Serum HMGB1 Levels Research Articles

Paeonol Alleviates Subarachnoid Hemorrhage Injury in Rats Through Upregulation of SIRT1 and Inhibition of HMGB1/TLR4/MyD88/NF‐κB Pathway

ABSTRACTPaeonol is a principle bioactive compound separated from the root bark of Cortex Moutan and has been shown to confer various biological functions, including antineuroinflammation and neuroprotection. Inflammation, blood–brain barrier (BBB), permeability, and apoptosis are three major underlying mechanisms involved in early brain injury (EBI) postsubarachnoid hemorrhage (SAH). This study aimed to detect the roles and mechanisms of paeonol in EBI following SAH. A SAH model was established by an endovascular perforation method in Sprague‐Dawley rats. The localizations of HMGB1 and p65 were identified by immunofluorescence staining. Protein levels were measured by western blot analysis. The serum levels of HMGB1 and the levels of inflammatory cytokines in the brain cortex were evaluated by ELISA. Hematoxylin and eosin staining was conducted to detect neuronal degeneration. Brain water content and Evans blue extravasation were assessed to determine EBI. Neuronal apoptosis was examined by TUNEL. Paeonol deacetylated HMGB1 by upregulating SIRT1 level. SIRT1 inhibition attenuated the protective effects of paeonol against neurological dysfunctions, brain edema, and BBB disruption. SIRT1 inhibition rescued the paeonol‐induced inhibition in inflammatory response. The paeonol‐induced decrease in neuronal apoptosis was restored by SIRT1 inhibitor. The paeonol‐mediated deactivated TLR4/MyD88/NF‐κB pathway was activated by SIRT1 inhibitor. Paeonol alleviates the SAH injury in rats by upregulating SIRT1 to inactivate the HMGB1/TLR4/MyD88/NF‐κB pathway.

PCSK9 and its relationship with HMGB1, TLR4, and TNFα in non-statin and statin-treated coronary artery disease patients.

Despite statin use in coronary artery disease (CAD), significant risk remains, potentially due to increased proprotein convertase subtilisin/kexin-type 9 (PCSK9) production, which raises LDL-C levels and induces inflammation. The exact relationship between PCSK9, inflammatory markers like TNFα, TLR4, CRP, and HMGB1, and monocyte subsets is poorly understood. This study aimed to explore these relationships in non-statin and statin-taking CAD patients. This case-control study included 91 controls and 91 stable CAD patients, divided into no-statin (NS, n = 25), low-dose statin (LDS, n = 25), and high-dose statin (HDS, n = 41) groups. Serum levels of LDL-C, CRP, PCSK9, TLR4, HMGB1, and TNFα were measured. Monocyte subsets were classified using flow cytometry into classical monocytes (CM), intermediate monocytes (IM), and non-classical monocytes (NCM). CAD patients showed elevated PCSK9, LDL-C, and inflammatory markers compared to controls. Statin groups (LDS, HDS) had lower LDL-C and inflammatory markers but higher PCSK9 than the NS group, with the HDS group showing the lowest LDL-C and inflammatory markers but the highest PCSK9. In the NS group, PCSK9 positively correlated with inflammatory markers (HMGB1, TNFα, TLR4, CRP) and monocyte subsets (IM%, NCM%). In the total statin group (LDS + HDS), PCSK9 negatively correlated with HMGB1, TLR4, and NCM%, for each, respectively, and positively with CM%. Multivariable linear regression showed significant associations between PCSK9 and HMGB1, NCM%, and IM% in the NS group, and HMGB1, NCM%, and TLR4 in the total statin group. In conclusion, we recommend combining PCSK9 inhibitors with statins in high-risk CAD patients. This may enhance statin efficacy, reduce LDL-C, and inhibit the TLR4/NF-кB inflammatory pathway, decreasing atherosclerotic inflammation.

Overexpression of serum HMGB1 and IDO in esophageal squamous cell carcinoma patients: potential clinical auxiliary diagnostic markers and immunotherapeutic targets.

