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      The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis

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          Abstract

          Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, which highlights the role of antioxidants in targeting mitochondrial function. However, low bioavailability and high dosage of KA leading to unavoidable side effects limits clinical transformation. The mechanisms of KA with poor bioavailability largely unexplored, hindering development of the efficient strategies to maximizing the medicinal effects of KA. Here, we engineered a novel thioketals (TK)-modified based on DSPE-PEG2000 liposomal codelivery system for improving bioavailability and avoiding side effects (denotes as DSPE-TK-PEG2000-KA, DTM@KA NPs). We demonstrated that the liposome exerts profound impacts on damaging intracellular redox homeostasis by reducing GSH depletion and activating Nrf2, which synergizes with KA to reinforce the inhibition of inadequate fission, excessive mitochondrial fusion and impaired mitophagy resulting in inflammation and apoptosis; and then, the restored mitochondrial homeostasis strengthens ATP supply for PAC renovation and homeostasis. Interestingly, TK bond was proved as the main functional structure to improve the above efficacy of KA compared with the absence of TK bond. Most importantly, DTM@KA NPs obviously suppresses PAC death with negligible side effects in vitro and vivo. Mechanismly, DTM@KA NPs facilitated STAT6-regulated mitochondrial precursor proteins transport via interacting with TOM20 to further promote Drp1-dependent fission and Pink1/Parkin-regulated mitophagy with enhanced lysosomal degradation for removing damaged mitochondria in PAC and then reduce inflammation and apoptosis. Generally, DTM@KA NPs synergistically improved mitochondrial homeostasis, redox homeostasis, energy metabolism and inflammation response via regulating TOM20-STAT6-Drp1 signaling and promoting mitophagy in SAP. Consequently, such a TCM’s active ingredients-based nanomedicine strategy is be expected to be an innovative approach for SAP therapy.

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          The online version contains supplementary material available at 10.1186/s12951-024-02439-y.

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          Most cited references34

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          Ferroptosis: machinery and regulation

          Ferroptosis is an iron-dependent, non-apoptotic form of regulated cell death caused by lipid peroxidation, which is controlled by integrated oxidation and antioxidant systems. The iron-containing enzyme lipoxygenase is the main promoter of ferroptosis by producing lipid hydroperoxides, and its function relies on the activation of ACSL4-dependent lipid biosynthesis. In contrast, the selenium-containing enzyme GPX4 is currently recognized as a central repressor of ferroptosis, and its activity depends on glutathione produced from the activation of the cystine-glutamate antiporter SLC7A11. Many metabolic (especially involving iron, lipids, and amino acids) and degradation pathways (macroautophagy/autophagy and the ubiquitin-proteasome system) orchestrate the complex ferroptotic response through direct or indirect regulation of iron accumulation or lipid peroxidation. Although the detailed mechanism of membrane injury during ferroptosis remains a mystery, ESCRT III-mediated plasma membrane repair can make cells resistant to ferroptosis. Here, we review the recent rapid progress in understanding the molecular mechanisms of ferroptosis and focus on the epigenetic, transcriptional, and posttranslational regulation of this process.Abbreviations: 2ME: beta-mercaptoethanol; α-KG: α-ketoglutarate; ccRCC: clear cell renal cell carcinoma; EMT: epithelial-mesenchymal transition; FAO: fatty acid beta-oxidation; GSH: glutathione; MEFs: mouse embryonic fibroblasts; MUFAs: monounsaturated fatty acids; NO: nitric oxide; NOX: NADPH oxidase; PPP: pentose phosphate pathway; PUFA: polyunsaturated fatty acid; RCD: regulated cell death; RNS: reactive nitrogen species; ROS: reactive oxygen species; RTAs: radical-trapping antioxidants; UPS: ubiquitin-proteasome system; UTR: untranslated region.
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            Organ Failure Due to Systemic Injury in Acute Pancreatitis

            Acute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure which is seen in approximately 20% of all cases of acute pancreatitis and defines ‘severe acute pancreatitis’. Organ failure typically develops early in the course of acute pancreatitis, but may also develop later due to infected pancreatic necrosis induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.
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              Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models.

              Little is known about the signaling pathways that initiate and promote acute pancreatitis (AP). The pathogenesis of AP has been associated with abnormal increases in cytosolic Ca2+, mitochondrial dysfunction, impaired autophagy, and endoplasmic reticulum (ER) stress. We analyzed the mechanisms of these dysfunctions and their relationships, and how these contribute to development of AP in mice and rats.
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                Author and article information

                Contributors
                zhigangwang@cqmu.edu.cn
                hejun328@126.com
                17882247002@163.com
                Journal
                J Nanobiotechnology
                J Nanobiotechnology
                Journal of Nanobiotechnology
                BioMed Central (London )
                1477-3155
                3 April 2024
                3 April 2024
                2024
                : 22
                : 148
                Affiliations
                [1 ]Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, ( https://ror.org/00r67fz39) No 76, Linjiang road, Chongqing, China
                [2 ]Precision Medicine Center, The Second Affiliated Hospital of Chongqing Medical University, ( https://ror.org/00r67fz39) Chongqing, China
                [3 ]Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, ( https://ror.org/00r67fz39) Chongqing, China
                [4 ]The First Affiliated Hospital of Chengdu Medical College, ( https://ror.org/03jckbw05) No.278, Baoguang Avenue, Xindu District, Chengdu, 610500 Sichuan China
                [5 ]Institute of Burn Research, State Key Lab of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Southwest Hospital, Third Military Medical University (Army Medical University), ( https://ror.org/02jn36537) No 76, Linjiang road, Chongqing, China
                Article
                2439
                10.1186/s12951-024-02439-y
                10993609
                38570776
                72f40676-b662-4962-b8a3-9d355e1b8c70
                © The Author(s) 2024

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 9 February 2024
                : 24 March 2024
                Funding
                Funded by: Chongqing Natural Science Foundation for postdoctoral
                Award ID: CSTB2023NSCQ- BHX0028
                Award Recipient :
                Funded by: National Natural Science Foundation of China
                Award ID: 82172092
                Award Recipient :
                Categories
                Research
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                © BioMed Central Ltd., part of Springer Nature 2024

                Biotechnology
                kaempferol,tk bond,nanosystem,mitochondrial homeostasis,severe acute pancreatitis
                Biotechnology
                kaempferol, tk bond, nanosystem, mitochondrial homeostasis, severe acute pancreatitis

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