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Qin Z, Zhang H, Zhang J, Li T, Kuca K, Liu J, Wu W. Deoxynivalenol induces pyroptosis and IL-1β secretion via P2X7R signal in murine RAW264.7 macrophages. Toxicon 2025; 263:108418. [PMID: 40381923 DOI: 10.1016/j.toxicon.2025.108418] [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: 04/12/2025] [Revised: 05/11/2025] [Accepted: 05/14/2025] [Indexed: 05/20/2025]
Abstract
Deoxynivalenol (DON), a trichothecene mycotoxin, exerts pro-inflammatory and immunomodulatory activity. Interleukin (IL)-1β serves a crucial part as a gate keeper of inflammation in DON-induced macrophages, but an overview of how DON exposure elicits IL-1β secretion from RAW264.7 cells has not been fully illustrated. Here we found that the cellular phenomenon, involved with a type of programmed cell death known as pyroptosis, contains: 1) increase of pro-IL-1β expression, 2) motivation of caspase-1, 3) caspase-1-dependent maturement of IL-1β, 4) caspase-1 fragmentation of gasdermin D (GSDMD), and 5) IL-1β secretion through GSDMD pore. Mechanistically, the present study certified that DON both as first and second signals engaged in IL-1β release is mediated by purinergic P2X7 receptor (P2X7R)-Src signaling. During this process, P2X7R signal is required for GSDMD pore forming course in ASC-independent manner. Moreover, blocking of K+ efflux, ROS formation, as well as cathepsin B activity decreases IL-1β export. Our data show that exposure to DON does cause pyroptosis and IL-1β secretion via P2X7R signal in RAW264.7 macrophages. Overall, these results provide new mechanistic clue for DON as a pro-inflammatory factor in innate immune signaling events.
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Affiliation(s)
- Zihui Qin
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China
| | - Huayue Zhang
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China; MOE Engineering Research Center of Bio-process, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China
| | - Jie Zhang
- School of Biology and Food Engineering, Changshu Institute of Technology, Suzhou, 215500, China
| | - Tushuai Li
- School of Biology and Food Engineering, Changshu Institute of Technology, Suzhou, 215500, China
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, 50003, Czech Republic
| | - Jiaguo Liu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China.
| | - Wenda Wu
- MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China; MOE Engineering Research Center of Bio-process, School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China; Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, 50003, Czech Republic.
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Komiya H, Takeuchi H, Ogasawara A, Ogawa Y, Kubota S, Hashiguchi S, Takahashi K, Kunii M, Tanaka K, Tada M, Doi H, Tanaka F. Siponimod inhibits microglial inflammasome activation. Neurosci Res 2025; 213:138-145. [PMID: 39921000 DOI: 10.1016/j.neures.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 01/16/2025] [Accepted: 02/04/2025] [Indexed: 02/10/2025]
Abstract
Siponimod is the first oral drug approved for active secondary progressive multiple sclerosis. It acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P1) through S1P1 internalization, and also serves an agonist of S1P5; however, the detailed mechanisms of its therapeutic effects on glial cells have yet to be elucidated. In this study, we investigated the anti-inflammatory mechanism of siponimod in microglia. Pretreatment with either siponimod or the S1P1 antagonist W146 significantly suppressed the production of interleukin-1β in activated microglia stimulated with lipopolysaccharide plus nigericin, an inflammasome activator. Furthermore, siponimod treatment reduced the protein levels of cleaved caspase-1 and inhibited the formation of aggregates of apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC specks) in microglia. Our data indicate that siponimod achieves its anti-inflammatory effects by inhibiting inflammasome activation in microglia via S1P1 antagonism. This process is inferred to play a crucial role in mitigating the secondary progression of multiple sclerosis, where microglial activation in the gray matter is considered a key pathological factor.
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Affiliation(s)
- Hiroyasu Komiya
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hideyuki Takeuchi
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Neurology, Graduate School of Medicine, International University of Health and Welfare, Narita, Japan; Center for Intractable Neurological Diseases and Dementia, International University of Health and Welfare Atami Hospital, Atami, Japan.
| | - Akihiro Ogasawara
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yuki Ogawa
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Shun Kubota
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Shunta Hashiguchi
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Keita Takahashi
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Misako Kunii
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kenichi Tanaka
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Mikiko Tada
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiroshi Doi
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Fumiaki Tanaka
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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Liu Y, Yao C, Sheng B, Zhi S, Chen X, Ding P, Zhang J, Tao Z, Li W, Zhuang Z, Mao J, Peng Z, Yan H, Jin W. Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH. Transl Stroke Res 2025; 16:448-466. [PMID: 38147294 PMCID: PMC11976779 DOI: 10.1007/s12975-023-01228-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 11/24/2023] [Accepted: 12/18/2023] [Indexed: 12/27/2023]
Abstract
Subarachnoid hemorrhage (SAH) is a type of stroke with a high disability and mortality rate. Apoptosis caused by massive damage to mitochondria in neuron cells and inflammatory responses caused by high extracellular ATP lead to poor outcomes. USP30 is a deubiquitinating enzyme that inhibits mitophagy, resulting in a failure to remove damaged mitochondria in a timely manner after SAH; nevertheless, the pathway through which USP30 inhibits mitophagy is unknown. This study evaluated the neuroprotective role and possible molecular basis by which inhibiting USP30 to attenuate SAH-induced EBI by promoting neuronal mitophagy. We used an in vitro model of hemoglobin exposure and an in vivo model of intravascular perforation. Increased expression of USP30 was found after SAH in vivo and in vitro, and USP30 inhibition expression in SAH mice treated with MF094 resulted in significant improvement of neurological injury and inflammatory response and mediated good outcomes, suggesting a neuroprotective effect of USP30 inhibition. In cultured neurons, inhibition of USP30 promoted ubiquitination modification of mitochondrial fusion protein 2 (MFN2) by E3 ubiquitin ligase (Parkin), separating damaged mitochondria from the healthy mitochondrial network and prompting mitophagy, causing early clearance of damaged intracellular mitochondria, and reducing the onset of apoptosis. The high extracellular ATP environment was meliorated, reversing the conversion of microglia to a pro-inflammatory phenotype and reducing inflammatory injury. USP30 inhibition had no autophagy-promoting effect on structurally and functionally sound mitochondria and did not inhibit normal intracellular ATP production. The findings suggest that USP30 inhibition has a neuroprotective effect after SAH by promoting early mitophagy after SAH to clear damaged mitochondria.
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Affiliation(s)
- Yang Liu
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, Jiangsu, China
| | - Chenbei Yao
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Bin Sheng
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Simin Zhi
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, Jiangsu, China
| | - Xiangxin Chen
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Pengfei Ding
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China
| | - Jiatong Zhang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Zhennan Tao
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Wei Li
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, Jiangsu, China
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China
| | - Zong Zhuang
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China
| | - Jiannan Mao
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Zheng Peng
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Huiying Yan
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China.
| | - Wei Jin
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, Jiangsu, China.
- Department of Neurosurgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, Jiangsu, China.
- Department of Neurosurgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China.
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Kim JE, Wang SH, Lee DS, Kim TH. Protein disulfide isomerase integrates toll-like receptor 4 and P2X7 receptor signaling pathways during lipopolysaccharide-induced neuroinflammation. Sci Rep 2025; 15:7906. [PMID: 40050375 PMCID: PMC11885452 DOI: 10.1038/s41598-025-92780-5] [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: 11/19/2024] [Accepted: 03/03/2025] [Indexed: 03/09/2025] Open
Abstract
P2X7 receptor (P2X7R) augments lipopolysaccharide (LPS)-toll-like receptor 4 (TLR4)-mediated neuroinflammation. These roles of P2X7R in neuroinflammation are relevant to nitrosative stress through nuclear factor-κB (NF-κB)-inducible nitric oxide synthase (iNOS) pathway, while the underlying mechanisms are largely unknown. In the present study, we investigated whether protein disulfide isomerase (PDI) is involved in the integration of TLR4-P2X7R functions in response to LPS in vivo. The present study showed that LPS elicited NF-κB-mediated PDI upregulation, iNOS induction and S-nitrosylated PDI (SNO-PDI) level, independent of S-nitrosylation of NF-κB p65 subunit, in P2X7R+/+ mice more than P2X7R-/- mice. SN50 (an NF-κB inhibitor) effectively diminished LPS-induced PDI upregulation in both P2X7R+/+ and P2X7R-/- mice. PDI knockdown attenuated LPS-induced p65 S276 phosphorylation and iNOS induction in both strains. Of interest, S-nitroso-N-acetyl-DL-penicillamine (SNAP, a NO donor) increased SNO-PDI level, surface P2X7R expression and p65 S276 phosphorylation in P2X7R+/+ mice under physiological condition. In P2X7R-/- mice, SNAP was less effective on NF-κB S276 phosphorylation, although SNO-PDI level was similar to that in P2X7R+/+ mice. Taken together, the present data demonstrate that PDI may be an intermediator to integrate TLR4- and P2X7R-mediated signaling pathways in a positive feedback loop, which would exert NF-κB-iNOS-mediated nitrosative stress during LPS-induced neuroinflammation.
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Affiliation(s)
- Ji-Eun Kim
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon, 24252, Korea.
- Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, 24252, Korea.
| | - Su Hyeon Wang
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon, 24252, Korea
- Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, 24252, Korea
| | - Duk-Shin Lee
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon, 24252, Korea
- Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, 24252, Korea
| | - Tae-Hyun Kim
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon, 24252, Korea
- Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, 24252, Korea
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Bano N, Khan S, Ahamad S, Dar NJ, Alanazi HH, Nazir A, Bhat SA. Microglial Autophagic Dysregulation in Traumatic Brain Injury: Molecular Insights and Therapeutic Avenues. ACS Chem Neurosci 2025; 16:543-562. [PMID: 39920904 DOI: 10.1021/acschemneuro.4c00617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2025] Open
Abstract
Traumatic brain injury (TBI) is a complex and multifaceted condition that can result in cognitive and behavioral impairments. One aspect of TBI that has received increasing attention in recent years is the role of microglia, the brain-resident immune cells, in the pathophysiology of the injury. Specifically, increasing evidence suggests that dysfunction in microglial autophagy, the process by which cells degrade and recycle their own damaged components, may contribute to the development and progression of TBI-related impairments. Here, we unravel the pathways by which microglia autophagic dysregulation predisposes the brain to secondary damage and neurological deficits following TBI. An overview of the role of autophagic dysregulation in perpetuation and worsening of the inflammatory response, neuroinflammation, and neuronal cell death in TBI follows. Further, we have evaluated several signaling pathways and processes that contribute to autophagy dysfunction-mediated inflammation, neurodegeneration, and poor outcome in TBI. Additionally, a discussion on the small molecule therapeutics employed to modulate these pathways and mechanisms to treat TBI have been presented. However, additional research is required to fully understand the processes behind these underlying pathways and uncover potential therapeutic targets for restoring microglial autophagic failure in TBI.
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Affiliation(s)
- Nargis Bano
- Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Sameera Khan
- Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Shakir Ahamad
- Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India
| | - Nawab John Dar
- CNB, SALK Institute of Biological Sciences, La Jolla, California 92037, United States
| | - Hamad H Alanazi
- Department of Clinical Laboratory Science, College of Applied Medical Sciences, Al Jouf University, Sakaka 77455, Saudi Arabia
| | - Aamir Nazir
- Division of Neuroscience and Ageing Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India
- Academy of Scientific and Innovative Research, New Delhi 201002, India
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Huang Y, Li H, Yu Q, Pan Y. A narrative review of autophagy in migraine. Front Neurosci 2025; 19:1500189. [PMID: 40027467 PMCID: PMC11868061 DOI: 10.3389/fnins.2025.1500189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 02/03/2025] [Indexed: 03/05/2025] Open
Abstract
Background and objective Autophagy is a natural process regulated by autophagy-related genes in eukaryotic cells that involves the degradation of cytoplasmic proteins and old or damaged organelles via the lysosomal pathway to help maintain cell homeostasis. Previous studies have suggested a potential association between autophagy and migraine, while the underlying mechanisms remain unclear. This review seeks to evaluate the possible involvement of autophagy in the pathophysiology of migraine, aiming to clarify its role and implications for future research and therapeutic strategies. Methods A search in PubMed was conducted for English-language articles until December 5, 2024. Key terms of "autophagy," "migraine," "microglia," "neurogenic inflammation," "central sensitization," "mitophagy" and "neuropathic pain" in different combinations. Results In the context of migraine, the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling pathway exerts a direct influence on the mammalian target of rapamycin (mTOR), leading to a reduction in autophagy levels. Moreover, the stimulation of purinergic ligand-gated ion channel type 7 receptor (P2X7R) in microglia can hinder autophagy by interfering with the fusion of autophagosomes and lysosomes, which impedes the degradation of substrates within the autophagolysosome. Increased levels of calcitonin gene-related peptide (CGRP) may also modulate autophagy through the Akt/mTOR or protein kinase A (PKA)/mTOR signaling pathways. Additionally, research indicates that mitophagy may be partially impaired in individuals suffering from migraine. Furthermore, autophagy could contribute to the dysregulation of synaptic plasticity by influencing the processes of long-term potentiation (LTP) and long-term depression (LTD), both of which are associated with central sensitization in chronic migraine. Conclusion These findings suggest that autophagy may play an important role in the pathophysiology of migraine, particularly in its development and central sensitization. Research on autophagy modulators related to migraine will provide valuable insights for treatment strategies.
