|
1
|
Li Z, Liu H, Xie Q, Yin G. Macrophage involvement in idiopathic inflammatory myopathy: pathogenic mechanisms and therapeutic prospects. J Inflamm (Lond) 2024; 21:48. [PMID: 39593038 PMCID: PMC11590228 DOI: 10.1186/s12950-024-00422-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 11/18/2024] [Indexed: 11/28/2024] Open
Abstract
Idiopathic inflammatory myopathies are a group of systemic autoimmune diseases characterized by chronic muscle inflammation and diverse clinical manifestations. Macrophages, pivotal components of innate immunity, are implicated in immune responses, inflammation resolution, and tissue repair. Distinct macrophage polarization states play vital roles in disease progression and resolution. Mechanistically, activated macrophages release proinflammatory cytokines, chemokines, and reactive oxygen species, perpetuating immune responses and tissue damage. Dysregulated macrophage polarization contributes to sustained inflammation. Here, we reviewed the intricate contributions of macrophages to IIM pathogenesis and explored novel therapeutic avenues. We discussed emerging strategies targeting macrophages, including receptor-based interventions and macrophage polarization modulation, for IIM treatment. This review underscores the multifaceted involvement of macrophages in IIM pathogenesis and offers insights into potential therapeutic approaches targeting these immune cells for disease management.
Collapse
Affiliation(s)
- Ziqi Li
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, China
| | - Huan Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, China
| | - Qibing Xie
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, China
| | - Geng Yin
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, China.
- Department of General Practice, West China Hospital, General Practice Medical Center, Sichuan University, Chengdu, China.
| |
Collapse
|
|
2
|
Bednarczyk M, Dąbrowska-Szeja N, Łętowski D, Dzięgielewska-Gęsiak S, Waniczek D, Muc-Wierzgoń M. Relationship Between Dietary Nutrient Intake and Autophagy-Related Genes in Obese Humans: A Narrative Review. Nutrients 2024; 16:4003. [PMID: 39683397 PMCID: PMC11643440 DOI: 10.3390/nu16234003] [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] [Received: 09/24/2024] [Revised: 11/14/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Obesity is one of the world's major public health challenges. Its pathogenesis and comorbid metabolic disorders share common mechanisms, such as mitochondrial or endoplasmic reticulum dysfunction or oxidative stress, gut dysbiosis, chronic inflammation and altered autophagy. Numerous pro-autophagy dietary interventions are being investigated for their potential obesity-preventing or therapeutic effects. We summarize current data on the relationship between autophagy and obesity, and discuss various dietary interventions as regulators of autophagy-related genes in the prevention and ultimate treatment of obesity in humans, as available in scientific databases and published through July 2024. Lifestyle modifications (such as calorie restriction, intermittent fasting, physical exercise), including following a diet rich in flavonoids, antioxidants, specific fatty acids, specific amino acids and others, have shown a beneficial role in the induction of this process. The activation of autophagy through various nutritional interventions tends to elicit a consistent response, characterized by the induction of certain kinases (including AMPK, IKK, JNK1, TAK1, ULK1, and VPS34) or the suppression of others (like mTORC1), the deacetylation of proteins, and the alleviation of inhibitory interactions between BECN1 and members of the Bcl-2 family. Significant health/translational properties of many nutrients (nutraceuticals) can affect chronic disease risk through various mechanisms that include the activation or inhibition of autophagy. The role of nutritional intervention in the regulation of autophagy in obesity and its comorbidities is not yet clear, especially in obese individuals.
Collapse
Affiliation(s)
- Martyna Bednarczyk
- Department of Cancer Prevention, Faculty of Public Health, Medical University of Silesia in Katowice, 40-055 Katowice, Poland; (M.B.); (N.D.-S.); (D.Ł.)
| | - Nicola Dąbrowska-Szeja
- Department of Cancer Prevention, Faculty of Public Health, Medical University of Silesia in Katowice, 40-055 Katowice, Poland; (M.B.); (N.D.-S.); (D.Ł.)
| | - Dariusz Łętowski
- Department of Cancer Prevention, Faculty of Public Health, Medical University of Silesia in Katowice, 40-055 Katowice, Poland; (M.B.); (N.D.-S.); (D.Ł.)
| | - Sylwia Dzięgielewska-Gęsiak
- Department of Internal Diseases Propaedeutics and Emergency Medicine, Faculty of Public Health in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland;
| | - Dariusz Waniczek
- Department of Oncological Surgery, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 40-055 Katowice, Poland;
| | - Małgorzata Muc-Wierzgoń
- Department of Internal Diseases Propaedeutics and Emergency Medicine, Faculty of Public Health in Bytom, Medical University of Silesia in Katowice, 40-055 Katowice, Poland;
| |
Collapse
|
|
3
|
Chu Y, Yuan X, Tao Y, Yang B, Luo J. Autophagy in Muscle Regeneration: Mechanisms, Targets, and Therapeutic Perspective. Int J Mol Sci 2024; 25:11901. [PMID: 39595972 PMCID: PMC11593790 DOI: 10.3390/ijms252211901] [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: 09/30/2024] [Revised: 10/31/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Autophagy maintains the stability of eukaryotic cells by degrading unwanted components and recycling nutrients and plays a pivotal role in muscle regeneration by regulating the quiescence, activation, and differentiation of satellite cells. Effective muscle regeneration is vital for maintaining muscle health and homeostasis. However, under certain disease conditions, such as aging, muscle regeneration can fail due to dysfunctional satellite cells. Dysregulated autophagy may limit satellite cell self-renewal, hinder differentiation, and increase susceptibility to apoptosis, thereby impeding muscle regeneration. This review explores the critical role of autophagy in muscle regeneration, emphasizing its interplay with apoptosis and recent advances in autophagy research related to diseases characterized by impaired muscle regeneration. Additionally, we discuss new approaches involving autophagy regulation to promote macrophage polarization, enhancing muscle regeneration. We suggest that utilizing cell therapy and biomaterials to modulate autophagy could be a promising strategy for supporting muscle regeneration. We hope that this review will provide new insights into the treatment of muscle diseases and promote muscle regeneration.
Collapse
Affiliation(s)
- Yun Chu
- Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.C.); (Y.T.); (B.Y.)
| | - Xinrun Yuan
- Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| | - Yiming Tao
- Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.C.); (Y.T.); (B.Y.)
| | - Bin Yang
- Department of Intensive Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (Y.C.); (Y.T.); (B.Y.)
| | - Jinlong Luo
- Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;
| |
Collapse
|
|
4
|
Hongfang G, Khan R, El-Mansi AA. Bioinformatics Analysis of miR-181a and Its Role in Adipogenesis, Obesity, and Lipid Metabolism Through Review of Literature. Mol Biotechnol 2024; 66:2710-2724. [PMID: 37773313 DOI: 10.1007/s12033-023-00894-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 09/04/2023] [Indexed: 10/01/2023]
Abstract
The miRNAs regulate various biological processes in the mammalian body system. The role of miR-181a in the development, progression, and expansion of cancers is well-documented. However, the role of miR-181a in adipogenesis; lipid metabolism; obesity; and obesity-related issues such as diabetes mellitus needs to be explored. Therefore, in the present study, the literature was searched and bioinformatics tools were applied to explore the role of miR-181a in adipogenesis. The list of adipogenic and lipogenic target genes validated through different publications were extracted and compiled. The network and functional analysis of these target genes was performed through in-silico analysis. The mature sequence of miR-181a of different species were extracted from and were found highly conserved among the curated species. Additionally, we also used various bioinformatics tools such as target gene extraction from Targetscan, miRWalk, and miRDB, and the list of the target genes from these different databases was compared, and common target genes were predicted. These common target genes were further subjected to the enrichment score and KEGG pathways analysis. The enrichment score of the vital KEGG pathways of the target genes is the key regulator of adipogenesis, lipogenesis, obesity, and obesity-related syndromes in adipose tissues. Therefore, the information presented in the current review will explore the regulatory roles of miR-181a in fat tissues and its associated functions and manifestations.
Collapse
Affiliation(s)
- Guo Hongfang
- Medical College of Xuchang University, No.1389, Xufan Road, Xuchang City, 461000, Henan Province, People's Republic of China
| | - Rajwali Khan
- Department of Livestock Management, Breeding and Genetics, The University of Agriculture, Peshawar, 25130, Pakistan.
| | - Ahmed A El-Mansi
- Biology Department, Faculty of Science, King Khalid University, Abha, Saudi Arabia
| |
Collapse
|
|
5
|
Yan K. Recent advances in the effect of adipose tissue inflammation on insulin resistance. Cell Signal 2024; 120:111229. [PMID: 38763181 DOI: 10.1016/j.cellsig.2024.111229] [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: 04/25/2024] [Revised: 05/13/2024] [Accepted: 05/14/2024] [Indexed: 05/21/2024]
Abstract
Obesity is one of the major risk factors for diabetes. Excessive accumulation of fat leads to inflammation of adipose tissue, which can increase the risk of developing diabetes. Obesity-related chronic inflammation can result in anomalies in glucose-lipid metabolism and insulin resistance, and it is a major cause of β-cell dysfunction in diabetes mellitus. Thus, a long-term tissue inflammatory response is crucial for metabolic diseases, particularly type 2 diabetes. Chronic inflammation associated with obesity increases oxidative stress, secretes inflammatory factors, modifies endocrine variables, and interferes with insulin signalling pathways, all of which contribute to insulin resistance and glucose tolerance. Insulin resistance and diabetes are ultimately caused by chronic inflammation in the stomach, pancreas, liver, muscle, and fat tissues. In this article, we systematically summarize the latest research progress on the mechanisms of adipose tissue inflammation and insulin resistance, as well as the mechanisms of cross-talk between adipose tissue inflammation and insulin resistance, with a view to providing some meaningful therapeutic strategies for the treatment of insulin resistance by controlling adipose tissue inflammation.
Collapse
Affiliation(s)
- Kaiyi Yan
- The Second Clinical College of China Medical University, Shenyang, Liaoning 110122, China.
| |
Collapse
|
|
6
|
Zubova SG, Morshneva AV. The role of autophagy and macrophage polarization in the processes of chronic inflammation and regeneration. ЦИТОЛОГИЯ 2024; 66:20-34. [DOI: 10.31857/s0041377124010023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The cause of many seriousillnesses, including diabetes, obesity, osteoporosis and neurodegenerative diseases is chronic inflammation that develops in adipose tissue, bones or the brain. This inflammation occurs due to a shift in the polarization of macrophages/microglia towards the pro-inflammatory phenotype M1. It has now been proven that the polarization of macrophages is determined by the intracellular level of autophagy in the macrophage. By modulating autophagy, it is possible to cause switching of macrophage activities towards M1 or M2. Summarizing the material accumulated in the literature, we believe that the activation of autophagy reprograms the macrophage towards M2, replacing its protein content, receptor apparatus and including a different type of metabolism. The term reprogramming is most suitable for this process, since it is followed by a change in the functional activity of the macrophage, namely, switching from cytotoxic pro-inflammatory activity to anti-inflammatory (regenerative). Modulation of autophagy can be an approach to the treatment of oncological diseases, neurodegenerative disorders, osteoporosis, diabetes and other serious diseases.
Collapse
Affiliation(s)
- S. G. Zubova
- Institute of Cytology of the Russian Academy of Sciences
| | | |
Collapse
|
|
7
|
Zubova SG, Morshneva AV. The Role of Autophagy and Macrophage Polarization in the Process of Chronic Inflammation and Regeneration. CELL AND TISSUE BIOLOGY 2024; 18:244-256. [DOI: 10.1134/s1990519x24700184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 09/04/2023] [Accepted: 09/21/2023] [Indexed: 01/04/2025]
|
|
8
|
Peng C, Chen J, Wu R, Jiang H, Li J. Unraveling the complex roles of macrophages in obese adipose tissue: an overview. Front Med 2024; 18:205-236. [PMID: 38165533 DOI: 10.1007/s11684-023-1033-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/15/2023] [Indexed: 01/03/2024]
Abstract
Macrophages, a heterogeneous population of innate immune cells, exhibit remarkable plasticity and play pivotal roles in coordinating immune responses and maintaining tissue homeostasis within the context of metabolic diseases. The activation of inflammatory macrophages in obese adipose tissue leads to detrimental effects, inducing insulin resistance through increased inflammation, impaired thermogenesis, and adipose tissue fibrosis. Meanwhile, adipose tissue macrophages also play a beneficial role in maintaining adipose tissue homeostasis by regulating angiogenesis, facilitating the clearance of dead adipocytes, and promoting mitochondrial transfer. Exploring the heterogeneity of macrophages in obese adipose tissue is crucial for unraveling the pathogenesis of obesity and holds significant potential for targeted therapeutic interventions. Recently, the dual effects and some potential regulatory mechanisms of macrophages in adipose tissue have been elucidated using single-cell technology. In this review, we present a comprehensive overview of the intricate activation mechanisms and diverse functions of macrophages in adipose tissue during obesity, as well as explore the potential of drug delivery systems targeting macrophages, aiming to enhance the understanding of current regulatory mechanisms that may be potentially targeted for treating obesity or metabolic diseases.
