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Bi D, Hu Y, Hua S, Liu J, Guo S. The regulatory mechanisms of mitophagy and oxidative stress in androgenetic alopecia. Cell Signal 2025; 132:111862. [PMID: 40373842 DOI: 10.1016/j.cellsig.2025.111862] [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: 04/05/2025] [Revised: 05/02/2025] [Accepted: 05/11/2025] [Indexed: 05/17/2025]
Abstract
Androgenetic alopecia (AGA), the most common type of non-scarring hair loss in dermatology, result from a multifaceted interplay of genetic susceptibility, abnormal androgen metabolism, and dysregulation within the follicular microenvironment. Recent studies have highlighted the crucial roles of mitophagy and oxidative stress in the pathogenesis and progression of AGA. Mitophagy, a selective process by which damaged mitochondria are eliminated, is essential for maintaining cellular energy metabolism homeostasis and redox balance. In contrast, oxidative stress results from excessive accumulation of reactive oxygen species (ROS), which induces cellular damage and accelerates disease progression. The disruption of the dynamic balance between mitophagy and oxidative stress is increasingly recognized as a key factor in the development and exacerbation of AGA. Despite initial studies elucidating the interaction between these two processes, the precise molecular mechanisms and regulatory networks governing AGA remain insufficiently understood. This review aims to systematically synthesize the latest findings concerning the interplay between mitophagy and oxidative stress in AGA. By examining their roles in the disease's onset and progression, we identify potential therapeutic targets for intervention. Additionally, we discuss relevant signaling pathways and cellular mechanisms, evaluating the therapeutic potential of targeting mitophagy and oxidative stress for the treatment of AGA.
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Affiliation(s)
- Dezhao Bi
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China; Nanjing University of Chinese Medicine, Nanjing, China
| | - Yunyao Hu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China; Nanjing University of Chinese Medicine, Nanjing, China
| | - Songmao Hua
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China; Nanjing University of Chinese Medicine, Nanjing, China
| | - Jia Liu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Shun Guo
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China; Nanjing University of Chinese Medicine, Nanjing, China.
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2
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Huang Y, Zhang Q, Wang J, Luan T, Guo L, Hao Z, Shi G, Chen R, Wu Z, Zhou X, Zhou S, Shen Q, Li J. Potential Molecular Mechanism of Bajitian-Niuxi Formula Delays Intervertebral Disc Degeneration: An Animal Experiment and Network Pharmacology. Chem Biodivers 2025:e202500048. [PMID: 40091422 DOI: 10.1002/cbdv.202500048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/16/2025] [Accepted: 03/14/2025] [Indexed: 03/19/2025]
Abstract
Intervertebral disc degeneration (IDD) continues to be a major health concern. The combination of Bajitian and Niuxi (B&N) is commonly used to treat musculoskeletal degenerative diseases. This study aimed to explore the potential of B&N in treating IDD through in vivo experiments and bioinformatics approaches. In vivo experiments found that the process of IDD in rats treated with B&N extracts was delayed. Through database screening and network pharmacology analysis, it was discovered that multiple key drug-active ingredients (DAIs) of B&N, such as wogonin, baicalein, 1-hydroxy-3-methoxy-9,10-anthraquinone, and beta-sitosterol, might play a role in the treatment of IDD, among which signaling pathways, such as PI3K-AKT, MAPK, and senescence signaling, might be the main drug-regulated pathways. The binding potential and position of the main DAIs to the core targets were verified by structural bioinformatics. Immunohistochemistry and qRT-PCR results indicated that B&N treatment could improve the expressions of Type II collagen (Col-2) and aggrecan (ACAN) in IDD rats, which might be related to the phosphorylation levels of AKT and p38. Therefore, the B&N formula might delay IDD in rats by regulating multiple signaling pathways through DAIs, which provides new approaches for further exploring the prevention and treatment strategies of IDD with traditional Chinese medicine.
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Affiliation(s)
- Yilong Huang
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
| | - Qi Zhang
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
| | - Junwu Wang
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
| | - Tian Luan
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
| | - Lanhong Guo
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
| | - Zhuowen Hao
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
| | - Guang Shi
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
| | - Renxin Chen
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
| | - Zijian Wu
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
| | - Xuan'ang Zhou
- College of Life Sciences, Wuhan University, Wuhan, China
| | - Shifeng Zhou
- Department of Orthopedics, Taizhou People's Hospital Affiliated with Nanjing Medical University, Taizhou, China
| | - Qixiao Shen
- Department of Orthopedics, Yangxin People's Hospital, Huangshi, China
| | - Jingfeng Li
- Department of Orthopedics, ZhongNan Hospital of Wuhan University, Wuhan, China
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3
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Zhou P, Li H, Li H, Chen Y, Lv Y. A possible important regulatory role of estrogen in obstructive sleep apnea hypoventilation syndrome. Front Med (Lausanne) 2025; 12:1369393. [PMID: 40098932 PMCID: PMC11911188 DOI: 10.3389/fmed.2025.1369393] [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: 01/12/2024] [Accepted: 02/17/2025] [Indexed: 03/19/2025] Open
Abstract
Obstructive sleep apnea-hypoventilation syndrome (OSAHS) is a prevalent clinical sleep breathing disorder that affects both pediatric and adult populations. If left untreated, OSAHS can induce or aggravate systemic dysfunction across multiple organ systems, with a particularly pronounced impact on cardiovascular health, thereby posing a substantial threat to overall human well-being. Notably, there exists a significant sex disparity in the prevalence and severity of OSAHS, with a higher incidence and greater severity observed in males. However, this disparity tends to diminish post-menopause. Research indicates that sex differences in OSAHS are associated with gonadal function, wherein estrogen exerts a protective effect by modulating pharyngeal muscle tone and mitigating oxidative stress. This regulatory role of estrogen partially reduces the incidence of OSAHS and attenuates its pathological impact. Conversely, OSAHS may adversely affect gonadal function, resulting in decreased estrogen levels, which can exacerbate the condition. This review examines the beneficial role of estrogen in the progression of OSAHS and explores the potential impact of OSAHS on estrogen levels.
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Affiliation(s)
- Pinyi Zhou
- Department of Sleep Medicine, The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Hongmei Li
- Department of Neurology, Yan'an Hospital Affiliated to Kunming Medical University, Kunming, China
| | - Hongyan Li
- Department of Sleep Medicine, The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Yan Chen
- Department of Sleep Medicine, The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
| | - Yunhui Lv
- Department of Sleep Medicine, The Affiliated Hospital of Kunming University of Science and Technology, The First People's Hospital of Yunnan Province, Kunming, China
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4
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Behera BP, Mishra SR, Patra S, Mahapatra KK, Bhol CS, Panigrahi DP, Praharaj PP, Klionsky DJ, Bhutia SK. Molecular regulation of mitophagy signaling in tumor microenvironment and its targeting for cancer therapy. Cytokine Growth Factor Rev 2025:S1359-6101(25)00004-8. [PMID: 39880721 DOI: 10.1016/j.cytogfr.2025.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 01/13/2025] [Indexed: 01/31/2025]
Abstract
Aberrations emerging in mitochondrial homeostasis are restrained by mitophagy to control mitochondrial integrity, bioenergetics signaling, metabolism, oxidative stress, and apoptosis. The mitophagy-accompanied mitochondrial processes that occur in a dysregulated condition act as drivers for cancer occurrence. In addition, the enigmatic nature of mitophagy in cancer cells modulates the cellular proteome, creating challenges for therapeutic interventions. Several reports found the role of cellular signaling pathways in cancer to modulate mitophagy to mitigate stress, immune checkpoints, energy demand, and cell death. Thus, targeting mitophagy to hinder oncogenic intracellular signaling by promoting apoptosis, in hindsight, might have an edge against cancer. This review highlights the receptors and adaptors, and the involvement of many proteins in mitophagy and their role in oncogenesis. It also provides insight into using mitophagy as a potential target for therapeutic intervention in various cancer types.
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Affiliation(s)
- Bishnu Prasad Behera
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, Odisha 769008, India
| | - Soumya Ranjan Mishra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, Odisha 769008, India
| | - Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, Odisha 769008, India
| | - Kewal Kumar Mahapatra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, Odisha 769008, India
| | - Chandra Sekhar Bhol
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, Odisha 769008, India
| | - Debasna Pritimanjari Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, Odisha 769008, India
| | - Prakash Priyadarshi Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, Odisha 769008, India
| | - Daniel J Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh, Odisha 769008, India.
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Zhang J, Zhang J, Yang C. Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities. J Transl Med 2025; 23:52. [PMID: 39806481 PMCID: PMC11727735 DOI: 10.1186/s12967-024-06063-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 12/27/2024] [Indexed: 01/16/2025] Open
Abstract
Autophagy is responsible for maintaining cellular balance and ensuring survival. Autophagy plays a crucial role in the development of diseases, particularly human cancers, with actions that can either promote survival or induce cell death. However, brain tumors contribute to high levels of both mortality and morbidity globally, with resistance to treatments being acquired due to genetic mutations and dysregulation of molecular mechanisms, among other factors. Hence, having knowledge of the role of molecular processes in the advancement of brain tumors is enlightening, and the current review specifically examines the role of autophagy. The discussion would focus on the molecular pathways that control autophagy in brain tumors, and its dual role as a tumor suppressor and a supporter of tumor survival. Autophagy can control the advancement of different types of brain tumors like glioblastoma, glioma, and ependymoma, demonstrating its potential for treatment. Autophagy mechanisms can influence metastasis and drug resistance in glioblastoma, and there is a complex interplay between autophagy and cellular responses to stress like hypoxia and starvation. Autophagy can inhibit the growth of brain tumors by promoting apoptosis. Hence, focusing on autophagy could offer fresh perspectives on creating successful treatments.
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Affiliation(s)
- Jiarui Zhang
- Department of Pathology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jinan Zhang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, China.
| | - Chen Yang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, China.
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Chang TD, Chen D, Luo JL, Wang YM, Zhang C, Chen SY, Lin ZQ, Zhang PD, Tang TX, Li H, Dong LM, Wu N, Tang ZH. The different paradigms of NK cell death in patients with severe trauma. Cell Death Dis 2024; 15:606. [PMID: 39168979 PMCID: PMC11339281 DOI: 10.1038/s41419-024-06992-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 08/07/2024] [Accepted: 08/09/2024] [Indexed: 08/23/2024]
Abstract
Lymphocyte decline, particularly the depletion of NK cells, is a prominent feature of immunosuppression following severe tissue injury, heightening the susceptibility of severe trauma patients to life-threatening infections. Previous research indicates that the reduction in the number of NK cells is closely associated with the process of cell death. Nonetheless, the precise mechanism of NK cell death remains unknown. Here, we discovered that following severe traumatic injury, NK cells undergo several cell death pathways, dominated by apoptosis and pyroptosis with coexistence of necrotic cell death, immunogenic cell death, ferroptosis, and autophagy. These NK cells with different paradigms of death have diverse cytokine expression profiles and diverse interactions with other immune cells. Further exploration revealed that hypoxia was strongly associated with this diverse paradigm of NK cell death. Detailed investigation of paradigms of cell death may help to enhance comprehension of lymphopenia post-severe trauma, to develop new strategy in preventing immunosuppression, and then to improve outcome for severe trauma population.
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Affiliation(s)
- Te-Ding Chang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Deng Chen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia-Liu Luo
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu-Man Wang
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong Zhang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shun-Yao Chen
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhi-Qiang Lin
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pei-Dong Zhang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting-Xuan Tang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Li
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li-Ming Dong
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ning Wu
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Zhao-Hui Tang
- Division of Trauma Surgery, Emergency Surgery & Surgical Critical, Tongji Trauma Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Emergency and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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7
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Meena D, Jha S. Autophagy in glioblastoma: A mechanistic perspective. Int J Cancer 2024; 155:605-617. [PMID: 38716809 DOI: 10.1002/ijc.34991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 03/28/2024] [Accepted: 04/12/2024] [Indexed: 06/20/2024]
Abstract
Glioblastoma (GBM) is one of the most lethal malignancies in humans. Even after surgical resection and aggressive radio- or chemotherapies, patients with GBM can survive for less than 14 months. Extreme inter-tumor and intra-tumor heterogeneity of GBM poses a challenge for resolving recalcitrant GBM pathophysiology. GBM tumor microenvironment (TME) exhibits diverse heterogeneity in cellular composition and processes contributing to tumor progression and therapeutic resistance. Autophagy is such a cellular process; that demonstrates a cell-specific and TME context-dependent role in GBM progression, leading to either the promotion or suppression of GBM progression. Autophagy can regulate GBM cell function directly via regulation of survival, migration, and invasion, or indirectly by affecting GBM TME composition such as immune cell population, tumor metabolism, and glioma stem cells. This review comprehensively investigates the role of autophagy in GBM pathophysiology.
