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Talukder M, Bi SS, Lv MW, Ge J, Zhang C, Li JL. Involvement of the heat shock response (HSR) regulatory pathway in cadmium-elicited cerebral damage. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:106648-106659. [PMID: 37730984 DOI: 10.1007/s11356-023-29880-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 09/10/2023] [Indexed: 09/22/2023]
Abstract
The heat shock response (HSR) is a cellular protective mechanism that is characterized by the induction of heat shock transcription factors (HSFs) and heat shock proteins (HSPs) in response to diverse cellular and environmental stressors, including cadmium (Cd). However, little is known about the relationship between the damaging effects of Cd and the HSR pathway in the chicken cerebrum following Cd exposure. To explore whether Cd exposure elicits cerebral damage and triggers the HSR pathway, chicks were exposed to Cd in the daily diet at different concentrations (35, 70, or 140 mg/kg feed) for 90 days, while a control group was fed the standard diet without Cd. Histopathological examination of cerebral tissue from Cd-exposed chickens showed neuronal damage, as evidenced by swelling and degeneration of neurons, loss of neurons, and capillary damage. Cd exposure significantly increased mRNA expression of HSF1, HSF2, and HSF3, and mRNA and protein expression of three major stress-inducible HSPs (HSP60, HSP70, and HSP90). Moreover, Cd exposure differentially modulated mRNA expression of small HSP (sHSPs), most notably reducing expression of HSP27 (HSPB1). Furthermore, Cd exposure increased TUNEL-positive neuronal apoptotic cells and up-regulated protein expression of caspase-1, caspase-8, caspase-3, and p53, leading to apoptosis. Taken together, these data demonstrate that activation of the HSR and apoptotic pathways by Cd exposure is involved in Cd-elicited cerebral damage in the chicken. Synopsis for the graphical abstract Cadmium (Cd)-induced neuronal damage triggers the heat shock response (HSR) by activating heat shock transcription factors (HSFs) and subsequent induction of major heat shock proteins (notably, HSP60, HSP70, and HSP90). Moreover, Cd exposure activates caspase-1, caspase-8, caspase-3, and p53 protein, thereby resulting in neuronal apoptosis in the chicken brain.
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Affiliation(s)
- Milton Talukder
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
- Department of Physiology and Pharmacology, Faculty of Animal Science and Veterinary Medicine, Patuakhali Science and Technology University, Barishal, 8210, Bangladesh
| | - Shao-Shuai Bi
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
- College of Biological and Pharmaceutical Engineering, West Anhui University, Luan, 237012, People's Republic of China
| | - Mei-Wei Lv
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Jing Ge
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Cong Zhang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
- College of Veterinary Medicine, Henan Agricultural University, 450046, Zhengzhou, Henan, People's Republic of China
| | - Jin-Long Li
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
- Key Laboratory of the Provincial Education, Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
- Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
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Chen C, Zhou Z, Yu S, Ma Y, Wang G, Han X, Jiao C, Luan J, Liu Z, Xu Y, Wang H, Zhang Q, Fu J, Zhou H, Pi J. Nrf2 protects against renal fibrosis induced by chronic cadmium exposure in mice. Food Chem Toxicol 2023; 178:113875. [PMID: 37286028 DOI: 10.1016/j.fct.2023.113875] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/02/2023] [Accepted: 06/03/2023] [Indexed: 06/09/2023]
Abstract
Environmental cadmium (Cd) exposure is a serious public health concern, as the kidney is the primary target for Cd exposure. The present study aimed to investigate the role and underlying mechanisms of nuclear factor erythroid-derived 2-like 2 (Nrf2) in renal fibrosis induced by chronic Cd exposure. Nrf2 knockout (Nrf2-KO) mice and their wild-type littermates (Nrf2-WT) were exposed to 100 or 200 ppm Cd in drinking water for up to 16 or 24 weeks. Following the Cd exposures, Nrf2-KO mice showed elevated urinary neutrophil gelatinase-associated lipocalin (NGAL) and BUN levels compared to Nrf2-WT mice. Masson's trichrome staining and expression of fibrosis-associated proteins revealed that more severe renal fibrosis occurred in Nrf2-KO than that in Nrf2-WT mice. Renal Cd content in the Nrf2-KO mice exposed to 200 ppm Cd was lower than that in Nrf2-WT mice, which might be a consequence of the severe renal fibrosis in the Nrf2-KO mice. Mechanistic studies showed that Nrf2-KO mice exhibited higher levels of oxidative damage, lower antioxidant levels, and more regulated cell death, apoptosis in particular, than those in Nrf2-WT mice caused by Cd exposure. In conclusion, Nrf2-KO mice were more prone to develop renal fibrosis induced by chronic Cd exposure, partially due to a weakened antioxidant, detoxification capacity and increased oxidative damage.
