|
1
|
Yu H, Xie M, Liufu X, Xu Y, Chen L. Kisspeptin-10 Prevents the Development of Cerebral Aneurysms by Reducing the Expression of Egr-1. CNS Neurosci Ther 2025; 31:e70413. [PMID: 40384564 DOI: 10.1111/cns.70413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 04/03/2025] [Accepted: 04/16/2025] [Indexed: 05/20/2025] Open
Abstract
AIMS Cerebral aneurysms (CAs) are a prevalent brain condition with poorly understood pathological features. The Kisspeptin-10 (KP-10)/G protein-coupled receptor 54 (GPR54) system is a vital neuroendocrine pathway primarily implicated in the regulation of reproductive functions and energy metabolism. This research explores the role of the KP-10/GPR54 system in CAs. MATERIALS AND METHODS Serum levels of KP-10 in CA patients and animal models were assessed using commercial ELISA kits. Mice were divided into five groups: WT, GPR54-/-, CA, CA + KP-10, and CA + GPR54-/- + KP-10. The CA profiles were evaluated using Verhoeff-van Gieson staining. Human brain microvascular endothelial cells (HBMVECs) were stimulated with Ang II (10-7 mol/L) with or without KP-10 (50, 100 nM). Angiogenic tube formation was then assessed. RESULTS We found that KP-10 levels were reduced in both CA patients and mouse models. In CA mice, Gpr54 expression in the Circle of Willis (COW) was also decreased. KP-10 reduced CA size in wild-type mice, but not in Gpr54 knockout mice. It also reduced matrix metalloproteinase-9 (MMP-9), macrophage infiltration, and vascular endothelial growth factor-A (VEGF-A) expression, effects that were absent in Gpr54 knockout mice. In vitro, KP-10 inhibited Ang II-induced proliferation, angiogenic tube formation, and VEGF-A expression in HBMVECs by reducing early growth response-1 (Egr-1). These effects were abolished when Gpr54 was knocked down, indicating that KP-10's action is dependent on Gpr54. CONCLUSION This study shows that KP-10 binding to Gpr54 inhibits Egr-1 expression, thereby suppressing MMP-9 and VEGF-A, reducing macrophage infiltration and angiogenesis, and preventing cerebral aneurysm development. Thus, the KP-10/Gpr54 system is a key therapeutic target for the treatment of cerebral aneurysms.
Collapse
Affiliation(s)
- Huimin Yu
- Department of Neurology, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, Guangdong Province, China
| | - Minghong Xie
- Department of Neurosurgery, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, Guangdong Province, China
| | - Xuancong Liufu
- Department of Neurosurgery, Dongguan Kanghua Hospital, Dongguan City, Guangdong Province, China
| | - Yezi Xu
- Department of Neurology, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, Guangdong Province, China
| | - Lei Chen
- Department of Neurosurgery, The First Dongguan Affiliated Hospital of Guangdong Medical University, Dongguan City, Guangdong Province, China
| |
Collapse
|
|
2
|
Inoko A, Soga N, Suzuki M, Kiyono T, Ikenouchi J, Kojima T, Sato Y, Saito D, Miyamoto T, Goshima N, Ito H, Kasai K. Long-term expansion of basal cells and the novel differentiation methods identify mechanisms for switching Claudin expression in normal epithelia. Sci Rep 2025; 15:12172. [PMID: 40204777 PMCID: PMC11982363 DOI: 10.1038/s41598-025-95463-3] [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: 12/09/2024] [Accepted: 03/21/2025] [Indexed: 04/11/2025] Open
Abstract
Epithelia are tightly connected cellular sheets, that shield our body from the external environment. They are continuously maintained by a pooled population of undifferentiated cells through differentiation. However, the maintenance mechanisms remain incompletely understood due to the difficulty of experimentally observing the differentiation process. To address this issue, we developed a culture method for long-term expansion of primary mammary basal cells with a set of compounds, that includes undifferentiated cells. An effective differentiation method regarding Claudin expression was also developed by simply removing compounds. To verify this differentiation-switching technique, we obtained microarray data comparing each differentiation state. Subsequent cellular analysis confirmed key transcription factors in each state: (1) EGR1 in undifferentiated basal cells is important for suppressing Claudin expression through maintaining the epithelial-mesenchymal transition (EMT) transcription factor TWIST1, (2) ELF3 in differentiated cells is important for actin organization and subsequent Claudin localization at the cell-cell border, that corresponds to the amount of GRHL3, an actin organizer. Their relevance was also observed in tissues and organoids. In summary, we present an effective tool for verifying molecular mechanisms that determine Claudin status in normal basal cell differentiation, that would be beneficial in epithelial cell biology, cancer biology, physiology, and regeneration research.
Collapse
Affiliation(s)
- Akihito Inoko
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan.
| | - Norihito Soga
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
- Department of Urology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Minako Suzuki
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Tohru Kiyono
- Project for Prevention of HPV-Related Cancer, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Junichi Ikenouchi
- Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan
| | - Takahiro Kojima
- Department of Urology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yoshikatsu Sato
- Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Japan
| | - Daisuke Saito
- Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan
| | - Tatsuo Miyamoto
- Department of Molecular and Cellular Physiology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Naoki Goshima
- Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan
| | - Hideaki Ito
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Kenji Kasai
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
| |
Collapse
|
|
3
|
Li Y, Xu F, Fang Y, Cui Y, Zhu Z, Wu Y, Tong Y, Hu J, Zhu L, Shen H. Inflammation-fibrosis interplay in inflammatory bowel disease: mechanisms, progression, and therapeutic strategies. Front Pharmacol 2025; 16:1530797. [PMID: 40093318 PMCID: PMC11906429 DOI: 10.3389/fphar.2025.1530797] [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: 11/19/2024] [Accepted: 02/05/2025] [Indexed: 03/19/2025] Open
Abstract
Background The incidence of intestinal fibrosis in Inflammatory bowel disease has increased in recent years, and the repair process is complex, leading to substantial economic and social burdens. Therefore, understanding the pathogenesis of intestinal fibrosis and exploring potential therapeutic agents is crucial. Purpose This article reviews the pathogenesis of IBD-related intestinal fibrosis, potential therapeutic targets, and the progress of research on Traditional Chinese Medicine (TCM) in inhibiting intestinal fibrosis. It also provides foundational data for developing innovative drugs to prevent intestinal fibrosis. Methods This article reviews the literature from the past decade on advancements in the cellular and molecular mechanisms underlying intestinal fibrosis. Data for this systematic research were obtained from electronic databases including PubMed, CNKI, SciFinder, and Web of Science. Additionally, a comprehensive analysis was conducted on reports regarding the use of TCM for the treatment of intestinal fibrosis. The study synthesizes and summarizes the research findings, presenting key patterns and trends through relevant charts. Results This study reviewed recent advancements in understanding the cellular and molecular mechanisms of intestinal fibrosis, the active ingredients of TCM that inhibit intestinal fibrosis, the efficacy of TCM formulae in preventing intestinal fibrosis, and dietary modification that may contribute to the inhibition of intestinal fibrosis. Conclusion This article examines the cellular and molecular mechanisms that promote the development of intestinal fibrosis, as well as potential therapeutic targets for its treatment. It also provides a theoretical basis for exploring and utilizing TCM resources in the management of intestinal fibrosis. Through the analysis of various TCM medicines, this article underscores the clinical significance and therapeutic potential of TCM and dietary modifications in treating intestinal fibrosis.
Collapse
Affiliation(s)
- Yanan Li
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Xu
- Department of Gastroenterology, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastroenterology, The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yulai Fang
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuan Cui
- Department of Gastroenterology, Ningxian second People's Hospital, Qing Yang, China
| | - Zhenxing Zhu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuguang Wu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yiheng Tong
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingyi Hu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Lei Zhu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hong Shen
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| |
Collapse
|
|
4
|
Lee M, Son S, Oh S, Shin E, Shin H, Kwon O, Hwang S, Song H, Lim HJ. Diet-Induced Obesity Alters Granulosa Cell Transcriptome and Ovarian Immune Environment in Mice. Life (Basel) 2025; 15:330. [PMID: 40141675 PMCID: PMC11943477 DOI: 10.3390/life15030330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/10/2025] [Accepted: 02/17/2025] [Indexed: 03/28/2025] Open
Abstract
Obesity affects female reproductive performance by impairing the ovarian and uterine environments. Using a diet-induced obesity mouse model, we examined whether a high-fat diet (HFD) regimen affects the gene expression profile in ovarian granulosa cells (GCs) and whether short-term HFD has similar effects on gene expression as long-term HFD. C57BL/6J mice were fed a HFD or normal diet (ND) for 16-18 weeks (long-term group) or 4 weeks (short-term group). GCs were collected from each group of mice for RNA-sequencing. RT-PCR and immunofluorescence staining were performed to validate the results. RNA-sequencing analyses of the GCs revealed that several immediate early genes, including early growth response 1 (Egr1), an important mediator of ovulation, were significantly downregulated in HFD GCs. Protein tyrosine phosphatase receptor type C (Ptprc) and hematopoietic type prostaglandin D synthase (Hpgds), both of which are associated with increased inflammation, were significantly upregulated in HFD GCs. Downregulation of Egr1 was also confirmed in the GCs of short-term HFD mice, suggesting that it constitutes an early change in response to a HFD. Increased expression of several transcription factors in HFD GCs suggests that a HFD may affect the overall transcriptional landscape. The results may indicate possible modulation of the immune environment in HFD ovaries. These results provide novel insights into the molecular changes in GCs in obese environments.
Collapse
Affiliation(s)
- Minseo Lee
- Department of Veterinary Medicine, School of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Sujin Son
- Department of Veterinary Medicine, School of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Surim Oh
- Department of Veterinary Medicine, School of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Eunbin Shin
- Department of Veterinary Medicine, School of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
| | - Hyejin Shin
- Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea
| | - Ohrim Kwon
- Department of Life Science, Graduate School, CHA University, Seongnam-si 13488, Gyeonggi-do, Republic of Korea
| | - Sohyun Hwang
- Department of Life Science, Graduate School, CHA University, Seongnam-si 13488, Gyeonggi-do, Republic of Korea
- Department of Pathology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam-si 13520, Gyeonggi-do, Republic of Korea
| | - Haengseok Song
- Department of Life Science, Graduate School, CHA University, Seongnam-si 13488, Gyeonggi-do, Republic of Korea
| | - Hyunjung Jade Lim
- Department of Veterinary Medicine, School of Veterinary Medicine, Konkuk University, Seoul 05029, Republic of Korea
- Department of Biomedical Science and Technology, Institute of Biomedical Science & Technology, Konkuk University, Seoul 05029, Republic of Korea
| |
Collapse
|
|
5
|
Morabbi A, Karimian M. Therapeutic potential of exosomal lncRNAs derived from stem cells in wound healing: focusing on mesenchymal stem cells. Stem Cell Res Ther 2025; 16:62. [PMID: 39934913 PMCID: PMC11816792 DOI: 10.1186/s13287-025-04200-0] [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: 07/12/2024] [Accepted: 01/30/2025] [Indexed: 02/13/2025] Open
Abstract
The self-renewal ability and multipotency of stem cells give them great potential for use in wound healing. Stem cell-derived exosomes, owing to their close biological resemblance to their parent cells, offer a more efficient, safer, and economical approach for facilitating cellular communication and interactions within different environments. This potential makes them particularly valuable in the treatment of both acute and chronic wounds, such as lacerations, burns, and diabetic ulcers. Long non-coding RNAs (lncRNAs) enclosed in exosomes, as one of the leading actors of these extracellular microvesicles, through interaction with miRNAs and regulation of various signaling pathways involved in inflammation, angiogenesis, cell proliferation, and migration, could heal the wounds. Exosome-derived lncRNAs from stem cells facilitate extracellular matrix remodeling through interaction between macrophages and fibroblasts. Moreover, alongside regulating the expression of inflammatory cytokines, controlling reactive oxygen species levels, and enhancing autophagic activity, they also modulate immune responses to support wound healing. Regulating the expression of genes and signaling pathways related to angiogenesis, by increasing blood supply and accelerating the delivery of essential substances to the wound environment, is another effect exosomal lncRNAs derived from stem cells for wound healing. These lncRNAs can also enhance skin wound healing by regulating homeostasis, increasing the proliferation and differentiation of cells involved in the wound-healing process, and enhancing fibroblast viability and migration to the injury site. Ultimately, exosome-derived lncRNAs from stem cells offer valuable and novel insights into the molecular mechanisms underlying improved wound healing. They can pave the way for potential therapeutic strategies, fostering further research for a better future. Meanwhile, exosomes derived from mesenchymal stem cells, due to their exceptional regenerative properties, as well as the lncRNAs derived from these exosomes, have emerged as one of the innovative tools in wound healing. This review article aims to narrate the cellular and molecular roles of exosome-derived lncRNAs from stem cells in enhancing wound healing with a focus on mesenchymal stem cells.
Collapse
Affiliation(s)
- Ali Morabbi
- Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, 47416-95447, Iran
| | - Mohammad Karimian
- Department of Molecular and Cell Biology, Faculty of Basic Sciences, University of Mazandaran, Babolsar, 47416-95447, Iran.
| |
Collapse
|
|
6
|
Petrikas M, Wingert RA. Slow down my beating heart: induction of cardiac fibrosis by Iroquois homeobox 2. Tissue Barriers 2025; 13:2309036. [PMID: 38282252 PMCID: PMC11875463 DOI: 10.1080/21688370.2024.2309036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 12/28/2023] [Indexed: 01/30/2024] Open
Abstract
Cardiovascular diseases are a significant global health challenge and pervasive cause of mortality worldwide. Heart failure due to cardiovascular disease is characterized by the inability of the heart to pump blood efficiently to meet the metabolic demands of the body. The pathophysiology of heart failure involves myocardial remodeling due to excessive deposition of extracellular matrix proteins by cardiac myofibroblasts - structural changes which impair contractility, reduce compliance, and ultimately reduce stroke volume. Now, a recent report has uncovered an essential role for Iroquois homeobox 2 in the transcriptional regulation of cardiac fibrosis, illuminating new mechanistic insights that can be applied to developing future clinical therapies.