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Affiliation(s)
- Durgesh Meena
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
| | - Sushmita Jha
- Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India
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Hill RM, Li C, Hughes JR, Rocha S, Grundy GJ, Parsons JL. Autophagy is the main driver of radioresistance of HNSCC cells in mild hypoxia. J Cell Mol Med 2024; 28:e18482. [PMID: 38899556 PMCID: PMC11187736 DOI: 10.1111/jcmm.18482] [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: 10/09/2023] [Revised: 05/20/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Hypoxia poses a significant challenge to the effectiveness of radiotherapy in head and neck squamous cell carcinoma (HNSCC) patients, and it is imperative to discover novel approaches to overcome this. In this study, we investigated the underlying mechanisms contributing to x-ray radioresistance in HPV-negative HNSCC cells under mild hypoxic conditions (1% oxygen) and explored the potential for autophagy modulation as a promising therapeutic strategy. Our findings show that HNSCC cells exposed to mild hypoxic conditions exhibit increased radioresistance, which is largely mediated by the hypoxia-inducible factor (HIF) pathway. We demonstrate that siRNA knockdown of HIF-1α and HIF-1β leads to increased radiosensitivity in HNSCC cells under hypoxia. Hypoxia-induced radioresistance was not attributed to differences in DNA double strand break repair kinetics, as these remain largely unchanged under normoxic and hypoxic conditions. Rather, we identify autophagy as a critical protective mechanism in HNSCC cells following irradiation under mild hypoxia conditions. Targeting key autophagy genes, such as BECLIN1 and BNIP3/3L, using siRNA sensitizes these cells to irradiation. Whilst autophagy's role in hypoxic radioresistance remains controversial, this study highlights the importance of autophagy modulation as a potential therapeutic approach to enhance the effectiveness of radiotherapy in HNSCC.
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Affiliation(s)
- Rhianna M. Hill
- Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Chun Li
- Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUK
| | - Jonathan R. Hughes
- Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUK
| | - Sonia Rocha
- Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Gabrielle J. Grundy
- Institute of Systems, Molecular and Integrative BiologyUniversity of LiverpoolLiverpoolUK
| | - Jason L. Parsons
- Institute of Cancer and Genomic SciencesUniversity of BirminghamBirminghamUK
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Qin P, Li Q, Zu Q, Dong R, Qi Y. Natural products targeting autophagy and apoptosis in NSCLC: a novel therapeutic strategy. Front Oncol 2024; 14:1379698. [PMID: 38628670 PMCID: PMC11019012 DOI: 10.3389/fonc.2024.1379698] [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: 01/31/2024] [Accepted: 03/18/2024] [Indexed: 04/19/2024] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the predominant type. The roles of autophagy and apoptosis in NSCLC present a dual and intricate nature. Additionally, autophagy and apoptosis interconnect through diverse crosstalk molecules. Owing to their multitargeting nature, safety, and efficacy, natural products have emerged as principal sources for NSCLC therapeutic candidates. This review begins with an exploration of the mechanisms of autophagy and apoptosis, proceeds to examine the crosstalk molecules between these processes, and outlines their implications and interactions in NSCLC. Finally, the paper reviews natural products that have been intensively studied against NSCLC targeting autophagy and apoptosis, and summarizes in detail the four most retrieved representative drugs. This paper clarifies good therapeutic effects of natural products in NSCLC by targeting autophagy and apoptosis and aims to promote greater consideration by researchers of natural products as candidates for anti-NSCLC drug discovery.
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Affiliation(s)
- Peiyi Qin
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
- Shandong College of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Qingchen Li
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qi Zu
- Shandong College of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Ruxue Dong
- Shandong College of Traditional Chinese Medicine, Yantai, Shandong, China
| | - Yuanfu Qi
- Department of Oncology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Sun L, Hui F, Tang GY, Shen HL, Cao XL, Gao JX, Li LF. Selective degradation of PL2L60 by metabolic stresses‑induced autophagy suppresses multi‑cancer growth. Oncol Rep 2024; 51:41. [PMID: 38624021 PMCID: PMC10823339 DOI: 10.3892/or.2024.8700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 11/08/2023] [Indexed: 04/17/2024] Open
Abstract
It has been reported that PL2L60 proteins, a product of PIWIL2 gene which might be activated by an intragenic promoter, could mediate a common pathway specifically for tumorigenesis. In the present study, it was further identified by using western blot assay that the PL2L60 proteins could be degraded in cancer cells through a mechanism of selective autophagy in response to oxidative stress. The PL2L60 was downregulated in various types of cancer cells under the hypoxic condition independently of HIF‑1α, resulting in apoptosis of cancer cells. Inhibition of autophagy by small interfering RNA targeting of either Beclin‑1 (BECN1) or Atg5 resulted in restoration of PL2L60 expression in hypoxic cancer cell. The hypoxic degradation of PL2L60 was also blocked by the attenuation of the autophagosome membrane protein Atg8/microtubule‑associated protein 1 light chain 3 (LC3) or autophagy cargo protein p62 expression. Surprisingly, Immunofluorescence analysis demonstrated that LC3 could be directly bound to PL2L60 and was required for the transport of PL2L60 from the nucleus to the cytoplasm for lysosomal flux under basal or activated autophagy in cancer cells. Moreover, flow cytometric analysis displayed that knocking down of PL2L60 mRNA but not PIWIL2 mRNA effectively inhibited cancer cell proliferation and promoted apoptosis of cancer cells. The similar results were obtained from in vivo tumorigenic experiment, in which PL2L60 downregulation in necroptosis areas was confirmed by immunohistochemistry. These results suggested that various cancer could be suppressed by promoting autophagy. The present study revealed a key role of autophagic degradation of PL2L60 in hypoxia‑induced cancer cell death, which could be used as a novel therapeutic target of cancer.
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Affiliation(s)
- Lei Sun
- The State Key Laboratory of Oncogenes and Related Genes, and The Laboratory of Tumorigenesis and Immunity, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, PuDong, Shanghai 200127, P.R. China
- Department of Oncology, First Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Fu Hui
- Department of Oncology, First Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Gao-Yan Tang
- Department of Oncology, First Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China
| | - Hai-Lian Shen
- Sam and Ann Barshop Institute for Longevity of Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78292, USA
| | - Xue-Lei Cao
- Department of Clinical Laboratory, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jian-Xin Gao
- The State Key Laboratory of Oncogenes and Related Genes, and The Laboratory of Tumorigenesis and Immunity, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, PuDong, Shanghai 200127, P.R. China
| | - Lin-Feng Li
- The State Key Laboratory of Oncogenes and Related Genes, and The Laboratory of Tumorigenesis and Immunity, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, PuDong, Shanghai 200127, P.R. China
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11
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Marzoog BA. Autophagy as an Anti-senescent in Aging Neurocytes. Curr Mol Med 2024; 24:182-190. [PMID: 36683318 DOI: 10.2174/1566524023666230120102718] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 11/23/2022] [Accepted: 11/28/2022] [Indexed: 01/24/2023]
Abstract
Neuron homeostasis is crucial for the organism, and its maintenance is multifactorial, including autophagy. The turnover of aberrant intracellular components is a fundamental pathogenetic mechanism for cell aging. Autophagy is involved in the acceleration of the neurocyte aging process and the modification of cell longevity. Neurocyte aging is a process of loss of cell identity through cellular and subcellular changes that include molecular loss of epigenetics, transcriptomic, proteomic, and autophagy dysfunction. Autophagy dysfunction is the hallmark of neurocyte aging. Cell aging is the credential feature of neurodegenerative diseases. Pathophysiologically, aged neurocytes are characterized by dysregulated autophagy and subsequently neurocyte metabolic stress, resulting in accelerated neurocyte aging. In particular, chaperone- mediated autophagy perturbation results in upregulated expression of aging and apoptosis genes. Aged neurocytes are also characterized by the down-regulation of autophagy-related genes, such as ATG5-ATG12, LC3-II / LC3-I ratio, Beclin-1, and p62. Slowing aging through autophagy targeting is sufficient to improve prognosis in neurodegenerative diseases. Three primary anti-senescent molecules are involved in the aging process: mTOR, AMPK, and Sirtuins. Autophagy therapeutic effects can be applied to reverse and slow aging. This article discusses current advances in the role of autophagy in neurocyte homeostasis, aging, and potential therapeutic strategies to reduce aging and increase cell longevity.
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Affiliation(s)
- Basheer Abdullah Marzoog
- National Research Mordovia State University, Bolshevitskaya Street, 68, Saransk, 430005, Rep. Mordovia, Russia
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12
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Danish F, Qureshi MA, Mirza T, Amin W, Sufiyan S, Naeem S, Arshad F, Mughal N. Investigating the Association between the Autophagy Markers LC3B, SQSTM1/p62, and DRAM and Autophagy-Related Genes in Glioma. Int J Mol Sci 2024; 25:572. [PMID: 38203743 PMCID: PMC10779014 DOI: 10.3390/ijms25010572] [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: 11/27/2023] [Revised: 12/27/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
High-grade gliomas are extremely fatal tumors, marked by severe hypoxia and therapeutic resistance. Autophagy is a cellular degradative process that can be activated by hypoxia, ultimately resulting in tumor advancement and chemo-resistance. Our study aimed to examine the link between autophagy markers' expression in low-grade gliomas (LGGs) and high-grade gliomas (HGGs). In 39 glioma cases, we assessed the protein expression of autophagy markers LC3B, SQSTM1/p62, and DRAM by immunohistochemistry (IHC) and the mRNA expression of the autophagy genes PTEN, PI3K, AKT, mTOR, ULK1, ULK2, UVRAG, Beclin 1, and VPS34 using RT-qPCR. LC3B, SQSTM1/p62, and DRAM expression were positive in 64.1%, 51.3%, and 28.2% of glioma cases, respectively. The expression of LC3B and SQSTM1/p62 was notably higher in HGGs compared to LGGs. VPS34 exhibited a significant differential expression, displaying increased fold change in HGGs compared to LGGs. Additionally, it exhibited robust positive associations with Beclin1 (rs = 0.768), UVRAG (rs = 0.802), and ULK2 (rs = 0.786) in HGGs. This underscores a potential association between autophagy and the progression of gliomas. We provide preliminary data for the functional analysis of autophagy using a cell culture model and to identify potential targets for therapeutic interventions.
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Affiliation(s)
- Farheen Danish
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences, Karachi 75300, Pakistan; (F.D.); (F.A.)
| | - Muhammad Asif Qureshi
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences, Karachi 75300, Pakistan; (F.D.); (F.A.)
| | - Talat Mirza
- Departments of Research & Molecular Medicine, Ziauddin University, Karachi 75600, Pakistan;
| | - Wajiha Amin
- Departments of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan; (W.A.); (S.S.); (S.N.)
| | - Sufiyan Sufiyan
- Departments of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan; (W.A.); (S.S.); (S.N.)
| | - Sana Naeem
- Departments of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan; (W.A.); (S.S.); (S.N.)
| | - Fatima Arshad
- Department of Pathology, Dow International Medical College, Dow University of Health Sciences, Karachi 75300, Pakistan; (F.D.); (F.A.)
| | - Nouman Mughal
- Departments of Biological and Biomedical Sciences, Aga Khan University, Karachi 74800, Pakistan; (W.A.); (S.S.); (S.N.)
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13
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Wen L, Shao M, Li Y, Zhang Y, Peng C, Yu H, Zhang K. Unveiling the hypoxia-induced mitophagy process through two-channel real-time imaging of NTR and viscosity under the same excitation. Talanta 2024; 266:125028. [PMID: 37549565 DOI: 10.1016/j.talanta.2023.125028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 07/30/2023] [Accepted: 08/02/2023] [Indexed: 08/09/2023]
Abstract
Mitophagy is an essential physiological process that eliminates damaged mitochondria via lysosomes. It is reported that hypoxia, inflammatory stimuli or other stress conditions could lead to mitochondrial damage and mitochondrial dysfunction, which induces the process of mitophagy. Herein, we report a novel fluorescent probe PC-NTR for imaging hypoxia-induced mitophagy by monitoring the change of nitroreductase and viscosity simultaneously. To our delight, PC-NTR could respond simultaneously to nitroreductase and viscosity at different fluorescence channels with no mutual interference under the same excitation wavelength. The fluorescence emission around 535 nm was enhanced dramatically after addition of nitroreductase while the fluorescence emission around 635 nm heightened as the viscosity increased. The probe would be able to selectively targeting of mitochondria in cells because of the positively charged pyridine salt structure of PC-NTR. The probe was successfully applied to assess the different levels of hypoxia and real-time imaging of mitochondrial autophagy in live cells. More importantly, using dual channel imaging, PC-NTR could be used to distinguish cancer cells from normal cells and was successfully applied to imaging experiments in HeLa-derived tumor-bearing nude mice. Therefore, PC-NTR would be an important molecular tool for hypoxia imaging and detecting solid tumors in vivo.
