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He Y, Feng L, Gao Y, Wang Y, Yang C, Han S, Ren Y, Zhai Y, Nie K. Huangqin decoction alleviated irinotecan-induced diarrhea by inhibiting endoplasmic reticulum stress through activating AMPK/mTOR-mediated autophagy. JOURNAL OF ETHNOPHARMACOLOGY 2025; 347:119790. [PMID: 40210175 DOI: 10.1016/j.jep.2025.119790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Revised: 03/28/2025] [Accepted: 04/08/2025] [Indexed: 04/12/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Huangqin decoction (HQD), a traditional Chinese antidiarrheal formula, is effective in treating chemotherapy-induced diarrhea (CID). However, its underlying mechanism has not been fully clarified. AIM OF THE STUDY This study aimed to determine whether the underlying mechanism of HQD against CID is related to the activation of AMPK/mTOR-mediated autophagy inhibiting endoplasmic reticulum (ER) stress. MATERIALS AND METHODS Network pharmacology was used to screen potential targets and pathways. The CID mouse model was induced by intraperitoneal injection of 75 mg/kg irinotecan consecutively for four days. The effectiveness of HQD against CID was evaluated through diarrhea score, intestinal epithelial permeability, etc. The histopathological changes of colon were evaluated by HE staining. Alcian blue and immunofluorescence staining were used to assess mucous layer and the expression of MUC2, TJP-1, Occludin, and LC3, relatively. The level of GRP78 and CHOP was assessed by RT-qPCR and WB. Furthermore, the levels of LC3II/I, Beclin-1, P62, AMPK, p-AMPK, mTOR, p-mTOR were evaluated by WB. RESULTS Network pharmacology highlighted that the therapeutic effects of HQD against CID may be related to ER stress, autophagy, AMPK, and mTOR signaling pathways, etc. Subsequently, we conducted animal experiments to validate the predicted results. HQD improved CID by attenuating diarrhea, intestinal permeability, etc. HQD could effectively repair intestinal mucous barrier by activating AMPK/mTOR-mediated autophagy to inhibit ER stress. CONCLUSION Irinotecan disrupted the intestinal barrier causing diarrhea, while HQD could repair intestinal barrier via inducing AMPK/mTOR-mediated autophagy inhibiting ER stress, thereby exerting therapeutic effects against CID.
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Affiliation(s)
- Yunjing He
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Lei Feng
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Yujie Gao
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Yusu Wang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Chenglu Yang
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Siyu Han
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Yuke Ren
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Yarong Zhai
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China
| | - Ke Nie
- School of Chinese Materia Medica, Guangdong Pharmaceutical University, Guangzhou, 510006, China.
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Zhao K, Chan ITC, Tse EHY, Xie Z, Cheung TH, Zeng YA. Autophagy in adult stem cell homeostasis, aging, and disease therapy. CELL REGENERATION (LONDON, ENGLAND) 2025; 14:14. [PMID: 40208372 PMCID: PMC11985830 DOI: 10.1186/s13619-025-00224-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/16/2025] [Accepted: 02/23/2025] [Indexed: 04/11/2025]
Abstract
Autophagy is a crucial cellular process that facilitates the degradation of damaged organelles and protein aggregates, and the recycling of cellular components for the energy production and macromolecule synthesis. It plays an indispensable role in maintaining cellular homeostasis. Over recent decades, research has increasingly focused on the role of autophagy in regulating adult stem cells (SCs). Studies suggest that autophagy modulates various cellular processes and states of adult SCs, including quiescence, proliferation, self-renewal, and differentiation. The primary role of autophagy in these contexts is to sustain homeostasis, withstand stressors, and supply energy. Notably, the dysfunction of adult SCs during aging is correlated with a decline in autophagic activity, suggesting that autophagy is also involved in SC- and aging-associated disorders. Given the diverse cellular processes mediated by autophagy and the intricate mechanisms governing adult SCs, further research is essential to elucidate both universal and cell type-specific regulatory pathways of autophagy. This review discusses the role of autophagy in regulating adult SCs during quiescence, proliferation, self-renewal, and differentiation. Additionally, it summarizes the relationship between SC aging and autophagy, providing therapeutical insights into treating and ameliorating aging-associated diseases and cancers, and ultimately promoting longevity.
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Affiliation(s)
- Ke Zhao
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China
- New Cornerstone Science Laboratory, State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Indigo T C Chan
- Division of Life Science, Center for Stem Cell Research, State Key Laboratory of Molecular Neuroscience, Daniel and Mayce Yu Molecular Neuroscience Center, HKUST-Nan Fung Life Sciences Joint Laboratory, the Hong Kong University of Science and Technology, Hong Kong, China
| | - Erin H Y Tse
- Division of Life Science, Center for Stem Cell Research, State Key Laboratory of Molecular Neuroscience, Daniel and Mayce Yu Molecular Neuroscience Center, HKUST-Nan Fung Life Sciences Joint Laboratory, the Hong Kong University of Science and Technology, Hong Kong, China
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
| | - Zhiyao Xie
- New Cornerstone Science Laboratory, State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Tom H Cheung
- Division of Life Science, Center for Stem Cell Research, State Key Laboratory of Molecular Neuroscience, Daniel and Mayce Yu Molecular Neuroscience Center, HKUST-Nan Fung Life Sciences Joint Laboratory, the Hong Kong University of Science and Technology, Hong Kong, China.
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China.
| | - Yi Arial Zeng
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
- New Cornerstone Science Laboratory, State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
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Wang M, Wang Z, Li Z, Qu Y, Zhao J, Wang L, Zhou X, Xu Z, Zhang D, Jiang P, Fan B, Liu Y. Targeting programmed cell death in inflammatory bowel disease through natural products: New insights from molecular mechanisms to targeted therapies. Phytother Res 2025; 39:1776-1807. [PMID: 38706097 DOI: 10.1002/ptr.8216] [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: 11/26/2023] [Revised: 03/14/2024] [Accepted: 04/11/2024] [Indexed: 05/07/2024]
Abstract
Inflammatory bowel disease (IBD) is an autoimmune disorder primarily characterized by intestinal inflammation and recurrent ulceration, leading to a compromised intestinal barrier and inflammatory infiltration. This disorder's pathogenesis is mainly attributed to extensive damage or death of intestinal epithelial cells, along with abnormal activation or impaired death regulation of immune cells and the release of various inflammatory factors, which contribute to the inflammatory environment in the intestines. Thus, maintaining intestinal homeostasis hinges on balancing the survival and functionality of various cell types. Programmed cell death (PCD) pathways, including apoptosis, pyroptosis, autophagy, ferroptosis, necroptosis, and neutrophil extracellular traps, are integral in the pathogenesis of IBD by mediating the death of intestinal epithelial and immune cells. Natural products derived from plants, fruits, and vegetables have shown potential in regulating PCD, offering preventive and therapeutic avenues for IBD. This article reviews the role of natural products in IBD treatment by focusing on targeting PCD pathways, opening new avenues for clinical IBD management.
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Affiliation(s)
- Mengjie Wang
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhiyuan Wang
- People's Hospital of Zhengzhou, Zhengzhou, China
| | - Zhichao Li
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuan Qu
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiting Zhao
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lei Wang
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xinpeng Zhou
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ziqi Xu
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Di Zhang
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ping Jiang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Bing Fan
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ying Liu
- The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Cune D, Pitasi CL, Rubiola A, Jamma T, Simula L, Boucher C, Fortun A, Adoux L, Letourneur F, Saintpierre B, Donnadieu E, Terris B, Bossard P, Chassaing B, Romagnolo B. Inhibition of Atg7 in intestinal epithelial cells drives resistance against Citrobacter rodentium. Cell Death Dis 2025; 16:112. [PMID: 39971913 PMCID: PMC11840101 DOI: 10.1038/s41419-025-07422-5] [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: 06/25/2024] [Revised: 01/14/2025] [Accepted: 02/03/2025] [Indexed: 02/21/2025]
Abstract
Autophagy, a cytoprotective mechanism in intestinal epithelial cells, plays a crucial role in maintaining intestinal homeostasis. Beyond its cell-autonomous effects, the significance of autophagy in these cells is increasingly acknowledged in the dynamic interplay between the microbiota and the immune response. In the context of colon cancer, intestinal epithelium disruption of autophagy has been identified as a critical factor influencing tumor development. This disruption modulates the composition of the gut microbiota, eliciting an anti-tumoral immune response. Here, we report that Atg7 deficiency in intestinal epithelial cells shapes the intestinal microbiota leading to an associated limitation of colitis induced by Citrobacter rodentium infection. Mice with an inducible, intestinal epithelial-cell-specific deletion of the autophagy gene, Atg7, exhibited enhanced clearance of C. rodentium, mitigated hyperplasia, and reduced pathogen-induced goblet cell loss. This protective effect is linked to a higher proportion of neutrophils and phagocytic cells in the early phase of infection. At later stages, it is associated with the downregulation of pro-inflammatory pathways and an increase in Th17 and Treg responses-immune responses known for their protective roles against C. rodentium infection, modulated by specific gut microbiota. Fecal microbiota transplantation and antibiotic treatment approaches revealed that the Atg7-deficiency-shapped microbiota, especially Gram-positive bacteria, playing a central role in driving resistance to C. rodentium infection. In summary, our findings highlight that inhibiting autophagy in intestinal epithelial cells contributes to maintaining homeostasis and preventing detrimental intestinal inflammation through microbiota-mediated colonization resistance against C. rodentium. This underscores the central role played by autophagy in shaping the microbiota in promoting immune-mediated resistance against enteropathogens.
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Affiliation(s)
- David Cune
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France
- Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France
| | - Caterina Luana Pitasi
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France
- Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France
| | - Alessia Rubiola
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France
- Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France
| | - Trinath Jamma
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani, Hyderabad, India
| | - Luca Simula
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France
| | - Camille Boucher
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France
- Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France
| | - Apolline Fortun
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France
- Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France
| | - Lucie Adoux
- Genomic Facility, Université de Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Franck Letourneur
- Genomic Facility, Université de Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | - Benjamin Saintpierre
- Genomic Facility, Université de Paris Cité, Institut Cochin, INSERM, CNRS, Paris, France
| | | | - Benoît Terris
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France
- Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France
- Pathology Department, AP-HP, Hôpital Cochin, Paris, France
| | - Pascale Bossard
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France
- Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France
| | - Benoît Chassaing
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France
- Microbiome-Host Interactions, Institut Pasteur, Université Paris Cité, INSERM, Paris, France
| | - Béatrice Romagnolo
- Université Paris Cité, Institut Cochin, Inserm, CNRS, Paris, France.
- Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France.
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Moreno-Blas D, Adell T, González-Estévez C. Autophagy in Tissue Repair and Regeneration. Cells 2025; 14:282. [PMID: 39996754 PMCID: PMC11853389 DOI: 10.3390/cells14040282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 02/01/2025] [Accepted: 02/13/2025] [Indexed: 02/26/2025] Open
Abstract
Autophagy is a cellular recycling system that, through the sequestration and degradation of intracellular components regulates multiple cellular functions to maintain cellular homeostasis and survival. Dysregulation of autophagy is closely associated with the development of physiological alterations and human diseases, including the loss of regenerative capacity. Tissue regeneration is a highly complex process that relies on the coordinated interplay of several cellular processes, such as injury sensing, defense responses, cell proliferation, differentiation, migration, and cellular senescence. These processes act synergistically to repair or replace damaged tissues and restore their morphology and function. In this review, we examine the evidence supporting the involvement of the autophagy pathway in the different cellular mechanisms comprising the processes of regeneration and repair across different regenerative contexts. Additionally, we explore how modulating autophagy can enhance or accelerate regeneration and repair, highlighting autophagy as a promising therapeutic target in regenerative medicine for the development of autophagy-based treatments for human diseases.
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Affiliation(s)
| | | | - Cristina González-Estévez
- Department of Genetics, Microbiology and Statistics, School of Biology and Institute of Biomedicine (IBUB), University of Barcelona, Av. Diagonal, 643, 08028 Barcelona, Spain; (D.M.-B.); (T.A.)
