High Mobility Group Box-1 Protein Research Articles

EXPRESS: SGK1-HDAC4-HMGB1 Signaling pathway in the spinal cord dorsal horn participates in diabetic neuropathic pain.

This study aimed to determine whether serum-and glucocorticoid-inducible kinase1 (SGK1) activation-dependent histone deacetylase 4 (HDAC4) phosphorylation, nucleocytoplasmic trafficking, and subsequent regulation of high-mobility group protein box 1 (HMGB1) expression are involved in type 2 diabetic neuropathic pain (DNP). The type 2 diabetic neuropathic pain model was established in rats by feeding them with a high-fat and high-sugar diet for 8 weeks and then fasting them for 12 hours, followed by a single intraperitoneal injection of streptozotocin (STZ, 35mg/kg). SGK1 was inhibited in the spinal cord by intrathecal administration of the SGK1 inhibitor GSK-650394. The present study revealed that pSGK1/tSGK1 was persistently upregulated in the spinal cord of rats with type-2 DNP. The downregulation of pSGK1/tSGK1 through the intrathecal injection of the SGK1 inhibitor GSK-650394 significantly ameliorated the pain hypersensitivity, relieved the abnormal expression of pHDAC4/tHDAC4 and HMGB1, and affected HDAC4 nucleocytoplasmic trafficking in DNP rats. Our data suggest that SGK1 in the spinal cord modulates type-2 DNP by regulating the HDAC4/HMGB1 pathway.

Targeting PGAM5 attenuates airway inflammation in asthma by inhibiting HMGB1 release in bronchial epithelium.

Previous studies have demonstrated that high-mobility group box protein 1(HMGB1) was increased and released to the extracellular and participated in the pathogenesis of steroid-insensitive asthma induced by toluene diisocyanate (TDI). Mitochondrial dysfunction of bronchial epithelia is a critical feature in TDI asthma. However, whether mitochondrial dysfunction regulated HMGB1 release in asthma remains unknown. The aim of this study was to explore whether phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein, can regulate HMGB1 release in TDI-induced asthma. The gene expression data series (GSE) 67472 from gene expression omnibus (GEO) database was analyzed to compare the levels of PGAM5 in airway epithelial cells from asthma patients and healthy individuals. Male C57BL/6J mice were sensitized and challenged with TDI and treated with the PGAM5 inhibitor LFHP-1c. In vitro, human bronchial epithelial cells(16HBE) were stimulated by TDI-human serum albumin (HSA) and pretreated with PGAM5 siRNA. In this study, we observed PGAM5 expression was notably increased in airway epithelial cells of asthma patients and TDI-induced asthma mice. In vivo, inhibition of PGAM5 significantly ameliorated airway inflammation, airway hyperresponsiveness (AHR) and mucus hypersecretion, coupled with the decrease of pulmonary HMGB1 expression and release in TDI-exposed mice. In vitro, inhibition of PGAM5 improved mitochondrial dysfunction, decreased the production of reactive oxygen species (ROS) in mitochondrial. Knockdown of PGAM5 reduced the release of cytochrome C (cyt c) and HMGB1 release in TDI-induced asthma. Mechanistically, PGAM5 in bronchial epithelial cells treated by TDI-HSA significantly increased the dephosphorylation of Bax at the S184 residue, promoted the translocation of Bax to mitochondria, and contributed to the activation of mitochondrial-dependent apoptosis in TDI-induced asthma. Based on these findings, we uncovered a novel regulatory mechanism by which high PGAM5 expression promotes airway inflammation by mediating HMGB1 release in TDI-induced asthma, identifying the therapeutic effects of targeting PGAM5 in steroid-insensitive asthma model.

HMGB1 mediates epithelial-mesenchymal transition and fibrosis in silicosis via RAGE/β-catenin signaling.