Collapse
Affiliation(s)
- Chang Peng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jun Chen
- Department of Prosthodontics, Shanghai Engineering Research Center of Advanced Dental Technology and Materials, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Rui Wu
- Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China
| | - Haowen Jiang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Jia Li
- Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310000, China.
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| |
Collapse
|
|
9
|
Ding Y, Cao Q, Yang W, Xu J, Xiao P. Macrophage: Hidden Criminal in Therapy Resistance. J Innate Immun 2024; 16:188-202. [PMID: 38442696 PMCID: PMC10990480 DOI: 10.1159/000538212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/29/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND Although substantial efforts have been made by researchers to develop drugs, a disappointing reality is that the emergence of drug resistance is an unavoidable reality for the majority of patients. In recent years, emerging evidence suggests a connection between drug resistance and immune dysregulation. SUMMARY As a ubiquitously distributed, versatile innate immune cell, macrophages play essential roles in maintaining tissue homeostasis in a steady state. Nevertheless, it is becoming aware that macrophages undermine the action of therapeutic drugs across various disease types. Reprogramming macrophage function has been proven to be effective in restoring patient responsiveness to treatment. Herein, we comprehensively reviewed how macrophages respond to drugs and the mechanisms by which they contribute to treatment unresponsiveness in cancer, inflammatory diseases, and metabolic diseases. In addition, future prospects in macrophage-based combination therapy were discussed. KEY MESSAGES Targeting macrophages is a promising strategy for overcoming drug resistance in immune disorders.
Collapse
Affiliation(s)
- Yimin Ding
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wenjuan Yang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
| | - Junjie Xu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng Xiao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Inflammatory Bowel Disease Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China
- The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China
| |
Collapse
|
|
10
|
Hu W, Xie N, Pan M, Zhang Q, Zhang H, Wang F, Qu F. Chinese herbal medicine alleviates autophagy and apoptosis in ovarian granulosa cells induced by testosterone through PI3K/AKT1/FOXO1 pathway. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117025. [PMID: 37567425 DOI: 10.1016/j.jep.2023.117025] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/08/2023] [Accepted: 08/09/2023] [Indexed: 08/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Polycystic ovary syndrome (PCOS) is a common gynecological endocrine and metabolic disorder. Chinese herbal medicine has some advantages in the treatment of PCOS with its unique theoretical system and rich clinical practice experiences. AIM OF THE STUDY The present study was to investigate the potential mechanisms of Bu-Shen-Jian-Pi Formula (BSJPF) on the treatment of PCOS. MATERIAL AND METHODS The combination of ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS/MS) rapid analysis, network pharmacology, molecular docking analysis and bio-experiments were firstly conducted to identify the main effective components of BSJPF, and to predict the potential mechanisms. The ovarian granulosa cell line (KGN) was treated with testosterone to construct the PCOS model in vitro, and the cells were further treated with the lyophilized powder of BSJPF. The levels of proliferation, autophagy and apoptosis were detected to explore the mechanisms of BSJPF on treating PCOS. RESULTS Firstly, thirty-six active compounds were identified in BSJPF and thirty-one potential targets on PCOS were found. Then, PI3K and PDK1 were verified to have good binding activity with the active compounds through molecular docking analysis. In bio-experiments, BSJPF significantly alleviated the arrested proliferation of KGN cells in G0/G1 phase and reduced the active levels of autophagy and apoptosis of KGN cells induced by testosterone. Additionally, the inhibition of autophagy diminished apoptosis, while the repression apoptosis enhanced autophagy. Finally, BSJPF significantly decreased the FOXO1 expression levels induced by testosterone, especially for nuclear FOXO1, and significantly activated the PI3K/AKT pathway. CONCLUSIONS BSJPF significantly alleviated the activated autophagy and apoptosis in KGN induced by testosterone through PI3K/AKT1/FOXO1pathway, which is an effective treatment for PCOS.
Collapse
Affiliation(s)
- Weihuan Hu
- Women's Hospital, School of Medicine, Zhejiang University, 310006, Hangzhou, Zhejiang, China
| | - Ningning Xie
- Women's Hospital, School of Medicine, Zhejiang University, 310006, Hangzhou, Zhejiang, China
| | - Manman Pan
- Women's Hospital, School of Medicine, Zhejiang University, 310006, Hangzhou, Zhejiang, China
| | - Qing Zhang
- Women's Hospital, School of Medicine, Zhejiang University, 310006, Hangzhou, Zhejiang, China
| | - Hui Zhang
- Zhejiang Vocational College of Special Education, Hangzhou, 310023, China
| | - Fangfang Wang
- Women's Hospital, School of Medicine, Zhejiang University, 310006, Hangzhou, Zhejiang, China
| | - Fan Qu
- Women's Hospital, School of Medicine, Zhejiang University, 310006, Hangzhou, Zhejiang, China.
| |
Collapse
|
|
11
|
Li Y, Ji Y, Li F. A review: Mechanism and prospect of gastrodin in prevention and treatment of T2DM and COVID-19. Heliyon 2023; 9:e21218. [PMID: 37954278 PMCID: PMC10637887 DOI: 10.1016/j.heliyon.2023.e21218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 09/15/2023] [Accepted: 10/18/2023] [Indexed: 11/14/2023] Open
Abstract
Gastrodin is an extract from the dried tuber of the Chinese herb Gastrodia elata (Tian ma), with anti-inflammatory, antioxidant, and antiviral properties. Recent studies have shown that, compared to commonly used diabetes drugs, gastrodin has antidiabetic effects in multiple ways, with characteristics of low cost, high safety, less side effects, protection of β-cell function, relieving insulin resistance and alleviating multiple complications. In addition, it is confirmed that gastrodin can protect the function of lung and other organs, enhance antiviral activity via upregulating the type I interferon (IFN-I), and inhibit angiotensin II (AngII), a key factor in "cytokine storm" caused by COVID-19. Therefore, we reviewed the effect and mechanism of gastrodin on type 2 diabetes mellitus (T2DM), and speculated other potential mechanisms of gastrodin in alleviating insulin resistance from insulin signal pathway, inflammation, mitochondrial and endoplasmic reticulum and its potential in the prevention and treatment of COVID-19. We hope to provide new direction and treatment strategy for basic research and clinical work: gastrodin is considered as a drug for the prevention and treatment of diabetes and COVID-19.
Collapse
Affiliation(s)
- Yi Li
- Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, China
| | - Yuanyuan Ji
- Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, China
| | - Fenglan Li
- Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, China
| |
Collapse
|
|
12
|
Sadeghi A, Niknam M, Momeni-Moghaddam MA, Shabani M, Aria H, Bastin A, Teimouri M, Meshkani R, Akbari H. Crosstalk between autophagy and insulin resistance: evidence from different tissues. Eur J Med Res 2023; 28:456. [PMID: 37876013 PMCID: PMC10599071 DOI: 10.1186/s40001-023-01424-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 10/03/2023] [Indexed: 10/26/2023] Open
Abstract
Insulin is a critical hormone that promotes energy storage in various tissues, as well as anabolic functions. Insulin resistance significantly reduces these responses, resulting in pathological conditions, such as obesity and type 2 diabetes mellitus (T2DM). The management of insulin resistance requires better knowledge of its pathophysiological mechanisms to prevent secondary complications, such as cardiovascular diseases (CVDs). Recent evidence regarding the etiological mechanisms behind insulin resistance emphasizes the role of energy imbalance and neurohormonal dysregulation, both of which are closely regulated by autophagy. Autophagy is a conserved process that maintains homeostasis in cells. Accordingly, autophagy abnormalities have been linked to a variety of metabolic disorders, including insulin resistance, T2DM, obesity, and CVDs. Thus, there may be a link between autophagy and insulin resistance. Therefore, the interaction between autophagy and insulin function will be examined in this review, particularly in insulin-responsive tissues, such as adipose tissue, liver, and skeletal muscle.
Collapse
Affiliation(s)
- Asie Sadeghi
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Niknam
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Maryam Shabani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Aria
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Alireza Bastin
- Clinical Research Development Center "The Persian Gulf Martyrs" Hospital, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Maryam Teimouri
- Department of Biochemistry, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Reza Meshkani
- Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamed Akbari
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran.
- Department of Clinical Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
| |
Collapse
|
|
13
|
Oh J, Park C, Kim S, Kim M, Kim CS, Jo W, Park S, Yi GS, Park J. High levels of intracellular endotrophin in adipocytes mediate COPII vesicle supplies to autophagosome to impair autophagic flux and contribute to systemic insulin resistance in obesity. Metabolism 2023:155629. [PMID: 37302692 DOI: 10.1016/j.metabol.2023.155629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/25/2023] [Accepted: 06/08/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND AND AIMS Extracellular matrix (ECM) homeostasis plays a crucial role in metabolic plasticity and endocrine function of adipose tissue. High levels of intracellular endotrophin, a cleavage peptide of type VI collagen alpha 3 chain (Col6a3), have been frequently observed in adipocyte in obesity and diabetes. However, how endotrophin intracellularly traffics and influences metabolic homeostasis in adipocyte remains unknown. Therefore, we aimed to investigate the trafficking of endotrophin and its metabolic effects in adipocytes depending on lean or obese condition. METHODS We used doxycycline-inducible adipocyte-specific endotrophin overexpressed mice for a gain-of-function study and CRISPR-Cas9 system-based Col6a3-deficient mice for a loss-of-function study. Various molecular and biochemical techniques were employed to examine the effects of endotrophin on metabolic parameters. RESULTS In adipocytes during obesity, the majority of endosomal endotrophin escapes lysosomal degradation and is released into the cytosol to mediate direct interactions between SEC13, a major component of coat protein complex II (COPII) vesicles, and autophagy-related 7 (ATG7), leading to the increased formation of autophagosomes. Autophagosome accumulation disrupts the balance of autophagic flux, resulting in adipocyte death, inflammation, and insulin resistance. These adverse metabolic effects were ameliorated by either suppressing ATG7 with siRNA ex vivo or neutralizing endotrophin with monoclonal antibodies in vivo. CONCLUSIONS High levels of intracellular endotrophin-mediated autophagic flux impairment in adipocyte contribute to metabolic dysfunction such as apoptosis, inflammation, and insulin resistance in obesity.
Collapse
Affiliation(s)
- Jiyoung Oh
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Chanho Park
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Sahee Kim
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Min Kim
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Chu-Sook Kim
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Woobeen Jo
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Sungho Park
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea
| | - Gwan-Su Yi
- Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
| | - Jiyoung Park
- Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
| |
Collapse
|
|
14
|
Ogino T, Takeda K. Immunoregulation by antigen-presenting cells in human intestinal lamina propria. Front Immunol 2023; 14:1138971. [PMID: 36845090 PMCID: PMC9947491 DOI: 10.3389/fimmu.2023.1138971] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
Antigen-presenting cells, including macrophages and dendritic cells, are a type of innate immune cells that can induce the differentiation of T cells and activate the adaptive immune response. In recent years, diverse subsets of macrophages and dendritic cells have been identified in the intestinal lamina propria of mice and humans. These subsets contribute to the maintenance of intestinal tissue homeostasis by regulating the adaptive immune system and epithelial barrier function through interaction with intestinal bacteria. Further investigation of the roles of antigen-presenting cells localized in the intestinal tract may lead to the elucidation of inflammatory bowel disease pathology and the development of novel treatment approaches.
