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Bai S, Zhang G, Chen S, Wu X, Li J, Wang J, Chen D, Liu X, Wang J, Li Y, Tang Y, Tang Z. MicroRNA-451 Regulates Angiogenesis in Intracerebral Hemorrhage by Targeting Macrophage Migration Inhibitory Factor. Mol Neurobiol 2024; 61:10481-10499. [PMID: 38743209 PMCID: PMC11584486 DOI: 10.1007/s12035-024-04207-3] [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: 05/31/2023] [Accepted: 04/22/2024] [Indexed: 05/16/2024]
Abstract
Intracerebral hemorrhage (ICH) is a subtype of stroke with the highest fatality and disability rate. Up to now, commonly used first-line therapies have limited value in improving prognosis. Angiogenesis is essential to neurological recovery after ICH. Recent studies have shown that microRNA-451(miR-451) plays an important role in angiogenesis by regulating the function of vascular endothelial cells. We found miR-451 was significantly decreased in the peripheral blood of ICH patients in the acute stage. Based on the clinical findings, we conducted this study to investigate the potential regulatory effect of miR-451 on angiogenesis after ICH. The expression of miR-451 in ICH mouse model and in a hemin toxicity model of human brain microvascular endothelial cells (hBMECs) was decreased the same as in ICH patients. MiR-451 negatively regulated the proliferation, migration, and tube formation of hBMECs in vitro. MiR-451 negatively regulated the microvessel density in the perihematoma tissue and affected neural functional recovery of ICH mouse model. Knockdown of miR-451 could recovered tight junction and protect the integrity of blood-brain barrier after ICH. Based on bioinformatic programs, macrophage migration inhibitory factor (MIF) was predicted to be the target gene and identified to be regulated by miR-451 inhibiting the protein translation. And p-AKT and p-ERK were verified to be downstream of MIF in angiogenesis. These results all suggest that miR-451 will be a potential target for regulating angiogenesis in ICH.
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Affiliation(s)
- Shuang Bai
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ge Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiling Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuan Wu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiarui Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingxuan Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Danyang Chen
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xia Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahui Wang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanwei Li
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingxin Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Zhouping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Xu Y, Yu C, Zhang H, Wang T, Liu Y, Wu L, Zhong S, Hong Z. Downregulation of Brf1 Induces Liver Failure and Inhibits Hepatocellular Carcinoma Progression by Promoting Apoptosis. J Cancer 2024; 15:5577-5593. [PMID: 39308682 PMCID: PMC11414613 DOI: 10.7150/jca.97277] [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: 07/29/2024] [Indexed: 09/25/2024] Open
Abstract
The occurrence and development of hepatocellular carcinoma (HCC) are closely related to abnormal apoptosis. Brf1 is highly expressed in HCC and has clinical prognostic value. Here, attenuation of Brf1-induced apoptosis was found, and the related mechanism was explored. In the study, general bioinformatics data for Brf1 were obtained from The Human Protein Atlas (HPA). Analyses of the clinical prognostic value of Brf1 in HCC were performed with the Xiantao Academic web server using R software. The basic data were obtained from the GTEx database and TCGA database. Brf1 conditional knockout mice were obtained by repeated mating of C57BL/6 Brf1LoxP/LoxP and C57BL/6 NS5A-alb-Cre-ERT2 mice and verified by genotyping. Liver function measurements, hematoxylin and eosin staining (HE), and immunohistochemistry (IHC) were performed to explore the cause of mouse death after Brf1 knockout. The Brf1 knockdown HCC cell model was generated using lentiviral vector-based shRNA transduction. Cell proliferation assays, plate colony formation assays, anchorage-independent colony formation assays and mouse subcutaneous tumor models were used to evaluate the progression of HCC. Western blot (WB) analysis, flow cytometry, and TUNEL assays were used to detect apoptosis. DNA sequencing, transcriptomics, and proteomics analyses were carried out to explore the antiapoptotic mechanism of Brf1. We found that Brf1 was highly expressed in HCC and had clinical prognostic value. Brf1 knockout led to liver failure and hepatocyte apoptosis in mice. Downregulation of Brf1 slowed HCC cell proliferation, colony growth, and mouse subcutaneous tumor growth and increased the sensitivity of HCC cells to apoptosis induced by chemotherapy drugs. The expression of Brf1 was positively related to that of the apoptosis gene Bcl-2. The sequencing, transcriptomics and proteomics analyses consistently showed that energy metabolism played an important role in Brf1 function, that protein-protein interaction was the primary mode, and that organelles such as mitochondria were the main sites. In Conclusions, downregulation of Brf1 inhibits HCC development by inducing apoptosis. Energy metabolism plays an important role in Brf1 function. These results provide a scientific basis for combating HCC.
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Affiliation(s)
- Yaping Xu
- Key laboratory of functional and clinical translational medicine, Fujian Province University, Xiamen Medical College, Xiamen, Fujian Province,China
| | - Chundong Yu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Biology, School of Life Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Hongbin Zhang
- Endoscopy Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, Fujian Province, China
| | - Tao Wang
- Department of General Surgery, Xinglin District of the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361022, Fujian Province, China
| | - Yujian Liu
- Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, Fujian Province, China
| | - Lupeng Wu
- Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, Fujian Province, China
| | - Shuping Zhong
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Zaifa Hong
- Department of Hepato-Biliary-Pancreatic and Vascular Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, Fujian Province, China
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3
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Zhao B, Zang Y, Gui L, Xiang Y, Zhang Z, Sun X, Fan J, Huang L. The effect of miR-223-3p on endothelial cells in coronary artery disease. In Vitro Cell Dev Biol Anim 2024; 60:151-160. [PMID: 38155264 DOI: 10.1007/s11626-023-00842-7] [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: 07/29/2023] [Accepted: 12/03/2023] [Indexed: 12/30/2023]
Abstract
Endothelial cell damage and dysfunction are crucial factors in the development and early stages of coronary artery disease (CAD) and apoptosis plays a significant role in this process. In this study, We aimed to simulate the CAD vascular microenvironment by treating endothelial cells with tumor necrosis factor alpha (TNF-α) to construct an endothelial cell apoptosis model. Our findings revealed that the TNF-α model resulted in increased micro-RNA 223-3p (miR-223-3p) mRNA and Bax protein expression, decreased kruppel-like factor 15 (KLF15) and Bcl-2 protein expression, and decreased cell viability. More importantly, in the TNF-α-induced endothelial cell apoptosis model, transfection with the miR-223-3p inhibitor reversed the effects of TNF-α on Bcl-2, Bax expression. We transfected miRNA-223-3p mimics or inhibitors into endothelial cells and assessed miR-223-3p levels using RT-PCR. Cell viability was detected using CCK8. Western blot technology was used to detect the expression of Bcl-2, Bax, and KLF15. In summary, this study demonstrates the role and possible mechanism of miR-223-3p in endothelial cells during CAD, suggesting that miR-223-3p may serve as a promising therapeutic target in CAD by regulating KLF15.
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Affiliation(s)
- Boxin Zhao
- Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Yunhui Zang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Lin Gui
- Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Yingyu Xiang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Zhiyong Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Xueyuan Sun
- Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Jingyao Fan
- Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China
| | - Lijuan Huang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
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Si Y, Liu L, Fan Z. Mechanisms and effects of NLRP3 in digestive cancers. Cell Death Discov 2024; 10:10. [PMID: 38182564 PMCID: PMC10770122 DOI: 10.1038/s41420-023-01783-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/09/2023] [Accepted: 12/15/2023] [Indexed: 01/07/2024] Open
Abstract
Inflammasomes are thought to be important mediators of host defense against microbial pathogens and maintenance of gastrointestinal tract homeostasis. They can modulate caspase-1 to promote IL-18 and IL-1β secretion and promote phagocytosis induced by bacterial pathogens. NLRP3 is an inflammasome comprising a multiprotein complex assembled by pattern recognition receptors in the cell cytoplasm. It is a crucial component of the innate immune system. Dysregulation of NLRP3 may contribute to inflammatory diseases and intestinal cancers. Recent research suggests that NLRP3 plays an essential role in tumor development; therefore, intensive study of its mechanism is warranted as it could play a key role in the treatment of digestive system tumors. In this review, we discuss the mechanism and role of NLRP3 in tumors of the digestive system and response strategies to modulate NLRP3 for potential use in tumor treatment.
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Affiliation(s)
- Yuxin Si
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China
- Department of General Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Lei Liu
- Laboratory of Pathogenic Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Zhe Fan
- Department of General Surgery, The Third People's Hospital of Dalian, Dalian Medical University, Dalian, China.
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Sergi CM. MASLD and aspartame: are new studies in the horizon? Front Med (Lausanne) 2023; 10:1266918. [PMID: 38143439 PMCID: PMC10739386 DOI: 10.3389/fmed.2023.1266918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 11/17/2023] [Indexed: 12/26/2023] Open
Abstract
Fatty liver disease has been on the rise in the past few decades, and there is no hope that it will stop. The terminology change that has been recently proposed may not be sufficient to advocate for a reduction of steatogenic foods and a change in lifestyle. A course change may be supported by the recent labeling of aspartame sweetener as a possible carcinogenic compound by the International Association for Research on Cancer (IARC), an agency of the World Health Organization (WHO). Aspartame sweeteners and other edulcorating molecular compounds besides colorings may trigger liver cancer other than fatty liver disease, despite limited data supporting it. An essential bias in human cohort studies is indeed the exclusion of all confounding factors, which may be barely impossible for human studies. In this perspective, we suggest that the activation of the NOD-like receptor-enclosing protein 3 (NLRP3) inflammasome and the stimulation of the tumor suppression gene TP53 may be critical in the progression from fatty liver to liver inflammation and liver cancer. Aspartame reduces a transcriptional coactivator, precisely the peroxisomal proliferator-initiated receptor-γ (gamma) coactivator 1-α (alpha) (or PGC1α). This coactivator upregulates mitochondrial bioformation, oxidative phosphorylation, respiratory capacity, and fatty acid β-oxidation. Aspartame acts in this way, probably through the activation of TP53. These events have been accountable for the variations in the lipid outline in serum and total lipid storage as well as for the impairment of gluconeogenesis in the liver, as supported by the downregulation of the gluconeogenic enzymes in experimental animals, and may be relevant in humans as well.