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Lyu Q, Chen R, Qiu Z, Wang C, Liu R. Druggable targets for Parkinson's disease: transcriptomics based Mendelian randomization study. Sci Rep 2024; 14:25763. [PMID: 39468243 PMCID: PMC11519603 DOI: 10.1038/s41598-024-77401-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 10/22/2024] [Indexed: 10/30/2024] Open
Abstract
Parkinson's disease (PD) is a prevalent neurodegenerative disorder. Currently available drugs for PD, can only relieve the symptoms of PD, but cannot prevent the progression of the disease and have serious side effects. Other new druggable therapeutic targets for PD are needed. First, six GEO datasets with transcriptomic data from the substantia nigra (SN) region of the brain were downloaded to find dysregulated druggable genes in PD. Then, Mendelian randomization (MR) and summary statistics-based MR (SMR) analysis were conducted using eQTL data from both brain tissue and blood to investigate the relationship between gene expression and PD. Next, the association between the expression of candidate druggable targets and disease stage was validated in an additional dataset GSE49036. Finally, a phenome-wide MR analysis was carried out to investigate the potential impact of candidate druggable genes on several other complex diseases or traits. Our study revealed 313 differentially expressed genes that may be directly targetable and have an impact on PD (FDR-p < 0.1). Through MR and SMR analysis, P2RX7 and RNASET2 were identified as feasible PD therapeutic targets, which were highly expressed in PD tissues and increased as the Braak stages increased. Phenome-wide MR analysis revealed other effects of targeting RNASET2. This study presents genetic support for the potential therapeutic properties of targeting P2RX7 and RNASET2, which will be useful for developing druggable therapeutic targets for PD.
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Affiliation(s)
- Qiong Lyu
- Department of Neurology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Rong Chen
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhengang Qiu
- Department of Neurology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
| | - Chuhuai Wang
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
| | - Rongrong Liu
- Department of Neurology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China.
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Tsourmas KI, Butler CA, Kwang NE, Sloane ZR, Dykman KJG, Maloof GO, Prekopa CA, Krattli RP, El-Khatib SM, Swarup V, Acharya MM, Hohsfield LA, Green KN. Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.21.619538. [PMID: 39484433 PMCID: PMC11526954 DOI: 10.1101/2024.10.21.619538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme (Hexb). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To understand how a microglial gene is involved in maintaining neuronal homeostasis, we demonstrated that β-hexosaminidase is secreted by microglia and integrated into the neuronal lysosomal compartment. To assess therapeutic relevance, we treated SD mice with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaced Hexb -/- microglia with Hexb-sufficient cells. This intervention reversed apoptotic gene signatures, improved behavior, restored enzymatic activity and Hexb expression, ameliorated substrate accumulation, and normalized neuronal lysosomal phenotypes. These results underscore the critical role of myeloid-derived β-hexosaminidase in neuronal lysosomal function and establish microglial replacement as a potential LSD therapy.
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Affiliation(s)
- Kate I. Tsourmas
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
| | - Claire A. Butler
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
| | - Nellie E. Kwang
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
| | - Zachary R. Sloane
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
| | - Koby J. G. Dykman
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
| | - Ghassan O. Maloof
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
| | - Christiana A. Prekopa
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
| | - Robert P. Krattli
- Department of Anatomy and Neurobiology; University of California; Irvine, CA 92697; USA
| | - Sanad M. El-Khatib
- Department of Anatomy and Neurobiology; University of California; Irvine, CA 92697; USA
| | - Vivek Swarup
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
| | - Munjal M. Acharya
- Department of Anatomy and Neurobiology; University of California; Irvine, CA 92697; USA
- Department of Radiation Oncology; University of California; Irvine, CA 92697; USA
| | - Lindsay A. Hohsfield
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
| | - Kim N. Green
- Department of Neurobiology and Behavior; University of California; Irvine, CA 92697; USA
- Institute for Memory Impairments and Neurological Disorders; University of California; Irvine, CA 92697; USA
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Simões JLB, de Carvalho Braga G, Eichler SW, da Silva GB, Bagatini MD. Implications of COVID-19 in Parkinson's disease: the purinergic system in a therapeutic-target perspective to diminish neurodegeneration. Purinergic Signal 2024; 20:487-507. [PMID: 38460075 PMCID: PMC11377384 DOI: 10.1007/s11302-024-09998-7] [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: 08/25/2023] [Accepted: 02/21/2024] [Indexed: 03/11/2024] Open
Abstract
The pathophysiology of Parkinson's disease (PD) is marked by degeneration of dopaminergic neurons in the substantia nigra. With advent of COVID-19, which is closely associated with generalized inflammation and multiple organ dysfunctions, the PD patients may develop severe conditions of disease leading to exacerbated degeneration. This condition is caused by the excessive release of pro-inflammatory markers, called cytokine storm, that is capable of triggering neurodegenerative conditions by affecting the blood-brain barrier (BBB). A possible SARS-CoV-2 infection, in serious cases, may compromise the immune system by triggering a hyperstimulation of the neuroimmune response, similar to the pathological processes found in PD. From this perspective, the inflammatory scenario triggers oxidative stress and, consequently, cellular dysfunction in the nervous tissue. The P2X7R seems to be the key mediator of the neuroinflammatory process, as it acts by increasing the concentration of ATP, allowing the influx of Ca2+ and the occurrence of mutations in the α-synuclein protein, causing activation of this receptor. Thus, modulation of the purinergic system may have therapeutic potential on the effects of PD, as well as on the damage caused by inflammation of the BBB, which may be able to mitigate the neurodegeneration caused by diseases. Considering all the processes of neuroinflammation, oxidative stress, and mitochondrial dysfunction that PD propose, we can conclude that the P2X7 antagonist acts in the prevention of viral diseases, and it also controls purinergic receptors formed by multi-target compounds directed to self-amplification circuits and, therefore, may be a viable strategy to obtain the desired disease-modifying effect. Thus, purinergic system receptor modulations have a high therapeutic potential for neurodegenerative diseases such as PD.
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Affiliation(s)
| | | | | | - Gilnei Bruno da Silva
- Multicentric Postgraduate Program in Biochemistry and Molecular Biology, State University of Santa Catarina, Lages, SC, Brazil
| | - Margarete Dulce Bagatini
- Graduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Chapecó, SC, Brazil.
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10
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Ge TQ, Guan PP, Wang P. Complement 3a induces the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms during the development and progression of Alzheimer's disease. Neurosci Biobehav Rev 2024; 165:105868. [PMID: 39218048 DOI: 10.1016/j.neubiorev.2024.105868] [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: 05/10/2024] [Revised: 08/08/2024] [Accepted: 08/25/2024] [Indexed: 09/04/2024]
Abstract
As a central molecule in complement system (CS), complement (C) 3 is upregulated in the patients and animal models of Alzheimer's disease (AD). C3 will metabolize to iC3b and C3a. iC3b is responsible for clearing β-amyloid protein (Aβ). In this scenario, C3 exerts neuroprotective effects against the disease via iC3b. However, C3a will inhibit microglia to clear the Aβ, leading to the deposition of Aβ and impair the functions of synapses. To their effects on AD, activation of C3a and C3a receptor (C3aR) will impair the mitochondria, leading to the release of reactive oxygen species (ROS), which activates the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasomes. The overloading of NLRP3 inflammasomes activate microglia, leading to the formation of inflammatory environment. The inflammatory environment will facilitate the deposition of Aβ and abnormal synapse pruning, which results in the progression of AD. Therefore, the current review will decipher the mechanisms of C3a inducing the synapse loss via C3aR in mitochondria-dependent NLRP3 activating mechanisms, which facilitates the understanding the AD.
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Affiliation(s)
- Tong-Qi Ge
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, PR China; College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China
| | - Pei-Pei Guan
- College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China.
| | - Pu Wang
- College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, PR China.
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11
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Huang Q, Ying J, Yu W, Dong Y, Xiong H, Zhang Y, Liu J, Wang X, Hua F. P2X7 Receptor: an Emerging Target in Alzheimer's Disease. Mol Neurobiol 2024; 61:2866-2880. [PMID: 37940779 PMCID: PMC11043177 DOI: 10.1007/s12035-023-03699-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 10/06/2023] [Indexed: 11/10/2023]
Abstract
Alzheimer's disease (AD) is a major cause of age-related dementia, which is becoming a global health crisis. However, the pathogenesis and etiology of AD are still not fully understood. And there are no valid treatment methods or precise diagnostic tools for AD. There is increasing evidence that P2X7R expression is upregulated in AD and is involved in multiple related pathological processes such as Aβ plaques, neurogenic fiber tangles, oxidative stress, and chronic neuroinflammation. This suggests that P2X7R may be a key player in the development of AD. P2X7R is a member of the ligand-gated purinergic receptor (P2X) family. It has received attention in neuroscience due to its role in a wide range of aging and age-related neurological disorders. In this review, we summarize current information on the roles of P2X7R in AD and suggest potential pharmacological interventions to slow down AD progression.
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Affiliation(s)
- Qiang Huang
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, 1# Minde Road, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, 330006, Nanchang City, Jiangxi Province, People's Republic of China
| | - Jun Ying
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, 1# Minde Road, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, 330006, Nanchang City, Jiangxi Province, People's Republic of China
| | - Wen Yu
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, 1# Minde Road, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, 330006, Nanchang City, Jiangxi Province, People's Republic of China
| | - Yao Dong
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, 1# Minde Road, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, 330006, Nanchang City, Jiangxi Province, People's Republic of China
| | - Hao Xiong
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, 1# Minde Road, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, 330006, Nanchang City, Jiangxi Province, People's Republic of China
| | - Yiping Zhang
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, 1# Minde Road, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, 330006, Nanchang City, Jiangxi Province, People's Republic of China
| | - Jie Liu
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, 1# Minde Road, Nanchang, 330006, Jiangxi, China
- Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, 330006, Nanchang City, Jiangxi Province, People's Republic of China
| | - Xifeng Wang
- Department of Anesthesiology, the First Affiliated Hospital of Nanchang University, 17# Yongwai Road, Nanchang, 330006, Jiangxi, China.
| | - Fuzhou Hua
- Department of Anesthesiology, the Second Affiliated Hospital of Nanchang University, 1# Minde Road, Nanchang, 330006, Jiangxi, China.
- Key Laboratory of Anesthesiology of Jiangxi Province, 1# Minde Road, 330006, Nanchang City, Jiangxi Province, People's Republic of China.
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12
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Huang YL, Huang DY, Klochkov V, Chan CM, Chen YS, Lin WW. NLRX1 Inhibits LPS-Induced Microglial Death via Inducing p62-Dependent HO-1 Expression, Inhibiting MLKL and Activating PARP-1. Antioxidants (Basel) 2024; 13:481. [PMID: 38671928 PMCID: PMC11047433 DOI: 10.3390/antiox13040481] [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: 03/11/2024] [Revised: 04/02/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
The activation of microglia and the production of cytokines are key factors contributing to progressive neurodegeneration. Despite the well-recognized neuronal programmed cell death regulated by microglial activation, the death of microglia themselves is less investigated. Nucleotide-binding oligomerization domain, leucine-rich repeat-containing X1 (NLRX1) functions as a scaffolding protein and is involved in various central nervous system diseases. In this study, we used the SM826 microglial cells to understand the role of NLRX1 in lipopolysaccharide (LPS)-induced cell death. We found LPS-induced cell death is blocked by necrostatin-1 and zVAD. Meanwhile, LPS can activate poly (ADP-ribose) polymerase-1 (PARP-1) to reduce DNA damage and induce heme oxygenase (HO)-1 expression to counteract cell death. NLRX1 silencing and PARP-1 inhibition by olaparib enhance LPS-induced SM826 microglial cell death in an additive manner. Less PARylation and higher DNA damage are observed in NLRX1-silencing cells. Moreover, LPS-induced HO-1 gene and protein expression through the p62-Keap1-Nrf2 axis are attenuated by NLRX1 silencing. In addition, the Nrf2-mediated positive feedback regulation of p62 is accordingly reduced by NLRX1 silencing. Of note, NLRX1 silencing does not affect LPS-induced cellular reactive oxygen species (ROS) production but increases mixed lineage kinase domain-like pseudokinase (MLKL) activation and cell necroptosis. In addition, NLRX1 silencing blocks bafilomycin A1-induced PARP-1 activation. Taken together, for the first time, we demonstrate the role of NLRX1 in protecting microglia from LPS-induced cell death. The underlying protective mechanisms of NLRX1 include upregulating LPS-induced HO-1 expression via Nrf2-dependent p62 expression and downstream Keap1-Nrf2 axis, mediating PARP-1 activation for DNA repair via ROS- and autophagy-independent pathway, and reducing MLKL activation.
