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Yeun J, Park S, Song Y, Yoon SH, Yu Sun S, Jeong B, Kim M, Lee KG, Im SG, Baek J. Reliable Harvest of Injectable Human Mesenchymal Stem Cell Sheets by Modulating Cell-Substrate Adhesion Strength. Adv Healthc Mater 2025:e2500135. [PMID: 40249130 DOI: 10.1002/adhm.202500135] [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: 01/09/2025] [Revised: 04/03/2025] [Indexed: 04/19/2025]
Abstract
Cell sheet engineering has emerged as a promising scaffold-free strategy in cell-based therapeutics, preserving essential cell-cell and cell-extracellular matrix (ECM) interactions. To enable minimally invasive delivery, a key challenge relies on making the cell sheets compatible with injection-based administration without subjecting sensitive cells to physical or thermal stresses. This study addresses a reliable method for controlling cell sheet dimensions by combining differential cell adhesion-guided micropatterning along with an isothermal detachment method. The surface composition of a copolymer, poly(ethylene glycol dimethacrylate-co-hydroxyethyl methacrylate) is delicately controlled via initiated chemical vapor deposition to ensure intact cell adhesion and rapid cell detachment under isothermal condition. The optimized surface further allows hydrophobic microcontact printing for creating micron-sized sheets. Human mesenchymal stem cell sheets harvested with this method show preserved ECM without compromising cell viability after both detachment and injection. Moreover, the injected cell sheets substantially enhance the angiogenic potential of human umbilical vein endothelial cells, demonstrating the sustained therapeutic activity of the cell sheet after injection. It is believed that this approach has great potential to broaden the scope of cell sheet engineering, serving as a robust platform for regenerative medicine.
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Affiliation(s)
- Jemin Yeun
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Seonghyeon Park
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Younseong Song
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Sung Hyun Yoon
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Sang Yu Sun
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Booseok Jeong
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Minkyung Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Kyoung G Lee
- Division of Nano-Bio Sensors/Chips Development, National NanoFab Center (NNFC), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Sung Gap Im
- Department of Chemical and Biomolecular Engineering and Graduate School of Stem cell & Regenerative Biology, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
| | - Jieung Baek
- Department of Mechanical and Biomedical Engineering and Graduate Program in System Health Science and Engineering, Ewha Woman's University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea
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2
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Liang LF, Zhao JQ, Wu YF, Chen HJ, Huang T, Lu XH. SMAD specific E3 ubiquitin protein ligase 1 accelerates diabetic macular edema progression by WNT inhibitory factor 1. World J Diabetes 2025; 16:101328. [PMID: 40093288 PMCID: PMC11885972 DOI: 10.4239/wjd.v16.i3.101328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 12/06/2024] [Accepted: 01/02/2025] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Diabetic macular edema (DME) is the most common cause of vision loss in people with diabetes. Tight junction disruption of the retinal pigment epithelium (RPE) cells has been reported to induce DME development. SMAD-specific E3 ubiquitin protein ligase (SMURF) 1 was associated with the tight junctions of cells. However, the mechanism of SMURF1 in the DME process remains unclear. AIM To investigate the role of SMURF1 in RPE cell tight junction during DME. METHODS ARPE-19 cells treated with high glucose (HG) and desferrioxamine mesylate (DFX) for establishment of the DME cell model. DME mice models were constructed by streptozotocin induction. The trans-epithelial electrical resistance and permeability of RPE cells were analyzed. The expressions of tight junction-related and autophagy-related proteins were determined. The interaction between insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) and SMURF1 mRNA was verified by RNA immunoprecipitation (RIP). SMURF1 N6-methyladenosine (m6A) level was detected by methylated RIP. RESULTS SMURF1 and vascular endothelial growth factor (VEGF) were upregulated in DME. SMURF1 knockdown reduced HG/DFX-induced autophagy, which protected RPE cell tight junctions and ameliorated retinal damage in DME mice. SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor (WIF) 1 ubiquitination and degradation. IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner. CONCLUSION M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation, which activated autophagy to inhibit RPE cell tight junctions, ultimately promoting DME progression.
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Affiliation(s)
- Li-Fang Liang
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Jia-Qi Zhao
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Yi-Fei Wu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Hui-Jie Chen
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Tian Huang
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
| | - Xiao-He Lu
- Department of Ophthalmology, Zhujiang Hospital, Southern Medical University, Guangzhou 515282, Guangdong Province, China
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Gil J, Kim D, Choi S, Bae ON. Cadmium-induced iron dysregulation contributes to functional impairment in brain endothelial cells via the ferroptosis pathway. Toxicol Appl Pharmacol 2025; 495:117233. [PMID: 39842614 DOI: 10.1016/j.taap.2025.117233] [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: 10/04/2024] [Revised: 01/12/2025] [Accepted: 01/15/2025] [Indexed: 01/24/2025]
Abstract
Cadmium (Cd2+) is a heavy metal that is a major hazardous environmental contaminant, ubiquitously present in the environment. Cd2+ exposure has been closely associated with an increased prevalence and severity of neurological and cardiovascular diseases (CVD). The blood-brain barrier (BBB) plays a crucial role in protecting the brain from external environmental factors. Mitochondria play an important role in maintaining the barrier function of brain endothelial cells by regulating energy metabolism and redox homeostasis. In this study, we aimed to assess the cytotoxic effects of Cd2+ on the integrity and function of brain endothelial cells. After 24 h of exposure, Cd2+ reduced cell survival, tight junction protein expression, and trans-endothelial electrical resistance (TEER) in bEnd.3 cells suggest a potential BBB integrity disruption by Cd2+ exposure. To clarify the underlying mechanism, we further investigated the role of mitochondria in iron overload-mediated cell death following Cd2+ exposure. Cd2+ induced a substantial reduction in mitochondrial basal respiration and ATP production in brain endothelial cells, suggesting mitochondrial dysfunction. In addition, Cd2+ exposure led to impaired autophagy, elevated iron levels, and increased lipid peroxidation, indicating the initiation of ferroptosis, a form of cell death triggered by iron. In summary, our research suggests that Cd2+ exposure can disrupt BBB function by causing mitochondrial dysfunction and disrupting iron homeostasis.
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Affiliation(s)
- Junkyung Gil
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University ERICA Campus, Ansan, South Korea.
| | - Donghyun Kim
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University ERICA Campus, Ansan, South Korea.
| | - Sungbin Choi
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University ERICA Campus, Ansan, South Korea.
| | - Ok-Nam Bae
- College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University ERICA Campus, Ansan, South Korea.
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4
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Rayat Pisheh H, Sani M. Mesenchymal stem cells derived exosomes: a new era in cardiac regeneration. Stem Cell Res Ther 2025; 16:16. [PMID: 39849585 PMCID: PMC11756228 DOI: 10.1186/s13287-024-04123-2] [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: 10/31/2024] [Accepted: 12/18/2024] [Indexed: 01/25/2025] Open
Abstract
Despite significant strides in medical treatments and surgical procedures for cardiovascular diseases, these conditions continue to be a major global health concern. The persistent need for innovative therapeutic approaches to mend damaged heart tissue highlights the complexity and urgency of this medical challenge. In recent years, stem cells have emerged as a promising tool for tissue regeneration, but challenges such as graft rejection and tumor formation have limited their clinical application. Exosomes, extracellular vesicles containing a diverse array of biomolecules, have garnered significant attention for their potential in regenerative medicine. The cardioprotective and reparative properties of mesenchymal stem cell-derived exosomes hold promise for the treatment of heart diseases. These exosomes can modulate various cellular processes, including angiogenesis, apoptosis, and inflammation, thereby enhancing cardiac function. Despite the growing interest, there remains a lack of comprehensive reviews synthesizing the molecular mechanisms, preclinical, and clinical evidence related to the specific role of MSC-derived exosomes in cardiac therapies. This review aims to fill that gap by exploring the potential of MSC-derived exosomes as a therapeutic strategy for cardiac diseases. This review explores the potential of mesenchymal stem cell-derived exosomes as a therapeutic strategy for cardiac diseases. We discuss the molecular mechanisms underlying their cardioprotective effects, summarize preclinical and clinical studies investigating their efficacy, and address the challenges and future perspectives of exosome-based therapies. The collective evidence suggests that MSC-derived exosomes hold promise as a novel and effective therapeutic approach for cardiac diseases.
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Affiliation(s)
- Hossein Rayat Pisheh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Shiraz Institute for Stem Cell & Regenerative Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Sani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
- Shiraz Institute for Stem Cell & Regenerative Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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5
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Zeng Y, Fu BM. Angiogenesis and Microvascular Permeability. Cold Spring Harb Perspect Med 2025; 15:a041163. [PMID: 38692737 PMCID: PMC11694756 DOI: 10.1101/cshperspect.a041163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
Angiogenesis, the formation of new blood microvessels, is a necessary physiological process for tissue generation and repair. Sufficient blood supply to the tissue is dependent on microvascular density, while the material exchange between the circulating blood and the surrounding tissue is controlled by microvascular permeability. We thus begin this article by reviewing the key signaling factors, particularly vascular endothelial growth factor (VEGF), which regulates both angiogenesis and microvascular permeability. We then review the role of angiogenesis in tissue growth (bone regeneration) and wound healing. Finally, we review angiogenesis as a pathological process in tumorigenesis, intraplaque hemorrhage, cerebral microhemorrhage, pulmonary fibrosis, and hepatic fibrosis. Since the glycocalyx is important for both angiogenesis and microvascular permeability, we highlight the role of the glycocalyx in regulating the interaction between tumor cells and endothelial cells (ECs) and VEGF-containing exosome release and uptake by tumor-associated ECs, all of which contribute to tumorigenesis and metastasis.
