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Yan J, Kim H, Kim B, Piao H, Jang JY, Kang TK, Lee W, Kim D, Jo S, Shin D, Abuzar SMD, Kim ML, Yang J, Jon S. Synthetic Bilirubin-Based Nanomedicine Protects Against Renal Ischemia/Reperfusion Injury Through Antioxidant and Immune-Modulating Activity. Adv Healthc Mater 2025; 14:e2403846. [PMID: 39846887 PMCID: PMC11912105 DOI: 10.1002/adhm.202403846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 01/09/2025] [Indexed: 01/24/2025]
Abstract
Renal ischemia/reperfusion injury (IRI) is a common form of acute kidney injury. The basic mechanism underlying renal IRI is acute inflammation, where oxidative stress plays an important role. Although bilirubin exhibits potent reactive oxygen species (ROS)-scavenging properties, its clinical application is hindered by problems associated with solubility, stability, and toxicity. In this study, BX-001N, a synthetic polyethylene glycol-conjugated bilirubin 3α nanoparticle is developed and assessed its renoprotective effects in renal IRI. Intravenous administration of BX-001N led to increase uptake in the kidneys with minimal migration to the brain after IRI. Peri-IRI BX-001N administration improves renal function and attenuates renal tissue injury and tubular apoptosis to a greater extent than free bilirubin on day 1 after IRI. BX-001N suppressed renal infiltration of inflammatory cells and reduced expression of TNF-α and MCP-1. Furthermore, BX-001N increases renal tubular regeneration on day 3 and suppresses renal fibrosis on day 28. BX-001N decreases the renal expressions of dihydroethidium, malondialdehyde, and nitrotyrosine after IRI. In conclusion, BX-001N, the first Good Manufacturing Practice-grade synthetic bilirubin-based nanomedicine attenuates acute renal injury and chronic fibrosis by suppressing ROS generation and inflammation after IRI. It shows adequate safety profiles and holds promise as a new therapy for renal IRI.
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Affiliation(s)
- Ji‐Jing Yan
- Division of NephrologyDepartment of Internal MedicineYonsei University College of MedicineSeoul03722Republic of Korea
- The Research Institute for TransplantationYonsei University College of MedicineSeoul03722Republic of Korea
| | - Hyunjin Kim
- BILIX.Co., Ltd.YonginGyeonggi‐do16942Republic of Korea
| | - Bomin Kim
- Division of NephrologyDepartment of Internal MedicineYonsei University College of MedicineSeoul03722Republic of Korea
- The Research Institute for TransplantationYonsei University College of MedicineSeoul03722Republic of Korea
| | - Honglin Piao
- Division of NephrologyDepartment of Internal MedicineYonsei University College of MedicineSeoul03722Republic of Korea
- The Research Institute for TransplantationYonsei University College of MedicineSeoul03722Republic of Korea
| | - Joon Young Jang
- Division of NephrologyDepartment of Internal MedicineYonsei University College of MedicineSeoul03722Republic of Korea
- The Research Institute for TransplantationYonsei University College of MedicineSeoul03722Republic of Korea
| | - Tae Kyeom Kang
- Natural Product Research CenterKorea Institute of Science & TechnologyGangneungGangwon‐do25451Republic of Korea
| | - Wook‐Bin Lee
- Natural Product Research CenterKorea Institute of Science & TechnologyGangneungGangwon‐do25451Republic of Korea
| | - Dohyeon Kim
- Department of Biological SciencesKAIST Institute for the BioCenturyCenter for Precision Bio‐NanomedicineKorea Advanced Institute of Science and TechnologyDaejeon34141Republic of Korea
| | - Seunghyun Jo
- BILIX.Co., Ltd.YonginGyeonggi‐do16942Republic of Korea
| | | | | | - Myung L. Kim
- BILIX.Co., Ltd.YonginGyeonggi‐do16942Republic of Korea
| | - Jaeseok Yang
- Division of NephrologyDepartment of Internal MedicineYonsei University College of MedicineSeoul03722Republic of Korea
- The Research Institute for TransplantationYonsei University College of MedicineSeoul03722Republic of Korea
| | - Sangyong Jon
- Department of Biological SciencesKAIST Institute for the BioCenturyCenter for Precision Bio‐NanomedicineKorea Advanced Institute of Science and TechnologyDaejeon34141Republic of Korea
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Fujiwara-Tani R, Nakashima C, Ohmori H, Fujii K, Luo Y, Sasaki T, Ogata R, Kuniyasu H. Significance of Malic Enzyme 1 in Cancer: A Review. Curr Issues Mol Biol 2025; 47:83. [PMID: 39996805 PMCID: PMC11854147 DOI: 10.3390/cimb47020083] [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: 01/02/2025] [Revised: 01/25/2025] [Accepted: 01/28/2025] [Indexed: 02/26/2025] Open
Abstract
Malic enzyme 1 (ME1) plays a key role in promoting malignant phenotypes in various types of cancer. ME1 promotes epithelial-mesenchymal transition (EMT) and enhances stemness via glutaminolysis, energy metabolism reprogramming from oxidative phosphorylation to glycolysis. As a result, ME1 promotes the malignant phenotypes of cancer cells and poor patient prognosis. In particular, ME1 expression is promoted in hypoxic environments associated with hypoxia-inducible factor (HIF1) α. ME1 is overexpressed in budding cells at the cancer invasive front, promoting cancer invasion and metastasis. ME1 also generates nicotinamide adenine dinucleotide (NADPH), which, together with glucose-6-phosphate dehydrogenase (G6PD) and isocitrate dehydrogenase (IDH1), expands the NADPH pool, maintaining the redox balance in cancer cells, suppressing cell death by neutralizing mitochondrial reactive oxygen species (ROS), and promoting stemness. This review summarizes the latest research insights into the mechanisms by which ME1 contributes to cancer progression. Because ME1 is involved in various aspects of cancer and promotes many of its malignant phenotypes, it is expected that ME1 will become a novel drug target in the near future.
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Affiliation(s)
- Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara 634-8521, Japan; (C.N.); (H.O.); (K.F.); (Y.L.); (T.S.); (R.O.)
| | | | | | | | | | | | | | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara 634-8521, Japan; (C.N.); (H.O.); (K.F.); (Y.L.); (T.S.); (R.O.)
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Xie Z, Hou Q, He Y, Xie Y, Mo Q, Wang Z, Zhao Z, Chen X, Peng T, Li L, Xie W. Ferritin Hinders Ferroptosis in Non-Tumorous Diseases: Regulatory Mechanisms and Potential Consequences. Curr Protein Pept Sci 2025; 26:89-104. [PMID: 39225224 DOI: 10.2174/0113892037315874240826112422] [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: 03/30/2024] [Revised: 07/19/2024] [Accepted: 07/25/2024] [Indexed: 09/04/2024]
Abstract
Ferritin, as an iron storage protein, has the potential to inhibit ferroptosis by reducing excess intracellular free iron concentrations and lipid reactive oxygen species (ROS). An insufficient amount of ferritin is one of the conditions that can lead to ferroptosis through the Fenton reaction mediated by ferrous iron. Consequently, upregulation of ferritin at the transcriptional or posttranscriptional level may inhibit ferroptosis. In this review, we have discussed the essential role of ferritin in ferroptosis and the regulatory mechanism of ferroptosis in ferritin-deficient individuals. The description of the regulatory factors governing ferritin and its properties in regulating ferroptosis as underlying mechanisms for the pathologies of diseases will allow potential therapeutic approaches to be developed.
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Affiliation(s)
- Zhongcheng Xie
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Qin Hou
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Yinling He
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Yushu Xie
- Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Qinger Mo
- Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Ziyi Wang
- Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Ziye Zhao
- Class of Clinical Medicine, University of South China, Hengyang 421001, Hunan, China
| | - Xi Chen
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Tianhong Peng
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Liang Li
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
| | - Wei Xie
- Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, Hengyang Medical School, University of South China, Hengyang 421001, Hunan, China
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Han H, Zhang G, Zhang X, Zhao Q. Nrf2-mediated ferroptosis inhibition: a novel approach for managing inflammatory diseases. Inflammopharmacology 2024; 32:2961-2986. [PMID: 39126567 DOI: 10.1007/s10787-024-01519-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 06/28/2024] [Indexed: 08/12/2024]
Abstract
Inflammatory diseases, including psoriasis, atherosclerosis, rheumatoid arthritis, and ulcerative colitis, are characterized by persistent inflammation. Moreover, the existing treatments for inflammatory diseases only provide temporary relief by controlling symptoms, and treatments of unstable and expensive. Therefore, new therapeutic solutions are urgently needed to address the underlying causes or symptoms of inflammatory diseases. Inflammation frequently coincides with a high level of (reactive oxygen species) ROS activation, serving as a fundamental element in numerous physiological and pathological phenotypes that can result in serious harm to the organism. Given its pivotal role in inflammation, oxidative stress, and ferroptosis, ROS represents a focal node for investigating the (nuclear factor E2-related factor 2) Nrf2 pathway and ferroptosis, both of which are intricately linked to ROS. Ferroptosis is mainly triggered by oxidative stress and involves iron-dependent lipid peroxidation. The transcription factor Nrf2 targets several genes within the ferroptosis pathway. Recent studies have shown that Nrf2 plays a significant role in three key ferroptosis-related routes, including the synthesis and metabolism of glutathione/glutathione peroxidase 4, iron metabolism, and lipid processes. As a result, ferroptosis-related treatments for inflammatory diseases have attracted much attention. Moreover, drugs targeting Nrf2 can be used to manage inflammatory conditions. This review aimed to assess ferroptosis regulation mechanism and the role of Nrf2 in ferroptosis inhibition. Therefore, this review article may provide the basis for more research regarding the treatment of inflammatory diseases through Nrf2-inhibited ferroptosis.
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Affiliation(s)
- Hang Han
- College of Pharmacy, Chongqing Medical University, Chongqing, Chongqing, 400016, China
| | - Guojiang Zhang
- College of Pharmacy, Chongqing Medical University, Chongqing, Chongqing, 400016, China
| | - Xiao Zhang
- College of Pharmacy, Chongqing Medical University, Chongqing, Chongqing, 400016, China.
| | - Qinjian Zhao
- College of Pharmacy, Chongqing Medical University, Chongqing, Chongqing, 400016, China.
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Fan B, Guo Q, Wang S. The application of alkaloids in ferroptosis: A review. Biomed Pharmacother 2024; 178:117232. [PMID: 39098181 DOI: 10.1016/j.biopha.2024.117232] [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: 05/25/2024] [Revised: 07/28/2024] [Accepted: 07/30/2024] [Indexed: 08/06/2024] Open
Abstract
Alkaloids have remarkable biological and pharmacological properties and have recently garnered extensive attention. Various alkaloids, including commercially available drugs such as berberine, substantially affect ferroptosis. In addition to the three main pathways of ferroptosis, iron metabolism, phospholipid metabolism, and the glutathione peroxidase 4-regulated pathway, novel mechanisms of ferroptosis are continuously being identified. Alkaloids can modulate the progression of various diseases through ferroptosis and exhibit the ability to exert varied effects depending on dosage and tissue type underscores their versatility. Therefore, this review comprehensively summarizes primary targets and the latest advancements of alkaloids in ferroptosis, as well as the dual roles of alkaloids in inhibiting and promoting ferroptosis.
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Affiliation(s)
- Bocheng Fan
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110013, China
| | - Qihao Guo
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110013, China
| | - Shu Wang
- Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province 110013, China.
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Luo J, Zhu Q, Huang K, Wen X, Peng Y, Chen G, Wei G. Atorvastatin inhibits Lipopolysaccharide (LPS)-induced vascular inflammation to protect endothelium by inducing Heme Oxygenase-1 (HO-1) expression. PLoS One 2024; 19:e0308823. [PMID: 39146322 PMCID: PMC11326635 DOI: 10.1371/journal.pone.0308823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 07/31/2024] [Indexed: 08/17/2024] Open
Abstract
PURPOSE This study aimed to explore the differential effects of varying doses of atorvastatin on antagonizing lipopolysaccharide (LPS)-induced endothelial inflammation based on heme oxygenase 1 (HO-1) expression. METHOD Vascular endothelial inflammatory injury was induced in 40 Sprague-Dawley rats by intraperitoneal injection of LPS. These rats were randomly divided into control, low-dose atorvastatin, high-dose atorvastatin, and HO-1 blocking groups. Seven days after treatment, all rats were sacrificed, and heart-derived peripheral blood was collected to measure the serum concentrations of bilirubin, alanine aminotransferase (ALT), total cholesterol, malondialdehyde, endothelial cell protein C receptor, endothelin-1, von Willebrand factor, and soluble thrombomodulin. Meanwhile, the number of circulating endothelial cells was determined using flow cytometry. Vascular tissues from descending aorta of rats from each group were extracted to detect the expression level of HO-1. RESULTS After different doses of atorvastatin intervention, the above inflammatory indices were decreased, and HO-1 expression and ALT concentration were increased in the atorvastatin-treated group of rats compared with the control group. These changes were more pronounced in the high-dose statin group (P < 0.05). Conversely, no significant decrease in the above inflammatory indices and no significant increase in HO-1 expression were observed in rats in the blocking group (P > 0.05). CONCLUSION For LPS-induced vascular inflammation, high-dose atorvastatin exerts potent anti-inflammatory and vascular endothelial protection effects by inducing HO-1 expression.