Collapse
Affiliation(s)
- Madeline Petrikas
- Department of Biological Sciences, University of Notre Dame, Notre Dame, USA
| | - Rebecca A. Wingert
- Department of Biological Sciences, University of Notre Dame, Notre Dame, USA
| |
Collapse
|
|
7
|
Oh ES, Lee JW, Song YN, Kim MO, Lee RW, Kang MJ, Lee J, Yun SH, Hong ST, Ro H, Lee SU. Tangeretin inhibits airway inflammatory responses by reducing early growth response 1 (EGR1) expression in mice exposed to cigarette smoke and lipopolysaccharide. Heliyon 2024; 10:e39797. [PMID: 39553588 PMCID: PMC11564960 DOI: 10.1016/j.heliyon.2024.e39797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 10/17/2024] [Accepted: 10/23/2024] [Indexed: 11/19/2024] Open
Abstract
Background Tangeretin, a natural polymethoxyflavone compound, possesses potent anti-inflammatory activity that improves respiratory inflammation in chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms underlying the anti-COPD effects of tangeretin remain unclear. In this study, we aimed to investigate the key molecular mechanisms by which tangeretin suppresses COPD-related inflammatory responses. Methods We conducted the investigation in phorbol-12-myristate-13-acetate (PMA)-stimulated human airway epithelial cells (in vitro) and cigarette smoke (CS)/lipopolysaccharide (LPS)-exposed mice (in vivo). Results Tangeretin decreased the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and mucin 5AC (MUC5AC), by suppressing early growth response 1 (EGR1) expression in vitro. Tangeretin and EGR1 small interfering ribonucleic acid (siRNA) combination showed a synergistic reduction in MUC5AC and TNF-α secretion. Tangeretin administration significantly inhibited the levels of reactive oxygen species (ROS) production, elastase activity, TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1) secretion, and macrophage and neutrophil numbers in the bronchoalveolar lavage fluid of CS/LPS-exposed mice. Tangeretin also prevented CS/LPS-induced abnormal pathological changes and excessive MUC5AC and EGR1 expression in lung tissue. Conclusion Comprehensively, tangeretin inhibits the lung inflammatory response associated with COPD by reducing EGR1 expression in PMA-induced human epithelial cells and in a CS/LPS-stimulated mouse model. This study shows that tangeretin has anti-COPD properties and can be a promising alternative (or complementary) treatment for inflammatory lung disease.
Collapse
Affiliation(s)
- Eun Sol Oh
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongju, Chungbuk, 28116, Republic of Korea
- College of Bioscience and Biotechnology, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Jae-Won Lee
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongju, Chungbuk, 28116, Republic of Korea
| | - Yu Na Song
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongju, Chungbuk, 28116, Republic of Korea
- College of Bioscience and Biotechnology, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Mun-Ock Kim
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongju, Chungbuk, 28116, Republic of Korea
| | - Ro Woon Lee
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongju, Chungbuk, 28116, Republic of Korea
| | - Myung-Ji Kang
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongju, Chungbuk, 28116, Republic of Korea
| | - Juhyun Lee
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongju, Chungbuk, 28116, Republic of Korea
| | - Seok Han Yun
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongju, Chungbuk, 28116, Republic of Korea
| | - Sung-Tae Hong
- Department of Anatomy & Cell Biology, Department of Medical Science, College of Medicine, Chungnam National University, 266, Munhwa-Ro, Daejeon, 35015, Republic of Korea
| | - Hyunju Ro
- College of Bioscience and Biotechnology, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Su Ui Lee
- Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang, Cheongju, Chungbuk, 28116, Republic of Korea
| |
Collapse
|
|
8
|
Li R, Wei R, Liu C, Zhang K, He S, Liu Z, Huang J, Tang Y, An Q, Lin L, Gan L, Zhao L, Zou X, Wang F, Ping Y, Ma Q. Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke. Acta Pharm Sin B 2024; 14:3983-4000. [PMID: 39309491 PMCID: PMC11413699 DOI: 10.1016/j.apsb.2024.05.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 03/05/2024] [Accepted: 03/15/2024] [Indexed: 09/25/2024] Open
Abstract
With the escalating prevalence of global heat waves, heat stroke has become a prominent health concern, leading to substantial liver damage. Unlike other forms of liver injury, heat stroke-induced damage is characterized by heat cytotoxicity and heightened inflammation, directly contributing to elevated mortality rates. While clinical assessments have identified elevated bilirubin levels as indicative of Kupffer cell dysfunction, their specific correlation with heat stroke liver injury remains unclear. Our hypothesis proposes the involvement of Kupffer cell ferroptosis during heat stroke, initiating IL-1β-mediated inflammation. Using single-cell RNA sequencing of murine macrophages, a distinct and highly susceptible Kupffer cell subtype, Clec4F+/CD206+, emerged, with heme oxygenase 1 (HMOX-1) playing a pivotal role. Mechanistically, heat-induced HMOX-1, regulated by early growth response factor 1, mediated ferroptosis in Kupffer cells, specifically in the Clec4F+/CD206+ subtype (KC2), activating phosphatidylinositol 4-kinase beta and promoting PI4P production. This cascade triggered NLRP3 inflammasome activation and maturation of IL-1β. These findings underscore the critical role of targeted therapy against HMOX-1 in ferroptosis within Kupffer cells, particularly in Clec4F+/CD206+ KCs. Such an approach has the potential to mitigate inflammation and alleviate acute liver injury in the context of heat stroke, offering a promising avenue for future therapeutic interventions.
Collapse
Affiliation(s)
- Ru Li
- The Seventh Affiliated Hospital, Southern Medical University, Foshan 528244, China
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
| | - Riqing Wei
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
| | - Chenxin Liu
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
| | - Keying Zhang
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
| | - Sixiao He
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
| | - Zhifeng Liu
- Medical Critical Care Medicine, General Hospital of Southern Theatre Command of PLA, Guangzhou 510000, China
- Guangdong Branch Center, National Clinical Research Center for Geriatric Diseases (Chinese PLA General Hospital), Guangzhou 510000, China
| | - Junhao Huang
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
| | - Youyong Tang
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
| | - Qiyuan An
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
| | - Ligen Lin
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China
| | - Lishe Gan
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 311402, China
| | - Liying Zhao
- Department of General Surgery, Nanfang Hospital, the First School of Clinical Medicine, Southern Medical University, Guangzhou 510000, China
| | - Xiaoming Zou
- The Seventh Affiliated Hospital, Southern Medical University, Foshan 528244, China
| | - Fudi Wang
- The Fourth Affiliated Hospital, the First Affiliated Hospital, School of Public Health, Institute of Translational Medicine, Cancer Center, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310000, China
- The First Affiliated Hospital, the Second Affiliated Hospital, Basic Medical Sciences, School of Public Health, Hengyang Medical School, University of South China, Hengyang 421200, China
| | - Yuan Ping
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310000, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 310000, China
| | - Qiang Ma
- Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
- Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510000, China
| |
Collapse
|
|
9
|
Kohl LM, Sumpter TL. The ART(N) of Keratinocytes Leading Neurons into the Skin. J Invest Dermatol 2024; 144:1676-1678. [PMID: 38613530 DOI: 10.1016/j.jid.2024.02.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 02/18/2024] [Accepted: 02/22/2024] [Indexed: 04/15/2024]
Affiliation(s)
- Lisa M Kohl
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany; Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Tina L Sumpter
- Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
| |
Collapse
|
|
10
|
Zheng SK, Zhao XK, Wu H, He DW, Xiong L, Cheng XG. Oxidative stress-induced EGR1 upregulation promotes NR4A3-mediated nucleus pulposus cells apoptosis in intervertebral disc degeneration. Aging (Albany NY) 2024; 16:10216-10238. [PMID: 38943627 PMCID: PMC11236312 DOI: 10.18632/aging.205920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/16/2024] [Indexed: 07/01/2024]
Abstract
This study aimed to reveal the specific role of early growth response protein 1 (EGR1) and nuclear receptor 4A3 (NR4A3) in nucleus pulposus cells (NPCs) and the related molecular mechanism and to identify a new strategy for treating intervertebral disc degeneration (IVDD). Bioinformatics analysis was used to explore and predict IVDD-related differentially expressed genes, and chromatin immunoprecipitation sequencing (ChIP-seq) revealed NR4A3 as the EGR1 target gene. An in vitro NPC model induced by tributyl hydrogen peroxide (TBHP) and a rat model induced by fibrous ring acupuncture were established. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical staining, immunofluorescence staining, and flow cytometry were used to detect the effects of EGR1 and NR4A3 knockdown and overexpression on NPC apoptosis and the expression of extracellular matrix (ECM) anabolism-related proteins. Interactions between EGR1 and NR4A3 were analyzed via ChIP-qPCR and dual luciferase assays. EGR1 and NR4A3 expression levels were significantly higher in severely degenerated discs (SDD) than in mildly degenerated discs (MDD), indicating that these genes are important risk factors in IVDD progression. ChIP-seq and RNA-seq revealed NR4A3 as a direct downstream target of EGR1, and this finding was verified by ChIP-qPCR and dual luciferase reporter experiments. Remarkably, the rescue experiments showed that EGR1 promotes TBHP-induced NPC apoptosis and impairs ECM anabolism, dependent on elevated NR4A3 expression. In summary, the EGR1-NR4A3 axis mediates the progression of NPC apoptosis and ECM impairment and is a potential therapeutic target in IVDD.
Collapse
Affiliation(s)
- Si-Kuan Zheng
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Xiao-Kun Zhao
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Hui Wu
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Ding-Wen He
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Long Xiong
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Xi-Gao Cheng
- Department of Orthopedics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
- Institute of Orthopedics of Jiangxi Province, Nanchang, Jiangxi 330006, China
- Institute of Minimally Invasive Orthopedics, Nanchang University, Nanchang, Jiangxi 330006, China
| |
Collapse
|
|
11
|
Huyan Y, Chen X, Chang Y, Hua X, Fan X, Shan D, Xu Z, Tao M, Zhang H, Liu S, Song J. Single-Cell Transcriptomic Analysis Reveals Myocardial Fibrosis Mechanism of Doxorubicin-Induced Cardiotoxicity. Int Heart J 2024; 65:487-497. [PMID: 38749755 DOI: 10.1536/ihj.23-302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Myocardial fibrosis is a pathological feature of doxorubicin-induced chronic cardiotoxicity that severely affects the prognosis of oncology patients. However, the specific cellular and molecular mediators driving doxorubicin-induced cardiac fibrosis, and the relative impact of different cell populations on cardiac fibrosis, remain unclear.This study aimed to explore the mechanism of doxorubicin-induced cardiotoxicity and myocardial fibrosis and to find potential therapeutic targets. Single-cell RNA sequencing was used to analyze the transcriptome of non-cardiomyocytes from normal and doxorubicin-induced chronic cardiotoxicity in mouse model heart tissue.We established a mouse model of doxorubicin-induced cardiotoxicity with a well-defined fibrotic phenotype. Analysis of single-cell sequencing results showed that fibroblasts were the major origin of extracellular matrix in doxorubicin-induced myocardial fibrosis. Further resolution of fibroblast subclusters showed that resting fibroblasts were converted to matrifibrocytes and then to myofibroblasts to participate in the myocardial remodeling process in response to doxorubicin treatment. Ctsb expression was significantly upregulated in fibroblasts after doxorubicin-induced.This study provides a comprehensive map of the non-cardiomyocyte landscape at high resolution, reveals multiple cell populations contributing to pathological remodeling of the cardiac extracellular matrix, and identifies major cellular sources of myofibroblasts and dynamic gene-expression changes in fibroblast activation. Finally, we used this strategy to detect potential therapeutic targets and identified Ctsb as a specific target for fibroblasts in doxorubicin-induced myocardial fibrosis.
Collapse
Affiliation(s)
- Yige Huyan
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Xiao Chen
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Yuan Chang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Xiumeng Hua
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Xuexin Fan
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Dan Shan
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Zhenyu Xu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Menghao Tao
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Hang Zhang
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Sheng Liu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Jiangping Song
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College
| |
Collapse
|
|
12
|
Jin R, Xu H, Zhou M, Lin F, Xu W, Xu A. EGR1 Mediated Reduction of Fibroblast Secreted-TGF-β1 Exacerbated CD8 + T Cell Inflammation and Migration in Vitiligo. Inflammation 2024; 47:503-512. [PMID: 37880426 DOI: 10.1007/s10753-023-01922-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/14/2023] [Accepted: 10/17/2023] [Indexed: 10/27/2023]
Abstract
Vitiligo is a T cell-mediated depigment skin disease caused by the complex interplay between melanocyte dysfunction, environmental stimulation, and dysregulated immune signals. Transforming growth factor-β1 (TGF-β1), which typically derives from regulatory T cells, has long been identified at low levels in the peripheral system of vitiligo patients. Here, through RNA-sequencing and transcription factor enrichment, we revealed that in response to CD8+ T cell-secreted interferon-gamma (IFN-γ), stromal fibroblast downregulates early growth response 1 (EGR1) activity, leading to TGF-β1 deficiency. The defective immune regulation loop further exacerbated local CD8+ T cell inflammation and promoted inflammatory cell migration in vitiligo. Thus, fibroblast-derived TGF-β1 plays an important stromal signal in vitiligo pathogenesis.