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Affiliation(s)
- Ye Zeng
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bingmei M Fu
- Department of Biomedical Engineering, The City College of the City University of New York, New York, New York 10031, USA
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Zhou XH, Luo YX, Yao XQ. Exercise-driven cellular autophagy: A bridge to systematic wellness. J Adv Res 2025:S2090-1232(24)00613-1. [PMID: 39756575 DOI: 10.1016/j.jare.2024.12.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/28/2024] [Accepted: 12/21/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Exercise enhances health by supporting homeostasis, bolstering defenses, and aiding disease recovery. It activates autophagy, a conserved cellular process essential for maintaining balance, while dysregulated autophagy contributes to disease progression. Despite extensive research on exercise and autophagy independently, their interplay remains insufficiently understood. AIM OF REVIEW This review explores the molecular mechanisms of exercise-induced autophagy in various tissues, focusing on key transduction pathways. It examines how different types of exercise trigger specific autophagic responses, supporting cellular balance and addressing systemic dysfunctions. The review also highlights the signaling pathways involved, their roles in protecting organ function, reducing disease risk, and promoting longevity, offering a clear understanding of the link between exercise and autophagy. KEY SCIENTIFIC CONCEPTS OF REVIEW Exercise-induced autophagy is governed by highly coordinated and dynamic pathways integrating direct and indirect mechanical forces and biochemical signals, linking physical activity to cellular and systemic health across multiple organ systems. Its activation is influenced by exercise modality, intensity, duration, and individual biological characteristics, including age, sex, and muscle fiber composition. Aerobic exercises primarily engage AMPK and mTOR pathways, supporting mitochondrial quality and cellular homeostasis. Anaerobic training activates PI3K/Akt signaling, modulating molecules like FOXO3a and Beclin1 to drive muscle autophagy and repair. In pathological contexts, exercise-induced autophagy enhances mitochondrial function, proteostasis, and tissue regeneration, benefiting conditions like sarcopenia, neurodegeneration, myocardial ischemia, metabolic disorders, and cancer. However, excessive exercise may lead to autophagic overactivation, leading to muscle atrophy or pathological cardiac remodeling. This underscores the critical need for balanced exercise regimens to maximize therapeutic efficacy while minimizing risks. Future research should prioritize identifying reliable biomarkers, optimizing exercise protocols, and integrating exercise with pharmacological strategies to enhance therapeutic outcomes.
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Affiliation(s)
- Xiao-Han Zhou
- Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Ya-Xi Luo
- Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China
| | - Xiu-Qing Yao
- Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China; Chongqing Municipality Clinical Research Center for Geriatric Medicine, Chongqing, PR China; Department of Rehabilitation Therapy, Chongqing Medical University, Chongqing, PR China.
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7
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Li G, Ma Y, Zhang S, Lin W, Yao X, Zhou Y, Zhao Y, Rao Q, Qu Y, Gao Y, Chen L, Zhang Y, Han F, Sun M, Zhao C. A mechanistic systems biology model of brain microvascular endothelial cell signaling reveals dynamic pathway-based therapeutic targets for brain ischemia. Redox Biol 2024; 78:103415. [PMID: 39520909 PMCID: PMC11584692 DOI: 10.1016/j.redox.2024.103415] [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: 10/21/2024] [Revised: 10/31/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024] Open
Abstract
Ischemic stroke is a significant threat to human health. Currently, there is a lack of effective treatments for stroke, and progress in new neuron-centered drug target development is relatively slow. On the other hand, studies have demonstrated that brain microvascular endothelial cells (BMECs) are crucial components of the neurovascular unit and play pivotal roles in ischemic stroke progression. To better understand the complex multifaceted roles of BMECs in the regulation of ischemic stroke pathophysiology and facilitate BMEC-based drug target discovery, we utilized a transcriptomics-informed systems biology modeling approach and constructed a mechanism-based computational multipathway model to systematically investigate BMEC function and its modulatory potential. Extensive multilevel data regarding complex BMEC pathway signal transduction and biomarker expression under various pathophysiological conditions were used for quantitative model calibration and validation, and we generated dynamic BMEC phenotype maps in response to various stroke-related stimuli to identify potential determinants of BMEC fate under stress conditions. Through high-throughput model sensitivity analyses and virtual target perturbations in model-based single cells, our model predicted that targeting succinate could effectively reverse the detrimental cell phenotype of BMECs under oxygen and glucose deprivation/reoxygenation, a condition that mimics stroke pathogenesis, and we experimentally validated the utility of this new target in terms of regulating inflammatory factor production, free radical generation and tight junction protection in vitro and in vivo. Our work is the first that complementarily couples transcriptomic analysis with mechanistic systems-level pathway modeling in the study of BMEC function and endothelium-based therapeutic targets in ischemic stroke.
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Affiliation(s)
- Geli Li
- School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China; Gusu School, Nanjing Medical University, 215000, Suzhou, China
| | - Yuchen Ma
- School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China
| | - Sujie Zhang
- School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China
| | - Wen Lin
- School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China
| | - Xinyi Yao
- School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China
| | - Yating Zhou
- The First Affiliated Hospital of Nanjing Medical University, 210000, Nanjing, China
| | - Yanyong Zhao
- School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China
| | - Qi Rao
- School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China
| | - Yuchen Qu
- School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China
| | - Yuan Gao
- QSPMed Technologies, 210000, Nanjing, China
| | - Lianmin Chen
- The First Affiliated Hospital of Nanjing Medical University, 210000, Nanjing, China
| | - Yu Zhang
- Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, 21205, Baltimore, USA
| | - Feng Han
- Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China.
| | - Meiling Sun
- School of Basic Medical Sciences, Nanjing Medical University, 210000, Nanjing, China.
| | - Chen Zhao
- School of Pharmacy, Nanjing Medical University, 210000, Nanjing, China; The First Affiliated Hospital of Nanjing Medical University, 210000, Nanjing, China.
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8
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Rajendran D, Oon CE. Navigating therapeutic prospects by modulating autophagy in colorectal cancer. Life Sci 2024; 358:123121. [PMID: 39389340 DOI: 10.1016/j.lfs.2024.123121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/25/2024] [Accepted: 10/05/2024] [Indexed: 10/12/2024]
Abstract
Colorectal cancer (CRC) remains a leading cause of death globally despite the improvements in cancer treatment. Autophagy is an evolutionarily conserved lysosomal-dependent degradation pathway that is critical in maintaining cellular homeostasis. However, in cancer, autophagy may have conflicting functions in preventing early tumour formation versus the maintenance of advanced-stage tumours. Defective autophagy has a broad and dynamic effect not just on cancer cells, but also on the tumour microenvironment which influences tumour progression and response to treatment. To add to the layer of complexity, somatic mutations in CRC including tumour protein p53 (TP53), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), Kirsten rat sarcoma viral oncogene homolog (KRAS), and phosphatase and tensin homolog (PTEN) can render chemoresistance by promoting a pro-survival advantage through autophagy. Recent studies have also reported autophagy-related cell deaths that are distinct from classical autophagy by employing parts of the autophagic machinery, which impacts strategies for autophagy regulation in cancer therapy. This review discusses the molecular processes of autophagy in the evolution of CRC and its role in the tumour microenvironment, as well as prospective therapeutic methods based on autophagy suppression or promotion. It also highlights clinical trials using autophagy modulators for treating CRC, underscoring the importance of autophagy regulation in CRC therapy.
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Affiliation(s)
- Deepa Rajendran
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
| | - Chern Ein Oon
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
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9
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Berkemeier QN, Deyhle MR, McCormick JJ, Escobar KA, Mermier CM. The Potential Interplay Between HIF-1α, Angiogenic, and Autophagic Signaling During Intermittent Hypoxic Exposure and Exercise. High Alt Med Biol 2024; 25:326-336. [PMID: 38700877 DOI: 10.1089/ham.2023.0090] [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] [Indexed: 12/05/2024] Open
Abstract
Berkemeier, Quint N., Michael R. Deyhle, James J. McCormick, Kurt A. Escobar, and Christine M. Mermier. The potential interplay between HIF-1α, angiogenic, and autophagic signaling during intermittent hypoxic exposure and exercise High Alt Med Biol. 25:326-336, 2024.-Environmental hypoxia as a result of decreased barometric pressure upon ascent to high altitudes (>2,500 m) presents increased physiological demands compared with low altitudes, or normoxic environments. Competitive athletes, mountaineers, wildland firefighters, military personnel, miners, and outdoor enthusiasts commonly participate in, or are exposed to, forms of exercise or physical labor at moderate to high altitudes. However, the majority of research on intermittent hypoxic exposure is centered around hematological markers, and the skeletal muscle cellular responses to exercise in hypoxic environments remain largely unknown. Two processes that may be integral for the maintenance of cellular health in skeletal muscle include angiogenesis, or the formation of new blood vessels from preexisting vasculature and autophagy, a process that removes and recycles damaged and dysfunctional cellular material in the lysosome. The purpose of this review is to is to examine the current body of literature and highlight the potential interplay between low-oxygen-sensing pathways, angiogenesis, and autophagy during acute and prolonged intermittent hypoxic exposure in conjunction with exercise. The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of Army, DOD, DOE, ORAU/ORISE or U.S. Government.
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Affiliation(s)
- Quint N Berkemeier
- Health, Exercise and Sports Sciences, University of New Mexico, Albuquerque, New Mexico, USA
- Military Performance Division, United States Army Research Institute of Environmental Medicine, Natick, Massachusetts, USA
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, Tennessee, USA
| | - Michael R Deyhle
- Health, Exercise and Sports Sciences, University of New Mexico, Albuquerque, New Mexico, USA
- Department of Cell Biology and Physiology, School of Medicine, University of New Mexico, Albuquerque, New Mexico, USA
| | - James J McCormick
- Human and Environmental Physiology Research Unit, School of Human Kinetics, University of Ottawa, Ottawa, Ontario, Canada
| | - Kurt A Escobar
- Department of Kinesiology, California State University, Long Beach, California, USA
| | - Christine M Mermier
- Health, Exercise and Sports Sciences, University of New Mexico, Albuquerque, New Mexico, USA
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10
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Harithpriya K, Kaussikaa S, Kavyashree S, Geetha A, Ramkumar KM. Pathological insights into cell death pathways in diabetic wound healing. Pathol Res Pract 2024; 264:155715. [PMID: 39550997 DOI: 10.1016/j.prp.2024.155715] [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] [Received: 09/04/2024] [Revised: 10/27/2024] [Accepted: 11/06/2024] [Indexed: 11/19/2024]
Abstract
Diabetic foot ulcers (DFUs) are a microvascular complication that affects almost 21 % of the diabetic population. DFUs are characterized by lower limb abnormalities, chronic inflammation, and a heightened hypoxic environment. The challenge of healing these chronic wounds arises from impaired blood flow, neuropathy, and dysregulated cell death processes. The pathogenesis of DFUs involves intricate mechanisms of programmed cell death (PCD) in different cell types, which include keratinocytes, fibroblasts, and endothelial cells. The modes of cell death comprise apoptosis, autophagy, ferroptosis, pyroptosis, and NETosis, each defined by distinct biochemical hallmarks. These diverse mechanisms contribute to tissue injury by inducing neutrophil extracellular traps and generating cellular stressors like endoplasmic reticulum stress, oxidative stress, and inflammation. Through a comprehensive review of experimental studies identified from literature databases, this review synthesizes current knowledge on the critical signaling cascades implicated in programmed cell death within the context of diabetic foot ulcer pathology.
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Affiliation(s)
- Kannan Harithpriya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, TN 603210, United States
| | - Srinivasan Kaussikaa
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, TN 603210, United States
| | - Srikanth Kavyashree
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, TN 603210, United States
| | - Avs Geetha
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, TN 603210, United States
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, TN 603210, United States.