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Affiliation(s)
- Chengjie Chen
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Zhengsheng Zhou
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Siqi Yu
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Yawei Ma
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Gang Wang
- Experimental and Teaching Center, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Xue Han
- Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Congcong Jiao
- Department of Nephrology, The Affiliated Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, PR China
| | - Junjun Luan
- Department of Nephrology, The Affiliated Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, PR China
| | - Zhiyuan Liu
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Yuanyuan Xu
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Huihui Wang
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Qiang Zhang
- Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA
| | - Jingqi Fu
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China
| | - Hua Zhou
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Department of Nephrology, The Affiliated Shengjing Hospital, China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, PR China.
| | - Jingbo Pi
- Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic (China Medical University), No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China; Program of Environmental Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning, 110122, PR China.
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Li H, Liu Y, Zhou J, Liu S, Liu Y, Yang Y, Wang W, Che Y, Inam M, Guan L. The protective mechanism of a novel polysaccharide from Lactobacillus-fermented Nostoc commune Vauch. on attenuating cadmium-induced kidney injury in mice. Int J Biol Macromol 2023; 226:1444-1454. [PMID: 36442563 DOI: 10.1016/j.ijbiomac.2022.11.256] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/17/2022] [Accepted: 11/23/2022] [Indexed: 11/27/2022]
Abstract
A novel polysaccharide (NCVP-F) from Lactobacillus-fermented Nostoc commune Vauch. was obtained to investigate its underlying mechanism in cadmium-induced kidney injury. Results indicated that in comparison with NCVP, NCVP-F with lower molecular weight of 365.369 kDa, exhibited higher mole percentage of Man and Glc-UA, whereas slightly lower mole percentage of other monosaccharides. NCVP-F is a α-pyran polysaccharide similar to NCVP. Meanwhile, NCVP-F can more effectively alleviate hepatorenal injury (ALT, AST, TG, BUN and SCr) and kidney tissue lesions in Cd-injured mice model by increasing antioxidant enzyme activity (SOD, GSH and GSH-Px), inhibiting cytokines levels (IL-6, IL-1β, TNF-α and IL-18). In addition, NCVP-F effectively inhibited apoptosis proteins (Bax, cytochrome c, a-caspase-9 and a-caspase-3) and enhanced anti-apoptotic protein (Bcl-2) probably via activating PI3K/AKT/mTOR pathway in the Cd-injury kidney. Furthermore, 16S rRNA sequencing results indicated that NCVP-F better enriched Lachnospiraceae, reduced Muribaculaceae, Alloprevotella and Blautia to regulate Cd-induced gut microbiota disorders, which was probably down-regulated 7 pathways including apoptosis and lipopolysaccharide biosynthesis, and up-regulated 63 pathways, such as carbohydrate metabolism and lipid metabolism. This study suggested that applying functional NCVP-F prepared by biotransformation with low molecular weight might be more beneficial.
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Affiliation(s)
- Hailong Li
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, Jilin, China
| | - Yingying Liu
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, Jilin, China
| | - Jiaming Zhou
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, Jilin, China
| | - Su Liu
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, Jilin, China
| | - Yue Liu
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, Jilin, China
| | - Yiting Yang
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, Jilin, China
| | - Wanting Wang
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, Jilin, China
| | - Yange Che
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, Jilin, China
| | - Muhammad Inam
- Department of Animal Sciences, Shaheed Benazir Bhutto University Sheringal, Dir Upper, Pakistan
| | - Lili Guan
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, Jilin, China; Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun 130118, China.
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Chen J, Lai W, Deng Y, Liu M, Dong M, Liu Z, Wang T, Li X, Zhao Z, Yin X, Yang J, Yu R, Liu L. MicroRNA-363-3p promotes apoptosis in response to cadmium-induced renal injury by down-regulating phosphoinositide 3-kinase expression. Toxicol Lett 2021; 345:12-23. [PMID: 33857584 DOI: 10.1016/j.toxlet.2021.04.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/03/2021] [Accepted: 04/09/2021] [Indexed: 12/09/2022]
Abstract
We previously determined that specific microRNAs (miRNAs) are involved in renal pathophysiological occurrences induced by cadmium (Cd) in rats. This study expands our studies on miRNAs, determining their role in Cd-induced nephrotoxicity in occupational workers. We performed miRNA microarray analyses of blood and urine samples from patients diagnosed as occupational chronic Cd poisoning (OCCP) with abnormally elevated concentrations of urinary beta-2-microglobulin (U-β2-MG), an indicator of tubular proteinuria. We also performed in vitro bioinformatics-based investigations of apoptosis-related genes targeted by miRNAs involved in the biological response to Cd exposure. We tested five differentially expressed miRNAs and determined a significant increase of sera miR-363-3p. Also, we determined that miR-363-3p increase is associated with phosphoinositide 3-kinase (PI3K) down-regulation and the suppressed proliferation and enhanced apoptosis of renal tubule epithelial cells. The obtained results suggest miR-363-3p involvement in the pathophysiology of Cd-induced renal injury in humans and maybe considered for possible interventional therapeutic strategies for Cd-associated kidney damage.