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Affiliation(s)
- Lei Wen
- Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China
| | - Mengqi Shao
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China
| | - Yinhui Li
- Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China.
| | - Yanjun Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China
| | - Chao Peng
- Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China
| | - Huan Yu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
| | - Kai Zhang
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, 646000, China.
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14
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Zhou Z, Zhang X, Wang S, Wang X, Mao J. A Powerful Tool in the Treatment of Myocardial Ischemia-Reperfusion Injury: Natural and Nanoscale Modified Small Extracellular Vesicles Derived from Mesenchymal Stem Cells. Int J Nanomedicine 2023; 18:8099-8112. [PMID: 38164265 PMCID: PMC10758182 DOI: 10.2147/ijn.s443716] [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: 10/08/2023] [Accepted: 12/12/2023] [Indexed: 01/03/2024] Open
Abstract
Myocardial ischemia-reperfusion injury (MI/RI) constitutes a pivotal determinant impacting the long-term prognosis of individuals afflicted by ischemic cardiomyopathy subsequent to reperfusion therapy. Stem cells have garnered extensive application within the realm of MI/RI investigation, yielding tangible outcomes. Stem cell therapy encounters certain challenges in its application owing to the complexities associated with stem cell acquisition, a diminished homing rate, and a brief in vivo lifespan. Small extracellular vesicles (sEV) originating from mesenchymal stem cells (MSCs) have been demonstrated to possess the benefits of abundant availability, reduced immunogenicity, and a diminished tumorigenic incidence. They can exert their effects on damaged organs, improving injuries by transporting a lot of constituents, including proteins, RNA, lipid droplets, and more. This phenomenon has garnered substantial attention in the context of MI/RI treatment. Simultaneously, MSC-derived sEV (MSC-sEV) can exhibit enhanced therapeutic advantages through bioengineering modifications, biomaterial incorporation, and natural drug interventions. Within this discourse, we shall appraise the utilization of MSC-sEV and their derivatives in the context of MI/RI treatment, aiming to offer valuable insights for future research endeavors related to MI/RI.
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Affiliation(s)
- Zhou Zhou
- Cardiovascular Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine/National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, People’s Republic of China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China
| | - Xuan Zhang
- Cardiovascular Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine/National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, People’s Republic of China
| | - Shuai Wang
- Cardiovascular Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine/National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, People’s Republic of China
| | - Xianliang Wang
- Cardiovascular Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine/National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, People’s Republic of China
| | - Jingyuan Mao
- Cardiovascular Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine/National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300381, People’s Republic of China
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15
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Dowling AL, Walbridge S, Ertekin C, Namagiri S, Camacho K, Chowdhury A, Bryant JP, Kohut E, Heiss JD, Brown DA, Kumbar SG, Banasavadi-Siddegowda YK. FKBP38 Regulates Self-Renewal and Survival of GBM Neurospheres. Cells 2023; 12:2562. [PMID: 37947640 PMCID: PMC10647221 DOI: 10.3390/cells12212562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/24/2023] [Accepted: 10/30/2023] [Indexed: 11/12/2023] Open
Abstract
Glioblastoma is the most common malignant primary brain tumor. The outcome is dismal, despite the multimodal therapeutic approach that includes surgical resection, followed by radiation and chemotherapy. The quest for novel therapeutic targets to treat glioblastoma is underway. FKBP38, a member of the immunophilin family of proteins, is a multidomain protein that plays an important role in the regulation of cellular functions, including apoptosis and autophagy. In this study, we tested the role of FKBP38 in glioblastoma tumor biology. Expression of FKBP38 was upregulated in the patient-derived primary glioblastoma neurospheres (GBMNS), compared to normal human astrocytes. Attenuation of FKBP38 expression decreased the viability of GBMNSs and increased the caspase 3/7 activity, indicating that FKBP38 is required for the survival of GBMNSs. Further, the depletion of FKBP38 significantly reduced the number of neurospheres that were formed, implying that FKBP38 regulates the self-renewal of GBMNSs. Additionally, the transient knockdown of FKBP38 increased the LC3-II/I ratio, suggesting the induction of autophagy with the depletion of FKBP38. Further investigation showed that the negative regulation of autophagy by FKBP38 in GBMNSs is mediated through the JNK/C-Jun-PTEN-AKT pathway. In vivo, FKBP38 depletion significantly extended the survival of tumor-bearing mice. Overall, our results suggest that targeting FKBP38 imparts an anti-glioblastoma effect by inducing apoptosis and autophagy and thus can be a potential therapeutic target for glioblastoma therapy.
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Affiliation(s)
- Aimee L. Dowling
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Stuart Walbridge
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Celine Ertekin
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Sriya Namagiri
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Krystal Camacho
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Ashis Chowdhury
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Jean-Paul Bryant
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - Eric Kohut
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
| | - John D. Heiss
- Clinical Neurology Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Desmond A. Brown
- Neurosurgical Oncology Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Sangamesh G. Kumbar
- Department of Orthopedic Surgery, University of Connecticut Health, Farmington, CT 06030, USA;
| | - Yeshavanth Kumar Banasavadi-Siddegowda
- Molecular & Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (A.C.); (J.-P.B.); (E.K.)
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16
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Lian N, Tong J, Zhu W, Meng Q, Jiang M, Bian M, Li Y. Ligustrazine and liguzinediol protect against doxorubicin-induced cardiomyocytes injury by inhibiting mitochondrial apoptosis and autophagy. Clin Exp Pharmacol Physiol 2023; 50:867-877. [PMID: 37574718 DOI: 10.1111/1440-1681.13811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 07/05/2023] [Accepted: 07/17/2023] [Indexed: 08/15/2023]
Abstract
Preventing or treating heart failure (HF) by blocking cardiomyocyte apoptosis is an effective strategy that improves survival and reduces ventricular remodelling and dysfunction in the chronic stage. Autophagy is a mechanism that degrades intracellular components and compensates for energy deficiency, which is commonly observed in cardiomyocytes of failed hearts. Cardiomyocytes activated by doxorubicin (DOX) exhibit strong autophagy. This study aims to investigate the potential protective effect of ligustrazine and its derivative liguzinediol on regulating DOX-induced cardiomyocyte apoptosis and explore the use of the embryonic rat heart-derived myoblast cell line H9C2 for identifying novel treatments for HF. The results indicated that it has been demonstrated to reverse myocardial infarction remodelling in failed hearts by promoting autophagy in salvaged cardiomyocytes and anti-apoptosis of cardiomyocytes in granulation tissue. Our study suggests that ligustrazine and liguzinediol can be a promising agents and autophagy is potential pathway in the management of HF.
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Affiliation(s)
- Naqi Lian
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jing Tong
- Xi'an International Medical Center Hospital, Xi'an, China
| | - Weijie Zhu
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Qinghai Meng
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Miao Jiang
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Mianli Bian
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu Li
- School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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17
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Xu R, Shen S, Wang D, Ye J, Song S, Wang Z, Yue Z. The role of HIF-1α-mediated autophagy in ionizing radiation-induced testicular injury. J Mol Histol 2023; 54:439-451. [PMID: 37728670 DOI: 10.1007/s10735-023-10153-6] [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: 10/10/2022] [Accepted: 09/04/2023] [Indexed: 09/21/2023]
Abstract
Testis, as a key organ for maintaining male fertility, are extremely sensitive to ionizing radiation (IR). IR-induced testicular dysfunction and infertility are common adverse effects of radiation therapy in patients with pelvic cancer. To study the phenotype and mechanism of IR-induced testicular injury, the mice were irradiated with different radiation doses (0, 2 and 5 Gy) below the semi-lethal dose for one month. Our present results showed that testicular weight and the serum testosterone levels significantly decreased with the structural injury of the testis in an IR dose-dependent manner, indicating that IR caused not only the structural damage of the testis, but also the functional damage. Further analysis by TUNEL staining and Western blotting found that IR induced the apoptosis in a dose-dependent manner as indicated by increased expressions of cleaved caspase3, p53 and Bax on Day 15 after IR treatment. Combined with significantly increased oxidative stress, these results indicated that IR-induced testicular damage may be a long-term, progressively aggravated process, accompanied by apoptosis. Given the role of autophagy in apoptosis, the present study also detected and analyzed the localization and expressions of autophagy-related proteins LC-3I/II, beclin1, p62 and Atg12 in testicular cells, and found that LC-3II, beclin1 and Atg12 expressions significantly increased in the testicular cells of mice irradiated with 2 Gy and 5 Gy, while p62 expression significantly decreased with 5 Gy, implying autophagy was involved in the apoptosis of testicular cells induced by IR. Furthermore, the expressions of HIF-1α and BNIP3 were significantly enhanced in the testis cells of mice irradiated with 2 Gy and 5 Gy, suggesting the potential role of HIF-1α/BNIP3-mediated autophagy in the apoptosis of testicular cells induced by IR. Taken together, our findings demonstrated that HIF-1α/BNIP3-mediated autophagy not only plays a protective effect on the testicular cells of mice irradiated with 2 Gy, but also induces the apoptosis of the testicular cells of mice irradiated with 5 Gy, indicating the double effects on apoptosis, which will help us further understanding the molecular mechanisms of IR-induced testicular injury, and will facilitate us further studies on testicular radioprotection.
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Affiliation(s)
- Renfeng Xu
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, 350007, China
- Department of Cell Biology and Medical Genetics, Carson International Cancer Center, Guangdong Key Laboratory for Genome Stability and Disease Prevention, Shenzhen University School of Medicine, Shenzhen, 518060, China
| | - Siting Shen
- Department of Cell Biology and Medical Genetics, Carson International Cancer Center, Guangdong Key Laboratory for Genome Stability and Disease Prevention, Shenzhen University School of Medicine, Shenzhen, 518060, China
| | - Defan Wang
- Fujian Provincial Key Laboratory of Reproductive Health Research, School of Medicine, Xiamen University, Xiamen, 361102, China
| | - Jianqing Ye
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, 350007, China
| | - Shiting Song
- Department of Cell Biology and Medical Genetics, Carson International Cancer Center, Guangdong Key Laboratory for Genome Stability and Disease Prevention, Shenzhen University School of Medicine, Shenzhen, 518060, China
| | - Zhengchao Wang
- Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, 350007, China.
| | - Zhicao Yue
- Department of Cell Biology and Medical Genetics, Carson International Cancer Center, Guangdong Key Laboratory for Genome Stability and Disease Prevention, Shenzhen University School of Medicine, Shenzhen, 518060, China.
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18
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Zhu X, Dingkao R, Sun N, Han L, Yu Q. The potential mediation of hypoxia-inducible factor-1α in heat shock protein 27 translocations, caspase-3 and calpain activities and yak meat tenderness during postmortem aging. Meat Sci 2023; 204:109264. [PMID: 37515863 DOI: 10.1016/j.meatsci.2023.109264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 05/12/2023] [Accepted: 06/19/2023] [Indexed: 07/31/2023]
Abstract
The present study aimed to characterize the influence of hypoxia-inducible factor-1α on heat shock protein 27 and cytochrome c translocation, yak meat microstructure destruction, and endogenous enzymes activities, refining the understanding of the tenderization process after slaughter. Postmortem yak longissimus thoracis et lumborum muscles were incubated with 0.9% saline or hypoxia-inducible factor-1α stabilizer dimethyloxaloylglycine at 4 °C for 6, 12, 24, 72, and 120 h. Results showed that hypoxia-inducible factor-1α activation promoted heat shock protein 27 migration and cytochrome c release, facilitating (P < 0.05) caspase-3 activity by mediating the heat shock protein 27/caspase-3 interaction but did not exert (P > 0.05) significant effects on the calpain-1 activity. Additionally, hypoxia-inducible factor-1α activation contributed to the mitochondrial apoptosis cascade, leading to a higher (P < 0.01) apoptosis rate. Therefore, these observations indicate that hypoxia-inducible factor-1α affects caspase-3 activity and tenderness of postmortem muscle through distinct regulatory mechanisms, possibly, in part, with heat shock protein 27 and cytochrome c mediation.
