- Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
- The Center for Bioenergy Innovation, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA
| |
Collapse
|
|
8
|
Zhang W, Shen M, Chu P, Wang T, Ji J, Ning X, Yin S, Zhang K. Molecular characterization of CIRBP from Takifugu fasciatus and its potential roles in cold-induced liver damage. Int J Biol Macromol 2024; 281:136492. [PMID: 39393746 DOI: 10.1016/j.ijbiomac.2024.136492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 10/13/2024]
Abstract
As a potent stressor, environmental cold stress induces severe mitochondrial dysfunction with the overproduction of reactive oxygen species (ROS) in fish, resulting in liver damage. However, the molecular mechanisms underlying the cold-induced liver damage remain unclear. In the present study, the cold-inducible RNA-binding protein (CIRBP) from Takifugu fasciatus was characterized, and its role in cold-induced oxidative stress damage was investigated. An acute liver injury model was constructed by exposing T. fasciatus individuals to temperatures of 25, 19, and 13 °C. Cold exposure markedly induced histomorphological liver injury and triggered endogenous apoptosis and NLRP3 inflammatory response. Cold treatment significantly increased CIRBP gene expression. A similar expression pattern was detected for thioredoxin (TRX), suggesting that these two proteins play a role in the establishment of cold adaptation. CIRBP binds directly to the 3'-UTR of TRX. Furthermore, in vivo experiment showed that, when CIRBP expression in T. fasciatus is knocked down, the time to loss equilibrium significantly shortened at 13 °C. Taken together, our study revealed that CIRBP is a critical protective factor against cold induced liver damage and that the CIRBP/TRX pathway could function as an underlying mechanism for cold adaptation in teleosts.
Collapse
Affiliation(s)
- Wenwen Zhang
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing 210023, China
| | - Minghao Shen
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing 210023, China
| | - Peng Chu
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing 210023, China
| | - Tao Wang
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing 210023, China; Co-Innovation Center for Marine Bio-Industry Technology, Lian Yungang, Jiangsu 222005, China
| | - Jie Ji
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing 210023, China; Co-Innovation Center for Marine Bio-Industry Technology, Lian Yungang, Jiangsu 222005, China
| | - Xianhui Ning
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing 210023, China; Co-Innovation Center for Marine Bio-Industry Technology, Lian Yungang, Jiangsu 222005, China
| | - Shaowu Yin
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing 210023, China; Co-Innovation Center for Marine Bio-Industry Technology, Lian Yungang, Jiangsu 222005, China.
| | - Kai Zhang
- College of Marine Science and Engineering, Nanjing Normal University, Jiangsu Province Engineering Research Center for Aquatic Animals Breeding and Green Efficient Aquacultural Technology, Nanjing 210023, China; Co-Innovation Center for Marine Bio-Industry Technology, Lian Yungang, Jiangsu 222005, China.
| |
Collapse
|
|
9
|
Gong T, Wang QD, Loughran PA, Li YH, Scott MJ, Billiar TR, Liu YT, Fan J. Mechanism of lactic acidemia-promoted pulmonary endothelial cells death in sepsis: role for CIRP-ZBP1-PANoptosis pathway. Mil Med Res 2024; 11:71. [PMID: 39465383 PMCID: PMC11514876 DOI: 10.1186/s40779-024-00574-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 09/30/2024] [Indexed: 10/29/2024] Open
Abstract
BACKGROUND Sepsis is often accompanied by lactic acidemia and acute lung injury (ALI). Clinical studies have established that high serum lactate levels are associated with increased mortality rates in septic patients. We further observed a significant correlation between the levels of cold-inducible RNA-binding protein (CIRP) in plasma and bronchoalveolar lavage fluid (BALF), as well as lactate levels, and the severity of post-sepsis ALI. The underlying mechanism, however, remains elusive. METHODS C57BL/6 wild type (WT), Casp8-/-, Ripk3-/-, and Zbp1-/- mice were subjected to the cecal ligation and puncture (CLP) sepsis model. In this model, we measured intra-macrophage CIRP lactylation and the subsequent release of CIRP. We also tracked the internalization of extracellular CIRP (eCIRP) in pulmonary vascular endothelial cells (PVECs) and its interaction with Z-DNA binding protein 1 (ZBP1). Furthermore, we monitored changes in ZBP1 levels in PVECs and the consequent activation of cell death pathways. RESULTS In the current study, we demonstrate that lactate, accumulating during sepsis, promotes the lactylation of CIRP in macrophages, leading to the release of CIRP. Once eCIRP is internalized by PVEC through a Toll-like receptor 4 (TLR4)-mediated endocytosis pathway, it competitively binds to ZBP1 and effectively blocks the interaction between ZBP1 and tripartite motif containing 32 (TRIM32), an E3 ubiquitin ligase targeting ZBP1 for proteasomal degradation. This interference mechanism stabilizes ZBP1, thereby enhancing ZBP1-receptor-interacting protein kinase 3 (RIPK3)-dependent PVEC PANoptosis, a form of cell death involving the simultaneous activation of multiple cell death pathways, thereby exacerbating ALI. CONCLUSIONS These findings unveil a novel pathway by which lactic acidemia promotes macrophage-derived eCIRP release, which, in turn, mediates ZBP1-dependent PVEC PANoptosis in sepsis-induced ALI. This finding offers new insights into the molecular mechanisms driving sepsis-related pulmonary complications and provides potential new therapeutic strategies.
Collapse
Affiliation(s)
- Ting Gong
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- Department of Anesthesiology, Shenzhen Hospital of Southern Medical University, Shenzhen, 518110, Guangdong, China.
| | - Qing-De Wang
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Patricia A Loughran
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Yue-Hua Li
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Melanie J Scott
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA
| | - You-Tan Liu
- Department of Anesthesiology, Shenzhen Hospital of Southern Medical University, Shenzhen, 518110, Guangdong, China.
| | - Jie Fan
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, 15240, USA.
| |
Collapse
|
|
10
|
Hu Z, Li J, Jacob A, Wang P. Harnessing extracellular cold-inducible RNA binding protein by PS-OMe miR130: A promising shield against hemorrhage-induced lung injury. J Trauma Acute Care Surg 2024; 97:581-589. [PMID: 38685193 DOI: 10.1097/ta.0000000000004361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2024]
Abstract
INTRODUCTION Hemorrhagic shock (HS) poses a life-threatening condition with the lungs being one of the most susceptible organs to its deleterious effects. Extracellular cold-inducible RNA binding protein has emerged as a pivotal mediator of inflammation, and its release has been observed as a case of HS-induced tissue injury. Previous studies unveiled a promising engineered microRNA, designated PS-OMe miR130, which inhibits extracellular cold-inducible RNA binding protein, thereby safeguarding vital organs. In this study, we hypothesized that PS-OMe miR130 serves as a protective shield against HS-induced lung injury by curtailing the overzealous inflammatory immune response. METHODS Hemorrhagic shock was induced in male C57BL6 mice by withdrawing blood via a femoral artery cannula to a mean arterial pressure of 30 mm Hg for 90 minutes. The mice were resuscitated with twice the shed blood volume with Ringer's lactate solution. They were then treated intravenously with either phosphate-buffered saline (vehicle) or 62.5 nmol PS-OMe miR130. At 4 hours later, blood and lungs were harvested. RESULTS Following PS-OMe miR130 treatment in HS mice, a substantial decrease was observed in serum injury markers including aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, and blood urea nitrogen. Serum interleukin (IL)-6 exhibited a similar reduction. In lung tissues, PS-OMe miR130 led to a significant decrease in the messenger RNA expressions of pro-inflammatory cytokines (IL-6, IL-1β, and tumor necrosis factor α), chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein 2), and an endothelial injury marker, E-selectin. PS-OMe miR130 also produced substantial inhibition of lung myeloperoxidase activity and resulted in a marked reduction in lung injury as evidenced by histological evaluation. This was further confirmed by the observation that PS-OMe miR130 significantly reduced the presence of lymphocyte antigen 6 family member G-positive neutrophils and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cells. CONCLUSION PS-OMe miR130 emerges as a potent safeguard against HS-induced lung injury by effectively inhibiting pro-inflammation and injuries, offering a promising therapeutic strategy in such critical clinical condition.
Collapse
Affiliation(s)
- Zhijian Hu
- From the Center for Immunology and Inflammation (Z.H., J.L., A.J., P.W.), Feinstein Institutes for Medical Research; and Departments of Surgery (A.J., P.W.) and Molecular Medicine (A.J., P.W.), Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York
| | | | | | | |
Collapse
|
|
11
|
Zhao J, Qiu C, Wan R, Wang Q, Zhang Y, Yang D, Yang Y, Sun X. Inhibition of CIRBP represses the proliferation and migration of vascular smooth muscle cells via inhibiting Rheb/mTORC1 axis. Biochem Biophys Res Commun 2024; 725:150248. [PMID: 38870847 DOI: 10.1016/j.bbrc.2024.150248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 06/09/2024] [Indexed: 06/15/2024]
Abstract
The excessive migration and proliferation of vascular smooth muscle cells (VSMCs) plays a vital role in vascular intimal hyperplasia. CIRBP is involved in the proliferation of various cancer cells. This study was aimed to explore the role of CIRBP in the proliferation and migration of VSMCs. Adenovirus was used to interfere with cold-inducible RNA-binding protein (CIRBP) expression, while lentivirus was used to overexpress Ras homolog enriched in brain (Rheb). Western blotting and qRT-PCR were used to evaluate the expression of CIRBP, Rheb, and mechanistic target of rapamycin complex 1 (mTORC1) activity. The cell proliferation was determined by Ki67 immunofluorescence staining and CCK-8 assay. The wound healing assay was performed to assess cell migration. Additionally, immunohistochemistry was conducted to explore the role of CIRBP in intimal hyperplasia after vascular injury. We found that silencing CIRBP inhibited the proliferation and migration of VSMCs, decreased the expression of Rheb and mTORC1 activity. Restoration of mTORC1 activity via insulin or overexpression of Rheb via lentiviral transfection both attenuated the inhibitory effects of silencing CIRBP on the proliferation and migration of VSMCs. Moreover, Rheb overexpression abolished the inhibitory effect of silencing CIRBP on mTORC1 activity in VSMCs. CIRBP was upregulated in the injured carotid artery. Silencing CIRBP ameliorated intimal hyperplasia after vascular injury. In the summary, silencing CIRBP attenuates mTORC1 activity via reducing Rheb expression, thereby supressing the proliferation and migration of VSMCs and intimal hyperplasia after vascular injury.
Collapse
MESH Headings
- Mechanistic Target of Rapamycin Complex 1/metabolism
- Ras Homolog Enriched in Brain Protein/metabolism
- Ras Homolog Enriched in Brain Protein/genetics
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/pathology
- Cell Proliferation
- Cell Movement
- Animals
- RNA-Binding Proteins/metabolism
- RNA-Binding Proteins/genetics
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- Myocytes, Smooth Muscle/cytology
- Cells, Cultured
- Signal Transduction
- Male
- Rats
- Rats, Sprague-Dawley
- Humans
Collapse
Affiliation(s)
- Jiaqi Zhao
- Department of Cardiology, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Chenming Qiu
- Department of Burn, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Rong Wan
- Department of Burn, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Qiang Wang
- Department of Cardiology, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Yan Zhang
- Department of Cardiology, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Dachun Yang
- Department of Cardiology, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Yongjian Yang
- Department of Cardiology, The General Hospital of Western Theater Command, Chengdu, 610083, China.
| | - Xiongshan Sun
- Department of Cardiology, The General Hospital of Western Theater Command, Chengdu, 610083, China.
| |
Collapse
|
|
12
|
Li C, Fei C, Le S, Lai Z, Yan B, Wang L, Zhang Z. Identification and validation of ferroptosis-related biomarkers in intervertebral disc degeneration. Front Cell Dev Biol 2024; 12:1416345. [PMID: 39351146 PMCID: PMC11439793 DOI: 10.3389/fcell.2024.1416345] [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: 04/12/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Introduction Ferroptosis plays a significant role in intervertebral disc degeneration (IDD). Understanding the key genes regulating ferroptosis in IDD could reveal fundamental mechanisms of the disease, potentially leading to new diagnostic and therapeutic targets. Methods Public datasets (GSE23130 and GSE70362) and the FerrDb database were analyzed to identify ferroptosis-related genes (DE-FRGs) involved in IDD. Single-cell RNA sequencing data (GSE199866) was used to validate the specific roles and expression patterns of these genes. Immunohistochemistry and Western blot analyses were subsequently conducted in both clinical samples and mouse models to assess protein expression levels across different tissues. Results The analysis identified seven DE-FRGs, including MT1G, CA9, AKR1C1, AKR1C2, DUSP1, CIRBP, and KLHL24, with their expression patterns confirmed by single-cell RNA sequencing. Immunohistochemistry and Western blot analysis further revealed that MT1G, CA9, AKR1C1, AKR1C2, DUSP1, and KLHL24 exhibited differential expression during the progression of IDD. Additionally, the study highlighted the potential immune-modulatory functions of these genes within the IDD microenvironment. Discussion Our study elucidates the critical role of ferroptosis in IDD and identifies specific genes, such as MT1G and CA9, as potential targets for diagnosis and therapy. These findings offer new insights into the molecular mechanisms underlying IDD and present promising avenues for future research and clinical applications.
