HMGB1 Research Articles

Aloperine Ameliorates Acetaminophen-Induced Acute Liver Injury through HMGB1/TLR4/NF-κB and NLRP3/Inflammasome Pathway.

Aloperine (ALO), an alkaloid isolated from Sophora alopecuroides L., possesses multiple pharmacological activities and holds a promise potential for the treatment of various clinical conditions, including skin hypersensitivity, cancer, and inflammatory disorders. The purpose of this study was to investigate the role of ALO in acetaminophen (N-acetyl-para-aminophenol (APAP))-induced acute liver injury and its underlying mechanisms. An animal model of acute liver injury was induced by intraperitoneal injection of APAP (150 mg/kg). Prior to APAP injection, ALO (40 mg/kg) was administered daily for 7 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels were then measured using an automated chemical analyzer. Histopathological changes were evaluated using hematoxylin and eosin staining. Oxidative stress levels were measured by detecting superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). Pro-inflammatory cytokines were detected in serum and liver tissues using ELISA and quantitative real-time polymerase chain reaction (q-PCR). The expression of members of the HMGB1/TLR4/NF-κB signaling pathway and NLRP3 inflammasome were determined by Western blot and/or q-PCR. In addition, the expression and location of NLRP3, cleaved caspase-1, high-mobility group box 1 (HMGB1), and phosphorylated p65 (p-p65) were detected by immunofluorescence. Pretreatment with ALO significantly protected mice from APAP-induced acute liver injury, with decreased MDA content, and significantly increased GSH and SOD activities. Furthermore, ALO pretreatment reduced the release of pro-inflammatory cytokines (IL-1β and TNF-α) and decreased the expression of caspase-1, cleaved caspase-1, and NLRP3. In addition, ALO pretreatment also inhibited the activation of the HMGB1/TLR4/NF-κB signaling pathway. Taken together, ALO can ameliorate APAP-induced acute liver injury by inhibiting oxidative stress, inflammation by inhibiting the HMGB1/TLR4/NF-κB, and NLRP3/inflammasome pathway.

Histone deacetylase 3-specific inhibitor RGFP966 attenuates oxidative stress and inflammation after traumatic brain injury by activating the Nrf2 pathway.

Oxidative stress (OS) and inflammatory reactions play pivotal roles in secondary brain injury after traumatic brain injury (TBI). Histone deacetylase 3 (HDAC3) controls the acetylation of histones and non-histones, which has a significant impact on the central nervous system's reaction to damage. This research determined the implications of RGFP966, a new and specific inhibitor of HDAC3, for the antioxidant (AO) systems mediated by nuclear factor erythroid2-related factor 2 (Nrf2) and the Nod-like receptor protein 3 (NLRP3) inflammasome in TBI. The study also studied the underlying mechanisms of RGFP966's actions. Our objective was to examine the impacts and underlying RGFP966 mechanisms in TBI. In vitro, a rat cortical neuron OS model was induced by H2O2, followed by the addition of RGFP966 to the culture medium. Neurons were collected after 24h for western blot (WB), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and 2'-7'-dichlorodihydrofluorescein diacetate staining. In vivo, RGFP966 (10mg/kg) was administered post-TBI. Brain tissue water content and modified neurological severity scores were assessed 72h post-injury. Cortical tissues surrounding the focal injury were subjected to western blot, TUNEL staining, Nissl staining and immunofluorescence/immunohistochemistry staining, and malondialdehyde level, hindered glutathione content and superoxide dismutase activity were measured. Serum was collected for the enzyme-linked immunosorbent assay. Nrf2-specific shRNA lentivirus was injected into the lateral ventricle of rats for 7days, and cerebral cortex tissue was analyzed by WB and real-time polymerase chain reaction. During in vitro and in vivo experiments, RGFP966 suppressed HDAC3 expression, promoted Nrf2 nuclear translocation, activated downstream AO enzymes, mitigated excessive reactive oxygen species production and alleviated nerve cell apoptosis. RGFP966 effectively reduced brain edema and histological damage and enhanced neurological and cognitive function in rats with TBI. RGFP966 markedly inhibited NLRP3 inflammasome activation mediated by high-mobility group box 1 (HMGB1)/toll-like receptor 4 (TLR4). Nrf2 knockdown in TBI rats attenuated the AO and anti-inflammatory, neuroprotective impacts of RGFP966. Overall, our findings demonstrate that RGFP966 can mitigate the first brain damage and neurological impairments in TBI. The underlying mechanism involves triggering the Nrf2-mediated AO system and negatively regulating the HMGB1/TLR4-mediated NLRP3 inflammasome pathway.