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Wang H, Sun N, Sun P, Zhang H, Yin W, Zheng X, Fan K, Sun Y, Li H. Matrine regulates autophagy in ileal epithelial cells in a porcine circovirus type 2-infected murine model. Front Microbiol 2024; 15:1455049. [PMID: 39588099 PMCID: PMC11587598 DOI: 10.3389/fmicb.2024.1455049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 10/15/2024] [Indexed: 11/27/2024] Open
Abstract
Introduction Porcine circovirus type 2 (PCV2) is an important pathogen that causes diarrhea in nursery and fattening pigs, resulting in huge economic losses for commercial pig farms. Protective efficacy of vaccines is compromised by mutations in pathogens. There is an urgent need to articulate the mechanism by which PCV2 destroys the host's intestinal mucosal barrier and to find effective therapeutic drugs. Increasing attention has been paid to the natural antiviral compounds extracted from traditional Chinese medicines. In the present study, we investigated the role of Matrine in mitigating PCV2-induced intestinal damage and enhancing autophagy as a potential therapeutic strategy in mice. Methods A total of 40 female, specific-pathogen-free-grade Kunming mice were randomly divided into four groups with 10 mice in each group: control, PCV2 infection, Matrine treatment (40 mg/kg Matrine), and Ribavirin treatment (40 mg/kg Ribavirin). Except for the control group, all mice were injected intraperitoneally with 0.5 mL 105.4 50% tissue culture infectious dose (TCID50)/mL PCV2. Results While attenuating PCV2-induced downregulation of ZO-1 and occludin and restoring intestinal barrier function in a PCV2 Kunming mouse model, treatment with Matrine (40 mg/kg) attenuated ultrastructural damage and improved intestinal morphology. Mechanistically, Matrine reversed PCV2-induced autophagosome accumulation by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation and upregulating Beclin1 protein expression, thus resisting viral hijacking of enterocyte autophagy. Discussion Our findings demonstrate that Matrine may be a novel, potential antiviral agent against PCV2 by activating intestine cellular autophagy, which provides a new strategy for host-directed drug discovery.
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Affiliation(s)
- Hong Wang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
- Department of Sports, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Na Sun
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Panpan Sun
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Hua Zhang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Wei Yin
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Xiaozhong Zheng
- Centre for Inflammation Research, Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom
| | - Kuohai Fan
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
- Laboratory Animal Center, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Yaogui Sun
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
| | - Hongquan Li
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, China
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Zhang X, Zhang H, Huang M, Mei Y, Hu C, Huang C, Zhang H, Wei X, Gao Y, Ma Z. Ferulic Acid Interferes with Radioactive Intestinal Injury Through the DJ-1-Nrf2 and Sirt1-NF-κB-NLRP3 Pathways. Molecules 2024; 29:5072. [PMID: 39519712 PMCID: PMC11547899 DOI: 10.3390/molecules29215072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/23/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
Radiation-induced intestinal injury is a common complication of radiotherapy for abdominal and pelvic malignancies. Due to its rapid proliferation, the small intestine is particularly sensitive to radiation, making it a critical factor limiting treatment. Ferulic acid (FA), a derivative of cinnamic acid, exhibits antioxidant, anti-inflammatory, and anti-radiation properties. In this study, we established a mouse model of radiation-induced intestinal injury using a dose of 11 Gy at a rate of 96.62 cGy/min. Our findings indicate that FA's protective effects against radiation-induced intestinal injury may be mediated through the parkinsonism-associated deglycase (DJ-1) nuclear factor erythroid 2-related factor 2 (Nrf2) and silent mating type information regulation 2 homolog 1 (Sirt1) nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) NOD-like receptor family, pyrin domain containing 3 (NLRP3). FA was found to mitigate changes in oxidative stress indices and inflammatory factors induced by radiation, as well as to attenuate radiation-induced pathological alterations in the small intestine. Furthermore, FA enhanced the expression of DJ-1 and Nrf2 at both the transcriptional and protein levels, inhibited NLRP3 protein fluorescence intensity, and reduced the expression of NLRP3, interleukin-18 (IL-18), and interleukin-1 beta (IL-1β). Additionally, FA suppressed the transcription and translation of NF-κB, NLRP3, cysteine-aspartic acid protease-1 (Caspase-1), IL-18, and IL-1β by upregulating Sirt1, thereby alleviating radiation-induced inflammatory injury in the small intestine. Thus, FA holds promise as an effective therapeutic agent for ameliorating radiation-induced intestinal injury.
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Affiliation(s)
- Xuemei Zhang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510720, China
| | - Haoyu Zhang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
| | - Mingyue Huang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
| | - Yu Mei
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
| | - Changkun Hu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
| | - Congshu Huang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
| | - Huiting Zhang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
| | - Xue Wei
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510720, China
| | - Yue Gao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510720, China
| | - Zengchun Ma
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, China; (X.Z.); (H.Z.); (M.H.); (Y.M.); (C.H.); (C.H.); (H.Z.); (X.W.)
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510720, China
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Zhang W, Zou M, Fu J, Xu Y, Zhu Y. Autophagy: A potential target for natural products in the treatment of ulcerative colitis. Biomed Pharmacother 2024; 176:116891. [PMID: 38865850 DOI: 10.1016/j.biopha.2024.116891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 05/16/2024] [Accepted: 06/05/2024] [Indexed: 06/14/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease primarily affecting the mucosa of the colon and rectum. UC is characterized by recurrent episodes, often necessitating lifelong medication use, imposing a significant burden on patients. Current conventional and advanced treatments for UC have the disadvantages of insufficient efficiency, susceptibility to drug resistance, and notable adverse effects. Therefore, developing effective and safe drugs has become an urgent need. Autophagy is an intracellular degradation process that plays an important role in intestinal homeostasis. Emerging evidence suggests that aberrant autophagy is involved in the development of UC, and modulating autophagy can effectively alleviate experimental colitis. A growing number of studies have established that autophagy can interplay with endoplasmic reticulum stress, gut microbiota, apoptosis, and the NLRP3 inflammasome, all of which contribute to the pathogenesis of UC. In addition, a variety of intestinal epithelial cells, including absorptive cells, goblet cells, and Paneth cells, as well as other cell types like neutrophils, antigen-presenting cells, and stem cells in the gut, mediate the development of UC through autophagy. To date, many studies have found that natural products hold the potential to exert therapeutic effects on UC by regulating autophagy. This review focuses on the possible effects and pharmacological mechanisms of natural products to alleviate UC with autophagy as a potential target in recent years, aiming to provide a basis for new drug development.
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Affiliation(s)
- Wei Zhang
- The First Clinical College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Menglong Zou
- The First Clinical College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Jia Fu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China
| | - Yin Xu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China.
| | - Ying Zhu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China.
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9
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Liang N, Zhang K. The link between autophagy and psoriasis. Acta Histochem 2024; 126:152166. [PMID: 38688157 DOI: 10.1016/j.acthis.2024.152166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/05/2024] [Accepted: 04/19/2024] [Indexed: 05/02/2024]
Abstract
Autophagy is a lysosome-dependent, self-renewal mechanism that degrades and recycles cellular components in eukaryotic cells to maintain the homeostasis of the intracellular environment. Psoriasis is featured by increased inflammatory response, epidermal hyperproliferation and abnormal differentiation, infiltration of immune cells and increased expression levels of both endothelial adhesion molecules and angiogenic mediators. Evidence indicates that autophagy has important roles in many different types of cells, such as lymphocytes, keratinocytes, monocytes and mesenchymal stem cells (MSCs). This paper will review the role of autophagy in the pathogenesis of psoriasis and strategies for therapeutic modulation. Key Message Autophagy regulates the functions of cutaneous cells (MSCs, KCs, T cells and endothelial cells). Since reduced autophagy contributes in part to the pathogenesis of psoriasis, enhancement of autophagy can be an alternative approach to mitigate psoriasis.
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Affiliation(s)
- Nannan Liang
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Kaiming Zhang
- Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
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Jin X, You L, Qiao J, Han W, Pan H. Autophagy in colitis-associated colon cancer: exploring its potential role in reducing initiation and preventing IBD-Related CAC development. Autophagy 2024; 20:242-258. [PMID: 37723664 PMCID: PMC10813649 DOI: 10.1080/15548627.2023.2259214] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/20/2023] Open
Abstract
ABBREVIATIONS A. muciniphila: Akkermansia muciniphila; AIEC: adherent invasive Escherichia coli; AOM/DSS: azoxymethane-dextran sodium sulfate; ATG: autophagy related; BECN1: beclin1, autophagy related; CAC: colitis-associated colon cancer; CCDC50: coiled-coil domain containing 50; CLDN2: claudin 2; CoPEC: colibactin-producing Escherichia coli; CRC: colorectal cancer; DAMPs: danger/damage-associated molecular patterns; DC: dendritic cell; DSS: dextran sulfate sodium; DTP: drug-resistant persistent; ER: endoplasmic reticulum; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; IBD: inflammatory bowel disease; IECs: intestinal epithelial cells; IKK: IkappaB kinase; IL: interleukin; IRGM1: immunity-related GTPase family M member 1; ISC: intestinal stem cell; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MDP: muramyl dipeptide; MELK: maternal embryonic leucine zipper kinase; MHC: major histocompatibility complex; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NLRP3: NLR family, pyrin domain containing 3; NOD2: nucleotide-binding oligomerization domain containing 2; NRBF2: nuclear receptor binding factor 2; PAMPs: pathogen-associated molecular patterns; PI3K: class I phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; PYCARD/ASC: PYD and CARD domain containing; RALGAPA2/RalGAPα2: Ral GTPase activating protein protein, alpha subunit 2 (catalytic); RIPK2/CARD3: receptor (TNFRSF)-interacting serine-threonine kinase 2; RIPK3: receptor-interacting serine-threonine kinase 3; ROS: reactive oxygen species; sCRC: sporadic colorectal cancer; SMARCA4/BRG1: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TNF/TNFA: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; UPR: unfolded protein response; WT: wild-type.
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Affiliation(s)
- Xuanhong Jin
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liangkun You
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jincheng Qiao
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Weidong Han
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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11
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Jackson BT, Finley LWS. Metabolic regulation of the hallmarks of stem cell biology. Cell Stem Cell 2024; 31:161-180. [PMID: 38306993 PMCID: PMC10842269 DOI: 10.1016/j.stem.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 01/02/2024] [Accepted: 01/03/2024] [Indexed: 02/04/2024]
Abstract
Stem cells perform many different functions, each of which requires specific metabolic adaptations. Over the past decades, studies of pluripotent and tissue stem cells have uncovered a range of metabolic preferences and strategies that correlate with or exert control over specific cell states. This review aims to describe the common themes that emerge from the study of stem cell metabolism: (1) metabolic pathways supporting stem cell proliferation, (2) metabolic pathways maintaining stem cell quiescence, (3) metabolic control of cellular stress responses and cell death, (4) metabolic regulation of stem cell identity, and (5) metabolic requirements of the stem cell niche.
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Affiliation(s)
- Benjamin T Jackson
- Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, New York, NY, USA
| | - Lydia W S Finley
- Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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12
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Yuan Y, Wang F, Liu X, Shuai B, Fan H. The Role of AMPK Signaling in Ulcerative Colitis. Drug Des Devel Ther 2023; 17:3855-3875. [PMID: 38170149 PMCID: PMC10759424 DOI: 10.2147/dddt.s442154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 12/22/2023] [Indexed: 01/05/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease characterized by inflammation and ulcer formation of the intestinal mucosa. Due to its high recurrence rate, prolonged course, limited curative options, and significant impact on patients' quality of life, along with a notable potential for malignant transformation, UC is designated as a refractory global health challenge by the World Health Organization (WHO). The elucidation of the pathogenesis and therapeutic strategies for UC requires further in-depth investigation. AMP-activated protein kinase (AMPK) serves as a central regulator of cellular energy metabolic homeostasis. Emerging evidence indicates that interventions involving traditional Chinese medicine (TCM) components, as well as other pharmacological measures, exert beneficial effects on the intestinal mucosal inflammation and epithelial barrier dysfunction in UC by modulating AMPK signaling, thereby influencing biological processes such as cellular autophagy, apoptosis, inflammatory responses, macrophage polarization, and NLRP3 inflammasome-mediated pyroptosis. The role of AMPK in UC is of significant importance. This manuscript provides a comprehensive overview of the mechanisms through which AMPK is involved in UC, as well as a compilation of pharmacological agents capable of activating the AMPK signaling pathway within the context of UC. The primary objective is to facilitate a deeper comprehension of the pivotal role of AMPK in UC among researchers and clinical practitioners, thereby advancing the identification of novel therapeutic targets for interventions in UC.