Collapse
Affiliation(s)
- Takayuki Ogino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
- Department of Therapeutics for Inflammatory Bowel Diseases, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Kiyoshi Takeda
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Japan
- Immunology Frontier Research Center, Osaka University, Suita, Japan
| |
Collapse
|
|
15
|
Chen Y, Xiao L, Xu J, Wang J, Yu Z, Zhao K, Zhang H, Cheng S, Sharma S, Liao A, Liu C. Recent insight into autophagy and immunity at the maternal-fetal interface. J Reprod Immunol 2023; 155:103781. [PMID: 36463798 DOI: 10.1016/j.jri.2022.103781] [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: 08/20/2022] [Revised: 11/01/2022] [Accepted: 11/27/2022] [Indexed: 11/30/2022]
Abstract
Autophagy is a lysosomal degradation pathway that supports metabolic adaptation and energy cycling. It is essential for cell homeostasis, differentiation, development, and survival. Recent studies have shown that autophagy could influence immune responses by regulating immune cell functions. Reciprocally, immune cells strongly influence autophagy. Immune cells at the maternal-fetal interface are thought to play essential roles in pregnancy. Here, we review the induction of autophagy at the maternal-fetal interface and its role in decidualization and placental development. Additionally, we emphasize the role of autophagy in the immune microenvironment at the maternal-fetal interface, including innate immunity, adaptive immunity, and immune tolerance molecules. It also suggests new research directions and prospects.
Collapse
Affiliation(s)
- Yuanyao Chen
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, PR China
| | - Lin Xiao
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, PR China
| | - Jia Xu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, PR China
| | - Jingming Wang
- Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, PR China
| | - Zhiquan Yu
- Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, PR China
| | - Kai Zhao
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, PR China
| | - Huiping Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, PR China
| | - Shibin Cheng
- Department of Pediatrics, Obstetrics and Gynecology and Pathology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Surendra Sharma
- Department of Pediatrics, Obstetrics and Gynecology and Pathology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Aihua Liao
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, PR China.
| | - Chunyan Liu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei 430030, PR China.
| |
Collapse
|
|
16
|
Acosta-Martinez M, Cabail MZ. The PI3K/Akt Pathway in Meta-Inflammation. Int J Mol Sci 2022; 23:ijms232315330. [PMID: 36499659 PMCID: PMC9740745 DOI: 10.3390/ijms232315330] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/22/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Obesity is a global epidemic representing a serious public health burden as it is a major risk factor for the development of cardiovascular disease, stroke and all-cause mortality. Chronic low-grade systemic inflammation, also known as meta-inflammation, is thought to underly obesity's negative health consequences, which include insulin resistance and the development of type 2 diabetes. Meta-inflammation is characterized by the accumulation of immune cells in adipose tissue, a deregulation in the synthesis and release of adipokines and a pronounced increase in the production of proinflammatory factors. In this state, the infiltration of macrophages and their metabolic activation contributes to complex paracrine and autocrine signaling, which sustains a proinflammatory microenvironment. A key signaling pathway mediating the response of macrophages and adipocytes to a microenvironment of excessive nutrients is the phosphoinositide 3-kinase (PI3K)/Akt pathway. This multifaceted network not only transduces metabolic information but also regulates macrophages' intracellular changes, which are responsible for their phenotypic switch towards a more proinflammatory state. In the present review, we discuss how the crosstalk between macrophages and adipocytes contributes to meta-inflammation and provide an overview on the involvement of the PI3K/Akt signaling pathway, and how its impairment contributes to the development of insulin resistance.
Collapse
Affiliation(s)
- Maricedes Acosta-Martinez
- Department of Physiology and Biophysics, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maria Zulema Cabail
- Biological Science Department, State University of New York-College at Old Westbury, Old Westbury, NY 11568, USA
- Correspondence:
| |
Collapse
|
|
17
|
Pant A, Yao X, Lavedrine A, Viret C, Dockterman J, Chauhan S, Chong-Shan Shi, Manjithaya R, Cadwell K, Kufer TA, Kehrl JH, Coers J, Sibley LD, Faure M, Taylor GA, Chauhan S. Interactions of Autophagy and the Immune System in Health and Diseases. AUTOPHAGY REPORTS 2022; 1:438-515. [PMID: 37425656 PMCID: PMC10327624 DOI: 10.1080/27694127.2022.2119743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
Autophagy is a highly conserved process that utilizes lysosomes to selectively degrade a variety of intracellular cargo, thus providing quality control over cellular components and maintaining cellular regulatory functions. Autophagy is triggered by multiple stimuli ranging from nutrient starvation to microbial infection. Autophagy extensively shapes and modulates the inflammatory response, the concerted action of immune cells, and secreted mediators aimed to eradicate a microbial infection or to heal sterile tissue damage. Here, we first review how autophagy affects innate immune signaling, cell-autonomous immune defense, and adaptive immunity. Then, we discuss the role of non-canonical autophagy in microbial infections and inflammation. Finally, we review how crosstalk between autophagy and inflammation influences infectious, metabolic, and autoimmune disorders.
Collapse
Affiliation(s)
- Aarti Pant
- Autophagy Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
| | - Xiaomin Yao
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, New York, United States of America
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Aude Lavedrine
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
- Equipe Labellisée par la Fondation pour la Recherche Médicale, FRM
| | - Christophe Viret
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
- Equipe Labellisée par la Fondation pour la Recherche Médicale, FRM
| | - Jake Dockterman
- Department of Immunology, Duke University, Medical Center, Durham, North Carolina, USA
| | - Swati Chauhan
- Cell biology and Infectious diseases, Institute of Life Sciences, Bhubaneswar, India
| | - Chong-Shan Shi
- Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Ravi Manjithaya
- Autophagy Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
- Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, India
| | - Ken Cadwell
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, New York, United States of America
- Department of Microbiology, New York University Grossman School of Medicine, New York, New York, United States of America
- Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, New York, United States of America
| | - Thomas A. Kufer
- Department of Immunology, Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - John H. Kehrl
- Laboratory of Immunoregulation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Jörn Coers
- Department of Immunology, Duke University, Medical Center, Durham, North Carolina, USA
- Department of Molecular Genetics and Microbiology, Duke University, Medical Center, Durham, North Carolina, USA
| | - L. David Sibley
- Department of Molecular Microbiology, Washington University Sch. Med., St Louis, MO, 63110, USA
| | - Mathias Faure
- CIRI, Centre International de Recherche en Infectiologie, Université de Lyon, Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
- Equipe Labellisée par la Fondation pour la Recherche Médicale, FRM
| | - Gregory A Taylor
- Department of Immunology, Duke University, Medical Center, Durham, North Carolina, USA
- Department of Molecular Genetics and Microbiology, Duke University, Medical Center, Durham, North Carolina, USA
- Department of Molecular Microbiology, Washington University Sch. Med., St Louis, MO, 63110, USA
- Geriatric Research, Education, and Clinical Center, VA Health Care Center, Durham, North Carolina, USA
- Departments of Medicine, Division of Geriatrics, and Center for the Study of Aging and Human Development, Duke University, Medical Center, Durham, North Carolina, USA
| | - Santosh Chauhan
- Cell biology and Infectious diseases, Institute of Life Sciences, Bhubaneswar, India
- CSIR–Centre For Cellular And Molecular Biology (CCMB), Hyderabad, Telangana
| |
Collapse
|
|
18
|
Li H, Meng Y, He S, Tan X, Zhang Y, Zhang X, Wang L, Zheng W. Macrophages, Chronic Inflammation, and Insulin Resistance. Cells 2022; 11:cells11193001. [PMID: 36230963 PMCID: PMC9562180 DOI: 10.3390/cells11193001] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/08/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
The prevalence of obesity has reached alarming levels, which is considered a major risk factor for several metabolic diseases, including type 2 diabetes (T2D), non-alcoholic fatty liver, atherosclerosis, and ischemic cardiovascular disease. Obesity-induced chronic, low-grade inflammation may lead to insulin resistance, and it is well-recognized that macrophages play a major role in such inflammation. In the current review, the molecular mechanisms underlying macrophages, low-grade tissue inflammation, insulin resistance, and T2D are described. Also, the role of macrophages in obesity-induced insulin resistance is presented, and therapeutic drugs and recent advances targeting macrophages for the treatment of T2D are introduced.
Collapse
Affiliation(s)
- He Li
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Ya Meng
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Shuwang He
- Shandong DYNE Marine Biopharmaceutical Co., Ltd., Rongcheng 264300, China
| | - Xiaochuan Tan
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Yujia Zhang
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Xiuli Zhang
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
| | - Lulu Wang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
- Correspondence: (L.W.); (W.Z.); Tel.: +86-010-63165233 (W.Z.)
| | - Wensheng Zheng
- Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
- Correspondence: (L.W.); (W.Z.); Tel.: +86-010-63165233 (W.Z.)
| |
Collapse
|
|
19
|
Ji Y, Xie Q, Meng X, Wang W, Li S, Lang X, Zhao C, Yuan Y, Ye H. Lactobacillus paracasei improves dietary fatty liver by reducing insulin resistance and inflammation in obese mice model. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
|
|
20
|
Use of Physical Activity and Exercise to Reduce Inflammation in Children and Adolescents with Obesity. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19116908. [PMID: 35682490 PMCID: PMC9180584 DOI: 10.3390/ijerph19116908] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/01/2022] [Accepted: 06/03/2022] [Indexed: 12/13/2022]
Abstract
Childhood obesity is a leading public health problem worldwide, as it is increasingly prevalent and therefore responsible for serious obesity-related comorbidities, not only in childhood but also in adulthood. In addition to cardio-metabolic obesity-related disorders, recent evidence suggests that excess adipose tissue in turn is associated with immune cell infiltration, increased adipokine release, and the development of low-grade systemic inflammation obesity. Exercise is considered a non-pharmacological intervention that can delay obesity-related comorbidities, improving cardiovascular fitness and modulating the inflammatory processes. It has been reported that the anti-inflammatory effect of regular exercise may be mediated by a reduction in visceral fat mass, with a subsequent decrease in the release of adipokines from adipose tissue (AT) and/or by the induction of an anti-inflammatory environment. In this narrative review, we discuss the role of AT as an endocrine organ associated with chronic inflammation and its role in obesity-related complications, focusing on the effect of exercise in reducing inflammation in children and adolescents with obesity. Regular physical exercise must be considered as a natural part of a healthy lifestyle, and promoting physical activity starting from childhood is useful to limit the negative effects of obesity on health. The crucial role of the immune system in the development of obesity-induced inflammatory processes and the efficacy of exercise as an anti-inflammatory, non-pharmacological intervention may provide possible targets for the development of new treatments and early preventive strategies.
Collapse
|
|
21
|
Chen W, Chen Y, Liu Y, Wang X. Autophagy in muscle regeneration: potential therapies for myopathies. J Cachexia Sarcopenia Muscle 2022; 13:1673-1685. [PMID: 35434959 PMCID: PMC9178153 DOI: 10.1002/jcsm.13000] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 12/19/2022] Open
Abstract
Autophagy classically functions as a physiological process to degrade cytoplasmic components, protein aggregates, and/or organelles, as a mechanism for nutrient breakdown, and as a regulator of cellular architecture. Its biological functions include metabolic stress adaptation, stem cell differentiation, immunomodulation and diseases regulation, and so on. Current researches have proved that autophagy dysfunction may contribute to the pathogenesis of some myopathies through impairment of myofibres regeneration. Studies of autophagy inhibition also indicate the importance of autophagy in muscle regeneration, while activation of autophagy can restore muscle function in some myopathies. In this review, we aim to report the mechanisms of action of autophagy on muscle regeneration to provide relevant references for the treatment of regenerating defective myopathies by regulating autophagy. Results have shown that one key mechanism of autophagy regulating the muscle regeneration is to affect the differentiation fate of muscle stem cells (MuSCs), including quiescence maintenance, activation and differentiation. The roles of autophagy (organelle/protein degradation, energy facilitation, and/or other) vary at different myogenic stages of the repair process. When the muscle is in homeostasis, basal autophagy can maintain the quiescence state and stemness of MuSCs by renewing organelle and protein. After injury, the increased autophagy flux contributes to meet biological energy demand of MuSCs during activation and proliferation. By mitochondrial remodelling, autophagy during differentiation can promote the metabolic transformation and balance mitochondrial-mediated apoptosis signals in myoblasts. Autophagy in mature myofibres is also essential for the degradation of necrotic myofibres, and may affect the dynamics of MuSCs by affecting the secretion spectrum of myofibres or the recruitment of supporting cells. Except for myogenic cells, autophagy also plays an important role in regulating the function of non-myogenic cells in the muscle microenvironment, which is also essential for successful muscle recovery. Autophagy can regulate the immune microenvironment during muscle regeneration through the recruitment and polarization of macrophages, while autophagy in endothelial cells can regulate muscle regeneration in an angiogenic or angiogenesis-independent manner. Drug or nutrition targeted autophagy has been preliminarily proved to restore muscle function in myopathies by promoting muscle regeneration, and further understanding the role and mechanism of autophagy in various cell types during muscle regeneration will enable more effective combinatorial therapeutic strategies.