Immunohistochemical analyses reveal FoxP3 expressions in spleen and colorectal cancer in mice treated with AOM/DSS, and their suppression by glycyrrhizin.

We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells.

Reactive oxygen species generation required for autophagy induction during butyrate- or propionate-induced release of damage-associated molecular patterns from dying gingival epithelial Ca9-22 cells.

Bacterial cells in mature dental plaque produce a high concentration of short-chain fatty acids (SCFAs) such as butyrate and propionate. SCFA-treatment on human gingival epithelial Ca9-22 cells induced cell death. However, the exact mechanism underlying cell death remains unclear. In this study, the relationship between reactive oxygen species (ROS) and autophagy induction during SCFA-induced cell death was examined. Human gingival epithelial Ca9-22 cells were treated with butyrate or propionate to induce cell death and the number of dead cells were measured using SYTOX-green dye. A siRNA for ATG5 and N-acetylcysteine (NAC) were used for autophagy reduction and ROS-scavenging, respectively. Release of damage-associated molecular patterns (DAMPs) such as Sin3A-associated protein 130 (SAP130) and high-mobility group box 1 (HMGB1) were detected using western blot. Reducing autophagy significantly suppressed SCFA-induced Ca9-22 cell death. ROS generation was observed upon SCFA treatment, and scavenging ROS with NAC decreased cell death. NAC also reduced the SCFA-induced increase in microtubule-associated protein 1 light chain 3B (LC3B)-I and LC3B-II, and mitigated the release of DAMPs. The findings suggest that ROS generation is necessary for autophagy, which is required for SCFA-induced cell death and accompanying DAMP release.

Non-Invasive Radiofrequency Hyperthermia Attenuates HMGB1/TLR4/NF-κB Inflammatory Axis in a Chronic Prostatitis/Chronic Pelvic Pain Syndrome Rat Model.

The primary goal of this study is to evaluate the effect of the non-invasive radiofrequency hyperthermia (RFHT) device on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) rat model and investigate the underlying mechanism. In this study, Sprague-Dawley rats were randomly distributed into three groups: (1) normal control group, (2) CP/CPPS group, and (3) RFHT group. CP/CPPS rat models were induced by 17β-estradiol and dihydrotestosterone for 4 weeks and RFHT was administered for 5 weeks after model establishment. During RFHT administration, core body temperatures were continuously monitored with a rectal probe. After administering RFHT, we assessed pain index for all groups and collected prostate tissues for Western blot analysis, immunofluorescence, and immunohistochemistry. We also collected adjacent organs to the prostate including urinary bladder, testes, and rectum for safety assessment via H&E staining along with a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. After administering RFHT, pain in rats was significantly alleviated compared to the CP/CPPS group. RFHT reduced high-mobility group box 1 (HMGB1) expression and improved inflammation by downregulating subsequent proinflammatory cytokines through inhibition of the toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) pathway. In prostate-adjacent organs, no significant histological alteration or inflammatory infiltration was detected. The area of cell death also did not increase significantly after RFHT. In conclusion, RFHT demonstrated anti-inflammatory effects by inhibiting the HMGB1-TLR4-NF-κB pathway in CP/CPPS rat models. This suggests that RFHT could serve as a safe and promising therapeutic strategy for CP/CPPS.