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Affiliation(s)
- Yu-Ling Huang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Duen-Yi Huang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Vladlen Klochkov
- Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City 23148, Taiwan
| | - Chi-Ming Chan
- Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City 23148, Taiwan
- School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan
| | - Yuan-Shen Chen
- Department of Neurosurgery, National Taiwan University, Yunlin Branch, Yunlin 640203, Taiwan
| | - Wan-Wan Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110301, Taiwan
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13
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Zhang GP, Liao JX, Liu YY, Zhu FQ, Huang HJ, Zhang WJ. Ion channel P2X7 receptor in the progression of cancer. Front Oncol 2024; 13:1297775. [PMID: 38273855 PMCID: PMC10808724 DOI: 10.3389/fonc.2023.1297775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 12/12/2023] [Indexed: 01/27/2024] Open
Abstract
P2X7 receptor (P2X7) is a non-selective and ATP-sensitive ligand-gated cation channel. Studies have confirmed that it is expressed in a variety of cells and correlates with their function, frequently in immune cells and tumor cells. We found increased expression of this receptor in many tumor cells, and it has a role in tumor survival and progression. In immune cells, upregulation of the receptor has a double effect on tumor suppression as well as tumor promotion. This review describes the structure of P2X7 and its role in the tumor microenvironment and presents possible mechanisms of P2X7 in tumor invasion and metastasis. Understanding the potential of P2X7 for tumor treatment, we also present several therapeutic agents targeting P2X7 and their mechanisms of action. In conclusion, the study of P2X7 is an important guideline for the use of clinical tumor therapy and may be able to provide a new idea for tumor treatment, but considering the complexity of the biological effects of P2X7, the drugs should be used with caution in clinical practice.
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Affiliation(s)
- Guang-ping Zhang
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
- Department of Critical Medicine, Ganzhou people’s Hospital, Ganzhou, Jiangxi, China
| | - Jun-xiang Liao
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Yi-yi Liu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Fu-qi Zhu
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Hui-jin Huang
- The Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
| | - Wen-jun Zhang
- Department of Rehabilitation Medicine, the Second Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China
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14
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Zhang HL, Sandai D, Zhang ZW, Song ZJ, Babu D, Tabana Y, Dahham SS, Adam Ahmed Adam M, Wang Y, Wang W, Zhang HL, Zhao R, Barakat K, Harun MSR, Shapudin SNM, Lok B. Adenosine triphosphate induced cell death: Mechanisms and implications in cancer biology and therapy. World J Clin Oncol 2023; 14:549-569. [PMID: 38179405 PMCID: PMC10762532 DOI: 10.5306/wjco.v14.i12.549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/08/2023] [Accepted: 11/21/2023] [Indexed: 12/22/2023] Open
Abstract
Adenosine triphosphate (ATP) induced cell death (AICD) is a critical cellular process that has garnered substantial scientific interest for its profound relevance to cancer biology and to therapeutic interventions. This comprehensive review unveils the intricate web of AICD mechanisms and their intricate connections with cancer biology. This review offers a comprehensive framework for comprehending the multifaceted role of AICD in the context of cancer. This is achieved by elucidating the dynamic interplay between systemic and cellular ATP homeostasis, deciphering the intricate mechanisms governing AICD, elucidating its intricate involvement in cancer signaling pathways, and scrutinizing validated key genes. Moreover, the exploration of AICD as a potential avenue for cancer treatment underscores its essential role in shaping the future landscape of cancer therapeutics.
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Affiliation(s)
- Hao-Ling Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Doblin Sandai
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Zhong-Wen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Dinesh Babu
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Yasser Tabana
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Sabbar Saad Dahham
- Department of Science, University of Technology and Applied Sciences Rustaq, Rustaq 10 P.C. 329, Oman
| | - Mowaffaq Adam Ahmed Adam
- Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182, United States
| | - Yong Wang
- Pathology Center, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Wei Wang
- College of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Hao-Long Zhang
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Khaled Barakat
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton AB T6G 2E1, Canada
| | - Mohammad Syamsul Reza Harun
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Siti Nurfatimah Mohd Shapudin
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
| | - Bronwyn Lok
- Department of Biomedical Science, Advanced Medical and Dental Institute, University Sains Malaysia, Penang 13200, Malaysia
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15
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Wang W, Zhang H, Sandai D, Zhao R, Bai J, Wang Y, Wang Y, Zhang Z, Zhang HL, Song ZJ. ATP-induced cell death: a novel hypothesis for osteoporosis. Front Cell Dev Biol 2023; 11:1324213. [PMID: 38161333 PMCID: PMC10755924 DOI: 10.3389/fcell.2023.1324213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/05/2023] [Indexed: 01/03/2024] Open
Abstract
ATP-induced cell death has emerged as a captivating realm of inquiry with profound ramifications in the context of osteoporosis. This study unveils a paradigm-shifting hypothesis that illuminates the prospective involvement of ATP-induced cellular demise in the etiology of osteoporosis. Initially, we explicate the morphological attributes of ATP-induced cell death and delve into the intricacies of the molecular machinery and regulatory networks governing ATP homeostasis and ATP-induced cell death. Subsequently, our focus pivots towards the multifaceted interplay between ATP-induced cellular demise and pivotal cellular protagonists, such as bone marrow-derived mesenchymal stem cells, osteoblasts, and osteoclasts, accentuating their potential contributions to secondary osteoporosis phenotypes, encompassing diabetic osteoporosis, glucocorticoid-induced osteoporosis, and postmenopausal osteoporosis. Furthermore, we probe the captivating interplay between ATP-induced cellular demise and alternative modalities of cellular demise, encompassing apoptosis, autophagy, and necroptosis. Through an all-encompassing inquiry into the intricate nexus connecting ATP-induced cellular demise and osteoporosis, our primary goal is to deepen our comprehension of the underlying mechanisms propelling this malady and establish a theoretical bedrock to underpin the development of pioneering therapeutic strategies.
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Affiliation(s)
- Wei Wang
- College of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Haolong Zhang
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Doblin Sandai
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Rui Zhao
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Jinxia Bai
- College of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Yanfei Wang
- College of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Yong Wang
- Pathology Center, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Zhongwen Zhang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Hao-Ling Zhang
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Zhi-Jing Song
- Clinical College of Chinese Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, China
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16
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Wu AYT, Sekar P, Huang DY, Hsu SH, Chan CM, Lin WW. Spatiotemporal roles of AMPK in PARP-1- and autophagy-dependent retinal pigment epithelial cell death caused by UVA. J Biomed Sci 2023; 30:91. [PMID: 37936170 PMCID: PMC10629085 DOI: 10.1186/s12929-023-00978-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 09/29/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND Although stimulating autophagy caused by UV has been widely demonstrated in skin cells to exert cell protection, it remains unknown the cellular events in UVA-treated retinal pigment epithelial (RPE) cells. METHODS Human ARPE-19 cells were used to measure cell viability, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial mass and lysosomal mass by flow cytometry. Mitochondrial oxygen consumption rate (OCR) was recorded using Seahorse XF flux analyzer. Confocal microscopic images were performed to indicate the mitochondrial dynamics, LC3 level, and AMPK translocation after UVA irradiation. RESULTS We confirmed mitochondrial ROS production and DNA damage are two major features caused by UVA. We found the cell death is prevented by autophagy inhibitor 3-methyladenine and gene silencing of ATG5, and UVA induces ROS-dependent LC3II expression, LC3 punctate and TFEB expression, suggesting the autophagic death in the UVA-stressed RPE cells. Although PARP-1 inhibitor olaparib increases DNA damage, ROS production, and cell death, it also blocks AMPK activation caused by UVA. Interestingly we found a dramatic nuclear export of AMPK upon UVA irradiation which is blocked by N-acetylcysteine and olaparib. In addition, UVA exposure gradually decreases lysosomal mass and inhibits cathepsin B activity at late phase due to lysosomal dysfunction. Nevertheless, cathepsin B inhibitor, CA-074Me, reverses the death extent, suggesting the contribution of cathepsin B in the death pathway. When examining the role of EGFR in cellular events caused by UVA, we found that UVA can rapidly transactivate EGFR, and treatment with EGFR TKIs (gefitinib and afatinib) enhances the cell death accompanied by the increased LC3II formation, ROS production, loss of MMP and mass of mitochondria and lysosomes. Although AMPK activation by ROS-PARP-1 mediates autophagic cell death, we surprisingly found that pretreatment of cells with AMPK activators (A769662 and metformin) reverses cell death. Concomitantly, both agents block UVA-induced mitochondrial ROS production, autophagic flux, and mitochondrial fission without changing the inhibition of cathepsin B. CONCLUSION UVA exposure rapidly induces ROS-PARP-1-AMPK-autophagic flux and late lysosomal dysfunction. Pre-inducing AMPK activation can prevent cellular events caused by UVA and provide a new protective strategy in photo-oxidative stress and photo-retinopathy.
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Affiliation(s)
- Anthony Yan-Tang Wu
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan
| | - Ponarulselvam Sekar
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
| | - Duen-Yi Huang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shu-Hao Hsu
- Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City, Taiwan
| | - Chi-Ming Chan
- Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City, Taiwan.
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
| | - Wan-Wan Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
- Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan.
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
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17
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Seeger AY, Zaidi F, Alhayek S, Jones RM, Zohair H, Holland RL, Kim IJ, Blanke SR. Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells. mBio 2023; 14:e0211723. [PMID: 37815365 PMCID: PMC10653863 DOI: 10.1128/mbio.02117-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 08/23/2023] [Indexed: 10/11/2023] Open
Abstract
IMPORTANCE Persistent human gastric infection with Helicobacter pylori is the single most important risk factor for development of gastric malignancy, which is one of the leading causes of cancer-related deaths worldwide. An important virulence factor for Hp colonization and severity of gastric disease is the protein exotoxin VacA, which is secreted by the bacterium and modulates functional properties of gastric cells. VacA acts by damaging mitochondria, which impairs host cell metabolism through impairment of energy production. Here, we demonstrate that intoxicated cells have the capacity to detect VacA-mediated damage, and orchestrate the repair of mitochondrial function, thereby restoring cellular health and vitality. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies.
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Affiliation(s)
- Ami Y. Seeger
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Faisal Zaidi
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Sammy Alhayek
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Rachel M. Jones
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Huzaifa Zohair
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
| | - Robin L. Holland
- Department of Pathobiology, University of Illinois, Urbana, Illinois, USA
| | - Ik-Jung Kim
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
- Buck Institute for Research on Aging, Novato, California, USA
| | - Steven R. Blanke
- Department of Microbiology, University of Illinois, Urbana, Illinois, USA
- Department of Pathobiology, University of Illinois, Urbana, Illinois, USA
- Department of Biomedical and Translational Medicine, University of Illinois, Urbana, Illinois, USA
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18
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Strogulski NR, Portela LV, Polster BM, Loane DJ. Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury. J Neurochem 2023; 167:129-153. [PMID: 37759406 PMCID: PMC10655864 DOI: 10.1111/jnc.15959] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023]
Abstract
Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain-infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro- and anti-inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro-inflammatory activation is associated with decreased mitochondrial respiration, whereas anti-inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post-traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non-resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post-traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.
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Affiliation(s)
- Nathan R. Strogulski
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Luis V. Portela
- Neurotrauma and Biomarkers Laboratory, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Brian M. Polster
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - David J. Loane
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
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19
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Zhang R, Su K, Yang L, Tang M, Zhao M, Ye N, Cai X, Jiang X, Li N, Peng J, Zhang X, Wang B, Wu W, Ma L, Ye H. Design, Synthesis, and Biological Evaluation of Novel P2X7 Receptor Antagonists for the Treatment of Septic Acute Kidney Injury. J Med Chem 2023; 66:11365-11389. [PMID: 37582195 DOI: 10.1021/acs.jmedchem.3c00837] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/17/2023]
Abstract
Sepsis-associated acute kidney injury (AKI) is a serious clinical problem, without effective drugs. Abnormal activation of the purinergic P2X7 receptor (P2X7R) in septic kidneys makes its antagonist a promising therapeutic approach. Herein, a series of novel P2X7R antagonists were designed, synthesized, and structurally optimized. Based on in vitro potency in human/mouse P2X7R using HEK293 cells, hepatic microsomal stability, and pharmacokinetic and preliminary in vivo assessments, compound 14a was identified by respective human and mouse P2X7R IC50 values of 64.7 and 10.1 nM, together with favorable pharmacokinetic properties. Importantly, 14a dose-dependently alleviated kidney dysfunction and pathological injury in both lipopolysaccharide (LPS)- and cecal ligation/perforation (CLP)-induced septic AKI mice with a good safety profile. Mechanistically, 14a could suppress NLRP3 inflammasome activation to inhibit the expression of cleaved caspase-1, gasdermin D, IL-1β, and IL-18 in the injured kidneys of septic mice. Collectively, these results highlighted that P2X7R antagonist 14a exerted a therapeutic potential against septic AKI.