Collapse
Affiliation(s)
- Rong Jin
- Department of Dermatology, Hangzhou Third People's Hospital, 38 Xihu Ave, Hangzhou, Zhejiang Province 310009, People's Republic of China
| | - Hao Xu
- Department of Dermatology, Hangzhou Third People's Hospital, 38 Xihu Ave, Hangzhou, Zhejiang Province 310009, People's Republic of China
| | - Miaoni Zhou
- Department of Dermatology, Hangzhou Third People's Hospital, 38 Xihu Ave, Hangzhou, Zhejiang Province 310009, People's Republic of China
| | - Fuquan Lin
- Department of Dermatology, Hangzhou Third People's Hospital, 38 Xihu Ave, Hangzhou, Zhejiang Province 310009, People's Republic of China
| | - Wen Xu
- Department of Dermatology, Hangzhou Third People's Hospital, 38 Xihu Ave, Hangzhou, Zhejiang Province 310009, People's Republic of China
| | - Aie Xu
- Department of Dermatology, Hangzhou Third People's Hospital, 38 Xihu Ave, Hangzhou, Zhejiang Province 310009, People's Republic of China.
| |
Collapse
|
|
13
|
Abel TR, Kosarek NN, Parvizi R, Jarnagin H, Torres GM, Bhandari R, Huang M, Toledo DM, Smith A, Popovich D, Mariani MP, Yang H, Wood T, Garlick J, Pioli PA, Whitfield ML. Single-cell epigenomic dysregulation of Systemic Sclerosis fibroblasts via CREB1/EGR1 axis in self-assembled human skin equivalents. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.22.586316. [PMID: 38585776 PMCID: PMC10996484 DOI: 10.1101/2024.03.22.586316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Systemic sclerosis (SSc) is an autoimmune disease characterized by skin fibrosis, internal organ involvement and vascular dropout. We previously developed and phenotypically characterized an in vitro 3D skin-like tissue model of SSc, and now analyze the transcriptomic (scRNA-seq) and epigenetic (scATAC-seq) characteristics of this model at single-cell resolution. SSc 3D skin-like tissues were fabricated using autologous fibroblasts, macrophages, and plasma from SSc patients or healthy control (HC) donors. SSc tissues displayed increased dermal thickness and contractility, as well as increased α-SMA staining. Single-cell transcriptomic and epigenomic analyses identified keratinocytes, macrophages, and five populations of fibroblasts (labeled FB1 - 5). Notably, FB1 APOE-expressing fibroblasts were 12-fold enriched in SSc tissues and were characterized by high EGR1 motif accessibility. Pseudotime analysis suggests that FB1 fibroblasts differentiate from a TGF-β1-responsive fibroblast population and ligand-receptor analysis indicates that the FB1 fibroblasts are active in macrophage crosstalk via soluble ligands including FGF2 and APP. These findings provide characterization of the 3D skin-like model at single cell resolution and establish that it recapitulates subsets of fibroblasts and macrophage phenotypes observed in skin biopsies.
Collapse
|
|
14
|
Mohan N, Dashwood RH, Rajendran P. A-Z of Epigenetic Readers: Targeting Alternative Splicing and Histone Modification Variants in Cancer. Cancers (Basel) 2024; 16:1104. [PMID: 38539439 PMCID: PMC10968829 DOI: 10.3390/cancers16061104] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/03/2024] [Accepted: 03/06/2024] [Indexed: 11/03/2024] Open
Abstract
Epigenetic 'reader' proteins, which have evolved to interact with specific chromatin modifications, play pivotal roles in gene regulation. There is growing interest in the alternative splicing mechanisms that affect the functionality of such epigenetic readers in cancer etiology. The current review considers how deregulation of epigenetic processes and alternative splicing events contribute to pathophysiology. An A-Z guide of epigenetic readers is provided, delineating the antagonistic 'yin-yang' roles of full-length versus spliced isoforms, where this is known from the literature. The examples discussed underscore the key contributions of epigenetic readers in transcriptional regulation, early development, and cancer. Clinical implications are considered, offering insights into precision oncology and targeted therapies focused on epigenetic readers that have undergone alternative splicing events during disease pathogenesis. This review underscores the fundamental importance of alternative splicing events in the context of epigenetic readers while emphasizing the critical need for improved understanding of functional diversity, regulatory mechanisms, and future therapeutic potential.
Collapse
Affiliation(s)
- Nivedhitha Mohan
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX 77030, USA
- Department of Translational Medical Sciences, Antibody & Biopharmaceuticals Core, Texas A&M School of Medicine, Houston, TX 77030, USA
| | - Roderick H. Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX 77030, USA
- Department of Translational Medical Sciences, Antibody & Biopharmaceuticals Core, Texas A&M School of Medicine, Houston, TX 77030, USA
| | - Praveen Rajendran
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX 77030, USA
- Department of Translational Medical Sciences, Antibody & Biopharmaceuticals Core, Texas A&M School of Medicine, Houston, TX 77030, USA
| |
Collapse
|
|
15
|
Jin Y, Wang C, Zhang B, Sun Y, Ji J, Cai Q, Jiang J, Zhang Z, Zhao L, Yu B, Zhang J. Blocking EGR1/TGF-β1 and CD44s/STAT3 Crosstalk Inhibits Peritoneal Metastasis of Gastric Cancer. Int J Biol Sci 2024; 20:1314-1331. [PMID: 38385088 PMCID: PMC10878142 DOI: 10.7150/ijbs.90598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 01/19/2024] [Indexed: 02/23/2024] Open
Abstract
Peritoneal metastasis (PM) continues to limit the clinical efficacy of gastric cancer (GC). Early growth response 1 (EGR1) plays an important role in tumor cell proliferation, angiogenesis and invasion. However, the role of EGR1 derived from the tumor microenvironment in reshaping the phenotypes of GC cells and its specific molecular mechanisms in increasing the potential for PM are still unclear. In this study, we reported that EGR1 was significantly up-regulated in mesothelial cells from GC peritoneal metastases, leading to enhanced epithelial-mesenchymal transformation (EMT) and stemness phenotypes of GC cells under co-culture conditions. These phenotypes were achieved through the transcription and secretion of TGF-β1 by EGR1 in mesothelial cells, which could regulate the expression and internalization of CD44s. After being internalized into the cytoplasm, CD44s interacted with STAT3 to promote STAT3 phosphorylation and activation, and induced EMT and stemness gene transcription, thus positively regulating the metastasis of GC cells. Moreover, TGF-β1 secretion in the PM microenvironment was significantly increased compared with the matched primary tumor. The blocking effect of SHR-1701 on TGF-β1 was verified by inhibiting peritoneal metastases in xenografts. Collectively, the interplay of EGR1/TGF-β1/CD44s/STAT3 signaling between mesothelial cells and GC cells induces EMT and stemness phenotypes, offering potential as a therapeutic target for PM of GC.
Collapse
Affiliation(s)
- Yangbing Jin
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chao Wang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Benyan Zhang
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Ying Sun
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jun Ji
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Qu Cai
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jinling Jiang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhihao Zhang
- Clinical Research and Development, Jiangsu Hengrui Pharmaceuticals Co. Ltd, Shanghai, 201203, China
| | - Liqin Zhao
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Beiqin Yu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Department of Oncology, Wuxi Branch of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No 197 Zhixian Road, Xinwu District, Wuxi, 214028, China
| |
Collapse
|
|
16
|
Garmaa G, Manzéger A, Haghighi S, Kökény G. HK-2 cell response to TGF-β highly depends on cell culture medium formulations. Histochem Cell Biol 2024; 161:69-79. [PMID: 37752256 PMCID: PMC10794419 DOI: 10.1007/s00418-023-02237-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2023] [Indexed: 09/28/2023]
Abstract
The immortalized human renal proximal tubular epithelial cell line HK-2 is most commonly used to study renal cell physiology and human kidney diseases with tubulointerstitial fibrosis such as diabetic nephropathy, obstructive uropathy or allograft fibrosis. Epithelial-to-mesenchymal transition (EMT) is the main pathological process of tubulointerstitial fibrosis in vitro. Transforming growth factor-beta (TGF-β) is a key inducer of EMT. Several pro-fibrotic gene expression differences have been observed in a TGF-β-induced EMT model of HK-2 cells. However, growth conditions and medium formulations might greatly impact these differences. We investigated gene and protein expression of HK-2 cells cultured in six medium formulations. TGF-β1 increased the expression of ACTA2, TGFB1, COL4A1, EGR2, VIM and CTGF genes while reducing PPARG in all medium formulations. Interestingly, TGF-β1 treatment either increased or decreased EGR1, FN, IL6 and C3 gene expression, depending on medium formulations. The cell morphology was slightly affected, but immunoblots revealed TGFB1 and vimentin protein overexpression in all media. However, fibronectin expression as well as the nuclear translocation of EGR1 was medium dependent. In conclusion, our study demonstrates that, using the HK-2 in vitro model of EMT, the meticulous selection of appropriate cell culture medium formulation is essential to achieve reliable scientific results.
Collapse
Affiliation(s)
- Gantsetseg Garmaa
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary
| | - Anna Manzéger
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary
| | - Samaneh Haghighi
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary
| | - Gábor Kökény
- Institute of Translational Medicine, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary.
- International Nephrology Research and Training Center, Semmelweis University, Nagyvárad tér 4, Budapest, 1089, Hungary.
| |
Collapse
|
|
17
|
Vicencio E, Nuñez-Belmar J, Cardenas JP, Cortés BI, Martin AJM, Maracaja-Coutinho V, Rojas A, Cafferata EA, González-Osuna L, Vernal R, Cortez C. Transcriptional Signatures and Network-Based Approaches Identified Master Regulators Transcription Factors Involved in Experimental Periodontitis Pathogenesis. Int J Mol Sci 2023; 24:14835. [PMID: 37834287 PMCID: PMC10573220 DOI: 10.3390/ijms241914835] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
Periodontitis is a chronic inflammatory disease characterized by the progressive and irreversible destruction of the periodontium. Its aetiopathogenesis lies in the constant challenge of the dysbiotic biofilm, which triggers a deregulated immune response responsible for the disease phenotype. Although the molecular mechanisms underlying periodontitis have been extensively studied, the regulatory mechanisms at the transcriptional level remain unclear. To generate transcriptomic data, we performed RNA shotgun sequencing of the oral mucosa of periodontitis-affected mice. Since genes are not expressed in isolation during pathological processes, we disclose here the complete repertoire of differentially expressed genes (DEG) and co-expressed modules to build Gene Regulatory Networks (GRNs) and identify the Master Transcriptional Regulators of periodontitis. The transcriptional changes revealed 366 protein-coding genes and 42 non-coding genes differentially expressed and enriched in the immune response. Furthermore, we found 13 co-expression modules with different representation degrees and gene expression levels. Our GRN comprises genes from 12 gene clusters, 166 nodes, of which 33 encode Transcription Factors, and 201 connections. Finally, using these strategies, 26 master regulators of periodontitis were identified. In conclusion, combining the transcriptomic analyses with the regulatory network construction represents a powerful and efficient strategy for identifying potential periodontitis-therapeutic targets.
Collapse
Affiliation(s)
- Emiliano Vicencio
- Escuela de Tecnología Médica, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile;
| | - Josefa Nuñez-Belmar
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago 8580745, Chile; (J.N.-B.); (J.P.C.)
| | - Juan P. Cardenas
- Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago 8580745, Chile; (J.N.-B.); (J.P.C.)
- Escuela de Biotecnología, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago 8580745, Chile
| | - Bastian I. Cortés
- Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile;
| | - Alberto J. M. Martin
- Laboratorio de Redes Biológicas, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Santiago 7780272, Chile;
- Escuela de Ingeniería, Facultad de Ingeniería, Arquitectura y Diseño, Universidad San Sebastián, Santiago 8420524, Chile
| | - Vinicius Maracaja-Coutinho
- Centro de Modelamiento Molecular, Biofísica y Bioinformática, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, Chile; (V.M.-C.); (A.R.)
- Advanced Center for Chronic Diseases—ACCDiS, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, Chile
| | - Adolfo Rojas
- Centro de Modelamiento Molecular, Biofísica y Bioinformática, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, Chile; (V.M.-C.); (A.R.)
| | - Emilio A. Cafferata
- Laboratorio de Biología Periodontal, Facultad de Odontología, Universidad de Chile, Santiago 8380492, Chile; (E.A.C.); (L.G.-O.); (R.V.)
| | - Luis González-Osuna
- Laboratorio de Biología Periodontal, Facultad de Odontología, Universidad de Chile, Santiago 8380492, Chile; (E.A.C.); (L.G.-O.); (R.V.)
| | - Rolando Vernal
- Laboratorio de Biología Periodontal, Facultad de Odontología, Universidad de Chile, Santiago 8380492, Chile; (E.A.C.); (L.G.-O.); (R.V.)
| | - Cristian Cortez
- Escuela de Tecnología Médica, Facultad de Ciencias, Pontificia Universidad Católica de Valparaíso, Valparaíso 2373223, Chile;
| |
Collapse
|
|
18
|
Jeong K, Je J, Dusabimana T, Kim H, Park SW. Early Growth Response 1 Contributes to Renal IR Injury by Inducing Proximal Tubular Cell Apoptosis. Int J Mol Sci 2023; 24:14295. [PMID: 37762598 PMCID: PMC10532368 DOI: 10.3390/ijms241814295] [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: 08/31/2023] [Revised: 09/17/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Renal ischemia-reperfusion (IR) causes acute kidney injury due to oxidative stress, tubular inflammation, and apoptosis. Early growth response 1 (Egr-1) is a transcription factor belonging to the immediate early gene family and is known to regulate cell proliferation, differentiation, and survival. Egr-1 expression is induced during renal IR; however, its pathogenic role and underlying mechanisms remain elusive. Here, we investigated the function of Egr-1 during renal IR using C57BL/6 mice and cultured renal proximal tubular HK-2 cells. Egr-1 expression increased immediately, 1-4 h after IR, whereas plasma creatinine and oxidative stress increased progressively over 24 h after IR. Egr-1 overexpression showed greater increases in plasma creatinine, renal tubular injury, and apoptosis than in the control after IR. Egr-1 overexpression also showed significant neutrophil infiltration and increased pro-inflammatory cytokines (TNF-α, MIP-2, and IL-6) after IR. Consistently, proximal tubular HK-2 cells showed immediate induction of Egr-1 at 1 h after hypoxia and reoxygenation, where its downstream target, p53, was also increased. Interestingly, Egr-1 overexpression enhanced p53 levels and tubular apoptosis, while the knockdown of Egr-1 reduced p53 levels and tubular apoptosis after H2O2 treatment. Egr-1 was recruited to the p53 promoter, which activates p53 transcription, and Egr-1 induction occurred through Erk/JNK signaling kinases, as the specific inhibitors blocked its expression. Taken together, these results show that Egr-1 is upregulated in proximal tubular cells and contributes to renal IR injury by inducing tubular apoptosis, mediated by p53 transcriptional activation. Thus, Egr-1 could be a potential therapeutic target for renal IR injury.
Collapse
Affiliation(s)
- Kyuho Jeong
- Department of Biochemistry, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea;
| | - Jihyun Je
- Department of Pharmacology, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea; (J.J.); (T.D.)
- Antiaging Bio Cell Factory-Regional Leading Research Center (ABC-RLRC), Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Theodomir Dusabimana
- Department of Pharmacology, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea; (J.J.); (T.D.)
- Antiaging Bio Cell Factory-Regional Leading Research Center (ABC-RLRC), Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Hwajin Kim
- Department of Pharmacology, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea; (J.J.); (T.D.)
- Antiaging Bio Cell Factory-Regional Leading Research Center (ABC-RLRC), Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Sang Won Park
- Department of Pharmacology, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju 52727, Republic of Korea; (J.J.); (T.D.)