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11
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Dergilev K, Gureenkov A, Parfyonova Y. Autophagy as a Guardian of Vascular Niche Homeostasis. Int J Mol Sci 2024; 25:10097. [PMID: 39337582 PMCID: PMC11432168 DOI: 10.3390/ijms251810097] [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: 08/21/2024] [Revised: 09/12/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
The increasing burden of vascular dysfunction on healthcare systems worldwide results in higher morbidity and mortality rates across pathologies, including cardiovascular diseases. Vasculopathy is suggested to be caused by the dysregulation of vascular niches, a microenvironment of vascular structures comprising anatomical structures, extracellular matrix components, and various cell populations. These elements work together to ensure accurate control of the vascular network. In recent years, autophagy has been recognized as a crucial regulator of the vascular microenvironment responsible for maintaining basic cell functions such as proliferation, differentiation, replicative senescence, and apoptosis. Experimental studies indicate that autophagy activation can be enhanced or inhibited in various pathologies associated with vascular dysfunction, suggesting that autophagy plays both beneficial and detrimental roles. Here, we review and assess the principles of autophagy organization and regulation in non-tumor vascular niches. Our analysis focuses on significant figures in the vascular microenvironment, highlighting the role of autophagy and summarizing evidence that supports the systemic or multiorgan nature of the autophagy effects. Finally, we discuss the critical organizational and functional aspects of the vasculogenic niche, specifically in relation to autophagy. The resulting dysregulation of the vascular microenvironment contributes to the development of vascular dysfunction.
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Affiliation(s)
- Konstantin Dergilev
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
| | - Alexandre Gureenkov
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
| | - Yelena Parfyonova
- National Medical Research Centre of Cardiology Named after Academician E.I. Chazov, 121552 Moscow, Russia
- Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia
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12
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Ehle C, Iyer-Bierhoff A, Wu Y, Xing S, Kiehntopf M, Mosig AS, Godmann M, Heinzel T. Downregulation of HNF4A enables transcriptomic reprogramming during the hepatic acute-phase response. Commun Biol 2024; 7:589. [PMID: 38755249 PMCID: PMC11099168 DOI: 10.1038/s42003-024-06288-1] [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: 09/15/2023] [Accepted: 05/03/2024] [Indexed: 05/18/2024] Open
Abstract
The hepatic acute-phase response is characterized by a massive upregulation of serum proteins, such as haptoglobin and serum amyloid A, at the expense of liver homeostatic functions. Although the transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has a well-established role in safeguarding liver function and its cistrome spans around 50% of liver-specific genes, its role in the acute-phase response has received little attention so far. We demonstrate that HNF4A binds to and represses acute-phase genes under basal conditions. The reprogramming of hepatic transcription during inflammation necessitates loss of HNF4A function to allow expression of acute-phase genes while liver homeostatic genes are repressed. In a pre-clinical liver organoid model overexpression of HNF4A maintained liver functionality in spite of inflammation-induced cell damage. Conversely, HNF4A overexpression potently impaired the acute-phase response by retaining chromatin at regulatory regions of acute-phase genes inaccessible to transcription. Taken together, our data extend the understanding of dual HNF4A action as transcriptional activator and repressor, establishing HNF4A as gatekeeper for the hepatic acute-phase response.
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Affiliation(s)
- Charlotte Ehle
- Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, 07745, Jena, Germany
| | - Aishwarya Iyer-Bierhoff
- Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, 07745, Jena, Germany
| | - Yunchen Wu
- Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, 07745, Jena, Germany
- Marshall Laboratory of Biomedical Engineering, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518060, China
| | - Shaojun Xing
- Marshall Laboratory of Biomedical Engineering, Department of Pathogen Biology, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong, 518060, China
| | - Michael Kiehntopf
- Department of Clinical Chemistry and Laboratory Diagnostics, Jena University Hospital, 07747, Jena, Germany
| | - Alexander S Mosig
- Institute of Biochemistry II, Center for Sepsis Control and Care, Jena University Hospital, 07747, Jena, Germany
| | - Maren Godmann
- Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, 07745, Jena, Germany
| | - Thorsten Heinzel
- Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University Jena, 07745, Jena, Germany.
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13
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Hu M, Ladowski JM, Xu H. The Role of Autophagy in Vascular Endothelial Cell Health and Physiology. Cells 2024; 13:825. [PMID: 38786047 PMCID: PMC11120581 DOI: 10.3390/cells13100825] [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: 03/27/2024] [Revised: 04/30/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Autophagy is a highly conserved cellular recycling process which enables eukaryotes to maintain both cellular and overall homeostasis through the catabolic breakdown of intracellular components or the selective degradation of damaged organelles. In recent years, the importance of autophagy in vascular endothelial cells (ECs) has been increasingly recognized, and numerous studies have linked the dysregulation of autophagy to the development of endothelial dysfunction and vascular disease. Here, we provide an overview of the molecular mechanisms underlying autophagy in ECs and our current understanding of the roles of autophagy in vascular biology and review the implications of dysregulated autophagy for vascular disease. Finally, we summarize the current state of the research on compounds to modulate autophagy in ECs and identify challenges for their translation into clinical use.
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Affiliation(s)
| | - Joseph M. Ladowski
- Transplant and Immunobiology Research, Department of Surgery, Duke University, Durham, NC 27710, USA;
| | - He Xu
- Transplant and Immunobiology Research, Department of Surgery, Duke University, Durham, NC 27710, USA;
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14
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Wu D, Huang W, Zhang J, He L, Chen S, Zhu S, Sang Y, Liu K, Hou G, Chen B, Xu Y, Liu B, Yao H. Downregulation of VEGFA accelerates AGEs-mediated nucleus pulposus degeneration through inhibiting protective mitophagy in high glucose environments. Int J Biol Macromol 2024; 262:129950. [PMID: 38320636 DOI: 10.1016/j.ijbiomac.2024.129950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 01/24/2024] [Accepted: 02/01/2024] [Indexed: 02/08/2024]
Abstract
Intervertebral disc degeneration (IVDD) contributes largely to low back pain. Recent studies have highlighted the exacerbating role of diabetes mellitus (DM) in IVDD, mainly due to the influence of hyperglycemia (HG) or the accumulation of advanced glycation end products (AGEs). Vascular endothelial growth factor A (VEGFA) newly assumed a distinct impact in nonvascular tissues through mitophagy regulation. However, the combined actions of HG and AGEs on IVDD and the involved role of VEGFA remain unclear. We confirmed the potential relation between VEGFA and DM through bioinformatics and biological specimen detection. Then we observed that AGEs induced nucleus pulposus (NP) cell degeneration by upregulating cellular reactive oxygen species (ROS), and HG further aggravated ROS level through breaking AGEs-induced protective mitophagy. Furthermore, this adverse effect could be strengthened by VEGFA knockdown. Importantly, we identified that the regulation of VEGFA and mitophagy were vital mechanisms in AGEs-HG-induced NP cell degeneration through Parkin/Akt/mTOR and AMPK/mTOR pathway. Additionally, VEGFA overexpression through local injection with lentivirus carrying VEGFA plasmids significantly alleviated NP degeneration and IVDD in STZ-induced diabetes and puncture rat models. In conclusion, the findings first confirmed that VEGFA protects against AGEs-HG-induced IVDD, which may represent a therapeutic strategy for DM-related IVDD.
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Affiliation(s)
- Depeng Wu
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR China
| | - Weijun Huang
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR China
| | - Junbin Zhang
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
| | - Lei He
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR China
| | - Siyu Chen
- Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, Guangzhou, PR China
| | - Sihan Zhu
- University Hospital, LMU Munich, 81377 Munich, Germany
| | - Yuan Sang
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
| | - Kaihua Liu
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
| | - Gang Hou
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
| | - Biying Chen
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
| | - Yichun Xu
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China
| | - Bin Liu
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China; Guangdong Provincial Center for Quality Control of Minimally Invasive Spine Surgery, Guangzhou, PR China; Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, PR China.
| | - Hui Yao
- Department of Orthopaedics, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China.
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15
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Iyer-Bierhoff A, Wieczorek M, Peter SM, Ward D, Bens M, Vettorazzi S, Guehrs KH, Tuckermann JP, Heinzel T. Acetylation-induced proteasomal degradation of the activated glucocorticoid receptor limits hormonal signaling. iScience 2024; 27:108943. [PMID: 38333702 PMCID: PMC10850750 DOI: 10.1016/j.isci.2024.108943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 11/30/2023] [Accepted: 01/15/2024] [Indexed: 02/10/2024] Open
Abstract
Glucocorticoid (GC) signaling is essential for mounting a stress response, however, chronic stress or prolonged GC therapy downregulates the GC receptor (GR), leading to GC resistance. Regulatory mechanisms that refine this equilibrium are not well understood. Here, we identify seven lysine acetylation sites in the amino terminal domain of GR, with lysine 154 (Lys154) in the AF-1 region being the dominant acetyl-acceptor. GR-Lys154 acetylation is mediated by p300/CBP in the nucleus in an agonist-dependent manner and correlates with transcriptional activity. Deacetylation by NAD+-dependent SIRT1 facilitates dynamic regulation of this mark. Notably, agonist-binding to both wild-type GR and an acetylation-deficient mutant elicits similar short-term target gene expression. In contrast, upon extended treatment, the polyubiquitination of the acetylation-deficient GR mutant is impaired resulting in higher protein stability, increased chromatin association and prolonged transactivation. Taken together, reversible acetylation fine-tunes duration of the GC response by regulating proteasomal degradation of activated GR.
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Affiliation(s)
- Aishwarya Iyer-Bierhoff
- Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany
| | - Martin Wieczorek
- Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany
| | - Sina Marielle Peter
- Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany
| | - Dima Ward
- Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany
| | - Martin Bens
- Core Facility Next Generation Sequencing, Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany
| | - Sabine Vettorazzi
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Karl-Heinz Guehrs
- Core Facility Proteomics, Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany
| | - Jan P. Tuckermann
- Institute of Comparative Molecular Endocrinology (CME), Ulm University, Helmholtzstrasse 8/1, 89081 Ulm, Germany
| | - Thorsten Heinzel
- Institute of Biochemistry and Biophysics, Centre for Molecular Biomedicine (CMB), Friedrich Schiller University, Hans-Knoell-Strasse 2, 07745 Jena, Germany
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16
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Wolkersdorfer AM, Jugovic I, Scheller L, Gutmann M, Hahn L, Diessner J, Lühmann T, Meinel L. PEGylation of Human Vascular Endothelial Growth Factor. ACS Biomater Sci Eng 2024; 10:149-155. [PMID: 37296497 DOI: 10.1021/acsbiomaterials.3c00253] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Vascular endothelial growth factor A-165 (VEGF-A165) positively modulates neointimal hyperplasia, lumen stenosis, and neovascularization. One challenge for the use of VEGF-A165 for potential therapy is its short serum half-life. Therefore, we are designing VEGF-A165 bioconjugates carrying polyethylene glycol (PEG). The purity of the recombinantly expressed human VEGF-A165 exceeded 90%. The growth factor had a half-maximal effective concentration of 0.9 ng/mL (EC50) and induced tube formation of human umbilical vein endothelial cells. PEGylation was conducted by Schiff base reaction followed by reductive amination. After purification, two species were obtained, with one or two PEG attached per VEGF-A165 dimer. Both resulting bioconjugates had a purity exceeding 90%, wild-type bioactivity, and increased hydrodynamic radii as required for prolonging the half-life.