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Affiliation(s)
- Ruijia Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kaiyue Su
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Letian Yang
- Division of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minghai Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Min Zhao
- Laboratory of Metabolomics and Drug-induced Liver Injury, Department of Gastroenterology & Hepatology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Neng Ye
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaoying Cai
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xueqin Jiang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Na Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Peng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinlu Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Bo Wang
- Division of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wenshuang Wu
- Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Liang Ma
- Division of Nephrology, Kidney Research Institute, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Haoyu Ye
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
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20
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Ahn D, Go RE, Choi KC. Oxygen consumption rate to evaluate mitochondrial dysfunction and toxicity in cardiomyocytes. Toxicol Res 2023; 39:333-339. [PMID: 37398565 PMCID: PMC10313613 DOI: 10.1007/s43188-023-00183-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/31/2023] [Accepted: 04/04/2023] [Indexed: 07/04/2023] Open
Abstract
The increase in the types and complexity of diseases has led to significant advances in diagnostic techniques and the availability of effective therapies. Recent studies have focused on the role of mitochondrial dysfunction in the pathogenesis of cardiovascular diseases (CVDs). Mitochondria are important organelles in cells that generate energy. Besides the production of adenosine triphosphate (ATP), the energy currency of cells, mitochondria are also involved in thermogenesis, control of intracellular calcium ions (Ca2+), apoptosis, regulation of reactive oxygen species (ROS), and inflammation. Mitochondrial dysfunction has been implicated in several diseases including cancer, diabetes, some genetic diseases, and neurogenerative and metabolic diseases. Furthermore, the cardiomyocytes of the heart are rich in mitochondria due to the large energy requirement for optimal cardiac function. One of the main causes of cardiac tissue injuries is believed to be mitochondrial dysfunction, which occurs via complicated pathways which have not yet been completely elucidated. There are various types of mitochondrial dysfunction including mitochondrial morphological change, unbalanced levels of substances to maintain mitochondria, mitochondrial damage by drugs, and mitochondrial deletion and synthesis errors. Most of mitochondrial dysfunctions are linked with symptoms and diseases, thus we focus on parts of mitochondrial dysfunction about fission and fusion in cardiomyocytes, and ways to understand the mechanism of cardiomyocyte damage by detecting oxygen consumption levels in the mitochondria.
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Affiliation(s)
- Dohee Ahn
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644 Republic of Korea
| | - Ryeo-Eun Go
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644 Republic of Korea
| | - Kyung-Chul Choi
- Laboratory of Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644 Republic of Korea
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21
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Sekar P, Hsiao G, Hsu SH, Huang DY, Lin WW, Chan CM. Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1. Redox Biol 2023; 64:102786. [PMID: 37348156 PMCID: PMC10363482 DOI: 10.1016/j.redox.2023.102786] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/24/2023] Open
Abstract
Diabetic retinopathy (DR) is a major cause of blindness in adult, and the accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is a precursor of AGEs. Although the therapeutic potential of metformin for retinopathy disorders has recently been elucidated, possibly through AMPK activation, it remains unknown how metformin directly affects the MGO-induced stress response in retinal pigment epithelial cells. Therefore, in this study, we compared the effects of metformin and the AMPK activator A769662 on MGO-induced DR in mice, as well as evaluated cytotoxicity, mitochondrial dynamic changes and dysfunction in ARPE-19 cells. We found MGO can induce mitochondrial ROS production and mitochondrial membrane potential loss, but reduce cytosolic ROS level in ARPE-19 cells. Although these effects of MGO can be reversed by both metformin and A769662, we demonstrated that reduction of mitochondrial ROS production rather than restoration of cytosolic ROS level contributes to cell protective effects of metformin and A769662. Moreover, MGO inhibits AMPK activity, reduces LC3II accumulation, and suppresses protein and gene expressions of MFN1, PGC-1α and TFAM, leading to mitochondrial fission, inhibition of mitochondrial biogenesis and autophagy. In contrast, these events of MGO were reversed by metformin in an AMPK-dependent manner as evidenced by the effects of compound C and AMPK silencing. In addition, we observed an AMPK-dependent upregulation of glyoxalase 1, a ubiquitous cellular enzyme that participates in the detoxification of MGO. In intravitreal drug-treated mice, we found that AMPK activators can reverse the MGO-induced cotton wool spots, macular edema and retinal damage. Functional, histological and optical coherence tomography analysis support the protective actions of both agents against MGO-elicited retinal damage. Metformin and A769662 via AMPK activation exert a strong protection against MGO-induced retinal pigment epithelial cell death and retinopathy. Therefore, metformin and AMPK activator can be therapeutic agents for DR.
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Affiliation(s)
- Ponarulselvam Sekar
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
| | - George Hsiao
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
| | - Shu-Hao Hsu
- Medical Research Center, Cardinal Tien Hospital, New Taipei City, Taiwan
| | - Duen-Yi Huang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wan-Wan Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
| | - Chi-Ming Chan
- Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City, Taiwan; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
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22
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Tao R, Han M, Yuan W, Xiao F, Huang J, Wang X, Luo X, Yan W, Wan X, Ning Q. Fibrinogen-like protein 2 promotes proinflammatory macrophage polarization and mitochondrial dysfunction in liver fibrosis. Int Immunopharmacol 2023; 117:109631. [PMID: 36878044 DOI: 10.1016/j.intimp.2022.109631] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 12/08/2022] [Accepted: 12/20/2022] [Indexed: 03/07/2023]
Abstract
Fibrinogen-like protein 2 (Fgl2) robustly activates macrophages in response to infection or inflammatory cytokine challenge and is markedly increased in the liver tissues of liver cirrhosis patientswithhepatitisCvirus(HCV) infection. However, the molecular mechanism underlying the involvement of Fgl2 in macrophage function in the pathogenesis of liver fibrosis remains unclear. In this study, we demonstrated that increased hepatic Fgl2 expression was associated with hepatic inflammation and high-grade liver fibrosis in patients with hepatitis B virus (HBV) infection and experimental models. Genetic ablation of Fgl2 alleviated hepatic inflammation and fibrosis progression. Fgl2 promoted M1 macrophage polarization and increased the production of proinflammatory cytokines that contribute to inflammatory damage and fibrosis development. In addition, Fgl2 augmented mitochondrial reactive oxygen species (ROS) production and modulated mitochondrial functions. Fgl2-mediated mtROS were involved in macrophage activation and polarization. We further demonstrated that in macrophages, Fgl2 localized to not only the cytosol but also mitochondria, where it bound to cytosolic and mitochondrial heat shock protein 90 (HSP90). Mechanistically, Fgl2 interacted with HSP90, hindering the interaction of HSP90 with its target protein Akt, significantly inhibiting Akt phosphorylation and downstream FoxO1 phosphorylation. These results reveal different layers of regulation of Fgl2 that are necessary for inflammatory damage and mitochondrial dysfunction in M1-polarized macrophages. Therefore, Fgl2 may be a potent target in liver fibrosis treatment.
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Affiliation(s)
- Ran Tao
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Meiwen Han
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wei Yuan
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Fang Xiao
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jiaquan Huang
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaojing Wang
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Weiming Yan
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Xiaoyang Wan
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Qin Ning
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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23
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Sekar P, Hsiao G, Chen YS, Lin WW, Chan CM. P2X7 Is Involved in the Mouse Retinal Degeneration via the Coordinated Actions in Different Retinal Cell Types. Antioxidants (Basel) 2023; 12:141. [PMID: 36671003 PMCID: PMC9854982 DOI: 10.3390/antiox12010141] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/02/2023] [Accepted: 01/03/2023] [Indexed: 01/11/2023] Open
Abstract
Adenosine triphosphate (ATP) released from dying cells with high concentrations is sensed as a danger signal by the P2X7 receptor. Sodium iodate (NaIO3) is an oxidative toxic agent, and its retinal toxicity has been used as the model of dry age-related macular degeneration (AMD). In this study, we used NaIO3-treated mice and cultured retinal cells, including BV-2 microglia, 661W photoreceptors, rMC1 Müller cells and ARPE-19 retinal epithelial cells, to understand the pathological action of P2X7 in retinal degeneration. We found that NaIO3 can significantly decrease the photoreceptor function by reducing a-wave and b-wave amplitudes in electroretinogram (ERG) analysis. Optical coherence tomography (OCT) analysis revealed the degeneration of retinal epithelium and ganglion cell layers. Interestingly, P2X7-/- mice were protected from the NaIO3-induced retinopathy and inflammatory NLRP3, IL-1β and IL-6 gene expression in the retina. Hematoxylin and eosin staining indicated that the retinal epithelium was less deteriorated in P2X7-/- mice compared to the WT group. Although P2X7 was barely detected in 661W, rMC1 and ARPE-19 cells, its gene and protein levels can be increased after NaIO3 treatment, leading to a synergistic cytotoxicity of BzATP [2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethyleneammonium)salt] and NaIO3 administration in ARPE-19 cells. In conclusion, the paracrine action of the ATP/P2X7 axis via cell-cell communication is involved in NaIO3-induced retinal injury. Our results show that P2X7 antagonist might be a potential therapy in inflammation-related retinal degeneration.
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Affiliation(s)
- Ponarulselvam Sekar
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110301, Taiwan
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - George Hsiao
- Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Yuan-Shen Chen
- Department of Neurosurgery, National Taiwan University, Yunlin Branch, Yunlin County 640203, Taiwan
| | - Wan-Wan Lin
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110301, Taiwan
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan
| | - Chi-Ming Chan
- Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City 23148, Taiwan
- School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan
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24
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Pang K, Wang W, Qin J, Shi Z, Hao L, Ma Y, Xu H, Wu Z, Pan D, Chen Z, Han C. Role of protein phosphorylation in cell signaling, disease, and the intervention therapy. MedComm (Beijing) 2022; 3:e175. [PMID: 36349142 PMCID: PMC9632491 DOI: 10.1002/mco2.175] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 08/18/2022] [Accepted: 08/22/2022] [Indexed: 11/06/2022] Open
Abstract
Protein phosphorylation is an important post-transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small-molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin-dependent protein kinase (CaMK) group, CMGC [Cyclin-dependent kinases (CDKs), Mitogen-activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and Cdc2-like kinases (CLKs)] group, sterile (STE)-MAPKs group, tyrosine kinases (TK) group, tyrosine kinase-like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.
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Affiliation(s)
- Kun Pang
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
| | - Wei Wang
- Department of Medical CollegeSoutheast UniversityNanjingJiangsuChina
| | - Jia‐Xin Qin
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
| | - Zhen‐Duo Shi
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
| | - Lin Hao
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
| | - Yu‐Yang Ma
- Graduate SchoolBengbu Medical CollegeBengbuAnhuiChina
| | - Hao Xu
- Graduate SchoolBengbu Medical CollegeBengbuAnhuiChina
| | - Zhuo‐Xun Wu
- Department of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesSt. John's University, QueensNew YorkNew YorkUSA
| | - Deng Pan
- Graduate SchoolBengbu Medical CollegeBengbuAnhuiChina
| | - Zhe‐Sheng Chen
- Department of Pharmaceutical SciencesCollege of Pharmacy and Health SciencesSt. John's University, QueensNew YorkNew YorkUSA
| | - Cong‐Hui Han
- Department of Urology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical CollegeThe Affiliated Xuzhou Hospital of Medical College of Southeast UniversityThe Affiliated Xuzhou Center Hospital of Nanjing University of Chinese MedicineXuzhouJiangsuChina
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25
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Peng L, Hu G, Yao Q, Wu J, He Z, Law BYK, Hu G, Zhou X, Du J, Wu A, Yu L. Microglia autophagy in ischemic stroke: A double-edged sword. Front Immunol 2022; 13:1013311. [PMID: 36466850 PMCID: PMC9708732 DOI: 10.3389/fimmu.2022.1013311] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 10/25/2022] [Indexed: 08/14/2023] Open
Abstract
Ischemic stroke (IS) is one of the major types of cerebrovascular diseases causing neurological morbidity and mortality worldwide. In the pathophysiological process of IS, microglia play a beneficial role in tissue repair. However, it could also cause cellular damage, consequently leading to cell death. Inflammation is characterized by the activation of microglia, and increasing evidence showed that autophagy interacts with inflammation through regulating correlative mediators and signaling pathways. In this paper, we summarized the beneficial and harmful effects of microglia in IS. In addition, we discussed the interplay between microglia autophagy and ischemic inflammation, as along with its application in the treatment of IS. We believe this could help to provide the theoretical references for further study into IS and treatments in the future.