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Affiliation(s)
- Jian Luo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Lu Zhou, China
| | - Qian Zhu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Lu Zhou, China
| | - Keming Huang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Lu Zhou, China
| | - Xue Wen
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Lu Zhou, China
| | - Yongquan Peng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Lu Zhou, China
| | - Gong Chen
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Lu Zhou, China
| | - Gang Wei
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Lu Zhou, China
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Kakoti BB, Alom S, Deka K, Halder RK. AMPK pathway: an emerging target to control diabetes mellitus and its related complications. J Diabetes Metab Disord 2024; 23:441-459. [PMID: 38932895 PMCID: PMC11196491 DOI: 10.1007/s40200-024-01420-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 03/07/2024] [Indexed: 06/28/2024]
Abstract
Purpose In this extensive review work, the important role of AMP-activated protein kinase (AMPK) in causing of diabetes mellitus has been highlighted. Structural feature of AMPK as well its regulations and roles are described nicely, and the association of AMPK with the diabetic complications like nephropathy, neuropathy and retinopathy are also explained along with the connection between AMPK and β-cell function, insulin resistivity, mTOR, protein metabolism, autophagy and mitophagy and effect on protein and lipid metabolism. Methods Published journals were searched on the database like PubMed, Medline, Scopus and Web of Science by using keywords such as AMPK, diabetes mellitus, regulation of AMPK, complications of diabetes mellitus, autophagy, apoptosis etc. Result After extensive review, it has been found that, kinase enzyme like AMPK is having vital role in management of type II diabetes mellitus. AMPK involve in enhance the concentration of glucose transporter like GLUT 1 and GLUT 4 which result in lowering of blood glucose level in influx of blood glucose into the cells; AMPK increases the insulin sensitivity and decreases the insulin resistance and further AMPK decreases the apoptosis of β-cells which result into secretion of insulin and AMPK is also involve in declining of oxidative stress, lipotoxicity and inflammation, owing to which organ damage due to diabetes mellitus can be lowered by activation of AMPK. Conclusion As AMPK activation leads to overall control of diabetes mellitus, designing and developing of small molecules or peptide that can act as AMPK agonist will be highly beneficial for control or manage diabetes mellitus.
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Affiliation(s)
- Bibhuti B. Kakoti
- Department of Pharmaceutical Sciences, Dibrugarh University, 786004 Dibrugarh, Assam India
| | - Shahnaz Alom
- Department of Pharmaceutical Sciences, Dibrugarh University, 786004 Dibrugarh, Assam India
- Department of Pharmacology, Girijananda Chowdhury Institute of Pharmaceutical Sciences, Girijananda Chowdhury University- Tezpur campus, 784501 Sonitpur, Assam India
| | - Kangkan Deka
- Department of Pharmaceutical Sciences, Dibrugarh University, 786004 Dibrugarh, Assam India
- Department of Pharmacognosy, NETES Institute of Pharmaceutical Science, NEMCARE Group of Institutions, 781125 Mirza, Kamrup, Assam India
| | - Raj Kumar Halder
- Ruhvenile Biomedical, Plot -8 OCF Pocket Institution, Sarita Vihar, 110076 Delhi, India
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Gazzin S, Bellarosa C, Tiribelli C. Molecular events in brain bilirubin toxicity revisited. Pediatr Res 2024; 95:1734-1740. [PMID: 38378754 DOI: 10.1038/s41390-024-03084-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/17/2024] [Accepted: 01/28/2024] [Indexed: 02/22/2024]
Abstract
The mechanisms involved in bilirubin neurotoxicity are still far from being fully elucidated. Several different events concur to damage mainly the neurons among which inflammation and alteration of the redox state play a major role. An imbalance of cellular calcium homeostasis has been recently described to be associated with toxic concentrations of bilirubin, and this disequilibrium may in turn elicit an inflammatory reaction. The different and age-dependent sensitivity to bilirubin damage must also be considered in describing the dramatic clinical picture of bilirubin-induced neurological damage (BIND) formerly known as kernicterus spectrum disorder (KSD). This review aims to critically address what is known and what is not in the molecular events of bilirubin neurotoxicity to provide hints for a better diagnosis and more successful treatments. Part of these concepts have been presented at the 38th Annual Audrey K. Brown Kernicterus Symposium of Pediatric American Society, Washington DC, May 1, 2023.
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Affiliation(s)
- Silvia Gazzin
- Liver-Brain Unit "Rita Moretti", Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149, Trieste, Italy
| | - Cristina Bellarosa
- Liver-Brain Unit "Rita Moretti", Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149, Trieste, Italy
| | - Claudio Tiribelli
- Liver-Brain Unit "Rita Moretti", Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149, Trieste, Italy.
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Wang Y, Fu X, Zeng L, Hu Y, Gao R, Xian S, Liao S, Huang J, Yang Y, Liu J, Jin H, Klaunig J, Lu Y, Zhou S. Activation of Nrf2/HO-1 signaling pathway exacerbates cholestatic liver injury. Commun Biol 2024; 7:621. [PMID: 38783088 PMCID: PMC11116386 DOI: 10.1038/s42003-024-06243-0] [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: 09/15/2023] [Accepted: 04/22/2024] [Indexed: 05/25/2024] Open
Abstract
Nuclear factor erythroid 2-related factor-2 (Nrf2) antioxidant signaling is involved in liver protection, but this generalization overlooks conflicting studies indicating that Nrf2 effects are not necessarily hepatoprotective. The role of Nrf2/heme oxygenase-1 (HO-1) in cholestatic liver injury (CLI) remains poorly defined. Here, we report that Nrf2/HO-1 activation exacerbates liver injury rather than exerting a protective effect in CLI. Inhibiting HO-1 or ameliorating bilirubin transport alleviates liver injury in CLI models. Nrf2 knockout confers hepatoprotection in CLI mice, whereas in non-CLI mice, Nrf2 knockout aggravates liver damage. In the CLI setting, oxidative stress activates Nrf2/HO-1, leads to bilirubin accumulation, and impairs mitochondrial function. High levels of bilirubin reciprocally upregulate the activation of Nrf2 and HO-1, while antioxidant and mitochondrial-targeted SOD2 overexpression attenuate bilirubin toxicity. The expression of Nrf2 and HO-1 is elevated in serum of patients with CLI. These results reveal an unrecognized function of Nrf2 signaling in exacerbating liver injury in cholestatic disease.
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Affiliation(s)
- Yi Wang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Xiaolong Fu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Li Zeng
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Yan Hu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Rongyang Gao
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Siting Xian
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Songjie Liao
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Jianxiang Huang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Yonggang Yang
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- School of Pharmacy, Zunyi Medical University, Zunyi, China
| | - Jilong Liu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Hai Jin
- Institute of Digestive Diseases of Affiliated Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - James Klaunig
- Department of Environmental and Occupational Health, School of Public Health, Indiana University, Bloomington, IN, USA
| | - Yuanfu Lu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.
- School of Pharmacy, Zunyi Medical University, Zunyi, China.
| | - Shaoyu Zhou
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China.
- School of Pharmacy, Zunyi Medical University, Zunyi, China.
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Luo W, Bu W, Chen H, Liu W, Lu X, Zhang G, Liu C, Li X, Ren H. Electroacupuncture reduces oxidative stress response and improves secondary injury of intracerebral hemorrhage in rats by activating the peroxisome proliferator-activated receptor-γ/nuclear factor erythroid2-related factor 2/γ-glutamylcysteine synthetase pathway. Neuroreport 2024; 35:499-508. [PMID: 38597270 PMCID: PMC11045547 DOI: 10.1097/wnr.0000000000002026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 02/19/2024] [Indexed: 04/11/2024]
Abstract
Intracerebral hemorrhage (ICH) is a severe stroke subtype. Secondary injury is a key factor leading to neurological deficits after ICH. Electroacupuncture (EA) can improve the neurological function after ICH, however, its internal mechanism is still unclear. The aim of this study is to investigate whether EA could ameliorate secondary injury after ICH through antioxidative stress and its potential regulatory mechanism. A rat model of ICH was established by injecting autologous blood into striatum. After the intervention of EA and EA combined with peroxisome proliferator-activated receptor-γ (PPARγ) blocker, Zea-longa scores, modified neurological severity scores and open field tests were used to evaluate the neurological function of the rats. Flow cytometry detected tissue reactive oxygen species (ROS) levels. Tissue tumor necrosis factor-α (TNF-α) levels were analyzed by enzyme-linked immunosorbent assays. The protein expressions of PPAR γ, nuclear factor erythroid2-related factor 2 (Nrf2) and γ-glutamylcysteine synthetase (γ-GCS) were detected by Western blot. Immunohistochemistry was used to observe the activation of microglia. The demyelination degree of axon myelin was observed by transmission electron microscope. Compared with the model group, EA intervention improved neurological function, decreased ROS and TNF-α levels, increased the protein expression of PPARγ, Nrf2 and γ-GCS, and reduced the activation of microglia, it also alleviated axonal myelin sheath damage. In addition, the neuroprotective effect of EA was partially attenuated by PPARγ blocker. EA ameliorated the neurological function of secondary injury after ICH in rats, possibly by activating the PPARγ/Nrf2/γ-GCS signaling pathway, reducing microglia activation, and inhibiting oxidative stress, thus alleviating the extent of axonal demyelination plays a role.
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Affiliation(s)
| | - Wei Bu
- Department of Neurosurgery, The Third Hospital of Hebei Medical University
| | - Hequn Chen
- Department of Neurosurgery, The Third Hospital of Hebei Medical University
| | | | - Xudong Lu
- Basic Medical College, Hebei Medical University, Shijiazhuang, China
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Zhao X, Duan B, Wu J, Huang L, Dai S, Ding J, Sun M, Lin X, Jiang Y, Sun T, Lu R, Huang H, Lin G, Chen R, Yao Q, Kou L. Bilirubin ameliorates osteoarthritis via activating Nrf2/HO-1 pathway and suppressing NF-κB signalling. J Cell Mol Med 2024; 28:e18173. [PMID: 38494841 PMCID: PMC10945086 DOI: 10.1111/jcmm.18173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 01/08/2024] [Accepted: 01/31/2024] [Indexed: 03/19/2024] Open
Abstract
Osteoarthritis (OA) is a chronic degenerative joint disease that affects worldwide. Oxidative stress plays a critical role in the chronic inflammation and OA progression. Scavenging overproduced reactive oxygen species (ROS) could be rational strategy for OA treatment. Bilirubin (BR) is a potent endogenous antioxidant that can scavenge various ROS and also exhibit anti-inflammatory effects. However, whether BR could exert protection on chondrocytes for OA treatment has not yet been elucidated. Here, chondrocytes were exposed to hydrogen peroxide with or without BR treatment. The cell viability was assessed, and the intracellular ROS, inflammation cytokines were monitored to indicate the state of chondrocytes. In addition, BR was also tested on LPS-treated Raw264.7 cells to test the anti-inflammation property. An in vitro bimimic OA microenvironment was constructed by LPS-treated Raw264.7 and chondrocytes, and BR also exert certain protection for chondrocytes by activating Nrf2/HO-1 pathway and suppressing NF-κB signalling. An ACLT-induced OA model was constructed to test the in vivo therapeutic efficacy of BR. Compared to the clinical used HA, BR significantly reduced cartilage degeneration and delayed OA progression. Overall, our data shows that BR has a protective effect on chondrocytes and can delay OA progression caused by oxidative stress.
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Affiliation(s)
- Xinyu Zhao
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Key Laboratory of Structural Malformations in Children of Zhejiang ProvinceWenzhouChina
| | - Baiqun Duan
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Key Laboratory of Structural Malformations in Children of Zhejiang ProvinceWenzhouChina
| | - Jianing Wu
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Key Laboratory of Structural Malformations in Children of Zhejiang ProvinceWenzhouChina
| | - Lihui Huang
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Key Laboratory of Structural Malformations in Children of Zhejiang ProvinceWenzhouChina
| | - Sheng Dai
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Key Laboratory of Structural Malformations in Children of Zhejiang ProvinceWenzhouChina
| | - Jie Ding
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Key Laboratory of Structural Malformations in Children of Zhejiang ProvinceWenzhouChina
| | - Meng Sun
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Key Laboratory of Structural Malformations in Children of Zhejiang ProvinceWenzhouChina
| | - Xinlu Lin
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Yiling Jiang
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Tuyue Sun
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Ruijie Lu
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Huirong Huang
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy TechnologyWenzhouChina
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouChina
| | - Guangyong Lin
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
| | - Ruijie Chen
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Key Laboratory of Structural Malformations in Children of Zhejiang ProvinceWenzhouChina
- Zhejiang‐Hong Kong Precision Theranostics of Thoracic Tumors Joint LaboratoryWenzhouChina
| | - Qing Yao
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- School of Pharmaceutical SciencesWenzhou Medical UniversityWenzhouChina
| | - Longfa Kou
- Wenzhou Municipal Key Laboratory of Pediatric Pharmacy, Department of PharmacyThe Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouChina
- Key Laboratory of Structural Malformations in Children of Zhejiang ProvinceWenzhouChina
- Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy TechnologyWenzhouChina
- Zhejiang‐Hong Kong Precision Theranostics of Thoracic Tumors Joint LaboratoryWenzhouChina
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12
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Jayanti S, Vitek L, Verde CD, Llido JP, Sukowati C, Tiribelli C, Gazzin S. Role of Natural Compounds Modulating Heme Catabolic Pathway in Gut, Liver, Cardiovascular, and Brain Diseases. Biomolecules 2024; 14:63. [PMID: 38254662 PMCID: PMC10813662 DOI: 10.3390/biom14010063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024] Open
Abstract
The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.