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Affiliation(s)
- Jiabin Chen
- Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510310, Guangdong, China
| | - Weina Lai
- Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510310, Guangdong, China; Department of Occupational and Environmental Health, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, Guangdong, China
| | - Yaotang Deng
- Department of Occupational Health and Occupational Medicine, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, Guangdong, China
| | - Min Liu
- Dongguan Maternal and Child Healthcare Hospital, Dongguan, 523700, Guangdong, China
| | - Ming Dong
- Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510310, Guangdong, China
| | - Zhidong Liu
- Huizhou Hospital for Occupational Disease Prevention and Treatment, Huizhou, 516008, Guangdong, China
| | - Ting Wang
- Huizhou Hospital for Occupational Disease Prevention and Treatment, Huizhou, 516008, Guangdong, China
| | - Xiang Li
- Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510310, Guangdong, China
| | - Zhiqiang Zhao
- Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510310, Guangdong, China
| | - Xiao Yin
- Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510310, Guangdong, China
| | - Jinmei Yang
- School of Public Health, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China
| | - Rian Yu
- Department of Occupational and Environmental Health, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, 510310, Guangdong, China
| | - Lili Liu
- Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, 510310, Guangdong, China.
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Fujiki K. [Involvement of Notch1 and ALK4/5 Signaling Pathways in Renal Tubular Cell Death: Their Application to Clarification of Cadmium Toxicity]. Nihon Eiseigaku Zasshi 2021; 75. [PMID: 33342936 DOI: 10.1265/jjh.20007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Renal tubular cell death is caused by various extracellular stresses including toxic amounts of cadmium, an occupational and environmental pollutant metal, and is responsible for renal dysfunction. While cadmium exposure disrupts many intracellular signaling pathways, the molecular mechanism underlying cadmium-induced renal tubular cell death has not yet been fully elucidated. We have recently identified two important intracellular signaling pathways that promote cadmium-induced renal tubular cell death: the Notch1 signaling and activin receptor-like kinase (ALK) 4/5 signaling (also known as the activin-transforming growth factor β receptor pathways). In this review paper, we introduce our previous experimental findings, focusing on Notch1 and ALK4/5 signaling pathways, which may uncover the molecular mechanisms involved in cadmium-induced renal tubular cell death.
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Affiliation(s)
- Kota Fujiki
- Department of Hygiene and Public Health, Tokyo Women's Medical University
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Hao R, Ge J, Ren Y, Song X, Jiang Y, Sun-Waterhouse D, Li F, Li D. Caffeic acid phenethyl ester mitigates cadmium-induced hepatotoxicity in mice: Role of miR-182-5p/TLR4 axis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 207:111578. [PMID: 33254423 DOI: 10.1016/j.ecoenv.2020.111578] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 10/16/2020] [Accepted: 10/27/2020] [Indexed: 06/12/2023]
Abstract
Cadmium (Cd), an environmental pollutant, is evidenced to cause hepatotoxicity. In this study, the potential protective effect of caffeic acid phenethyl ester (CAPE) on cadmium-induced liver damage was investigated. Forty male mice were treated daily with either CdCl2 (1.5 mg/kg body weight (b.w.), gavage) or CAPE (10 μmol/kg b.w., gavage) or both for 4 weeks. CAPE administration significantly reduced Cd level and liver and body weight, and increased AST, ALT and ALP level. Moreover, CAPE prevented CdCl2-induced oxidative stress via PI3K/Akt/mTOR pathway and inhibited apoptosis by regulating apoptosis markers. CAPE also suppressed the CdCl2-induced inflammation by reducing the inflammatory mediators, including TNF-α, IL-6 and IL-1β. Furthermore, CAPE alleviated CdCl2-induced reduction of TLR4. It should be noted that this effect was achieved by targeting miR-182-5p, and CAPE improved miR-182-5p level. The improvement of the liver tissue histopathology by CAPE confirmed the biochemical data. These results show for the first time that miR-182-5p/TLR4 axis involved in CAPE's protection against CdCl2-induced hepatotoxicity, and may provide novel insights into the treatment of cadmium-related diseases.
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Affiliation(s)
- Rili Hao
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, Taian 271018, People's Republic of China
| | - Junlin Ge
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, Taian 271018, People's Republic of China
| | - Yongfeng Ren
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, Taian 271018, People's Republic of China
| | - Xinyu Song
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, Taian 271018, People's Republic of China
| | - Yang Jiang
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, Taian 271018, People's Republic of China
| | - Dongxiao Sun-Waterhouse
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, Taian 271018, People's Republic of China; School of Chemical Sciences, The University of Auckland, Auckland, New Zealand
| | - Feng Li
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, Taian 271018, People's Republic of China.
| | - Dapeng Li
- College of Food Science and Engineering, Shandong Agricultural University, Key Laboratory of Food Processing Technology and Quality Control of Shandong Higher Education Institutes, Taian 271018, People's Republic of China.