Epithelial-mesenchymal transition (EMT) is implicated in the pathogenesis of silicosis. High mobility group box 1 (HMGB1) has been found to induce EMT in fibrotic diseases. Previous studies have revealed a critical role of HMGB1 in silicosis, whereas the detail mechanisms still obscure. Here, we observed that HMGB1 protein was increased in the serum of silicosis patients and in the lung tissues of silicotic mice. The levels of HMGB1, receptor for advanced glycation end products (RAGE) and β-catenin protein were increased in the alveolar EMT cell model established by the treatment of transforming growth factor β1 (TGF-β1) and conditioned mediums derived from silica-stimulated macrophages. The activation of HMGB1, RAGE, β-catenin, EMT process, as well as cell migration triggered by TGF-β1 in RLE-6TN cells could be enhanced by treatment with recombinant HMGB1 protein (rHMGB1) and decreased by HMGB1 chemical inhibitor glycyrrhizin or RAGE inhibitor FPS-ZM1. And RAGE suppression could alleviate HMGB1-mediated the aggravation of β-catenin signaling, cell migration and EMT process induced by TGF-β1. Furthermore, both HMGB1 inhibition and RAGE knockout effectively alleviated the lung function impairment, EMT process, pulmonary inflammation and fibrosis in silicotic mice. These findings suggested that HMGB1 might promote EMT through RAGE/β-catenin axis in silicosis. And HMGB1 might constitute a therapeutic target for ameliorating the fibrosis of silicosis.

Roles of the Receptor for Advanced Glycation End Products and Its Ligands in the Pathogenesis of Alzheimer's Disease.

The Receptor for Advanced Glycation End Products (RAGE), part of the immunoglobulin superfamily, plays a significant role in various essential functions under both normal and pathological conditions, especially in the progression of Alzheimer's disease (AD). RAGE engages with several damage-associated molecular patterns (DAMPs), including advanced glycation end products (AGEs), beta-amyloid peptide (Aβ), high mobility group box 1 (HMGB1), and S100 calcium-binding proteins. This interaction impairs the brain's ability to clear Aβ, resulting in increased Aβ accumulation, neuronal injury, and mitochondrial dysfunction. This further promotes inflammatory responses and oxidative stress, ultimately leading to a range of age-related diseases. Given RAGE's significant role in AD, inhibitors that target RAGE and its ligands hold promise as new strategies for treating AD, offering new possibilities for alleviating and treating this serious neurodegenerative disease. This article reviews the various pathogenic mechanisms of AD and summarizes the literature on the interaction between RAGE and its ligands in various AD-related pathological processes, with a particular focus on the evidence and mechanisms by which RAGE interactions with AGEs, HMGB1, Aβ, and S100 proteins induce cognitive impairment in AD. Furthermore, the article discusses the principles of action of RAGE inhibitors and inhibitors targeting RAGE-ligand interactions, along with relevant clinical trials.

HMGB1-mediated CIITA super-enhancers are critical for DC trained immunity in acute-to-chronic progression of allograft rejection.

Chronic allograft rejection is mainly mediated by indirect recognition. Dendritic cells (DCs), as the major antigen-presenting cells in indirect recognition, exhibit an enhanced antigen-presenting ability in chronic rejection, but the specific mechanism is still unclear. Here, we found that pretreatment with high mobility group box-1 protein (HMGB1) in vivo can induce trained immunity in DCs. These trained DCs demonstrated an enhanced ability to present alloantigen, accelerating allograft rejection in a CTLA4-Ig-induced chronic rejection model by upregulating the expression of MHC-II and class II major histocompatibility complex transactivator (CIITA) molecules. Mechanistically, we found that HMGB1 promoted the formation of super-enhancers (SEs) of CIITA, epigenetically reprogramming DCs and promoting trained immunity. The SEs inhibitor JQ1 reduced the expression of CIITA and MHC-II in DCs, thereby delaying the occurrence of chronic rejection. Interestingly, we identified HMGB1 as a specific inducer of SE formation in a newly named SEa region of CIITA. Targeted knockout of the CIITA's SEa region inhibited HMGB1-induced trained immunity in DCs. Taken together, our data confirm that HMGB1 can induce the formation of the SEs of CIITA, promote trained immunity in DCs, and accelerate allograft rejection, thus offering a new potential target for the treatment of chronic rejection.