Collapse
Affiliation(s)
- Wei Chen
- College of Animal Sciences, Zhejiang University, Hangzhou, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Yushi Chen
- College of Animal Sciences, Zhejiang University, Hangzhou, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Yuxi Liu
- College of Animal Sciences, Zhejiang University, Hangzhou, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Xinxia Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, China.,Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China.,Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China.,Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| |
Collapse
|
|
22
|
He F, Wang M, Zhao H, Xie D, Lv J, Liu W, Yu W, Wang Q, Chen B, Xu C, Yamamoto T, Koyama H, Cheng J. Autophagy protects against high uric acid-induced hepatic insulin resistance. Mol Cell Endocrinol 2022; 547:111599. [PMID: 35181437 DOI: 10.1016/j.mce.2022.111599] [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: 11/25/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 10/19/2022]
Abstract
Uric acid (UA), the end-product of purine metabolism, is closely related to hepatic insulin resistance (IR). Autophagy is a conserved intracellular degradation process maintaining cellular homeostasis. Autophagy plays a protective role in obesity-related hepatic IR, but whether it occurs in high uric acid (HUA)-induced hepatic IR is unclear. In this study, spontaneously elevated UA level induced hepatic IR and facilitated hepatic autophagy degradation in uricase knockout (Uox-/-) mice. In vitro, HepG2 cells stimulated with HUA medium showed decreased glucose uptake and inhibition of insulin signaling pathways, concomitant with activation of autophagy, as manifested by increased conversion of LC3B-I to -II. Rapamycin, the autophagy activator, alleviated but the autophagy inhibitor trimethyl adenine (3-MA) aggravated HUA-induced IR in HepG2 cells. Similarly, rapamycin ameliorated and 3-MA worsened HUA-induced blood glucose level and hepatic IR in Uox-/- mice. Mechanistically, HUA enhanced AMPKα phosphorylation (p-AMPKα) and inhibited mammalian target of rapamycin phosphorylation (p-mTOR) in HepG2 cells. The levels of p-AMPKα and LC3B-II/I were downregulated in HepG2 cells transfected with small interfering RNA (siRNA) against AMPKα, which suggests that the AMPKα-mTOR pathway was involved in HUA-induced autophagy. Antioxidant N-acetyl-L-cysteine reversed elevated reactive oxygen species levels induced by HUA in HepG2 cells, and AMPKα level was also inhibited, which suggests that AMPKα activation may be derived from reactive oxygen species. Collectively, these findings demonstrate that HUA increased hepatic autophagy, and autophagy activation plays a protective role in hepatic IR, which may suggest a potential therapeutic target for hepatic IR derived from HUA.
Collapse
Affiliation(s)
- Furong He
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China
| | - Mei Wang
- Yunnan Provincial Key Laboratory of Entomological Biopharmaceutical R&D, Dali University, Dali, China
| | - Hairong Zhao
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China
| | - De Xie
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China
| | - Jiaming Lv
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China
| | - Weidong Liu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China
| | - Wei Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China
| | - Qiang Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China
| | - Binyang Chen
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China
| | - Chenxi Xu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China
| | - Tetsuya Yamamoto
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Hidenori Koyama
- Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Jidong Cheng
- Department of Endocrinology, Xiang'an Hospital of Xiamen University. Xiamen, Fujian, China; Department of Diabetes, Endocrinology and Clinical Immunology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
| |
Collapse
|
|
23
|
Park K, Lee MS. Current Status of Autophagy Enhancers in Metabolic Disorders and Other Diseases. Front Cell Dev Biol 2022; 10:811701. [PMID: 35237600 PMCID: PMC8882819 DOI: 10.3389/fcell.2022.811701] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/13/2022] [Indexed: 12/21/2022] Open
Abstract
Autophagy is pivotal in the maintenance of organelle function and intracellular nutrient balance. Besides the role of autophagy in the homeostasis and physiology of the individual tissues and whole organism in vivo, dysregulated autophagy has been incriminated in the pathogenesis of a variety of diseases including metabolic diseases, neurodegenerative diseases, cardiovascular diseases, inflammatory or immunological disorders, cancer and aging. Search for autophagy modulators has been widely conducted to amend dysregulation of autophagy or pharmacologically modulate autophagy in those diseases. Current data support the view that autophagy modulation could be a new modality for treatment of metabolic syndrome associated with lipid overload, human-type diabetes characterized by deposition of islet amyloid or other diseases including neurodegenerative diseases, infection and cardiovascular diseases. While clinically available bona fide autophagy modulators have not been developed yet, it is expected that on-going investigation will lead to the development of authentic autophagy modulators that can be safely administered to patients in the near future and will open a new horizon for treatment of incurable or difficult diseases.
Collapse
|
|
24
|
Zhu L, Liu L. New Insights Into the Interplay Among Autophagy, the NLRP3 Inflammasome and Inflammation in Adipose Tissue. Front Endocrinol (Lausanne) 2022; 13:739882. [PMID: 35432210 PMCID: PMC9008752 DOI: 10.3389/fendo.2022.739882] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 03/09/2022] [Indexed: 12/12/2022] Open
Abstract
Obesity is a feature of metabolic syndrome with chronic inflammation in obese subjects, characterized by adipose tissue (AT) expansion, proinflammatory factor overexpression, and macrophage infiltration. Autophagy modulates inflammation in the enlargement of AT as an essential step for maintaining the balance in energy metabolism and waste elimination. Signaling originating from dysfunctional AT, such as AT containing hypertrophic adipocytes and surrounding macrophages, activates NOD-like receptor family 3 (NLRP3) inflammasome. There are interactions about altered autophagy and NLRP3 inflammasome activation during the progress in obesity. We summarize the current studies and potential mechanisms associated with autophagy and NLRP3 inflammasome in AT inflammation and aim to provide further evidence for research on obesity and obesity-related complications.
Collapse
Affiliation(s)
- Liyuan Zhu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province, Changsha, China
- Cardiovascular Disease Research Center of Hunan Province, Changsha, China
| | - Ling Liu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
- Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, China
- Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province, Changsha, China
- Cardiovascular Disease Research Center of Hunan Province, Changsha, China
- *Correspondence: Ling Liu,
| |
Collapse
|
|
25
|
Zhang Y, Lu J, Zhong YJ, Yang CF, Chen L, Wu D, Song MW, Shi L, Ma ZH, Li L, Li YW. Methyl ferulic acid ameliorates alcohol-induced hepatic insulin resistance via miR-378b-mediated activation of PI3K-AKT pathway. Biomed Pharmacother 2021; 145:112462. [PMID: 34844105 DOI: 10.1016/j.biopha.2021.112462] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 11/13/2021] [Accepted: 11/19/2021] [Indexed: 12/18/2022] Open
Abstract
A previous study indicated that microRNA-378b (miR-378b) plays a critical role in controlling hepatic insulin resistance by targeting insulin receptor (IR) and p110α in alcoholic liver disease (ALD). Methyl ferulic acid (MFA), a bioactive ingredient in Securidaca inappendiculata Hassk rhizomes, exhibits multiple pharmacological activities. It has been reported that MFA ameliorates insulin resistance in ALD, whereas the underlying molecular mechanism remains unclear. The objective of study was to evaluate the influence of MFA on insulin sensitivity in ethanol-induced L-02 cells as well as alcohol-fed mice and illuminate the function of miR-378b-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in system. MFA was found to remarkably down-regulate miR-378b level and increase IR and p110α expressions. Furthermore, the effect of MFA on modulating miR-378b/PI3K-AKT pathway to enhance insulin sensitivity was corroborated by overexpressing and inhibiting miR-378b. Taken together, MFA exhibited a positive effect against ALD by attenuating the inhibition of miR-378b on IR/p110α and partly activating the insulin signaling to alleviate alcohol-induced hepatic insulin resistance.
Collapse
Affiliation(s)
- Yan Zhang
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Jun Lu
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Yu-Juan Zhong
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Cheng-Fang Yang
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Li Chen
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Dan Wu
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Meng-Wei Song
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Lin Shi
- College of Pharmacy, Guilin Medical University, Guilin, China
| | - Zu-Heng Ma
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Li Li
- College of Pharmacy, Guilin Medical University, Guilin, China.
| | - Yong-Wen Li
- College of Pharmacy, Guilin Medical University, Guilin, China; Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin, China.
| |
Collapse
|
|
26
|
Kumariya S, Ubba V, Jha RK, Gayen JR. Autophagy in ovary and polycystic ovary syndrome: role, dispute and future perspective. Autophagy 2021; 17:2706-2733. [PMID: 34161185 PMCID: PMC8526011 DOI: 10.1080/15548627.2021.1938914] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 05/30/2021] [Accepted: 06/02/2021] [Indexed: 02/05/2023] Open
Abstract
Polycystic ovary syndrome (PCOS) is a unification of endocrine and metabolic disorders and has become immensely prevalent among women of fertile age. The prime organ affected in PCOS is the ovary and its distressed functioning elicits disturbed reproductive outcomes. In the ovary, macroautophagy/autophagy performs a pivotal role in directing the chain of events starting from oocytes origin until its fertilization. Recent discoveries demonstrate a significant role of autophagy in the pathogenesis of PCOS. Defective autophagy in the follicular cells during different stages of follicles is observed in the PCOS ovary. Exploring different autophagy pathways provides a platform for predicting the possible cause of altered ovarian physiology in PCOS. In this review, we have emphasized autophagy's role in governing follicular development under normal circumstances and in PCOS, including significant abnormalities associated with PCOS such as anovulation, hyperandrogenemia, metabolic disturbances, and related abnormality. So far, few studies have linked autophagy and PCOS and propose its essential role in PCOS progression. However, detailed knowledge in this area is lacking. Here we have summarized the latest knowledge related to autophagy associated with PCOS. This review's main objective is to provide a background of autophagy in the ovary, its possible connection with PCOS and suggested a novel proposal for future studies to aid a better understanding of PCOS pathogenesis.Abbreviations: AE: androgen excess; AF: antral follicle; AKT/PKB: AKT serine/threonine kinase; AMH: anti-Mullerian hormone; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; BMP: bone morphogenetic protein; CASP3: caspase 3; CL: corpus luteum; CYP17A1/P450C17: cytochrome P450 family 17 subfamily A member 1; CYP19A1: cytochrome P450 family 19 subfamily A member 1; DHEA: dehydroepiandrosterone; EH: endometrial hyperplasia; FF: follicular fluid; FOXO: forkhead box O; FSH: follicle stimulating hormone; GC: granulosa cell; GDF: growth differentiation factor; HA: hyperandrogenemia; HMGB1: high mobility group box 1; IGF1: insulin like growth factor 1; INS: insulin; IR: insulin resistance; LHCGR/LHR: luteinizing hormone/choriogonadotropin receptor; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK/ERK: mitogen-activated protein kinase; MAPK8/JNK: mitogen-activated protein kinase 8; MTOR: mechanistic target of rapamycin kinase; MTORC: mechanistic target of rapamycin complex; NAFLD: nonalcoholic fatty liver disease; NFKB: nuclear factor kappa B; OLR1/LOX-1: oxidized low density lipoprotein receptor 1; oxLDL: oxidized low-density lipoproteins; PA: palmitic acid; PCOS: polycystic ovary syndrome; PF: primary follicle; PGC: primordial germ cell; PI3K: phosphoinositide 3-kinase; PMF: primordial follicle; ROS: reactive oxygen species; RP: resting pool; SIRT1: sirtuin 1; SQSTM1/p62: sequestosome 1; T2DM: type 2 diabetes mellitus; TC: theca cell; TUG1: taurine up-regulated 1.