High mobility group box 1 (HMGB1) and indoleamino-2, 3-dioxygenase (IDO) participate in the occurrence and development of esophageal squamous cell carcinoma (ESCC), regulate the tumor immune microenvironment, and are closely related to tumor growth and metastasis. However, the regulatory mechanism of serum HMGB1 and IDO has not been clarified and needs further exploration. Blood samples of 55 ESCC patients initially hospitalized in the Fourth Hospital of Hebei Medical University from August 2021 to January 2022 were selected as the ESCC group, and relevant clinical data were collected, and blood samples from 40 healthy people during the same period were selected as the control group. Serum HMGB1 and IDO levels were determined by ELISA, and lymphocyte subsets in peripheral blood of all subjects were detected by flow cytometry. The correlation between the expression levels of HMGB1 and IDO in ESCC cells was detected by Western blot. Serum HMGB1 and IDO levels were significantly increased in ESCC patients, and with the progression of ESCC patients, serum HMGB1 and IDO levels were also gradually increased; serum HMGB1 was significantly correlated with IDO; serum HMGB1 and IDO combined with CEA and SCC-Ag were of high value in predicting the clinical progression of ESCC patients; the absolute counts of CD4+CD28+T cells and CD8+CD28+T cells in high HMGB1 group were significantly lower than those in low HMGB1 group, while the percentage of CD4+PD-1+T cells was significantly higher than that in low HMGB1 group; the percentage and absolute counts of CD4+CD28+T cells and the absolute counts of CD8+CD28+T cells in high IDO group were significantly lower than those in the low IDO group, while the percentage of CD8+PD-1+T cells was significantly higher than that in the low IDO group; increased serum HMGB1 and IDO expression levels were closely related to poor prognosis in ESCC patients; and HMGB1 may promote IDO expression by activating NF-κB signaling pathway. Serum HMGB1 and IDO have a synergistic effect, they inhibit immune function and promote tumor progression in ESCC patients, and also lead to poor prognosis.

Activating α7nAChR suppresses systemic inflammation by mitigating neuroinflammation of the medullary visceral zone in sepsis in a rat model.

Our previous studies have shown that activating α7nAChRs suppresses systemic inflammation and immunity through the cholinergic anti-inflammatory pathway (CAP) in early sepsis. Now that the medullary visceral zone (MVZ) is the center of CAP and responsible for regulating systemic inflammation, what changes will occur in MVZ's pathology and function in sepsis, especially when interfering with α7nAChRs? Does activation of MVZ's α7nAChRs contribute to the inhibition of systemic inflammation? To clarify these issues, we explored the systemic inflammation and immunity state by detecting serum levels of TNF-α, IL-6, HMGB1, sCD14, and CD4+CD25+Treg and TH17 lymphocytes percentage, meanwhile, we analyzed the apoptosis of cholinergic and catecholaminergic neurons and the expressions of tyrosine hydroxylase (TH) and choline acetyltransferase (CHAT) in MVZ in sepsis and the interfering effects on α7nAChRs. In this study, we found that in sepsis, serum TNF-α, IL-6, HMGB1, sCD14, CD4+CD25+Treg, and TH17 lymphocytes significantly increased and the ratio of Treg/TH17 significantly decreased, cholinergic and catecholaminergic neurons underwent apoptosis with low expressions of TH and CHAT in MVZ; activation of α7nAChRs not only significantly decreased the levels of septic serum TNF-α, IL-6, HMGB1, sCD14, and TH17 lymphocytes (P ＜ 0.05), but also significantly reduced cholinergic and catecholaminergic neurons' apoptosis, and promoted expressions of TH/CHAT. Our study reveals that sepsis undermines MVZ through neuroinflammation which contributes to the uncontrolled systemic inflammation. Activating central α7nAChRs is not only helpful to restore MVZ's structure and function but also beneficial to subside the inflammatory storm in sepsis. Even if MVZ is damaged in sepsis, cholinergic neurons in MVZ still regulate the systemic inflammation stably.

