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Luo J, Lu W, Chen Y, Li G, Feng J, Huang Y, Yu Y, Cai S, Jian J, Yang S. SQSTM1/p62 from Litopenaeus vannamei is involved in the immune response to Vibrio infection. FISH & SHELLFISH IMMUNOLOGY 2025; 158:110161. [PMID: 39890038 DOI: 10.1016/j.fsi.2025.110161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/24/2025] [Accepted: 01/26/2025] [Indexed: 02/03/2025]
Abstract
Sequestosome 1 (SQSTM1 or p62) has multiple functional domains, and it can not only be involved in autophagy process, but also defend against oxidative stress by invoking the Keap1/Nrf2 signaling pathway. However, the role of p62 in the response of Pacific whiteleg shrimp Litopenaeus vannamei to bacterial infection is still unclear. This study successfully identified p62 from L. vannamei (Lv-p62). The length of the open reading frame (ORF) of Lv-p62 is 1908 bp, which encoded 635 amino acids, and had Phox and Bem1p domain (PB1), Zinc-binding and ubiquitin-associated (UBA) domains. The expression level of Lv-p62 in the hepatopancreas of healthy L. vannamei is the highest, and it could be significantly induced under the stimulation of Vibrio harveyi. Besides, knocking down Lv-p62 by using RNA interference technology could reduce the expression levels of Nrf2 (nuclear factor erythroid 2-related factor 2), LC3 (microtubule-associated protein 1 light chain 3) and autophagy-related gene (ATG3, ATG5 and ATG12). Compared with the stimulation with V. harveyi alone, stimulation with V. harveyi after knocking down Lv-p62 could reduce the expression of antioxidant-, autophagy- and apoptosis-related genes in L. vannamei. Moreover, knocking down Lv-p62 could reduce the apoptosis signal of hepatopancreas and the abnormal tissue structure caused by V. harveyi. These results indicated that Lv-p62 is involved in the immune response to Vibrio infection in L. vannamei, which further enriched the regulatory function of p62 and its role in the innate immunity of shrimp.
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Affiliation(s)
- Junliang Luo
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China
| | - Wei Lu
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China
| | - Yanghui Chen
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China
| | - Guojian Li
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China
| | - Jinyuan Feng
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China
| | - Yanru Huang
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China
| | - Yu Yu
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China
| | - Shuanghu Cai
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China
| | - Jichang Jian
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China
| | - Shiping Yang
- Fisheries College of Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Animal Disease Control and Healthy Culture & Key Laboratory of Control for Disease of Aquatic Animals of Guangdong Higher Education Institutes, Zhanjiang, China.
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2
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Zhang X, Wang SJ, Wan SC, Li X, Chen G. Ozone: complicated effects in central nervous system diseases. Med Gas Res 2025; 15:44-57. [PMID: 39436168 PMCID: PMC11515058 DOI: 10.4103/mgr.medgasres-d-24-00005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 06/20/2024] [Accepted: 08/25/2024] [Indexed: 10/23/2024] Open
Abstract
Oxidative stress is closely related to various diseases. Ozone can produce redox reactions through its unique response. As a source of the oxidative stress response, the strong oxidizing nature of ozone can cause severe damage to the body. On the other hand, low ozone concentrations can activate various mechanisms to combat oxidative stress and achieve therapeutic effects. Some animal experiments and clinical studies have revealed the potential medical value of ozone, indicating that ozone is not just a toxic gas. By reviewing the mechanism of ozone and its therapeutic value in treating central nervous system diseases (especially ischemic stroke and Alzheimer's disease) and the toxic effects of ozone, we find that ozone inhalation and a lack of antioxidants or excessive exposure lead to harmful impacts. However, with adequate antioxidants, ozone can transmit oxidative stress signals, reduce inflammation, reduce amyloid β peptide levels, and improve tissue oxygenation. Similar mechanisms to those of possible new drugs for treating ischemic stroke and Alzheimer's disease indicate the potential of ozone. Nevertheless, limited research has restricted the application of ozone. More studies are needed to reveal the exact dose-effect relationship and healing effect of ozone.
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Affiliation(s)
- Xu Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Shi-Jun Wang
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Si-Cen Wan
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Xiang Li
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Gang Chen
- Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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Severino MB, Morelli AP, Pavan ICB, Mancini MCS, Góis MM, Borges RJ, Braga RR, da Silva LGS, Quintero-Ruiz N, Costa MM, Oliveira WDL, Bezerra RMN, Ropelle ER, Simabuco FM. A CRISPR-edited isoform of the AMPK kinase LKB1 improves the response to cisplatin in A549 lung cancer cells. J Biol Chem 2025:108308. [PMID: 39955067 DOI: 10.1016/j.jbc.2025.108308] [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: 04/03/2024] [Revised: 01/23/2025] [Accepted: 02/09/2025] [Indexed: 02/17/2025] Open
Abstract
Lung cancer presents the highest mortality rate in the world when compared to other cancer types and often presents chemotherapy resistance to cisplatin. The A549 non-small cell lung cancer (NSCLC) line is widely used as a model for lung adenocarcinoma studies since it presents a high proliferative rate and a nonsense mutation in the STK11 gene. The LKB1 protein, encoded by the STK11 gene, is one of the major regulators of cellular metabolism through AMPK activation under nutrient deprivation. Mutation in the STK11 gene in A549 cells potentiates cancer hallmarks, such as deregulation of cellular metabolism, aside from the Warburg effect, mTOR activation, autophagy inhibition, and NRF2 and redox activation. In this study, we investigated the integration of these pathways associated with the metabolism regulation by LKB1/AMPK to improve cisplatin response in the A549 cell line. We first used the CRISPR/Cas9 system to generate cell lines with a CRISPR-edited LKB1 isoform (called Super LKB1), achieved through the introduction of a +1 adenine insertion in the first exon of the STK11 gene after NHEJ mediated repair. This insertion led to the expression of a higher molecular weight protein containing an alternative exon described in the Peutz-Jeghers Syndrome (PJS). Through metabolic regulation by Super LKB1 expression and AMPK activation, we found an increase in autophagy flux (LC3 GFP/RFP p<0.05), as well as a reduction in the phosphorylation of mTORC1 downstream targets (S6K2 phospho-Serine 423; p<0.05; and S6 ribosomal protein phospho-Serine 240/244; p<0.03). The NRF2 protein exhibited increased levels and more nuclear localization in A549 WT (wild-type) cells compared to the edited cells (p<0.01). We also observed lower levels of H2O2 in the WT A549 cells, as a possible result of NRF2 activation, and a higher requirement of cisplatin to achieve the IC50 (WT: 10 μM; c2SL+: 5.5 μM; c3SL+: 6 μM). The data presented here suggests that the regulation of molecular pathways by the novel Super LKB1 in A549 cells related to metabolism, mTORC1, and autophagy promotes a better response of lung cancer cells to cisplatin. This NHEJ-CRISPR-based approach may be potentially used for lung cancer gene therapy.
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Affiliation(s)
- Matheus Brandemarte Severino
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Ana Paula Morelli
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Isadora Carolina Betim Pavan
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Mariana Camargo Silva Mancini
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Mariana Marcela Góis
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Rafael Junqueira Borges
- Department of Physics and Biophysics, Biosciences Institute, State University of São Paulo, Botucatu, Brazil
| | - Renata Rosseto Braga
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas, Limeira, Brazil
| | | | - Nathalia Quintero-Ruiz
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Maíra Maftoum Costa
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Wesley de Lima Oliveira
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Rosângela Maria Neves Bezerra
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Eduardo Rochete Ropelle
- Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Fernando Moreira Simabuco
- Multidisciplinary Laboratory of Food and Health, School of Applied Sciences, University of Campinas, Limeira, Brazil; Department of Biochemistry, Federal University of São Paulo, São Paulo, Brazil.
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4
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Tamatta R, Pai V, Jaiswal C, Singh I, Singh AK. Neuroinflammaging and the Immune Landscape: The Role of Autophagy and Senescence in Aging Brain. Biogerontology 2025; 26:52. [PMID: 39907842 PMCID: PMC11799035 DOI: 10.1007/s10522-025-10199-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: 12/14/2024] [Accepted: 01/29/2025] [Indexed: 02/06/2025]
Abstract
Neuroinflammation is closely linked to aging, which damages the structure and function of the brain. It is caused by the intricate interactions of immune cells in the aged brain, such as the dysregulated glial cells and the dysfunctional astrocytes. Aging-associated chronic low inflammation, referred to as neuroinflammaging, shows an upregulated proinflammatory response. Autophagy and senescence play crucial roles as moderators of aging and neuroinflammatory responses. The dysregulated neuroimmune system, dystrophic glial cells, and release of proinflammatory factors alter blood-brain barrier, causing a neuroinflammatory landscape. Chronic inflammation combined with deteriorating neurons exacerbate neurological disorders and decline in cognitive function. This review highlights the neuroinflammaging and mechanism associated with immune cells interplay with central nervous system and aging, cellular senescence, and autophagy regulation in the brain's immune system under neuroinflammatory conditions. Moreover, the roles of microglia and peripheral immune cells in the neuroinflammatory process in the aging brain have also been discussed. Determining treatment targets and comprehending mechanisms that influence immune cells in the aged brain is necessary to decrease neuroinflammation.
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Affiliation(s)
- Rajesh Tamatta
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576104, India
| | - Varsha Pai
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576104, India
| | - Charu Jaiswal
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576104, India
| | - Ishika Singh
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576104, India
| | - Abhishek Kumar Singh
- Manipal Centre for Biotherapeutics Research, Manipal Academy of Higher Education, Karnataka, Manipal, 576104, India.
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5
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Dastghaib S, Shafiee SM, Ramezani F, Ashtari N, Tabasi F, Saffari-Chaleshtori J, Siri M, Vakili O, Igder S, Zamani M, Niknam M, Nasery MM, Kokabi F, Wiechec E, Mostafavi-Pour Z, Mokarram P, Ghavami S. NRF-mediated autophagy and UPR: Exploring new avenues to overcome cancer chemo-resistance. Eur J Pharmacol 2025; 988:177210. [PMID: 39706466 DOI: 10.1016/j.ejphar.2024.177210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/06/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
The development of chemo-resistance remains a significant hurdle in effective cancer therapy. NRF1 and NRF2, key regulators of redox homeostasis, play crucial roles in the cellular response to oxidative stress, with implications for both tumor growth and resistance to chemotherapy. This study delves into the dualistic role of NRF2, exploring its protective functions in normal cells and its paradoxical support of tumor survival and drug resistance in cancerous cells. We investigate the interplay between the PERK/NRF signaling pathway, ER stress, autophagy, and the unfolded protein response, offering a mechanistic perspective on how these processes contribute to chemoresistance. Our findings suggest that targeting NRF signaling pathways may offer new avenues for overcoming resistance to chemotherapeutic agents, highlighting the importance of a nuanced approach to redox regulation in cancer treatment. This research provides a molecular basis for the development of NRF-targeted therapies, potentially enhancing the efficacy of existing cancer treatments and offering hope for more effective management of resistant tumors.
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Affiliation(s)
- Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, 7193635899, Shiraz, Iran
| | - Sayed Mohammad Shafiee
- Autophagy Research Center, Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran
| | - Fatemeh Ramezani
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 51664, Tabriz, Iran
| | - Niloufar Ashtari
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada
| | - Farhad Tabasi
- Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, 52242, USA
| | - Javad Saffari-Chaleshtori
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran; Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, 8813833435, Shahrekord, Iran
| | - Morvarid Siri
- Autophagy Research Center, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran
| | - Omid Vakili
- Autophagy Research Center, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran; Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, 73461-81746, Isfahan, Iran
| | - Somayeh Igder
- Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, 6135715794, Ahvaz, Iran
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran
| | - Maryam Niknam
- Autophagy Research Center, Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran
| | - Mahshid Moballegh Nasery
- Nanomedicine Research Association (NRA), Universal Scientific Education and Research Network (USERN), 7616911319, Tehran, Iran
| | - Fariba Kokabi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, 9177948564, Mashhad, Iran
| | - Emilia Wiechec
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Academy of Silesia, Faculty of Medicine, Rolna 43, 40-555, Katowice, Poland; Department of Otorhinolaryngology in Linköping, Anaesthetics, Operations and Specialty Surgery Center, Region Östergotland, 58185, Linköping, Sweden
| | - Zohreh Mostafavi-Pour
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran.
| | - Pooneh Mokarram
- Autophagy Research Center, Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, 7134845794, Shiraz, Iran.
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, R3E 0J9, Canada; Academy of Silesia, Faculty of Medicine, Rolna 43, 40-555, Katowice, Poland; Research Institutes of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, MB, R3E 0V9, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada.
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6
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Feng C, Cheng X, Na M, Zhang F, Duan J, Ji L, Jiang J. Green preparation of low-molecular-weight galactomannan from Gleditsia sinensis and mechanistic investigation on ameliorating nonalcoholic fatty liver disease. Food Res Int 2025; 201:115647. [PMID: 39849749 DOI: 10.1016/j.foodres.2024.115647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/29/2024] [Accepted: 12/28/2024] [Indexed: 01/25/2025]
Abstract
Galactomannan comes from a wide range of plant resources and has some biological activities, but its bioavailability is limited due to its large molecular weight and complex structure. In this study, three degradation methods (H2O2, ultrasound, and β-mannanase) combined with ethanol fractional precipitation (25 %, 50 %, and 75 %) were used to degrade and separate Gleditsia sinensis galactomannans (GSG), and the physicochemical properties and biological activities of GSG after degradation were analyzed. Comprehensive comparison indicates that H2O2 exhibits had a better degradation effect. After 4 h of degradation using 4 % H2O2, the yield of GSG precipitated with 50 % ethanol was 37.06 % (the yield of undigested GSG is 1.80 %). Simultaneously, the molecular weight (reduced from 225.25 to 36.87 kDa) and viscosity were significantly reduced under this condition, while the solubility was increased. In addition, the low-molecular-weight GSG (LGSG) obtained by 4 % H2O2/50 % ethanol showed the strongest free radical scavenging activity in vitro. Furthermore, the results of in vivo antioxidant assays showed that LGSG inhibited Aflatoxin B1-induced developmental toxicity by regulating gene expression in the Keap1/Nrf2 pathway. LGSG also promoted Nrf2-mediated expression of the lipid metabolism genes ppar-α and cpt1, while suppressing expression of the fatty acid synthesis genes fas and scd-1. Therefore, the liver recovered from lipid peroxidation induced nonalcoholic fatty liver disease (NAFLD). The present study introduces a method for green and efficient preparation of LGSG, indicates its potential as a nutritional product.
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Affiliation(s)
- Chi Feng
- Department of Chemistry and Chemical Engineering, State Key Laboratory of Efficient Production of Forest Resources, Engineering Research Center of Forestry Biomass Materials and Bioenergy (Ministry of Education), Beijing Forestry University, Beijing 100083, China
| | - Xichuang Cheng
- Department of Chemistry and Chemical Engineering, State Key Laboratory of Efficient Production of Forest Resources, Engineering Research Center of Forestry Biomass Materials and Bioenergy (Ministry of Education), Beijing Forestry University, Beijing 100083, China
| | - Mula Na
- Inner Mongolia Minzu Universities, Coll Anim Sci & Technol, Tongliao, Inner Mongolia 028000, China
| | - Fenglun Zhang
- Nanjing Institute for Comprehensive Utilization of Wild Plants, Nanjing 211111, China
| | - Jiufang Duan
- Department of Chemistry and Chemical Engineering, State Key Laboratory of Efficient Production of Forest Resources, Engineering Research Center of Forestry Biomass Materials and Bioenergy (Ministry of Education), Beijing Forestry University, Beijing 100083, China
| | - Li Ji
- Department of Chemistry and Chemical Engineering, State Key Laboratory of Efficient Production of Forest Resources, Engineering Research Center of Forestry Biomass Materials and Bioenergy (Ministry of Education), Beijing Forestry University, Beijing 100083, China
| | - Jianxin Jiang
- Department of Chemistry and Chemical Engineering, State Key Laboratory of Efficient Production of Forest Resources, Engineering Research Center of Forestry Biomass Materials and Bioenergy (Ministry of Education), Beijing Forestry University, Beijing 100083, China.