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Affiliation(s)
- Alena Maria Wolkersdorfer
- Institute of Pharmacy and Food Chemistry, University of Würzburg, University, Am Hubland, Würzburg DE-97074, Germany
| | - Isabelle Jugovic
- Institute of Pharmacy and Food Chemistry, University of Würzburg, University, Am Hubland, Würzburg DE-97074, Germany
| | - Lena Scheller
- Institute of Pharmacy and Food Chemistry, University of Würzburg, University, Am Hubland, Würzburg DE-97074, Germany
| | - Marcus Gutmann
- Institute of Pharmacy and Food Chemistry, University of Würzburg, University, Am Hubland, Würzburg DE-97074, Germany
| | - Lukas Hahn
- Institute of Pharmacy and Food Chemistry, University of Würzburg, University, Am Hubland, Würzburg DE-97074, Germany
| | - Joachim Diessner
- University of Würzburg, Department of Obstetrics and Gynecology, Josef-Schneider-Straße 14, Würzburg DE-97080, Germany
| | - Tessa Lühmann
- Institute of Pharmacy and Food Chemistry, University of Würzburg, University, Am Hubland, Würzburg DE-97074, Germany
| | - Lorenz Meinel
- Institute of Pharmacy and Food Chemistry, University of Würzburg, University, Am Hubland, Würzburg DE-97074, Germany
- Helmholtz Centre for Infection Research, Helmholtz-Institute for RNA-based Infection Research (HIRI), Josef-Schneider-Strasse 2/D15, Würzburg 97080, Germany
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17
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Wang J, Zhou L, Hou H, Li J, Zhao X, Li J, Li J, Niu X, Hou R, Zhang K. IL-17A is involved in the hyperplasia of blood vessels in local lesions of psoriasis by inhibiting autophagy. J Cosmet Dermatol 2024; 23:326-338. [PMID: 37635345 DOI: 10.1111/jocd.15975] [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: 03/28/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/29/2023]
Abstract
OBJECTIVE Increased angiogenesis is a pathological feature of psoriasis, but the pathomechanisms of angiogenesis in psoriasis are not clear. Interleukin-17A (IL-17A) is the major effect factor in the pathogenesis of psoriasis. Our results showed that IL-17A can promote angiogenesis and cause endothelial cell inflammation. Autophagy plays an important role not only in regulating inflammation, but also in regulating angiogenesis. Whether angiogenesis in psoriasis is related to autophagy remains unclear. In this study, we treated human umbilical vein endothelial cells (HUVECs) with IL-17A to simulate increased angiogenesis to study whether increased angiogenesis in psoriasis is related to autophagy. METHODS AND RESULTS Our results showed that treatment of HUVECs with IL-17A significantly increased angiogenesis and expression levels of mRNA for multiple proinflammatory cytokines (CCL20, IL-8, CCL2, IL-6, and IL-1β) and, while decreasing intracellular levels of nitric oxide (NO) and NO synthase (NOS) activity. Moreover, IL-17A inhibited autophagy as shown that IL-17A significantly increased expression levels of LC3II and p62 proteins. Induction of autophagy ameliorated IL-17A-mediated inflammatory response and inhibited angiogenesis, accompanied by increased p-AMPKα(Thr172) and p-ULK1(Ser555) expression, and decreased p-mTOR(Ser2448) and p-ULK1(Ser757) expression. Furthermore, inhibition of either AMPK or lysosomal acidification completely overrode autophagy-induced changes in angiogenesis and NOS activity. Finally, induction of autophagy decreased apoptosis and caspase-3 activity in IL-17A-treated HUVECs. CONCLUSIONS These results showed that IL-17A is involved in angiogenesis and inflammatory response by inhibiting autophagy through AMPK signaling pathway, suggesting that autophagy may be a new therapeutic target for psoriasis.
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Affiliation(s)
- Juanjuan Wang
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Ling Zhou
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Hui Hou
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Jiao Li
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Xincheng Zhao
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Jiajie Li
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Junqin Li
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Xuping Niu
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Ruixia Hou
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, China
| | - Kaiming Zhang
- Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan City Central Hospital, Taiyuan, China
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18
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Xue C, Chen K, Gao Z, Bao T, Dong L, Zhao L, Tong X, Li X. Common mechanisms underlying diabetic vascular complications: focus on the interaction of metabolic disorders, immuno-inflammation, and endothelial dysfunction. Cell Commun Signal 2023; 21:298. [PMID: 37904236 PMCID: PMC10614351 DOI: 10.1186/s12964-022-01016-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/11/2022] [Indexed: 11/01/2023] Open
Abstract
Diabetic vascular complications (DVCs), including macro- and micro- angiopathy, account for a high percentage of mortality in patients with diabetes mellitus (DM). Endothelial dysfunction is the initial and role step for the pathogenesis of DVCs. Hyperglycemia and lipid metabolism disorders contribute to endothelial dysfunction via direct injury of metabolism products, crosstalk between immunity and inflammation, as well as related interaction network. Although physiological and phenotypic differences support their specified changes in different targeted organs, there are still several common mechanisms underlying DVCs. Also, inhibitors of these common mechanisms may decrease the incidence of DVCs effectively. Thus, this review may provide new insights into the possible measures for the secondary prevention of DM. And we discussed the current limitations of those present preventive measures in DVCs research. Video Abstract.
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Affiliation(s)
- Chongxiang Xue
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Keyu Chen
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Zezheng Gao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Tingting Bao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - LiShuo Dong
- Changchun University of Traditional Chinese Medicine, Changchun, 130117, China
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China.
| | - Xiaolin Tong
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China.
| | - Xiuyang Li
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China.
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
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19
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Doshi H, Spengler K, Godbole A, Gee YS, Baell J, Oakhill JS, Henke A, Heller R. AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1. Microbiol Spectr 2023; 11:e0041723. [PMID: 37702499 PMCID: PMC10580915 DOI: 10.1128/spectrum.00417-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 07/06/2023] [Indexed: 09/14/2023] Open
Abstract
Herpes simplex virus type 1 (HSV-1) is a widespread contagious pathogen, mostly causing mild symptoms on the mucosal entry side. However, systemic distribution, in particular upon reactivation of the virus in immunocompromised patients, may trigger an innate immune response and induce damage of organs. In these conditions, HSV-1 may infect vascular endothelial cells, but little is known about the regulation of HSV-1 replication and possible defense mechanisms in these cells. The current study addresses the question of whether the host cell protein AMP-activated protein kinase (AMPK), an important metabolic sensor, can control HSV-1 replication in endothelial cells. We show that downregulation of the catalytic subunits AMPKα1 and/or AMPKα2 increased HSV-1 replication as monitored by TCID50 titrations, while a potent AMPK agonist, MK-8722, strongly inhibited it. MK-8722 induced a persistent phosphorylation of the AMPK downstream targets acetyl-CoA carboxylase (ACC) and the rapamycin-sensitive adaptor protein of mTOR (Raptor) and, related to this, impairment of ACC1-mediated lipid synthesis and the mechanistic target of the rapamycin complex-1 (mTORC1) pathway. Since blockade of mTOR by Torin-2 as well as downregulation of ACC1 by siRNA also decreased HSV-1 replication, MK-8722 is likely to exert its anti-viral effect via mTORC1 and ACC1 inhibition. Importantly, MK-8722 was able to reduce virus replication even when added after HSV-1. Together, our data highlight the importance of endothelial cells as host cells for HSV-1 replication upon systemic infection and identify AMPK, a metabolic host cell protein, as a potential target for antiviral strategies against HSV-1 infection and its severe consequences. IMPORTANCE Herpes simplex virus type 1 (HSV-1) is a common pathogen that causes blisters or cold sores in humans. It remains latent in infected individuals and can be reactivated multiple times. In adverse conditions, for instance, in immunocompromised patients, HSV-1 can lead to serious complications such as encephalitis, meningitis, or blindness. In these situations, infection of endothelial cells lining the surface of blood vessels may contribute to the manifestation of disease. Here, we describe the role of AMP-activated protein kinase (AMPK), a potent regulator of cellular energy metabolism, in HSV-1 replication in endothelial cells. While downregulation of AMPK potentiates HSV-1 replication, pharmacological AMPK activation inhibits it by limiting the availability of required host cell macromolecules such as proteins or fatty acids. These data highlight the role of metabolic host cell proteins as antiviral targets and reveal activation of endothelial AMPK as a potential strategy to protect from severe consequences of HSV-1 infection.
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Affiliation(s)
- Heena Doshi
- Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
| | - Katrin Spengler
- Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
| | - Amod Godbole
- Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
| | - Yi Sing Gee
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Jonathan Baell
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China
| | - Jonathan S. Oakhill
- Metabolic Signaling Laboratory, St. Vincent’s Institute of Medical Research, Fitzroy, Victoria, Australia
- Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia
| | - Andreas Henke
- Section of Experimental Virology, Institute of Medical Microbiology, Jena University Hospital, Jena, Germany
| | - Regine Heller
- Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
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20
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Avrutsky MI, Chen CW, Lawson JM, Snipas SJ, Salvesen GS, Troy CM. Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in a mouse model of retinal vein occlusion. Front Neurosci 2023; 17:1209527. [PMID: 37449272 PMCID: PMC10336837 DOI: 10.3389/fnins.2023.1209527] [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: 04/20/2023] [Accepted: 06/05/2023] [Indexed: 07/18/2023] Open
Abstract
Purpose Retinal vein occlusion (RVO) is a sight-threatening condition typically treated with intravitreal injection of vascular endothelial growth factor (VEGF) antagonists. Treatment response to anti-VEGF therapies is highly variable, with poor visual outcomes and treatment response in patients with significant retinal nonperfusion following RVO. Recently, caspase-9 has been identified as a potent regulator of edema, gliosis, and neuronal dysfunction during acute retinal hypoxia. The purpose of this study was to compare the therapeutic effect of caspase-9 inhibition against VEGF-neutralization in an established mouse model of RVO. Methods Adult male C57Bl/6 J mice were randomized to induction of RVO and treatment with either vehicle, intravitreal injection of anti-VEGF antibody, topical administration of a selective caspase-9 inhibitor (Pen1-XBir3), or a combination therapy. Animals were followed on days 1, 2, and 8 after RVO with fundus retinal imaging, and with optical coherence tomography (OCT) to capture retinal swelling, capillary nonperfusion (measured by disorganization of retinal inner layers, DRIL), hyperreflective foci (HRF), and retinal atrophy. Focal electroretinography (ERG) measurements were performed on day 7. Histology was performed on retinal sections from day 8. Results Both VEGF neutralization and caspase-9 inhibition showed significant retinal protection from RVO compared to vehicle treatment arm. Retinal reperfusion of occluded veins was accelerated in eyes receiving caspase-9 inhibitor, but not significantly different from vehicle in the anti-VEGF group. Retinal edema was suppressed in all treatment groups, with approximately 2-fold greater edema reduction with caspase-9 inhibition compared to VEGF neutralization. HRF were reduced similarly across all treatment groups compared to vehicle. Retinal detachment was reduced only in eyes treated with caspase-9 inhibitor monotherapy. Caspase-9 inhibition reduced retinal atrophy and preserved ERG response; VEGF neutralization did not prevent neurodegeneration following RVO. Conclusion Caspase-9 inhibition confers stronger neuronal and vascular protection compared to VEGF neutralization in the mouse laser-induced model of RVO.
