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Zhong Y, Zhang C, Li Y, Chen D, Tang C, Zheng X, Zhu Z. MicroRNA-669f-5p targeting deoxycytidinephosphate deaminase contributes to sevoflurane-induced cognitive impairments in aged mice via the TLR2/4-MyD88-NF-κB pathway. Brain Res Bull 2025:111381. [PMID: 40379035 DOI: 10.1016/j.brainresbull.2025.111381] [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: 10/28/2024] [Revised: 04/18/2025] [Accepted: 05/08/2025] [Indexed: 05/19/2025]
Abstract
BACKGROUND Postoperative cognitive dysfunction (POCD) is a common complication associated with sevoflurane anaesthesia in the aged population. MicroRNAs have been implicated in sevoflurane-induced cognitive deficits; however, the role and underlying mechanism of microRNA (miR)-669f-5p remain unclear. METHODS Eighteen-month-old mice and mouse hippocampal neurons (HT22) were exposed to sevoflurane. Cognitive function was assessed using the Morris water maze test. Neuroapoptosis and cellular proliferation were evaluated by terminal-deoxynucleotidyl transferase-mediated nick end-labelling staining and Cell Counting Kit-8 assays, respectively. The downstream molecular mechanisms of miR-669f-5p were investigated using bioinformatics analysis, western blotting, quantitative real-time polymerase chain reaction, immunofluorescence and dual-luciferase reporter assays. RESULTS Bioinformatics analysis of the Gene Expression Omnibus database revealed upregulation of miR-669f-5p in hippocampal tissue from mice with POCD. Inhibition of miR-669f-5p substantially improved sevoflurane-induced cognitive impairment in aged mice. Deoxycytidinephosphate deaminase (Dctd) was identified as a direct target of miR-669f-5p. Overexpression of Dctd reversed the effects of miR-669f-5p mimics on apoptosis and proliferation in HT22 cells and suppressed activation of the TLR2/4-MyD88-NF-κB signalling pathway. Moreover, Dctd overexpression ameliorated sevoflurane-induced cognitive impairment in aged mice. CONCLUSION MicroRNA-669f-5p contributes to sevoflurane-induced cognitive impairment in aged mice by targeting Dctd and activating the TLR2/4-MyD88-NF-κB pathway. These findings provide new insights into potential therapeutic strategies for anaesthesia-related POCD.
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Affiliation(s)
- Yuanping Zhong
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou 563003, PR China
| | - Chao Zhang
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou 563003, PR China
| | - Yuan Li
- Department of Anesthesiology, Zunyi Medical University, Zunyi, Guizhou Province, 563000, PR China
| | - Dongqin Chen
- Department of Anesthesiology, Zunyi Medical University, Zunyi, Guizhou Province, 563000, PR China
| | - Chunchun Tang
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou 563003, PR China
| | - Xue Zheng
- Department of Anesthesiology, Zunyi Maternal And Child Health Care Hospital, 287#, Zhonghua Road, Zunyi 563000, Guizhou Province, PR China
| | - Zhaoqiong Zhu
- Department of Anesthesiology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou 563003, PR China; Early Clinical Research Ward, Affiliated Hospital of Zunyi Medical University，149 Dalian Road, Huichuan District, Zunyi, Guizhou 563003, PR China.
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Yang D, Su J, Chen Y, Chen G. The NF-κB pathway: Key players in neurocognitive functions and related disorders. Eur J Pharmacol 2024; 984:177038. [PMID: 39369877 DOI: 10.1016/j.ejphar.2024.177038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 10/03/2024] [Accepted: 10/04/2024] [Indexed: 10/08/2024]
Abstract
Perioperative neurocognitive disorder (PND) is a common complication of surgical anesthesia, yet its precise etiology remains unclear. Neuroinflammation is a key feature of PND, influenced by both patient -related and surgical variables. The nuclear factor-κB (NF-κB) transcription factor family plays a critical role in regulating the body's immunological proinflammatory response, which is pivotal in the development of PND. Surgery and anesthesia trigger the activation of the NF-κB signaling pathway, leading to the initiation of inflammatory cascades, disruption of the blood-brain barrier, and neuronal injury. Immune cells and glial cells are central to these pathological processes in PND. Furthermore, this study explores the interactions between NF-κB and various signaling molecules, including Tlr4, P2X, α7-nAChR, ROS, HIF-1α, PI3K/Ak, MicroRNA, Circular RNA, and histone deacetylases, within the context of PND. Targeting NF-κB as a therapeutic approach for PND shows promise as a potential treatment strategy.