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7
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Ren J, Chen X, Wang HY, Yang T, Zhang KR, Lei SY, Qi LY, Feng CL, Zhou R, Zhou H, Tang W. Gentiopicroside ameliorates psoriasis-like skin lesions in mice via regulating the Keap1-Nrf2 pathway and inhibiting keratinocyte activation. Acta Pharmacol Sin 2025:10.1038/s41401-024-01449-8. [PMID: 39779965 DOI: 10.1038/s41401-024-01449-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 11/27/2024] [Accepted: 11/27/2024] [Indexed: 01/11/2025] Open
Abstract
Psoriasis is a chronic, systemic immune-mediated skin disease. Although many new strategies for psoriasis treatment have been developed, there is great need in clinic for treating psoriasis. Gentiopicroside (GPS), derived from Gentiana manshurica Kitagawa, has multiple pharmacological activities including anti-inflammatory, anti-oxidative and antiviral activities. In this study, we investigated the potential effects of GPS in imiquimod (IMQ)-induced psoriasis mouse model and the underlying mechanisms. The mice were sensitized on their shaved back with IMQ cream for 7 days with or without topical application of 1% or 2% GPS cream. We showed that the application of GPS cream significantly ameliorated psoriasis-like skin lesions; GPS effect was better than that of calcipotriol. GPS rectified the immune cells infiltration and keratinocytes activation in the skin lesions, and significantly inhibited TNF-α/IFN-γ stimulated human keratinocyte (HaCaT) activation in vitro. Proteomic analysis from keratinocytes with and without GPS treatment prompted that GPS regulated the Keap1-Nrf2 pathway, which was the most important pathway in regulating oxidative stress and inflammation. We demonstrated that GPS regulated the protein expression of p62 and Keap1, induced Nrf2 nuclear translocation followed by transcription of Nrf2 downstream antioxidant genes in HaCaT cells. Furthermore, the antioxidant effects of GPS were abolished in Nrf2-/- keratinocytes. Simultaneously, Nrf2-/- mice showed increased psoriasiform symptoms with a diminished protective effect in response to GPS treatment. Collectively, the study discloses that GPS inhibits keratinocyte activation and ameliorates psoriasis-like skin lesions in an Nrf2-dependent manner.
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Affiliation(s)
- Jing Ren
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xin Chen
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hao-Yu Wang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Tao Yang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Kai-Rong Zhang
- School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, China
| | - Shu-Yue Lei
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lu-Yao Qi
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Chun-Lan Feng
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Rong Zhou
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hu Zhou
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Wei Tang
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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8
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Liu X, Tuerxun H, Zhao Y, Li Y, Wen S, Li X, Zhao Y. Crosstalk between ferroptosis and autophagy: broaden horizons of cancer therapy. J Transl Med 2025; 23:18. [PMID: 39762980 PMCID: PMC11702107 DOI: 10.1186/s12967-024-06059-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025] Open
Abstract
Ferroptosis and autophagy are two main forms of regulated cell death (RCD). Ferroptosis is a newly identified RCD driven by iron accumulation and lipid peroxidation. Autophagy is a self-degradation system through membrane rearrangement. Autophagy regulates the metabolic balance between synthesis, degradation and reutilization of cellular substances to maintain intracellular homeostasis. Numerous studies have demonstrated that both ferroptosis and autophagy play important roles in cancer pathogenesis and cancer therapy. We also found that there are intricate connections between ferroptosis and autophagy. In this article, we tried to clarify how different kinds of autophagy participate in the process of ferroptosis and sort out the common regulatory pathways between ferroptosis and autophagy in cancer. By exploring the complex crosstalk between ferroptosis and autophagy, we hope to broaden horizons of cancer therapy.
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Affiliation(s)
- Xingyu Liu
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Halahati Tuerxun
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yixin Zhao
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yawen Li
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Shuhui Wen
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Xi Li
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yuguang Zhao
- Cancer Center, The First Hospital of Jilin University, Changchun, 130021, China.
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Sethi P, Mehan S, Khan Z, Maurya PK, Kumar N, Kumar A, Tiwari A, Sharma T, Das Gupta G, Narula AS, Kalfin R. The SIRT-1/Nrf2/HO-1 axis: Guardians of neuronal health in neurological disorders. Behav Brain Res 2025; 476:115280. [PMID: 39368713 DOI: 10.1016/j.bbr.2024.115280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/10/2024] [Accepted: 09/30/2024] [Indexed: 10/07/2024]
Abstract
SIRT1 (Sirtuin 1) is a NAD+-dependent deacetylase that functions through nucleoplasmic transfer and is present in nearly all mammalian tissues. SIRT1 is believed to deacetylate its protein substrates, resulting in neuroprotective actions, including reduced oxidative stress and inflammation, increased autophagy, increased nerve growth factors, and preserved neuronal integrity in aging or neurological disease. Nrf2 is a transcription factor that regulates the genes responsible for oxidative stress response and substance detoxification. The activation of Nrf2 guards cells against oxidative damage, inflammation, and carcinogenic stimuli. Several neurological abnormalities and inflammatory disorders have been associated with variations in Nrf2 activation caused by either pharmacological or genetic factors. Recent evidence indicates that Nrf2 is at the center of a complex cellular regulatory network, establishing it as a transcription factor with genuine pleiotropy. HO-1 is most likely a component of a defense mechanism in cells under stress, as it provides negative feedback for cell activation and mediator synthesis. This mediator is upregulated by Nrf2, nitric oxide (NO), and other factors in various inflammatory states. HO-1 or its metabolites, such as CO, may mitigate inflammation by modulating signal transduction pathways. Neurological diseases may be effectively treated by modulating the activity of HO-1. Multiple studies have demonstrated that SIRT1 and Nrf2 share an important connection. SIRT1 enhances Nrf2, activates HO-1, protects against oxidative injury, and decreases neuronal death. This has been associated with numerous neurodegenerative and neuropsychiatric disorders. Therefore, activating the SIRT1/Nrf2/HO-1 pathway may help treat various neurological disorders. This review focuses on the current understanding of the SIRT1 and Nrf2/HO-1 neuroprotective processes and the potential therapeutic applications of their target activators in neurodegenerative and neuropsychiatric disorders.
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Affiliation(s)
- Pranshul Sethi
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Sidharth Mehan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India.
| | - Zuber Khan
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Pankaj Kumar Maurya
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh 201204, India
| | - Aakash Kumar
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Aarti Tiwari
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Tarun Sharma
- Division of Neuroscience, Department of Pharmacology, ISF College of Pharmacy, Moga (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Ghanshyam Das Gupta
- Department of Pharmaceutics, ISF College of Pharmacy (Affiliated to IK Gujral Punjab Technical University, Jalandhar), Moga, Punjab 144603, India
| | - Acharan S Narula
- Narula Research, LLC, 107 Boulder Bluff, Chapel Hill, NC 27516, USA
| | - Reni Kalfin
- Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev St., Block 23, Sofia 1113, Bulgaria; Department of Healthcare, South-West University "NeofitRilski", Ivan Mihailov St. 66, Blagoevgrad 2700, Bulgaria
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10
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Moradi N, Champsi S, Hood DA. Sulforaphane, Urolithin A, and ZLN005 induce time-dependent alterations in antioxidant capacity, mitophagy, and mitochondrial biogenesis in muscle cells. SPORTS MEDICINE AND HEALTH SCIENCE 2025; 7:16-27. [PMID: 39649792 PMCID: PMC11624366 DOI: 10.1016/j.smhs.2024.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/14/2024] [Accepted: 03/29/2024] [Indexed: 12/11/2024] Open
Abstract
Efficient signal transduction that mediates mitochondrial turnover is a strong determinant of metabolic health in skeletal muscle. Of these pathways, our focus was aimed towards the enhancement of antioxidant capacity, mitophagy, and mitochondrial biogenesis. While physical activity is an excellent inducer of mitochondrial turnover, its ability to ubiquitously activate and enhance mitochondrial turnover prevents definitive differentiation of the contribution made by each pathway. Therefore, we employed three agents, Sulforaphane (SFN), Urolithin A (UroA), and ZLN005 (ZLN), which are activators of important biological markers involved in antioxidant signaling, mitophagy, and biogenesis, respectively. We investigated the time-dependent changes in proteins related to each mechanism in C2C12 myotubes. SFN treatment resulted in increased nuclear localization of the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) after 4 hour (h), with subsequent 2-fold increases in the antioxidant enzymes Nicotinamide Quinone Oxidoreductase 1 (NQO1) and Heme-Oxygenase-1 (HO-1) by 24 h and 48 h. Mitochondrial respiration and ATP production were significantly increased by both 24 h and 48 h. UroA showed a 2-fold increase in AMP-activated Protein Kinase (AMPK) after 4 h, which led to a modest 30% increase in whole cell mitophagy markers p62 and LC3, after 48 h. This was accompanied by a reduction in cellular Reactive Oxygen Species (ROS), detected with the CellROX Green reagent. Mitophagy flux measurements showed mitophagy activation as both LC3-II and p62 flux increased with UroA at 24-h and 48-h time points, respectively. Finally, AMPK activation was observed by 4 h, in addition to a 2-fold increase in Mitochondrial Transcription Factor A (TFAM) promoter activity by 24 h of ZLN treatment following transient transfection of a TFAM promoter-luciferase construct. Mitochondrial respiration and ATP production were enhanced by 24 h. Our results suggest that early time points of treatment increase upstream pathway activity, whereas later time points represent the increased phenotypic expression of related downstream markers. Our findings suggest that the spatiotemporal progression of these mechanisms following drug treatment is another important factor to consider when examining subcellular changes towards mitochondrial turnover in muscle.
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Affiliation(s)
- Neushaw Moradi
- Muscle Health Research Center, School of Kinesiology and Health Science, York University, Toronto, ON, M3J 1P3, Canada
| | - Sabrina Champsi
- Muscle Health Research Center, School of Kinesiology and Health Science, York University, Toronto, ON, M3J 1P3, Canada
| | - David A. Hood
- Muscle Health Research Center, School of Kinesiology and Health Science, York University, Toronto, ON, M3J 1P3, Canada
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11
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Hong C, Wang L, Zhou X, Zou L, Xiang X, Deng H, Li Q, Wu Y, Liu L, Li T. Protective Effects of Mdivi-1 on Cognition Disturbance Following Sepsis in Mice via Alleviating Microglia Activation and Polarization. CNS Neurosci Ther 2025; 31:e70149. [PMID: 39791542 PMCID: PMC11719124 DOI: 10.1111/cns.70149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 10/09/2024] [Accepted: 10/20/2024] [Indexed: 01/30/2025] Open
Abstract
BACKGROUND Neuroinflammation is one of the essential pathogeneses of cognitive damage suffering from sepsis-associated encephalopathy (SAE). Lots of evidences showed the microglia presented mitochondrial fragmentation during SAE. This study investigated the protective effects and novel mechanisms of inhibiting microglia mitochondrial fragmentation via mitochondrial division inhibitor 1 (Mdivi-1) on cognitive damage in SAE. METHODS The SAE model was performed by cecal ligation and puncture (CLP), and Mdivi-1 was administrated via intraperitoneal injection. Morris water maze was performed to assess cognitive function. Mitochondrial morphology was observed by electron microscope or MitoTracker staining. The qRT-PCR, immunofluorescence staining, and western blots were used to detect the inflammatory factors and protein content, respectively. Flow cytometry was used to detect the polarization of hippocampal microglia. Bioinformatics analysis was used to verify hypotheses. RESULTS Mdivi-1 administration alleviated sepsis-induced mitochondrial fragmentation, microglia activation, polarization, and cognitive damage. The mechanisms study showed neuroinflammation and oxidative stress were suppressed via NF-κB and Keap1/Nrf2/HO-1 pathways following Mdivi-1 administration; meanwhile, pyroptosis in microglia was reduced, which was associated with enhanced autophagosome formation via p62 elevation following Mdivi-1 administration. CONCLUSION Inhibition of microglia mitochondrial fragmentation is beneficial to SAE cognitive disturbance, the mechanisms are related to alleviating neuroinflammation, oxidative stress, and pyroptosis.
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Affiliation(s)
- Chen Hong
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
| | - Li Wang
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
| | - Xiaowei Zhou
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
| | - Liyong Zou
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
| | - Xinming Xiang
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
| | - Haoyue Deng
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
| | - Qinghui Li
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
| | - Yue Wu
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
| | - Liangming Liu
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
| | - Tao Li
- Shock and Transfusion Department, Research Institute of Surgery, Daping HospitalArmy Medical UniversityChongqingChina
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12
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Yang J, Ni S, Wang A, Wang K, Deng J, Li Z, Cai Y, Chen Y, Chen G, Lin D. Myrtenol promotes skin flap survival by inhibiting apoptosis and promoting autophagy via the MEK/ERK pathway. Arch Biochem Biophys 2025; 763:110230. [PMID: 39603374 DOI: 10.1016/j.abb.2024.110230] [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: 09/13/2024] [Revised: 11/05/2024] [Accepted: 11/23/2024] [Indexed: 11/29/2024]
Abstract
Skin flaps are often used for repair and reconstruction, including oral cavity and palate. However, postoperative flap necrosis limited applications. Myrtenol, a plant-derived bicyclic monoterpene, has pharmacological effects including inhibiting apoptosis and promoting autophagy. But any impact on skin flaps survival remains unclear. Thus, we established modified McFarlane flaps on 24 Sprague-Dawley rats and applied myrtenol. They were randomly divided into low-dose myrtenol (L-Myr), high-dose myrtenol (H-Myr), inhibitor and control groups. On postoperative day 7, flap survival rate was increased and Laser Doppler images showed blood circulation improvement under myrtenol treatment. Hematoxylin and eosin staining (H&E) results indicated that it increased micro vessel density (MVD) and decreased neutrophil numbers. Besides, kits detection showed that it improved anti-oxidant stress factors activities and reduced pro-oxidant stress factors contents. Moreover, immunofluorescence and Western blot results demonstrated that it upregulated the expression of pro-angiogenic factors, anti-apoptotic proteins, pro-autophagic proteins, mitogen-activated protein kinase 1/2 (MEK1/2) and extracellular signal-regulated kinases 1/2 (ERK1/2) and downregulated the expression of pro-inflammatory cytokines, pro-apoptotic proteins and anti-autophagic proteins. The specific inhibitor U0126 of MEK/ERK pathway partially reversed these effects. Overall, Myrtenol promoted angiogenesis, reduced oxidative stress, ameliorated inflammation, inhibited apoptosis and upregulated autophagy via MEK/ERK pathway to promote flap survival.