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Zhuang J, Nie G, Yang F, Cao H, Xing C, Dai X, Hu G, Zhang C. Molybdenum and Cadmium co-induced the levels of autophagy-related genes via adenosine 5'-monophosphate-activated protein kinase/mammalian target of rapamycin signaling pathway in Shaoxing Duck (Anas platyrhyncha) kidney. Poult Sci 2020; 98:6533-6541. [PMID: 31424537 PMCID: PMC8913950 DOI: 10.3382/ps/pez477] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 07/31/2019] [Indexed: 12/14/2022] Open
Abstract
To investigate Molybdenum (Mo) and Cadmium (Cd) co-induced the levels of autophagy-related genes via AMPK/mTOR signaling pathway in Shaoxing Duck (Anas platyrhyncha) kidney, 60 healthy 11-day-old ducks were randomly divided into 6 groups, which were treated with Mo or/and Cd at different doses on the basal diet for 120 d. Kidney samples were collected on day 120 to determine the mRNA expression levels of adenosine 5′-monophosphate (AMP)-activated protein kinase α1 (AMPKα1), mammalian target of rapamycin (mTOR), Beclin-1, autophagy-related gene-5 (Atg5), microtubule-associated protein light chain A (LC3A), microtubule-associated protein light chain B (LC3B), sequestosome-1, and Dynein by real-time quantitative polymerase chain reaction. Meanwhile, ultrastructural changes of the kidney were observed. The results indicated that the mTOR and P62 mRNA expression levels were significantly downregulated, but the Atg5 and Beclin-1 mRNA levels were remarkably upregulated in all treated groups compared to control group, and their changes were greater in joint groups. Additionally, compared to control group, the Dynein mRNA expression level was apparently downregulated in co-treated groups, the LC3B, LC3A, and AMPKα1 expression levels were dramatically upregulated in single treated groups and they were not obviously different in co-treated groups. Ultrastructural changes showed that Mo and Cd could markedly increase the number of autophagosomes. Taken together, it suggested that dietary Mo and Cd might induce autophagy via AMPK/mTOR signaling pathway in duck kidney, and it showed a possible synergistic relationship between the 2 elements.
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Affiliation(s)
- Jionghan Zhuang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Economic and Technological Development District, Nanchang 330045, Jiangxi, P. R. China
| | - Gaohui Nie
- School of Information Technology, Jiangxi University of Finance and Economics, Economic and Technological Development District, Nanchang 330032, Jiangxi, P. R. China
| | - Fan Yang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Economic and Technological Development District, Nanchang 330045, Jiangxi, P. R. China
| | - Huabin Cao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Economic and Technological Development District, Nanchang 330045, Jiangxi, P. R. China
| | - Chenghong Xing
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Economic and Technological Development District, Nanchang 330045, Jiangxi, P. R. China
| | - Xueyan Dai
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Economic and Technological Development District, Nanchang 330045, Jiangxi, P. R. China
| | - Guoliang Hu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Economic and Technological Development District, Nanchang 330045, Jiangxi, P. R. China
| | - Caiying Zhang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Economic and Technological Development District, Nanchang 330045, Jiangxi, P. R. China
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Gao M, Dong Z, Sun J, Liu W, Xu M, Li C, Zhu P, Yang X, Shang X, Wu Y, Liu S. Liver-derived exosome-laden lncRNA MT1DP aggravates cadmium-induced nephrotoxicity. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 258:113717. [PMID: 31864927 DOI: 10.1016/j.envpol.2019.113717] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Revised: 11/29/2019] [Accepted: 11/30/2019] [Indexed: 06/10/2023]
Abstract
Cadmium (Cd) is a well-characterized toxic heavy metal which could cause severe kidney injury. However, currently the knowledge of Cd toxicity towards kidney is still insufficient. Our previous data has identified that MT1DP (metallothionein 1D pseudogene) could promote Cd-induced detrimental effects on hepatocytes. Herein, we further found that MT1DP was also an important intermediate to aggravate Cd-induced nephrotoxicity. Through analyzing the data of 100 residents from Cd-contaminated area in Southern China, we found that the blood MT1DP levels correlated to the urine Cd content and the extent of nephrotoxicity. Although MT1DP was predominantly induced by hepatocytes in the liver, liver-secreted MT1DP was found to be packaged into extracellular cargoes: exosomes, by which MT1DP was delivered into circulation and thereafter targeted kidney cells. Furthermore, exosome-laden MT1DP worsened Cd-induced nephrotoxicity, as evidenced in both Cd-poisoned individuals and in vitro cells. Moreover, MT1DP was found to reinforce Cd-induced toxicity in kidney cells by indirectly breaking the equilibrium between the pro-apoptotic and anti-apoptotic effects conducted by BAX and Bcl-xL, respectively. Collectively, our data unveiled that hepatocyte-derived MT1DP depends on the delivery of exosomes to wreak considerable havoc in Cd nephrotoxicity. This study offers new insights into the molecular mechanisms of Cd-induced kidney injury.
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Affiliation(s)
- Ming Gao
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zheng Dong
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jinfang Sun
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China
| | - Wei Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ming Xu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Changying Li
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Pan Zhu
- Guangdong Provincial Center of Disease Control and Prevention, Qujiang City Guangzhou, 511430, Southern China
| | - Xingfeng Yang
- Guangdong Provincial Center of Disease Control and Prevention, Qujiang City Guangzhou, 511430, Southern China; Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, 100022, China
| | - Xiaohong Shang
- NHC Key Laboratory for Food Safety Risk Assessment, Food Safety Research Unit (2019RU014) of Chinese Academy of Medical Science, China National Centre for Food Safety Risk Assessment, Beijing, 100022, China
| | - Yongning Wu
- Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, 100022, China; NHC Key Laboratory for Food Safety Risk Assessment, Food Safety Research Unit (2019RU014) of Chinese Academy of Medical Science, China National Centre for Food Safety Risk Assessment, Beijing, 100022, China.
