High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the ex...High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.展开更多
High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental auto...High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.展开更多
OBJECTIVE:To explore the effect of Chang’an decoction(肠安方,CAD)of ameliorating the immune imbalances in ulcerative colitis(UC)by regulating Rab27 in the P53/high mobility group box 1 pathway.METHODS:The functions a...OBJECTIVE:To explore the effect of Chang’an decoction(肠安方,CAD)of ameliorating the immune imbalances in ulcerative colitis(UC)by regulating Rab27 in the P53/high mobility group box 1 pathway.METHODS:The functions and important signaling pathways of the Rab27-and UC-related genes were analyzed viathe use of microarray data from the gene expression omnibus database,gene ontology database,Kyoto encyclopedia of genes and genomes database and gene set enrichment analysis.Dextran sulfate sodium salt-induced colitis mouse model was used to verify the bioinformatics results.Colon length,body weight,and disease activity index were measured.Hematoxylin and eosin staining was applied to validate the histopathology.Tight junction proteins were detected by immunohistochemistry.The proportions of T helper 17 cells(Th17)and regulatory T cells(Treg)in mesenteric lymph nodes were measured viaflow cytometry.Proinflammatory cytokines like interleukin(IL)17(IL-17),IL-21 and IL-22 and anti-inflammatory cytokines like transforming growth factorβand IL-10 in the serum and colon of mice were detected by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction,respectively.The expression levels of high mobility group box 1(HMGB1),P53 and phospho-P53(P-P53)in colonic tissues were detected by immunofluorescence and Western blotting.RESULTS:Bioinformatics analysis revealed that compared with normal tissues,the expression of Rab27 was significantly increased in UC tissues.Receiver operating characteristic curve showed that Rab27 has the potential to be used as a biomarker for the diagnosis of disease activity.Enrichment analysis showed that UC and Rab27 were mainly associated with small molecule transport,nutrient metabolism,transmembrane transport and the downstream pathway of P53.According to animal experiments,the expression of Rab27 was increased in UC tissues,which aggravated the colonic pathological damage,activated the expression of HMGB1,and also leaded to the imbalance of Th17 and Treg cells.After CAD intervention,Rab27 overexpression,weight loss,colon shortening,and pathological damage were substantial reduced,the expression of tight junction proteins,zona occludens 1 and Occludin were increased.The effect of CAD at high-dose was more obvious.In addition,CAD upgraded the number of Treg cells and the production of TGF-βand IL-10,while decreasing the number of Th17 cells and the expression of inflammatory cytokines(IL-17,IL-21,and IL-22).Moreover,colon inflammation was alleviated by CAD,as indicated by the regulation of HMGB1 and P-P53 expression.CONCLUSION:The expression of Rab27,HMGB1 and P-P53 could be decreased by CAD,and the balance of Th17 and Treg cells as well as their related cytokines could be regulated by CAD.展开更多
基金supported by a grant of the M.D.-Ph.D./Medical Scientist Training Program through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(to HK)+3 种基金supported by National Research Foundation of Korea(NRF)grants funded by the Korean government(MSITMinistry of Science and ICT)(NRF2019R1A5A2026045 and NRF-2021R1F1A1061819)a grant from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(HR21C1003)New Faculty Research Fund of Ajou University School of Medicine(to JYC)。
文摘High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.
基金supported by the National Natural Science Foundation of China(82001281 and 82371195)Hubei Provincial Natural Science Foundation of China for Distinguished Young Scholars(2022CFA104)the Research Fund of Jianghan University(2022XKZX28).
文摘High mobility group box 1(HMGB1),when released extracellularly,plays a pivotal role in the development of spinal cord synapses and exacerbates autoimmune diseases within the central nervous system.In experimental autoimmune encephalomyelitis(EAE),a condition that models multiple sclerosis,the levels of extracellular HMGB1 and interleukin-33(IL-33)have been found to be inversely correlated.However,the mechanism by which IL-33 deficiency enhances HMGB1 release during EAE remains elusive.Our study elucidates a potential signaling pathway whereby the absence of IL-33 leads to increased binding of P300/CBP-associated factor with HMGB1 in the nuclei of astrocytes,upregulating HMGB1 acetylation and promoting its release from astrocyte nuclei in the spinal cord of EAE mice.Conversely,the addition of IL-33 counteracts the TNF-α-induced increase in HMGB1 and acetylated HMGB1 levels in primary astrocytes.These findings underscore the potential of IL-33-associated signaling pathways as a therapeutic target for EAE treatment.
基金Supported by Lingnan Medical Research Center of Guangzhou University of Chinese MedicineNational Natural Science Foundation of China:Mechanism of Chang’an Decoction in Intestinal Mucosal Immunity of Ulcerative Colitis on Exocrine Mediated Rab27(81903963)Natural Science Foundation of Guangdong Province:the Role of the Neuropeptide Spexin-associated Gycogen Synthase Kinase-3βSignaling Pathway in Regulating the Enteric Nervous-immune Network in Ulcerative Colitis and the Intervention Mechanism of Chang’an Formula(2018A030310614)。
文摘OBJECTIVE:To explore the effect of Chang’an decoction(肠安方,CAD)of ameliorating the immune imbalances in ulcerative colitis(UC)by regulating Rab27 in the P53/high mobility group box 1 pathway.METHODS:The functions and important signaling pathways of the Rab27-and UC-related genes were analyzed viathe use of microarray data from the gene expression omnibus database,gene ontology database,Kyoto encyclopedia of genes and genomes database and gene set enrichment analysis.Dextran sulfate sodium salt-induced colitis mouse model was used to verify the bioinformatics results.Colon length,body weight,and disease activity index were measured.Hematoxylin and eosin staining was applied to validate the histopathology.Tight junction proteins were detected by immunohistochemistry.The proportions of T helper 17 cells(Th17)and regulatory T cells(Treg)in mesenteric lymph nodes were measured viaflow cytometry.Proinflammatory cytokines like interleukin(IL)17(IL-17),IL-21 and IL-22 and anti-inflammatory cytokines like transforming growth factorβand IL-10 in the serum and colon of mice were detected by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction,respectively.The expression levels of high mobility group box 1(HMGB1),P53 and phospho-P53(P-P53)in colonic tissues were detected by immunofluorescence and Western blotting.RESULTS:Bioinformatics analysis revealed that compared with normal tissues,the expression of Rab27 was significantly increased in UC tissues.Receiver operating characteristic curve showed that Rab27 has the potential to be used as a biomarker for the diagnosis of disease activity.Enrichment analysis showed that UC and Rab27 were mainly associated with small molecule transport,nutrient metabolism,transmembrane transport and the downstream pathway of P53.According to animal experiments,the expression of Rab27 was increased in UC tissues,which aggravated the colonic pathological damage,activated the expression of HMGB1,and also leaded to the imbalance of Th17 and Treg cells.After CAD intervention,Rab27 overexpression,weight loss,colon shortening,and pathological damage were substantial reduced,the expression of tight junction proteins,zona occludens 1 and Occludin were increased.The effect of CAD at high-dose was more obvious.In addition,CAD upgraded the number of Treg cells and the production of TGF-βand IL-10,while decreasing the number of Th17 cells and the expression of inflammatory cytokines(IL-17,IL-21,and IL-22).Moreover,colon inflammation was alleviated by CAD,as indicated by the regulation of HMGB1 and P-P53 expression.CONCLUSION:The expression of Rab27,HMGB1 and P-P53 could be decreased by CAD,and the balance of Th17 and Treg cells as well as their related cytokines could be regulated by CAD.
