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Dong PF, Liu TB, Chen K, Li D, Li Y, Lian CY, Wang ZY, Wang L. Cadmium targeting transcription factor EB to inhibit autophagy-lysosome function contributes to acute kidney injury. J Adv Res 2025; 72:653-669. [PMID: 39033876 DOI: 10.1016/j.jare.2024.07.013] [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: 10/06/2023] [Revised: 01/03/2024] [Accepted: 07/13/2024] [Indexed: 07/23/2024] Open
Abstract
INTRODUCTION Environmental and occupational exposure to cadmium (Cd) has been shown to cause acute kidney injury (AKI). Previous studies have demonstrated that autophagy inhibition and lysosomal dysfunction are important mechanisms of Cd-induced AKI. OBJECTIVES Transcription factor EB (TFEB) is a critical transcription regulator that modulates autophagy-lysosome function, but its role in Cd-induced AKI is yet to be elucidated. Thus, in vivo and in vitro studies were conducted to clarify this issue. METHODS AND RESULTS Data firstly showed that reduced TFEB expression and nuclear translocation were evident in Cd-induced AKI models, accompanied by autophagy-lysosome dysfunction. Pharmacological and genetic activation of TFEB improved Cd-induced AKI via alleviating autophagy inhibition and lysosomal dysfunction, whereas Tfeb knockdown further aggravated this phenomenon, suggesting the key role of TFEB in Cd-induced AKI by regulating autophagy. Mechanistically, Cd activated mechanistic target of rapamycin complex 1 (mTORC1) to enhance TFEB phosphorylation and thereby inhibiting TFEB nuclear translocation. Cd also activated chromosome region maintenance 1 (CRM1) to promote TFEB nuclear export. Meanwhile, Cd activated general control non-repressed protein 5 (GCN5) to enhance nuclear TFEB acetylation, resulting in the decreased TFEB transcriptional activity. Moreover, inhibition of CRM1 or GCN5 alleviated Cd-induced AKI by enhancing TFEB activity, respectively. CONCLUSION In summary, these findings reveal that TFEB phosphorylation, nuclear export and acetylation independently suppress TFEB activity to cause Cd-induced AKI via regulating autophagy-lysosome function, suggesting that TFEB activation might be a promising treatment strategy for Cd-induced AKI.
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Affiliation(s)
- Peng-Fei Dong
- College of Veterinary Medicine, Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, 7 Panhe Street, Tai'an City, 271017, Shandong Province, China
| | - Tian-Bin Liu
- New Drug Evaluation Center of Shandong Academy of Pharmaceutical Sciences, Shandong Academy of Pharmaceutical Sciences, 989 Xinluo Street, Ji'nan City, 250101, Shandong Province, China
| | - Kai Chen
- New Drug Evaluation Center of Shandong Academy of Pharmaceutical Sciences, Shandong Academy of Pharmaceutical Sciences, 989 Xinluo Street, Ji'nan City, 250101, Shandong Province, China
| | - Dan Li
- Shandong Medicine Technician College, 999 Fengtian Street, Tai'an City, 271016, Shandong Province, China
| | - Yue Li
- College of Veterinary Medicine, Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, 7 Panhe Street, Tai'an City, 271017, Shandong Province, China
| | - Cai-Yu Lian
- College of Veterinary Medicine, Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, 7 Panhe Street, Tai'an City, 271017, Shandong Province, China
| | - Zhen-Yong Wang
- College of Veterinary Medicine, Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, 7 Panhe Street, Tai'an City, 271017, Shandong Province, China
| | - Lin Wang
- College of Veterinary Medicine, Shandong Provincial Key Laboratory of Zoonoses, Shandong Agricultural University, 7 Panhe Street, Tai'an City, 271017, Shandong Province, China.
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Gu J, Ruan J, Guo C, Li Z, Fu H, Xie Y, Xie H, Gong X, Shi H. Organelles Ca 2+ redistribution contributes to cadmium-induced EMT of renal cancer cells through p-cPLA 2-mediated arachidonic acid release. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 298:118317. [PMID: 40383071 DOI: 10.1016/j.ecoenv.2025.118317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 04/28/2025] [Accepted: 05/10/2025] [Indexed: 05/20/2025]
Abstract
Cadmium ion (Cd2+) is a non-essential metal that can increase cancer risk, including potentially renal cell carcinoma (RCC), though this link is not definitive. Cd2+ exposure impairs fatty acid metabolism in the kidneys, particularly affecting arachidonic acid (AA) levels, which are crucial for health. Previous studies have suggested that Cd2+-altered the AA metabolism associates with renal dysfunction. However, the role and mechanism of Cd2+-regulated AA source in promoting RCC progression are still unclear. This study aims to investigate how Cd2+ exposure affects AA levels in renal cancer cells and its role in promoting cell migration. Cd2+ exposure increases AA levels through cPLA2-mediated release. It also induces calcium ion (Ca2+) redistribution from the endoplasmic reticulum (ER) to mitochondria, activating the p38 MAPK/cPLA2 signaling pathway, and epithelial-mesenchymal transition (EMT) of Caki-1 cells. Cd2+-induced ER Ca2+ release, p38 MAPK/cPLA2 signaling activation, AA levels, and EMT of Caki-1 cells were effectively reversed by siRNA knockdown of IP3R. Both exogenous AA treatments and Cd2+-induced AA metabolite PGD2 promoted EMT and cell migration of Caki-1 cells. This study highlights Cd2+'s impact on fatty acid metabolism and organelle function in renal cancer cells, identifying potential therapeutic targets for RCC.
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Affiliation(s)
- Jie Gu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212000, China.
| | - Jiacheng Ruan
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212000, China
| | - Chuanzhi Guo
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212000, China
| | - Zehua Li
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212000, China
| | - Huilin Fu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212000, China
| | - Yimin Xie
- Affiliated Hospital of Jiangsu University-Yixing Hospital, Yixing, Jiangsu 214200, China
| | - Hebing Xie
- Jiangsu Shenhou Pharmaceutical Research Co., Ltd., Nantong, 226133, China
| | - Xun Gong
- Department of Rheumatology & Immunology, Affiliated Hospital of Jiangsu University, Zhenjiang 212013, China
| | - Haifeng Shi
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212000, China.
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Dagher DM, Zaghloul MS, Suddek GM. Modulation of AMPK/mTOR Autophagic Pathway Using Dapagliflozin Protects Against Cadmium-Induced Testicular and Renal Injury in Rats. J Biochem Mol Toxicol 2025; 39:e70257. [PMID: 40233265 DOI: 10.1002/jbt.70257] [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: 09/24/2024] [Revised: 02/03/2025] [Accepted: 03/31/2025] [Indexed: 04/17/2025]
Abstract
Cadmium is a widely distributed heavy metal found in the environment that poses serious hazards to human health. Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, exhibited antioxidant, antiapoptotic, and anti-inflammatory properties. Our data assessed the effect of DAPA against Cd-triggered renal and testicular impairment in rats, as well as the underlying mechanisms. Cd (30 mg/kg) and DAPA (5 and 10 mg/kg) were administrated by oral gavage to rats and continued for 21 days. DAPA attenuated Cd-triggered renal and testicular injury as shown by diminishing serum creatinine, BUN, and urinary total protein concentration in addition to increasing creatinine clearance, urinary creatinine, and serum testosterone. Moreover, it diminished renal and testicular histopathological alterations induced by Cd. DAPA stimulated the impaired autophagy flux as seen by significantly elevating the p-AMPK/total AMPK, decreasing p-mTOR/total mTOR ratios, and diminishing p62 & LC3 protein levels. Additionally, DAPA significantly lowered MDA content, increased GSH level and SOD activity. Moreover, it augmented the cytoprotective Nrf2/HO-1 signaling pathway. Furthermore, it attenuated renal and testicular apoptotic cell death via decreasing caspase-3 expression. Conclusion: Boosting autophagic events and combating oxidative stress and apoptosis by DAPA were engaged in alleviating Cd-induced renal and testicular impairment. This was accomplished by modulating the AMPK/mTOR and enhancing the Nrf2/HO-1 pathways.
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Affiliation(s)
- Doha M Dagher
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Marwa S Zaghloul
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Egypt
| | - Ghada M Suddek
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Lee H, Han JH, Jeong RG, Kang YJ, Choi BH, Kim SR, Cheon CK, Hur J, Lee SY. Oral trehalose improves histological and behavior symptoms of mucopolysaccharidosis type II in iduronate 2-sulfatase deficient mice. Sci Rep 2025; 15:4882. [PMID: 39929944 PMCID: PMC11811122 DOI: 10.1038/s41598-025-88362-0] [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: 11/13/2024] [Accepted: 01/28/2025] [Indexed: 02/13/2025] Open
Abstract
Mucopolysaccharidosis type II (MPS II) is caused by a deficiency in iduronate-2-sulfatase (Ids), an enzyme that catabolizes glycosaminoglycan (GAG). Ids insufficiency results in the accumulation of GAG in various organs, ultimately resulting in multisystemic disease. Trehalose, a non-reducing disaccharide, has shown protective effects against various diseases. However, its potential utility through oral administration in MPS II has not yet been explored. In the present study, to investigate the efficacy of oral trehalose in Ids-knock-out (KO) mice, Ids-KO and wild type (WT) mice were treated with 2% trehalose dissolved in distilled water ad libitum for 24 weeks. Histological analysis revealed that almost all tissues from Ids-KO mice exhibited abnormal changes, including large vacuolization, inflammatory cell infiltration, and GAG deposition. However, oral administration of trehalose significantly suppressed GAG levels, vacuolization, inflammation and apoptosis in the spleen and brain. Additionally, oral trehalose considerably improved cognitive functions, such as short-term spatial learning and working memory, alongside limited improvements in walking capacity in Ids-KO mice. These results suggest that oral trehalose can reduce GAG accumulation, vacuolization and the number of apoptotic and inflammatory cells in pathological tissues including the brain, ultimately considerably improving spontaneous alteration behavior and could be a promising treatment option for MPS II.
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Affiliation(s)
- Hyesook Lee
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
| | - Jung-Hwa Han
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
| | - Roo Gam Jeong
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
| | - Yun Jeong Kang
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
| | - Byung Hyun Choi
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
| | - Seo Rin Kim
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
- Division of Nephrology, Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea
| | - Chong Kun Cheon
- Department of Pediatrics, School of Medicine, Pusan National University Children's Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea.
| | - Jin Hur
- Department of Convergence Medicine, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea.
- PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea.
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea.
| | - Soo Yong Lee
- Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea.
- Division of Cardiology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea.
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Arab HH, Althobaiti MM, Alharthi AS, Almalki EO, Alsoubie SS, Qattan JM, Almalki SA, Ashour AM, Eid AH. Repurposing Dapagliflozin for Mitigation of the Kidney Injury Triggered by Cadmium in Rats: Role of Autophagy, Apoptosis, and the SIRT1/Nrf2/HO-1 Pathway. Pharmaceuticals (Basel) 2024; 17:1690. [PMID: 39770532 PMCID: PMC11678783 DOI: 10.3390/ph17121690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: The antioxidant/antiapoptotic features of dapagliflozin (DPG) have mediated its beneficial actions against several experimental models. However, no studies have been conducted to determine whether DPG mitigates the renal injury triggered by cadmium (Cd). Herein, DPG was studied for its potential to attenuate kidney damage in Cd-intoxicated rats, as well as to unravel the mechanisms involving oxidative events, autophagy, and apoptosis. Methods: Histopathological analysis, immunohistochemical staining, and ELISA were conducted on kidney tissue samples. Results: Cd administration (5 mg/kg/day; p.o.) prompted significant renal damage, as evidenced by histopathological changes, elevated kidney injury molecule-1 (KIM-1) expression, and increased serum creatinine and urea. Interestingly, DPG (1 mg/kg/day; p.o.) significantly mitigated these harmful effects without affecting renal Cd metal accumulation. Mechanistically, DPG curbed Cd-induced renal pro-oxidant response and stimulated the antioxidant sirtuin 1 (SIRT1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) axis. Moreover, DPG restored autophagy by decreasing sequestosome-1/protein 62 (SQSTM-1/p62) accumulation and stimulating the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathway. In tandem, DPG suppressed Cd-induced apoptosis by lowering renal Bcl-2 associated-x protein (Bax) and cytochrome C (Cyt C) levels and caspase 3 activity. Conclusions: These findings indicate that DPG attenuates Cd-induced nephrotoxicity by enhancing the SIRT1/Nrf2/HO-1 antioxidant pathway, promoting AMPK/mTOR-directed autophagy, and inhibiting apoptotic cell death.
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Affiliation(s)
- Hany H. Arab
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Musaad M. Althobaiti
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | | | - Emad O. Almalki
- College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Saif S. Alsoubie
- College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Jawad M. Qattan
- College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Saeed A. Almalki
- College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Ahmed M. Ashour
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah 21955, Saudi Arabia
| | - Ahmed H. Eid
- Department of Pharmacology, Egyptian Drug Authority (EDA)—Formerly NODCAR, Giza 12654, Egypt
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6
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Yang X, Huang J, Wang J, Sun H, Li J, Wang Z, Song Q. The protective effect of glucose selenol on cadmium-induced testicular toxicity in male rat. Reprod Toxicol 2024; 129:108679. [PMID: 39121979 DOI: 10.1016/j.reprotox.2024.108679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 07/13/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024]
Abstract
This study aimed to investigate the protective effects of glucose selenol on cadmium (Cd)-induced testicular toxicity. Twenty-four male Sprague-Dawley (SD) rats were randomly divided into four groups. Cd was administered orally at a dose of 40 mg/L or in combination with orally administered glucose selenol at doses of 0.15 mg/L and 0.4 mg/L for 30 days. The results showed that sperm quality decreased and testicular tissue was damaged in the Cd group; Glucose selenol significantly attenuated the negative effects by improving sperm quality and reducing testicular damage. Transcriptome sequencing analysis showed that Cd stress affected spermatogenesis, sperm motility, oxidative stress, blood-testis barrier and protein metabolism. Four clusters were obtained using the R Mfuzz package, which clustered highly expressed genes under different administrations, and 36 items were enriched. Notably, protein phosphorylation was enriched in the Cd group and is considered to play a key role in the response to Cd stress. We identified fifty-six target selenium (Se) and Cd co-conversion differentially expressed genes (DEGs), including three genes relating to spermatogenesis (Dnah8, Spata31d1b, Spata31d1c). In addition, the obtained DEGs were used to construct a protein-protein interaction network, co-processed with Se and Cd, and 5 modules were constructed. Overall, the analyses of rat testicular physiology and gene expression levels offer new insights into the reproductive toxicity of Cd in rats, and provide potential application prospects for glucose selenol in alleviating the impact of Cd-induced testicular damage.