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Affiliation(s)
- Danfeng Yang
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Junwei Su
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Yeru Chen
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China
| | - Gang Chen
- Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
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Yan F, Chen B, Ma Z, Chen Q, Jin Z, Wang Y, Qu F, Meng Q. Exploring molecular mechanisms of postoperative delirium through multi-omics strategies in plasma exosomes. Sci Rep 2024; 14:29466. [PMID: 39604493 PMCID: PMC11603267 DOI: 10.1038/s41598-024-80865-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 11/22/2024] [Indexed: 11/29/2024] Open
Abstract
Currently, the diagnosis of delirium is solely based on clinical observation, lacking objective diagnostic tools, and the regulatory networks and pathological mechanisms behind it are not yet fully understood. Exosomes have garnered considerable interest as potential biomarkers for a variety of illnesses. This research aimed to delineate both the proteomic and metabolomic landscapes inherent to exosomes, assessing their diagnostic utility in postoperative delirium (POD) and understanding the underlying pathophysiological frameworks. Integrated analyses of proteomics and metabolomics were conducted on exosomes derived from plasma of individuals from both the non-postoperative delirium (NPOD) control group and the POD group. Subsequently, the study utilized the Connectivity Map (CMap) methodology for the identification of promising small-molecule drugs and carried out molecular docking assessments to explore the binding affinities with the enzyme MMP9 of these identified molecules. We identified significant differences in exosomal metabolites and proteins between the POD and control groups, highlighting pathways related to neuroinflammation and blood-brain barrier (BBB) integrity. Our CMap analysis identified potential small-molecule therapeutics, and molecular docking studies revealed two compounds with high affinity to MMP9, suggesting a new therapeutic avenue for POD. This study highlights MMP9, TLR2, ICAM1, S100B, and glutamate as key biomarkers in the pathophysiology of POD, emphasizing the roles of neuroinflammation and BBB integrity. Notably, molecular docking suggests mirin and orantinib as potential inhibitors targeting MMP9, providing new therapeutic avenues. The findings broaden our understanding of POD mechanisms and suggest targeted strategies for its management, reinforcing the importance of multidimensional biomarker analysis and molecular targeting in POD intervention.
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Affiliation(s)
- Fuhui Yan
- School of Clinical Medicine, Jining Medical University, Jining, China
| | - Bowang Chen
- Department of Intensive Care Unit, Affiliated Jining First People's Hospital of Shandong First Medical University, Jining, Shandong, China
| | - Zhen Ma
- Department of Intensive Care Unit, Affiliated Jining First People's Hospital of Shandong First Medical University, Jining, Shandong, China
| | - Qirong Chen
- Department of Intensive Care Unit, Affiliated Jining First People's Hospital of Shandong First Medical University, Jining, Shandong, China
| | - Zhi Jin
- Department of Intensive Care Unit, Affiliated Jining First People's Hospital of Shandong First Medical University, Jining, Shandong, China
| | - Yujie Wang
- School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China
| | - Feng Qu
- Department of Intensive Care Unit, Affiliated Jining First People's Hospital of Shandong First Medical University, Jining, Shandong, China.
| | - Qiang Meng
- Department of Intensive Care Unit, Affiliated Jining First People's Hospital of Shandong First Medical University, Jining, Shandong, China.
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Chen Z, Meng D, Pang X, Guo J, Li T, Song J, Peng Y. Deer antler stem cells immortalization by modulation of hTERT and the small extracellular vesicles characters. Front Vet Sci 2024; 11:1440855. [PMID: 39430380 PMCID: PMC11486761 DOI: 10.3389/fvets.2024.1440855] [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: 05/30/2024] [Accepted: 09/12/2024] [Indexed: 10/22/2024] Open
Abstract
Background Deer antler stem cells (AnSCs) exhibit properties of both embryonic and mesenchymal stem cells, with superior self-renewal and proliferation, which drive rapid antler growth and regeneration. AnSCs and their derived small extracellular vesicles (sEVs) hold promising potential for applications in regeneration medicine. Due to the restricted proliferative capacity inherent in primary cells, the production capacity of AnSCs and their sEVs are limited. Human telomerase reverse transcriptase (hTERT) is the most important telomerase subunit, hTERT gene insertion has been successfully employed in generating immortalized cell lines. Results In this study, we successfully established immortalized AnSCs by transducing the hTERT gene using lentivirus. Compared to primary AnSCs, hTERT-AnSCs demonstrated extended passage potential and accelerated proliferation rates while maintaining the mesenchymal stem cell surface markers CD44 and CD90. Additionally, hTERT-AnSCs retained the capacity for osteogenic, adipogenic, and chondrogenic differentiation. sEVs derived from hTERT-AnSCs exhibited a particle size distribution similar to that of AnSCs, both displaying a cup-shaped morphology and expressing CD81, ALIX, and TSG101, while notably lacking GM130 expression. Conclusion We successfully isolated primary stem cells from deer antler and established the immortalized hTERT-AnSCs. Remarkably, this cell line maintains its stem cell characteristics even after 40 passages. The sEVs derived from these cells exhibit identical morphological and structural features to those of primary AnSCs. This research provides essential technical support for the application of AnSCs and their sEVs in regenerative medicine.
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Affiliation(s)
- Ze Chen
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Deshuang Meng
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Xin Pang
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
- School of Chemistry and Life Science, Changchun University of Technology, Changchun, China
| | - Jia Guo
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Tiejun Li
- Dongfeng Sika Deer Industry Development Service Center, Dongfeng, China
| | - Jun Song
- Dongfeng Sika Deer Industry Development Service Center, Dongfeng, China
| | - Yinghua Peng
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
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Fang Y, Shen P, Xu L, Shi Y, Wang L, Yang M. PDTC improves cognitive impairment in LPS-induced ARDS by regulating miR-181c/NF-κB axis-mediated neuroinflammation. Brain Inj 2024; 38:918-927. [PMID: 38828532 DOI: 10.1080/02699052.2024.2361623] [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: 08/30/2022] [Revised: 04/02/2024] [Accepted: 05/27/2024] [Indexed: 06/05/2024]
Abstract
BACKGROUND Cognitive impairment is a severe complication of acute respiratory distress syndrome (ARDS). Emerging studies have revealed the effects of pyrrolidine dithiocarbamate (PDTC) on improving surgery-induced cognitive impairment. The major aim of the study was to investigate whether PDTC protected against ARDS-induced cognitive dysfunction and to identify the underlying mechanisms involved. METHODS The rat model of ARDS was established by intratracheal instillation of lipopolysaccharide (LPS), followed by treatment with PDTC. The cognitive function of rats was analyzed by the Morris Water Maze, and pro-inflammatory cytokines were assessed by quantitative real-time PCR, enzyme-linked immunosorbent assay, and western blot assays. A dual-luciferase reporter gene assay was performed to identify the relationship between miR-181c and its target gene, TAK1 binding protein 2 (TAB2). RESULTS The results showed that PDTC improved cognitive impairment and alleviated neuroinflammation in the hippocampus in LPS-induced ARDS model. Furthermore, we demonstrated that miR-181c expression was downregulated in the hippocampus of the ARDS rats, which was restored by PDTC treatment. In vitro studies showed that miR-181c alleviated LPS-induced pro-inflammatory response by inhibiting TAB2, a critical molecule in the nuclear factor (NF)-κB signaling pathway. CONCLUSION PDTC improves cognitive impairment in LPS-induced ARDS by regulating miR-181c/NF-κB axis-mediated neuroinflammation, providing a potential opportunity for the treatment of this disease.
