|
1
|
Zheng BX, Long W, Zeng YX, She MT, Zheng Y, Zheng WD, Wang YK, Chan KH, Leung ASL, Chan CM, Lu YJ, Wong WL. A mitochondria-targeting and G-quadruplex structure-binding ligand inducing calcium overload and ferroptosis in human cancer cells. Br J Pharmacol 2025. [PMID: 40344208 DOI: 10.1111/bph.70061] [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: 09/15/2024] [Revised: 03/01/2025] [Accepted: 03/15/2025] [Indexed: 05/11/2025] Open
Abstract
BACKGROUND AND PURPOSE Regulation of mitochondrial calcium overload and ferroptosis with mitochondria-targeting ligands is an attractive anticancer strategy but it remains a challenge. The aim of the present study was to demonstrate that a mitochondria-targeting and mtDNA G-quadruplex-binding ligand, BYB, induced mitochondrial calcium overload and ferroptosis in HeLa cells and showed potent in vitro and in vivo anticancer activity. EXPERIMENTAL APPROACH Cellular functions and molecular mechanism were studied using cell viability assay, live-cell imaging, western blotting, immunofluorescence, cell uptake, cell cycle arrest and apoptosis analysis, mitochondrial metabolism analysis, Comet assay, and wound-healing analysis. Pharmacokinetic studies were conducted in rat. In vivo antitumor activity was studied in a cervical cancer HeLa cell xenograft mouse model. KEY RESULTS Cellular results showed that BYB induced mitochondrial calcium overload, attributed to ligand-induced mitochondrial dysfunction via the mechanism of inhibiting mitochondrial DNA replication and transcription. The expression of respiratory chain complexes was markedly downregulated in BYB-treated HeLa cells. The respiratory chain function was also dysregulated. Mitophagy and mitochondrial calcium overload were induced in BYB-treated HeLa cells. Mitochondrial calcium overload markedly induced mtROS production. The induced mtDNA stress activated cGAS-STING pathway, leading to autophagy-dependent ferroptosis. The antitumour efficacy of BYB, evaluated in a HeLa tumour xenograft mouse model, achieved over 60% tumour weight reduction. CONCLUSION AND IMPLICATIONS BYB, via targeting mitochondria and mtDNA G-quadruplexes, induced mitochondrial calcium overload and ferroptosis, exhibited high in vivo antitumour efficacy and low toxicity. It shows high potential to be a mitochondria-targeting lead compound for chemical biology and drug discovery.
Collapse
Affiliation(s)
- Bo-Xin Zheng
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Wei Long
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Yao-Xun Zeng
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Meng-Ting She
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Yingying Zheng
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
| | - Wen-De Zheng
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Ya-Kun Wang
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Ka-Hin Chan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Alan Siu-Lun Leung
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Chun-Ming Chan
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Yu-Jing Lu
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China
| | - Wing-Leung Wong
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, China
| |
Collapse
|
|
2
|
Lei S, Liu Y. Identifying blood mitochondrial DNA copy number as a biomarker for development of neurodegenerative diseases: Evidence from Mendelian randomization analysis. Neuroscience 2025; 573:421-429. [PMID: 40185386 DOI: 10.1016/j.neuroscience.2025.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 03/20/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
Mitochondrial dysfunction has been associated with neurodegenerative diseases (NDDs). This study aimed to explore the association between blood mitochondrial DNA copy number (mtDNA-CN) and development of NDDs. This study was based on two-sample Mendelian randomization (MR) analysis. The genome wide association study (GWAS) data of NDDs including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), age-related macular degeneration (AMD), multiple sclerosis (MS), Parkinson's disease (PD), primary open-angle glaucoma (POAG), and vascular dementia (VD) was obtained from FinnGen consortium. Inverse-variance weighted (IVW) was applied as the primary approach for MR estimation. MR results revealed that blood mtDNA-CN exhibited a significant relationship with the incidence of AD (IVW-P = 0.011, odds ratio [OR] = 0.65) and AMD (IVW-P = 0.038, OR = 0.64). However, there was no significant association observed between blood mtDNA-CN and other NDDs (IVW-P > 0.05). Our findings supported the relationship between mitochondrial dysfunction and development of AD and AMD, and that blood mtDNA-CN may serve as a potential biomarker for the incidence of these two NDDs.
Collapse
Affiliation(s)
- Shizhen Lei
- Department of Ophthalmology, Wuhan No.1 Hospital, Wuhan, Hubei, China.
| | - Yani Liu
- Department of Otolaryngology & Head and Neck Surgery, Wuhan No.1 Hospital, Wuhan, Hubei, China
| |
Collapse
|
|
3
|
Yang Y, Zhao B, Wang Y, Lan H, Liu X, Hu Y, Cao P. Diabetic neuropathy: cutting-edge research and future directions. Signal Transduct Target Ther 2025; 10:132. [PMID: 40274830 PMCID: PMC12022100 DOI: 10.1038/s41392-025-02175-1] [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: 08/19/2024] [Revised: 12/12/2024] [Accepted: 02/08/2025] [Indexed: 04/26/2025] Open
Abstract
Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.
Collapse
Affiliation(s)
- Yang Yang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Bing Zhao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuanzhe Wang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongli Lan
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xinyu Liu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue Hu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peng Cao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| |
Collapse
|
|
4
|
Gupta G, Samuel VP, M RM, Rani B, Sasikumar Y, Nayak PP, Sudan P, Goyal K, Oliver BG, Chakraborty A, Dua K. Caspase-independent cell death in lung cancer: from mechanisms to clinical applications. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04149-0. [PMID: 40257494 DOI: 10.1007/s00210-025-04149-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/05/2025] [Indexed: 04/22/2025]
Abstract
Caspase-independent cell death (CICD) has recently become a very important mechanism in lung cancer, in particular, to overcome a critical failure in apoptotic cell death that is common to disease progression and treatment failures. The pathways involved in CICD span from necroptosis, ferroptosis, mitochondrial dysfunction, and autophagy-mediated cell death. Its potential therapeutic applications have been recently highlighted. Glutathione peroxidase 4 (GPX4) inhibition-driven ferroptosis has overcome drug resistance in non-small cell lung cancer (NSCLC). In addition, necroptosis involving RIPK1 and RIPK3 causes tumor cell death and modulation of immune responses in the tumor microenvironment (TME). Mitochondrial pathways are critical for CICD through modulation of metabolic and redox homeostasis. Ferroptosis is amplified by mitochondrial reactive oxygen species (ROS) and lipid peroxidation in lung cancer cells, and mitochondrial depolarization induces oxidative stress and leads to cell death. In addition, mitochondria-mediated autophagy, or mitophagy, results in the clearance of damaged organelles under stress conditions, while this function is also linked to CICD when dysregulated. The role of cell death through autophagy regulated by ATG proteins and PI3K/AKT/mTOR pathway is dual: to suppress tumor and to sensitize cells to therapy. A promising approach to enhancing therapeutic outcomes involves targeting mechanisms of CICD, including inducing ferroptosis by SLC7A11 inhibition, modulating mitochondrial ROS generation, or combining inhibition of autophagy with chemotherapy. Here, we review the molecular underpinnings of CICD, particularly on mitochondrial pathways and their potential to transform lung cancer treatment.
Collapse
Affiliation(s)
- Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, 140401, India
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Vijaya Paul Samuel
- Department of Anatomy, RAK College of Medicine, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE
| | - Rekha M M
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Bindu Rani
- Department of Medicine, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Y Sasikumar
- Department of CHEMISTRY, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
| | - Priya Priyadarshini Nayak
- Department of Medical Oncology IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to Be University), Bhubaneswar, Odisha, 751003, India
| | - Puneet Sudan
- Department of Pharmacy, Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India
| | - Kavita Goyal
- Department of Biotechnology, Graphic Era (Deemed to Be University), Clement Town, Dehradun, 248002, India
| | - Brian G Oliver
- Woolcock Institute of Medical Research, Macquarie University, Sydney, NSW, Australia
- School of Life Sciences, University of Technology Sydney, Ultimo, NSW, 2007, Australia
| | - Amlan Chakraborty
- Faculty of Biology, Medicine and Health, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK
- Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Kamal Dua
- Woolcock Institute of Medical Research, Macquarie University, Sydney, NSW, Australia.
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
| |
Collapse
|
|
5
|
Zhang W, Wang R, Guo R, Yi Z, Wang Y, Wang H, Li Y, Li X, Song J. The multiple biological activities of hyperoside: from molecular mechanisms to therapeutic perspectives in neoplastic and non-neoplastic diseases. Front Pharmacol 2025; 16:1538601. [PMID: 40098612 PMCID: PMC11911483 DOI: 10.3389/fphar.2025.1538601] [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: 12/03/2024] [Accepted: 02/13/2025] [Indexed: 03/19/2025] Open
Abstract
In recent years, hyperoside (quercetin 3-O-β-D-galactopyranoside) has garnered significant attention due to its diverse biological effects, which include vasoprotective, antioxidant, anti-inflammatory, and anti-tumor properties. Notably, hyperoside has shown remarkable potential in cancer therapy by targeting multiple mechanisms; it induces apoptosis, inhibits proliferation, blocks angiogenesis, and reduces the metastatic potential of cancer cells. Furthermore, hyperoside enhances the sensitivity of cancer cells to chemotherapy by modulating key signaling pathways. Beyond neoplastic diseases, hyperoside also presents promising therapeutic applications in managing non-cancerous conditions such as diabetes, Alzheimer's disease, and pulmonary fibrosis. This review comprehensively examines the molecular mechanisms underlying hyperoside's anti-cancer effects and highlights its role in the treatment of cancers, including lung and colorectal cancers. Additionally, it explores the latest research on hyperoside's potential in addressing non-neoplastic conditions, such as pulmonary fibrosis, diabetes, and Parkinson's disease. By summarizing current findings, this review underscores the unique therapeutic value of hyperoside and its potential as a multifunctional treatment in both neoplastic and non-neoplastic contexts.
Collapse
Affiliation(s)
- Weisong Zhang
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
- Medical School of Nantong University, Nantong, China
| | - Rui Wang
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
- Medical School of Nantong University, Nantong, China
| | - Rongqi Guo
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
- Medical School of Nantong University, Nantong, China
| | - Zhongquan Yi
- Central Laboratory, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
| | - Yihao Wang
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
- Medical School of Nantong University, Nantong, China
| | - Hao Wang
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
- Medical School of Nantong University, Nantong, China
| | - Yangyang Li
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
- Medical School of Nantong University, Nantong, China
| | - Xia Li
- Department of General Medicine, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
| | - Jianxiang Song
- Department of Thoracic Surgery, Affiliated Hospital 6 of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
| |
Collapse
|
|
6
|
Hashem MM, Hassanen EI, Hassan NH, Ibrahim MA, Issa MY, Farag MA, Hamdy SA. Physalis peruviana calyces extract ameliorate oxidative stress, inflammation, and immune loss in rats-exposed to hexaflumuron. BMC Complement Med Ther 2025; 25:21. [PMID: 39844243 PMCID: PMC11756176 DOI: 10.1186/s12906-025-04750-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: 05/12/2024] [Accepted: 01/06/2025] [Indexed: 01/24/2025] Open
Abstract
BACKGROUND Hexaflumuron (HFM), a common pesticide, can disrupt the immune system and cause oxidative stress. This study investigated the potential of Physalis peruviana L. calyces extract (PP) to counteract these effects in rats. METHODS Rats were divided into 6 groups including control, PP-treated, HFM-exposed, and co-treated (HFM + PP) groups. Immune function, antioxidant activity, and organ damage were assessed. Furthermore, UPLC-MS/MS analysis identified potential bioactive compounds in PP extract. RESULTS HFM exposure suppressed immune responses and caused organ damage. Notably, the co-administration of PP extract with HFM reversed these effects, indicating its ability to reduce oxidative stress and protect the immune system. UPLC-MS/MS analysis of PP calyces ethanolic extract revealed its richness in various health-promoting metabolites, including acyl sucrose sugar, withanolides, and flavonoids, which may provide valuable insight into the underlying mechanisms of PP's calyces protective effects against HFM toxicity. CONCLUSIONS This study provides novel insights into the potential of P. peruviana L. calyces ethanolic extract as a natural agent to counteract the harmful effects of HFM exposure. These findings have significant implications for developing effective strategies to mitigate pesticide-induced toxicity and promote human health.