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Affiliation(s)
- Consolato M. Sergi
- Department of Laboratory Medicine, University of Alberta, Edmonton, AB, Canada
- Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada
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Arrè V, Scialpi R, Centonze M, Giannelli G, Scavo MP, Negro R. The 'speck'-tacular oversight of the NLRP3-pyroptosis pathway on gastrointestinal inflammatory diseases and tumorigenesis. J Biomed Sci 2023; 30:90. [PMID: 37891577 PMCID: PMC10612184 DOI: 10.1186/s12929-023-00983-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/23/2023] [Indexed: 10/29/2023] Open
Abstract
The NLRP3 inflammasome is an intracellular sensor and an essential component of the innate immune system involved in danger recognition. An important hallmark of inflammasome activation is the formation of a single supramolecular punctum, known as a speck, per cell, which is the site where the pro-inflammatory cytokines IL-1β and IL-18 are converted into their bioactive form. Speck also provides the platform for gasdermin D protein activation, whose N-terminus domain perforates the plasma membrane, allowing the release of mature cytokines alongside with a highly inflammatory form of cell death, namely pyroptosis. Although controlled NLRP3 inflammasome-pyroptosis pathway activation preserves mucosal immunity homeostasis and contributes to host defense, a prolonged trigger is deleterious and could lead, in genetically predisposed subjects, to the onset of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, as well as to gastrointestinal cancer. Experimental evidence shows that the NLRP3 inflammasome has both protective and pathogenic abilities. In this review we highlight the impact of the NLRP3-pyroptosis axis on the pathophysiology of the gastrointestinal tract at molecular level, focusing on newly discovered features bearing pro- and anti-inflammatory and neoplastic activity, and on targeted therapies tested in preclinical and clinical trials.
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Affiliation(s)
- Valentina Arrè
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Rosanna Scialpi
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Matteo Centonze
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Maria Principia Scavo
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy
| | - Roberto Negro
- Personalized Medicine Laboratory, National Institute of Gastroenterology "S. de Bellis", IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, BA, Italy.
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7
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Han X, Liu K, Gao F, Yang M, Wang F. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene. Open Med (Wars) 2023; 18:20230754. [PMID: 37533740 PMCID: PMC10390750 DOI: 10.1515/med-2023-0754] [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: 12/26/2022] [Revised: 06/23/2023] [Accepted: 06/26/2023] [Indexed: 08/04/2023] Open
Abstract
Irreversible cardiomyopathy was caused by the therapeutic of anthracyclines in the chemotherapy of cancers. The cell apoptosis and autophagy were induced by anthracyclines in AC16 cells. MiR-223-3p ascends in anthracycline-treated AC16, but the expression of nuclear factor I-A (NFIA) was specifically down-regulated. However, the underlying molecular mechanism between NFIA and miR-223-3p is unclear now in AC16 cells. In our research, NFIA expression was dampened in AC16 cells by miR-223-3p mimics. Additionally, miR-223-3p knockdown hindered the apoptosis and autophagy in anthracycline-treated AC16. Furthermore, NFIA was predicted and verified as a miR-223-3p's downstream target and rescued the functions of miR-223-3p. These findings illustrated that miR-223-3p advances anthracycline-stimulated cardiomyocyte damage progression by targeting NFIA, implying the promising therapeutic function of miR-223-3p on cardiomyocyte damage in cancer patients.
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Affiliation(s)
- Xiao Han
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226001, China
| | - Kun Liu
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Fumin Gao
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Mingjun Yang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
| | - Fei Wang
- Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China
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Xu L, Cheng J, Li Z, Wen X, Sun Y, Xia M, Leng J. The intervention effect of Aitongxiao prescription on primary liver cancer rats was evaluated based on high-throughput miRNA sequencing and bioinformatics analysis. Front Oncol 2023; 13:1050069. [PMID: 37313461 PMCID: PMC10259654 DOI: 10.3389/fonc.2023.1050069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 04/19/2023] [Indexed: 06/15/2023] Open
Abstract
Liver cancer is a common malignant tumor known for its difficult treatment and poor prognosis. As a traditional Chinese medicine prescription, Aitongxiao prescription (ATXP) has been used in clinical treatment of primary liver cancer (PLC) for more than ten years, and its therapeutic effect is obvious and has been verified over time. However, the mechanism of ATXP in treating PLC has not been fully elucidated. This study aimed to detect the liver-protective effect of ATXP on a PLC rat model and explore its potential mechanism from the perspective of plasma extracellular vesicle miRNAs. Fifty SPF male SD rats were randomly selected, with six rats as the control group, and the remaining rats were injected with DEN to establish a primary liver cancer model. The model rats were randomly divided into the model group and the ATXP group. After 4 weeks of intervention, the liver-protective effect of ATXP was evaluated using plasma biochemical indicators and histopathological methods. Plasma extracellular vesicles were isolated and extracted, and identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. Significant differentially expressed miRNAs in extracellular vesicles were screened by Illumina sequencing to explore the therapeutic targets of ATXP and conduct functional analysis. The results showed that ATXP significantly reduced plasma liver function in PLC rats and alleviated liver pathological damage. In addition, plasma extracellular vesicles were isolated and identified. According to the results of GO and KEGG analysis, they were related to multiple biological processes and covered multiple signaling pathways (PI3K-Akt and MAPK signaling pathways, etc.). The interaction between miR-199a-3p and MAP3K4 was determined by bioinformatics methods and dual-luciferase reporter gene detection, confirming that MAP3K4 is the target gene of miR-199a-3p. In conclusion, ATXP protects the liver from DEN-induced PLC, which may be related to the regulation of plasma extracellular vesicle miR-199a-3p. This study further reveals the mechanism of ATXP in treating liver cancer and provides a theoretical basis for subsequent research.
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Affiliation(s)
- Lijing Xu
- Basic Medical College, Guangxi University of Chinese Medicine, Nanning, China
| | - Jinlai Cheng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhuoxian Li
- Basic Medical College, Guangxi University of Chinese Medicine, Nanning, China
| | - Xiaoyu Wen
- Rehabilitation College, Guilin Life and Health Career Technical College, Guilin, China
| | - Yuhao Sun
- Institute of Microbiology and Genetics, Department of Molecular Genetics, University of Göttingen, Göttingen, Germany
| | - Meng Xia
- Basic Medical College, Guangxi University of Chinese Medicine, Nanning, China
| | - Jing Leng
- Basic Medical College, Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Key Laboratory of Translational Medicine for Treating High-Incidence Infectious Diseases with Integrative Medicine, Guangxi University of Chinese Medicine, Nanning, China
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Da'as SI, Ahmed I, Hasan WH, Abdelrahman DA, Aliyev E, Nisar S, Bhat AA, Joglekar MV, Hardikar AA, Fakhro KA, Akil ASAS. The link between glycemic control measures and eye microvascular complications in a clinical cohort of type 2 diabetes with microRNA-223-3p signature. J Transl Med 2023; 21:171. [PMID: 36869348 PMCID: PMC9985290 DOI: 10.1186/s12967-023-03893-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 01/16/2023] [Indexed: 03/05/2023] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is a critical healthcare challenge and priority in Qatar which is listed amongst the top 10 countries in the world, with its prevalence presently at 17% double the global average. MicroRNAs (miRNAs) are implicated in the pathogenesis of (T2D) and long-term microvascular complications including diabetic retinopathy (DR). METHODS In this study, a T2D cohort that accurately matches the characteristics of the general population was employed to find microRNA (miRNA) signatures that are correlated with glycemic and β cell function measurements. Targeted miRNA profiling was performed in (471) T2D individuals with or without DR and (491) (non-diabetic) healthy controls from the Qatar Biobank. Discovery analysis identified 20 differentially expressed miRNAs in T2D compared to controls, of which miR-223-3p was significantly upregulated (fold change:5.16, p = 3.6e-02) and positively correlated with glucose and hemoglobin A1c (HbA1c) levels (p-value = 9.88e-04 and 1.64e-05, respectively), but did not show any significant associations with insulin or C-peptide. Accordingly, we performed functional validation using a miR-223-3p mimic (overexpression) under control and hyperglycemia-induced conditions in a zebrafish model. RESULTS Over-expression of miR-223-3p alone was associated with significantly higher glucose (42.7 mg/dL, n = 75 vs 38.7 mg/dL, n = 75, p = 0.02) and degenerated retinal vasculature, and altered retinal morphology involving changes in the ganglion cell layer and inner and outer nuclear layers. Assessment of retinal angiogenesis revealed significant upregulation in the expression of vascular endothelial growth factor and its receptors, including kinase insert domain receptor. Further, the pancreatic markers, pancreatic and duodenal homeobox 1, and the insulin gene expressions were upregulated in the miR-223-3p group. CONCLUSION Our zebrafish model validates a novel correlation between miR-223-3p and DR development. Targeting miR-223-3p in T2D patients may serve as a promising therapeutic strategy to control DR in at-risk individuals.
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Affiliation(s)
- Sahar I Da'as
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar.,Zebrafish Functional Genomics, Integrated Genomic Services Core Facility, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar
| | - Ikhlak Ahmed
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Waseem H Hasan
- Zebrafish Functional Genomics, Integrated Genomic Services Core Facility, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Doua A Abdelrahman
- Zebrafish Functional Genomics, Integrated Genomic Services Core Facility, Research Branch, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Elbay Aliyev
- Laboratory of Genomic Medicine-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Sabah Nisar
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Ajaz Ahmad Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Mugdha V Joglekar
- Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Narellan Road & Gilchrist Drive, Campbelltown, NSW, 2560, Australia
| | - Anandwardhan A Hardikar
- Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Narellan Road & Gilchrist Drive, Campbelltown, NSW, 2560, Australia.,Department of Science and Environment, Roskilde University, Universitetsvej 1, 4000, Roskilde, Denmark
| | - Khalid A Fakhro
- Laboratory of Genomic Medicine-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar.,Department of Genetic Medicine, Weill Cornell Medical College, P.O. Box 24144, Doha, Qatar
| | - Ammira S Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar. .,Laboratory of Genomic Medicine-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
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10
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Wong VCL, Wong MI, Lee VHF, Man K, Ng KTP, Cheung TT. Prognostic MicroRNA Fingerprints Predict Recurrence of Early-Stage Hepatocellular Carcinoma Following Hepatectomy. J Cancer 2023; 14:480-489. [PMID: 36860918 PMCID: PMC9969587 DOI: 10.7150/jca.79593] [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: 10/06/2022] [Accepted: 12/24/2022] [Indexed: 02/15/2023] Open
Abstract
Purpose: This study aims to develop liquid biopsy assays for early HCC diagnosis and prognosis. Methods: Twenty-three microRNAs were first consolidated as a panel (HCCseek-23 panel) based on their reported functions in HCC development. Serum samples were collected from 103 early-stage HCC patients before and after hepatectomy. Quantitative PCR and machine learning random forest models were applied to develop diagnostic and prognostic models. Results: For HCC diagnosis, HCCseek-23 panel demonstrated 81% sensitivity and 83% specificity for identifying HCC in the early-stage; it showed 93% sensitivity for identifying alpha-fetoprotein (AFP)-negative HCC. For HCC prognosis, the differential expressions of 8 microRNAs (HCCseek-8 panel: miR-145, miR-148a, miR-150, miR-221, miR-223, miR-23a, miR-374a, and miR-424) were significantly associated with disease-free survival (DFS) (Log-rank test p-value = 0.001). Further model improvement using these HCCseek-8 panel in combination with serum biomarkers (i.e. AFP, ALT, and AST) demonstrated a significant association with DFS (Log-rank p-value = 0.011 and Cox proportional hazards analyses p-value = 0.002). Conclusion: To the best of our knowledge, this is the first report to integrate circulating miRNAs, AST, ALT, AFP, and machine learning for predicting DFS in early HCC patients undergoing hepatectomy. In this setting, HCCSeek-23 panel is a promising circulating microRNA assay for diagnosis, while HCCSeek-8 panel is promising for prognosis to identify early HCC recurrence.