Collapse
Affiliation(s)
- Chenglong Li
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chengshuo Fei
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shiyong Le
- Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Academy of Orthopedics, Guangzhou, China
| | - Zhongming Lai
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bo Yan
- Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Academy of Orthopedics, Guangzhou, China
| | - Liang Wang
- Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Academy of Orthopedics, Guangzhou, China
| | - Zhongmin Zhang
- Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
|
13
|
Redon L, Constant T, Smith S, Habold C, Giroud S. Understanding seasonal telomere length dynamics in hibernating species. J Therm Biol 2024; 123:103913. [PMID: 39002254 DOI: 10.1016/j.jtherbio.2024.103913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/15/2024]
Abstract
Oxidative stress is thought to be one of the main causes of ageing as it progressively damages cell components throughout life, eventually causing cellular failure and apoptosis. In many organisms, telomeres shorten throughout life under the effect of, amongst other factors, oxidative stress, and are therefore commonly used as marker of biological ageing. However, hibernators, which are regularly exposed to acute oxidative stress when rewarming from torpor, are unexpectedly long-lived. In this review, we explore the causes of oxidative stress associated with hibernation and its impact on telomere dynamics in different taxa, focussing on hibernating rodents. We then speculate on the adaptive mechanisms of hibernators to compensate for the effects of oxidative stress, which may explain their increased longevity. Because winter hibernation appears to be associated with high oxidative stress, hibernators, particularly rodents, may periodically invest in repair mechanisms and antioxidant defences, resulting in seasonal variations in telomere lengths. This research shows how species with a slow life-history strategy deal with large changes in oxidative stress, unifying evolutionary and physiological theories of ageing. Because of the marked seasonal variation in telomere length, we also draw attention when using telomeres as markers for biological aging in seasonal heterotherms and possibly in other highly seasonal species.
Collapse
Affiliation(s)
- Lilian Redon
- Research Institute of Wildlife Ecology, Department of Interdisciplinary Life Sciences, University of Veterinary Medicine Vienna, Austria.
| | - Théo Constant
- Department of Ecology Physiology Ethology, Pluridisciplinary Institute Hubert Curien, UMR 7179 CNRS/UdS, Strasbourg, France
| | - Steve Smith
- Konrad Lorenz Institute of Ethology, Department of Interdisciplinary Life Sciences, University of Veterinary Medicine Vienna, Austria
| | - Caroline Habold
- Department of Ecology Physiology Ethology, Pluridisciplinary Institute Hubert Curien, UMR 7179 CNRS/UdS, Strasbourg, France
| | - Sylvain Giroud
- Research Institute of Wildlife Ecology, Department of Interdisciplinary Life Sciences, University of Veterinary Medicine Vienna, Austria.
| |
Collapse
|
|
14
|
Dai S, Ji J, Li R, Gao L, He X. Stellate Ganglion Block Attenuates LPS-Induced Acute Lung Injury by Activating Sirt3 Regulation of Oxidative Stress and Inflammation. Biomedicines 2024; 12:1148. [PMID: 38927355 PMCID: PMC11200983 DOI: 10.3390/biomedicines12061148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/03/2024] [Accepted: 05/12/2024] [Indexed: 06/28/2024] Open
Abstract
Stellate ganglion blocks (SGBs) has been applied in clinics to alleviate pain-related syndromes for almost a century. In recent years, it has been reported that SGB can attenuate acute lung injury (ALI) in animals. However, the details of these molecular mechanisms remain complex and unclear. In this study, rats were randomly divided into four groups: group C (receiving no treatment), group NS (receiving the intratracheal instillation of normal saline), group L (receiving the intratracheal instillation of LPS) and group LS (receiving SGB after the intratracheal instillation of LPS). The pathological damage of lung tissue, arterial blood gases, the differentiation of alveolar macrophages (AMs) and inflammatory cytokines (IL-1β, IL-6, IL-10) were detected. Furthermore, the oxidative stress indexes (ROS, CYP-D, T-SOD, Mn-SOD and CAT) in serum and the levels of Sirt3 signaling-associated proteins (JAK2/STAT3, NF-κb p65, CIRP and NLRP3) in the lungs were measured. The results revealed that SGB could attenuate lung tissue damage, improve pulmonary oxygenation, promote the differentiation of AMs to the M2 phenotype, decrease the secretion of IL-1β and IL-6, and increase the secretion of IL-10. Meanwhile, SGB was found to inhibit the production of ROS and CYP-D, and enhance the activities of T-SOD, Mn-SOD and CAT. Furthermore, SGB upregulated Sirt3 and downregulated JAK2/STAT3 and NF-κb p65 phosphorylation, CIRP and NLRP3. Our work revealed that SGB could attenuate LPS-induced ALI by activating the Sirt3-mediated regulation of oxidative stress and pulmonary inflammation; this may shed new light upon the protection of SGB and provide a novel prophylactic strategy for LPS-induced ALI.
Collapse
Affiliation(s)
- Shiyun Dai
- Department of Anesthesiology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China; (S.D.)
- Department of Anesthesiology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jun Ji
- Department of Anesthesiology, Air Force Medical Center, Air Force Medical University, PLA, Beijing 100142, China
| | - Rongrong Li
- Department of Anesthesiology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China; (S.D.)
| | - Lu Gao
- Department of Physiology, Naval Medical University, Shanghai 200433, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200433, China
| | - Xingying He
- Department of Anesthesiology, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, China; (S.D.)
| |
Collapse
|
|
15
|
Zhang J, Liu T, Wei Y, Peng J, Zeng G, Zhong P. Upregulation of CIRP by its agonist prevents the development of heart failure in myocardial infarction rats. BMC Cardiovasc Disord 2024; 24:185. [PMID: 38539067 PMCID: PMC10967100 DOI: 10.1186/s12872-024-03852-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 03/20/2024] [Indexed: 04/02/2024] Open
Abstract
BACKGROUND Downregulated expression of cold-inducible RNA binding protein (CIRP), a stress-response protein, has been demonstrated in the hearts of patients with heart failure (HF). However, whether CIRP plays a critical role in the pathogenesis of HF remains unknown. Zr17-2 is a recently identified CIRP agonist, which can enhance the expression of CIRP in hearts. Herein, we evaluated the effects of zr17-2 on the development of HF in a rat model of myocardial infarction (MI). METHODS Male SD rats were pretreated with CIRP agonist zr17-2 or vehicle saline for 6 consecutive days, followed by MI induction. 1-week post-MI, cardiac function, and structural and molecular changes were determined by echocardiography and molecular biology methods. RESULTS Excitingly, we found that pretreatment with zr17-2 significantly attenuated MI-induced cardiac dysfunction and dilation, coupled with reduced infarction size and cardiac remodeling. In addition, increased inflammatory response in the peri-infarcted heart including macrophage infiltration and the expression of inflammatory genes were all significantly decreased by zr17-2 pretreatment, suggesting an anti-inflammatory effect of zr17-2. Moreover, zr17-2 pretreatment also upregulated the antioxidant genes (e.g. NQO-1, Nrf2, and HO-1) level in the hearts. In isolated cultured cardiomyocytes, pretreatment with zr17-2 markedly attenuated cell injury and apoptosis induced by oxidative injury, along with elevation of Nrf2-related antioxidant genes and CIRP. However, silencing CIRP abolished zr17-2's antioxidant effects against oxidative injury, confirming that zr17-2's role is dependent on CIRP. CONCLUSION Collectively, our study suggests CIRP plays a crucial role in the development of HF and a beneficial effect of CIRP agonist in preventing MI-induced HF, possibly via anti-inflammatory and anti-oxidant pathways.
Collapse
Affiliation(s)
- Jingjing Zhang
- Department of Cardiology Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Tao Liu
- Department of Cardiology Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Yanzhao Wei
- Department of Cardiology Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China
- Hubei Key Laboratory of Cardiology, Wuhan, 430060, China
| | - Jianye Peng
- The Second Affiliated Hospital, Department of Cardiovascular Medicine, Hengyang Medical School, University of South China, Hengyang, China
- The Second Affiliated Hospital, Key laboratory of Heart Failure Prevention & Treatment of Hengyang, Hengyang Medical School, University of South China, Hengyang, 421001, China
- Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, University of South China, Hengyang, 421001, China
| | - Gaofeng Zeng
- The Second Affiliated Hospital, Department of Cardiovascular Medicine, Hengyang Medical School, University of South China, Hengyang, China.
- The Second Affiliated Hospital, Key laboratory of Heart Failure Prevention & Treatment of Hengyang, Hengyang Medical School, University of South China, Hengyang, 421001, China.
- Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, University of South China, Hengyang, 421001, China.
| | - Peng Zhong
- Department of Cardiology Research Institute, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China.
- Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.
- Hubei Key Laboratory of Cardiology, Wuhan, 430060, China.
| |
Collapse
|
|
16
|
Lin TY, Jia JS, Luo WR, Lin XL, Xiao SJ, Yang J, Xia JW, Zhou C, Zhou ZH, Lin SJ, Li QW, Yang ZZ, Lei Y, Yang WQ, Shen HF, Huang SH, Wang SC, Chen LB, Yang YL, Xue SW, Li YL, Dai GQ, Zhou Y, Li YC, Wei F, Rong XX, Luo XJ, Zhao BX, Huang WH, Xiao D, Sun Y. ThermomiR-377-3p-induced suppression of Cirbp expression is required for effective elimination of cancer cells and cancer stem-like cells by hyperthermia. J Exp Clin Cancer Res 2024; 43:62. [PMID: 38419081 PMCID: PMC10903011 DOI: 10.1186/s13046-024-02983-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 02/12/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND In recent years, the development of adjunctive therapeutic hyperthermia for cancer therapy has received considerable attention. However, the mechanisms underlying hyperthermia resistance are still poorly understood. In this study, we investigated the roles of cold‑inducible RNA binding protein (Cirbp) in regulating hyperthermia resistance and underlying mechanisms in nasopharyngeal carcinoma (NPC). METHODS CCK-8 assay, colony formation assay, tumor sphere formation assay, qRT-PCR, Western blot were employed to examine the effects of hyperthermia (HT), HT + oridonin(Ori) or HT + radiotherapy (RT) on the proliferation and stemness of NPC cells. RNA sequencing was applied to gain differentially expressed genes upon hyperthermia. Gain-of-function and loss-of-function experiments were used to evaluate the effects of RNAi-mediated Cirbp silencing or Cirbp overexpression on the sensitivity or resistance of NPC cells and cancer stem-like cells to hyperthermia by CCK-8 assay, colony formation assay, tumorsphere formation assay and apoptosis assay, and in subcutaneous xenograft animal model. miRNA transient transfection and luciferase reporter assay were used to demonstrate that Cirbp is a direct target of miR-377-3p. The phosphorylation levels of key members in ATM-Chk2 and ATR-Chk1 pathways were detected by Western blot. RESULTS Our results firstly revealed that hyperthermia significantly attenuated the stemness of NPC cells, while combination treatment of hyperthermia and oridonin dramatically increased the killing effect on NPC cells and cancer stem cell (CSC)‑like population. Moreover, hyperthermia substantially improved the sensitivity of radiation‑resistant NPC cells and CSC‑like cells to radiotherapy. Hyperthermia noticeably suppressed Cirbp expression in NPC cells and xenograft tumor tissues. Furthermore, Cirbp inhibition remarkably boosted anti‑tumor‑killing activity of hyperthermia against NPC cells and CSC‑like cells, whereas ectopic expression of Cirbp compromised tumor‑killing effect of hyperthermia on these cells, indicating that Cirbp overexpression induces hyperthermia resistance. ThermomiR-377-3p improved the sensitivity of NPC cells and CSC‑like cells to hyperthermia in vitro by directly suppressing Cirbp expression. More importantly, our results displayed the significantly boosted sensitization of tumor xenografts to hyperthermia by Cirbp silencing in vivo, but ectopic expression of Cirbp almost completely counteracted hyperthermia-mediated tumor cell-killing effect against tumor xenografts in vivo. Mechanistically, Cirbp silencing-induced inhibition of DNA damage repair by inactivating ATM-Chk2 and ATR-Chk1 pathways, decrease in stemness and increase in cell death contributed to hyperthermic sensitization; conversely, Cirbp overexpression-induced promotion of DNA damage repair, increase in stemness and decrease in cell apoptosis contributed to hyperthermia resistance. CONCLUSION Taken together, these findings reveal a previously unrecognized role for Cirbp in positively regulating hyperthermia resistance and suggest that thermomiR-377-3p and its target gene Cirbp represent promising targets for therapeutic hyperthermia.