Ondansetron or beta-sitosterol antagonizes inflammatory responses in liver, kidney, lung and heart tissues of irradiated arthritic rats model.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder mainly affecting joints, yet the systemic inflammation can influence other organs and tissues. The objective of this study was to unravel the ameliorative capability of Ondansetron (O) or β-sitosterol (BS) against inflammatory reactions and oxidative stress that complicates Extra-articular manifestations (EAM) in liver, kidney, lung, and heart of arthritic and arthritic irradiated rats. This was accomplished by exposing adjuvant-induced arthritis (AIA) rats to successive weekly fractions of total body γ-irradiation (2Gray (Gy)/fraction once per week for four weeks, up to a total dose of 8Gy). Arthritic and/or arthritic irradiated rats were either treated with BS (40mg/kg b.wt. /day, orally) or O (2mg/kg) was given ip) or were kept untreated as model groups. Body weight changes, paw circumference, oxidative stress indices, inflammatory response biomarkers, expression of Janus kinase-2 (JAK-2), Signal transducer and activator of transcription 3 (STAT3), high mobility group box1 (HMGB1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), as well as pro- and anti-inflammatory mediators in the target organs, besides histopathological examination of ankle joints and extra-articular tissues. Treatment of arthritic and/or arthritic irradiated rats with BS or O powerfully alleviated changes in body weight gain, paw swelling, oxidative stress, inflammatory reactions, and histopathological degenerative alterations in articular and non-articular tissues. The obtained data imply that BS or O improved the articular and EAM by regulating oxidative and inflammatory indices in arthritic and arthritic irradiated rats.

Oleate alters the immune response in non-small cell lung adenocarcinoma through regulation of HMGB1 release.

Background: Cancer cell evasion of the immune response is critical to cancer development and metastases. Clinicians' ability to kickstart the immune system to target these rogue cells is an ever-growing area of research and medicine. This study delved into the relationship between lipid metabolism, High Mobility Group Box 1 protein (HMGB1)-a pro-inflammatory damage-associated molecular pattern protein-and immune regulation within non-small cell lung adenocarcinoma (NSCLC). Method: To address this question, we used a combination of proteomics, molecular biology, and bioinformatic techniques to investigate the relationship between fatty acids and immune signals within NSCLC. Results: We found that the expression of stearoyl CoA desaturase 1 (SCD1) was decreased in NSCLC tumors compared to normal tissues. This emphasized the critical role of lipid metabolism in tumor progression. Interestingly, monounsaturated fatty acid (MUFA) availability affected the expression of programmed death ligand-1 (PD-L1), a pivotal immune checkpoint target in lung cancer cells and immune cells, as well as HMGB1, suggesting a novel approach to modulating the immune response. This study uncovered a complex interplay between SCD1, PD-L1, and HMGB1, influencing the immunological sensitivity of tumors. Conclusion: Our work underscores the critical importance of understanding the intricate relationships between lipid metabolism and immune modulation to develop more effective NSCLC treatments and personalized therapies. As we continue to explore these connections, we hope to contribute significantly to the ever-evolving field of cancer research, improving patient outcomes and advancing precision medicine in NSCLC.

Leaky gut and inflammatory biomarkers in a medication overuse headache model in male rats.