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Affiliation(s)
- Sri Jayanti
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
- Eijkman Research Centre for Molecular Biology, Research Organization for Health, National Research and Innovation Agency, Cibinong 16915, Indonesia
| | - Libor Vitek
- Institute of Medical Biochemistry and Laboratory Diagnostics, and 4th Department of Internal Medicine, General University Hospital and 1st Faculty of Medicine, Charles University, 12000 Prague, Czech Republic;
| | - Camilla Dalla Verde
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
- Department of Life Sciences, University of Trieste, 34139 Trieste, Italy
| | - John Paul Llido
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
- Department of Life Sciences, University of Trieste, 34139 Trieste, Italy
- Department of Science and Technology, Philippine Council for Health Research and Development, Bicutan, Taguig City 1631, Philippines
| | - Caecilia Sukowati
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
- Eijkman Research Centre for Molecular Biology, Research Organization for Health, National Research and Innovation Agency, Cibinong 16915, Indonesia
| | - Claudio Tiribelli
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
| | - Silvia Gazzin
- Liver brain Unit “Rita Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163,5, Basovizza, 34149 Trieste, Italy or (S.J.); (C.D.V.); (J.P.L.); or (C.S.); (C.T.)
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13
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Xia Y, Tan W, Yuan F, Lin M, Luo H. Luteolin Attenuates Oxidative Stress and Colonic Hypermobility in Water Avoidance Stress Rats by Activating the Nrf2 Signaling Pathway. Mol Nutr Food Res 2024; 68:e2300126. [PMID: 38037466 DOI: 10.1002/mnfr.202300126] [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: 03/05/2023] [Revised: 07/30/2023] [Indexed: 12/02/2023]
Abstract
SCOPE Irritable bowel syndrome (IBS) is an intestinal disorder, whose symptoms can be alleviated by certain dietary phytochemicals. This study explores the role and potential mechanisms of a natural flavonoid luteolin (LUT) in alleviating the excessive motility of colonic smooth muscles and reducing oxidative stress in IBS with diarrhea (IBS-D) rats. METHODS AND RESULTS LUT reduces excessive intestinal motility and lowers reactive oxygen species (ROS) levels in a water avoidance stress (WAS) rat model. Moreover, LUT increases the protein expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), activates the nuclear translocation of Nrf2, and greatly reduces the hydrogen peroxide (H2 O2 )-induced oxidative damage in intestinal epithelial cells. CONCLUSIONS LUT, a phyto-active component, protects against excessive intestinal motility and diarrhea by regulating the Nrf2 signaling pathway and effectively reduces oxidative stress damage in the colon.
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Affiliation(s)
- Yuan Xia
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Wei Tan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Fangting Yuan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Mengjuan Lin
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Hesheng Luo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
- Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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14
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Liang Q, Zhang Y, Liang J. Elevated Serum Total Bilirubin Might Indicate Poor Coronary Conditions for Unstable Angina Pectoris Patients beyond as a Cardiovascular Protector. Cardiovasc Ther 2023; 2023:5532917. [PMID: 37705934 PMCID: PMC10497366 DOI: 10.1155/2023/5532917] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/26/2023] [Accepted: 07/11/2023] [Indexed: 09/15/2023] Open
Abstract
Backgrounds Serum total bilirubin (STB) is recently more regarded as an antioxidant with vascular protective effects. However, we noticed that elevated STB appeared in unstable angina pectoris (UAP) patients with diffused coronary lesions. We aimed to explore STB's roles in UAP patients, which have not been reported by articles. Methods and Results 1120 UAP patients were retrospectively screened, and 296 patients were finally enrolled. They were grouped by Canadian Cardiovascular Society (CCS) angina grades. The synergy between PCI with TAXUS stent and cardiac surgery score (SYNTAX score) and corrected thrombolysis in myocardial infarction flow count (CTFC) were adopted to profile coronary features. The results showed that STB, mean platelet volume (MPV), hs-CRP, fasting blood glucose (FBG), red blood cell width (RDW), and CTFC elevated significantly in the CCS high-risk group. STB (B = 0.59, 95% CI: 0.39-0.74, P < 0.01) and MPV (B = 0.86, 95% CI: 0.42-1.31, P < 0.01) could indicate SYNTAX score changes for these patients. STB (≥21.7 μmol/L) could even indicate a coronary slow flow condition (AUC: 0.88, 95% CI: 0.84-0.93, P < 0.01). Moreover, UAP patients with elevated STB had a lower event-free survival rate by the Kaplan-Meier curve. STB ≥21.7 μmol/L could reflect a poor coronary flow status and indicate 1-year poor outcomes for these patients (HR: 2.01, 95% CI: 1.06-3.84, P < 0.01). Conclusion Elevated STB in UAP patients has a close relationship with changes in SYNTAX score. STB (over 21.7 μmol/L) could even indicate a coronary slow flow condition and poor outcomes for the UAP patients.
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Affiliation(s)
- Qi Liang
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta Rd, Shaanxi, Xi'an 710061, China
| | - Yongjian Zhang
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta Rd, Shaanxi, Xi'an 710061, China
| | - Jin Liang
- Department of Medical Insurance, Xi'an Affiliated Hospital of the Shaanxi University of Chinese Medicine, China
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15
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Kasprzak MP, Gryszczyńska B, Olasińska-Wiśniewska A, Urbanowicz T, Jawień A, Krasiński Z, Formanowicz D. Blb-NRF2-PON1 Cross-Talk in Abdominal Aortic Aneurysm Progression. Antioxidants (Basel) 2023; 12:1568. [PMID: 37627563 PMCID: PMC10451880 DOI: 10.3390/antiox12081568] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
The progression of an abdominal aortic aneurysm (AAA) is an important issue, especially as AAA is becoming more common, and potentially life-threatening. This study aimed to understand better the mechanisms underlying AAA progression. For this purpose, we have focused on assessing the selected biomarkers whose potentially common denominator is the NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor, that determines the selected antioxidant enzymes' activation. The study group consisted of 44 AAA male patients (71.41 ± 7.80 years aged). They were divided into three groups based on the aneurism diameter: group I (below 55 mm), group II (between 55 and 70 mm), and group III (over 70 mm). The laboratory analyses of PON1 (paraoxonase-1), NRF2, and HO-1 (heme oxygenase 1) were performed based on commercial ELISA tests; Blb (bilirubin) and hsCRP (high sensitivity C-reactive protein) were assessed during routine morphology examinations after admission to the hospital. Multiple linear regression showed that both bilirubin and NRF2 determined the PON1 concentration in the entire study group. The correlations between the examined parameters within the three studied groups suggest the capitulation of NRF2-dependent antioxidant mechanisms to pro-inflammatory processes. We showed that HO-1 and hsCRP may play a crucial role in the development of inflammation aneurism progression. Moreover, in patients with medium-sized aneurysms, antioxidant mechanisms were depressed, and inflammatory processes began to dominate, which may lead to uncontrolled growth aneurysm rupture. Our study is one of the first to indicate that the chronically activated antioxidant pathway using NRF2 may be a source of reduction stress.
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Affiliation(s)
- Magdalena P. Kasprzak
- Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, Rokietnicka 8, 60-806 Poznan, Poland
| | - Bogna Gryszczyńska
- Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, Rokietnicka 8, 60-806 Poznan, Poland
| | - Anna Olasińska-Wiśniewska
- Department of Cardiac Surgery and Transplantology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Tomasz Urbanowicz
- Department of Cardiac Surgery and Transplantology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Andrzej Jawień
- Department of Vascular and Endovascular Surgery Angiology and Phlebology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Zbigniew Krasiński
- Department of Vascular and Endovascular Surgery Angiology and Phlebology, Poznan University of Medical Sciences, 61-701 Poznan, Poland
| | - Dorota Formanowicz
- Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, Rokietnicka 8, 60-806 Poznan, Poland
- Department of Stem Cells and Regenerative Medicine, Institute of Natural Fibres and Medicinal Plants-National Research, Kolejowa 2, 62-064 Plewiska, Poland
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16
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Llido JP, Jayanti S, Tiribelli C, Gazzin S. Bilirubin and Redox Stress in Age-Related Brain Diseases. Antioxidants (Basel) 2023; 12:1525. [PMID: 37627520 PMCID: PMC10451892 DOI: 10.3390/antiox12081525] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 07/26/2023] [Accepted: 07/27/2023] [Indexed: 08/27/2023] Open
Abstract
Cellular redox status has a crucial role in brain physiology, as well as in pathologic conditions. Physiologic senescence, by dysregulating cellular redox homeostasis and decreasing antioxidant defenses, enhances the central nervous system's susceptibility to diseases. The reduction of free radical accumulation through lifestyle changes, and the supplementation of antioxidants as a prophylactic and therapeutic approach to increase brain health, are strongly suggested. Bilirubin is a powerful endogenous antioxidant, with more and more recognized roles as a biomarker of disease resistance, a predictor of all-cause mortality, and a molecule that may promote health in adults. The alteration of the expression and activity of the enzymes involved in bilirubin production, as well as an altered blood bilirubin level, are often reported in neurologic conditions and neurodegenerative diseases (together denoted NCDs) in aging. These changes may predict or contribute both positively and negatively to the diseases. Understanding the role of bilirubin in the onset and progression of NCDs will be functional to consider the benefits vs. the drawbacks and to hypothesize the best strategies for its manipulation for therapeutic purposes.
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Affiliation(s)
- John Paul Llido
- Liver Brain Unit “Rita Moretti”, Italian Liver Foundation, Bldg. Q, AREA Science Park, Basovizza, 34149 Trieste, Italy; (J.P.L.); or (S.J.); (S.G.)
- Department of Science and Technology, Philippine Council for Health Research and Development, Bicutan, Taguig City 1631, Philippines
- Department of Life Sciences, University of Trieste, 34139 Trieste, Italy
| | - Sri Jayanti
- Liver Brain Unit “Rita Moretti”, Italian Liver Foundation, Bldg. Q, AREA Science Park, Basovizza, 34149 Trieste, Italy; (J.P.L.); or (S.J.); (S.G.)
- Eijkman Research Centre for Molecular Biology, Research Organization for Health, National Research and Innovation Agency, Cibinong 16911, Indonesia
| | - Claudio Tiribelli
- Liver Brain Unit “Rita Moretti”, Italian Liver Foundation, Bldg. Q, AREA Science Park, Basovizza, 34149 Trieste, Italy; (J.P.L.); or (S.J.); (S.G.)
| | - Silvia Gazzin
- Liver Brain Unit “Rita Moretti”, Italian Liver Foundation, Bldg. Q, AREA Science Park, Basovizza, 34149 Trieste, Italy; (J.P.L.); or (S.J.); (S.G.)
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17
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Zhang L, Chen Y, Zhou Z, Wang Z, Fu L, Zhang L, Xu C, Loor JJ, Wang G, Zhang T, Dong X. Vitamin C injection improves antioxidant stress capacity through regulating blood metabolism in post-transit yak. Sci Rep 2023; 13:10233. [PMID: 37353533 PMCID: PMC10290073 DOI: 10.1038/s41598-023-36779-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 06/09/2023] [Indexed: 06/25/2023] Open
Abstract
Transportation stress is one of the most serious issues in the management of yak. Previous studies have demonstrated that transport stress is caused by a pro-oxidant state in the animal resulting from an imbalance between pro-oxidant and antioxidant status. In this context, vitamin C has the ability to regulate reactive oxygen species (ROS) synthesis and alleviate oxidative stress. Although this effect of vitamin C is useful in pigs, goats and cattle, the effect of vitamin C on the mitigation of transport stress in yaks is still unclear. The purpose of this study was to better assess the metabolic changes induced by the action of vitamin C in yaks under transportation stress, and whether these changes can influence antioxidant status. After the yaks arrived at the farm, control or baseline blood samples were collected immediately through the jugular vein (VC_CON). Then, 100 mg/kg VC was injected intramuscularly, and blood samples were collected on the 10th day before feeding in the morning (VC). Relative to the control group, the VC injection group had higher levels of VC. Compared with VC_CON, VC injection significantly (P < 0.05) decreased the blood concentrations of ALT, AST, T-Bil, D-Bil, IDBIL, UREA, CRP and LDH. However, VC injection led to greater (P < 0.05) AST/ALT and CREA-S relative to VC_CON. There was no difference (P > 0.05) in GGT, ALP, TBA, TP, ALBII, GLO, A/G, TC, TG, HDL-C, LDL-C, GLU and L-lactate between VC_CON and VC. The injection of VC led to greater (P < 0.05) concentration of MDA, but did not alter (P > 0.05) the serum concentrations of LPO and ROS. The injection of VC led to greater (P < 0.05) serum concentrations of POD, CAT and GSH-PX. In contrast, lower (P < 0.05) serum concentrations of SOD, POD and TPX were observed in VC relative to VC_CON. No difference (P > 0.05) in GSH, GSH-ST and GR was observed between VC_CON and VC. Compared with the control group, metabolomics using liquid chromatography tandem-mass spectrometry identified 156 differential metabolites with P < 0.05 and a variable importance in projection (VIP) score > 1.5 in the VC injection group. The injection of VC resulted in significant changes to the intracellular amino acid metabolism of glutathione, glutamate, cysteine, methionine, glycine, phenylalanine, tyrosine, tryptophan, alanine and aspartate. Overall, our study indicated that VC injections were able to modulate antioxidant levels by affecting metabolism to resist oxidative stress generated during transport.