- Antiaging Bio Cell Factory-Regional Leading Research Center (ABC-RLRC), Gyeongsang National University, Jinju 52828, Republic of Korea
- Department of Convergence Medical Science, Gyeongsang National University Graduate School, Jinju 52727, Republic of Korea
| |
Collapse
|
|
19
|
Shen L, Yin H, Sun L, Zhang Z, Jin Y, Cao S, Fu Q, Fan C, Bao C, Lu L, Zhan Y, Xu X, Chen X, Yan Q. Iguratimod attenuated fibrosis in systemic sclerosis via targeting early growth response 1 expression. Arthritis Res Ther 2023; 25:151. [PMID: 37596660 PMCID: PMC10439582 DOI: 10.1186/s13075-023-03135-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 08/02/2023] [Indexed: 08/20/2023] Open
Abstract
BACKGROUND The early growth response 1 (EGR1) is a central transcription factor involved in systemic sclerosis (SSc) pathogenesis. Iguratimod is a synthesized anti-rheumatic disease-modifying drug, which shows drastic inhibition to EGR1 expression in B cells. This study is aiming to investigate the anti-fibrotic effect of iguratimod in SSc. METHODS EGR1 was detected by immunofluorescence staining real-time PCR or western blot. Iguratimod was applied in EGR1 overexpressed or knockdown human dermal fibroblast, bleomycin pre-treated mice, tight skin 1 mice, and SSc skin xenografts. RNA sequencing was performed in cultured fibroblast and xenografts to identify the iguratimod regulated genes. RESULTS EGR1 overexpressed predominantly in non-immune cells of SSc patients. Iguratimod reduced EGR1 expression in fibroblasts and neutralized changes of EGR1 response genes regulated by TGFβ. The extracellular matrix (ECM) production and activation of fibroblasts were attenuated by iguratimod while EGR1 overexpression reversed this effect of iguratimod. Iguratimod ameliorated the skin fibrosis induced by bleomycin and hypodermal fibrosis in TSK-1 mice. Decreasing in the collagen content as well as the density of EGR1 or TGFβ positive fibroblasts of skin xenografts from naïve SSc patients was observed after local treatment of iguratimod. CONCLUSION Targeting EGR1 expression is a probable underlying mechanism for the anti-fibrotic effect of iguratimod.
Collapse
Affiliation(s)
- Lichong Shen
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Hanlin Yin
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Li Sun
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhiliang Zhang
- Department of Plastic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Yuyang Jin
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Shan Cao
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Qiong Fu
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Chaofan Fan
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Chunde Bao
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Liangjing Lu
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China
| | - Yifan Zhan
- Department of Drug Discovery, Shanghai Huaota Biopharm, Shanghai, 201203, China
| | - Xiaojiang Xu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
| | - Xiaoxiang Chen
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
- Department of Rheumatology, Nantong First People's Hospital, Affiliated Hospital 2 of Nantong Universuty, Nantong Hospital of Renji Hospital Affiliated to Shanghai Jiao Tong Universuty School of Medicine, Nantong, 226006, China.
| | - Qingran Yan
- Department of Rheumatology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
| |
Collapse
|
|
20
|
Ma ZG, Yuan YP, Fan D, Zhang X, Teng T, Song P, Kong CY, Hu C, Wei WY, Tang QZ. IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice. Nat Commun 2023; 14:4967. [PMID: 37587150 PMCID: PMC10432509 DOI: 10.1038/s41467-023-40639-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 08/03/2023] [Indexed: 08/18/2023] Open
Abstract
Cardiac fibrosis is a common feature of chronic heart failure. Iroquois homeobox (IRX) family of transcription factors plays important roles in heart development; however, the role of IRX2 in cardiac fibrosis has not been clarified. Here we report that IRX2 expression is significantly upregulated in the fibrotic hearts. Increased IRX2 expression is mainly derived from cardiac fibroblast (CF) during the angiotensin II (Ang II)-induced fibrotic response. Using two CF-specific Irx2-knockout mouse models, we show that deletion of Irx2 in CFs protect against pathological fibrotic remodelling and improve cardiac function in male mice. In contrast, Irx2 gain of function in CFs exaggerate fibrotic remodelling. Mechanistically, we find that IRX2 directly binds to the promoter of the early growth response factor 1 (EGR1) and subsequently initiates the transcription of several fibrosis-related genes. Our study provides evidence that IRX2 regulates the EGR1 pathway upon Ang II stimulation and drives cardiac fibrosis.
Collapse
Affiliation(s)
- Zhen-Guo Ma
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China
| | - Yu-Pei Yuan
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China
| | - Di Fan
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China
| | - Xin Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China
| | - Teng Teng
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China
| | - Peng Song
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China
| | - Chun-Yan Kong
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China
| | - Can Hu
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China
| | - Wen-Ying Wei
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China
| | - Qi-Zhu Tang
- Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China.
- Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China.
- Hubei Key Laboratory of Metabolic and Chronic Diseases, 430060, Wuhan, PR China.
| |
Collapse
|
|
21
|
Lee SY, Park SY, Lee SH, Kim H, Kwon JH, Yoo JY, Kim K, Park MS, Lee CG, Elias JA, Sohn MH, Shim HS, Yoon HG. The deubiquitinase UCHL3 mediates p300-dependent chemokine signaling in alveolar type II cells to promote pulmonary fibrosis. Exp Mol Med 2023; 55:1795-1805. [PMID: 37524875 PMCID: PMC10474292 DOI: 10.1038/s12276-023-01066-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 05/31/2023] [Indexed: 08/02/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, fatal, fibrotic, interstitial lung disease of unknown cause. Despite extensive studies, the underlying mechanisms of IPF development remain unknown. Here, we found that p300 was upregulated in multiple epithelial cells in lung samples from patients with IPF and mouse models of lung fibrosis. Lung fibrosis was significantly diminished by the alveolar type II (ATII) cell-specific deletion of the p300 gene. Moreover, we found that ubiquitin C-terminal hydrolase L3 (UCHL3)-mediated deubiquitination of p300 led to the transcriptional activation of the chemokines Ccl2, Ccl7, and Ccl12 through the cooperative action of p300 and C/EBPβ, which consequently promoted M2 macrophage polarization. Selective blockade of p300 activity in ATII cells resulted in the reprogramming of M2 macrophages into antifibrotic macrophages. These findings demonstrate a pivotal role for p300 in the development of lung fibrosis and suggest that p300 could serve as a promising target for IPF treatment.
Collapse
Affiliation(s)
- Soo Yeon Lee
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Soo-Yeon Park
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Seung-Hyun Lee
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Hyunsik Kim
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Jae-Hwan Kwon
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Jung-Yoon Yoo
- Department of Biomedical Laboratory Science, Yonsei University Mirae Campus, Wonju, South Korea
| | - Kyunggon Kim
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Moo Suk Park
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Chun Geun Lee
- Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
- Department of Internal Medicine, Hanyang University, Seoul, 04763, Korea
| | - Jack A Elias
- Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Myung Hyun Sohn
- Department of Pediatrics and Institute of Allergy, Severance Medical Research Institute, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, 03722, Korea
| | - Hyo Sup Shim
- Department of Pathology, Yonsei University College of Medicine, Seoul, 03722, Korea.
| | - Ho-Geun Yoon
- Department of Biochemistry and Molecular Biology, Severance Medical Research Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Korea.
| |
Collapse
|
|
22
|
Guo Y, Miao X, Sun X, Li L, Zhou A, Zhu X, Xu Y, Wang Q, Li Z, Fan Z. Zinc finger transcription factor Egf1 promotes non-alcoholic fatty liver disease. JHEP Rep 2023; 5:100724. [PMID: 37234276 PMCID: PMC10206499 DOI: 10.1016/j.jhepr.2023.100724] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/19/2023] [Accepted: 02/22/2023] [Indexed: 05/27/2023] Open
Abstract
Background & Aims Non-alcoholic fatty liver disease (NAFLD) contributes to the global epidemic of metabolic syndrome and is considered a prelude to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. During NAFLD pathogenesis, hepatic parenchymal cells (hepatocytes) undergo both morphological and functional changes owing to a rewired transcriptome. The underlying mechanism is not entirely clear. In the present study, we investigated the involvement of early growth response 1 (Egr1) in NAFLD. Methods Quantitative PCR, Western blotting, and histochemical staining were used to assess gene expression levels. Chromatin immunoprecipitation was used to evaluate protein binding to DNA. NAFLD was evaluated in leptin receptor-deficient (db/db) mice. Results We report here that Egr1 was upregulated by pro-NAFLD stimuli in vitro and in vivo. Further analysis revealed that serum response factor (SRF) was recruited to the Egr1 promoter and mediated Egr1 transactivation. Importantly, Egr1 depletion markedly mitigated NAFLD in db/db mice. RNA sequencing revealed that Egr1 knockdown in hepatocytes, on the one hand, boosted fatty acid oxidation (FAO) and, on the other hand, suppressed the synthesis of chemoattractants. Mechanistically, Egr1 interacted with peroxisome proliferator-activated receptor α (PPARα) to repress PPARα-dependent transcription of FAO genes by recruiting its co-repressor NGFI-A binding protein 1 (Nab1), which potentially led to promoter deacetylation of FAO genes. Conclusions Our data identify Egr1 as a novel modulator of NAFLD and a potential target for NAFLD intervention. Impact and Implications Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper, we describe a novel mechanism whereby early growth response 1 (Egr1), a transcription factor, contributes to NAFLD pathogenesis by regulating fatty acid oxidation. Our data provide novel insights and translational potential for NAFLD intervention.
Collapse
Affiliation(s)
- Yan Guo
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Xiulian Miao
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Xinyue Sun
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Luyang Li
- Department of Oral Medicine, Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Anqi Zhou
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China
| | - Xi Zhu
- Department of Infectious Diseases, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, China
| | - Yong Xu
- Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Qinghua Wang
- Department of Gastroenterology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, China
| | - Zilong Li
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Zhiwen Fan
- Department of Pathology, Affiliated Nanjing Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, China
| |
Collapse
|
|
23
|
Jia X, Lin W, Wang W. Regulation of chromatin organization during animal regeneration. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:19. [PMID: 37259007 DOI: 10.1186/s13619-023-00162-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/21/2023] [Indexed: 06/02/2023]
Abstract
Activation of regeneration upon tissue damages requires the activation of many developmental genes responsible for cell proliferation, migration, differentiation, and tissue patterning. Ample evidence revealed that the regulation of chromatin organization functions as a crucial mechanism for establishing and maintaining cellular identity through precise control of gene transcription. The alteration of chromatin organization can lead to changes in chromatin accessibility and/or enhancer-promoter interactions. Like embryogenesis, each stage of tissue regeneration is accompanied by dynamic changes of chromatin organization in regeneration-responsive cells. In the past decade, many studies have been conducted to investigate the contribution of chromatin organization during regeneration in various tissues, organs, and organisms. A collection of chromatin regulators were demonstrated to play critical roles in regeneration. In this review, we will summarize the progress in the understanding of chromatin organization during regeneration in different research organisms and discuss potential common mechanisms responsible for the activation of regeneration response program.
Collapse
Affiliation(s)
- Xiaohui Jia
- National Institute of Biological Sciences, Beijing, 102206, China
- China Agricultural University, Beijing, 100083, China
| | - Weifeng Lin
- National Institute of Biological Sciences, Beijing, 102206, China
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100084, China
| | - Wei Wang
- National Institute of Biological Sciences, Beijing, 102206, China.
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 100084, China.
| |
Collapse
|
|
24
|
Qian Y, Han Z, Yang D, Cai Y, Jin J, Yang Z. Metal-Organic Frameworks Facilitate Nucleic Acids for Multimode Synergistic Therapy of Breast Cancer. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2023. [PMID: 37236267 DOI: 10.1021/acs.langmuir.3c00667] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Compared with traditional medical methods, gene therapy and photodynamic therapy are the new fields of cancer treatment, and they more accurately and effectively obtain preferable therapeutic effects. In this study, a chemotherapy drug-free nanotherapeutic system based on ZIF-90 encapsulated with Ce6-G3139 and Ce6-DNAzyme for gene and photodynamic therapies was constructed. Once entering the cancer cell, the therapy system will decompose and release Zn2+, Ce6-G3139, and Ce6-DNAzyme in the acidic environment. On the one hand, G3139 binds to the antiapoptotic gene BCL-2 in tumor cells and downregulates related proteins to inhibit tumor proliferation. On the other hand, Zn2+ produced by the decomposition of ZIF-90 can be used as a cofactor to activate the cleavage activity of DNAzyme to initiate gene therapy. Proliferation and metastasis of tumors were further inhibited by DNAzyme, targeting and cutting the gene of human early growth factor-1 (EGR-1). In addition, the photosensitizer Ce6 carried by the nucleic acid will produce cytotoxic ROS to kill cancer cells after irradiation. The results of this study demonstrated that the designed nanoplatform, which synergistically combines gene and photodynamic therapies, has shown great potential for cancer treatment.
Collapse
Affiliation(s)
- Yue Qian
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Zhaoyu Han
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Dutao Yang
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Yanfei Cai
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Jian Jin
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| | - Zhaoqi Yang
- School of Life Sciences and Health Engineering, Jiangnan University, Wuxi 214122, China
| |
Collapse
|
|
25
|
Billah M, Naz A, Noor R, Bhindi R, Khachigian LM. Early Growth Response-1: Friend or Foe in the Heart? Heart Lung Circ 2023; 32:e23-e35. [PMID: 37024319 DOI: 10.1016/j.hlc.2023.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 04/07/2023]
Abstract
Cardiovascular disease is a major cause of mortality and morbidity worldwide. Early growth response-1 (Egr-1) plays a critical regulatory role in a range of experimental models of cardiovascular diseases. Egr-1 is an immediate-early gene and is upregulated by various stimuli including shear stress, oxygen deprivation, oxidative stress and nutrient deprivation. However, recent research suggests a new, underexplored cardioprotective side of Egr-1. The main purpose of this review is to explore and summarise the dual nature of Egr-1 in cardiovascular pathobiology.