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Affiliation(s)
- Ying Fang
- Department of Pathology, The First Hospital of Jiaxing & Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Peng Shen
- Department of Intensive Care Unit, The First Hospital of Jiaxing & Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Longsheng Xu
- Department of Central Laboratory, The First Hospital of Jiaxing & Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Yunchao Shi
- Department of Intensive Care Unit, The First Hospital of Jiaxing & Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Liyan Wang
- Department of General Practice, The First Hospital of Jiaxing & Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Maoxian Yang
- Department of Intensive Care Unit, The First Hospital of Jiaxing & Affiliated Hospital of Jiaxing University, Jiaxing, China
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Gao X, Lin C, Feng Y, You Y, Jin Z, Li M, Zhou Y, Chen K. Akkermansia muciniphila-derived small extracellular vesicles attenuate intestinal ischemia-reperfusion-induced postoperative cognitive dysfunction by suppressing microglia activation via the TLR2/4 signaling. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119630. [PMID: 37967793 DOI: 10.1016/j.bbamcr.2023.119630] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 11/17/2023]
Abstract
Akkermansia muciniphila (AKK) bacteria improve the functions of theere intestinal and blood-brain barriers (BBB) via their extracellular vesicles (AmEvs). However, their role in postoperative cognitive dysfunction (POCD) and its underlying mechanisms remain unclear. To investigate, we used C57BL/6 J mice divided into five groups: Sham, POCD, POCD+Akk, POCD+Evs, and POCD+Evs + PLX5622. POCD was induced through intestinal ischemia-reperfusion (I/R). The mice's cognitive function was assessed using behavioral tests, and possible mechanisms were explored by examining gut and BBB permeability, inflammation, and microglial function. Toll-like receptor (TLR) 2/4 pathway-related proteins were also investigated both in vitro and in vivo. PLX5622 chow was employed to eliminate microglial cells. Our findings revealed a negative correlation between AKK abundance and POCD symptoms. Supplementation with either AKK or AmEvs improved cognitive function, improved the performance of the intestinal barrier and BBB, and decreased inflammation and microglial activation in POCD mice compared to controls. Moreover, AmEvs treatment inhibited TLR2/4 signaling in the brains of POCD mice and LPS-treated microglial cells. In microglial-ablated POCD mice, however, AmEvs failed to protect BBB integrity. Overall, AmEvs is a potential therapeutic strategy for managing POCD by enhancing gut and BBB integrity and inhibiting microglial-mediated TLR2/4 signaling.
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Affiliation(s)
- Xiang Gao
- Department of Anesthesiology, Fujian Maternity and Child Health Hospital, Fuzhou, 350000, China; College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, China
| | - Chuantao Lin
- Department of Anesthesiology, Fujian Maternity and Child Health Hospital, Fuzhou, 350000, China; College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, China
| | - Yebin Feng
- Department of Science and Education, Fujian Maternity and Child Health Hospital, Fuzhou, 350000, China; College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, China
| | - Yi You
- Department of Anesthesiology, Fujian Maternity and Child Health Hospital, Fuzhou, 350000, China; College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350000, China
| | - Zhe Jin
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Mengyun Li
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Yufeng Zhou
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Kai Chen
- Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
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Wei P, Jia M, Liu PM, Meng L, Li J, Yang JJ. Stem cell-based therapy and its potential in perioperative neurocognitive disorders. Br J Anaesth 2023; 131:e139-e142. [PMID: 37587005 DOI: 10.1016/j.bja.2023.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/02/2023] [Accepted: 07/12/2023] [Indexed: 08/18/2023] Open
Affiliation(s)
- Penghui Wei
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, PR China
| | - Min Jia
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Pan-Miao Liu
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Liying Meng
- Department of Medical Experimental Center, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, PR China
| | - Jianjun Li
- Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, PR China
| | - Jian-Jun Yang
- Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
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Liu Q, Li J, Chang J, Guo Y, Wen D. The characteristics and medical applications of antler stem cells. Stem Cell Res Ther 2023; 14:225. [PMID: 37649124 PMCID: PMC10468909 DOI: 10.1186/s13287-023-03456-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 08/17/2023] [Indexed: 09/01/2023] Open
Abstract
Antlers are the only fully regenerable mammalian appendages whose annual renewal is initiated by antler stem cells (ASCs), defined as a specialized type of mesenchymal stem cells (MSCs) with embryonic stem cell properties. ASCs possess the same biological features as MSCs, including the capacity for self-renewal and multidirectional differentiation, immunomodulatory functions, and the maintenance of stem cell characteristics after multiple passages. Several preclinical studies have shown that ASCs exhibit promising potential in wound healing, bone repair, osteoarthritis, anti-tissue fibrosis, anti-aging, and hair regeneration. Medical applications based on ASCs and ASC-derived molecules provide a new source of stem cells and therapeutic modalities for regenerative medicine. This review begins with a brief description of antler regeneration and the role of ASCs. Then, the properties and advantages of ASCs are described. Finally, medical research advances regarding ASCs are summarized, and the prospects and challenges of ASCs are highlighted.