Medication overuse is common among chronic migraine patients and nonsteroidal antiinflammatory drugs (NSAIDs) are the most frequently overused drugs. The pathophysiological mechanisms underlying medication overuse headache (MOH) are not completely understood. Intestinal hyperpermeability and leaky gut are reported in patients using NSAIDs. The aim of the study is to investigate the role of leaky gut and inflammation in an MOH model MOH model in male rats. The study was conducted in male Sprague Dawley rats. There were two experimental groups. The first group was the chronic NSAID group in which the rats received mefenamic acid (n = 8) for four weeks intraperitoneally (ip) and the second group was the vehicle group (n = 8) that received 5% dimethyl sulfoxide+sesame oil (ip) for 4 weeks. We assessed spontaneous pain-like behavior, periorbital mechanical withdrawal thresholds, and anxiety-like behavior using an elevated plus maze test. After behavioral testing, serum levels of occludin and lipopolysaccharide-binding protein (LBP) and brain levels of IL-17, IL-6, and high mobility group box 1 protein (HMGB1) were evaluated with ELISA.Results: Serum LBP and occludin levels and brain IL-17 and HMGB1 levels were significantly elevated in the chronic NSAID group compared to its vehicle (p = 0.006, p = 0.016, p = 0.016 and p = 0.016 respectively) while brain IL-6 levels were comparable (p = 0.67) between the groups. The chronic NSAID group showed pain-like and anxiety-like behavior in behavioral tests. Brain IL-17 level was positively correlated with number of head shakes (r = 0.64, p = 0.045), brain IL-6 level was negatively correlated with periorbital mechanical withdrawal thresholds (r = -0.71, p = 0.049), and serum occludin level was positively correlated with grooming duration (r = 0.73, p = 0.032) in chronic NSAID group. Elevated serum occludin and LBP levels and brain IL-17 and HMGB1 levels indicate a possible role of leaky gut and inflammation in an MOH model in male rats. Additionally, a significant correlation between pain behavior and markers of inflammation and intestinal hyperpermeability, supports the role of inflammation and leaky gut in MOH pathophysiology.

Gallic acid attenuates torsion/detorsion-induced testicular injury in rats through suppressing of HMGB1/NF-κB axis and endoplasmic reticulum stress.

It was aimed to evaluate whether gallic acid (GA) have a beneficial effect in the testicular ischemia/reperfusion injury (IRI) model in rats for the first time. Testicular malondialdehyde, 8-hydroxy-2'-deoxyguanosine, superoxide dismutase, catalase, high mobility group box 1 protein, nuclear factor kappa B, tumor necrosis factoralpha, interleukin-6, myeloperoxidase, 78-kDa glucose-regulated protein, activating transcription factor 6, CCAAT-enhancer-binding protein homologous protein and caspase-3 levels were determined using colorimetric methods. The oxidative stress, inflammation, endoplasmic reticulum stress and apoptosis levels increased statistically significantly in the IRI group compared with the sham operated group (p < 0.05). GA application improved these damage significantly (p < 0.05). Moreover, it was found that the results of histological examinations supported the biochemical results to a statistically significant extent. Our findings suggested that GA may be evaluated as a protective agent against testicular IRI.

Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Cognitive Impairment and Intestinal Microecological Dysfunction Induced by High-Fat Diet in Rats.

Consuming a high-fat diet (HFD) is widely recognized to cause obesity and result in chronic brain inflammation that impairs cognitive function. Repetitive transcranial magnetic stimulation (rTMS) has shown effectiveness in both weight loss and cognitive improvement, although the exact mechanism is still unknown. Our study examined the effects of rTMS on the brain and intestinal microecological dysfunction. rTMS successfully reduced cognitive decline caused by an HFD in behavioral assessments involving the Y maze and novel object recognition. This was accompanied by an increase in the number of new neurons and the transcription level of genes related to synaptic plasticity (spindlin 1, synaptophysin, and postsynaptic protein-95) in the hippocampus. It was reached that rTMS decreased the release of high mobility group box1, activation of microglia, and inflammation in the brains of HFD rats. rTMS also reduced hypothalamic hypocretin levels and improved peripheral blood lipid metabolism. In addition, rTMS recovered the HFD-induced gut microbiome imbalances, metabolic disorders, and, in particular, reduced levels of the microvirus. Our research emphasized that rTMS enhanced cognitive abilities, resulting in positive impacts on brain inflammation, neurodegeneration, and the microbiota in the gut, indicating the potential connection between the brain and gut, proposing that rTMS could be a new approach to addressing cognitive deficits linked to obesity.