Collapse
Affiliation(s)
- Muntasir Billah
- Department of Cardiology, Kolling Institute of Medical Research, Northern Sydney Local Health District, Sydney, NSW, Australia; Sydney Medical School Northern, The University of Sydney, Sydney, NSW, Australia.
| | - Adiba Naz
- Department of Molecular Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia
| | - Rashed Noor
- School of Environmental and Life Sciences, Independent University Bangladesh, Dhaka, Bangladesh
| | - Ravinay Bhindi
- Department of Cardiology, Kolling Institute of Medical Research, Northern Sydney Local Health District, Sydney, NSW, Australia; Sydney Medical School Northern, The University of Sydney, Sydney, NSW, Australia
| | - Levon M Khachigian
- Vascular Biology and Translational Research, School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
| |
Collapse
|
|
26
|
CircCOL5A1 inhibits proliferation, migration, invasion, and extracellular matrix production of keloid fibroblasts by regulating the miR-877-5p/EGR1 axis. Burns 2023; 49:137-148. [PMID: 35184918 DOI: 10.1016/j.burns.2021.12.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 12/10/2021] [Accepted: 12/30/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND Circular RNA (circRNA) has been proved to mediate the biological functions of fibroblasts to participate in the regulation of keloid formation. However, the role of circCOL5A1 in keloid formation remains to be further confirmed. METHODS Primary keloid fibroblasts were isolated form keloid tissues. The expression of circCOL5A1, microRNA (miR)- 877-5p, and early growth response 1 (EGR1) were determined by quantitative real-time PCR. Transfection experiments were carried out to explore the effects of circCOL5A1, miR-877-5p, and EGR1 on cell functions. Cell proliferation, migration, invasion and apoptosis were detected using cell counting kit 8 assay, colony formation assay, transwell assay and flow cytometry. The protein levels of apoptosis markers, extracellular matrix (ECM) markers and EGR1 were measured by western blot analysis. The mechanism of circCOL5A1 was confirmed by RNA pull-down assay, dual-luciferase reporter assay and RIP assay. RESULTS Our data showed that circCOL5A1 was upregulated in keloid tissues and fibroblasts. Silencing of circCOL5A1 had an inhibition effect on proliferation, migration, invasion and ECM production, while had a promotion effect on apoptosis in keloid fibroblasts. MiR-877-5p could be sponged by circCOL5A1, and its overexpression could repress the biological functions of keloid fibroblasts. The rescue experiments showed that miR-877-5p inhibitor could reverse the suppressive effect of circCOL5A1 knockdown on the biological functions of keloid fibroblasts. In addition, EGR1 was a target of miR-877-5p, and its expression was positively regulated by circCOL5A1. The inhibition effect of miR-877-5p on the biological functions of keloid fibroblasts could be abolished by EGR1 overexpression. CONCLUSION In summary, circCOL5A1 facilitates keloid fibroblast proliferation, migration, invasion and ECM production through the miR-877-5p/EGR1 axis, thereby potentially promoting keloid formation.
Collapse
|
|
27
|
Körbelin J, Klein J, Matuszcak C, Runge J, Harbaum L, Klose H, Hennigs JK. Transcription factors in the pathogenesis of pulmonary arterial hypertension-Current knowledge and therapeutic potential. Front Cardiovasc Med 2023; 9:1036096. [PMID: 36684555 PMCID: PMC9853303 DOI: 10.3389/fcvm.2022.1036096] [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: 09/03/2022] [Accepted: 11/21/2022] [Indexed: 01/09/2023] Open
Abstract
Pulmonary arterial hypertension (PAH) is a disease characterized by elevated pulmonary vascular resistance and pulmonary artery pressure. Mortality remains high in severe cases despite significant advances in management and pharmacotherapy. Since currently approved PAH therapies are unable to significantly reverse pathological vessel remodeling, novel disease-modifying, targeted therapeutics are needed. Pathogenetically, PAH is characterized by vessel wall cell dysfunction with consecutive remodeling of the pulmonary vasculature and the right heart. Transcription factors (TFs) regulate the process of transcribing DNA into RNA and, in the pulmonary circulation, control the response of pulmonary vascular cells to macro- and microenvironmental stimuli. Often, TFs form complex protein interaction networks with other TFs or co-factors to allow for fine-tuning of gene expression. Therefore, identification of the underlying molecular mechanisms of TF (dys-)function is essential to develop tailored modulation strategies in PAH. This current review provides a compendium-style overview of TFs and TF complexes associated with PAH pathogenesis and highlights their potential as targets for vasculoregenerative or reverse remodeling therapies.
Collapse
Affiliation(s)
- Jakob Körbelin
- ENDomics Lab, Department of Medicine, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,*Correspondence: Jakob Körbelin,
| | - Julius Klein
- ENDomics Lab, Department of Medicine, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,Division of Pneumology and Center for Pulmonary Arterial Hypertension Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christiane Matuszcak
- ENDomics Lab, Department of Medicine, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,Division of Pneumology and Center for Pulmonary Arterial Hypertension Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Runge
- ENDomics Lab, Department of Medicine, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,Division of Pneumology and Center for Pulmonary Arterial Hypertension Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lars Harbaum
- Division of Pneumology and Center for Pulmonary Arterial Hypertension Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans Klose
- Division of Pneumology and Center for Pulmonary Arterial Hypertension Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Jan K. Hennigs
- ENDomics Lab, Department of Medicine, Center of Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,Division of Pneumology and Center for Pulmonary Arterial Hypertension Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,Jan K. Hennigs,
| |
Collapse
|
|
28
|
Brock S, Jackson DB, Soldatos TG, Hornischer K, Schäfer A, Diella F, Emmert MY, Hoerstrup SP. Whole patient knowledge modeling of COVID-19 symptomatology reveals common molecular mechanisms. FRONTIERS IN MOLECULAR MEDICINE 2023; 2:1035290. [PMID: 39086962 PMCID: PMC11285600 DOI: 10.3389/fmmed.2022.1035290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 12/12/2022] [Indexed: 08/02/2024]
Abstract
Infection with SARS-CoV-2 coronavirus causes systemic, multi-faceted COVID-19 disease. However, knowledge connecting its intricate clinical manifestations with molecular mechanisms remains fragmented. Deciphering the molecular basis of COVID-19 at the whole-patient level is paramount to the development of effective therapeutic approaches. With this goal in mind, we followed an iterative, expert-driven process to compile data published prior to and during the early stages of the pandemic into a comprehensive COVID-19 knowledge model. Recent updates to this model have also validated multiple earlier predictions, suggesting the importance of such knowledge frameworks in hypothesis generation and testing. Overall, our findings suggest that SARS-CoV-2 perturbs several specific mechanisms, unleashing a pathogenesis spectrum, ranging from "a perfect storm" triggered by acute hyper-inflammation, to accelerated aging in protracted "long COVID-19" syndromes. In this work, we shortly report on these findings that we share with the community via 1) a synopsis of key evidence associating COVID-19 symptoms and plausible mechanisms, with details presented within 2) the accompanying "COVID-19 Explorer" webserver, developed specifically for this purpose (found at https://covid19.molecularhealth.com). We anticipate that our model will continue to facilitate clinico-molecular insights across organ systems together with hypothesis generation for the testing of potential repurposing drug candidates, new pharmacological targets and clinically relevant biomarkers. Our work suggests that whole patient knowledge models of human disease can potentially expedite the development of new therapeutic strategies and support evidence-driven clinical hypothesis generation and decision making.
Collapse
Affiliation(s)
| | | | - Theodoros G. Soldatos
- Molecular Health GmbH, Heidelberg, Germany
- SRH Hochschule, University of Applied Science, Heidelberg, Germany
| | | | | | | | - Maximilian Y. Emmert
- Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland
- Wyss Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
- Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Berlin, Germany
- Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Simon P. Hoerstrup
- Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland
- Wyss Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| |
Collapse
|
|
29
|
Tian H, Xu F, Zhao F, Pan N, Lu S, Jia X, Zhou Y. Early-immediate gene Egr1 is associated with TGFβ1 regulation of epigenetic reader Bromodomain-containing protein 4 via the canonical Smad3 signaling in hepatic stellate cells in vitro and in vivo. FASEB J 2022; 36:e22605. [PMID: 36250963 DOI: 10.1096/fj.202201263r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Revised: 09/17/2022] [Accepted: 09/29/2022] [Indexed: 12/31/2022]
Abstract
Upon chronic damage to the liver, multiple cytokines stimulate hepatic stellate cells (HSCs), causing the alterations of gene expression profiles and thus leading to HSC activation, a key step in liver fibrogenesis. Activated HSCs are the dominant contributors to liver fibrosis. Bromodomain containing protein 4 (BrD4), an important epigenetic reader, was demonstrated to concentrate on hundreds of enhancers associated with genes involved in multiple profibrotic pathways, thereby directing HSC activation and the fibrotic responses. The present studies were designed to examine the effect of transforming growth factor beta-1 (TGFβ1), the most potent pro-fibrotic cytokine, on BrD4 expression in HSCs and, if so, elucidated the underlying mechanisms in vitro and in vivo. The experiments employed the heterogeneous TGFβ1 knockout (TGFβ1+/- ) mice, gene knockdown in vivo, and a model of thioacetamide (TAA)-induced liver injury. The results revealed that TGFβ1 enhanced BrD4 expression in HSCs, which was mediated, at least, by Smad3 signaling and early-immediate gene Egr1 (early growth response-1). TGFβ1-induced Smad3 signaling increased Egr1 expression and promoted Egr1 binding to BrD4 promoter at a site around -111 bp, promoting BrD4 expression. Egr1 knockdown reduced BrD4 expression in HSCs in a mouse model of TAA-induced liver injury and lessened liver fibrosis. Double fluorescence staining demonstrated a strong increase in BrD4 expression in activated HSCs in fibrotic areas of the human livers, paralleling the upregulation of p-Smad3 and Egr1. This research suggested novel molecular events underlying the roles of the master pro-fibrotic cytokine TGFβ1 in HSC activation and liver fibrogenesis.
Collapse
Affiliation(s)
- Haimeng Tian
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Nantong, China
| | - Feifan Xu
- Department of Clinical Laboratory, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), Nantong, China
| | - Feifei Zhao
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Nantong, China
| | - Nachuan Pan
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
| | - Sidan Lu
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Nantong, China
| | - Xin Jia
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Nantong, China
| | - Yajun Zhou
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Nantong, China
| |
Collapse
|
|
30
|
Hao M, Duan M, Yang Z, Zhou H, Li S, Xiang J, Wu H, Liu H, Chang L, Wang D, Liu W. Engineered stem cell exosomes for oral and maxillofacial wound healing. Front Bioeng Biotechnol 2022; 10:1038261. [PMID: 36353739 PMCID: PMC9637828 DOI: 10.3389/fbioe.2022.1038261] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/13/2022] [Indexed: 09/12/2023] Open
Abstract
Wound healing of the oral and maxillofacial area affects the quality of life and mental health of the patient; therefore, effective therapies are required to promote wound healing. However, traditional treatment methods have limited efficacy. Exosomes secreted by stem cells used for oral and maxillofacial wound healing have shown outstanding results. Stem cell-derived exosomes possess the regenerative and repair ability of stem cells. Moreover, they are nontumorigenic and have good biosafety. However, the application of natural stem cell exosomes is limited owing to their low yield, impurity, lack of targeting, and low drug delivery rate. Many modification methods have been developed to engineered stem cell exosomes with beneficial properties, such as modifying parent cells and directly processing stem cell exosomes. These methods include coincubation, genetic engineering, electroporation, ultrasound, and artificial synthesis of engineered stem cell exosomes. These engineered stem cell exosomes can cargo nucleic acids, proteins, and small molecules. This gives them anti-inflammatory and cell proliferation regulatory abilities and enables the targeted promotion of efficient soft tissue repair after trauma. Engineered stem cell exosomes can decrease inflammation, promote fibroblast proliferation, and angiogenesis, and decrease scar formation to promote oral and maxillofacial wound healing, including diabetic and burn wounds. Thus, engineered stem cell exosomes are an effective treatment that has the potential for oral and maxillofacial wound healing.
Collapse
Affiliation(s)
- Ming Hao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - MengNa Duan
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, Jilin, China
| | - Zhijing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Hengzong Zhou
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Shuangji Li
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Jingcheng Xiang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Han Wu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Huimin Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Lu Chang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| |
Collapse
|
|
31
|
Woodson CM, Kehn-Hall K. Examining the role of EGR1 during viral infections. Front Microbiol 2022; 13:1020220. [PMID: 36338037 PMCID: PMC9634628 DOI: 10.3389/fmicb.2022.1020220] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 09/26/2022] [Indexed: 09/06/2023] Open
Abstract
Early growth response 1 (EGR1) is a multifunctional mammalian transcription factor capable of both enhancing and/or inhibiting gene expression. EGR1 can be activated by a wide array of stimuli such as exposure to growth factors, cytokines, apoptosis, and various cellular stress states including viral infections by both DNA and RNA viruses. Following induction, EGR1 functions as a convergence point for numerous specialized signaling cascades and couples short-term extracellular signals to influence transcriptional regulation of genes required to initiate the appropriate biological response. The role of EGR1 has been extensively studied in both physiological and pathological conditions of the adult nervous system where it is readily expressed in various regions of the brain and is critical for neuronal plasticity and the formation of memories. In addition to its involvement in neuropsychiatric disorders, EGR1 has also been widely examined in the field of cancer where it plays paradoxical roles as a tumor suppressor gene or oncogene. EGR1 is also associated with multiple viral infections such as Venezuelan equine encephalitis virus (VEEV), Kaposi's sarcoma-associated herpesvirus (KSHV), herpes simplex virus 1 (HSV-1), human polyomavirus JC virus (JCV), human immunodeficiency virus (HIV), and Epstein-Barr virus (EBV). In this review, we examine EGR1 and its role(s) during viral infections. First, we provide an overview of EGR1 in terms of its structure, other family members, and a brief overview of its roles in non-viral disease states. We also review upstream regulators of EGR1 and downstream factors impacted by EGR1. Then, we extensively examine EGR1 and its roles, both direct and indirect, in regulating replication of DNA and RNA viruses.