Collapse
Affiliation(s)
- Tao-Yan Lin
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jun-Shuang Jia
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Wei-Ren Luo
- Cancer Research Institute, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen Third People's Hospital, Shenzhen, 518112, China
| | - Xiao-Lin Lin
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510315, China
| | - Sheng-Jun Xiao
- Department of Pathology, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
| | - Jie Yang
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
- Department of Imaging, Central Hospital of Shaoyang, Shaoyang, 422000, China
| | - Jia-Wei Xia
- The Third People's Hospital of Kunming (The Sixth Affiliated Hospital of Dali University), Kunming, 650041, China
| | - Chen Zhou
- Department of Pathology, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
| | - Zhi-Hao Zhou
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Shu-Jun Lin
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Qi-Wen Li
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zhi-Zhi Yang
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Ye Lei
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Wen-Qing Yang
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Hong-Fen Shen
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Shi-Hao Huang
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Sheng-Chun Wang
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
- Department of Pathology, School of Basic Medicine, Guangdong Medical University, Dongguan, 523808, China
| | - Lin-Bei Chen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Yu-Lin Yang
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Shu-Wen Xue
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Yong-Long Li
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Guan-Qi Dai
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Ying Zhou
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Ying-Chun Li
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Fang Wei
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xiao-Xiang Rong
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guang‑zhou, 510515, China
| | - Xiao-Jun Luo
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510315, China
| | - Bing-Xia Zhao
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Wen-Hua Huang
- Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
- Guangdong Medical Innovation Platform for Translation of 3D Printing Application, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, 510000, China.
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, 524001, China.
| | - Dong Xiao
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
- Guangzhou Southern Medical Laboratory Animal Sci.&Tech. Co.,Ltd, Guangzhou, 510515, China.
- National Demonstration Center for Experimental Education of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
- Department of Stomatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
| | - Yan Sun
- Laboratory Animal Management Center, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
| |
Collapse
|
|
17
|
Li Z, Sun S, Xiao Q, Tan S, Jin H, Hu B. Neuron Derived Cold-Inducible RNA-Binding Protein Promotes NETs Formation to Exacerbate Brain Endothelial Barrier Disruption after Ischemic Stroke. Aging Dis 2024; 16:AD.2024.0204-1. [PMID: 38377019 PMCID: PMC11745456 DOI: 10.14336/ad.2024.0204-1] [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: 10/19/2023] [Accepted: 02/04/2024] [Indexed: 02/22/2024] Open
Abstract
In ischemic stroke, neutrophils are the first-line peripheral immune cells infiltrating the brain tissue to form neutrophil extracellular traps (NETs). The present study aimed to investigate the role of neuronal cold-inducible RNA-binding protein (CIRP) in promoting NETs-induced brain endothelial barrier destruction and cerebral edema after ischemic stroke. We found that the expression of NETs and neuronal CIRP in the penumbra increased at 6 hours after transient middle cerebral artery occlusion (tMCAO) and increased significantly at 24 hours, reaching a peak at 3 days. NETs degradation or CIRP inhibition can alleviate the leakage of brain endothelial barrier and reverse the decreased expression of tight junction proteins (zonula occludens-1, claudin-5 and occludin) in tMCAO mice. Oxygen-glucose deprivation/reperfusion treated primary neurons or recombinant CIRP could induce NETs formation via TLR4/p38 signaling pathway in vitro. Transcription factor specificity protein 1 (sp1) was responsible for the increased neuronal CIRP expression and the inhibition of sp1 could suppress the increased CIRP expression, reduce NETs formation, and diminish brain endothelial barrier leakage in tMCAO mice. We also found the upregulated CIRP level was associated with severe cerebral edema in patients with acute ischemic stroke. In conclusion, the increased expression of transcription factor sp1 after ischemic stroke can lead to elevated CIRP expression and release from the neurons, which subsequently interacts with neutrophils and promotes NETs formation, resulting in brain endothelial barrier destruction and cerebral edema.
Collapse
Affiliation(s)
- Zhifang Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Shuai Sun
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qinghui Xiao
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Senwei Tan
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Huijuan Jin
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Bo Hu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| |
Collapse
|
|
18
|
Corre M, Lebreton A. Regulation of cold-inducible RNA-binding protein (CIRBP) in response to cellular stresses. Biochimie 2024; 217:3-9. [PMID: 37037339 DOI: 10.1016/j.biochi.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/29/2023] [Accepted: 04/07/2023] [Indexed: 04/12/2023]
Abstract
Cold-inducible RNA-Binding Protein (CIRBP) is a general stress-response factor in vertebrates harboring two domains: an RNA-recognition motif and a regulatory domain rich in RG/RGG motifs. CIRBP has been described to bind mRNAs upon various stress conditions (cold, infections, UV, hypoxia …) and regulate their stability and translation. The proteins encoded by its targets are involved in key stress-responsive cellular pathways including apoptosis, inflammation, cell proliferation or translation, thus allowing their coordination. Due to its role in regulating central cellular functions, the expression of CIRBP is tightly controlled. We review here current understanding of the multiple mechanistic layers affecting CIRBP expression and function. Beyond transcriptional regulation by cold-responsive elements and the use of alternative promoters and transcription start sites, CIRBP undergoes various alternative splicing (AS) events which, depending on conditions, modulate the stability of CIRBP transcripts and/or impact the sequence of the encoded polypeptide. Typically, whilst CIRBP expression is induced in the context of hypothermia or viral infection, AS events preferentially address alternative isoforms towards mRNA degradation pathways in response to heat stress or to bacterial-secreted pore forming toxins. Post-translational modifications of CIRBP, mostly in its RGG domain, also condition CIRBP subcellular localization and access to its targets, thereby promoting or inhibiting their expression. For instance, phosphorylation and methylation events gate CIRBP nuclear to cytoplasmic translocation and control its recruitment to stress granules. Considering the therapeutic potential of modulating the expression and function of this central player in stress responses, a fine understanding of CIRBP regulation mechanisms deserves further attention.
Collapse
Affiliation(s)
- Morgane Corre
- Institut de biologie de l'ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005, Paris, France
| | - Alice Lebreton
- Institut de biologie de l'ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005, Paris, France; INRAE, Micalis Institute, 78350, Jouy-en-Josas, France.
| |
Collapse
|
|
19
|
Yoon T, Ha JW, Pyo JY, Song JJ, Park YB, Ahn SS, Lee SW. Circulating cold-inducible RNA-binding protein levels in microscopic polyangiitis and granulomatosis with polyangiitis : Correlation with disease activity. Z Rheumatol 2024; 83:230-235. [PMID: 36732449 DOI: 10.1007/s00393-023-01320-x] [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] [Accepted: 01/05/2023] [Indexed: 02/04/2023]
Abstract
OBJECTIVE This study investigated whether circulating cold-inducible RNA-binding protein (CIRP) could be a biomarker to reflect the current activity, function, and damage status in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS This study selected 39 MPA and 26 GPA patients. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-specific indices include the Birmingham Vasculitis Activity Index (BVAS), five-factor score (FFS), the Korean version of the Short-Form 36-Item Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS), and the vasculitis damage index (VDI). The highest tertile of BVAS was defined as high activity of AAV. RESULTS The median age of the study subjects was 65.0 years and 53.8% were women. The median BVAS, FFS, SF-36 PCS, MCS, and VDI scores were 12.0, 2.0, 47.5, 50.3, and 3.0, respectively. The median circulating CIRP level was 6.4 ng/mL. Among the four AAV-specific indices, circulating CIRP was significantly correlated with BVAS (r = 0.256). Using the receiver operator characteristic curve, the cut-off of circulating CIRP for high activity of AAV was 6.16 ng/mL. High activity of AAV was identified more frequently in patients with circulating CIRP ≥ 6.16 ng/mL than in those with circulating CIRP < 6.16 ng/mL (48.6% vs. 21.4%). In addition, patients with circulating CIRP ≥ 6.16 ng/mL exhibited a significantly higher risk for high activity of AAV than those with circulating CIRP < 6.16 ng/mL (relative risk 3.474). CONCLUSION This study suggests the clinical potential of circulating CIRP as a biomarker for reflecting the current BVAS and predicting high activity of AAV in patients with MPA and GPA.
Collapse
Affiliation(s)
- Taejun Yoon
- Department of Medical Science, BK21 Plus Project, Yonsei University, College of Medicine, Seoul, Korea (Republic of)
| | - Jang Woo Ha
- Division of Rheumatology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, 363 Dongbaekjukjeon-daero, Giheung-gu, 16995, Yongin, Gyeonggi-do, Korea (Republic of)
| | - Jung Yoon Pyo
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Korea (Republic of)
| | - Jason Jungsik Song
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Korea (Republic of)
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea (Republic of)
| | - Yong-Beom Park
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Korea (Republic of)
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea (Republic of)
| | - Sung Soo Ahn
- Division of Rheumatology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, 363 Dongbaekjukjeon-daero, Giheung-gu, 16995, Yongin, Gyeonggi-do, Korea (Republic of).
| | - Sang-Won Lee
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Korea (Republic of).
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea (Republic of).
| |
Collapse
|
|
20
|
Feng Z, Cao X, Zhao C, Niu J, Yan Y, Shi T, Hao J, Zheng X. Serum CIRP increases the risk of acute kidney injury after cardiac surgery. Front Med (Lausanne) 2024; 10:1258622. [PMID: 38235271 PMCID: PMC10791772 DOI: 10.3389/fmed.2023.1258622] [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: 07/14/2023] [Accepted: 11/20/2023] [Indexed: 01/19/2024] Open
Abstract
Introduction Acute kidney injury (AKI) is a frequent perioperative complication. The underlying mechanisms of cardiac surgery-associated AKI are still not completely elucidated. Cold-induced RNA-binding protein (CIRP) has been subsequently found to be regulated by various stress conditions. During cardiac surgery and cardiopulmonary bypass (CPB), the host is subjected to hypothermia and inadequate organ perfusion, resulting in an upregulation of CIRP secretion. The aim of this study is to evaluate the role of elevated extracellular CIRP level as a contributing factor in the development of AKI. Methods A total of 292 patients who underwent cardiac surgery were retrospectively enrolled and their serum samples were collected preoperative and postoperative. Demographic data, intraoperative data, in-hospital outcomes, and the occurrence of AKI were also collected for the patients. The correlation between CIRP and intraoperative procedures, as well as its association with postoperative outcomes were analyzed. Results In multivariable analysis, higher ΔCIRP (p = 0.036) and body mass index (p = 0.015) were independent risk factors for postoperative AKI. Meanwhile, patients with postoperative AKI exhibited lower survival rate in 2-year follow-up (p = 0.008). Compared to off-pump coronary artery bypass grafting surgery, patients who underwent on-pump coronary artery bypass grafting, valve surgery, aortic dissection and other surgery showed higher ΔCIRP, measuring 1,093, 666, 914 and 258 pg/mL, respectively (p < 0.001). The levels of ΔCIRP were significantly higher in patients who underwent CPB compared to those who did not (793.0 ± 648.7 vs. 149.5 ± 289.1 pg/mL, p < 0.001). Correlation analysis revealed a positive correlation between ΔCIRP levels and the duration of CPB (r = 0.502, p < 0.001). Patients with higher CIRP levels are at greater risk of postoperative AKI (OR: 1.67, p = 0.032), especially the stage 2-3 AKI (OR: 2.11, p = 0.037). Conclusion CIRP secretion increases with prolonged CPB time after cardiac surgery, and CIRP secretion is positively correlated with the duration of CPB. Cardiac surgeries with CPB exhibited significantly higher levels of CIRP compared to non-CPB surgeries. Elevation of CIRP level is an independent risk factor for the incidence of AKI, especially the severe AKI, and were associated with adverse in-hospital outcomes.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Xinglong Zheng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, Shaanxi, China
| |
Collapse
|
|
21
|
Corre M, Boehm V, Besic V, Kurowska A, Viry A, Mohammad A, Sénamaud-Beaufort C, Thomas-Chollier M, Lebreton A. Alternative splicing induced by bacterial pore-forming toxins sharpens CIRBP-mediated cell response to Listeria infection. Nucleic Acids Res 2023; 51:12459-12475. [PMID: 37941135 PMCID: PMC10711537 DOI: 10.1093/nar/gkad1033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 10/09/2023] [Accepted: 10/20/2023] [Indexed: 11/10/2023] Open
Abstract
Cell autonomous responses to intracellular bacteria largely depend on reorganization of gene expression. To gain isoform-level resolution of these modes of regulation, we combined long- and short-read transcriptomic analyses of the response of intestinal epithelial cells to infection by the foodborne pathogen Listeria monocytogenes. Among the most striking isoform-based types of regulation, expression of the cellular stress response regulator CIRBP (cold-inducible RNA-binding protein) and of several SRSFs (serine/arginine-rich splicing factors) switched from canonical transcripts to nonsense-mediated decay-sensitive isoforms by inclusion of 'poison exons'. We showed that damage to host cell membranes caused by bacterial pore-forming toxins (listeriolysin O, perfringolysin, streptolysin or aerolysin) led to the dephosphorylation of SRSFs via the inhibition of the kinase activity of CLK1, thereby driving CIRBP alternative splicing. CIRBP isoform usage was found to have consequences on infection, since selective repression of canonical CIRBP reduced intracellular bacterial load while that of the poison exon-containing isoform exacerbated it. Consistently, CIRBP-bound mRNAs were shifted towards stress-relevant transcripts in infected cells, with increased mRNA levels or reduced translation efficiency for some targets. Our results thus generalize the alternative splicing of CIRBP and SRSFs as a common response to biotic or abiotic stresses by extending its relevance to the context of bacterial infection.