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
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9
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Liu Y, Li Y, Xia Y, Liu K, Ren L, Ji Y. The Dysbiosis of Gut Microbiota Caused by Low-Dose Cadmium Aggravate the Injury of Mice Liver through Increasing Intestinal Permeability. Microorganisms 2020; 8:microorganisms8020211. [PMID: 32033263 PMCID: PMC7074735 DOI: 10.3390/microorganisms8020211] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 01/29/2020] [Accepted: 01/31/2020] [Indexed: 12/31/2022] Open
Abstract
Cadmium (Cd), widely present in food and drinking water at low doses, can cause health risks. However, the mechanistic effects of long-term Cd exposure at low dose through dietary intake is poorly studied. The aim of this study is to elucidate whether the dysbiosis of gut microbiota caused by Cd at an environmental low dose can aggravate the injury of mice liver, and the possible mechanism is investigated. In order to explore the potential underlying mechanism, the analyses of the variation of gut microbiota composition, intestinal permeability, and hepatic transcriptome were conducted. Our results showed that gut microbiota was disturbed. The rise of intestinal permeability induced by the dysbiosis of gut microbiota resulted in more Cd ions accumulating in mice liver, but it could be restored partly through depleting gut microbiota by antibiotics cocktail. Transcriptomic analyses indicated that 162 genes were significantly differentially expressed including 59 up-regulated and 103 down-regulated in Cd treatment. These genes were involved in several important pathways. Our findings provide a better understanding about the health risks of cadmium in the environment.
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Affiliation(s)
- Yehao Liu
- School of Public Health, Anhui Medical University, Hefei 230032, Anhui, China; (Y.L.); (K.L.); (L.R.)
| | - Yuhui Li
- Department of Biological and Environmental Engineering, Hefei University, Hefei 230032, Anhui, China;
| | - Yuhong Xia
- School of Public Health, Anhui Medical University, Hefei 230032, Anhui, China; (Y.L.); (K.L.); (L.R.)
| | - Kaiyong Liu
- School of Public Health, Anhui Medical University, Hefei 230032, Anhui, China; (Y.L.); (K.L.); (L.R.)
| | - Lingling Ren
- School of Public Health, Anhui Medical University, Hefei 230032, Anhui, China; (Y.L.); (K.L.); (L.R.)
| | - Yanli Ji
- School of Public Health, Anhui Medical University, Hefei 230032, Anhui, China; (Y.L.); (K.L.); (L.R.)
- Correspondence:
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10
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Shariatinia Z, Esmaeilzadeh A. Hybrid silica aerogel nanocomposite adsorbents designed for Cd(II) removal from aqueous solution. WATER ENVIRONMENT RESEARCH : A RESEARCH PUBLICATION OF THE WATER ENVIRONMENT FEDERATION 2019; 91:1624-1637. [PMID: 31206828 DOI: 10.1002/wer.1162] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/10/2019] [Accepted: 06/11/2019] [Indexed: 06/09/2023]
Abstract
Hybrid silica aerogel (HSA) nanoparticles were synthesized by sol-gel method and drying at ambient pressure. Also, two magnetic nanocomposites of HSA with Fe3 O4 nanoparticles and chitosan (CS) were prepared including HSA-Fe3 O4 and HSA-Fe3 O4 -CS. The morphology, structure, and magnetic properties of the HSA as well as its nanocomposites were analyzed by SEM, XRD, TGA, VSM, and ATR-FTIR techniques. The saturation magnetization (Ms ) values for the Fe3 O4 NPs, HSA-Fe3 O4, and HSA-Fe3 O4 -CS nanocomposite film were 69.93, 19.04, and 5.77 emu/g, respectively. Furthermore, the abilities of the HSA, HSA-Fe3 O4 , CS, and HSA-Fe3 O4 -CS adsorbents were assessed for removal of cadmium(II) heavy metal ions (100 ppm) from aqueous solution. All adsorbents removed/adsorbed the maximum Cd(II) ions in 120 min when adsorbent dosage = 20 mg and pH = 8. Moreover, the highest adsorption capacities were 58.5, 69.4, 65.8, and 71.9 mg/g for the HSA, CS, HSA-Fe3 O4, and HSA-Fe3 O4 -CS, respectively. Kinetic studies using all adsorbents verified that Cd(II) adsorption obeyed the second-order model illustrating the analyte chemisorption was happened on the adsorbent surfaces. All adsorption data were well consistent with the Langmuir isotherms. The reusability experiment confirmed that all of adsorbents could preserve >95% of their initial adsorption capacities even after five series of adsorption/desorption tests. PRACTITIONER POINTS: Hybrid silica aerogel (HSA), HSA-Fe3 O4, and HSA-Fe3 O4 -CS adsorbents were produced. Nanocomposites were characterized by XRD, TGA, SEM, VSM, and ATR-FTIR analysis. Adsorption of cadmium(II) ions by adsorbents was examined in aqueous solution. The highest adsorption capacity was obtained for the HSA-Fe3 O4 -CS (71.9 mg/g). Cd(II) adsorption followed second-order kinetics and Langmuir isotherm model.