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Affiliation(s)
- Maria I. Avrutsky
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Claire W. Chen
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Jacqueline M. Lawson
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Scott J. Snipas
- NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Guy S. Salvesen
- NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Carol M. Troy
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
- The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
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21
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Cao Y, Li J, Qiu S, Ni S, Duan Y. LncRNA XIST facilitates hypertrophy of ligamentum flavum by activating VEGFA-mediated autophagy through sponging miR-302b-3p. Biol Direct 2023; 18:25. [PMID: 37226251 DOI: 10.1186/s13062-023-00383-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 05/19/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Increasing evidences have shown that long non-coding RNAs (lncRNAs) display crucial regulatory roles in the occurrence and development of numerous diseases. However, the function and underlying mechanisms of lncRNAs in hypertrophy of ligamentum flavum (HLF) have not been report. METHODS The integrated analysis of lncRNAs sequencing, bioinformatics analysis and real-time quantitative PCR were used to identify the key lncRNAs involved in HLF progression. Gain- and loss-function experiments were used to explore the functions of lncRNA X inactive specific transcript (XIST) in HLF. Mechanistically, bioinformatics binding site analysis, RNA pull-down, dual-luciferase reporter assay, and rescue experiments were utilized to investigate the mechanism by which XIST acts as a molecular sponge of miR-302b-3p to regulate VEGFA-mediated autophagy. RESULTS We identified that XIST was outstandingly upregulated in HLF tissues and cells. Moreover, the up-regulation of XIST strongly correlated with the thinness and fibrosis degree of LF in LSCS patients. Functionally, knockdown of XIST drastically inhibited proliferation, anti-apoptosis, fibrosis and autophagy of HLF cells in vitro and suppressed hypertrophy and fibrosis of LF tissues in vivo. Intestinally, we uncovered that overexpression of XIST significantly promoted proliferation, anti-apoptosis and fibrosis ability of HLF cells by activating autophagy. Mechanistic studies illustrated that XIST directly medullated the VEGFA-mediated autophagy through sponging miR-302b-3p, thereby enhancing the development and progression of HLF. CONCLUSION Our findings highlighted that the XIST/miR-302b-3p/VEGFA-mediated autophagy axis is involved in development and progression of HLF. At the same time, this study will complement the blank of lncRNA expression profiles in HLF, which laid the foundation for further exploration of the relationship between lncRNAs and HLF in the future.
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Affiliation(s)
- Yanlin Cao
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jianjun Li
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Sujun Qiu
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Songjia Ni
- Department of Orthopaedic Trauma, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Duan
- Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
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22
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Salemkour Y, Lenoir O. Endothelial Autophagy Dysregulation in Diabetes. Cells 2023; 12:947. [PMID: 36980288 PMCID: PMC10047205 DOI: 10.3390/cells12060947] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/14/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
Diabetes mellitus is a major public health issue that affected 537 million people worldwide in 2021, a number that is only expected to increase in the upcoming decade. Diabetes is a systemic metabolic disease with devastating macro- and microvascular complications. Endothelial dysfunction is a key determinant in the pathogenesis of diabetes. Dysfunctional endothelium leads to vasoconstriction by decreased nitric oxide bioavailability and increased expression of vasoconstrictor factors, vascular inflammation through the production of pro-inflammatory cytokines, a loss of microvascular density leading to low organ perfusion, procoagulopathy, and/or arterial stiffening. Autophagy, a lysosomal recycling process, appears to play an important role in endothelial cells, ensuring endothelial homeostasis and functions. Previous reports have provided evidence of autophagic flux impairment in patients with type I or type II diabetes. In this review, we report evidence of endothelial autophagy dysfunction during diabetes. We discuss the mechanisms driving endothelial autophagic flux impairment and summarize therapeutic strategies targeting autophagy in diabetes.
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Affiliation(s)
| | - Olivia Lenoir
- PARCC, Inserm, Université Paris Cité, 75015 Paris, France
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23
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The Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor Empagliflozin Reverses Hyperglycemia-Induced Monocyte and Endothelial Dysfunction Primarily through Glucose Transport-Independent but Redox-Dependent Mechanisms. J Clin Med 2023; 12:jcm12041356. [PMID: 36835891 PMCID: PMC9962711 DOI: 10.3390/jcm12041356] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023] Open
Abstract
PURPOSE Hyperglycaemia-induced oxidative stress and inflammation contribute to vascular cell dysfunction and subsequent cardiovascular events in T2DM. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin significantly improves cardiovascular mortality in T2DM patients (EMPA-REG trial). Since SGLT-2 is known to be expressed on cells other than the kidney cells, we investigated the potential ability of empagliflozin to regulate glucose transport and alleviate hyperglycaemia-induced dysfunction of these cells. METHODS Primary human monocytes were isolated from the peripheral blood of T2DM patients and healthy individuals. Primary human umbilical vein endothelial cells (HUVECs) and primary human coronary artery endothelial cells (HCAECs), and fetoplacental endothelial cells (HPECs) were used as the EC model cells. Cells were exposed to hyperglycaemic conditions in vitro in 40 ng/mL or 100 ng/mL empagliflozin. The expression levels of the relevant molecules were analysed by RT-qPCR and confirmed by FACS. Glucose uptake assays were carried out with a fluorescent derivative of glucose, 2-NBDG. Reactive oxygen species (ROS) accumulation was measured using the H2DFFDA method. Monocyte and endothelial cell chemotaxis were measured using modified Boyden chamber assays. RESULTS Both primary human monocytes and endothelial cells express SGLT-2. Hyperglycaemic conditions did not significantly alter the SGLT-2 levels in monocytes and ECs in vitro or in T2DM conditions. Glucose uptake assays carried out in the presence of GLUT inhibitors revealed that SGLT-2 inhibition very mildly, but not significantly, suppressed glucose uptake by monocytes and endothelial cells. However, we detected the significant suppression of hyperglycaemia-induced ROS accumulation in monocytes and ECs when empagliflozin was used to inhibit SGLT-2 function. Hyperglycaemic monocytes and endothelial cells readily exhibited impaired chemotaxis behaviour. The co-treatment with empagliflozin reversed the PlGF-1 resistance phenotype of hyperglycaemic monocytes. Similarly, the blunted VEGF-A responses of hyperglycaemic ECs were also restored by empagliflozin, which could be attributed to the restoration of the VEGFR-2 receptor levels on the EC surface. The induction of oxidative stress completely recapitulated most of the aberrant phenotypes exhibited by hyperglycaemic monocytes and endothelial cells, and a general antioxidant N-acetyl-L-cysteine (NAC) was able to mimic the effects of empagliflozin. CONCLUSIONS This study provides data indicating the beneficial role of empagliflozin in reversing hyperglycaemia-induced vascular cell dysfunction. Even though both monocytes and endothelial cells express functional SGLT-2, SGLT-2 is not the primary glucose transporter in these cells. Therefore, it seems likely that empagliflozin does not directly prevent hyperglycaemia-mediated enhanced glucotoxicity in these cells by inhibiting glucose uptake. We identified the reduction of oxidative stress by empagliflozin as a primary reason for the improved function of monocytes and endothelial cells in hyperglycaemic conditions. In conclusion, empagliflozin reverses vascular cell dysfunction independent of glucose transport but could partially contribute to its beneficial cardiovascular effects.
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24
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Blasiak J, Kaarniranta K. Secretory autophagy: a turn key for understanding AMD pathology and developing new therapeutic targets? Expert Opin Ther Targets 2022; 26:883-895. [PMID: 36529978 DOI: 10.1080/14728222.2022.2157260] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Age-related macular degeneration (AMD) is an eye disease leading to vision loss with poorly known pathogenesis and limited therapeutic options. Degradative autophagy (DA) is impaired in AMD, but emerging evidence points to secretary autophagy (SA) as a key element in AMD pathogenesis. AREAS COVERED SA may cause the release of proteins and protein aggregates, lipofuscin, beta amyloid, faulty mitochondria, pro-inflammatory and pro-angiogenic factors from the retinal pigment epithelium (RPE) that may contribute to drusen formation and choroidal neovascularization. SA may replace DA, when formation of autolysosome is impaired, and then a harmful cargo, instead of being degraded, is extruded from the RPE contributing to drusen and/or angiogenic environment. Therefore, the interplay between DA and SA may be critical for drusen formation and choroidal neovascularization, so it can be a turn key to understand AMD pathogenesis. EXPERT OPINION Although SA fulfills some beneficial functions, it is detrimental for the retina in many cases. Therefore, inhibiting SA may be a therapeutic strategy in AMD, but it is challenged by the development of selective SA inhibitors that would not affect DA. The TRIM16, SEC22B and RAB8A proteins, specific for secretory autophagosome, may be primary candidates as therapeutic targets, but their action is not limited to autophagy and therefore requires further studies.