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Affiliation(s)
- Xinyi Yang
- College of Life Science, Hunan Normal University, Changsha, Hunan 410006, China
| | - Jinzhou Huang
- College of Life Science, Hunan Normal University, Changsha, Hunan 410006, China
| | - Juan Wang
- College of Life Science, Hunan Normal University, Changsha, Hunan 410006, China
| | - Huimin Sun
- College of Life Science, Hunan Normal University, Changsha, Hunan 410006, China
| | - JinJin Li
- College of Life Science, Hunan Normal University, Changsha, Hunan 410006, China
| | - Zhi Wang
- College of Life Science, Hunan Normal University, Changsha, Hunan 410006, China.
| | - Qisheng Song
- Division of Plant Sciences and Technology, University of Missouri, Columbia, MO 65211, USA
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7
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Zhu J, Gong Z, Wang X, Zhang K, Ma Y, Zou H, Song R, Zhao H, Liu Z, Dong W. mTORC1 and mTORC2 Co-Protect against Cadmium-Induced Renal Tubular Epithelial Cell Apoptosis and Acute Kidney Injury by Regulating Protein Kinase B. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:19667-19679. [PMID: 39219293 PMCID: PMC11404484 DOI: 10.1021/acs.jafc.4c05702] [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: 06/26/2024] [Revised: 08/28/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024]
Abstract
The potential threat of cadmium (Cd)-induced acute kidney injury (AKI) is increasing. In this study, our primary goal was to investigate the individual roles played by mTOR complexes, specifically mTORC1 and mTORC2, in Cd-induced apoptosis in mouse kidney cells. We constructed a mouse model with specific deletion of Raptor/Rictor renal cells. Inhibitors and activators of mTORC1 or mTORC2 were also applied. The effects of protein kinase B (AKT) activation and autophagy were studied. Both mTORC1 and mTORC2 were found to mediate the antiapoptotic mechanism of renal cells by regulating the AKT activity. Inhibition of mTORC1 or mTORC2 exacerbated Cd-induced kidney cell apoptosis, suggesting that both proteins exert antiapoptotic effects under Cd exposure. We further found that the AKT activation plays a key role in mTORC1/TORC2-mediated antiapoptosis, protecting Cd-exposed kidney cells from apoptosis. We also found that mTOR activators inhibited excessive autophagy, alleviated apoptosis, and promoted cell survival. These findings provide new insights into the regulatory mechanisms of mTOR in renal diseases and provide a theoretical basis for the development of novel therapeutic strategies to treat renal injury.
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Affiliation(s)
- Jiaqiao Zhu
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Institute
of Agricultural Science and Technology Development (Joint International
Research Laboratory of Agriculture and Agri-Product Safety of the
Ministry of Education of China), Yangzhou
University, Yangzhou, Jiangsu 225009, China
- Jiangsu
Co-Innovation Center for Prevention and Control of Important Animal
Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, China
| | - Zhonggui Gong
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Agricultural
High-tech Industrial Demonstration Area of the Yellow River Delta
of Shandong Province, Dongying, Shandong 257000, China
- National
Technological Innovation Center for Comprehensive Utilization of Saline-Alkali
Land, Dongying, Shandong 257000, China
| | - Xueru Wang
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Institute
of Agricultural Science and Technology Development (Joint International
Research Laboratory of Agriculture and Agri-Product Safety of the
Ministry of Education of China), Yangzhou
University, Yangzhou, Jiangsu 225009, China
- Jiangsu
Co-Innovation Center for Prevention and Control of Important Animal
Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, China
| | - Kanglei Zhang
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Institute
of Agricultural Science and Technology Development (Joint International
Research Laboratory of Agriculture and Agri-Product Safety of the
Ministry of Education of China), Yangzhou
University, Yangzhou, Jiangsu 225009, China
- Jiangsu
Co-Innovation Center for Prevention and Control of Important Animal
Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, China
| | - Yonggang Ma
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Institute
of Agricultural Science and Technology Development (Joint International
Research Laboratory of Agriculture and Agri-Product Safety of the
Ministry of Education of China), Yangzhou
University, Yangzhou, Jiangsu 225009, China
- Jiangsu
Co-Innovation Center for Prevention and Control of Important Animal
Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, China
| | - Hui Zou
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Institute
of Agricultural Science and Technology Development (Joint International
Research Laboratory of Agriculture and Agri-Product Safety of the
Ministry of Education of China), Yangzhou
University, Yangzhou, Jiangsu 225009, China
- Jiangsu
Co-Innovation Center for Prevention and Control of Important Animal
Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, China
| | - Ruilong Song
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Institute
of Agricultural Science and Technology Development (Joint International
Research Laboratory of Agriculture and Agri-Product Safety of the
Ministry of Education of China), Yangzhou
University, Yangzhou, Jiangsu 225009, China
- Jiangsu
Co-Innovation Center for Prevention and Control of Important Animal
Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, China
| | - Hongyan Zhao
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Institute
of Agricultural Science and Technology Development (Joint International
Research Laboratory of Agriculture and Agri-Product Safety of the
Ministry of Education of China), Yangzhou
University, Yangzhou, Jiangsu 225009, China
- Jiangsu
Co-Innovation Center for Prevention and Control of Important Animal
Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, China
| | - Zongping Liu
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Institute
of Agricultural Science and Technology Development (Joint International
Research Laboratory of Agriculture and Agri-Product Safety of the
Ministry of Education of China), Yangzhou
University, Yangzhou, Jiangsu 225009, China
- Jiangsu
Co-Innovation Center for Prevention and Control of Important Animal
Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, China
| | - Wenxuan Dong
- College
of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China
- Laboratory
of Animal Nutrition Metabolic and Poisoning Diseases, College of Veterinary
Medicine, Qingdao Agricultural University, Qingdao, Shandong 266109, China
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Fujiki K, Tanabe K, Suzuki S, Mochizuki A, Mochizuki-Kashio M, Sugaya T, Mizoguchi T, Itoh M, Nakamura-Ishizu A, Inamura H, Matsuoka M. Blockage of Akt activation suppresses cadmium-induced renal tubular cellular damages through aggrephagy in HK-2 cells. Sci Rep 2024; 14:14552. [PMID: 38914593 PMCID: PMC11196260 DOI: 10.1038/s41598-024-64579-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 06/11/2024] [Indexed: 06/26/2024] Open
Abstract
We have reported that an environmental pollutant, cadmium, promotes cell death in the human renal tubular cells (RTCs) through hyperactivation of a serine/threonine kinase Akt. However, the molecular mechanisms downstream of Akt in this process have not been elucidated. Cadmium has a potential to accumulate misfolded proteins, and proteotoxicity is involved in cadmium toxicity. To clear the roles of Akt in cadmium exposure-induced RTCs death, we investigated the possibility that Akt could regulate proteotoxicity through autophagy in cadmium chloride (CdCl2)-exposed HK-2 human renal proximal tubular cells. CdCl2 exposure promoted the accumulation of misfolded or damaged proteins, the formation of aggresomes (pericentriolar cytoplasmic inclusions), and aggrephagy (selective autophagy to degrade aggresome). Pharmacological inhibition of Akt using MK2206 or Akti-1/2 enhanced aggrephagy by promoting dephosphorylation and nuclear translocation of transcription factor EB (TFEB)/transcription factor E3 (TFE3), lysosomal transcription factors. TFEB or TFE3 knockdown by siRNAs attenuated the protective effects of MK2206 against cadmium toxicity. These results suggested that aberrant activation of Akt attenuates aggrephagy via TFEB or TFE3 to facilitate CdCl2-induced cell death. Furthermore, these roles of Akt/TFEB/TFE3 were conserved in CdCl2-exposed primary human RTCs. The present study shows the molecular mechanisms underlying Akt activation that promotes cadmium-induced RTCs death.
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Affiliation(s)
- Kota Fujiki
- Department of Hygiene and Public Health, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
| | - K Tanabe
- Institute for Comprehensive Medical Sciences, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
| | - S Suzuki
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
| | - A Mochizuki
- Department of Bio-Medical Engineering, School of Engineering, Tokai University, Kanagawa, 259-1143, Japan
| | - M Mochizuki-Kashio
- Department of Microanatomy and Development Biology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
| | - T Sugaya
- Division of Nephrology and Hypertension, St. Marianna University School of Medicine, Kanagawa, 216-8511, Japan
| | - T Mizoguchi
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
| | - M Itoh
- Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, 260-8675, Japan
| | - A Nakamura-Ishizu
- Department of Microanatomy and Development Biology, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
| | - H Inamura
- Department of Hygiene and Public Health, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - M Matsuoka
- Department of Hygiene and Public Health, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
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Zhang K, Li J, Dong W, Huang Q, Wang X, Deng K, Ali W, Song R, Zou H, Ran D, Liu G, Liu Z. Luteolin Alleviates Cadmium-Induced Kidney Injury by Inhibiting Oxidative DNA Damage and Repairing Autophagic Flux Blockade in Chickens. Antioxidants (Basel) 2024; 13:525. [PMID: 38790630 PMCID: PMC11117664 DOI: 10.3390/antiox13050525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 04/22/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Chickens are a major source of meat and eggs in human food and have significant economic value. Cadmium (Cd) is a common environmental pollutant that can contaminate feed and drinking water, leading to kidney injury in livestock and poultry, primarily by inducing the generation of free radicals. It is necessary to develop potential medicines to prevent and treat Cd-induced nephrotoxicity in poultry. Luteolin (Lut) is a natural flavonoid compound mainly extracted from peanut shells and has a variety of biological functions to defend against oxidative damage. In this study, we aimed to demonstrate whether Lut can alleviate kidney injury under Cd exposure and elucidate the underlying molecular mechanisms. Renal histopathology and cell morphology were observed. The indicators of renal function, oxidative stress, DNA damage and repair, NAD+ content, SIRT1 activity, and autophagy were analyzed. In vitro data showed that Cd exposure increased ROS levels and induced oxidative DNA damage and repair, as indicated by increased 8-OHdG content, increased γ-H2AX protein expression, and the over-activation of the DNA repair enzyme PARP-1. Cd exposure decreased NAD+ content and SIRT1 activity and increased LC3 II, ATG5, and particularly p62 protein expression. In addition, Cd-induced oxidative DNA damage resulted in PARP-1 over-activation, reduced SIRT1 activity, and autophagic flux blockade, as evidenced by reactive oxygen species scavenger NAC application. The inhibition of PARP-1 activation with the pharmacological inhibitor PJ34 restored NAD+ content and SIRT1 activity. The activation of SIRT1 with the pharmacological activator RSV reversed Cd-induced autophagic flux blockade and cell injury. In vivo data demonstrated that Cd treatment caused the microstructural disruption of renal tissues, reduced creatinine, and urea nitrogen clearance, raised MDA content, and decreased the activities or contents of antioxidants (GSH, T-SOD, CAT, and T-AOC). Cd treatment caused oxidative DNA damage and PARP-1 activation, decreased NAD+ content, decreased SIRT1 activity, and impaired autophagic flux. Notably, the dietary Lut supplement observably alleviated these alterations in chicken kidney tissues induced by Cd. In conclusion, the dietary Lut supplement alleviated Cd-induced chicken kidney injury through its potent antioxidant properties by relieving the oxidative DNA damage-activated PARP-1-mediated reduction in SIRT1 activity and repairing autophagic flux blockade.
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Affiliation(s)
- Kanglei Zhang
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Jiahui Li
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Wenxuan Dong
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266000, China;
| | - Qing Huang
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Xueru Wang
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Kai Deng
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Waseem Ali
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Di Ran
- College of Veterinary Medicine, Southwest University, Chongqing 400715, China;
- College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Gang Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China; (K.Z.); (J.L.); (Q.H.); (X.W.); (K.D.); (W.A.); (R.S.); (H.Z.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
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Xue J, Liu H, Yin T, Zhou X, Song X, Zou Y, Li L, Jia R, Fu Y, Zhao X, Yin Z. Rat Hepatocytes Protect against Lead-Cadmium-Triggered Apoptosis Based on Autophagy Activation. TOXICS 2024; 12:285. [PMID: 38668508 PMCID: PMC11055059 DOI: 10.3390/toxics12040285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/08/2024] [Accepted: 04/10/2024] [Indexed: 04/29/2024]
Abstract
Lead and cadmium are foodborne contaminants that threaten human and animal health. It is well known that lead and cadmium produce hepatotoxicity; however, defense mechanisms against the co-toxic effects of lead and cadmium remain unknown. We investigated the mechanism of autophagy (defense mechanism) against the co-induced toxicity of lead and cadmium in rat hepatocytes (BRL-3A cells). Cultured rat liver BRL-3A cell lines were co-cultured with 10, 20, 40 μM lead and 2.5, 5, 10 μM cadmium alone and in co-culture for 12 h and exposed to 5 mM 3-Methyladenine (3-MA), 10 μM rapamycin (Rapa), and 50 nM Beclin1 siRNA to induce cellular autophagy. Our results show that treatment of BRL-3A cells with lead and cadmium significantly decreased the cell viability, increased intracellular reactive oxygen species levels, decreased mitochondrial membrane potential levels, and induced apoptosis, which are factors leading to liver injury, and cell damage was exacerbated by co-exposure to lead-cadmium. In addition, the results showed that lead and cadmium co-treatment induced autophagy. We further observed that the suppression of autophagy with 3-MA or Beclin1 siRNA promoted lead-cadmium-induced apoptosis, whereas enhancement of autophagy with Rapa suppressed lead-cadmium-induced apoptosis. These results demonstrated that co-treatment with lead and cadmium induces apoptosis in BRL-3A cells. Interestingly, the activation of autophagy provides cells with a self-protective mechanism against induced apoptosis. This study provides insights into the role of autophagy in lead-cadmium-induced apoptosis, which may be beneficial for the treatment of lead-cadmium-induced liver injury.
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Affiliation(s)
- Junshu Xue
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Huimao Liu
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Tianyi Yin
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xun Zhou
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xu Song
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Yuanfeng Zou
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Lixia Li
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Renyong Jia
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China; (X.Z.)
| | - Yuping Fu
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Xinghong Zhao
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
| | - Zhongqiong Yin
- Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
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11
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M J AW, G T, S AM, S M, A NA, A B, V R, A S SH. A comparative study on targeted gene expression in zebrafish and its gill cell line exposed to chlorpyrifos. In Vitro Cell Dev Biol Anim 2024; 60:397-410. [PMID: 38589735 DOI: 10.1007/s11626-024-00892-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 03/03/2024] [Indexed: 04/10/2024]
Abstract
Chlorpyrifos (CPF) is an organophosphorus-based insecticide, which is known to pose a serious risk to aquatic animals. However, the mechanisms of CPF toxicity in animals still remain unclear. The present investigation aimed to compare the potential effects of CPF in zebrafish (Danio rerio) and its gill cell line (DrG cells). Based on the in vivo study, the LC50 was calculated as 18.03 µg/L and the chronic toxic effect of CPF was studied by exposing the fish to 1/10th (1.8 µg/L) and 1/5th (3.6 µg/L) of the LC50 value. Morphological changes were observed in fish and DrG cells which were exposed to sublethal concentrations of CPF. The results of MTT and NR assays showed significant decline in the survival of cells exposed to CPF at 96 h. The production of reactive oxygen species in DrG cells and expression levels of antioxidant markers, inflammatory response genes (cox2a and cox2b), cyp1a, proapoptotic genes (bax), antiapoptotic gene (bcl2), apoptotic genes (cas3 and p53), and neuroprotective gene (ache) were determined in vivo using zebrafish and in vitro using DrG cells after exposure to CPF. Significant changes were found in the ROS production (DrG cells) and in the expression of inflammatory, proapoptotic, and apoptotic genes. This study showed that DrG cells are potential alternative tools to replace the use of whole fish for toxicological studies.