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Affiliation(s)
- Jialong Yang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Shenchuyue Ni
- School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, 325000, China
| | - An Wang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Kaitao Wang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Jiapeng Deng
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Zijie Li
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, The First School of Clinical Medical, Wenzhou Medical University, Wenzhou, 325000, China
| | - Yizhen Cai
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Yiqi Chen
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Guodong Chen
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China
| | - Dingsheng Lin
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325000, China.
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13
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Hsu CM, Kao SY, Yen CH, Hsiao CE, Cho SF, Wang HC, Yeh TJ, Du JS, Wang MH, Hsieh TY, Hsiao SY, Tsai Y, Hung LC, Liu YC, Chang KC, Hsiao HH. Biomarker potential of nuclear Nrf2 activation in the ABC subtype of diffuse large B‑cell lymphoma. Oncol Lett 2025; 29:30. [PMID: 39512504 PMCID: PMC11542154 DOI: 10.3892/ol.2024.14776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/07/2024] [Indexed: 11/15/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma characterized by distinct subtypes and heterogeneous treatment outcomes. Oxidative stress and the dysregulation of related regulatory genes are prevalent in DLBCL, prompting an investigation into the nuclear factor erythroid 2-related factor 2 (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) signaling pathway and associated genes. The present study assessed pathological specimens and clinical data from 43 newly diagnosed patients with DLBCL, comparing the associations and correlations between the expression of Nrf2, Keap1, microtubule-associated protein 1 light chain 3β (LC3B) and nitrotyrosine and the activated B-cell (ABC) and germinal center B-cell (GCB) subtypes of DLBCL using immunohistochemistry and digital image analysis software. Nuclear Nrf2 activation was observed in 33.3% of patients with DLBCL ABC, demonstrating a higher prevalence of hepatitis B surface antigen positivity, calcium ions and significant body weight loss (P<0.05). Total Nrf2 expression was associated with the DLBCL GCB subtype and inversely correlated with Keap1 expression in the DLBCL ABC subtype. Furthermore, a positive correlation was demonstrated between Nrf2 and LC3, indicating that total Nrf2 is inhibited by Keap1 and regulates LC3 expression. The ABC subtype was also associated with lower white blood cell counts and more frequent chemotherapy courses than the GCB subtype. These findings suggest that nuclear Nrf2 could be a biomarker for DLBCL clinical diagnosis.
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Affiliation(s)
- Chin-Mu Hsu
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
| | - Shih-Yu Kao
- Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
| | - Chia-Hung Yen
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| | - Chi-En Hsiao
- Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
| | - Shih-Feng Cho
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| | - Hui-Ching Wang
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| | - Tsung-Jang Yeh
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| | - Jeng-Shiun Du
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| | - Min-Hong Wang
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| | - Tzu-Yu Hsieh
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
| | - Samuel Yien Hsiao
- Center for Computational and Integrative Biology, University of Rutgers-Camden, Camden, NJ 08102, USA
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Yuhsin Tsai
- Graduate Institute of Chinese Medicine, School of Chinese Medicine, China Medical University, Taichung 404328, Taiwan, R.O.C
| | - Li-Chuan Hung
- Department of Long-Term Care and Health Management, Cheng Shiu University, Kaohsiung 833301, Taiwan, R.O.C
| | - Yi-Chang Liu
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
- Cellular Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
| | - Kung-Chao Chang
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan, R.O.C
| | - Hui-Hua Hsiao
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan, R.O.C
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan, R.O.C
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Chuang HY, Chan HW, Shih KC. Suppression of colorectal cancer growth: Interplay between curcumin and metformin through DMT1 downregulation and ROS-mediated pathways. Biofactors 2025; 51:e2137. [PMID: 39607347 DOI: 10.1002/biof.2137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 10/09/2024] [Indexed: 11/29/2024]
Abstract
The rising incidence of colorectal cancer (CRC) poses significant healthcare challenges. This study explored the therapeutic potential of combined curcumin (CUR) and metformin (MET) treatment in CRC models. Our findings indicate that the combination treatment (COMB) effectively downregulates the expression of divalent metal transporter-1 (DMT-1), leading to a reduction in cell proliferation aligned with suppression of the pAKT/mTOR/Cyclin D1 signaling pathway. The COMB increased reactive oxygen species (ROS) production, triggering activation of the NRF2/KEAP1 pathway. This pathway elicits an antioxidant response to manage oxidative stress in CRC cell lines. Interestingly, the response of NRF2 varied between CT26 and HCT116 cells. Moreover, our study highlights the induction of apoptosis and autophagy, as evidenced by upregulations in Bax/Bcl-2 ratios and autophagy-related protein expressions. Notably, the COMB promoted lipid peroxidation and downregulated xCT levels, suggesting the induction of ferroptosis. Ferroptosis has been shown to activate autophagy, which helps eliminate cells potentially damaged by the increased oxidative stress. Furthermore, the COMB effectively diminished the migratory ability of CRC cells. In vivo experiments using CRC-bearing mouse models, the results confirmed the anti-tumor efficacy of the COMB, leading to substantial inhibition of tumor growth without inducing general toxicity. In conclusion, our study suggests that combining CUR with MET holds promise as a potential option for CRC treatment, with critical mechanisms likely involving ROS elevation, autophagy, and ferroptosis.
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Affiliation(s)
- Hui-Yen Chuang
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hui-Wen Chan
- Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Kuang-Chung Shih
- Division of Endocrinology and Metabolism, Department of Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan
- Division of Endocrinology & Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- School of Medicine, National Defense Medical Center, Taipei, Taiwan
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15
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Wang H, Zuo Q, Li X, Liu Y, Gan L, Wang L, Rao Y, Pan R, Dong J. p62 Binding to Protein Kinase C Regulates HIV-1 gp120 V3 Loop Induced Microglial Inflammation. Inflammation 2024:10.1007/s10753-024-02229-6. [PMID: 39731677 DOI: 10.1007/s10753-024-02229-6] [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: 07/18/2024] [Revised: 11/12/2024] [Accepted: 12/22/2024] [Indexed: 12/30/2024]
Abstract
The main pathogenic mechanism of HIV-associated neurocognitive disorders (HAND) is neuronal apoptosis induced by inflammatory mediators, in which microglial inflammation plays a crucial role. However, the exact pathogenic mechanism remains unclear. Previous studies have shown that the HIV-1 gp120 V3 loop can trigger inflammation in CHME-5 microglia. p62 is a post-translational modified multidomain protein that is involved in the regulation of autophagy and is closely related to neuroinflammation. In this study, we found that p62 knockout down-regulated the expression of MCP-1, IL-6 and COX-2, and improved the inflammation of HIV-1 gp120 V3 loop induced microglia, while overexpression of p62 up-regulated the expression of MCP-1, IL-6 and COX-2, and promoted the inflammation of microglia. In addition, protein kinase C (PKC) knockout down-regulated the expression of MCP-1, IL-6 and COX-2 and inhibited the activation of IKK/ NF-κ B pathway, while tumor necrosis factor receptor-associated factor 6 (TRAF6) knockout had no significant effect on the expression of MCP-1, IL-6 and COX-2. Co-immunoprecipitation showed that p62 was bound and interacted with PKC. Inhibition of IKK/ NF-κ B pathway can down-regulate the expression of MCP-1, IL-6 and COX-2, and improve the inflammatory response of microglia. Our research further found that inhibition of IKK/ NF-κ B can decrease the expression of Caspase-3 and reduce the apoptosis of neurons in the co-culture of CHME-5 microglia and primary mouse neurons. The results of this study suggest that HIV-1 gp120 V3 loop induced CHME-5 microglial inflammation may be activated by the direct binding of p62 and PKC through the IKK/ NF-κ B signaling pathway, and these findings provide an important reference for the prevention and treatment of HAND.
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Affiliation(s)
- Huili Wang
- Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China
| | - Qin Zuo
- Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China
| | - Xinyi Li
- Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China
| | - Yuanyuan Liu
- Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China
| | - Limeng Gan
- Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China
| | - Linlin Wang
- Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China
| | - Yin Rao
- Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China
| | - Rui Pan
- Department of Orthopedics, The First Affiliated Hospital, Medical College of Jinan University, Guangzhou, Guangdong Province, China
| | - Jun Dong
- Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China.
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China.
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16
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Sui X, Gao B, Zhang L, Wang Y, Ma J, Wu X, Zhou C, Liu M, Zhang L. Scutellaria barbata D.Don and Hedyotis diffusa Willd herb pair combined with cisplatin synergistically inhibits ovarian cancer progression through modulating oxidative stress via NRF2-FTH1 autophagic degradation pathway. J Ovarian Res 2024; 17:246. [PMID: 39702302 DOI: 10.1186/s13048-024-01570-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/30/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Cisplatin (DDP) is one of the most effective anticancer drugs, commonly used to treat advanced ovarian cancer (OC). However, DDP has significant limitations of platinum-based drugs, including chemical resistance and high-dose toxic side effects. Traditional Chinese medicines (TCMs) often presented in the form of formula, in which the herb pair was the basic unit. Scutellaria barbata D.Don and Hedyotis diffusa Willd (SB-HD) are famous TCMs herb pair that have been shown to help treat multiple types of cancers. However, the synergistic effects and mechanism of combination of SB-HD and DDP to enhance DDP chemosensitivity in OC are still unknown. RESULTS In vitro, we found that the optimal proportion of SB-HD to inhibit the proliferation of OC cells was 2:1, SB-HD and DDP were shown to synergistically reduce the viability of OC cells, inhibit the colony formation, promote cell cycle arrest and apoptosis, as well as inhibit cell migration and invasion. In vivo, combination treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice and reduced the toxic side effects of DDP. Mechanistically, SB-HD and DDP combination treatment significantly promoted oxidative stress response, decreased MMP, inhibited ATP production, decreased ROS levels and increased SOD activity, increased the expression of NRF2, HO-1, ATG5 and LC3, decreased the expression of p62 and FTH1 both in OC cells and tumor tissue of mice. Inhibitor 3-MA (Methyladenine, autophagy inhibitor) and Fer-1 (Ferrostatin-1, iron ion inhibitor) can effectively reverse the expression changes of the key target proteins, but not ZnPP (Zinc protoporphyrin, HO-1 inhibitor). Through bioinformatics analysis, it was found that the abnormal expression level of NRF2 and FTH1 mRNA has a high prognostic value, at the same time, the other four key proteins respectively or interacting with NRF2 and FTH1, also play important roles in the occurrence and development of OC. CONCLUSION Our findings uncover a synergistic effect of SB-HD and DDP against OC through modulating oxidative stress via NRF2-FTH1 autophagic degradation pathway, which may provide an important theoretical foundation for the use of SB-HD and a new strategy for enhancing DDP chemosensitivity as well as reducing toxic side effects.
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Affiliation(s)
- Xue Sui
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Bingqing Gao
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
- School of Pharmacy, Anhui Xinhua University, Hefei, 230088, China
| | - Liu Zhang
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
- Department of Dermatology, Dalian Lvshunkou District Hospital of Traditional Chinese Medicine, Dalian, 116041, China
| | - Yanmin Wang
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Junnan Ma
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Xingchen Wu
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Chenyu Zhou
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China
| | - Min Liu
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China.
| | - Lin Zhang
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, 116044, China.
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17
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Lv B, Xing S, Wang Z, Zhang A, Wang Q, Bian Y, Pei Y, Sun H, Chen Y. NRF2 inhibitors: Recent progress, future design and therapeutic potential. Eur J Med Chem 2024; 279:116822. [PMID: 39241669 DOI: 10.1016/j.ejmech.2024.116822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 08/29/2024] [Accepted: 08/30/2024] [Indexed: 09/09/2024]
Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2) is a crucial transcription factor involved in oxidative stress response, which controls the expression of various cytoprotective genes. Recent research has indicated that constitutively activated NRF2 can enhance patients' resistance to chemotherapy drugs, resulting in unfavorable prognosis. Therefore, the development of NRF2 inhibitors has emerged as a promising approach for overcoming drug resistance in cancer treatment. However, there are limited reports and reviews focusing on NRF2 inhibitors. This review aims to provide a comprehensive analysis of the structure and regulation of the NRF2 signaling pathway, followed by a comprehensive review of reported NRF2 inhibitors. Moreover, the current design strategies and future prospects of NRF2 inhibitors will be discussed, aiming to establish a foundation for the development of more effective NRF2 inhibitors.
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Affiliation(s)
- Bingbing Lv
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Shuaishuai Xing
- School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China
| | - Zhiqiang Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Ao Zhang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Qinjie Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Yaoyao Bian
- Jiangsu Provincial Engineering Center of TCM External Medication Researching and Industrializing, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Yuqiong Pei
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China
| | - Haopeng Sun
- School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, People's Republic of China.
| | - Yao Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.
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18
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Ayala-Cosme EG, Yang D, Vences K, Davis LO, Borgini M. State-of-the-Art Nrf2 Inhibitors: Therapeutic Opportunities in Non-Cancer Diseases. ChemMedChem 2024; 19:e202400377. [PMID: 39083752 DOI: 10.1002/cmdc.202400377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/22/2024] [Accepted: 07/31/2024] [Indexed: 08/02/2024]
Abstract
Nuclear factor erythroid 2-related factor (Nrf2) is a cytoprotective transcription factor that induces the transcription of genes responsible for the cell's response to oxidative stress. While Nrf2 activation has led to the development of clinically relevant therapeutics, the oncogenic role of Nrf2 in the proliferation of cancer cells has underscored the complex nature of Nrf2 and the necessity for the development of Nrf2 inhibitors. Although the application of Nrf2 inhibitors appears limited as anticancer agents, recent studies have begun to pinpoint the impairment of autophagy in diseases as a cellular marker that shifts Nrf2 from a protective to a deleterious state. Therefore, the cytoplasmic accumulation of Nrf2 can lead to the accumulation of lipid hydroperoxides and, ultimately, to ferroptosis. However, some studies aimed at elucidating the role of Nrf2 in non-cancer diseases have yielded conflicting results, attributed to differences in approaches used to inhibit or activate Nrf2, as well as variations in in vitro and/or in vivo disease models. Overall, these results highlight the necessity for a deeper evaluation of Nrf2's role in diseases, especially chronic diseases. In this review, we discuss diseases where Nrf2 inhibition holds potential for beneficial therapeutic effects and summarize recently reported Nrf2 inhibitors exploiting medicinal chemistry approaches suitable for targeting transcription factors like Nrf2.