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Affiliation(s)
- Yuyi Yuan
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China
| | - Fang Wang
- Department of Rehabilitation Medicine, Jingshan Union Hospital, Union Hospital, Huazhong University of Science and Technology, Jingshan, Hubei, 431800, People’s Republic of China
| | - Xingxing Liu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China
| | - Bo Shuai
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China
| | - Heng Fan
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People’s Republic of China
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13
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Lu Q, Liang Y, Tian S, Jin J, Zhao Y, Fan H. Radiation-Induced Intestinal Injury: Injury Mechanism and Potential Treatment Strategies. TOXICS 2023; 11:1011. [PMID: 38133412 PMCID: PMC10747544 DOI: 10.3390/toxics11121011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/01/2023] [Accepted: 12/08/2023] [Indexed: 12/23/2023]
Abstract
Radiation-induced intestinal injury (RIII) is one of the most common intestinal complications caused by radiotherapy for pelvic and abdominal tumors and it seriously affects the quality of life of patients. However, the treatment of acute RIII is essentially symptomatic and nutritional support treatment and an ideal means of prevention and treatment is lacking. Researchers have conducted studies at the cellular and animal levels and found that some chemical or biological agents have good therapeutic effects on RIII and may be used as potential candidates for clinical treatment. This article reviews the injury mechanism and potential treatment strategies based on cellular and animal experiments to provide new ideas for the diagnosis and treatment of RIII in clinical settings.
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Affiliation(s)
- Qianying Lu
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (S.T.); (J.J.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Yangfan Liang
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (S.T.); (J.J.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Sijia Tian
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (S.T.); (J.J.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Jie Jin
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (S.T.); (J.J.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Yanmei Zhao
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (S.T.); (J.J.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Haojun Fan
- Institute of Disaster and Emergency Medicine, Tianjin University, Tianjin 300072, China; (Q.L.); (Y.L.); (S.T.); (J.J.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
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14
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Taraborrelli L, Şenbabaoğlu Y, Wang L, Lim J, Blake K, Kljavin N, Gierke S, Scherl A, Ziai J, McNamara E, Owyong M, Rao S, Calviello AK, Oreper D, Jhunjhunwala S, Argiles G, Bendell J, Kim TW, Ciardiello F, Wongchenko MJ, de Sauvage FJ, de Sousa E Melo F, Yan Y, West NR, Murthy A. Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer. Nat Commun 2023; 14:5945. [PMID: 37741832 PMCID: PMC10517947 DOI: 10.1038/s41467-023-41618-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 09/12/2023] [Indexed: 09/25/2023] Open
Abstract
Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene ATG16L1 is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of Atg16l1 in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure. ATG16L1 deficiency enhances programmed cell death of colon cancer organoids induced by IFN-γ and TNF, thus increasing their sensitivity to host immunity. In parallel, ATG16L1 deficiency reduces tumor stem-like populations in vivo independently of adaptive immune pressure. This work reveals autophagy as a clinically relevant mechanism of immune evasion and tumor fitness in MSS-CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.
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Affiliation(s)
- Lucia Taraborrelli
- Department of Cancer Immunology, Genentech Inc., South San Francisco, USA
| | - Yasin Şenbabaoğlu
- Department of Oncology Bioinformatics, Genentech Inc., South San Francisco, USA
| | - Lifen Wang
- Department of Cancer Immunology, Genentech Inc., South San Francisco, USA
| | - Junghyun Lim
- Department of Cancer Immunology, Genentech Inc., South San Francisco, USA
| | - Kerrigan Blake
- Department of Cancer Immunology, Genentech Inc., South San Francisco, USA
| | - Noelyn Kljavin
- Department of Molecular Oncology, Genentech Inc., South San Francisco, USA
| | - Sarah Gierke
- Center for Advanced Light Microscopy, Genentech Inc., South San Francisco, USA
- Department of Pathology, Genentech Inc., South San Francisco, USA
| | - Alexis Scherl
- Department of Pathology, Genentech Inc., South San Francisco, USA
| | - James Ziai
- Department of Pathology, Genentech Inc., South San Francisco, USA
| | - Erin McNamara
- Department of In Vivo Pharmacology, Genentech Inc., South San Francisco, USA
| | - Mark Owyong
- Department of In Vivo Pharmacology, Genentech Inc., South San Francisco, USA
| | - Shilpa Rao
- Department of Oncology Bioinformatics, Genentech Inc., South San Francisco, USA
| | | | - Daniel Oreper
- Department of Oncology Bioinformatics, Genentech Inc., South San Francisco, USA
| | - Suchit Jhunjhunwala
- Department of Oncology Bioinformatics, Genentech Inc., South San Francisco, USA
| | - Guillem Argiles
- Vall d'Hebrón Institute of Oncology, Vall d'Hebrón University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Johanna Bendell
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA
| | - Tae Won Kim
- Department of Oncology, Medical Center, University of Ulsan, Seoul, Korea
| | - Fortunato Ciardiello
- Department of Precision Medicine, Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy
| | | | | | | | - Yibing Yan
- Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA
| | - Nathaniel R West
- Department of Cancer Immunology, Genentech Inc., South San Francisco, USA.
| | - Aditya Murthy
- Department of Cancer Immunology, Genentech Inc., South San Francisco, USA.
- Gilead Sciences, Foster City, USA.
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15
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Li Y, Wu Z, Hu J, Liu G, Hu H, Ouyang F, Yang J. Hydrogen sulfide ameliorates abdominal aorta coarctation-induced myocardial fibrosis by inhibiting pyroptosis through regulating eukaryotic translation initiation factor 2α phosphorylation and activating PI3K/AKT1 pathway. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2023; 27:345-356. [PMID: 37386832 PMCID: PMC10316187 DOI: 10.4196/kjpp.2023.27.4.345] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/31/2022] [Accepted: 11/01/2022] [Indexed: 07/01/2023]
Abstract
This study aimed to assess the effects of exogenous hydrogen sulfide (H2S) on abdominal aorta coarctation (AAC) induced myocardial fibrosis (MF) and autophagy in rats. Forty-four Sprague-Dawley rats were randomly divided into control group, AAC group, AAC + H2S group, and H2S control group. After a model of rats with AAC was built surgically, AAC + H2S group and H2S group were injected intraperitoneally with H2S (100 μmol/kg) daily. The rats in the control group and the AAC group were injected with the same amount of PBS. We observed that H2S can improve left ventricular function and the deposition of myocardial collagen fibers, inhibit pyroptosis, down-regulate the expression of P-eif2α in myocardial tissue, and inhibit cell autophagy by activating the phosphatidylinositol 3-kinase (PI3K)/AKT1 signaling pathway (p < 0.05). In addition, angiotensin II (1 μM) H9c2 cardiomyocytes were injured in vitro experiments, and it was also observed that pyroptosis was inhibited after H2S (400 μmol/kg) intervention, the expression of P-eif2α in cardiomyocytes was significantly down-regulated, and the PI3K/AKT1 signaling pathway was activated at the same time. Therefore, increasing the expression of P-eif2α reverses the activation of the PI3K/AKT1 signaling pathway by H2S. In conclusion, these findings suggest that exogenous H2S can ameliorate MF in rats with AAC by inhibiting pyroptosis, and the mechanism may be associated with inhibiting the phosphorylation of eif2α and activating the PI3K/AKT1 signaling pathway to inhibit excessive cell autophagy.
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Affiliation(s)
- Yaling Li
- Department of Cardiology, Zhuzhou Central Hospital, Zhuzhou 412000, China
| | - Zhixiong Wu
- Department of Cardiology, Zhuzhou Central Hospital, Zhuzhou 412000, China
| | - Jiangping Hu
- Department of Cardiology, Zhuzhou Central Hospital, Zhuzhou 412000, China
| | - Gongli Liu
- Department of Cardiology, Zhuzhou Central Hospital, Zhuzhou 412000, China
| | - Hongming Hu
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang 421001, China
| | - Fan Ouyang
- Department of Cardiology, Zhuzhou Central Hospital, Zhuzhou 412000, China
| | - Jun Yang
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang 421001, China
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16
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Watanabe-Yasuoka Y, Gotou A, Shimizu S, Sashihara T. Lactiplantibacillus plantarum OLL2712 Induces Autophagy via MYD88 and Strengthens Tight Junction Integrity to Promote the Barrier Function in Intestinal Epithelial Cells. Nutrients 2023; 15:2655. [PMID: 37375559 DOI: 10.3390/nu15122655] [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: 05/24/2023] [Revised: 06/03/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Autophagy is an important system conserved in eukaryotes that maintains homeostasis by degrading abnormal proteins. Autophagy incompetence in intestinal epithelial cells causes the abnormal function of intestinal stem cells and other cells and damages intestinal barrier function. The disruption of the intestinal barrier causes chronic inflammation throughout the body, followed by impaired glucose and lipid metabolism. Lactiplantibacillus plantarum OLL2712 (OLL2712) is a lactic acid bacterium that induces interleukin-10 production from immune cells, alleviates chronic inflammation, and improves glucose and lipid metabolism. In this study, we hypothesized that OLL2712 exerts anti-inflammatory effects by inducing autophagy and ameliorating intestinal barrier dysfunction, and we investigated its autophagy-inducing activities and functions. Caco-2 cells stimulated with OLL2712 for 24 h showed an increased number of autolysosomes per cell, compared with unstimulated cells. Therefore, the permeability of fluorescein isothiocyanate dextran 4000 (FD-4) was suppressed by inducing autophagy. In contrast, mucin secretion in HT-29-MTX-E12 cells was also increased by OLL2712 but not via autophagy induction. Finally, the signaling pathway involved in autophagy induction by OLL2712 was found to be mediated by myeloid differentiation factor 88 (MYD88). In conclusion, our findings suggest that OLL2712 induces autophagy in intestinal epithelial cells via MYD88, and that mucosal barrier function is strengthened by inducing autophagy.
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Affiliation(s)
- Yumiko Watanabe-Yasuoka
- Food Microbiology and Function Research Laboratories, Division of Research and Development, Meiji Co., Ltd., Hachiouji, Tokyo 192-0919, Japan
| | - Ayako Gotou
- Food Microbiology and Function Research Laboratories, Division of Research and Development, Meiji Co., Ltd., Hachiouji, Tokyo 192-0919, Japan
| | - Shigeomi Shimizu
- Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
| | - Toshihiro Sashihara
- Food Microbiology and Function Research Laboratories, Division of Research and Development, Meiji Co., Ltd., Hachiouji, Tokyo 192-0919, Japan
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17
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Wang Z, Qu YJ, Cui M. Modulation of stem cell fate in intestinal homeostasis, injury and repair. World J Stem Cells 2023; 15:354-368. [PMID: 37342221 PMCID: PMC10277971 DOI: 10.4252/wjsc.v15.i5.354] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/31/2023] [Accepted: 04/24/2023] [Indexed: 05/26/2023] Open
Abstract
The mammalian intestinal epithelium constitutes the largest barrier against the external environment and makes flexible responses to various types of stimuli. Epithelial cells are fast-renewed to counteract constant damage and disrupted barrier function to maintain their integrity. The homeostatic repair and regeneration of the intestinal epithelium are governed by the Lgr5+ intestinal stem cells (ISCs) located at the base of crypts, which fuel rapid renewal and give rise to the different epithelial cell types. Protracted biological and physicochemical stress may challenge epithelial integrity and the function of ISCs. The field of ISCs is thus of interest for complete mucosal healing, given its relevance to diseases of intestinal injury and inflammation such as inflammatory bowel diseases. Here, we review the current understanding of the signals and mechanisms that control homeostasis and regeneration of the intestinal epithelium. We focus on recent insights into the intrinsic and extrinsic elements involved in the process of intestinal homeostasis, injury, and repair, which fine-tune the balance between self-renewal and cell fate specification in ISCs. Deciphering the regulatory machinery that modulates stem cell fate would aid in the development of novel therapeutics that facilitate mucosal healing and restore epithelial barrier function.