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Affiliation(s)
- Abdul Wazith M J
- Aquatic Animal Health Laboratory, PG and Research Department of Zoology, C. Abdul Hakeem College, Melvisharam, Tamil Nadu, 632509, India
| | - Taju G
- Aquatic Animal Health Laboratory, PG and Research Department of Zoology, C. Abdul Hakeem College, Melvisharam, Tamil Nadu, 632509, India.
| | - Abdul Majeed S
- Aquatic Animal Health Laboratory, PG and Research Department of Zoology, C. Abdul Hakeem College, Melvisharam, Tamil Nadu, 632509, India
| | - Mithra S
- Aquatic Animal Health Laboratory, PG and Research Department of Zoology, C. Abdul Hakeem College, Melvisharam, Tamil Nadu, 632509, India
| | - Nafeez Ahmed A
- Aquatic Animal Health Laboratory, PG and Research Department of Zoology, C. Abdul Hakeem College, Melvisharam, Tamil Nadu, 632509, India
| | - Badhusha A
- Aquatic Animal Health Laboratory, PG and Research Department of Zoology, C. Abdul Hakeem College, Melvisharam, Tamil Nadu, 632509, India
| | - Rajkumar V
- Aquatic Animal Health Laboratory, PG and Research Department of Zoology, C. Abdul Hakeem College, Melvisharam, Tamil Nadu, 632509, India
| | - Sahul Hameed A S
- Aquatic Animal Health Laboratory, PG and Research Department of Zoology, C. Abdul Hakeem College, Melvisharam, Tamil Nadu, 632509, India.
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Hedayati-Moghadam M, Seyedi F, Hosseini M, Mansouri M, Sotoudeh MM, Beheshti F, Askarpour H, Kheirkhah A, Baghcheghi Y. Selenium prevented renal tissue damage in lipopolysaccharide-treated rats. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2024; 21:53-60. [PMID: 38112326 DOI: 10.1515/jcim-2023-0154] [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: 09/10/2023] [Accepted: 11/19/2023] [Indexed: 12/21/2023]
Abstract
OBJECTIVES Kidney diseases are one of the common diseases, which are one of the main causes of death in society and impose costs on the health system of the society. A growing body of evidence has well documented that inflammatory responses and oxidative damage play a significant role in the progress of various kidney diseases. METHODS This study examined whether selenium (Sel) could prevent the detrimental influences of lipopolysaccharide (LPS) in rats. Four groups of Wistar rats were considered: control, LPS (1 mg/kg, i.p., for 14 days), LPS-Sel 1 (0.1 mg/kg, i.p., for 14 days), and LPS-Sel 2 (0.2 mg/kg, i.p., for 14 days). RESULTS Sel treatment markedly attenuated oxidative stress damage in the kidney tissue in LPS-induced renal toxicity. Generally, the administration of Sel resulted in improved antioxidant indicators such as catalase (CAT) and superoxide dismutase (SOD) activities, or total thiol content, and decreased malondialdehyde (MDA) in the kidney tissue. It also decreased interleukin-6 in kidney homogenates. Furthermore, Se treatment significantly inhibited the elevation of serum biochemical markers of kidney function including serum, BUN, and creatinine. CONCLUSIONS Based on the findings of the current study, it seems that the administration of Sel to LPS-treated rats improves renal function by reducing oxidative damage and inflammation in kidney tissue. However, more research is needed to reveal the accurate mechanisms for the effect of Sel on renal outcomes of LPS in human subjects.
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Affiliation(s)
- Mahdiyeh Hedayati-Moghadam
- Department of Physiology, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Fatemeh Seyedi
- Department of Anatomical Sciences, School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Mahmoud Hosseini
- Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mostafa Mansouri
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Farimah Beheshti
- Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
- Department of Physiology, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Hedyeh Askarpour
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Aliasghar Kheirkhah
- Clinical Research Development Center of Imam Khomeini Hospital, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Yousef Baghcheghi
- Student Research Committee, Jiroft University of Medical Sciences, Jiroft, Iran
- Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran
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Nakashima M, Suga N, Ikeda Y, Yoshikawa S, Matsuda S. Inspiring Tactics with the Improvement of Mitophagy and Redox Balance for the Development of Innovative Treatment against Polycystic Kidney Disease. Biomolecules 2024; 14:207. [PMID: 38397444 PMCID: PMC10886467 DOI: 10.3390/biom14020207] [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: 12/21/2023] [Revised: 01/31/2024] [Accepted: 02/08/2024] [Indexed: 02/25/2024] Open
Abstract
Polycystic kidney disease (PKD) is the most common genetic form of chronic kidney disease (CKD), and it involves the development of multiple kidney cysts. Not enough medical breakthroughs have been made against PKD, a condition which features regional hypoxia and activation of the hypoxia-inducible factor (HIF) pathway. The following pathology of CKD can severely instigate kidney damage and/or renal failure. Significant evidence verifies an imperative role for mitophagy in normal kidney physiology and the pathology of CKD and/or PKD. Mitophagy serves as important component of mitochondrial quality control by removing impaired/dysfunctional mitochondria from the cell to warrant redox homeostasis and sustain cell viability. Interestingly, treatment with the peroxisome proliferator-activated receptor-α (PPAR-α) agonist could reduce the pathology of PDK and might improve the renal function of the disease via the modulation of mitophagy, as well as the condition of gut microbiome. Suitable modulation of mitophagy might be a favorable tactic for the prevention and/or treatment of kidney diseases such as PKD and CKD.
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Affiliation(s)
| | | | | | | | - Satoru Matsuda
- Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506, Japan
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Zhang K, Long M, Dong W, Li J, Wang X, Liu W, Huang Q, Ping Y, Zou H, Song R, Liu G, Ran D, Liu Z. Cadmium Induces Kidney Iron Deficiency and Chronic Kidney Injury by Interfering with the Iron Metabolism in Rats. Int J Mol Sci 2024; 25:763. [PMID: 38255838 PMCID: PMC10815742 DOI: 10.3390/ijms25020763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 12/29/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Cadmium (Cd) is a common environmental pollutant and occupational toxicant that seriously affects various mammalian organs, especially the kidney. Iron ion is an essential trace element in the body, and the disorder of iron metabolism is involved in the development of multiple pathological processes. An iron overload can induce a new type of cell death, defined as ferroptosis. However, whether iron metabolism is abnormal in Cd-induced nephrotoxicity and the role of ferroptosis in Cd-induced nephrotoxicity need to be further elucidated. Sprague Dawley male rats were randomly assigned into three groups: a control group, a 50 mg/L CdCl2-treated group, and a 75 mg/L CdCl2-treated group by drinking water for 1 month and 6 months, respectively. The results showed that Cd could induce renal histopathological abnormalities and dysfunction, disrupt the mitochondria's ultrastructure, and increase the ROS and MDA content. Next, Cd exposure caused GSH/GPX4 axis blockade, increased FTH1 and COX2 expression, decreased ACSL4 expression, and significantly decreased the iron content in proximal tubular cells or kidney tissues. Further study showed that the expression of iron absorption-related genes SLC11A2, CUBN, LRP2, SLC39A14, and SLC39A8 decreased in proximal tubular cells or kidneys after Cd exposure, while TFRC and iron export-related gene SLC40A1 did not change significantly. Moreover, Cd exposure increased SLC11A2 gene expression and decreased SLC40A1 gene expression in the duodenum. Finally, NAC or Fer-1 partially alleviated Cd-induced proximal tubular cell damage, while DFO and Erastin further aggravated Cd-induced cell damage. In conclusion, our results indicated that Cd could cause iron deficiency and chronic kidney injury by interfering with the iron metabolism rather than typical ferroptosis. Our findings suggest that an abnormal iron metabolism may contribute to Cd-induced nephrotoxicity, providing a novel approach to preventing kidney disease in clinical practice.
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Affiliation(s)
- Kanglei Zhang
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Mengfei Long
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Wenxuan Dong
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Jiahui Li
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Xueru Wang
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Wenjing Liu
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Qing Huang
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Yuyu Ping
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Gang Liu
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
- College of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Di Ran
- College of Veterinary Medicine, Southwest University, Chongqing 400715, China;
- College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou 225009, China; (K.Z.); (M.L.); (W.D.); (J.L.); (X.W.); (W.L.); (Q.H.); (Y.P.); (H.Z.); (R.S.); (G.L.)
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
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Shen S, Shao Y, Li C. Different types of cell death and their shift in shaping disease. Cell Death Discov 2023; 9:284. [PMID: 37542066 PMCID: PMC10403589 DOI: 10.1038/s41420-023-01581-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 07/16/2023] [Accepted: 07/26/2023] [Indexed: 08/06/2023] Open
Abstract
Cell death is the irreversible stop of life. It is also the basic physiological process of all organisms which involved in the embryonic development, organ maintenance and autoimmunity of the body. In recent years, we have gained more comprehension of the mechanism in cell death and have basically clarified the different types of "programmed cell death", such as apoptosis, necroptosis, autophagy, and pyroptosis, and identified some key genes in these processes. However, in these previous studies, the conversion between different cell death modes and their application in diseases are rarely explored. To sum up, although many valued discoveries have been discovered in the field of cell death in recent years, there are still many unknown problems to be solved in this field. Facts have proved that cell death is a very complex game, and a series of core players have the ability to destroy the delicate balance of the cell environment, from survival to death, from anti-inflammatory to pro-inflammatory. With the thorough research of the complex regulatory mechanism of cell death, there will certainly be exciting new research in this field in the next few years. The sake of this paper is to emphasize the complex mechanism of overturning the balance between different cell fates and provide relevant theoretical basis for the connection between cell death transformation and disease treatment in the future.
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Affiliation(s)
- Sikou Shen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, PR China
| | - Yina Shao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, PR China
| | - Chenghua Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, PR China.
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, PR China.
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16
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Huang Z, Liu W, Ma T, Zhao H, He X, Liu B. Slow Cooling and Controlled Ice Nucleation Enabling the Cryopreservation of Human T Lymphocytes with Low-Concentration Extracellular Trehalose. Biopreserv Biobank 2023; 21:417-426. [PMID: 36001824 DOI: 10.1089/bio.2022.0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Cryopreservation of human T lymphocytes has become a key strategy for supporting cell-based immunotherapy. However, the effects of ice seeding on the cryopreservation of cells under relatively slow cooling have not been well researched. The cryopreservation strategy with a nontoxic, single-ingredient, and injectable cryoprotective solution remains to be developed. We conducted ice seeding for the cells in a solution of normal saline with 1% (v/v) dimethyl sulfoxide (Me2SO), 0.1 M trehalose, and 4% (w/v) human serum albumin (HSA) under different slow cooling rates. With the positive results, we further applied seeding in the solution of 0.2 M trehalose and 4% (w/v) HSA under the same cooling rates. The optimal concentration of trehalose in the Me2SO-free solutions was then investigated under the optimized cooling rate with seeding, with control groups without seeding, and in a freezing container. In vitro toxicity of the cryoprotective solutions to the cells was also tested. We found that the relative viability of cells (1% [v/v] Me2SO, 0.1 M trehalose and 4% [w/v] HSA) was improved significantly from 88.6% to 94.1% with ice seeding, compared with that without seeding (p < 0.05). The relative viability of cells (0.2 M trehalose and 4% [w/v] HSA) with seeding was significantly higher than that without seeding, 96.3% and 92.0%, respectively (p < 0.05). With no significant difference in relative viability between the solutions of 0.2 M trehalose or 0.3 M trehalose with 4% (w/v) HSA (92.4% and 94.6%, respectively, p > 0.05), the solution of 0.2 M trehalose and 4% (w/v) HSA was selected as the optimized Me2SO-free solution. This strategy could cryopreserve human T lymphocytes without any toxic cryoprotectant and boost the application of cell products in humans by intravenous injection, with the osmolality of the low-concentration cryoprotective solution close to that of human plasma.
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Affiliation(s)
- Zhiyong Huang
- Institute of Bio-Thermal Science and Technology, University of Shanghai for Science and Technology, Shanghai, China
| | - Wei Liu
- Institute of Bio-Thermal Science and Technology, University of Shanghai for Science and Technology, Shanghai, China
| | | | | | - Xiaowen He
- Origincell Technology Group Co., Shanghai, China
| | - Baolin Liu
- Institute of Bio-Thermal Science and Technology, University of Shanghai for Science and Technology, Shanghai, China
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17
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Mireault M, Xiao Y, Barbeau B, Jumarie C. Cadmium affects autophagy in the human intestinal cells Caco-2 through ROS-mediated ERK activation. Cell Biol Toxicol 2023; 39:945-966. [PMID: 34580807 PMCID: PMC10406703 DOI: 10.1007/s10565-021-09655-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 09/10/2021] [Indexed: 10/20/2022]
Abstract
Cadmium is a toxic metal that enters the food chain. Following oral ingestion, the intestinal epithelium has the capacity to accumulate high levels of this metal. We have previously shown that Cd induces ERK1/2 activation in differentiated but not proliferative human enterocytic-like Caco-2 cells. As autophagy is a dynamic process that plays a critical role in intestinal mucosa, we aimed the present study 1) to investigate the role of p-ERK1/2 in constitutive autophagy in proliferative Caco-2 cells and 2) to investigate whether Cd-induced activation of ERK1/2 modifies autophagic activity in postconfluent Caco-2 cell monolayers. Western blot analyses of ERK1/2 and autophagic markers (LC3, SQSTM1), and cellular staining with acridine orange showed that ERK1/2 and autophagic activities both decreased with time in culture. GFP-LC3 fluorescence was also associated with proliferative cells and the presence of a constitutive ERK1/2-dependent autophagic flux was demonstrated in proliferative but not in postconfluent cells. In the latter condition, serum and glucose deprivation triggered autophagy via a transient phosphorylation of ERK1/2, whereas Cd-modified autophagy via a ROS-dependent sustained activation of ERK1/2. Basal autophagy flux in proliferative cells and Cd-induced increases in autophagic markers in postconfluent cells both involved p-ERK1/2. Whether Cd blocks autophagic flux in older cell cultures remains to be clarified but our data suggest dual effects. Our results prompt further studies investigating the consequences that Cd-induced ERK1/2 activation and the related effect on autophagy may have on the intestinal cells, which may accumulate and trap high levels of Cd under some nutritional conditions.
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Affiliation(s)
- Myriam Mireault
- Département des Sciences Biologiques, Groupe TOXEN, Université du Québec à Montréal, C.P. 8888, succ Centre ville, Montréal, Québec, H3C 3P8, Canada
- Département des Sciences Biologiques, centre CERMO-FC, Université du Québec à Montréal, Montréal, Québec, Canada
| | - Yong Xiao
- Département des Sciences Biologiques, centre CERMO-FC, Université du Québec à Montréal, Montréal, Québec, Canada
| | - Benoît Barbeau
- Département des Sciences Biologiques, centre CERMO-FC, Université du Québec à Montréal, Montréal, Québec, Canada
| | - Catherine Jumarie
- Département des Sciences Biologiques, Groupe TOXEN, Université du Québec à Montréal, C.P. 8888, succ Centre ville, Montréal, Québec, H3C 3P8, Canada.