HMBG-1: A Biomarker in the Management of Diabetic Retinopathy

Introduction: High mobility group box (HMGB)-1 protein is a promising prognostic marker for predicting the course of retinopathy and the prognosis in patients with diabetic retinopathy (DR). The aim of this study is to investigate whether serum HMGB-1 protein levels can be used as a biomarker about the severity of the disease in patients with diabetic retinopathy. Material and methods: This study was carried out in the internal medicine and ophthalmology departments of the Gaziantep Medicalpark Hospital. The records of 50 patients diagnosed with type 2 diabetes mellitus with diabetic retinopathy and 47 healthy subjects who applied to our clinic between January 2016 and December 2018 were retrospectively scanned. Five cc of venous blood was taken from the patients, and control groups were included in the study for routine laboratory tests and serum HMGB-1 levels to be studied under appropriate conditions. Human HMGB-1 levels were measured using the ELISA method. Results: There was a significant difference among the groups in terms of HMGB-1 levels (p<0.001) (Table-1). There was a positive correlation between blood glucose and HMGB-1 in the diabetic retinopathy group (Spearman's rho (ρ)=0.07). Similarly, there was a positive correlation between HbA1c and HMGB-1 levels in the diabetic retinopathy group. (Spearman's rho (ρ)=0.06). Conclusions: Our study suggests that HMGB-1 may be a useful biomarker in managing DR, aiding in the prediction and treatment of microvascular complications.

Effect of remote ischemic preconditioning intervention on serum levels of microRNA-582–5p/HMGB1 in patients with acute cerebral infarction

ObjectiveAcute cerebral infarction (ACI) contributes to disability and death accross the globe. Remote ischemic preconditioning (RIPC) reduces cerebral infarct size and improves neurological function in ACI. We conducted this research to reveal the effects of RIPC intervention on serum levels of microRNA-582–5p (miR-582–5p)/high mobility group box-1 protein (HMGB1), inflammation, oxidative stress and neurological function in patients with ACI. MethodsIn this study, 158 patients with ACI were prospectively selected and randomized into the control (administered symptomatic medication alone) and the RIPC (underwent RIPC of the limbs based on medication) groups, with their clinical baseline data documented. Serum levels of miR-582–5p, and HMGB1 and inflammatory factors [tumor necrosis factor alpha (TNF-α)/interleukin-1beta (IL-1β)/IL-10] were assessed by RT-qPCR/ELISA, followed by comparisons of oxidative stress indices [glutathione-peroxidase (GSH-Px)/catalase (CAT)/superoxide dismutase (SOD)] using a fully automatic biochemical analyzer. Correlations between serum miR-582–5p with serum HMGB1, and between their levels with TNF-α/IL-1β/IL-10 were analyzed by Pearson analysis. The NIHSS score/Barthel Index scale were used to assess neurological function/daily living ability. Intervention safety for ACI patients was evaluated. ResultsRIPC intervention increased serum miR-582–5p levels and decreased serum HMGB1 levels in ACI patients. RIPC intervention significantly reduced inflammation (diminished TNF-α/IL-1β levels, increased IL-10 level) and oxidative stress (elevated GSH-Px/CAT/SOD levels) in ACI patients. Serum miR-582–5p was negatively correlated with TNF-α and IL-1β levels, while positively correlated with IL-10 level, while HMGB1 was positively correlated with TNF-α and IL-1β levels, while negatively correlated with IL-10 level. miR-582–5p was negatively correlated with HMGB1. RIPC intervention improved neurological function (reduced NIHSS, increased Barthel scores) in ACI patients to some extent. RIPC had certain effectiveness and safety in the treatment of ACI. ConclusionAfter RIPC intervention, serum miR-582–5p levels were increased, HMGB1 levels were decreased, and inflammation and oxidative stress were reduced in ACI patients, which mitigated neurological deficits, improved patients’ ability to perform life activities, and exerted neuroprotective effects to some extent.