Mechanism of miR-130b-3p in relieving airway inflammation in asthma through HMGB1-TLR4-DRP1 axis

Asthma is a chronic inflammatory respiratory disease characterized by recurrent breathing difficulties caused by airway obstruction and hypersensitivity. Although there is diversity in their specific mechanisms, microRNAs (miRNAs) have a significant impact on the development of asthma. Currently, the contribution of miR-130b-3p to asthma remains elusive. The goal of this study was to examine whether miR-130b-3p attenuates house dust mite (HDM)-induced asthma through High-mobility group box protein 1 (HMGB1)/Toll-like receptor 4 (TLR4)/mitochondrial fission protein (DRP1) signaling pathway. We elucidate that miR-130b-3p can bind to the HMGB1 3'UTR, attenuating HMGB1 mRNA and protein levels, and nucleo-cytoplasmic translocation of HMGB1. We observed that miR-130b-3p agomir or HMGB1 CKO attenuated HDM-induced airway inflammation and hyperresponsiveness, and decreased Th2-type cytokines in bronchoalveolar lavage fluid (BALF) and mediastinal lymph nodes. Further, HMGB1 CKO contributes to alleviating Th2 inflammation in AT-II cells (CD45.2−/CD31−/Epcam−+/proSP-C+/MHC-II+) from lung single cell suspensions of asthmatic mice by flow cytometry. Our findings identified miR-130b-3p as a potent regulator in asthma that exerts its anti-inflammatory effects by targeting HMGB1 and the subsequent HMGB1/TLR4/DRP1axis, presenting a prospective novel therapeutic avenue for asthma management.

Targeting Non-Apoptotic Pathways with the Cell Permeable TAT-Conjugated NOTCH1 RAM Fragment for Leukemia and Lymphoma Cells.

Targeting nonapoptotic cell death offers a promising strategy for overcoming apoptosis resistance in cancer. In this study, we developed Tat-Ram13, a 25-mer peptide that fuses the NOTCH1 intracellular domain fragment RAM13 with a cell-penetrating HIV-1 TAT, for the treatment of T-cell acute lymphoblastic leukemia with aberrant NOTCH1 mutation. Tat-Ram13 significantly downregulated NOTCH1-target genes in T-ALL cell lines. Furthermore, the peptide had potent cytotoxic effects on various human leukemia and lymphoma cell lines. However, it did not affect normal lymphocytes and monocytes, some subsets of leukemia cells, or adherent tumor cells. This cell-selective cytotoxic activity was closely correlated with the peptide uptake via macropinocytosis in leukemia cells. In leukemia cells, Tat-Ram13 triggered rapid cell death. This cell death involved mitochondrial membrane depolarization and extracellular release of lactate dehydrogenase and high-mobility group box-1 protein without activation of caspase-3 or cleavage of PARP-1. These results suggest that Tat-Ram13 cell death is nonapoptotic and mediated by rapid plasma membrane rupture. Moreover, alanine scanning analysis identified four critical hydrophobic amino acids in the RAM13 domain essential for its cytotoxicity. Consequently, these results suggest that Tat-Ram13 is a tumor-selective, nonapoptotic cell death-inducing agent for treating refractory leukemia and lymphomas with apoptosis resistance.

Mechanism of chrysophanol in inhibiting ox-LDL-induced macrophage foaminess through NF-κB/HMGB1-PI3K/Akt/mTOR pathway