Collapse
Affiliation(s)
- Mona M Hashem
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr el Aini st, P.B. 11562, Cairo, Egypt
| | - Eman I Hassanen
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Neven H Hassan
- Department of Physiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Marwa A Ibrahim
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Marwa Y Issa
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr el Aini st, P.B. 11562, Cairo, Egypt
| | - Mohamed A Farag
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr el Aini st, P.B. 11562, Cairo, Egypt.
| | - Sherif A Hamdy
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr el Aini st, P.B. 11562, Cairo, Egypt
| |
Collapse
|
|
7
|
Wang ZQ, Wu ZX, Chen JW, Li HF, Wu HD, Bao JX, Cheng Y, Dai YW, Wang OC, Dai XX. Cyclovirobuxine D inhibits triple-negative breast cancer via YAP/TAZ suppression and activation of the FOXO3a/PINK1-Parkin pathway-induced mitophagy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 136:156287. [PMID: 39615216 DOI: 10.1016/j.phymed.2024.156287] [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: 06/07/2024] [Revised: 10/31/2024] [Accepted: 11/21/2024] [Indexed: 01/16/2025]
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is characterized by its rapid progression and aggressive nature, with limited effective therapeutic interventions currently available. Cyclovirobuxine D (CVB-D), a natural alkaloid extracted from the traditional Chinese herb Buxus sinica, is renowned for its cardioprotective and anti-ischemic effects, demonstrating notable anti-cancer properties. Nevertheless, the anti-tumor effects of CVB-D on TNBC remain unverified. PURPOSE This study seeks to investigate the effects of CVB-D on TNBC and to uncover the underlying mechanisms. STUDY DESIGN Network pharmacology, SPR, DSF, and cell-based functional assays were conducted on TNBC cells to assess the impact of CVB-D. Findings were further corroborated using xenograft mouse models. METHODS Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine, transwell assays, flow cytometry, wound healing assays, immunofluorescence, and immunoblotting were employed to evaluate CVB-D's influence on TNBC cell lines. SPR, DSF and molecular docking techniques were utilized to assess the binding affinity of CVB-D to Yes-associated protein (YAP). The interaction between CVB-D and autophagy/mitophagy was further analyzed through plasmid transient transfection, JC-1 assay, TUNEL assay, and the use of autophagy inhibitors. The anti-TNBC mechanism of CVB-D was elucidated by overexpressing YAP in MDA-MB-231 cells. Additionally, the in vivo efficacy and safety of CVB-D were assessed in a xenograft mouse model. RESULTS In vitro analyses revealed that CVB-D effectively suppressed G1 phase arrest and inhibited TNBC cell proliferation. Moreover, CVB-D induced mitochondrial-dependent apoptosis and reduced cell migration by antagonizing epithelial-mesenchymal transition. Mechanistically, CVB-D exerted its anti-cancer effects by directly binding to YAP, thereby inhibiting the nuclear translocation of YAP/TAZ and suppressing the transcription of downstream oncogenic target genes. Furthermore, CVB-D triggered excessive mitophagy by activating the FOXO3a/PINK1-Parkin axis, promoting apoptosis and leading to mitochondrial dysfunction in TNBC cells. Elevated YAP expression counteracted the effects of CVB-D on TNBC, including the suppression of mitophagy-related protein expression induced by CVB-D, suggesting that YAP modulates mitophagy through the FOXO3a/PINK1-Parkin axis. The anti-tumor efficacy of CVB-D and its underlying mechanisms were further substantiated using a subcutaneous xenograft model. CONCLUSIONS This study is the first to demonstrate that CVB-D can directly bind to the YAP target, proposing a novel therapeutic strategy for TNBC. CVB-D may serve both as a YAP/TAZ inhibitor and as an activator of the FOXO3a/PINK1-Parkin axis, leading to excessive mitophagy.
Collapse
Affiliation(s)
- Zi-Qiong Wang
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Zhi-Xuan Wu
- Department of Colorectal Surgery, Sir Run Shaw Hospital of Zhejiang University, Hangzhou, Zhejiang 310016, PR China
| | - Jia-Wei Chen
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Hong-Feng Li
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Hao-Dong Wu
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Jing-Xia Bao
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Yao Cheng
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Yin-Wei Dai
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China
| | - Ou-Chen Wang
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China; Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, PR China.
| | - Xuan-Xuan Dai
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China; Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, PR China.
| |
Collapse
|
|
8
|
Xu W, Feng Y, Chen S, Wang H, Wen J, Zheng G, Wang G, Zou S. Establishment and identification of the gill cell line from the blunt snout bream (Megalobrama amblycephala) and its application in studying gill remodeling under hypoxia. FISH PHYSIOLOGY AND BIOCHEMISTRY 2024; 50:2475-2488. [PMID: 39222227 DOI: 10.1007/s10695-024-01393-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/10/2024] [Indexed: 09/04/2024]
Abstract
To probe the mechanisms of gill remodeling in blunt snout bream under hypoxic conditions, we selected gill tissue for primary cell culture to establish and characterize the first blunt snout bream gill cell line, named MAG. The gill cells were efficiently passaged in M199 medium supplemented with 8% antibiotics and 15% fetal bovine serum at 28 °C, exhibiting primarily an epithelial-fibroblast mixed type. Additionally, the MAG cells (17th generation) were subjected to four experimental conditions-normoxia, hypoxia 12 h, hypoxia 24 h, and reoxygenation 24 h (R24h)-to evaluate the effects of hypoxia and reoxygenation on MAG cells during gill remodeling. We found that the MAG cell morphology underwent shrinkage and mitochondrial potential gradually lost, even leading to gradual apoptosis with increasing hypoxia duration and increased reactive oxygen species (ROS) activity. Upon reoxygenation, MAG cells gradually regain cellular homeostasis, accompanied by a decrease in ROS activity. Analysis of superoxide dismutase (SOD), glutathione (GSH), lactate dehydrogenase (LDH), catalase (CAT), anti-superoxide anion, and other enzyme activities revealed enhanced antioxidant enzyme activity in MAG cells during hypoxia, aiding in adapting to hypoxic stress and preserving cell morphology. After reoxygenation, the cells gradually returned to normoxic levels. Our findings underscore the MAG cells can be used to study hypoxic cell apoptosis during gill remodeling. Therefore, the MAG cell line will serve as a vital in vitro model for exploring gill remodeling in blunt snout bream under hypoxia.
Collapse
Affiliation(s)
- Wenya Xu
- Genetics and Breeding Center for Blunt Snout Bream, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Yahui Feng
- Genetics and Breeding Center for Blunt Snout Bream, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Songlin Chen
- Genetics and Breeding Center for Blunt Snout Bream, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Huihu Wang
- Genetics and Breeding Center for Blunt Snout Bream, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Jian Wen
- Genetics and Breeding Center for Blunt Snout Bream, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Guodong Zheng
- Genetics and Breeding Center for Blunt Snout Bream, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, 201306, China
| | - Ganxiang Wang
- Pinghu Fisheries Technology Promotion Center, Pinghu, 314200, Zhejiang, China.
| | - Shuming Zou
- Genetics and Breeding Center for Blunt Snout Bream, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China.
- Key Laboratory of Freshwater Aquatic Genetic Resources, Ministry of Agriculture and Rural Affairs, Shanghai Ocean University, Shanghai, 201306, China.
- National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai, 201306, China.
- College of Fisheries and Life Science, Shanghai Ocean University, Hucheng Ring Road 999, Shanghai, 201306, China.
| |
Collapse
|
|
9
|
Tahir R, Samra, Afzal F, Khan H, Ghaffar A, Qazi IH, Al-Khattaf FS, Liulan Z, Yan H, Kuo H, Shrestha A, Jamil H, Naseer S, Habib H, Yang S. Chronic bisphenol A induced neurotoxicity: Exposure risk, molecular fate within carp and its potential phytoremediation. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 954:175876. [PMID: 39244053 DOI: 10.1016/j.scitotenv.2024.175876] [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: 06/21/2024] [Revised: 08/24/2024] [Accepted: 08/28/2024] [Indexed: 09/09/2024]
Abstract
Bisphenol A (BPA) is an endocrine-disrupting toxicant commonly used in the plastics industry, as a result, it is present in large quantities in the environment. Therefore, current study was designed to assess BPA induced neurotoxicity and molecular fate within common carp (Cyprinus carpio), largely used edible fish. Following 6 weeks exposure to BPA 1/5th of 96 h LC50 (1.31 mg/L), brain exhibited oxidative damage, which was evidenced by compromised antioxidant system (CAT, SOD, GSH) and increased level of biomacromolecule peroxidation (MDA and 8-OHDG). Functional damage to the brain observed in the form of blood-brain barrier disruption (decreased tight junction gene expression) and nerve conduction impairment (reduced acetylcholinesterase activity). Mechanistically, apoptotic cell death indicated by characteristic alteration in key biomarkers (bcl-2, caspase, and p53-related gene family). Whereas, coadministration of powdered PP (pomegranate peel) (8 %) with BPA effectively mitigated the BPA toxicity, as evidenced by the restoration of the above-mentioned bioindicators. Thereby, BPA-induced neurotoxicity could be potentially detoxified by applying PP dietary enrichment.
Collapse
Affiliation(s)
- Rabia Tahir
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China; Department of Zoology, The Islamia University of Bahawalpur, Bahawalpur, Punjab 63100, Pakistan
| | - Samra
- School of Life Sciences, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Fozia Afzal
- Department of Zoology, The Islamia University of Bahawalpur, Bahawalpur, Punjab 63100, Pakistan
| | - Hamid Khan
- Department of Biochemistry, Quaid i Azam University, Islamabad 45320, Pakistan
| | - Abdul Ghaffar
- Department of Zoology, The Islamia University of Bahawalpur, Bahawalpur, Punjab 63100, Pakistan
| | - Izhar Hyder Qazi
- College of Animal Science, South China Agricultural University, Guangzhou 510642, China
| | - Fatimah Saleh Al-Khattaf
- Department of Botany and Microbiology, College of Science, King Saudi University, Riyadh 11451, Saudi Arabia
| | - Zhao Liulan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Haoxiao Yan
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - He Kuo
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Abhimanyu Shrestha
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China
| | - Habiba Jamil
- Department of Zoology, The Islamia University of Bahawalpur, Bahawalpur, Punjab 63100, Pakistan
| | - Sameera Naseer
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Hamza Habib
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Song Yang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan 611130, China.
| |
Collapse
|
|
10
|
Su B, Ren Y, Yao W, Su Y, He Q. Mitochondrial dysfunction and NLRP3 inflammasome: key players in kidney stone formation. BJU Int 2024; 134:696-713. [PMID: 38967108 DOI: 10.1111/bju.16454] [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] [Indexed: 07/06/2024]
Abstract
The mitochondrion serves as a critical intracellular organelle, engaging in essential roles in the regulation of energy production, oxidative stress management, calcium homeostasis, and apoptosis. One such disease that has been particularly associated with these functions is kidney stone disease (KSD), specifically calcium oxalate (CaOx). It is underpinned by oxidative stress and tissue inflammation. Recent studies have shed light on the vital involvement of mitochondrial dysfunction, the nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) inflammasome, endoplasmic reticulum stress and subsequent cell death in CaOx crystal retention and aggregation. These processes are pivotal in the pathogenesis of kidney stone formation. This review focuses on the pivotal roles of mitochondria in renal cell functions and provides an overview of the intricate interconnectedness between mitochondrial dysfunction and NLRP3 inflammasome activation in the context of KSD. It is essential to recognise the utmost significance of gaining a comprehensive understanding of the mechanisms that safeguard mitochondrial function and regulate the NLRP3 inflammasome. Such knowledge carries significant scientific implications and opens up promising avenues for the development of innovative strategies to prevent the formation of kidney stones.
Collapse
Affiliation(s)
- Boyan Su
- Department of Urology, Key Laboratory of Disease of Urological Systems, Gansu Nepho-Urological Clinical Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - YaLin Ren
- Department of Urology, Key Laboratory of Disease of Urological Systems, Gansu Nepho-Urological Clinical Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- College of Animal Science and Technology, Guangxi University, Nanning, Guangxi, China
| | - Weimin Yao
- Department of Urology, Tongji Medical College Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yue Su
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Qiqi He
- Department of Urology, Key Laboratory of Disease of Urological Systems, Gansu Nepho-Urological Clinical Center, Lanzhou University Second Hospital, Lanzhou, Gansu, China
| |
Collapse
|
|
11
|
Zheng H, Xiao X, Han Y, Wang P, Zang L, Wang L, Zhao Y, Shi P, Yang P, Guo C, Xue J, Zhao X. Research progress of propofol in alleviating cerebral ischemia/reperfusion injury. Pharmacol Rep 2024; 76:962-980. [PMID: 38954373 DOI: 10.1007/s43440-024-00620-6] [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: 01/30/2024] [Revised: 06/21/2024] [Accepted: 06/23/2024] [Indexed: 07/04/2024]
Abstract
Ischemic stroke is a leading cause of adult disability and death worldwide. The primary treatment for cerebral ischemia patients is to restore blood supply to the ischemic region as quickly as possible. However, in most cases, more severe tissue damage occurs, which is known as cerebral ischemia/reperfusion (I/R) injury. The pathological mechanisms of brain I/R injury include mitochondrial dysfunction, oxidative stress, excitotoxicity, calcium overload, neuroinflammation, programmed cell death and others. Propofol (2,6-diisopropylphenol), a short-acting intravenous anesthetic, possesses not only sedative and hypnotic effects but also immunomodulatory and neuroprotective effects. Numerous studies have reported the protective properties of propofol during brain I/R injury. In this review, we summarize the potential protective mechanisms of propofol to provide insights for its better clinical application in alleviating cerebral I/R injury.