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Affiliation(s)
- Xijin Zhu
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, Gansu 730070, PR China
| | - Renqing Dingkao
- Animal Science and Veterinary Institute of Gannan Prefecture, Gannan Tibetan Autonomous Prefecture, Gansu 747000, PR China
| | - Nan Sun
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, Gansu 730070, PR China
| | - Ling Han
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, Gansu 730070, PR China.
| | - Qunli Yu
- College of Food Science and Engineering, Gansu Agricultural University, Lanzhou, Gansu 730070, PR China.
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19
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Falfushynska H, Sokolova IM. Intermittent hypoxia differentially affects metabolic and oxidative stress responses in two species of cyprinid fish. Biol Open 2023; 12:bio060069. [PMID: 37670684 PMCID: PMC10537972 DOI: 10.1242/bio.060069] [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: 07/08/2023] [Accepted: 08/24/2023] [Indexed: 09/07/2023] Open
Abstract
Oxygen fluctuations are common in freshwater habitats and aquaculture and can impact ecologically and economically important species of fish like cyprinids. To gain insight into the physiological responses to oxygen fluctuations in two common cyprinid species, we evaluated the impact of short-term intermittent hypoxia on oxidative stress and metabolic parameters (including levels of prooxidants and oxidative lesions, antioxidants, mitochondrial enzyme activities, mitochondrial swelling, markers of apoptosis, autophagy and cytotoxicity) in silver carp Hypophthalmichthys molitrix and gibel carp Carassius gibelio. During hypoxia, gibel carp showed higher baseline levels of antioxidants and less pronounced changes in oxidative and metabolic biomarkers in the tissues than silver carp. Reoxygenation led to a strong shift in metabolic and redox-related parameters and tissue damage, indicating high cost of post-hypoxic recovery in both species. Species-specific differences were more strongly associated with oxidative stress status, whereas metabolic indices and nitrosative stress parameters were more relevant to the response to hypoxia-reoxygenation. Overall, regulation of energy metabolism appears more critical than the regulation of antioxidants in the response to oxygen deprivation in the studied species. Further research is needed to establish whether prioritizing metabolic over redox regulation during hypoxia-reoxygenation stress is common in freshwater cyprinids.
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Affiliation(s)
- Halina Falfushynska
- Department of Marine Biology, Institute for Biological Sciences, University of Rostock, Rostock 18059, Germany
- Department of Electrical, Mechanical and Industrial Engineering, Anhalt University for Applied Sciences, Köthen 06366, Germany
| | - Inna M. Sokolova
- Department of Marine Biology, Institute for Biological Sciences, University of Rostock, Rostock 18059, Germany
- Department of Maritime Systems, Interdisciplinary Faculty, University of Rostock, Rostock 18059, Germany
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20
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Zhang J, Xiang Q, Wu M, Lao YZ, Xian YF, Xu HX, Lin ZX. Autophagy Regulators in Cancer. Int J Mol Sci 2023; 24:10944. [PMID: 37446120 PMCID: PMC10341480 DOI: 10.3390/ijms241310944] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/22/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Autophagy plays a complex impact role in tumor initiation and development. It serves as a double-edged sword by supporting cell survival in certain situations while also triggering autophagic cell death in specific cellular contexts. Understanding the intricate functions and mechanisms of autophagy in tumors is crucial for guiding clinical approaches to cancer treatment. Recent studies highlight its significance in various aspects of cancer biology. Autophagy enables cancer cells to adapt to and survive unfavorable conditions by recycling cellular components. However, excessive or prolonged autophagy can lead to the self-destruction of cancer cells via a process known as autophagic cell death. Unraveling the molecular mechanisms underlying autophagy regulation in cancer is crucial for the development of targeted therapeutic interventions. In this review, we seek to present a comprehensive summary of current knowledge regarding autophagy, its impact on cancer cell survival and death, and the molecular mechanisms involved in the modulation of autophagy for cancer therapy.
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Affiliation(s)
- Juan Zhang
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China; (J.Z.); (Y.-F.X.)
| | - Qian Xiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Q.X.); (M.W.); (Y.-Z.L.)
| | - Man Wu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Q.X.); (M.W.); (Y.-Z.L.)
| | - Yuan-Zhi Lao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Q.X.); (M.W.); (Y.-Z.L.)
| | - Yan-Fang Xian
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China; (J.Z.); (Y.-F.X.)
| | - Hong-Xi Xu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; (Q.X.); (M.W.); (Y.-Z.L.)
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhi-Xiu Lin
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China; (J.Z.); (Y.-F.X.)
- Hong Kong Institute of Integrative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
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21
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Tang Z, Liu L, Borlak J. Combined inhibition of histone deacetylase and cytidine deaminase improves epigenetic potency of decitabine in colorectal adenocarcinomas. Clin Epigenetics 2023; 15:89. [PMID: 37208732 DOI: 10.1186/s13148-023-01500-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 05/03/2023] [Indexed: 05/21/2023] Open
Abstract
BACKGROUND Targeting the epigenome of cancerous diseases represents an innovative approach, and the DNA methylation inhibitor decitabine is recommended for the treatment of hematological malignancies. Although epigenetic alterations are also common to solid tumors, the therapeutic efficacy of decitabine in colorectal adenocarcinomas (COAD) is unfavorable. Current research focuses on an identification of combination therapies either with chemotherapeutics or checkpoint inhibitors in modulating the tumor microenvironment. Here we report a series of molecular investigations to evaluate potency of decitabine, the histone deacetylase inhibitor PBA and the cytidine deaminase (CDA) inhibitor tetrahydrouridine (THU) in patient derived functional and p53 null colon cancer cell lines (CCCL). We focused on the inhibition of cell proliferation, the recovery of tumor suppressors and programmed cell death, and established clinical relevance by evaluating drug responsive genes among 270 COAD patients. Furthermore, we evaluated treatment responses based on CpG island density. RESULTS Decitabine caused marked repression of the DNMT1 protein. Conversely, PBA treatment of CCCL recovered acetylation of histone 3 lysine residues, and this enabled an open chromatin state. Unlike single decitabine treatment, the combined decitabine/PBA treatment caused > 95% inhibition of cell proliferation, prevented cell cycle progression especially in the S and G2-phase and induced programmed cell death. Decitabine and PBA differed in their ability to facilitate re-expression of genes localized on different chromosomes, and the combined decitabine/PBA treatment was most effective in the re-expression of 40 tumor suppressors and 13 genes typically silenced in cancer-associated genomic regions of COAD patients. Furthermore, this treatment repressed expression of 11 survival (anti-apoptotic) genes and augmented expression of X-chromosome inactivated genes, especially the lncRNA Xist to facilitate p53-mediated apoptosis. Pharmacological inhibition of CDA by THU or its gene knockdown prevented decitabine inactivation. Strikingly, PBA treatment recovered the expression of the decitabine drug-uptake transporter SLC15A1, thus enabling high tumor drug-loads. Finally, for 26 drug responsive genes we demonstrated improved survival in COAD patients. CONCLUSION The combined decitabine/PBA/THU drug treatment improved drug potency considerably, and given their existing regulatory approval, our findings merit prospective clinical trials for the triple combination in COAD patients.
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Affiliation(s)
- Zijiao Tang
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany
| | - Lu Liu
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany
| | - Jürgen Borlak
- Hannover Medical School, Centre for Pharmacology and Toxicology, Carl-Neuberg-Str.1, 30625, Hannover, Germany.
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22
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Ke X, Yu S, Situ S, Lin Z, Yuan Y. Morroniside inhibits Beclin1-dependent autophagic death and Bax-dependent apoptosis in cardiomyocytes through repressing BCL2 phosphorylation. In Vitro Cell Dev Biol Anim 2023:10.1007/s11626-023-00768-0. [PMID: 37155079 DOI: 10.1007/s11626-023-00768-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 04/13/2023] [Indexed: 05/10/2023]
Abstract
Morroniside can prevent myocardial injury caused by ischemia and hypoxia, which can be used to treat acute myocardial infarction (AMI). Hypoxia can cause apoptosis and autophagic death of cardiomyocytes. Morroniside has the ability to inhibit apoptosis and autophagy. However, the relationship between Morroniside-protected cardiomyocytes and two forms of death is unclear. The effects of Morroniside on the proliferation, apoptosis level, and autophagic activity of rat cardiomyocyte line H9c2 under hypoxia were first observed. Next, the roles of Morroniside in the phosphorylation of JNK and BCL2, BCL2-Beclin1, and BCL2-Bax complexes as well as mitochondrial membrane potential in H9c2 cells were evaluated upon hypoxia. Finally, the significance of BCL2 or JNK in Morroniside-regulated autophagy, apoptosis, and proliferation in H9c2 cells was assessed by combining Morroniside and BCL2 competitive inhibitor (ABT-737) or JNK activator (Anisomycin). Our results showed that hypoxia promoted autophagy and apoptosis of H9c2 cells, and inhibited their proliferation. However, Morroniside could block the effect of hypoxia on H9c2 cells. In addition, Morroniside could inhibit JNK phosphorylation, BCL2 phosphorylation at the Ser70 and Ser87 sites, and the dissociation of BCL2-Beclin1 and BCL2-Bax complexes in H9c2 cells upon hypoxia. Moreover, the reduction of mitochondrial membrane potential in H9c2 cells caused by hypoxia was improved by Morroniside administration. Importantly, the inhibited autophagy, apoptosis, and promoted proliferation in H9c2 cells by Morroniside were reversed by the application of ABT-737 or Anisomycin. Overall, Morroniside inhibits Beclin1-dependent autophagic death and Bax-dependent apoptosis via JNK-mediated BCL2 phosphorylation, thereby improving the survival of cardiomyocytes under hypoxia.
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Affiliation(s)
- Xueping Ke
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
- The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, 528200, China
| | - Shicheng Yu
- Department of Medicine, Liwan Central Hospital of Guangzhou, Guangzhou, 510145, China
| | - Shubiao Situ
- Department of Medicine, Liwan Central Hospital of Guangzhou, Guangzhou, 510145, China
| | - Zhenqian Lin
- Department of Cardiology, Henan Provincial Chest Hospital, Zhengzhou, 450008, Henan, China
| | - Yiqiang Yuan
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
- Department of Cardiology, Zheng Zhou NO.7 People's Hospital, No.17, Jingnan 5th Road, Zhengzhou Economic and Technological Development Zone, Zhengzhou, 450016, China.
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23
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Laribee RN, Boucher AB, Madireddy S, Pfeffer LM. The STAT3-Regulated Autophagy Pathway in Glioblastoma. Pharmaceuticals (Basel) 2023; 16:671. [PMID: 37242454 PMCID: PMC10223172 DOI: 10.3390/ph16050671] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Glioblastoma (GBM) is the most common primary brain malignancy in adults with a dismal prognosis. Despite advances in genomic analysis and surgical technique and the development of targeted therapeutics, most treatment options are ineffective and mainly palliative. Autophagy is a form of cellular self-digestion with the goal of recycling intracellular components to maintain cell metabolism. Here, we describe some recent findings that suggest GBM tumors are more sensitive to the excessive overactivation of autophagy leading to autophagy-dependent cell death. GBM cancer stem cells (GSCs) are a subset of the GBM tumor population that play critical roles in tumor formation and progression, metastasis, and relapse, and they are inherently resistant to most therapeutic strategies. Evidence suggests that GSCs are able to adapt to a tumor microenvironment of hypoxia, acidosis, and lack of nutrients. These findings have suggested that autophagy may promote and maintain the stem-like state of GSCs as well as their resistance to cancer treatment. However, autophagy is a double-edged sword and may have anti-tumor properties under certain conditions. The role of the STAT3 transcription factor in autophagy is also described. These findings provide the basis for future research aimed at targeting the autophagy-dependent pathway to overcome the inherent therapeutic resistance of GBM in general and to specifically target the highly therapy-resistant GSC population through autophagy regulation.