The aim of this study was to investigate the underlying mechanism of chrysophanol(Chr) in reducing inflammation and foam cell formation induced by oxidized low-density lipoprotein(ox-LDL) and to investigate the targets and pathways related to effects of Chr on coronary atherosclerosis, providing a theoretical basis for the development of new clinical drugs. RAW264.7 macrophages were cultured in vitro, and after determining the appropriate concentrations of Chr and ox-LDL for treating RAW264.7 macrophages using a cell counting kit-8(CCK-8), the macrophages were treated with different concentrations of Chr(10, 15 μmol·L~(-1)) and ox-LDL(with or without 80 mg·mL~(-1)) for 24 h. RAW264.7 macrophages were divided into four groups: control group, model group(80 mg·mL~(-1) ox-LDL), treatment group(80 mg·mL~(-1) ox-LDL+10 μmol·L~(-1) Chr), and treatment group(80 mg·mL~(-1) ox-LDL+15 μmol·L~(-1) Chr). Lipid accumulation in each group was detected by oil red O staining. CD36 expression was analyzed by flow cytometry. Western blot was used to detect the expression of scavenger receptor class A1(SR-A1), scavenger receptor class B type Ⅰ(SR-B1), autophagy-related protein 5(Atg5), Beclin-1, autophagy adaptor protein p62(P62), the ratio of microtubule-associated protein light chain 3(LC3)Ⅱ to LC3Ⅰ(LC3Ⅱ/LC3Ⅰ), nuclear factor kappa B P65(NF-κB P65), inhibitor of κB kinase β(IKKβ), nuclear factor of κB inhibitor(IκB), high mobility group box protein 1(HMGB1), phosphatidylinositol 3-kinase(PI3K), protein kinase B(Akt), and phosphorylated mammalian target of rapamycin(mTOR). Real-time quantitative polymerase chain reaction(RT-qPCR) was used to detect the mRNA expression levels of ATP-binding cassette transporter A1(ABCA1), ATP-binding cassette transporter G1(ABCG1), interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), HMGB1, inducible nitric oxide synthase(iNOS), arginase 1(Arg1), macrophage galactose-type lectin-1(Mgl-1), and NF-κB P65. Immunofluorescence analysis was performed to determine the localization of HMGB1 in RAW264.7 cells in each group. The autophagy inhibitor 3-methyladenine(3-MA) was added as a control for reverse validation, and the RAW264.7 macrophages were divided into four groups again: control group, model group(80 mg·mL~(-1) ox-LDL), treatment group(80 mg·mL~(-1) ox-LDL + 15 μmol·L~(-1) Chr), and inhibitor group(80 mg·mL~(-1) ox-LDL+15 μmol·L~(-1) Chr+3-MA). The results showed that Chr effectively reduced foam cell formation by regulating the expression levels of SR-A1, ABCA1, ABCG1, the LC3Ⅱ/LC3Ⅰ ratio, Atg5, Beclin-1, and p62, and inhibited the NF-κB/HMGB1-PI3K/Akt/mTOR signaling pathway. Moreover, the inhibitory effects of Chr on autophagy and the NF-κB/HMGB1-PI3K/Akt/mTOR pathway were reversed by the autophagy inhibitor 3-MA. In conclusion, Chr exhibits therapeutic potential for the treatment of atherosclerosis by inducing autophagy and modulating the NF-κB/HMGB1 and PI3K/Akt/mTOR pathways to inhibit the formation of macrophage inflammatory foam cells.

Serum High Mobility Group Box1 Protein and Toll-like Receptor 4 Correlation with Lipid Profile in Patients with Non-alcoholic Fatty Liver Disease

Serum High Mobility Group Box1 Protein and Toll-like Receptor 4 Correlation with Lipid Profile in Patients with Non-alcoholic Fatty Liver Disease

Inhibition of TOX exerts anti-tumor effects in acute myeloid leukemia by upregulating IRF7 expression

Thymocyte selection-associated high mobility group box protein (TOX) is regarded as a crucial transcription factor involved in T cell exhaustion in acute myeloid leukemia (AML). Previous studies have identified aberrant TOX expression as a major oncogenic driver in hematologic malignancies, indicating that TOX may potentially be both an immune biomarker and an immunotherapy target. However, due to heterogeneity in the distribution patterns of TOX and its correlation with clinical prognosis, the mechanism underlying TOX-mediated tumor immune responses remains unclear. In this study, we demonstrate that high TOX expression in AML patients is associated with poor prognosis, and TOX overexpression promotes AML cell proliferation and restricts apoptosis. In vitro TOX inhibition promoted the apoptosis of AML cells, suppressed cell viability, and induced cell cycle arrest in the G0/G1 phase. Moreover, TOX knockdown could reduce tumor burden in vivo in immunodeficient mice and prolong their survival. Furthermore, the anti-AML effects of inhibiting TOX may act through activation of the IFN-α signal pathway and upregulating IRF7 expression. In summary, we report for the first time that TOX knockdown exerts powerful anti-tumor effects in AML. These findings will provide a theoretical basis for targeted therapy in AML patients.

