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      Several Alkaloids in Chinese Herbal Medicine Exert Protection in Acute Kidney Injury: Focus on Mechanism and Target Analysis

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          Abstract

          Objectives

          Acute kidney injury (AKI) is a loose set of kidney diseases accompanied by a variety of syndromes, which is a serious threat to human life and health. Some alkaloids are derived from various Chinese herbs have been widely concerned in the improvement of AKI. This review provides the research progress of alkaloids in AKI experimental models and discusses the related molecular mechanisms. Key Findings. Alkaloids can protect AKI through various mechanisms including antioxidant stress, improvement of mitochondrial damage, reduction of cell death, induction of autophagy, and inhibition of inflammation. These mechanisms are mainly related to the activation of Nrf2/HO-1 signaling pathway, inhibition of ferroptosis and apoptosis, regulation of PINK1/Parkin pathway, inhibition of TLR4/NF- κB pathway and NLRP3 inflammatory bodies, upregulation of Klotho protein level and so on. In addition, there are a few alkaloids that have certain toxicity on the kidney.

          Conclusion

          Alkaloids have been shown to significantly improve AKI, but only in pharmacological studies. This paper summarizes the main experimental models currently used in AKI research and describes some representative alkaloids based on recent research. Their potential roles in the prevention and treatment of AKI through different mechanisms are highlighted.

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          Most cited references120

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          Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

          Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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            Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice.

            Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.
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              The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation

              The NLRP3 inflammasome is a critical component of the innate immune system that mediates caspase-1 activation and the secretion of proinflammatory cytokines IL-1β/IL-18 in response to microbial infection and cellular damage. However, the aberrant activation of the NLRP3 inflammasome has been linked with several inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, and atherosclerosis. The NLRP3 inflammasome is activated by diverse stimuli, and multiple molecular and cellular events, including ionic flux, mitochondrial dysfunction, and the production of reactive oxygen species, and lysosomal damage have been shown to trigger its activation. How NLRP3 responds to those signaling events and initiates the assembly of the NLRP3 inflammasome is not fully understood. In this review, we summarize our current understanding of the mechanisms of NLRP3 inflammasome activation by multiple signaling events, and its regulation by post-translational modifications and interacting partners of NLRP3.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2022
                13 May 2022
                : 2022
                : 2427802
                Affiliations
                1State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China
                2Department of Pharmacology, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China
                3College of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
                Author notes

                Academic Editor: Liang-Jun Yan

                Author information
                https://orcid.org/0000-0003-1174-3865
                https://orcid.org/0000-0001-8342-1043
                https://orcid.org/0000-0002-8349-2930
                https://orcid.org/0000-0002-3943-3765
                https://orcid.org/0000-0002-8664-6499
                https://orcid.org/0000-0003-2090-4288
                Article
                10.1155/2022/2427802
                9122709
                35602100
                c92e734e-3afd-4585-a521-8b3a57e115e0
                Copyright © 2022 Yixin Rui et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 December 2021
                : 3 April 2022
                : 21 April 2022
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 82074094
                Award ID: 81503277
                Funded by: Department of Science and Technology of Sichuan Province
                Award ID: 2020YJ0388
                Funded by: Chengdu University of Traditional Chinese Medicine
                Award ID: 2020XSGG002
                Award ID: CDTD2018014
                Award ID: QNXZ2018022
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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