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Affiliation(s)
- Li Peng
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China
- Department of Medicine Imaging, School of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Guangqiang Hu
- Department of Anatomy, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Qianfang Yao
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Jianming Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Ziyang He
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Betty Yuen-Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Guishan Hu
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xiaogang Zhou
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Junrong Du
- Key Laboratory of Drug Targeting and Drug Delivery Systems of Ministry of Education, Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Anguo Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Lu Yu
- Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, School of Pharmacy, Southwest Medical University, Luzhou, China
- Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China
- Department of Medicine Imaging, School of Clinical Medicine, Southwest Medical University, Luzhou, China
- Department of Chemistry, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
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26
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Zelentsova AS, Deykin AV, Soldatov VO, Ulezko AA, Borisova AY, Belyaeva VS, Skorkina MY, Angelova PR. P2X7 Receptor and Purinergic Signaling: Orchestrating Mitochondrial Dysfunction in Neurodegenerative Diseases. eNeuro 2022; 9:ENEURO.0092-22.2022. [PMID: 36376084 PMCID: PMC9665882 DOI: 10.1523/eneuro.0092-22.2022] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 07/14/2022] [Accepted: 08/09/2022] [Indexed: 11/15/2022] Open
Abstract
Mitochondrial dysfunction is one of the basic hallmarks of cellular pathology in neurodegenerative diseases. Since the metabolic activity of neurons is highly dependent on energy supply, nerve cells are especially vulnerable to impaired mitochondrial function. Besides providing oxidative phosphorylation, mitochondria are also involved in controlling levels of second messengers such as Ca2+ ions and reactive oxygen species (ROS). Interestingly, the critical role of mitochondria as producers of ROS is closely related to P2XR purinergic receptors, the activity of which is modulated by free radicals. Here, we review the relationships between the purinergic signaling system and affected mitochondrial function. Purinergic signaling regulates numerous vital biological processes in the CNS. The two main purines, ATP and adenosine, act as excitatory and inhibitory neurotransmitters, respectively. Current evidence suggests that purinergic signaling best explains how neuronal activity is related to neuronal electrical activity and energy homeostasis, especially in the development of Alzheimer's and Parkinson's diseases. In this review, we focus on the mechanisms underlying the involvement of the P2RX7 purinoreceptor in triggering mitochondrial dysfunction during the development of neurodegenerative disorders. We also summarize various avenues by which the purine signaling pathway may trigger metabolic dysfunction contributing to neuronal death and the inflammatory activation of glial cells. Finally, we discuss the potential role of the purinergic system in the search for new therapeutic approaches to treat neurodegenerative diseases.
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27
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Genetzakis E, Gilchrist J, Kassiou M, Figtree GA. Development and clinical translation of P2X7 receptor antagonists: A potential therapeutic target in coronary artery disease? Pharmacol Ther 2022; 237:108228. [DOI: 10.1016/j.pharmthera.2022.108228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/17/2022] [Accepted: 06/06/2022] [Indexed: 12/12/2022]
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28
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Liu Q, Huang Y, Duan M, Yang Q, Ren B, Tang F. Microglia as Therapeutic Target for Radiation-Induced Brain Injury. Int J Mol Sci 2022; 23:8286. [PMID: 35955439 PMCID: PMC9368164 DOI: 10.3390/ijms23158286] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 12/10/2022] Open
Abstract
Radiation-induced brain injury (RIBI) after radiotherapy has become an increasingly important factor affecting the prognosis of patients with head and neck tumor. With the delivery of high doses of radiation to brain tissue, microglia rapidly transit to a pro-inflammatory phenotype, upregulate phagocytic machinery, and reduce the release of neurotrophic factors. Persistently activated microglia mediate the progression of chronic neuroinflammation, which may inhibit brain neurogenesis leading to the occurrence of neurocognitive disorders at the advanced stage of RIBI. Fully understanding the microglial pathophysiology and cellular and molecular mechanisms after irradiation may facilitate the development of novel therapy by targeting microglia to prevent RIBI and subsequent neurological and neuropsychiatric disorders.
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Affiliation(s)
- Qun Liu
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (Q.L.); (Y.H.)
| | - Yan Huang
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (Q.L.); (Y.H.)
| | - Mengyun Duan
- Department of Pharmacology, School of Medicine, Yangtze University, Jingzhou 434023, China; (M.D.); (Q.Y.)
| | - Qun Yang
- Department of Pharmacology, School of Medicine, Yangtze University, Jingzhou 434023, China; (M.D.); (Q.Y.)
| | - Boxu Ren
- The School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China; (Q.L.); (Y.H.)
| | - Fengru Tang
- Radiation Physiology Laboratory, Singapore Nuclear Research and Safety Initiative, National University of Singapore, Singapore 138602, Singapore
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29
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Hua SQ, Hu JL, Zou FL, Liu JP, Luo HL, Hu DX, Wu LD, Zhang WJ. P2X7 receptor in inflammation and pain. Brain Res Bull 2022; 187:199-209. [PMID: 35850190 DOI: 10.1016/j.brainresbull.2022.07.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/15/2022] [Accepted: 07/13/2022] [Indexed: 11/02/2022]
Abstract
Different studies have confirmed P2X7 receptor-mediated inflammatory mediators play a key role in the development of pain. P2X7 receptor activation can induce the development of pain by mediating the release of inflammatory mediators. In view of the fact that P2X7 receptor is expressed in the nervous system and immune system, it is closely related to the stability and maintenance of the nervous system function. ATP activates P2X7 receptor, opens non-selective cation channels, activates multiple intracellular signaling, releases multiple inflammatory cytokines, and induces pain. At present, the role of P2X7 receptor in inflammatory response and pain has been widely recognized and affirmed. Therefore, in this paper, we discussed the pathological mechanism of P2X7 receptor-mediated inflammation and pain, focused on the internal relationship between P2X7 receptor and pain. Moreover, we also described the effects of some antagonists on pain relief by inhibiting the activities of P2X7 receptor. Thus, targeting to inhibit activation of P2X7 receptor is expected to become another potential target for the relief of pain.
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Affiliation(s)
- Shi-Qi Hua
- Nanchang University, Nanchang City 343000, Jiangxi Province, China
| | - Jia-Ling Hu
- Emergency Department, The Second Affiliated Hospital, Nanchang University, Nanchang City 343000, Jiangxi Province, China
| | - Fei-Long Zou
- Gastrointestinal Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang City 343000, Jiangxi Province, China
| | - Ji-Peng Liu
- Gastrointestinal Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang City 343000, Jiangxi Province, China
| | - Hong-Liang Luo
- Gastrointestinal Surgery, The Second Affiliated Hospital, Nanchang University, Nanchang City 343000, Jiangxi Province, China
| | - Dong-Xia Hu
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang City 343000, Jiangxi Province, China.
| | - Li-Dong Wu
- Emergency Department, The Second Affiliated Hospital, Nanchang University, Nanchang City 343000, Jiangxi Province, China.
| | - Wen-Jun Zhang
- Department of Rehabilitation Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang City 343000, Jiangxi Province, China.
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30
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Jiao P, Wang Y, Sang T, Jiao J, Li Y. Molecular mechanism of betulin palliative therapy for chronic obstructive pulmonary disease (COPD) based on P2X7 receptor target of gated ion channel. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:707. [PMID: 35845496 PMCID: PMC9279764 DOI: 10.21037/atm-22-2629] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/20/2022] [Indexed: 11/07/2022]
Abstract
Background The aim of this study was to discover the molecular mechanism of betulin palliative therapy for chronic obstructive pulmonary disease (COPD) based on the P2X7 receptor target of gated ion channel. Methods A COPD mouse model was developed. Changes in pulmonary ventilation function, pulmonary airway and vascular remodeling indicators, inflammatory cells, and inflammatory factors were determined after betulin intervention, and the pathological alterations of lung tissues were detected. An in vitro experimental model was constructed to observe the influence of betulin at varying concentrations on the proliferation of human bronchial epidermal cell line (16-HBE) cells and changes in inflammatory factors in cell supernatant. The expression levels of key proteins in 16-HBE cells transfected with overexpressed or silenced P2X7 genes were determined through quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. Results After betulin intervention, pulmonary ventilation function in the 20 mg/kg betulin and 40 mg/kg betulin groups was improved. Levels of white blood cells (WBCs), neutrophils (Ns), tumor necrosis factor (TNF), TNF-ɑ, interleukin (IL)-1β, and IL-6 in the 2 groups also decreased significantly (all P<0.05). The pathological changes in COPD mice were detected. After betulin intervention, the pathological injury of the lung was reduced, the pathological score decreased significantly, and the remodeling indicators of pulmonary airway and pulmonary vessels diminished remarkably (all P<0.05). Betulin had no effect on the proliferation of 16-HBE cells in vitro. After cigarette smoke extract (CSE) stimulation, the rate of survival for 16-HBE cells decreased significantly. After betulin treatment, the survival rate of 16-HBE cells augmented remarkably, and the levels of TNF-ɑ, IL-6, and IL-1β in cell supernatant reduced substantially (all P<0.05). 16-HBE with overexpression and knockdown of P2X7 was constructed. After being treated with betulin, the relative expression levels of messenger RNA (mRNA) of ERK, JNK, rho-associated protein kinase (ROCK), nuclear factor-κB (NF-κB), and p38 in 16-HBE cells with P2X7 overexpression or knockdown were decreased significantly (all P<0.05), but the above indicators were largely unchanged (all P>0.05). Conclusions Betulin relieved lung pathological injury, ameliorated lung ventilation function, and diminished the level of inflammatory factors in COPD mice, playing a therapeutic role via the P2X7 signaling pathway.
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Affiliation(s)
- Pengfei Jiao
- Department of Respiration and Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingrui Wang
- Department of Hematology Oncology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Tianqing Sang
- The First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou, China
| | - Jing Jiao
- Department of Respiration and Intensive Care Unit, The First People's Hospital of Lingbao, Lingbao, China
| | - Yameng Li
- Department of Respiration and Intensive Care Unit, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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31
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Hiu JJ, Yap MKK. The myth of cobra venom cytotoxin: More than just direct cytolytic actions. Toxicon X 2022; 14:100123. [PMID: 35434602 PMCID: PMC9011113 DOI: 10.1016/j.toxcx.2022.100123] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 03/03/2022] [Accepted: 03/31/2022] [Indexed: 12/26/2022] Open
Abstract
Cobra venom cytotoxin (CTX) is a non-enzymatic three-finger toxin that constitutes 40-60% of cobra venom. Thus, it plays an important role in the pathophysiology of cobra envenomation, especially in local dermonecrosis. The three-finger hydrophobic loops of CTX determine the cytotoxicity. Nevertheless, the actual mechanisms of cytotoxicity are not fully elucidated as they involve not only cytolytic actions but also intracellular signalling-mediated cell death pathways. Furthermore, the possible transition cell death pattern remains to be explored. The actual molecular mechanisms require further studies to unveil the relationship between different CTXs from different cobra species and cell types which may result in differential cell death patterns. Here, we discuss the biophysical interaction of CTX with the cell membrane involving four binding modes: electrostatic interaction, hydrophobic partitioning, isotropic phase, and oligomerisation. Oligomerisation of CTX causes pore formation in the membrane lipid bilayer. Additionally, the CTX-induced apoptotic pathway can be executed via death receptor-mediated extrinsic pathways and mitochondrial-mediated intrinsic pathways. We also discuss lysosomal-mediated necrosis and the occurrence of necroptosis following CTX action. Collectively, we provided an insight into concentration-dependent transition of cell death pattern which involves different mechanistic actions. This contributes a new direction for further investigation of cytotoxic pathways activated by the CTXs for future development of biotherapeutics targeting pathological effects caused by CTX.
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Affiliation(s)
- Jia Jin Hiu
- School of Science, Monash University Malaysia, Bandar Sunway, Malaysia
| | - Michelle Khai Khun Yap
- School of Science, Monash University Malaysia, Bandar Sunway, Malaysia.,Tropical Medicine and Biology Multidisciplinary Platform, Monash University Malaysia, Bandar Sunway, Malaysia
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32
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Chiang CH, Cheng CY, Lien YT, Huang KC, Lin WW. P2X7 Activation Enhances Lipid Accumulation During Adipocytes Differentiation Through Suppressing the Expression of Sirtuin-3, Sirtuin-5, and Browning Genes. Front Pharmacol 2022; 13:852858. [PMID: 35462937 PMCID: PMC9019299 DOI: 10.3389/fphar.2022.852858] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/18/2022] [Indexed: 11/24/2022] Open
Abstract
P2X7 signaling has been explored in adipose tissue because of its potential to promote ATP-activated inflammatory cascades during obesogenic environments. However, limited literature has investigated the role of the P2X7 receptor in lipid metabolism during adipocyte differentiation. This study sought to explore the regulatory roles of P2X7 in adipocytes. This study utilized the in vitro 3T3-L1 differentiation model. Lipid accumulation, intracellular triglyceride, and extracellular glycerol were determined. The selective P2X7 agonist BzATP and antagonist A438079 were administered to investigate the functions of P2X7. We found that the expression of P2X7 and the lipid accumulation increased during adipocyte differentiation from D0 to D4. When administered at D0/D2, A438079 attenuated, while BzATP enhanced the degree of lipid accumulation during adipocyte differentiation. Neither did BzATP and A438079 administration affect the expression of PPARγ and C/EBPα genes that increased at D4. In addition, both intracellular triglyceride and extracellular glycerol levels at D4 were reduced by A438079 treatment and enhanced by BzATP administration. When administered at stage 2 of adipocyte differentiation, BzATP consistently enhanced lipid accumulation and intracellular triglyceride and extracellular glycerol levels without affecting mRNA and protein levels of PPARγ and C/EBPα that increased at D4. However, treating A438079 or BzATP at D4 did not affect intracellular triglyceride formation and extracellular glycerol release in differentiated adipocytes at D7. Notably, BzATP administration at stage 2 exerted a concentration-dependent inhibition on the enhanced expression of PRDM16, PGC-1α, and UCP-1 at D4. Furthermore, BzATP administration at D0/D2 inhibited the protein and mRNA levels of sirtuin-3/5 at D4. BzATP treatment at stage 2 also suppressed the mRNA levels of sirtuin-3/5 genes upregulated by insulin. In conclusion, this study demonstrated P2X7 enhances lipid accumulation during adipogenesis by suppressing the expression of sirtuin-3/5 and the browning genes.