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Affiliation(s)
- Qi Liu
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jiannan Li
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jinghui Chang
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yu Guo
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Dacheng Wen
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China.
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Muscat SM, Deems NP, Butler MJ, Scaria EA, Bettes MN, Cleary SP, Bockbrader RH, Maier SF, Barrientos RM. Selective TLR4 Antagonism Prevents and Reverses Morphine-Induced Persistent Postoperative Cognitive Dysfunction, Dysregulation of Synaptic Elements, and Impaired BDNF Signaling in Aged Male Rats. J Neurosci 2023; 43:155-172. [PMID: 36384680 PMCID: PMC9838714 DOI: 10.1523/jneurosci.1151-22.2022] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 11/07/2022] [Accepted: 11/10/2023] [Indexed: 11/18/2022] Open
Abstract
Perioperative neurocognitive disorders (PNDs) are characterized by confusion, difficulty with executive function, and episodic memory impairment in the hours to months following a surgical procedure. Postoperative cognitive dysfunction (POCD) represents such impairments that last beyond 30 d postsurgery and is associated with increased risk of comorbidities, progression to dementia, and higher mortality. While it is clear that neuroinflammation plays a key role in PND development, what factors underlie shorter self-resolving versus persistent PNDs remains unclear. We have previously shown that postoperative morphine treatment extends POCD from 4 d (without morphine) to at least 8 weeks (with morphine) in aged male rats, and that this effect is likely dependent on the proinflammatory capabilities of morphine via activation of toll-like receptor 4 (TLR4). Here, we extend these findings to show that TLR4 blockade, using the selective TLR4 antagonist lipopolysaccharide from the bacterium Rhodobacter sphaeroides (LPS-RS Ultrapure), ameliorates morphine-induced POCD in aged male rats. Using either a single central preoperative treatment or a 1 week postoperative central treatment regimen, we demonstrate that TLR4 antagonism (1) prevents and reverses the long-term memory impairment associated with surgery and morphine treatment, (2) ameliorates morphine-induced dysregulation of the postsynaptic proteins postsynaptic density 95 and synaptopodin, (3) mitigates reductions in mature BDNF, and (4) prevents decreased activation of the BDNF receptor TrkB (tropomyosin-related kinase B), all at 4 weeks postsurgery. We also reveal that LPS-RS Ultrapure likely exerts its beneficial effects by preventing endogenous danger signal HMGB1 (high-mobility group box 1) from activating TLR4, rather than by blocking continuous activation by morphine or its metabolites. These findings suggest TLR4 as a promising therapeutic target to prevent or treat PNDs.SIGNIFICANCE STATEMENT With humans living longer than ever, it is crucial that we identify mechanisms that contribute to aging-related vulnerability to cognitive impairment. Here, we show that the innate immune receptor toll-like receptor 4 (TLR4) is a key mediator of cognitive dysfunction in aged rodents following surgery and postoperative morphine treatment. Inhibition of TLR4 both prevented and reversed surgery plus morphine-associated memory impairment, dysregulation of synaptic elements, and reduced BDNF signaling. Together, these findings implicate TLR4 in the development of postoperative cognitive dysfunction, providing mechanistic insight and novel therapeutic targets for the treatment of cognitive impairments following immune challenges such as surgery in older individuals.
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Affiliation(s)
- Stephanie M Muscat
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
- Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio 43210
| | - Nicholas P Deems
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
- Neuroscience Graduate Program, The Ohio State University, Columbus, Ohio 43210
| | - Michael J Butler
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
| | - Emmanuel A Scaria
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
| | - Menaz N Bettes
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
| | - Sean P Cleary
- Campus Chemical Instrumentation Center, The Ohio State University, Columbus, Ohio 43210
| | - Ross H Bockbrader
- Pharmaceutical Sciences Graduate Program, Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, Ohio 43210
| | - Steven F Maier
- Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado 80309
| | - Ruth M Barrientos
- Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
- Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, Ohio 43210
- Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
- Chronic Brain Injury Program, The Ohio State University, Columbus, Ohio 43210
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Cheng C, Wan H, Cong P, Huang X, Wu T, He M, Zhang Q, Xiong L, Tian L. Targeting neuroinflammation as a preventive and therapeutic approach for perioperative neurocognitive disorders. J Neuroinflammation 2022; 19:297. [PMID: 36503642 PMCID: PMC9743533 DOI: 10.1186/s12974-022-02656-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022] Open
Abstract
Perioperative neurocognitive disorders (PND) is a common postoperative complication associated with regional or general anesthesia and surgery. Growing evidence in both patient and animal models of PND suggested that neuroinflammation plays a critical role in the development and progression of this problem, therefore, mounting efforts have been made to develop novel therapeutic approaches for PND by targeting specific factors or steps alongside the neuroinflammation. Multiple studies have shown that perioperative anti-neuroinflammatory strategies via administering pharmacologic agents or performing nonpharmacologic approaches exert benefits in the prevention and management of PND, although more clinical evidence is urgently needed to testify or confirm these results. Furthermore, long-term effects and outcomes with respect to cognitive functions and side effects are needed to be observed. In this review, we discuss recent preclinical and clinical studies published within a decade as potential preventive and therapeutic approaches targeting neuroinflammation for PND.