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Affiliation(s)
- Emil G Ayala-Cosme
- Department of Chemistry and Biochemistry, Augusta University, Augusta, 30912, GA, U.S.A
| | - Deborah Yang
- Department of Chemistry and Biochemistry, Augusta University, Augusta, 30912, GA, U.S.A
| | - Kyara Vences
- Department of Chemistry and Biochemistry, Augusta University, Augusta, 30912, GA, U.S.A
| | - Lindsey O Davis
- Department of Chemistry and Biochemistry, Augusta University, Augusta, 30912, GA, U.S.A
| | - Matteo Borgini
- Department of Chemistry and Biochemistry, Augusta University, Augusta, 30912, GA, U.S.A
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19
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Tang CT, Liu ZD, Wang P, Zeng CY, Chen YX. Lipopolysaccharide-regulated RNF31/NRF2 axis in colonic epithelial cells mediates homeostasis of the intestinal barrier in ulcerative colitis. Cell Signal 2024; 124:111480. [PMID: 39437901 DOI: 10.1016/j.cellsig.2024.111480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/05/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND Although previous studies have shown that the Ring Finger Protein 31 (RNF31) gene confers susceptibility to inflammatory disease and colorectal cancer, the exact function of this protein in ulcerative colitis (UC) has not been determined. METHODS A mouse dextran sulfate sodium (DSS)-induced experimental colitis model was used to study RNF31 and NRF2 in colitis. RNF31 silencing or overexpression in vitro was applied to address the role of RNF31 in colonic mucosal barrier damage. Immunohistochemistry and silico analysis was performed to investigate the expression of RNF31 via taking advantage of UC tissue samples and Gene Expression Omnibus (GEO) data, respectively. The cycloheximide (CHX)-chase experiment and Co-Immunoprecipitation (Co-IP) assays were conducted to explore the association of RNF31 protein with NRF2 and P62. RESULTS RNF31 is highly expressed in UC patients, in inflamed murine colon induced DSS and Lipopolysaccharide (LPS)-treated epithelial cells, while the express of NRF2 was Tabdecreased. RNF31-knockdown mice in the DSS-induced colitis model had a less severe phenotype, which was associated with a more integrated barrier of colon epithelial cells. While depletion of NRF2 in colitis model exacerbated intestinal inflammation. Mechanistically, RNF31 promoted the degradation of NRF2 by regulating its ubiquitination. Upon stimulation by RNF31, NRF2 is K63 ubiquitinated, which is associated with the C871 residue of RNF31. Moreover, downregulated NRF2 mediates inflammation by promoting the secretion of IL1β and IL18, leading to damage of the intestinal barrier. Upon LPS stimulation, the interaction of the PUB domain of RNF31 with the UBA domain of P62 increased, resulting in decreased degradation of the RNF31 protein via autophagy. CONCLUSION Overall, depletion of RNF31 effectively relieves DSS-induced colitis in mice by inhibiting NRF2 degradation, suggesting that RNF31 may be a potential therapy for human ulcerative colitis.
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Affiliation(s)
- Chao-Tao Tang
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Postdoctoral Innovation Practice Base, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China
| | - Zi-de Liu
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China
| | - Peng Wang
- Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Chun-Yan Zeng
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Department of Gastroenterology, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang 330003, China.
| | - You-Xiang Chen
- Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
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20
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Wang K, Wang A, Deng J, Yang J, Chen G, Chen Q, Ye M, Lin D. Tert-butylhydroquinone promotes skin flap survival by inhibiting oxidative stress mediated by the Nrf2/HO-1 signalling pathway. Br J Pharmacol 2024; 181:4845-4858. [PMID: 39233316 DOI: 10.1111/bph.17321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 07/11/2024] [Accepted: 07/15/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND AND PURPOSE Skin flaps are among the most important means of wound repair in clinical settings. However, partial or even total distal necrosis may occur after a flap operation, with severe consequences for both patients and doctors. This study investigated whether tert-butylhydroquinone (TBHQ), a known agonist of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), and an antioxidant, could promote skin flap survival. EXPERIMENTAL APPROACH McFarlane skin flap models were established in male Sprague-Dawley rats and then randomly divided into control, low-dose TBHQ, and high-dose TBHQ treatment groups. On postoperative day 7, the survival and blood flow of the skin flaps were assessed. Using flap tissue samples, angiogenesis, inflammation, apoptosis, autophagy, and Nrf2/haem oxygenase 1 (HO-1) signalling pathway activity were measured with immunohistochemical techniques and western blotting. KEY RESULTS TBHQ dose-dependently stimulated the Nrf2/HO-1 signalling pathway, inducing autophagy through the up-regulation of LC3B and beclin 1 and concurrently suppressing p62 expression. Additionally, TBHQ hindered apoptosis by enhancing Bcl-2 expression while inhibiting the expression of Bax. It suppressed inflammation by inhibiting the expression of interleukin 1β, interleukin 6, and tumour necrosis factor-α and enhanced angiogenesis by promoting the expression of vascular endothelial growth factor. CONCLUSION AND IMPLICATIONS In summary, TBHQ promoted flap survival in rats by up-regulating the Nrf2/HO-1 signalling pathway. As TBHQ is already widely used as a food additive, it could offer an acceptable means of improving clinical outcomes following skin flap surgery in patients.
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Affiliation(s)
- Kaitao Wang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - An Wang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Jiapeng Deng
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Jialong Yang
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Guodong Chen
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Qingyu Chen
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Minle Ye
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Dingsheng Lin
- Department of Hand and Plastic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
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21
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Bozdemir N, Kablan T, Sukur G, Cinar O, Uysal F. Obesity induced by a high-fat diet changes p62 protein levels in mouse reproductive organs. J Mol Histol 2024; 56:13. [PMID: 39611975 DOI: 10.1007/s10735-024-10310-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 10/01/2024] [Indexed: 11/30/2024]
Abstract
Obesity is one of the major risk factor for infertility since it causes decreased quality and quantity of gametes and a disrupted uterine environment which might result in miscarriage, stillbirth, and fetal abnormal growth. Obesity induces oxidative stress which is strongly associated with infertility. The clearing of oxidative stress by autophagy is maintained through the p62/ Keap1/Nrf2 pathway. In this pathway, oxidative stress induces p62 for binding to Keap1, thereby Keap1 cannot bind to the Nrf2 transcription factor. Then, Nrf2 translocates into the nucleus and initiates antioxidant-related gene expression. While p62, bound to Keap1, acts as an adaptor protein between autophagosome and damaged substrates which needs to be degraded for homeostasis. Up to date, obesity is strongly linked to abnormal autophagy activity. However, p62 protein expression has not been investigated in the obese ovary, testis, and uterus in detail. Thus, in the present study, we aimed to evaluate the effects of a high-fat diet (HFD)-induced obesity on p62 protein levels of the ovary, testis, and uterus in mice. Our results demonstrated that the p62 expression level was significantly altered by HFD in uterine glands, epithelium, myometrium, and stroma, and in the ovarian corpus luteum, testicular spermatogonium and spermatocytes.
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Affiliation(s)
- Nazlican Bozdemir
- Department of Histology and Embryology, Ankara Medipol University School of Medicine, Altindag, Ankara, 06050, Turkey
| | - Tuba Kablan
- Department of Histology and Embryology, Ankara Medipol University School of Medicine, Altindag, Ankara, 06050, Turkey
| | - Gozde Sukur
- Department of Histology and Embryology, Ankara University School of Medicine, Ankara, Turkey
| | - Ozgur Cinar
- Department of Histology and Embryology, Ankara University School of Medicine, Ankara, Turkey
| | - Fatma Uysal
- Department of Histology and Embryology, Ankara Medipol University School of Medicine, Altindag, Ankara, 06050, Turkey.
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22
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Wang H, Wang M, Wang T, Li X, Wen C, He Z, Huang L. High Humidity Alters Myeloid-Derived Suppressor Cells in Spleen Tissue: Insights into Rheumatoid Arthritis Progression. J Inflamm Res 2024; 17:9805-9822. [PMID: 39606638 PMCID: PMC11602200 DOI: 10.2147/jir.s490860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024] Open
Abstract
Background Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and bone destruction, leading to severe complications. Previous research has suggested that high humidity conditions may exacerbate RA, however, the underlying mechanisms remain unclear. Furthermore, there is a lack of evidence linking humidity to the worsening of RA symptoms in animal models. Methods The Collagen-induced arthritis (CIA) mouse model was established using C57BL/6 mice. The arthritis status of the mice was evaluated under two distinct humidity conditions (50% and 80%). The aim of the present study was to investigate the impact of elevated humidity levels on the types of splenic cells present using mass spectrometry flow. Additionally, the study utilized MDSCs, which are significantly upregulated by high humidity, to assess the levels of oxidative stress and conducted mRNA sequencing of sorted MDSCs to investigate their impact on arthritis in CIA mice. Results Compared to normal humidity, high humidity exacerbated arthritis incidence in mice, resulting in increased arthritis scores, swelling, serum autoantibodies (anti-COII and anti-CCP), and upregulation of pro-inflammatory cytokines. Significant variations were observed in the spleen index under high humidity condition, accompanied by noticeable inflammatory alterations. Moreover, elevated humidity levels induced a substantial modulation in MDSCs population in the spleen of CIA mice, along with alterations in oxidative stress markers such as heightened serum ROS levels, and increased expression of COX, SOD, and Nrf2 mRNA. Following successful sorting of MDSCs, mRNA sequencing revealed a decrease in the expression of Rap1 signaling pathway under high humidity environment, which may contribute to the increase of MDSCs cells and aggravate the progression of RA disease. Conclusion A comprehensive analysis of the available data reveals a detrimental impact of high humidity on MDSCs numbers within spleen tissue, with potential implications for the development of RA.
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Affiliation(s)
- Hongli Wang
- Research Institute of Chinese Medical Clinical Foundation and Immunology, School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Mingzhu Wang
- Research Institute of Chinese Medical Clinical Foundation and Immunology, School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Tengyue Wang
- Research Institute of Chinese Medical Clinical Foundation and Immunology, School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Xuanlin Li
- Research Institute of Chinese Medical Clinical Foundation and Immunology, School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Chengping Wen
- Research Institute of Chinese Medical Clinical Foundation and Immunology, School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Zhixing He
- Research Institute of Chinese Medical Clinical Foundation and Immunology, School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
| | - Lin Huang
- Research Institute of Chinese Medical Clinical Foundation and Immunology, School of Basic Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
- Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, 310053, People’s Republic of China
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23
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Zheng Y, Sun J, Luo Z, Li Y, Huang Y. Emerging mechanisms of lipid peroxidation in regulated cell death and its physiological implications. Cell Death Dis 2024; 15:859. [PMID: 39587094 PMCID: PMC11589755 DOI: 10.1038/s41419-024-07244-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: 08/09/2024] [Revised: 11/08/2024] [Accepted: 11/12/2024] [Indexed: 11/27/2024]
Abstract
Regulated cell death (RCD) refers to the form of cell death that can be regulated by various biomacromolecules. Each cell death modalities have their distinct morphological changes and molecular mechanisms. However, intense evidences suggest that lipid peroxidation can be the common feature that initiates and propagates the cell death. Excessive lipid peroxidation alters the property of membrane and further damage the proteins and nucleic acids, which is implicated in various human pathologies. Here, we firstly review the classical chain process of lipid peroxidation, and further clarify the current understanding of the myriad roles and molecular mechanisms of lipid peroxidation in various RCD types. We also discuss how lipid peroxidation involves in diseases and how such intimate association between lipid peroxidation-driven cell death and diseases can be leveraged to develop rational therapeutic strategies.
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Affiliation(s)
- Yongxin Zheng
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou Institute of Respiratory Health Guangzhou, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou, China
| | - Junlu Sun
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou Institute of Respiratory Health Guangzhou, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou, China
- Guangzhou National Laboratory, Guangzhou, China
| | - Zhiting Luo
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou Institute of Respiratory Health Guangzhou, Guangzhou, China
- State Key Laboratory of Respiratory Diseases, Guangzhou, China
- Guangzhou National Laboratory, Guangzhou, China
| | - Yimin Li
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- Guangzhou Institute of Respiratory Health Guangzhou, Guangzhou, China.
- State Key Laboratory of Respiratory Diseases, Guangzhou, China.
- Guangzhou National Laboratory, Guangzhou, China.
| | - Yongbo Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- Guangzhou Institute of Respiratory Health Guangzhou, Guangzhou, China.
- State Key Laboratory of Respiratory Diseases, Guangzhou, China.
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Wang T, Liu M, Li X, Zhang S, Gu H, Wei X, Wang X, Xu Z, Shen T. Naturally-derived modulators of the Nrf2 pathway and their roles in the intervention of diseases. Free Radic Biol Med 2024; 225:560-580. [PMID: 39368519 DOI: 10.1016/j.freeradbiomed.2024.09.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 09/19/2024] [Accepted: 09/23/2024] [Indexed: 10/07/2024]
Abstract
Cumulative evidence has verified that persistent oxidative stress is involved in the development of various chronic diseases, including pulmonary, neurodegenerative, kidney, cardiovascular, and liver diseases, as well as cancers. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in regulating cellular oxidative stress and inflammatory reactions, making it a focal point for disease prevention and treatment strategies. Natural products are essential resources for discovering leading molecules for new drug research and development. In this review, we comprehensively outlined the progression of the knowledge on the Nrf2 pathway, Nrf2 activators in clinical trials, the naturally-derived Nrf2 modulators (particularly from 2014-present), as well as their effects on the pathogenesis of chronic diseases.
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Affiliation(s)
- Tian Wang
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Mingjie Liu
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xinyu Li
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Sen Zhang
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Haoran Gu
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xuan Wei
- Shandong Center for Food and Drug Evaluation and Inspection, Jinan, Shandong, PR China
| | - Xiaoning Wang
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Zhenpeng Xu
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
| | - Tao Shen
- Key Lab of Chemical Biology (MOE), Shandong Engineering Research Center for Traditional Chinese Medicine Standard, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
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Bhat AA, Moglad E, Goyal A, Afzal M, Thapa R, Almalki WH, Kazmi I, Alzarea SI, Ali H, Gaur A, Singh TG, Singh SK, Dua K, Gupta G. Nrf2 pathways in neuroprotection: Alleviating mitochondrial dysfunction and cognitive impairment in aging. Life Sci 2024; 357:123056. [PMID: 39277133 DOI: 10.1016/j.lfs.2024.123056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/27/2024] [Accepted: 09/11/2024] [Indexed: 09/17/2024]
Abstract
Mitochondrial dysfunction and cognitive impairment are widespread phenomena among the elderly, being crucial factors that contribute to neurodegenerative diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of cellular defense systems, including that against oxidative stress. As such, increased Nrf2 activity may serve as a strategy to avert mitochondrial dysfunction and cognitive decline. Scientific data on Nrf2-mediated neuroprotection was collected from PubMed, Google Scholar, and Science Direct, specifically addressing mitochondrial dysfunction and cognitive impairment in older people. Search terms included "Nrf2", "mitochondrial dysfunction," "cognitive impairment," and "neuroprotection." Studies focusing on in vitro and in vivo models and clinical investigations were included to review Nrf2's therapeutic potential comprehensively. The relative studies have demonstrated that increased Nrf2 activity could improve mitochondrial performance, decrease oxidative pressure, and mitigate cognitive impairment. To a large extent, this is achieved through the modulation of critical cellular signalling pathways such as the Keap1/Nrf2 pathway, mitochondrial biogenesis, and neuroinflammatory responses. The present review summarizes the recent progress in comprehending the molecular mechanisms regarding the neuroprotective benefits mediated by Nrf2 through its substantial role against mitochondrial dysfunction and cognitive impairment. This review also emphasizes Nrf2-target pathways and their contribution to cognitive function improvement and rescue from mitochondria-related abnormalities as treatment strategies for neurodegenerative diseases that often affect elderly individuals.
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Affiliation(s)
- Asif Ahmad Bhat
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, U.P., India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Riya Thapa
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, 21589 Jeddah, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, 72341 Sakaka, Al-Jouf, Saudi Arabia
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan
| | - Ashish Gaur
- Graphic Era (Deemed to be University), Clement Town, Dehradun 248002, India; Graphic Era Hill University, Clement Town, Dehradun 248002, India
| | | | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India; Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.