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Affiliation(s)
- Zahra Shariatinia
- Department of Chemistry, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| | - Alireza Esmaeilzadeh
- Department of Chemistry, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
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11
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Zhou G, Li Z, Sun S, Fang Y, Wei Z. TGF-β1 alleviates HgCl 2 induced apoptosis via P38 MAPK signaling pathway in human trophoblast cells. Toxicol In Vitro 2019; 61:104626. [PMID: 31419505 DOI: 10.1016/j.tiv.2019.104626] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Revised: 08/10/2019] [Accepted: 08/12/2019] [Indexed: 12/31/2022]
Abstract
It is well known that embryonic development can be perturbed by environmental factors such as heavy metals. Mercury is one of the most significant threats to the environment and human health. Mercury can damage many parts of the human body, including lungs, kidneys, nerves and fetus. However, the effect of mercury on human embryo remains unknown. Here, we showed that HgCl2 treatment resulted in a significant increase in apoptosis in HTR-8/SVneo cells. However, the effect of HgCl2 on apoptosis was partially reduced by the combination treatment with TGF-β1 and HgCl2 in HTR-8/SVneo cells. Moreover, HgCl2 treatment gradually decreased the expression of TGF-β1 in a dose dependent manner. Furthermore, a P38 MAPK inhibitor, SB202190, decreased the cell apoptosis and caspase activation induced by HgCl2 in trophoblast cells. In addition, TGF-β1 alleviated HgCl2 induced apoptosis of HTR-8/SVneo cells via p38 MAPK signaling pathway, which was involved in the TAK1 expression. These results might provide a theoretical basis for mercury induced trophoblast associated embryo damage and a potential avenue of intervention.
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Affiliation(s)
- Guiju Zhou
- Reproductive Medicine Center, The First Affiliated Hospital, Anhui Medical University, Hefei, China; Department Gynecology, The Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Zhifang Li
- Anqing Municipal Hospital, Anhui Medical University, Anqing, China
| | - Shiying Sun
- Department Gynecology, The Second Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Yuan Fang
- Reproductive Medicine Center, The First Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Zhaolian Wei
- Reproductive Medicine Center, The First Affiliated Hospital, Anhui Medical University, Hefei, China.
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12
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Yang J, Chen Y, Yu Z, Ding H, Ma Z. The influence of PM 2.5 on lung injury and cytokines in mice. Exp Ther Med 2019; 18:2503-2511. [PMID: 31572502 PMCID: PMC6755482 DOI: 10.3892/etm.2019.7839] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 01/18/2019] [Indexed: 12/14/2022] Open
Abstract
Exposure to particulate matter ≤2.5 µm in diameter (PM2.5) profoundly affects human health. However, the role of PM2.5 on lung injury and cytokine levels in mice is currently unknown. The aim was to examine the effect of PM2.5 pollution on lung injury in mice fed at an underground parking lot. A total of 20 female Kunming mice were randomly divided into control and polluted groups, with 10 rats in each group. The control group was kept in the laboratory, while the pollution group was fed in an underground parking lot. The concentrations of pollutants were measured using ambient air quality monitoring instruments. After 3 months of treatment, the lungs were collected and examined using electron microscopy, and the morphological structures were assessed using hematoxylin and eosin staining. The polarization of macrophages was evaluated by immunofluorescence. The concentration of interleukin (IL)-4, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 in peripheral sera were assessed by ELISA. The mRNA and protein levels of IL-4, TNF-α, and TGF-β1 in lung tissues were assessed by reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. In the polluted group, the levels of CO, NOx and PM2.5 were significantly higher compared with the control group. Compared with the controls, intracellular edema, an increased number of microvilli and lamellar bodies, smaller lamellar bodies in type II alveolar epithelial cells, and abundant particles induced by PM2.5 in macrophages were observed in the polluted group. The lung ultrastructure changed in the polluted group, revealing exhaust-induced lung injury: The tissues were damaged, and the number of inflammatory cells, neutrophils, polylymphocytes and eosinophils increased in the polluted group compared with the control group. The authors also observed that the number of M1 and M2 macrophages markedly increased after the exhaust treatment. The levels of IL-4, TNF-α and TGF-β1 in the sera and tissues were significantly increased in the polluted group. PM2.5 pollutants in underground garages can lead to lung injury and have a significant impact on the level of inflammatory cytokines in mice. Therefore, the authors suggest that PM2.5 can activate the inflammatory reaction and induce immune dysfunction, leading to ultrastructural damage.