Collapse
Affiliation(s)
- Morgane Corre
- Group Bacterial infection, response & dynamics, Institut de biologie de l’ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France
| | - Volker Boehm
- Institute for Genetics, University of Cologne, 50674 Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
| | - Vinko Besic
- Group Bacterial infection, response & dynamics, Institut de biologie de l’ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France
| | - Anna Kurowska
- Group Bacterial infection, response & dynamics, Institut de biologie de l’ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France
| | - Anouk Viry
- Group Bacterial infection, response & dynamics, Institut de biologie de l’ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France
| | - Ammara Mohammad
- GenomiqueENS, Institut de Biologie de l’ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France
| | - Catherine Sénamaud-Beaufort
- GenomiqueENS, Institut de Biologie de l’ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France
| | - Morgane Thomas-Chollier
- Group Bacterial infection, response & dynamics, Institut de biologie de l’ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France
- GenomiqueENS, Institut de Biologie de l’ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France
| | - Alice Lebreton
- Group Bacterial infection, response & dynamics, Institut de biologie de l’ENS (IBENS), École normale supérieure, CNRS, INSERM, Université PSL, 75005 Paris, France
- INRAE, Micalis Institute, 78350 Jouy-en-Josas, France
| |
Collapse
|
|
22
|
Li W, Li X, Gao Y, Xiong C, Tang Z. Emerging roles of RNA binding proteins in intervertebral disc degeneration and osteoarthritis. Orthop Surg 2023; 15:3015-3025. [PMID: 37803912 PMCID: PMC10694020 DOI: 10.1111/os.13851] [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: 03/02/2023] [Revised: 07/06/2023] [Accepted: 07/19/2023] [Indexed: 10/08/2023] Open
Abstract
The etiology of intervertebral disc degeneration (IDD) and osteoarthritis (OA) is complex and multifactorial. Both predisposing genes and environmental factors are involved in the pathogenesis of IDD and OA. Moreover, epigenetic modifications affect the development of IDD and OA. Dysregulated phenotypes of nucleus pulposus (NP) cells and OA chondrocytes, including apoptosis, extracellular matrix disruption, inflammation, and angiogenesis, are involved at all developmental stages of IDD and OA. RNA binding proteins (RBPs) have recently been recognized as essential post-transcriptional regulators of gene expression. RBPs are implicated in many cellular processes, such as proliferation, differentiation, and apoptosis. Recently, several RBPs have been reported to be associated with the pathogenesis of IDD and OA. This review briefly summarizes the current knowledge on the RNA-regulatory networks controlled by RBPs and their potential roles in the pathogenesis of IDD and OA. These initial findings support the idea that specific modulation of RBPs represents a promising approach for managing IDD and OA.
Collapse
Affiliation(s)
- Wen Li
- Department of EmergencyGeneral Hospital of Central Theater Command of PLAWuhanChina
| | - Xing‐Hua Li
- Department of EmergencyGeneral Hospital of Central Theater Command of PLAWuhanChina
| | - Yang Gao
- Department of OrthopaedicGeneral Hospital of Central Theater Command of PLAWuhanChina
| | - Cheng‐Jie Xiong
- Department of OrthopaedicGeneral Hospital of Central Theater Command of PLAWuhanChina
| | - Zhong‐Zhi Tang
- Department of EmergencyGeneral Hospital of Central Theater Command of PLAWuhanChina
| |
Collapse
|
|
23
|
Liu A, Zhang Y, Xun S, Zhou G, Hu J, Liu Y. Targeting of cold-inducible RNA-binding protein alleviates sepsis via alleviating inflammation, apoptosis and oxidative stress in heart. Int Immunopharmacol 2023; 122:110499. [PMID: 37392569 DOI: 10.1016/j.intimp.2023.110499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/05/2023] [Accepted: 06/11/2023] [Indexed: 07/03/2023]
Abstract
A systemic inflammatory response is observed in patients undergoing shock and sepsis. This study aimed to explore the effects of cold-inducible RNA-binding protein (CIRP) on sepsis-associated cardiac dysfunction and the underlying mechanism. In vivo and in vitro lipopolysaccharide (LPS)-induced sepsis models were established in mice and neonatal rat cardiomyocytes (NRCMs), respectively. CRIP expressions were increased in the mouse heart and NRCMs treated with LPS. CIRP knockdown alleviated LPS-induced decreases of left ventricular ejection fraction and fractional shortening. CIRP downregulation attenuated the increases of inflammatory factors in the LPS-induced septic mouse heart, and NRCMs. The enhanced oxidative stress in the LPS-induced septic mouse heart and NRCMs was suppressed after CIRP knockdown. By contrast, CIRP overexpression yielded the opposite results. Our current study indicates that the knockdown of CIRP protects against sepsis-induced cardiac dysfunction through alleviating inflammation, apoptosis and oxidative stress of cardiomyocytes.
Collapse
Affiliation(s)
- Aijun Liu
- Department of Cardiology, Binhai People's Hospital, Yancheng 224500, China.
| | - Yonglin Zhang
- Department of Cardiology, Binhai People's Hospital, Yancheng 224500, China
| | - Shucan Xun
- Department of Cardiology, Binhai People's Hospital, Yancheng 224500, China
| | - Guangzhi Zhou
- Department of Cardiology, Binhai People's Hospital, Yancheng 224500, China
| | - Jing Hu
- Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Yun Liu
- Department of Intensive Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| |
Collapse
|
|
24
|
Moftah NH, Alnos H, Rashed L, Hamdino M. Evaluation of serum and tissue levels of cold-inducible RNA-binding protein in non-segmental Vitiligo. Arch Dermatol Res 2023; 315:2065-2071. [PMID: 36920542 PMCID: PMC10366246 DOI: 10.1007/s00403-023-02586-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/12/2023] [Accepted: 02/16/2023] [Indexed: 03/16/2023]
Abstract
Damage-associated molecular patterns (DAMPs) play a role in the pathogenesis of vitiligo. It has been established that the cold-inducible RNA-binding protein (CIRP), a member of the family of cold-shock proteins that respond to stress, is a DAMP molecule that promotes inflammation. The objective was to evaluate the serum and tissue CIRP expression in non-segmental vitiligo (NSV) patients. A sample of 40 participants, 20 NSV patients and 20 control groups of age- and sex-matched healthy individuals were included in this case-control study where the enzyme-linked immunosorbent assay was used in detecting the serum and tissue CIRP levels in participants. The serum and tissue CIRP levels significantly increased in NSV patients compared with the healthy controls, (165.35 ± 24.42, 226.29 ± 24.00 versus 59.81 ± 12.10, 105.86 ± 11.27 pg/ml, respectively) (P < 0.01). Serum and tissue CIRP are significantly correlated with each other (r = 0.641, P = 0.002). Except for a statistically significant positive correlation between CIRP tissue level and VASI (r = 0.539, P = 0.014), the CIRP Serum and tissue did not show any statistically significant correlations with different clinical parameters in patients. ROC curve shows that the cut-off point for serum and tissue CIRP level to differentiate between patients and controls was 86.5, 124.3 pg/ml, respectively, with 100.0% sensitivity, 100.0% specificity and 1.000 AUC for each of them. It is concluded that CIRP may have a crucial role in the pathogenesis of NSV and could be used as a marker for vitiligo and its extent with the need for further large-scale study.
Collapse
Affiliation(s)
- Nayera Hassan Moftah
- Dermatology and Venereology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt.
| | - Huda Alnos
- Dermatology and Venereology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| | - Laila Rashed
- Biochemistry Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mervat Hamdino
- Dermatology and Venereology Department, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt
| |
Collapse
|
|
25
|
Sadowska-Bartosz I, Bartosz G. Antioxidant defense of Deinococcus radiodurans: how does it contribute to extreme radiation resistance? Int J Radiat Biol 2023; 99:1803-1829. [PMID: 37498212 DOI: 10.1080/09553002.2023.2241895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 06/28/2023] [Accepted: 07/08/2023] [Indexed: 07/28/2023]
Abstract
PURPOSE Deinococcus radiodurans is an extremely radioresistant bacterium characterized by D10 of 10 kGy, and able to grow luxuriantly under chronic ionizing radiation of 60 Gy/h. The aim of this article is to review the antioxidant system of D. radiodurans and its possible role in the unusual resistance of this bacterium to ionizing radiation. CONCLUSIONS The unusual radiation resistance of D. radiodurans has apparently evolved as a side effect of the adaptation of this extremophile to other damaging environmental factors, especially desiccation. The antioxidant proteins and low-molecular antioxidants (especially low-molecular weight Mn2+ complexes and carotenoids, in particular, deinoxanthin), as well as protein and non-protein regulators, are important for the antioxidant defense of this species. Antioxidant protection of proteins from radiation inactivation enables the repair of DNA damage caused by ionizing radiation.
Collapse
Affiliation(s)
- Izabela Sadowska-Bartosz
- Laboratory of Analytical Biochemistry, Institute of Food Technology and Nutrition, College of Natural Sciences, University of Rzeszow, Rzeszow, Poland
| | - Grzegorz Bartosz
- Department of Bioenergetics, Food Analysis and Microbiology, Institute of Food Technology and Nutrition, College of Natural Sciences, University of Rzeszow, Rzeszow, Poland
| |
Collapse
|
|
26
|
Haniffa S, Narain P, Hughes MA, Petković A, Šušić M, Mlambo V, Chaudhury D. Chronic social stress blunts core body temperature and molecular rhythms of Rbm3 and Cirbp in mouse lateral habenula. Open Biol 2023; 13:220380. [PMID: 37463657 PMCID: PMC10353891 DOI: 10.1098/rsob.220380] [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: 12/26/2022] [Accepted: 06/29/2023] [Indexed: 07/19/2023] Open
Abstract
Chronic social stress in mice causes behavioural and physiological changes that result in perturbed rhythms of body temperature, activity and sleep-wake cycle. To further understand the link between mood disorders and temperature rhythmicity in mice that are resilient or susceptible to stress, we measured core body temperature (Tcore) before and after exposure to chronic social defeat stress (CSDS). We found that Tcore amplitudes of stress-resilient and susceptible mice are dampened during exposure to CSDS. However, following CSDS, resilient mice recovered temperature amplitude faster than susceptible mice. Furthermore, the interdaily stability (IS) of temperature rhythms was fragmented in stress-exposed mice during CSDS, which recovered to control levels following stress. There were minimal changes in locomotor activity after stress exposure which correlates with regular rhythmic expression of Prok2 - an output signal of the suprachiasmatic nucleus. We also determined that expression of thermosensitive genes Rbm3 and Cirbp in the lateral habenula (LHb) were blunted 1 day after CSDS. Rhythmic expression of these genes recovered 10 days later. Overall, we show that CSDS blunts Tcore and thermosensitive gene rhythms. Tcore rhythm recovery is faster in stress-resilient mice, but Rbm3 and Cirbp recovery is uniform across the phenotypes.