Effects of electroacupuncture on expression of miR-218 and HMGB1/TLR4 signaling pathway in rats with focal cerebral ischemia

To observe the effect of electroacupuncture (EA) on high mobility group box 1 (HMGB1) / toll-like receptor 4 (TLR4) signaling pathway and inflammatory injury in rats with focal cerebral ischemia (FCI), so as to explore its mechanisms underlying amelioration of ischemic stroke. Male SD rats were randomly divided into sham operation (n=18), model (n=18) and EA (n=18) groups. The FCI model was established according to Longa's method. In the EA group, 24 h after modeling, EA stimulation was applied to "Baihui"(GV20), "Fengfu"(GV16), and "Neiguan" (PC6) and "Xinshu" (BL15) on the left side for 20 min, once a day for 1 week. The neurological deficit severity was evaluated by the modified neurological severity score (mNSS), and the morphological changes of neurons were observed after H.E. staining. The expression of HMGB1 and TLR4 proteins were detected by immunofluorescence staining. The contents of tumor necrosis factor(TNF)-α and interleukin(IL)-6 in the ischemic area tissue of the brain were detected using ELISA. The mRNA expressions of HMGB1 and TLR4 as well as the expression of miR-218 in the ischemic cortex were detected by PCR. Compared with the sham operation group, the mNSS at 2 h, 48 h and 7 day (d), IL-6 and TNF-α contents, HMGB1 and TLR4 immunoactivity and mRNA expression at 48 h and 7 d were significantly increased (P<0.01), while miR-218 expression at 48 h and 7 d was obviously down-regulated (P<0.01) in the model group. In comparison with the model group, the mNSS at 7 d, IL-6 and TNF-α contents, HMGB1 and TLR4 immunoactivity and mRNA expression at 7 d not at 48 h were significantly decreased (P<0.01, P<0.05), while the expression of miR-218 at 7 d was apparently up-regulated (P<0.05) in the EA group. H.E. staining showed that there were signs of neuronal necrosis including blurred outline of the cells, disordered internal structure, dense cytoplasm, shrunk nuclei, etc. in the ischemic area of the brain at 48 h and 7 d in the model group, which was evidently milder on day 7 in the EA group. EA can reduce the inflammatory injury of brain tissue and improve the neurological impairment in rats with FCI, which may be associated with its effects in inhibiting HMGB1/TLR4 signaling and down-regulating the level of pro-inflammatory cytokines.

HMGB1 Modulates Macrophage Metabolism and Polarization in Ulcerative Colitis by Inhibiting Cpt1a Expression.

Macrophage polarization is involved in the development of ulcerative colitis (UC). This study investigated the mechanism by which high mobility group box-1 protein (HMGB1) regulates macrophage polarization through metabolic reprogramming, thereby contributing to the pathogenesis of UC. Dextran sulfate sodium (DSS) was used to induce colitis in mice. RAW264.7 cells were polarized to M1 or M2 macrophages in vitro by stimulating with lipopolysaccharide (LPS)/interferon-γ (IFN-γ) or Interleukin-4 (IL-4), respectively. Macrophage infiltration and distribution within colon tissue were assessed by immunohistochemistry and flow cytometry. Glycolysis, fatty acid oxidation (FAO), and inflammatory factors were evaluated using relevant reagent kits. Chromatin Immunoprecipitation (ChIP) and luciferase reporter experiments were performed to study the regulation of Carnitine palmitoyltransferase 1A (Cpt1a) promoter transcriptional activity by HMGB1. The mouse UC model showed upregulated HMGB1 and increased macrophage infiltration. Overexpression of HMGB1 promoted M1 macrophage polarization, increased glycolysis, and reduced FAO, whereas knockdown of HMGB1 promoted M2 macrophage polarization, reduced glycolysis, and increased FAO. HMGB1 negatively regulated Cpt1a expression by inhibiting transcription of the Cpt1a promoter. Knockdown of Cpt1a reversed the effects of small interfering RNA targeting HMGB1 (si-HMGB1) on macrophage metabolism and polarization. Administration of adeno-associated virus (AAV)-shHMGB1 in vivo caused a reduction in UC symptoms and inflammation. HMGB1 modulates macrophage metabolism in UC by inhibiting Cpt1a expression, leading to increased M1 polarization. This provides a theoretical basis for the clinical application of HMGB1 inhibitors in the treatment of UC.