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Affiliation(s)
- Victor Chun-Lam Wong
- OncoSeek Limited, Hong Kong Science and Technology Parks, Hong Kong Special Administrative Region, People's Republic of China,✉ Corresponding author: Department of Surgery, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China; OncoSeek Limited, Hong Kong Science and Technology Parks, Hong Kong Special Administrative Region, People's Republic of China. E-mail addresses: (TC), (VW); Phone: (+852) 2255 3025 (TC); (+852) 3188 9335 (VW)
| | - Ming-In Wong
- OncoSeek Limited, Hong Kong Science and Technology Parks, Hong Kong Special Administrative Region, People's Republic of China
| | - Victor Ho-Fun Lee
- Department of Clinical Oncology, Queen Mary Hospital, LKS Faculty of Medicine, The Hong Kong Special Administrative Region, People's Republic of China
| | - Kwan Man
- Department of Surgery, Queen Mary Hospital, LKS Faculty of Medicine, The Hong Kong Special Administrative Region, People's Republic of China
| | - Kevin Tak-Pan Ng
- Department of Surgery, Queen Mary Hospital, LKS Faculty of Medicine, The Hong Kong Special Administrative Region, People's Republic of China
| | - Tan To Cheung
- Department of Surgery, Queen Mary Hospital, LKS Faculty of Medicine, The Hong Kong Special Administrative Region, People's Republic of China,✉ Corresponding author: Department of Surgery, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China; OncoSeek Limited, Hong Kong Science and Technology Parks, Hong Kong Special Administrative Region, People's Republic of China. E-mail addresses: (TC), (VW); Phone: (+852) 2255 3025 (TC); (+852) 3188 9335 (VW)
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11
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Zhao H, Zhang Y, Zhang Y, Chen C, Liu H, Yang Y, Wang H. The role of NLRP3 inflammasome in hepatocellular carcinoma. Front Pharmacol 2023; 14:1150325. [PMID: 37153780 PMCID: PMC10157400 DOI: 10.3389/fphar.2023.1150325] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023] Open
Abstract
Inflammasomes play an important role in innate immunity. As a signal platform, they deal with the excessive pathogenic products and cellular products related to stress and injury. So far, the best studied and most characteristic inflammasome is the NLR-family pyrin domain-containing protein 3(NLRP3) inflammasome, which is composed of NLRP3, apoptosis associated speck like protein (ASC) and pro-caspase-1. The formation of NLRP3 inflammasome complexes results in the activation of caspase-1, the maturation of interleukin (IL)-1β and IL-18, and pyroptosis. Many studies have demonstrated that NLRP3 inflammasome not only participates in tumorigenesis, but also plays a protective role in some cancers. Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Currently, due to the lack of effective treatment methods for HCC, the therapeutic effect of HCC has not been ideal. Therefore, it is particularly urgent to explore the pathogenesis of HCC and find its effective treatment methods. The increasing evidences indicate that NLRP3 inflammasome plays a vital role in HCC, however, the related mechanisms are not fully understood. Hence, we focused on the recent progress about the role of NLRP3 inflammasome in HCC, and analyzed the relevant mechanisms in detail to provide reference for the future in-depth researches.
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Affiliation(s)
- Huijie Zhao
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Yiming Zhang
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
| | - Yanting Zhang
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Chaoran Chen
- Institute of Nursing and Health, School of Nursing and Health, Henan University, Kaifeng, Henan, China
- *Correspondence: Honggang Wang, ; Chaoran Chen,
| | - Huiyang Liu
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Yihan Yang
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
| | - Honggang Wang
- Institute of Chronic Disease Risks Assessment, Henan University, Kaifeng, China
- *Correspondence: Honggang Wang, ; Chaoran Chen,
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12
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Li S, Chen Z, Zhou R, Wang S, Wang W, Liu D, Li M, Guo T. Hsa_circ_0048674 facilitates hepatocellular carcinoma progression and natural killer cell exhaustion depending on the regulation of miR-223-3p/PDL1. Histol Histopathol 2022; 37:1185-1199. [PMID: 35187630 DOI: 10.14670/hh-18-440] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Circular RNAs (circRNAs) play vital regulatory roles in human cancers, including hepatocellular carcinoma (HCC). In this study, we aimed to explore the functions of hsa_circ_0048674 in HCC development. METHODS Quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to detect hsa_circ_0048674, ubiquitin-like with PHD and RING finger domains 1 (UHRF1), microRNA-223-3p (miR-223-3p) and programmed death ligand 1 (PDL1). RNase R assay and Actinomycin D assay were employed to analyze the stability of hsa_circ_0048674. Cell Counting Kit-8 (CCK-8) assay, colony formation assay and 5-ethynyl-2'- deoxyuridine (EdU) assay were conducted to assess cell proliferation. Flow cytometry analysis, transwell assay and tube formation assay were carried out for cell apoptosis, migration, invasion and angiogenesis, respectively. Western blot assay was adopted for protein levels. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to analyze the relationship between miR-223-3p and hsa_circ_0048674 or PDL1. Murine xenograft model assay was conducted for the function of hsa_circ_0048674 in vivo. Immunohistochemistry (IHC) assay was used to detect Ki-67 level in tumor tissues. Enzyme linked immunosorbent assay (ELISA) kits were employed for the concentrations of inflammatory factors. RESULTS Hsa_circ_0048674 was highly expressed in HCC tissues and cells. Silencing of hsa_circ_0048674 repressed cell growth, migration, invasion and angiogenesis and promoted apoptosis in HCC cells in vitro and hampered tumor growth in vivo. Hsa_circ_0048674 served as an miR-223-3p sponge to alter PDL1 expression. MiR-223-3p inhibition or PDL1 overexpression restored the impacts of hsa_circ_0048674 silencing on HCC malignant behaviors. In addition, hsa_circ_0048674 knockdown promoted natural killer (NK) cell-mediated cytotoxicity to HCC cells. CONCLUSION Hsa_circ_0048674 knockdown decelerated HCC progression through the mediation of the miR-223-3p/PDL1 axis.
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Affiliation(s)
- Suihui Li
- Tumor Center, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Zhuangzhong Chen
- Tumor Center, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Ruisheng Zhou
- Institute of Tumor, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Sisi Wang
- Tumor Center, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Wenping Wang
- Tumor Center, First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - De Liu
- Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Mengquan Li
- Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Tiansheng Guo
- Department of Oncology, Panyu Hospital of Chinese Medicine, Guangzhou, Guangdong, China.
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13
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Sevoflurane-induced POCD-associated exosomes delivered miR-584-5p regulates the growth of human microglia HMC3 cells through targeting BDNF. Aging (Albany NY) 2022; 14:9890-9907. [PMID: 36455873 PMCID: PMC9831737 DOI: 10.18632/aging.204398] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 11/17/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND Inhalation of sevoflurane can cause neuronal apoptosis, and cognitive disorders, inducing to the occurrence and progression of post operative cognitive dysfunction (POCD). This study aimed to explore the roles of sevoflurane-induced POCD-associated exosomes on HMC3 cells and its related mechanisms. METHODS Exosomes were isolated from the plasma of sevoflurane-induced POCD or non-POCD patients, and were then sent for small RNA sequencing. Real-time quantitative PCR (RT-qPCR) was used to verify the sequencing results, and miR-584-5p was chosen for subsequent study. HMC3 cells were respectively transfected with POCD-derived exosomes and miR-584-5p mimics, and cell viability and apoptosis were measured. Dual-luciferase reporter gene assay was applied to confirm the target of miR-584-5p. RESULTS After sequencing, 301 differentially expressed miRNAs were identified, including 184 up-regulated miRNAs and 117 down-regulated miRNAs, and were significantly enriched in 3577 GO terms and 121 KEGG pathways. Due to the high level of miR-584-5p in sevoflurane-treated POCD-derived exosomes, HMC3 cells with miR-584-5p enrichment were successfully established. Compared with the control group, POCD-derived exosomes and miR-584-5p significantly inhibited viability and promoted apoptosis of HMC3 cells (P < 0.05). The IL-1β and TNF-α levels were significantly increased after POCD-derived exosomes and miR-584-5p mimics treatment compared to the control group (P < 0.05). Besides, POCD-derived exosomes and miR-584-5p mimics significantly down-regulated the expression levels of BDNF and p-TrkB, and up-regulated Caspase 3 and IL-1β. Finally, BDNF was confirmed to be the target of miR-584-5p. CONCLUSIONS Sevoflurane-induced POCD-associated exosomes delivered miR-584-5p may regulate the growth of HMC3 cells via targeting BDNF.
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14
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Zhu S, Kong X, Song M, Chi M, Liu Y, Zhang P, Zhang Q, Shang P, Feng F. MiR-223-3p attenuates the migration and invasion of NSCLC cells by regulating NLRP3. Front Oncol 2022; 12:985962. [PMID: 36276078 PMCID: PMC9583869 DOI: 10.3389/fonc.2022.985962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 09/23/2022] [Indexed: 11/13/2022] Open
Abstract
Lung cancer is the malignant tumor with high invasion and metastasis, which seriously threatens public health. Previous study showed that NLRP3 could promote the occurrence of lung tumors in B(a)P-induced mice. MicroRNAs are closely related to the progression and metastasis of lung cancer by regulating target genes. However, which miRNAs affect the migration and invasion of lung cancer cells through regulating NLRP3 remains poorly defined. In this study, the miRNAs targeting NLRP3 were selected from TargetScan and miRDB database and finally miR-223-3p was chosen due to the consistent expression in both A549 and H520 cells. Then, the migration and invasion of lung cancer cells were detected with miR-223-3p mimic and inhibitor using Transwell assay, at the same time the expression of NLRP3, cleaved caspase-1, IL-1β and IL-18 was determined using Western Blot and immunohistochemistry assay. Our data demonstrated that miR-223-3p was upregulated in both A549 and H520 cells. Furthermore, the migration and invasion of A549 and H520 cells were promoted after inhibiting miR-223-3p. Besides, the levels of NLRP3, cleaved caspase-1, IL-1β and IL-18 were increased in the two lung cancer cells. And the corresponding results were contrary in miR-223-3p mimic group. Taken together, miR-223-3p attenuates the migration and invasion of NSCLC cells by regulating NLRP3, which provides evidence for the prevention and targeted treatment of NSCLC.