Collapse
Affiliation(s)
- Haijing Zheng
- Basic Medical College, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China
- Zhengzhou Central Hospital, Zhengzhou, China
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China
| | - Xian Xiao
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China
| | - Yiming Han
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China
| | - Pengwei Wang
- Department of Pharmacy, the First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui, Henan, 453100, China
| | - Lili Zang
- Department of Surgery, the First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui, China
| | - Lilin Wang
- Department of Pediatric Surgery, the First Affiliated Hospital of Xinxiang Medical University, No. 88 Jiankang Road, Weihui, China
| | - Yinuo Zhao
- Basic Medical College, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China
| | - Peijie Shi
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China
| | - Pengfei Yang
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China.
| | - Chao Guo
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China.
| | - Jintao Xue
- College of Pharmacy, Henan International Joint Laboratory of Cardiovascular Remodeling and Drug Intervention, Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China.
| | - Xinghua Zhao
- Basic Medical College, Xinxiang Medical University, 601, Jin Sui Avenue, Xinxiang, Henan, China.
| |
Collapse
|
|
12
|
Wang Y, Wang S, Zang Z, Li B, Liu G, Huang H, Zhao X. Molecular and transcriptomic analysis of the ovary during laying and brooding stages in Zhedong white geese ( Anser cygnoides domesticus). Br Poult Sci 2024; 65:631-644. [PMID: 38916443 DOI: 10.1080/00071668.2024.2364351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 05/13/2024] [Indexed: 06/26/2024]
Abstract
1. This study investigates the molecular mechanisms affecting brooding in Zhedong white geese by examining differences in reproductive endocrine levels, ovarian histology and transcriptomics.2. Twenty 18-month-old Zhedong white geese were selected to examine their ovaries using histological, biochemical, molecular biological, and high-throughput sequencing techniques during the laying and brooding periods.3. The results showed that the number of atretic follicles and apoptotic cells in the ovaries increased significantly (p < 0.05), the levels of follicle-stimulating hormone, luteinising hormone, gonadotropin-releasing hormone and oestradiol decreased significantly (p < 0.05), and the level of prolactin increased significantly (p < 0.01) during the brooding stage.4. In broody geese, the expression of CASP3, CASP9, P53, BAX, and Cyt-c were considerably higher (p < 0.05), but BCL2 expression was significantly lower (p < 0.05).5. In ovarian tissues, 260 differentially expressed lncRNAs, 13 differentially expressed miRNA and 60 differentially expressed mRNA were all discovered using transcriptome sequencing analysis. Functional enrichment analysis revealed that the differentially expressed mRNA and non-coding RNA target genes were primarily involved in ECM-receptor interaction, cell adhesion, cardiac muscle contraction, mTOR signalling, and the calcium signalling pathway.6. In conclusion, follicular atrophy and apoptosis occurred in the ovaries and serum reproductive hormone levels were significantly changed during the brooding period of Zhedong white geese. COL3A1, COL1A2, GRIA1, RNF152, miR-192, and miR-194 may be important candidates for the regulation of brooding behaviour, with the mTOR signalling pathway playing a key role.
Collapse
Affiliation(s)
- Y Wang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - S Wang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - Z Zang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - B Li
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - G Liu
- Animal Husbandry Institute, Heilongjiang Academy of Agricultural Sciences, Harbin, People's Republic of China
| | - H Huang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, People's Republic of China
| | - X Zhao
- Animal Husbandry Institute, Heilongjiang Academy of Agricultural Sciences, Harbin, People's Republic of China
| |
Collapse
|
|
13
|
Zhu H, Zhou L, Tang J, Xu Y, Wang W, Shi W, Li Z, Zhang L, Ding Z, Xi K, Gu Y, Chen L. Reactive Oxygen Species-Responsive Composite Fibers Regulate Oxidative Metabolism through Internal and External Factors to Promote the Recovery of Nerve Function. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2401241. [PMID: 38660829 DOI: 10.1002/smll.202401241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 03/28/2024] [Indexed: 04/26/2024]
Abstract
It is challenging to sufficiently regulate endogenous neuronal reactive oxygen species (ROS) production, reduce neuronal apoptosis, and reconstruct neural networks under spinal cord injury conditions. Here, hydrogel surface grafting and microsol electrospinning are used to construct a composite biomimetic scaffold with "external-endogenous" dual regulation of ROS. The outer hydrogel enhances local autophagy through responsive degradation and rapid release of rapamycin (≈80% within a week), neutralizing extracellular ROS and inhibiting endogenous ROS production, further reducing neuronal apoptosis. The inner directional fibers continuously supply brain-derived neurotrophic factors to guide axonal growth. The results of in vitro co-culturing show that the dual regulation of oxidative metabolism by the composite scaffold approximately doubles the neuronal autophagy level, reduces 60% of the apoptosis induced by oxidative stress, and increases the differentiation of neural stem cells into neuron-like cells by ≈2.5 times. The in vivo results show that the composite fibers reduce the ROS levels by ≈80% and decrease the formation of scar tissue. RNA sequencing results show that composite scaffolds upregulate autophagy-associated proteins, antioxidase genes, and axonal growth proteins. The developed composite biomimetic scaffold represents a therapeutic strategy to achieve neurofunctional recovery through programmed and accurate bidirectional regulation of the ROS cascade response.
Collapse
Affiliation(s)
- Hongyi Zhu
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Liang Zhou
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Jincheng Tang
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Yichang Xu
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Wei Wang
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Wenxiao Shi
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Ziang Li
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Lichen Zhang
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Zhouye Ding
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Kun Xi
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Yong Gu
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| | - Liang Chen
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu, 215006, P. R. China
| |
Collapse
|
|
14
|
Pan T, Yang B, Yao S, Wang R, Zhu Y. Exploring the multifaceted role of adenosine nucleotide translocase 2 in cellular and disease processes: A comprehensive review. Life Sci 2024; 351:122802. [PMID: 38857656 DOI: 10.1016/j.lfs.2024.122802] [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: 03/07/2024] [Revised: 05/04/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
Adenosine nucleotide translocases (ANTs) are a family of proteins abundant in the inner mitochondrial membrane, primarily responsible for shuttling ADP and ATP across the mitochondrial membrane. Additionally, ANTs are key players in balancing mitochondrial energy metabolism and regulating cell death. ANT2 isoform, highly expressed in undifferentiated and proliferating cells, is implicated in the development and drug resistance of various tumors. We conduct a detailed analysis of the potential mechanisms by which ANT2 may influence tumorigenesis and drug resistance. Notably, the significance of ANT2 extends beyond oncology, with roles in non-tumor cell processes including blood cell development, gastrointestinal motility, airway hydration, nonalcoholic fatty liver disease, obesity, chronic kidney disease, and myocardial development, making it a promising therapeutic target for multiple pathologies. To better understand the molecular mechanisms of ANT2, this review summarizes the structural properties, expression patterns, and basic functions of the ANT2 protein. In particular, we review and analyze the controversy surrounding ANT2, focusing on its role in transporting ADP/ATP across the inner mitochondrial membrane, its involvement in the composition of the mitochondrial permeability transition pore, and its participation in apoptosis.
Collapse
Affiliation(s)
- Tianhui Pan
- Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, PR China
| | - Bin Yang
- Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, PR China
| | - Sheng Yao
- Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, PR China
| | - Rui Wang
- Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, PR China
| | - Yongliang Zhu
- Laboratory of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, PR China.
| |
Collapse
|
|
15
|
Zhong J, He G, Ma X, Ye J, Tao ZY, Li Z, Zhang F, Feng P, Wang Y, Lan X, Su YX. Triterpene-Based Prodrug for Self-Boosted Drug Release and Targeted Oral Squamous Cell Carcinoma Chemotherapy. ACS APPLIED MATERIALS & INTERFACES 2024; 16:41960-41972. [PMID: 39082953 DOI: 10.1021/acsami.4c10175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/16/2024]
Abstract
Chemotherapy is one of the main treatments for oral squamous cell carcinoma (OSCC), especially as a combined modality approach with and after surgery or radiotherapy. Limited therapeutic efficiency and serious side effects greatly restrict the clinical performance of chemotherapeutic drugs. The development of smart nanomedicines has provided new research directions, to some extent. However, the involvement of complex carrier compositions inevitably brings biosafety concerns and greatly limits the "bench-to-bed" translation of most nanomedicines reported. In this study, a carrier-free self-assembled prodrug was fabricated by two triterpenes (glycyrrhetinic acid, GA and ginsenoside Rh2, Rh2) isolated from medicinal plants, licorice, and ginseng, for the targeted and highly effective treatment of OSCC. Reactive oxygen species (ROS) self-supplied molecule TK-GA2 was synthesized with ROS-responsive thioketal linker and prodrug was prepared by a rapid-solvent-exchange method with TK-GA2 and Rh2. After administration, oral tumor cells transported large amounts of prodrugs with glucose ligands competitively. Endogenous ROS in oral tumor cells then promoted the release of GA and Rh2. GA further evoked the generation of a large number of ROS to help self-boosted drug release and increase oxidative stress, synergistically causing tumor cell apoptosis with Rh2. Overall, this carrier-free triterpene-based prodrug might provide a preeminent opinion on the design of effective chemotherapeutics with low systemic toxicity against OSCC.
Collapse
Affiliation(s)
- Jie Zhong
- Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
- Division of Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Guantong He
- Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
| | - Xu Ma
- National Center for Nanoscience and Technology, Beijing 100190, China
| | - Jinhai Ye
- Department of Oral and Maxillofacial Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhuo-Ying Tao
- Division of Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Zhongxian Li
- National Center for Nanoscience and Technology, Beijing 100190, China
| | - Fuxue Zhang
- Department of Chemistry, University of Copenhagen, Copenhagen DK-2100, Denmark
| | - Peijian Feng
- Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
| | - Yuji Wang
- Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
| | - Xinmiao Lan
- Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
| | - Yu-Xiong Su
- Division of Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR 999077, China
| |
Collapse
|
|
16
|
Wu A, Zhong C, Song X, Yuan W, Tang M, Shu T, Huang H, Yang P, Liu Q. The activation of LBH-CRYAB signaling promotes cardiac protection against I/R injury by inhibiting apoptosis and ferroptosis. iScience 2024; 27:109510. [PMID: 38660406 PMCID: PMC11039335 DOI: 10.1016/j.isci.2024.109510] [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: 09/10/2023] [Revised: 12/29/2023] [Accepted: 03/13/2024] [Indexed: 04/26/2024] Open
Abstract
Myocardial ischemia-reperfusion (I/R) injury stands out among cardiovascular diseases, and current treatments are considered unsatisfactory. For cardiomyocytes (CMs) in ischemic tissues, the upregulation of Limb-bud and Heart (LBH) and αB-crystallin (CRYAB) and their subsequent downregulation in the context of cardiac fibrosis have been verified in our previous research. Here, we focused on the effects and mechanisms of activated LBH-CRYAB signaling on damaged CMs during I/R injury, and confirmed the occurrence of mitochondrial apoptosis and ferroptosis during I/R injury. The application of inhibitors, ectopic expression vectors, and knockout mouse models uniformly verified the role of LBH in alleviating both apoptosis and ferroptosis of CMs. p53 was identified as a mutual downstream effector for both LBH-CRYAB-modulated apoptosis and ferroptosis inhibition. In mouse models, LBH overexpression was confirmed to exert enhanced cardiac protection against I/R-induced apoptosis and ferroptosis, suggesting that LBH could serve as a promising target for the development of I/R therapy.
Collapse
Affiliation(s)
- Anbiao Wu
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Laboratory of Heart Center, Department of Cardiology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China
- Beijing Institute of Basic Medical Sciences, Beijing 100850, People’s Republic of China
| | - Chongbin Zhong
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Laboratory of Heart Center, Department of Cardiology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China
| | - Xudong Song
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Laboratory of Heart Center, Department of Cardiology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China
| | - Wen Yuan
- Experimental Animal Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China
| | - Mintian Tang
- Experimental Animal Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China
| | - Tao Shu
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Laboratory of Heart Center, Department of Cardiology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China
| | - Houda Huang
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Laboratory of Heart Center, Department of Cardiology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China
| | - Pingzhen Yang
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Laboratory of Heart Center, Department of Cardiology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China
| | - Qicai Liu
- Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Laboratory of Heart Center, Department of Cardiology, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, People’s Republic of China
| |
Collapse
|
|
17
|
Zhang H, Zhou M, Ye C, Qin J, Lu X, Wang C, Wang X, Jin X. Betulinic acid inhibits the proliferation of human laryngeal carcinoma cells through reactive oxygen species-mediate mitochondrial apoptotic pathway. Toxicol In Vitro 2024; 95:105756. [PMID: 38061603 DOI: 10.1016/j.tiv.2023.105756] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 11/30/2023] [Indexed: 12/30/2023]
Abstract
Betulinic acid (BA), a natural pentacyclic triterpene, was extracted from the white birch tree, Triphyophyllum peltatum and the jujube tree. In a variety of human cancer cell lines, this substance displays anticancer properties. In this study, we examined how BA works to inhibit human laryngeal cancer growth. We discovered that BA minimally exhibited cytotoxicity in normal cells (human normal cell line GES-1), while remarkably inhibiting viability of AMC-HN-8, TU212, HEp-2 and M4e cells in a concentration-dependent manner. In AMC-HN-8 cancer cells, BA induced apoptosis, activated caspase-3/9/PARP, significantly reduced mitochondrial membrane potential (MMP), increased the expression of cytochrome C in the cytoplasm, transported Bax to the mitochondria, increased the production of reactive oxygen species (ROS), and the ROS scavenger N-acetylcysteine can reduce apoptosis. All data showed that BA triggered apoptosis via the mitochondrial pathway, in which ROS production was likely involved. The findings support the development of BA as a viable drug for the treatment of human laryngeal carcinoma.