Collapse
Affiliation(s)
- Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute CSIR-Central Drug Research Institute, Lucknow, India
| | - Vaibhave Ubba
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Rajesh K. Jha
- Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
| | - Jiaur R. Gayen
- Pharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute CSIR-Central Drug Research Institute, Lucknow, India
- Academy of Scientific and Innovative Research, Ghaziabad, India
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India
| |
Collapse
|
|
27
|
Liao Y, Xu J, Qin B, Shi J, Qin C, Xie F, Ou S, Tang J, Wang W, Wu F, Bai L. Advanced oxidation protein products impair autophagic flux in macrophage by inducing lysosomal dysfunction via activation of PI3K-Akt-mTOR pathway in Crohn's disease. Free Radic Biol Med 2021; 172:33-47. [PMID: 34029692 DOI: 10.1016/j.freeradbiomed.2021.05.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/26/2021] [Accepted: 05/08/2021] [Indexed: 12/14/2022]
Abstract
Dysfunction in macrophages is involved in the pathogenesis of various diseases, including Crohn's disease (CD). Previously, we found that advanced oxidation protein products (AOPPs) were predominantly deposited in macrophages in the intestinal lamina propria of CD patients. However, whether AOPPs contributes to macrophage dysfunction in CD and the underlying mechanism remains unknown. This study aimed to investigate the effects of AOPPs on macrophages functions in CD. In the present study, we discovered increased AOPPs levels were positively correlated with impaired autophagy in macrophages of CD patients. AOPPs could impair autophagic flux by inducing lysosomal dysfunction in RAW264.7 cell line and macrophages in AOPPs-treated mice, evidenced by increased number of autophagosomes, blocked degradation of autophagy-related proteins (LC3B-II and SQSTM1/p62), and decreased activity of lysosomal proteolytic enzymes after AOPPs challenge. Besides, AOPPs could also promote M1 polarization in RAW264.7 cells and bone marrow derived macrophages (BMDMs) in AOPPs-treated mice. In addition, our study revealed that PI3K-AKT-mTOR-TFEB pathway was activated by AOPPs in macrophages. Inhibition of the PI3K pathway effectively alleviated AOPPs-induced autophagy impairment and M1 polarization both in vitro and in vivo, thus reducing intestinal inflammation in AOPPs-challenged mice. Together, this study demonstrates that AOPPs-induced autophagy impairment in macrophages is crucial for CD progression.
Collapse
Affiliation(s)
- Yan Liao
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Jiahui Xu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510260, China
| | - Biyan Qin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Jie Shi
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Caolitao Qin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Fang Xie
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Shiyu Ou
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Jing Tang
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Weidong Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Fengfei Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Lan Bai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
| |
Collapse
|
|
28
|
Frendo-Cumbo S, Tokarz VL, Bilan PJ, Brumell JH, Klip A. Communication Between Autophagy and Insulin Action: At the Crux of Insulin Action-Insulin Resistance? Front Cell Dev Biol 2021; 9:708431. [PMID: 34336862 PMCID: PMC8319997 DOI: 10.3389/fcell.2021.708431] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/24/2021] [Indexed: 01/18/2023] Open
Abstract
Insulin is a paramount anabolic hormone that promotes energy-storage in adipose tissue, skeletal muscle and liver, and these responses are significantly attenuated in insulin resistance leading to type 2 diabetes. Contrasting with insulin's function, macroautophagy/autophagy is a physiological mechanism geared to the degradation of intracellular components for the purpose of energy production, building-block recycling or tissue remodeling. Given that both insulin action and autophagy are dynamic phenomena susceptible to the influence of nutrient availability, it is perhaps not surprising that there is significant interaction between these two major regulatory mechanisms. This review examines the crosstalk between autophagy and insulin action, with specific focus on dysregulated autophagy as a cause or consequence of insulin resistance.
Collapse
Affiliation(s)
- Scott Frendo-Cumbo
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Victoria L. Tokarz
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
| | - Philip J. Bilan
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
| | - John H. Brumell
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- SickKids Inflammatory Bowel Disease (IBD) Centre, Hospital for Sick Children, Toronto, ON, Canada
| | - Amira Klip
- Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada
- Department of Physiology, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
29
|
Bjørklund G, Peana M, Pivina L, Dosa A, Aaseth J, Semenova Y, Chirumbolo S, Medici S, Dadar M, Costea DO. Iron Deficiency in Obesity and after Bariatric Surgery. Biomolecules 2021; 11:biom11050613. [PMID: 33918997 PMCID: PMC8142987 DOI: 10.3390/biom11050613] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 04/10/2021] [Accepted: 04/16/2021] [Indexed: 02/06/2023] Open
Abstract
Iron deficiency (ID) is particularly frequent in obese patients due to increased circulating levels of acute-phase reactant hepcidin and adiposity-associated inflammation. Inflammation in obese subjects is closely related to ID. It induces reduced iron absorption correlated to the inhibition of duodenal ferroportin expression, parallel to the increased concentrations of hepcidin. Obese subjects often get decreased inflammatory response after bariatric surgery, accompanied by decreased serum hepcidin and therefore improved iron absorption. Bariatric surgery can induce the mitigation or resolution of obesity-associated complications, such as hypertension, insulin resistance, diabetes mellitus, and hyperlipidemia, adjusting many parameters in the metabolism. However, gastric bypass surgery and sleeve gastrectomy can induce malabsorption and may accentuate ID. The present review explores the burden and characteristics of ID and anemia in obese patients after bariatric surgery, accounting for gastric bypass technique (Roux-en-Y gastric bypass-RYGB) and sleeve gastrectomy (SG). After bariatric surgery, obese subjects' iron status should be monitored, and they should be motivated to use adequate and recommended iron supplementation.
Collapse
Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine, Toften 24, 8610 Mo i Rana, Norway
- Correspondence: (G.B.); (M.P.)
| | - Massimiliano Peana
- Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy;
- Correspondence: (G.B.); (M.P.)
| | - Lyudmila Pivina
- Department of Neurology, Ophthalmology and Otolaryngology, Semey Medical University, 071400 Semey, Kazakhstan; (L.P.); (Y.S.)
- CONEM Kazakhstan Environmental Health and Safety Research Group, Semey Medical University, 071400 Semey, Kazakhstan
| | - Alexandru Dosa
- Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania; (A.D.); (D.-O.C.)
| | - Jan Aaseth
- Research Department, Innlandet Hospital Trust, 2380 Brumunddal, Norway;
| | - Yuliya Semenova
- Department of Neurology, Ophthalmology and Otolaryngology, Semey Medical University, 071400 Semey, Kazakhstan; (L.P.); (Y.S.)
- CONEM Kazakhstan Environmental Health and Safety Research Group, Semey Medical University, 071400 Semey, Kazakhstan
| | - Salvatore Chirumbolo
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy;
- CONEM Scientific Secretary, 37134 Verona, Italy
| | - Serenella Medici
- Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100 Sassari, Italy;
| | - Maryam Dadar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj 31975/148, Iran;
| | - Daniel-Ovidiu Costea
- Faculty of Medicine, Ovidius University of Constanta, 900470 Constanta, Romania; (A.D.); (D.-O.C.)
| |
Collapse
|
|
30
|
Kim J, Kim SH, Kang H, Lee S, Park SY, Cho Y, Lim YM, Ahn JW, Kim YH, Chung S, Choi CS, Jang YJ, Park HS, Heo Y, Kim KH, Lee MS. TFEB-GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response. Nat Metab 2021; 3:410-427. [PMID: 33758420 DOI: 10.1038/s42255-021-00368-w] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 02/18/2021] [Indexed: 01/01/2023]
Abstract
TFEB, a key regulator of lysosomal biogenesis and autophagy, is induced not only by nutritional deficiency but also by organelle stress. Here, we find that Tfeb and its downstream genes are upregulated together with lipofuscin accumulation in adipose tissue macrophages (ATMs) of obese mice or humans, suggestive of obesity-associated lysosomal dysfunction/stress in ATMs. Macrophage-specific TFEB-overexpressing mice display complete abrogation of diet-induced obesity, adipose tissue inflammation and insulin resistance, which is independent of autophagy, but dependent on TFEB-induced GDF15 expression. Palmitic acid induces Gdf15 expression through lysosomal Ca2+-mediated TFEB nuclear translocation in response to lysosomal stress. In contrast, mice fed a high-fat diet with macrophage-specific Tfeb deletion show aggravated adipose tissue inflammation and insulin resistance, accompanied by reduced GDF15 level. Finally, we observe activation of TFEB-GDF15 in ATMs of obese humans as a consequence of lysosomal stress. These findings highlight the importance of the TFEB-GDF15 axis as a lysosomal stress response in obesity or metabolic syndrome and as a promising therapeutic target for treatment of these conditions.
Collapse
Affiliation(s)
- Jinyoung Kim
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Seong Hun Kim
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
- Discovery 1 team, GI Innovation, Seoul, Korea
| | - Hyereen Kang
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Soyeon Lee
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Shi-Young Park
- Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon, Korea
| | - Yoonil Cho
- Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon, Korea
| | - Yu-Mi Lim
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Woong Ahn
- Brain Korea 21 Project for Medical Science, Department of Physiology, Yonsei University College of Medicine, Seoul, Korea
| | - Young-Hwan Kim
- Brain Korea 21 Project for Medical Science, Department of Physiology, Yonsei University College of Medicine, Seoul, Korea
| | - Seungsoo Chung
- Brain Korea 21 Project for Medical Science, Department of Physiology, Yonsei University College of Medicine, Seoul, Korea
| | - Cheol Soo Choi
- Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine, Incheon, Korea
- Endocrinology, Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
| | - Yeon Jin Jang
- Department of Physiology, University of Ulsan College of Medicine, Seoul, Korea
| | - Hye Soon Park
- Department of Family Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Yoonseok Heo
- Department of General Surgery, Inha University, College of Medicine, Incheon, Korea
| | - Kook Hwan Kim
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
- Discovery 1 team, GI Innovation, Seoul, Korea.
| | - Myung-Shik Lee
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
| |
Collapse
|
|
31
|
Maisonneuve C, Tsang DKL, Foerster EG, Robert LM, Mukherjee T, Prescott D, Tattoli I, Lemire P, Winer DA, Winer S, Streutker CJ, Geddes K, Cadwell K, Ferrero RL, Martin A, Girardin SE, Philpott DJ. Nod1 promotes colorectal carcinogenesis by regulating the immunosuppressive functions of tumor-infiltrating myeloid cells. Cell Rep 2021; 34:108677. [PMID: 33503439 DOI: 10.1016/j.celrep.2020.108677] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 11/23/2020] [Accepted: 12/30/2020] [Indexed: 01/01/2023] Open
Abstract
Pioneering studies from the early 1980s suggested that bacterial peptidoglycan-derived muramyl peptides (MPs) could exert either stimulatory or immunosuppressive functions depending, in part, on chronicity of exposure. However, this Janus-faced property of MPs remains largely unexplored. Here, we demonstrate the immunosuppressive potential of Nod1, the bacterial sensor of diaminopimelic acid (DAP)-containing MPs. Using a model of self-limiting peritonitis, we show that systemic Nod1 activation promotes an autophagy-dependent reprogramming of macrophages toward an alternative phenotype. Moreover, Nod1 stimulation induces the expansion of myeloid-derived suppressor cells (MDSCs) and maintains their immunosuppressive potential via arginase-1 activity. Supporting the role of MDSCs and tumor-associated macrophages in cancer, we demonstrate that myeloid-intrinsic Nod1 expression sustains intra-tumoral arginase-1 levels to foster an immunosuppressive and tumor-permissive microenvironment during colorectal cancer (CRC) development. Our findings support the notion that bacterial products, via Nod1 detection, modulate the immunosuppressive activity of myeloid cells and fuel tumor progression in CRC.