Collapse
Affiliation(s)
- Caitlin M. Woodson
- Department of Biomedical Science and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
- Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
| | - Kylene Kehn-Hall
- Department of Biomedical Science and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
- Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, United States
| |
Collapse
|
|
32
|
Qin D, Liu P, Zhou H, Jin J, Gong W, Liu K, Chen S, Huang J, Fan W, Tao Z, Xu Y. TIM-4 in macrophages contributes to nasal polyp formation through the TGF-β1–mediated epithelial to mesenchymal transition in nasal epithelial cells. Front Immunol 2022; 13:941608. [PMID: 35990621 PMCID: PMC9389014 DOI: 10.3389/fimmu.2022.941608] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/13/2022] [Indexed: 12/02/2022] Open
Abstract
Chronic rhinosinusitis with nasal polyps (CRSwNP) is caused by prolonged inflammation of the paranasal sinus mucosa. The epithelial to mesenchymal transition (EMT) is involved in the occurrence and development of CRSwNP. The T-cell immunoglobulin domain and the mucin domain 4 (TIM-4) is closely related to chronic inflammation, but its mechanism in CRSwNP is poorly understood. In our study, we found that TIM-4 was increased in the sinonasal mucosa of CRSwNP patients and, especially, in macrophages. TIM-4 was positively correlated with α-SMA but negatively correlated with E-cadherin in CRS. Moreover, we confirmed that TIM-4 was positively correlated with the clinical parameters of the Lund-Mackay and Lund-Kennedy scores. In the NP mouse model, administration of TIM-4 neutralizing antibody significantly reduced the polypoid lesions and inhibited the EMT process. TIM-4 activation by stimulating with tissue extracts of CRSwNP led to a significant increase of TGF-β1 expression in macrophages in vitro. Furthermore, coculture of macrophages and human nasal epithelial cells (hNECs) results suggested that the overexpression of TIM-4 in macrophages made a contribution to the EMT process in hNECs. Mechanistically, TIM-4 upregulated TGF-β1 expression in macrophages via the ROS/p38 MAPK/Egr-1 pathway. In conclusion, TIM-4 contributes to the EMT process and aggravates the development of CRSwNP by facilitating the production of TGF-β1 in macrophages. Inhibition of TIM-4 expression suppresses nasal polyp formation, which might provide a new therapeutic approach for CRSwNP.
Collapse
Affiliation(s)
- Danxue Qin
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Peiqiang Liu
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Huiqin Zhou
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jing Jin
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wanyang Gong
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Kunyu Liu
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Siyuan Chen
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jingyu Huang
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wenjun Fan
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zezhang Tao
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yu Xu
- Department of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- Research Institute of Otolaryngology-Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Yu Xu,
| |
Collapse
|
|
33
|
Lanzi C, Favini E, Dal Bo L, Tortoreto M, Arrighetti N, Zaffaroni N, Cassinelli G. Upregulation of ERK-EGR1-heparanase axis by HDAC inhibitors provides targets for rational therapeutic intervention in synovial sarcoma. J Exp Clin Cancer Res 2021; 40:381. [PMID: 34857011 PMCID: PMC8638516 DOI: 10.1186/s13046-021-02150-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 10/21/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Synovial sarcoma (SS) is an aggressive soft tissue tumor with limited therapeutic options in advanced stage. SS18-SSX fusion oncogenes, which are the hallmarks of SS, cause epigenetic rewiring involving histone deacetylases (HDACs). Promising preclinical studies supporting HDAC targeting for SS treatment were not reflected in clinical trials with HDAC inhibitor (HDACi) monotherapies. We investigated pathways implicated in SS cell response to HDACi to identify vulnerabilities exploitable in combination treatments and improve the therapeutic efficacy of HDACi-based regimens. METHODS Antiproliferative and proapoptotic effects of the HDACi SAHA and FK228 were examined in SS cell lines in parallel with biochemical and molecular analyses to bring out cytoprotective pathways. Treatments combining HDACi with drugs targeting HDACi-activated prosurvival pathways were tested in functional assays in vitro and in a SS orthotopic xenograft model. Molecular mechanisms underlying synergisms were investigated in SS cells through pharmacological and gene silencing approaches and validated by qRT-PCR and Western blotting. RESULTS SS cell response to HDACi was consistently characterized by activation of a cytoprotective and auto-sustaining axis involving ERKs, EGR1, and the β-endoglycosidase heparanase, a well recognized pleiotropic player in tumorigenesis and disease progression. HDAC inhibition was shown to upregulate heparanase by inducing expression of the positive regulator EGR1 and by hampering negative regulation by p53 through its acetylation. Interception of HDACi-induced ERK-EGR1-heparanase pathway by cell co-treatment with a MEK inhibitor (trametinib) or a heparanase inhibitor (SST0001/roneparstat) enhanced antiproliferative and pro-apoptotic effects. HDAC and heparanase inhibitors had opposite effects on histone acetylation and nuclear heparanase levels. The combination of SAHA with SST0001 prevented the upregulation of ERK-EGR1-heparanase induced by the HDACi and promoted caspase-dependent cell death. In vivo, the combined treatment with SAHA and SST0001 potentiated the antitumor efficacy against the CME-1 orthotopic SS model as compared to single agent administration. CONCLUSIONS The present study provides preclinical rationale and mechanistic insights into drug combinatory strategies based on the use of ERK pathway and heparanase inhibitors to improve the efficacy of HDACi-based antitumor therapies in SS. The involvement of classes of agents already clinically available, or under clinical evaluation, indicates the transferability potential of the proposed approaches.
Collapse
Affiliation(s)
- Cinzia Lanzi
- Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy
| | - Enrica Favini
- Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy
| | - Laura Dal Bo
- Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy
| | - Monica Tortoreto
- Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy
| | - Noemi Arrighetti
- Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy
| | - Nadia Zaffaroni
- Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy
| | - Giuliana Cassinelli
- Department of Applied Research and Technological Development, Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy.
| |
Collapse
|
|
34
|
Hamed O, Joshi R, Michi AN, Kooi C, Giembycz MA. β 2-Adrenoceptor Agonists Promote Extracellular Signal-Regulated Kinase 1/2 Dephosphorylation in Human Airway Epithelial Cells by Canonical, cAMP-Driven Signaling Independently of β-Arrestin 2. Mol Pharmacol 2021; 100:388-405. [PMID: 34341099 DOI: 10.1124/molpharm.121.000294] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 07/07/2021] [Indexed: 11/22/2022] Open
Abstract
Chronic use of β 2-adrenoceptor agonists as a monotherapy in asthma is associated with a loss of disease control and an increased risk of mortality. Herein, we tested the hypothesis that β 2-adrenoceptor agonists, including formoterol, promote biased, β-arrestin (Arr) 2-dependent activation of the mitogen-activated protein kinases, ERK1/2, in human airway epithelial cells and, thereby, effect changes in gene expression that could contribute to their adverse clinical outcomes. Three airway epithelial cell models were used: the BEAS-2B cell line, human primary bronchial epithelial cells (HBEC) grown in submersion culture, and HBEC that were highly differentiated at an air-liquid interface. Unexpectedly, treatment of all epithelial cell models with formoterol decreased basal ERK1/2 phosphorylation. This was mediated by cAMP-dependent protein kinase and involved the inactivation of C-rapidly-activated fibrosarcoma, which attenuated downstream ERK1/2 activity, and the induction of dual-specificity phosphatase 1. Formoterol also inhibited the basal expression of early growth response-1, an ERK1/2-regulated gene that controls cell growth and repair in the airways. Neither carvedilol, a β 2-adrenoceptor agonist biased toward βArr2, nor formoterol promoted ERK1/2 phosphorylation in BEAS-2B cells, although β 2-adrenoceptor desensitization was compromised in ARRB2-deficient cells. Collectively, these results contest the hypothesis that formoterol activates ERK1/2 in airway epithelia by nucleating a βArr2 signaling complex; instead, they indicate that β 2-adrenoceptor agonists inhibit constitutive ERK1/2 activity in a cAMP-dependent manner. These findings are the antithesis of results obtained using acutely challenged native and engineered HEK293 cells, which have been used extensively to study mechanisms of ERK1/2 activation, and highlight the cell type dependence of β 2-adrenoceptor-mediated signaling. SIGNIFICANCE STATEMENT: It has been proposed that the adverse effects of β 2-adrenoceptor agonist monotherapy in asthma are mediated by genomic mechanisms that occur principally in airway epithelial cells and are the result of β-arrestin 2-dependent activation of ERK1/2. This study shows that β 2-adrenoceptor agonists, paradoxically, reduced ERK1/2 phosphorylation in airway epithelia by disrupting upstream rat sarcoma-C-rapidly accelerated fibrosarcoma complex formation and inducing dual-specificity phosphatase 1. Moreover, these effects were cAMP-dependent protein kinase-dependent, suggesting that β 2-adrenoceptor agonists were not biased toward β-arrestin 2 and acted via canonical, cAMP-dependent signaling.
Collapse
Affiliation(s)
- Omar Hamed
- Airways Inflammation Research Group, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Radhika Joshi
- Airways Inflammation Research Group, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Aubrey N Michi
- Airways Inflammation Research Group, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Cora Kooi
- Airways Inflammation Research Group, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Mark A Giembycz
- Airways Inflammation Research Group, Department of Physiology & Pharmacology, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| |
Collapse
|
|
35
|
A mechanism of cooling hot tumors: Lactate attenuates inflammation in dendritic cells. iScience 2021; 24:103067. [PMID: 34541473 PMCID: PMC8441070 DOI: 10.1016/j.isci.2021.103067] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/02/2021] [Accepted: 08/26/2021] [Indexed: 11/22/2022] Open
Abstract
Turning non-inflamed (cold) tumors into inflamed (hot) tumors is important for maximizing the effect of immune checkpoint inhibitors (ICIs) against malignancies. We showed that lactate, a product of the Warburg effect, inhibited the efficacy of ICIs and suppressed IL-12 p40 expression in dendritic cells (DCs) through reducing NF-κB p65, p50, and c-Rel DNA-binding activity to the IL-12 p40 promoter. Additionally, lactate promoted the expression of early growth response protein 1 (EGR1), whose expression was increased in human invasive melanoma compared with non-invasive melanoma. We also found that EGR1 interacts with serum response factor (SRF) and represses the expression of CD80 in DCs. These findings suggest that lactate and its induced EGR1 are key factors that turn hot tumors into cold tumors and may represent targets in cancer treatment with ICIs.
Lactate suppressed IL-12 p40 expression in dendritic cells Lactate promoted the expression of early growth response protein 1 (EGR1) EGR1 interacts with serum response factor (SRF) and represses the expression of CD80 Lactate and EGR1 switch inflamed (hot) tumors to non-inflamed (cold) tumors
Collapse
|
|
36
|
Park M, Park SH, Park H, Kim HR, Lim HJ, Song H. ADAMTS-1: a novel target gene of an estrogen-induced transcription factor, EGR1, critical for embryo implantation in the mouse uterus. Cell Biosci 2021; 11:155. [PMID: 34348778 PMCID: PMC8336340 DOI: 10.1186/s13578-021-00672-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/28/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Recently, we demonstrated that estrogen (E2) induces early growth response 1 (Egr1) to mediate its actions on the uterine epithelium by controlling progesterone receptor signaling for successful embryo implantation. EGR1 is a transcription factor that regulates the spectrum of target genes in many different tissues, including the uterus. E2-induced EGR1 regulates a set of genes involved in epithelial cell remodeling during embryo implantation in the uterus. However, only few target genes of EGR1 in the uterus have been identified. RESULT The expression of ADAM metallopeptidase with thrombospondin type 1 motif 1 (Adamts-1) was significantly downregulated in the uteri of E2-treated ovariectomized (OVX) Egr1(-/-) mice. Immunostaining of ADAMTS-1 revealed its exclusive expression in the uterine epithelium of OVX wild-type but not Egr1(-/-) mice treated with E2. The expression profiles of Adamts-1 and Egr1 were similar in the uteri of E2-treated OVX mice at various time points tested. Pre-treatment with ICI 182, 780, a nuclear estrogen receptor (ER) antagonist, effectively inhibited the E2-dependent induction of Egr1 and Adamts-1. Pharmacologic inhibition of E2-induced ERK1/2 or p38 phosphorylation interfered with the induction of EGR1 and ADAMTS-1. Furthermore, ADAMTS-1, as well as EGR1, was induced in stroma cells surrounding the implanting blastocyst during embryo implantation. Transient transfection with EGR1 expression vectors significantly induced the expression of ADAMTS-1. Luciferase activity of the Adamts-1 promoter containing EGR1 binding sites (EBSs) was increased by EGR1 in a dose-dependent manner, suggesting functional regulation of Adamts-1 transcription by EGR1. Site-directed mutagenesis of EBS on the Adamts-1 promoter demonstrated that EGR1 directly binds to the EBS at -1151/-1134 among four putative EBSs. CONCLUSIONS Collectively, we have demonstrated that Adamts-1 is a novel target gene of E2-ER-MAPK-EGR1, which is critical for embryo implantation in the mouse uterus during early pregnancy.
Collapse
Affiliation(s)
- Mira Park
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | - So Hee Park
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | - Hyunsun Park
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | - Hye-Ryun Kim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | - Hyunjung J Lim
- Department of Veterinary Medicine, School of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea.
| | - Haengseok Song
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea.
| |
Collapse
|
|
37
|
Han J, Wang P, Xia X, Zhang L, Zhang H, Huang Y, Li X, Zhao W, Zhang L. EGR1 promoted anticancer effects of Scutellarin via regulating LINC00857/miR-150-5p/c-Myc in osteosarcoma. J Cell Mol Med 2021; 25:8479-8489. [PMID: 34346162 PMCID: PMC8419195 DOI: 10.1111/jcmm.16809] [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: 03/31/2021] [Revised: 07/02/2021] [Accepted: 07/09/2021] [Indexed: 11/27/2022] Open
Abstract
Scutellarin, an active flavone extracted from Erigeron breviscapus, is known to exhibit antitumour activity in many cancers. However, the effects of Scutellarin on osteosarcoma remain unclear. In this study, we found that Scutellarin suppressed osteosarcoma cell growth, induced cell apoptosis and inhibited tumorigenesis. Mechanistically, our data revealed that EGR1 was significantly increased under Scutellarin treatment. Increased EGR1 enhanced tumour‐suppressive effects of Scutellarin on osteosarcoma cells via transcriptionally downregulating LINC00857 expression. Additionally, we found that LINC00857 acted as a competitive endogenous RNA of miR‐150‐5p and inhibited the activity of miR‐150‐5p, which resulted in c‐Myc increase. Scutellarin could suppress c‐Myc protein levels through decreasing LINC00857 expression in osteosarcoma. Thus, these findings demonstrate that EGR1/ LINC00857/miR‐150‐5p/c‐Myc axis plays a key role in promoting anticancer effects of Scutellarin and Scutellarin might have potential clinical implication in osteosarcoma clinical treatment.