Collapse
Affiliation(s)
- Huamin Zhang
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China
| | - Mengru Zhou
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, Liaoning, China
| | - Chongtao Ye
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, Liaoning, China
| | - Jiahao Qin
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, Liaoning, China
| | - Xuan Lu
- China College of life and health, Dalian University, Dalian 116622, Liaoning, China
| | - Chunyan Wang
- College of Food and Biology Engineering, Xuzhou University of Technology, Xuzhou 221018, Jiangsu, China.
| | - Xude Wang
- Chronic Disease Research Center, Medical College, Dalian University, Dalian 116622, Liaoning, China.
| | - Xuejun Jin
- Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
| |
Collapse
|
|
18
|
Han G, Lee DG. Urechistachykinin I triggers mitochondrial dysfunction leading to a ferroptosis-like response in Saccharomyces cerevisiae. J Appl Microbiol 2024; 135:lxae011. [PMID: 38268406 DOI: 10.1093/jambio/lxae011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 12/22/2023] [Accepted: 01/23/2024] [Indexed: 01/26/2024]
Abstract
AIMS The purpose of this paper was to demonstrate the antimicrobial activity of urechistachykinin I (LRQSQFVGSR-NH2) extracted from Urechis unicinctus,and its mode of action dependent on mitochondrial dysfunction. METHODS AND RESULTS The antifungal activity of urechistachykinin I generated reactive oxygen species (ROS), as demonstrated with MitoSOX Red and hydroxyphenyl fluorescein (HPF). Overaccumulation of ROS caused oxidative damage to cells by inducing mitochondrial dysfunction. Mitochondrial disruption resulted in cell death, creating several hallmarks that included lipid peroxidation, glutathione oxidation, and depolarization. Moreover, the loss of mitochondria changed the calcium ion imbalance by depolarization of the mitochondrial membrane. In particular, iron accumulation and DNA fragmentation measurement determined the type of cell death. Our results indicate that urechistachykinin I treatment induced ferroptosis-like death in Saccharomyces cerevisiae via mitochondrial dysfunction. CONCLUSIONS Urechistachykinin I treatment induced mitochondrial dysfunction in S. cerevisiae by generating ROS, and the subsequent oxidative damage caused the ferroptosis-like cell death.
Collapse
Affiliation(s)
- Giyeol Han
- School of Life Sciences, BK 21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea
| | - Dong Gun Lee
- School of Life Sciences, BK 21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea
| |
Collapse
|
|
19
|
Ge K, Du X, Liu H, Meng R, Wu C, Zhang Z, Liang X, Yang J, Zhang H. The cytotoxicity of microcystin-LR: ultrastructural and functional damage of cells. Arch Toxicol 2024; 98:663-687. [PMID: 38252150 DOI: 10.1007/s00204-023-03676-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024]
Abstract
Microcystin-LR (MC-LR) is a toxin produced by cyanobacteria, which is widely distributed in eutrophic water bodies and has multi-organ toxicity. Previous cytotoxicity studies have mostly elucidated the effects of MC-LR on intracellular-related factors, proteins, and DNA at the molecular level. However, there have been few studies on the adverse effects of MC-LR on cell ultrastructure and function. Therefore, research on the cytotoxicity of MC-LR in recent years was collected and summarized. It was found that MC-LR can induce a series of cytotoxic effects, including decreased cell viability, induced autophagy, apoptosis and necrosis, altered cell cycle, altered cell morphology, abnormal cell migration and invasion as well as leading to genetic damage. The above cytotoxic effects were related to the damage of various ultrastructure and functions such as cell membranes and mitochondria. Furthermore, MC-LR can disrupt cell ultrastructure and function by inducing oxidative stress and inhibiting protein phosphatase activity. In addition, the combined toxic effects of MC-LR and other environmental pollutants were investigated. This review explored the toxic targets of MC-LR at the subcellular level, which will provide new ideas for the prevention and treatment of multi-organ toxicity caused by MC-LR.
Collapse
Affiliation(s)
- Kangfeng Ge
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Xingde Du
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Haohao Liu
- Department of Public Health, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450001, China
| | - Ruiyang Meng
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Chunrui Wu
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Zongxin Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Xiao Liang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Jun Yang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China
| | - Huizhen Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, 450001, China.
| |
Collapse
|
|
20
|
Jing J, Wang J, Xiang X, Yin S, Tang J, Wang L, Jia G, Liu G, Chen X, Tian G, Cai J, Kang B, Che L, Zhao H. Selenomethionine alleviates chronic heat stress-induced breast muscle injury and poor meat quality in broilers via relieving mitochondrial dysfunction and endoplasmic reticulum stress. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2024; 16:363-375. [PMID: 38362514 PMCID: PMC10867585 DOI: 10.1016/j.aninu.2023.12.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 12/18/2023] [Accepted: 12/25/2023] [Indexed: 02/17/2024]
Abstract
In the present study, the chronic heat stress (CHS) broiler model was developed to investigate the potential protection mechanism of organic selenium (selenomethionine, SeMet) on CHS-induced skeletal muscle growth retardation and poor meat quality. Four hundred Arbor Acres male broilers (680 ± 70 g, 21 d old) were grouped into 5 treatments with 8 replicates of 10 broilers per replicate. Broilers in the control group were raised in a thermoneutral environment (22 ± 2 °C) and fed with a basal diet. The other four treatments were exposed to hyperthermic conditions (33 ± 2 °C, 24 h in each day) and fed on the basal diet supplied with SeMet at 0.0, 0.2, 0.4, and 0.6 mg Se/kg, respectively, for 21 d. Results showed that CHS reduced (P < 0.05) the growth performance, decreased (P < 0.05) the breast muscle weight and impaired the meat quality of breast muscle in broilers. CHS induced protein metabolic disorder in breast muscle, which increased (P < 0.05) the expression of caspase 3, caspase 8, caspase 9 and ubiquitin proteasome system related genes, while decreased the protein expression of P-4EBP1. CHS also decreased the antioxidant capacity and induced mitochondrial stress and endoplasmic reticulum (ER) stress in breast muscle, which increased (P < 0.05) the ROS levels, decreased the concentration of ATP, increased the protein expression of HSP60 and CLPX, and increased (P < 0.05) the expression of ER stress biomarkers. Dietary SeMet supplementation linearly increased (P < 0.05) breast muscle Se concentration and exhibited protective effects via up-regulating the expression of the selenotranscriptome and several key selenoproteins, which increased (P < 0.05) body weight, improved meat quality, enhanced antioxidant capacity and mitigated mitochondrial stress and ER stress. What's more, SeMet suppressed protein degradation and improved protein biosynthesis though inhibiting the caspase and ubiquitin proteasome system and promoting the mTOR-4EBP1 pathway. In conclusion, dietary SeMet supplementation increases the expression of several key selenoproteins, alleviates mitochondrial dysfunction and ER stress, improves protein biosynthesis, suppresses protein degradation, thus increases the body weight and improves meat quality of broilers exposed to CHS.
Collapse
Affiliation(s)
- Jinzhong Jing
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Jiayi Wang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Xiaoyu Xiang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Shenggang Yin
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Jiayong Tang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Longqiong Wang
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Gang Jia
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Guangmang Liu
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Xiaoling Chen
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Gang Tian
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Jingyi Cai
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Bo Kang
- College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Lianqiang Che
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| | - Hua Zhao
- Key Laboratory for Animal Disease-Resistance Nutrition of Ministry of Education, of China Ministry of Agriculture and Rural Affairs, of Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, Sichuan, China
| |
Collapse
|
|
21
|
Chen B, Liu X, Wu S, Hou J, Shang P, Chamba Y, Mehmood K, Fouad D, Li Y, Zhang H. Inhalation of ammonia promotes apoptosis and induces autophagy in hepatocytes via Bax/BCl-2 and m-TOR/ATG5/LC-3bII axes. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 912:169036. [PMID: 38061639 DOI: 10.1016/j.scitotenv.2023.169036] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 11/20/2023] [Accepted: 11/30/2023] [Indexed: 01/18/2024]
Abstract
Ammonia (NH3) is an irritating gas and atmospheric pollutant that endangers the health of humans and animals by stimulating respiratory tract's mucosa and causing liver damage. However, physiological role of ammonia gas in hepatotoxicity remains unclear. To investigate the hepatotoxic effects of inhaled ammonia gas, experiments were conducted using mouse model exposed to 100 ppm of ammonia gas for 21 days. The exposed mice exhibited signs of depression, emaciation, and reduced growth. This study revealed that inhalation of ammonia led to significant decrease in water (P < 0.0001) and food intake (P < 0.05), resulting in slower growth. Histopathological analysis showed that ammonia stress alters the microstructure of the liver by enlarging the gap between hepatic lobule and fibrosis. Moreover, ammonia-induced stress significantly reduces the expression of the anti-apoptotic protein BCl-2 (P < 0.001), while elevates the mRNA expression of the pro-apoptotic gene Bax (P < 0.001). Furthermore, ammonia inhalation significantly increases the protein expression of LC-3bII (P < 0.05) and the mRNA expression of autophagy-related gene 5 (ATG5) (P < 0.05) and p62 (P < 0.05) while remarkably decreases the mRNA expression of mammalian target of rapamycin (m-TOR) (P < 0.05). In conclusion, this study demonstrates that inhalation of ammonia gas causes liver damage and suggests autophagy happening via m-TOR/p62/LC-3bII and pro-apoptosis effect mediated by Bax/BCl-2 in the liver damage caused by ammonia inhalation. Our study provides a new perspective on ammonia-induced hepatotoxicity.
Collapse
Affiliation(s)
- Bohan Chen
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Xiaoqing Liu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Shouyan Wu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Junhong Hou
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Peng Shang
- Animal Science College, Tibet Agriculture & Animal Husbandry University, Linzhi 860000, China
| | - Yangzom Chamba
- Animal Science College, Tibet Agriculture & Animal Husbandry University, Linzhi 860000, China
| | - Khalid Mehmood
- Faculty of Veterinary and Animal Sciences, The Islamia University of Bahawalpur, 63100, Pakistan
| | - Dalia Fouad
- Department of Zoology, College of Science, King Saud University, PO Box 22452, Riyadh 11495, Saudi Arabia
| | - Ying Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
| | - Hui Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
| |
Collapse
|
|
22
|
Cai Q, Chen M, Wang B, Wang J, Xia L, Li J. Phytosphingosine inhibits the growth of lung adenocarcinoma cells by inducing G2/M-phase arrest, apoptosis, and mitochondria-dependent pathway cell death in vitro and in vivo. Chem Biol Interact 2024; 387:110795. [PMID: 37956922 DOI: 10.1016/j.cbi.2023.110795] [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: 06/08/2023] [Revised: 10/23/2023] [Accepted: 11/03/2023] [Indexed: 11/21/2023]
Abstract
In order to search for novel antitumor drugs with high efficiency and low toxicity, the anti-lung cancer activity of phytosphingosine was studied. Phytosphingosine is widely distributed in fungi, plants, animals, and has several biological activities, including anti-inflammation and anti-tumor. However, its anti-lung cancer activity needs to be further investigated. The effects and pharmacological mechanisms of phytosphingosine on lung cancer treatment were investigated both in vitro and in vivo. The results showed that phytosphingosine inhibited the growth of lung cancer cell lines. Phytosphingosine induced apoptosis through a mitochondria-mediated pathway, phytosphingosine arrested the cell cycle at the G2/M phase and induced apoptosis in a dose-dependent manner by increasing Bax/Bcl-2 ratio, which caused the decrease of mitochondrial membrane potential to promote the release of cytochrome C, caspase 9 and 3, and degrade PARP in A549 cells. The results showed that phytosphingosine could damage the mitochondrial functions, increase ROS levels, and arrest the cell cycle at the G2/M stages. Finally, phytosphingosine also inhibited the growth of tumor in mice. Taken together, phytosphingosine suppressed the growth of lung cancer cells both in vitro and in vivo and had potential application in the research and development of antitumor drugs. The aim of the present study was to explain the theoretical basis of phytosphingosine therapy for lung cancer and providing new possibilities for lung cancer treatment.
Collapse
Affiliation(s)
- Qi Cai
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China.
| | - Min Chen
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China.
| | - Bo Wang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China.
| | - Jin Wang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China.
| | - Lijie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China.
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China.
| |
Collapse
|
|
23
|
Klemmensen MM, Borrowman SH, Pearce C, Pyles B, Chandra B. Mitochondrial dysfunction in neurodegenerative disorders. Neurotherapeutics 2024; 21:e00292. [PMID: 38241161 PMCID: PMC10903104 DOI: 10.1016/j.neurot.2023.10.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Accepted: 10/07/2023] [Indexed: 01/21/2024] Open
Abstract
Recent advances in understanding the role of mitochondrial dysfunction in neurodegenerative diseases have expanded the opportunities for neurotherapeutics targeting mitochondria to alleviate symptoms and slow disease progression. In this review, we offer a historical account of advances in mitochondrial biology and neurodegenerative disease. Additionally, we summarize current knowledge of the normal physiology of mitochondria and the pathogenesis of mitochondrial dysfunction, the role of mitochondrial dysfunction in neurodegenerative disease, current therapeutics and recent therapeutic advances, as well as future directions for neurotherapeutics targeting mitochondrial function. A focus is placed on reactive oxygen species and their role in the disruption of telomeres and their effects on the epigenome. The effects of mitochondrial dysfunction in the etiology and progression of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease are discussed in depth. Current clinical trials for mitochondria-targeting neurotherapeutics are discussed.