Effects of pericapsular nerve group block on early postoperative cognitive function in older people undergoing hip arthroplasty: a randomized controlled clinical trial

BackgroundPericapsular nerve group (PENG) block has emerged as a reliable analgesia technique for hip arthroplasty (HA). However, the effects of PENG block on perioperative neurocognitive disorder (PND) after HA has not yet been assessed. The present study aimed to investigate the effects of PENG block on early postoperative cognitive function in older people undergoing hip arthroplasty.MethodsSixty older patients undergoing HA under spinal anesthesia were randomly assigned to group P (n = 30) receiving PENG block with ropivacaine and patient-controlled intravenous analgesia (PCIA) pump with sufentanil after surgery or group C (n = 30) only receiving PCIA pump with sufentanil after surgery. The primary outcome was the Mini-Mental State Examination (MMSE) score at 7 days postoperatively. Secondary outcomes consisted of the incidence of PND 7 days postoperatively, the static VAS pain scores at 6, 12, 24, and 48 h postoperatively; cumulative sufentanil consumption and the requirement of rescue analgesia during the 0–24 h period after surgery; quality of recovery-15 (QoR-15) scale scores at 24 h postoperatively; and the plasma levels of high mobility group box protein 1 (HMGB1) preoperatively and 1 day after surgery, and adverse events.ResultsAfter surgery, the PENG block group had higher MMSE score than the control group at 7 days postoperatively (27.0 ± 1.8 vs. 26.1 ± 1.7, P = 0.048), with a mean difference of 0.9 (95%CI, 0.1–0.9). The incidence of PND at 7 days postoperatively was 6.7% in group P, lower than that of 30% in group C (P = 0.044). In group P, the static VAS scores at 6, 12, and 24 h postoperatively were significantly lower than those in group C (all P < 0.05). Compared with group C, the cumulative sufentanil consumption and the number of patients required rescue analgesia during the 0–24 h period after surgery were significantly lower in group P (all P < 0.05). The scores of QoR-15 scale were higher in group P at 24 h postoperatively than those in group C (P < 0.05). Patients in group P showed lower plasma levels of HMGB1 than group C at 1 day after surgery (P < 0.05), and the rate of complications didn’t differ between both groups.ConclusionsOlder people undergoing HA receiving a PENG block for perioperative analgesia experience improved early postoperative cognitive function, reduced postoperative pain, higher quality of recovery, and less postoperative inflammatory response.Trial registrationChictr.org.cn identifier ChiCTR2200061055 (Date of registry: 15/06/2022, prospectively registered).

Serum High Mobility Group Box 1 (HMGB1) Protein Levels and Cognitive Function in Epilepsy Patients: A Cross-Sectional Study

Background: Epilepsy is a neurological disease with a high incidence rate. Cognitive decline is one of the consequences of recurrent seizures. Neuroinflammation is closely related to the development of epilepsy and cognitive impairment. An increase in the expression and translocation of High Mobility Group Box 1 (HMGB1) from the nucleus to the extracellular space has been observed in epilepsy patients and experimental animal models. This study aimed to investigate the relationship between serum HMGB1 levels and cognitive function in epilepsy patients. Methods: This cross-sectional observational study involved 45 epilepsy patients. Cognitive function was assessed using the Indonesian version of the Montreal Cognitive Assessment (MoCA-Ina), and serum HMGB1 levels were measured using the ELISA technique. The relationship between cognitive function and HMGB1 levels was analyzed using the Kruskal-Wallis test, with a significance level set at p &lt; 0.05. Results: The mean age of the participants was 28.5 years, with a higher proportion of females. The mean serum HMGB1 level was 22.6 ng/ml. No significant relationship was found between serum HMGB1 levels and cognitive function in epilepsy patients (p = 0.188). Conclusion: Serum HMGB1 protein levels were not associated with cognitive function in this sample of epilepsy patients.

Clinical and biochemical assessments of circulating High Mobility Group Box Protein1 in children with epilepsy: relation to cognitive function and drug responsiveness

BackgroundChildhood epilepsy is a major health concern posing a significant burden and having disastrous consequences for cognitive function. High Mobility Group Box1 (HMGB1) is an activator of neuroinflammation, and it is possibly involved in the initiation and progression of epilepsy. We aimed to investigate circulating HMGB1 in children with epilepsy and its connection to cognitive function and drug responsiveness.MethodsCase-control research included 100 epileptic youngsters and 100 healthy matched controls. Serum HMGB1 was measured using a commercially available ELISA assay. Cognitive functions were evaluated by the Stanford-Binet test 5th edition.ResultsDrug-resistant epilepsy (DRE) was found in 37% of the investigated patients. Epileptic children have lower cognitive function parameter levels versus the control group and lower cognitive function in the DRE group compared to the drug-responsive group (P-value < 0.0001). HMGB1 levels were significantly higher in the patients’ group (6.279 µg/L) compared to the control group (2.093 µg/L) and in the drug-resistant group (14.26 µg/L) versus the drug-responsive group (4.88 µg/L). A significant negative correlation was detected between HMGB1 with Full-scale IQ (r = − 0.547, P = 0.000), Visual-spatial reasoning (r = − 0.501, P = 0.000), fluid reasoning (r = − 0.510, P = 0.000), and working memory (r = − 0.555, P = 0.000). Serum HMGB1 cut-off levels > 6.85 µg/L differentiate drug-responsive from resistant patients.ConclusionElevated HMGB1 levels, especially in patients with drug-resistant epilepsy, correlate negatively with cognitive performance, emphasizing its importance as a potential marker for early prediction of drug resistance and impairment of cognitive function.