Collapse
Affiliation(s)
- Charles Maisonneuve
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Derek K L Tsang
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | | | | | - Tapas Mukherjee
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Dave Prescott
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Ivan Tattoli
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Paul Lemire
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Daniel A Winer
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pathology, Toronto General Hospital, University of Toronto, Toronto, ON M5S 1A8, Canada; Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Shawn Winer
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Saint Michael's Hospital, Toronto, ON M5B 1W8, Canada
| | - Catherine J Streutker
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Saint Michael's Hospital, Toronto, ON M5B 1W8, Canada
| | - Kaoru Geddes
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Ken Cadwell
- Kimmel Center for Biology and Medicine at the Skirball Institute, New York Grossman University Grossman School of Medicine, New York, NY 10016, USA; Department of Microbiology, New York University Grossman School of Medicine, New York, NY 10016, USA; Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Richard L Ferrero
- Department of Molecular and Translational Sciences, Monash University, Clayton, 3800 VIC, Australia; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, 3168 VIC, Australia; Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, 3800 VIC, Australia
| | - Alberto Martin
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Stephen E Girardin
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
| |
Collapse
|
|
32
|
García-Pérez BE, González-Rojas JA, Salazar MI, Torres-Torres C, Castrejón-Jiménez NS. Taming the Autophagy as a Strategy for Treating COVID-19. Cells 2020; 9:E2679. [PMID: 33322168 PMCID: PMC7764362 DOI: 10.3390/cells9122679] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/01/2020] [Accepted: 12/08/2020] [Indexed: 02/06/2023] Open
Abstract
Currently, an efficient treatment for COVID-19 is still unavailable, and people are continuing to die from complications associated with SARS-CoV-2 infection. Thus, the development of new therapeutic approaches is urgently needed, and one alternative is to target the mechanisms of autophagy. Due to its multifaceted role in physiological processes, many questions remain unanswered about the possible advantages of inhibiting or activating autophagy. Based on a search of the literature in this field, a novel analysis has been made to highlight the relation between the mechanisms of autophagy in antiviral and inflammatory activity in contrast with those of the pathogenesis of COVID-19. The present analysis reveals a remarkable coincidence between the uncontrolled inflammation triggered by SARS-CoV-2 and autophagy defects. Particularly, there is conclusive evidence about the substantial contribution of two concomitant factors to the development of severe COVID-19: a delayed or absent type I and III interferon (IFN-I and IFN-III) response together with robust cytokine and chemokine production. In addition, a negative interplay exists between autophagy and an IFN-I response. According to previous studies, the clinical decision to inhibit or activate autophagy should depend on the underlying context of the pathological timeline of COVID-19. Several treatment options are herein discussed as a guide for future research on this topic.
Collapse
Affiliation(s)
- Blanca Estela García-Pérez
- Department of Microbiology, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico; (J.A.G.-R.), (M.I.S.)
| | - Juan Antonio González-Rojas
- Department of Microbiology, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico; (J.A.G.-R.), (M.I.S.)
| | - Ma Isabel Salazar
- Department of Microbiology, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, Alcaldía Miguel Hidalgo, Mexico City 11340, Mexico; (J.A.G.-R.), (M.I.S.)
| | - Carlos Torres-Torres
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Ingeniería Mecánica y Eléctrica, Unidad Zacatenco, Instituto Politécnico Nacional, Gustavo A. Madero, Mexico City 07738, Mexico;
| | - Nayeli Shantal Castrejón-Jiménez
- Área Académica de Medicina Veterinaria y Zootecnia, Instituto de Ciencias Agropecuarias-Universidad Autónoma del Estado de Hidalgo, Av. Universidad km. 1. Exhacienda de Aquetzalpa A.P. 32, Tulancingo, Hidalgo 43600, Mexico;
| |
Collapse
|
|
33
|
DE Nunzio C, Giglio S, Baldassarri V, Cirombella R, Mallel G, Nacchia A, Tubaro A, Vecchione A. Impairment of autophagy may represent the molecular mechanism behind the relationship between obesity and inflammation in patients with BPH and LUTS. Minerva Urol Nephrol 2020; 73:631-637. [PMID: 33200897 DOI: 10.23736/s2724-6051.20.03992-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Aim of this study was to evaluate the roles of inflammation and autophagy in obese patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). METHODS We analyzed 150 surgical specimens from patients underwent transurethral resection of the prostate (TURP) for LUTS/BPH (Median age 70.3±8.1 years, median BMI 25.7±4.0 kg/m2 and median PSA 6.0±5.4 ng/mL). All surgical specimens were investigated for the presence inflammatory infiltrates, according to the standardized classification of chronic prostatitis of the National Institute of Health. The inflammatory score (IS Score) was calculated. High IS score was defined as ≥7. Each sample was stained for anti-LC3B (cell signaling) and for anti-P62/SQSTM1 (MBL) according to manufacturer's suggestions and scored as follow: 0 (no dots); 1 (detectable dots in 5-25% of cells); 2 (readily detectable dots in 25-75% of cells); 3 (dots in >75% of cells). High percentage of p62 or LC3B was defined as >25%, whereas low percentage of p62 or LC3B was defined as <25% of cells with dots. RESULTS Overall 74/150 (49.3%) patients were overweight or obese (BMI >25 kg/m2). Obese patients presented a higher inflammatory score. Obese/overweight patients presented a lower percentage of LC3B (58/74; 78.4%) and higher of p62 (49/74; 66.2%) compared to those of normal weight, which it means a deactivated autophagy (P<0.05). At multivariate analysis LC3B (OR=0.22; CI: 0.069-0.70; P=0.01) percentage and BMI (OR=1.118; CI: 1.001-1.250; P=0.04) were independent risk factors of prostatic inflammation (IS≥7). CONCLUSIONS Here we confirm the association between obesity and prostatic inflammatory infiltrates and present the first evidence of autophagy deregulation in obese patients with LUTS/BPH. Further studies should better investigate this relationship and provide new possible therapeutic targets.
Collapse
Affiliation(s)
| | - Simona Giglio
- Unit of Urology and Surgical Pathology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | | | - Roberto Cirombella
- Unit of Urology and Surgical Pathology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | - Giuseppe Mallel
- Unit of Urology and Surgical Pathology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | | | - Andrea Tubaro
- Sant'Andrea Hospital, Sapienza University, Rome, Italy
| | - Andrea Vecchione
- Sant'Andrea Hospital, Sapienza University, Rome, Italy.,Unit of Urology and Surgical Pathology, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University, Rome, Italy
| |
Collapse
|
|
34
|
The Role of Metabolic Enzymes in the Regulation of Inflammation. Metabolites 2020; 10:metabo10110426. [PMID: 33114536 PMCID: PMC7693344 DOI: 10.3390/metabo10110426] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/19/2020] [Accepted: 10/19/2020] [Indexed: 12/26/2022] Open
Abstract
Immune cells undergo dramatic metabolic reprogramming in response to external stimuli. These metabolic pathways, long considered as simple housekeeping functions, are increasingly understood to critically regulate the immune response, determining the activation, differentiation, and downstream effector functions of both lymphoid and myeloid cells. Within the complex metabolic networks associated with immune activation, several enzymes play key roles in regulating inflammation and represent potential therapeutic targets in human disease. In some cases, these enzymes control flux through pathways required to meet specific energetic or metabolic demands of the immune response. In other cases, key enzymes control the concentrations of immunoactive metabolites with direct roles in signaling. Finally, and perhaps most interestingly, several metabolic enzymes have evolved moonlighting functions, with roles in the immune response that are entirely independent of their conventional enzyme activities. Here, we review key metabolic enzymes that critically regulate inflammation, highlighting mechanistic insights and opportunities for clinical intervention.
Collapse
|
|
35
|
Jeong JH, Choi EB, Jang HM, Ahn YJ, An HS, Lee JY, Park G, Jeong EA, Shin HJ, Lee J, Kim KE, Roh GS. The Role of SHIP1 on Apoptosis and Autophagy in the Adipose Tissue of Obese Mice. Int J Mol Sci 2020; 21:ijms21197225. [PMID: 33007882 PMCID: PMC7582772 DOI: 10.3390/ijms21197225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 09/28/2020] [Indexed: 01/22/2023] Open
Abstract
Obesity-induced adipocyte apoptosis promotes inflammation and insulin resistance. Src homology domain-containing inositol 5'-phosphatase 1 (SHIP1) is a key factor of apoptosis and inflammation. However, the role of SHIP1 in obesity-induced adipocyte apoptosis and autophagy is unclear. We found that diet-induced obesity (DIO) mice have significantly greater crown-like structures and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive cells than ob/ob or control mice. Using RNA sequencing (RNA-seq) analysis, we identified that the apoptosis- and inflammation-related gene Ship1 is upregulated in DIO and ob/ob mice compared with control mice. In particular, DIO mice had more SHIP1-positive macrophages and lysosomal-associated membrane protein 1 (LAMP1) as well as a higher B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 ratio compared with ob/ob or control mice. Furthermore, caloric restriction attenuated adipose tissue inflammation, apoptosis, and autophagy by reversing increases in SHIP1-associated macrophages, Bax/Bcl2-ratio, and autophagy in DIO and ob/ob mice. These results demonstrate that DIO, not ob/ob, aggravates adipocyte inflammation, apoptosis, and autophagy due to differential SHIP1 expression. The evidence of decreased SHIP1-mediated inflammation, apoptosis, and autophagy indicates new therapeutic approaches for obesity-induced chronic inflammatory diseases.
Collapse
|
|
36
|
Sanguisorba officinalis L. derived from herbal medicine prevents intestinal inflammation by inducing autophagy in macrophages. Sci Rep 2020; 10:9972. [PMID: 32561763 PMCID: PMC7305163 DOI: 10.1038/s41598-020-65306-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 05/04/2020] [Indexed: 01/05/2023] Open
Abstract
Disturbed activation of autophagy is implicated in the pathogenesis of inflammatory bowel disease. Accordingly, several autophagy-related genes have been identified as Crohn's disease susceptibility genes. We screened the autophagy activators from a library including 3,922 natural extracts using a high-throughput assay system. The extracts identified as autophagy activators were administered to mice with 2% dextran sodium sulfate (DSS). Among the autophagy inducers, Sanguisorba officinalis L. (SO) suppressed DSS-induced colitis. To identify the mechanism by which SO ameliorates colitis, epithelial cell and innate myeloid cells-specific Atg7-deficient mice (Villin-cre; Atg7f/f and LysM-cre; Atg7f/f mice, respectively) were analyzed. SO-mediated inhibition of colitis was observed in Villin-cre; Atg7f/f mice. However, SO and a mixture of its components including catechin acid, ellagic acid, gallic acid, and ziyuglycoside II (Mix4) did not suppressed colitis in LysM-cre; Atg7f/f mice. In large intestinal macrophages (Mφ) of Atg7f/f mice, SO and Mix4 upregulated the expression of marker genes of anti-inflammatory Mφ including Arg1, Cd206, and Relma. However, these alterations were not induced in LysM-cre; Atg7f/f mice. These findings indicate that SO and its active components ameliorate DSS-induced colitis by providing intestinal Mφ with anti-inflammatory profiles via promotion of Atg7-dependent autophagy.
Collapse
|
|
37
|
Clemente-Postigo M, Tinahones A, El Bekay R, Malagón MM, Tinahones FJ. The Role of Autophagy in White Adipose Tissue Function: Implications for Metabolic Health. Metabolites 2020; 10:metabo10050179. [PMID: 32365782 PMCID: PMC7281383 DOI: 10.3390/metabo10050179] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/27/2020] [Accepted: 04/28/2020] [Indexed: 02/07/2023] Open
Abstract
White adipose tissue (WAT) is a highly adaptive endocrine organ that continuously remodels in response to nutritional cues. WAT expands to store excess energy by increasing adipocyte number and/or size. Failure in WAT expansion has serious consequences on metabolic health resulting in altered lipid, glucose, and inflammatory profiles. Besides an impaired adipogenesis, fibrosis and low-grade inflammation also characterize dysfunctional WAT. Nevertheless, the precise mechanisms leading to impaired WAT expansibility are yet unresolved. Autophagy is a conserved and essential process for cellular homeostasis, which constitutively allows the recycling of damaged or long-lived proteins and organelles, but is also highly induced under stress conditions to provide nutrients and remove pathogens. By modulating protein and organelle content, autophagy is also essential for cell remodeling, maintenance, and survival. In this line, autophagy has been involved in many processes affected during WAT maladaptation, including adipogenesis, adipocyte, and macrophage function, inflammatory response, and fibrosis. WAT autophagy dysregulation is related to obesity and diabetes. However, it remains unclear whether WAT autophagy alteration in obese and diabetic patients are the cause or the consequence of WAT malfunction. In this review, current data regarding these issues are discussed, focusing on evidence from human studies.