Collapse
Affiliation(s)
- Madelyn M Klemmensen
- University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA
| | - Seth H Borrowman
- Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Colin Pearce
- Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Benjamin Pyles
- Aper Funis Research, Union River Innovation Center, Ellsworth, ME 04605, USA
| | - Bharatendu Chandra
- University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA 52242, USA; Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.
| |
Collapse
|
|
24
|
Lu MX, He FJ, Zhu F, Du YZ. The regulation of inhibitor of apoptosis proteins (IAPs) during the apoptosis of Cotesia chilonis. Front Physiol 2023; 14:1328167. [PMID: 38192740 PMCID: PMC10773855 DOI: 10.3389/fphys.2023.1328167] [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: 10/26/2023] [Accepted: 12/07/2023] [Indexed: 01/10/2024] Open
Abstract
Inhibitor of apoptosis proteins (IAPs) are crucial components of apoptosis that perform vital roles in the regulation of caspase activity in organisms. In this study, two IAPs genes were identified from Cotesia chilonis, the dominant parasitic wasp of Chilo suppressalis. CcIAP1 gene is a typical IAP and contains two BIR domains and a RING domain, whereas CcIAP gene is an atypical IAP1 only containing two BIR domains. Phylogenetic analysis indicated that CcIAP1 and CcIAP were grouped with other Hymenopteran IAPs and IAP1 in C. suppressalis. Real-time quantitative PCR revealed that CcIAP1 and CcIAP genes were both highly induced at -6°C and 30°C, and expression was highest at the third instar stage. The expression of CcIAP1 and CcIAP genes were significantly induced during parasitism of C. suppressalis, and the 7-d time point resulted in the highest expression levels for both genes, in which was an advanced stage of larval development of C. chilonis. RNAi experiments showed that CcIAP1 gene was the key IAP in the regulation of apoptosis of C. chilonis and its host. In conclusion, CcIAP1 and CcIAP correlate with the development of C. chilonis and their responses to temperature stress.
Collapse
Affiliation(s)
- Ming-Xing Lu
- College of Plant Protection and Institute of Applied Entomology, Yangzhou University, Yangzhou, China
| | - Fu-Jing He
- Plant Protection and Quarantine Station of Jiangsu Province, Nanjing, China
| | - Feng Zhu
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Yangzhou University, Yangzhou, China
| | - Yu-Zhou Du
- College of Plant Protection and Institute of Applied Entomology, Yangzhou University, Yangzhou, China
- Wuxi Vocational Institute of Commerce, Wuxi, China
| |
Collapse
|
|
25
|
Sagadevan S, Oh WC. Comprehensive utilization and biomedical application of MXenes - A systematic review of cytotoxicity and biocompatibility. J Drug Deliv Sci Technol 2023; 85:104569. [DOI: 10.1016/j.jddst.2023.104569] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
|
|
26
|
Wu T, Yan S, Yeh YW, Fang Y, Xiang Z. FcγR-dependent apoptosis regulates tissue persistence of mucosal and connective tissue mast cells. Eur J Immunol 2023; 53:e2250221. [PMID: 37137469 DOI: 10.1002/eji.202250221] [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: 10/18/2022] [Revised: 04/29/2023] [Accepted: 05/02/2023] [Indexed: 05/05/2023]
Abstract
Rodent mast cells can be divided into two major subtypes: the mucosal mast cell (MMC) and the connective tissue mast cell (CTMC). A decade-old observation revealed a longer lifespan for CTMC compared with MMC. The precise mechanisms underlying such differential tissue persistence of mast cell subsets have not been described. In this study, we have discovered that mast cells expressing only one receptor, either FcγRIIB or FcγRIIIA, underwent caspase-independent apoptosis in response to IgG immune complex treatment. Lower frequencies of CTMC in mice that lacked either FcγRIIB or FcγRIIIA compared with WT mice were recorded, especially in aged mice. We proposed that this paradigm of FcγR-mediated mast cell apoptosis could account for the more robust persistence of CTMC, which express both FcγRIIB and FcγRIIIA, than MMC, which express only FcγRIIB. Importantly, we reproduced these results using a mast cell engraftment model, which ruled out possible confounding effects of mast cell recruitment or FcγR expression by other cells on mast cell number regulation. In conclusion, our work has uncovered an FcγR-dependent mast cell number regulation paradigm that might provide a mechanistic explanation for the long-observed differential mast cell subset persistence in tissues.
Collapse
Affiliation(s)
- Tongqian Wu
- Center for Clinical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, P. R. China
- School for Clinical Laboratory, Guizhou Medical University, Guiyang, 550004, P. R. China
| | - Shirong Yan
- Center for Clinical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, P. R. China
- School for Clinical Laboratory, Guizhou Medical University, Guiyang, 550004, P. R. China
| | - Yu-Wen Yeh
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Hong Kong, P. R. China
| | - Yu Fang
- Center for Clinical Laboratory, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, P. R. China
- School for Clinical Laboratory, Guizhou Medical University, Guiyang, 550004, P. R. China
| | - Zou Xiang
- Department of Health Technology and Informatics, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Hong Kong, P. R. China
- Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
|
27
|
Velazquez-Soto H, Groman-Lupa S, Cruz-Aguilar M, Salazar AL, Zenteno JC, Jimenez-Martinez MC. Exogenous CFH Modulates Levels of Pro-Inflammatory Mediators to Prevent Oxidative Damage of Retinal Pigment Epithelial Cells with the At-Risk CFH Y402H Variant. Antioxidants (Basel) 2023; 12:1540. [PMID: 37627535 PMCID: PMC10451625 DOI: 10.3390/antiox12081540] [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: 06/13/2023] [Revised: 07/13/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Age-related macular degeneration (AMD) is a complex, progressive degenerative retinal disease. Retinal pigment epithelial (RPE) cells play an important role in the immune defense of the eye and their dysfunction leads to the progressive irreversible degeneration of photoreceptors. Genetic factors, chronic inflammation, and oxidative stress have been implicated in AMD pathogenesis. Oxidative stress causes RPE injury, resulting in a chronic inflammatory response and cell death. The Y402H polymorphism in the complement factor H (CFH) protein is an important risk factor for AMD. However, the functional significance of CFH Y402H polymorphism remains unclear. In the present study, we investigated the role of CFH in the pro-inflammatory response using an in vitro model of oxidative stress in the RPE with the at-risk CFH Y402H variant. ARPE-19 cells with the at-risk CFH Y402H variant were highly susceptible to damage caused by oxidative stress, with increased levels of inflammatory mediators and pro-apoptotic factors that lead to cell death. Pretreatment of the ARPE-19 cell cultures with exogenous CFH prior to the induction of oxidative stress prevented damage and cell death. This protective effect may be related to the negative regulation of pro-inflammatory cytokines. CFH contributes to cell homeostasis and is required to modulate the pro-inflammatory cytokine response under oxidative stress in the ARPE-19 cells with the at-risk CFH Y402H variant.
Collapse
Affiliation(s)
- Henry Velazquez-Soto
- Department of Immunology, Research Unit, Institute of Ophthalmology “Conde de Valenciana Foundation”, Mexico City 06800, Mexico; (H.V.-S.)
| | - Sergio Groman-Lupa
- Department of Immunology, Research Unit, Institute of Ophthalmology “Conde de Valenciana Foundation”, Mexico City 06800, Mexico; (H.V.-S.)
| | - Marisa Cruz-Aguilar
- Department of Immunology, Research Unit, Institute of Ophthalmology “Conde de Valenciana Foundation”, Mexico City 06800, Mexico; (H.V.-S.)
| | - Alberto L. Salazar
- Department of Immunology, Research Unit, Institute of Ophthalmology “Conde de Valenciana Foundation”, Mexico City 06800, Mexico; (H.V.-S.)
| | - Juan C. Zenteno
- Department of Genetics, Institute of Ophthalmology “Conde de Valenciana Foundation”, Mexico City 06800, Mexico
- Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | - Maria C. Jimenez-Martinez
- Department of Immunology, Research Unit, Institute of Ophthalmology “Conde de Valenciana Foundation”, Mexico City 06800, Mexico; (H.V.-S.)
- Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| |
Collapse
|
|
28
|
Bassal MA. The Interplay between Dysregulated Metabolism and Epigenetics in Cancer. Biomolecules 2023; 13:944. [PMID: 37371524 DOI: 10.3390/biom13060944] [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: 04/24/2023] [Revised: 05/21/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023] Open
Abstract
Cellular metabolism (or energetics) and epigenetics are tightly coupled cellular processes. It is arguable that of all the described cancer hallmarks, dysregulated cellular energetics and epigenetics are the most tightly coregulated. Cellular metabolic states regulate and drive epigenetic changes while also being capable of influencing, if not driving, epigenetic reprogramming. Conversely, epigenetic changes can drive altered and compensatory metabolic states. Cancer cells meticulously modify and control each of these two linked cellular processes in order to maintain their tumorigenic potential and capacity. This review aims to explore the interplay between these two processes and discuss how each affects the other, driving and enhancing tumorigenic states in certain contexts.
Collapse
Affiliation(s)
- Mahmoud Adel Bassal
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
- Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA
| |
Collapse
|
|
29
|
Zhuang J, Wang B, Chen H, Zhang K, Li N, Zhao N, Tang BZ. Efficient NIR-II Type-I AIE Photosensitizer for Mitochondria-Targeted Photodynamic Therapy through Synergistic Apoptosis-Ferroptosis. ACS NANO 2023; 17:9110-9125. [PMID: 37144959 DOI: 10.1021/acsnano.2c12319] [Citation(s) in RCA: 78] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Hypoxia, the hallmark of malignant tumors, has been recognized as a major obstacle for photodynamic therapy (PDT). Precisely targeting cancer cells in intricate biological scenarios by a hypoxia-resistant photosensitizer (PS) is the cornerstone to conquer the inevitable tumor recurrence and metastasis. Herein, we describe an organic NIR-II PS (TPEQM-DMA) possessing potent type-I phototherapeutic efficacy to overcome the intrinsic pitfalls of PDT in combating hypoxic tumors. TPEQM-DMA exhibited prominent NIR-II emission (>1000 nm) with an aggregation-induced emission feature and efficiently produced superoxide anion and hydroxyl radical in the aggregate state under white light irradiation exclusively through a low-O2-dependent type-I photochemical process. The suitable cationic nature assisted TPEQM-DMA to accumulate in cancerous mitochondria. Meanwhile, the PDT of TPEQM-DMA impaired the cellular redox homeostasis, led to the mitochondrial dysfunction, and raised the level of lethal peroxidized lipids, which induced cellular apoptosis and ferroptosis. This synergistic cell death modality enabled TPEQM-DMA to suppress the growth of cancer cells, multicellular tumor spheroids, and tumors. To improve the pharmacological properties of TPEQM-DMA, TPEQM-DMA nanoparticles were prepared by encapsulation of polymer. In vivo experiments proved the appealing NIR-II fluorescence imaging-guided PDT effect of TPEQM-DMA nanoparticles for tumors.
Collapse
Affiliation(s)
- Jiabao Zhuang
- Key Laboratory of Applied Surface and Colloid Chemistry of MOE, Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710119, China
| | - Bing Wang
- Key Laboratory of Applied Surface and Colloid Chemistry of MOE, Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710119, China
| | - Huan Chen
- Key Laboratory of Applied Surface and Colloid Chemistry of MOE, Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710119, China
| | - Keyi Zhang
- Key Laboratory of Applied Surface and Colloid Chemistry of MOE, Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710119, China
| | - Nan Li
- Key Laboratory of Applied Surface and Colloid Chemistry of MOE, Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710119, China
| | - Na Zhao
- Key Laboratory of Applied Surface and Colloid Chemistry of MOE, Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Chemical Engineering, Shaanxi Normal University, Xi'an 710119, China
| | - Ben Zhong Tang
- School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China
| |
Collapse
|
|
30
|
Khan T, Waseem R, Zehra Z, Aiman A, Bhardwaj P, Ansari J, Hassan MI, Islam A. Mitochondrial Dysfunction: Pathophysiology and Mitochondria-Targeted Drug Delivery Approaches. Pharmaceutics 2022; 14:pharmaceutics14122657. [PMID: 36559149 PMCID: PMC9785072 DOI: 10.3390/pharmaceutics14122657] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/02/2022] Open
Abstract
Mitochondria are implicated in a wide range of functions apart from ATP generation, and, therefore, constitute one of the most important organelles of cell. Since healthy mitochondria are essential for proper cellular functioning and survival, mitochondrial dysfunction may lead to various pathologies. Mitochondria are considered a novel and promising therapeutic target for the diagnosis, treatment, and prevention of various human diseases including metabolic disorders, cancer, and neurodegenerative diseases. For mitochondria-targeted therapy, there is a need to develop an effective drug delivery approach, owing to the mitochondrial special bilayer structure through which therapeutic molecules undergo multiple difficulties in reaching the core. In recent years, various nanoformulations have been designed such as polymeric nanoparticles, liposomes, inorganic nanoparticles conjugate with mitochondriotropic moieties such as mitochondria-penetrating peptides (MPPs), triphenylphosphonium (TPP), dequalinium (DQA), and mitochondrial protein import machinery for overcoming barriers involved in targeting mitochondria. The current approaches used for mitochondria-targeted drug delivery have provided promising ways to overcome the challenges associated with targeted-drug delivery. Herein, we review the research from past years to the current scenario that has identified mitochondrial dysfunction as a major contributor to the pathophysiology of various diseases. Furthermore, we discuss the recent advancements in mitochondria-targeted drug delivery strategies for the pathologies associated with mitochondrial dysfunction.