May high mobility group box protein-1 be a biomarker for major depressive disorder?

High Mobility Group Box Protein-1 (HMGB1), which has proinflammatory properties, is known to be involved in psychiatric disorders as far as we know, there are only one clinical studies investigating the role of HMGB1 in major depressive disorder (MDD). In this study, we aimed to investigate the role of HMGB1 in the etiopathogenesis of MDD and whether HMGB1 can be used as a biomarker in MDD by measuring the serum HMGB1 levels of depressed patients in the episode and remission periods. This study included 30 patients diagnosed with MDD in episode, 30 patients in remission and 30 healthy controls. Each group comprised 20 female and 10 male participants. In this study, serum HMGB1 levels were found to be lower in the patient group in the episode compared to the patient group in the remission period and the healthy control group. There was no significant difference between the patient group in remission and the healthy control group in terms of serum HMGB1 levels. The fact that serum HMGB1 levels were lower in the patient group in the episode compared to the patient group in the remission period and the control group may be related to the neuroprotective effects of HMGB1. HMGB1 may be used as a biomarker for MDD.

Impact of immunosuppressive drugs on efficacy of mesenchymal stem cell therapy for suppressing renal fibrosis.

Preemptive regenerative medicine using mesenchymal stem cells (MSCs) may provide a novel therapeutic approach to prevent the progression from organ damage to organ failure. Although immunosuppressive drugs are often used in patients with organ disorder, their impact on MSC therapy remains unclear. We investigated the effects of immunosuppressive drugs on the therapeutic efficacy of MSCs. We created unilateral ureteral obstruction models, as a well-established model of renal fibrosis, a preliminary stage of organ failure. Three immunosuppressive drugs (methylprednisolone, cyclosporine, and cyclophosphamide) were intraperitoneally administered 3 days after surgery, and MSCs were injected via tail vein the following day. Preadministration of methylprednisolone or cyclophosphamide interfered with MSC activation by reducing expression of interferon-gamma (IFN-γ) and high-mobility group box-1 protein, thus significantly attenuating the therapeutic efficacy of MSCs. Preadministration of cyclophosphamide downregulated the expression of stromal cell-derived factor-1/C-X-C motif ligand 12, which is a potent migration factor for MSCs, resulting in reduced MSC engraftment in the renal cortex. IFN-γ-preconditioned activated MSCs were unaffected by these drugs and maintained their beneficial therapeutic effects. Cyclosporine preadministration had no effect on the therapeutic efficacy of MSCs. Our study demonstrated that the administration of certain immunosuppressive drugs interfered with MSC activation and engraftment at the site of injury, resulting in a significant attenuation of their therapeutic efficacy. These findings provide crucial information for selecting patients suitable for MSC therapy. Use of MSCs preactivated with IFN-γ or other means is preferred for patients on methylprednisolone or cyclophosphamide.

High mobility group box-1 protein promotes astrocytic CCL5 production through the MAPK/NF-κB pathway following spinal cord injury