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Affiliation(s)
- Jie Yang
- Department of Dermatology, Guangdong Academy of Medical Sciences (Guangdong General Hospital), Guangzhou, Guangdong 510080, P.R. China
| | - Yi Chen
- Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Zhi Yu
- Research Center of Intelligent Transportation System, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510275, P.R. China
| | - Hui Ding
- Research Center of Intelligent Transportation System, School of Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510275, P.R. China
| | - Zhongfu Ma
- Department of General Internal Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
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13
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Kpemissi M, Eklu-Gadegbeku K, Veerapur VP, Potârniche AV, Adi K, Vijayakumar S, Banakar SM, Thimmaiah NV, Metowogo K, Aklikokou K. Antioxidant and nephroprotection activities of Combretum micranthum: A phytochemical, in-vitro and ex-vivo studies. Heliyon 2019; 5:e01365. [PMID: 30976670 PMCID: PMC6441829 DOI: 10.1016/j.heliyon.2019.e01365] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 01/21/2019] [Accepted: 03/13/2019] [Indexed: 12/18/2022] Open
Abstract
Management of chronic renal failure is exceedingly expensive. Despite of encouraging experimental outcomes, there is a lack of potent nephroprotective drugable molecules in a clinics or market. To develop a nephroprotective phytomedicine, the present study was designed to do a literature survey on reported phytochemical and biological analysis of Combretum micranthum and to carry out chemoprofiling, in-vitro antioxidant and ex-vivo nephroprotective capacity of the title plant. The phytochemical and biological activity survey of C. micranthum has reveals the presence of many bioactive compounds such as flavonoids, terpenoids, steroids and alkaloids with many biological activities. Phytochemical investigation re-confirmed the presence of these compounds. Hydroalcoholic extract of C. micranthum (CM extract) showed a strong antioxidant activity by scavenging AAPH, DPPH, nitric oxide, hydrogen peroxide and chelating metal ions. CM extract exhibited significant (P < 0.001) dose dependent inhibition of ferric chloride-ascorbic acid induced lipid peroxidation. Diabetic nephropathy is a serious and common complication leading to end stage renal disease. Therefore, in the present study, glucose-induced toxicity was also studied in human embryonic kidney cells (HEK-293) as an in vitro model for diabetic nephropathy. The results showed that exposure of cells to high glucose (100 mM) for 72 h significantly reduced the cell viability resulting in morphological changes such as cell shrinkage, rounded cell shape and cytoplasmic vacuolation. Treatment with CM extract at 10 and 25 μg/mL resulted in significant improvement in cell viability from 10 to 23% compared to the high glucose control. This study demonstrated the potential antioxidant and nephroprotective properties of C. micranthum, justifying its traditional use in the treatment of various diseases.
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Affiliation(s)
- Mabozou Kpemissi
- Faculty of Sciences, University of Lomé, Togo.,University of Agricultural Science and Veterinary Medicine, Manastur Street. 3-5, 400372, Cluj-Napoca, Romania.,Sree Siddaganga College of Pharmacy, B.H. Road, Tumkur 572 102, Karnataka, India
| | | | - Veeresh P Veerapur
- Sree Siddaganga College of Pharmacy, B.H. Road, Tumkur 572 102, Karnataka, India
| | - Adrian-Valentin Potârniche
- University of Agricultural Science and Veterinary Medicine, Manastur Street. 3-5, 400372, Cluj-Napoca, Romania
| | - Kodjo Adi
- Faculty of Sciences, University of Lomé, Togo
| | - S Vijayakumar
- Sree Siddaganga College of Pharmacy, B.H. Road, Tumkur 572 102, Karnataka, India
| | - Siddalingesh M Banakar
- Anthem Biosciences Pvt. Ltd., Industrial Area Phase I, Bommasandra, Hosur Road, Bangalore, 560099, India
| | - N V Thimmaiah
- Anthem Biosciences Pvt. Ltd., Industrial Area Phase I, Bommasandra, Hosur Road, Bangalore, 560099, India
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14
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Handl J, Čapek J, Majtnerová P, Petira F, Hauschke M, Roušarová E, Roušar T. Transient increase in cellular dehydrogenase activity after cadmium treatment precedes enhanced production of reactive oxygen species in human proximal tubular kidney cells. Physiol Res 2019; 68:481-490. [PMID: 30904015 DOI: 10.33549/physiolres.934121] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cadmium is a heavy metal causing toxicity especially in kidney cells. The toxicity is linked also with enhanced oxidative stress leading to cell death. On the other hand, our recent experiments have shown that an increase of total intracellular dehydrogenases activity can also occur in kidney cells before declining until cell death. The aim of the present study, therefore, was to evaluate this transient enhancement in cell viability after cadmium treatment. The human kidney HK-2 cell line was treated with CdCl(2) at concentrations 0-200 microM for 2-24 h and intracellular dehydrogenase activity was tested. In addition, we measured reactive oxygen species (ROS) production, glutathione levels, mitochondrial membrane potential, and C-Jun-N-terminal kinase (JNK) activation. We found that significantly increased dehydrogenase activity could occur in cells treated with 25, 100, and 200 microM CdCl(2). Moreover, the results showed an increase in ROS production linked with JNK activation following the enhancement of dehydrogenase activity. Other tests detected no relationship with the increased in intracellular dehydrogenase activity. Hence, the transient increase in dehydrogenase activity in HK-2 cells preceded the enhancement of ROS production and our finding provides new evidence in cadmium kidney toxicity.