Collapse
Affiliation(s)
- Tanzeel Khan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Rashid Waseem
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Zainy Zehra
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Ayesha Aiman
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
- Department of Biosciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Priyanka Bhardwaj
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Jaoud Ansari
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Md. Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Asimul Islam
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
- Correspondence:
| |
Collapse
|
|
31
|
[STE029 Overcomes EGFR-TKI Resistance in Human Lung Adenocarcinoma]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:771-781. [PMID: 36419390 PMCID: PMC9720680 DOI: 10.3779/j.issn.1009-3419.2022.102.46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Acquired and primary resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is still the bottleneck of clinical treatment of advanced non-small cell lung cancer (NSCLC). STE029 is a novel anticancer drug which consists of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) inhibitor and novel cancer cell membrane targeting molecular. This study aimed to investigate the reversal mechanism of EGFR-TKI resistance by STE029 in lung adenocarcinoma. METHODS CCK8 test was used to test the cell viability and survival rate of EGFR mutated PC9 cell (Gefitinib sensitive), PC9/BB4 cell (acquired Gefitinib resistant), and EGFR wild type A549 cell after treatment of STE029, Gefitinib or combination of both. EdU test was applied to detect changes in cell cycle and Hoechst 33258 was applied to detect apoptosis rate in overcoming the EGFR-TKI resistance. The activity of EGFR/PI3K/Akt, cell cycle and apoptosis signal pathways were examined. In vivo, nude mice were exposed to STE029, Gefitinib and STE029+Gefitinib for 5 wk. And the the tumor volume was measured and tumor weight was obtained on the last day. RESULTS (1) PC9 cells was highly sensitive to Gefitinib, while PC9/BB4 and A549 cell showed significant resistance to Gefitinib treatment; (2) STE029+Gefitinib treatment could significantly decrease the 50% inhibitory concentrarion (IC₅₀) of Gefitinib in PC9, PC9/BB4 and A549 cells (P<0.05, respectively); (3) In PC9 and PC9/BB4 cells, STE029+Gefitinib can block cell cycle and inhibit cell proliferation (P<0.001), while there was no significant difference in apoptosis rate among three drug intervention groups (P>0.05); However, apoptosis rate was increased in STE029+Gefitinib group in A549 cell (P<0.01), while no significance detected in cell proliferation (P>0.05). (4) In PC9 and PC9/BB4 cells, the combination of STE029 and Gefitinib could downregulate p-EGFR, p-Akt, p-Cyclin D1 and Cyclin D1 (P<0.001), and upregulate the expression of GSK-3β (P<0.001), and the expression of cleaved caspase-8, caspase-8 cleaved caspase-9, caspase-9 showed no difference among groups (P>0.05). In A549 cells, the combination of STE029 and Gefitinib could downregulate p-Akt (P<0.001) and upregulate cleaved caspase-8 and cleaved caspase-9 (P<0.001); (5)In vivo, the combination of STE029 and Gefitinib effectively inhibited tumor development and progression compared to STE029 alone or Gefitinib alone, with significant difference (P<0.05) in PC9 and PC9/BB4 xenografted tumor. CONCLUSIONS STE029 could sensitize Gefitinib by inhibiting EGFR/PI3K/Akt pathway, blocking the tumor cell cycle and proliferation and inducing apoptosis through caspase-8 and caspase-9 dependent pathway. STE029 deserves further investigations in overcoming EGFR-TKI resistance in lung cancer.
Collapse
|
|
32
|
De Silva E, Paul M, Kim H. Apoptosis in platelets is independent of the actin cytoskeleton. PLoS One 2022; 17:e0276584. [PMID: 36378629 PMCID: PMC9665360 DOI: 10.1371/journal.pone.0276584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 10/11/2022] [Indexed: 11/17/2022] Open
Abstract
Homeostasis between platelet production and clearance is essential for human health. A critical facet of the balance that facilitates platelet clearance from the circulation is apoptosis (programmed cell death). The precise cellular mechanisms that underpin platelet apoptosis are not defined. In nucleated cells, reorganization of the actin cytoskeleton is known to regulate platelet apoptosis. However, the role of the actin cytoskeleton in regulating apoptosis in platelets has not been extensively studied as they are anucleate and exhibit a distinctive physiology. Here, apoptosis was induced in washed human platelets using ABT-737, a BH3-mimetic drug. Mitochondrial depolarization was measured using the ratiometric dye JC-1; surface phosphatidylserine (PS) exposure was measured by annexin V binding; caspase-3 activation was measured by Western blotting. All three apoptotic markers were unaffected by the presence of either the actin depolymerizing drug cytochalasin D or the actin polymerizing drug jasplakinolide. Moreover, platelets were isolated from wild-type (WT) mice and mice deficient in gelsolin (Gsn), an actin-binding protein that is essential for normal cytoskeletal remodeling. In response to ABT-737, gelsolin-null (Gsn-/-) platelets initially showed accelerated PS exposure relative to WT platelets, however, both WT and Gsn-/- platelets exhibited similar levels of mitochondrial depolarization and caspase-3 activation in response to ABT-737. We conclude that ABT-737 induces established markers of platelet apoptosis in an actin-independent manner.
Collapse
Affiliation(s)
- Enoli De Silva
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Manoj Paul
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hugh Kim
- Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
- * E-mail:
| |
Collapse
|
|
33
|
Li S, Luo X, Liao Z, Xu H, Liang M, Mai K, Zhang Y. Additional supplementation of sulfur-containing amino acids in the diets improves the intestinal health of turbot fed high-lipid diets. FISH & SHELLFISH IMMUNOLOGY 2022; 130:368-379. [PMID: 36115604 DOI: 10.1016/j.fsi.2022.09.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/29/2022] [Accepted: 09/10/2022] [Indexed: 06/15/2023]
Abstract
An eight-week feeding trial was conducted to investigate the effects of diets supplemented with three sulfur-containing amino acids (SAA), namely, methionine, cysteine, and taurine, on the intestinal health status of juvenile turbot (Scophthalmus maximus) fed high-lipid diets. Four diets were formulated, namely, a high-lipid control diet (16% lipid, HL) and three SAA-supplemented diets, which were formulated by supplementing 1.5% methionine (HLM), 1.5% cysteine (HLC), and 1.5% taurine (HLT) into the HL control diet, respectively. Each diet was assigned to triplicate tanks, and each tank was stocked with 30 juvenile fish (appr. initial weight, 8 g). The histological and morphometric results showed that dietary SAA supplementation obviously improved the intestinal morphology and integrity, in particular as reflected by higher height of microvilli and mucosal folds. Dietary SAA supplementation, in particular cysteine, up-regulated the gene expression of mucin-2 and tight junction proteins (ZO-1, Tricellilun and JAM). Dietary SAA supplementation remarkably down-regulated the gene expression of apoptosis-related factors such as p38, JNK, and Bax, expression of pro-inflammatory factors (e.g., NF-κB, AP-1 IL-1β, IL-8, and TNF-α). SAA supplementation resulted in higher antioxidative abilities in the intestine. Additionally, dietary SAA supplementation largely altered the communities of intestinal microbiota. Compared with the HL group, higher relative abundance of potential beneficial bacteria, and lower relative abundance of opportunistic pathogens were observed in SAA-supplemented groups. Dietary taurine supplementation significantly increased the relative abundance of Ligilactobacillus (in particular Lactobacillus murinus) and Limosilactobacillus (especially Lactobacillus reuteri). In conclusion, dietary sulfur-containing amino acids supplementation have promising potential in ameliorating the intestinal inflammation of turbot fed high-lipid diets. Especially dietary cysteine and taurine supplementation have more positive effects on the communities of the intestinal microbiota of turbot.
Collapse
Affiliation(s)
- Sihui Li
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture, The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China
| | - Xing Luo
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, China
| | - Zhangbin Liao
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, China
| | - Houguo Xu
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, China; Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, 266237, China.
| | - Mengqing Liang
- Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, China; Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, 266237, China
| | - Kangsen Mai
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture, The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China; Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, 266237, China
| | - Yanjiao Zhang
- Key Laboratory of Aquaculture Nutrition and Feed, Ministry of Agriculture, The Key Laboratory of Mariculture, Ministry of Education, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China; Qingdao National Laboratory for Marine Science and Technology, 1 Wenhai Road, Qingdao, 266237, China.
| |
Collapse
|
|
34
|
Chen X, Liu W, Li H, Zhang J, Hu C, Liu X. The adverse effect of heat stress and potential nutritional interventions. Food Funct 2022; 13:9195-9207. [PMID: 36040720 DOI: 10.1039/d2fo01813f] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Heat stress can cause tissue damage and metabolic disturbances, including intestinal and liver dysfunction, acid-base imbalance, oxidative damage, inflammatory response, and immune suppression. Serious cases can lead to heatstroke, which can be life-threatening. The body often finds it challenging to counteract these adverse effects, and traditional cooling methods are limited by the inconvenience of tool portability and the difficulty of determining the cooling endpoint. Consequently, more research was conducted to prevent and mitigate the negative effect of heat stress via nutritional intervention. This article reviewed the pathological changes and altered metabolic mechanisms caused by heat stress and discussed the protein (amino acid), vitamin, trace element, and electrolyte action pathways and mechanisms to mitigate heat stress and prevent heat-related disease. The main food sources for these nutrients and the recommended micronutrient supplementation forms were summarized to provide scientific dietary protocols for special populations.
Collapse
Affiliation(s)
- Xinwei Chen
- National Soybean Processing Industry Technology Innovation Center, School of Food and Health, Beijing Technology and Business University, Beijing, China.
| | - Wanlu Liu
- National Soybean Processing Industry Technology Innovation Center, School of Food and Health, Beijing Technology and Business University, Beijing, China.
| | - He Li
- National Soybean Processing Industry Technology Innovation Center, School of Food and Health, Beijing Technology and Business University, Beijing, China.
| | - Jian Zhang
- National Soybean Processing Industry Technology Innovation Center, School of Food and Health, Beijing Technology and Business University, Beijing, China.
| | - Changli Hu
- Jinmailang Beverage Corporation Limited, Beijing, China
| | - Xinqi Liu
- National Soybean Processing Industry Technology Innovation Center, School of Food and Health, Beijing Technology and Business University, Beijing, China.
| |
Collapse
|
|
35
|
Mandal AK. Mitochondrial targeting of potent nanoparticulated drugs in combating diseases. J Biomater Appl 2022; 37:614-633. [PMID: 35790487 DOI: 10.1177/08853282221111656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Mitochondrial dysfunction, characterized by the electron transport chain (ETC) leakage and reduced adenosine tri-phosphate synthesis, occurs primarily due to free radicals -induced mutations in either the mitochondrial deoxyribonucleic acid (mtDNA) or nuclear (n) DNA caused by pathogenic infections, toxicant exposures, adverse drug-effects, or other environmental exposures, leading to secondary dysfunction affecting ischemic, diabetic, cancerous, and degenerative diseases. In these concerns, mitochondria-targeted remedies may include a significant role in the protection and treatment of mitochondrial function to enhance its activity. Coenzyme Q10 pyridinol and pyrimidinol antioxidant analogues and other potent drug-compounds for their multifunctional radical quencher and other anti-toxic activities may take a significant therapeutic effectivity for ameliorating mitochondrial dysfunction. Moreover, the encapsulation of these bioactive ligands-attached potent compounds in vesicular system may enable them a superb biological effective for the treatment of mitochondria-targeted dysfunction-related diseases with least side effects. This review depicts mainly on mitochondrial enzymatic dysfunction and their amelioration by potent drugs with the usages of nanoparticulated delivery system against mitochondria-affected diseases.
Collapse
|
|
36
|
Pawar A, Kamble R. Design and development of novel docetaxel –loaded DQAsomes for inducing apoptosis and anti-cancer effect on the breast cancer cells, an in vitro study. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
|
|
37
|
Delgado M, Rainwater RR, Heflin B, Urbaniak A, Butler K, Davidson M, Protacio RM, Baldini G, Edwards A, Reed MR, Raney KD, Chambers TC. Primary acute lymphoblastic leukemia cells are susceptible to microtubule depolymerization in G1 and M phases through distinct cell death pathways. J Biol Chem 2022; 298:101939. [PMID: 35436470 PMCID: PMC9123221 DOI: 10.1016/j.jbc.2022.101939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 12/01/2022] Open
Abstract
Microtubule targeting agents (MTAs) are widely used cancer chemotherapeutics which conventionally exert their effects during mitosis, leading to mitotic or postmitotic death. However, accumulating evidence suggests that MTAs can also generate death signals during interphase, which may represent a key mechanism in the clinical setting. We reported previously that vincristine and other microtubule destabilizers induce death not only in M phase but also in G1 phase in primary acute lymphoblastic leukemia cells. Here, we sought to investigate and compare the pathways responsible for phase-specific cell death. Primary acute lymphoblastic leukemia cells were subjected to centrifugal elutriation, and cell populations enriched in G1 phase (97%) or G2/M phases (80%) were obtained and treated with vincristine. We found death of M phase cells was associated with established features of mitochondrial-mediated apoptosis, including Bax activation, loss of mitochondrial transmembrane potential, caspase-3 activation, and nucleosomal DNA fragmentation. In contrast, death of G1 phase cells was not associated with pronounced Bax or caspase-3 activation but was associated with loss of mitochondrial transmembrane potential, parylation, nuclear translocation of apoptosis-inducing factor and endonuclease G, and supra-nucleosomal DNA fragmentation, which was enhanced by inhibition of autophagy. The results indicate that microtubule depolymerization induces distinct cell death pathways depending on during which phase of the cell cycle microtubule perturbation occurs. The observation that a specific type of drug can enter a single cell type and induce two different modes of death is novel and intriguing. These findings provide a basis for advancing knowledge of clinical mechanisms of MTAs.