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18
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Li K, Guo C, Ruan J, Ning B, Wong CKC, Shi H, Gu J. Cadmium Disrupted ER Ca 2+ Homeostasis by Inhibiting SERCA2 Expression and Activity to Induce Apoptosis in Renal Proximal Tubular Cells. Int J Mol Sci 2023; 24:ijms24065979. [PMID: 36983052 PMCID: PMC10053525 DOI: 10.3390/ijms24065979] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 03/30/2023] Open
Abstract
Cadmium (Cd2+) exposure induces chronic kidney disease and renal cancers, which originate from injury and cancerization of renal tubular cells. Previous studies have shown that Cd2+ induced cytotoxicity by disrupting the intracellular Ca2+ homeostasis that is physically regulated by the endoplasmic reticulum (ER) Ca2+ store. However, the molecular mechanism of ER Ca2+ homeostasis in Cd2+-induced nephrotoxicity remains unclear. In this study, our results firstly revealed that the activation of calcium-sensing receptor (CaSR) by NPS R-467 could protect against Cd2+ exposure-induced cytotoxicity of mouse renal tubular cells (mRTEC) by restoring ER Ca2+ homeostasis through the ER Ca2+ reuptake channel sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Cd2+-induced ER stress and cell apoptosis were effectively abrogated by SERCA agonist CDN1163 and SERCA2 overexpression. In addition, in vivo, and in vitro results proved that Cd2+ reduced the expressions of SERCA2 and its activity regulator phosphorylation phospholamban (p-PLB) in renal tubular cells. Cd2+-induced SERCA2 degradation was suppressed by the treatment of proteasome inhibitor MG132, which suggested that Cd2+ reduced SERCA2 protein stability by promoting the proteasomal protein degradation pathway. These results suggested that SERCA2 played pivotal roles in Cd2+-induced ER Ca2+ imbalance and stress to contribute to apoptosis of renal tubular cells, and the proteasomal pathway was involved in regulating SERCA2 stability. Our results proposed a new therapeutic approach targeting SERCA2 and associated proteasome that might protect against Cd2+-induced cytotoxicity and renal injury.
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Affiliation(s)
- Kongdong Li
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Chuanzhi Guo
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Jiacheng Ruan
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Bo Ning
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | | | - Haifeng Shi
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
| | - Jie Gu
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China
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19
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Gong Z, Liu W, Song R, Dong W, Zhang K, Li J, Zou H, Zhu J, Ma Y, Liu G, Liu Z. Nuclear factor-kappaB mediates the survival of rat kidney cells after cadmium exposure via promoting autophagy and inhibiting apoptosis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 249:114465. [PMID: 38321684 DOI: 10.1016/j.ecoenv.2022.114465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/17/2022] [Accepted: 12/21/2022] [Indexed: 02/08/2024]
Abstract
Cadmium (Cd) is a heavy metal pollutant in the environment, and the kidney is one of the target organs after Cd exposure. Previous studies have shown that apoptosis and autophagy disorders are the main mechanisms of Cd-induced nephrotoxicity in rats. As a transcription factor that balances cell survival and death, nuclear factor-kappaB (NF-κB) protein plays dual regulatory effects on apoptosis and autophagy in multiple renal diseases. However, the regulatory mechanisms of NF-κB in Cd-induced kidney injury remain unclear. Therefore, the normal rat kidney cell line (NRK-52E cells) was applied to investigate the above questions in this study. Here, we found that Cd promotes the nuclear translocation and activation of NF-κB in a concentration-dependent manner, and activated NF-κB mediates NRK-52E cells survival after Cd exposure. Next, our study elaborated the mechanisms of NF-κB in antagonizing Cd-induced renal cytotoxicity. Inhibition of NF-κB by inhibitor BAY 11-7082 (BAY) and NF-κB p65 siRNA (siNF-κB p65) exacerbate Cd-induced apoptosis and autophagy inhibition, and then aggravate Cd-induced NRK-52E cells injury. Activation of NF-κB by activator phorbol-12-myristate-13-acetate (PMA) alleviates Cd-induced apoptosis and autophagy inhibition, and then attenuates Cd-induced NRK-52E cells injury. In conclusion, Cd exposure promotes the activation of NF-κB, and activated NF-κB mediates the survival of NRK-52E cells after Cd exposure via promoting autophagy and inhibiting apoptosis.
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Affiliation(s)
- Zhonggui Gong
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China
| | - Wenjing Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China
| | - Wenxuan Dong
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China
| | - Kanglei Zhang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China
| | - Jiahui Li
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China
| | - Jiaqiao Zhu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China
| | - Yonggang Ma
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China
| | - Gang Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Important Animal Infectious Diseases and Zoonoses of Jiangsu Higher Education Institutions; Yangzhou, Jiangsu PR China.
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20
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Wan XM, Zheng C, Zhou XL. Puerarin prevents cadmium-induced mitochondrial fission in AML-12 cells via Sirt1-dependent pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 248:114302. [PMID: 36399995 DOI: 10.1016/j.ecoenv.2022.114302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/23/2022] [Accepted: 11/14/2022] [Indexed: 06/16/2023]
Abstract
Recent investigations have revealed that puerarin (PU) alleviates cadmium (Cd)-caused hepatic damage via inhibiting oxidative stress. Mitochondria are dynamic organelles and play a critical part in regulating the occurrence of oxidative stress, but the role of mitochondria in the protection of PU against hepatocellular damage caused by Cd exposure remains unknown. Thus, this study was aimed to clarify this issue using mouse hepatocyte AML-12 cell line. Transmission electron microscopy analysis firstly showed that PU prevents Cd-induced mitochondrial ultrastructure damage. Mitochondrial network image analysis by confocal microscopy revealed that PU exerts the protection against Cd-induced cytotoxicity via restoring mitochondrial network fragmentation. Also, mitochondrial dynamic protein expression profiles showed that enhanced fission protein levels and inhibited fusion protein levels in Cd-treated cells were significantly reversed by PU, suggesting the protective effect of PU against Cd-induced mitochondrial fission. Moreover, changes of intracellular ATP level and protein levels of key regulators involving in mitochondrial biogenesis indicated that Sirtuin-1(Sirt1) pathway may be involved in the protection of Cd-impaired mitochondrial function by PU. Next, Sirt1 protein levels in treated cells were effectively regulated by genetic knockdown or chemical agonist SRT1720. Accordingly, alleviation of Cd-induced mitochondrial fission assays and cell viability by PU was markedly regulated by SRT1720 or Sirt1 knockdown, suggesting the indispensable role of Sirt1 in this process. Collectively, these findings highlight that PU prevents Cd-induced mitochondrial fission to alleviate cytotoxicity via Sirt1-dependent pathway, which provide novel evidences to fully understand the hepatoprotective action of PU against heavy metal toxicity.
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Affiliation(s)
- Xue-Mei Wan
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, Sichuan 610072, China
| | - Chuan Zheng
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611130, China.
| | - Xue-Lei Zhou
- Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu, Sichuan 610072, China.
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21
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Lu L, Liu JB, Wang JQ, Lian CY, Wang ZY, Wang L. Glyphosate-induced mitochondrial reactive oxygen species overproduction activates parkin-dependent mitophagy to inhibit testosterone synthesis in mouse leydig cells. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 314:120314. [PMID: 36183875 DOI: 10.1016/j.envpol.2022.120314] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 06/16/2023]
Abstract
Glyphosate (GLY), one of the most extensively used herbicides in the world, has been shown to inhibit testosterone synthesis in male animals. Mitochondria are crucial organelles for testosterone synthesis and its dysfunction has been demonstrated to induce the inhibition of testosterone biosynthesis. However, whether low-dose GLY exposure targets mitochondria to inhibit testosterone synthesis and its underlying mechanism remains unclear. Here, an in vitro model of 10 μM GLY-exposed mouse Leydig (TM3) cells was established to elucidate this issue. Data firstly showed that mitochondrial malfunction, mainly manifested by ultrastructure damage, disturbance of mitochondrial dynamics and mitochondrial reactive oxygen species (mtROS) overproduction, was responsible for GLY-decreased protein levels of steroidogenic enzymes, which leads to the inhibition of testosterone synthesis. Enhancement of autophagic flux and activation of mitophagy were shown in GLY-treated TM3 cells, and further studies have revealed that GLY-activated mitophagy is parkin-dependent. Notably, GLY-inhibited testosterone production was significantly improved by parkin knockdown. Finally, data showed that treatment with mitochondria-targeted antioxidant Mito-TEMPO (M-T) markedly reversed GLY-induced mitochondrial network fragmentation, activation of parkin-dependent mitophagy and consultant testosterone reduction. Overall, these findings demonstrate that GLY induces mtROS overproduction to activate parkin-dependent mitophagy, which contributes to the inhibition of testosterone synthesis. This study provides a potential mechanistic explanation for how GLY inhibits testosterone synthesis in mouse Leydig cells.
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Affiliation(s)
- Lu Lu
- College of Animal Science and Veterinary Medicine, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Jing-Bo Liu
- College of Biological and Brewing Engineering, Taishan University, 525 Dongyue Street, Tai'an City, Shandong Province, 271000, China
| | - Jin-Qiu Wang
- Department of Animal Husbandry and Veterinary Medicine, Beijing Vocational College of Agriculture, Beijing, 102442, China
| | - Cai-Yu Lian
- College of Animal Science and Veterinary Medicine, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Zhen-Yong Wang
- College of Animal Science and Veterinary Medicine, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Lin Wang
- College of Animal Science and Veterinary Medicine, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China.
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22
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Ma Y, Su Q, Yue C, Zou H, Zhu J, Zhao H, Song R, Liu Z. The Effect of Oxidative Stress-Induced Autophagy by Cadmium Exposure in Kidney, Liver, and Bone Damage, and Neurotoxicity. Int J Mol Sci 2022; 23:13491. [PMID: 36362277 PMCID: PMC9659299 DOI: 10.3390/ijms232113491] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 10/26/2022] [Accepted: 11/02/2022] [Indexed: 08/11/2023] Open
Abstract
Environmental and occupational exposure to cadmium has been shown to induce kidney damage, liver injury, neurodegenerative disease, and osteoporosis. However, the mechanism by which cadmium induces autophagy in these diseases remains unclear. Studies have shown that cadmium is an effective inducer of oxidative stress, DNA damage, ER stress, and autophagy, which are thought to be adaptive stress responses that allow cells exposed to cadmium to survive in an adverse environment. However, excessive stress will cause tissue damage by inducing apoptosis, pyroptosis, and ferroptosis. Evidently, oxidative stress-induced autophagy plays different roles in low- or high-dose cadmium exposure-induced cell damage, either causing apoptosis, pyroptosis, and ferroptosis or inducing cell survival. Meanwhile, different cell types have different sensitivities to cadmium, which ultimately determines the fate of the cell. In this review, we provided a detailed survey of the current literature on autophagy in cadmium-induced tissue damage. A better understanding of the complex regulation of cell death by autophagy might contribute to the development of novel preventive and therapeutic strategies to treat acute and chronic cadmium toxicity.
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Affiliation(s)
- Yonggang Ma
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Qunchao Su
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Chengguang Yue
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Jiaqiao Zhu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Hongyan Zhao
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture and Agri-Product Safety, Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
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23
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Cui T, Wang X, Hu J, Lin T, Hu Z, Guo H, Huang G, Hu G, Zhang C. Molybdenum and cadmium co-exposure induces CaMKKβ/AMPK/mTOR pathway mediated-autophagy by subcellular calcium redistribution in duck renal tubular epithelial cells. J Inorg Biochem 2022; 236:111974. [PMID: 36027844 DOI: 10.1016/j.jinorgbio.2022.111974] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 08/06/2022] [Accepted: 08/16/2022] [Indexed: 12/15/2022]
Abstract
Excessive molybdenum (Mo) and cadmium (Cd) are toxic environmental pollutants. Our previous research confirmed excessive Mo and Cd co-induced calcium homeostasis disorder and autophagy in duck kidneys, but how calcium ion (Ca2+) regulates autophagy is unclear. The results revealed that the Mo- and/or Cd-induced cytosolic Ca2+ concentration ([Ca2+]c) increase mainly came from intracellular calcium stores. Mo and/or Cd caused mitochondrial Ca2+ content ([Ca2+]mit) and [Ca2+]c increase with endoplasmic reticulum (ER) Ca2+ content ([Ca2+]ER) decrease and upregulated calcium homeostasis-related factor expression levels, but 2-Aminoethoxydiphenyl borate (2-APB) reversed subcellular Ca2+ redistribution. Increased Phospholipase C (PLC) and inositol 1,4,5-trisphosphate (IP3) activities and inositol 1,4,5-trisphosphate receptor (IP3R) expression level were observed in Mo- and/or Cd-treated cells, which was reversed by the PLC inhibitor U-73122. 2-APB and 1,2-Bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) addition mitigated [Ca2+]c and autophagy (variations in microtubule-associated protein light chain 3 (LC3), LC3B-II/LC3B-I, autophagy related 5 (ATG5), sequestosome-1(P62), programmed cell death-1 (Beclin-1) and Dynein expression levels, LC3 puncta, autophagosomes and acid vesicle organelles) under Mo and/or Cd treatment, respectively, while thapsigargin (TG) had the opposite impacts. Additionally, the calmodulin-dependent protein kinase kinase β (CaMKKβ) inhibitor STO-609 reversed the increased CaMKKβ, adenosine 5'-monophosphate-activated protein kinase (AMPK), Beclin-1, and LC3B-II/LC3B-I protein expression levels and reduced mammalian target of rapamycin (mTOR) and P62 protein expression levels in Mo- and/or Cd-exposed cells. Collectively, the results confirmed that [Ca2+]c overload resulted from PLC/IP3/IP3R pathway-mediated ER Ca2+ release, and then activated autophagy by the CaMKKβ/AMPK/mTOR pathway in Mo- and/or Cd-treated duck renal tubular epithelial cells.
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Affiliation(s)
- Ting Cui
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Xueru Wang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Junyu Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Tianjin Lin
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Zhisheng Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Huiling Guo
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Gang Huang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Guoliang Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China
| | - Caiying Zhang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang, Jiangxi, China..
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Honokiol Antagonizes Cadmium-Induced Nephrotoxicity in Quail by Alleviating Autophagy Dysfunction, Apoptosis and Mitochondrial UPR Inhibition with Its Antioxidant Properties. LIFE (BASEL, SWITZERLAND) 2022; 12:life12101574. [PMID: 36295008 PMCID: PMC9604973 DOI: 10.3390/life12101574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/04/2022] [Accepted: 10/05/2022] [Indexed: 11/06/2022]
Abstract
Japanese quail is a highly economically valuable bird due to its commercial production for meat and eggs. Although studies have reported Cadmium (Cd) is a ubiquitous heavy metal that can cause injury to various organs, the molecular mechanisms of Cd on quail kidney injury remain largely unknown. It has been reported that Honokiol (HKL), a highly functional antioxidant, can protect cells against oxidative stress effectively. This study was conducted to investigate the effects of Cd on quail kidneys injury and the protective effect of HKL on Cd-induced nephrotoxicity. A total of 40 Japanese quails were randomly divided into four groups: the control group, Cd treatment group, Co-treatment group and HKL treatment group. The results showed that Cd resulted in significant changes in growth performance, kidney histopathology and kidney biochemical status, antioxidant enzymes and oxidative stress parameters, and ultrastructure of renal tubular epithelial cells, compared with controls. Cd increased the expression of autophagy-related and apoptosis-related genes, but decreased expression of lysosomal function-related and UPRmt-related genes. The co-treatment group ameliorated Cd-induced nephrotoxicity by alleviating oxidative stress, inhibiting apoptosis, repairing autophagy dysfunction and UPRmt disorder. In conclusion, dietary supplementation of HKL showed beneficial effects on Japanese quail kidney injury caused by Cd.