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Affiliation(s)
- J Handl
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Pardubice, Czech Republic.
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15
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Fujiki K, Inamura H, Sugaya T, Matsuoka M. Blockade of ALK4/5 signaling suppresses cadmium- and erastin-induced cell death in renal proximal tubular epithelial cells via distinct signaling mechanisms. Cell Death Differ 2019; 26:2371-2385. [PMID: 30804470 DOI: 10.1038/s41418-019-0307-8] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 01/22/2019] [Accepted: 02/08/2019] [Indexed: 12/30/2022] Open
Abstract
Various types of cell death, including apoptosis, necrosis, necroptosis, and ferroptosis, are induced in renal tubular epithelial cells following exposure to environmental stresses and toxicants such as osmotic stress, ischemia/reperfusion injury, cisplatin, and cadmium. This is known to cause renal dysfunction, but the cellular events preceding stress-induced cell death in renal tubules are not fully elucidated. The activin receptor-like kinase (ALK) 4/5, also known as activin-transforming growth factor (TGF) β receptor, is involved in stress-induced renal injury. We, therefore, studied the role of ALK4/5 signaling in HK-2 human proximal tubular epithelial cell death induced by cisplatin, cadmium, hyperosmotic stress inducer, sorbitol, and the ferroptosis activator, erastin. We found that ALK4/5 signaling is involved in cadmium- and erastin-induced cell death, but not sorbitol- or cisplatin-induced apoptotic cell death. Cadmium exposure elevated the level of phosphorylated Smad3, and treatment with the ALK4/5 kinase inhibitors, SB431542 or SB505124, suppressed cadmium-induced HK-2 cell death. Cadmium-induced cell death was attenuated by siRNA-mediated ALK4 or Smad3 silencing, or by treatment with SIS3, a selective inhibitor of TGFβ1-dependent Smad3 phosphorylation. Furthermore, ALK4/5 signaling activated Akt signaling to promote cadmium-induced HK-2 cell death. In contrast, siRNA-mediated Inhibin-bA silencing or treatment with TGFβ1 or activin A had little effect on cadmium-induced HK-2 cell death. On the other hand, treatment with SB431542 or SB505124 attenuated erastin-induced ferroptosis by hyperactivating Nrf2 signaling in HK-2 cells. These results suggest that blockade of ALK4/5 signaling protects against cadmium- and erastin-induced HK-2 cell death via Akt and Nrf2 signaling pathways, respectively.
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Affiliation(s)
- Kota Fujiki
- Department of Hygiene and Public Health, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.
| | - Hisako Inamura
- Department of Hygiene and Public Health, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
| | - Takeshi Sugaya
- Division of Nephrology and Hypertension, St. Marianna University School of Medicine, Kanagawa, 216-8511, Japan
| | - Masato Matsuoka
- Department of Hygiene and Public Health, Tokyo Women's Medical University, Tokyo, 162-8666, Japan
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16
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Shen J, Wang X, Zhou D, Li T, Tang L, Gong T, Su J, Liang P. Modelling cadmium-induced cardiotoxicity using human pluripotent stem cell-derived cardiomyocytes. J Cell Mol Med 2018; 22:4221-4235. [PMID: 29993192 PMCID: PMC6111808 DOI: 10.1111/jcmm.13702] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 04/27/2018] [Indexed: 12/29/2022] Open
Abstract
Cadmium, a highly ubiquitous toxic heavy metal, has been widely recognized as an environmental and industrial pollutant, which confers serious threats to human health. The molecular mechanisms of the cadmium-induced cardiotoxicity (CIC) have not been studied in human cardiomyocytes at the cellular level. Here we showed that human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) can recapitulate the CIC at the cellular level. The cadmium-treated hPSC-CMs exhibited cellular phenotype including reduced cell viability, increased apoptosis, cardiac sarcomeric disorganization, elevated reactive oxygen species, altered action potential profile and cardiac arrhythmias. RNA-sequencing analysis revealed a differential transcriptome profile and activated MAPK signalling pathway in cadmium-treated hPSC-CMs, and suppression of P38 MAPK but not ERK MAPK or JNK MAPK rescued CIC phenotype. We further identified that suppression of PI3K/Akt signalling pathway is sufficient to reverse the CIC phenotype, which may play an important role in CIC. Taken together, our data indicate that hPSC-CMs can serve as a suitable model for the exploration of molecular mechanisms underlying CIC and for the discovery of CIC cardioprotective drugs.
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Affiliation(s)
- Jiaxi Shen
- Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Xiaochen Wang
- Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Danni Zhou
- Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Tongyu Li
- Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Ling Tang
- Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Tingyu Gong
- The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Jun Su
- Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University, Hangzhou, China
| | - Ping Liang
- Key Laboratory of combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, China.,Institute of Translational Medicine, Zhejiang University, Hangzhou, China
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