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Affiliation(s)
- Chun Cheng
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Hanxi Wan
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Peilin Cong
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Xinwei Huang
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Tingmei Wu
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Mengfan He
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Qian Zhang
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Lize Xiong
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
| | - Li Tian
- Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Shanghai, 200434 China ,grid.24516.340000000123704535Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200434 China ,grid.24516.340000000123704535Clinical Research Center for Anesthesiology and Perioperative Medicine, Tongji University, Shanghai, 200434 China
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Yang YS, He SL, Chen WC, Wang CM, Huang QM, Shi YC, Lin S, He HF. Recent progress on the role of non-coding RNA in postoperative cognitive dysfunction. Front Cell Neurosci 2022; 16:1024475. [PMID: 36313620 PMCID: PMC9608859 DOI: 10.3389/fncel.2022.1024475] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
Postoperative cognitive dysfunction (POCD), especially in elderly patients, is a serious complication characterized by impairment of cognitive and sensory modalities after surgery. The pathogenesis of POCD mainly includes neuroinflammation, neuronal apoptosis, oxidative stress, accumulation of Aβ, and tau hyperphosphorylation; however, the exact mechanism remains unclear. Non-coding RNA (ncRNA) may play an important role in POCD. Some evidence suggests that microRNA, long ncRNA, and circular RNA can regulate POCD-related processes, making them promising biomarkers in POCD diagnosis, treatment, and prognosis. This article reviews the crosstalk between ncRNAs and POCD, and systematically discusses the role of ncRNAs in the pathogenesis and diagnosis of POCD. Additionally, we explored the possible mechanisms of ncRNA-associated POCD, providing new knowledge for developing ncRNA-based treatments for POCD.
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Affiliation(s)
- Yu-Shen Yang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Shi-Ling He
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Wei-Can Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Cong-Mei Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Qiao-Mei Huang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yan-Chuan Shi
- Neuroendocrinology Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
- Faculty of Medicine, UNSW Sydney, Sydney, NSW, Australia
- *Correspondence: Yan-Chuan Shi,
| | - Shu Lin
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
- Neuroendocrinology Group, Garvan Institute of Medical Research, Sydney, NSW, Australia
- Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
- Shu Lin,
| | - He-fan He
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
- He-fan He,
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12
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Mesenchymal Stem Cell-Derived Exosomes Ameliorate Delayed Neurocognitive Recovery in Aged Mice by Inhibiting Hippocampus Ferroptosis via Activating SIRT1/Nrf2/HO-1 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3593294. [PMID: 36238648 PMCID: PMC9553403 DOI: 10.1155/2022/3593294] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 09/13/2022] [Accepted: 09/19/2022] [Indexed: 12/14/2022]
Abstract
Delayed neurocognitive recovery (dNCR) is a prevalent perioperative neurological complication in older patients and has common characteristics such as acute cognitive dysfunction, impaired memory, and inattention. Mesenchymal stem cell-derived exosomes (MSCs-Exo) are enclosed by a lipid bilayer contain proteins, DNA, miRNA, and other components, which are important mediators of intercellular communication. It has been reported that exosomes could play an important role in the treatment of neurodegenerative diseases, nerve injury, and other neurological diseases. In this study, we examined the effects of MSCs-Exo on dNCR aged mice after exploratory laparotomy and evaluated their potential regulatory mechanisms. We found that MSCs-Exo treatment ameliorated cognitive impairment in dNCR aged mice. MSCs-Exo inhibit hippocampus ferroptosis and increase the expression of silent information regulator 1 (SIRT1), factor nuclear factor-erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) in dNCR aged mice. Interestingly, the above effects of MSCs-Exo on dNCR aged mice were abolished by SIRT1 selective inhibitor EX-527. In conclusion, these findings indicated that MSCs-Exo can ameliorate cognitive impairment by inhibiting hippocampus ferroptosis in dNCR aged mice via activating SIRT1/Nrf2/HO-1 signaling pathway, providing a potential avenue for the treatment of dNCR.
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13
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Squillace S, Salvemini D. Toll-like receptor-mediated neuroinflammation: relevance for cognitive dysfunctions. Trends Pharmacol Sci 2022; 43:726-739. [PMID: 35753845 PMCID: PMC9378500 DOI: 10.1016/j.tips.2022.05.004] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/13/2022] [Accepted: 05/27/2022] [Indexed: 10/17/2022]
Abstract
Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) with a well-documented role in the innate and adaptive immune responses. Interestingly, TLR activation has also been linked to several brain functions including neurogenesis and synaptogenesis. Increasing evidence supports TLR involvement in peripheral and central inflammation underlying normal aging and the pathogenesis of clinical conditions characterized by cognitive decline. These include not only major neurodegenerative diseases but also traumatic brain injuries, surgeries, and alcohol consumption- and chemotherapy-induced cognitive impairment. We first summarize the physiological roles of TLRs in the nervous system, and then illustrate the emerging involvement of TLRs in cognitive functions, pointing to these receptors as novel enticing pharmacological targets to develop more efficient drugs for the treatment of cognitive impairment.
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Affiliation(s)
- Silvia Squillace
- Department of Pharmacology and Physiology, and the Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104, USA
| | - Daniela Salvemini
- Department of Pharmacology and Physiology, and the Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104, USA.