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Chen DW, Li HJ, Liu Y, Ma LN, Pu JH, Lu J, Tang XJ, Gao YS. Protective effects of fowl-origin cadmium-tolerant lactobacillus against sub-chronic cadmium-induced toxicity in chickens. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:76036-76049. [PMID: 35665891 DOI: 10.1007/s11356-022-19113-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 02/03/2022] [Indexed: 06/15/2023]
Abstract
Cadmium (Cd) directly endangers poultry health and indirectly causes harm to human health by food chain. Numerous studies have focused on removing Cd using lactic acid bacteria (LAB). However, there is still a lack of in vivo studies to validate whether Cd can be absorbed successfully by LAB to alleviate Cd toxicity. Here, we aimed to isolated and screened poultry-derived Cd-tolerant LAB with the strongest adsorption capacity in vitro and investigate the protective effect of which on sub-chronic Cd toxicity in chickens. First, nine Cd-tolerant LAB strains were selected preliminarily by isolating, screening, and identifying from poultry farms. Next, four strains with the strongest adsorption capacity were used to explore the influence of different physical and chemical factors on the ability of LAB to adsorb Cd as well as its probiotic properties in terms of acid tolerance, bile salt tolerance, drug resistance, and antibacterial effects. Resultantly, the CLF9-1 strain with the best comprehensive ability was selected for further animal protection test. The Cd-tolerant LAB treatment promoted the growth performance of chickens and reduced the Cd-elevated liver and kidney coefficients. Moreover, Cd-induced liver, kidney, and duodenum injuries were alleviated significantly by high-dose LAB treatment. Furthermore, LAB treatment also increased the elimination of Cd in feces and markedly reduced the Cd buildup in the liver and kidney. In summary, these findings determine that screened Cd-tolerant LAB strain exerts a protective effect on chickens against sub-chronic cadmium poisoning, thus providing an essential guideline for the public health and safety of livestock and poultry.
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Affiliation(s)
- Da-Wei Chen
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, Jiangsu, 225125, People's Republic of China
| | - Hui-Jia Li
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an, Shandong, 271018, People's Republic of China
| | - YinYin Liu
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, Jiangsu, 225125, People's Republic of China
| | - Li-Na Ma
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, Jiangsu, 225125, People's Republic of China
| | - Jun-Hua Pu
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, Jiangsu, 225125, People's Republic of China
| | - JunXian Lu
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, Jiangsu, 225125, People's Republic of China
| | - Xiu-Jun Tang
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, Jiangsu, 225125, People's Republic of China
| | - Yu-Shi Gao
- Poultry Institute, Chinese Academy of Agricultural Sciences, Yangzhou, Jiangsu, 225125, People's Republic of China.
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26
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Chen K, Liu JB, Tie CZ, Wang L. Trehalose prevents glyphosate-induced testicular damage in roosters via its antioxidative properties. Res Vet Sci 2022; 152:314-322. [PMID: 36084373 DOI: 10.1016/j.rvsc.2022.08.029] [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: 04/02/2022] [Revised: 08/16/2022] [Accepted: 08/30/2022] [Indexed: 10/14/2022]
Abstract
Glyphosate (GLY), an active ingredient of the most commonly used herbicide, when in crops and feed, is deleterious to male reproductive health. Trehalose (Tre), a naturally non-reducing disaccharide, is shown to counteract the adverse stresses due to its antioxidation effect. Thus, this study was designed to investigate whether Tre can improve GLY-induced testicular damage via suppressing oxidative stress. 60 healthy Hy-Line Brown breeder roosters were utilized to assess the protective effects of Tre supplementation against testicular oxidative damage caused by GLY. Data showed that Tre administration significantly alleviated GLY- induced reduction in testis weight, decreased GLY level in the testis tissues, and alleviated GLY-caused testicular pathological damage. Concurrently, GLY treatment significantly elevated serum malondialdehyde (MDA) and testicular reactive oxygen species (ROS) levels, decreased serum total anti-oxidation capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, which were all notably reversed by Tre administration. Moreover, GLY- inhibited nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in rooster testis, a master regulator of oxidative stress, was markedly recovered by Tre administration. In summary, these findings demonstrated that Tre can prevent GLY-induced testicular damage in roosters by ameliorating oxidative stress.
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Affiliation(s)
- Kai Chen
- New Drug Evaluation Center of Shandong Academy of Pharmaceutical Sciences, Shandong Academy of Pharmaceutical Sciences, 989 Xinluo Street, Ji'nan City 250101, Shandong Province, China; Shandong Technology Innovation Center of Artificial Phage Drug, 989 Xinluo Street, Ji'nan City 250101, Shandong Province, China
| | - Jing-Bo Liu
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China
| | - Cheng-Zhu Tie
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China
| | - Lin Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China.
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Pupyshev AB, Klyushnik TP, Akopyan AA, Singh SK, Tikhonova MA. Disaccharide Trehalose in Experimental Therapies for Neurodegenerative Disorders: Molecular Targets and Translational Potential. Pharmacol Res 2022; 183:106373. [PMID: 35907433 DOI: 10.1016/j.phrs.2022.106373] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/23/2022] [Accepted: 07/26/2022] [Indexed: 10/16/2022]
Abstract
Induction of autophagy is a prospective approach to the treatment of neurodegeneration. In the recent decade, trehalose attracted special attention. It is an autophagy inducer with negligible adverse effects and is approved for use in humans according to FDA requirements. Trehalose has a therapeutic effect in various experimental models of diseases. This glucose disaccharide with a flexible α-1-1'-glycosidic bond has unique properties: induction of mTOR-independent autophagy (with kinase AMPK as the main target) and a chaperone-like effect on proteins imparting them natural spatial structure. Thus, it can reduce the accumulation of neurotoxic aberrant/misfolded proteins. Trehalose has an anti-inflammatory effect and inhibits detrimental oxidative stress partially owing to the enhancement of endogenous antioxidant defense represented by the Nrf2 protein. The disaccharide activates lysosome and autophagosome biogenesis pathways through the protein factors TFEB and FOXO1. Here we review various mechanisms of the neuroprotective action of trehalose and touch on the possibility of pleiotropic effects. Current knowledge about specific features of trehalose pharmacodynamics is discussed. The neuroprotective effects of trehalose in animal models of major neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are examined too. Attention is given to translational transition to clinical trials of this drug, especially oral and parenteral routes of administration. Besides, the possibility of enhancing the therapeutic benefit via a combination of mTOR-dependent and mTOR-independent autophagy inducers is analyzed. In general, trehalose appears to be a promising multitarget tool for the inhibition of experimental neurodegeneration and requires thorough investigation of its clinical capabilities.
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Affiliation(s)
- Alexander B Pupyshev
- Scientific Research Institute of Neurosciences and Medicine (SRINM); Timakova Str. 4, Novosibirsk 630117, Russia.
| | - Tatyana P Klyushnik
- Mental Health Research Center, Kashirskoye shosse 34, Moscow 115522, Russia.
| | - Anna A Akopyan
- Scientific Research Institute of Neurosciences and Medicine (SRINM); Timakova Str. 4, Novosibirsk 630117, Russia.
| | - Sandeep Kumar Singh
- Indian Scientific Education and Technology Foundation, Krishna Bhawan, 594 Kha/123, Shahinoor Colony, Nilmatha, Uttar Pradesh, Lucknow 226002, India.
| | - Maria A Tikhonova
- Scientific Research Institute of Neurosciences and Medicine (SRINM); Timakova Str. 4, Novosibirsk 630117, Russia.
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Lin T, Nie G, Hu R, Luo J, Xing C, Hu G, Zhang C. Involvement of calcium homeostasis and unfolded protein response in autophagy co-induced by molybdenum and cadmium in duck (Anas platyrhyncha) brain. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:38303-38314. [PMID: 35076842 DOI: 10.1007/s11356-022-18738-6] [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: 09/10/2021] [Accepted: 01/14/2022] [Indexed: 06/14/2023]
Abstract
Excess molybdenum (Mo) and cadmium (Cd) are harmful to animals, but neurotoxicity caused by Mo and Cd co-exposure in ducks is yet unknown. To assess joint impacts of Mo and Cd on autophagy via calcium homeostasis and unfolded protein response (UPR) in duck brain, 40 healthy 7-day-old ducks (Anas platyrhyncha) were assigned to 4 groups at random and fed diets supplemented with different doses of Mo or/and Cd for 16 weeks, respectively. Brain tissues were excised for experiment. Results exhibited that Mo or/and Cd disturbed calcium homeostasis by decreased ATPase activities and increased calcium (Ca) content, and upregulated calcium homeostasis-related factors Ca2+/CAM-dependent kinase IIɑ (CaMKIIɑ), calcineurin (CaN), inositol-1,4,5-trisphosphate receptor (IP3R), and calreticulin (CRT) expression levels. Meanwhile, the upregulation of UPR-related factor expression levels indicated that Mo or/and Cd activated UPR. Moreover, Mo or/and Cd triggered autophagy through promoting the number of autophagosomes and LC3II immunofluorescence intensity and altering autophagy key factor expression levels. Correlation analysis showed that there were obvious connections among Ca2+ homeostasis, endoplasmic reticulum (ER) stress, and autophagy induced by Mo or/and Cd. Thence, it can be speculated that autophagy initiated by Mo or/and Cd may be associated with interfering Ca2+ homeostasis and triggering UPR.
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Affiliation(s)
- Tianjin Lin
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Economic and Technological Development District, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Nanchang, 330045, Jiangxi, People's Republic of China
| | - Gaohui Nie
- School of Information Technology, Jiangxi University of Finance and Economics, No. 665 Yuping West Street, Economic and Technological Development District, Nanchang, 330032, Jiangxi, People's Republic of China
| | - Ruiming Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Economic and Technological Development District, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Nanchang, 330045, Jiangxi, People's Republic of China
| | - Junrong Luo
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Economic and Technological Development District, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Nanchang, 330045, Jiangxi, People's Republic of China
| | - Chenghong Xing
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Economic and Technological Development District, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Nanchang, 330045, Jiangxi, People's Republic of China
| | - Guoliang Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Economic and Technological Development District, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Nanchang, 330045, Jiangxi, People's Republic of China
| | - Caiying Zhang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Economic and Technological Development District, Jiangxi Agricultural University, No. 1101 Zhimin Avenue, Nanchang, 330045, Jiangxi, People's Republic of China.
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Tong X, Yu G, Liu Q, Zhang X, Bian J, Liu Z, Gu J. Puerarin alleviates cadmium-induced oxidative damage to bone by reducing autophagy in rats. ENVIRONMENTAL TOXICOLOGY 2022; 37:720-729. [PMID: 34897960 DOI: 10.1002/tox.23437] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 11/28/2021] [Accepted: 12/05/2021] [Indexed: 06/14/2023]
Abstract
Autophagy is a regulatory mechanism involved in cadmium (Cd)-induced bone toxicity and is suppressed by various stimuli, including oxidative stress. Puerarin is an isoflavonoid compound isolated from Pueraria, a plant used in traditional Chinese medicine. The underlying mechanisms of action of puerarin remain unclear. The objective of this study was to explore the mitigating effects of puerarin on cadmium-induced oxidative damage in the bones of rats. Cadmium exposure increased oxidative damage in rat bones; this was markedly decreased by puerarin treatment, as demonstrated by changes in the activity of antioxidative enzymes. Cadmium-induced blockage of the expression of key bone regulatory proteins, autophagy-related markers, and signaling molecules was also alleviated by puerarin treatment. Additionally, cadmium reduced expression of the autophagic protein Rab7 and of late endosomal/lysosomal adaptor and MAPK and mTOR activator 1 (LAMTOR1); the decrease in these proteins was not restored by puerarin treatment. We speculate that puerarin relieves the inhibition of fusion of autophagosomes with lysosomes that is induced by cadmium; however, this specific effect of puerarin and downstream effects on bone regulatory mechanisms require further investigation. In conclusion, puerarin alleviates cadmium-induced oxidative damage in the bones of rats by attenuating autophagy, which is likely associated with the antioxidant activity of puerarin.
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Affiliation(s)
- Xishuai Tong
- Institutes of Agricultural Science and Technology Development, Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, P. R. China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, P. R. China
| | - Gengsheng Yu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, P. R. China
| | - Qingyang Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, P. R. China
| | - Xueqing Zhang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, P. R. China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, P. R. China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, P. R. China
| | - Zongping Liu
- Institutes of Agricultural Science and Technology Development, Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, P. R. China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, P. R. China
| | - Jianhong Gu
- Institutes of Agricultural Science and Technology Development, Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, P. R. China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu, P. R. China
- Jiangsu Key Laboratory of Zoonosis, Yangzhou, Jiangsu, P. R. China
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Antar SA, El-Gammal MA, Hazem RM, Moustafa YM. Etanercept Mitigates Cadmium Chloride-induced Testicular Damage in Rats "An Insight into Autophagy, Apoptosis, Oxidative Stress and Inflammation". ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:28194-28207. [PMID: 34993805 DOI: 10.1007/s11356-021-18401-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/25/2021] [Indexed: 06/14/2023]
Abstract
RATIONALE Cadmium (Cd) is an environmental and occupational toxin that represents a serious health hazard to humans and other animals. One of the negative consequences of cadmium exposure is testicular injury. OBJECTIVE This study aimed to investigate the therapeutic effect of etanercept against cadmium chloride-induced testicular damage and the probable underlying mechanisms of its action. METHODS A total of sixty rats were divided into six groups: control, cadmium chloride (CdCl2) (7 mg/ kg i.p.), and CdCl2 treated with etanercept (5,10 and 15 mg/kg s.c.) and etanercept only (15 mg/kg s.c.). CdCl2 was administrated as a single dose, while etanercept was administered every 3 days for 3 weeks. RESULTS CdCl2 reduced serum testosterone, testicular glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). However, it elevated the levels of malondialdehyde (MDA) and microtubule-associated protein light chain 3B (LC3B) in the testes. Cadmium caused pathogenic alterations as well as increased levels of inflammatory biomarkers such as tumor necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB). Besides, the gene expressions of caspase-3 and inducible nitric oxide synthase (i-NOS) and Beclin-1 protein increased with CdCl2 exposure. Interestingly, etanercept relieved the previous toxic effects induced by CdCl2 in a dose-dependent manner as evidenced by inhibition of oxidative stress, inflammatory markers, Beclin-1, LC3B, and caspase-3 accompanied by improvement in histopathological changes. CONCLUSION Etanercept provides a potential therapeutic approach to treat testicular tissue against the damaging effects of Cd by reducing oxidative stress, inflammation, apoptosis, and autophagy.