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Affiliation(s)
- Ronald Nicholas Laribee
- Department of Pathology and Laboratory Medicine, The Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
| | - Andrew B. Boucher
- Department of Neurosurgery, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
| | - Saivikram Madireddy
- College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
| | - Lawrence M. Pfeffer
- Department of Pathology and Laboratory Medicine, The Center for Cancer Research, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, USA;
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24
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Huang KY, Liu S, Yu YW, Wu BS, Lin ZH, Zhu CX, Song DY, Xue YJ, Ji KT. 3,4-benzopyrene aggravates myocardial ischemia-reperfusion injury-induced pyroptosis through inhibition of autophagy-dependent NLRP3 degradation. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 254:114701. [PMID: 36871353 DOI: 10.1016/j.ecoenv.2023.114701] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 02/13/2023] [Accepted: 02/26/2023] [Indexed: 06/18/2023]
Abstract
Polycyclic aromatic hydrocarbons (PAHs) are produced during combustion of organic matter, such as during cigarette smoking, and they exist widely in the environment. Exposure to 3,4-benzo[a]pyrene (BaP), as the most widely studied PAHs, relates to many cardiovascular diseases. However, the underlying mechanism of its involvement remains largely unclear. In this study, we developed a myocardial ischemia-reperfusion (I/R) injury mouse model and an oxygen and glucose deprivation-reoxygenation H9C2 cell model to evaluate the effect of BaP in I/R injury. After BaP exposure, the expression of autophagy-related proteins, the abundance of NLRP3 inflammasomes, and the degree of pyroptosis were measured. Our results show that BaP aggravates myocardial pyroptosis in a autophagy-dependent manner. In addition, we found that BaP activates the p53-BNIP3 pathway via the aryl hydrocarbon receptor to decrease autophagosome clearance. Our findings present new insights into the mechanisms underlying cardiotoxicity and reveal that the p53-BNIP3 pathway, which is involved in autophagy regulation, is a potential therapeutic target for BaP-induced myocardial I/R injury. Because PAHs are omnipresent in daily life, the toxic effects of these harmful substances should not be underestimated.
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Affiliation(s)
- Kai-Yu Huang
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Shuai Liu
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yong-Wei Yu
- Intensive Care Unit, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
| | - Bo-Sen Wu
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Zhi-Hui Lin
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Chen-Xi Zhu
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Dong-Yan Song
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Yang-Jing Xue
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Kang-Ting Ji
- Department of Cardiology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
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25
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He R, Xu Y, Yu L, Meng N, Wang H, Cui Y, Yam JWP. Extracellular Vesicles Act as Carriers for Cargo Delivery and Regulate Wnt Signaling in the Hepatocellular Carcinoma Tumor Microenvironment. Cancers (Basel) 2023; 15:cancers15072088. [PMID: 37046749 PMCID: PMC10093647 DOI: 10.3390/cancers15072088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/22/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
As the primary type of liver cancer, hepatocellular carcinoma (HCC) causes a large number of deaths every year. Despite extensive research conducted on this disease, the prognosis of HCC remains unclear. Recently, research has largely focused on extracellular vesicles (EVs), and they have been found to participate in various ways in the development of various diseases, including HCC, such as by regulating cell signaling pathways. However, recent studies have reported the mechanisms underlying the regulation of Wnt signaling by EVs in HCC, primarily focusing on the regulation of the canonical pathways. This review summarizes the current literature on the regulation of Wnt signaling by EVs in HCC and their underlying mechanisms. In addition, we also present future research directions in this field. This will deepen the understanding of HCC and provide new ideas for its treatment.
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Affiliation(s)
- Risheng He
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
- Key Laboratory of Basic Pharmacology of Ministry of Education, Zunyi Medical University, Zunyi 563006, China
- Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen 361000, China
- Jiangsu Province Engineering Research Center of Tumor Targeted Nano Diagnostic and Therapeutic Materials, Yancheng Teachers University, Yancheng 224007, China
- Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang Province, Hangzhou 310063, China
- Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China
- State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China
- Key Laboratory of Intelligent Pharmacy and Individualized Therapy of Huzhou, Department of Pharmacy, Changxing People’s Hospital, Changxing 313000, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Liang Yu
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Nanfeng Meng
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Hang Wang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China
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26
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Zhao LL, Liao L, Yan HX, Tang XH, He K, Liu Q, Luo J, Du ZJ, Chen SY, Zhang X, Cheng Z, Yang S. Physiological responses to acute hypoxia in the liver of largemouth bass by alteration of mitochondrial function and Ca 2+ exchange. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2023; 256:106436. [PMID: 36822139 DOI: 10.1016/j.aquatox.2023.106436] [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: 04/10/2022] [Revised: 12/23/2022] [Accepted: 02/16/2023] [Indexed: 06/18/2023]
Abstract
Oxygen is a critical factor for most organisms and this is especially true for aquatic animals. Unfortunately, high-density aquaculture farming practices and environmental degradation will inevitably lead to hypoxic stress in fishes such as largemouth bass (Micropterus salmoides). Thus, characterizing the physiological responses during acute hypoxia exposure is extremely important for understanding the adaptation mechanisms of largemouth bass to hypoxia. The present study aimed to investigate mitochondrial function and Ca2+ exchange in largemouth bass under hypoxic conditions. Largemouth bass were subjected to hypoxia (1.2 ± 0.2 mg/L) for 24 h Liver mitochondria and endoplasmic reticulum (ER) parameters were analyzed. We used Liquid chromatography-mass spectrometry (LC-MS) to further elucidate the pattern of energy metabolism. Changes of Ca2+ concentrations were observed in primary hepatocytes of largemouth bass under hypoxic conditions. Our results indicate that the morphology and function of the mitochondria and ER were altered under hypoxia. First, the occurrence of autophagy was accompanied by reactive oxygen species (ROS) generation and electron transport chain (ETC) activity modulation under hypoxia. Second, hypoxia enhanced mitochondrial fusion and fission, mitochondrial biosynthesis, and ER quality control in the early stages of hypoxic stress (before 8 h). Third, hypoxia modulated tricarboxylic acid (TCA) cycle flux and caused the accumulation of TCA intermediate metabolites (citric acid and oxoglutaric acid). Additionally, Ca2+ efflux in the ER was observed., and the genes for Ca2+ transporters presented high expression levels in cellular and mitochondrial membranes. Collectively, the above physiological responses of the mitochondria and ER contributed to maintaining energy production to withstand the hypoxic stress in largemouth bass. These results provide novel insights into the physiological and metabolic changes in largemouth bass under hypoxic conditions.
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Affiliation(s)
- Liu Lan Zhao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Lei Liao
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Hao Xiao Yan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Xiao Hong Tang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Kuo He
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Qiao Liu
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Jie Luo
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Zong Jun Du
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Shi Yi Chen
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Xin Zhang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Zhang Cheng
- College of Environment, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Song Yang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China.
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27
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Diabetes-Induced Autophagy Dysregulation Engenders Testicular Impairment via Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:4365895. [PMID: 36778206 PMCID: PMC9918358 DOI: 10.1155/2023/4365895] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 11/01/2022] [Accepted: 11/24/2022] [Indexed: 02/05/2023]
Abstract
Testes produce sperms, and gamete generation relies on a proper niche environment. The disruption of hierarchical regulatory homeostasis in Leydig or Sertoli cells may evoke a sterile phenotype in humans. In this study, we recapitulated type 2 diabetes mellitus by using a high-fat diet- (HFD-) fed mouse model to identify the phenotype and potential mechanism of diabetes-induced testicular impairment. At the end of the study, blood glucose levels, testosterone structure, testicular antioxidant capacity, and testosterone level and the expression of hypoxia-inducible factor- (HIF-) 1α, apoptosis-related protein cleaved-caspase3, and autophagy-related proteins such as LC3I/II, p62, and Beclin1 were evaluated. We found that long-term HFD treatment causes the development of diabetes mellitus, implicating increased serum glucose level, cell apoptosis, and testicular atrophy (P < 0.05 vs. Ctrl). Mechanistically, the results showed enhanced expression of HIF-1α in both Sertoli and Leydig cells (P < 0.05 vs. Ctrl). Advanced glycation end products (AGEs) were demonstrated to be a potential factor leading to HIF-1α upregulation in both cell types. In Sertoli cells, high glucose treatment had minor effects on Sertoli cell autophagy. However, AGE treatment stagnated the autophagy flux and escalated cell apoptosis (P < 0.05 vs. Ctrl+Ctrl). In Leydig cells, high glucose treatment was adequate to encumber autophagy induction and enhance oxidative stress. Similarly, AGE treatment facilitated HIF-1α expression and hampered testosterone production (P < 0.05 vs. Ctrl+Ctrl). Overall, these findings highlight the dual effects of diabetes on autophagy regulation in Sertoli and Leydig cells while imposing oxidative stress in both cell types. Furthermore, the upregulation of HIF-1α, which could be triggered by AGE treatment, may negatively affect both cell types. Together, these findings will help us further understand the molecular mechanism of diabetes-induced autophagy dysregulation and testicular impairment, enriching the content of male reproductive biology in diabetic patients.
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28
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Seo J, Yan L, Kageyama T, Nanmo A, Chun YS, Fukuda J. Hypoxia inducible factor-1α promotes trichogenic gene expression in human dermal papilla cells. Sci Rep 2023; 13:1478. [PMID: 36707659 PMCID: PMC9883512 DOI: 10.1038/s41598-023-28837-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/25/2023] [Indexed: 01/29/2023] Open
Abstract
Dermal papilla cells (DPCs) play critical roles in hair follicle development, but the underlying mechanisms that contribute to hair regeneration have yet to be fully elucidated, particularly in terms of alterations in androgenetic alopecia patients. In this study, we demonstrated that hypoxia-inducible factor-1α (HIF-1α) is suppressed in scalp tissues of androgenetic alopecia patients and potentially associated with hair follicle development. Using RT-qPCR and western blot, we found that mRNA and protein levels of trichogenic genes, LEF1 and versican (VCAN), were attenuated in HIF-1α knockdown DPCs. Under an in vivo mimicked environment in a three-dimensional spheroid culture, HIF-1α-suppressed DPCs downregulated the expression of hair induction-related genes. Finally, treatment with a HIF-1α activator resulted in the elevated expression of trichogenic genes in DPCs. This study highlights the importance of dermal HIF-1α expression in regulating trichogenic genes and provides a promising therapeutic target and a fundamental tissue engineering approach for hair loss treatment.
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Affiliation(s)
- Jieun Seo
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, Japan.,Kanagawa Institute of Industrial Science and Technology, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa, 213-0012, Japan
| | - Lei Yan
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, Japan.,Kanagawa Institute of Industrial Science and Technology, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa, 213-0012, Japan
| | - Tatsuto Kageyama
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, Japan.,Kanagawa Institute of Industrial Science and Technology, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa, 213-0012, Japan
| | - Ayaka Nanmo
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, Japan
| | - Yang-Sook Chun
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Junji Fukuda
- Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, Japan. .,Kanagawa Institute of Industrial Science and Technology, 3-2-1 Sakado, Takatsu-ku, Kawasaki, Kanagawa, 213-0012, Japan.
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29
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Bednarczyk M, Kociszewska K, Grosicka O, Grosicki S. The role of autophagy in acute myeloid leukemia development. Expert Rev Anticancer Ther 2023; 23:5-18. [PMID: 36563329 DOI: 10.1080/14737140.2023.2161518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Autophagy is a highly conservative self-degradative process. It aims at elimination-impaired proteins and cellular organelles. Previous research confirmed the autophagy role in cancer pathogenesis. AREAS COVERED This article discusses the role of autophagy in the development of AML. Autophagy seems to be a 'double-sword' mechanism, hence, either its suppression or induction could promote neoplasm growth. This mechanism could also be the aim of the 'molecular targeted therapy.' Chemo- and radiotherapy induce cellular stress in neoplasm cells with subsequent autophagy suppression. Simultaneously, it is claimed that the autophagy suppression increases chemosensitivity 'in neoplastic cells. Some agents, like bortezomib, in turn could promote autophagy process, e.g. in AML (acute myeloid leukemia). However, currently there are not many studies focusing on the role of autophagy in patients suffering for AML. In this review, we summarize the research done so far on the role of autophagy in the development of AML. EXPERT OPINION The analysis of autophagy genes expression profiling in AML could be a relevant factor in the diagnostic process and treatment 'individualization.' Autophagy modulation seems to be a relevant target in the oncological therapy - it could limit disease progression and increase the effectiveness of treatment.