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Affiliation(s)
- Li Zhang
- Chongqing Academy of Animal Sciences, Rongchang, 402460, China
| | - Yi Chen
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection; Chongqing Key Laboratory of Nano/Micro Composite Material and Device, College of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China
| | - Ziyao Zhou
- Chongqing Academy of Animal Sciences, Rongchang, 402460, China
- The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, China
| | - Zhiyu Wang
- The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, 611130, China
| | - Lin Fu
- Chongqing Academy of Animal Sciences, Rongchang, 402460, China
| | - Lijun Zhang
- Tibet Leowuqi Animal Husbandry Station, Changdu Tibet, 855600, China
| | - Changhui Xu
- Tibet Leowuqi Animal Husbandry Station, Changdu Tibet, 855600, China
| | - Juan J Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, 61801, USA
| | - Gaofu Wang
- Chongqing Academy of Animal Sciences, Rongchang, 402460, China
| | - Tao Zhang
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection; Chongqing Key Laboratory of Nano/Micro Composite Material and Device, College of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China.
| | - Xianwen Dong
- Chongqing Academy of Animal Sciences, Rongchang, 402460, China.
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18
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Mori S, Fujiwara-Tani R, Gyoten M, Nukaga S, Sasaki R, Ikemoto A, Ogata R, Kishi S, Fujii K, Kuniyasu H. Berberine Induces Combined Cell Death in Gastrointestinal Cell Lines. Int J Mol Sci 2023; 24:ijms24076588. [PMID: 37047563 PMCID: PMC10094831 DOI: 10.3390/ijms24076588] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/21/2023] [Accepted: 03/29/2023] [Indexed: 04/05/2023] Open
Abstract
Berberine (BBR) is a plant alkaloid that has various biological activities. The effects of BBR on gastrointestinal cancer (GIC) have also been investigated and anti-tumor effects such as induction of cell death have been reported. However, the mechanism of BBR-induced cell death has not been fully elucidated. To this end, we investigated the effects of BBR using three GIC cell lines. Our analyses revealed that BBR inhibited cell proliferation, invasion, sphere formation, and anticancer drug resistance in all of the cell lines. BBR also induced an increase in mitochondrial superoxide, lipid peroxide and Fe2+ levels, decreased mitochondrial membrane potential and respiration, decreased glutathione peroxidase 4 expression and glutathione and induced Parkin/PINK1-associated mitophagy. BBR, as well as rotenone, inhibited mitochondrial complex I and enhanced complex II, which were associated with autophagy, reactive oxidative species production, and cell death. Inhibition of complex II by malonate abrogated these changes. BBR-induced cell death was partially rescued by ferrostatin-1, deferoxamine, Z-VAD-FMK, and ATG5 knockdown. Furthermore, oral administration of BBR significantly reduced tumor weight and ascites in a syngeneic mouse peritoneal metastasis model using CT26 GIC cells. These findings suggest that BBR induced a combined type of cell death via complex I inhibition and autophagy. The marked anti-tumor and anti-stemness effects are expected to be useful as a new cell death-inducing agent for the treatment of GIC.
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Affiliation(s)
- Shiori Mori
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Momoko Gyoten
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Shota Nukaga
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Rika Sasaki
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Ayaka Ikemoto
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Ruiko Ogata
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Shingo Kishi
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Kiyomu Fujii
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Japan
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19
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Anti-Metastatic Activity of Tagitinin C from Tithonia diversifolia in a Xenograft Mouse Model of Hepatocellular Carcinoma. LIVERS 2022. [DOI: 10.3390/livers2040030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Sesquiterpenoid tagitinin C, present in Tithonia diversifolia leaves, has been known to have anti-hepatoma properties. Therefore, we investigated the anti-metastatic potential of tagitinin C in xenograft models of hepatocellular carcinoma (HCC). We isolated tagitinin C from a methanolic extract of the leaves of T. diversifolia. HepG-2 and Huh 7 hepatoma cells were treated with tagitinin C, and cell viability, migration, and matrix metalloproteinase (MPP) activity were assessed using the 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide assay, scratch migration assay, and MMP activity assay, respectively. We used magnetic resonance spectroscopy to determine the tumorigenicity of xenografts inoculated with Hep-G2 and Huh 7 cells. Tagitinin C was cytotoxic against Hep-G2 and Huh 7 cells, with IC50 values of 2.0 ± 0.1 µg/mL and 1.2 ± 0.1 µg/mL, respectively, and it showed an anti-metastatic effect in vitro. Additionally, MRS assays revealed that tagitinin C (15 g/mouse/day) reduced the tumorigenicity of Hep-G2 and Huh 7 cell xenografts. Tagitinin C demonstrated significant antitumor and anti-metastatic activity in the two human hepatoma cell lines. Tagitinin C might be used as an alternative or auxiliary therapy for the treatment of HCC, and its effect should be further investigated in clinical settings.
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20
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Jayanti S, Moretti R, Tiribelli C, Gazzin S. Bilirubin Prevents the TH + Dopaminergic Neuron Loss in a Parkinson's Disease Model by Acting on TNF-α. Int J Mol Sci 2022; 23:14276. [PMID: 36430754 PMCID: PMC9693357 DOI: 10.3390/ijms232214276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/09/2022] [Accepted: 11/16/2022] [Indexed: 11/19/2022] Open
Abstract
Parkinson's disease (PD), the fastest-growing movement disorder, is still challenged by the unavailability of disease-modifying therapy. Mildly elevated levels of unconjugated bilirubin (UCB, PubChem CID 5280352) have been shown to be protective against several extra-CNS diseases, and the effect is attributed to its well-known anti-oxidant and anti-inflammatory capability. We explored the neuroprotective effect of low concentrations of UCB (from 0.5 to 4 µM) in our PD model based on organotypic brain cultures of substantia nigra (OBCs-SN) challenged with a low dose of rotenone (Rot). UCB at 0.5 and 1 µM fully protects against the loss of TH+ (dopaminergic) neurons (DOPAn). The alteration in oxidative stress is involved in TH+ positive neuron demise induced by Rot, but is not the key player in UCB-conferred protection. On the contrary, inflammation, specifically tumor necrosis factor alpha (TNF-α), was found to be the key to UCB protection against DOPAn sufferance. Further work will be needed to introduce the use of UCB into clinical settings, but determining that TNF-α plays a key role in PD may be crucial in designing therapeutic options.
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Affiliation(s)
- Sri Jayanti
- The Liver-Brain Unit “Rita-Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy
- Faculty of Medicine, University of Hasanuddin, Makassar 90245, Indonesia
- Molecular Biomedicine Ph.D. Program, Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Rita Moretti
- Neurology Clinic, Department of Medical, Surgical and Health Sciences, University of Trieste, 34139 Trieste, Italy
| | - Claudio Tiribelli
- The Liver-Brain Unit “Rita-Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy
| | - Silvia Gazzin
- The Liver-Brain Unit “Rita-Moretti”, Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy
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21
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Protective effect of berberine in diabetic nephropathy: A systematic review and meta-analysis revealing the mechanism of action. Pharmacol Res 2022; 185:106481. [DOI: 10.1016/j.phrs.2022.106481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/25/2022] [Accepted: 09/29/2022] [Indexed: 12/09/2022]
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22
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Biliverdin modulates the long non-coding RNA H19/microRNA-181b-5p/endothelial cell specific molecule 1 axis to alleviate cerebral ischemia reperfusion injury. Biomed Pharmacother 2022; 153:113455. [PMID: 36076490 DOI: 10.1016/j.biopha.2022.113455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 07/11/2022] [Accepted: 07/20/2022] [Indexed: 11/17/2022] Open
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23
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Shao L, Chen S, Ma L. Secondary Brain Injury by Oxidative Stress After Cerebral Hemorrhage: Recent Advances. Front Cell Neurosci 2022; 16:853589. [PMID: 35813506 PMCID: PMC9262401 DOI: 10.3389/fncel.2022.853589] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 05/16/2022] [Indexed: 11/25/2022] Open
Abstract
Intracerebral hemorrhage (ICH) is a clinical syndrome in which blood accumulates in the brain parenchyma because of a nontraumatic rupture of a blood vessel. Because of its high morbidity and mortality rate and the lack of effective therapy, the treatment of ICH has become a hot research topic. Meanwhile, Oxidative stress is one of the main causes of secondary brain injury(SBI) after ICH. Therefore, there is a need for an in-depth study of oxidative stress after ICH. This review will discuss the pathway and effects of oxidative stress after ICH and its relationship with inflammation and autophagy, as well as the current antioxidant therapy for ICH with a view to deriving better therapeutic tools or targets for ICH.
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24
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Huang Z, Shi Y, Wang H, Chun C, Chen L, Wang K, Lu Z, Zhao Y, Li X. Protective Effects of Chitosan-Bilirubin Nanoparticles Against Ethanol-Induced Gastric Ulcers. Int J Nanomedicine 2022; 16:8235-8250. [PMID: 34992363 PMCID: PMC8709796 DOI: 10.2147/ijn.s344805] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 12/03/2021] [Indexed: 12/21/2022] Open
Abstract
Purpose Gastric ulcers (GU) are a disease of the gastrointestinal tract that can be caused by excessive alcohol consumption and heavy use of nonsteroidal anti-inflammatory drugs. GU manifests predominantly as pathological damage, such as extensive inflammatory erosion and superficial bleeding of the gastric mucosa. Oxidative stress damage and the inflammatory response are now considered important predisposing factors for GU, suggesting that antioxidant and anti-inflammatory drugs could be treatments for GU. Nanoparticle drug carriers offer many advantages over conventional drugs, such as improved drug efficiency, increased drug stability, and increased half-life. Methods We designed chitosan-bilirubin conjugate (CS-BR) nanoparticles and assessed the anti-inflammatory and antioxidant abilities of CS-BR in gastric epithelial cells. Then, we evaluated the intragastric retention time and the anti-ulcer effects of CS-BR in vivo. Results The in vitro data showed that CS-BR nanoparticles protect gastric epithelial cells against oxidative/inflammatory injury. The in vivo study demonstrated that CS-BR nanoparticles accumulate permanently in the stomach and exert powerful antioxidant and anti-inflammatory effects against GU. Conclusion This study applied bilirubin to the treatment of GU and confirmed that CS-BR nanoparticles are effective at alleviating acute GU in an experimental model. The findings provide innovative ideas for prophylaxis against or treatment of GU.
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Affiliation(s)
- Zhiwei Huang
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.,School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.,Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Yannan Shi
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Hengcai Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Changju Chun
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Longwang Chen
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.,Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou, 325035, People's Republic of China
| | - Kang Wang
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.,Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou, 325035, People's Republic of China
| | - Zhongqiu Lu
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.,Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou, 325035, People's Republic of China
| | - Yingzheng Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, People's Republic of China
| | - Xinze Li
- Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, People's Republic of China.,Wenzhou Key Laboratory of Emergency and Disaster Medicine, Wenzhou, 325035, People's Republic of China
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25
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Zhu Y, Ji H, Niu Z, Liu H, Wu X, Yang L, Wang Z, Chen J, Fang Y. Biochemical and Endocrine Parameters for the Discrimination and Calibration of Bipolar Disorder or Major Depressive Disorder. Front Psychiatry 2022; 13:875141. [PMID: 35795028 PMCID: PMC9251015 DOI: 10.3389/fpsyt.2022.875141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/13/2022] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Conventional biochemical indexes may have predictive values in clinical identification between bipolar disorder (BD) and major depressive disorder (MDD). METHODS This study included 2,470 (BD/MDD = 1,333/1,137) hospitalized patients in Shanghai as training sets and 2,143 (BD/MDD = 955/1,188) in Hangzhou as test sets. A total of 35 clinical biochemical indexes were tested, including blood cells, immuno-inflammatory factors, liver enzymes, glycemic and lipid parameters, and thyroid and gonadal hormones. A stepwise analysis of a multivariable logistic regression was performed to build a predictive model to identify BD and MDD. RESULTS Most of these biochemical indexes showed significant differences between BD and MDD groups, such as white blood cell (WBC) in the hematopoietic system, uric acid (UA) in immuno-inflammatory factors, direct bilirubin (DBIL) in liver function, lactic dehydrogenase (LDH) in enzymes, and fasting blood glucose (FBG) and low-density lipoprotein (LDL) in glucolipid metabolism (p-values < 0.05). With these predictors for discrimination, we observed the area under the curve (AUC) of the predictive model to distinguish between BD and MDD to be 0.772 among men and 0.793 among women, with the largest AUC of 0.848 in the luteal phase of women. The χ2 values of internal and external validation for male and female datasets were 2.651/10.264 and 10.873/6.822 (p-values < 0.05), respectively. The AUCs of the test sets were 0.696 for males and 0.707 for females. CONCLUSION Discrimination and calibration were satisfactory, with fair-to-good diagnostic accuracy and external calibration capability in the final prediction models. Female patients may have a higher differentiability with a conventional biochemical index than male patients. TRIAL REGISTRATION ICTRP NCT03949218. Registered on 20 November 2018. Retrospectively registered. https://www.clinicaltrials.gov/ct2/show/NCT03949218?id=NCT03949218&rank=1.