Collapse
Affiliation(s)
- Salma Haniffa
- Department of Biology, Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Priyam Narain
- Centre for Genomics and Systems Biology (CGSB), New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Michelle Ann Hughes
- Department of Biology, Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Aleksa Petković
- Department of Biology, Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Marko Šušić
- Department of Biology, Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Vongai Mlambo
- Department of Biology, Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Dipesh Chaudhury
- Department of Biology, Science Division, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
| |
Collapse
|
|
27
|
Wu J, Li G, Guo H, Huang B, Li G, Dai S. Acute cold stress induces intestinal injury via CIRP-TLR4-IRE1 signaling pathway in pre-starter broilers. Mol Biol Rep 2023:10.1007/s11033-023-08487-1. [PMID: 37253919 DOI: 10.1007/s11033-023-08487-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 04/26/2023] [Indexed: 06/01/2023]
Abstract
BACKGROUND Cold stress is a common environmental stress in broiler chicks. Cold-inducible RNA-binding protein (CIRP) is a conserved cold shock protein that can regulate inflammatory response through Toll-like receptor 4 (TLR4). The mechanism that how CIRP involves in the regulation of cold stress in broilers remains unclear. METHODS AND RESULTS In this study, 360 7-day-old healthy male SZ901 chicks were selected and randomly allocated to four groups, and then subjected to acute cold exposure at the ambient temperature of 12 ± 1 °C for 0 h, 4 h, 8 h, and 12 h, respectively. After cold exposure, abdominall skin temperature, gene expression of CIRP-TLR4-IRE1 signaling pathway in ileum mucosa, and small intestinal structure were measured. The results showed that cold exposure decreased abdominall skin temperature, upregulated the gene expression of endoplasmic reticulum stress (ERS) markers IRE1, inflammatory factors IL-1β, IL-6, IL-10, TNF-α, and tight junction proteins ZO-1 and Occludin in ileum of chicks compared with the control group with no (0 h) cold exposure. Compared with the control group, a long time cold exposure upregulated the gene expression of CIRP, TLR4, GRP78, NF-κB in ileum mucosa, and decreased the villus height and V/C of small intestine. CONCLUSIONS The above results suggest that acute cold stress induces endoplasmic reticulum stress via upregulating the gene expression of CIRP-TLR4-IRE1 signaling pathway, and results in the structural damage of chick intestine.
Collapse
Affiliation(s)
- Juanjuan Wu
- College of Animal Science and Technology, Jiangxi Agriculture University, Nanchang, 330045, Jiangxi, China
| | - Guiyao Li
- College of Animal Science and Technology, Jiangxi Agriculture University, Nanchang, 330045, Jiangxi, China
| | - Haoneng Guo
- College of Animal Science and Technology, Jiangxi Agriculture University, Nanchang, 330045, Jiangxi, China
| | - Bo Huang
- Department of Pharmaceutical and Life Sciences, Jiujiang University, Jiujiang, 332005, Jiangxi, China
| | - Guanhong Li
- College of Animal Science and Technology, Jiangxi Agriculture University, Nanchang, 330045, Jiangxi, China
| | - Sifa Dai
- Department of Pharmaceutical and Life Sciences, Jiujiang University, Jiujiang, 332005, Jiangxi, China.
- Jiujiang Bozheng Institute of Biotechnology Industry, Jiujiang, 332005, Jiangxi, China.
| |
Collapse
|
|
28
|
Zhang P, Bai L, Tong Y, Guo S, Lu W, Yuan Y, Wang W, Jin Y, Gao P, Liu J. CIRP attenuates acute kidney injury after hypothermic cardiovascular surgery by inhibiting PHD3/HIF-1α-mediated ROS-TGF-β1/p38 MAPK activation and mitochondrial apoptotic pathways. Mol Med 2023; 29:61. [PMID: 37127576 PMCID: PMC10152741 DOI: 10.1186/s10020-023-00655-0] [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: 09/12/2022] [Accepted: 04/18/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND The ischemia-reperfusion (IR) environment during deep hypothermic circulatory arrest (DHCA) cardiovascular surgery is a major cause of acute kidney injury (AKI), which lacks preventive measure and treatment. It was reported that cold inducible RNA-binding protein (CIRP) can be induced under hypoxic and hypothermic stress and may have a protective effect on multiple organs. The purpose of this study was to investigate whether CIRP could exert renoprotective effect during hypothermic IR and the potential mechanisms. METHODS Utilizing RNA-sequencing, we compared the differences in gene expression between Cirp knockout rats and wild-type rats after DHCA and screened the possible mechanisms. Then, we established the hypothermic oxygen-glucose deprivation (OGD) model using HK-2 cells transfected with siRNA to verify the downstream pathways and explore potential pharmacological approach. The effects of CIRP and enarodustat (JTZ-951) on renal IR injury (IRI) were investigated in vivo and in vitro using multiple levels of pathological and molecular biological experiments. RESULTS We discovered that Cirp knockout significantly upregulated rat Phd3 expression, which is the key regulator of HIF-1α, thereby inhibiting HIF-1α after DHCA. In addition, deletion of Cirp in rat model promoted apoptosis and aggravated renal injury by reactive oxygen species (ROS) accumulation and significant activation of the TGF-β1/p38 MAPK inflammatory pathway. Then, based on the HK-2 cell model of hypothermic OGD, we found that CIRP silencing significantly stimulated the expression of the TGF-β1/p38 MAPK inflammatory pathway by activating the PHD3/HIF-1α axis, and induced more severe apoptosis through the mitochondrial cytochrome c-Apaf-1-caspase 9 and FADD-caspase 8 death receptor pathways compared with untransfected cells. However, silencing PHD3 remarkably activated the expression of HIF-1α and alleviated the apoptosis of HK-2 cells in hypothermic OGD. On this basis, by pretreating HK-2 and rats with enarodustat, a novel HIF-1α stabilizer, we found that enarodustat significantly mitigated renal cellular apoptosis under hypothermic IR and reversed the aggravated IRI induced by CIRP defect, both in vitro and in vivo. CONCLUSION Our findings indicated that CIRP may confer renoprotection against hypothermic IRI by suppressing PHD3/HIF-1α-mediated apoptosis. PHD3 inhibitors and HIF-1α stabilizers may have clinical value in renal IRI.
Collapse
Affiliation(s)
- Peiyao Zhang
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 102308, China
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Liting Bai
- Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Yuanyuan Tong
- Department of Anesthesiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China
| | - Shengwen Guo
- Department of Anesthesiology, Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, Fujian, 361000, China
| | - Wenlong Lu
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 102308, China
| | - Yue Yuan
- Department of Endocrinology, Drum Tower Hospital affiliated to Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, 210008, China
| | - Wenting Wang
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Yu Jin
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Peng Gao
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China
| | - Jinping Liu
- Department of Cardiopulmonary Bypass, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.167, North Lishi Road, Xicheng District, Beijing, 100037, China.
| |
Collapse
|
|
29
|
Omori I, Sumida H, Sugimori A, Sakakibara M, Urano-Takaoka M, Iwasawa O, Saito H, Matsuno A, Sato S. Serum cold-inducible RNA-binding protein levels as a potential biomarker for systemic sclerosis-associated interstitial lung disease. Sci Rep 2023; 13:5017. [PMID: 36977758 PMCID: PMC10050418 DOI: 10.1038/s41598-023-32231-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
AbstractSystemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrotic, inflammatory, and vascular dysfunction. Danger-associated molecular patterns (DAMPs)-mediated inflammasome activation has been reported to be involved in the pathogenesis of SSc. Cold-inducible RNA-binding protein (CIRP) is newly identified as a DAMP. Here we examined the clinical significance of serum levels of CIRP in 60 patients with SSc and 20 healthy control patients (HCs) using an enzyme-linked immunosorbent assay. Serum CIRP levels in diffuse cutaneous SSc (dcSSc) patients were significantly increased compared with limited cutaneous SSc (lcSSc) patients or HCs. When examining the relationship with SSc-specific parameters, serum CIRP levels with the presence of interstitial lung disease (ILD) were higher than those without ILD. In detail, serum CIRP levels correlated negatively with the percent predicted diffusing capacity for carbon monoxide and positively with levels of Krebs von den Lungen-6. In addition, elevated serum CIRP levels declined along with decreased SSc-ILD activity in patients who received immunosuppressive therapy. These results suggest that CIRP may play a role in the development of ILD in SSc. Moreover, CIRP could serve as a useful serological marker of SSc-ILD in terms of disease activity and therapeutic effects.
Collapse
|
|
30
|
Haniffa S, Narain P, Hughes MA, Petković A, Šušić M, Mlambo V, Chaudhury D. Chronic social stress blunts core body temperature and molecular rhythms of Rbm3and Cirbpin mouse lateral habenula.. [DOI: 10.1101/2023.01.02.522528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/19/2023]
Abstract
AbstractChronic social stress in mice causes behavioral and physiological changes that result in perturbed rhythms of body temperature, activity and sleep-wake cycle. To further understand the link between mood disorders and temperature rhythmicity in mice that are resilient or susceptible to stress, we measured core body temperature (Tcore) before and after exposure to chronic social defeat stress (CSDS). We found that Tcore amplitudes of stress-resilient and susceptible mice are dampened during exposure to CSDS. However, following CSDS, resilient mice recovered temperature amplitude faster than susceptible mice. Furthermore, the interdaily stability (IS) of temperature rhythms was fragmented in stress-exposed mice during CSDS, which recovered to control levels following stress. There were minimal changes in locomotor activity after stress exposure which correlates with regular rhythmic expression ofProk2- an output signal of the suprachiasmatic nucleus. We also determined that expression of thermosensitive genesRbm3andCirbpin the lateral habenula (LHb) were blunted 1-day after CSDS. Rhythmic expression of these genes recovered 10 days later. Overall, we show that CSDS blunts Tcore and thermosensitive gene rhythms. Tcore rhythm recovery is faster in stress-resilient mice, butRbm3andCirbprecovery is uniform across the phenotypes.
Collapse
|
|
31
|
Overexpressed cold inducible RNA-binding protein improves cell viability and EGF expression in glial cells. BMC Mol Cell Biol 2022; 23:58. [PMID: 36526996 PMCID: PMC9756664 DOI: 10.1186/s12860-022-00460-3] [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: 08/04/2022] [Accepted: 12/09/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Cold inducible RNA-binding protein (CIRP) is a key protein in the hypothermic therapy. Highly expressed CIRP exerts a neuroprotective effect on neurons. The aim of this study is to provide the evidence of the protective effects of CIRP on the glial cells and explore the downstream pathway of CIRP. RESULTS The results of this study demonstrated that the cell viability of the glial cells with CIRP overexpression was increased significantly compared to the control. With CIRP overexpression, the epidermal growth factor (EGF) mRNA expression was found increasing significantly and the mRNA expressions of derived neurotrophic factor (BDNF), bcl-2, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) were not upregulated compared to the control. EGF and CIRP co-expression was demonstrated on the glial cells. With CIRP expression, EGF expression on the glial cells was increased statistically compared to the control. CONCLUSION CIRP overexpression increases the cell viability of the glial cells, exerting a neuroprotective effect. EGF expression is activated on the glial cells with CIRP overexpression, implying a pathway of CIRP neuroprotection via EGF activation.