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Al Saihati HA, Badr OA, Dessouky AA, Mostafa O, Samir Farid A, Aborayah NH, Abdullah Aljasir M, Baioumy B, Mahmoud Taha N, El-Sherbiny M, Hamed Al-Serwi R, Ramadan MM, Salim RF, Shaheen D, E M Ali F, Ebrahim N. Exploring the cytoprotective role of mesenchymal stem Cell-Derived exosomes in chronic liver Fibrosis: Insights into the Nrf2/Keap1/p62 signaling pathway. Int Immunopharmacol 2024; 141:112934. [PMID: 39178516 DOI: 10.1016/j.intimp.2024.112934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 08/03/2024] [Accepted: 08/12/2024] [Indexed: 08/26/2024]
Abstract
Hepatic fibrosis is a common pathology present in most chronic liver diseases. Autophagy is a lysosome-mediated intracellular catabolic and recycling process that plays an essential role in maintaining normal hepatic functions. Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor responsible for the regulation of cellular anti-oxidative stress response. This study was designed to assess the cytoprotective effect of mesenchymal stem cell-derived exosomes (MSC-exos) on endothelial-mesenchymal transition (EMT) in Carbon Tetrachloride (CCL4) induced liver fibrosis. Rats were treated with 0.1 ml of CCL4 twice weekly for 8 weeks, followed by administration of a single dose of MSC-exos. Rats were then sacrificed after 4 weeks, and liver samples were collected for gene expression analyses, Western blot, histological studies, immunohistochemistry, and transmission electron microscopy. Our results showed that MSC-exos administration decreased collagen deposition, apoptosis, and inflammation. Exosomes modulate the Nrf2/Keap1/p62 pathway, restoring autophagy and Nrf2 levels through modulation of the non-canonical pathway of Nrf2/Keap1/p62. Additionally, MSC-exos regulated miR-153-3p, miR-27a, miR-144 and miRNA-34a expression. In conclusion, the present study shed light on MSC-exos as a cytoprotective agent against EMT and tumorigenesis in chronic liver inflammation.
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Affiliation(s)
- Hajir A Al Saihati
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hafr Albatin, Saudi Arabia.
| | - Omnia A Badr
- Department of Genetics and Genetic Engineering, Faculty of Agriculture, Benha University, Egypt.
| | - Arigue A Dessouky
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Zagazig University, 44519 Zagazig, Egypt.
| | - Ola Mostafa
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Egypt.
| | - Ayman Samir Farid
- Department of Clinical Pathology, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh 13736, Qalyubia, Egypt.
| | - Nashwa H Aborayah
- Department of Clinical Pharmacology, Faculty of Medicine, Benha University, Egypt, Department of Pharmacology, Mutah University, Mutah 61710, Jordan.
| | - Mohammad Abdullah Aljasir
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia.
| | - Bodour Baioumy
- Department of Anatomy and Embryology, Faculty of Medicine, Benha University, Egypt.
| | | | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia; Department of Anatomy, Faculty of Medicine, Mansoura University, Egypt.
| | - Rasha Hamed Al-Serwi
- Department of Basic Dental Sciences, College of Dentistry, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
| | - Mahmoud M Ramadan
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah City, United Arab Emirates; Department of Cardiology, Faculty of Medicine, Mansoura University, Mansoura City, Egypt.
| | - Rabab F Salim
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha Universit, Egypt.
| | - Dalia Shaheen
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
| | - Nesrine Ebrahim
- Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Stem Cell Unit, Egypt.
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Ma K, Miao L, Li B, Yu W, Liu F, Liu K, Li Y, Huang C, Yang Z. Mechanism of action of Nrf2 and its related natural regulators in rheumatoid arthritis. J Orthop Surg Res 2024; 19:759. [PMID: 39543632 PMCID: PMC11566362 DOI: 10.1186/s13018-024-05221-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 10/29/2024] [Indexed: 11/17/2024] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis that can lead to joint deformities. To date, more than 18 million individuals worldwide have been diagnosed with RA, making it one of the most prevalent autoimmune diseases globally and posing a significant threat to public health and safety. Due to the complex pathogenesis of the disease, which involves autoimmunity, genetics, inflammation and oxidative stress in the body's tissues, the current drug therapy generally targets a single molecule, and effective and efficient drugs involving multiple levels and targets are lacking; thus, there is an urgent need for high-quality research and treatment in this field. Nuclear transcription factor erythroid 2-associated factor 2 (Nrf2) plays a crucial role in cellular resistance to oxidative stress and electrophilic attacks and is a potential pharmacological target for chronic disease treatment. While currently no drugs that target Nrf2 have been approved specifically for RA treatment, such an approach holds great significance. In recent years, the use of natural products to treat RA and other chronic conditions has become increasingly widespread because of their superior efficacy and minimal side effects. Therefore, this article provides a review of the mechanism of Nrf2 in RA and summarizes natural products that target Nrf2 and its associated pathways in the treatment of RA, aiming to offer new insights and strategies for the prevention and management of RA.
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Affiliation(s)
- Ke Ma
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Lili Miao
- Department of Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Bo Li
- Department of Orthopaedics, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Wenfei Yu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Fengzhao Liu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Kun Liu
- Department of Orthopaedics, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Yang Li
- Department of Orthopaedics, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China
| | - Chengcheng Huang
- Department of Endocrinology, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, 250014, Shandong, China
| | - Zhenguo Yang
- Department of Orthopaedics, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, Shandong, China.
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Eldakhakhny B, Bima A, Alamoudi AA, Alnami A, Abo-Elkhair SM, Sakr H, Almoghrabi Y, Ghoneim FM, Nagib RM, Elsamanoudy A. The role of low-carbohydrate, high-fat diet in modulating autophagy and endoplasmic reticulum stress in aortic endothelial dysfunction of metabolic syndrome animal model. Front Nutr 2024; 11:1467719. [PMID: 39610878 PMCID: PMC11603365 DOI: 10.3389/fnut.2024.1467719] [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: 07/20/2024] [Accepted: 10/30/2024] [Indexed: 11/30/2024] Open
Abstract
Background Endothelial dysfunction (ED) is induced by insulin resistance, mediated by endoplasmic reticulum (ER) stress and disturbed autophagy. This study investigates the protective role of a low-carbohydrate, high-fat (LCHF) diet on ED, ER stress, and autophagy dysregulation in an experimental animal model of metabolic syndrome. Methods Forty male Sprague-Dawley rats were divided into four groups: a Control group (standard diet) and three Dexamethasone (DEX) treated groups. Group II continued the standard diet, Group III received an LCHF diet, and Group IV received a high-carbohydrate, low-fat (HCLF) diet. At the end of the experiment, aortic tissue samples were obtained and used for histological, immunohistochemical (Endothelin and PCNA, biochemical MDA, TCA, NO, 8-OH-dG, and Nrf2/ARE protein) and molecular (Endothelin, eNOS, Nrf-2 α, p62, LC3, BECN-1, PINK1, CHOP, BNIP3, PCNA) analysis. Results Oxidative stress, autophagy markers, and ED markers are increased in the metabolic syndrome group. LCHF diet mitigates the adverse effects of DEX on endothelial dysfunction and oxidative stress, as evidenced by reduced BMI, HOMA-IR, and improved histological and molecular parameters. Conclusion Oxidative stress, autophagy dysregulation, and ER stress play crucial roles in the pathogenesis of insulin resistance-induced endothelial dysfunction. An LCHF diet offers protective benefits against insulin resistance and related comorbidities, including endothelial dysfunction.
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Affiliation(s)
- Basmah Eldakhakhny
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Food, Nutrition, and Lifestyle Research Unit, King Fahd for Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abdulhadi Bima
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Aliaa A. Alamoudi
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abrar Alnami
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Salwa Mohamed Abo-Elkhair
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hussein Sakr
- Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Yousef Almoghrabi
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Fatma Mohamed Ghoneim
- MBBS Program, Department of Physiological Sciences, Fakeeh College for Medical Sciences, Jeddah, Saudi Arabia
- Department of Medical Histology and Cell Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Reham Mohamed Nagib
- Department of Anatomical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ayman Elsamanoudy
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Food, Nutrition, and Lifestyle Research Unit, King Fahd for Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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Zhang X, Li H, Chen L, Wu Y, Li Y. NRF2 in age-related musculoskeletal diseases: Role and treatment prospects. Genes Dis 2024; 11:101180. [PMID: 39281838 PMCID: PMC11400624 DOI: 10.1016/j.gendis.2023.101180] [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: 05/10/2023] [Revised: 10/06/2023] [Accepted: 10/31/2023] [Indexed: 09/18/2024] Open
Abstract
The NRF2 pathway is a metabolic- and redox-sensitive signaling axis in which the transcription factor controls the expression of a multitude of genes that enable cells to survive environmental stressors, such as oxidative stress, mainly by inducing the expression of cytoprotective genes. Basal NRF2 levels are maintained under normal physiological conditions, but when exposed to oxidative stress, cells activate the NRF2 pathway, which is crucial for supporting cell survival. Recently, the NRF2 pathway has been found to have novel functions in metabolic regulation and interplay with other signaling pathways, offering novel insights into the treatment of various diseases. Numerous studies have shown that targeting its pathway can effectively investigate the development and progression of age-related musculoskeletal diseases, such as sarcopenia, osteoporosis, osteoarthritis, and intervertebral disc degeneration. Appropriate regulation of the NRF2 pathway flux holds promise as a means to improve musculoskeletal function, thereby providing a new avenue for drug treatment of age-related musculoskeletal diseases in clinical settings. The review summarized an overview of the relationship between NRF2 and cellular processes such as oxidative stress, apoptosis, inflammation, mitochondrial dysfunction, ferroptosis, and autophagy, and explores the potential of targeted NRF2 regulation in the treatment of age-related musculoskeletal diseases.
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Affiliation(s)
- Xiangyu Zhang
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Hengzhen Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lin Chen
- Department of Health and Physical Education, Jianghan University, Wuhan, Hubei 430056, China
| | - Yuxiang Wu
- Department of Health and Physical Education, Jianghan University, Wuhan, Hubei 430056, China
| | - Yusheng Li
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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30
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Vacario BGL, da Silva IM, Machado MG, Orrutéa JFG, Campos AGH, Matos RO, Federige ACL, Koizumi BY, Leite MB, Komori IMS, Dos Santos Jaques H, Rech D, Guembarovski RL, Amarante MK, Serpeloni JM, Panis C. Pesticide exposure and oxidative stress generation are linked to poor prognosis outcomes in breast cancer women carrying the allelic variant rs7438135 in the UGT2B7 gene. J Biochem Mol Toxicol 2024; 38:e70013. [PMID: 39392214 DOI: 10.1002/jbt.70013] [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: 06/20/2024] [Revised: 08/27/2024] [Accepted: 10/02/2024] [Indexed: 10/12/2024]
Abstract
Pesticide exposure is a risk factor for the development of several diseases, including breast cancer (BC). The enzyme UGT2B7 participate in detoxification of pesticides and the presence rs7438135 (G > A) variant in your gene increases its glucuronidation potential, contributing to oxidative stress metabolites neutralization. Here we investigated the impact of occupational pesticide exposure on the systemic oxidative stress generation from 228 women with BC depending on their UGT2B7 rs7438135 (G > A) status. q-PCR investigated the presence of the rs7438135 variant, and oxidative stress markers (lipid peroxidation levels, total antioxidant capacity-TRAP, and nitric oxide metabolites-NOx) were measured in plasma. Pesticide exposure induced significant augment in the systemic lipid peroxidation in the presence of the variant for several clinicopathological conditions, including tumors with high proliferation index (ki67) and with high aggressiveness. NOx was augmented in high ki67, positive progesterone receptors, high-grade and triple-negative/Luminal B tumors, and low-risk stratified patients. TRAP was depleted in young patients at menopause and those with triple-negative/Luminal B tumors, as well as those stratified as at low risk for death and recurrence. These findings showed that the presence of the variant was not able to protect from pesticide-induced oxidative stress generation in BC patients.
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Affiliation(s)
- Beatriz Geovana Leite Vacario
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
- Laboratory of Tumor Biology, State University of West Paraná (UNIOESTE), Francisco Beltrão, Paraná, Brazil
| | - Isabely Mayara da Silva
- Laboratory of Mutagenesis and Oncogenetics, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Murilo Galvani Machado
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | | | | | - Rafaela Oliveira Matos
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Ana Carolina Lopes Federige
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Bruna Yukie Koizumi
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Maikely Bruna Leite
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Isabela Mitsu Suo Komori
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Hellen Dos Santos Jaques
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Daniel Rech
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Roberta Losi Guembarovski
- Laboratory of Mutagenesis and Oncogenetics, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Marla Karine Amarante
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Juliana Mara Serpeloni
- Laboratory of Mutagenesis and Oncogenetics, State University of Londrina (UEL), Londrina, Paraná, Brazil
| | - Carolina Panis
- Laboratory and Clinical Physiopathology Program, State University of Londrina (UEL), Londrina, Paraná, Brazil
- Laboratory of Tumor Biology, State University of West Paraná (UNIOESTE), Francisco Beltrão, Paraná, Brazil
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Li Z, Xing J. Nuclear factor erythroid 2-related factor-mediated signaling alleviates ferroptosis during cerebral ischemia-reperfusion injury. Biomed Pharmacother 2024; 180:117513. [PMID: 39341075 DOI: 10.1016/j.biopha.2024.117513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/22/2024] [Accepted: 09/25/2024] [Indexed: 09/30/2024] Open
Abstract
Cardiac arrest (CA) is a significant challenge for emergency physicians worldwide and leads to increased morbidity and mortality rates. The poor prognosis of CA primarily stems from the complexity and irreversibility of cerebral ischemia-reperfusion injury (CIRI). Ferroptosis, a form of programmed cell death characterized by iron overload and lipid peroxidation, plays a crucial role in the progression and treatment of CIRI. In this review, we highlight the mechanisms of ferroptosis within the context of CIRI, focusing on its role as a key contributor to neuronal damage and dysfunction post-CA. We explore the crucial involvement of the nuclear factor erythroid 2-related factor (Nrf2)-mediated signaling pathway in modulating ferroptosis-associated processes during CIRI. Through comprehensive analysis of the regulatory role of Nrf2 in the cellular responses to oxidative stress, we highlight its potential as a therapeutic target for mitigating ferroptotic cell death and improving the neurological prognosis of patients experiencing CA. Furthermore, we discuss interventions targeting the Kelch-like ECH-associated protein 1/Nrf2/antioxidant response element pathway, including the use of traditional Chinese medicine and Western medicine, which demonstrate potential for attenuating ferroptosis and preserving neuronal function in CIRI. Owing to the limitations in the safety, specificity, and effectiveness of Nrf2-targeted drugs, as well as the technical difficulties and ethical constraints in obtaining the results related to the brain pathological examination of patients, most of the studies focusing on Nrf2-related regulation of ferroptosis in CIRI are still in the basic research stage. Overall, this review aims to provide a comprehensive understanding of the mechanisms underlying ferroptosis in CIRI, offering insights into novel therapeutics aimed at enhancing the clinical outcomes of patients with CA.