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Affiliation(s)
- Shasha Zhu
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Xiangbing Kong
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Mengru Song
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Mingyang Chi
- College of Medicine, Zhengzhou University, Zhengzhou, China
| | - Yitong Liu
- College of Public Health, University of Southern California, Los Angeles, CA, United States
| | - Peng Zhang
- Department of Bone and Soft Tissue Cancer, The Affiliated Cancer Hospital of Zhengzhou University (Henan Cancer Hospital), Zhengzhou, China
| | - Qiao Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Pingping Shang
- Key Laboratory of Tobacco Chemistry, Zhengzhou Tobacco Research Institute, CNTC, Zhengzhou, China
- *Correspondence: Feifei Feng, ; Pingping Shang,
| | - Feifei Feng
- College of Public Health, Zhengzhou University, Zhengzhou, China
- *Correspondence: Feifei Feng, ; Pingping Shang,
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15
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Ye D, Yao J, Du W, Chen C, Yang Y, Yan K, Li J, Xu Y, Zang S, Zhang Y, Rong X, Zhang R, Xu A, Guo J. Neutrophil Extracellular Traps Mediate Acute Liver Failure in Regulation of miR-223/Neutrophil Elastase Signaling in Mice. Cell Mol Gastroenterol Hepatol 2022; 14:587-607. [PMID: 35660025 PMCID: PMC9307949 DOI: 10.1016/j.jcmgh.2022.05.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Marked enhancement of neutrophil infiltration in the liver is a hallmark of acute liver failure (ALF), a severe life-threatening disease with varying etiologies. However, the mechanisms and pathophysiological role corresponding to hepatic neutrophil infiltration during ALF development remain poorly characterized. METHODS Experimental ALF was induced in 10-week-old male microRNA-223 (miR-223) knockout (KO) mice, neutrophil elastase (NE) KO mice, and wild-type controls by intraperitoneal injection of galactosamine hydrochloride and lipopolysaccharide. Age-matched mice were injected with phosphate-buffered saline and served as vehicle controls. RESULTS Mouse liver with ALF showed evident formation of neutrophil extracellular traps (NETs), which were enhanced markedly in miR-223 KO mice. The blockade of NETs by pharmacologic inhibitor GSK484 significantly attenuated neutrophil infiltration and massive necrosis in mouse liver with ALF. ALF-related hepatocellular damage and mortality in miR-223 KO mice were aggravated significantly and accompanied by potentiated neutrophil infiltration in the liver when compared with wild-type controls. Transcriptomic analyses showed that miR-223 deficiency in bone marrow predominantly caused the enrichment of pathways involved in neutrophil degranulation. Likewise, ALF-induced hepatic NE enrichment was potentiated in miR-223 KO mice. Genetic ablation of NE blunted the formation of NETs in parallel with significant attenuation of ALF in mice. Pharmaceutically, pretreatment with the NE inhibitor sivelestat protected mice against ALF. CONCLUSIONS The present study showed the miR-223/NE axis as a key modulator of NETs, thereby exacerbating oxidative stress and neutrophilic inflammation to potentiate hepatocellular damage and liver necrosis in ALF development, and offering potential targets against ALF.
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Affiliation(s)
- Dewei Ye
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China,Guangdong Traditional Chinese Medicine Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China,Correspondence Address correspondence to: Dewei Ye, PhD, Lab 406, 4th Floor, Science and Technology Building, Guangdong Pharmaceutical University, 280 Waihuan East Road, Guangzhou Higher Education Mega, Guangzhou, 510006, China.
| | - Jianyu Yao
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China,Guangdong Traditional Chinese Medicine Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Wenfa Du
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China,Guangdong Traditional Chinese Medicine Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Cuishan Chen
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China,Guangdong Traditional Chinese Medicine Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yong Yang
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China,Guangdong Traditional Chinese Medicine Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Kaixuan Yan
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China,Guangdong Traditional Chinese Medicine Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Jufei Li
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China,Guangdong Traditional Chinese Medicine Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Metabolic Phenotyping in Model Animals, Guangdong Pharmaceutical University, Guangzhou, China
| | - Ying Xu
- School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, China
| | - Shufei Zang
- Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China
| | - Yuying Zhang
- Central Laboratory, Shenzhen Longhua Maternity and Child Healthcare Hospital, Shenzhen, China
| | - Xianglu Rong
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China,Guangdong Traditional Chinese Medicine Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China
| | - Rongxin Zhang
- Guangdong Province Key Laboratory for Biotechnology Drug Candidates, Institute of Basic Medical Sciences, Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China,Prof. Aimin Xu, State Key Laboratory of Pharmaceutical Biotechnology, and Department of Medicine, The University of Hong Kong, Room L8-39, Lab Block, 21 Sassoon Road, Hong Kong. Fax: +00852-2816 2095.
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou, China,Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangdong Pharmaceutical University, Guangzhou, China,Guangdong Traditional Chinese Medicine Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China,Prof. Jiao Guo, Room 403, 4th Floor, Science and Technology Building, Guangdong Pharmaceutical University, 280 Waihuan East Road, Guangzhou Higher Education Mega, 510006, China.
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16
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Öksüz Z, Üçbilek E, Serin MS, Yaraş S, Temel GÖ, Sezgin O. hsa-miR-17-5p: A Possible Predictor of Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir ± Ribavirin Therapy Efficacy in Hepatitis C Infection. Curr Microbiol 2022; 79:186. [PMID: 35524830 DOI: 10.1007/s00284-022-02882-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 04/18/2022] [Indexed: 11/25/2022]
Abstract
Although persistent sustained viral response rates are increased in hepatitis C infection following administration of direct-acting antiviral (DAA) agents, the pre-use predictive parameters of these antivirals and the clinical progression in patients post-treatment remain unknown. To obtain data pertaining to the predictive parameters prior to the use of ombitavir/paritaprevir/ritonavir + dasabuvir and the clinical progression in patients following antiviral treatment. The expression profiles of miR-223-3p, miR-17-5p, miR-24-3p, and TLR2 - 196 to - 174 del/ins polymorphisms from the blood/serum of 34 hepatitis C virus (HCV)-infected patients pre- and post-ombitavir/paritaprevir/ritonavir + dasabuvir treatment were determined by RT-qPCR. The expression levels of miR-17-5p (P < 0.001) and miR-24-3p (P = 0.011) were significantly downregulated post-treatment as compared with those pre-treatment; however, there was no significant difference between these two groups in terms of miR-223-3p expression. In addition, there was no significant difference in TLR2 genotype or allele distribution between pre-and post-treatment (P > 0.05); nevertheless, the TLR2 del allele was decreased post-treatment (16.2%) as compared with that pre-treatment (19.1%), although the difference was not statistically significant. Moreover, a significant difference was found between the mRNA levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and HCV RNA pre-and post-treatment (P < 0.05). Further, miR-17-5p expression correlated with both ALT and AST mRNA levels post-treatment (P.
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Affiliation(s)
- Zehra Öksüz
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
| | - Enver Üçbilek
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Mehmet Sami Serin
- Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Serkan Yaraş
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Gülhan Örekici Temel
- Department of Biostatistics, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Orhan Sezgin
- Department of Gastroenterology, Faculty of Medicine, Mersin University, Mersin, Turkey
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17
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Xue C, Gu X, Bao Z, Su Y, Lu J, Li L. The Mechanism Underlying the ncRNA Dysregulation Pattern in Hepatocellular Carcinoma and Its Tumor Microenvironment. Front Immunol 2022; 13:847728. [PMID: 35281015 PMCID: PMC8904560 DOI: 10.3389/fimmu.2022.847728] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/04/2022] [Indexed: 12/16/2022] Open
Abstract
HCC is one of the most common malignant tumors and has an extremely poor prognosis. Accumulating studies have shown that noncoding RNA (ncRNA) plays an important role in hepatocellular carcinoma (HCC) development. However, the details of the related mechanisms remain unclear. The heterogeneity of the tumor microenvironment (TME) calls for ample research with deep molecular characterization, with the hope of developing novel biomarkers to improve prognosis, diagnosis and treatment. ncRNAs, particularly microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have been found to be correlated with HCC neogenesis and progression. In this review, we summarized the aberrant epigenetic and genetic alterations caused by dysregulated ncRNAs and the functional mechanism of classical ncRNAs in the regulation of gene expression. In addition, we focused on the role of ncRNAs in the TME in the regulation of tumor cell proliferation, invasion, migration, immune cell infiltration and functional activation. This may provide a foundation for the development of promising potential prognostic/predictive biomarkers and novel therapies for HCC patients.
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Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhengyi Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yuanshuai Su
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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18
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Gu J, Xu H, Chen Y, Li N, Hou X. MiR-223 as a Regulator and Therapeutic Target in Liver Diseases. Front Immunol 2022; 13:860661. [PMID: 35371024 PMCID: PMC8965842 DOI: 10.3389/fimmu.2022.860661] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 02/23/2022] [Indexed: 12/20/2022] Open
Abstract
MicroRNAs (miRNAs) are endogenous non-coding single-stranded small molecule RNAs consisting of 20–24 nucleotides that are highly conserved in species evolution. Expression of miRNAs is strictly tissue-specific, and it is chronological in fungi and plants, as well as in animals. MiR-223 has been shown to play a key role in innate immunity, and dysregulation of its expression contributes to the pathogenesis of multiple inflammatory diseases, and cancers. In this article the biosynthesis and functions of miR-223 in innate immunity are reviewed, and the role of miR-223 in liver physiopathology and therapeutic prospects are highlighted.