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Affiliation(s)
- Zhe Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Yan-Ji Qu
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Min Cui
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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18
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Williams PA, Naughton KE, Simon LA, Soto GE, Parham LR, Ma X, Danan CH, Hu W, Friedman ES, McMillan EA, Mehta H, Stoltz MA, Ocaña JS, Zackular JP, Bittinger K, Whelan KA, Karakasheva TA, Hamilton KE. Intestinal epithelial autophagy is required for the regenerative benefit of calorie restriction. Am J Physiol Gastrointest Liver Physiol 2023; 324:G354-G368. [PMID: 36852920 PMCID: PMC10069975 DOI: 10.1152/ajpgi.00248.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/30/2023] [Accepted: 02/16/2023] [Indexed: 03/01/2023]
Abstract
Calorie restriction can enhance the regenerative capacity of the injured intestinal epithelium. Among other metabolic changes, calorie restriction can activate the autophagy pathway. Although independent studies have attributed the regenerative benefit of calorie restriction to downregulation of mTORC1, it is not known whether autophagy itself is required for the regenerative benefit of calorie restriction. We used mouse and organoid models with autophagy gene deletion to evaluate the contribution of autophagy to intestinal epithelial regeneration following calorie restriction. In the absence of injury, mice with intestinal epithelial-specific deletion of autophagy gene Atg7 (Atg7ΔIEC) exhibit weight loss and histological changes similar to wild-type mice following calorie restriction. Conversely, calorie-restricted Atg7ΔIEC mice displayed a significant reduction in regenerative crypt foci after irradiation compared with calorie-restricted wild-type mice. Targeted analyses of tissue metabolites in calorie-restricted mice revealed an association between calorie restriction and reduced glycocholic acid (GCA) in wild-type mice but not in Atg7ΔIEC mice. To evaluate whether GCA can directly modulate epithelial stem cell self-renewal, we performed enteroid formation assays with or without GCA. Wild-type enteroids exhibited reduced enteroid formation efficiency in response to GCA treatment, suggesting that reduced availability of GCA during calorie restriction may be one mechanism by which calorie restriction favors epithelial regeneration in a manner dependent upon epithelial autophagy. Taken together, our data support the premise that intestinal epithelial Atg7 is required for the regenerative benefit of calorie restriction, due in part to its role in modulating luminal GCA with direct effects on epithelial stem cell self-renewal.NEW & NOTEWORTHY Calorie restriction is associated with enhanced intestinal regeneration after irradiation, but the requirement of autophagy for this process is not known. Our data support the premise that intestinal epithelial autophagy is required for the regenerative benefit of calorie restriction. We also report that luminal levels of primary bile acid glycocholic acid are modulated by epithelial cell autophagy during calorie restriction with direct effects on epithelial stem cell function.
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Affiliation(s)
- Patrick A Williams
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Kaitlyn E Naughton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Lauren A Simon
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Gloria E Soto
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Louis R Parham
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Xianghui Ma
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Charles H Danan
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Weiming Hu
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Elliot S Friedman
- Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Emily A McMillan
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Hritik Mehta
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Madison A Stoltz
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Joshua Soto Ocaña
- Division of Protective Immunity, Children's Hospital of Philadelphia, Pennsylvania United States
| | - Joseph P Zackular
- Division of Protective Immunity, Children's Hospital of Philadelphia, Pennsylvania United States
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Kyle Bittinger
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Kelly A Whelan
- Department of Pathology & Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
- Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, United States
| | - Tatiana A Karakasheva
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
| | - Kathryn E Hamilton
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
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19
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Tran S, Juliani J, Fairlie WD, Lee EF. The emerging roles of autophagy in intestinal epithelial cells and its links to inflammatory bowel disease. Biochem Soc Trans 2023; 51:811-826. [PMID: 37052218 PMCID: PMC10212545 DOI: 10.1042/bst20221300] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/14/2023]
Abstract
Landmark genome-wide association studies (GWAS) identified that mutations in autophagy genes correlated with inflammatory bowel disease (IBD), a heterogenous disease characterised by prolonged inflammation of the gastrointestinal tract, that can reduce a person's quality of life. Autophagy, the delivery of intracellular components to the lysosome for degradation, is a critical cellular housekeeping process that removes damaged proteins and turns over organelles, recycling their amino acids and other constituents to supply cells with energy and necessary building blocks. This occurs under both basal and challenging conditions such as nutrient deprivation. An understanding of the relationship between autophagy, intestinal health and IBD aetiology has improved over time, with autophagy having a verified role in the intestinal epithelium and immune cells. Here, we discuss research that has led to an understanding that autophagy genes, including ATG16L, ATG5, ATG7, IRGM, and Class III PI3K complex members, contribute to innate immune defence in intestinal epithelial cells (IECs) via selective autophagy of bacteria (xenophagy), how autophagy contributes to the regulation of the intestinal barrier via cell junctional proteins, and the critical role of autophagy genes in intestinal epithelial secretory subpopulations, namely Paneth and goblet cells. We also discuss how intestinal stem cells can utilise autophagy. Importantly, mouse studies have provided evidence that autophagy deregulation has serious physiological consequences including IEC death and intestinal inflammation. Thus, autophagy is now established as a key regulator of intestinal homeostasis. Further research into how its cytoprotective mechanisms can prevent intestinal inflammation may provide insights into the effective management of IBD.
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Affiliation(s)
- Sharon Tran
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Victoria 3086, Australia
| | - Juliani Juliani
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
| | - W. Douglas Fairlie
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Victoria 3086, Australia
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
| | - Erinna F. Lee
- Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria 3084, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Victoria 3086, Australia
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
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20
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Liu Y, Liu Z, Hu L, He L, Yang L, Qin Z, Xie Y, Peng X, Dai L. Function of stem cells in radiation-induced damage. Int J Radiat Biol 2023; 99:1483-1494. [PMID: 36912588 DOI: 10.1080/09553002.2023.2188935] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 02/27/2023] [Indexed: 03/14/2023]
Abstract
PURPOSE The aim of this review is to discuss previous studies on the function of stem cells in radiation-induced damage, and the factors affecting these processes, in the hope of improving our understanding of the different stem cells and the communication networks surrounding them. This is essential for the development of effective stem cell-based therapies to regenerate or replace normal tissues damaged by radiation. CONCLUSION In salivary glands, senescence-associated cytokines and inflammation-associated cells have a greater effect on stem cells. In the intestinal glands, Paneth cells strongly affect stem cell-mediated tissue regeneration after radiation treatment. In the pancreas, β-cells as well as protein C receptor positive (Procr) cells are expected to be key cells in the treatment of diabetes. In the bone marrow, a variety of cytokines such as CXC-chemokine ligand 12 (CXCL12) and stem cell factor (SCF), contribute to the functional recovery of hematopoietic stem cells after irradiation.
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Affiliation(s)
- Yingtong Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, and Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Zheran Liu
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Liqiang Hu
- West China-California Research Center for Predictive Intervention Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Ling He
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Lianlian Yang
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Zijian Qin
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yuping Xie
- Department of Oncology, Chengdu First People's Hospital, Chengdu, Sichuan, China
| | - Xingchen Peng
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Lei Dai
- State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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21
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Otte ML, Lama Tamang R, Papapanagiotou J, Ahmad R, Dhawan P, Singh AB. Mucosal healing and inflammatory bowel disease: Therapeutic implications and new targets. World J Gastroenterol 2023; 29:1157-1172. [PMID: 36926666 PMCID: PMC10011951 DOI: 10.3748/wjg.v29.i7.1157] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/16/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
Mucosal healing (MH) is vital in maintaining homeostasis within the gut and protecting against injury and infections. Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair. However, when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results, particularly inflammatory bowel disease (IBD). Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions, with the mechanisms of regulation just beginning to be understood. Consequently, there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes, so tissue damage in the gastrointestinal tract of patients, even those in clinical remission, persists. With increased understanding of the molecular mechanisms of IBD and MH, tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response. In this review, we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.
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Affiliation(s)
- Megan Lynn Otte
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Raju Lama Tamang
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Julia Papapanagiotou
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Amar B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
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22
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Foerster EG, Tsang DKL, Goyal S, Robertson SJ, Robert LM, Maughan H, Streutker CJ, Girardin SE, Philpott DJ. ATG16L1 protects from interferon-γ-induced cell death in the small intestinal crypt. Mucosal Immunol 2023; 16:135-152. [PMID: 36792009 DOI: 10.1016/j.mucimm.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/02/2023] [Accepted: 02/03/2023] [Indexed: 02/15/2023]
Abstract
The breakdown of the intestinal mucosal barrier is thought to underlie the progression to Crohn disease (CD), whereby numerous risk factors contribute. For example, a genetic polymorphism of the autophagy gene ATG16L1, associated with an increased risk of developing CD, contributes to the perturbation of the intestinal epithelium. We examined the role of Atg16l1 in protecting the murine small intestinal epithelium from T-cell-mediated damage using the anti-CD3 model of enteropathy. Our work showed that mice specifically deleted for Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1ΔIEC) had exacerbated intestinal damage, characterized by crypt epithelial cell death, heightened inflammation, and decreased survival. Moreover, Atg16l1 deficiency delayed the recovery of the intestinal epithelium, and Atg16l1-deficient IECs were impaired in their proliferative response. Pathology was largely driven by interferon (IFN)-γ signaling in Atg16l1ΔIEC mice. Mechanistically, although survival was rescued by blocking tumor necrosis factor or IFN-γ independently, only anti-IFN-γ treatment abrogated IEC death in Atg16l1ΔIEC mice, thereby decoupling IEC death and survival. In summary, our findings suggest differential roles for IFN-γ and tumor necrosis factor in acute enteropathy and IEC death in the context of autophagy deficiency and suggest that IFN-γ-targeted therapy may be appropriate for patients with CD with variants in ATG16L1.
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Affiliation(s)
| | - Derek K L Tsang
- Department of Immunology, University of Toronto, Toronto, Canada
| | - Shawn Goyal
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | | | - Lukian M Robert
- Department of Immunology, University of Toronto, Toronto, Canada
| | | | - Catherine J Streutker
- Department of Laboratory Medicine, St. Michael's Hospital, Unity Health, Toronto, Canada
| | - Stephen E Girardin
- Department of Immunology, University of Toronto, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
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23
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Kasprzak A. Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia. Int J Mol Sci 2023; 24:ijms24043665. [PMID: 36835075 PMCID: PMC9959216 DOI: 10.3390/ijms24043665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/02/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common human malignancies worldwide. Along with apoptosis and inflammation, autophagy is one of three important mechanisms in CRC. The presence of autophagy/mitophagy in most normal mature intestinal epithelial cells has been confirmed, where it has mainly protective functions against reactive oxygen species (ROS)-induced DNA and protein damage. Autophagy regulates cell proliferation, metabolism, differentiation, secretion of mucins and/or anti-microbial peptides. Abnormal autophagy in intestinal epithelial cells leads to dysbiosis, a decline in local immunity and a decrease in cell secretory function. The insulin-like growth factor (IGF) signaling pathway plays an important role in colorectal carcinogenesis. This is evidenced by the biological activities of IGFs (IGF-1 and IGF-2), IGF-1 receptor type 1 (IGF-1R) and IGF-binding proteins (IGF BPs), which have been reported to regulate cell survival, proliferation, differentiation and apoptosis. Defects in autophagy are found in patients with metabolic syndrome (MetS), inflammatory bowel diseases (IBD) and CRC. In neoplastic cells, the IGF system modulates the autophagy process bidirectionally. In the current era of improving CRC therapies, it seems important to investigate the exact mechanisms not only of apoptosis, but also of autophagy in different populations of tumor microenvironment (TME) cells. The role of the IGF system in autophagy in normal as well as transformed colorectal cells still seems poorly understood. Hence, the aim of the review was to summarize the latest knowledge on the role of the IGF system in the molecular mechanisms of autophagy in the normal colon mucosa and in CRC, taking into account the cellular heterogeneity of the colonic and rectal epithelium.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
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24
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An L, Wirth U, Koch D, Schirren M, Drefs M, Koliogiannis D, Niess H, Andrassy J, Guba M, Bazhin AV, Werner J, Kühn F. Metabolic Role of Autophagy in the Pathogenesis and Development of NAFLD. Metabolites 2023; 13:metabo13010101. [PMID: 36677026 PMCID: PMC9864958 DOI: 10.3390/metabo13010101] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 12/31/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disease, ranging from simple steatosis to hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver fibrosis, which portends a poor prognosis in NAFLD, is characterized by the excessive accumulation of extracellular matrix (ECM) proteins resulting from abnormal wound repair response and metabolic disorders. Various metabolic factors play crucial roles in the progression of NAFLD, including abnormal lipid, bile acid, and endotoxin metabolism, leading to chronic inflammation and hepatic stellate cell (HSC) activation. Autophagy is a conserved process within cells that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. Accumulating evidence has shown the importance of autophagy in NAFLD and its close relation to NAFLD progression. Thus, regulation of autophagy appears to be beneficial in treating NAFLD and could become an important therapeutic target.
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25
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Zhang K, Huang Q, Peng L, Lin S, Liu J, Zhang J, Li C, Zhai S, Xu Z, Wang S. The multifunctional roles of autophagy in the innate immune response: Implications for regulation of transplantation rejection. Front Cell Dev Biol 2022; 10:1007559. [PMID: 36619861 PMCID: PMC9810636 DOI: 10.3389/fcell.2022.1007559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 11/04/2022] [Indexed: 12/24/2022] Open
Abstract
Organ transplantation is the main treatment for end-stage organ failure, which has rescued tens of thousands of lives. Immune rejection is the main factor affecting the survival of transplanted organs. How to suppress immune rejection is an important goal of transplantation research. A graft first triggers innate immune responses, leading to graft inflammation, tissue injury and cell death, followed by adaptive immune activation. At present, the importance of innate immunity in graft rejection is poorly understood. Autophagy, an evolutionarily conserved intracellular degradation system, is proven to be involved in regulating innate immune response following graft transplants. Moreover, there is evidence indicating that autophagy can regulate graft dysfunction. Although the specific mechanism by which autophagy affects graft rejection remains unclear, autophagy is involved in innate immune signal transduction, inflammatory response, and various forms of cell death after organ transplantation. This review summarizes how autophagy regulates these processes and proposes potential targets for alleviating immune rejection.
