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      Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke

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          Abstract

          Abstract

          Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury. Low-density lipoprotein receptor, a classic cholesterol regulatory receptor, has been found to inhibit NLR family pyrin domain containing protein 3 (NLRP3) inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease. However, little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke. To address this issue in the present study, we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models. First, we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis. We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen–glucose deprivation/reoxygenation. Second, we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus. Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype. Finally, we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen–glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin, an NLRP3 agonist, restored the neurotoxic astrocyte phenotype. These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

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          Neurotoxic reactive astrocytes are induced by activated microglia

          A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
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            Animal models of necrotizing enterocolitis: review of the literature and state of the art

            Abstract Necrotizing enterocolitis (NEC) remains the leading cause of gastrointestinal surgical emergency in preterm neonates. Over the last five decades, a variety of experimental models have been developed to study the pathophysiology of this disease and to test the effectiveness of novel therapeutic strategies. Experimental NEC is mainly modeled in neonatal rats, mice and piglets. In this review, we focus on these experimental models and discuss the major advantages and disadvantages of each. We also briefly discuss other models that are not as widely used but have contributed to our current knowledge of NEC.
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              The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research

              Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the “ARRIVE Essential 10,” which constitutes the minimum requirement, and the “Recommended Set,” which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.
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                Author and article information

                Journal
                Neural Regen Res
                Neural Regen Res
                NRR
                Neural Regen Res
                Neural Regeneration Research
                Wolters Kluwer - Medknow (India )
                1673-5374
                1876-7958
                February 2025
                16 April 2024
                : 20
                : 2
                : 491-502
                Affiliations
                [1 ]Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
                [2 ]Department of Neurology, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu Province, China
                Author notes
                [* ] Correspondence to: Hongdong Zhao, redeastzh@ 123456126.com ; Ye Hong, hongye19920920@ 123456163.com .
                [#]

                Both authors contributed equally to this work.

                Author contributions: Conceptualization: SF, JL, HZ and YH; data curation: TL and SH; formal analysis: JL, TL, and XC; funding acquisition: YH; methodology: SF, JL, and SL; supervision: HZ and YH; writing – original draft: SF and JL; writing – review & editing: JZ, HZ, and YH. All authors have read and agreed to the published version of the manuscript.

                Author information
                https://orcid.org/0009-0003-8630-2586
                https://orcid.org/0000-0001-8271-1487
                Article
                NRR-20-491
                10.4103/NRR.NRR-D-23-01263
                11317962
                38819062
                02169497-ede6-4e0a-bdc7-9b46bfe4c00d
                Copyright: © 2025 Neural Regeneration Research

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                : 28 July 2023
                : 26 December 2023
                : 23 February 2024
                Funding
                Funding: This work was supported by the National Natural Science Foundation of China, No. 82201460 (to YH); Nanjing Medical University Science and Technology Development Fund, No. NMUB20210202 (to YH).
                Categories
                Research Article

                inflammation,ischemia/reperfusion injury,ischemic stroke,low-density lipoprotein receptor,neuroprotective astrocytes,neurotoxic astrocytes,nlrp3 inflammasome,polarization

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