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Affiliation(s)
- Jiarong Gu
- School of Medicine, Ningbo University, Ningbo, China
| | - Hao Xu
- School of Medicine, Ningbo University, Ningbo, China
| | - Yandong Chen
- School of Medicine, Ningbo University, Ningbo, China
| | - Na Li
- School of Medicine, Ningbo University, Ningbo, China
| | - Xin Hou
- School of Medicine, Ningbo University, Ningbo, China.,The Affiliated Hospital of Medical School, Ningbo University, Ningbo, China
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19
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Gedefaw L, Ullah S, Lee TMH, Yip SP, Huang CL. Targeting Inflammasome Activation in COVID-19: Delivery of RNA Interference-Based Therapeutic Molecules. Biomedicines 2021; 9:1823. [PMID: 34944639 PMCID: PMC8698532 DOI: 10.3390/biomedicines9121823] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 11/22/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023] Open
Abstract
Mortality and morbidity associated with COVID-19 continue to be significantly high worldwide, owing to the absence of effective treatment strategies. The emergence of different variants of SARS-CoV-2 is also a considerable source of concern and has led to challenges in the development of better prevention and treatment strategies, including vaccines. Immune dysregulation due to pro-inflammatory mediators has worsened the situation in COVID-19 patients. Inflammasomes play a critical role in modulating pro-inflammatory cytokines in the pathogenesis of COVID-19 and their activation is associated with poor clinical outcomes. Numerous preclinical and clinical trials for COVID-19 treatment using different approaches are currently underway. Targeting different inflammasomes to reduce the cytokine storm, and its associated complications, in COVID-19 patients is a new area of research. Non-coding RNAs, targeting inflammasome activation, may serve as an effective treatment strategy. However, the efficacy of these therapeutic agents is highly dependent on the delivery system. MicroRNAs and long non-coding RNAs, in conjunction with an efficient delivery vehicle, present a potential strategy for regulating NLRP3 activity through various RNA interference (RNAi) mechanisms. In this regard, the use of nanomaterials and other vehicle types for the delivery of RNAi-based therapeutic molecules for COVID-19 may serve as a novel approach for enhancing drug efficacy. The present review briefly summarizes immune dysregulation and its consequences, the roles of different non-coding RNAs in regulating the NLRP3 inflammasome, distinct types of vectors for their delivery, and potential therapeutic targets of microRNA for treatment of COVID-19.
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Affiliation(s)
- Lealem Gedefaw
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China; (L.G.); (S.U.)
| | - Sami Ullah
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China; (L.G.); (S.U.)
| | - Thomas M. H. Lee
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong, China;
| | - Shea Ping Yip
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China; (L.G.); (S.U.)
| | - Chien-Ling Huang
- Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, China; (L.G.); (S.U.)
- Research Institute for Future Food, The Hong Kong Polytechnic University, Hong Kong, China
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20
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Houshmandfar S, Saeedi-Boroujeni A, Rashno M, Khodadadi A, Mahmoudian-Sani MR. miRNA-223 as a regulator of inflammation and NLRP3 inflammasome, the main fragments in the puzzle of immunopathogenesis of different inflammatory diseases and COVID-19. Naunyn Schmiedebergs Arch Pharmacol 2021; 394:2187-2195. [PMID: 34590186 PMCID: PMC8481106 DOI: 10.1007/s00210-021-02163-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022]
Abstract
Millions of people around the world are involved with COVID-19 due to infection with SARS-CoV-2. Virological features of SARS-CoV-2, including its genomic sequence, have been identified but the mechanisms governing COVID-19 immunopathogenesis have remained uncertain. miR-223 is a hematopoietic cell-derived miRNA that is implicated in regulating monocyte-macrophage differentiation, neutrophil recruitment, and pro-inflammatory responses. The miR-223 controls inflammation by targeting a variety of factors, including TRAF6, IKKα, HSP-70, FOXO1, TLR4, PI3K/AKT, PARP-1, HDAC2, ITGB3, CXCL2, CCL3, IL-6, IFN-I, STMN1, IL-1β, IL-18, Caspase-1, NF-κB, and NLRP3. The key role of miR-223 in regulating the inflammatory process and its antioxidant and antiviral role can suggest this miRNA as a potential regulatory factor in the process of COVID-19 immunopathogenesis.
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Affiliation(s)
- Sheyda Houshmandfar
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Saeedi-Boroujeni
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Abadan University of Medical Sciences, Abadan, Iran.,Immunology Today, Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohammad Rashno
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Cellular & Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Khodadadi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad-Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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21
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Wei L, Wang G, Yang C, Zhang Y, Chen Y, Zhong C, Li Q. MicroRNA-550a-3-5p controls the brain metastasis of lung cancer by directly targeting YAP1. Cancer Cell Int 2021; 21:491. [PMID: 34530822 PMCID: PMC8444378 DOI: 10.1186/s12935-021-02197-z] [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: 05/21/2021] [Accepted: 09/06/2021] [Indexed: 02/08/2023] Open
Abstract
Background This study aimed to explore the potential regulatory mechanisms of brain metastasis and to identify novel underlying targets of lung cancer with brain metastasis. Methods Exosomes were isolated from the plasma of lung cancer patients with or without brain metastasis and low or high metastatic lung cancer cells, and small RNA from plasma-derived exosomes were sequenced. Differentially expressed miRNAs (DE-miRNAs) were identified. Human brain microvascular endothelial cells (HBMECs) were transfected with miR-550a-3-5p mimics or inhibitors and exosomes. Cell viability, migration, and apoptosis/cycle were determined using Cell Counting Kit-8 (CCK-8), Transwell, and flow cytometry, respectively. Western blotting was used to measure the expression of the associated proteins. Finally, a dual-luciferase reporter gene assay was performed to confirm the miR-550a-3-5p target. Results Transmission electron microscopy, NanoSight, and western blotting showed that exosomes were successfully isolated and cell-derived exosomes could be taken up by HBMECs. Sequencing identified 22 DE-miRNAs which were enriched in the MAPK, chemokine, PPAR, and Wnt signaling pathways. MiR-550a-3-5p was significantly enriched in brain metastatic exosomes. Cellular experiments showed that miR-550a-3-5p and exosome enrichment significantly inhibited cell viability and migration, promoted apoptosis, and regulated the cell cycle of HBMECs compared with the controls (P < 0.05). Compared with the controls, high levels of both miR-550a-3-5p and exosomes markedly upregulated cleaved-PARP expression, but downregulated the expression of pRB, CDK6, YAP1, CTGF, and CYR61 (P < 0.05). Finally, YAP1 was confirmed to bind directly to miR-550a-3-5p. Conclusion Our results indicate that miR-550a-3-5p and YAP1 may be novel potential targets for controlling brain metastasis. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-02197-z.
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Affiliation(s)
- Liang Wei
- Department of Neurosurgery, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Guangxue Wang
- Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Cheng Yang
- Department of Neurosurgery, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Yanfei Zhang
- Department of Neurosurgery, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Yiming Chen
- Department of Neurosurgery, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Chunlong Zhong
- Department of Neurosurgery, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China.
| | - Qinchuan Li
- Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China. .,Department of Cardiothoracic Surgery, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China.
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22
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Wong VCL, Wong MI, Lam CT, Lung ML, Lam KO, Lee VHF. Hallmark microRNA signature in liquid biopsy identifies hepatocellular carcinoma and differentiates it from liver metastasis. J Cancer 2021; 12:4585-4594. [PMID: 34149922 PMCID: PMC8210546 DOI: 10.7150/jca.59933] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/19/2021] [Indexed: 12/25/2022] Open
Abstract
Purpose: This study aims to develop a liquid biopsy assay to identify HCC and differentially diagnose hepatocellular carcinoma (HCC) from colorectal carcinoma (CRC) liver metastasis. Methods: Thirty-two microRNAs (“HallMark-32” panel) were designed to target the ten cancer hallmarks in HCC. Quantitative PCR and supervised machine learning models were applied to develop an HCC-specific diagnostic model. One hundred thirty-three plasma samples from intermediate-stage HCC patients, colorectal cancer (CRC) patients with liver metastasis, and healthy individuals were examined. Results: Six differentially expressed microRNAs (“Signature-Six” panel) were identified after comparing HCC and healthy individuals. The microRNA miR-221-3p, miR-223-3p, miR-26a-5p, and miR-30c-5p were significantly down-regulated in the plasma of HCC samples, while miR-365a-3p and miR-423-3p were significantly up-regulated. Machine learning models combined with HallMark-32 and Signature-Six panels demonstrated promising performance with an AUC of 0.85-0.96 (p ≤ 0.018) and 0.84-0.93 (p ≤ 0.021), respectively. Further modeling improvement by adjusting sample quality variation in the HallMark-32 panel boosted the accuracy to 95% ± 0.01 and AUC to 0.991 (95% CI 0.96-1, p = 0.001), respectively. Even in alpha fetoprotein (AFP)-negative (< 20ng/mL) HCC samples, HallMark-32 still achieved 100% sensitivity in identifying HCC. The Cancer Genome Atlas (TCGA, n=372) analysis demonstrated a significant association between HallMark-32 and HCC patient survival. Conclusion: To the best of our knowledge, this is the first report to utilize circulating miRNAs and machine learning to differentiate HCC from CRC liver metastasis. In this setting, HallMark-32 and Signature-Six are promising non-invasive tests for HCC differential diagnosis and distinguishing HCC from healthy individuals.
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Affiliation(s)
- Victor Chun-Lam Wong
- OncoSeek Limited, Hong Kong Science and Technology Parks, Hong Kong Special Administrative Region, People's Republic of China
| | - Ming-In Wong
- OncoSeek Limited, Hong Kong Science and Technology Parks, Hong Kong Special Administrative Region, People's Republic of China
| | - Chi-Tat Lam
- OncoSeek Limited, Hong Kong Science and Technology Parks, Hong Kong Special Administrative Region, People's Republic of China
| | - Maria Li Lung
- Department of Clinical Oncology, LKS Faculty of Medicine, The Hong Kong Special Administrative Region, People's Republic of China
| | - Ka-On Lam
- Department of Clinical Oncology, LKS Faculty of Medicine, The Hong Kong Special Administrative Region, People's Republic of China
| | - Victor Ho-Fun Lee
- Department of Clinical Oncology, LKS Faculty of Medicine, The Hong Kong Special Administrative Region, People's Republic of China
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23
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Targeting the NLRP3 Inflammasome as a New Therapeutic Option for Overcoming Cancer. Cancers (Basel) 2021; 13:cancers13102297. [PMID: 34064909 PMCID: PMC8151587 DOI: 10.3390/cancers13102297] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/04/2021] [Accepted: 05/06/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammasomes are multiprotein complexes that regulate the maturation and secretion of the proinflammatory cytokines interleukin-1beta (IL-1β and interleukin-18 (IL-18) in response to various intracellular stimuli. As a member of the inflammasomes family, NLRP3 is the most studied and best characterized inflammasome and has been shown to be involved in several pathologies. Recent findings have made it increasingly apparent that the NLRP3 inflammasome may also play a central role in tumorigenesis, and it has attracted attention as a potential anticancer therapy target. In this review, we discuss the role of NLRP3 in the development and progression of cancer, offering a detailed summary of NLRP3 inflammasome activation (and inhibition) in the pathogenesis of various forms of cancer. Moreover, we focus on the therapeutic potential of targeting NLRP3 for cancer therapy, emphasizing how understanding NLRP3 inflammasome-dependent cancer mechanisms might guide the development of new drugs that target the inflammatory response of tumor-associated cells.