Collapse
|
|
32
|
Liu F, Jiang X, Yang J, Tao J, Zhang M. A chronotherapeutics-applicable multi-target therapeutics based on AI: Example of therapeutic hypothermia. Brief Bioinform 2022; 23:6694809. [PMID: 36088545 PMCID: PMC9487598 DOI: 10.1093/bib/bbac365] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/15/2022] [Accepted: 08/03/2022] [Indexed: 11/24/2022] Open
Abstract
Nowadays, the complexity of disease mechanisms and the inadequacy of single-target therapies in restoring the biological system have inevitably instigated the strategy of multi-target therapeutics with the analysis of each target individually. However, it is not suitable for dealing with the conflicts between targets or between drugs. With the release of high-precision protein structure prediction artificial intelligence, large-scale high-precision protein structure prediction and docking have become possible. In this article, we propose a multi-target drug discovery method by the example of therapeutic hypothermia (TH). First, we performed protein structure prediction for all protein targets of each group by AlphaFold2 and RoseTTAFold. Then, QuickVina 2 is used for molecular docking between the proteins and drugs. After docking, we use PageRank to rank single drugs and drug combinations of each group. The ePharmaLib was used for predicting the side effect targets. Given the differences in the weights of different targets, the method can effectively avoid inhibiting beneficial proteins while inhibiting harmful proteins. So it could minimize the conflicts between different doses and be friendly to chronotherapeutics. Besides, this method also has potential in precision medicine for its high compatibility with bioinformatics and promotes the development of pharmacogenomics and bioinfo-pharmacology.
Collapse
Affiliation(s)
- Fei Liu
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Institute of Emergency Medicine, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
| | - Xiangkang Jiang
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Institute of Emergency Medicine, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
| | - Jingyuan Yang
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Institute of Emergency Medicine, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
| | - Jiawei Tao
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Institute of Emergency Medicine, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
| | - Mao Zhang
- Department of Emergency Medicine, Second Affiliated Hospital of Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Institute of Emergency Medicine, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
- Key Laboratory of The Diagnosis and Treatment of Severe Trauma and Burn of Zhejiang Province, Zhejiang University , Hangzhou 310009, Zhejiang Province, China
| |
Collapse
|
|
33
|
Downregulation of CIRP Prone Cells to Oxidative Injury via Regulating Nrf2 Signaling Pathway. BIOMED RESEARCH INTERNATIONAL 2022; 2022:2416787. [PMID: 35800223 PMCID: PMC9256419 DOI: 10.1155/2022/2416787] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 04/22/2022] [Accepted: 05/06/2022] [Indexed: 12/03/2022]
Abstract
Cold-inducible RNA-binding protein (CIRP) is a cellular stress-response protein, whose expression can be induced by a variety of stress conditions. Our previous study showed that intracellular CIRP is a protective factor against cellular oxidative stress and silencing of CIRP gene prone cells to apoptosis. However, the underlying mechanism remains unknown. The present study was aimed at investigating the possible mechanisms underlying the protective role of CIRP in oxidative stress injury. Herein, we used HEK293T cells as our cell model to investigate the relation between CIRP and the possible antioxidant pathways by using the latest genetic silencing technologies. Our results showed that silencing CIRP by using SaiRNA-based genetic silencing tool leads to the downregulation of Nrf2 and Nrf2-regulated antioxidant genes in HEK293T cells. Taken together, our study identified the antioxidant Nrf2 signaling pathway as a downstream target of CIRP, and silencing CIRP may prone cells to apoptosis by downregulating the Nrf2 antioxidant pathway in response to oxidative injury.
Collapse
|
|
34
|
Ignatz EH, Hori TS, Kumar S, Benfey TJ, Braden LM, Runighan CD, Westcott JD, Rise ML. RNA-Seq Analysis of the Growth Hormone Transgenic Female Triploid Atlantic Salmon (Salmo salar) Hepatic Transcriptome Reveals Broad Temperature-Mediated Effects on Metabolism and Other Biological Processes. Front Genet 2022; 13:852165. [PMID: 35677560 PMCID: PMC9168996 DOI: 10.3389/fgene.2022.852165] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 05/02/2022] [Indexed: 12/13/2022] Open
Abstract
This study examined the impact of rearing temperature (10.5, 13.5 or 16.5°C) on the hepatic transcriptome of AquAdvantage Salmon (growth hormone transgenic female triploid Atlantic salmon) at an average weight of 800 g. Six stranded PE libraries were Illumina-sequenced from each temperature group, resulting in an average of over 100 M raw reads per individual fish. RNA-sequencing (RNA-seq) results showed the greatest difference in the number of differentially expressed transcripts (1750 DETs), as revealed by both DESeq2 and edgeR (q < 0.05; fold-change > |1.5|), was between the 10.5 and 16.5°C temperature groups. In contrast, 172 and 52 DETs were found in the 10.5 vs. 13.5°C and the 13.5 vs. 16.5°C comparisons, respectively. Considering the DETs between the 10.5 and 16.5°C groups, 282 enriched gene ontology (GO) terms were identified (q < 0.05), including “response to stress”, “immune system process”, “lipid metabolic process”, “oxidation-reduction process”, and “cholesterol metabolic process”, suggesting elevated temperature elicited broad effects on multiple biological systems. Pathway analysis using ClueGO showed additional impacts on amino acid and lipid metabolism. There was a significant positive correlation between RNA-seq and real-time quantitative polymerase chain reaction (RT-qPCR) results for 8 of 9 metabolic-related transcripts tested. RT-qPCR results also correlated to changes in fillet tissue composition previously reported in these salmon (e.g., methionine and lysine concentrations positively correlated with hsp90ab1 transcript expression), suggesting that rearing temperature played a significant role in mediating metabolic/biosynthetic pathways of AquAdvantage Salmon. Many transcripts related to lipid/fatty acid metabolism (e.g., elovl2, fabpi, hacd2, mgll, s27a2, thrsp) were downregulated at 16.5°C compared to both other temperature groups. Additionally, enrichment of stress-, apoptosis- and catabolism-relevant GO terms at 16.5°C suggests that this temperature may not be ideal for commercial production when using freshwater recirculating aquaculture systems (RAS). This study relates phenotypic responses to transcript-specific findings and therefore aids in the determination of an optimal rearing temperature for AquAdvantage Salmon. With approval to grow and sell AquAdvantage Salmon in the United States and Canada, the novel insights provided by this research can help industry expansion by promoting optimal physiological performance and health.
Collapse
Affiliation(s)
- Eric H. Ignatz
- Department of Ocean Sciences, Memorial University of Newfoundland and Labrador, St. John’s, NL, Canada
- *Correspondence: Eric H. Ignatz, ; Matthew L. Rise,
| | | | - Surendra Kumar
- Department of Ocean Sciences, Memorial University of Newfoundland and Labrador, St. John’s, NL, Canada
| | - Tillmann J. Benfey
- Department of Biology, University of New Brunswick, Fredericton, NB, Canada
| | - Laura M. Braden
- AquaBounty Canada, Inc., Souris, PE, Canada
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE, Canada
| | | | - Jillian D. Westcott
- Fisheries and Marine Institute, Memorial University of Newfoundland and Labrador, St. John’s, NL, Canada
| | - Matthew L. Rise
- Department of Ocean Sciences, Memorial University of Newfoundland and Labrador, St. John’s, NL, Canada
- *Correspondence: Eric H. Ignatz, ; Matthew L. Rise,
| |
Collapse
|
|
35
|
Gardela J, Ruiz-Conca M, García-Sanmartín J, Martínez A, Mogas T, López-Béjar M, Álvarez-Rodríguez M. Mild hypothermia and vitrification increase the mRNA expression of cold-inducible proteins in bovine oocytes and cumulus cells. Theriogenology 2022; 185:16-23. [DOI: 10.1016/j.theriogenology.2022.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 03/09/2022] [Accepted: 03/11/2022] [Indexed: 12/01/2022]
|
|
36
|
Bazid H, Shoeib M, Elsayed A, Mostafa M, Shoeib M, El Gayed EMA, Abdallah R. Expression of cold-inducible RNA binding protein in psoriasis. J Immunoassay Immunochem 2022; 43:384-402. [DOI: 10.1080/15321819.2022.2039183] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- Heba Bazid
- Dermatology and Andrology Department, Faculty of Medicine, Menoufia University
| | - Mohamed Shoeib
- Clinical Pathology Department, National Research Center, Cairo, Egypt
| | - Asmaa Elsayed
- Dermatology and Andrology Department, National Research Center, Cairo, Egypt
| | - Mohammed Mostafa
- Medical Biochemistry Depaetment, Faculty of Medicine, Menoufia University
| | - May Shoeib
- Pathology Department, Faculty of Medicine, Menoufia University
| | | | | |
Collapse
|
|
37
|
Borjas T, Jacob A, Yen H, Patel V, Coppa G, Aziz M, Wang P. Inhibition of the Interaction of TREM-1 and eCIRP Attenuates Inflammation and Improves Survival in Hepatic Ischemia/Reperfusion. Shock 2022; 57:246-255. [PMID: 34864782 PMCID: PMC8758526 DOI: 10.1097/shk.0000000000001894] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Triggering receptor expressed on myeloid cells-1 (TREM-1) has important implications in sepsis and inflammation and is a novel receptor for extracellular cold-inducible RNA-binding protein (eCIRP). We hypothesize that the inhibition of TREM-1 via its interaction with eCIRP by novel peptide inhibitor M3 or knockout gene will attenuate the inflammation and injury associated with severe hepatic ischemia/reperfusion (I/R). METHODS Wild-type (WT) C57BL/6 and TREM-1-/- mice underwent 60 min of 70% hepatic ischemia, with 24 h of reperfusion. Additionally, WT mice underwent hepatic I/R and were treated with M3 (10 mg/kg body weight) or vehicle (normal saline) at the start of reperfusion. Blood and ischemic liver tissues were collected, and analysis was performed using enzymatic assays, enzyme-linked immunosorbent assay, reverse-transcription quantitative polymerase chain reaction, and pathohistology techniques. For survival surgery, mice additionally underwent resection of non-ischemic lobes of the liver and survival was monitored for 10 days. RESULTS There was an increase in serum levels of tissue markers including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase as well as cytokine levels (IL-6) and histological scoring of hematoxylin and eosin sections in WT I/R mice. These markers decreased substantially in TREM-1-/- mice. Additionally, neutrophil infiltration markers and markers of local inflammation (myeloperoxidase, macrophage inflammatory protein-2, cyclooxygenase-2) were attenuated in TREM-1-/- mice. Similarly, we show a significant decrease in injury and inflammation markers with M3 treatment. Additionally, we demonstrate decreased apoptosis with TREM-1 inhibition. Finally, M3 treatment improved the survival rate from 42% to 75% after hepatic I/R. CONCLUSION TREM-1 is an important eCIRP receptor in the inflammatory response of hepatic I/R, and deficiency of TREM-1 via knockout gene or peptide inhibition attenuated liver injury and inflammation, and improved survival. Inhibition of the TREM-1 and eCIRP interaction in hepatic I/R may have important therapeutic potential.
Collapse
Affiliation(s)
- Timothy Borjas
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Asha Jacob
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - HaoTing Yen
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Vihas Patel
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
| | - Gene Coppa
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
| | - Monowar Aziz
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| | - Ping Wang
- Department of Surgery, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY
| |
Collapse
|
|
38
|
Dynamic alternative polyadenylation during iPSC differentiation into cardiomyocytes. Comput Struct Biotechnol J 2022; 20:5859-5869. [DOI: 10.1016/j.csbj.2022.10.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 10/18/2022] [Accepted: 10/18/2022] [Indexed: 11/20/2022] Open
|
|
39
|
Becskei A, Rahaman S. The life and death of RNA across temperatures. Comput Struct Biotechnol J 2022; 20:4325-4336. [PMID: 36051884 PMCID: PMC9411577 DOI: 10.1016/j.csbj.2022.08.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/04/2022] [Accepted: 08/04/2022] [Indexed: 11/05/2022] Open
Abstract
Temperature is an environmental condition that has a pervasive effect on cells along with all the molecules and reactions in them. The mechanisms by which prototypical RNA molecules sense and withstand heat have been identified mostly in bacteria and archaea. The relevance of these phenomena is, however, broader, and similar mechanisms have been recently found throughout the tree of life, from sex determination in reptiles to adaptation of viral RNA polymerases, to genetic disorders in humans. We illustrate the temperature dependence of RNA metabolism with examples from the synthesis to the degradation of mRNAs, and review recently emerged questions. Are cells exposed to greater temperature variations and gradients than previously surmised? How do cells reconcile the conflicting thermal stability requirements of primary and tertiary structures of RNAs? To what extent do enzymes contribute to the temperature compensation of the reaction rates in mRNA turnover by lowering the energy barrier of the catalyzed reactions? We conclude with the ecological, forensic applications of the temperature-dependence of RNA degradation and the biotechnological aspects of mRNA vaccine production.