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14
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Xiong J, Quan J, Qin C, Wang X, Dong Q, Zhang B. Remifentanil pretreatment attenuates brain nerve injury in response to cardiopulmonary bypass by blocking AKT/NRF2 signal pathway. Immunopharmacol Immunotoxicol 2022; 44:574-585. [PMID: 35485905 DOI: 10.1080/08923973.2022.2069577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE This study aimed to explore the effect and mechanism of remifentanil on cardiopulmonary bypass (CPB)-induced cerebral nerve injury. METHODS After pretreating with remifentanil, or dexmedetomidine (DEX), SD rats were subjected to the CPB for 2 h. The data of body temperature, blood gas and mean arterial pressure (MAP) and hematocrit (HCT) were recorded at different time points. The cerebral tissue water content of rats was determined and immunohistochemical (IHC) and H&E assays on the hippocampal CA1 region of rats was performed. The levels of interleukin (IL)-6, IL-10, soluble protein-100β (S100β) and neuron-specific enolase (NSE) were analyzed by ELISA, and those of the indexes for oxidative stress (malondialdehyde (MDA) and superoxide dismutase (SOD)) were detected by the commercial kits. Morris water maze was used to evaluate the learning and memory abilities. Western blot/qRT-PCR were used to detect the protein/mRNA expressions in hippocampus. RESULTS CPB increased the levels/expressions of IL-6, IL-10, S100β, NSE, MDA, cleaved caspase-3, Bax and decreased those of Bcl-2, SOD, p-AKT, HO-1, in serum and parietal cortex tissue, with increased brain water content, lesions in the hippocampal CA1 area, swimming distance, brain nerve injury and decreased escape latency, retention time on platform and times of crossing the platform of rats. The preconditioning of remifentanil or DEX partially attenuated CPB-induced injury and -decreased expressions on p-AKT and HO-1, while further promoting CPB-induced expression of nuclear Nrf2 expression and inhibiting that of cytoplasm Nrf2. CONCLUSION This paper demonstrates that remifentanil preconditioning could partially attenuate CPB-induced brain nerve injury of rats.
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Affiliation(s)
- Jijun Xiong
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China.,Department of Neurology, People's Hospital of Guilin, Gunlin, Guangxi Province, China
| | - Jie Quan
- Department of Neurology, People's Hospital of Guilin, Gunlin, Guangxi Province, China
| | - Chaosheng Qin
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xiaogang Wang
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Qinghua Dong
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Bingdong Zhang
- Department of Anesthesiology, the First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
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15
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Ponce-Polo Á, RitoréHidalgo A, Martínez AA, Guijarro RIO. Use of patent information to characterize trends in the therapeutic applications of extracellular vesicles derived from mesenchymal stem cells (MSC-EVs). Recent Pat Biotechnol 2022; 16:243-255. [PMID: 35240977 DOI: 10.2174/1872208316666220303095217] [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: 10/18/2021] [Revised: 01/03/2022] [Accepted: 01/05/2022] [Indexed: 12/12/2022]
Abstract
Extracellular vesicles derived from mesenchymal stromal cells (MSC-EVs) are gaining interest for medical purposes. The promising therapeutic effects exhibited in both preclinical and clinical studies suggest that they may become an alternative for certain applications to cell-based therapies, which are subjected to stricter regulations. The commercial exploitation of these candidates requires a proper patent strategy from both the industry and public research organizations. Here, we raise a global patent literature analysis to identify key players and therapeutic applications in the field. Our results show an increasing rate of patent publications since 2009, with Asia (specifically China) leading the patenting activity. The therapeutic use of MSC-EVs within patent literature covers a wide range of diseases, in which "Dermal and Wounds", "Neurology" and "Cardiovascular" are the main therapeutic areas. Moreover, most of these patents include "product-by-process" claims, since the therapeutic effects of MSC-EVs could be influenced by their manufacturing process. Our results follow scientific and clinical literature trends.
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Affiliation(s)
- Ángela Ponce-Polo
- Andalusian Network for the design and translation of Advanced Therapies (ANd&tAT), Public Foundation of Andalusia Progress and Health, Seville, Spain
| | - Alvaro RitoréHidalgo
- Andalusian Network for the design and translation of Advanced Therapies (ANd&tAT), Public Foundation of Andalusia Progress and Health, Seville, Spain
| | - Arturo Argüello Martínez
- Andalusian Public Health System Technology Transfer Office, Public Foundation of Andalusia Progress and Health, Seville, Spain
| | - Roke Iñaki Oruezabal Guijarro
- Andalusian Network for the design and translation of Advanced Therapies (ANd&tAT), Public Foundation of Andalusia Progress and Health, Seville, Spain
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16
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Sun Y, Yuan Y, Wang L, Sun S. Effect of LncRNA OIP5-AS1/microRNA-186-5p on isoflurane-induced cognitive dysfunction in aged rats. Hum Exp Toxicol 2022; 41:9603271221116276. [PMID: 36000339 DOI: 10.1177/09603271221116276] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Post-operative recognition dysfunction (POCD) is a kind of central nervous system complication that appears after operative anesthesia. Recent studies on the mechanism of long non-coding RNA (lncRNA) in neurodegenerative diseases are abundant. AIMS The study aimed to explore the expression pattern and role of lncRNA OIP5-AS1 in POCD and to investigate its underlying mechanism in old rats. METHODS The old rats were exposed to isoflurane to mimic the POCD in the elderly, and their cognitive function was tested via Morris water maze (MWM) test. Enzyme linked immunosorbent assay was applied for the concentration detection of inflammation and oxidative stress-related factors. Luciferase reporter assay was done for the target gene analysis. RESULTS Downregulation of OIP5-AS1 was accompanied by isoflurane treatment in rats, overexpression of OIP5-AS1 induced the rats to spend more time in the target quadrant, and shorten escape latency time. OIP5-AS1 inhibited the release of TNF-α, IL-6 and IL-1β, GSH and superoxide dismutase, decreased the activation of caspase-3, but promoted malondialdehyde release. miR-186-5p was a target miRNA of OIP5-AS1, and exhibited high expression in rats after isoflurane exposure. miR-186-5p can abolish the beneficial role of OIP5-AS1 against cognitive impairment, inflammatory response, oxidative stress and neuron apoptosis. CONCLUSION OIP5-AS1 plays a neuroprotective role in elderly POCD rats through sponging miR-186-5p, and it is related to OIP5-AS1/miR-186-5p mediated inflammatory response, oxidative stress and neuron apoptosis.