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Affiliation(s)
- Chien-Hsieh Chiang
- Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Family Medicine, National Taiwan University Hospital & College of Medicine, Taipei, Taiwan
| | - Ching-Yuan Cheng
- Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Ting Lien
- Department of Family Medicine, National Taiwan University Hospital & College of Medicine, Taipei, Taiwan
| | - Kuo-Chin Huang
- Department of Family Medicine, National Taiwan University Hospital & College of Medicine, Taipei, Taiwan
| | - Wan-Wan Lin
- Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.,Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
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Santos SACS, Persechini PM, Henriques-Santos BM, Bello-Santos VG, Castro NG, Costa de Sousa J, Genta FA, Santiago MF, Coutinho-Silva R, Savio LEB, Kurtenbach E. P2X7 Receptor Triggers Lysosomal Leakage Through Calcium Mobilization in a Mechanism Dependent on Pannexin-1 Hemichannels. Front Immunol 2022; 13:752105. [PMID: 35222364 PMCID: PMC8863609 DOI: 10.3389/fimmu.2022.752105] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/10/2022] [Indexed: 12/24/2022] Open
Abstract
The P2X7 receptor is a critical purinergic receptor in immune cells. Its activation was associated with cathepsin release into macrophage cytosol, suggesting its involvement in lysosomal membrane permeabilization (LMP) and leakage. Nevertheless, the mechanisms by which P2X7 receptor activation induces LMP and leakage are unclear. This study investigated cellular mechanisms associated with endosomal and lysosomal leakage triggered by P2X7 receptor activation. We found that ATP at 500 μM and 5 mM (but not 50 μM) induced LMP in non-stimulated peritoneal macrophages. This effect was not observed in P2X7-deficient or A740003-pretreated macrophages. We found that the P2X7 receptor and pannexin-1 channels mediate calcium influx that might be important for activating specific ion channels (TRPM2 and two-pore channels) on the membranes of late endosomes and lysosomes leading to LMP leakage and consequent cathepsin release. These findings suggest the critical role of the P2X7 receptor in inflammatory and infectious diseases via lysosomal dysfunction.
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Affiliation(s)
- Stephanie Alexia Cristina Silva Santos
- Laboratory of Molecular Biology and Biochemistry of Proteins, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Pedro Muanis Persechini
- Laboratory of Immuno-Biophysics, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Bianca Monteiro Henriques-Santos
- Laboratory of Insect Physiology and Biochemistry, Oswaldo Cruz Institute - Oswaldo Cruz Foundation (IOC-FIOCRUZ), Rio de Janeiro, Brazil
| | - Victória Gabriela Bello-Santos
- Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Newton G Castro
- Laboratory of Molecular Pharmacology, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Júlia Costa de Sousa
- Laboratory of Molecular Biology and Biochemistry of Proteins, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernando Ariel Genta
- Laboratory of Insect Physiology and Biochemistry, Oswaldo Cruz Institute - Oswaldo Cruz Foundation (IOC-FIOCRUZ), Rio de Janeiro, Brazil
| | - Marcelo Felippe Santiago
- Laboratory of Molecular Biology and Biochemistry of Proteins, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Robson Coutinho-Silva
- Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luiz Eduardo Baggio Savio
- Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Eleonora Kurtenbach
- Laboratory of Molecular Biology and Biochemistry of Proteins, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Ma Y, Di R, Zhao H, Song R, Zou H, Liu Z. P2X7 receptor knockdown suppresses osteoclast differentiation by inhibiting autophagy and Ca 2+/calcineurin signaling. Mol Med Rep 2022; 25:160. [PMID: 35266012 PMCID: PMC8941524 DOI: 10.3892/mmr.2022.12677] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 01/11/2022] [Indexed: 11/06/2022] Open
Abstract
Bone is continuously remodeled in a dynamic process maintained by osteoclasts and osteoblasts, and imbalances in the relative activities of these cell types can cause various pathological conditions, including rheumatoid arthritis and osteoporosis. Osteoclasts are multinucleated cells that serve an important role in regulating the development of osteoporosis. Furthermore, P2X7 receptor activation has a vital role in physiological and pathological reactions in bone, including bone disease. Therefore, the present study aimed to investigate the effect of P2X7 receptor on osteoclast differentiation and to explore the underlying molecular mechanism by western blotting and tartrate‑resistant acid phosphatase staining. The results indicated that the expression levels of P2X7 receptor and intracellular Ca2+ concentration levels were very high in mature osteoclasts. Furthermore, P2X7 receptor overexpression increased the number of multinucleated osteoclasts and the expression of osteoclastogenesis‑related proteins. P2X7 receptor overexpression was also associated with downstream activation of Ca2+/calcineurin/nuclear factor of activated T cells c1 (NFATc1) signaling and increased expression of autophagy‑related proteins during osteoclast differentiation. By contrast, knockdown of P2X7 receptor exerted the opposite effects. Notably, FK506 (a Ca2+/calcineurin/NFATc1 signaling inhibitor) abrogated P2X7 receptor overexpression‑induced osteoclast differentiation and activation of autophagy. Moreover, 3‑MA (an autophagy inhibitor) significantly suppressed P2X7 receptor overexpression‑induced osteoclast differentiation. In conclusion, P2X7 receptor knockdown may suppress osteoclast differentiation by modulating autophagy and the Ca2+/calcineurin/NFATc1 signaling pathway.
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Affiliation(s)
- Yonggang Ma
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Ran Di
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Hongyan Zhao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, P.R. China
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35
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Glial Purinergic Signaling-Mediated Oxidative Stress (GPOS) in Neuropsychiatric Disorders. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:1075440. [PMID: 35281471 PMCID: PMC8916856 DOI: 10.1155/2022/1075440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 01/21/2022] [Accepted: 02/09/2022] [Indexed: 11/17/2022]
Abstract
Oxidative stress (OS) has been implicated in the progression of multiple neuropsychiatric disorders, including schizophrenia (SZ), major depressive disorder (MDD), bipolar disorder, and autism. However, whether glial purinergic signaling interaction with oxidative/antioxidative system displays an important role in neuropsychiatric disorders is still unclear. In this review, we firstly summarize the oxidative/antioxidative pathways shared in different glial cells and highlight the cell type-specific difference in response to OS. Then, we collect the evidence showing the regulation of purinergic signaling in OS with an emphasis on adenosine and its receptors, P2Y1 receptor in the P2Y family and P2X7receptor in the P2X family. Available data shows that the activation of P1 receptors and P2X accelerates the OS; reversely, the activation of the P2Y family (P2Y1) causes protective effect against OS. Finally, we discuss current findings demonstrating the contribution of the purinergic signaling system to neuropsychiatric disorders and point out the potential role of OS in this process to propose a “glial purinergic-oxidative stress” (“GPOS”) hypothesis for future development of therapeutic strategies against a variety of neuropsychiatric disorders.
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36
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Yang Y, Zhang K, Huang S, Chen W, Mao H, Ouyang X, Chen L, Li L. Apelin‐13/APJ induces cardiomyocyte hypertrophy by activating the Pannexin‐1/P2X7 axis and FAM134B‐dependent reticulophagy. J Cell Physiol 2022; 237:2230-2248. [DOI: 10.1002/jcp.30685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/16/2021] [Accepted: 01/11/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Yiyuan Yang
- School of Pharmaceutical Science Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study University of South China Hengyang China
| | - Kai Zhang
- School of Pharmaceutical Science Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study University of South China Hengyang China
| | - Shifang Huang
- School of Pharmaceutical Science Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study University of South China Hengyang China
| | - Wei Chen
- School of Pharmaceutical Science Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study University of South China Hengyang China
| | - Hui Mao
- School of Pharmaceutical Science Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study University of South China Hengyang China
| | - Xueqian Ouyang
- School of Pharmaceutical Science Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study University of South China Hengyang China
| | - Linxi Chen
- School of Pharmaceutical Science Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study University of South China Hengyang China
| | - Lanfang Li
- School of Pharmaceutical Science Institute of Pharmacy and Pharmacology, Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study University of South China Hengyang China
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37
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Deng Y, Zhou M, Zhao X, Xue X, Liao L, Wang J, Li Y. Immune response studies based on P2X7 receptors: A Mini-Review. Curr Pharm Des 2022; 28:993-999. [PMID: 35100953 DOI: 10.2174/1381612828666220131091325] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/28/2021] [Indexed: 11/22/2022]
Abstract
Inflammation, as a complex immunopathological process, is the organism's natural defense response to the organism against harmful, foreign, and destructive immune or non-immune factors. It is the main pathological form of various diseases, such as tumors, neurodegenerative diseases, periodontitis, alcoholic steatohepatitis, asthma, and other diseases. The P2X7 receptor (P2X7R) is widely distributed in vivo and up--regulated in various inflammatory pathological states. Studies have shown that milder chronic inflammation is related to a deficiency or inhibition of P2X7R, which is an indispensable part of the pro-inflammatory mechanism in vivo. P2X7R, a unique subtype of seven purinergic P2X receptors, is an ATP-gated nonselective cationic channel. P2X7R will promote the influx of Ca2+ and the outflow of K+ after being stimulated. The influx of Ca2+ is essential for activating the body's innate immune response and inducing the production of inflammatory factors. This paper reviews the regulation of P2X7R on inflammation from the perspectives of innate immunity and adaptive immunity.
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Affiliation(s)
- Ying Deng
- State Key laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China
- School of pharmacy, Chengdu university of Traditional Chinese Medicine, Chengdu 611137, China
- Key laboratory of standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu 611137, China
| | - Mengting Zhou
- State Key laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China
- School of pharmacy, Chengdu university of Traditional Chinese Medicine, Chengdu 611137, China
- Key laboratory of standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu 611137, China
| | - Xingtao Zhao
- State Key laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China
- School of pharmacy, Chengdu university of Traditional Chinese Medicine, Chengdu 611137, China
- Key laboratory of standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu 611137, China
| | - Xinyan Xue
- State Key laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China
- School of pharmacy, Chengdu university of Traditional Chinese Medicine, Chengdu 611137, China
- Key laboratory of standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu 611137, China
| | - Li Liao
- State Key laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China
- School of pharmacy, Chengdu university of Traditional Chinese Medicine, Chengdu 611137,
- Key laboratory of standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu 611137, China
| | - Jing Wang
- State Key laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China
- School of pharmacy, Chengdu university of Traditional Chinese Medicine, Chengdu 611137, China
- Key laboratory of standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu 611137, China
| | - Yunxia Li
- State Key laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China
- School of pharmacy, Chengdu university of Traditional Chinese Medicine, Chengdu 611137, China
- Key laboratory of standardization for Chinese Herbal Medicine, Ministry of Education, Chengdu 611137, China
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Wang Z, Yang Z, Liu J, Hao Y, Sun B, Wang J. Potential Health Benefits of Whole Grains: Modulation of Mitochondrial Biogenesis and Energy Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:14065-14074. [PMID: 34775748 DOI: 10.1021/acs.jafc.1c05527] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Mitochondria play an essential role in maintaining cellular metabolic homeostasis. However, its dysfunction will cause different pathophysiological consequences. A specific mechanism of action has been developed by cells to adapt to changes in physiological conditions or in response to different stimuli, by meditating mitochondrial number, structure, and energy metabolism. Whole grains are considered healthier than refined grains for their higher amounts of bioactive components, with proven multiple health benefits. The modulation of an appropriate mitochondrial function contributes to the bioactive-component-based health improvements. Thus, this review aims to represent current studies that identify the impact of natural bioactive components in whole grains against metabolic disorders by modulating mitochondrial biogenesis and energy metabolism. It seems most attractive to aim nutritional intervention at the prevention or treatment of metabolic abnormalities and hence to target dietary management at improvement of mitochondrial function.