Lipopolysaccharide, VE-cadherin, HMGB1, and HIF-1α levels are elevated in the systemic circulation in chronic migraine patients with medication overuse headache: evidence of leaky gut and inflammation

ObjectiveMedication overuse headache (MOH) was recently shown to be associated with leaky gut in rodents. We aimed to investigate whether chronic migraine (CM) patients with MOH have elevated lipopolysaccharide levels and inflammatory molecules in blood circulation.Materials and methodsThe study included women participants (40 CM patients with NSAID overuse headache, 35 episodic migraine (EM) patients, and 20 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, MigSCog, HADS-D, HADS-A, and HIT-6 scores were recorded. Serum samples were collected to measure circulating LPS, LPS binding protein (LBP), tight junction protein occludin, adherens junction protein vascular endothelial cadherin (VE-cadherin), CGRP, HMGB1, HIF-1α, IL-6, and IL-17 levels.ResultsSerum LPS, VE-Cadherin, CGRP, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the EM group and healthy controls while serum LBP and HMGB1 were higher in the CM + MOH group compared to healthy controls. IL-17 and occludin levels were comparable between the three groups. Serum HMGB1 levels in EM patients were higher compared to the control group. Mig-SCog and HIT-6 scores were higher in the CM + MOH group compared to EM patients. HADS-A and HADS-D scores were significantly higher in the CM + MOH group compared to EM patients and healthy controls, and they were also higher in EM patients compared to healthy subjects. LPS levels were correlated with VE-cadherin and occludin levels. The number of monthly migraine headache days was positively correlated with serum LPS, HIF-1α, VE-cadherin, and IL-6 levels, HADS-A, HADS-D, HIT-6, and MigSCog scores.ConclusionWe have evidence for the first time that CM + MOH is associated with elevated serum LPS and LBP levels suggestive of LPS leak into the systemic circulation. Higher levels of nociceptive and/or pro-inflammatory molecules such as HMGB1, HIF-1α, IL-6, and CGRP may play a role in trigeminal sensitization and neurobiology of MOH. Intestinal hyperpermeability and consequent inflammatory response should be considered as a potential contributory factor in patients with MOH.Graphical

High Mobility Group Box 1 Gene Polymorphism and Serum High Mobility Group Box 1, Interleukin 1 Beta, and Alpha-Klotho Crosstalk in Severe COVID-19 Patients

ABSTRACT Aim To evaluate the serum levels of HMGB1, IL1β, and α-klotho in COVID-19 patients with different disease severity, investigate their association with clinicopathological parameters, and to assess HMGB1 rs1045411 polymorphism and its relation with clinical severity. Methods 120 COVID-19 patients (89 critically ill, 15 severe, and 16 moderately severe) along with 80 healthy control were enrolled.The serum levels of HMGB1,IL1β, and α-klotho were determined by ELISA. The HMGB1 rs1045411 polymorphism was detected by RT- PCR. Results The serum levels of HMGB1, IL1β, and α-klotho were significantly higher in critically ill COVID-19 patients compared to other groups. The HMGB1rs1045411 polymorphism revealed a significant decrease in the percentage of T/T genotypes in COVID-19 patients compared to controls. The (ROC) analysis showed moderate diagnostic potential for serum HMGB1, IL1β, and α-klotho. Conclusion The serum HMGB1, IL1β, and α-klotho may be severity markers and promising therapeutic targets for COVID-19 patients.

Intestinal Epithelia and Myeloid Immune Cells Shape Colitis Severity and Colorectal Carcinogenesis via High-mobility Group Box Protein 1.