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Affiliation(s)
- Samar A Antar
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta, 34518, Egypt.
| | - Mohamad A El-Gammal
- Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta, 34518, Egypt
| | - Reem M Hazem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Yasser M Moustafa
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University, Badr University Cairo, 11829, Egypt
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Cai J, Yang J, Chen X, Zhang H, Zhu Y, Liu Q, Zhang Z. Melatonin ameliorates trimethyltin chloride-induced cardiotoxicity: The role of nuclear xenobiotic metabolism and Keap1-Nrf2/ARE axis-mediated pyroptosis. Biofactors 2022; 48:481-497. [PMID: 34570919 DOI: 10.1002/biof.1787] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 09/14/2021] [Indexed: 12/19/2022]
Abstract
Trimethyltin chloride (TMT) is a stabilizer for polyvinyl chloride plastics that causes serious health hazards in nontarget organisms. Melatonin (MT) exhibits powerful protective effects in cardiac diseases. As a new environmental pollutant, TMT-induced cardiotoxicity and the protective effects of MT remain unclear. To explore this, the mice were treated with TMT (2.8 mg/kg) and/or MT (10 mg/kg) for 7 days. Firstly, the histopathological and ultrastructural evaluation showed that TMT induced cardiac damage, tumescent rupture and nuclear pyknosis. Moreover, TMT elevated the expressions of pyroptosis genes NLRP3, ASC and Cas1 and inflammation factors IL-6, IL-17 and TNFα. Secondly, TMT reduced antioxidant enzymes (GSH, CAT and T-AOC) via decreasing the expression of genes associated with the Keap1-Nrf2/ARE pathway to increase oxidative stress. Thirdly, TMT decreased the expression of genes associated with the ARE-driven drug metabolizing enzymes (DMEs), including Akr7a3, Akr1b8, and Akr1b10. Besides, TMT upregulated the mRNA expression of nuclear Xenobiotic metabolism on cytochrome P450s enzymes via increasing the expression of CAR, PXP, and AHR genes. Furthermore, MT treatment mitigated the aforementioned adverse changes induced by TMT. Overall, these results demonstrated that TMT caused pyroptosis and inflammation to aggravate cardiac damage via inducing excessive oxidative stress, imbalance of DMEs homeostasis, and nuclear Xenobiotic metabolism disorder, which could be alleviated by MT.
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Affiliation(s)
- Jingzeng Cai
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Jie Yang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Xiaoming Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Haoran Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Yue Zhu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Qi Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
| | - Ziwei Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, P.R. China
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Harbin, P.R. China
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Arab HH, Ashour AM, Eid AH, Arafa ESA, Al Khabbaz HJ, Abd El-Aal SA. Targeting oxidative stress, apoptosis, and autophagy by galangin mitigates cadmium-induced renal damage: Role of SIRT1/Nrf2 and AMPK/mTOR pathways. Life Sci 2022; 291:120300. [PMID: 34999115 DOI: 10.1016/j.lfs.2021.120300] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/29/2021] [Accepted: 12/31/2021] [Indexed: 01/18/2023]
Abstract
BACKGROUND Galangin, a bioactive flavonoid with remarkable antioxidant and anti-apoptotic actions, has demonstrated promising amelioration of experimental hepatotoxicity, cardiomyopathy, and colitis. Yet, its impact on cadmium-induced renal injury has not been explored. Herein, we aimed at exploring the potential of galangin to attenuate cadmium-induced nephrotoxicity in rats, focusing on oxidative stress, apoptosis, and autophagy. METHODOLOGY Cadmium chloride (5 mg/kg/day) and galangin (15 mg/kg/day) were received by oral gavage and the kidney tissues were inspected using ELISA, biochemical measurements, histology, and immunohistochemistry. KEY FINDINGS Galangin attenuated cadmium-induced renal damage by diminishing the histopathological alterations alongside KIM-1, BUN, and creatinine. At the molecular level, galangin attenuated the oxidative insult by significantly lowering the lipid peroxides and NOX-1 and augmenting GSH and GPx antioxidants. It also activated the cytoprotective SIRT1/Nrf2/HO-1 pathway by significantly upregulating the protein expression of SIRT1, Nrf2, and HO-1. Consistently, galangin suppressed renal apoptotic cell death by significantly lowering the protein expression of Bax and cytochrome C and activity of caspase-3 alongside upregulating the protein expression of the anti-apoptotic Bcl-2. Additionally, galangin activated the impaired autophagy flux as seen by diminishing the accumulation of SQSTM1/p62 and increasing the protein expression of Beclin 1. Meanwhile, galangin stimulated the autophagy-linked AMPK/mTOR pathway by significantly increasing the p-AMPK/total AMPK and lowering p-mTOR/total mTOR ratios. CONCLUSION Galangin mitigated cadmium-induced nephrotoxicity thanks to its promising antioxidant, anti-apoptotic, and pro-autophagic effects. In perspective, galangin stimulated the SIRT1/Nrf2/HO-1 and AMPK/mTOR pathways. Hence, it may act as a complementary tool for the management of cadmium-induced renal injury.
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Affiliation(s)
- Hany H Arab
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
| | - Ahmed M Ashour
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah 21955, Saudi Arabia
| | - Ahmed H Eid
- Department of Pharmacology, Egyptian Drug Authority (EDA), formerly NODCAR, Giza, Egypt
| | - El-Shaimaa A Arafa
- College of Pharmacy and Health Sciences, Ajman University, Ajman 346, United Arab Emirates; Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-suef University, Beni-suef 62514, Egypt
| | - Hana J Al Khabbaz
- Biochemistry Division, College of Pharmacy, Riyadh Elm University, Riyadh 11681, Saudi Arabia
| | - Sarah A Abd El-Aal
- Department of Pharmacy, Kut University College, Al Kut, Wasit 52001, Iraq
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Gong ZG, Zhao Y, Wang ZY, Fan RF, Liu ZP, Wang L. Epigenetic regulator BRD4 is involved in cadmium-induced acute kidney injury via contributing to lysosomal dysfunction, autophagy blockade and oxidative stress. JOURNAL OF HAZARDOUS MATERIALS 2022; 423:127110. [PMID: 34523489 DOI: 10.1016/j.jhazmat.2021.127110] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/23/2021] [Accepted: 08/30/2021] [Indexed: 06/13/2023]
Abstract
Cadmium (Cd) is a known nephrotoxic heavy metal and proximal tubules are the major target of Cd-induced acute kidney injury (AKI). We previously demonstrated that lysosomal dysfunction and dysregulated autophagy contribute to Cd-induced AKI. Recent studies have revealed that bromodomain-containing protein 4 (BRD4) is a transcriptional repressor of autophagy and lysosomal function. Hence, in vivo and in vitro studies were performed to clarify the role of BRD4 in Cd-induced AKI. Firstly, Cd has no effect on BRD4 expression levels, but increases H4K16 acetylation. Resultantly, Cd promotes the recruitment of BRD4 to lysosomal gene promoter regions to make it as a transcriptional regulator. Pharmacological and genetic inhibition of BRD4 alleviates Cd-inhibited lysosomal gene transcript levels and lysosomal function, leading to the alleviation of Cd-induced autophagy inhibition. Moreover, inhibition of BRD4 relieves Cd-induced oxidative stress and concurrent cytotoxicity, which is counteracted by the inhibition of autophagy via Atg5 knockdown, indicating that alleviation of oxidative stress by BRD4 inhibition is ascribed to its restoration of autophagic flux. Collectively, these results demonstrate that BRD4 acts as a transcriptional repressor to mediate lysosomal dysfunction, autophagy blockade and oxidative stress during Cd exposure, which may be a potential therapeutic target for Cd-induced AKI.
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Affiliation(s)
- Zhong-Gui Gong
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China; College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou, Jiangsu Province 225009, People's Republic of China
| | - Yuan Zhao
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China
| | - Zhen-Yong Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China
| | - Rui-Feng Fan
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China
| | - Zong-Ping Liu
- College of Veterinary Medicine, Yangzhou University, 12 East Wenhui Road, Yangzhou, Jiangsu Province 225009, People's Republic of China.
| | - Lin Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, People's Republic of China.
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Cao P, Nie G, Luo J, Hu R, Li G, Hu G, Zhang C. Cadmium and molybdenum co-induce pyroptosis and apoptosis by PTEN/PI3K/AKT axis in the liver of ducks. Food Funct 2022; 13:2142-2154. [DOI: 10.1039/d1fo02855c] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Cadmium (Cd) and excessive molybdenum (Mo) have adverse impacts on animals. However, the hepatotoxicity co-induced by Cd and Mo in ducks has not been fully elucidated. In order to explore...
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Wang S, Hou L, Wang M, Feng R, Lin X, Pan S, Zhao Q, Huang H. Selenium-Alleviated Testicular Toxicity by Modulating Inflammation, Heat Shock Response, and Autophagy Under Oxidative Stress in Lead-Treated Chickens. Biol Trace Elem Res 2021; 199:4700-4712. [PMID: 33452669 DOI: 10.1007/s12011-021-02588-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 01/10/2021] [Indexed: 12/23/2022]
Abstract
Lead (Pb), a toxic pollutant, is toxic to the testis. However, biological events during testicular Pb poisoning were not well understood. Selenium (Se) has the ability to antagonize Pb toxicity. The purpose of this research was to clarify the relief mechanism of Se on testicular toxicity of Pb from the perspective of oxidative stress, inflammation, heat shock response, and autophagy in a chicken model. Sixty male Hyline chickens (7-day-old) were randomly assigned into four groups. The feeding program consisted of a commercial diet, a Se-supplemented diet (1 mg kg-1 Se), a Pb-supplemented diet (350 mg L-1 Pb), and a Se- and Pb-supplemented diet, respectively. On the 12th week, serums were collected to measure testosterone level and testes were removed to determine testis weight, histological structure, Pb and Se concentrations, oxidative stress indicators, and mRNA and protein expression of inflammatory cytokines, heat shock proteins, and autophagy-related genes. The results showed that Pb poisoning changed the histological structure of testes; decreased serum testosterone level, testis weight, catalase, glutathione-s-transferase, and total antioxidative capacity activities; increased hydrogen peroxide content; inhibited interleukin (IL)-2 and mammalian target of rapamycin expression; and promoted IL-4, IL-12β, heat shock proteins, Beclin 1, Dynein, autophagy-related proteins 5, light chain 3 (LC3)-I, and LC3-II expression in the testes of chickens. Se intervention mitigated the aforementioned alterations induced by Pb. In conclusion, Pb led to oxidative stress, which triggered inflammation, heat shock response, and autophagy. Se administration mitigated testicular toxicity of Pb mainly by mitigating oxidative stress in male chickens.
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Affiliation(s)
- Size Wang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Lulu Hou
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Min Wang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Rui Feng
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Xu Lin
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Shifeng Pan
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People's Republic of China
| | - Qian Zhao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - He Huang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
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Ning B, Guo C, Kong A, Li K, Xie Y, Shi H, Gu J. Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease. Cells 2021; 10:cells10113204. [PMID: 34831428 PMCID: PMC8622220 DOI: 10.3390/cells10113204] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/09/2021] [Accepted: 11/13/2021] [Indexed: 12/15/2022] Open
Abstract
The kidney is an important organ for the maintenance of Ca2+ homeostasis in the body. However, disruption of Ca2+ homeostasis will cause a series of kidney diseases, such as acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemia/reperfusion (I/R) injury, autosomal dominant polycystic kidney disease (ADPKD), podocytopathy, and diabetic nephropathy. During the progression of kidney disease, Ca2+ signaling plays key roles in various cell activities such as necrosis, apoptosis, eryptosis and autophagy. Importantly, there are complex Ca2+ flux networks between the endoplasmic reticulum (ER), mitochondria and lysosomes which regulate intracellular Ca2+ signaling in renal cells and contribute to kidney disease. In addition, Ca2+ signaling also links the crosstalk between various cell deaths and autophagy under the stress of heavy metals or high glucose. In this regard, we present a review of Ca2+ signaling in cell death and crosstalk with autophagy and its potential as a therapeutic target for the development of new and efficient drugs against kidney diseases.
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Affiliation(s)
- Bo Ning
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Chuanzhi Guo
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Anqi Kong
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Kongdong Li
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
| | - Yimin Xie
- Affiliated Hospital of Jiangsu University—Yixing Hospital, Yixing 214200, China;
| | - Haifeng Shi
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China
| | - Jie Gu
- School of Life Sciences, Jiangsu University, Zhenjiang 212013, China; (B.N.); (C.G.); (A.K.); (K.L.); (H.S.)
- Correspondence: ; Tel.: +86-0511-88791923
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Chen J, Shao B, Wang J, Shen Z, Liu H, Li S. Chlorpyrifos caused necroptosis via MAPK/NF-κB/TNF-α pathway in common carp (Cyprinus carpio L.) gills. Comp Biochem Physiol C Toxicol Pharmacol 2021; 249:109126. [PMID: 34217843 DOI: 10.1016/j.cbpc.2021.109126] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 06/16/2021] [Accepted: 06/27/2021] [Indexed: 12/18/2022]
Abstract
Chlorpyrifos (CPF) is an organophosphate insecticide and can cause cell death of animals. In the study, the common carp were exposed to CPF at 0 μg/L (the control group), 1.16 μg/L (the low dose group), 11.6 μg/L (the medium dose group), and 116 μg/L (the high dose group), respectively. The carp were euthanized at the 30th day and gills were collected immediately. The ultrastructural and histopathological observations showed obvious necrosis characteristics and inflammatory injury in the CPF-treated groups. CPF exposure activated the MAPK pathway, in which the mRNA and protein expressions of extracellular signal-regulated (ERK), p38 MAP kinase (p38), and c-Jun N-terminal kinase (JNK) were increased; the mRNAs and proteins of NF-κB and TNF-α were activated; and the mRNAs and proteins of necroptosis related genes were changed (the mRNA and protein expression of RIPK1, RIPK3, MLKL, and FADD were increased and caspase-8 was decreased) with concentration dependency. Taken together, we concluded that CPF exposure activated the MAPK/NF-κB/TNF-α pathway, promoted inflammatory injure and evoked necroptosis in common carp gills. In addition, CPF-induced inflammation and necroptosis was concentration dependency. The toxic effects of CPF on gills provided data for both aquaculture and toxicological studies.
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Affiliation(s)
- Jianqing Chen
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Bing Shao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China
| | - Jinliang Wang
- Shandong Binzhou Animal Science & Veterinary Medicine Academy, Binzhou 256600, China
| | - Zhiqiang Shen
- Shandong Binzhou Animal Science & Veterinary Medicine Academy, Binzhou 256600, China
| | - Honggui Liu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China.
| | - Shu Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China.