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Affiliation(s)
- Kunli Zhang
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China
| | - Qiuyan Huang
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Laru Peng
- Guangzhou Laboratory, Guangzhou International BioIsland, Guangzhou, China
| | - Sen Lin
- Sericultural & Agri-Food Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Jie Liu
- Guangdong Yantang Dairy Co, Ltd, Guangzhou, China
| | - Jianfeng Zhang
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China,Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming, China
| | - Chunling Li
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China
| | - Shaolun Zhai
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China
| | - Zhihong Xu
- Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangdong Provincial Key Laboratory of Livestock Disease Prevention Guangdong Province, Scientific Observation and Experiment Station of Veterinary Drugs and Diagnostic Techniques of Guangdong Province, Ministry of Agriculture and Rural Affairs, Guangzhou, China,*Correspondence: Zhihong Xu, ; Sutian Wang,
| | - Sutian Wang
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China,Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming, China,*Correspondence: Zhihong Xu, ; Sutian Wang,
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26
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Ma Q, Li X, Wang S, Wang Q, Li Y, Li K, Wang J, Zhang Q, Wu J, Chen H. Niche-Dependent Regulation of Lkb1 in the Proliferation of Lung Epithelial Progenitor Cells. Int J Mol Sci 2022; 23:15065. [PMID: 36499390 PMCID: PMC9735896 DOI: 10.3390/ijms232315065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022] Open
Abstract
Lung homeostasis and regeneration depend on lung epithelial progenitor cells. Lkb1 (Liver Kinase B1) has known roles in the differentiation of airway epithelial cells during embryonic development. However, the effects of Lkb1 in adult lung epithelial progenitor cell regeneration and its mechanisms of action have not been determined. In this study, we investigated the mechanism by which Lkb1 regulates lung epithelial progenitor cell regeneration. Organoid culture showed that loss of Lkb1 significantly reduced the proliferation of club cells and alveolar type 2 (AT2) cells in vitro. In the absence of Lkb1, there is a slower recovery rate of the damaged airway epithelium in naphthalene-induced airway epithelial injury and impaired expression of surfactant protein C during bleomycin-induced alveolar epithelial damage. Moreover, the expression of autophagy-related genes was reduced in club cells and increased in AT2 cells, but the expression of Claudin-18 was obviously reduced in AT2 cells after Lkb1 knockdown. On the whole, our findings indicated that Lkb1 may promote the proliferation of lung epithelial progenitor cells via a niche-dependent pathway and is required for the repair of the damaged lung epithelium.
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Affiliation(s)
- Qingwen Ma
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Jinnan District, Tianjin 300350, China
| | - Xue Li
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Jinnan District, Tianjin 300350, China
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Sisi Wang
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Jinnan District, Tianjin 300350, China
| | - Qi Wang
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Yu Li
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Kuan Li
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Jianhai Wang
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Qiuyang Zhang
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
| | - Junping Wu
- Department of Tuberculosis, Haihe Hospital, Tianjin University, Jinnan District, Tianjin 300350, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Jinnan District, Tianjin 300350, China
| | - Huaiyong Chen
- Department of Basic Medicine, Haihe Clinical School, Tianjin Medical University, Jinnan District, Tianjin 300350, China
- Department of Basic Medicine, Haihe Hospital, Tianjin University, Jinan District, Tianjin 300350, China
- Key Research Laboratory for Infectious Disease Prevention for State Administration of Traditional Chinese Medicine, Tianjin Institute of Respiratory Diseases, Jinnan District, Tianjin 300350, China
- Tianjin Key Laboratory of Lung Regenerative Medicine, Jinnan District, Tianjin 300350, China
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27
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Johnson NM, Parham LR, Na J, Monaghan KE, Kolev HM, Klochkova A, Kim MS, Danan CH, Cramer Z, Simon LA, Naughton KE, Adams‐Tzivelekidis S, Tian Y, Williams PA, Leu NA, Sidoli S, Whelan KA, Li N, Lengner CJ, Hamilton KE. Autophagic state prospectively identifies facultative stem cells in the intestinal epithelium. EMBO Rep 2022; 23:e55209. [PMID: 36120829 PMCID: PMC9638868 DOI: 10.15252/embr.202255209] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 08/24/2022] [Accepted: 09/05/2022] [Indexed: 01/25/2023] Open
Abstract
The intestinal epithelium exhibits a rapid and efficient regenerative response to injury. Emerging evidence supports a model where plasticity of differentiated cells, particularly those in the secretory lineages, contributes to epithelial regeneration upon ablation of injury-sensitive stem cells. However, such facultative stem cell activity is rare within secretory populations. Here, we ask whether specific functional properties predict facultative stem cell activity. We utilize in vivo labeling combined with ex vivo organoid formation assays to evaluate how cell age and autophagic state contribute to facultative stem cell activity within secretory lineages. Strikingly, we find that cell age (time elapsed since cell cycle exit) does not correlate with secretory cell plasticity. Instead, high autophagic vesicle content predicts plasticity and resistance to DNA damaging injury independently of cell lineage. Our findings indicate that autophagic status prior to injury serves as a lineage-agnostic marker for the prospective identification of facultative stem cells.
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Affiliation(s)
- Nicolette M Johnson
- Medical Scientist Training Program, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Louis R Parham
- Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Division of Gastroenterology, Hepatology, and NutritionChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
| | - Jeeyoon Na
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Keara E Monaghan
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Hannah M Kolev
- Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Alena Klochkova
- Fels Institute for Cancer Research & Molecular BiologyLewis Katz School of Medicine at Temple UniversityPhiladelphiaPennsylvaniaUSA
| | - Melissa S Kim
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Charles H Danan
- Medical Scientist Training Program, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Division of Gastroenterology, Hepatology, and NutritionChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
| | - Zvi Cramer
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Lauren A Simon
- Division of Gastroenterology, Hepatology, and NutritionChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
| | - Kaitlyn E Naughton
- Division of Gastroenterology, Hepatology, and NutritionChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
| | - Stephanie Adams‐Tzivelekidis
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Yuhua Tian
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Patrick A Williams
- Division of Gastroenterology, Hepatology, and NutritionChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
| | - N Adrian Leu
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Simone Sidoli
- Department of BiochemistryAlbert Einstein College of MedicineBronxNew YorkUSA
| | - Kelly A Whelan
- Fels Institute for Cancer Research & Molecular BiologyLewis Katz School of Medicine at Temple UniversityPhiladelphiaPennsylvaniaUSA
- Department of Pathology & Laboratory MedicineLewis Katz School of Medicine at Temple UniversityPhiladelphiaPennsylvaniaUSA
| | - Ning Li
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Institute for Regenerative MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Christopher J Lengner
- Department of Biomedical Sciences, School of Veterinary MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Institute for Regenerative MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Cell & Developmental Biology, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Kathryn E Hamilton
- Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Division of Gastroenterology, Hepatology, and NutritionChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
- Institute for Regenerative MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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28
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Zhang F, Liu T, Huang HC, Zhao YY, He M, Yuan W, Li L, Li J, Wu DM, Xu Y. Activation of pyroptosis and ferroptosis is involved in radiation-induced intestinal injury in mice. Biochem Biophys Res Commun 2022; 631:102-109. [DOI: 10.1016/j.bbrc.2022.09.073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/02/2022]
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29
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Wang YC, Leng XX, Zhou CB, Lu SY, Tsang CK, Xu J, Zhang MM, Chen HM, Fang JY. Non-enzymatic role of SOD1 in intestinal stem cell growth. Cell Death Dis 2022; 13:882. [PMID: 36266264 PMCID: PMC9585064 DOI: 10.1038/s41419-022-05267-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 09/09/2022] [Accepted: 09/14/2022] [Indexed: 11/05/2022]
Abstract
Superoxide dismutase 1 (SOD1) modulates intestinal barrier integrity and intestinal homeostasis as an antioxidant enzyme. Intestinal homeostasis is maintained by the intestinal stem cells (ISCs). However, whether and how SOD1 regulates ISCs is unknown. In this study, we established intestinal organoids from tamoxifen-inducible intestinal epithelial cell-specific Sod1 knockout (Sod1f/f; Vil-creERT2) mice. We found that loss of Sod1 in organoids suppressed the proliferation and survival of cells and Lgr5 gene expression. SOD1 is known for nearly half a century for its canonical role as an antioxidant enzyme. We identified its enzyme-independent function in ISC: inhibition of SOD1 enzymatic activity had no impact on organoid growth, and enzymatically inactive Sod1 mutants could completely rescue the growth defects of Sod1 deficient organoids, suggesting that SOD1-mediated ISC growth is independent of its enzymatic activity. Moreover, Sod1 deficiency did not affect the ROS levels of the organoid, but induced the elevated WNT signaling and excessive Paneth cell differentiation, which mediates the occurrence of growth defects in Sod1 deficient organoids. In vivo, epithelial Sod1 loss induced a higher incidence of apoptosis in the stem cell regions and increased Paneth cell numbers, accompanied by enhanced expression of EGFR ligand Epiregulin (EREG) in the stromal tissue, which may compensate for Sod1 loss and maintain intestinal structure in vivo. Totally, our results show a novel enzyme-independent function of SOD1 in ISC growth under homeostasis.
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Affiliation(s)
- Ying-Chao Wang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Xu Leng
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Cheng-Bei Zhou
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shi-Yuan Lu
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chi Kwan Tsang
- Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jie Xu
- Institutes of Biomedical Sciences, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China
| | - Ming-Ming Zhang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hui-Min Chen
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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30
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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.
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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
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31
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Fan J, Lin B, Fan M, Niu T, Gao F, Tan B, Du X. Research progress on the mechanism of radiation enteritis. Front Oncol 2022; 12:888962. [PMID: 36132154 PMCID: PMC9483210 DOI: 10.3389/fonc.2022.888962] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 08/10/2022] [Indexed: 12/12/2022] Open
Abstract
Radiation enteritis (Re) is one of the most common complications of radiation therapy for abdominal tumors. The efficacy of cancer treatment by radiation is often limited by the side effects of Re. Re can be acute or chronic. Treatment of acute Re is essentially symptomatic. However, chronic Re usually requires surgical procedures. The underlying mechanisms of Re are complex and have not yet been elucidated. The purpose of this review is to provide an overview of the pathogenesis of Re. We reviewed the role of intestinal epithelial cells, intestinal stem cells (ISCs), vascular endothelial cells (ECs), intestinal microflora, and other mediators of Re, noting that a better understanding of the pathogenesis of Re may lead to better treatment modalities.
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Affiliation(s)
- Jinjia Fan
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
| | - Binwei Lin
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
| | - Mi Fan
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
| | - Tintin Niu
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
| | - Feng Gao
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
| | - Bangxian Tan
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
| | - Xiaobo Du
- Departmant of Oncology, National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology, Mianyang, China
- Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nan Chong, China
- *Correspondence: Xiaobo Du,
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32
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Luo H, Li M, Wang F, Yang Y, Wang Q, Zhao Y, Du F, Chen Y, Shen J, Zhao Q, Zeng J, Wang S, Chen M, Li X, Li W, Sun Y, Gu L, Wen Q, Xiao Z, Wu X. The role of intestinal stem cell within gut homeostasis: Focusing on its interplay with gut microbiota and the regulating pathways. Int J Biol Sci 2022; 18:5185-5206. [PMID: 35982910 PMCID: PMC9379405 DOI: 10.7150/ijbs.72600] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 07/29/2022] [Indexed: 12/05/2022] Open
Abstract
Intestinal stem cells (ISCs) play an important role in maintaining intestinal homeostasis via promoting a healthy gut barrier. Within the stem cell niche, gut microbiota linking the crosstalk of dietary influence and host response has been identified as a key regulator of ISCs. Emerging insights from recent research reveal that ISC and gut microbiota interplay regulates epithelial self-renewal. This article reviews the recent knowledge on the key role of ISC in their local environment (stem cell niche) associating with gut microbiota and their metabolites as well as the signaling pathways. The current progress of intestinal organoid culture is further summarized. Subsequently, the key challenges and future directions are discussed.