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Affiliation(s)
- Martyna Bednarczyk
- Department of Hematology and Cancer Prevention, School of Public Health in Bytom, Medical University of Silesia in Katowice, Katowice, Poland
| | - Karolina Kociszewska
- Department of Hematology and Cancer Prevention, School of Public Health in Bytom, Medical University of Silesia in Katowice, Katowice, Poland
| | | | - Sebastian Grosicki
- Department of Hematology and Cancer Prevention, School of Public Health in Bytom, Medical University of Silesia in Katowice, Katowice, Poland
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30
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Ciclopirox drives growth arrest and autophagic cell death through STAT3 in gastric cancer cells. Cell Death Dis 2022; 13:1007. [PMID: 36443287 PMCID: PMC9705325 DOI: 10.1038/s41419-022-05456-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/29/2022]
Abstract
Ciclopirox (CPX), an antifungal drug, has recently been identified as a promising agent for cancer treatment. However, the effects and underlying mechanism of CPX as an antitumor agent of gastric cancer (GC) remain largely unknown. Here, we found that CPX dramatically suppresses GC xenograft growth in vitro via inhibiting proliferation and stimulating autophagic cell death rather than apoptosis. Moreover, CPX (20 mg/kg, intraperitoneally) substantially inhibits GC xenograft tumor growth in vivo. Mechanistically, CPX promotes growth arrest and autophagic cell death through suppressing the phosphorylation of signal transducers and activators of transcription 3 (STAT3) at tyrosine 705 (Tyr705) and serine 727 (Ser727) sites, respectively. Additionally, CPX induces STAT3 ubiquitination, which subsequently leads to a decrease in the p-STAT3 (Ser727) level. On the other hand, CPX represses the p-STAT3 (Tyr705) level via p-Src (Tyr416) inhibition. Collectively, our findings unmask a novel mechanism by which CPX regulates growth and autophagic cell death in GC cells via regulating the phosphorylation of STAT3 both at Tyr705 and Ser727 residues, and suggest that CPX may be a potential treatment for GC.
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31
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Sanati M, Binabaj MM, Ahmadi SS, Aminyavari S, Javid H, Mollazadeh H, Bibak B, Mohtashami E, Jamialahmadi T, Afshari AR, Sahebkar A. Recent advances in glioblastoma multiforme therapy: A focus on autophagy regulation. Biomed Pharmacother 2022; 155:113740. [PMID: 36166963 DOI: 10.1016/j.biopha.2022.113740] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/14/2022] [Accepted: 09/21/2022] [Indexed: 11/02/2022] Open
Abstract
Despite conventional treatment options including chemoradiation, patients with the most aggressive primary brain tumor, glioblastoma multiforme (GBM), experience an average survival time of less than 15 months. Regarding the malignant nature of GBM, extensive research and discovery of novel treatments are urgently required to improve the patients' prognosis. Autophagy, a crucial physiological pathway for the degradation and recycling of cell components, is one of the exciting targets of GBM studies. Interventions aimed at autophagy activation or inhibition have been explored as potential GBM therapeutics. This review, which delves into therapeutic techniques to block or activate autophagy in preclinical and clinical research, aims to expand our understanding of available therapies battling GBM.
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Affiliation(s)
- Mehdi Sanati
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran; Experimental and Animal Study Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Maryam Moradi Binabaj
- Non-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Seyed Sajad Ahmadi
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Samaneh Aminyavari
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran
| | - Hamid Mollazadeh
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Bahram Bibak
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Elmira Mohtashami
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir R Afshari
- Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran; Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran.
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Precise gliomas therapy: Hypoxia-activated prodrugs sensitized by nano-photosensitizers. Biomaterials 2022; 289:121770. [DOI: 10.1016/j.biomaterials.2022.121770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/25/2022] [Accepted: 08/28/2022] [Indexed: 11/18/2022]
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Qi YL, Wang HR, Chen LL, Duan YT, Yang SY, Zhu HL. Recent advances in small-molecule fluorescent probes for studying ferroptosis. Chem Soc Rev 2022; 51:7752-7778. [PMID: 36052828 DOI: 10.1039/d1cs01167g] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Ferroptosis is an iron-dependent, non-apoptotic form of programmed cell death driven by excessive lipid peroxidation (LPO). Mounting evidence suggests that the unique modality of cell death is involved in the development and progression of several diseases including cancer, cardiovascular diseases (CVDs), neurodegenerative disorders, etc. However, the pathogenesis and signalling pathways of ferroptosis are not fully understood, possibly due to the lack of robust tools for the highly selective and sensitive imaging of ferroptosis analytes in complex living systems. Up to now, various small-molecule fluorescent probes have been applied as promising chemosensors for studying ferroptosis through tracking the biomolecules or microenvironment-related parameters in vitro and in vivo. In this review, we comprehensively reviewed the recent development of small-molecule fluorescent probes for studying ferroptosis, with a focus on the analytes, design strategies and bioimaging applications. We also provided new insights to overcome the major challenges in this emerging field.
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Affiliation(s)
- Ya-Lin Qi
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China. .,Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.,State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.,Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA.
| | - Hai-Rong Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Li-Li Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Yong-Tao Duan
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China. .,Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China
| | - Sheng-Yu Yang
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA, USA.
| | - Hai-Liang Zhu
- Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China. .,Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.,State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
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Ki YS, Chung KS, Lee HW, Choi JH, Tapondjou LA, Jang E, Lee KT. Pennogenin-3-O-α-L-Rhamnopyranosyl-(1→2)-[α-L-Rhamnopyranosyl-(1→3)]-β-D-Glucopyranoside (Spiroconazol A) Isolated from Dioscorea bulbifera L. var. sativa Induces Autophagic Cell Death by p38 MAPK Activation in NSCLC Cells. Pharmaceuticals (Basel) 2022; 15:ph15070893. [PMID: 35890190 PMCID: PMC9319756 DOI: 10.3390/ph15070893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/15/2022] [Accepted: 07/18/2022] [Indexed: 02/01/2023] Open
Abstract
In our previous study, we reported the isolation of pennogenin-3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-β-D-glucopyranoside (spiroconazol A), a steroidal saponin, from the flowers of Dioscorea bulbifera L. var. sativa. In the present study, we aimed to investigate the effects of spiroconazol A on autophagy and its underlying mechanisms in A549 and NCI-H358 human non-small cell lung cancer (NSCLC) cells. Spiroconazol A inhibited the proliferation of NSCLC cells in a concentration- and time-dependent manner. To determine the type of programmed cell death induced by spiroconazol A, we performed a characterization of apoptosis in spiroconazol A-treated A549 cells. Our results showed that spiroconazol A significantly suppressed A549 cell viability but did not influence cell apoptosis because phosphatidylserine and caspase activation were not detected. Furthermore, spiroconazol A treatment upregulated the expression of LC3-II and autophagy-related Beclin-1 protein, suggesting that spiroconazol A induces autophagy in A549 cells. Moreover, spiroconazol A activated the phosphorylation of p38 mitogen-activated protein kinase (MAPK) but did not affect the phosphorylation of Janus kinase or ERK1/2. Notably, SB203580, a p38 MAPK inhibitor, had a significant inhibitory effect on spiroconazol A-induced autophagic cell death in A549 cells. Our results indicated that spiroconazol A-induced autophagy is dependent on p38 MAPK signaling and has potential as a therapeutic target in NSCLC.
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Affiliation(s)
- Yo Sook Ki
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea; (Y.S.K.); (K.-S.C.); (H.-W.L.)
| | - Kyung-Sook Chung
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea; (Y.S.K.); (K.-S.C.); (H.-W.L.)
| | - Heon-Woo Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea; (Y.S.K.); (K.-S.C.); (H.-W.L.)
| | - Jung-Hye Choi
- Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea;
| | - Léon Azefack Tapondjou
- Department of Chemistry, Faculty of Science, University of Dschang, Dschang P.O. Box 183, Cameroon;
| | - Eungyeong Jang
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea;
- Department of Internal Medicine, Kyung Hee University Korean Medicine Hospital, 23, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
| | - Kyung-Tae Lee
- Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Korea; (Y.S.K.); (K.-S.C.); (H.-W.L.)
- Correspondence: ; Tel.: +82-2-961-0860
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Petrosyan E, Fares J, Cordero A, Rashidi A, Arrieta VA, Kanojia D, Lesniak MS. Repurposing autophagy regulators in brain tumors. Int J Cancer 2022; 151:167-180. [PMID: 35179776 PMCID: PMC9133056 DOI: 10.1002/ijc.33965] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 01/25/2022] [Accepted: 01/31/2022] [Indexed: 11/09/2022]
Abstract
Malignant brain tumors, such as glioblastoma multiforme (GBM) and brain metastases, continue to be an unmet medical challenge. Despite advances in cancer diagnostics and therapeutics, tumor cell colonization in the central nervous system renders most treatment options ineffective. This is primarily due to the selective permeability of the blood-brain barrier (BBB), which hinders the crossing of targeting agents into the brain. As such, repositioning medications that demonstrate anticancer effects and possess the ability to cross the BBB can be a promising option. Antidepressants, which are BBB-permeable, have been reported to exhibit cytotoxicity against tumor cells. Autophagy, specifically, has been identified as one of the common key mediators of antidepressant's antitumor effects. In this work, we provide a comprehensive overview of US Food and Drug Administration (FDA)-approved antidepressants with reported cytotoxic activities in different tumor models, where autophagy dysregulation was demonstrated to play the main part. As such, imipramine, maprotiline, fluoxetine and escitalopram were shown to induce autophagy, whereas nortriptyline, clomipramine and paroxetine were identified as autophagy inhibitors. Sertraline and desipramine, depending on the neoplastic context, were demonstrated to either induce or inhibit autophagy. Collectively, these medications were associated with favorable therapeutic outcomes in a variety of cancer cell models, including brain tumors.
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Affiliation(s)
- Edgar Petrosyan
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Jawad Fares
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Alex Cordero
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Aida Rashidi
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Víctor A. Arrieta
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Deepak Kanojia
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
| | - Maciej S Lesniak
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
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Zhao F, Satyanarayana G, Zhang Z, Zhao J, Ma XL, Wang Y. Endothelial Autophagy in Coronary Microvascular Dysfunction and Cardiovascular Disease. Cells 2022; 11:2081. [PMID: 35805165 PMCID: PMC9265562 DOI: 10.3390/cells11132081] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/22/2022] [Accepted: 06/28/2022] [Indexed: 02/06/2023] Open
Abstract
Coronary microvascular dysfunction (CMD) refers to a subset of structural and/or functional disorders of coronary microcirculation that lead to impaired coronary blood flow and eventually myocardial ischemia. Amid the growing knowledge of the pathophysiological mechanisms and the development of advanced tools for assessment, CMD has emerged as a prevalent cause of a broad spectrum of cardiovascular diseases (CVDs), including obstructive and nonobstructive coronary artery disease, diabetic cardiomyopathy, and heart failure with preserved ejection fraction. Of note, the endothelium exerts vital functions in regulating coronary microvascular and cardiac function. Importantly, insufficient or uncontrolled activation of endothelial autophagy facilitates the pathogenesis of CMD in diverse CVDs. Here, we review the progress in understanding the pathophysiological mechanisms of autophagy in coronary endothelial cells and discuss their potential role in CMD and CVDs.
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Affiliation(s)
- Fujie Zhao
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | | | - Zheng Zhang
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | - Jianli Zhao
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | - Xin-Liang Ma
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
| | - Yajing Wang
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA; (F.Z.); (Z.Z.); (J.Z.); (X.-L.M.)
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Gao K, Zong H, Hou K, Zhang Y, Zhang R, Zhao D, Guo X, Luo Y, Jia S. p53N236S Activates Autophagy in Response to Hypoxic Stress Induced by DFO. Genes (Basel) 2022; 13:genes13050763. [PMID: 35627147 PMCID: PMC9141750 DOI: 10.3390/genes13050763] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/16/2022] [Accepted: 04/20/2022] [Indexed: 11/16/2022] Open
Abstract
Hypoxia can lead to stabilization of the tumor suppressor gene p53 and cell death. However, p53 mutations could promote cell survival in a hypoxic environment. In this study, we found that p53N236S (p53N239S in humans, hereinafter referred to as p53S) mutant mouse embryonic fibroblasts (MEFs) resistant to deferoxamine (DFO) mimic a hypoxic environment. Further, Western blot and flow cytometry showed reduced apoptosis in p53S/S cells compared to WT after DFO treatment, suggesting an antiapoptosis function of p53S mutation in response to hypoxia-mimetic DFO. Instead, p53S/S cells underwent autophagy in response to hypoxia stress presumably through inhibition of the AKT/mTOR pathway, and this process was coupled with nuclear translocation of p53S protein. To understand the relationship between autophagy and apoptosis in p53S/S cells in response to hypoxia, the autophagic inhibitor 3-MA was used to treat both WT and p53S/S cells after DFO exposure. Both apoptotic signaling and cell death were enhanced by autophagy inhibition in p53S/S cells. In addition, the mitochondrial membrane potential (MMP) and the ROS level results indicated that p53S might initiate mitophagy to clear up damaged mitochondria in response to hypoxic stress, thus increasing the proportion of intact mitochondria and maintaining cell survival. In conclusion, the p53S mutant activates autophagy instead of inducing an apoptotic process in response to hypoxia stress to protect cells from death.