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Affiliation(s)
- Yuncheng Zhu
- Division of Mood Disorders, Shanghai Hongkou Mental Health Center, Shanghai, China.,Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haifeng Ji
- Division of Psychiatry, Shanghai Changning Mental Health Center, Shanghai, China
| | - Zhiang Niu
- Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongmei Liu
- Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaohui Wu
- Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lu Yang
- Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zuowei Wang
- Division of Mood Disorders, Shanghai Hongkou Mental Health Center, Shanghai, China
| | - Jun Chen
- Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiru Fang
- Clinical Research Center and Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, China.,Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
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26
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Ding M, Tang Z, Liu W, Shao T, Yuan P, Chen K, Zhou Y, Han J, Zhang J, Wang G. Burdock Fructooligosaccharide Attenuates High Glucose-Induced Apoptosis and Oxidative Stress Injury in Renal Tubular Epithelial Cells. Front Pharmacol 2021; 12:784187. [PMID: 34955856 PMCID: PMC8695902 DOI: 10.3389/fphar.2021.784187] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/26/2021] [Indexed: 12/17/2022] Open
Abstract
Hyperglycemia-induced apoptosis and oxidative stress injury are thought to play important roles in the pathogenesis of diabetic nephropathy (DN). Attenuating high glucose (HG)-induced renal tubular epithelial cell injury has become a potential approach to ameliorate DN. In recent years, burdock fructooligosaccharide (BFO), a water-soluble inulin-type fructooligosaccharide extracted from burdock root, has been shown to have a wide range of pharmacological activities, including antiviral, anti-inflammatory, and hypolipidemic activities. However, the role and mechanism of BFO in rat renal tubular epithelial cells (NRK-52E cells) have rarely been investigated. The present study investigated the protective effect of BFO on HG-induced damage in NRK-52E cells. BFO could protect NRK-52E cells against the reduced cell viability and significantly increased apoptosis rate induced by HG. These anti-oxidative stress effects of BFO were related to the significant inhibition of the production of reactive oxygen species, stabilization of mitochondrial membrane potential, and increased antioxidant (superoxide dismutase and catalase) activities. Furthermore, BFO increased the expression of Nrf2, HO-1, and Bcl-2 and decreased the expression of Bax. In conclusion, these findings suggest that BFO protects NRK-52E cells against HG-induced damage by inhibiting apoptosis and oxidative stress through the Nrf2/HO-1 signaling pathway.
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Affiliation(s)
- Mengru Ding
- Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Zhiyan Tang
- Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Wei Liu
- Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, China
| | - Taili Shao
- Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, China.,Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines, Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wuhu, China.,Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu, China
| | - Pingchuan Yuan
- Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, China.,Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines, Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wuhu, China.,Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu, China
| | - Kaoshan Chen
- Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, China.,Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines, Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wuhu, China.,Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu, China
| | - Yuyan Zhou
- Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, China.,Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines, Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wuhu, China.,Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu, China
| | - Jun Han
- Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, China.,Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines, Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wuhu, China.,Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu, China
| | - Jing Zhang
- Department of Nephrology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Guodong Wang
- Drug Research and Development Center, School of Pharmacy, Wannan Medical College, Wuhu, China.,Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines, Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wuhu, China.,Anhui Province Key Laboratory of Active Biological Macromolecules, Wuhu, China
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27
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Cortesi V, Manzoni F, Raffaeli G, Cavallaro G, Fattizzo B, Amelio GS, Gulden S, Amodeo I, Giannotta JA, Mosca F, Ghirardello S. Severe Presentation of Congenital Hemolytic Anemias in the Neonatal Age: Diagnostic and Therapeutic Issues. Diagnostics (Basel) 2021; 11:diagnostics11091549. [PMID: 34573891 PMCID: PMC8467765 DOI: 10.3390/diagnostics11091549] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 01/22/2023] Open
Abstract
Congenital hemolytic anemias (CHAs) are a group of diseases characterized by premature destruction of erythrocytes as a consequence of intrinsic red blood cells abnormalities. Suggestive features of CHAs are anemia and hemolysis, with high reticulocyte count, unconjugated hyperbilirubinemia, increased lactate dehydrogenase (LDH), and reduced haptoglobin. The peripheral blood smear can help the differential diagnosis. In this review, we discuss the clinical management of severe CHAs presenting early on in the neonatal period. Appropriate knowledge and a high index of suspicion are crucial for a timely differential diagnosis and management. Here, we provide an overview of the most common conditions, such as glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and hereditary spherocytosis. Although rare, congenital dyserythropoietic anemias are included as they may be suspected in early life, while hemoglobinopathies will not be discussed, as they usually manifest at a later age, when fetal hemoglobin (HbF) is replaced by the adult form (HbA).
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Affiliation(s)
- Valeria Cortesi
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (V.C.); (F.M.); (G.S.A.); (S.G.); (F.M.)
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (G.C.); (I.A.)
| | - Francesca Manzoni
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (V.C.); (F.M.); (G.S.A.); (S.G.); (F.M.)
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (G.C.); (I.A.)
| | - Genny Raffaeli
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (V.C.); (F.M.); (G.S.A.); (S.G.); (F.M.)
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (G.C.); (I.A.)
- Correspondence: ; Tel.: +39-(25)-5032234; Fax: +39-(25)-503221
| | - Giacomo Cavallaro
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (G.C.); (I.A.)
| | - Bruno Fattizzo
- UO Ematologia, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (B.F.); (J.A.G.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Giacomo Simeone Amelio
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (V.C.); (F.M.); (G.S.A.); (S.G.); (F.M.)
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (G.C.); (I.A.)
| | - Silvia Gulden
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (V.C.); (F.M.); (G.S.A.); (S.G.); (F.M.)
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (G.C.); (I.A.)
| | - Ilaria Amodeo
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (G.C.); (I.A.)
| | - Juri Alessandro Giannotta
- UO Ematologia, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (B.F.); (J.A.G.)
| | - Fabio Mosca
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; (V.C.); (F.M.); (G.S.A.); (S.G.); (F.M.)
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (G.C.); (I.A.)
| | - Stefano Ghirardello
- Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
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Shaikh SS, Bawazir A, Yahya BA. Phytochemical, Histochemical and in-vitro Antimicrobial Study of Various Solvent Extracts of Costus speciosus (J.Koenig) Sm. and Costus pictus D. Don. Turk J Pharm Sci 2021; 19:116-124. [DOI: 10.4274/tjps.galenos.2021.08683] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Bilirubin Oxidation End Products (BOXes) Induce Neuronal Oxidative Stress Involving the Nrf2 Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8869908. [PMID: 34373769 PMCID: PMC8349295 DOI: 10.1155/2021/8869908] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 06/04/2021] [Accepted: 06/22/2021] [Indexed: 11/25/2022]
Abstract
Delayed ischemic neurological deficit (DIND) is a severe complication after subarachnoid hemorrhage (SAH). Previous studies have suggested that bilirubin oxidation end products (BOXes) are probably associated with the DIND after SAH, but there is a lack of direct evidence yet even on cellular levels. In the present study, we aim to explore the potential role of BOXes and the involved mechanisms in neuronal function. We synthesized high-purity (>97%) BOX A and BOX B isomers. The pharmacokinetics showed they are permeable to the blood-brain barrier. Exposure of a moderate concentration (10 or 30 μM) of BOX A or BOX B to isolated primary cortical neurons increased the production of reactive oxygen species. In the human neuroblastoma SH-SY5Y cells, BOX A and BOX B decreased the mitochondrial membrane potential and enhanced nuclear accumulation of the protein Nrf2 implicated in oxidative injury repair. In addition, both chemicals increased the mRNA and protein expression levels of multiple antioxidant response genes including Hmox1, Gsta3, Blvrb, Gclm, and Srxn1, indicating that the antioxidant response element (ARE) transcriptional cascade driven by Nrf2 is activated. In conclusion, we demonstrated that primary cortical neurons and neuroblastoma cells undergo an adaptive response against BOX A- and BOX B-mediated oxidative stress by activation of multiple antioxidant responses, in part through the Nrf2 pathway, which provides in-depth insights into the pathophysiological mechanism of DIND after SAH or other neurological dysfunctions related to cerebral hemorrhage.
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Wu Q, Shang Y, Shen T, Liu F, Zhang W. Biochanin A protects SH-SY5Y cells against isoflurane-induced neurotoxicity by suppressing oxidative stress and apoptosis. Neurotoxicology 2021; 86:10-18. [PMID: 34216683 DOI: 10.1016/j.neuro.2021.06.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 04/14/2021] [Accepted: 06/28/2021] [Indexed: 12/28/2022]
Abstract
Biochanin A (BCA) is a natural organic O-methylated isoflavone with a variety of pharmacological effects, and has been reported to have neuroprotective properties. Here, we explored whether BCA protects neurocytes against isoflurane-induced neurotoxicity and investigated the underlying mechanism. Cell viability was tested by cell counting kit-8 and lactate dehydrogenase release assays. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase-3/7 activity assays. Superoxide dismutase (SOD) and catalase (CAT) activities and levels of glutathione (GSH) and malondialdehyde (MDA) were measured to assess oxidative stress. Expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO1) was determined by western blotting. Treatment with BCA significantly attenuated the reduction of cell viability induced by isoflurane in SH-SY5Y cells. In addition, BCA treatment reversed isoflurane-induced SOD and CAT activity reduction, GSH level decline and MDA level increase. Isoflurane-induced apoptosis was also attenuated by treatment with BCA. The increase in nuclear Nrf2, HO-1 and NQO1 expression induced by isoflurane was amplified by treatment with BCA. These inhibitory effects of BCA on isoflurane-induced oxidative stress, viability reduction and cell apoptosis were attenuated in Nrf2 knockdown SH-SY5Y cells. Our findings indicate that BCA protects SH-SY5Y cells against isoflurane-induced neurotoxicity via inducing the Nrf2/ARE pathway.
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Affiliation(s)
- Qiaoling Wu
- Department of Anesthesiology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China
| | - You Shang
- Department of Anesthesiology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China
| | - Tu Shen
- Department of Anesthesiology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China.
| | - Feifei Liu
- Department of Anesthesiology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China
| | - Wei Zhang
- Department of Anesthesiology, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121000, China
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Wei R, Zhao Y, Wang J, Yang X, Li S, Wang Y, Yang X, Fei J, Hao X, Zhao Y, Gui L, Ding X. Tagitinin C induces ferroptosis through PERK-Nrf2-HO-1 signaling pathway in colorectal cancer cells. Int J Biol Sci 2021; 17:2703-2717. [PMID: 34345202 PMCID: PMC8326123 DOI: 10.7150/ijbs.59404] [Citation(s) in RCA: 264] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 06/08/2021] [Indexed: 01/03/2023] Open
Abstract
Rationale: Colorectal cancer (CRC) is a common malignant tumor of the digestive system. However, the efficacy of surgery and chemotherapy is limited. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD) and plays a vital role in tumor suppression. Ferroptosis inducing agents have been studied extensively as a novel promising way to fight against therapy resistant cancers. The aim of this study is to investigate the mechanism of action of tagitinin C (TC), a natural product, as a novel ferroptosis inducer in tumor suppression. Methods: The response of CRC cells to tagitinin C was assessed by cell viability assay, clonogenic assay, transwell migration assay, cell cycle assay and apoptosis assay. Molecular approaches including Western blot, RNA sequencing, quantitative real-time PCR and immunofluorescence were employed as well. Results: Tagitinin C, a sesquiterpene lactone isolated from Tithonia diversifolia, inhibits the growth of colorectal cancer cells including HCT116 cells, and induced an oxidative cellular microenvironment resulting in ferroptosis of HCT116 cells. Tagitinin C-induced ferroptosis was accompanied with the attenuation of glutathione (GSH) levels and increased in lipid peroxidation. Mechanistically, tagitinin C induced endoplasmic reticulum (ER) stress and oxidative stress, thus activating nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). As a downstream gene (effector) of Nrf2, heme oxygenase-1 (HO-1) expression increased significantly with the treatment of tagitinin C. Upregulated HO-1 led to the increase in the labile iron pool, which promoted lipid peroxidation, meanwhile tagitinin C showed synergistic anti-tumor effect together with erastin. Conclusion: In summary, we provided the evidence that tagitinin C induces ferroptosis in colorectal cancer cells and has synergistic effect together with erastin. Mechanistically, tagitinin C induces ferroptosis through ER stress-mediated activation of PERK-Nrf2-HO-1 signaling pathway. Tagitinin C, identified as a novel ferroptosis inducer, may be effective chemosensitizer that can expand the efficacy and range of chemotherapeutic agents.