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24
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Balahura LR, Selaru A, Dinescu S, Costache M. Inflammation and Inflammasomes: Pros and Cons in Tumorigenesis. J Immunol Res 2020; 2020:2549763. [PMID: 33015196 PMCID: PMC7520695 DOI: 10.1155/2020/2549763] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/13/2020] [Accepted: 09/01/2020] [Indexed: 12/17/2022] Open
Abstract
Over the past decade, it has been well established that tumorigenesis is affected by chronic inflammation. During this event, proinflammatory cytokines are produced by numerous types of cells, such as fibroblasts, endothelial cells, macrophages, and tumor cells, and are able to promote the initiation, progression, and metastasis of different types of cancer. When persistent inflammation occurs, activation of inflammasome complexes is initiated, leading to its assembly and further activation of caspase, production of proinflammatory cytokines, and pyroptosis induction. The function of this multiprotein complex is not only to reassure inflammation and to promote cell death, through caspase activity, but also has been identified to have significant contributions during tumorigenesis and cancer development. So far, many efforts have been made in order to extend the knowledge of inflammasome implications and how its components could be targeted as therapeutic agents. Additionally, microRNAs (miRNAs), evolutionary conserved noncoding molecules, have emerged as pivotal players during numerous biological events by regulating gene and protein expression. Therefore, dysregulations of miRNA expressions have been correlated with inflammation during tumor development. In this review, we aim to highlight the dual role of inflammasomes and proinflammatory cytokines during carcinogenesis paired with the distinguished effects of miRNAs upon inflammation cascades during tumor growth and progression.
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Affiliation(s)
- Liliana R Balahura
- Department of Immunology, National Institute for Research and Development in Biomedical Pathology and Biomedical Sciences "Victor Babes", Bucharest 050096, Romania
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest 050095, Romania
| | - Aida Selaru
- Department of Immunology, National Institute for Research and Development in Biomedical Pathology and Biomedical Sciences "Victor Babes", Bucharest 050096, Romania
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest 050095, Romania
| | - Sorina Dinescu
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest 050095, Romania
- The Research Institute of the University of Bucharest, Bucharest 050663, Romania
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest 050095, Romania
- The Research Institute of the University of Bucharest, Bucharest 050663, Romania
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25
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Wang L, Wang Y, Quan J. Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy. Mol Med 2020; 26:81. [PMID: 32873229 PMCID: PMC7465359 DOI: 10.1186/s10020-020-00207-w] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 07/28/2020] [Indexed: 02/06/2023] Open
Abstract
Background Activation of hepatic stellate cells (HSCs) is a prominent driver of liver fibrosis. We previously demonstrated that exosomes derived from natural killer (NK) cells (NK-Exo) attenuated TGF-β1-induced HSC activation. Herein, this study was designed to investigate the mechanism underlying the action of NK-Exo. Methods NK-Exo was isolated from NK-92MI cells and then administered into TGF-β1-treated LX-2 (human HSC line) cells. MiR-223 expression in NK-Exo was downregulated by transfecting NK-92MI cells with miR-223 inhibitor followed by exosome isolation. The HSC activation was evaluated by determining cell proliferation using CCK-8 assay and measuring the protein levels of α-SMA and CoL1A1 using western blot in LX-2 cells. The expression of miR-223 was detected by qRT-PCR. The interaction between miR-223 and ATG7 was analyzed by a dual-luciferase activity assay. The autophagy was evaluated by measuring the autophagy-related proteins using western blot. Results miR-223 was highly expressed in NK-Exo and inhibition of miR-223 expression in NK-Exo abrogated the inhibitory effect of NK-Exo on TGF-β-induced HSC activation. ATG7 was confirmed as a direct target of miR-223. Furthermore, treatment with the autophagy activator rapamycin and ATG7 overexpression in LX-2 cells abolished the HSC activation-suppressive effect of NK-Exo. Conclusion NK-Exo attenuated TGF-β-induced HSC activation by transferring miR-223 that inhibited autophagy via targeting ATG7.
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Affiliation(s)
- Ling Wang
- Department of Infectious Diseases, Xiangya Hospital of Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, China
| | - Yinghao Wang
- Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Jun Quan
- Department of Infectious Diseases, Xiangya Hospital of Central South University, No. 87 Xiangya Road, Changsha, 410008, Hunan, China.
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26
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Jiang SB, Lu YS, Liu T, Li LM, Wang HX, Wu Y, Gao XH, Chen HD. UVA influenced the SIRT1-miR-27a-5p-SMAD2-MMP1/COL1/BCL2 axis in human skin primary fibroblasts. J Cell Mol Med 2020; 24:10027-10041. [PMID: 32790210 PMCID: PMC7520305 DOI: 10.1111/jcmm.15610] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 06/10/2020] [Accepted: 06/17/2020] [Indexed: 12/21/2022] Open
Abstract
Both SIRT1 and UVA radiation are involved in cellular damage processes such as apoptosis, senescence and ageing. MicroRNAs (miRNAs) have been reported to be closely related to UV radiation, as well as to SIRT1. In this study, we investigated the connections among SIRT1, UVA and miRNA in human skin primary fibroblasts. Our results showed that UVA altered the protein level of SIRT1 in a time point–dependent manner. Using miRNA microarray, bioinformatics analysis, we found that knocking down SIRT1 could cause up‐regulation of miR‐27a‐5p and the latter could down‐regulate SMAD2, and these results were verified by qRT‐PCR or Western blot. Furthermore, UVA radiation (5 J/cm2), knocking down SIRT1 or overexpression of miR‐27a‐5p led to increased expression of MMP1, and decreased expressions of COL1 and BCL2. We also found additive impacts on MMP1, COL1 and BCL2 under the combination of UVA radiation + Sirtinol (SIRT1 inhibitor), or UVA radiation + miR‐27a‐5p mimic. SIRT1 activator resveratrol could reverse damage changes caused by UVA radiation. Besides, absent of SIRT1 or overexpression of miR‐27a‐5p increased cell apoptosis and induced cell arrest in G2/M phase. Taken together, these results demonstrated that UVA could influence a novel SIRT1‐miR‐27a‐5p‐SMAD2‐MMP1/COL1/BCL2 axis in skin primary fibroblasts, and may provide potential therapeutic targets for UVA‐induced skin damage.
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Affiliation(s)
- Shi-Bin Jiang
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
| | - Yan-Song Lu
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
| | - Tao Liu
- Department of Urinary Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Liang-Man Li
- Department of Orthopedics, The First Hospital of China Medical University, Shenyang, China
| | - He-Xiao Wang
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
| | - Yan Wu
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
| | - Xing-Hua Gao
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
| | - Hong-Duo Chen
- Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
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27
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Li P, Liu Y, He Q. Anisodamine Suppressed the Growth of Hepatocellular Carcinoma Cells, Induced Apoptosis and Regulated the Levels of Inflammatory Factors by Inhibiting NLRP3 Inflammasome Activation. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1609-1620. [PMID: 32425506 PMCID: PMC7196779 DOI: 10.2147/dddt.s243383] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 03/17/2020] [Indexed: 12/24/2022]
Abstract
Introduction Hepatocellular carcinoma (HCC) is a primary liver cancer with a 5-year incidence of over 70%. Anisodamine (ANI), an alkaloid extracted from Anisodus, has a good therapeutic effect in septic shock and morphine addiction. Our study designed to investigate the anticancer effect of anisodamine (ANI) on HCC. Materials and Methods HepG2 cells were subcutaneously injected into BALB/C nude mice and the tumor tissue was subcutaneously inoculated to construct the transplanted tumor. Mice were randomly divided into 10 groups (n = 5): control group, ANI-10 group, ANI-50 group, ANI-200 group, ANI-200+pcDNA-NLRP3 group, ANI-200+EV group, sh-NLRP3 group, ANI-200 + sh-NLRP3 group, normal group and normal+ANI-200 group. Results Studies indicated that ANI inhibited the growth of HCC xenografts and reduced liver damage in a dose-dependent manner. Besides, ANI increased the survival rate of tumor-bearing mice and suppressed the expression of NLRP3 in a dose-dependent manner. It is worth noting that NLRP3 overexpression reversed the inhibitory effect of ANI on HCC xenografts. In addition, TUNEL analysis showed that ANI-induced apoptosis of tumor cells, and NLRP3 overexpression reversed the inhibitory effect of ANI on HCC. Moreover, ANI further regulated the levels of IFN-γ, TNF-α, IL-4 and IL-27. Notably, low expression of NLRP3 enhanced the inhibitory effect of ANI on the development of HCC xenografts in mice. Discussion These findings indicate that ANI suppressed the growth of HCC cells, induced apoptosis and regulated the levels of inflammatory factors by inhibiting NLRP3 inflammasome activation.
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Affiliation(s)
- Ping Li
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Yu Liu
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
| | - Qiang He
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
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28
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Pratedrat P, Chuaypen N, Nimsamer P, Payungporn S, Pinjaroen N, Sirichindakul B, Tangkijvanich P. Diagnostic and prognostic roles of circulating miRNA-223-3p in hepatitis B virus-related hepatocellular carcinoma. PLoS One 2020; 15:e0232211. [PMID: 32330203 PMCID: PMC7182200 DOI: 10.1371/journal.pone.0232211] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Accepted: 04/09/2020] [Indexed: 02/06/2023] Open
Abstract
Background Circulating microRNAs (miRNAs) have been shown to dysregulate in many cancer types including hepatocellular carcinoma (HCC). The purpose of this study was to examine the potential diagnostic or prognostic roles of circulating miRNAs in patients with hepatitis B virus (HBV)-related HCC. Methods Paired cancerous and adjacent non-cancerous liver tissue specimens of patients with HBV-related HCC were used as a discovery set for screening 800 miRNAs by a Nanostring quantitative assay. Differentially expressed miRNAs were then examined by SYBR green quantitative RT-PCR in a validation cohort of serum samples obtained from 70 patients with HBV-related HCC, 70 HBV patients without HCC and 50 healthy controls. Results The discovery set identified miR-223-3p, miR-199a-5p and miR-451a significantly lower expressed in cancerous tissues compared with non-cancerous tissues. In the validated cohort, circulating miR-223-3p levels were significantly lower in the HCC group compared with the other groups. The combined use of serum alpha-fetoprotein and miR-223-3p displayed high sensitivity for detecting early HCC (85%) and intermediate/advanced stage HCC (100%). Additionally, serum miR-223-3p had a negative correlation with tumor size and BCLC stage. On multivariate analysis, serum miR-223-3p was identified as an independent prognostic factor of overall survival in patients with HCC. In contrast, circulating miRNA-199a-5p and miR-451a did not show any clinical benefit for the diagnosis and prognostic prediction of HCC. Conclusions Our results demonstrated that miR-223-3p was differentially expressed in cancerous compared with paired adjacent non-cancerous tissues. In addition, circulating miRNA-223-3p could represent a novel diagnostic and prognostic marker for patients with HBV-related HCC.