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Affiliation(s)
- Janusz Blasiak
- Department of Molecular Genetics, University of Lodz, Lodz, Poland
| | - Kai Kaarniranta
- Department of Ophthalmology, University of Eastern Finland, Kuopio, Finland.,Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
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25
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Oxidative Glucose Metabolism Promotes Senescence in Vascular Endothelial Cells. Cells 2022; 11:cells11142213. [PMID: 35883656 PMCID: PMC9322806 DOI: 10.3390/cells11142213] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/05/2022] [Accepted: 07/13/2022] [Indexed: 11/21/2022] Open
Abstract
Vascular aging is based on the development of endothelial dysfunction, which is thought to be promoted by senescent cells accumulating in aged tissues and is possibly affected by their environment via inflammatory mediators and oxidative stress. Senescence appears to be closely interlinked with changes in cell metabolism. Here, we describe an upregulation of both glycolytic and oxidative glucose metabolism in replicative senescent endothelial cells compared to young endothelial cells by employing metabolic profiling and glucose flux measurements and by analyzing the expression of key metabolic enzymes. Senescent cells exhibit higher glycolytic activity and lactate production together with an enhanced expression of lactate dehydrogenase A as well as increases in tricarboxylic acid cycle activity and mitochondrial respiration. The latter is likely due to the reduced expression of pyruvate dehydrogenase kinases (PDHKs) in senescent cells, which may lead to increased activity of the pyruvate dehydrogenase complex. Cellular and mitochondrial ATP production were elevated despite signs of mitochondrial dysfunction, such as an increased production of reactive oxygen species and extended mitochondrial mass. A shift from glycolytic to oxidative glucose metabolism induced by pharmacological inhibition of PDHKs in young endothelial cells resulted in premature senescence, suggesting that alterations in cellular glucose metabolism may act as a driving force for senescence in endothelial cells.
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26
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Mameli E, Martello A, Caporali A. Autophagy at the interface of endothelial cell homeostasis and vascular disease. FEBS J 2022; 289:2976-2991. [PMID: 33934518 DOI: 10.1111/febs.15873] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 03/16/2021] [Accepted: 04/09/2021] [Indexed: 12/19/2022]
Abstract
Autophagy is an essential intracellular process for cellular quality control. It enables cell homeostasis through the selective degradation of harmful protein aggregates and damaged organelles. Autophagy is essential for recycling nutrients, generating energy to maintain cell viability in most tissues and during adverse conditions such as hypoxia/ischaemia. The progressive understanding of the mechanisms modulating autophagy in the vasculature has recently led numerous studies to link intact autophagic responses with endothelial cell (EC) homeostasis and function. Preserved autophagic flux within the ECs has an essential role in maintaining their physiological characteristics, whereas defective autophagy can promote endothelial pro-inflammatory and atherogenic phenotype. However, we still lack a good knowledge of the complete molecular repertoire controlling various aspects of endothelial autophagy and how this is associated with vascular diseases. Here, we provide an overview of the current state of the art of autophagy in ECs. We review the discoveries that have so far defined autophagy as an essential mechanism in vascular biology and analyse how autophagy influences ECs behaviour in vascular disease. Finally, we emphasise opportunities for compounds to regulate autophagy in ECs and discuss the challenges of exploiting them to resolve vascular disease.
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Affiliation(s)
- Eleonora Mameli
- University/BHF Centre for Cardiovascular Science, QMRI, University of Edinburgh, UK
| | | | - Andrea Caporali
- University/BHF Centre for Cardiovascular Science, QMRI, University of Edinburgh, UK
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27
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5-Bromo-3,4-dihydroxybenzaldehyde Promotes Hair Growth through Activation of Wnt/β-Catenin and Autophagy Pathways and Inhibition of TGF-β Pathways in Dermal Papilla Cells. Molecules 2022; 27:molecules27072176. [PMID: 35408575 PMCID: PMC9000556 DOI: 10.3390/molecules27072176] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Various studies addressing the increasing problem of hair loss, using natural products with few side effects, have been conducted. 5-bromo-3,4-dihydroxybenzaldehyde (BDB) exhibited anti-inflammatory effects in mouse models of atopic dermatitis and inhibited UVB-induced oxidative stress in keratinocytes. Here, we investigated its stimulating effect and the underlying mechanism of action on hair growth using rat vibrissa follicles and dermal papilla cells (DPCs), required for the regulation of hair cycle and length. BDB increased the length of hair fibers in rat vibrissa follicles and the proliferation of DPCs, along with causing changes in the levels of cell cycle-related proteins. We investigated whether BDB could trigger anagen-activating signaling pathways, such as the Wnt/β-catenin pathway and autophagy in DPCs. BDB induces activation of the Wnt/β-catenin pathway through the phosphorylation of GSG3β and β-catenin. BDB increased the levels of autophagic vacuoles and autophagy regulatory proteins Atg7, Atg5, Atg16L, and LC3B. We also investigated whether BDB inhibits the TGF-β pathway, which promotes transition to the catagen phase. BDB inhibited the phosphorylation of Smad2 induced by TGF-β1. Thus, BDB can promote hair growth by modulating anagen signaling by activating Wnt/β-catenin and autophagy pathways and inhibiting the TGF-β pathway in DPCs.
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28
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Zhang MY, Zhu L, Zheng X, Xie TH, Wang W, Zou J, Li Y, Li HY, Cai J, Gu S, Yao Y, Wei TT. TGR5 Activation Ameliorates Mitochondrial Homeostasis via Regulating the PKCδ/Drp1-HK2 Signaling in Diabetic Retinopathy. Front Cell Dev Biol 2022; 9:759421. [PMID: 35096809 PMCID: PMC8795816 DOI: 10.3389/fcell.2021.759421] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 12/07/2021] [Indexed: 01/07/2023] Open
Abstract
Background: Diabetic retinopathy (DR) is one of the most important microvascular diseases of diabetes. Our previous research demonstrated that bile acid G-protein-coupled membrane receptor (TGR5), a novel cell membrane receptor of bile acid, ameliorates the vascular endothelial cell dysfunction in DR. However, the precise mechanism leading to this alteration remains unknown. Thus, the mechanism of TGR5 in the progress of DR should be urgently explored. Methods: In this study, we established high glucose (HG)-induced human retinal vascular endothelial cells (RMECs) and streptozotocin-induced DR rat in vitro and in vivo. The expression of TGR5 was interfered through the specific agonist or siRNA to study the effect of TGR5 on the function of endothelial cell in vitro. Western blot, immunofluorescence and fluorescent probes were used to explore how TGR5 regulated mitochondrial homeostasis and related molecular mechanism. The adeno-associated virus serotype 8-shTGR5 (AAV8-shTGR5) was performed to evaluate retinal dysfunction in vivo and further confirm the role of TGR5 in DR by HE staining, TUNEL staining, PAS staining and Evans Blue dye. Results: We found that TGR5 activation alleviated HG-induced endothelial cell apoptosis by improving mitochondrial homeostasis. Additionally, TGR5 signaling reduced mitochondrial fission by suppressing the Ca2+-PKCδ/Drp1 signaling and enhanced mitophagy through the upregulation of the PINK1/Parkin signaling pathway. Furthermore, our result indicated that Drp1 inhibited mitophagy by facilitating the hexokinase (HK) 2 separation from the mitochondria and HK2-PINK1/Parkin signaling. In vivo, intraretinal microvascular abnormalities, including retinal vascular leakage, acellular capillaries and apoptosis, were poor in AAV8-shTGR5-treated group under DR, but this effect was reversed by pretreatment with the mitochondrial fission inhibitor Mdivi-1 or autophagy agonist Rapamycin. Conclusion: Overall, our findings indicated that TGR5 inhibited mitochondrial fission and enhanced mitophagy in RMECs by regulating the PKCδ/Drp1-HK2 signaling pathway. These results revealed the molecular mechanisms underlying the protective effects of TGR5 and suggested that activation of TGR5 might be a potential therapeutic strategy for DR.
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Affiliation(s)
- Meng-Yuan Zhang
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Lingpeng Zhu
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Xinhua Zheng
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Tian-Hua Xie
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Wenjuan Wang
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jian Zou
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yan Li
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Hong-Ying Li
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jiping Cai
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Shun Gu
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Yong Yao
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China.,Department of Ophthalmology, The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University, Wuxi, China
| | - Ting-Ting Wei
- Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
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29
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Zhao X, Jiang Y, Ren J, Wang Y, Zhao Y, Feng X. Deciphering the Mechanism of Bushen Huoxue Decotion on Decidualization by Intervening Autophagy via AMPK/mTOR/ULK1: A Novel Discovery for URSA Treatment. Front Pharmacol 2022; 13:794938. [PMID: 35140613 PMCID: PMC8819596 DOI: 10.3389/fphar.2022.794938] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 01/04/2022] [Indexed: 11/13/2022] Open
Abstract
Impaired decidualization was recognized as one of the crucial pathomechanisms accounting for unexplained recurrent spontaneous abortion (URSA). Currently, the exact molecular mechanism and targeted clinical decision are still in exploration. Bushen Huoxue decoction (BSHXD) has previously been proved effective in treating URSA, but its mechanism remains to be elucidated. This study aimed to explore the regulation mechanism of BSHXD in decidualization from its intervention in autophagy so as to rationalize its potential as a novel therapeutic regime for URSA. Decidua tissues were collected from patients with URSA and healthy pregnant women who underwent legal terminations for non-medical reasons at the first trimester. Besides, cell line T-hESCs was utilized to establish induced decidualization model, and were randomly divided into ESC group, DSC group, 3-MA group, AMPK siRNA group, scrambled siRNA group and AMPK siRNA + BSHXD group. Transmission electron microscopy, Monodansylcadaverine (MDC) assay, qRT-PCR, immunohistochemistry, immunofluorescence and Western blotting were used to evaluate the level of decidualization, autophagy and activation of AMPK signaling pathway in decidua tissues and cell experiments. Experiments on decidua tissues showed that decidualization was impaired in URSA with inhibited autophagy. Besides, pAMPK T172 and pULK1 S556 were decreased, and pmTOR S2448 and pULK1 S757 were increased. Cell experiments showed that the level of autophagy increased during induced decidualization, but when autophagy was inhibited, decidualization was impaired. In addition, AMPK/mTOR/ULK1 affected decidualization by mediating autophagy, and BSHXD improved decidualization through this mechanism. In conclusion, this study clarified that the inhibition of autophagy mediated by AMPK/mTOR/ULK1 was associated with impaired decidualization, and the intervention of BSHXD on this pathological process may be a vital mechanism for its treatment of URSA. This study laid the foundation for further research and application of BSHXD.