Collapse
Affiliation(s)
- Magdalena Delgado
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Randall R Rainwater
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Billie Heflin
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Alicja Urbaniak
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Kaitlynn Butler
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Mari Davidson
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Reine M Protacio
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Giulia Baldini
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Andrea Edwards
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Megan R Reed
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Kevin D Raney
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
| | - Timothy C Chambers
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
| |
Collapse
|
|
38
|
Umeda S, Kanda M, Shimizu D, Nakamura S, Sawaki K, Inokawa Y, Hattori N, Hayashi M, Tanaka C, Nakayama G, Kodera Y. Lysosomal-associated membrane protein family member 5 promotes the metastatic potential of gastric cancer cells. Gastric Cancer 2022; 25:558-572. [PMID: 35226222 DOI: 10.1007/s10120-022-01284-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 02/02/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Metastatic gastric cancer (GC) has a poor prognosis, and elucidating the molecular mechanisms involved in metastasis may lead to the development of novel therapeutic modalities. METHODS Transcriptome analysis of surgically resected metastatic tissue from GC patients and noncancerous tissue was performed to identify novel metastasis-related genes. Analyses of in vitro cell function, apoptosis, the cell cycle and cancer stemness were performed using GC cell lines with a stable knockout of a candidate gene. In vivo percutaneous, peritoneal dissemination and liver metastasis xenograft models were also generated. PCR array and proteome analyses were performed. Expression of the candidate gene was analyzed in GC tissues from 300 patients. RESULTS Lysosomal Associated Membrane Protein Family Member 5 (LAMP5) was upregulated in the metastatic tissues. LAMP5 knockout significantly suppressed proliferation, invasion, and migration of GC cells and increased apoptosis, cell cycle arrest and cancer stemness. LAMP5 knockout virtually suppressed tumor growth in in vivo percutaneous, peritoneal dissemination and liver metastasis models. EMT- and autophagy-related genes were associated with LAMP5. High LAMP5 mRNA levels were significantly associated with a worse prognosis. CONCLUSION LAMP5 plays a vital role in metastasis formation and may be a promising novel target of drug development for metastatic GC in the future.
Collapse
Affiliation(s)
- Shinichi Umeda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shunsuke Nakamura
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Koichi Sawaki
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yoshikuni Inokawa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Norifumi Hattori
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| |
Collapse
|
|
39
|
Zhao Y, Peng Y, Yang Z, Lu J, Li R, Shi Y, Du Y, Zhao Z, Hai L, Wu Y. pH-redox responsive cascade-targeted liposomes to intelligently deliver doxorubicin prodrugs and lonidamine for glioma. Eur J Med Chem 2022; 235:114281. [PMID: 35344903 DOI: 10.1016/j.ejmech.2022.114281] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 11/26/2022]
Abstract
To synergistically treat glioma with a combination chemotherapy, we design and prepare novel cascade-targeted liposomes (Lip-TPGS) using glucose and triphenylphosphonium (TPP) as targeting moieties, which could intelligently deliver redox-sensitive doxorubicin (DOX) prodrugs (SDOX) and chemotherapeutic sensitizer lonidamine (LND). The pH-responsive ligand Chol-TPG modified by PEGylated glucose can overcome the blood-brain barrier and reach tumor cells. Combined with the modification of mitochondria targeting ligand (Chol-TPP), Lip-TPGS are endowed with pH-responsive charge regulation function and multi-stage targeting abilities. After triggered by the excessive glutathione in tumor cells, Lip-TPGS could sufficiently release the parent drugs DOX, which would significantly reduce side effects without compromising anti-glioma efficacy. Therefore, Lip-TPGS possess these characteristics: good pharmacokinetic behavior, superior brain targeting ability, specific tumor recognition and internalization capability, and strong endo/lysosome escaping and mitochondria targeting potential. Furthermore, Lip-TPGS exhibit significant advantages on anti-glioma by inhibiting proliferation, promoting apoptosis, inducing mitochondria dysfunction, inhibiting migration and invasion, prolonging the survival time, narrowing tumor areas, limiting lung metastasis, and reducing toxicity to normal organs. In summary, Lip-TPGS, with cascade targeting abilities from tissue/cell to organelle levels and highly controlled drug release properties, would become a promising drug delivery system for glioma treatment.
Collapse
Affiliation(s)
- Yi Zhao
- Department of Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Yao Peng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Zhongzhen Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Jiaqi Lu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Ru Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yuesen Shi
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yaxin Du
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Ze Zhao
- Department of Orthopedics, The First Affiliated Hospital of Henan Polytechnic University (the Second People's Hospital of Jiaozuo City), Jiaozuo, 454001, China
| | - Li Hai
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yong Wu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| |
Collapse
|
|
40
|
Apoptotic mechanism in human brain microvascular endothelial cells triggered by 4'-iodo-α-pyrrolidinononanophenone: Contribution of decrease in antioxidant properties. Toxicol Lett 2022; 355:127-140. [PMID: 34863860 DOI: 10.1016/j.toxlet.2021.11.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/08/2021] [Accepted: 11/30/2021] [Indexed: 11/20/2022]
Abstract
In this study, we newly synthesized four α-pyrrolidinononanophenone (α-PNP) derivatives [4'-halogenated derivatives and α-pyrrolidinodecanophenone (α-PDP)], and then performed the structure-cytotoxicity relationship analyses. The results showed the rank order for the cytotoxic effects, α-PNP < α-PDP < 4'-fluoro-α-PNP < 4'-chrolo-α-PNP < 4'-bromo-α-PNP < 4'-iodo-α-PNP (I-α-PNP), and suggest that cytotoxicities of 4'-halogenated derivatives were more intensive than that of elongation of the hydrocarbon chain (α-PDP). We also surveyed the apoptotic mechanism of I-α-PNP in brain microvascular endothelial (HBME) cells that are utilized as the in vitro model of the blood-brain barrier. HBME cell treatment with I-α-PNP facilitated the apoptotic events (caspase-3 activation, externalization of phosphatidylserine, and DNA fragmentation), which were almost completely abolished by pretreating with antioxidants. In addition, the immunofluorescent staining revealed the enhanced production of hydroxyl radical in mitochondria by the I-α-PNP treatment, inferring that the I-α-PNP treatment triggers the apoptotic mechanism dependent on the enhanced ROS production in mitochondria. The treatment with I-α-PNP increased the production of cytotoxic aldehyde 4-hydroxy-2-nonenal and decreased the amount of reduced glutathione. Additionally, the treatment decreased the 26S proteasome-based proteolytic activities and aggresome formation. These results suggest that decrease in the antioxidant properties is also ascribable to HBME cell apoptosis elicited by I-α-PNP.
Collapse
|
|
41
|
Interferon regulatory factor-1 regulates cisplatin-induced apoptosis and autophagy in A549 lung cancer cells. Med Oncol 2022; 39:38. [PMID: 35092496 PMCID: PMC8800914 DOI: 10.1007/s12032-021-01638-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/23/2021] [Indexed: 11/15/2022]
Abstract
This study aimed to investigate the expression and function of interferon regulatory factor-1 (IRF-1) in non-small cell lung cancer (NSCLC). IRF-1 expression and its prognostic value were investigated through bioinformatic analysis. The protein expression levels of IRF-1, cleaved caspase 3, and LC3-I/II were analyzed by western blotting. A lentiviral vector was used to overexpress or knockdown IRF-1 in vitro. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were analyzed by JC-1 and DCFH-DA staining, respectively. ATP, SOD, MDA, cell viability, LDH release, and caspase 3 activity were evaluated using commercial kits. Compared to the levels in normal tissues, IRF-1 expression was significantly lower in lung cancer tissues and was a prognostic factor for NSCLC. Cisplatin treatment-induced IRF-1 activation, ROS production, ATP depletion, SOD consumption, and MDA accumulation in A549 lung cancer cells. IRF-1 overexpression promoted mitochondrial depolarization, oxidative stress, and apoptotic cell death and inhibited autophagy in A549 cells, and these effects could be reversed by IRF-1 knockdown. These data suggest that IRF-1 regulates apoptosis, autophagy and oxidative stress, which might be served as a potential target for increasing chemotherapy sensitivity of lung cancer.
Collapse
|
|
42
|
Zhu S, Liu Y, Li Y, Yi J, Yang B, Li Y, Ouyang Z, Liu B, Shang P, Mehmood K, Abbas RZ, Ahmed S, Chang YF, Guo J, Pan J, Hu L, Tang Z, Li Y, Zhang H. The potential risks of herbicide butachlor to immunotoxicity via induction of autophagy and apoptosis in the spleen. CHEMOSPHERE 2022; 286:131683. [PMID: 34351278 DOI: 10.1016/j.chemosphere.2021.131683] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/22/2021] [Accepted: 07/25/2021] [Indexed: 06/13/2023]
Abstract
Butachlor being an important member of chloroacetanilide herbicides, is frequently used in agriculture to control unwanted weeds. Exposure to butachlor can induce cancer, human lymphocyte aberration, and immunotoxic effects in animals. The current experimental trial was executed to determine the potential risks of herbicide butachlor to immunotoxicity and its mechanism of adverse effects on the spleen. For this purpose, mice were exposed to 8 mg/kg butachlor for 28 days, and the toxicity of butachlor on the spleen of mice was evaluated. We found that butachlor exposure led to an increase in serum ALB, GLU, TC, TG, and TP and changes in the morphological structure of the spleen of mice. More importantly, results showed that butachlor significantly increased the expression level of ATG-5, decreased the protein expression of LC3B and M-TOR, and significantly decreased the mRNA content of M-TOR and p62. Results revealed that the mRNA contents of APAF-1, CYTC, and CASP-9 related genes were significantly decreased after butachlor treatment. Subsequently, the mRNA levels of inflammatory cytokines (IL-1β, TNF-α, IL-10) were reduced in the spleen of treated mice. This study suggested that butachlor induce spleen toxicity and activate the immune response of spleen tissue by targeting the CYTC/BCL2/M-TOR pathway and caspase cascading activation of spleen autophagy and apoptosis pathways which may ultimately lead to immune system disorders.
Collapse
Affiliation(s)
- Shanshan Zhu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Yingwei Liu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Yangwei Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Jiangnan Yi
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Bijing Yang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Yuanliang Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Zhuanxu Ouyang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Bingxian Liu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Peng Shang
- College of Animal Science, Tibet Agriculture and Animal Husbandry College, Linzhi, Tibet, China.
| | - Khalid Mehmood
- Department of Clinical Medicine and Surgery, Faculty of Veterinary and Animal Sciences, The Islamia University of Bahawalpur, 63100, Pakistan
| | - Rao Zahid Abbas
- Department of Parasitology, Faculty of Veterinary Science, University of Agriculture Faisalabad, Pakistan
| | - Shakeel Ahmed
- Instituto de Farmacia, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja, Valdivia, 5090000, Chile
| | - Yung-Fu Chang
- College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Jianying Guo
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Jiaqiang Pan
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Lianmei Hu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Zhaoxin Tang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Ying Li
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
| | - Hui Zhang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
| |
Collapse
|
|
43
|
Wang L, Cao J, Xu Q, Lu X, Yang X, Song Q, Chen S, Du K, Huang R, Zou C. 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione Ameliorates Diabetic Cognitive Impairment Through Inhibiting Hif3α and Apoptosis. Front Pharmacol 2021; 12:708141. [PMID: 34975464 PMCID: PMC8716628 DOI: 10.3389/fphar.2021.708141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 11/15/2021] [Indexed: 11/13/2022] Open
Abstract
Diabetes mellitus (DM) is an independent risk factor for cognitive impairment. Although the etiology of diabetic cognitive impairment is complex and multifactorial, the hippocampus neuronal apoptosis is recognized as a main cause of diabetes-induced cognitive impairment. 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) was purified from the roots of Averrhoa carambola L. Previous research demonstrated that DMDD was safe and effective in delaying some diabetic complications. However, the efficacy of DMDD to ameliorate diabetic cognitive impairment in type 2 diabetes mice has not been reported. In the present study, the behavioral evaluation was performed by Y maze and novel object recognition in db/db mice. Gene expression profiles were detected using mouse lncRNA microarray analysis in the hippocampi of db/db mice. Changes in the neurodegeneration-associated proteins and the apoptosis-related proteins were determined in both db/db mice and high glucose-treated HT22 cells by Western blotting. We observed that DMDD treatment significantly ameliorated the spatial working memory and object recognition memory impairment in db/db mice. Further study showed that neurodegeneration-associated protein tau was decreased after DMDD treatment in the hippocampi of db/db mice. Eleven lncRNAs and four mRNAs including pro-apoptotic gene Hif3a were significantly differently expressed after DMDD treatment in the hippocampi of db/db mice. The expression of Hif3a, cleaved parp, and caspase 3 proteins was significantly increased in the hippocampi of diabetic db/db mice compared with db/m control mice and then decreased after DMDD treatment. Similar beneficial effects of DMDD were observed in HG-treated HT22 cells. These data indicate that DMDD can alleviate cognitive impairment by inhibiting neuronal apoptosis through decreasing the expression of pro-apoptotic protein Hif3a. In conclusion, our study suggests that DMDD has great potential to be a new preventive and therapeutic compound for diabetic cognitive impairment.