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Zhao C, Yu D, He Z, Bao L, Feng L, Chen L, Liu Z, Hu X, Zhang N, Wang T, Fu Y. Endoplasmic reticulum stress-mediated autophagy activation is involved in cadmium-induced ferroptosis of renal tubular epithelial cells. Free Radic Biol Med 2021; 175:236-248. [PMID: 34520822 DOI: 10.1016/j.freeradbiomed.2021.09.008] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 09/08/2021] [Accepted: 09/10/2021] [Indexed: 12/24/2022]
Abstract
Acute cadmium (Cd) exposure is a significant risk factor for renal injury and lacks effective treatment strategies. Ferroptosis is a recently identified iron-dependent form of nonapoptotic cell death mediated by membrane damage resulting from lipid peroxidation, and it is implicated in many diseases. However, whether ferroptosis is involved in Cd-induced renal injury and, if so, how it operates. Here, we show that Cd can induce ferroptosis in kidney and renal tubular epithelial cells, as demonstrated by elevation of intracellular iron levels and lipid peroxidation, as well as impaired antioxidant production. Treatment with a ferroptosis inhibitor alleviated Cd-induced cell death. Intriguingly, we established that Cd-induced ferroptosis depended on endoplasmic reticulum (ER) stress, by demonstrating that Cd activated the PERK-eIF2α-ATF4-CHOP pathway and that inhibition of ER stress reduced ferroptosis caused by Cd. We further found that autophagy was required for Cd-induced ferroptosis because the inhibition of autophagy by chloroquine mitigated Cd-induced ferroptosis. Furthermore, we showed that iron dysregulation by ferritinophagy contributed to Cd-induced ferroptosis, by showing that the iron chelator desferrioxamine alleviated Cd-induced cell death and lipid peroxidation. In addition, ER stress is likely activated by MitoROS which trigger autophagy and ferroptosis. Collectively, our results indicate that ferroptosis is involved in Cd-induced renal toxicity and regulated by the MitoROS-ER stress-ferritinophagy axis.
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Affiliation(s)
- Caijun Zhao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, China
| | - Duo Yu
- Department of Radiotherapy, The Second Affiliated Hospital of Jilin University, Changchun, Jilin Province, 130062, China
| | - Zhaoqi He
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, China
| | - Lijuan Bao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, China
| | - Lianjun Feng
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, China
| | - Luotong Chen
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, China
| | - Zhuoyu Liu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, China
| | - Xiaoyu Hu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, China
| | - Naisheng Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, China
| | - Tiejun Wang
- Department of Radiotherapy, The Second Affiliated Hospital of Jilin University, Changchun, Jilin Province, 130062, China.
| | - Yunhe Fu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Jilin University, Changchun, Jilin Province, 130062, China.
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Fan RF, Tang KK, Wang ZY, Wang L. Persistent activation of Nrf2 promotes a vicious cycle of oxidative stress and autophagy inhibition in cadmium-induced kidney injury. Toxicology 2021; 464:152999. [PMID: 34695510 DOI: 10.1016/j.tox.2021.152999] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 10/12/2021] [Accepted: 10/18/2021] [Indexed: 01/07/2023]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) serves as the master regulator of antioxidant signaling and inhibition or hyperactivation of Nrf2 pathway will result in the redox imbalance to induce tissue injury. Herein, we established cadmium (Cd)-exposed rat kidney injury model by intraperitoneal injection with CdCl2 (1.5 mg/kg body weight) and cytotoxicity model of NRK-52E cells by CdCl2 (5 μM) exposure to reveal the role of Nrf2 hyperactivation in Cd-induced nephrotoxicity. Data from the in vitro and in vivo study showed that Cd caused Nrf2 nuclear retention due to nuclear-cytoplasmic depletion of Kelch-like ECH-associated protein 1 (Keap1) and Sequestosome-1(SQSTM1/p62) accumulation, leading to the persistent activation of Nrf2. Moreover, we established inhibited models of Cd-induced prolonged Nrf2 activation using siRNA-mediated gene silencing in vitro and pharmacological inhibition in vivo for subsequent assays. First, Cd-induced cytotoxicity, renal injury and concomitant oxidative stress were markedly alleviated by Nrf2 inhibition. Second, Cd-induced autophagy inhibition was notably alleviated by Nrf2 inhibition. Further, we revealed underlying molecular mechanisms of the crosstalk between persistent activation of Nrf2 and autophagy inhibition in Cd-induced nephrotoxicity. Data showed that Cd-induced lysosomal dysfunction evidenced by impaired lysosomal biogenesis and degradation capacity was markedly recovered by Nrf2 inhibition. Meanwhile, Cd-impaired autophagosome-lysosome fusion was obviously restored by Nrf2 inhibition. In conclusion, our findings revealed that persistent activation of Nrf2 promoted a vicious cycle of oxidative stress and autophagy inhibition in Cd-induced nephrotoxicity.
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Affiliation(s)
- Rui-Feng Fan
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Kou-Kou Tang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Zhen-Yong Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Lin Wang
- College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China.
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Han Q, Liu H, Zhang R, Yang X, Bao J, Xing H. Selenomethionine protects against ammonia-induced apoptosis through inhibition of endoplasmic reticulum stress in pig kidneys. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 223:112596. [PMID: 34352572 DOI: 10.1016/j.ecoenv.2021.112596] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 07/31/2021] [Accepted: 07/31/2021] [Indexed: 06/13/2023]
Abstract
Ammonia (NH3) emission is a common threat to farm animals. Selenium (Se) is known for its antioxidant property and can resist several stressors affecting farm animals. The aims of this study were (Ⅰ) to determine how excess NH3 exert nephrotoxic effects in pigs and (Ⅱ) to investigate whether selenomethionine has an alleviative effect on NH3 toxicity. Two diets supplemented with different doses of Se (0.22 mg/kg or 0.50 mg/kg) and two concentrations of NH3 (< 5 mg/m3 or 89.8 mg/m3) were used in a 2 × 2 factorial design trial for a period of 30 days. The results showed that NH3 exposure caused apoptosis and increased the number of apoptotic cells in pig kidneys. Further, the activities of antioxidant enzymes were decreased, and the transcriptional and translational levels of endoplasmic reticulum stress-related genes, Bcl-2 and Caspase family members were increased under NH3 exposure. In addition, Wnt/β-catenin signaling pathway was suppressed after NH3 treatment. Dietary supplement with selenomethionine appears to offer protection against NH3-induced kidney injury in pigs and the pathologic changes above were alleviated. Our findings provide additional insight into the mechanism of NH3 toxicity in pigs while elucidating the role of Se as a potential antidote against NH3 poisoning.
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Affiliation(s)
- Qi Han
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Honggui Liu
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Swine Facilities Engineering, Ministry of Agriculture and Rural Affairs, Harbin, China
| | - Runxiang Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Xuesong Yang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China
| | - Jun Bao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China; Key Laboratory of Swine Facilities Engineering, Ministry of Agriculture and Rural Affairs, Harbin, China.
| | - Houjuan Xing
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, China.
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Kong A, Zhang Y, Ning B, Li K, Ren Z, Dai S, Chen D, Zhou Y, Gu J, Shi H. Cadmium induces triglyceride levels via microsomal triglyceride transfer protein (MTTP) accumulation caused by lysosomal deacidification regulated by endoplasmic reticulum (ER) Ca 2+ homeostasis. Chem Biol Interact 2021; 348:109649. [PMID: 34516972 DOI: 10.1016/j.cbi.2021.109649] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/29/2021] [Accepted: 09/09/2021] [Indexed: 01/11/2023]
Abstract
Cadmium (Cd) exposure induced lipid metabolic disorder with changes in lipid composition, as well as triglyceride (TG) levels. Liver is the main organ maintaining body TG level and previous studies suggested that Cd exposure might increase TG synthesis but reduce TG uptake in liver. However, the effects of Cd exposure on TG secretion from liver and underlying mechanism are still unclear. In the present study, the data revealed that Cd exposure increased TG levels in the HepG2 cells and the cultured medium by increasing the expression of microsomal triglyceride transfer protein (MTTP), which was abrogated by siRNA knockdown of MTTP. MTTP was synergistically accumulated after Cd exposure or treated with proteasome inhibitor MG132 and lysosome inhibitor chloroquine (CQ), which suggested the Cd increased MTTP protein stability by inhibiting both the proteasome and the lysosomal protein degradation pathways. In addition, our results demonstrated that Cd exposure inhibited the lysosomal acidic degradation pathway through disrupting endoplastic reticulum (ER) Ca2+ homeostasis. Cd-induced MTTP protein and TG levels were significantly reduced by pretreatments of BAPTA/AM chelation of intracellular Ca2+, 2-APB inhibition of ER Ca2+ release channel inositol 1,4,5-trisphosphate receptor (IP3R) and CDN1163 activation of ER Ca2+ reuptake pump sarcoplasmic reticulum Ca2+-ATPase (SERCA). These results suggest that Cd-induced ER Ca2+ release impaired the lysosomal acidity, which associated with MTTP protein accumulation and contributed to increased TG levels.
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Affiliation(s)
- Anqi Kong
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Yao Zhang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Bo Ning
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Kongdong Li
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Zhen Ren
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Shuya Dai
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Dongfeng Chen
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Yang Zhou
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Jie Gu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.
| | - Haifeng Shi
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, 212013, China; School of Food and Biological Engineering, Zhenjiang, Jiangsu, 212013, China.
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Luan P, Sun Y, Zhu Y, Qiao S, Hu G, Liu Q, Zhang Z. Cadmium exposure promotes activation of cerebrum and cerebellum ferroptosis and necrosis in swine. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 224:112650. [PMID: 34403946 DOI: 10.1016/j.ecoenv.2021.112650] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 08/11/2021] [Accepted: 08/11/2021] [Indexed: 06/13/2023]
Abstract
Cadmium(Cd) is a toxic and carcinogenic heavy metal pollutant leading to serious damage in various organs. Ferroptosis and necrosis as inflammation-related cell death are involved in several diseases of nervous system. In the present study, 10 weaning piglets with similar weight for 6 weeks were randomly divided into two groups. The daily grain containing 0 mg and 20 mg/kg of Cd chloride was fed in 20-26 ℃ environment, animals were sacrificed to collect cerebrum and cerebellum tissues after 40 days. Morphology and ultrastructure results were observed using HE and TEM. Moreover, molecular biological technologies western blot and qRT-PCR were used to detect the expression abundance of genes. Cerebrum and cerebellum injury was observed in Cd-exposed group, antioxidant capacity decreased significantly and oxidative stress increased; immunofluorescence, real-time quantification, and western blot results showed decreased necrosis genes and increased ferroptosis pathway genes abundance in cerebrum, whereas the results were reversed in cerebellum. These results indicated that Cd exposure can activated necrosis and ferroptosis pathways by increased oxidative stress, further resulting in cerebrum and cerebellum damage in pigs. These findings may provide a theoretical basis for early monitoring of Cd exposure in environment.
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Affiliation(s)
- Peixian Luan
- Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 0150070, PR China; Key Laboratory of Freshwater Aquatic Biotechnology and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150070, PR China
| | - Yue Sun
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yue Zhu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Senqiu Qiao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Guo Hu
- Heilongjiang River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Harbin 0150070, PR China; Key Laboratory of Freshwater Aquatic Biotechnology and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150070, PR China.
| | - Qi Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
| | - Ziwei Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
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Gong Z, Liu G, Liu W, Zou H, Song R, Zhao H, Yuan Y, Gu J, Bian J, Zhu J, Liu Z. The epigenetic regulator BRD4 is involved in cadmium-triggered inflammatory response in rat kidney. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 224:112620. [PMID: 34392152 DOI: 10.1016/j.ecoenv.2021.112620] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/05/2021] [Accepted: 08/08/2021] [Indexed: 06/13/2023]
Abstract
Cadmium (Cd) has been described as a potential inflammatory inducer, while increasing evidence shows that inappropriate inflammation is a contributing factor to kidney injury. Hence, research on Cd-triggered inflammatory response is of great significance for elucidating the mechanism of Cd-induced nephrotoxicity. Bromodomain-containing 4 (BRD4) is an important epigenetic regulator involved in the development of many inflammatory diseases, but its regulatory roles in Cd-triggered inflammatory response remain to be clarified. Here, we found that treatment with Cd in Sprague-Dawley rats (2 mg/kg bw, i.p., 5 consecutive days) and in rat kidney cell line (NRK-52E, 0-10 μM, 12 h) induced the transcription of inflammatory cytokines, which could be reduced by JQ1 (BRD4 inhibitor, 25 mg/kg bw, i.p., 3 consecutive days in vivo; 0.5 μM, 12 h in vitro) or BRD4 small interfering RNA (siRNA, in vitro), suggesting that BRD4 participates in Cd-triggered inflammatory response. Next, our study clarified the roles of BRD4 in Cd-triggered inflammatory response. The inhibition of BRD4 decreased Cd-promoted NF-κB nuclear translocation and activation in vivo and in vitro. Cd increased the acetylation level of RelA K310 and enhanced BRD4 binding to acetylated NF-κB RelA in vivo and in vitro, which were abrogated by inhibiting BRD4. In summary, our study suggests that BRD4 is involved in Cd-triggered transcription of inflammatory cytokines by mediating the activation of NF-κB signaling pathway and increasing itself binding to acetylated NF-κB RelA in rat kidney, therefore, BRD4 could be a potential therapeutic target for Cd-induced renal diseases.
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Affiliation(s)
- Zhonggui Gong
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China
| | - Gang Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China
| | - Wenjing Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China
| | - Hui Zou
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China
| | - Ruilong Song
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China
| | - Hongyan Zhao
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China
| | - Yan Yuan
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China
| | - Jianhong Gu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China
| | - Jianchun Bian
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China
| | - Jiaqiao Zhu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China.
| | - Zongping Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China.
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Yiming Z, Zhaoyi L, Jing L, Jinliang W, Zhiqiang S, Guangliang S, Shu L. Cadmium induces the thymus apoptosis of pigs through ROS-dependent PTEN/PI3K/AKT signaling pathway. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:39982-39992. [PMID: 33765263 DOI: 10.1007/s11356-021-13517-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/15/2021] [Indexed: 06/12/2023]
Abstract
Cadmium (Cd) is a transition metal that is toxic to living organisms in the environment and endangers living organisms. To explore whether Cd induces apoptosis in pig thymus and its possible mechanism, the role Cd induction of the PTEN/PI3K/Akt pathway in apoptosis of thymus cells was studied in pigs. We found that Cd exposure (the feed is treated with Cd) significantly increased Cd accumulation in the thymus of pigs. The TUNEL assay confirmed the typical apoptotic characteristics of thymus in Cd group. Moreover, in the Cd group, the activities of antioxidant indices decreased significantly, while the levels of oxidative stress indexes increased significantly, and the mRNA levels of GSH, CAT, Gpx1, GST, SOD1, and SOD2 decreased obviously. Moreover, the mRNA and protein levels of PTEN/PI3K/AKT and apoptosis-related genes were detected by qPCR and western blotting. The results show that the expressions of PI3K and AKT decreased, while the expression of PTEN increased, indicating that pathway activated. With the PTEN/PI3K/AKT pathway regulating, Bcl-2 expression decreased. Conversely, the mRNA and protein expression of apoptosis-related genes were up-regulated. In conclusion, accumulation of Cd in the pigs caused oxidative damage to immune tissues. In addition, Cd-induced oxidative stress activates the PTEN/PI3K/AKT pathway, inducing apoptosis in the thymus of pigs.