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Affiliation(s)
- Xiaoxuan Zhao
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yuepeng Jiang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiajie Ren
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yunrui Wang
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yan Zhao
- Department of Gynecology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Xiaoling Feng
- Department of Gynecology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
- *Correspondence: Xiaoling Feng,
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30
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Watanabe K, Shiga K, Maeda A, Harata S, Yanagita T, Suzuki T, Ushigome H, Maeda Y, Hirokawa T, Ogawa R, Hara M, Takahashi H, Matsuo Y, Mitsui A, Kimura M, Takiguchi S. Chitinase 3-like 1 secreted from cancer-associated fibroblasts promotes tumor angiogenesis via interleukin-8 secretion in colorectal cancer. Int J Oncol 2022; 60:3. [PMID: 34913066 PMCID: PMC8698746 DOI: 10.3892/ijo.2021.5293] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/19/2021] [Indexed: 12/12/2022] Open
Abstract
The cancer‑stromal interaction has been demonstrated to promote tumor progression, and cancer-associated fibroblasts (CAFs), which are the main components of stromal cells, have attracted attention as novel treatment targets. Chitinase 3-like 1 (CHI3L1) is a chitinase-like protein, which affects cell proliferation and angiogenesis. However, the mechanisms through which cells secrete CHI3L1 and through which CHI3L1 mediates tumor progression in the cancer microenvironment are still unclear. Accordingly, the present study assessed the secretion of CHI3L1 in the microenvironment of colorectal cancer and evaluated how CHI3L1 affects tumor angiogenesis. CAFs and normal fibroblasts (NFs) established from colorectal cancer tissue, and human colon cancer cell lines were evaluated using immunostaining, cytokine antibody array, RNA interference, reverse transcription-quantitative PCR (RT-qPCR), ELISA, western blotting and angiogenesis assays. The expression and secretion of CHI3L1 in CAFs were stronger than those in NFs and colorectal cancer cell lines. In addition, interleukin-13 receptor α2 (IL-13Rα2), a receptor for CHI3L1, was not expressed in colorectal cancer cell lines, but was expressed in fibroblasts, particularly CAFs. Furthermore, the expression and secretion of IL-8 in CAFs was stronger than that in NFs and cancer cell lines, and recombinant CHI3L1 addition increased IL-8 expression in CAFs, whereas knockdown of CHI3L1 suppressed IL-8 expression. Furthermore, IL-13Rα2 knockdown suppressed the enhancement of IL-8 expression induced by CHI3L1 treatment in CAFs. For vascular endothelial growth factor-A (VEGFA), similar results to IL-8 were observed in an ELISA for comparison of secretion between CAFs and NFs and for changes in secretion after CHI3L1 treatment in CAFs; however, no significant differences were observed for changes in expression after CHI3L1 treatment or IL-13Rα2 knockdown in CAFs assessed using RT-qPCR assays. Angiogenesis assays revealed that tube formation in vascular endothelial cells was suppressed by conditioned medium from CAFs with the addition of human CHI3L1 neutralizing antibodies compared with control IgG, and also suppressed by conditioned medium from CAFs transfected with CHI3L1, IL-8 or VEGFA small interfering RNA compared with negative control small interfering RNA. Overall, the present findings indicated that CHI3L1 secreted from CAFs acted on CAFs to increase the secretion of IL-8, thereby affecting tumor angiogenesis in colorectal cancer.
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Affiliation(s)
- Kaori Watanabe
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Kazuyoshi Shiga
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Anri Maeda
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Shinnosuke Harata
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Takeshi Yanagita
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Takuya Suzuki
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Hajime Ushigome
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Yuzo Maeda
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Takahisa Hirokawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Ryo Ogawa
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Masayasu Hara
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Hiroki Takahashi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Yoichi Matsuo
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Akira Mitsui
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Masahiro Kimura
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
| | - Shuji Takiguchi
- Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan
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Chen H, Hu Z, Sang M, Ni S, Lin Y, Wu C, Mu Y, Liu K, Wu S, Li N, Xu G. Identification of an Autophagy-Related lncRNA Prognostic Signature and Related Tumor Immunity Research in Lung Adenocarcinoma. Front Genet 2021; 12:767694. [PMID: 34956321 PMCID: PMC8692741 DOI: 10.3389/fgene.2021.767694] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/26/2021] [Indexed: 12/25/2022] Open
Abstract
Autophagy is closely associated with the tumor immune microenvironment (TIME) and prognosis of patients with lung adenocarcinoma (LUAD). In the present study, we established a signature on the basis of long noncoding RNAs (lncRNAs) related to autophagy (ARlncRNAs) to investigate the TIME and survival of patients with LUAD. We selected ARlncRNAs associated with prognosis to construct a model and divided each sample into different groups on the basis of risk score. The ARlncRNA signature could be recognized as an independent prognostic factor for patients with LUAD, and patients in the low-risk group had a greater survival advantage. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis suggested that several immune functions and pathways were enriched in different groups. A high-risk score correlated significantly negatively with high abundance of immune cells and stromal cells around the tumor and high tumor mutational burden. Low-risk patients had a higher PD-1, CTLA-4, and HAVCR2 expression and had a better efficacy of immune checkpoint inhibitors, including PD-1/CTLA-4 inhibitor. A reliable signature on the basis of ARlncRNAs was constructed to explore the TIME and prognosis of patients with LUAD, which could provide valuable information for individualized LUAD treatment.
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Affiliation(s)
- Hang Chen
- Medical School, Ningbo University, Ningbo, China
| | - Zeyang Hu
- Medical School, Ningbo University, Ningbo, China
| | - Menglu Sang
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Saiqi Ni
- Department of Urology, Ningbo City First Hospital, Ningbo, China
| | - Yao Lin
- Medical School, Ningbo University, Ningbo, China
| | - Chengfang Wu
- Medical School, Ningbo University, Ningbo, China
| | - Yinyu Mu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Kaitai Liu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Shibo Wu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Ni Li
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
| | - Guodong Xu
- Department of Cardiothoracic Surgery, The Affiliated Lihuili Hospital, Ningbo University, Ningbo, China
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32
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Li X, Wen Y, Sheng L, Guo R, Zhang Y, Shao L. Icariin activates autophagy to trigger TGFβ1 upregulation and promote angiogenesis in EA.hy926 human vascular endothelial cells. Bioengineered 2021; 13:164-177. [PMID: 34847836 PMCID: PMC8805869 DOI: 10.1080/21655979.2021.2011637] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Angiogenesis plays an important role in tissue development and repair, and how to regulate angiogenesis effectively is a widely studied problem in the biomedical field. In recent years, the role of autophagy in vascular endothelial cells has attracted extensive attention. Icariin (ICA) is a traditional Chinese medicine that has been proven to have outstanding protective effects on the vascular system and to regulate cellular autophagy effectively. However, at present, it has not been reported whether ICA can affect the angiogenic ability of endothelial cells by affecting autophagy. In this study, we aimed to investigate whether ICA affects the angiogenesis capacity of EA.hy926 human vascular endothelial cells through autophagy and explain the underlying potential mechanisms. First, we determined that ICA at appropriate concentrations has the ability to promote cell migration and angiogenesis using wound healing assays and tube formation assays. Then, at the molecular level, we observed the upregulation of VEGFA, VEGFR2, ANGI, ANGII, and Tie2 mRNA and detected the upregulation of TGFβ1 protein by Western blotting. We also demonstrated that angiogenic concentrations of ICA can effectively activate autophagy. The autophagy inhibitor 3-MA significantly suppressed TGFβ1 expression and tube formation in EA.hy926 cells. Overall, we hope that our studies might help to further understand the effect of ICA on vascular endothelial cells and provide a theoretical basis for future angiogenic applications of ICA
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Affiliation(s)
- Xiaolong Li
- Foshan Stomatological Hospital, School of Medicine, Foshan University, Foshan, PR China
| | - Yujie Wen
- Foshan Stomatological Hospital, School of Medicine, Foshan University, Foshan, PR China
| | - Liyuan Sheng
- Shenzhen Institute, Peking University, Shenzhen, China
| | - Rui Guo
- Department of Biomedical Engineering, Jinan University, Guangzhou, China
| | - Yanli Zhang
- Stomatological Hospital, Southern Medical University, Guangzhou, China
| | - Longquan Shao
- Stomatological Hospital, Southern Medical University, Guangzhou, China
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33
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Di Sanzo S, Spengler K, Leheis A, Kirkpatrick JM, Rändler TL, Baldensperger T, Dau T, Henning C, Parca L, Marx C, Wang ZQ, Glomb MA, Ori A, Heller R. Mapping protein carboxymethylation sites provides insights into their role in proteostasis and cell proliferation. Nat Commun 2021; 12:6743. [PMID: 34795246 PMCID: PMC8602705 DOI: 10.1038/s41467-021-26982-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 10/29/2021] [Indexed: 12/19/2022] Open
Abstract
Posttranslational mechanisms play a key role in modifying the abundance and function of cellular proteins. Among these, modification by advanced glycation end products has been shown to accumulate during aging and age-associated diseases but specific protein targets and functional consequences remain largely unexplored. Here, we devise a proteomic strategy to identify sites of carboxymethyllysine modification, one of the most abundant advanced glycation end products. We identify over 1000 sites of protein carboxymethylation in mouse and primary human cells treated with the glycating agent glyoxal. By using quantitative proteomics, we find that protein glycation triggers a proteotoxic response and indirectly affects the protein degradation machinery. In primary endothelial cells, we show that glyoxal induces cell cycle perturbation and that carboxymethyllysine modification reduces acetylation of tubulins and impairs microtubule dynamics. Our data demonstrate the relevance of carboxymethyllysine modification for cellular function and pinpoint specific protein networks that might become compromised during aging.
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Affiliation(s)
- Simone Di Sanzo
- grid.418245.e0000 0000 9999 5706Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Katrin Spengler
- grid.275559.90000 0000 8517 6224Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07743 Jena, Germany
| | - Anja Leheis
- grid.275559.90000 0000 8517 6224Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07743 Jena, Germany
| | - Joanna M. Kirkpatrick
- grid.418245.e0000 0000 9999 5706Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), 07745 Jena, Germany ,grid.451388.30000 0004 1795 1830Present Address: Proteomics Science Technology Platform, The Francis Crick Institute, MW1 1AT London, UK
| | - Theresa L. Rändler
- grid.275559.90000 0000 8517 6224Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07743 Jena, Germany
| | - Tim Baldensperger
- grid.9018.00000 0001 0679 2801Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, 06120 Halle/Saale, Germany
| | - Therese Dau
- grid.418245.e0000 0000 9999 5706Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Christian Henning
- grid.9018.00000 0001 0679 2801Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, 06120 Halle/Saale, Germany
| | - Luca Parca
- grid.413503.00000 0004 1757 9135Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Italy
| | - Christian Marx
- grid.418245.e0000 0000 9999 5706Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), 07745 Jena, Germany
| | - Zhao-Qi Wang
- grid.418245.e0000 0000 9999 5706Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), 07745 Jena, Germany ,grid.9613.d0000 0001 1939 2794Faculty of Biological Sciences, Friedrich-Schiller-University of Jena, Jena, Germany
| | - Marcus A. Glomb
- grid.9018.00000 0001 0679 2801Institute of Chemistry, Food Chemistry, Martin-Luther-University Halle-Wittenberg, 06120 Halle/Saale, Germany
| | - Alessandro Ori
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), 07745, Jena, Germany.
| | - Regine Heller
- Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07743, Jena, Germany.