Collapse
Affiliation(s)
- Mercedes Clemente-Postigo
- Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)-Reina Sofia University Hospital, University of Cordoba, Edificio IMIBIC, Av. Menéndez Pidal s/n, 14004 Córdoba, Spain;
- Correspondence: (M.C.-P.); (F.J.T.); Tel.: +34-957213728 (M.C.-P.); +34-951032648 (F.J.T.)
| | - Alberto Tinahones
- Unidad de Gestión Clínica de Endocrinología y Nutrición (Hospital Universitario Virgen de la Victoria), Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Campus Teatinos s/n, 29010 Málaga, Spain;
| | - Rajaa El Bekay
- Unidad de Gestión Clínica de Endocrinología y Nutrición (Hospital Universitario Regional de Málaga), Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Campus Teatinos s/n, 29010 Málaga, Spain;
- Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - María M. Malagón
- Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)-Reina Sofia University Hospital, University of Cordoba, Edificio IMIBIC, Av. Menéndez Pidal s/n, 14004 Córdoba, Spain;
- Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Francisco J. Tinahones
- Unidad de Gestión Clínica de Endocrinología y Nutrición (Hospital Universitario Virgen de la Victoria), Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Campus Teatinos s/n, 29010 Málaga, Spain;
- Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Correspondence: (M.C.-P.); (F.J.T.); Tel.: +34-957213728 (M.C.-P.); +34-951032648 (F.J.T.)
| |
Collapse
|
|
38
|
Festuccia WT. Regulation of Adipocyte and Macrophage Functions by mTORC1 and 2 in Metabolic Diseases. Mol Nutr Food Res 2020; 65:e1900768. [DOI: 10.1002/mnfr.201900768] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 02/06/2020] [Indexed: 12/13/2022]
Affiliation(s)
- William T. Festuccia
- Department of Physiology and Biophysics Institute of Biomedical Sciences University of Sao Paulo Sao Paulo 05508000 Brazil
| |
Collapse
|
|
39
|
Koschade SE, Brandts CH. Selective Autophagy in Normal and Malignant Hematopoiesis. J Mol Biol 2020; 432:261-282. [DOI: 10.1016/j.jmb.2019.06.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 06/18/2019] [Accepted: 06/18/2019] [Indexed: 12/16/2022]
|
|
40
|
Zhao D, Zhang S, Wang X, Gao D, Liu J, Cao K, Chen L, Liu R, Liu J, Long J. ATG7 regulates hepatic Akt phosphorylation through the c-JUN/PTEN pathway in high fat diet-induced metabolic disorder. FASEB J 2019; 33:14296-14306. [PMID: 31645130 DOI: 10.1096/fj.201901414rr] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Accepted: 09/17/2019] [Indexed: 12/12/2022]
Abstract
Growing evidence has suggested that autophagy-related protein 7 (ATG7) plays an important role in insulin signaling, but the mechanism of ATG7 in hepatic insulin sensitivity is not fully understood. The purpose of the present study is to clarify the underlying molecular mechanisms of ATG7 in obesity development. Serum and liver samples from mice fed a high fat diet (HFD) were evaluated for metabolic profile data and ATG expressions during obesity development. We found that compared with other ATGs, ATG7 expression increased earlier with lower hepatic insulin sensitivity in the 4-wk HFD-fed mice. For in vitro analyses, silencing ATG7 significantly up-regulated insulin-stimulated phosphorylation of protein kinase B (Akt) and down-regulated phosphatase and tension homolog deleted on chromosome ten (PTEN) in HepG2 cells. Replenishing PTEN to ATG7-silenced hepatocytes restored the phosphorylated Akt level. Furthermore, ATG7 silencing led to higher c-JUN expression, which transcriptionally reduced PTEN expression. These results reveal a novel mechanism by which ATG7 regulates Akt phosphorylation via the c-JUN/PTEN pathway at the early stage of HFD-induced metabolic disorder.-Zhao, D., Zhang, S., Wang, X., Gao, D., Liu, J., Cao, K., Chen, L., Liu, R., Liu, J., Long, J. ATG7 regulates hepatic Akt phosphorylation through the c-JUN/PTEN pathway in high fat diet-induced metabolic disorder.
Collapse
Affiliation(s)
- Daina Zhao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Shuangxi Zhang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Xueqiang Wang
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Dan Gao
- Department of Anatomy, Histology, and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China
| | - Jing Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Ke Cao
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Lei Chen
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Run Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiankang Liu
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiangang Long
- Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| |
Collapse
|
|
41
|
Javaheri A, Bajpai G, Picataggi A, Mani S, Foroughi L, Evie H, Kovacs A, Weinheimer CJ, Hyrc K, Xiao Q, Ballabio A, Lee JM, Matkovich SJ, Razani B, Schilling JD, Lavine KJ, Diwan A. TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy. JCI Insight 2019; 4:127312. [PMID: 31672943 DOI: 10.1172/jci.insight.127312] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 09/25/2019] [Indexed: 12/13/2022] Open
Abstract
Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1β secretion are implicated in myocardial infarction (MI) and resultant heart failure; however, little is known about how macrophage lysosomes regulate these processes. In mice subjected to cardiac ischemia/reperfusion (IR) injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal impairment in macrophages. Inducible macrophage-specific overexpression of transcription factor EB (TFEB), a master regulator of lysosome biogenesis (Mϕ-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor Mϕ-TFEB-mediated attenuation of postinfarction myocardial dysfunction required intact ATG5-dependent macroautophagy (hereafter termed "autophagy"). RNA-seq of flow-sorted macrophages postinfarction revealed that Mϕ-TFEB upregulated key targets involved in lysosomal lipid metabolism. Specifically, inhibition of the TFEB target, lysosomal acid lipase, in vivo abrogated the beneficial effect of Mϕ-TFEB on postinfarction ventricular function. Thus, TFEB reprograms macrophage lysosomal lipid metabolism to attenuate remodeling after IR, suggesting an alternative paradigm whereby lysosome function affects inflammation.
Collapse
Affiliation(s)
- Ali Javaheri
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Geetika Bajpai
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Antonino Picataggi
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Smrithi Mani
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Layla Foroughi
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Hosannah Evie
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Attila Kovacs
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Carla J Weinheimer
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | | | - Qingli Xiao
- Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Andrea Ballabio
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.,Medical Genetics, Department of Medical and Translational Sciences, Federico II University, Naples, Italy.,Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.,Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Jin-Moo Lee
- Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, Missouri, USA
| | - Scot J Matkovich
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Babak Razani
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine.,John Cochran Veterans Affairs Medical Center, Saint Louis, Missouri, USA
| | - Joel D Schilling
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Kory J Lavine
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine
| | - Abhinav Diwan
- Cardiovascular Division and Center for Cardiovascular Research, Department of Medicine.,John Cochran Veterans Affairs Medical Center, Saint Louis, Missouri, USA
| |
Collapse
|
|
42
|
Abstract
Significance: Alterations in adipose tissue function have profound consequences on whole body energy homeostasis because this tissue is central for fat accumulation, energy expenditure, glucose and insulin metabolism, and hormonal regulation. With the obesity reaching epidemic proportions globally, it is important to understand the mechanisms leading to adipose tissue malfunction. Recent Advances: Autophagy has originally been viewed as an adaptive response to cellular stress, but in recent years this process was shown to regulate important cellular processes. In adipose tissue, autophagy is a key regulator of white adipose tissue (WAT) and brown adipose tissue (BAT) adipogenesis, and dysregulated autophagy impairs fat accumulation both in vitro and in vivo. Animal studies have also suggested an important role for autophagy and mitophagy during the transition from beige to white fat. Human studies have provided evidence for altered autophagy in WAT, and these alterations correlated with the degree of insulin resistance. Critical Issues: Despite these important advances in the study of autophagy in adipose tissue, we still do not understand the physiological role of autophagy in mature white and brown adipocytes. Furthermore, several human studies involving autophagy assessment were performed on whole adipose tissue, which complicates the interpretation of the results considering the cellular heterogeneity of this tissue. Future Directions: Future studies will undoubtedly expand our understanding of the role of autophagy in fully differentiated adipocytes, and uncover novel cross-talks between this tissue and other organs in regulating lipid metabolism, redox signaling, energy homeostasis, and insulin sensitivity.
Collapse
Affiliation(s)
- Maroua Ferhat
- Program in Molecular Medicine, Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, Utah
| | - Katsuhiko Funai
- Program in Molecular Medicine, Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, Utah
| | - Sihem Boudina
- Program in Molecular Medicine, Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, Utah
| |
Collapse
|
|
43
|
Li X, Qi J, Zhu Q, He Y, Wang Y, Lu Y, Wu H, Sun Y. The role of androgen in autophagy of granulosa cells from PCOS. Gynecol Endocrinol 2019; 35:669-672. [PMID: 31056990 DOI: 10.1080/09513590.2018.1540567] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
Abstract
Hyperandrogenism is one of the most common causes for anovulation in women and increases the risk for metabolic disorder in PCOS patients. Autophagy plays an important role in dysfunction of endocrine and anovulation. However, the relationship between hyperandrogenism and autophagy in human granulosa cells of PCOS patients remains unclear. By collecting granulosa cells from PCOS patients and non-PCOS patients, we found that the abundance of autophagy-related genes ATG5, ATG7, BECN1 mRNA and the ratio of autophagy marker protein light chain 3B II/I (LC3 II/I) were significantly increased whereas the abundance of the autophagy substrate SQSTM1/p62 was decreased in ovarian granulosa cells from PCOS patients. Furthermore, we demonstrated that BECN1 mRNA abundance in human granulosa cells positively correlated with the basal level of serum total testosterone and androgen up-regulated the abundance of BECN1 mRNA and the ratio of LC3II/LC3I in a dose-dependent manner in cultured granulosa cells. These observations indicated that androgen-induced activation of autophagy may play an important role in the development of PCOS and to explore the autophagy mechanisms involved in PCOS yield new insight into the pathophysiology and therapy of the disorder.
Collapse
Affiliation(s)
- Xiaoxue Li
- a Center for Reproductive Medicine , School of Medicine , Renji Hospital, Shanghai Jiao Tong University , Shanghai , PR China
- b Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics , Shanghai , PR China
| | - Jia Qi
- a Center for Reproductive Medicine , School of Medicine , Renji Hospital, Shanghai Jiao Tong University , Shanghai , PR China
- b Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics , Shanghai , PR China
| | - Qinling Zhu
- a Center for Reproductive Medicine , School of Medicine , Renji Hospital, Shanghai Jiao Tong University , Shanghai , PR China
- b Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics , Shanghai , PR China
| | - Yaqiong He
- a Center for Reproductive Medicine , School of Medicine , Renji Hospital, Shanghai Jiao Tong University , Shanghai , PR China
- b Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics , Shanghai , PR China
| | - Yuan Wang
- a Center for Reproductive Medicine , School of Medicine , Renji Hospital, Shanghai Jiao Tong University , Shanghai , PR China
- b Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics , Shanghai , PR China
| | - Yao Lu
- a Center for Reproductive Medicine , School of Medicine , Renji Hospital, Shanghai Jiao Tong University , Shanghai , PR China
- b Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics , Shanghai , PR China
| | - Hasiximuke Wu
- a Center for Reproductive Medicine , School of Medicine , Renji Hospital, Shanghai Jiao Tong University , Shanghai , PR China
- b Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics , Shanghai , PR China
| | - Yun Sun
- a Center for Reproductive Medicine , School of Medicine , Renji Hospital, Shanghai Jiao Tong University , Shanghai , PR China
- b Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics , Shanghai , PR China
| |
Collapse
|
|
44
|
Suppression of Brown Adipocyte Autophagy Improves Energy Metabolism by Regulating Mitochondrial Turnover. Int J Mol Sci 2019; 20:ijms20143520. [PMID: 31323770 PMCID: PMC6678363 DOI: 10.3390/ijms20143520] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 07/15/2019] [Accepted: 07/16/2019] [Indexed: 12/18/2022] Open
Abstract
The high abundance of mitochondria and the expression of mitochondrial uncoupling protein 1 (UCP1) confer upon brown adipose tissue (BAT) the unique capacity to convert chemical energy into heat at the expense of ATP synthesis. It was long believed that BAT is present only in infants, and so, it was not considered as a potential therapeutic target for metabolic syndrome; however, the discovery of metabolically active BAT in adult humans has re-stimulated interest in the contributions of BAT metabolic regulation and dysfunction to health and disease. Here we demonstrate that brown adipocyte autophagy plays a critical role in the regulation BAT activity and systemic energy metabolism. Mice deficient in brown adipocyte autophagy due to BAT-specific deletion of Atg7-a gene essential for autophagosome generation-maintained higher mitochondrial content due to suppression of mitochondrial clearance and exhibited improved insulin sensitivity and energy metabolism. Autophagy was upregulated in BAT of older mice compared to younger mice, suggesting its involvement in the age-dependent decline of BAT activity and metabolic rate. These findings suggest that brown adipocyte autophagy plays a crucial role in metabolism and that targeting this pathway may be a potential therapeutic strategy for metabolic syndrome.