Aging aggravates liver fibrosis through downregulated hepatocyte SIRT1-induced liver sinusoidal endothelial cell dysfunction.

Aging increases the susceptibility to chronic liver diseases and hastens liver fibrosis deterioration, but the underlying mechanisms remain partially understood. The aim of this study was to investigate the effect of aging and chronic liver diseases on hepatocyte Sirtuin 1 (SIRT1) and LSECs and their contribution to liver fibrosis pathogeneses. Young (8-12wk) and aged (18-20mo) mice were subjected to carbon tetrachloride-induced liver fibrosis. Primary HSCs and LSECs were isolated and cocultured for in vitro experiments. Liver tissues and blood samples from healthy controls and patients with liver fibrosis were analyzed. Downregulated hepatocytes SIRT1 in aged mice increased high mobility group box 1 acetylation, cytoplasmic translocation, and extracellular secretion, causing LSECs dysfunction by means of the toll-like receptor 4/AK strain transforming (AKT)/endothelial nitric oxide synthase pathway, ultimately activating HSCs and increasing susceptibility to liver injury and fibrosis. Adeno-associated virus-mediated overexpression of SIRT1 in hepatocytes suppressed the abovementioned alterations and attenuated carbon tetrachloride-induced liver injury and fibrosis in liver fibrosis mice, and there were no significant differences in liver injury and fibrosis indicators between young and aged mice after SIRT1 overexpression treatment. In vitro experiments demonstrated that SIRT1 overexpression and endothelial nitric oxide synthase agonist YC-1 improved LSECs function and inhibited HSCs activation, mediated by nitric oxide. Similarly, downregulated hepatocytes SIRT1 and LSECs dysfunction were observed in the livers of aged individuals compared to young individuals and were more pronounced in aged patients with liver fibrosis. Aging aggravates liver fibrosis through downregulated hepatocytes SIRT1-induced LSECs dysfunction, providing a prospective curative approach for preventing and treating liver fibrosis.

High mobility group box protein 1 sensitizes mononuclear cells to further contact with lipopolysaccharide.

Fever is an adaptive host-defense response to infection and nowadays is rightly considered to be an expression of a healthy body and a well-functioning immune system. The condition is that it must be tightly regulated. Therefore, in individual cases, fever may be detrimental and should be treated. Specific excessive febrile reaction to pathogens which occurs after aseptic injuries is one among such cases. We previously found that among necrotic products, high mobility group box protein 1 (HMGB1) released from the site of aseptic injury affects immune effectors (cells) to mediate higher fever in response to further contact with bacterial lipopolysaccharide (LPS). Here we observed that intraperitoneal (i.p.) pre-injection of recombinant HMGB1 (5 µg/rat i.p.) provoked an increase in plasma levels of prostaglandin E2 (PGE2) in rats and augmented release of interleukin (IL)-1β and IL-6 after LPS administration at a dose of 50 µg/kg i.p. compared to rats pre-injected with saline or heat-denatured HMGB1. Furthermore, peripheral blood mononuclear cells (PBMCs) isolated from rats injected with HMGB1 were more sensitized to produce enhanced levels of IL-1β and PGE2 when stimulated with LPS in vitro (1 µg/ml/106 cells for 4 h) compared to control animals injected with saline or heat-denatured HMGB1. We also noted a significant increase in activation of nuclear factor κB (NF-κB) in cells isolated from rats injected with HMGB1. Altogether, the obtained results suggest that HMGB1 participates in priming of immune cells to further contact with pathogens.

Macrophage reprogramming combined with enhanced photodynamic therapy increases the patency of malignant esophageal obstruction after stenting.