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Affiliation(s)
- Pornpitra Pratedrat
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pattaraporn Nimsamer
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sunchai Payungporn
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nutcha Pinjaroen
- Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- * E-mail:
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29
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Schölwer I, Habib P, Voelz C, Rolfes L, Beyer C, Slowik A. NLRP3 Depletion Fails to Mitigate Inflammation but Restores Diminished Phagocytosis in BV-2 Cells After In Vitro Hypoxia. Mol Neurobiol 2020; 57:2588-2599. [PMID: 32239449 DOI: 10.1007/s12035-020-01909-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 03/23/2020] [Indexed: 12/30/2022]
Abstract
Post-hypoxic/ischemic neuroinflammation is selectively driven by sterile inflammation, which implies the interplay of brain-intrinsic immune cells with other neural cells and immigrated peripheral immune cells. The resultant inflammatory cascade evolves extra- and intracellular pathogen and danger-associated receptors. The latter interacts with multiprotein complexes termed inflammasomes. The NLRP3 inflammasome is one of the best-described inflammasomes. However, its impact on post-ischemic neuroinflammation and its role in neuroprotection after ischemic stroke are still under debate. Microglial cells are known to be the main source of neuroinflammation; hence, we depleted NLRP3 in BV-2 microglial cells using shRNA to investigate its role in IL-1β maturation and phagocytosis after hypoxia (oxygen-glucose-deprivation (OGD)). We also examined the expression profiles of other inflammasomes (NLRC4, AIM2, ASC) and caspase-1 activity after OGD. OGD triggered caspase-1 activity and increased IL-1β secretion in BV-2 cells with no alteration after NLRP3 depletion. The expression of the AIM2 inflammasome was significantly higher after OGD in NLRP3-depleted cells, whereas NLRC4 was unaltered in all groups. Interestingly, OGD induced a complete inactivation of phagocytic activity in wild-type cells, while in NLRP3-depleted BV-2, this inactivity was restored after hypoxia. Our findings indicate a minor role of NLRP3 in the inflammatory response after hypoxic/ischemic stimulus. However, NLRP3 seems to play a pivotal role in the regulation of post-ischemic phagocytosis. This might be a prerequisite for the putative neuroprotective effect.
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Affiliation(s)
- Isabelle Schölwer
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Pardes Habib
- Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Clara Voelz
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Leoni Rolfes
- Neurology Clinic and Institute for Translational Neurology, University of Muenster, Münster, Germany
| | - Cordian Beyer
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany
- JARA-Brain, RWTH Aachen University, Aachen, Germany
| | - Alexander Slowik
- Institute of Neuroanatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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Shi C, Yang H, Zhang Z. Involvement of Nucleotide-Binding Oligomerization Domain-Like Receptor Family Pyrin Domain Containing 3 Inflammasome in the Pathogenesis of Liver Diseases. Front Cell Dev Biol 2020; 8:139. [PMID: 32211410 PMCID: PMC7075939 DOI: 10.3389/fcell.2020.00139] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 02/19/2020] [Indexed: 12/13/2022] Open
Abstract
The inflammasome is widely acknowledged for its crucial role in the pathogenesis of cancers and many neurodegenerative, metabolic, and auto-inflammatory diseases in recent years. Multiple types of inflammasomes exist. However, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most often investigated inflammasome and has come to limelight in recent studies. NLRP3 inflammasome is a multi-protein complex. Its activation can cause the cleavage of inactive pro-caspase-1 into activated caspase-1, that ultimately promotes the transformation of pro-interleukin (IL)-1β and pro-IL-18 into biologically-active IL-1β and IL-18, respectively. These processes lead to the local inflammatory responses and induce pyroptosis, causing disparaging effects. Recently, numerous studies have shown that NLRP3 inflammasome plays an important role in the pathogenesis of liver diseases, including non-alcoholic fatty liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver diseases have become a severe health burden worldwide, and there is adequate evidence indicating that the regulation of NLRP3 inflammasome acts as a guard against hazard to liver. In this review, we provide a straightforward overview of NLRP3 inflammasome as well as several frequent liver diseases. We then discuss the contribution and regulation of NLRP3 inflammasome during the pathogenesis of liver diseases, which may provide an important indication for the prevention and treatment of various liver diseases.
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Affiliation(s)
- Congjian Shi
- Provincial Key Laboratory for Developmental Biology and Neurosciences, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Hongqin Yang
- Provincial Key Laboratory for Developmental Biology and Neurosciences, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
| | - Zhenghong Zhang
- Provincial Key Laboratory for Developmental Biology and Neurosciences, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, Fuzhou, China
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31
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Macartney-Coxson D, Danielson K, Clapham J, Benton MC, Johnston A, Jones A, Shaw O, Hagan RD, Hoffman EP, Hayes M, Harper J, Langston MA, Stubbs RS. MicroRNA Profiling in Adipose Before and After Weight Loss Highlights the Role of miR-223-3p and the NLRP3 Inflammasome. Obesity (Silver Spring) 2020; 28:570-580. [PMID: 32090515 PMCID: PMC7046053 DOI: 10.1002/oby.22722] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 10/20/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Adipose tissue plays a key role in obesity-related metabolic dysfunction. MicroRNA (miRNA) are gene regulatory molecules involved in intercellular and inter-organ communication. It was hypothesized that miRNA levels in adipose tissue would change after gastric bypass surgery and that this would provide insights into their role in obesity-induced metabolic dysregulation. METHODS miRNA profiling (Affymetrix GeneChip miRNA 2.0 Array) of omental and subcutaneous adipose (n = 15 females) before and after gastric bypass surgery was performed. RESULTS One omental and thirteen subcutaneous adipose miRNAs were significantly differentially expressed after gastric bypass, including downregulation of miR-223-3p and its antisense relative miR-223-5p in both adipose tissues. mRNA levels of miR-223-3p targets NLRP3 and GLUT4 were decreased and increased, respectively, following gastric bypass in both adipose tissues. Significantly more NLRP3 protein was observed in omental adipose after gastric bypass (P = 0.02). Significant hypomethlyation of NLRP3 and hypermethylation of miR-223 were observed in both adipose tissues after gastric bypass. In subcutaneous adipose, significant correlations were observed between both miR-223-3p and miR-223-5p and glucose and between NLRP3 mRNA and protein levels and blood lipids. CONCLUSIONS This is the first report detailing genome-wide miRNA profiling of omental adipose before and after gastric bypass, and it further highlights the association of miR-223-3p and the NLRP3 inflammasome with obesity.
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Affiliation(s)
- Donia Macartney-Coxson
- Human Genomics, Institute of Environmental Science and
Research (ESR), Wellington, New Zealand
- corresponding author. Contact Info:
Donia Macartney-Coxson, Human Genomics, Institute of Environmental Science and
Research (ESR), Wellington, 5022, New Zealand. Telephone: +64 4 917 5931, Fax:
+64 4 914 0770,
| | - Kirsty Danielson
- Department of Surgery and Anaesthesia, University of Otago
Wellington, Wellington, New Zealand
| | - Jane Clapham
- Human Genomics, Institute of Environmental Science and
Research (ESR), Wellington, New Zealand
| | - Miles C Benton
- Human Genomics, Institute of Environmental Science and
Research (ESR), Wellington, New Zealand
| | - Alice Johnston
- Human Genomics, Institute of Environmental Science and
Research (ESR), Wellington, New Zealand
| | - Angela Jones
- Human Genomics, Institute of Environmental Science and
Research (ESR), Wellington, New Zealand
| | - Odette Shaw
- Arthritis and Inflammation Group, The Malaghan Institute of
Medical Research, Victoria University of Wellington, New Zealand
| | - Ronald D Hagan
- Department of Electrical Engineering & Computer
Science, University of Tennessee, Knoxville, USA
| | - Eric P Hoffman
- Department of Pharmaceutical Sciences, School of Pharmacy
and Pharmaceutical Sciences, Binghamton University - SUNY, Binghamton, NY,
USA
| | - Mark Hayes
- The Wakefield Biomedical Research Unit, Wellington, New
Zealand
| | - Jacquie Harper
- Arthritis and Inflammation Group, The Malaghan Institute of
Medical Research, Victoria University of Wellington, New Zealand
| | - Michael A Langston
- Department of Electrical Engineering & Computer
Science, University of Tennessee, Knoxville, USA
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Liu P, Chen Y, Wang B, Wang Z, Li C, Wang Y. Expression of microRNAs in the plasma of patients with acute gouty arthritis and the effects of colchicine and etoricoxib on the differential expression of microRNAs. Arch Med Sci 2019; 15:1047-1055. [PMID: 31360199 PMCID: PMC6657241 DOI: 10.5114/aoms.2018.75502] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 03/28/2018] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION To determine the microRNA (miRNA) expression profiles in the plasma of acute gouty arthritis (AGA) patients and investigate the effects of colchicine and etoricoxib treatment on the differential expression of miRNAs. MATERIAL AND METHODS Exiqon miRCURYLNA microRNA Array was used for miRNA expression profiling in AGA. Two of the 21 differentially expressed miRNAs were confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). A randomized, double-blind, parallel-controlled design was used to divide 160 AGA patients into colchicine and etoricoxib groups. Changes in 2 differentially expressed miRNAs, interleukin-1 (IL-1) β, cyclooxygenase-2 (COX-2) and joint pain scores were detected. RESULTS Compared with normal subjects and asymptomatic hyperuricemia (HUA) patients, plasma of AGA contained 21 differentially expressed miRNAs. qRT-PCR indicated specific downregulation of miR-223-3p and miR-451a in AGA. There were no statistically significant differences in the baseline characteristics between colchicine and etoricoxib groups. Furthermore, no significant difference in joint pain scores after 5- and 10-day treatment were found between groups (p > 0.05). Comparison of differences between pre- and 5-day post-treatment values confirmed that the upregulation of miR-223-3p and downregulation of IL-1β induced by colchicine were more significant than etoricoxib (p < 0.05). However, the latter outperformed the former in the upregulation of miR-451a and downregulation of COX-2 (p < 0.05). After 10-day treatment, the magnitude of miR-223-3p upregulation and IL-1β downregulation in the colchicine group was significantly higher than in the etoricoxib group, while the etoricoxib group had higher expression of miR-451a and lower expression of COX-2 than the colchicine group (p < 0.05). CONCLUSIONS In AGA patients, 21 differentially expressed miRNAs were detected in the plasma. Colchicine could upregulate miR-223-3p and downregulate IL-1β in the plasma, while etoricoxib may treat AGA by upregulating miR-451a and downregulating COX-2.