Collapse
|
|
45
|
Ginkgo Biloba Leaf Extract Attenuates Atherosclerosis in Streptozotocin-Induced Diabetic ApoE-/- Mice by Inhibiting Endoplasmic Reticulum Stress via Restoration of Autophagy through the mTOR Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8134678. [PMID: 31080547 PMCID: PMC6442448 DOI: 10.1155/2019/8134678] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 12/03/2018] [Accepted: 12/13/2018] [Indexed: 12/26/2022]
Abstract
Background There is a crosstalk between endoplasmic reticulum stress (ERS) and autophagy, and autophagy could attenuate endoplasmic reticulum stress-mediated apoptosis. Ginkgo biloba leaf extract (GBE) exerts vascular protection functions. The purpose of the present study is to investigate the role of autophagy in diabetic atherosclerosis (AS) and the effect of GBE on autophagy and ERS. Methods Network pharmacology was utilized to predict the targets and pathways of the active chemical compounds of Gingko biloba leaf to attenuate AS. ApoE−/− mice were rendered diabetic by intraperitoneal ingestion with streptozotocin combined with a high-fat diet. The diabetic mice were divided into five groups: model group, atorvastatin group, rapamycin group, and low- and high-dose GBE groups. Serum and tissue markers of autophagy or ERS markers, including the protein expression, were examined. Results The mammalian target of rapamycin (mTOR) and NF-κB signaling pathways were targeted by the active chemical compounds of GBE to attenuate AS predicted by network pharmacology. GBE reduced the plaque area/lumen area and the plaque lipid deposition area/intimal area and inhibited the expressions of CD68, MMP2, and MMP9. Rapamycin and GBE inhibited the expression of mTOR and SQSTM1/p62 which increased in the aorta of diabetic mice. In addition, GBE reduced the expression of ERS markers in diabetic mice. GBE reduced the serum lipid metabolism levels, blood glucose, and inflammatory cytokines. Conclusion Impaired autophagy and overactive endoplasmic reticulum stress contributed to diabetic atherosclerosis. mTOR inhibitor rapamycin and GBE attenuated diabetic atherosclerosis by inhibiting ERS via restoration of autophagy through inhibition of mTOR.
Collapse
|
|
46
|
Lee DE, Bareja A, Bartlett DB, White JP. Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration. Cells 2019; 8:cells8020183. [PMID: 30791569 PMCID: PMC6406986 DOI: 10.3390/cells8020183] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 01/30/2019] [Accepted: 02/14/2019] [Indexed: 12/11/2022] Open
Abstract
Skeletal muscle has remarkable regenerative capacity, relying on precise coordination between resident muscle stem cells (satellite cells) and the immune system. The age-related decline in skeletal muscle regenerative capacity contributes to the onset of sarcopenia, prolonged hospitalization, and loss of autonomy. Although several age-sensitive pathways have been identified, further investigation is needed to define targets of cellular dysfunction. Autophagy, a process of cellular catabolism, is emerging as a key regulator of muscle regeneration affecting stem cell, immune cell, and myofiber function. Muscle stem cell senescence is associated with a suppression of autophagy during key phases of the regenerative program. Macrophages, a key immune cell involved in muscle repair, also rely on autophagy to aid in tissue repair. This review will focus on the role of autophagy in various aspects of the regenerative program, including adult skeletal muscle stem cells, monocytes/macrophages, and corresponding age-associated dysfunction. Furthermore, we will highlight rejuvenation strategies that alter autophagy to improve muscle regenerative function.
Collapse
Affiliation(s)
- David E Lee
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA.
| | - Akshay Bareja
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA.
| | - David B Bartlett
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA.
- Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA.
- Duke Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27701, USA.
| | - James P White
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27701, USA.
- Duke Center for the Study of Aging and Human Development, Duke University School of Medicine, Durham, NC 27701, USA.
- Division of Hematology, Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA.
| |
Collapse
|
|
47
|
Giordano FM, Burattini S, Buontempo F, Canonico B, Martelli AM, Papa S, Sampaolesi M, Falcieri E, Salucci S. Diet Modulation Restores Autophagic Flux in Damaged Skeletal Muscle Cells. J Nutr Health Aging 2019; 23:739-745. [PMID: 31560032 DOI: 10.1007/s12603-019-1245-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVES Autophagy is a physiological and highly regulated mechanism, crucial for cell homeostasis maintenance. Its impairment seems to be involved in the onset of several diseases, including muscular dystrophies, myopathies and sarcopenia. According to few papers, chemotherapeutic drug treatment is able to trigger side effects on skeletal muscle tissue and, among these, a defective autophagic activation, which leads to the persistence of abnormal organelles within cells and, finally, to myofiber degeneration. The aim of this work is to find a strategy, based on diet modulation, to prevent etoposide-induced damage, in a model of in vitro skeletal muscle cells. METHODS Glutamine supplementation and nutrient deprivation have been chosen as pre-treatments to counteract etoposide effect, a chemotherapeutic drug known to induce oxidative stress and cell death. Cell response has been evaluated by means of morpho-functional, cytofluorimetric and molecular analyses. RESULTS Etoposide treated cells, if compared to control, showed dysfunctional mitochondria presence, ER stress and lysosomal compartment damage, confirmed by molecular investigations. CONCLUSIONS Interestingly, both dietary approaches were able to rescue myofiber from etoposide-induced damage. Glutamine supplementation, in particular, seemed to be a good strategy to preserve cell ultrastructure and functionality, by preventing the autophagic impairment and partially restoring the normal lysosomal activity, thus maintaining skeletal muscle homeostasis.
Collapse
Affiliation(s)
- F M Giordano
- Sara Salucci, Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy,
| | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Merkley SD, Chock CJ, Yang XO, Harris J, Castillo EF. Modulating T Cell Responses via Autophagy: The Intrinsic Influence Controlling the Function of Both Antigen-Presenting Cells and T Cells. Front Immunol 2018; 9:2914. [PMID: 30619278 PMCID: PMC6302218 DOI: 10.3389/fimmu.2018.02914] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 11/28/2018] [Indexed: 12/17/2022] Open
Abstract
Autophagy is a homeostatic and inducible process affecting multiple aspects of the immune system. This intrinsic cellular process is involved in MHC-antigen (Ag) presentation, inflammatory signaling, cytokine regulation, and cellular metabolism. In the context of T cell responses, autophagy has an influential hand in dictating responses to self and non-self by controlling extrinsic factors (e.g., MHC-Ag, cytokine production) in antigen-presenting cells (APC) and intrinsic factors (e.g., cell signaling, survival, cytokine production, and metabolism) in T cells. These attributes make autophagy an attractive therapeutic target to modulate T cell responses. In this review, we examine the impact autophagy has on T cell responses by modulating multiple aspects of APC function; the importance of autophagy in the activation, differentiation and homeostasis of T cells; and discuss how the modulation of autophagy could influence T cell responses.
Collapse
Affiliation(s)
- Seth D Merkley
- Clinical and Translational Science Center, University of New Mexico Health Sciences Albuquerque, NM, United States
| | - Cameron J Chock
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Albuquerque, NM, United States
| | - Xuexian O Yang
- Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Albuquerque, NM, United States.,Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Albuquerque, NM, United States
| | - James Harris
- Rheumatology Group, Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University Clayton, VIC, Australia
| | - Eliseo F Castillo
- Clinical and Translational Science Center, University of New Mexico Health Sciences Albuquerque, NM, United States.,Autophagy Inflammation and Metabolism Center of Biomedical Research Excellence, University of New Mexico Health Sciences Albuquerque, NM, United States.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico School of Medicine Albuquerque, NM, United States
| |
Collapse
|
|
49
|
Reactive oxygen species (ROS) in macrophage activation and function in diabetes. Immunobiology 2018; 224:242-253. [PMID: 30739804 DOI: 10.1016/j.imbio.2018.11.010] [Citation(s) in RCA: 374] [Impact Index Per Article: 53.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 11/27/2018] [Accepted: 11/27/2018] [Indexed: 12/14/2022]
Abstract
In a diabetic milieu high levels of reactive oxygen species (ROS) are induced. This contributes to the vascular complications of diabetes. Recent studies have shown that ROS formation is exacerbated in diabetic monocytes and macrophages due to a glycolytic metabolic shift. Macrophages are important players in the progression of diabetes and promote inflammation through the release of pro-inflammatory cytokines and proteases. Because ROS is an important mediator for the activation of pro-inflammatory signaling pathways, obesity and hyperglycemia-induced ROS production may favor induction of M1-like pro-inflammatory macrophages during diabetes onset and progression. ROS induces MAPK, STAT1, STAT6 and NFκB signaling, and interferes with macrophage differentiation via epigenetic (re)programming. Therefore, a comprehensive understanding of the impact of ROS on macrophage phenotype and function is needed in order to improve treatment of diabetes and its vascular complications. In the current comprehensive review, we dissect the role of ROS in macrophage polarization, and analyze how ROS production links metabolism and inflammation in diabetes and its complications. Finally, we discuss the contribution of ROS to the crosstalk between macrophages and endothelial cells in diabetic complications.
Collapse
|
|
50
|
Peña-Oyarzun D, Bravo-Sagua R, Diaz-Vega A, Aleman L, Chiong M, Garcia L, Bambs C, Troncoso R, Cifuentes M, Morselli E, Ferreccio C, Quest AFG, Criollo A, Lavandero S. Autophagy and oxidative stress in non-communicable diseases: A matter of the inflammatory state? Free Radic Biol Med 2018; 124:61-78. [PMID: 29859344 DOI: 10.1016/j.freeradbiomed.2018.05.084] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 05/22/2018] [Accepted: 05/28/2018] [Indexed: 12/11/2022]
Abstract
Non-communicable diseases (NCDs), also known as chronic diseases, are long-lasting conditions that affect millions of people around the world. Different factors contribute to their genesis and progression; however they share common features, which are critical for the development of novel therapeutic strategies. A persistently altered inflammatory response is typically observed in many NCDs together with redox imbalance. Additionally, dysregulated proteostasis, mainly derived as a consequence of compromised autophagy, is a common feature of several chronic diseases. In this review, we discuss the crosstalk among inflammation, autophagy and oxidative stress, and how they participate in the progression of chronic diseases such as cancer, cardiovascular diseases, obesity and type II diabetes mellitus.
Collapse
Affiliation(s)
- Daniel Peña-Oyarzun
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | - Roberto Bravo-Sagua
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Alexis Diaz-Vega
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Larissa Aleman
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Mario Chiong
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Lorena Garcia
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Claudia Bambs
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rodrigo Troncoso
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile
| | - Mariana Cifuentes
- Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Eugenia Morselli
- Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catterina Ferreccio
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Departamento de Salud Pública, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Andrew F G Quest
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Alfredo Criollo
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile.
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Center for Studies of Exercise, Metabolism and Cancer Studies (CEMC), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile; Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| |
Collapse
|