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Affiliation(s)
- Yujing Sun
- Department of Anesthesia Surgery, Dongying Hospital of Traditional Chinese Medicine, Dongying, China
| | - Yawei Yuan
- Department of Anesthesiology, Shanghai First Maternity and Infant Hospital, School of Medicine, 12476Tongji University, Shanghai, China
| | - Long Wang
- Department of Pain Medicine, the First Medical Center, 104607Chinese PLA General Hospital, Beijing, China
| | - Sen Sun
- Department of Anesthesiology, Shanghai Pulmonary Hospital, Shanghai, China
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17
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Zhang W, Ke CH, Guo HH, Xiao L. Antler stem cells and their potential in wound healing and bone regeneration. World J Stem Cells 2021; 13:1049-1057. [PMID: 34567424 PMCID: PMC8422928 DOI: 10.4252/wjsc.v13.i8.1049] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/10/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
Compared to other vertebrates, the regenerative capacity of appendages in mammals is very limited. Deer antlers are an exception and can fully regenerate annually in postnatal mammals. This process is initiated by the antler stem cells (AnSCs). AnSCs can be divided into three types: (1) Antlerogenic periosteum cells (for initial pedicle and first antler formation); (2) Pedicle periosteum cells (for annual antler regeneration); and (3) Reserve mesenchyme cells (RMCs) (for rapid antler growth). Previous studies have demonstrated that AnSCs express both classic mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs), and are able to differentiate into multiple cell types in vitro. Thus, AnSCs were defined as MSCs, but with partial ESC attributes. Near-perfect generative wound healing can naturally occur in deer, and wound healing can be achieved by the direct injection of AnSCs or topical application of conditioned medium of AnSCs in rats. In addition, in rabbits, the use of both implants with AnSCs and cell-free preparations derived from AnSCs can stimulate osteogenesis and repair defects of bone. A more comprehensive understanding of AnSCs will lay the foundation for developing an effective clinical therapy for wound healing and bone repair.
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Affiliation(s)
- Wei Zhang
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510080, Guangdong Province, China
- Research & Development Center, YZ Health-tech Inc., Zhuhai 519000, Guangdong Province, China
| | - Chang-Hong Ke
- Research & Development Center, YZ Health-tech Inc., Zhuhai 519000, Guangdong Province, China
- School of Pharmacy, Jinan University, Guangzhou 510080, Guangdong Province, China
| | - Hai-Hua Guo
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, Guangdong Province, China
| | - Li Xiao
- Guangdong Laboratory Animals Monitoring Institute and Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou 510080, Guangdong Province, China
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Role of Extracellular Vesicles in Placental Inflammation and Local Immune Balance. Mediators Inflamm 2021; 2021:5558048. [PMID: 34239366 PMCID: PMC8235987 DOI: 10.1155/2021/5558048] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/26/2021] [Accepted: 05/25/2021] [Indexed: 02/07/2023] Open
Abstract
Background Pregnancy maintenance depends on the formation of normal placentas accompanied by trophoblast invasion and vascular remodeling. Various types of cells, such as trophoblasts, endothelial cells, immune cells, mesenchymal stem cells (MSCs), and adipocytes, mediate cell-to-cell interactions through soluble factors to maintain normal placental development. Extracellular vesicles (EVs) are diverse nanosized to microsized membrane-bound particles released from various cells. EVs contain tens to thousands of different RNA, proteins, small molecules, DNA fragments, and bioactive lipids. EV-derived microRNAs (miRNAs) and proteins regulate inflammation and trophoblast invasion in the placental microenvironment. Maternal-fetal communication through EV can regulate the key signaling pathways involved in pregnancy maintenance, from implantation to immune regulation. Therefore, EVs and the encapsulating factors play important roles in pregnancy, some of which might be potential biomarkers. Conclusion In this review, we have summarized published studies about the EVs in the placentation and pregnancy-related diseases. By summarizing the role of EVs and their delivering active molecules in pregnancy-related diseases, it provides novel insight into the diagnosis and treatment of diseases.