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Affiliation(s)
- Kang Gao
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China; (K.G.); (H.Z.); (K.H.); (Y.Z.); (R.Z.); (D.Z.); (X.G.)
| | - Huanhuan Zong
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China; (K.G.); (H.Z.); (K.H.); (Y.Z.); (R.Z.); (D.Z.); (X.G.)
| | - Kailong Hou
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China; (K.G.); (H.Z.); (K.H.); (Y.Z.); (R.Z.); (D.Z.); (X.G.)
| | - Yanduo Zhang
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China; (K.G.); (H.Z.); (K.H.); (Y.Z.); (R.Z.); (D.Z.); (X.G.)
| | - Ruyi Zhang
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China; (K.G.); (H.Z.); (K.H.); (Y.Z.); (R.Z.); (D.Z.); (X.G.)
| | - Dan Zhao
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China; (K.G.); (H.Z.); (K.H.); (Y.Z.); (R.Z.); (D.Z.); (X.G.)
| | - Xin Guo
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China; (K.G.); (H.Z.); (K.H.); (Y.Z.); (R.Z.); (D.Z.); (X.G.)
| | - Ying Luo
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Development on Common Chronic Diseases, School of Basic Medicine, Guizhou Medical University, Guiyang 550000, China;
| | - Shuting Jia
- Laboratory of Molecular Genetics of Aging and Tumor, Medical School, Kunming University of Science and Technology, Kunming 650500, China; (K.G.); (H.Z.); (K.H.); (Y.Z.); (R.Z.); (D.Z.); (X.G.)
- Correspondence: ; Tel.: +86-0871-6592-0751
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Park JH, Lee HK. Current Understanding of Hypoxia in Glioblastoma Multiforme and Its Response to Immunotherapy. Cancers (Basel) 2022; 14:1176. [PMID: 35267480 PMCID: PMC8909860 DOI: 10.3390/cancers14051176] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 02/20/2022] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Hypoxia is a hallmark of glioblastoma multiforme (GBM), the most aggressive cancer of the central nervous system, and is associated with multiple aspects of tumor pathogenesis. For example, hypoxia induces resistance to conventional cancer therapies and inhibits antitumor immune responses. Thus, targeting hypoxia is an attractive strategy for GBM therapy. However, traditional studies on hypoxia have largely excluded the immune system. Recently, the critical role of the immune system in the defense against multiple tumors has become apparent, leading to the development of effective immunotherapies targeting numerous cancer types. Critically, however, GBM is classified as a "cold tumor" due to poor immune responses. Thus, to improve GBM responsiveness against immunotherapies, an improved understanding of both immune function in GBM and the role of hypoxia in mediating immune responses within the GBM microenvironment is needed. In this review, we discuss the role of hypoxia in GBM from a clinical, pathological, and immunological perspective.
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Affiliation(s)
| | - Heung Kyu Lee
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea;
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The complex interplay between autophagy and cell death pathways. Biochem J 2022; 479:75-90. [PMID: 35029627 DOI: 10.1042/bcj20210450] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/21/2021] [Accepted: 12/23/2021] [Indexed: 12/26/2022]
Abstract
Autophagy is a universal cellular homeostatic process, required for the clearance of dysfunctional macromolecules or organelles. This self-digestion mechanism modulates cell survival, either directly by targeting cell death players, or indirectly by maintaining cellular balance and bioenergetics. Nevertheless, under acute or accumulated stress, autophagy can also contribute to promote different modes of cell death, either through highly regulated signalling events, or in a more uncontrolled inflammatory manner. Conversely, apoptotic or necroptotic factors have also been implicated in the regulation of autophagy, while specific factors regulate both processes. Here, we survey both earlier and recent findings, highlighting the intricate interaction of autophagic and cell death pathways. We, Furthermore, discuss paradigms, where this cross-talk is disrupted, in the context of disease.
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40
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Wang J, Sun C, Li J, Jiang H, Qiu Y, Gong M. Knockdown of ETV4 promotes autophagy-dependent apoptosis in GBM cells by reducing the transcriptional activation of EMP1. Oncol Lett 2022; 23:41. [PMID: 34976153 PMCID: PMC8674874 DOI: 10.3892/ol.2021.13159] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/05/2021] [Indexed: 11/10/2022] Open
Abstract
ETS variant transcription factor 4 (ETV4) is a common cancer-promoting transcription factor and its expression has been found to be significantly upregulated in glioblastoma multiforme (GBM), as determined via analysis of the Gene Expression Profiling Interactive Analysis (GEPIA) database. In addition, our previous study demonstrated that ETV4 expression was highly positively correlated with epithelial membrane protein 1 (EMP1). The present study aimed to determine whether ETV4 could influence the activation of the PI3K/AKT/mTOR signaling pathway to affect the autophagy and apoptosis of GBM cells by regulating the transcriptional activity of EMP1. In addition to the analysis of the GEPIA database, the expression levels of ETV4 were also investigated in several different GBM cell lines. After interfering with the expression of ETV4, western blotting was used to detect the expression levels of autophagy- and apoptosis-related proteins, and a TUNEL assay was used to detect the levels of cell apoptosis. Dual luciferase reporter and chromatin immunoprecipitation assays were used to verify the potential binding site of ETV4 on EMP1. Western blotting was also used to analyze the expression levels of PI3K/AKT/mTOR signaling pathway-related proteins. The results of the current study revealed that the expression levels of ETV4 were significantly upregulated in GBM cell lines compared with those in normal glial cells. In the GBM cell line, LN-229, ETV4 was discovered to bind to the EMP1 promoter and positively regulate the expression of EMP1. The knockdown of ETV4 expression inhibited the PI3K/AKT/mTOR signaling pathway activity to promote autophagy and apoptosis, and this effect could be partially reversed by overexpressing EMP1. In conclusion, these findings indicated that the knockdown of ETV4 in GBM cells may reduce the transcriptional activation of EMP1 and thereby inhibit PI3K/AKT/mTOR signaling pathway activity to promote autophagy and apoptosis. This provides a novel insight into potential strategies for the treatment of GBM via the induction of autophagy-dependent apoptosis.
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Affiliation(s)
- Junxiang Wang
- Department of Neurosurgery, Changshu No. 2 People's Hospital, The Affiliated Changshu Hospital of Xuzhou Medical University, Changshu, Suzhou, Jiangsu 215500, P.R. China
| | - Chengfa Sun
- Department of Neurosurgery, Changshu No. 2 People's Hospital, The Affiliated Changshu Hospital of Xuzhou Medical University, Changshu, Suzhou, Jiangsu 215500, P.R. China
| | - Jian Li
- Department of Neurosurgery, Changshu No. 2 People's Hospital, The Affiliated Changshu Hospital of Xuzhou Medical University, Changshu, Suzhou, Jiangsu 215500, P.R. China
| | - Hua Jiang
- Department of Neurosurgery, Changshu No. 2 People's Hospital, The Affiliated Changshu Hospital of Xuzhou Medical University, Changshu, Suzhou, Jiangsu 215500, P.R. China
| | - Yun Qiu
- Department of Neurosurgery, Changshu No. 2 People's Hospital, The Affiliated Changshu Hospital of Xuzhou Medical University, Changshu, Suzhou, Jiangsu 215500, P.R. China
| | - Mingjie Gong
- Department of Neurosurgery, Changshu No. 2 People's Hospital, The Affiliated Changshu Hospital of Xuzhou Medical University, Changshu, Suzhou, Jiangsu 215500, P.R. China
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Overexpression of BNIP3 in rat intervertebral disk cells triggers autophagy and apoptosis. ARCH BIOL SCI 2022. [DOI: 10.2298/abs220310013w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Excessive apoptosis of intervertebral disk cells and intervertebral disk
degeneration (IDD) is the prime cause of low back pain. B-cell lymphoma 2
(Bcl-2) and adenovirus E1B 19 kDa interacting protein 3 (BNIP3), a member of
the Bcl-2 family, are involved in cell autophagy and apoptosis. The roles
and mechanisms of BNIP3 in intervertebral disk cell autophagy and apoptosis
are unclear. In this study, primary rat intervertebral disk cells were
prepared to study the effect of BNIP3 overexpression on their autophagy and
apoptosis. The cell counting kit (CCK)-8 assay showed that BNIP3
overexpression decreased cell viability. Real-time PCR and Western blotting
showed that BNIP3 overexpression significantly upregulated the expression of
autophagy-related proteins and pro-apoptotic proteins, including
hypoxia-inducible factor-1?, apoptotic protease activating factor 1, caspase
3 and cleaved caspase 3, microtubule-associated proteins 1A/1B light chain 3
(LC3) and Beclin-1 while downregulating the expression of anti-apoptotic
protein Bcl-2. Cell staining detection of autophagy and apoptosis showed
that BNIP3 overexpression significantly increased the autophagy and
apoptosis of rat intervertebral disk cells. BNIP3 RNA interference revealed
that the effects of BNIP3 overexpression can be reversed. These findings
suggested that BNIP3 enhanced the autophagy and apoptosis in the rat
intervertebral disk cells in vitro, which might promote IDD development.
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Zhang X, Feng J, Li X, Wu D, Wang Q, Li S, Shi C. Mitophagy in Diabetic Kidney Disease. Front Cell Dev Biol 2021; 9:778011. [PMID: 34957109 PMCID: PMC8703169 DOI: 10.3389/fcell.2021.778011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/10/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease worldwide and is the main microvascular complication of diabetes. The increasing prevalence of diabetes has increased the need for effective treatment of DKD and identification of new therapeutic targets for better clinical management. Mitophagy is a highly conserved process that selectively removes damaged or unnecessary mitochondria via the autophagic machinery. Given the important role of mitophagy in the increased risk of DKD, especially with the recent surge in COVID-19-associated diabetic complications, in this review, we provide compelling evidence for maintaining homeostasis in the glomeruli and tubules and its underlying mechanisms, and offer new insights into potential therapeutic approaches for treatment of DKD.
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Affiliation(s)
| | | | | | | | | | - Shuyu Li
- School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Changhua Shi
- School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing, China
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43
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Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3. Cell Death Dis 2021; 12:1105. [PMID: 34824192 PMCID: PMC8617186 DOI: 10.1038/s41419-021-04402-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 11/01/2021] [Accepted: 11/09/2021] [Indexed: 12/31/2022]
Abstract
Systemic hypoxia is a common element in most perinatal emergencies and is a known driver of Bnip3 expression in the neonatal heart. Bnip3 plays a prominent role in the evolution of necrotic cell death, disrupting ER calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests a cardioprotective role for the prostaglandin E1 analog misoprostol during periods of hypoxia, but the mechanisms for this protection are not completely understood. Using a combination of mouse and cell models, we tested if misoprostol is cardioprotective during neonatal hypoxic injury by altering Bnip3 function. Here we report that hypoxia elicits mitochondrial-fragmentation, MPT, reduced ejection fraction, and evidence of necroinflammation, which were abrogated with misoprostol treatment or Bnip3 knockout. Through molecular studies we show that misoprostol leads to PKA-dependent Bnip3 phosphorylation at threonine-181, and subsequent redistribution of Bnip3 from mitochondrial Opa1 and the ER through an interaction with 14-3-3 proteins. Taken together, our results demonstrate a role for Bnip3 phosphorylation in the regulation of cardiomyocyte contractile/metabolic dysfunction, and necroinflammation. Furthermore, we identify a potential pharmacological mechanism to prevent neonatal hypoxic injury.
