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      Anti-inflammatory effects of two lupane-type triterpenes from leaves of Acanthopanax gracilistylus on LPS-induced RAW264.7 macrophages


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          Abstract Acanthopanax gracilistylus W.W.Smith (AGS) is an traditional Chinese medicine and its leaves that have rich biological activities has been long used as a fresh vegetable in Chinese folk. There are two lupane-type triterpenoids, 3α,11α-dihydroxy-23-oxo-lup-20(29)-en-28-oic acid (1) and 3α,11α,23-trihydroxy-lup-20(29)-en-28-oic acid (2), were isolated as the active constituents from leaves of AGS. However, the anti-inflammatory effects and potential mechanisms of 1 and 2 on LPS-induced RAW264.7 Macrophages have not been evaluated. In this study, the results shown that compounds 1 and 2 reduced the levels of early pro-inflammatory cytokines TNF-α, IL-1β, the secretion of late pro-inflammatory cytokine HMGB1, as well as the activation of transcription factor NF-κB in RAW 264.7 macrophages induced by LPS. In conclusion, two lupane-type triterpenes (1 and 2) have anti-inflammatory activities in LPS-induced RAW264.7 cells through inhibiting expression of proinflammatory cytokines and NF‐κB activation and could be potentially used in treatment of inflammatory-related diseases in the future.

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          HMGB1 in health and disease.

          Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock.

            To study the systemic release and kinetics of high mobility group box-1 protein (HMGB1) in relation to clinical features in a population of patients with severe sepsis or septic shock and to compare these with the kinetics of the cytokines interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha. Prospective study of two cohorts of patients. Intensive care unit and infectious disease clinic at Karolinska University Hospital Huddinge. Twenty-six patients with severe sepsis, 33 patients with septic shock, and a reference group of five patients with sepsis. None. Sixty-four patients were included, ten of whom died within 28 days. Cytokine levels were measured at five time points during the first week after admission and were correlated to Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores. Two HMGB1 assays were used. Both demonstrated delayed kinetics for HMGB1 with high levels on inclusion that remained high throughout the study period. Serum concentration at 144 hrs, the last sampling point, was 300 times higher, 34,000 +/- 76,000 pg/mL (mean +/- sd), than any of the other cytokines. This study, however, found no predictable correlation between serum levels of HMGB1 and severity of infection. We did quite unexpectedly find significantly lower levels of HMGB1 in nonsurvivors compared with survivors as measured by our main assay, but the other showed no difference between the two groups. Levels of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-alpha correlated significantly with severity of disease, and all were significantly higher in patients with septic shock compared with those with severe sepsis. Neither of these comparisons showed significant correlations for HMGB1. This is the first prospective study assessing the release over time of HMGB1 in a population of patients with sepsis, severe sepsis, or septic shock. Levels remained high in the majority of patients up to 1 wk after admittance, indicating that the cytokine indeed is a downstream and late mediator of inflammation. Further studies are required to fully define the relationship of HMGB1 to severity of disease.
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              TNF‐α/HMGB1 inflammation signalling pathway regulates pyroptosis during liver failure and acute kidney injury

              Abstract Objective Acute kidney injury (AKI) is a common complication of acute liver failure (ALF). Pyroptosis is a necrosis type related to inflammation. This study aimed to investigate the role of TNF‐α/HMGB1 pathway in pyroptosis during ALF and AKI. Methods An ALF and AKI mouse model was generated using LPS/D‐Gal, and a TNF‐α inhibitor, CC‐5013, was used to treat the mice. THP‐1 cells were induced to differentiate into M1 macrophages, then challenged with either CC‐5013 or an HMGB1 inhibitor, glycyrrhizin. pLVX‐mCMVZsGreen‐PGK‐Puros plasmids containing TNF‐α wild‐type (WT), mutation A94T of TNF‐α and mutation P84L of TNF‐α were transfected into M1 macrophages. Results Treatment with CC‐5013 decreased the activation of TNF‐α/HMGB1 pathway and pyroptosis in the treated mice and cells compared with the control mice and cells. CC‐5013 also ameliorated liver and kidney pathological changes and improved liver and renal functions in treated mice, and the number of M1 macrophages in the liver and kidney tissues also decreased. The activation of TNF‐α/HMGB1 pathway and pyroptosis increased in the M1 macrophage group compared with the normal group. Similarly, the activation of TNF‐α/HMGB1 pathway and pyroptosis in the LPS + WT group also increased. By contrast, the activation of the TNF‐α/HMGB1 pathway and pyroptosis decreased in the LPS + A94T and LPS + P84L groups. Moreover, glycyrrhizin inhibited pyroptosis. Conclusion The TNF‐α/HMGB1 inflammation signalling pathway plays an important role in pyroptosis during ALF and AKI.

                Author and article information

                Food Science and Technology
                Food Sci. Technol
                Sociedade Brasileira de Ciência e Tecnologia de Alimentos (Campinas, SP, Brazil )
                [03] Kwanak goo Seoul city orgnameKyunghee Korean Pharmacy Korea
                [02] Ganzhou Jiangxi orgnameGannan Medical University orgdiv1College of Pharmaceutical Sciences China
                [07] Seoul orgnameKyung Hee University orgdiv1College of Pharmacy Korea
                [01] Changsha orgnameHunan University of Chinese Medicine orgdiv1School of Pharmacy China
                [04] Changsha Hunan orgnameCentral South University orgdiv1Xiangya Medical College orgdiv2Department of Clinical Biochemistry China
                [06] Hangzhou orgnameZhejiang Sci-Tech University orgdiv1College of Life Sciences and Medicine China
                [05] Seoul orgnameChung-Ang University orgdiv1College of Pharmacy Korea
                63207 S0101-20612021005063207 S0101-2061(21)00000063207

                This work is licensed under a Creative Commons Attribution 4.0 International License.

                : 13 August 2021
                : 24 September 2021
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                SciELO Brazil

                Acanthopanax gracilistylus W.W. Smith,lupane-type triterpenes,RAW 264.7 macrophages,proinflammatory cytokines,HMGB1,NF-κB


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