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Lin F, Shan W, Zheng Y, Pan L, Zuo Z. Toll-like receptor 2 activation and up-regulation by high mobility group box-1 contribute to post-operative neuroinflammation and cognitive dysfunction in mice. J Neurochem 2021; 158:328-341. [PMID: 33871050 DOI: 10.1111/jnc.15368] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/31/2021] [Accepted: 04/12/2021] [Indexed: 12/17/2022]
Abstract
Post-operative cognitive dysfunction (POCD) is common and is associated with poor clinical outcome. Toll-like receptor (TLR) 3 and 4 have been implied in the development of POCD. The role of TLR2, a major brain TLR, in POCD is not clear. High mobility group box-1 (HMGB1) is a delayed inflammatory mediator and may play a role in POCD. The interaction between HMGB1 and TLRs in the perioperative period is not known. We hypothesize that TLR2 contributes to the development of POCD and that HMGB1 regulates TLR2 for this effect. To test these hypotheses, 6- to 8-week old male mice were subjected to right carotid artery exposure under isoflurane anesthesia. CU-CPT22, a TLR1/TLR2 inhibitor, at 3 mg/kg was injected intraperitoneally 30 min before surgery and 1 day after surgery. Glycyrrhizin, a HMGB1 antagonist, at 200 mg/kg was injected intraperitoneally 30 min before surgery. Mice were subjected to Barnes maze and fear conditioning tests from 1 week after surgery. Hippocampus and cerebral cortex were harvested 6 hr or 12 hr after the surgery for Western blotting, ELISA, immunofluorescent staining, and chromatin immunoprecipitation. There were neuroinflammation and impairment of learning and memory in mice with surgery. Surgery increased the expression of TLR2 and TLR4 but not TLR9 in the brain of CD-1 male mice. CU-CPT22 attenuated surgery-induced neuroinflammation and cognitive impairment. Similarly, surgery induced neuroinflammation and cognitive dysfunction in C57BL/6J mice but not in TLR2-/- mice. TLR2 staining appeared in neurons and microglia. Surgery increased HMGB1 in the cell nuclei of the cerebral cortex and hippocampus. Glycyrrhizin ameliorated this increase and the increase of TLR2 in the hippocampus after surgery. Surgery also increased the amount of tlr2 DNA precipitated by an anti-HMGB1 antibody in the hippocampus. Our results suggest that TLR2 contributes to surgery-induced neuroinflammation and cognitive impairment. HMGB1 up-regulates TLR2 expression in the hippocampus after surgery to facilitate this contribution. Thus, TLR2 and HMGB1 are potential targets for reducing POCD.
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Affiliation(s)
- Fei Lin
- Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA.,Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Weiran Shan
- Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA
| | - Yuxin Zheng
- Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA.,Department of Anesthesiology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Linghui Pan
- Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Zhiyi Zuo
- Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA
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20
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Chen B, Feng M, Sheng C, Wang Y, Cao W. The risk factors for delayed recovery in patients with cardiopulmonary bypass: Why should we care? Medicine (Baltimore) 2021; 100:e23931. [PMID: 33725927 PMCID: PMC7982232 DOI: 10.1097/md.0000000000023931] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 11/27/2020] [Indexed: 01/05/2023] Open
Abstract
Cardiopulmonary bypass (CPB) is very commonly performed among the cardiovascular surgeries, and delayed recovery (DR) is a kind of serious complications in patients with CPB. It is necessary to assess the risk factors for DR in patients with CPB, to provide evidence into the management of CPB patients.Patients undergoing CPB in our hospital from January 2018 to March 2020 were included. Cases that consciousness has not recovered 12 hours after anesthesia were considered as DR. The preoperative and intraoperative variables of CPB patients were collected and analyzed. Logistic regressions were conducted to analyze the potential influencing factor.A total of 756 CPB patients were included, and the incidence of DR was 9.79%. There were significant differences on the age, aspartate aminotransferase (AST), glutamic pvruvic transaminase (ALT), blood urea nitrogen (BUN), and serum creatinine (SCr) between patients with and without DR (all P < .05); there were no significant differences in the types of surgical procedure (all P > .05); there were significant differences on the duration of CPB, duration of aortic cross clamp (ACC), duration of surgery, minimum nasopharyngeal temperature, and transfusion of packed red blood cells between patients with and without DR (all P < .05). Logistic regression analysis indicated that duration of CPB ≥132 minutes (odds ratio [OR] 4.12, 1.02-8.33), BUN ≥9 mmol/L (OR 4.05, 1.37-8.41), infusion of red blood cell suspension (OR 3.93, 1.25-7.63), duration of surgery ≥350 minutes (OR 3.17, 1.24-5.20), age ≥6 (OR 3.01, 1.38-6.84) were the independent risk factors for DR in patients with CPB (all P < .05).Extra attention and care are needed for those CPB patients with duration of CPB ≥132 minutes, BUN ≥9 mmol/L, infusion of red blood cell suspension, duration of surgery ≥350 minutes, and age ≥60.
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Affiliation(s)
| | | | | | - Yinhua Wang
- People's Hospital of Linqing City, Shandong Province, China
| | - Wenya Cao
- People's Hospital of Linqing City, Shandong Province, China
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21
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Mesenchymal Stem Cell-Derived Exosomes as New Remedy for the Treatment of Neurocognitive Disorders. Int J Mol Sci 2021; 22:ijms22031433. [PMID: 33535376 PMCID: PMC7867043 DOI: 10.3390/ijms22031433] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cell (MSC)-derived exosomes (MSC-Exo) are nano-sized extracellular vesicles enriched with MSC-sourced neuroprotective and immunomodulatory microRNAs, neural growth factors, and anti-inflammatory cytokines, which attenuate neuro-inflammation, promote neo-vascularization, induce neurogenesis, and reduce apoptotic loss of neural cells. Accordingly, a large number of experimental studies demonstrated MSC-Exo-dependent improvement of cognitive impairment in experimental animals. In this review article, we summarized current knowledge about molecular and cellular mechanisms that were responsible for MSC-Exo-based restoration of cognitive function, emphasizing therapeutic potential of MSC-Exos in the treatment of neurocognitive disorders.
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