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Affiliation(s)
- Peng Liu
- Department of Endocrinology, the Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Endocrinology, Laiwu Hospital Affiliated to Taishan Medical College, Laiwu, China
| | - Ying Chen
- Department of Endocrinology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Bin Wang
- Department of Endocrinology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhongchao Wang
- Department of Endocrinology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Changgui Li
- Department of Endocrinology, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yangang Wang
- Department of Endocrinology, the Affiliated Hospital of Qingdao University, Qingdao, China
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Tezcan G, Martynova EV, Gilazieva ZE, McIntyre A, Rizvanov AA, Khaiboullina SF. MicroRNA Post-transcriptional Regulation of the NLRP3 Inflammasome in Immunopathologies. Front Pharmacol 2019; 10:451. [PMID: 31118894 PMCID: PMC6504709 DOI: 10.3389/fphar.2019.00451] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Accepted: 04/08/2019] [Indexed: 12/13/2022] Open
Abstract
Inflammation has a crucial role in protection against various pathogens. The inflammasome is an intracellular multiprotein signaling complex that is linked to pathogen sensing and initiation of the inflammatory response in physiological and pathological conditions. The most characterized inflammasome is the NLRP3 inflammasome, which is a known sensor of cell stress and is tightly regulated in resting cells. However, altered regulation of the NLRP3 inflammasome is found in several pathological conditions, including autoimmune disease and cancer. NLRP3 expression was shown to be post-transcriptionally regulated and multiple miRNA have been implicated in post-transcriptional regulation of the inflammasome. Therefore, in recent years, miRNA based post-transcriptional control of NLRP3 has become a focus of much research, especially as a potential therapeutic approach. In this review, we provide a summary of the recent investigations on the role of miRNA in the post-transcriptional control of the NLRP3 inflammasome, a key regulator of pro-inflammatory IL-1β and IL-18 cytokine production. Current approaches to targeting the inflammasome product were shown to be an effective treatment for diseases linked to NLRP3 overexpression. Although utilizing NLRP3 targeting miRNAs was shown to be a successful therapeutic approach in several animal models, their therapeutic application in patients remains to be determined.
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Affiliation(s)
- Gulcin Tezcan
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | | | - Zarema E. Gilazieva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Alan McIntyre
- Centre for Cancer Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, United Kingdom
| | - Albert A. Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Svetlana F. Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
- Department of Microbiology and Immunology, University of Nevada, Reno, Reno, NV, United States
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Jeffries J, Zhou W, Hsu AY, Deng Q. miRNA-223 at the crossroads of inflammation and cancer. Cancer Lett 2019; 451:136-141. [PMID: 30878527 DOI: 10.1016/j.canlet.2019.02.051] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 02/11/2019] [Accepted: 02/13/2019] [Indexed: 02/06/2023]
Abstract
miR-223 is an evolutionarily conserved anti-inflammatory microRNA primarily expressed in myeloid cells. miR-223 post-transcriptionally regulates many genes essential in inflammation, cell proliferation, and invasion. Recent studies show that miR-223 is either endogenously expressed or transferred in exosomes or extracellular vesicles to non-phagocytic cells including cancer cells, where it exerts biological functions. In cancerous cells, miR-223 acts either as an oncomiR promoting tumors or as a tumor suppressor in a context-dependent manner. Taken together, miR-223 can regulate tumorigenesis at multiple levels, including by suppressing the inflammatory tumor microenvironment and modulating malignancy of cancer cells.
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Affiliation(s)
- Jacob Jeffries
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Wenqing Zhou
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Alan Y Hsu
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Qing Deng
- Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA; Purdue Institute for Inflammation, Immunology, and Infectious Disease, Purdue University, West Lafayette, IN, 47907, USA; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA.
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Dadmanesh M, Ranjbar MM, Ghorban K. Inflammasomes and their roles in the pathogenesis of viral hepatitis and their related complications: An updated systematic review. Immunol Lett 2019; 208:11-18. [PMID: 30831142 PMCID: PMC7112799 DOI: 10.1016/j.imlet.2019.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 02/26/2019] [Accepted: 03/01/2019] [Indexed: 02/06/2023]
Abstract
Inflammasomes are a set of innate receptors which are the responsible molecules for activation of pro-interleukin (IL)-1β and IL-18 and induction of inflammation. Due to the key roles of the inflammasomes in the induction of inflammation, it has been hypothesized that the molecules may be the main parts of immune responses against viral infections and the tissue damage. Because some cases of viral hepatitis infections, including hepatitis B and C, are diagnosed as chronic and may be associated with various complications such as liver cirrhosis and hepatocellular carcinoma (HCC), several studies focused on the roles played by the inflammation on the pathogenesis of viral hepatitis. Based on the roles played by inflammasomes in induction of inflammation, it has been hypothesized that inflammasomes may be the main parts of the puzzle of the viral hepatitis complications. This article reviews the roles of the inflammasomes in the pathogenesis of hepatitis B and C viral infections and their complications, liver cirrhosis, and HCC.
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Affiliation(s)
- Maryam Dadmanesh
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Infectious Diseases, Medical School, Aja University of Medical Sciences, Tehran, Iran
| | - Mohammad Mehdi Ranjbar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran.
| | - Khodayar Ghorban
- Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; Department of Immunology, Medical School, Aja University of Medical Sciences, Tehran, Iran.
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Marycz K, Smieszek A, Trynda J, Sobierajska P, Targonska S, Grosman L, Wiglusz RJ. Nanocrystalline Hydroxyapatite Loaded with Resveratrol in Colloidal Suspension Improves Viability, Metabolic Activity and Mitochondrial Potential in Human Adipose-Derived Mesenchymal Stromal Stem Cells (hASCs). Polymers (Basel) 2019; 11:E92. [PMID: 30960076 PMCID: PMC6402024 DOI: 10.3390/polym11010092] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 12/27/2018] [Accepted: 01/01/2019] [Indexed: 12/22/2022] Open
Abstract
In response to the demand for new multifunctional materials characterized by high biocompatibility, hydrogel (HG) nanocomposites as a platform for bioactive compound delivery have been developed and fabricated. A specific crosslinking/copolymerization chemistry was used to construct hydrogels with a controlled network organization. The hydrogels were prepared using 3,6-anhydro-α-l-galacto-β-d-galactan (galactose hydrogel) together with resveratrol (trans-3,5,4'-trihydroxystilbene) and calcium hydroxyapatite nanoparticles. The resveratrol was introduced in three different concentrations of 0.1, 0.5, and 1 mM. Nanosized calcium hydroxyapatite was synthesized by a microwave-assisted hydrothermal technique, annealed at 500 °C for 3 h, and introduced at a concentration 10% (m/v). The morphology and structural properties of Ca10(PO₄)₆(OH)₂ and its composite were determined by using XRPD (X-ray powder diffraction) techniques, as well as the absorption and IR (infrared) spectroscopy. The average nanoparticle size was 35 nm. The water affinity, morphology, organic compound release profile, and cytocompatibility of the obtained materials were studied in detail. The designed hydrogels were shown to be materials of biological relevance and of great pharmacological potential as carriers for bioactive compound delivery. Their cytocompatibility was tested using a model of human multipotent stromal cells isolated from adipose tissue (hASCs). The biomaterials increased the proliferative activity and viability of hASCs, as well as reduced markers of oxidative stress. In light of the obtained results, it has been thought that the designed materials meet the requirements of the tissue engineering triad, and may find application in regenerative medicine, especially for personalized therapies.
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Affiliation(s)
- Krzysztof Marycz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, ul. Norwida 27B, 50-375 Wroclaw, Poland.
- Faculty of Veterinary Medicine, Equine Clinic-Equine Surgery, Justus-Liebig-University, 35392 Giessen, Germany.
| | - Agnieszka Smieszek
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, ul. Norwida 27B, 50-375 Wroclaw, Poland.
| | - Justyna Trynda
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, ul. Norwida 27B, 50-375 Wroclaw, Poland.
| | - Paulina Sobierajska
- Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okolna 2, 50-422 Wroclaw, Poland.
| | - Sara Targonska
- Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okolna 2, 50-422 Wroclaw, Poland.
| | - Lukasz Grosman
- Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okolna 2, 50-422 Wroclaw, Poland.
| | - Rafal J Wiglusz
- Institute of Low Temperature and Structure Research, Polish Academy of Sciences, Okolna 2, 50-422 Wroclaw, Poland.
- Centre for Advanced Materials and Smart Structures, Polish Academy of Sciences, Okolna 2, 50-950 Wroclaw, Poland.
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Wang TZ, Lin DD, Jin BX, Sun XY, Li N. Plasma microRNA: A novel non-invasive biomarker for HBV-associated liver fibrosis staging. Exp Ther Med 2018; 17:1919-1929. [PMID: 30783469 DOI: 10.3892/etm.2018.7117] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 09/06/2018] [Indexed: 02/06/2023] Open
Abstract
The aim of the present study was to evaluate the potential use of 7 plasma miRNAs for liver fibrosis staging in patients with chronic hepatitis B virus (HBV) infection. Relative levels of miRNAs were measured using quantitative polymerase chain reaction and used to develop a diagnostic panel. A receiver operating characteristic (ROC) curve was drawn to evaluate the performance of individual miRNAs and the whole panel. It was identified that hsa-miR-122 exhibited significantly different expression levels between F4 and F3, F2, F1, and F0 fibrosis stages (P<0.05), and between F2 and F1 stages (P=0.045); hsa-miR-146a-5p, hsa-miR-29c-3p and hsa-miR-223 exhibited significantly different expression levels between F4 and F0 stages. ROC analysis revealed that hsa-miR-122-5p, hsa-miR-223 and hsa-miR-29c-3p identified patients with ≥F2 fibrosis with area under the curve (AUC) =0.745, 0.631 and 0.670, respectively. hsa-miR-122-5p identified patients with ≥F3 disease (AUC=0.783). hsa-miR-122-5p, hsa-miR-223 and hsa-miR-29c-3p identified patients with cirrhosis with AUC=0.776, 0.617 and 0.619, respectively. The miRNA panel exhibited a higher accuracy compared with individual miRNAs in discriminating between ≥F2, ≥F3 and F4 fibrosis stages with AUC=0.904, 0.889 and 0.835, respectively. hsa-miR-122-5p, hsa-miR-146a, hsa-miR-29c and hsa-miR-223 were positively correlated with fibrosis stage. hsa-miR-122-5p and hsa-miR-381-3p were negatively correlated with alanine aminotransferase, aspartate transaminase and HBV viral DNA load. These 7 miRNAs may serve as potential biomarkers of liver fibrosis in patients with HBV-associated fibrosis. The miRNA panel may serve as a novel non-invasive method for liver fibrosis staging.
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Affiliation(s)
- Tie-Zheng Wang
- Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Dong-Dong Lin
- Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Bo-Xun Jin
- Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Xiang-Ying Sun
- Beijing QuantoBio Biotechnology Co. Ltd., Beijing Economic-Technological Development Area, Beijing 100176, P.R. China
| | - Ning Li
- Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
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Lorente L. New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma. World J Gastroenterol 2018; 24:4230-4242. [PMID: 30310256 PMCID: PMC6175764 DOI: 10.3748/wjg.v24.i37.4230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C-reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife 38320, Spain
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