Collapse
Affiliation(s)
- Jian Han
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Peng Wang
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Xin Xia
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Li Zhang
- Laboratory of Pathogenic Biology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - He Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Yu Huang
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Xiaodong Li
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Wenzhi Zhao
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | - Lu Zhang
- The Second Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| |
Collapse
|
|
38
|
Huang Z, Huang B, Wei Q, Su X, Li X, Qin S, Huang W. The Protective Effects of Benzbromarone Against Propofol-Induced Inflammation and Injury in Human Brain Microvascular Endothelial Cells (HBMVECs). Neurotox Res 2021; 39:1449-1458. [PMID: 34216363 DOI: 10.1007/s12640-021-00387-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 05/13/2021] [Accepted: 06/11/2021] [Indexed: 12/12/2022]
Abstract
It has been widely reported that severe neurotoxicity can be induced by the application of propofol, which is closely related to the disruption of the blood-brain barrier (BBB) induced by inflammation and injury in the human brain microvascular endothelial cells (HBMVECs). Benzbromarone is a classic anti-gout agent that has been recently reported to exert anti-inflammatory and anti-oxidative stress effects. In the present study, we aim to investigate the protective property of Benzbromarone against propofol-induced injury on HBMVECs and the underlying mechanism. CCK8 assay was used to detect the cell viability of treated HBMVECs. Oxidative stress in HBMVECs was evaluated by measuring the levels of MDA and mitochondrial ROS. ELISA and qRT-PCR assay were used to determine the production of IL-1β, IL-8, MCP-1, ICAM-1, and VCAM-1 by treated HBMVECs. Calcein-AM staining was utilized to evaluate the attachment of U937 monocytes to HBMVECs. The expression level of Egr-1 was determined by qRT-PCR and Western blot assay. Firstly, the decreased cell viability of HBMVECs induced by propofol was significantly elevated by treatment with Benzbromarone. The increased levels of MDA and mitochondrial ROS induced by propofol were dramatically suppressed by Benzbromarone. Secondly, the excessive production of inflammatory factors (IL-1β, IL-8, and MCP-1) and adhesion molecules (ICAM-1 and VCAM-1) triggered by propofol was pronouncedly inhibited by Benzbromarone. Benzbromarone ameliorated propofol-induced attachment of U937 monocytes to HBMVECs. Lastly, Benzbromarone downregulated propofol-induced expression of the transcriptional factor Egr-1 in HBMVECs. Benzbromarone protected against propofol-induced inflammation and injury through suppressing Egr-1 in human brain vascular endothelial cells.
Collapse
Affiliation(s)
- Zehan Huang
- Department of Anesthesiology, Affiliated Hospital of Youjiang Medical University, Baise City, Guangxi, 533000, China
| | - Bo Huang
- Department of Anesthesiology, People's Hospital of Tiandong, Baise City, Guangxi, 533000, China
| | - Qiaosong Wei
- Department of Anesthesiology, People's Hospital of Baise, Baise City, Guangxi, 533000, China
| | - Xiaomei Su
- Department of Anesthesiology, People's Hospital of Baise, Baise City, Guangxi, 533000, China
| | - Xisong Li
- Department of Anesthesiology, People's Hospital of Baise, Baise City, Guangxi, 533000, China
| | - Siping Qin
- Department of Anesthesiology, People's Hospital of Baise, Baise City, Guangxi, 533000, China
| | - Wei Huang
- Department of Anesthesiology, People's Hospital of Baise, Baise City, Guangxi, 533000, China.
| |
Collapse
|
|
39
|
Hao L, Huang F, Yu X, Xu B, Liu Y, Zhang Y, Zhu Y. The Role of Early Growth Response Family Members 1-4 in Prognostic Value of Breast Cancer. Front Genet 2021; 12:680132. [PMID: 34178038 PMCID: PMC8220134 DOI: 10.3389/fgene.2021.680132] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 04/26/2021] [Indexed: 12/20/2022] Open
Abstract
Early growth response family members (EGRs), EGR1–4, have increasingly attracted attention in multiple cancers. However, the exact expression patterns and prognostic values of EGRs in the progress of breast cancer (BRCA) remain largely unknown. The mRNA expression and prognostic characteristics of EGRs were examined by the Cancer Genome Atlas (TCGA), Oncomine, and Kaplan-Meier plotter. Enrichment analyses were conducted based on protein-protein interaction (PPI) network. The Tumor Immune Estimation Resource (TIMER) database and MethSurv were further explored. The protein expression of EGR1 in BRCA was measured by western blotting and immunohistochemistry. The migration of mammary epithelial cells was determined by Boyden chamber assay. The transcriptional levels of EGR1/2/3 displayed significantly low expression in BRCA compared with that in normal tissues, while EGR4 was shown adverse expression pattern. Survival analysis revealed upregulated EGR1–4 were remarkably associated with favorable relapse-free survival (RFS). A close correlation with specific tumor-infiltrating immune cells (TIICs) and several CpG sites of EGRs were exhibited. Immunohistochemistry assays showed that the protein expression of EGR1 was remarkably downregulated in BRCA compared with that in paracancerous tissues. The migration of MCF10A mammary epithelial cells was increased after the silence of EGR1 by siRNA transfection. This study provides a novel insight to the role of EGRs in the prognostic value of BRCA.
Collapse
Affiliation(s)
- Leiyu Hao
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Fengru Huang
- Research Division of Clinical Pharmacology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xinqian Yu
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Bujie Xu
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Yan Liu
- Department of Physiology, Nanjing Medical University, Nanjing, China
| | - Yan Zhang
- Department of Gynecology and Obstetrics, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Yichao Zhu
- Department of Physiology, Nanjing Medical University, Nanjing, China.,State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
40
|
Lee JY, Kim JH, Bang H, Cho J, Ko YH, Kim SJ, Kim WS. EGR1 as a potential marker of prognosis in extranodal NK/T-cell lymphoma. Sci Rep 2021; 11:10342. [PMID: 33990633 PMCID: PMC8121831 DOI: 10.1038/s41598-021-89754-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 04/19/2021] [Indexed: 12/11/2022] Open
Abstract
Extranodal natural killer T-cell lymphoma (ENKTL) is an aggressive malignancy with a dismal prognosis. In the present study, gene expression profiling was performed to provide more information on ENKTL molecular signature and offer a rationale for further investigation of prognostic markers in ENKTL. NanoString nCounter Analysis encompassing 133 target genes was used to compare gene expression levels of 43 ENKTL tumor samples. The majority of the patients were under 60 years of age (79.1%); 32 (74.4%) patients had nasal type ENKTL and 23 patients (53.5%) had intermediate/high risk ENKTL based on the prognostic index for natural killer cell lymphoma (PINK). The median follow-up was 15.9 months and the median overall survival (OS) was 16.1 months (95% CI 13.0-69.8). EGR1 upregulation was consistently identified in the localized stage with a low risk of prognostic index based on the PINK. Among the six significantly relevant genes for EGR1 expression, high expression levels of genes, including CD59, GAS1, CXCR7, and RAMP3, were associated with a good survival prognosis. The in vitro test showed EGR1 modulated the transcriptional activity of the target genes including CD59, GAS1, CXCR7, and RAMP3. Downregulation of EGR1 and its target genes significantly inhibited apoptosis and decreased chemosensitivity and attenuated radiation-induced apoptosis. The findings showed EGR1 may be a candidate for prognostic markers in ENKTL. Considerable additional characterization may be necessary to fully understand EGR1.
Collapse
Affiliation(s)
- Ji Yun Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Joo Hyun Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Heejin Bang
- Department of Pathology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Junhun Cho
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Hyeh Ko
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seok Jin Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea
| | - Won Seog Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, South Korea.
| |
Collapse
|
|
41
|
Guo H, Zhang L. EGR1/2 Inhibits Papillary Thyroid Carcinoma Cell Growth by Suppressing the Expression of PTEN and BAX. Biochem Genet 2021; 59:1544-1557. [PMID: 33973090 DOI: 10.1007/s10528-021-10075-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 04/22/2021] [Indexed: 12/14/2022]
Abstract
Early growth response (EGR) proteins have been reported to be involved in cell growth and apoptosis in a variety of cancer types and could inhibit tumor development. However, the role of EGR1/2 in papillary thyroid carcinoma (PTC) has not been elucidated. The expression pattern of EGR1/2 in adjacent tissues and cancer tissues and the clinical prognosis of EGR1/2 were analyzed by using the samples from TCGA database. The cell viability was detected by MTT assay. Luciferase reporter assay was used to demonstrate the binding of EGR1/2 to the target gene promotor region. Our results showed that EGR1/2 was significantly downregulated in tumor tissues and correlated with poor prognosis. Overexpression of EGR1/2 inhibited proliferation of IHH-4 and BCPAP cells, and knockdown of EGR1/2 showed a reverse effect. Overexpression of EGR1 or EGR2 promoted phosphatase and tension homolog (PTEN) or Bcl-2-associated X (BAX) expression, and EGR1 or EGR2 was able to directly bind to the promoter region of PTEN or BAX. In conclusion, we found that the altered expression of EGR1/2 affected the proliferation of PTC cells and regulated the expression of PTEN and BAX.
Collapse
Affiliation(s)
- Hao Guo
- Department of General Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Linlei Zhang
- Department of General Surgery, The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China.
| |
Collapse
|
|
42
|
Xie Y, Ma J, Yang M, Fan L, Chen W. Extracellular signal-regulated kinase signaling pathway and silicosis. Toxicol Res (Camb) 2021; 10:487-494. [PMID: 34141162 DOI: 10.1093/toxres/tfaa109] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/16/2020] [Accepted: 12/11/2020] [Indexed: 12/15/2022] Open
Abstract
Silicosis is a scarring lung disease caused by inhaling fine particles of crystalline silica in the workplace of many industries. Due to the lack of effective treatment and management, the continued high incidence of silicosis remains a major public health concern worldwide, especially in the developing countries. Till now, related molecular mechanisms underlying silicosis are still not completely understood. Multiple pathways have been reported to be participated in the pathological process of silicosis, and more complex signaling pathways are receiving attention. The activated extracellular signal-regulated kinase (ERK) signaling pathway has been recognized to control some functions in the cell. Recent studies have identified that the ERK signaling pathway contributes to the formation and development of silicosis through regulating the processes of oxidative stress, inflammatory response, proliferation and activation of fibroblasts, epithelial-mesenchymal transformation, autophagy, and apoptosis of cells. In this review article, we summarize the latest findings on the role of ERK signaling pathway in silica-induced experimental models of silicosis, as well as clinical perspectives.
Collapse
Affiliation(s)
- Yujia Xie
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jixuan Ma
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Meng Yang
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lieyang Fan
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Weihong Chen
- Department of Occupational & Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.,Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| |
Collapse
|
|
43
|
Chrysin Inhibits TNFα-Induced TSLP Expression through Downregulation of EGR1 Expression in Keratinocytes. Int J Mol Sci 2021; 22:ijms22094350. [PMID: 33919431 PMCID: PMC8122459 DOI: 10.3390/ijms22094350] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/13/2021] [Accepted: 04/16/2021] [Indexed: 01/26/2023] Open
Abstract
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that acts as a critical mediator in the pathogenesis of atopic dermatitis (AD). Various therapeutic agents that prevent TSLP function can efficiently relieve the clinical symptoms of AD. However, the downregulation of TSLP expression by therapeutic agents remains poorly understood. In this study, we investigated the mode of action of chrysin in TSLP suppression in an AD-like inflammatory environment. We observed that the transcription factor early growth response (EGR1) contributed to the tumor necrosis factor alpha (TNFα)-induced transcription of TSLP. Chrysin attenuated TNFα-induced TSLP expression by downregulating EGR1 expression in HaCaT keratinocytes. We also showed that the oral administration of chrysin improved AD-like skin lesions in the ear and neck of BALB/c mice challenged with 2,4-dinitrochlorobenzene. We also showed that chrysin suppressed the expression of EGR1 and TSLP by inhibiting the extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 mitogen-activated protein kinase pathways. Collectively, the findings of this study suggest that chrysin improves AD-like skin lesions, at least in part, through the downregulation of the ERK1/2 or JNK1/2-EGR1-TSLP signaling axis in keratinocytes.
Collapse
|
|
44
|
Tariq MU, Din NU, Abdul-Ghafar J, Park YK. The many faces of solitary fibrous tumor; diversity of histological features, differential diagnosis and role of molecular studies and surrogate markers in avoiding misdiagnosis and predicting the behavior. Diagn Pathol 2021; 16:32. [PMID: 33879215 PMCID: PMC8059036 DOI: 10.1186/s13000-021-01095-2] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/12/2021] [Indexed: 12/17/2022] Open
Abstract
Background Solitary Fibrous Tumor (SFT) is a distinct soft tissue neoplasm associated with NAB2-STAT6 gene fusion. It can involve a number of anatomic sites and exhibits a wide spectrum of histological features. Main body Apart from diversity in morphological features seen even in conventional SFT, two histologic variants (fat-forming and giant cell-rich) are also recognized. In addition, a malignant form and dedifferentiation are well recognized. Owing to diverse histological features and involvement of diverse anatomic locations, SFT can mimic other soft tissue neoplasms of different lineages including schwannoma, spindle cell lipoma, dermatofibrosarcoma protuberans, liposarcoma, gastrointestinal stromal tumor (GIST), malignant peripheral nerve sheath tumor (MPNST), and synovial sarcoma. SFT is classified as an intermediate (rarely metastasizing) tumor according to World Health Organization Classification of Tumors of Soft tissue and Bone, 5th edition. The management and prognosis of SFT differs from its malignant mimics and correct diagnosis is therefore important. Although SFT expresses a distinct immunohistochemical (IHC) profile, the classic histomorphological and IHC profile is not seen in all cases and diagnosis can be challenging. NAB2-STAT6 gene fusion has recently emerged as a sensitive and specific molecular marker and its IHC surrogate marker signal transducer and activator of transcription 6 (STAT6) has also shown significant sensitivity and specificity. However, few recent studies have reported STAT6 expression in other soft tissue neoplasms. Conclusion This review will focus on describing the diversity of histological features of SFT, differential diagnoses and discussing the features helpful in distinguishing SFT from its histological mimics.