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Affiliation(s)
- Ziyuan Wang
- China-Canada Joint Lab of Food Nutrition and Health (Beijing), Beijing Technology & Business University, Beijing 100048, People's Republic of China
| | - Zihui Yang
- China-Canada Joint Lab of Food Nutrition and Health (Beijing), Beijing Technology & Business University, Beijing 100048, People's Republic of China
| | - Jie Liu
- China-Canada Joint Lab of Food Nutrition and Health (Beijing), Beijing Technology & Business University, Beijing 100048, People's Republic of China
| | - Yiming Hao
- China-Canada Joint Lab of Food Nutrition and Health (Beijing), Beijing Technology & Business University, Beijing 100048, People's Republic of China
| | - Baoguo Sun
- China-Canada Joint Lab of Food Nutrition and Health (Beijing), Beijing Technology & Business University, Beijing 100048, People's Republic of China
| | - Jing Wang
- China-Canada Joint Lab of Food Nutrition and Health (Beijing), Beijing Technology & Business University, Beijing 100048, People's Republic of China
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Li Z, Huang Z, Zhang H, Lu J, Tian Y, Piao S, Lin Z, Bai L. Moderate-intensity exercise alleviates pyroptosis by promoting autophagy in osteoarthritis via the P2X7/AMPK/mTOR axis. Cell Death Dis 2021; 7:346. [PMID: 34759265 PMCID: PMC8580998 DOI: 10.1038/s41420-021-00746-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 10/19/2021] [Accepted: 10/27/2021] [Indexed: 01/17/2023]
Abstract
Instability and excessive use of the knee joint can cause osteoarthritis (OA). Reasonable exercise can enhance the stability of the knee joint and prevent and relieve the occurrence and development of OA. As a key switch for inflammation, P2X purinoceptor 7 (P2X7) has attracted much attention in studies of OA. Exercise can regulate P2X7 expression and activation. However, the role of P2X7 in exercise-based prevention and treatment of OA is unknown. We previously showed that moderate-intensity exercise can significantly alleviate OA symptoms. Accordingly, in this study, we evaluated the effects of exercise on P2X7 expression and activation in chondrocytes. Micro-computed tomography, hematoxylin, and eosin staining, Toluidine Blue O staining, immunohistochemistry, and terminal deoxynucleotidyl transferase dUTP nick-end labeling experiments showed that P2X7 expression was lower in the moderate-intensity exercise group than in the inflammation and low- and high-intensity exercise groups. Additionally, chondrocyte death, cartilage destruction, and the degree and severity of pyroptosis were significantly reduced, whereas autophagy levels were significantly increased in the moderate-intensity exercise group. Cell Counting Kit-8 assay, lactate dehydrogenase release, flow cytometry, enzyme-linked immunosorbent assay, cell fluorescence, western blot, reverse transcription-quantitative polymerase chain reaction, and transmission electron microscopy experiments showed that moderate activation of P2X7 promoted autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway and promoted autolysosome targeting for degradation of the inflammasome component NLRP3, thereby inhibiting pyroptosis. Additionally, the use of AMPK and mTOR activators and inhibitors indicated that the AMPK-mTOR signaling pathway, as the downstream of P2X7, played a key role in delaying the occurrence and development of OA. We propose that moderate-intensity exercise promoted chondrocyte autophagy through the P2X7/AMPK/mTOR signal axis to alleviate pyroptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA.
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Affiliation(s)
- Zihao Li
- grid.412467.20000 0004 1806 3501Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110024 China
| | - Ziyu Huang
- grid.412531.00000 0001 0701 1077Foreign Languages College, Shanghai Normal University, Shanghai, 200234 China
| | - He Zhang
- grid.412467.20000 0004 1806 3501Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110024 China
| | - Jinghan Lu
- grid.412467.20000 0004 1806 3501Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110024 China
| | - Yicheng Tian
- grid.412467.20000 0004 1806 3501Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110024 China
| | - Shang Piao
- grid.412467.20000 0004 1806 3501Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110024 China
| | - Zhiming Lin
- grid.412467.20000 0004 1806 3501Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110024 China
| | - Lunhao Bai
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110024, China.
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40
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Liu X, Xie Z, Li S, He J, Cao S, Xiao Z. PRG-1 relieves pain and depressive-like behaviors in rats of bone cancer pain by regulation of dendritic spine in hippocampus. Int J Biol Sci 2021; 17:4005-4020. [PMID: 34671215 PMCID: PMC8495398 DOI: 10.7150/ijbs.59032] [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: 02/15/2021] [Accepted: 09/06/2021] [Indexed: 12/15/2022] Open
Abstract
Rationale: Pain and depression, which tend to occur simultaneously and share some common neural circuits and neurotransmitters, are highly prevalent complication in patients with advanced cancer. Exploring the underlying mechanisms is the cornerstone to prevent the comorbidity of chronic pain and depression in cancer patients. Plasticity-related gene 1 (PRG-1) protein regulates synaptic plasticity and brain functional reorganization during neuronal development or after cerebral lesion. Purinergic P2X7 receptor has been proposed as a therapeutic target for various pain and neurological disorders like depression in rodents. In this study, we investigated the roles of PRG-1 in the hippocampus in the comorbidity of pain and depressive-like behaviors in rats with bone cancer pain (BCP). Methods: The bone cancer pain rat model was established by intra-tibial cell inoculation of SHZ-88 mammary gland carcinoma cells. The animal pain behaviors were assessed by measuring the thermal withdrawal latency values by using radiant heat stimulation and mechanical withdrawal threshold by using electronic von Frey anesthesiometer, and depressive-like behavior was assessed by sucrose preference test and forced swim test. Alterations in the expression levels of PRG-1 and P2X7 receptor in hippocampus were separately detected by using western blot, immunofluorescence and immunohistochemistry analysis. The effects of intra-hippocampal injection of FTY720 (a PRG-1/PP2A interaction activator), PRG-1 overexpression or intra-hippocampal injection of A438079 (a selective competitive P2X7 receptor antagonist) were also observed. Results: Carcinoma intra-tibia injection caused thermal hyperalgesia, mechanical allodynia and depressive-like behaviors in rats, and also induced the deactivation of neurons and dendritic spine structural anomalies in the hippocampus. Western blot, immunofluorescence and immunohistochemistry analysis showed an increased expression of PRG-1 and P2X7 receptor in the hippocampus of BCP rats. Intra-hippocampal injection of FTY720 or A438079 attenuated both pain and depressive-like behaviors. Furthermore, overexpression of PRG-1 in hippocampus has similar analgesic efficacy to FTY720. In addition, they rescued neuron deactivation and dendritic spine anomalies. Conclusion: The results suggest that both PRG-1 and P2X7 receptor in the hippocampus play important roles in the development of pain and depressive-like behaviors in bone cancer condition in rats by dendritic spine regulation via P2X7R/PRG-1/PP2A pathway.
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Affiliation(s)
- Xingfeng Liu
- Guizhou Key Laboratory of Brain Science, Zunyi Medical University, Zunyi 563000, China.,Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical University, Zunyi 563000, China
| | - Zhuo Xie
- Graduate School, Zunyi Medical University, Zunyi 563000, China
| | - Site Li
- Graduate School, Zunyi Medical University, Zunyi 563000, China
| | - Jingxin He
- Graduate School, Zunyi Medical University, Zunyi 563000, China
| | - Song Cao
- Department of Pain Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Zhi Xiao
- Guizhou Key Laboratory of Brain Science, Zunyi Medical University, Zunyi 563000, China.,Guizhou Key Laboratory of Anesthesia and Organ Protection, Zunyi Medical University, Zunyi 563000, China
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41
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Zhao Y, Liu X, Zheng Y, Liu W, Ding C. Aronia melanocarpa polysaccharide ameliorates inflammation and aging in mice by modulating the AMPK/SIRT1/NF-κB signaling pathway and gut microbiota. Sci Rep 2021; 11:20558. [PMID: 34663844 PMCID: PMC8523697 DOI: 10.1038/s41598-021-00071-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 10/06/2021] [Indexed: 12/11/2022] Open
Abstract
Aronia melanocarpa is a natural medicinal plant that has a variety of biological activities, its fruit is often used for food and medicine. Aronia melanocarpa polysaccharide (AMP) is the main component of the Aronia melanocarpa fruit. This research evaluated the delay and protection of AMP obtained from Aronia melanocarpa fruit on aging mice by D-Galactose (D-Gal) induction and explored the effect of supplementing AMP on the metabolism of the intestinal flora of aging mice. The aging model was established by intraperitoneal injection of D-Gal (200 mg/kg to 1000 mg/kg) once per 3 days for 12 weeks. AMP (100 and 200 mg/kg) was given daily by oral gavage after 6 weeks of D-Gal-induced. The results showed that AMP treatment significantly improved the spatial learning and memory impairment of aging mice determined by the eight-arm maze test. H&E staining showed that AMP significantly reversed brain tissue pathological damage and structural disorders. AMP alleviated inflammation and oxidative stress injury in aging brain tissue by regulating the AMPK/SIRT1/NF-κB and Nrf2/HO-1 signaling pathways. Particularly, AMP reduced brain cell apoptosis and neurological deficits by activating the PI3K/AKT/mTOR signaling pathway and its downstream apoptotic protein family. Importantly, 16S rDNA analysis indicated the AMP treatment significantly retarded the aging process by improving the composition of intestinal flora and abundance of beneficial bacteria. In summary, this study found that AMP delayed brain aging in mice by inhibiting inflammation and regulating intestinal microbes, which providing the possibility for the amelioration and treatment of aging and related metabolic diseases.
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Affiliation(s)
- Yingchun Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Xinglong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Yinan Zheng
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
- National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun, 130118, China
| | - Wencong Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China.
- National & Local Joint Engineering Research Center for Ginseng Breeding and Development, Changchun, 130118, China.
| | - Chuanbo Ding
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China.
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Li Z, Huang Z, Zhang H, Lu J, Wei Y, Yang Y, Bai L. IRE1-mTOR-PERK Axis Coordinates Autophagy and ER Stress-Apoptosis Induced by P2X7-Mediated Ca 2+ Influx in Osteoarthritis. Front Cell Dev Biol 2021; 9:695041. [PMID: 34222263 PMCID: PMC8248364 DOI: 10.3389/fcell.2021.695041] [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: 04/14/2021] [Accepted: 05/27/2021] [Indexed: 01/18/2023] Open
Abstract
Moderate-intensity exercise can help delay the development of osteoarthritis (OA). Previous studies have shown that the purinergic receptor P2X ligand gated ion channel 7 (P2X7) is involved in OA development and progression. To investigate the effect of exercise on P2X7 activation and downstream signaling in OA, we used the anterior cruciate ligament transection (ACLT)-induced OA rat model and primary chondrocyte culture system. Our in vivo experiments confirmed that treadmill exercise increased P2X7 expression and that this effect was more pronounced at the later time points. Furthermore, P2X7 activation induced endoplasmic reticulum (ER) stress and increased the expression levels of ER stress markers, such as 78 kDa glucose-regulated protein (GRP78), protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1), and activating transcription factor 6 (ATF6). At the early time points, IRE1 and PERK were activated, and mTOR was inhibited. At the later time points, mTOR was activated, mediating PERK to promote ER stress-apoptosis, whereas IRE1 and autophagy were inhibited. To confirm our observations in vitro, we treated primary chondrocytes with the P2X7 agonist benzoylbenzoyl-ATP (Bz-ATP). Our results confirmed that P2X7-mediated Ca2+ influx activated IRE1-mediated autophagic flux and induced PERK-mediated ER stress-apoptosis. To further investigate the role of P2X7 in OA, we injected mTOR antagonist rapamycin or P2X7 antagonist A740003 into the knee joints of ACLT rats. Our results demonstrated that mTOR inhibition induced autophagy, decreased apoptosis, and reduced cartilage loss. However, injection of mTOR agonist MHY1485 or Bz-ATP had the opposite effect. In summary, our results indicated that during the early stages of moderate-intensity exercise, P2X7 was activated and autophagic flux was increased, delaying OA development. At the later stages, P2X7 became over-activated, and the number of apoptotic cells increased, promoting OA development. We propose that the IRE1-mTOR-PERK signaling axis was involved in the regulation of autophagy inhibition and the induction of apoptosis. Our findings provide novel insights into the positive and preventative effects of exercise on OA, suggesting that the intensity and duration of exercise play a critical role. We also demonstrated that on a molecular level, P2X7 and its downstream pathways could be potential therapeutic targets for OA.
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Affiliation(s)
- Zihao Li
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ziyu Huang
- Foreign Languages College, Shanghai Normal University, Shanghai, China
| | - He Zhang
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jinghan Lu
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yingliang Wei
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yue Yang
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lunhao Bai
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
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Theofani E, Xanthou G. Autophagy: A Friend or Foe in Allergic Asthma? Int J Mol Sci 2021; 22:ijms22126314. [PMID: 34204710 PMCID: PMC8231495 DOI: 10.3390/ijms22126314] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/04/2021] [Accepted: 06/10/2021] [Indexed: 12/20/2022] Open
Abstract
Autophagy is a major self-degradative process through which cytoplasmic material, including damaged organelles and proteins, are delivered and degraded in the lysosome. Autophagy represents a dynamic recycling system that produces new building blocks and energy, essential for cellular renovation, physiology, and homeostasis. Principal autophagy triggers include starvation, pathogens, and stress. Autophagy plays also a pivotal role in immune response regulation, including immune cell differentiation, antigen presentation and the generation of T effector responses, the development of protective immunity against pathogens, and the coordination of immunometabolic signals. A plethora of studies propose that both impaired and overactive autophagic processes contribute to the pathogenesis of human disorders, including infections, cancer, atherosclerosis, autoimmune and neurodegenerative diseases. Autophagy has been also implicated in the development and progression of allergen-driven airway inflammation and remodeling. Here, we provide an overview of recent studies pertinent to the biology of autophagy and molecular pathways controlling its activation, we discuss autophagy-mediated beneficial and detrimental effects in animal models of allergic diseases and illuminate new advances on the role of autophagy in the pathogenesis of human asthma. We conclude contemplating the potential of targeting autophagy as a novel therapeutic approach for the management of allergic responses and linked asthmatic disease.