Esophageal cancer (EC) is a disease characterized by progressive malignant obstruction. Stent implantation restores lumen patency, but tumor progression is likely to cause re-occlusion shortly. An esophageal stent loaded with Ce6-SiO2@MnO2 nanoparticles was designed, for which a dense δ-MnO2 coating was synthesized using a novel one-step REDOX reaction. This stent reverses the hypoxic tumor microenvironment (TME) via explosive oxygen generation, thereby increasing the efficacy of photodynamic therapy (PDT). Furthermore, Mn2+ reprograms the polarity of tumor associated macrophages (TAMs) in the immunosuppressed TME to effectively activate innate anti-tumor immunity in combination with PDT. Mn2+ downregulates the high mobility group box 1 protein (HMGB1), upregulates the signal transducer and activator of transcription 1 (STAT1) mRNA, and ultimately expresses the tumor inhibition effect of TAMs. Additionally, Ce6-SiO2@MnO2 effectively suppresses the apoptosis of TAMs to enhance their anti-tumor effect. The proposed strategy highlights the multifaceted role of Ce6-SiO2@MnO2 in the treatment of advanced esophageal cancer.

Alcohol, HMGB1, and Innate Immune Signaling in the Brain.

Binge drinking (i.e., consuming enough alcohol to achieve a blood ethanol concentration of 80 mg/dL, approximately 4-5 drinks within 2 hours), particularly in early adolescence, can promote progressive increases in alcohol drinking and alcohol-related problems that develop into compulsive use in the chronic relapsing disease, alcohol use disorder (AUD). Over the past decade, neuroimmune signaling has been discovered to contribute to alcohol-induced changes in drinking, mood, and neurodegeneration. This review presents a mechanistic hypothesis supporting high mobility group box protein 1 (HMGB1) and Toll-like receptor (TLR) signaling as key elements of alcohol-induced neuroimmune signaling across glia and neurons, which shifts gene transcription and synapses, altering neuronal networks that contribute to the development of AUD. This hypothesis may help guide further research on prevention and treatment. The authors used the search terms "HMGB1 protein," "alcohol," and "brain" across PubMed, Scopus, and Embase to find articles published between 1991 and 2023. The database search found 54 references in PubMed, 47 in Scopus, and 105 in Embase. A total of about 100 articles were included. In the brain, immune signaling molecules play a role in normal development that differs from their functions in inflammation and the immune response, although cellular receptors and signaling are shared. In adults, pro-inflammatory signals have emerged as contributing to brain adaptation in stress, depression, AUD, and neurodegenerative diseases. HMGB1, a cytokine-like signaling protein released from activated cells, including neurons, is hypothesized to activate pro-inflammatory signals through TLRs that contribute to adaptations to binge and chronic heavy drinking. HMGB1 alone and in heteromers with other molecules activates TLRs and other immune receptors that spread signaling across neurons and glia. Both blood and brain levels of HMGB1 increase with ethanol exposure. In rats, an adolescent intermittent ethanol (AIE) binge drinking model persistently increases brain HMGB1 and its receptors; alters microglia, forebrain cholinergic neurons, and neuronal networks; and increases alcohol drinking and anxiety while disrupting cognition. Studies of human postmortem AUD brain have found elevated levels of HMGB1 and TLRs. These signals reduce cholinergic neurons, whereas microglia, the brain's immune cells, are activated by binge drinking. Microglia regulate synapses through complement proteins that can change networks affected by AIE that increase drinking, contributing to risks for AUD. Anti-inflammatory drugs, exercise, cholinesterase inhibitors, and histone deacetylase epigenetic inhibitors prevent and reverse the AIE-induced pathology. Further, HMGB1 antagonists and other anti-inflammatory treatments may provide new therapies for alcohol misuse and AUD. Collectively, these findings suggest that restoring the innate immune signaling balance is central to recovering from alcohol-related pathology.

Drosophila kikkawai - Sox102F.