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Affiliation(s)
- Zheng Li
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
| | - Jihong Xing
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
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Li CH, Yang TM, Fitriana I, Fang TC, Wu LH, Hsiao G, Cheng YW. Maintaining KEAP1 levels in retinal pigment epithelial cells preserves their viability during prolonged exposure to artificial blue light. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2024; 260:113037. [PMID: 39332313 DOI: 10.1016/j.jphotobiol.2024.113037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/07/2024] [Accepted: 09/22/2024] [Indexed: 09/29/2024]
Abstract
Exposure to artificial blue light, one of the most energetic forms of visible light, can increase oxidative stress in retinal cells, potentially enhancing the risk of macular degeneration. Retinal pigment epithelial (RPE) cells play a crucial role in this process; the loss of RPE cells is the primary pathway through which retinal degeneration occurs. In RPE cells, Kelch-like ECH-associated protein 1 (KEAP1) is located in both the nucleus and cytosol, where it binds to nuclear factor erythroid 2-related factor 2 (NRF2) and p62 (sequestosome-1), respectively. Blue light exposure activates the NRF2-heme oxygenase 1 (HMOX1) axis through both canonical and noncanonical p62 pathways thereby reducing oxidative damage, and initiates autophagy, which helps remove damaged proteins. These protective responses may support the survival of RPE cells. However, extended exposure to blue light drastically decreases the viability of RPE cells. This exposure diminishes the ability of KEAP1 to bind to p62 and reduces the level of KEAP1. Inhibition of autophagy does not prevent KEAP1 degradation, the NRF2-HMOX1 axis, or blue-light-induced cytotoxicity. However, proteasome inhibitor along with a transient increase in the amount of KEAP1 in RPE cells, partially restores the p62-KEAP1 complex and reduces blue-light-induced cytotoxicity. In vivo studies confirmed the downregulation of KEAP1 in damaged RPE cells. Mice subjected to periodic blue light exposure exhibited significant atrophy in the outer retina, particularly in the peripheral areas. Additionally, there was a significant decrease in c-wave electroretinography and pupillary light reflex, indicating functional impairments in both visual and nonvisual physiological processes. These data underscore the essential role of KEAP1 in managing oxidative defense and autophagy pathways triggered by blue light exposure in RPE cells.
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Affiliation(s)
- Ching-Hao Li
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Tsung-Min Yang
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Ida Fitriana
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Department of Pharmacology, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Te-Chao Fang
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Taipei Medical University-Research Center of Urology and Kidney (RCUK), School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
| | - Liang-Huan Wu
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - George Hsiao
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
| | - Yu-Wen Cheng
- School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
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Baral K, Joshi S, Lopez A, Mugon G, Chanda A, Chandrasheker AA, Hinton C, Thapa K, Mercer A, Spade L, Liu G, Bhetwal BP, Fang J, Khambu B. Transcriptional changes impact hepatic proteome in autophagy-impaired liver. FEBS Open Bio 2024; 14:1851-1863. [PMID: 39284785 PMCID: PMC11532973 DOI: 10.1002/2211-5463.13898] [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: 08/09/2024] [Revised: 08/09/2024] [Accepted: 09/09/2024] [Indexed: 11/05/2024] Open
Abstract
Hepatic proteomes are intricately controlled through biosynthesis, extracellular secretion, and intrahepatic degradation. Autophagy governs lysosome-mediated intrahepatic degradation and the hepatic proteome. When autophagy is impaired, it leads to the accumulation of intrahepatic proteins, causing proteinopathy. This study investigates whether autophagy can modulate the hepatic proteome non-degradatively. Utilizing conditional, inducible, and hepatotoxin models of hepatic autophagy impairment, we assessed the overall hepatic proteome expression using Coomassie brilliant blue (CBB) staining and liquid chromatography-tandem mass spectrometry (LC/MS). We pinpointed and confirmed four specific hepatic proteins-Cps1, Ahcy, Ca3, and Gstm1-that were selectively modified in autophagy-deficient livers. Expression of Cps1, Ahcy, and Ca3 were significantly reduced, while Gstm1 expression increased in livers with autophagy impairment. Interestingly, these changes in hepatic protein levels were not due to defective autophagic degradation but were associated with alterations in mRNA transcript levels. Moreover, as a result of autophagic dysfunction, sustained activation of the nuclear erythroid-derived 2-like 2 (Nrf2) transcription factor, transcriptionally regulated the mRNA levels of these proteins. Our findings indicate that autophagy can influence hepatic proteins not solely via traditional degradative routes but also through non-degradative transcriptional processes by modulating Nrf2.
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Affiliation(s)
- Kamal Baral
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLAUSA
| | | | - Adriana Lopez
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLAUSA
| | - Gavisha Mugon
- Department of Biochemistry and Molecular BiologyTulane University School of MedicineNew OrleansLAUSA
| | - Aroma Chanda
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLAUSA
| | - Arya A. Chandrasheker
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLAUSA
| | - Cameron Hinton
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLAUSA
| | - Kapil Thapa
- Department of Cell and Molecular BiologySchool of Science and EngineeringNew OrleansLAUSA
| | - Arissa Mercer
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLAUSA
| | - Leah Spade
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLAUSA
| | - Gang Liu
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLAUSA
| | | | - Jia Fang
- Department of Biochemistry and Molecular BiologyTulane University School of MedicineNew OrleansLAUSA
| | - Bilon Khambu
- Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLAUSA
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Al-Salam S, Hashmi S, Jagadeesh GS, Sudhadevi M, Awwad A, Nemmar A. Early Cardiac Ischemia-Reperfusion Injury: Interactions of Autophagy with Galectin-3 and Oxidative Stress. Biomedicines 2024; 12:2474. [PMID: 39595040 PMCID: PMC11591886 DOI: 10.3390/biomedicines12112474] [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: 09/27/2024] [Revised: 10/20/2024] [Accepted: 10/25/2024] [Indexed: 11/28/2024] Open
Abstract
Background: Cardiovascular diseases are the leading cause of death worldwide, including the United Arab Emirates. Ischemia-reperfusion (IR) injury results in the death of cardiac myocytes that were viable immediately before myocardial reperfusion. We aim to investigate the role of galectin-3 (Gal-3) in autophagy during ischemia-reperfusion injuries. Methods: Male C57B6/J and Gal-3 knockout (KO) mice were used for the murine model of IR injury. Heart samples and serum were collected 24 h post-IR and were processed for immunohistochemical and immunofluorescent labeling and an enzyme-linked immunosorbent assay. Results: There was a significant increase in left ventricle (LV) concentrations of Gal-3 in Gal-3 wild-type mice compared to sham mice. There were significantly higher concentrations of LV autophagy proteins and phospho-AMPK in IR Gal-3 KO mice than in IR Gal-3 wild-type mice, compared to lower concentrations of LV phospho-mTOR and p62 in IR Gal-3 KO than in IR wild-type mice. Antioxidant activities were higher in the LVs of IR Gal-3 wild-type mice, while oxidative stress was higher in the LVs of IR Gal-3 KO mice. Conclusions: Our study supports the interaction of Gal-3 with autophagy proteins, oxidative stress, and antioxidant proteins and demonstrates that the absence of Gal-3 can enhance autophagy in the heart after IR injury.
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Affiliation(s)
- Suhail Al-Salam
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (G.S.J.); (M.S.)
| | - Satwat Hashmi
- Department of Biological and Biomedical Sciences, Agha Khan University, Karachi City 74000, Pakistan;
| | - Govindan S. Jagadeesh
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (G.S.J.); (M.S.)
| | - Manjusha Sudhadevi
- Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (G.S.J.); (M.S.)
| | - Aktham Awwad
- Department of Laboratory Medicine, Tawam Hospital, Al Ain P.O. Box 5674, United Arab Emirates;
| | - Abderrahim Nemmar
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
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Ma X, Li W, Ma J, Han Z, Deng S, Wang S. Autophagy is a promising process for linking inflammation and redox homeostasis in Down syndrome. Front Pharmacol 2024; 15:1491563. [PMID: 39415838 PMCID: PMC11479988 DOI: 10.3389/fphar.2024.1491563] [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: 09/05/2024] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
Trisomy 21, characterized by the presence of an additional chromosome 21, leads to a set of clinical features commonly referred to as Down syndrome (DS). The pathological phenotypes observed in DS are caused by a combination of factors, such as mitochondrial dysfunction, neuroinflammation, oxidative stress, disrupted metabolic patterns, and changes in protein homeostasis and signal transduction, and these factors collectively induce neurological alterations. In DS, the triplication of chromosome 21 and the micronuclei arising from the missegregation of chromosomes are closely associated with inflammation and the development of redox imbalance. Autophagy, an essential biological process that affects cellular homeostasis, is a powerful tool to facilitate the degradation of redundant or dysfunctional cytoplasmic components, thereby enabling the recycling of their constituents. Targeting the autophagy process has been suggested as a promising method to balance intracellular inflammation and oxidative stress and improve mitochondrial dysfunction. In this review, we summarize the role of autophagy in regulating inflammation and redox homeostasis in DS and discuss their crosslinks. A comprehensive elucidation of the roles of autophagy in DS offers novel insights for the development of therapeutic strategies aimed at aneuploidy-associated diseases.
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Affiliation(s)
- Xuehai Ma
- Xinjiang Key Laboratory of Mental Development and Learning Science, College of Psychology, Xinjiang Normal University, Urumqi, Xinjiang, China
| | - Weimin Li
- College of Physical Education and Health, East China Normal University, Shanghai, China
- Institute of Physical Education, Xinjiang Normal University, Urumqi, China
| | - Jun Ma
- Xinjiang Urumqi Youai Hospital, Urumqi, Xinjiang, China
| | - Zhongcheng Han
- People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Shoulong Deng
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
| | - Sutian Wang
- State Key Laboratory of Swine and Poultry Breeding Industry, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
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Shilovsky GA. p62: Intersection of Antioxidant Defense and Autophagy Pathways. Mol Biol 2024; 58:822-835. [DOI: 10.1134/s0026893324700390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/20/2024] [Accepted: 05/07/2024] [Indexed: 01/05/2025]
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Yun JH, Yang YH, Han CH, Kang SU, Kim CH. Non-thermal atmospheric pressure plasma induces selective cancer cell apoptosis by modulating redox homeostasis. Cell Commun Signal 2024; 22:452. [PMID: 39327567 PMCID: PMC11426099 DOI: 10.1186/s12964-024-01810-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 08/29/2024] [Indexed: 09/28/2024] Open
Abstract
BACKGROUND Anticancer treatments aim to selectively target cancer cells without harming normal cells. While non-thermal atmospheric pressure plasma (NTAPP) has shown anticancer potential across various studies, the mechanisms behind its selective action on cancer cells remain inadequately understood. This study explores the mechanism of NTAPP-induced selective cell death and assesses its application in cancer therapy. METHODS We treated HT1080 fibrosarcoma cells with NTAPP and assessed the intracellular levels of mitochondria-derived reactive oxygen species (ROS), mitochondrial function, and cell death mechanisms. We employed N-acetylcysteine to investigate ROS's role in NTAPP-induced cell death. Additionally, single-cell RNA sequencing was used to compare gene expression in NTAPP-treated HT1080 cells and human normal fibroblasts (NF). Western blotting and immunofluorescence staining examined the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2), a key antioxidant gene transcription factor. We also evaluated autophagy activity through fluorescence staining and transmission electron microscopy. RESULTS NTAPP treatment increased ROS levels and induced mitochondrial dysfunction, leading to apoptosis in HT1080 cells. The involvement of ROS in selective cancer cell death was confirmed by N-acetylcysteine treatment. Distinct gene expression patterns were observed between NTAPP-treated NF and HT1080 cells, with NF showing upregulated antioxidant gene expression. Notably, NRF2 expression and nuclear translocation increased in NF but not in HT1080 cells. Furthermore, autophagy activity was significantly higher in normal cells compared to cancer cells. CONCLUSIONS Our study demonstrates that NTAPP induces selective cell death in fibrosarcoma cells through the downregulation of the NRF2-induced ROS scavenger system and inhibition of autophagy. These findings suggest NTAPP's potential as a cancer therapy that minimizes damage to normal cells while effectively targeting cancer cells.
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Affiliation(s)
- Ju Hyun Yun
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Ewha Womans University, Seoul, Korea, 07985
| | - Yoon Hee Yang
- Department of Biomedical Sciences, Graduate School of Medicine, Ajou University, Suwon, Korea, 16499
| | - Chang Hak Han
- Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea, 16499
| | - Sung Un Kang
- Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea, 16499.
| | - Chul-Ho Kim
- Department of Otolaryngology, School of Medicine, Ajou University, Suwon, Korea, 16499.
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Kumari S, Singh P, Singh R. Repeated Silica exposures lead to Silicosis severity via PINK1/PARKIN mediated mitochondrial dysfunction in mice model. Cell Signal 2024; 121:111272. [PMID: 38944258 DOI: 10.1016/j.cellsig.2024.111272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 06/11/2024] [Accepted: 06/22/2024] [Indexed: 07/01/2024]
Abstract
BACKGROUND AND OBJECTIVES Silicosis, one of the occupational health illnesses is caused by inhalation of crystalline silica. Deposition of extracellular matrix and fibroblast proliferation in lungs are linked to silicosis development. Mitochondrial dysfunction plays critical role in some diseases, but how these processes progress and regulated in silicosis, remains limited. Detailed study of silica induced pulmonary fibrosis in mouse model, its progression and severity may be helpful in designing future therapeutic strategies. METHODS In present study, mice model of silicosis has been developed after repeated silica exposures which may closely resemble clinical symptoms of silicosis in human. In addition to efficiently mimicking the acute/chronic transformation processes of silicosis, this is practical and efficient in terms of time and output, which avoids mechanical injury to the upper respiratory tract due to surgical interventions. Sonicated sterile silica suspension (120 mg/kg) was administered through intranasal route thrice a week at regular intervals (21, 28 and 35 days). RESULTS Presence of minute to larger silicotic nodules in H&E-stained lung sections were observed in all silica induced model groups. Enhanced ECM deposition was noted in MT stained lung sections of silica exposure groups as compared to control which were confirmed by significantly higher MMP9 expression levels and hydroxyproline content in silica 35 days group. Increase in Reactive oxygen species (ROS), inflammatory cell recruitment mainly, neutrophils and macrophage were observed in all three silica exposure groups. Transmission electron microscopic analysis has confirmed presence of many aberrant shaped mitochondria (swollen, round shape) in 35 days model where autophagosomes were minimum. Western blot analysis of mitophagy and autophagy markers such as Pink1, Parkin, Cytochrome c, SQSTM1/p62, the ratio of light chain LC3B II/LC3B I was found higher in 21 and 28 days which were significantly reduced in 35 days silica model. CONCLUSIONS Higher MMP9 activity and MMP9 /TIMP1 ratio demonstrate excessive extracellular matrix damage and deposition in 35 days model. Significantly reduced expressions of autophagy and mitophagy markers have also confirmed progression in fibrosis severity and its association with repeated silica exposures in 35 days model group.
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Affiliation(s)
- Sneha Kumari
- Department of Zoology, MMV, Banaras Hindu University, Varanasi 221005, India
| | - Payal Singh
- Department of Zoology, MMV, Banaras Hindu University, Varanasi 221005, India
| | - Rashmi Singh
- Department of Zoology, MMV, Banaras Hindu University, Varanasi 221005, India.