Collapse
|
|
40
|
Nissa MU, Pinto N, Mukherjee A, Reddy PJ, Ghosh B, Sun Z, Ghantasala S, Chetanya C, Shenoy SV, Moritz RL, Goswami M, Srivastava S. Organ-Based Proteome and Post-Translational Modification Profiling of a Widely Cultivated Tropical Water Fish, Labeo rohita. J Proteome Res 2021; 21:420-437. [PMID: 34962809 DOI: 10.1021/acs.jproteome.1c00759] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Proteomics has enormous applications in human and animal research. However, proteomic studies in fisheries science are quite scanty particularly for economically important species. Few proteomic studies have been carried out in model fish species, but comprehensive proteomics of aquaculture species are still scarce. This study aimed to perform a comprehensive organ-based protein profiling of important tissue samples for one of the most important aquaculture species,Labeo rohita.Deep proteomic profiling of 17 histologically normal tissues, blood plasma, and embryo provided mass-spectrometric evidence for 8498 proteins at 1% false discovery rate that make up about 26% of the total annotated protein-coding sequences in Rohu. Tissue-wise expression analysis was performed, and the presence of several biologically important proteins was also verified using a targeted proteomic approach. We identified the global post-translational modifications (PTMs) in terms of acetylation (N-terminus and lysine), methylation (N-terminus, lysine, and arginine), and phosphorylation (serine, threonine, and tyrosine) to present a comprehensive proteome resource. An interactive web-based portal has been developed for an overall landscape of protein expression across the studied tissues of Labeo rohita (www.fishprot.org). This draft proteome map of Labeo rohita would advance basic and applied research in aquaculture to meet the most critical challenge of providing food and nutritional security to an increasing world population.
Collapse
Affiliation(s)
- Mehar Un Nissa
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Nevil Pinto
- Central Institute of Fisheries Education, Indian Council of Agricultural Research, Versova, Mumbai, Maharashtra 400061, India
| | - Arijit Mukherjee
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | | | - Biplab Ghosh
- Regional Centre for Biotechnology, Faridabad 121001, India
| | - Zhi Sun
- Institute for Systems Biology, Seattle, Washington 98109, United States
| | - Saicharan Ghantasala
- Centre for Research in Nanotechnology and Science, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Chetanya Chetanya
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Sanjyot Vinayak Shenoy
- Department of Mathematics, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Robert L Moritz
- Institute for Systems Biology, Seattle, Washington 98109, United States
| | - Mukunda Goswami
- Central Institute of Fisheries Education, Indian Council of Agricultural Research, Versova, Mumbai, Maharashtra 400061, India
| | - Sanjeeva Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| |
Collapse
|
|
41
|
Zhong P, Zhou M, Zhang J, Peng J, Zeng G, Huang H. The role of Cold-Inducible RNA-binding protein in respiratory diseases. J Cell Mol Med 2021; 26:957-965. [PMID: 34953031 PMCID: PMC8831972 DOI: 10.1111/jcmm.17142] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/25/2021] [Accepted: 12/09/2021] [Indexed: 12/28/2022] Open
Abstract
Cold‐inducible RNA‐binding protein (CIRP) is a stress‐response protein that is expressed in various types of cells and acts as an RNA chaperone, modifying the stability of its targeted mRNA. Intracellular CIRP could also be released into extracellular space and once released, extracellular CIRP (eCIRP) acts as a damage‐associated molecular pattern (DAMP) to induce and amplify inflammation. Recent studies have found that eCIRP could promote acute lung injury (ALI) via activation of macrophages, neutrophils, pneumocytes and lung vascular endothelial cells in context of sepsis, haemorrhagic shock, intestinal ischemia/reperfusion injury and severe acute pancreatitis. In addition, CIRP is also highly expressed in the bronchial epithelial cells and its expression is upregulated in the bronchial epithelial cells of patients with chronic obstructive pulmonary diseases (COPD) and rat models with chronic bronchitis. CIRP is a key contributing factor in the cold‐induced exacerbation of COPD by promoting the expression of inflammatory genes and hypersecretion of airway mucus in the bronchial epithelial cells. Besides, CIRP is also involved in regulating pulmonary fibrosis, as eCIRP could directly activate and induce an inflammatory phenotype in pulmonary fibroblast. This review summarizes the findings of CIRP investigation in respiratory diseases and the underlying molecular mechanisms.
Collapse
Affiliation(s)
- Peng Zhong
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, China.,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Miao Zhou
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jingjing Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, China.,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Jianye Peng
- The Second Affiliated Hospital, Department of Cardiovascular Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, Hengyang, Hunan, China.,Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, Hengyang, Hunan, China
| | - Gaofeng Zeng
- The Second Affiliated Hospital, Department of Cardiovascular Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China.,Key Laboratory of Heart Failure Prevention & Treatment of Hengyang, Hengyang, Hunan, China.,Clinical Medicine Research Center of Arteriosclerotic Disease of Hunan Province, Hengyang, Hunan, China
| | - He Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.,Cardiovascular Research Institute of Wuhan University, Wuhan, Hubei, China.,Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| |
Collapse
|
|
42
|
Zhang W, Wang Y, Li C, Xu Y, Wang X, Wu D, Gao Z, Qian H, You Z, Zhang Z, He B, Wang G. Extracellular CIRP-Impaired Rab26 Restrains EPOR-Mediated Macrophage Polarization in Acute Lung Injury. Front Immunol 2021; 12:768435. [PMID: 34925338 PMCID: PMC8671298 DOI: 10.3389/fimmu.2021.768435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/09/2021] [Indexed: 12/31/2022] Open
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a condition with an imbalanced inflammatory response and delayed resolution of inflammation. Macrophage polarization plays an important role in inflammation and resolution. However, the mechanism of macrophage polarization in ALI/ARDS is not fully understood. We found that mice with lipopolysaccharide administration developed lung injury with the accumulation of extracellular cold-inducible RNA-binding protein (eCIRP) in the lungs. eCIRP, as a damage-associated molecular pattern (DAMP), inhibited M2 macrophage polarization, thereby tipping the balance toward inflammation rather than resolution. Anti-CIRP antibodies reversed such phenotypes. The levels of macrophage erythropoietin (EPO) receptor (EPOR) were reduced after eCIRP treatment. Myeloid-specific EPOR-deficient mice displayed restrained M2 macrophage polarization and impaired inflammation resolution. Mechanistically, eCIRP impaired Rab26, a member of Ras superfamilies of small G proteins, and reduced the transportation of surface EPOR, which resulted in macrophage polarization toward the M1 phenotype. Moreover, EPO treatment hardly promotes M2 polarization in Rab26 knockout (KO) macrophages through EPOR. Collectively, macrophage EPOR signaling is impaired by eCIRP through Rab26 during ALI/ARDS, leading to the restrained M2 macrophage polarization and delayed inflammation resolution. These findings identify a mechanism of persistent inflammation and a potential therapy during ALI/ARDS.
Collapse
Affiliation(s)
- Wen Zhang
- Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Yao Wang
- Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Chuanwei Li
- Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Yu Xu
- Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Xia Wang
- Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Di Wu
- Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Zhan Gao
- Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Hang Qian
- Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Zaichun You
- Department of General Practice, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Zhiren Zhang
- Institute of Immunology, Third Military Medical University, Chongqing, China
| | - Binfeng He
- Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China.,Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Guansong Wang
- Institute of Respiratory Diseases, Department of Pulmonary and Critical Care Medicine, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| |
Collapse
|
|
43
|
Arteriogenesis and Therapeutic Angiogenesis-An Update. Int J Mol Sci 2021; 22:ijms222413244. [PMID: 34948041 PMCID: PMC8709312 DOI: 10.3390/ijms222413244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 12/06/2021] [Indexed: 11/17/2022] Open
Abstract
Vascular occlusive diseases such myocardial infarction, peripheral artery disease of the lower extremities, or stroke still represent a substantial health burden worldwide [...].
Collapse
|
|
44
|
Murao A, Tan C, Jha A, Wang P, Aziz M. Exosome-Mediated eCIRP Release From Macrophages to Induce Inflammation in Sepsis. Front Pharmacol 2021; 12:791648. [PMID: 34938194 PMCID: PMC8687456 DOI: 10.3389/fphar.2021.791648] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular cold-inducible RNA-binding protein (eCIRP) is an important damage-associated molecular pattern (DAMP). Despite our understanding of the potentially harmful effects of eCIRP in sepsis, how eCIRP is released from cells remains elusive. Exosomes are endosome-derived extracellular vesicles, which carry proteins, lipids, and nucleic acids to facilitate intercellular communication and several extracellular functions. We hypothesized that eCIRP is released via exosomes to induce inflammation in sepsis. Exosomes isolated from the supernatants of LPS-treated macrophage culture and serum of endotoxemia and polymicrobial sepsis mice showed high purity, as revealed by their unique median sizes ranging between 70 and 126 nm in diameter. eCIRP levels of the exosomes were significantly increased after LPS treatment in the supernatants of macrophage culture, mouse serum, and cecal ligation and puncture (CLP)-induced sepsis mouse serum. Protease protection assay demonstrated the majority of eCIRP was present on the surface of exosomes. Treatment of WT macrophages and mice with exosomes isolated from LPS-treated WT mice serum increased TNFα and IL-6 production. However, treatment with CIRP-/- mice serum exosomes significantly decreased these levels compared with WT exosome-treated conditions. CIRP-/- mice serum exosomes significantly decreased neutrophil migration in vitro compared with WT exosomes. Treatment of mice with serum exosomes isolated from CIRP-/- mice significantly reduced neutrophil infiltration into the peritoneal cavity. Our data suggest that eCIRP can be released via exosomes to induce cytokine production and neutrophil migration. Thus, exosomal eCIRP could be a potential target to inhibit inflammation.
Collapse
Affiliation(s)
- Atsushi Murao
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Chuyi Tan
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Alok Jha
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States
- Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, United States
| |
Collapse
|
|
45
|
Bugg WS, Yoon GR, Brandt C, Earhart ML, Anderson WG, Jeffries KM. The effects of population and thermal acclimation on the growth, condition and cold responsive mRNA expression of age-0 lake sturgeon (Acipenser fulvescens). JOURNAL OF FISH BIOLOGY 2021; 99:1912-1927. [PMID: 34476812 DOI: 10.1111/jfb.14897] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/02/2021] [Accepted: 08/30/2021] [Indexed: 06/13/2023]
Abstract
In Manitoba, Canada, wild lake sturgeon (Acipenser fulvescens) populations exist along a latitudinal gradient and are reared in hatcheries to bolster threatened populations. We reared two populations of lake sturgeon, one from each of the northern and southern ends of Manitoba and examined the effects of typical hatchery temperatures (16°C) as well as 60-day acclimation to elevated rearing temperatures (20°C) on mortality, growth and condition throughout early development. Additionally, we examined the cold shock response, which may be induced during stocking, through the hepatic mRNA expression of genes involved in the response to cold stress and homeoviscous adaptation (HSP70, HSP90a, HSP90b, CIRP and SCD). Sturgeon were sampled after 1 day and 1 week following stocking into temperatures of 8, 6 and 4°C in a controlled laboratory environment. The southern population showed lower condition and higher mortality during early life than the northern population while increased rearing temperature impacted the growth and condition of developing northern sturgeon. During the cold shock, HSP70 and HSP90a mRNA expression increased in all sturgeon treatments as stocking temperature decreased, with higher expression observed in the southern population. Expression of HSP90b, CIRP and SCD increased as stocking temperature decreased in northern sturgeon with early acclimation to 20°C. Correlation analyses indicated the strongest molecular relationships were in the expression of HSP90b, CIRP and SCD, across all treatments, with a correlation between HSP90b and body condition in northern sturgeon with early acclimation to 20°C. Together, these observations highlight the importance of population and rearing environment throughout early development and on later cellular responses induced by cold stocking temperatures.