Collapse
Affiliation(s)
- Muhammad Usman Tariq
- Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Nasir Ud Din
- Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi, Pakistan
| | - Jamshid Abdul-Ghafar
- Department of Pathology and Clinical Laboratory, French Medical Institute for Mothers and Children (FMIC), Kabul, Afghanistan.
| | - Yong-Koo Park
- Emeritus Professor, Kyung Hee University, School of Medicine Vice President of Asia, International Academy of Pathology, U2Labs, Jangwon Medical Foundation 68 Geoma-ro, Songpa-gu, Seoul, 05755, South Korea
| |
Collapse
|
|
45
|
Romano E, Rosa I, Fioretto BS, Cerinic MM, Manetti M. The Role of Pro-fibrotic Myofibroblasts in Systemic Sclerosis: from Origin to Therapeutic Targeting. Curr Mol Med 2021; 22:209-239. [PMID: 33823766 DOI: 10.2174/0929867328666210325102749] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 03/02/2021] [Accepted: 03/09/2021] [Indexed: 11/22/2022]
Abstract
Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disorder characterized by multisystem clinical manifestations resulting from immune dysregulation/autoimmunity, vasculopathy and, most notably, progressive fibrosis of the skin and internal organs. In recent years, it has emerged that the main drivers of SSc-related tissue fibrosis are myofibroblasts, a type of mesenchymal cells with both the extracellular matrix-synthesizing features of fibroblasts and the cytoskeletal characteristics of contractile smooth muscle cells. The accumulation and persistent activation of pro-fibrotic myofibroblasts during SSc development and progression result into elevated mechanical stress and reduced matrix plasticity within the affected tissues and may be ascribed to a reduced susceptibility of these cells to pro-apoptotic stimuli, as well as their increased formation from tissue-resident fibroblasts or transition from different cell types. Given the crucial role of myofibroblasts in SSc pathogenesis, finding the way to inhibit myofibroblast differentiation and accumulation by targeting their formation, function and survival may represent an effective approach to hamper the fibrotic process or even halt or reverse established fibrosis. In this review, we discuss the role of myofibroblasts in SSc-related fibrosis, with a special focus on their cellular origin and the signaling pathways implicated in their formation and persistent activation. Furthermore, we provide an overview of potential therapeutic strategies targeting myofibroblasts that may be able to counteract fibrosis in this pathological condition.
Collapse
Affiliation(s)
- Eloisa Romano
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence. Italy
| | - Irene Rosa
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence. Italy
| | - Bianca Saveria Fioretto
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence. Italy
| | - Marco Matucci Cerinic
- Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence. Italy
| | - Mirko Manetti
- Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, University of Florence, Florence. Italy
| |
Collapse
|
|
46
|
Huang W, Shimizu H, Bianchi J, Matovinovic K, Ayares DL, Gotoh M, Korbutt GS, Rajotte RV, Rayat GR. Impact of donor and prolonged cold ischemia time of neonatal pig pancreas on neonatal pig islet transplant outcome. Xenotransplantation 2021; 28:e12663. [PMID: 33230864 DOI: 10.1111/xen.12663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 10/14/2020] [Accepted: 11/09/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Genetically modified pigs (GMP) have been developed to alleviate the shortage of donors in human islet transplantation and rejection. In this study, we characterized and compared the islets from GalTKO, GalTKO/hCD46, GalTKO/hCD46/hCD39, and wild-type (WT) neonatal pigs. METHODS Islets were isolated from GMP and WT pig pancreases that have been packaged with ice pack for at least 24 hours. The difference in gene expression and function of islets were evaluated by microarray analysis and transplantation of islets under the kidney capsule of streptozotocin-induced diabetic immune-deficient mice, respectively. Blood glucose levels of these mice were monitored weekly post-transplantation for >100 days, and islet grafts were collected and evaluated for the presence of endocrine cells. RESULTS The genes involved in extracellular components, cell adhesion, glucose metabolism, and inflammatory response are differentially expressed between GMP and WT pig islets. Variation in the ability of pig islets in correcting the diabetic state of the mouse recipients appears to be dependent on the pig donor. In addition, prolonged cold ischemia time had a negative effect on the transplant outcome. All normoglycemic mice were able to respond well to glucose challenge despite the initial differences in the ability of islet transplants to reverse their diabetic state. Islet xenografts of normoglycemic mice contained abundant insulin- and glucagon-positive cells. CONCLUSION The effect of GMP and WT neonatal pig islet transplants on hyperglycemia in mice appears to be dependent on the pig donor, and prolonged cold ischemia time negatively affects the neonatal pig islet transplant outcome.
Collapse
Affiliation(s)
- Wenlong Huang
- Faculty of Medicine and Dentistry, Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, University of Alberta, Edmonton, AB, Canada
- General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Hirofumi Shimizu
- Department of Surgery, Fukushima Medical University, Fukushima, Japan
| | | | - Kaja Matovinovic
- Faculty of Medicine and Dentistry, Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, University of Alberta, Edmonton, AB, Canada
| | | | - Mitsukazu Gotoh
- Department of Surgery, Fukushima Medical University, Fukushima, Japan
| | - Gregory S Korbutt
- Faculty of Medicine and Dentistry, Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, University of Alberta, Edmonton, AB, Canada
| | - Ray V Rajotte
- Faculty of Medicine and Dentistry, Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, University of Alberta, Edmonton, AB, Canada
| | - Gina R Rayat
- Faculty of Medicine and Dentistry, Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
47
|
Bieg M, Moskalev EA, Will R, Hebele S, Schwarzbach M, Schmeck S, Hohenberger P, Jakob J, Kasper B, Gaiser T, Ströbel P, Wardelmann E, Kontny U, Braunschweig T, Sirbu H, Grützmann R, Meidenbauer N, Ishaque N, Eils R, Wiemann S, Hartmann A, Agaimy A, Fritchie K, Giannini C, Haller F. Gene Expression in Solitary Fibrous Tumors (SFTs) Correlates with Anatomic Localization and NAB2-STAT6 Gene Fusion Variants. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:602-617. [PMID: 33497701 DOI: 10.1016/j.ajpath.2020.12.015] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 11/27/2020] [Accepted: 12/31/2020] [Indexed: 12/17/2022]
Abstract
Solitary fibrous tumors (SFTs) harbor recurrent NAB2-STAT6 gene fusions, promoting constitutional up-regulation of oncogenic early growth response 1 (EGR1)-dependent gene expression. SFTs with the most common canonical NAB2 exon 4-STAT6 exon 2 fusion variant are often located in the thorax (pleuropulmonary) and are less cellular with abundant collagen. In contrast, SFTs with NAB2 exon 6-STAT6 exon 16/17 fusion variants typically display a cellular round to ovoid cell morphology and are often located in the deep soft tissue of the retroperitoneum and intra-abdominal pelvic region or in the meninges. Here, we employed next-generation sequencing-based gene expression profiling to identify significant differences in gene expression associated with anatomic localization and NAB2-STAT6 gene fusion variants. SFTs with the NAB2 exon 4-STAT6 exon 2 fusion variant showed a transcriptional signature enriched for genes involved in DNA binding, gene transcription, and nuclear localization, whereas SFTs with the NAB2 exon 6-STAT6 exon 16/17 fusion variants were enriched for genes involved in tyrosine kinase signaling, cell proliferation, and cytoplasmic localization. Specific transcription factor binding motifs were enriched among differentially expressed genes in SFTs with different fusion variants, implicating co-transcription factors in the modification of chimeric NGFI-A binding protein 2 (NAB2)-STAT6-dependent deregulation of EGR1-dependent gene expression. In summary, this study establishes a potential molecular biologic basis for clinicopathologic differences in SFTs with distinct NAB2-STAT6 gene fusion variants.
Collapse
Affiliation(s)
- Matthias Bieg
- Center for Digital Health, Berlin Institute of Health and Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Evgeny A Moskalev
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Rainer Will
- Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany
| | - Simone Hebele
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | | | - Sanja Schmeck
- Institute of Pathology, Clinical Center Frankfurt Höchst, Frankfurt, Germany
| | - Peter Hohenberger
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Jens Jakob
- Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Bernd Kasper
- Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Timo Gaiser
- Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Philip Ströbel
- Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany
| | - Eva Wardelmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Udo Kontny
- Division of Pediatric Hematology Oncology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | | | - Horia Sirbu
- Department of Thoracic Surgery, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Robert Grützmann
- Department of Surgery, University Hospital Erlangen, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Norbert Meidenbauer
- Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Naveed Ishaque
- Center for Digital Health, Berlin Institute of Health and Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Roland Eils
- Center for Digital Health, Berlin Institute of Health and Charité-Universitätsmedizin Berlin, Berlin, Germany; Health Data Science Unit, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan Wiemann
- Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany; Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Abbas Agaimy
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Karen Fritchie
- Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, Italy
| | - Caterina Giannini
- Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, Italy; Anatomic Pathology, Dipartimento di Scienze Biomediche e NeuroMotorie-DIBINEM-Alma Mater Studiorum-Università di Bologna, Bologna, Italy
| | - Florian Haller
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
| |
Collapse
|
|
48
|
Guan X, Deng H, Choi UL, Li Z, Yang Y, Zeng J, Liu Y, Zhang X, Li G. EZH2 overexpression dampens tumor-suppressive signals via an EGR1 silencer to drive breast tumorigenesis. Oncogene 2020; 39:7127-7141. [PMID: 33009487 DOI: 10.1038/s41388-020-01484-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 08/27/2020] [Accepted: 09/21/2020] [Indexed: 02/08/2023]
Abstract
The mechanism underlying EZH2 overexpression in breast cancer and its involvement in tumorigenesis remain poorly understood. In this study, we developed an approach to systematically identify the trans-acting factors regulating the EZH2 expression, and identified more than 20 such factors. We revealed reciprocal regulation of early growth response 1 (EGR1) and EZH2: EGR1 activates the expression of EZH2, and EZH2 represses EGR1 expression. Using CRISPR-mediated genome/epigenome editing, we demonstrated that EHZ2 represses EGR1 expression through a silencer downstream of the EGR1 gene. Deletion of the EGR1 silencer resulted in reduced cell growth, invasion, tumorigenicity of breast cancer cells, and extensive changes in gene expression, such as upregulation of GADD45, DDIT3, and RND1; and downregulation of genes encoding cholesterol biosynthesis pathway enzymes. We hypothesize that EZH2/PRC2 acts as a "brake" for EGR1 expression by targeting the EGR1 silencer, and EZH2 overexpression dampens tumor-suppressive signals mediated by EGR1 to drive breast tumorigenesis.
Collapse
Affiliation(s)
- Xiaowen Guan
- Faculty of Health Sciences, University of Macau, Macau, China.,Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Houliang Deng
- Faculty of Health Sciences, University of Macau, Macau, China.,Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Un Lam Choi
- Faculty of Health Sciences, University of Macau, Macau, China.,Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Zhengfeng Li
- Faculty of Health Sciences, University of Macau, Macau, China.,Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Yiqi Yang
- Faculty of Health Sciences, University of Macau, Macau, China.,Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Jianming Zeng
- Faculty of Health Sciences, University of Macau, Macau, China.,Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Yunze Liu
- Faculty of Health Sciences, University of Macau, Macau, China.,Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Xuanjun Zhang
- Faculty of Health Sciences, University of Macau, Macau, China.,Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China.,Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China
| | - Gang Li
- Faculty of Health Sciences, University of Macau, Macau, China. .,Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China. .,Centre of Reproduction, Development and Aging, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China.
| |
Collapse
|
|
49
|
Nasiri G, Azarpira N, Alizadeh A, Goshtasbi S, Tayebi L. Shedding light on the role of keratinocyte-derived extracellular vesicles on skin-homing cells. Stem Cell Res Ther 2020; 11:421. [PMID: 32993791 PMCID: PMC7523352 DOI: 10.1186/s13287-020-01929-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/08/2020] [Indexed: 01/03/2023] Open
Abstract
Extracellular vesicles (EVs) are secretory lipid membranes with the ability to regulate cellular functions by exchanging biological components between different cells. Resident skin cells such as keratinocytes, fibroblasts, melanocytes, and inflammatory cells can secrete different types of EVs depending on their biological state. These vesicles can influence the physiological properties and pathological processes of skin, such as pigmentation, cutaneous immunity, and wound healing. Since keratinocytes constitute the majority of skin cells, secreted EVs from these cells may alter the pathophysiological behavior of other skin cells. This paper reviews the contents of keratinocyte-derived EVs and their impact on fibroblasts, melanocytes, and immune cells to provide an insight for better understanding of the pathophysiological mechanisms of skin disorders and their use in related therapeutic approaches.
Collapse
Affiliation(s)
- Golara Nasiri
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street, Shiraz, 7193711351 Iran
| | - Aliakbar Alizadeh
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sanaz Goshtasbi
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street, Shiraz, 7193711351 Iran
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI 53233 USA
| |
Collapse
|
|
50
|
Tian S, Jing R, Zhang W. Network-Based Approach to Identify the Antiproliferative Mechanisms of Bruceine D in Breast Cancer From the Cancer Genome Atlas. Front Oncol 2020; 10:1001. [PMID: 32714860 PMCID: PMC7343963 DOI: 10.3389/fonc.2020.01001] [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: 12/26/2019] [Accepted: 05/20/2020] [Indexed: 12/18/2022] Open
Abstract
Bruceine D (BD) is a natural compound extracted from a Chinese herb Brucea javanica that has been used for anti-inflammatory and anti-cancer treatment. However, little is reported about BD's effects in breast cancer tumorigenesis. In this paper, we aimed to investigate the effect of BD in breast cancer and elucidate the potential mechanism of BD by integrated multiple databases. Our data suggested BD inhibited MCF-7 and MDA-MB-231 cells proliferation and promoted cells apoptosis. We integrated multiple bioinformatics analysis strategies to identify genes, hub modules and pathways associated with BD treatment. Three key pathways, including AMIT_SERUM_RESPONSE_40_MCF10A, BILD_HRAS_ONCOGENIC_SIGNATURE, and NAGASHIMA_NRG1_SIGNALING_UP were identified to be associated with therapeutic effects of BD in breast cancer. Additionally, we validated the key genes by using quantitative real-time PCR and western blot. In conclusion, these findings revealed potential molecular mechanisms of BD to treat breast cancer by affecting AMIT_SERUM_RESPONSE_40_MCF10A, BILD_HRAS_ONCOGENIC_SIGNATURE, and NAGASHIMA_NRG1_SIGNALING_UP pathways and regulating expression of ZFP36, EGR1, and FOS.
Collapse
Affiliation(s)
- Saisai Tian
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Rui Jing
- School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Weidong Zhang
- School of Pharmacy, Second Military Medical University, Shanghai, China.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|