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Affiliation(s)
- Ruiran Wei
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, 550004, Guiyang, China
| | - Yueqin Zhao
- State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201, Kunming, China
| | - Juan Wang
- State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201, Kunming, China
| | - Xu Yang
- State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201, Kunming, China
| | - Shunlin Li
- State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201, Kunming, China
| | - Yinyuan Wang
- State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201, Kunming, China
| | - Xingzhi Yang
- State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201, Kunming, China
| | - Jimin Fei
- Yunnan Cancer Hospital & The Third Affiliated Hospital of Kunming Medical University, 650118, Kunming, China
| | - Xiaojiang Hao
- State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201, Kunming, China
| | - Yuhan Zhao
- State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201, Kunming, China
| | - Liming Gui
- Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, 550004, Guiyang, China
| | - Xiao Ding
- State Key Laboratory of Phytochemistry and Plant Resource in West China, Kunming Institute of Botany, Chinese Academy of Sciences, 650201, Kunming, China
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Jayanti S, Moretti R, Tiribelli C, Gazzin S. Bilirubin: A Promising Therapy for Parkinson's Disease. Int J Mol Sci 2021; 22:6223. [PMID: 34207581 PMCID: PMC8228391 DOI: 10.3390/ijms22126223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 05/28/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023] Open
Abstract
Following the increase in life expectancy, the prevalence of Parkinson's disease (PD) as the most common movement disorder is expected to rise. Despite the incredibly huge efforts in research to find the definitive biomarker, to date, the diagnosis of PD still relies mainly upon clinical symptoms. A wide range of treatments is available for PD, mainly alleviating the clinical symptoms. However, none of these current therapies can stop or even slow down the disease evolution. Hence, disease-modifying treatment is still a paramount unmet medical need. On the other side, bilirubin and its enzymatic machinery and precursors have offered potential benefits by targeting multiple mechanisms in chronic diseases, including PD. Nevertheless, only limited discussions are available in the context of neurological conditions, particularly in PD. Therefore, in this review, we profoundly discuss this topic to understand bilirubin's therapeutical potential in PD.
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Affiliation(s)
- Sri Jayanti
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (C.T.); (S.G.)
- Faculty of Medicine, University of Hasanuddin, Makassar 90245, Indonesia
- Molecular Biomedicine Ph.D. Program, University of Trieste, 34127 Trieste, Italy
| | - Rita Moretti
- Neurology Clinic, Department of Medical, Surgical, and Health Sciences, University of Trieste, 34139 Trieste, Italy;
| | - Claudio Tiribelli
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (C.T.); (S.G.)
| | - Silvia Gazzin
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (C.T.); (S.G.)
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Kawakami K, Moritani C, Hatanaka T, Suzaki E, Tsuboi S. Hepatoprotective Activity of Yellow Chinese Chive against Acetaminophen-Induced Acute Liver Injury via Nrf2 Signaling Pathway. J Nutr Sci Vitaminol (Tokyo) 2021; 66:357-363. [PMID: 32863309 DOI: 10.3177/jnsv.66.357] [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] [Indexed: 11/27/2022]
Abstract
Glutathione, the most abundant intracellular antioxidant, protects cells against reactive oxygen species induced oxidative stress and regulates intracellular redox status. We previously demonstrated that yellow Chinese chive (ki-nira) increased the intracellular glutathione levels. Acetaminophen (APAP) is a commonly used analgesic. However, an overdose of APAP causes severe hepatotoxicity via depletion of the hepatic glutathione. In this study, we investigated the hepatoprotective effects of yellow Chinese chive extract (YCE) against APAP-induced hepatotoxicity in mice. YCE (25 or 100 mg/kg) was administered once daily for 7 d, and then APAP (700 mg/kg) was injected at 6 h before the mice were sacrificed. APAP treatment markedly increased the serum biological markers of liver injury such as alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase. Pretreatment with YCE significantly prevented the increases in the serum levels of these enzymes. Histopathological evaluation of the livers also revealed that YCE prevented APAP-induced centrilobular necrosis. Pretreatment with YCE dose-dependently elevated glutathione levels, but the difference was not significant. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in APAP-induced hepatotoxicity by regulating the antioxidant defense system. Therefore, we investigated the expression of Nrf2 and its target antioxidant enzyme. YCE led to an increased expression of Nrf2 and its target antioxidant enzymes, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase (GPx), cystine uptake transporter (xCT), especially hemeoxygenase-1 (HO-1) in mice livers. These results suggest that YCE could induce HO-1 expression via activation of the Nrf2 antioxidant pathway, and protect against APAP-induced hepatotoxicity in mice.
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Affiliation(s)
| | | | - Tadashi Hatanaka
- Okayama Prefectural Technology Center for Agriculture, Forestry and Fisheries, Research Institute for Biological Sciences (RIBS)
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Khosrokhavar R, Dizaji R, Nazari F, Sharafi A, Tajkey J, Hosseini MJ. The role of PGC-1α and metabolic signaling pathway in kidney injury following chronic administration with 3-MCPD as a food processing contaminant. J Food Biochem 2021; 45:e13744. [PMID: 33913518 DOI: 10.1111/jfbc.13744] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/09/2021] [Accepted: 04/12/2021] [Indexed: 12/11/2022]
Abstract
3-Monochloropropane-1,2-diol (3-MCPD) as a byproduct of food processing and a carcinogenic agent has attracted much attention in the last decades. Kidney is the main target organ that is sensitive to the toxicity of 3-MCPD. Due to limited evidence about possible 3-MCPD toxicity, we design an investigation to determine the role of mitochondrial biogenesis following chronic oral administration of 3-MCPD (2, 4, 8 and 32 mg/kg) for 2 months in male C57 mice. The present study evaluated the affects of 3-MCPD in modulating metabolic signalling which is associated with Il-18, PGC-1α, Nrf-2 and Sir3 which are the major transcription factors. Our data confirms controversial behaviors after chronic exposure with 3-MCPD. Over expression of the PGC-1α and Sir3 and IL-18 were observed after exposure with 2,4 & 8 mg kg-1 day-1 of 3-MCPD. In front, PGC-1α down-regulation occurs at the highest dose (32 mg/kg) resulted in kidney injury. Based on the findings, PGC-1α plays an important role in the restoration of the mitochondrial function during the recovery from chronic kidney injury. We suggest that the PGC-1α can be consider as a therapeutic target in prevention and treatment of kidney injury after chronic exposure of 3-MCPD. PRACTICAL APPLICATIONS: 3-Monochloropropane-1, 2-diol (3-MCPD) existed in several foods, can induce nephrotoxicity, progressive nephropathy and renal tubule dilation following acute and chronic exposure. It revealed that 3-MCPD toxicity is related to metabolites which can cause oxidative stress and activation of cell death signaling. It seems that cytotoxicity of 3-MCPD has disruptive effect on kidney cells due to rise in ROS production and decrease in mitochondrial membrane permeability. These effects can lead to MPT pore opening, cytochrome c release and activation of programed cell death signaling pathway. Therefore, present study was investigated the role of PGC-1a and the metabolic signaling involved in 3-MCPD-induced nephrotoxicity for the first time. Our data revealed that up-regulation of mitochondrial biogenesis following chronic exposure with 3-MCPD accelerates recovery of mitochondrial and cellular function in kidney by deacetylation of histones, overexpression of transcription factors (PGC-1α, Nrf-2, and Sir3) and maintaining cellular homeostasis.
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Affiliation(s)
- Roya Khosrokhavar
- Food and Drug Laboratory Research Center, Food and Drug Administration, MOH&ME, Tehran, Iran
| | - Rana Dizaji
- Department of Food Safety and Hygiene, School of Public Health, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Firouzeh Nazari
- Food and Drug Administration, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Sharafi
- Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Javad Tajkey
- Department of Pharmacology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mir-Jamal Hosseini
- Zanjan Applied Pharmacology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.,Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran
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Rosa AC, Corsi D, Cavi N, Bruni N, Dosio F. Superoxide Dismutase Administration: A Review of Proposed Human Uses. Molecules 2021; 26:1844. [PMID: 33805942 PMCID: PMC8037464 DOI: 10.3390/molecules26071844] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 12/12/2022] Open
Abstract
Superoxide dismutases (SODs) are metalloenzymes that play a major role in antioxidant defense against oxidative stress in the body. SOD supplementation may therefore trigger the endogenous antioxidant machinery for the neutralization of free-radical excess and be used in a variety of pathological settings. This paper aimed to provide an extensive review of the possible uses of SODs in a range of pathological settings, as well as describe the current pitfalls and the delivery strategies that are in development to solve bioavailability issues. We carried out a PubMed query, using the keywords "SOD", "SOD mimetics", "SOD supplementation", which included papers published in the English language, between 2012 and 2020, on the potential therapeutic applications of SODs, including detoxification strategies. As highlighted in this paper, it can be argued that the generic antioxidant effects of SODs are beneficial under all tested conditions, from ocular and cardiovascular diseases to neurodegenerative disorders and metabolic diseases, including diabetes and its complications and obesity. However, it must be underlined that clinical evidence for its efficacy is limited and consequently, this efficacy is currently far from being demonstrated.
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Affiliation(s)
- Arianna Carolina Rosa
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (D.C.); (N.C.); (F.D.)
| | - Daniele Corsi
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (D.C.); (N.C.); (F.D.)
| | - Niccolò Cavi
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (D.C.); (N.C.); (F.D.)
| | - Natascia Bruni
- Istituto Farmaceutico Candioli, Strada Comunale di None, 1, 10092 Beinasco, Italy;
| | - Franco Dosio
- Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy; (D.C.); (N.C.); (F.D.)
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Zhao YZ, Huang ZW, Zhai YY, Shi Y, Du CC, Zhai J, Xu HL, Xiao J, Kou L, Yao Q. Polylysine-bilirubin conjugates maintain functional islets and promote M2 macrophage polarization. Acta Biomater 2021; 122:172-185. [PMID: 33387663 DOI: 10.1016/j.actbio.2020.12.047] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/26/2020] [Accepted: 12/18/2020] [Indexed: 12/19/2022]
Abstract
Macrophage polarization is one of the main factors contributing to the proinflammatory milieu of transplanted islets. It causes significant islet loss. Bilirubin exhibits protective effects during the islet transplantation process, but the mode of delivering drugs along with the islet graft has not yet been developed. In addition, it remains unclear whether bilirubin or its derivatives can modulate macrophage polarization during islet transplantation. Therefore, this study aimed to develop an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets for protection and to explore its macrophage modulation activities. In in vitro studies, the PLL-BR was shown to tightly adhere to the islet surface. It also exhibited enhanced cytoprotective effects against oxidative and inflammatory conditions by promoting M2-type macrophage polarization. In in vivo studies, the PLL-BR-protected islets successfully prolonged the euglycemia period in diabetic mice and accelerated the blood glucose clearance rate by maintaining the insulin secretion function. Compared to the untreated islets, the PLL-BR-encapsulated islets induced anti-inflammatory responses that were characterized by elevated levels of M2 macrophage markers and local vascularization. In conclusion, PLL-BR can be used as a tool for reprograming macrophage polarization while providing a more efficient immune protection for transplanted islets. STATEMENT OF SIGNIFICANCE: Macrophage polarization is one main factor that caused significant loss of transplanted islets. Bilirubin possesses protective effects toward pancreatic islet, but how to deliver the drug along with the islet graft has not yet been harnessed. More importantly, whether bilirubin or its derivatives could modulate macrophage polarization during the host rejections has also not been answered. In this study, we developed an ε-polylysine-bilirubin conjugate (PLL-BR) to encapsulate the islets and explore its role in macrophage modulation activities. PLL-BR could attach to the surface of islets and exerted high oxidation resistance and anti-inflammatory effect. For the first time, we demonstrate that bilirubin and its derivatives effectively promoted the M2-type macrophage polarization, and optimize the immune microenvironment for islets survival and function.
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Lee S, Seo YH, Song JH, Kim WJ, Lee JH, Moon BC, Ang MJ, Kim SH, Moon C, Lee J, Kim JS. Neuroprotective Effect of Protaetia brevitarsis seulensis' Water Extract on Trimethyltin-Induced Seizures and Hippocampal Neurodegeneration. Int J Mol Sci 2021; 22:ijms22020679. [PMID: 33445535 PMCID: PMC7827571 DOI: 10.3390/ijms22020679] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/25/2020] [Accepted: 01/08/2021] [Indexed: 12/22/2022] Open
Abstract
This study aimed to investigate whether the Protaetia brevitarsis seulensis (PB)’ water extract (PBWE) ameliorates trimethyltin (TMT)-induced seizures and hippocampal neurodegeneration. To investigate the potential neuroprotective effect of the PBWE in vitro, a lactate dehydrogenase (LDH) assay was conducted in TMT-treated primary cultures of mouse hippocampal neurons. In TMT-treated adult C57BL/6 mice, behavioral and histopathological changes were evaluated by seizure scoring and Fluoro-Jade C staining, respectively. In our in vitro assay, we observed that pretreating mice hippocampal neuron cultures with the PBWE reduced TMT-induced cytotoxicity, as indicated by the decreased LDH release. Furthermore, pretreatment with the PBWE alleviated seizures and hippocampal neurodegeneration in TMT-treated mice. The antioxidant activity of the PBWE increased in a dose-dependent manner; moreover, pretreatment with the PBWE mitigated the TMT-induced Nrf2 stimulation. In addition, six major compounds, including adenine, hypoxanthine, uridine, adenosine, inosine, and benzoic acid, were isolated from the PBWE, and among them, inosine and benzoic acid have been confirmed to have an essential antioxidative activity. In conclusion, the PBWE ameliorated TMT-induced toxicity in hippocampal neurons in both in vitro and in vivo assays, through a potential antioxidative effect. Our findings suggest that the PBWE may have pharmacotherapeutic potential in neurodegenerative diseases such as seizures or epilepsy.