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Affiliation(s)
- Zhang Yiming
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Liu Zhaoyi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China
| | - Lan Jing
- Quality and Safety Institute of Agricultural Products, Heilongjiang Academy of Agricultural Sciences, Harbin, 150000, China
| | - Wang Jinliang
- Shandong Binzhou Anim Sci & Vet Med Acad, Binzhou, 256600, People's Republic of China
| | - Shen Zhiqiang
- Shandong Binzhou Anim Sci & Vet Med Acad, Binzhou, 256600, People's Republic of China
| | - Shi Guangliang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China.
| | - Li Shu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, China.
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Zhang Y, Liu Z, He Q, Wu F, Xiao Y, Chen W, Jin Y, Yu D, Wang Q. Construction of Mode of Action for Cadmium-Induced Renal Tubular Dysfunction Based on a Toxicity Pathway-Oriented Approach. Front Genet 2021; 12:696892. [PMID: 34367254 PMCID: PMC8343180 DOI: 10.3389/fgene.2021.696892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 06/14/2021] [Indexed: 12/30/2022] Open
Abstract
Although it is recognized that cadmium (Cd) causes renal tubular dysfunction, the mechanism of Cd-induced nephrotoxicity is not yet fully understood. Mode of action (MOA) is a developing tool for chemical risk assessment. To establish the mechanistic MOA of Cd-induced renal tubular dysfunction, the Comparative Toxicogenomics Database (CTD) was used to obtain genomics data of Cd-induced nephrotoxicity, and Ingenuity® Pathway Analysis (IPA) software was applied for bioinformatics analysis. Based on the perturbed toxicity pathways during the process of Cd-induced nephrotoxicity, we established the MOA of Cd-induced renal tubular dysfunction and assessed its confidence with the tailored Bradford Hill criteria. Bioinformatics analysis showed that oxidative stress, DNA damage, cell cycle arrest, and cell death were the probable key events (KEs). Assessment of the overall MOA of Cd-induced renal tubular dysfunction indicated a moderate confidence, and there are still some evidence gaps to be filled by rational experimental designs.
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Affiliation(s)
- Yangchun Zhang
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Ziqi Liu
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Qianmei He
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Fei Wu
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yongmei Xiao
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Wen Chen
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yuan Jin
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Dianke Yu
- Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China
| | - Qing Wang
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China
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Cadmium exposure induces inflammation and necroptosis in porcine adrenal gland via activating NF-κB/MAPK pathway. J Inorg Biochem 2021; 223:111516. [PMID: 34237625 DOI: 10.1016/j.jinorgbio.2021.111516] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023]
Abstract
Cadmium (Cd) is a heavy metal harmful to animals and humans. Cd exposure causes inflammation or necroptosis in many tissues, including adrenal tissue. However, the current researches on the effects of Cd2+ in adrenal tissues are not enough. Therefore, in our experiment Cd chloride (CdCl2) was added to the piglet's diet at a concentration of 20 mg/kg to study the effects of Cd2+ exposure on the porcine adrenal tissue. Our results showed that Cd2+ exposure could cause inflammation by activating the nuclear factor kappa-B (NF-κB) pathway, which in turn induced necroptosis in adrenal tissue with the activated mitogen-activated protein kinase (MAPK) pathway. The expression increase of inflammatory factors and necroptosis downstream genes, and the downregualtion of cysteinyl aspartate specific proteinase 8 (Caspase 8) proved that Cd2+ exposure caused inflammation and necroptosis in adrenal tissue. We conclude that this report provides more basic theoretical data for exploring the mechanism of adrenal injury.
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Regulation of TRPML1 channel activity and inflammatory exosome release by endogenously produced reactive oxygen species in mouse podocytes. Redox Biol 2021; 43:102013. [PMID: 34030116 PMCID: PMC8163985 DOI: 10.1016/j.redox.2021.102013] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/02/2021] [Accepted: 05/14/2021] [Indexed: 12/17/2022] Open
Abstract
The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome in podocytes has been implicated in the initiation of glomerular inflammation during hyperhomocysteinemia (hHcy). However, the mechanism by which NLRP3 inflammasome products are released from podocytes remains unknown. The present study tested whether exosome secretion from podocytes is enhanced by NADPH oxidase-produced reactive oxygen species (ROS), which may serve as a pathogenic mechanism mediating the release of inflammatory cytokines produced by the NLRP3 inflammasome in podocytes after Hcy stimulation. We first demonstrated the remarkable elevation of endogenously produced ROS in podocytes treated with Hcy compared with control podocytes, which was abolished by pre-treatment with the NADPH oxidase inhibitors, gp91 ds-tat peptide and diphenyleneiodonium (DPI). In addition, Hcy induced activation in podocytes of NLRP3 inflammasomes and the formation of multivesicular bodies (MVBs) containing inflammatory cytokines, which were prevented by treatment with gp91 ds-tat or the ROS scavenger, catalase. Given the importance of the transient receptor potential mucolipin 1 (TRPML1) channel in Ca2+-dependent lysosome trafficking and consequent lysosome-MVB interaction, we tested whether lysosomal Ca2+ release through TRPML1 channels is inhibited by endogenously produced ROS in podocytes after Hcy stimulation. By GCaMP3 Ca2+ imaging, we confirmed the inhibition of TRPML1 channel activity by Hcy which was remarkably ameliorated by catalase and gp91 ds-tat peptide. By structured illumination microscopy (SIM) and nanoparticle tracking analysis (NTA), we found that ML-SA1, a TRPML1 channel agonist, significantly enhanced lysosome-MVB interaction and reduced exosome release in podocytes, which were attenuated by Hcy. Pre-treatment of podocytes with catalase or gp91 ds-tat peptide restored ML-SA1-induced changes in lysosome-MVB interaction and exosome secretion. Moreover, we found that hydrogen peroxide (H2O2) mimicked the effect of Hcy on TRPML1 channel activity, lysosome-MVB interaction, and exosome secretion in podocytes. Based on these results, we conclude that endogenously produced ROS importantly contributes to inflammatory exosome secretion from podocytes through inhibition of TRPML1 channel activity, which may contribute to the initiation of glomerular inflammation during hHcy.
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Shi Z, Song Y, Gao X, Loor JJ, Aboragah A, Yu H, Fang Z, Zhu Y, Du X, Li X, Gao W, Liu G. Disruption of endoplasmic reticulum homeostasis exacerbates liver injury in clinically ketotic cows. J Dairy Sci 2021; 104:9130-9141. [PMID: 34001360 DOI: 10.3168/jds.2021-20238] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 04/10/2021] [Indexed: 12/19/2022]
Abstract
Disruption of endoplasmic reticulum (ER) homeostasis, a condition termed "ER stress," contributes to the development of liver injury in nonruminants. Because liver injury is a prominent pathological feature associated with overproduction of ketone bodies in dairy cows with ketosis, understanding the ER stress state and its functional consequences on liver injury is of particular interest. Here, 30 multiparous cows (within 3 wk postpartum) classified based on blood β-hydroxybutyrate (BHB) as healthy (n = 15, BHB <0.6 mM) or clinically ketotic (n = 15, BHB >3.0 mM) were used. Compared with healthy cows, ketotic cows had greater levels of serum fatty acids and activities of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, γ-glutamyl transferase, and glutamate dehydrogenase but lower serum glucose. Furthermore, dairy cows with ketosis had greater protein abundance of ER stress markers in liver tissue, including protein kinase RNA-like ER kinase (PERK), inositol-requiring protein-1α (IRE1α), and cleaved activating transcription factor-6 (ATF6). Cows with ketosis also had higher mRNA levels of hepatic 78-kDa glucose-regulated protein (GRP78) and spliced X-box binding protein 1 (sXBP1). These data confirmed an enhanced ER stress state in clinically ketotic cows. To explore whether enhanced hepatic ER stress was induced by elevated ketone bodies and the possible contribution of ER stress to liver injury, in vitro experiments were then performed using isolated primary calf hepatocytes treated with incremental concentrations of BHB (0, 0.6, 1.2, 3.0, and 4.8 mM) for 12 h with or without overexpression of GRP78 (the master regulator of unfolded protein response). Phosphorylation levels of PERK and IRE1α proteins, level of cleaved ATF6 protein, and mRNA abundance of GRP78 and sXBP1 in hepatocytes increased after treatment with high (3.0 and 4.8 mM) BHB, indicating a mechanistic link between excessive BHB and enhanced hepatic ER stress. Furthermore, treatment with 3.0 and 4.8 mM BHB markedly elevated activities of aspartate aminotransferase and alanine aminotransferase in cell supernatant, indicating exacerbated hepatocyte damage after ER stress was enhanced. Overexpression of GRP78 attenuated both BHB-induced ER stress and the ensuing cellular damage, suggesting that hepatocyte damage caused by excessive BHB can be mediated via enhanced ER stress. Overall, the present study revealed that ER stress may exacerbate liver injury development in clinically ketotic cows, underscoring the biological relevance of this pathway in the context of liver injury.
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Affiliation(s)
- Zhen Shi
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Yuxiang Song
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Xinxing Gao
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Juan J Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Ahmad Aboragah
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Hao Yu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Zhiyuan Fang
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Yiwei Zhu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Xiliang Du
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Xinwei Li
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China
| | - Wenwen Gao
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China.
| | - Guowen Liu
- Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, 5333 Xi'an Road, Changchun, Jilin Province, 130062, China.
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Zhao H, Wang Y, Mu M, Guo M, Yu H, Xing M. Lycopene alleviates sulfamethoxazole-induced hepatotoxicity in grass carp ( Ctenopharyngodon idellus) via suppression of oxidative stress, inflammation and apoptosis. Food Funct 2021; 11:8547-8559. [PMID: 33026005 DOI: 10.1039/d0fo01638a] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Antibiotics are used worldwide to treat diseases in humans and other animals; most of them and their secondary metabolites are discharged into the aquatic environment, posing a serious threat to human health. However, the toxicity of antibiotics on aquatic organisms, especially the effects on the detoxification system and immune system, has not been thoroughly studied. Lycopene (LYC) is a naturally occurring hydrocarbon carotenoid, which has received extensive attention as a potential antioxidant. The aim of this study was to investigate whether LYC alleviates exogenous toxicity in carp induced by sulfamethoxazole (SMZ) and the underlying molecular mechanisms. The grass carp were treated with SMZ (0.3 μg L-1) and/or LYC (10 mg per kg body weight) for 30 days. Indexes, such as hepatic function-related including histopathological changes and biochemical parameters, detoxification system-related including the cytochrome P450 enzyme system and antioxidant system, and immune system-related including inflammatory and apoptosis processes were detected. The results showed that SMZ stress leads to significant pathological damage of the liver and induction of oxidative stress. LYC coadministration recovered the cytochrome p450-1A1 homeostasis and decreased SMZ-induced accumulation of intracellular reactive oxygen species (ROS). Mechanistically, indicators in the innate immune system (such as toll like receptors (TLRs), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6 and IL-8) and the apoptosis pathway (p53, PUMA, B-cell lymphoma-2 (Bcl-2), BCL2-associated X (Bax), and Caspase-9/3) disclosed adaptive activation under SMZ exposure; these anomalies returned to normal or close-to-normal levels after LYC coadministration. Therefore, LYC dietary supplement possesses liver protective function against exogenous toxic compounds like SMZ, making LYC a functional aquatic feed ingredient for aquiculture.
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Affiliation(s)
- Hongjing Zhao
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
| | - Yu Wang
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
| | - Mengyao Mu
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
| | - Menghao Guo
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
| | - Hongxian Yu
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
| | - Mingwei Xing
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, 150040, Heilongjiang, PR China.
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Carnevale R, Nocella C, Schiavon S, Cammisotto V, Cotugno M, Forte M, Valenti V, Marchitti S, Vecchio D, Biondi Zoccai G, Rubattu S, Martinelli O, Pignatelli P, Violi F, Volpe M, Versaci F, Frati L, Frati G, Sciarretta S. Beneficial effects of a combination of natural product activators of autophagy on endothelial cells and platelets. Br J Pharmacol 2021; 178:2146-2159. [PMID: 33512008 DOI: 10.1111/bph.15399] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 01/16/2021] [Accepted: 01/18/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND PURPOSE Oxidative stress and insufficient autophagy activity are associated with inflammatory processes and are common features of many cardiovascular diseases (CVDs). We investigated if a combination of natural activators of autophagy could modulate oxidative stress, platelet aggregation and endothelial cell survival and function in response to stress. EXPERIMENTAL APPROACH Ex vivo platelet aggregation and activation, H2 O2 production and autophagy were measured in platelets of subjects at high cardiovascular risk, including smokers, patients with metabolic syndrome (MetS) and patients with atrial fibrillation (AF). In vitro, the effects of a mixture of natural pro-autophagy molecules and antioxidants on platelets and human umbilical vein endothelial cells (HUVECs) were evaluated. KEY RESULT Autophagy appeared to be inhibited, whereas aggregation was increased in platelets from AF and MetS patients and in smokers, as compared with healthy subjects. Treatment of platelets isolated from these patients with a mixture composed of trehalose, spermidine, catechin and epicatechin (Mix1) or with a mixture composed of trehalose, spermidine and nicotinamide (Mix2), significantly reduced platelet activation and oxidative stress, and increased autophagy, compared with the effect of each compound alone. Similarly, treatment of HUVECs with a combination of these compounds exhibited beneficial effects and increased endothelial cell survival, nitric oxide bioavailability and angiogenesis in response to stress in a potentiated manner. CONCLUSION AND IMPLICATIONS A combination of natural activators of autophagy could inhibit platelet activity and oxidative stress and improve endothelial cell survival and function in a potentiated manner representing a useful strategy to reduce the effect of risk factors on CVD occurrence. LINKED ARTICLES This article is part of a themed issue on Cellular metabolism and diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.10/issuetoc.
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Affiliation(s)
- Roberto Carnevale
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro-Napoli, Naples, Italy
| | - Cristina Nocella
- Department of Clinical Internal, Anestesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Sonia Schiavon
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Vittoria Cammisotto
- Department of General Surgery and Surgical Speciality Paride Stefanini, Sapienza University of Rome, Rome, Italy
| | - Maria Cotugno
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy
| | - Maurizio Forte
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy
| | - Valentina Valenti
- Department of Cardiology, Ospedale Santa Maria Goretti, Latina, Italy
| | - Simona Marchitti
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy
| | - Daniele Vecchio
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Giuseppe Biondi Zoccai
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro-Napoli, Naples, Italy
| | - Speranza Rubattu
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy
- Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Ombretta Martinelli
- Unit of Vascular Surgery, Department "Paride Stefanini", Sapienza University of Rome, Rome, Italy
| | - Pasquale Pignatelli
- Mediterranea Cardiocentro-Napoli, Naples, Italy
- Department of Clinical Internal, Anestesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Francesco Violi
- Mediterranea Cardiocentro-Napoli, Naples, Italy
- Department of Clinical Internal, Anestesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Massimo Volpe
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy
- Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Rome, Italy
| | - Francesco Versaci
- Department of Cardiology, Ospedale Santa Maria Goretti, Latina, Italy
| | - Luigi Frati
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy
| | - Giacomo Frati
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy
| | - Sebastiano Sciarretta
- Department of Angio-Cardio-Neurology, IRCCS Neuromed, Località Camerelle, Pozzilli, Italy
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti and Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, 04100, Italy
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