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Affiliation(s)
- Haoming Luo
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Fang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yifei Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Qin Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qianyun Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Jiuping Zeng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yuhong Sun
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Li Gu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Qinglian Wen
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
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33
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Qiao L, Yan S, Dou X, Song X, Chang J, Pi S, Zhang X, Xu C. Biogenic Selenium Nanoparticles Alleviate Intestinal Epithelial Barrier Damage through Regulating Endoplasmic Reticulum Stress-Mediated Mitophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3982613. [PMID: 36035212 PMCID: PMC9410834 DOI: 10.1155/2022/3982613] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/06/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022]
Abstract
The intestinal barrier plays a fundamental role in body health. Intracellular redox imbalance can trigger endoplasmic reticulum stress (ERS) and mitophagy, leading to intestinal barrier damage. Our previous studies demonstrated that mitophagy is closely associated with the protective effects of biogenic selenium nanoparticles (SeNPs) on intestinal epithelial barrier function. Thus, we hypothesize that ERS and mitophagy are likely involved in the regulatory effects of SeNPs on oxidative stress-induced intestinal epithelial barrier dysfunction. The results showed that oxidative stress or ERS caused the increase of intestinal epithelial permeability. SeNPs effectively alleviated hydrogen peroxide (H2O2-)-induced structural damage of endoplasmic reticulum (ER) and mitochondria of porcine jejunal epithelial cells (IPEC-J2). SeNPs significantly decreased intracellular inositol triphosphate (IP3) and Ca2+ concentration, down-regulated inositol trisphosphate receptor (IP3R) expression level, and up-regulated ER-resident selenoproteins mRNA levels in IPEC-J2 cells exposed to H2O2. In addition, SeNPs pretreatment significantly decreased the intracellular Ca2+, IP3, IP3R, and reactive oxygen species (ROS) levels; protected the structure and function of ER and mitochondria; and effectively alleviated the increase of intestinal epithelial permeability of IPEC-J2 cells exposed to tunicamycin (TM). Moreover, SeNPs significantly inhibited the colocalization of mitochondria and lysosomes. Furthermore, compared with TM model group, SeNPs significantly inhibited the activation of PERK/eIF2α/ATF4 and AMPK/mTOR/PINK1 signaling pathway. The PERK agonist (CCT020312) and the AMPK agonist (AICAR) could reverse the protective effects of SeNPs on IPEC-J2 cells. The PERK inhibitor (GSK2656157) and the AMPK inhibitor (compound C) had a similar effect on IPEC-J2 cells as that of SeNPs. In summary, the protective effects of SeNPs on intestinal barrier dysfunction are closely associated with ERS-related PERK and mitophagy-related AMPK signaling pathway.
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Affiliation(s)
- Lei Qiao
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Shuqi Yan
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xina Dou
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xiaofan Song
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Jiajing Chang
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Shanyao Pi
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Xinyi Zhang
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
| | - Chunlan Xu
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi 710072, China
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34
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Zhao L, Hu X, Xiao F, Zhang X, Zhao L, Wang M. Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus. Front Immunol 2022; 13:929520. [PMID: 35958572 PMCID: PMC9358979 DOI: 10.3389/fimmu.2022.929520] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/28/2022] [Indexed: 12/12/2022] Open
Abstract
Nucleic acid autoantibodies, increase type I interferon (IFN-α) levels, and immune cell hyperactivation are hallmarks of systemic lupus erythematosus (SLE). Notably, immune cell activation requires high level of cellular energy that is predominately generated by the mitochondria. Mitochondrial reactive oxygen species (mROS), the byproduct of mitochondrial energy generation, serves as an essential mediator to control the activation and differentiation of cells and regulate the antigenicity of oxidized nucleoids within the mitochondria. Recently, clinical trials on normalization of mitochondrial redox imbalance by mROS scavengers and those investigating the recovery of defective mitophagy have provided novel insights into SLE prophylaxis and therapy. However, the precise mechanism underlying the role of oxidative stress-related mitochondrial molecules in skewing the cell fate at the molecular level remains unclear. This review outlines distinctive mitochondrial functions and pathways that are involved in immune responses and systematically delineates how mitochondrial dysfunction contributes to SLE pathogenesis. In addition, we provide a comprehensive overview of damaged mitochondrial function and impaired metabolic pathways in adaptive and innate immune cells and lupus-induced organ tissues. Furthermore, we summarize the potential of current mitochondria-targeting drugs for SLE treatment. Developing novel therapeutic approaches to regulate mitochondrial oxidative stress is a promising endeavor in the search for effective treatments for systemic autoimmune diseases, particularly SLE.
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Affiliation(s)
- Like Zhao
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianda Hu
- Beijing Tibetan Hospital, China Tibetology Research Center, Beijing, China
| | - Fei Xiao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Clinical Biobank, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lidan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science and Technology, Beijing, China
- *Correspondence: Min Wang, ; Lidan Zhao,
| | - Min Wang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Min Wang, ; Lidan Zhao,
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35
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Yang Y, Gomez M, Marsh T, Poillet-Perez L, Sawant A, Chen L, Park NR, Jackson SR, Hu Z, Alon N, Liu C, Debnath J, Guan JL, Davidson S, Verzi M, White E. Autophagy in PDGFRα+ mesenchymal cells is essential for intestinal stem cell survival. Proc Natl Acad Sci U S A 2022; 119:e2202016119. [PMID: 35537042 PMCID: PMC9173755 DOI: 10.1073/pnas.2202016119] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 03/15/2022] [Indexed: 12/14/2022] Open
Abstract
Autophagy defects are a risk factor for inflammatory bowel diseases (IBDs) through unknown mechanisms. Whole-body conditional deletion of autophagy-related gene (Atg) Atg7 in adult mice (Atg7Δ/Δ) causes tissue damage and death within 3 mo due to neurodegeneration without substantial effect on intestine. In contrast, we report here that whole-body conditional deletion of other essential Atg genes Atg5 or Fip200/Atg17 in adult mice (Atg5Δ/Δ or Fip200Δ/Δ) caused death within 5 d due to rapid autophagy inhibition, elimination of ileum stem cells, and loss of barrier function. Atg5Δ/Δ mice lost PDGFRα+ mesenchymal cells (PMCs) and Wnt signaling essential for stem cell renewal, which were partially rescued by exogenous Wnt. Matrix-assisted laser desorption ionization coupled to mass spectrometry imaging (MALDI-MSI) of Atg5Δ/Δ ileum revealed depletion of aspartate and nucleotides, consistent with metabolic insufficiency underlying PMC loss. The difference in the autophagy gene knockout phenotypes is likely due to distinct kinetics of autophagy loss, as deletion of Atg5 more gradually extended lifespan phenocopying deletion of Atg7 or Atg12. Thus, autophagy is required for PMC metabolism and ileum stem cell and mammalian survival. Failure to maintain PMCs through autophagy may therefore contribute to IBD.
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Affiliation(s)
- Yang Yang
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903
| | - Maria Gomez
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903
- Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544
| | - Timothy Marsh
- Department of Pathology, University of California, San Francisco, CA 94143
| | | | - Akshada Sawant
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903
| | - Lei Chen
- Department of Genetics, Rutgers University, Piscataway, NJ, 08854
| | - Noel R. Park
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - S. RaElle Jackson
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544
| | - Zhixian Hu
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903
- Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544
| | - Noa Alon
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903
- School of Art Sciences, Rutgers University, New Brunswick, NJ 08901
| | - Chen Liu
- Department of Pathology and Laboratory Medicine, Robert Wood Johnson University Hospital, New Brunswick, NJ 08903
| | - Jayanta Debnath
- Department of Pathology, University of California, San Francisco, CA 94143
| | - Jun-Lin Guan
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267
| | - Shawn Davidson
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544
| | - Michael Verzi
- Department of Genetics, Rutgers University, Piscataway, NJ, 08854
| | - Eileen White
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903
- Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544
- School of Art Sciences, Rutgers University, New Brunswick, NJ 08901
- Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854
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36
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A Promising Insight: The Potential Influence and Therapeutic Value of the Gut Microbiota in GI GVHD. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2124627. [PMID: 35571252 PMCID: PMC9098338 DOI: 10.1155/2022/2124627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/13/2022] [Indexed: 02/07/2023]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HSCT) is a reconstruction process of hematopoietic and immune functions that can be curative in patients with hematologic malignancies, but it carries risks of graft-versus-host disease (GVHD), thrombotic microangiopathy (TMA), Epstein–Barr virus (EBV) infection, cytomegalovirus infection, secondary hemophagocytic lymphohistiocytosis (sHLH), macrophage activation syndrome (MAS), bronchiolitis obliterans, and posterior reversible encephalopathy syndrome (PRES). Gastrointestinal graft-versus-host disease (GI GVHD), a common complication of allo-HSCT, is one of the leading causes of transplant-related death because of its high treatment difficulty, which is affected by preimplantation, antibiotic use, dietary changes, and intestinal inflammation. At present, human trials and animal studies have proven that a decrease in intestinal bacterial diversity is associated with the occurrence of GI GVHD. Metabolites produced by intestinal bacteria, such as lipopolysaccharides, short-chain fatty acids, and secondary bile acids, can affect the development of GVHD through direct or indirect interactions with immune cells. The targeted damage of GVHD on intestinal stem cells (ISCs) and Paneth cells results in intestinal dysbiosis or dysbacteriosis. Based on the effect of microbiota metabolites on the gastrointestinal tract, the clinical treatment of GI GVHD can be further optimized. In this review, we describe the mechanisms of GI GVHD and the damage it causes to intestinal cells and we summarize recent studies on the relationship between intestinal microbiota and GVHD in the gastrointestinal tract, highlighting the role of intestinal microbiota metabolites in GI GVHD. We hope to elucidate strategies for immunomodulatory combined microbiota targeting in the clinical treatment of GI GVHD.
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Abstract
Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function. Recent work has, however, provided evidence that stem cells do have a metabolic signature that is distinct from that of restricted progenitors and that metabolic changes influence tissue homeostasis and regeneration. Stem cell maintenance throughout life in many tissues depends upon minimizing anabolic pathway activation and cell division. Consequently, stem cell activation by tissue injury is associated with changes in mitochondrial function, lysosome activity and lipid metabolism, potentially at the cost of eroding self-renewal potential. Stem cell metabolism is also regulated by the environment: stem cells metabolically interact with other cells in their niches and are able to sense and adapt to dietary changes. The accelerating understanding of stem cell metabolism is revealing new aspects of tissue homeostasis with the potential to promote tissue regeneration and cancer suppression.
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Singh V, Ahlawat S, Mohan H, Gill SS, Sharma KK. Balancing reactive oxygen species generation by rebooting gut microbiota. J Appl Microbiol 2022; 132:4112-4129. [PMID: 35199405 DOI: 10.1111/jam.15504] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/16/2022] [Accepted: 02/17/2022] [Indexed: 11/30/2022]
Abstract
Reactive oxygen species (ROS; free radical form O2 •‾ , superoxide radical; OH• , hydroxyl radical; ROO• , peroxyl; RO• , alkoxyl and non-radical form 1 O2 , singlet oxygen; H2 O2 , hydrogen peroxide) are inevitable companions of aerobic life with crucial role in gut health. But, overwhelming production of ROS can cause serious damage to biomolecules. In this review, we have discussed several sources of ROS production that can be beneficial or dangerous to the human gut. Microorganisms, organelles and enzymes play crucial role in ROS generation, where, NOX1 is the main intestinal enzyme, which produce ROS in the intestine epithelial cells. Previous studies have reported that probiotics play significant role in gut homeostasis by checking the ROS generation, maintaining the antioxidant level, immune system and barrier protection. With current knowledge, we have critically analyzed the available literature and presented the outcome in the form of bubble maps to suggest the probiotics that help in controlling the ROS-specific intestinal diseases, such as inflammatory bowel disease (IBD) and colon cancer. Finally, it has been concluded that rebooting of the gut microbiota with probiotics, postbiotics or fecal microbiota transplantation (FMT) can have crucial implications in the structuring of gut communities for the personalized management of the gastrointestinal (GI) diseases.
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Affiliation(s)
- Vandna Singh
- Department of Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Shruti Ahlawat
- Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India.,Presently at SGT University, Badli Road Chandu, Budhera, Gurugr, Gurgaon, Haryana, India
| | - Hari Mohan
- Department of Medical Biotechnology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Sarvajeet Singh Gill
- Department of Plant Biotechnology, Maharshi Dayanand University, Rohtak, Haryana, India
| | - Krishna Kant Sharma
- Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak, Haryana, India
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Nowosad A, Besson A. Lysosomes at the Crossroads of Cell Metabolism, Cell Cycle, and Stemness. Int J Mol Sci 2022; 23:ijms23042290. [PMID: 35216401 PMCID: PMC8879101 DOI: 10.3390/ijms23042290] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/11/2022] [Accepted: 02/16/2022] [Indexed: 02/07/2023] Open
Abstract
Initially described as lytic bodies due to their degradative and recycling functions, lysosomes play a critical role in metabolic adaptation to nutrient availability. More recently, the contribution of lysosomal proteins to cell signaling has been established, and lysosomes have emerged as signaling hubs that regulate diverse cellular processes, including cell proliferation and cell fate. Deciphering these signaling pathways has revealed an extensive crosstalk between the lysosomal and cell cycle machineries that is only beginning to be understood. Recent studies also indicate that a number of lysosomal proteins are involved in the regulation of embryonic and adult stem cell fate and identity. In this review, we will focus on the role of the lysosome as a signaling platform with an emphasis on its function in integrating nutrient sensing with proliferation and cell cycle progression, as well as in stemness-related features, such as self-renewal and quiescence.