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Zeng A, Wang SR, He YX, Yan Y, Zhang Y. Progress in understanding of the stalk and tip cells formation involvement in angiogenesis mechanisms. Tissue Cell 2021; 73:101626. [PMID: 34479073 DOI: 10.1016/j.tice.2021.101626] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 08/13/2021] [Accepted: 08/14/2021] [Indexed: 12/28/2022]
Abstract
Vascular sprouting is a key process of angiogenesis and mainly related to the formation of stalk and tip cells. Many studies have found that angiogenesis has a great clinical significance in promoting the functional repair of impaired tissues and anti-angiogenesis is a key to treatment of many tumors. Therefore, how the pathways regulate angiogenesis by regulating the formation of stalk and tip cells is an urgent problem for researchers. This review mainly summarizes the research progress of pathways affecting the formation of stalk and tip cells during angiogenesis in recent years, including the main signaling pathways (such as VEGF-VEGFR-Dll4-Notch signaling pathway, ALK-Smad signaling pathway,CCN1-YAP/YAZ signaling pathway and other signaling pathways) and cellular actions (such as cellular metabolisms, intercellular tension and other actions), aiming to further give the readers an insight into the mechanism of regulating the formation of stalk and tip cells during angiogenesis and provide more targets for anti-angiogenic drugs.
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Affiliation(s)
- Ao Zeng
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China
| | - Shu-Rong Wang
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China
| | - Yu-Xi He
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China
| | - Yu Yan
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China
| | - Yan Zhang
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun, 130041, Jilin Province, China.
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35
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Neill T, Kapoor A, Xie C, Buraschi S, Iozzo RV. A functional outside-in signaling network of proteoglycans and matrix molecules regulating autophagy. Matrix Biol 2021; 100-101:118-149. [PMID: 33838253 PMCID: PMC8355044 DOI: 10.1016/j.matbio.2021.04.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 02/07/2023]
Abstract
Proteoglycans and selected extracellular matrix constituents are emerging as intrinsic and critical regulators of evolutionarily conversed, intracellular catabolic pathways. Often, these secreted molecules evoke sustained autophagy in a variety of cell types, tissues, and model systems. The unique properties of proteoglycans have ushered in a paradigmatic shift to broaden our understanding of matrix-mediated signaling cascades. The dynamic cellular pathway controlling autophagy is now linked to an equally dynamic and fluid signaling network embedded in a complex meshwork of matrix molecules. A rapidly emerging field of research encompasses multiple matrix-derived candidates, representing a menagerie of soluble matrix constituents including decorin, biglycan, endorepellin, endostatin, collagen VI and plasminogen kringle 5. These matrix constituents are pro-autophagic and simultaneously anti-angiogenic. In contrast, perlecan, laminin α2 chain, and lumican have anti-autophagic functions. Mechanistically, each matrix constituent linked to intracellular catabolic events engages a specific cell surface receptor that often converges on a common core of the autophagic machinery including AMPK, Peg3 and Beclin 1. We consider this matrix-evoked autophagy as non-canonical given that it occurs in an allosteric manner and is independent of nutrient availability or prevailing bioenergetics control. We propose that matrix-regulated autophagy is an important outside-in signaling mechanism for proper tissue homeostasis that could be therapeutically leveraged to combat a variety of diseases.
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Affiliation(s)
- Thomas Neill
- Department of Pathology, Anatomy, and Cell Biology, and the Translational Cellular Oncology Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
| | - Aastha Kapoor
- Department of Pathology, Anatomy, and Cell Biology, and the Translational Cellular Oncology Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Christopher Xie
- Department of Pathology, Anatomy, and Cell Biology, and the Translational Cellular Oncology Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Simone Buraschi
- Department of Pathology, Anatomy, and Cell Biology, and the Translational Cellular Oncology Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Renato V Iozzo
- Department of Pathology, Anatomy, and Cell Biology, and the Translational Cellular Oncology Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
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36
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Protein kinase A negatively regulates VEGF-induced AMPK activation by phosphorylating CaMKK2 at serine 495. Biochem J 2021; 477:3453-3469. [PMID: 32869834 DOI: 10.1042/bcj20200555] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/19/2020] [Accepted: 09/01/2020] [Indexed: 02/07/2023]
Abstract
Activation of AMP-activated protein kinase (AMPK) in endothelial cells by vascular endothelial growth factor (VEGF) via the Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) represents a pro-angiogenic pathway, whose regulation and function is incompletely understood. This study investigates whether the VEGF/AMPK pathway is regulated by cAMP-mediated signalling. We show that cAMP elevation in endothelial cells by forskolin, an activator of the adenylate cyclase, and/or 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterases, triggers protein kinase A (PKA)-mediated phosphorylation of CaMKK2 (serine residues S495, S511) and AMPK (S487). Phosphorylation of CaMKK2 by PKA led to an inhibition of its activity as measured in CaMKK2 immunoprecipitates of forskolin/IBMX-treated cells. This inhibition was linked to phosphorylation of S495, since it was not seen in cells expressing a non-phosphorylatable CaMKK2 S495C mutant. Phosphorylation of S511 alone in these cells was not able to inhibit CaMKK2 activity. Moreover, phosphorylation of AMPK at S487 was not sufficient to inhibit VEGF-induced AMPK activation in cells, in which PKA-mediated CaMKK2 inhibition was prevented by expression of the CaMKK2 S495C mutant. cAMP elevation in endothelial cells reduced basal and VEGF-induced acetyl-CoA carboxylase (ACC) phosphorylation at S79 even if AMPK was not inhibited. Together, this study reveals a novel regulatory mechanism of VEGF-induced AMPK activation by cAMP/PKA, which may explain, in part, inhibitory effects of PKA on angiogenic sprouting and play a role in balancing pro- and anti-angiogenic mechanisms in order to ensure functional angiogenesis.
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37
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Omarjee O, Mathieu AL, Quiniou G, Moreews M, Ainouze M, Frachette C, Melki I, Dumaine C, Gerfaud-Valentin M, Duquesne A, Kallinich T, Tahir Turanli E, Malcus C, Viel S, Pescarmona R, Georgin-Lavialle S, Jamilloux Y, Larbre JP, Sarrabay G, Magnotti F, Rice GI, Bleicher F, Reboulet J, Merabet S, Henry T, Crow YJ, Faure M, Walzer T, Belot A. LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages. J Exp Med 2021; 218:211815. [PMID: 33606008 PMCID: PMC7901146 DOI: 10.1084/jem.20201006] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 09/16/2020] [Accepted: 12/22/2020] [Indexed: 12/20/2022] Open
Abstract
Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.
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Affiliation(s)
- Ommar Omarjee
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France.,National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France
| | - Anne-Laure Mathieu
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France.,National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France
| | - Gaëlle Quiniou
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France
| | - Marion Moreews
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France
| | - Michelle Ainouze
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France
| | - Cécile Frachette
- National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France.,Pediatric Nephrology, Rheumatology, Dermatology Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Isabelle Melki
- National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France.,General Pediatrics, Infectious Disease and Internal Medicine Department, Hôpital Robert Debre, Assistance Publique-Hôpitaux de Paris, Paris, France.,Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris, France
| | - Cécile Dumaine
- General Pediatrics, Infectious Disease and Internal Medicine Department, Hôpital Robert Debre, Assistance Publique-Hôpitaux de Paris, Paris, France
| | | | - Agnès Duquesne
- National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France.,Pediatric Nephrology, Rheumatology, Dermatology Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
| | - Tilmann Kallinich
- Pediatric Pneumology, Immunology and Intensive Care Medicine, Charité University Medicine Berlin, German Rheumatism Research Center, Leibniz Association, Berlin Institute of Health, Berlin, Germany
| | - Eda Tahir Turanli
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Technical University, Istanbul, Turkey.,Molecular Development of the Immune System Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Christophe Malcus
- National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France.,Immunology Department, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Sébastien Viel
- National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France.,Immunology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Rémi Pescarmona
- National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France.,Immunology Department, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Sophie Georgin-Lavialle
- Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Sorbonne Université, Service de Médecine Interne, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses d'Origine Inflammatoire, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Université Pierre-et-Marie-Curie-Paris 6, Institut National de la Santé et de la Recherche Médicale UMRS 933, Paris, France
| | - Yvan Jamilloux
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France.,Internal Medicine, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| | - Jean-Paul Larbre
- National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France.,Rheumatology Unit, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Guillaume Sarrabay
- Centre Hospitalier Universitaire Montpellier, University of Montpellier, Laboratory of Rare and Autoinflammatory Genetic Diseases and Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses d'Origine Inflammatoire, Montpellier, France
| | - Flora Magnotti
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France
| | - Gillian I Rice
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Francoise Bleicher
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Lyon, France
| | - Jonathan Reboulet
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Lyon, France
| | - Samir Merabet
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, Lyon, France
| | - Thomas Henry
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France
| | - Yanick J Crow
- Laboratory of Neurogenetics and Neuroinflammation, Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Hôpital Necker, Paris, France.,Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Mathias Faure
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France
| | - Thierry Walzer
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France.,National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France
| | - Alexandre Belot
- Centre International de Recherche en Infectiologie/International Center for Infectiology Research, Institut National de la Santé et de la Recherche Médicale, U1111, Ecole Normale Supérieure de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique, UMR5308, Lyon, France.,National Referee Centre for Rheumatic and Autoimmune Diseases in Children, RAISE, Paris and Lyon, France.,Pediatric Nephrology, Rheumatology, Dermatology Department, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France
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38
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Perrotta C, Cattaneo MG, Molteni R, De Palma C. Autophagy in the Regulation of Tissue Differentiation and Homeostasis. Front Cell Dev Biol 2020; 8:602901. [PMID: 33363161 PMCID: PMC7758408 DOI: 10.3389/fcell.2020.602901] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 11/20/2020] [Indexed: 12/14/2022] Open
Abstract
Autophagy is a constitutive pathway that allows the lysosomal degradation of damaged components. This conserved process is essential for metabolic plasticity and tissue homeostasis and is crucial for mammalian post-mitotic cells. Autophagy also controls stem cell fate and defective autophagy is involved in many pathophysiological processes. In this review, we focus on established and recent breakthroughs aimed at elucidating the impact of autophagy in differentiation and homeostasis maintenance of endothelium, muscle, immune system, and brain providing a suitable framework of the emerging results and highlighting the pivotal role of autophagic response in tissue functions, stem cell dynamics and differentiation rates.
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Affiliation(s)
- Cristiana Perrotta
- Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università degli Studi di Milano, Milan, Italy
| | - Maria Grazia Cattaneo
- Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy
| | - Raffaella Molteni
- Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy
| | - Clara De Palma
- Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy
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