Collapse
Affiliation(s)
- William S Bugg
- Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Gwangseok R Yoon
- Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Catherine Brandt
- Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- North/South Consultants Inc., Winnipeg, Manitoba, Canada
| | - Madison L Earhart
- Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada
| | - W Gary Anderson
- Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ken M Jeffries
- Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| |
Collapse
|
|
46
|
Cold-Inducible RNA-Binding Protein but Not Its Antisense lncRNA Is a Direct Negative Regulator of Angiogenesis In Vitro and In Vivo via Regulation of the 14q32 angiomiRs-microRNA-329-3p and microRNA-495-3p. Int J Mol Sci 2021; 22:ijms222312678. [PMID: 34884485 PMCID: PMC8657689 DOI: 10.3390/ijms222312678] [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: 09/27/2021] [Revised: 11/04/2021] [Accepted: 11/20/2021] [Indexed: 12/14/2022] Open
Abstract
Inhibition of the 14q32 microRNAs, miR-329-3p and miR-495-3p, improves post-ischemic neovascularization. Cold-inducible RNA-binding protein (CIRBP) facilitates maturation of these microRNAs. We hypothesized that CIRBP deficiency improves post-ischemic angiogenesis via downregulation of 14q32 microRNA expression. We investigated these regulatory mechanisms both in vitro and in vivo. We induced hindlimb ischemia in Cirp−/− and C57Bl/6-J mice, monitored blood flow recovery with laser Doppler perfusion imaging, and assessed neovascularization via immunohistochemistry. Post-ischemic angiogenesis was enhanced in Cirp−/− mice by 34.3% with no effects on arteriogenesis. In vivo at day 7, miR-329-3p and miR-495-3p expression were downregulated in Cirp−/− mice by 40.6% and 36.2%. In HUVECs, CIRBP expression was upregulated under hypothermia, while miR-329-3p and miR-495-3p expression remained unaffected. siRNA-mediated CIRBP knockdown led to the downregulation of CIRBP-splice-variant-1 (CIRBP-SV1), CIRBP antisense long noncoding RNA (lncRNA-CIRBP-AS1), and miR-495-3p with no effects on the expression of CIRBP-SV2-4 or miR-329-3p. siRNA-mediated CIRBP knockdown improved HUVEC migration and tube formation. SiRNA-mediated lncRNA-CIRBP-AS1 knockdown had similar long-term effects. After short incubation times, however, only CIRBP knockdown affected angiogenesis, indicating that the effects of lncRNA-CIRBP-AS1 knockdown were secondary to CIRBP-SV1 downregulation. CIRBP is a negative regulator of angiogenesis in vitro and in vivo and acts, at least in part, through the regulation of miR-329-3p and miR-495-3p.
Collapse
|
|
47
|
Kübler M, Beck S, Peffenköver LL, Götz P, Ishikawa-Ankerhold H, Preissner KT, Fischer S, Lasch M, Deindl E. The Absence of Extracellular Cold-Inducible RNA-Binding Protein (eCIRP) Promotes Pro-Angiogenic Microenvironmental Conditions and Angiogenesis in Muscle Tissue Ischemia. Int J Mol Sci 2021; 22:ijms22179484. [PMID: 34502391 PMCID: PMC8431021 DOI: 10.3390/ijms22179484] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/27/2021] [Accepted: 08/30/2021] [Indexed: 12/11/2022] Open
Abstract
Extracellular Cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern, is released from cells upon hypoxia and cold-stress. The overall absence of extra- and intracellular CIRP is associated with increased angiogenesis, most likely induced through influencing leukocyte accumulation. The aim of the present study was to specifically characterize the role of eCIRP in ischemia-induced angiogenesis together with the associated leukocyte recruitment. For analyzing eCIRPs impact, we induced muscle ischemia via femoral artery ligation (FAL) in mice in the presence or absence of an anti-CIRP antibody and isolated the gastrocnemius muscle for immunohistological analyses. Upon eCIRP-depletion, mice showed increased capillary/muscle fiber ratio and numbers of proliferating endothelial cells (CD31+/CD45−/BrdU+). This was accompanied by a reduction of total leukocyte count (CD45+), neutrophils (MPO+), neutrophil extracellular traps (NETs) (MPO+CitH3+), apoptotic area (ascertained via TUNEL assay), and pro-inflammatory M1-like polarized macrophages (CD68+/MRC1−) in ischemic muscle tissue. Conversely, the number of regenerative M2-like polarized macrophages (CD68+/MRC1+) was elevated. Altogether, we observed that eCIRP depletion similarly affected angiogenesis and leukocyte recruitment as described for the overall absence of CIRP. Thus, we propose that eCIRP is mainly responsible for modulating angiogenesis via promoting pro-angiogenic microenvironmental conditions in muscle ischemia.
Collapse
Affiliation(s)
- Matthias Kübler
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Sebastian Beck
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Lisa Lilian Peffenköver
- Department of Biochemistry, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany; (L.L.P.); (K.T.P.); (S.F.)
| | - Philipp Götz
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
| | - Hellen Ishikawa-Ankerhold
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Department of Internal Medicine I, Faculty of Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Klaus T. Preissner
- Department of Biochemistry, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany; (L.L.P.); (K.T.P.); (S.F.)
| | - Silvia Fischer
- Department of Biochemistry, Faculty of Medicine, Justus Liebig University, 35392 Giessen, Germany; (L.L.P.); (K.T.P.); (S.F.)
| | - Manuel Lasch
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
| | - Elisabeth Deindl
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-Universität München, 81377 Munich, Germany; (M.K.); (S.B.); (P.G.); (H.I.-A.); (M.L.)
- Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Ludwig- Maximilians-Universität München, 82152 Planegg-Martinsried, Germany
- Correspondence: ; Tel.: +49-(0)-89-2180-76504
| |
Collapse
|
|
48
|
Fujita Y, Yago T, Asano T, Matsumoto H, Matsuoka N, Temmoku J, Sato S, Yashiro-Furuya M, Suzuki E, Watanabe H, Kawakami A, Migita K. Clinical relevance for circulating cold-inducible RNA-binding protein (CIRP) in patients with adult-onset Still's disease. PLoS One 2021; 16:e0255493. [PMID: 34351954 PMCID: PMC8341607 DOI: 10.1371/journal.pone.0255493] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 07/17/2021] [Indexed: 11/18/2022] Open
Abstract
Background Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease in which danger-associated molecular patterns (DAMPs)-mediated inflammasome activation seems to be involved in the disease pathogenesis. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that respond to cellular stress and has been identified as a DAMP that triggers the inflammatory response. The aim of this study is to investigate the clinical significance of serum CIRP levels in AOSD. Methods Serum samples were obtained from 44 patients with active AOSD or 50 patients with rheumatoid arthritis (RA), 20 patients with systemic lupus erythematosus (SLE), and 15 healthy control patients (HCs). Serum levels of CIRP and IL-18 were determined using enzyme-linked immunosorbent assay. Results were compared among AOSD patients, RA patients, SLE patients and HCs. Results were also analyzed according to the clinical features of AOSD. Results Serum CIRP levels were significantly higher in AOSD patients compared with RA patients (median: 9.6 ng/mL, IQR [5.7–14.4] versus 3.2 ng/mL, IQR [1.9–3.8]; p < 0.001) and with HCs (2.8 ng/mL, [IQR; 1.4–4.9], p < 0.001). There was a significant positive correlation between serum CIRP levels and AOSD disease activity score (Pouchot’s score r = 0.45, p = 0.003) as well as between AOSD-specific biomarkers ferritin and IL-18. However, there was no significant difference in the serum CIRP levels among AOSD patients with three different disease phenotypes. Conclusions These results suggest that CIRP may play a significant role in the pathophysiology of AOSD and could be a potential biomarker for monitoring the disease activity of AOSD.
Collapse
Affiliation(s)
- Yuya Fujita
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
- * E-mail:
| | - Toru Yago
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tomoyuki Asano
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Haruki Matsumoto
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Naoki Matsuoka
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Jumpei Temmoku
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shuzo Sato
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Makiko Yashiro-Furuya
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Eiji Suzuki
- Department of Rheumatology, Ohta-Nishinouchi Hospital, Koriyama, Fukushima, Japan
| | - Hiroshi Watanabe
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kiyoshi Migita
- Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| |
Collapse
|
|
49
|
Liu Y, Liu P, Hu Y, Cao Y, Lu J, Yang Y, Lv H, Lian S, Xu B, Li S. Cold-Induced RNA-Binding Protein Promotes Glucose Metabolism and Reduces Apoptosis by Increasing AKT Phosphorylation in Mouse Skeletal Muscle Under Acute Cold Exposure. Front Mol Biosci 2021; 8:685993. [PMID: 34395524 PMCID: PMC8358400 DOI: 10.3389/fmolb.2021.685993] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/13/2021] [Indexed: 11/13/2022] Open
Abstract
The main danger of cold stress to animals in cold regions is systemic metabolic changes and protein synthesis inhibition. Cold-induced RNA-binding protein is a cold shock protein that is rapidly up-regulated under cold stimulation in contrast to the inhibition of most proteins and participates in multiple cellular physiological activities by regulating targets. Therefore, this study was carried out to investigate the possible mechanism of CIRP-mediated glucose metabolism regulation and survival promotion in skeletal muscle after acute cold exposure. Skeletal muscle and serum from mice were obtained after 0, 2, 4 and 8 h of acute hypothermia exposure. Subsequently, the changes of CIRP, metabolism and apoptosis were examined. Acute cold exposure increased energy consumption, enhanced glycolysis, increased apoptosis, and up-regulated CIRP and phosphorylation of AKT. In addition, CIRP overexpression in C2C12 mouse myoblasts at each time point under 37°C and 32°C mild hypothermia increased AKT phosphorylation, enhanced glucose metabolism, and reduced apoptosis. CIRP knockdown by siRNA interference significantly reduced the AKT phosphorylation of C2C12 cells. Wortmannin inhibited the AKT phosphorylation of skeletal muscle after acute cold exposure, thereby inhibiting glucose metabolism and aggravating apoptosis. Taken together, acute cold exposure up-regulates CIRP in mouse skeletal muscle, which regulates glucose metabolism and maintains energy balance in skeletal muscle cells through the AKT signaling pathway, thus slowing down the apoptosis of skeletal muscle cells.
Collapse
Affiliation(s)
- Yang Liu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Peng Liu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Yajie Hu
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Yu Cao
- 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
| | - Yuying Yang
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Hongming Lv
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Shuai Lian
- 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
| | - Shize Li
- National Experimental Teaching Demonstration Center of Animal Medicine Foundation, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing, China
| |
Collapse
|
|
50
|
Beemelmanns A, Zanuzzo FS, Sandrelli RM, Rise ML, Gamperl AK. The Atlantic salmon's stress- and immune-related transcriptional responses to moderate hypoxia, an incremental temperature increase, and these challenges combined. G3 (BETHESDA, MD.) 2021; 11:jkab102. [PMID: 34015123 PMCID: PMC8613830 DOI: 10.1093/g3journal/jkab102] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/29/2021] [Indexed: 12/13/2022]
Abstract
The marine environment is predicted to become warmer, and more hypoxic, and these conditions may negatively impact the health and survival of coastal fish species, including wild and farmed Atlantic salmon (Salmo salar). Thus, we examined how: (1) moderate hypoxia (∼70% air saturation) at 12°C for 3 weeks; (2) an incremental temperature increase from 12°C to 20°C (at 1°C week-1) followed by 4 weeks at 20°C; and (3) treatment "2" combined with moderate hypoxia affected transcript expression in the liver of post-smolts as compared to control conditions (normoxia, 12°C). Specifically, we assessed the expression of 45 genes related to the heat shock response, oxidative stress, apoptosis, metabolism and immunity using a high-throughput qPCR approach (Fluidigm Biomark™ HD). The expression profiles of 27 "stress"-related genes indicated that: (i) moderate hypoxia affected the expression of several stress genes at 12°C; (ii) their expression was impacted by 16°C under normoxic conditions, and this effect increased until 20°C; (iii) the effects of moderate hypoxia were not additive to those at temperatures above 16°C; and (iv) long-term (4 weeks) exposure to 20°C, with or without hypoxia, resulted in a limited acclimatory response. In contrast, the expression of 15 immune-related genes was not greatly affected until temperatures reached 20°C, and this effect was particularly evident in fish exposed to the added challenge of hypoxia. These results provide valuable information on how these two important environmental factors affect the "stress" physiology and immunology of Atlantic salmon, and we identify genes that may be useful as hypoxia and/or temperature biomarkers in salmonids and other fishes.
Collapse
Affiliation(s)
- Anne Beemelmanns
- Department of Ocean Sciences, Memorial University,
St. John’s, NL A1C 5S7, Canada
| | - Fábio S Zanuzzo
- Department of Ocean Sciences, Memorial University,
St. John’s, NL A1C 5S7, Canada
| | - Rebeccah M Sandrelli
- Department of Ocean Sciences, Memorial University,
St. John’s, NL A1C 5S7, Canada
| | - Matthew L Rise
- Department of Ocean Sciences, Memorial University,
St. John’s, NL A1C 5S7, Canada
| | - A Kurt Gamperl
- Department of Ocean Sciences, Memorial University,
St. John’s, NL A1C 5S7, Canada
| |
Collapse
|