The Drosophila kikkawai feature with NCBI Gene ID 108084518 was determined to be an ortholog of Drosophila melanogaster Sox102F , a member of the FlyBase High Mobility Group Box Transcription Factors gene group (FBgg0000748). Five isoforms were constructed using the GEP F element annotation protocol, the longest being novel isoform Sox102F-PNE (identified using the XM_017180752 RefSeq prediction and RNA-seq data). Among the isoforms found in both D. melanogaster and D. kikkawai , Sox102F-PB is the longest and exhibits a 1.18x coding span expansion due to transposable element insertion into an intron. All D. kikkawai protein isoforms contain the conserved domain HMG_box_dom (IPR009071).

The Role of High Mobility Group Box B-1 in the Prognosis of Colorectal Cancer Based on the Changes in the Intestinal Mucosal Barrier.

Background: To investigate the expression of high mobility group box B-1 (HMGB-1) in patients with colorectal cancer (CRC) and its association with clinicopathological features and prognosis in colorectal carcinoma by combining bioinformatics and clinical data analysis, and to clarify the role of HMGB-1. To examine whether HMGB-1 expression is related to the damage of the intestinal mucosal barrier, and then explore the potential HMGB-1-dependent mechanisms affecting the progression of CRC. Methods: CRC datasets of GSE12945, GSE17536, and GSE17537 from the public gene chip database were screened and downloaded. Clinical information and CRC tissue samples from patients with stage I-III CRC from the hospital were collected. Serum samples of patients were applied by enzyme-linked immunosorbent assay on HMGB-1, and were divided into high and low HMGB-1 expression, which was examined by 16S rDNA sequencing. Immunohistochemistry was performed to examine the relationship between the expression of HMGB-1 and tight junction protein, occludin, tumor necrosis factor-α, and interferon-γ. Results: Based on the Cutoff value of 10.24 ng/mL, the CRC patients were divided into high and low expression groups. In the HMGB-1H patient group, the TNM staging, overall survival, disease-free survival, recurrence, and metastasis were inferior to the HMGB-1L group. The results of 16S rDNA sequencing demonstrated that the Providencia genus was found to be enriched in the HMGB-1L group. Immunohistochemical results showed that HMGB-1 expression was negatively correlated with the expression of ZO-1 and occludin (R = 0.035, R = 0.003, P < .05), but was positively correlated with the expression of TNF-α and IFN-γ (R = 0.016, R = 0.001, P < .05). Conclusion: The survival of CRC patients with positive HMGB-1 expression was significantly shortened, which may be related to the decrease of Rovitensis content, the decreased expression of ZO-1 and occludin, and the increased levels of TNF-α and IFN-γ, which in turn damage the intestinal mucosal barrier, leading to the development of CRC.

KLRG1-expressing CD8+ T cells are exhausted and polyfunctional in patients with chronic hepatitis B.

Killer cell lectin-like receptor G1 (KLRG1) has traditionally been regarded as an inhibitory receptor of T cell exhaustion in chronic infection and inflammation. However, its exact role in hepatitis B virus (HBV) infection remains elusive. CD8+ T cells from 190 patients with chronic hepatitis B were analyzed ex vivo for checkpoint and apoptosis markers, transcription factors, cytokines and subtypes in 190 patients with chronic hepatitis B. KLRG1+ and KLRG1- CD8+ T cells were sorted for transcriptome analysis. The impact of the KLRG1-E-cadherin pathway on the suppression of HBV replication mediated by virus-specific T cells was validated in vitro. As expected, HBV-specific CD8+ T cells expressed higher levels of KLRG1 and showed an exhausted molecular phenotype and function. However, despite being enriched for the inhibitory molecules, thymocyte selection-associated high mobility group box protein (TOX), eomesodermin (EOMES), and Helios, CD8+ T cells expressing KLRG1 produced significant levels of tumour necrosis factor (TNF)-α, interferon (IFN)-γ, perforin, and granzyme B, demonstrating not exhausted but active function. Consistent with the in vitro phenotypic assay results, RNA sequencing (RNA-seq) data showed that signature effector T cell and exhausted T cell genes were enriched in KLRG1+ CD8+ T cells. Furthermore, in vitro testing confirmed that KLRG1-E-cadherin binding inhibits the antiviral efficacy of HBV-specific CD8+ T cells. Based on these findings, we concluded that KLRG1+ CD8+ T cells are not only a terminally exhausted subgroup but also exhibit functional diversity, despite inhibitory signs in HBV infection.