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Affiliation(s)
- Ada Nowosad
- Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France;
- Department of Oncology, KULeuven, Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, 3000 Leuven, Belgium
| | - Arnaud Besson
- Molecular, Cellular and Developmental Biology Department (MCD), Centre de Biologie Intégrative (CBI), University of Toulouse, CNRS, UPS, 31062 Toulouse, France;
- Correspondence: ; Tel.: +33-561558486
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40
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Foerster EG, Mukherjee T, Cabral-Fernandes L, Rocha JD, Girardin SE, Philpott DJ. How autophagy controls the intestinal epithelial barrier. Autophagy 2022; 18:86-103. [PMID: 33906557 PMCID: PMC8865220 DOI: 10.1080/15548627.2021.1909406] [Citation(s) in RCA: 213] [Impact Index Per Article: 71.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 03/15/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023] Open
Abstract
Macroautophagy/autophagy is a cellular catabolic process that results in lysosome-mediated recycling of organelles and protein aggregates, as well as the destruction of intracellular pathogens. Its role in the maintenance of the intestinal epithelium is of particular interest, as several autophagy-related genes have been associated with intestinal disease. Autophagy and its regulatory mechanisms are involved in both homeostasis and repair of the intestine, supporting intestinal barrier function in response to cellular stress through tight junction regulation and protection from cell death. Furthermore, a clear role has emerged for autophagy not only in secretory cells but also in intestinal stem cells, where it affects their metabolism, as well as their proliferative and regenerative capacity. Here, we review the physiological role of autophagy in the context of intestinal epithelial maintenance and how genetic mutations affecting autophagy contribute to the development of intestinal disease.Abbreviations: AKT1S1: AKT1 substrate 1; AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; APC: APC regulator of WNT signaling pathway; ATF6: activating transcription factor 6; ATG: autophagy related; atg16l1[ΔIEC] mice: mice with a specific deletion of Atg16l1 in intestinal epithelial cells; ATP: adenosine triphosphate; BECN1: beclin 1; bsk/Jnk: basket; CADPR: cyclic ADP ribose; CALCOCO2: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CD: Crohn disease; CDH1/E-cadherin: cadherin 1; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator; CGAS: cyclic GMP-AMP synthase; CLDN2: claudin 2; CoPEC: colibactin-producing E. coli; CRC: colorectal cancer; CYP1A1: cytochrome P450 family 1 subfamily A member 1; DC: dendritic cell; DDIT3: DNA damage inducible transcript 3; DEPTOR: DEP domain containing MTOR interacting protein; DSS: dextran sulfate sodium; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; EIF2AK4/GCN2: eukaryotic translation initiation factor 2 alpha kinase 4; ER: endoplasmic reticulum; ERN1: endoplasmic reticulum to nucleus signaling 1; GABARAP: GABA type A receptor-associated protein; HMGB1: high mobility group box 1; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; IBD: inflammatory bowel disease; IEC: intestinal epithelial cell; IFN: interferon; IFNG/IFNγ:interferon gamma; IL: interleukin; IRGM: immunity related GTPase M; ISC: intestinal stem cell; LGR5: leucine rich repeat containing G protein-coupled receptor 5; LRRK2: leucine rich repeat kinase 2; MAP1LC3A/LC3: microtubule associated protein 1 light chain 3 alpha; MAPK/JNK: mitogen-activated protein kinase; MAPK14/p38 MAPK: mitogen-activated protein kinase 14; MAPKAP1: MAPK associated protein 1; MAVS: mitochondrial antiviral signaling protein; miRNA: microRNA; MLKL: mixed lineage kinase domain like pseudokinase; MLST8: MTOR associated protein, LST8 homolog; MNV: murine norovirus; MTOR: mechanistic target of rapamycin kinase; NBR1: NBR1 autophagy cargo receptor; NLRP: NLR family pyrin domain containing; NOD: nucleotide binding oligomerization domain containing; NRBF2: nuclear receptor binding factor 2; OPTN: optineurin; OXPHOS: oxidative phosphorylation; P: phosphorylation; Patj: PATJ crumbs cell polarity complex component; PE: phosphatidyl-ethanolamine; PI3K: phosphoinositide 3-kinase; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PPARG: peroxisome proliferator activated receptor gamma; PRR5: proline rich 5; PRR5L: proline rich 5 like; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol 3-phosphate; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RER: rough endoplasmic reticulum; RHEB: Ras homolog, MTORC1 binding; RICTOR: RPTOR independent companion of MTOR complex 2; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; RPTOR: regulatory associated protein of MTOR complex 1; RPS6KB1: ribosomal protein S6 kinase B1; SH3GLB1: SH3 domain containing GRB2 like, endophilin B1; SNP: single-nucleotide polymorphism; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; STING1: stimulator of interferon response cGAMP interactor 1; TA: transit-amplifying; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; TGM2: transglutaminase 2; TJ: tight junction; TJP1/ZO1: tight junction protein 1; TNBS: 2,4,6-trinitrobenzene sulfonic acid; TNF/TNFα: tumor necrosis factor; Tor: target of rapamycin; TRAF: TNF receptor associated factor; TRIM11: tripartite motif containing 11; TRP53: transformation related protein 53; TSC: TSC complex subunit; Ub: ubiquitin; UC: ulcerative colitis; ULK1: unc-51 like autophagy activating kinase 1; USO1/p115: USO1 vesicle transport factor; UVRAG: UV radiation resistance associated; WIPI: WD repeat domain, phosphoinositide interacting; WNT: WNT family member; XBP1: X-box binding protein 1; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.
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Affiliation(s)
| | - Tapas Mukherjee
- Department of Immunology, University of Toronto, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | | | | | - Stephen E. Girardin
- Department of Immunology, University of Toronto, Toronto, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Dana J. Philpott
- Department of Immunology, University of Toronto, Toronto, Canada
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Zhang K, Huang Q, Deng S, Yang Y, Li J, Wang S. Mechanisms of TLR4-Mediated Autophagy and Nitroxidative Stress. Front Cell Infect Microbiol 2021; 11:766590. [PMID: 34746034 PMCID: PMC8570305 DOI: 10.3389/fcimb.2021.766590] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 10/04/2021] [Indexed: 01/23/2023] Open
Abstract
Pathogenic infections have badly affected public health and the development of the breeding industry. Billions of dollars are spent every year fighting against these pathogens. The immune cells of a host produce reactive oxygen species and reactive nitrogen species which promote the clearance of these microbes. In addition, autophagy, which is considered an effective method to promote the destruction of pathogens, is involved in pathological processes. As research continues, the interplay between autophagy and nitroxidative stress has become apparent. Autophagy is always intertwined with nitroxidative stress. Autophagy regulates nitroxidative stress to maintain homeostasis within an appropriate range. Intracellular oxidation, in turn, is a strong inducer of autophagy. Toll-like receptor 4 (TLR4) is a pattern recognition receptor mainly involved in the regulation of inflammation during infectious diseases. Several studies have suggested that TLR4 is also a key regulator of autophagy and nitroxidative stress. In this review, we describe the role of TLR4 in autophagy and oxidation, and focus on its function in influencing autophagy-nitroxidative stress interactions.
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Affiliation(s)
- Kunli Zhang
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China.,Institute of Animal Health, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Qiuyan Huang
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Shoulong Deng
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Yecheng Yang
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China.,Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding/Guangdong Provincial Research Center of Gene Editing Engineering Technology, Foshan University, Foshan, China
| | - Jianhao Li
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Sutian Wang
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
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Characterisation of autophagy disruption in the ileum of pigs infected with Lawsonia intracellularis. Vet Res Commun 2021; 46:585-592. [PMID: 34669106 PMCID: PMC9165227 DOI: 10.1007/s11259-021-09847-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 10/06/2021] [Indexed: 11/27/2022]
Abstract
Lawsonia intracellularis is the aetiological agent of proliferative enteropathy, an enteric disease endemic in swine. Survival in its intracellular niche of the ileum epithelial lining requires the capacity to subvert, repress or exploit the host immune response to create an environment conducive to bacterial propagation. To better understand how L. intracellularis survives in its intracellular niche, we have performed an investigation into the dynamic relationship between infection and the host autophagy response by immunohistochemistry in experimentally infected porcine ileum samples. Beclin1, a protein required early in the autophagy pathway was observed to be distributed with a basal to apical concentration gradient in the crypts of healthy piglets, whilst infected piglets were observed to have no gradient of distribution and an increase in the presence of Beclin1 in crypts with histological characteristics of L. intracellularis residence. Detecting microtubule-associated protein light chain 3 (LC3) is used as a method for monitoring autophagy progression as it associates with mature autophagosomes. For LC3 there was no notable change in signal intensity between crypts with characteristic L. intracellularis infection and healthy crypts of uninfected pigs. Finally, as p62 is degraded with the internal substrate of an autophagosome it was used to measure autophagic flux. There was no observed reduction or redistribution of p62. These preliminary results of the autophagy response in the ileum suggest that L. intracellularis affects autophagy. This disruption to host ileum homeostasis may provide a mechanism that assists in bacterial propagation and contributes to pathogenesis.
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43
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Qin H, Zhang H, Zhang S, Zhu S, Wang H. Protective Effect of Sirt1 against Radiation-Induced Damage. Radiat Res 2021; 196:647-657. [PMID: 34459925 DOI: 10.1667/rade-20-00139.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 08/11/2021] [Indexed: 11/03/2022]
Abstract
Radiotherapy is an important method for the treatment of malignant tumors. It can directly or indirectly lead to the formation of free radicals and DNA damage, resulting in a series of biological effects, including tumor cell death and normal tissue damage. These radiation effects are typically accompanied by the abnormal expression of sirtuin 1 (Sirt1), which deacetylates histones and non-histones. These Sirt1 substrates, including transcription factors and some catalytic enzymes, play a crucial role in anti-oxidative stress, DNA damage repair, autophagy regulation, anti-senescence, and apoptosis, which are closely related to triggering cell defense and survival in radiation-induced damage. In this article, we review the mechanisms underlying cellular responses to ionizing radiation and the role of Sirt1 in the process, with the aim of providing a theoretical basis for protection against radiation by Sirt1 as well as novel targets for developing radioprotective agents.
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Affiliation(s)
- Haoren Qin
- Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Heng Zhang
- Department of Oncology, Institute of Integrative Oncology, Tianjin Union Medical Center of Nankai University, Tianjin, P.R. China
| | - Shiwu Zhang
- Department of Pathology, Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, P.R. China
| | - Siwei Zhu
- Department of Oncology, Institute of Integrative Oncology, Tianjin Union Medical Center of Nankai University, Tianjin, P.R. China
| | - Hui Wang
- Department of Oncology, Institute of Integrative Oncology, Tianjin Union Medical Center of Nankai University, Tianjin, P.R. China
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Konjar Š, Pavšič M, Veldhoen M. Regulation of Oxygen Homeostasis at the Intestinal Epithelial Barrier Site. Int J Mol Sci 2021; 22:ijms22179170. [PMID: 34502078 PMCID: PMC8431628 DOI: 10.3390/ijms22179170] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/28/2021] [Accepted: 08/19/2021] [Indexed: 12/25/2022] Open
Abstract
The unique biology of the intestinal epithelial barrier is linked to a low baseline oxygen pressure (pO2), characterised by a high rate of metabolites circulating through the intestinal blood and the presence of a steep oxygen gradient across the epithelial surface. These characteristics require tight regulation of oxygen homeostasis, achieved in part by hypoxia-inducible factor (HIF)-dependent signalling. Furthermore, intestinal epithelial cells (IEC) possess metabolic identities that are reflected in changes in mitochondrial function. In recent years, it has become widely accepted that oxygen metabolism is key to homeostasis at the mucosae. In addition, the gut has a vast and diverse microbial population, the microbiota. Microbiome–gut communication represents a dynamic exchange of mediators produced by bacterial and intestinal metabolism. The microbiome contributes to the maintenance of the hypoxic environment, which is critical for nutrient absorption, intestinal barrier function, and innate and/or adaptive immune responses in the gastrointestinal tract. In this review, we focus on oxygen homeostasis at the epithelial barrier site, how it is regulated by hypoxia and the microbiome, and how oxygen homeostasis at the epithelium is regulated in health and disease.