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Pang K, Wang S, Li M, Zhou Z. Autophagy in Femoral Head Necrosis of Broilers Bone Metabolism Parameters and Autophagy-Related Gene Expression in Femoral Head Necrosis Induced by Glucocorticoid in Broilers. Front Vet Sci 2021; 8:746087. [PMID: 34796226 PMCID: PMC8592919 DOI: 10.3389/fvets.2021.746087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 10/07/2021] [Indexed: 11/22/2022] Open
Abstract
Objectives: In this study, the influence of methylprednisolone (MP) and 3-methyladenine (3-MA) on chondrocyte autophagy and bone quality were determined to investigate the mechanisms of femoral head necrosis in broilers. Methods: Chickens were divided into four groups: control, MP, 3-MA, and 3-MA+MP groups. Blood and bone samples were collected for biochemistry assay and bone quality determination. Cartilage was separated from the femoral head for histopathological analysis and gene expression detection. Results: The results indicated that MP treatment significantly affected blood levels of alkaline phosphatase, high-density lipoprotein, calcium, phosphorus, bone alkaline phosphatase, and osteocalcin in broilers. Additionally, MP treatment significantly increased blood levels of cholesterol, low-density lipoprotein, triglyceride, carboxy-terminal telopeptide of type-I collagen, and tartrate-resistant acid phosphatase 5. MP treatment also significantly decreased the levels of bone parameters compared with these values in controls, inhibited the expression of collagen-2, aggrecan, and mammalian target of rapamycin, and increased the expression of beclin1 and microtubule-associated protein 1 light chain 3, hypoxia-inducible factor 1 alpha, phosphoinositide 3-kinase, protein kinase B and autophagy-related gene 5 of the femoral head. Furthermore, following co-treatment with 3-MA and MP, 3-MA mitigated the effects of MP. Conclusions: Our findings demonstrated that autophagy may be involved in the pathogenesis of femoral head necrosis induced by MP in broilers, and this study provides new treatment and prevention ideas for femoral head necrosis caused by glucocorticoids.
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Affiliation(s)
- Kaiyi Pang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Shujie Wang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Meng Li
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Zhenlei Zhou
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
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45
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Chen Y, Zhang Z, Henson ES, Cuddihy A, Haigh K, Wang R, Haigh JJ, Gibson SB. Autophagy inhibition by TSSC4 (tumor suppressing subtransferable candidate 4) contributes to sustainable cancer cell growth. Autophagy 2021; 18:1274-1296. [PMID: 34530675 DOI: 10.1080/15548627.2021.1973338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Cancer cell growth is dependent upon the sustainability of proliferative signaling and resisting cell death. Macroautophagy/autophagy promotes cancer cell growth by providing nutrients to cells and preventing cell death. This is in contrast to autophagy promoting cell death under some conditions. The mechanism regulating autophagy-mediated cancer cell growth remains unclear. Herein, we demonstrate that TSSC4 (tumor suppressing subtransferable candidate 4) is a novel tumor suppressor that suppresses cancer cell growth and tumor growth and prevents cell death induction during excessive growth by inhibiting autophagy. The oncogenic proteins ERBB2 (erb-b2 receptor tyrosine kinase 2) and the activation EGFR mutant (EGFRvIII, epidermal growth factor receptor variant III) promote cell growth and TSSC4 expression in breast cancer and glioblastoma multiforme (GBM) cells, respectively. In EGFRvIII-expressing GBM cells, TSSC4 knockout shifted the function of autophagy from a pro-cell survival role to a pro-cell death role during prolonged cell growth. Furthermore, the interaction of TSSC4 with MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) via its conserved LC3-interacting region (LIR) contributes to its inhibition of autophagy. Finally, TSSC4 suppresses tumorsphere formation and tumor growth by inhibiting autophagy and maintaining cell survival in tumorspheres. Taken together, sustainable cancer cell growth can be achieved by autophagy inhibition via TSSC4 expression.ABBREVIATIONS: 3-MA: 3-methyladenine; ACTB: actin beta; CQ: chloroquine; EGFRvIII: epidermal growth factor receptor variant III; ERBB2: erb-b2 receptor tyrosine kinase 2; GBM: glioblastoma multiforme; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule Associated protein 1 light chain 3; TSSC4: tumor suppressing subtransferable candidate 4.
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Affiliation(s)
- Yongqiang Chen
- CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Zhaoying Zhang
- CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Elizabeth S Henson
- CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Andrew Cuddihy
- CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Katharina Haigh
- CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ruobing Wang
- CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Jody J Haigh
- CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.,Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Spencer B Gibson
- CancerCare Manitoba Research Institute, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada.,Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada.,Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
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46
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Bienia A, Wiecheć-Cudak O, Murzyn AA, Krzykawska-Serda M. Photodynamic Therapy and Hyperthermia in Combination Treatment-Neglected Forces in the Fight against Cancer. Pharmaceutics 2021; 13:1147. [PMID: 34452108 PMCID: PMC8399393 DOI: 10.3390/pharmaceutics13081147] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/26/2021] [Accepted: 07/16/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer is one of the leading causes of death in humans. Despite the progress in cancer treatment, and an increase in the effectiveness of diagnostic methods, cancer is still highly lethal and very difficult to treat in many cases. Combination therapy, in the context of cancer treatment, seems to be a promising option that may allow minimizing treatment side effects and may have a significant impact on the cure. It may also increase the effectiveness of anti-cancer therapies. Moreover, combination treatment can significantly increase delivery of drugs to cancerous tissues. Photodynamic therapy and hyperthermia seem to be ideal examples that prove the effectiveness of combination therapy. These two kinds of therapy can kill cancer cells through different mechanisms and activate various signaling pathways. Both PDT and hyperthermia play significant roles in the perfusion of a tumor and the network of blood vessels wrapped around it. The main goal of combination therapy is to combine separate mechanisms of action that will make cancer cells more sensitive to a given therapeutic agent. Such an approach in treatment may contribute toward increasing its effectiveness, optimizing the cancer treatment process in the future.
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Affiliation(s)
| | | | | | - Martyna Krzykawska-Serda
- Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Kraków, Poland; (A.B.); (O.W.-C.); (A.A.M.)
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47
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Rashid M, Zadeh LR, Baradaran B, Molavi O, Ghesmati Z, Sabzichi M, Ramezani F. Up-down regulation of HIF-1α in cancer progression. Gene 2021; 798:145796. [PMID: 34175393 DOI: 10.1016/j.gene.2021.145796] [Citation(s) in RCA: 161] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/25/2021] [Accepted: 06/22/2021] [Indexed: 12/19/2022]
Abstract
Hypoxia induicible factor-1 alpha (HIF-1α) is a key transcription factor in cancer progression and target therapy in cancer. HIF-1α acts differently depending on presence or absence of Oxygen. In an oxygen-immersed environment, HIF-1α completely deactivated and destroyed by the ubiquitin proteasome pathway (UPP). In contrast, in the oxygen-free environment, it escapes destruction and enters to the nucleus of cells then upregulates many genes involved in cancer progression. Overexpressed HIF-1α and downstream genes support cancer progression through various mechanisms including angiogenesis, proliferation and survival of cells, metabolism reprogramming, invasion and metastasis, cancer stem cell maintenance, induction of genetic instability, and treatment resistance. HIF-1α can be provoked by signaling pathways unrelated to hypoxia during cancer progression. Therefore, cancer development and progression can be modulated by targeting HIF-1α and its downstream signaling molecules. In this regard, HIF-1α inhibitors which are categorized into the agents that regulate HIF-1α in gene, mRNA and protein levels used as an efficient way in cancer treatment. Also, HIF-1α expression can be negatively affected by the agents suppressing the activation of mTOR, PI3k/Akt and MAPK pathways.
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Affiliation(s)
- Mohsen Rashid
- Department of Molecular Medicine, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Rostami Zadeh
- Department of Molecular Medicine, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Department of Molecular Medicine, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ommoleila Molavi
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeinab Ghesmati
- Department of Medical Biotechnology, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Sabzichi
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Fatemeh Ramezani
- Department of Molecular Medicine, School of Advanced Medical Science, Tabriz University of Medical Sciences, Tabriz, Iran.
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48
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Jandrey EHF, Bezerra M, Inoue LT, Furnari FB, Camargo AA, Costa ÉT. A Key Pathway to Cancer Resilience: The Role of Autophagy in Glioblastomas. Front Oncol 2021; 11:652133. [PMID: 34178638 PMCID: PMC8222785 DOI: 10.3389/fonc.2021.652133] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
There are no effective strategies for the successful treatment of glioblastomas (GBM). Current therapeutic modalities effectively target bulk tumor cells but leave behind marginal GBM cells that escape from the surgical margins and radiotherapy field, exhibiting high migratory phenotype and resistance to all available anti-glioma therapies. Drug resistance is mostly driven by tumor cell plasticity: a concept associated with reactivating transcriptional programs in response to adverse and dynamic conditions from the tumor microenvironment. Autophagy, or "self-eating", pathway is an emerging target for cancer therapy and has been regarded as one of the key drivers of cell plasticity in response to energy demanding stress conditions. Many studies shed light on the importance of autophagy as an adaptive mechanism, protecting GBM cells from unfavorable conditions, while others recognize that autophagy can kill those cells by triggering a non-apoptotic cell death program, called 'autophagy cell death' (ACD). In this review, we carefully analyzed literature data and conclude that there is no clear evidence indicating the presence of ACD under pathophysiological settings in GBM disease. It seems to be exclusively induced by excessive (supra-physiological) stress signals, mostly from in vitro cell culture studies. Instead, pre-clinical and clinical data indicate that autophagy is an emblematic example of the 'dark-side' of a rescue pathway that contributes profoundly to a pro-tumoral adaptive response. From a standpoint of treating the real human disease, only combinatorial therapy targeting autophagy with cytotoxic drugs in the adjuvant setting for GBM patients, associated with the development of less toxic and more specific autophagy inhibitors, may inhibit adaptive response and enhance the sensibility of glioma cells to conventional therapies.
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Affiliation(s)
| | - Marcelle Bezerra
- Molecular Oncology Center, Hospital Sírio-Libanês, São Paulo, Brazil
| | | | - Frank B. Furnari
- Ludwig Institute for Cancer Research, University of California San Diego (UCSD), San Diego, CA, United States
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49
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Batara DCR, Choi MC, Shin HU, Kim H, Kim SH. Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis. Cells 2021; 10:1411. [PMID: 34204169 PMCID: PMC8227518 DOI: 10.3390/cells10061411] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/30/2021] [Accepted: 06/03/2021] [Indexed: 02/07/2023] Open
Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy's pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM.
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Affiliation(s)
- Don Carlo Ramos Batara
- Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju 61186, Korea; (D.C.R.B.); (H.-U.S.)
| | - Moon-Chang Choi
- Department of Biomedical Science, Chosun University, Gwangju 61452, Korea;
| | - Hyeon-Uk Shin
- Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju 61186, Korea; (D.C.R.B.); (H.-U.S.)
| | - Hyunggee Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea;
| | - Sung-Hak Kim
- Department of Animal Science, College of Agriculture and Life Sciences, Chonnam National University, Gwangju 61186, Korea; (D.C.R.B.); (H.-U.S.)
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50
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van Schaik TA, Chen KS, Shah K. Therapy-Induced Tumor Cell Death: Friend or Foe of Immunotherapy? Front Oncol 2021; 11:678562. [PMID: 34141622 PMCID: PMC8204251 DOI: 10.3389/fonc.2021.678562] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/03/2021] [Indexed: 12/13/2022] Open
Abstract
Combinatory treatments using surgery, radiotherapy and/or chemotherapy together with immunotherapy have shown encouraging results for specific subsets of tumors, but a significant proportion of tumors remains unsusceptible. Some of these inconsistencies are thought to be the consequence of an immunosuppressive tumor microenvironment (TME) caused by therapy-induced tumor cell death (TCD). An increased understanding of the molecular mechanisms governing TCD has provided valuable insights in specific signaling cascades activated by treatment and the subsequent effects on the TME. Depending on the treatment variables of conventional chemo-, radio- and immunotherapy and the genetic composition of the tumor cells, particular cell death pathways are activated. Consequently, TCD can either have tolerogenic or immunogenic effects on the local environment and thereby affect the post-treatment anti-tumor response of immune cells. Thus, identification of these events can provide new rationales to increase the efficacy of conventional therapies combined with immunotherapies. In this review, we sought to provide an overview of the molecular mechanisms initiated by conventional therapies and the impact of treatment-induced TCD on the TME. We also provide some perspectives on how we can circumvent tolerogenic effects by adequate treatment selection and manipulation of key signaling cascades.
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Affiliation(s)
- Thijs A van Schaik
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, MA, United States.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Kok-Siong Chen
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, MA, United States.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Khalid Shah
- Center for Stem Cell Therapeutics and Imaging (CSTI), Harvard Medical School, Boston, MA, United States.,Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.,Harvard Stem Cell Institute, Harvard University, Cambridge, MA, United States
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