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Vikram A, Patel SK, Singh A, Pathania D, Ray RS, Upadhyay AK, Dwivedi A. Natural autophagy activators: A promising strategy for combating photoaging. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155508. [PMID: 38901286 DOI: 10.1016/j.phymed.2024.155508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 02/22/2024] [Accepted: 02/28/2024] [Indexed: 06/22/2024]
Abstract
BACKGROUND Photodamage to the skin stands out as one of the most widespread epidermal challenges globally. Prolonged exposure to sunlight containing ultraviolet radiation (UVR) instigates stress, thereby compromising the skin's functionality and culminating in photoaging. Recent investigations have shed light on the importance of autophagy in shielding the skin from photodamage. Despite the acknowledgment of numerous phytochemicals possessing photoprotective attributes, their potential to induce autophagy remains relatively unexplored. PURPOSE Diminished autophagy activity in photoaged skin underscores the potential benefits of restoring autophagy through natural compounds to enhance photoprotection. Consequently, this study aims to highlight the role of natural compounds in safeguarding against photodamage and to assess their potential to induce autophagy via an in-silico approach. METHODS A thorough search of the literature was done using several databases, including PUBMED, Science Direct, and Google Scholar, to gather relevant studies. Several keywords such as Phytochemical, Photoprotection, mTOR, Ultraviolet Radiation, Reactive oxygen species, Photoaging, and Autophagy were utilized to ensure thorough exploration. To assess the autophagy potential of phytochemicals through virtual screening, computational methodologies such as molecular docking were employed, utilizing tools like AutoDock Vina. Receptor preparation for docking was facilitated using MGLTools. RESULTS The initiation of structural and functional deterioration in the skin due to ultraviolet radiation (UVR) or sunlight-induced reactive oxygen species/reactive nitrogen species (ROS/RNS) involves the modulation of various pathways. Natural compounds like phenolics, flavonoids, flavones, and anthocyanins, among others, possess chromophores capable of absorbing light, thereby offering photoprotection by modulating these pathways. In our molecular docking study, these phytochemicals have shown binding affinity with mTOR, a negative regulator of autophagy, indicating their potential as autophagy modulators. CONCLUSION This integrated review underscores the photoprotective characteristics of natural compounds, while the in-silico analysis reveals their potential to modulate autophagy, which could significantly contribute to their anti-photoaging properties. The findings of this study hold promise for the advancement of cosmeceuticals and therapeutics containing natural compounds aimed at addressing photoaging and various skin-related diseases. By leveraging their dual benefits of photoprotection and autophagy modulation, these natural compounds offer a multifaceted approach to combatting skin aging and related conditions.
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Affiliation(s)
- Apeksha Vikram
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow-226001 Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002 Uttar Pradesh, India
| | - Sunil Kumar Patel
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow-226001 Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002 Uttar Pradesh, India
| | - Arshwinder Singh
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala-147004 Punjab, India
| | - Diksha Pathania
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow-226001 Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002 Uttar Pradesh, India
| | - Ratan Singh Ray
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow-226001 Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002 Uttar Pradesh, India
| | - Atul Kumar Upadhyay
- Department of Biotechnology, Thapar Institute of Engineering & Technology, Patiala-147004 Punjab, India.
| | - Ashish Dwivedi
- Photobiology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR- Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhawan 31, Mahatma Gandhi Marg, Lucknow-226001 Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002 Uttar Pradesh, India.
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Yang Y, Zhang T, Li Q, Ling Y, Ma Y, Tao S. SQSTM1 improves acute lung injury via inhibiting airway epithelium ferroptosis in a vitamin D receptor/autophagy-mediated manner. Free Radic Biol Med 2024; 222:588-600. [PMID: 38996820 DOI: 10.1016/j.freeradbiomed.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 07/06/2024] [Accepted: 07/08/2024] [Indexed: 07/14/2024]
Abstract
Emerging evidence has reported that acute lung injury (ALI), characterized by inflammation and oxidative stress in airway epithelium, is regulated by programmed cell death. Ferroptosis, a regulated form of cell death spurred by uncontrolled lipid peroxidation, has been proven to implicate various diseases. Inhibiting ferroptosis represents a feasible strategy for ALI through the suppression of lipid peroxidation, while the mechanism remains to be further elucidated. Here, we identified Sequestosome 1 (SQSTM1) as a negative regulator of airway epithelium ferroptosis during ALI. SQSTM1 knockdown cells manifested higher sensitivity to ferroptosis. Mechanistically, SQSTM1 was found to directly interact with vitamin D receptor (VDR) through its nuclear receptor (NR) box motif, facilitating its nuclear translocation and initiating autophagy at the transcriptional level. To further validate these findings, an in vivo preventive model utilizing spermidine, a proven inducer of SQSTM1 was established. The results consistently demonstrated that spermidine supplementation significantly induced SQSTM1 and ameliorated ALI by mitigating airway epithelial ferroptosis. Notably, these effects were abrogated in the absence of SQSTM1. Taken together, this study identified SQSTM1 as a negative regulator of airway epithelium ferroptosis in a VDR-mediated autophagy manner, making it a potential therapeutic target for the treatment of ALI.
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Affiliation(s)
- Youjing Yang
- Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China; Chongqing Key Laboratory of Emergency Medicine, Chongqing, China.
| | - Tao Zhang
- Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China; Chongqing Key Laboratory of Emergency Medicine, Chongqing, China
| | - Qianmin Li
- Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China
| | - Yi Ling
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Yu Ma
- Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China; Chongqing Key Laboratory of Emergency Medicine, Chongqing, China
| | - Shasha Tao
- Chongqing Emergency Medical Center, Chongqing University Central Hospital, School of Medicine, Chongqing University, Chongqing, China; Chongqing Key Laboratory of Emergency Medicine, Chongqing, China.
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Koszła O, Sołek P. Misfolding and aggregation in neurodegenerative diseases: protein quality control machinery as potential therapeutic clearance pathways. Cell Commun Signal 2024; 22:421. [PMID: 39215343 PMCID: PMC11365204 DOI: 10.1186/s12964-024-01791-8] [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: 06/04/2024] [Accepted: 08/15/2024] [Indexed: 09/04/2024] Open
Abstract
The primary challenge in today's world of neuroscience is the search for new therapeutic possibilities for neurodegenerative disease. Central to these disorders lies among other factors, the aberrant folding, aggregation, and accumulation of proteins, resulting in the formation of toxic entities that contribute to neuronal degeneration. This review concentrates on the key proteins such as β-amyloid (Aβ), tau, and α-synuclein, elucidating the intricate molecular events underlying their misfolding and aggregation. We critically evaluate the molecular mechanisms governing the elimination of misfolded proteins, shedding light on potential therapeutic strategies. We specifically examine pathways such as the endoplasmic reticulum (ER) and unfolded protein response (UPR), chaperones, chaperone-mediated autophagy (CMA), and the intersecting signaling of Keap1-Nrf2-ARE, along with autophagy connected through p62. Above all, we emphasize the significance of these pathways as protein quality control mechanisms, encompassing interventions targeting protein aggregation, regulation of post-translational modifications, and enhancement of molecular chaperones and clearance. Additionally, we focus on current therapeutic possibilities and new, multi-target approaches. In conclusion, this review systematically consolidates insights into emerging therapeutic strategies predicated on protein aggregates clearance.
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Affiliation(s)
- Oliwia Koszła
- Department of Biopharmacy, Medical University of Lublin, 4A Chodzki St., Lublin, 20-093, Poland.
| | - Przemysław Sołek
- Department of Biopharmacy, Medical University of Lublin, 4A Chodzki St., Lublin, 20-093, Poland
- Department of Biochemistry and Toxicology, University of Life Sciences, 13 Akademicka St, Lublin, 20-950, Poland
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Tian Y, Tang L, Wang X, Ji Y, Tu Y. Nrf2 in human cancers: biological significance and therapeutic potential. Am J Cancer Res 2024; 14:3935-3961. [PMID: 39267682 PMCID: PMC11387866 DOI: 10.62347/lzvo6743] [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: 02/28/2024] [Accepted: 08/07/2024] [Indexed: 09/15/2024] Open
Abstract
The nuclear factor-erythroid 2-related factor 2 (Nrf2) is able to control the redox balance in the cells responding to oxidative damage and other stress signals. The Nrf2 upregulation can elevate the levels of antioxidant enzymes to support against damage and death. In spite of protective function of Nrf2 in the physiological conditions, the stimulation of Nrf2 in the cancer has been in favour of tumorigenesis. Since the dysregulation of molecular pathways and mutations/deletions are common in tumors, Nrf2 can be a promising therapeutic target. The Nrf2 overexpression can prevent cell death in tumor and by increasing the survival rate of cancer cells, ensures the carcinogenesis. Moreover, the induction of Nrf2 can promote the invasion and metastasis of tumor cells. The Nrf2 upregulation stimulates EMT to increase cancer metastasis. Furthermore, regarding the protective function of Nrf2, its stimulation triggers chemoresistance. The natural products can regulate Nrf2 in the cancer therapy and reverse drug resistance. Moreover, nanostructures can specifically target Nrf2 signaling in cancer therapy. The current review discusses the potential function of Nrf2 in the proliferation, metastasis and drug resistance. Then, the capacity of natural products and nanostructures for suppressing Nrf2-mediated cancer progression is discussed.
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Affiliation(s)
- Yu Tian
- Research Center, Huizhou Central People's Hospital, Guangdong Medical University Huizhou, Guangdong, China
- School of Public Health, Benedictine University Lisle, Illinois, USA
| | - Lixin Tang
- Department of Respiratory, Chongqing Public Health Medical Center Chongqing, China
| | - Xin Wang
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School Boston, Massachusetts, USA
| | - Yanqin Ji
- Department of Administration, Huizhou Central People's Hospital, Guangdong Medical University Huizhou, Guangdong, China
| | - Yanyang Tu
- Research Center, Huizhou Central People's Hospital, Guangdong Medical University Huizhou, Guangdong, China
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Wang D, Sun Y, Liu J, Sun J, Fan B, Lu C, Wang F. Research on the Anti-Fatigue Effects and Mechanisms of Arecoline in Sleep-Deprived Mice. Nutrients 2024; 16:2783. [PMID: 39203919 PMCID: PMC11357251 DOI: 10.3390/nu16162783] [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: 06/17/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/03/2024] Open
Abstract
The betel nut is one of the most widely consumed addictive substances in the world after nicotine, ethanol, and caffeine. Arecoline is an active ingredient from the areca nut. It has many pharmacological effects and can affect the central nervous system. In this study, we found that arecoline can relieve fatigue behavior. OBJECTIVE This research aims to estimate the anti-fatigue effects of arecoline and explore its underlying mechanisms using a murine model of central fatigue precipitated by sleep deprivation (SD). METHODS Seventy-two male C57BL/6 mice were randomly assigned to six groups: a control group, an SD-induced fatigue model group, a group that received Rhodiola Rosea capsules (2.5 mg/kg), and three arecoline groups, which were administered at low, medium, and high doses (10, 20, and 40 mg/kg, respectively). Following 28 days of continuous administrations, the effects of arecoline on mouse fatigue-related behaviors were assessed by behavioral tests, including grip strength, rotarod performance, and weight-bearing swimming endurance. The release levels of the related biochemical markers were measured by enzyme-linked immunosorbent assays (ELISAs). Western blotting was employed to quantify the expression levels of nuclear factor erythroid 2-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase 1 (HO-1), sequestosome-1 (p62), and NADPH quinone oxidoreductase 1 (NQO1) in the gastrocnemius muscle. RESULTS Arecoline administration notably enhanced grip strength, delayed the onset of fatigue as evidenced by extended latencies in rotarod tests, and increased the duration of weight-bearing swimming in mice. In the elevated plus maze, arecoline obviously decreased both the number of entries and the total distance traveled in the open arms. Arecoline markedly decreased the contents of creatine kinase, blood urea nitrogen, lactate dehydrogenase, triglycerides, and cholesterol in the serum, while it elevated the levels of total testosterone, lactate dehydrogenase, and immunoglobulin G. Furthermore, it significantly increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase in the gastrocnemius muscle, reduced malondialdehyde levels, augmented hippocampal SOD and CAT activity, and elevated glycogen stores in both liver and muscle tissues. Neurotransmitter levels showed significant increases, cytokine levels were markedly reduced, and the expressions of Nrf2, Keap1, NQO1, p62, and HO-1 in brain tissues were significantly upregulated. CONCLUSIONS This study demonstrates that arecoline has anti-fatigue activity, and the specific mechanisms are associated with elevating glucose and lipid metabolism levels, relieving oxidative stress damage, inhibiting neuroinflammatory response, and regulating neurotransmitter levels and the Keap1/Nrf2/HO-1 signaling pathway. The research provides a new direction for arecoline's potential in preventing and improving fatigue.
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Affiliation(s)
- Danyang Wang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China; (D.W.); (Y.S.); (J.L.); (J.S.); (B.F.)
- College of Food Science and Engineering, Shanxi Agricultural University, Jinzhong 030801, China
| | - Yuan Sun
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China; (D.W.); (Y.S.); (J.L.); (J.S.); (B.F.)
| | - Jiameng Liu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China; (D.W.); (Y.S.); (J.L.); (J.S.); (B.F.)
| | - Jing Sun
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China; (D.W.); (Y.S.); (J.L.); (J.S.); (B.F.)
| | - Bei Fan
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China; (D.W.); (Y.S.); (J.L.); (J.S.); (B.F.)
| | - Cong Lu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China; (D.W.); (Y.S.); (J.L.); (J.S.); (B.F.)
- College of Food Science and Engineering, Shanxi Agricultural University, Jinzhong 030801, China
- National Nanfan Research Institute (Sanya), Chinese Academy of Agricultural Sciences, Sanya 572024, China
| | - Fengzhong Wang
- Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100193, China; (D.W.); (Y.S.); (J.L.); (J.S.); (B.F.)
- College of Food Science and Engineering, Shanxi Agricultural University, Jinzhong 030801, China
- National Nanfan Research Institute (Sanya), Chinese Academy of Agricultural Sciences, Sanya 572024, China
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Zhang H, Liu R, Fang Z, Nie L, Ma Y, Sun F, Mei J, Song Z, Ginzburg YZ, Liu J, Chen H. Mitoxantrone ameliorates ineffective erythropoiesis in a β-thalassemia intermedia mouse model. Blood Adv 2024; 8:4017-4024. [PMID: 38861356 PMCID: PMC11339037 DOI: 10.1182/bloodadvances.2024012679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 05/15/2024] [Accepted: 06/03/2024] [Indexed: 06/13/2024] Open
Abstract
ABSTRACT β-thalassemia is a condition characterized by reduced or absent synthesis of β-globin resulting from genetic mutations, leading to expanded and ineffective erythropoiesis. Mitoxantrone has been widely used clinically as an antitumor agent considering its ability to inhibit cell proliferation. However, its therapeutic effect on expanded and ineffective erythropoiesis in β-thalassemia is untested. We found that mitoxantrone decreased α-globin precipitates and ameliorated anemia, splenomegaly, and ineffective erythropoiesis in the HbbTh3/+ mouse model of β-thalassemia intermedia. The partially reversed ineffective erythropoiesis is a consequence of effects on autophagy as mitochondrial retention and protein levels of mTOR, P62, and LC3 in reticulocytes decreased in mitoxantrone-treated HbbTh3/+ mice. These data provide significant preclinical evidence for targeting autophagy as a novel therapeutic approach for β-thalassemia.