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Affiliation(s)
- Špela Konjar
- Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
- Instituto de Medicina Molecular, João Lobo Antunes, Faculdade de Medicina de Lisboa, 1649-028 Lisbon, Portugal;
- Correspondence:
| | - Miha Pavšič
- Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia;
| | - Marc Veldhoen
- Instituto de Medicina Molecular, João Lobo Antunes, Faculdade de Medicina de Lisboa, 1649-028 Lisbon, Portugal;
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Chen S, Wang W, Tan HY, Lu Y, Li Z, Qu Y, Wang N, Wang D. Role of Autophagy in the Maintenance of Stemness in Adult Stem Cells: A Disease-Relevant Mechanism of Action. Front Cell Dev Biol 2021; 9:715200. [PMID: 34414192 PMCID: PMC8369482 DOI: 10.3389/fcell.2021.715200] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/15/2021] [Indexed: 01/07/2023] Open
Abstract
Autophagy is an intracellular scavenging mechanism induced to eliminate damaged, denatured, or senescent macromolecular substances and organelles in the body. The regulation of autophagy plays essential roles in the processes of cellular homeostasis and senescence. Dysregulated autophagy is a common feature of several human diseases, including cancers and neurodegenerative disorders. The initiation and development of these disorders have been shown to be associated with the maintenance of disease-specific stem cell compartments. In this review, we summarize recent advances in our understanding of the role of autophagy in the maintenance of stemness. Specifically, we focus on the intersection between autophagy and adult stem cells in the initiation and progression of specific diseases. Accordingly, this review highlights the role of autophagy in stemness maintenance from the perspective of disease-associated mechanisms, which may be fundamental to our understanding of the pathogeneses of human diseases and the development of effective therapies.
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Affiliation(s)
- Shanshan Chen
- School of Life Sciences, Jilin University, Changchun, China
| | - Wenqi Wang
- School of Life Sciences, Jilin University, Changchun, China
| | - Hor-Yue Tan
- Centre for Chinese Herbal Medicine Drug Development, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Yuanjun Lu
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Zhiping Li
- School of Life Sciences, Jilin University, Changchun, China
| | - Yidi Qu
- School of Life Sciences, Jilin University, Changchun, China
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Di Wang
- School of Life Sciences, Jilin University, Changchun, China
- Engineering Research Center of Chinese Ministry of Education for Edible and Medicinal Fungi, Jilin Agricultural University, Changchun, China
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Li YH, He Q, Chen YZ, Du YF, Guo YX, Xu JY, Qin LQ. p-Coumaric acid ameliorates ionizing radiation-induced intestinal injury through modulation of oxidative stress and pyroptosis. Life Sci 2021; 278:119546. [PMID: 33915129 DOI: 10.1016/j.lfs.2021.119546] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/16/2021] [Accepted: 04/23/2021] [Indexed: 11/30/2022]
Abstract
AIMS Intestinal injury is a clinical problem related to radiotherapy or accidental exposure to ionizing radiation. This study aimed to investigate the protective effect of p-coumaric acid (CA) against radiation induced intestinal injury. MAIN METHODS The present study orally administered CA to C57BL/6 male mice at 30 min before total body irradiation and continued for 3 days post irradiation. Then, the mice were sacrificed at day 3.5 or 14 after irradiation, respectively. The blood was collected to analyze the inflammatory cytokines. The antioxidant indexes of jejunum tissues were determined. Hematoxylin and eosin staining and apoptosis analysis was studied to investigate the pathological changes of the jejunum tissues. In addition, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were carried out to determine the changes in mRNA and protein levels of jejunum tissues. KEY FINDINGS Compared with the only irradiated group, treatment with CA improved intestinal morphology and apoptosis, increased the villus height and the ratio of villus height to crypt depth. It also reduced the oxidative stress and inflammatory response. The molecular mechanism analysis showed that CA significantly inhibited the pyroptosis genes (Caspase-1, NLRP3 and AIM2) mRNA expression and improved the intestinal barrier genes expression. SIGNIFICANCE The results suggested that CA ameliorates ionizing radiation-induced intestinal injury by inhibition of oxidative stress, inflammatory response and pyroptosis.
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Affiliation(s)
- Yun-Hong Li
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Qian He
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Yu-Zhong Chen
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Ya-Fang Du
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Ya-Xin Guo
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou 215123, Jiangsu Province, China
| | - Jia-Ying Xu
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, Jiangsu Province, China.
| | - Li-Qiang Qin
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, Jiangsu Province, China.
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Qin H, Zhang H, Zhang X, Zhang S, Zhu S, Wang H. Resveratrol protects intestinal epithelial cells against radiation-induced damage by promoting autophagy and inhibiting apoptosis through SIRT1 activation. JOURNAL OF RADIATION RESEARCH 2021; 62:574-581. [PMID: 33912959 PMCID: PMC8273810 DOI: 10.1093/jrr/rrab035] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 01/02/2021] [Indexed: 05/10/2023]
Abstract
Intrinsic autophagy is important for the maintenance of intestinal homeostasis and intestinal regeneration. Ionizing radiation suppresses intrinsic autophagy and reduces damage-induced regeneration in the intestine, resulting in intestinal injury. Resveratrol, a sirtuin 1 (SIRT1) agonist, promotes autophagy and exerts radioprotective effect. In this study, the protective effect of resveratrol against radiation-induced intestinal injury and its potential mechanism were investigated. Intestinal epithelial cells (IEC-6) were exposed to 10 Gy ionizing radiation and resveratrol (0.1-40.0 μM). Cell viability was investigated using Cell Counting Kit 8 (CCK8), apoptosis was observed by Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining and flow cytometry, and the expression of apoptotic and autophagic proteins was determined by western blotting. Resveratrol exerted a high toxicity against IEC-6 cells, but at low concentrations, it inhibited ionizing radiation-induced apoptosis. Resveratrol increased SIRT1 expression after irradiation and inhibited ionizing radiation-induced p53 acetylation and pro-apoptotic protein, Bax, expression. Furthermore, resveratrol promoted autophagy via the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, thereby protecting IEC-6 cells against radiation-induced damage. These results suggest that resveratrol reduces radiation-induced IEC-6 cell damage by inhibiting apoptosis and promoting autophagy via the activation of SIRT1, and that the PI3K/AKT/mTOR signaling pathway is involved in the induction of autophagy.
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Affiliation(s)
- Haoren Qin
- Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Heng Zhang
- Tianjin Union Medical Center of Nankai University, Department of Oncology, Tianjin 300121, China
| | - Xipeng Zhang
- Tianjin Union Medical Center of Nankai University, Department of Colorectal Surgery, Tianjin 300121, China
| | - Shiwu Zhang
- Tianjin Union Medical Center of Nankai University, Department of Pathology, Tianjin 300121, China
| | - Siwei Zhu
- Tianjin Union Medical Center of Nankai University, Department of Oncology, Tianjin 300121, China
| | - Hui Wang
- Corresponding author. Tianjin Union Medical Center of Nankai University, Department of Oncology, 190, Jieyuan Road, Hongqiao District, 300121, Tianjin, Tianjin, China. Tel: (+86)022-27557544; Fax number: 008602227557544; E-mail:
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Superoxide Dismutase 3-Transduced Mesenchymal Stem Cells Preserve Epithelial Tight Junction Barrier in Murine Colitis and Attenuate Inflammatory Damage in Epithelial Organoids. Int J Mol Sci 2021; 22:ijms22126431. [PMID: 34208517 PMCID: PMC8233984 DOI: 10.3390/ijms22126431] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/04/2021] [Accepted: 06/11/2021] [Indexed: 01/08/2023] Open
Abstract
Superoxide dismutase 3 (SOD3), also known as extracellular superoxide dismutase, is an enzyme that scavenges reactive oxygen species (ROS). It has been reported that SOD3 exerts anti-inflammatory abilities in several immune disorders. However, the effect of SOD3 and the underlying mechanism in inflammatory bowel disease (IBD) have not been uncovered. Therefore, in the present study, we investigated whether SOD3 can protect intestinal cells or organoids from inflammation-mediated epithelial damage. Cells or mice were treated with SOD3 protein or SOD3-transduced mesenchymal stem cells (MSCs). Caco-2 cells or intestinal organoids stimulated with pro-inflammatory cytokines were used to evaluate the protective effect of SOD3 on epithelial junctional integrity. Dextran sulfate sodium (DSS)-induced colitis mice received SOD3 or SOD3-transduced MSCs (SOD3-MSCs), and were assessed for severity of disease and junctional protein expression. The activation of the mitogen-activated protein kinase (MAPK) pathway and elevated expression of cytokine-encoding genes decreased in TNF-α-treated Caco-2 cells or DSS-induced colitis mice when treated with SOD3 or SOD3-MSCs. Moreover, the SOD3 supply preserved the expression of tight junction (ZO-1, occludin) or adherence junction (E-cadherin) proteins when inflammation was induced. SOD3 also exerted a protective effect against cytokine- or ROS-mediated damage to intestinal organoids. These results indicate that SOD3 can effectively alleviate enteritis symptoms by maintaining the integrity of epithelial junctions and regulating inflammatory- and oxidative stress.
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Morris O, Jasper H. Reactive Oxygen Species in intestinal stem cell metabolism, fate and function. Free Radic Biol Med 2021; 166:140-146. [PMID: 33600942 DOI: 10.1016/j.freeradbiomed.2021.02.015] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/08/2021] [Accepted: 02/09/2021] [Indexed: 12/16/2022]
Abstract
Long dismissed as merely harmful respiratory by-products, Reactive Oxygen Species (ROS) have emerged as critical intracellular messengers during cell growth and differentiation. ROS's signaling roles are particularly prominent within the intestine, whose high regenerative capacity is maintained by Intestinal Stem Cells (ISCs). In this review, we outline roles for ROS in ISCs as revealed by studies using Drosophila and mouse model systems. We focus particularly on recent studies highlighting how ROS ties to metabolic adaptations, which ensure energy supply matches demand during ISC activation and differentiation. We describe how declines in these adaptive mechanisms, through aging or pathology, promote reciprocal changes in ISC metabolism and ROS signaling. These changes ultimately contribute to aberrant ISC function, a loss of tissue homeostasis, and a shortened lifespan.
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Affiliation(s)
- Otto Morris
- Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Heinrich Jasper
- Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA; Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945-1400, USA.
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Qin H, Zhang H, Zhang X, Zhang S, Zhu S, Wang H. Resveratrol attenuates radiation enteritis through the SIRT1/FOXO3a and PI3K/AKT signaling pathways. Biochem Biophys Res Commun 2021; 554:199-205. [PMID: 33812084 DOI: 10.1016/j.bbrc.2021.03.122] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 03/22/2021] [Indexed: 01/05/2023]
Abstract
Radiation enteritis (RE) is the most common radiotherapy complication, and effective RE treatments are lacking. Resveratrol exerts beneficial effects on radiation injury. However, the effect of resveratrol in radiation-induced intestinal injury and the underlying mechanism remain unclear. Here, a C57BL/6 mouse model of RE was established and an intestinal epithelial cell line was used to evaluate the protective effects of resveratrol against radiation-induced intestinal injury and the underlying mechanisms. Resveratrol improved radiation-induced oxidative stress and cell apoptosis via upregulating antioxidant enzymes and downregulating p53 acetylation. In vivo, resveratrol-treated mice exhibited longer survival; longer villi; more intestinal crypt cells; upregulated expression of Ki67, catalase, and superoxide dismutase 2; and fewer inflammatory proteins and apoptotic cells. These protective effects were suppressed by inhibition of SIRT1. These results demonstrate that resveratrol can reduce radiation-induced intestinal injury by inhibiting oxidative stress and apoptosis via the SIRT1/FOXO3a and PI3K/AKT pathways.
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Affiliation(s)
- Haoren Qin
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Heng Zhang
- Department of Oncology, Institute of Integrative Oncology, Tianjin Union Medical Center of Nankai University, Tianjin, China
| | - Xipeng Zhang
- Department of Colorectal Surgery, Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Institute of Translational Medicine, Tianjin Union Medical Center of Nankai University, Tianjin, China
| | - Siwei Zhu
- Department of Oncology, Institute of Integrative Oncology, Tianjin Union Medical Center of Nankai University, Tianjin, China
| | - Hui Wang
- Department of Oncology, Institute of Integrative Oncology, Tianjin Union Medical Center of Nankai University, Tianjin, China.
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