Collapse
Affiliation(s)
- Lihui Wang
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
- Department of Pharmacology, Guangxi Medical University, Nanning, China
| | - Jinjin Cao
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Qianqian Xu
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Xiaomei Lu
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Xin Yang
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Qiong Song
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Shuai Chen
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Kechen Du
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
| | - Renbin Huang
- Department of Pharmacology, Guangxi Medical University, Nanning, China
- *Correspondence: Renbin Huang, ; Chunlin Zou,
| | - Chunlin Zou
- Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China
- *Correspondence: Renbin Huang, ; Chunlin Zou,
| |
Collapse
|
|
44
|
Vascular endothelial growth factor ameliorated palmitate-induced cardiomyocyte injury via JNK pathway. In Vitro Cell Dev Biol Anim 2021; 57:886-895. [PMID: 34791626 PMCID: PMC8632857 DOI: 10.1007/s11626-021-00616-z] [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: 06/01/2021] [Accepted: 08/16/2021] [Indexed: 11/02/2022]
Abstract
Enhanced apoptosis of cardiomyocytes in suffering overloaded saturated fatty acids (SFAs) can result in myocardial infarction and cardiac dysfunction. The function of vascular endothelial growth factor (VEGF) in cardiomyocyte protection was not clearly described. To investigate the preservative effects of VEGF sensitization on ceramide-mediated programmed cell death of cardiomyocytes, palmitate-induced injury in H9c2 cells was established as an in vitro model. Results revealed that 0.5 mM palmitate application effectively led to debased viability and activated apoptotic factors. A significant time-dependent relation between PAL and cardiomyocyte injury was observed. The apoptosis rate was increased greatly after 16 h of treatment with 0.5 mM PAL. In addition, cell viability was restored by VEGF overexpression during treatment with 0.5 mM PAL. Reduced apoptosis rate and expression of caspase 3, Bax, and NF-κB p65 were observed in this process, while boosted Bcl-2, p-JNK/JNK expression and activity of caspase 3 were checked. However, p-ERK/ERK levels did not exhibit a significant change. These findings indicated the protective effects of VEGF in confronting the ceramide-induced cardiomyocyte apoptosis, and would devote therapeutic targets for cardiovascular safeguard in dealing with fatty acid stress.
Collapse
|
|
45
|
Xia Z, Bi H, Li C, Geng L, Usman M, Du Y, Wei L. Neurotoxicity of β-HgS differs from environmental mercury pollutants (MeHgCl and HgCl 2) in Neuro-2a cell. INTERNATIONAL JOURNAL OF ENVIRONMENTAL HEALTH RESEARCH 2021; 31:861-871. [PMID: 31793343 DOI: 10.1080/09603123.2019.1692792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 11/11/2019] [Indexed: 06/10/2023]
Abstract
β-HgS, differing from environmental mercury pollutants (MeHgCl and HgCl2) in chemical form, is used as traditional medicine in Asian countries for thousands of years. In this study, Neuro-2a cells were exposed to β-HgS, MeHgCl and HgCl2 (5 µM) for 6-24 h. The cell viability of β-HgS was higher than MeHgCl with 25.9% and 72.4% in 12 h and 24 h respectively. As the incubation time increased, MeHgCl had obvious damage to cell morphology, decreased the ratio of Bcl-2 and Bak and increased the expressions of TNF-α, IL-6 and IL-1β significantly. Furthermore, the expressions of IL-1β and IL-6 in HgCl2 group were increased significantly in 6 h and 24 h. The apoptotic rates in MeHgCl and HgCl2 group were respectively higher than β-HgS with 32.2% and 7.30% in 24 h. Our findings indicate that β-HgS is much less neurotoxicity than MeHgCl and HgCl2 in Neuro-2a cells.
Collapse
Affiliation(s)
- Zhenghua Xia
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
- College of life sciences, University of Chinese Academy of Sciences, Beijing, China
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
| | - Hongtao Bi
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
| | - Cen Li
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
| | - Lujing Geng
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
- College of life sciences, University of Chinese Academy of Sciences, Beijing, China
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
| | - Muhammad Usman
- Department of Biotechnology, Virtual University of Pakistan, Lahore, Pakistan
| | - Yuzhi Du
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
| | - Lixin Wei
- Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
- Qinghai Provincial Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, Qinghai, China
| |
Collapse
|
|
46
|
Singh A, Tandon S, Nandi SP, Kaur T, Tandon C. Downregulation of inflammatory mediators by ethanolic extract of Bergenia ligulata (Wall.) in oxalate injured renal epithelial cells. JOURNAL OF ETHNOPHARMACOLOGY 2021; 275:114104. [PMID: 33836258 DOI: 10.1016/j.jep.2021.114104] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 03/05/2021] [Accepted: 04/03/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In the Indian traditional system of medicine, Bergenia ligulata (Wall.) Engl. has been used for treatment of urolithiasis. Its efficacious nature has led to its incorporation in various commercial herbal formulations such as Cystone and Neeri which are prescribed for kidney related ailments. AIM OF THE STUDY To assess whether ethanolic extract of B. ligulata can mitigate the cascade of inflammatory responses that cause oxidative stress and ultimately cell death in renal epithelial cells exposed to hyperoxaluric conditions. MATERIAL AND METHODS Bioactivity guided fractionation using solvents of varying polarities was employed to evaluate the potential of the extracts of B. ligulata to inhibit the crystallization process. Modulation of crystal morphology was visualized through Scanning electron microscopy (SEM) analysis. Cell death was assessed using flow cytometry based assays. Alteration in the inflammatory mediators was evaluated using real time PCR and immunocytochemistry. Phytochemical characterization of the ethanolic extract was carried out using FTIR, LC-MS and GC-MS. RESULTS Bioactivity guided fractionation for the assessment of antilithiatic activity revealed dose dependent inhibition of nucleation and aggregation process of calcium oxalate crystals in the presence of various extracts, however ethanolic extract showed maximum inhibition and was chosen for further experiments. Studies on renal epithelial NRK-52E cells showed, cytoprotective efficacy of B. ligulata extract against oxalate injury. SEM anaysis further revealed the potential of the extract to modulate the crystal structure and adhesion to renal cell surface. Exposure of the renal cells to the extract led to conversion of the calcium oxalate monohydrate (COM) crystals to the less injurious calcium oxalate dihydrate (COD) form. Expression analysis for oxidative stress and inflammatory biomarkers in NRK-52E cells revealed up-regulation of Mitogen activated protein kinase (MAPK), Osteopontin (OPN) and Nuclear factor- ĸB (NF-ĸB), in response to calcium oxalate insult; which was drastically reduced in the presence of B. ligulata extract. Flow cytometric evaluation pointed to caspase 3 mediated apoptotic cell death in oxalate injured cells, which was attenuated by B. ligulata extract. CONCLUSION Considering the complex multifactorial etiology of urolithiasis, ethanolic extract from B. ligulata can be a promising option for the management of kidney stones, as it has the potential to limit inflammation and the subsequent cell death.
Collapse
Affiliation(s)
- Anubha Singh
- Amity Institute of Biotechnology, Amity University, Noida, India
| | - Simran Tandon
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, India
| | - Shoma Paul Nandi
- Amity Institute of Biotechnology, Amity University, Noida, India
| | - Tanzeer Kaur
- Department of Biophysics, Panjab University, Chandigarh, India
| | | |
Collapse
|
|
47
|
Wang X, Zhao ZQ, Huang XM, Ding XY, Zhao CX, Li MW, Wu YC, Liu QN, Wang XY. Bmcas-1 plays an important role in response against BmNPV infection in vitro. ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY 2021; 107:e21793. [PMID: 33949719 DOI: 10.1002/arch.21793] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/19/2021] [Accepted: 04/05/2021] [Indexed: 06/12/2023]
Abstract
Apoptosis, as one kind of innate immune system, is involved in host response against pathogens innovation. Caspases play a vital role in the execution stage of host cell apoptosis. It has been reported that Bmcaspase-1 (Bmcas-1) has a close relationship with Bombyx mori nucleopolyhedrovirus (BmNPV) infection for its differentially expressed patterns after viral infection. However, its underlying response mechanism is still unclear. The significant differential expression of Bmcas-1 in different tissues of differentially resistant strains revealed its vital role in BmNPV infection. To further validate its role in BmNPV infection, budded virus (BV)-eGFP was analyzed after knockdown and overexpression of Bmcas-1 by small interfering RNA and the pIZT-mCherry vector, respectively. The reproduction of BV-eGFP obviously increased at 72 h after knockdown of Bmcas-1, and decreased after overexpression in BmN cells. Moreover, the conserved functional domain of Cas-1 among different species and the closed evolutionary relationship of Cas-1 in Lepidoptera hinted that Bmcas-1 might be associated with apoptosis, and this was also validated by the apoptosis inducer, Silvestrol, and the inhibitor, Z-DEVD-FMK. Therefore, Bmcas-1 plays an essential antiviral role by activating apoptosis, and this result lays a fundament for clarifying the molecular mechanism of silkworm in response against BmNPV infection and breeding of resistant strains.
Collapse
Affiliation(s)
- Xin Wang
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
| | - Zi-Qin Zhao
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
| | - Xin-Ming Huang
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
| | - Xin-Yi Ding
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
| | - Chun-Xiao Zhao
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
| | - Mu-Wang Li
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
- Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Research Institute, Chinese Academy of Agricultural Science, Zhenjiang, Jiangsu, China
| | - Yang-Chun Wu
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
- Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Research Institute, Chinese Academy of Agricultural Science, Zhenjiang, Jiangsu, China
| | - Qiu-Ning Liu
- Jiangsu Key Laboratory for Bioresources of Saline Soils, Jiangsu Synthetic Innovation Center for Coastal Bio-agriculture, Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources and Environmental Protection, School of Wetland, Yancheng, Jiangsu, China
| | - Xue-Yang Wang
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu, China
| |
Collapse
|
|
48
|
Effect of the polysaccharides derived from Dendrobium officinale stems on human HT-29 colorectal cancer cells and a zebrafish model. FOOD BIOSCI 2021. [DOI: 10.1016/j.fbio.2021.100995] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
49
|
Su ZH, Gao YH, Cheng S, Wen Y, Tang XD, Li MW, Wu YC, Wang XY. Identification of the in vitro antiviral effect of BmNedd2-like caspase in response to Bombyx mori nucleopolyhedrovirus infection. J Invertebr Pathol 2021; 183:107625. [PMID: 34058216 DOI: 10.1016/j.jip.2021.107625] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 05/19/2021] [Accepted: 05/24/2021] [Indexed: 10/21/2022]
Abstract
Bombyx mori nucleopolyhedrovirus (BmNPV) is one of the most serious pathogens in sericulture, and the underlying antiviral mechanism in silkworm is still unclear. Bombyx mori Nedd2-like caspase (BmNc) has been identified as a candidate antiviral gene from previous transcriptome data, since it is differentially expressed in the midgut of differentially resistant silkworm strains following BmNPV infection. However, the molecular mechanism by which BmNc responds to BmNPV is unknown. In this study, the relationship between BmNc and BmNPV was confirmed by its significantly different expression in different tissues of differentially resistant strains after BmNPV infection. Moreover, the antiviral role of BmNc was confirmed by the significantly higher fluorescence signals of BV-eGFP after knockdown of BmNc in BmN cells, and a reduced signal after overexpression. This was further verified by the capsid gene vp39 expression, DNA copy number, and GP64 protein level in the RNAi and overexpression groups. Furthermore, the antiviral phenomenon of BmNc was found to be associated with apoptosis. In brief, BmNc showed a relatively high expression level in the metamorphosis stages, and the effect of BmNc on BmNPV infection following RNAi and overexpression was eliminated after treatment with the inducer, Silvestrol, and the inhibitor, Z-DEVD-FMK, respectively. Therefore, it is reasonable to conclude that BmNc is involved in anti-BmNPV infection via the mitochondrial apoptosis pathway. The results provide valuable information for elucidating the molecular mechanism of silkworm resistance to BmNPV infection.
Collapse
Affiliation(s)
- Zhi-Hao Su
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212100, China.
| | - Yi-Han Gao
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212100, China.
| | - Shuang Cheng
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212100, China.
| | - Yan Wen
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212100, China.
| | - Xu-Dong Tang
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212100, China; Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Research Institute, Chinese Academy of Agricultural Science, Zhenjiang, Jiangsu 212100, China.
| | - Mu-Wang Li
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212100, China; Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Research Institute, Chinese Academy of Agricultural Science, Zhenjiang, Jiangsu 212100, China.
| | - Yang-Chun Wu
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212100, China; Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Research Institute, Chinese Academy of Agricultural Science, Zhenjiang, Jiangsu 212100, China.
| | - Xue-Yang Wang
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212100, China; Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Research Institute, Chinese Academy of Agricultural Science, Zhenjiang, Jiangsu 212100, China.
| |
Collapse
|
|
50
|
Metformin induces caspase-dependent and caspase-independent apoptosis in human bladder cancer T24 cells. Anticancer Drugs 2021; 31:655-662. [PMID: 32568826 PMCID: PMC7365670 DOI: 10.1097/cad.0000000000000966] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Bladder cancer (BC) is the sixth most common cancer in men. Moreover, chemotherapy for BC leads to various side effects. Metformin is known to induce apoptosis in vitro in many types of cancer. Furthermore, it has feasibility as a drug repositioning used for the treatment of cancer. The molecular mechanism of metformin mediating apoptosis in BC is still unclear. In this study, we showed that metformin stimulated the caspase-dependent apoptotic signaling pathway in T24 cells, a human BC cell line. Moreover, the induced apoptosis was partially inhibited by a general caspase inhibitor, z-VAD-fmk, which suggested that metformin-induced apoptosis in T24 cells is partially caspase-independent. Notably, we observed the nuclear translocation of apoptosis-inducing factors (AIFs) in metformin-promoted apoptosis, which is a typical characteristic of the caspase-independent apoptotic pathway. In addition, we found that metformin-mediated apoptosis occurred via degradation of the cellular FADD-like interleukin-1β-converting enzyme inhibitory protein (c-FLIP) by facilitating ubiquitin/proteasome-mediated c-FLIPL degradation. Furthermore, treatment with the reactive oxygen species scavenger N-acetylcysteine, failed to suppress metformin-induced apoptosis and c-FLIPL protein degradation in metformin-treated T24 cells. In conclusion, these results indicate that metformin-induced apoptosis was mediated through AIF-promoted caspase-independent pathways as well as caspase-dependent pathways in T24 cells. As such, metformin could be used as a possible apoptotic agent for the treatment of BC.
Collapse
|