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Affiliation(s)
- Sueun Lee
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju 58245, Korea; (S.L.); (Y.H.S.); (J.H.S.); (W.J.K.); (J.H.L.); (B.C.M.)
| | - Young Hye Seo
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju 58245, Korea; (S.L.); (Y.H.S.); (J.H.S.); (W.J.K.); (J.H.L.); (B.C.M.)
| | - Jun Ho Song
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju 58245, Korea; (S.L.); (Y.H.S.); (J.H.S.); (W.J.K.); (J.H.L.); (B.C.M.)
| | - Wook Jin Kim
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju 58245, Korea; (S.L.); (Y.H.S.); (J.H.S.); (W.J.K.); (J.H.L.); (B.C.M.)
| | - Ji Hye Lee
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju 58245, Korea; (S.L.); (Y.H.S.); (J.H.S.); (W.J.K.); (J.H.L.); (B.C.M.)
| | - Byeong Cheol Moon
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju 58245, Korea; (S.L.); (Y.H.S.); (J.H.S.); (W.J.K.); (J.H.L.); (B.C.M.)
| | - Mary Jasmin Ang
- College of Veterinary Medicine and BK21 Plus Project Team, Chonnam National University, Gwangju 61186, Korea; (M.J.A.); (S.H.K.); (C.M.)
| | - Sung Ho Kim
- College of Veterinary Medicine and BK21 Plus Project Team, Chonnam National University, Gwangju 61186, Korea; (M.J.A.); (S.H.K.); (C.M.)
| | - Changjong Moon
- College of Veterinary Medicine and BK21 Plus Project Team, Chonnam National University, Gwangju 61186, Korea; (M.J.A.); (S.H.K.); (C.M.)
| | - Jun Lee
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju 58245, Korea; (S.L.); (Y.H.S.); (J.H.S.); (W.J.K.); (J.H.L.); (B.C.M.)
- Correspondence: (J.L.); (J.S.K.); Tel.: +82-61-338-7129 (J.L.); +82-61-338-7111 (J.S.K.)
| | - Joong Sun Kim
- Herbal Medicine Resources Research Center, Korea Institute of Oriental Medicine, Naju 58245, Korea; (S.L.); (Y.H.S.); (J.H.S.); (W.J.K.); (J.H.L.); (B.C.M.)
- Correspondence: (J.L.); (J.S.K.); Tel.: +82-61-338-7129 (J.L.); +82-61-338-7111 (J.S.K.)
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Gazzin S, Dal Ben M, Montrone M, Jayanti S, Lorenzon A, Bramante A, Bottin C, Moretti R, Tiribelli C. Curcumin Prevents Cerebellar Hypoplasia and Restores the Behavior in Hyperbilirubinemic Gunn Rat by a Pleiotropic Effect on the Molecular Effectors of Brain Damage. Int J Mol Sci 2020; 22:299. [PMID: 33396688 PMCID: PMC7795686 DOI: 10.3390/ijms22010299] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/23/2020] [Accepted: 12/25/2020] [Indexed: 01/08/2023] Open
Abstract
Bilirubin toxicity to the central nervous system (CNS) is responsible for severe and permanent neurologic damage, resulting in hearing loss, cognitive, and movement impairment. Timely and effective management of severe neonatal hyperbilirubinemia by phototherapy or exchange transfusion is crucial for avoiding permanent neurological consequences, but these therapies are not always possible, particularly in low-income countries. To explore alternative options, we investigated a pharmaceutical approach focused on protecting the CNS from pigment toxicity, independently from serum bilirubin level. To this goal, we tested the ability of curcumin, a nutraceutical already used with relevant results in animal models as well as in clinics in other diseases, in the Gunn rat, the spontaneous model of neonatal hyperbilirubinemia. Curcumin treatment fully abolished the landmark cerebellar hypoplasia of Gunn rat, restoring the histological features, and reverting the behavioral abnormalities present in the hyperbilirubinemic rat. The protection was mediated by a multi-target action on the main bilirubin-induced pathological mechanism ongoing CNS damage (inflammation, redox imbalance, and glutamate neurotoxicity). If confirmed by independent studies, the result suggests the potential of curcumin as an alternative/complementary approach to bilirubin-induced brain damage in the clinical scenario.
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Affiliation(s)
- Silvia Gazzin
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (M.D.B.); (M.M.); (S.J.); (C.T.)
| | - Matteo Dal Ben
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (M.D.B.); (M.M.); (S.J.); (C.T.)
| | - Michele Montrone
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (M.D.B.); (M.M.); (S.J.); (C.T.)
| | - Sri Jayanti
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (M.D.B.); (M.M.); (S.J.); (C.T.)
| | - Andrea Lorenzon
- SPF Animal Facility, CBM Scarl, Bldg. Q2, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (A.L.); (A.B.)
| | - Alessandra Bramante
- SPF Animal Facility, CBM Scarl, Bldg. Q2, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (A.L.); (A.B.)
| | - Cristina Bottin
- Department of Medical Sciences, Ospedale di Cattinara, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy;
| | - Rita Moretti
- Neurology Clinic, Department of Medical, Surgical, and Health Sciences, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy;
| | - Claudio Tiribelli
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (M.D.B.); (M.M.); (S.J.); (C.T.)
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Fabrizio FP, Sparaneo A, Muscarella LA. NRF2 Regulation by Noncoding RNAs in Cancers: The Present Knowledge and the Way Forward. Cancers (Basel) 2020; 12:cancers12123621. [PMID: 33287295 PMCID: PMC7761714 DOI: 10.3390/cancers12123621] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/23/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The NRF2 pathway represents one of the most intriguing pathways that promotes chemo- and radioresistance of neoplastic cells. Increasing findings suggest that the NRF2 signaling can be modulated by multiple epigenetic factors such as noncoding RNAs, which influence a large number of oncogenic mechanisms, both at transcriptional and at post-transcriptional levels. As a consequence, the identification and characterization of specific noncoding RNAs as biomarkers related to oxidative stress may help to clarify the relationship between them and NRF2 signaling in the tumor context, in terms of positive and negative modulation, also referring to their intersection with other NRF2 crosstalking pathways. In this review, we summarize the recent updates on NRF2 network regulation by noncoding RNAs in tumors, thus paving the way toward the potential translational role of these small RNAs as key tumor biomarkers of neoplastic processes. Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is the key transcription factor triggered by oxidative stress that moves in cells of the antioxidant response element (ARE)-antioxidant gene network against reactive oxygen species (ROS) cellular damage. In tumors, the NRF2 pathway represents one of the most intriguing pathways that promotes chemo- and radioresistance of neoplastic cells and its activity is regulated by genetic and epigenetic mechanisms; some of these being poorly investigated in cancer. The noncoding RNA (ncRNA) network is governed by microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) and modulates a variety of cellular mechanisms linked to cancer onset and progression, both at transcriptional and post-transcriptional levels. In recent years, the scientific findings about the effects of ncRNA landscape variations on NRF2 machines are rapidly increasing and need to be continuously updated. Here, we review the latest knowledge about the link between NRF2 and ncRNA networks in cancer, thus focusing on their potential translational significance as key tumor biomarkers.
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Jayanti S, Vítek L, Tiribelli C, Gazzin S. The Role of Bilirubin and the Other "Yellow Players" in Neurodegenerative Diseases. Antioxidants (Basel) 2020; 9:900. [PMID: 32971784 PMCID: PMC7555389 DOI: 10.3390/antiox9090900] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/16/2020] [Accepted: 09/20/2020] [Indexed: 02/07/2023] Open
Abstract
Bilirubin is a yellow endogenous derivate of the heme catabolism. Since the 1980s, it has been recognized as one of the most potent antioxidants in nature, able to counteract 10,000× higher intracellular concentrations of H2O2. In the recent years, not only bilirubin, but also its precursor biliverdin, and the enzymes involved in their productions (namely heme oxygenase and biliverdin reductase; altogether the "yellow players"-YPs) have been recognized playing a protective role in diseases characterized by a chronic prooxidant status. Based on that, there is an ongoing effort in inducing their activity as a therapeutic option. Nevertheless, the understanding of their specific contributions to pathological conditions of the central nervous system (CNS) and their role in these diseases are limited. In this review, we will focus on the most recent evidence linking the role of the YPs specifically to neurodegenerative and neurological conditions. Both the protective, as well as potentially worsening effects of the YP's activity will be discussed.
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Affiliation(s)
- Sri Jayanti
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (S.J.); (C.T.)
- Faculty of Medicine, Universitas Hasanuddin, Makassar 90245, Indonesia
- Molecular Biomedicine Ph.D. Program, University of Trieste, 34127 Trieste, Italy
| | - Libor Vítek
- Institute of Medical Biochemistry and Laboratory Diagnostics, and 4th Department of Internal Medicine, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 12000 Prague, Czech Republic;
| | - Claudio Tiribelli
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (S.J.); (C.T.)
| | - Silvia Gazzin
- Fondazione Italiana Fegato-Onlus, Bldg. Q, AREA Science Park, ss14, Km 163.5, Basovizza, 34149 Trieste, Italy; (S.J.); (C.T.)
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Ayinde KS, Olaoba OT, Ibrahim B, Lei D, Lu Q, Yin X, Adelusi TI. AMPK allostery: A therapeutic target for the management/treatment of diabetic nephropathy. Life Sci 2020; 261:118455. [PMID: 32956662 DOI: 10.1016/j.lfs.2020.118455] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/08/2020] [Accepted: 09/13/2020] [Indexed: 12/11/2022]
Abstract
Diabetic nephropathy (DN) is a chronic complication of diabetes mellitus (DM) with approximately 30-40% of patients with DM developing nephropathy, and it is the leading cause of end-stage renal diseases and diabetic morbidity. The pathogenesis of DN is primarily associated with irregularities in the metabolism of glucose and lipid leading to hyperglycemia-induced oxidative stress, which has been a major target together with blood pressure regulation in the control of DN progression. However, the regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a highly conserved protein kinase for maintaining energy balance and cellular growth and repair has been implicated in the development of DM and its complications. Therefore, targeting AMPK pathway has been explored as a therapeutic strategy for the treatment of diabetes and its complication, although most of the mechanisms have not been fully elucidated. In this review, we discuss the structure of AMPK relevant to understanding its allosteric regulation and its role in the pathogenesis and progression of DN. We also identify therapeutic agents that modulate AMPK and its downstream targets with their specific mechanisms of action in the treatment of DN.
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Affiliation(s)
| | - Olamide Tosin Olaoba
- Laboratory of Functional and Structural Biochemistry, Federal University of Sao Carlos, Sao Carlos, SP, Brazil
| | - Boyenle Ibrahim
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Du Lei
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Qian Lu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Temitope Isaac Adelusi
- Computational Biology/Drug Discovery Laboratory, Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Nigeria; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
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Hansen TWR, Wong RJ, Stevenson DK. Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn. Physiol Rev 2020; 100:1291-1346. [PMID: 32401177 DOI: 10.1152/physrev.00004.2019] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.
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Affiliation(s)
- Thor W R Hansen
- Division of Paediatric and Adolescent Medicine, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; and Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - Ronald J Wong
- Division of Paediatric and Adolescent Medicine, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; and Department of Pediatrics, Stanford University School of Medicine, Stanford, California
| | - David K Stevenson
- Division of Paediatric and Adolescent Medicine, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; and Department of Pediatrics, Stanford University School of Medicine, Stanford, California
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Hayashida M, Hashioka S, Hayashida K, Miura S, Tsuchie K, Araki T, Izuhara M, Kanayama M, Otsuki K, Nagahama M, Jaya MA, Arauchi R, Wake R, Oh-Nishi A, Horiguchi J, Miyaoka T, Inagaki M, Morita E. Low Serum Levels of Fibroblast Growth Factor 2 in Gunn Rats: A Hyperbilirubinemia Animal Model of Schizophrenic Symptoms. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2020; 19:503-508. [PMID: 32729434 DOI: 10.2174/1871527319999200729153907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 06/06/2020] [Accepted: 06/07/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Fibroblast Growth Factor (FGF) 2 (also referred to as basic FGF) is a multifunctional growth factor that plays a pivotal role in the pro-survival, pro-migration and prodifferentiation of neurons. METHOD Because alterations in FGF2 levels are suggested to contribute to the pathogenesis of schizophrenia, we investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms. RESULTS The enzyme-linked immunosorbent assay showed that the serum levels of FGF2 in Gunn rats were 5.09 ± 0.236 pg/mL, while those in the normal strain Wistar rats, serum levels were 11.90 ± 2.142 pg/mL. The serum FGF2 levels in Gunn rats were significantly lower than those in Wistar rats. We also measured serum levels of Unconjugated Bilirubin (UCB) and found a significant negative correlation between UCB and FGF2 in terms of serum levels in all the rats studied. CONCLUSION Since it is known that FGF2 regulates dopaminergic neurons and have antineuroinflammatory effects, our finding suggests that low FGF2 levels may contribute to the pathogenesis of schizophrenia, in which imbalanced dopamin-ergic signaling and neuroinflammation are supposed to play certain roles.