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Affiliation(s)
- Haihang Zhang
- Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China
| | - Rui Liu
- Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China
| | - Zheng Fang
- College of Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Ling Nie
- Xiangya Hospital, Central South University, Changsha, China
| | - Yanlin Ma
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Department of Reproductive Medicine, Hainan Provincial Clinical Research Center for Thalassemia, Key Laboratory of Reproductive Health Diseases Research and Translation (Hainan Medical University), Ministry of Education, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China
| | - Fei Sun
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Department of Reproductive Medicine, Hainan Provincial Clinical Research Center for Thalassemia, Key Laboratory of Reproductive Health Diseases Research and Translation (Hainan Medical University), Ministry of Education, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China
| | - Jingjing Mei
- Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Department of Reproductive Medicine, Hainan Provincial Clinical Research Center for Thalassemia, Key Laboratory of Reproductive Health Diseases Research and Translation (Hainan Medical University), Ministry of Education, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China
| | - Zhiyin Song
- College of Life Sciences, Taikang Center for Life and Medical Sciences, Frontier Science Center for Immunology and Metabolism, Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yelena Z. Ginzburg
- Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jing Liu
- Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China
| | - Huiyong Chen
- Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China
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Nicolás-Morala J, Mascaraque-Checa M, Gallego-Rentero M, Barahona A, Abarca-Lachen E, Carrasco E, Gilaberte Y, González S, Juarranz Á. The m-TORC1 inhibitor Sirolimus increases the effectiveness of Photodynamic therapy in the treatment of cutaneous Squamous Cell Carcinoma, impairing NRF2 antioxidant signaling. Int J Biol Sci 2024; 20:4238-4257. [PMID: 39247827 PMCID: PMC11379070 DOI: 10.7150/ijbs.94883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 06/17/2024] [Indexed: 09/10/2024] Open
Abstract
Squamous Cell Carcinoma (SCC) is a subtype of Non-Melanoma Skin Cancer, the most common group of malignancies worldwide. Photodynamic therapy (PDT) is a non-invasive treatment approved for specific subtypes of SCC. Some malignancies resist PDT, forming more aggressive tumors and multiple relapses. Thus, new approaches aimed at optimizing the response to PDT are needed. The mTORC1 inhibitor rapamycin, also known as Sirolimus (SRL), interferes with protein synthesis and cell metabolism. The use of SRL as an immunosuppressant is associated to lower rates of SCC in kidney-transplanted patients, which are frequently affected by this pathology. We have evaluated SRL pre-treatment efficacy to enhance the damage induced by PDT with Methyl 5-aminolevulinate in two different cutaneous SCC established cell lines (SCC13 and A431) in vitro and therapy sensitization in PDT-resistant cell lines. We tested for the first time the SRL + PDT combination in a SKH-1 mouse model of photocarcinogenesis, diminishing the frequency of lesions and restraining tumor growth. Molecular studies revealed that protoporphyrin IX and reactive oxygen species production induced by PDT were promoted by SRL pre-treatment. Lastly, SRL modifies the expression and intracellular location of NRF2, interfering with the downstream antioxidant response modulated by NQO1 and HO-1. In conclusion, we propose SRL as a potential adjuvant to enhance PDT efficacy for SCC treatment.
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Affiliation(s)
- Jimena Nicolás-Morala
- Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain
- Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación Sanitaria, IRYCIS, 28034 Madrid, Spain
| | - Marta Mascaraque-Checa
- Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain
- Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación Sanitaria, IRYCIS, 28034 Madrid, Spain
| | - María Gallego-Rentero
- Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain
- Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación Sanitaria, IRYCIS, 28034 Madrid, Spain
| | - Andrea Barahona
- Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain
| | - Edgar Abarca-Lachen
- Faculty of Health Sciences, Universidad San Jorge, 50830 Villanueva de Gállego, Spain
| | - Elisa Carrasco
- Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain
- Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación Sanitaria, IRYCIS, 28034 Madrid, Spain
- Centro de Biología Molecular Severo Ochoa (CBM), Instituto Universitario de Biología Molecular-IUBM (Universidad Autónoma de Madrid), Madrid, Spain
| | - Yolanda Gilaberte
- Dermatology service, Hospital Miguel Servet, Zaragoza (50009), Spain
| | - Salvador González
- Department of Medicine and Medical Specialties, Universidad Alcalá de Henares, 28805 Madrid, Spain
| | - Ángeles Juarranz
- Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain
- Department of Experimental Dermatology and Skin Biology, Instituto Ramón y Cajal de Investigación Sanitaria, IRYCIS, 28034 Madrid, Spain
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Ye C, Yan C, Bian SJ, Li XR, Li Y, Wang KX, Zhu YH, Wang L, Wang YC, Wang YY, Li TS, Qi SH, Luo L. Momordica charantia L.-derived exosome-like nanovesicles stabilize p62 expression to ameliorate doxorubicin cardiotoxicity. J Nanobiotechnology 2024; 22:464. [PMID: 39095755 PMCID: PMC11297753 DOI: 10.1186/s12951-024-02705-z] [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: 02/27/2024] [Accepted: 07/05/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Doxorubicin (DOX) is a first-line chemotherapeutic drug for various malignancies that causes cardiotoxicity. Plant-derived exosome-like nanovesicles (P-ELNs) are growing as novel therapeutic agents. Here, we investigated the protective effects in DOX cardiotoxicity of ELNs from Momordica charantia L. (MC-ELNs), a medicinal plant with antioxidant activity. RESULTS We isolated MC-ELNs using ultracentrifugation and characterized them with canonical mammalian extracellular vesicles features. In vivo studies proved that MC-ELNs ameliorated DOX cardiotoxicity with enhanced cardiac function and myocardial structure. In vitro assays revealed that MC-ELNs promoted cell survival, diminished reactive oxygen species, and protected mitochondrial integrity in DOX-treated H9c2 cells. We found that DOX treatment decreased the protein level of p62 through ubiquitin-dependent degradation pathway in H9c2 and NRVM cells. However, MC-ELNs suppressed DOX-induced p62 ubiquitination degradation, and the recovered p62 bound with Keap1 promoting Nrf2 nuclear translocation and the expressions of downstream gene HO-1. Furthermore, both the knockdown of Nrf2 and the inhibition of p62-Keap1 interaction abrogated the cardioprotective effect of MC-ELNs. CONCLUSIONS Our findings demonstrated the therapeutic beneficials of MC-ELNs via increasing p62 protein stability, shedding light on preventive approaches for DOX cardiotoxicity.
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Affiliation(s)
- Cong Ye
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou city, Jiangsu Province, 221004, PR China
| | - Chen Yan
- Department of Rheumatology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang city, Jiangxi Province, PR China
| | - Si-Jia Bian
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou city, Jiangsu Province, 221004, PR China
| | - Xin-Ran Li
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou city, Jiangsu Province, 221004, PR China
| | - Yu Li
- Department of Anesthesiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang city, Jiangxi Province, PR China
| | - Kai-Xuan Wang
- Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou city, Jiangsu Province, PR China
| | - Yu-Hua Zhu
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou city, Jiangsu Province, 221004, PR China
| | - Liang Wang
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou city, Jiangsu Province, 221004, PR China
| | - Ying-Chao Wang
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou city, Jiangsu Province, 221004, PR China
| | - Yi-Yuan Wang
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou city, Jiangsu Province, 221004, PR China
| | - Tao-Sheng Li
- Department of Stem Cell Biology, Atomic Bomb Disease Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
| | - Su-Hua Qi
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou city, Jiangsu Province, 221004, PR China.
| | - Lan Luo
- School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou city, Jiangsu Province, 221004, PR China.
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Yin L, Yuan L, Li J, Jiang B. The liquid-liquid phase separation in programmed cell death. Cell Signal 2024; 120:111215. [PMID: 38740235 DOI: 10.1016/j.cellsig.2024.111215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/23/2024] [Accepted: 05/07/2024] [Indexed: 05/16/2024]
Abstract
In recent years, the physical phenomenon of liquid-liquid phase separation has been widely introduced into biological research. Membrane-free organelles have been found to exist in cells that were driven by liquid-liquid phase separation. Intermolecular multivalent interactions can drive liquid-liquid phase separation to form condensates that are independent of other substances in the environment and thus can play an effective role in regulating multiple biological processes in the cell. The way of cell death has also long been a focus in multiple research. In the face of various stresses, cell death-related mechanisms are crucial for maintaining cellular homeostasis and regulating cell fate. With the in-depth study of cell death pathways, it has been found that the process of cell death was also accompanied by the regulation of liquid-liquid phase separation and played a key role. Therefore, this review summarized the roles of liquid-liquid phase separation in various cell death pathways, and explored the regulation of cell fate by liquid-liquid phase separation, with the expectation that the exploration of the mechanism of liquid-liquid phase separation would provide new insights into the treatment of diseases caused by regulated cell death.
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Affiliation(s)
- Leijing Yin
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, PR China; Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Changsha, Hunan 410078, PR China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan 410078, PR China.
| | - Ludong Yuan
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, PR China; Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Changsha, Hunan 410078, PR China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan 410078, PR China
| | - Jing Li
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, PR China; Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Changsha, Hunan 410078, PR China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan 410078, PR China
| | - Bimei Jiang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, 410078, PR China; Sepsis Translational Medicine Key Lab of Hunan Province, Central South University, Changsha, Hunan 410078, PR China; National Medicine Functional Experimental Teaching Center, Central South University, Changsha, Hunan 410078, PR China.
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Zeng X, Lin GX, Zeng X, Zheng J, Ren C, Luo Z, Xiao K, Sun N, Zhang L, Rui G, Chen X. Penfluridol regulates p62 / Keap1 / Nrf2 signaling pathway to induce ferroptosis in osteosarcoma cells. Biomed Pharmacother 2024; 177:117094. [PMID: 38996707 DOI: 10.1016/j.biopha.2024.117094] [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: 02/06/2024] [Revised: 06/24/2024] [Accepted: 07/02/2024] [Indexed: 07/14/2024] Open
Abstract
The cure rate for patients with osteosarcoma (OS) has stagnated over the past few decades. Penfluridol, a first-generation antipsychotic, has demonstrated to prevent lung and esophageal malignancies from proliferation and metastasis. However, the effect of penfluridol on OS and its underlying molecular mechanism remains unclear. This study revealed that penfluridol effectively inhibited cell proliferation and migration, and induced G2/M phase arrest in OS cells. In addition, penfluridol treatment was found to increased reactive oxygen species (ROS) levels in OS cells. Combined with the RNA-Seq results, the anti-OS effect of penfluridol was hypothesized to be attributed to the induction of ferroptosis. Western blot results showed that penfluridol promoted intracellular Fe2+ concentration, membrane lipid peroxidation, and decreased intracellular GSH level to induce ferroptosis. Further studies showed that p62/Keap1/Nrf2 signaling pathway was implicated in penfluridol-induced ferroptosis in OS cells. Overexpression of p62 effectively reversed penfluridol-induced ferroptosis. In vivo, penfluridol effectively inhibited proliferation and prolonged survival in xenograft tumor model. Therefore, penfluridol is a promising drug targeting OS in the future.
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Affiliation(s)
- Xiangchen Zeng
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China
| | - Guang-Xun Lin
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China
| | - Xianhui Zeng
- Department of Infectious Diseases, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou 570206, China
| | - Jiyuan Zheng
- The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China
| | - Chong Ren
- School of Medicine, Xiamen University, Xiamen 361102, China
| | - Zhong Luo
- School of Medicine, Xiamen University, Xiamen 361102, China
| | - Keyi Xiao
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China
| | - Naikun Sun
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China
| | - Long Zhang
- Department of Pain, Zhejiang Provincial People's Hospital, Affiliated People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.
| | - Gang Rui
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China.
| | - Xiaohui Chen
- Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361001, China; School of Medicine, Xiamen University, Xiamen 361102, China.
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Luo QH, Chen HJ, Zhong QY, He HE, Huang YQ, Liu YC, Lan B, Wen YQ, Deng SL, Du XH, Lin BQ, Zhan YX. Prevention of supercritical carbon dioxide fluid extract from Chrysanthemum indicum Linnén on cutaneous squamous cell carcinomas progression following UV irradiation in mice. Exp Ther Med 2024; 28:330. [PMID: 38979021 PMCID: PMC11229401 DOI: 10.3892/etm.2024.12619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 04/26/2024] [Indexed: 07/10/2024] Open
Abstract
Chrysanthemum indicum Linnén (C. indicum), a medicinal and food herb with various bioactive components, may be of beneficial use in cosmetics and the treatment of skin-related diseases. However, to date, few studies have been reported on its potential preventive and therapeutic effects on skin cancer. Therefore, the present study aimed to investigate the effect and potential mechanism of action of supercritical carbon dioxide extract from C. indicum (CISCFE) on UV-induced skin cancer in a mouse model. Kunming mice were allocated randomly to five treatment groups: Sham, model, low concentration CISCFE, high concentration CISCFE and positive control nicotinamide groups. The dorsal skin of mice was irradiated with UV light for 31 weeks. Histopathological changes, ELISA assays, immunohistochemical analysis and western blotting were performed to investigate the potential therapeutic effects of CISCFE. The results showed that CISCFE alleviated skin oxidative and inflammatory damage in a UV-induced mouse model of skin cancer. Moreover, CISCFE suppressed abnormal activation of proto-oncogene c-Myc and the overexpression of Ki-67 and VEGF, and increased expression of the anti-oncogene PTEN, thereby reducing abnormal proliferation of the epidermis and blood vessels. Additionally, CISCFE increased the protein expression levels of NAD-dependent protein deacetylase sirtuin-1 (SIRT1), Kelch-like ECH associated protein 1 (Keap1) and inhibited the expression of nuclear factor 2 erythroid 2-related factor 2 (Nrf2), phosphorylated (p)-p62 (Ser 349), p-p65 and acetyl-p65 proteins in a UV-induced skin cancer mouse model. In summary, CISCFE exhibited potent anti-skin cancer activity, which may be attributed its potential effects on the p62/Keap1-Nrf2 and SIRT1/NF-κB pathways.
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Affiliation(s)
- Qi-Hong Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Hong-Juan Chen
- Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Qing-Yuan Zhong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Hao-En He
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Ying-Qi Huang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - You-Chen Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Bin Lan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Yao-Qi Wen
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Si-Liang Deng
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Xian-Hua Du
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
| | - Bao-Qin Lin
- Experimental Center, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China
| | - Ya-Xian Zhan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China
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Xi H, Wang Z, Li M, Duan X, Li Y. Paeoniflorin Promotes Ovarian Development in Mice by Activating Mitophagy and Preventing Oxidative Stress. Int J Mol Sci 2024; 25:8355. [PMID: 39125927 PMCID: PMC11313479 DOI: 10.3390/ijms25158355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 07/22/2024] [Accepted: 07/24/2024] [Indexed: 08/12/2024] Open
Abstract
During the development of animal organs, various adverse stimuli or toxic environments can induce oxidative stress and delay ovarian development. Paeoniflorin (PF), the main active ingredient of the traditional Chinese herb Paeonia lactiflora Pall., has protective effects on various diseases by preventing oxidative stress. However, the mechanism by which PF attenuates oxidative damage in mouse ovaries remains unclear. We evaluated the protective effects of PF on ovaries in an H2O2-induced mouse oxidative stress model. The H2O2-induced mouse ovarian oxidative stress model was used to explore the protective effect of PF on ovarian development. Histology and follicular development were observed. We then detected related indicators of cell apoptosis, oxidative stress, and autophagy in mouse ovaries. We found that PF inhibited H2O2-induced ovarian cell apoptosis and ferroptosis and promoted granulosa cell proliferation. PF prevented oxidative stress by increasing nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression levels. In addition, the autophagic flux of ovarian cells was activated and was accompanied by increased lysosomal biogenesis. Moreover, PF-mediated autophagy was involved in clearing mitochondria damaged by H2O2. Importantly, PF administration significantly increased the number of primordial follicles, primary follicles, secondary follicles, and antral follicles. PF administration improved ovarian sizes compared with the H2O2 group. The present study suggested that PF administration reversed H2O2-induced ovarian developmental delay and promoted follicle development. PF-activated mitophagy is crucial for preventing oxidative stress and improving mitochondrial quality.
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Affiliation(s)
| | | | | | - Xing Duan
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou 311300, China; (H.X.)
| | - Yuan Li
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Zhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou 311300, China; (H.X.)
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