Plasma High-Mobility Group Box-1 and Galectin-9 in Patients with Trauma and Their Prognostic Potentials.

Plasma High-Mobility Group Box-1 and Galectin-9 in Patients with Trauma and Their Prognostic Potentials.

Expression of HMGB1 and NF-κB in Fetal Membranes of Premature Rupture of Membranes

Background: Inflammation, either sterile or infection-related, may lead to premature rupture of membranes (PROM). The non-histone nuclear proteins, high mobility group box-1 (HMGB1), and nuclear factor kappa-B (NF-κB) transcription factors have been extensively investigated in many disorders involving inflammatory reactions. This study aimed to determine the expression of HMGB1 and NF-κB in fetal membranes of PROM compared with non-PROM.Methods: This study was an analytical observational study with a case-control design, performed from November 2021 to January 2022, including 40 fetal membrane samples (20 PROM and 20 non-PROM), which were obtained from pregnant women treated in the emergency unit of a hospital in Surabaya from August to November 2019 using the non-probability sampling method. The HMGB1 and NF-κB expressions were examined using the immunohistochemical method and further viewed under a light microscope (400x magnification), then assessed by Image-J software. The values were then compared between PROM and non-PROM, and analyzed using the Mann-Whitney U test.Results: There was a significant difference (p&lt;0.001) in the expression of HMGB1 and NF-κB in PROM and non-PROM for HMGB1 45.86± 14.21% vs. 8.50± 5.66% expression/mm2; and NF-κB 33.47±5.45% vs. 7.29±4.90% expression/mm2, respectively.Conclusions: PROM groups have significantly higher expression of HMGB1 and NF-κB s, indicating their higher activity and contribution to PROM.

Influences of microRNA-451 on the expression of HMGB1 in myocardial cells and its mechanism in ischemia-reperfusion injury.

This work aimed to understand the underlying mechanism of micro-ribonucleic acid (MicroRNA) (miR)-451 in ischemia-reperfusion injury (IRI) and the influences of miR-451 on high mobility group box 1 protein (HMGB1) in myocardial cells, 30 specific pathogen-free (SPF) male rats were selected and randomly rolled into 5 groups, which were a sham operation control (Control), an ischemia-reperfusion (I/R), aI/R+Ad-GFP, amiR-451 up-regulation (I/R+Ad-miR-451), and a miR-451 down-regulation groups (I/R+Ad-asmiR-451). There were 6 cases in each group. Myocardial cell apoptosis, the contents of serum lactic acid dehydrogenase (LDH), creatine kinase (CK), and malondialdehyde (MDA), the activity of superoxide dismutase (SOD), and the expressions of miR-451 and HMGB1mRNA were detected. Relative to those in I/R and I/R+Ad-GFP groups, the expressions of CD3+, CD4+, and CD4+/ CD8+ in I/R+Ad-miR-451 group reduced (P<0.05). The expressions of serum LDH and CK decreased (P<0.05). In contrast, MDA content and SOD activity enhanced (P<0.05). HMGB1 and Cleaved-caspase3 declined (P<0.05). Besides, miR-451 improved while the expression of HMGB1mRNA significantly reduced (P<0.05). miR-451 can regulate the expressions of HMGB1mRNA and its protein at the transcriptional level. miR-451 up-regulation can inhibit HMGB1 expression, relieve IRI, and protect myocardial cells, which may be achieved by improving oxidative stress injury and inhibiting cell apoptosis.