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Affiliation(s)
- Maiko Hayashida
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Sadayuki Hashioka
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Kenji Hayashida
- Division of Plastic Surgery, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Shoko Miura
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Keiko Tsuchie
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Tomoko Araki
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Muneto Izuhara
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Misako Kanayama
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Koji Otsuki
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Michiharu Nagahama
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Muhammad Alim Jaya
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Ryosuke Arauchi
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Rei Wake
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Arata Oh-Nishi
- Department of Immuno-Neuropsychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Jun Horiguchi
- Department of Immuno-Neuropsychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Tsuyoshi Miyaoka
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Masatoshi Inagaki
- Department of Psychiatry, Faculty of Medicine, Shimane University, Matsue, Japan
| | - Eishin Morita
- Department of Dermatology, Faculty of Medicine, Shimane University, Matsue, Japan
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Zhang X, Wang L, Li H, Zhang L, Zheng X, Cheng W. Crosstalk between noncoding RNAs and ferroptosis: new dawn for overcoming cancer progression. Cell Death Dis 2020; 11:580. [PMID: 32709863 PMCID: PMC7381619 DOI: 10.1038/s41419-020-02772-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023]
Abstract
Cancer progression including proliferation, metastasis, and chemoresistance has become a serious hindrance to cancer therapy. This phenomenon mainly derives from the innate insensitive or acquired resistance of cancer cells to apoptosis. Ferroptosis is a newly discovered mechanism of programmed cell death characterized by peroxidation of the lipid membrane induced by reactive oxygen species. Ferroptosis has been confirmed to eliminate cancer cells in an apoptosis-independent manner, however, the specific regulatory mechanism of ferroptosis is still unknown. The use of ferroptosis for overcoming cancer progression is limited. Noncoding RNAs have been found to play an important roles in cancer. They regulate gene expression to affect biological processes of cancer cells such as proliferation, cell cycle, and cell death. Thus far, the functions of ncRNAs in ferroptosis of cancer cells have been examined, and the specific mechanisms by which noncoding RNAs regulate ferroptosis have been partially discovered. However, there is no summary of ferroptosis associated noncoding RNAs and their functions in different cancer types. In this review, we discuss the roles of ferroptosis-associated noncoding RNAs in detail. Moreover, future work regarding the interaction between noncoding RNAs and ferroptosis is proposed, the possible obstacles are predicted and associated solutions are put forward. This review will deepen our understanding of the relationship between noncoding RNAs and ferroptosis, and provide new insights in targeting noncoding RNAs in ferroptosis associated therapeutic strategies.
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Affiliation(s)
- Xuefei Zhang
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China
| | - Lingling Wang
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China
| | - Haixia Li
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China
| | - Lei Zhang
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China.
| | - Xiulan Zheng
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China.
| | - Wen Cheng
- Department of Ultrasonography, Harbin Medical University Cancer Hospital, 150 Haping Road, 150040, Harbin, China.
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Zheng F, Gonçalves FM, Abiko Y, Li H, Kumagai Y, Aschner M. Redox toxicology of environmental chemicals causing oxidative stress. Redox Biol 2020; 34:101475. [PMID: 32336668 PMCID: PMC7327986 DOI: 10.1016/j.redox.2020.101475] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 02/18/2020] [Accepted: 02/20/2020] [Indexed: 12/17/2022] Open
Abstract
Living organisms are surrounded with heavy metals such as methylmercury, manganese, cobalt, cadmium, arsenic, as well as pesticides such as deltamethrin and paraquat, or atmospheric pollutants such as quinone. Extensive studies have demonstrated a strong link between environmental pollutants and human health. Redox toxicity is proposed as one of the main mechanisms of chemical-induced pathology in humans. Acting as both a sensor of oxidative stress and a positive regulator of antioxidants, the nuclear factor erythroid 2-related factor 2 (NRF2) has attracted recent attention. However, the role NRF2 plays in environmental pollutant-induced toxicity has not been systematically addressed. Here, we characterize NRF2 function in response to various pollutants, such as metals, pesticides and atmospheric quinones. NRF2 related signaling pathways and epigenetic regulations are also reviewed.
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Affiliation(s)
- Fuli Zheng
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, 350122, China; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 209, 1300 Morris Park Avenue, Bronx, NY, 10461, United States.
| | - Filipe Marques Gonçalves
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 209, 1300 Morris Park Avenue, Bronx, NY, 10461, United States
| | - Yumi Abiko
- Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan
| | - Huangyuan Li
- Department of Preventive Medicine, School of Public Health, Fujian Medical University, Fuzhou, Fujian, 350122, China.
| | - Yoshito Kumagai
- Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, 305-8575, Japan.
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 209, 1300 Morris Park Avenue, Bronx, NY, 10461, United States.
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Hang H, Wang L, Wu G, Ren S. Up-regulation of PPARγ, Nrf2 and HO-1 in microglia activated by thrombin. BRAIN HEMORRHAGES 2020. [DOI: 10.1016/j.hest.2020.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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Tan N, Hu S, Hu Z, Wu Z, Wang B. Quantitative proteomic characterization of microvesicles/exosomes from the cerebrospinal fluid of patients with acute bilirubin encephalopathy. Mol Med Rep 2020; 22:1257-1268. [PMID: 32468033 PMCID: PMC7339682 DOI: 10.3892/mmr.2020.11194] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 05/06/2020] [Indexed: 01/10/2023] Open
Abstract
Severe hyperbilirubinemia causes neurotoxicity and may lead to acute bilirubin encephalopathy (ABE) during the critical period of central nervous system development. The aim of the present study was to identify differentially expressed proteins (DEPs) in microvesicles/exosomes (MV/E) isolated from the cerebrospinal fluid (CSF) of patients with ABE. Co-precipitation was used to isolate the MV/E from the CSF of patients with ABE and age-matched controls. Isobaric tagging for relative and absolute quantification-based proteomic technology combined with liquid chromatography/tandem mass spectrometry was used to identify DEPs in the MV/E. Bioinformatics analysis was subsequently performed to investigate Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes enriched signaling pathways of these DEPs. A total of four proteins were selected for further validation via western blotting. A total of 291 dysregulated proteins were identified by comparing the patients with ABE with the controls. Bioinformatics analysis indicated the involvement of immune-inflammation-associated cellular processes and signaling pathways in the pathophysiology of ABE. In conclusion, the present study identified the proteomic profile of MV/E isolated from the CSF of patients with ABE. These results may provide an improved understanding of the pathogenesis of ABE and may help to identify early diagnostic biomarkers and therapeutic targets.
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Affiliation(s)
- Ning Tan
- Department of Pediatrics, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Shuiwang Hu
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhen Hu
- National and Local Joint Engineering Laboratory for High‑through Molecular Diagnosis Technology, Translational Medicine Institute, Collaborative Research Center for Post‑doctoral Mobile Stations of Central South University, Affiliated The First People's Hospital of Chenzhou, Southern Medical University, University of South China, Chenzhou, Hunan 423000, P.R. China
| | - Zhouli Wu
- Department of Neonatology, Affiliated The First People's Hospital of Chenzhou, Southern Medical University, University of South China, Chenzhou, Hunan 423000, P.R. China
| | - Bin Wang
- Department of Pediatrics, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
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Huang B, Liu J, Fu S, Zhang Y, Li Y, He D, Ran X, Yan X, Du J, Meng T, Gao X, Liu D. α-Cyperone Attenuates H 2O 2-Induced Oxidative Stress and Apoptosis in SH-SY5Y Cells via Activation of Nrf2. Front Pharmacol 2020; 11:281. [PMID: 32322198 PMCID: PMC7156596 DOI: 10.3389/fphar.2020.00281] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 02/27/2020] [Indexed: 01/04/2023] Open
Abstract
α-Cyperone, extracted from Cyperus rotundus, has been reported to inhibit microglia-mediated neuroinflammation. Oxidative stress and apoptosis play crucial roles in the course of Parkinson’s disease (PD). PD is a common neurodegenerative disease characterized by selective death of dopaminergic neurons. This study was designed to investigate the neuroprotective effects of α-cyperone against hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis in dopaminergic neuronal SH-SY5Y cells. Neurotoxicity was assessed by MTT assay and the measurement of lactic dehydrogenase (LDH) release. The level of reactive oxygen species (ROS) was measured by dichlorodihydrofluorescin diacetate (DCFH-DA) staining. The apoptosis of SH-SY5Y cells was evaluated by annexin-V-FITC staining. The translocation of NF-E2-related factor 2 (Nrf2) was determined by western blot and immunofluorescence staining. Western blot analysis was conducted to determine the expression level of cleaved-caspase-3, the pro-apoptotic factor Bax, and the anti-apoptotic factor, Bcl-2. The results showed that α-cyperone substantially decreased H2O2-induced death, release of LDH, and the production of ROS in SH-SY5Y cells. In addition, we found that α-cyperone attenuated H2O2-induced cellular apoptosis. Moreover, α-cyperone remarkably reduced the expression of cleaved-caspase-3 and Bax, and upregulated Bcl-2. Furthermore, α-cyperone enhanced the nuclear translocation of Nrf2. Pretreatment with brusatol (BT, an Nrf2 inhibitor) attenuated α-cyperone-mediated suppression of ROS, cleaved-caspase-3, and Bax, as well as α-cyperone-induced Bcl-2 upregulation in H2O2-treated SH-SY5Y cells. α-cyperone neuroprotection required Nrf2 activation. In conclusion, α-cyperone attenuated H2O2-induced oxidative stress and apoptosis in SH-SY5Y cells via the activation of Nrf2, suggesting the potential of this compound in the prevention and treatment of PD.
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Affiliation(s)
- Bingxu Huang
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Juxiong Liu
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Shoupeng Fu
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Yufei Zhang
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Yuhang Li
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Dewei He
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Xin Ran
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Xuan Yan
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Jian Du
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Tianyu Meng
- Department of Food Quality and Safety, College of Food Science and Engineering, Jilin University, Changchun, China
| | - Xiyu Gao
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
| | - Dianfeng Liu
- Department of Basic Veterinary Medicine, College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China
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Hang H, Wang LK, Ren SY, Song AJ, Wu GF. Activating PPARγ Increases NQO1 and γ-GCS Expression via Nrf2 in Thrombin-activated Microglia. Curr Med Sci 2020; 40:55-62. [PMID: 32166665 DOI: 10.1007/s11596-020-2146-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 10/09/2019] [Indexed: 01/24/2023]
Abstract
The present study aimed to explore the molecular mechanisms underlying the increase of nicotinamide adenine dinucleotide phosphate:quinine oxidoreductase 1 (NQO1) and γ-glutamylcysteine synthetase (γ-GCS) in brain tissues after intracerebral hemorrhage (ICH). The microglial cells obtained from newborn rats were cultured and then randomly divided into the normal control group (NC group), model control group (MC group), rosiglitazone (RSG) intervention group (RSG group), retinoic-acid intervention group (RSG+RA group), and sulforaphane group (RSG+SF group). The expression levels of NQO1, γ-GCS, and nuclear factor E2-related factor 2 (Nrf2) were measured by real-time polymerase chain reaction (RT-PCR) and Western blotting, respectively. The results showed that the levels of NQO1, γ-GCS and Nrf2 were significantly increased in the MC group and the RSG group as compared with those in the NC group (P<0.01). They were found to be markedly decreased in the RSG+RA group and increased in the RSG+SF group when compared with those in the MC group or the RSG group (P<0.01). The RSG+SF group displayed the highest levels of NQO1, γ-GCS, and Nrf2 among the five groups. In conclusion, a medium dose of RSG increased the anti-oxidative ability of thrombin-activated microglia by increasing the expression of NQO1 and γ-GCS. The molecular mechanisms underlying the increase of NQO1 and γ-GCS in thrombin-activated microglia may be associated with the activation of Nrf2.
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Affiliation(s)
- Hang Hang
- Department of Emergency, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Li-Kun Wang
- Department of Emergency, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
| | - Si-Ying Ren
- Department of Emergency, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - An-Jun Song
- Department of Emergency, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Guo-Feng Wu
- Department of Emergency, The Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
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Bilirubin disrupts calcium homeostasis in neonatal hippocampal neurons: a new pathway of neurotoxicity. Arch Toxicol 2020; 94:845-855. [DOI: 10.1007/s00204-020-02659-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 02/03/2020] [Indexed: 12/22/2022]
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