Astrocytes act as immune cells that can produce a series of chemokines to attract large numbers of leucocytes to the lesion site, where they contribute to excessive inflammation following spinal cord injury (SCI). However, the relevant regulatory mechanism involved in chemokine production by astrocytes has not been fully elucidated. In the present study, we examined the correlation between C-C motif chemokine ligand 5 (CCL5) and high mobility group box-1 protein (HMGB1) in a T8–T10 spinal cord contusion model. Our results revealed that SCI-induced CCL5 protein levels increased synchronously with the increase in HMGB1. Administration of an HMGB1-neutralizing antibody significantly reduced the protein expression of CCL5 in the context of SCI. An in vitro study revealed that HMGB1 binding with TLR2/4 receptors potently facilitates the production of CCL5 by astrocytes by activating the intracellular ERK/JNK-mediated NF-κB pathway. Furthermore, the HMGB1-induced release of CCL5 from astrocytes is involved in promoting microglia/macrophage accumulation and M1 polarization. The inhibition of HMGB1 activity reduces microglia/macrophage infiltration by decreasing the expression of CCL5 and improves motor functional recovery following SCI. Our results provide insights into the new functions of HMGB1-mediated astrocytic CCL5 production, which elicits inflammatory cell recruitment to the site of injury; this recruitment is associated with excessive inflammation activation. These data may provide a new therapeutic strategy for central nervous system (CNS) inflammation.

Plasmodium berghei HMGB1 controls the host immune responses and splenic clearance by regulating the expression of pir genes

High mobility group box (HMGB) proteins belong to the high mobility group (HMG) superfamily of non-histone nuclear proteins that are involved in chromatin remodeling, regulation of gene expression, and DNA repair. When extracellular, HMGBs serve as alarmins inducing inflammation, and this is attributed to the proinflammatory activity of box B. Here, we show that Plasmodium HMGB1 has key amino acid changes in box B resulting in the loss of TNF-α stimulatory activity. Site-directed mutagenesis of the critical amino acids in box B with respect to mouse HMGB1 renders recombinant Plasmodium berghei (Pb) HMGB1 capable of inducing TNF-α release. Targeted deletion of PbHMGB1 and a detailed invivo phenotyping show that PbHMGB1 knockout (KO) parasites can undergo asexual stage development. Interestingly, Balb/c mice-infected with PbHMGB1KO parasites display a protective phenotype with subsequent clearance of blood parasitemia and develop long-lasting protective immunity against the challenges performed with Pb wildtype parasites. The characterization of splenic responses shows prominent germinal centers leading to effective humoral responses and enhanced T follicular helper cells. There is also complete protection from experimental cerebral malaria in CBA/CaJ mice susceptible to cerebral pathogenesis with subsequent parasite clearance. Transcriptomic studies suggest the involvement of PbHMGB1 in pir expression. Our findings highlight the gene regulatory function of parasite HMGB1 and its invivo significance in modulating the host immune responses. Further, clearance of asexual stages in PbHMGB1KO-infected mice underscores the important role of parasite HMGB1 in host immune evasion. These findings have implications in developing attenuated blood-stage vaccines for malaria.

Target Gene-Based Association Study of High Mobility Group Box Protein 1 in Intracranial Aneurysms in Koreans.

Objective: We investigated the effect of high mobility group box 1 (HMGB1) on intracranial aneurysms (IAs) by analyzing single-nucleotide polymorphisms (SNPs) based on genome-wide association study (GWAS) data. HMGB1 mRNA and protein expression levels in plasma were also analyzed. Methods: This study was a comprehensive analysis of a GWAS dataset, including 250 patients with IAs and 294 controls. The HMGB1 gene region was targeted within SNP rs3742305 ± 10 kbp. Multivariate logistic regression analysis determined its association with IAs after adjusting for relevant clinical factors. HMGB1 mRNA expression was analyzed in the plasma of 24 patients selected from the GWAS dataset. The HMGB1 protein was analyzed by Western blotting. Results: A total of seven polymorphisms, including rs1360485, rs185382445, rs2039338, rs1045411, rs3742305, rs2249825, and rs189034241, were observed. Two SNPs, including rs1045411 (UTR-3) and rs3742305 (intron), showed strong linkage disequilibrium (r2 = 0.99). However, none of the seven SNPs associated with IAs had an adjusted p-value of < 0.0016 on multiple comparison analysis. HMGB1 mRNA levels (2-ΔCt) did not differ significantly between patients with IAs and the control subjects [1.07 (1.00-1.15) in patients with IAs vs. 1.05 (0.94-1.12) in controls; p = 0.67)]. Also, no significant difference in the degree of plasma HMGB1 protein expression was seen between the two groups (p = 0.82). Conclusions: The number of SNPs associated with HMGB1 and the degree of HMGB1 mRNA and protein expression were not significantly different between patients diagnosed with IAs and the controls.