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Affiliation(s)
- Efthymia Theofani
- Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11547 Athens, Greece;
- 1st Department of Respiratory Medicine, “Sotiria” Regional Chest Diseases Hospital, Medical School, National Kapodistrian University of Athens, 11547 Athens, Greece
| | - Georgina Xanthou
- Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 11547 Athens, Greece;
- Correspondence: ; Tel.: +30-210-65-97-336
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P2X7 receptor in multifaceted cellular signalling and its relevance as a potential therapeutic target in different diseases. Eur J Pharmacol 2021; 906:174235. [PMID: 34097884 DOI: 10.1016/j.ejphar.2021.174235] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 05/28/2021] [Accepted: 06/02/2021] [Indexed: 02/07/2023]
Abstract
P2X7 receptor, a purinergic receptor family member, is abundantly expressed on many cells, including immune, muscle, bone, neuron, and glia. It acts as an ATP-activated cation channel that permits the influx of Ca2+, Na+ and efflux of K+ ions. The P2X7 receptor plays crucial roles in many physiological processes including cytokine and chemokine secretion, NLRP3 inflammasome activation, cellular growth and differentiation, locomotion, wound healing, transcription factors activation, cell death and T-lymphocyte survival. Past studies have demonstrated the up-regulation and direct association of this receptor in many pathophysiological conditions such as cancer, diabetics, arthritis, tuberculosis (TB) and inflammatory diseases. Hence, targeting this receptor is considered a worthwhile approach to lessen the afflictions associated with the disorders mentioned above by understanding the receptor architecture and downstream signalling processes. Here, in the present review, we have dissected the structural and functional aspects of the P2X7 receptor, emphasizing its role in various diseased conditions. This information will provide in-depth knowledge about the receptor and help to develop apt curative methodologies for the betterment of humanity in the coming years.
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Campagno KE, Mitchell CH. The P2X 7 Receptor in Microglial Cells Modulates the Endolysosomal Axis, Autophagy, and Phagocytosis. Front Cell Neurosci 2021; 15:645244. [PMID: 33790743 PMCID: PMC8005553 DOI: 10.3389/fncel.2021.645244] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/22/2021] [Indexed: 01/18/2023] Open
Abstract
Microglial cells regulate neural homeostasis by coordinating both immune responses and clearance of debris, and the P2X7 receptor for extracellular ATP plays a central role in both functions. The P2X7 receptor is primarily known in microglial cells for its immune signaling and NLRP3 inflammasome activation. However, the receptor also affects the clearance of extracellular and intracellular debris through modifications of lysosomal function, phagocytosis, and autophagy. In the absence of an agonist, the P2X7 receptor acts as a scavenger receptor to phagocytose material. Transient receptor stimulation induces autophagy and increases LC3-II levels, likely through calcium-dependent phosphorylation of AMPK, and activates microglia to an M1 or mixed M1/M2 state. We show an increased expression of Nos2 and Tnfa and a decreased expression of Chil3 (YM1) from primary cultures of brain microglia exposed to high levels of ATP. Sustained stimulation can reduce lysosomal function in microglia by increasing lysosomal pH and slowing autophagosome-lysosome fusion. P2X7 receptor stimulation can also cause lysosomal leakage, and the subsequent rise in cytoplasmic cathepsin B activates the NLRP3 inflammasome leading to caspase-1 cleavage and IL-1β maturation and release. Support for P2X7 receptor activation of the inflammasome following lysosomal leakage comes from data on primary microglia showing IL-1β release following receptor stimulation is inhibited by cathepsin B blocker CA-074. This pathway bridges endolysosomal and inflammatory roles and may provide a key mechanism for the increased inflammation found in age-dependent neurodegenerations characterized by excessive lysosomal accumulations. Regardless of whether the inflammasome is activated via this lysosomal leakage or the better-known K+-efflux pathway, the inflammatory impact of P2X7 receptor stimulation is balanced between the autophagic reduction of inflammasome components and their increase following P2X7-mediated priming. In summary, the P2X7 receptor modulates clearance of extracellular debris by microglial cells and mediates lysosomal damage that can activate the NLRP3 inflammasome. A better understanding of how the P2X7 receptor alters phagocytosis, lysosomal health, inflammation, and autophagy can lead to therapies that balance the inflammatory and clearance roles of microglial cells.
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Affiliation(s)
- Keith E Campagno
- Department of Basic and Translational Science, University of Pennsylvania, Philadelphia, PA, United States
| | - Claire H Mitchell
- Department of Basic and Translational Science, University of Pennsylvania, Philadelphia, PA, United States.,Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA, United States.,Department of Physiology, University of Pennsylvania, Philadelphia, PA, United States
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Pan YG, Huang MT, Sekar P, Huang DY, Lin WW, Hsieh SL. Decoy Receptor 3 Inhibits Monosodium Urate-Induced NLRP3 Inflammasome Activation via Reduction of Reactive Oxygen Species Production and Lysosomal Rupture. Front Immunol 2021; 12:638676. [PMID: 33746978 PMCID: PMC7966727 DOI: 10.3389/fimmu.2021.638676] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/01/2021] [Indexed: 12/27/2022] Open
Abstract
Gout is a common inflammatory arthritis caused by the deposition of monosodium urate (MSU) crystals in the joints. This activates the macrophages into a proinflammatory state by inducing NLRP3-dependent interleukin-1β (IL-1β) secretion, resulting in neutrophil recruitment. Soluble decoy receptor 3 (DcR3) is an immune modulator and can exert biological functions via decoy and non-decoy actions. Previously, we showed that DcR3 suppresses lipopolysaccharides (LPS)- and virus-induced inflammatory responses in the macrophages and promotes the macrophages into the M2 phenotype. In this study, we clarified the actions of DcR3 and its non-decoy action motif heparin sulfate proteoglycan (HSPG) binding domain (HBD) in the MSU crystal-induced NLRP3 inflammasome activation in the macrophages and in mice. In bone marrow-derived macrophages, THP-1 and U937 cells, we found that the MSU crystal-induced secretion of IL-1β and activation of NLRP3 were suppressed by both DcR3.Fc and HBD.Fc. The suppression of the MSU-induced NLRP3 inflammasome activation is accompanied by the inhibition of lysosomal rupture, mitochondrial production of the reactive oxygen species (ROS), expression of cathepsins, and activity of cathepsin B, without affecting the crystal uptake and the expression of NLRP3 or pro-IL-1β. In the air pouch mice model of gout, MSU induced less amounts of IL-1β and chemokines secretion, an increased M2/M1 macrophage ratio, and a reduction of neutrophil recruitment in DcR3-transgenic mice, which expresses DcR3 in myeloid cells. Similarly, the mice intravenously treated with DcR3.Fc or HBD.Fc displayed less inflammation response. These findings indicate that HBD of DcR3 can reduce MSU crystal-induced NLRP3 inflammasome activation via modulation of mitochondrial and lysosomal functions. Therefore, we, for the first time, demonstrate a new therapeutic potential of DcR3 for the treatment of gout.
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Affiliation(s)
- Yi-Gen Pan
- Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | | | - Ponarulselvam Sekar
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
| | - Duen-Yi Huang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wan-Wan Lin
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
- Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan
| | - Shie-Liang Hsieh
- Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
- Institute of Clinical Medicine & Immunology Research Center, National Yang-Ming Chiao Tung University, Taipei, Taiwan
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
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Abstract
Ion exchange between intracellular and extracellular spaces is the basic mechanism for controlling cell metabolism and signal transduction. This process is mediated by ion channels and transporters on the plasma membrane, or intracellular membranes that surround various organelles, in response to environmental stimuli. Macroautophagy (hereafter referred to as autophagy) is one of the lysosomal-dependent degradation pathways that maintains homeostasis through the degradation and recycling of cellular components (e.g., dysfunctional proteins and damaged organelles). Although autophagy-related (ATG) proteins play a central role in regulating the formation of autophagy-related member structures (e.g., phagophores, autophagosomes, and autolysosomes), the autophagic process also involves changes in expression and function of ion channels and transporters. Here we discuss current knowledge of the mechanisms that regulate autophagy in mammalian cells, with special attention to the ion channels and transporters. We also highlight prospects for the development of drugs targeting ion channels and transporters in autophagy.
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Affiliation(s)
- Ruoxi Zhang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Daniel J Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA
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Li Z, Huang Z, Bai L. The P2X7 Receptor in Osteoarthritis. Front Cell Dev Biol 2021; 9:628330. [PMID: 33644066 PMCID: PMC7905059 DOI: 10.3389/fcell.2021.628330] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 01/22/2021] [Indexed: 12/11/2022] Open
Abstract
Osteoarthritis (OA) is the most common joint disease. With the increasing aging population, the associated socio-economic costs are also increasing. Analgesia and surgery are the primary treatment options in late-stage OA, with drug treatment only possible in early prevention to improve patients' quality of life. The most important structural component of the joint is cartilage, consisting solely of chondrocytes. Instability in chondrocyte balance results in phenotypic changes and cell death. Therefore, cartilage degradation is a direct consequence of chondrocyte imbalance, resulting in the degradation of the extracellular matrix and the release of pro-inflammatory factors. These factors affect the occurrence and development of OA. The P2X7 receptor (P2X7R) belongs to the purinergic receptor family and is a non-selective cation channel gated by adenosine triphosphate. It mediates Na+, Ca2+ influx, and K+ efflux, participates in several inflammatory reactions, and plays an important role in the different mechanisms of cell death. However, the relationship between P2X7R-mediated cell death and the progression of OA requires investigation. In this review, we correlate potential links between P2X7R, cartilage degradation, and inflammatory factor release in OA. We specifically focus on inflammation, apoptosis, pyroptosis, and autophagy. Lastly, we discuss the therapeutic potential of P2X7R as a potential drug target for OA.
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Affiliation(s)
- Zihao Li
- Department of Orthopedic Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ziyu Huang
- Foreign Languages College, Shanghai Normal University, Shanghai, China
| | - Lunhao Bai
- Department of Orthopedic Surgery, Shengjing Hospital of China Medical University, Shenyang, China
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Madruga E, Maestro I, Martínez A. Mitophagy Modulation, a New Player in the Race against ALS. Int J Mol Sci 2021; 22:ijms22020740. [PMID: 33450997 PMCID: PMC7828440 DOI: 10.3390/ijms22020740] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/09/2021] [Accepted: 01/11/2021] [Indexed: 02/06/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.
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Affiliation(s)
- Enrique Madruga
- Centro de Investigaciones Biológicas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain; (E.M.); (I.M.)
| | - Inés Maestro
- Centro de Investigaciones Biológicas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain; (E.M.); (I.M.)
| | - Ana Martínez
- Centro de Investigaciones Biológicas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain; (E.M.); (I.M.)
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain
- Correspondence: ; Tel.: +34-918373112
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50
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Song M, Zhao X, Song F. Aging-Dependent Mitophagy Dysfunction in Alzheimer's Disease. Mol Neurobiol 2021; 58:2362-2378. [PMID: 33417222 DOI: 10.1007/s12035-020-02248-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) is the most common late-onset dementia characterized by the deposition of extracellular amyloid plaques and formation of intracellular neurofibrillary tangles, which eventually lead to neuronal loss and cognitive deficits. Multiple lines of evidence indicate that mitochondrial dysfunction is involved in the initiation and progression of AD. As essential machinery for mitochondrial quality control, mitophagy plays a housekeeping role in neuronal cells by eliminating dysfunctional or excessive mitochondria. At present, mounting evidence support that the activity of mitophagy markedly declines in human brains during aging. Impaired mitophagy and mitochondrial dysfunction were causally linked to bioenergetic deficiency, oxidative stress, microglial activation, and chronic inflammation, thereby aggravating the Aβ and tau pathologies and leading to neuron loss in AD. This review summarizes recent evidence for age-associated mitophagy decline during human aging and provides an overview of mitochondrial dysfunction involved in the process of AD. It also discusses the underlying mechanisms through which defective mitophagy leads to neuronal cell death in AD. Therapeutic interventions aiming to restore mitophagy functions can be used as a strategy for ameliorating AD pathogenesis.
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Affiliation(s)
- Mingxue Song
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China
| | - Xiulan Zhao
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China
| | - Fuyong Song
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, Shandong, People's Republic of China.
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