High-mobility group box protein 1 [HMGB1] is a ubiquitous nucleoprotein with immune-regulatory properties following cellular secretion or release in sterile and in infectious inflammation. Stool and serum HMGB1 levels correlate with colitis severity and colorectal cancer [CRC] progression, yet recent reports indicate that HMGB1 mainly operates as an intracellular determinant of enterocyte fate during colitis, and investigations into the roles of HMGB1 in CRC are lacking. Using mice with conditional HMGB1-knockout in enterocytes [Hmgb1ΔIEC] and myeloid cells [Hmgb1ΔLysM], respectively, we explored functions of HMGB1 in pathogenetically diverse contexts of colitis and colitis-associated CRC. HMGB1 is overexpressed in human inflammatory bowel disease and gastrointestinal cancers, and HMGB1 protein localises in enterocytes and stromal cells in colitis and CRC specimens from humans and rodents. As previously described, enterocyte HMGB1 deficiency aggravates severe chemical-induced intestinal injury, but not Citrobacter rodentium or T cell transfer colitis in mice. HMGB1-deficient enterocytes and organoids do not exhibit deviant apoptotic or autophagic activity, altered proliferative or migratory capacity, abnormal intestinal permeability, or aberrant DSS-induced organoid inflammation in vitro. Instead, we observed altered in vivo reprogramming of both intestinal epithelia and infiltrating myeloid cells in Hmgb1ΔIEC early during colitis, suggesting HMGB1-mediated paracrine injury signalling. Hmgb1ΔIEC had higher CRC burden than wild types in the Apc+/min model, whereas inflammatory CRC was attenuated in Hmgb1ΔLysM. Cellular and molecular phenotyping of Hmgb1ΔIEC and Hmgb1ΔLysM cancers indicates context-dependent transcriptional modulation of immune signalling and extracellular matrix remodelling via HMGB1. Enterocytes and myeloid cells context-dependently regulate host responses to severe colitis and maladaptive intestinal wound healing via HMGB1.

Age-Dependent and Aβ-Induced Dynamic Changes in the Subcellular Localization of HMGB1 in Neurons and Microglia in the Brains of an Animal Model of Alzheimer's Disease.

HMGB1 is a prototypical danger-associated molecular pattern (DAMP) molecule that co-localizes with amyloid beta (Aβ) in the brains of patients with Alzheimer's disease. HMGB1 levels are significantly higher in the cerebrospinal fluid of patients. However, the cellular and subcellular distribution of HMGB1 in relation to the pathology of Alzheimer's disease has not yet been studied in detail. Here, we investigated whether HMGB1 protein levels in brain tissue homogenates (frontal cortex and striatum) and sera from Tg-APP/PS1 mice, along with its cellular and subcellular localization in those regions, differed. Total HMGB1 levels were increased in the frontal cortices of aged wildtype (7.5 M) mice compared to young (3.5 M) mice, whereas total HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice (7.5 M) were significantly lower than those in age-matched wildtype mice. In contrast, total serum HMGB1 levels were enhanced in aged wildtype (7.5 M) mice and Tg-APP/PS1 mice (7.5 M). Further analysis indicated that nuclear HMGB1 levels in the frontal cortices of Tg-APP/PS1 mice were significantly reduced compared to those in age-matched wildtype controls, and cytosolic HMGB1 levels were also significantly decreased. Triple-fluorescence immunohistochemical analysis indicated that HMGB1 appeared as a ring shape in the cytoplasm of most neurons and microglia in the frontal cortices of 9.5 M Tg-APP/PS1 mice, indicating that nuclear HMGB1 is reduced by aging and in Tg-APP/PS1 mice. Consistent with these observations, Aβ treatment of both primary cortical neuron and primary microglial cultures increased HMGB1 secretion in the media, in an Aβ-dose-dependent manner. Our results indicate that nuclear HMGB1 might be translocated from the nucleus to the cytoplasm in both neurons and microglia in the brains of Tg-APP/PS1 mice, and that it may subsequently be secreted extracellularly.

Increased expression of NLRP3 associated with elevated levels of HMGB1 in children with febrile seizures: a case–control study

BackgroundHigh mobility group box-1 (HMGB1) is an endogenous danger signal that mediates activation of the innate immune response including NLR pyrin domain containing 3 (NLRP3) inflammasome activation and proinflammatory cytokine release. Although HMGB1 and NLRP3 have been implicated in the pathophysiology of seizures, the correlation between HMGB1 and NLRP3 expression has not been determined in children with febrile seizures (FS). To explore the relationship between extra-cellular HMGB1 and NLRP3 in children with FS, we analyzed serum HMGB1, NLRP3, caspase-1, and proinflammatory cytokines in patients with FS.MethodsThirty children with FS and thirty age-matched febrile controls were included in this study. Blood was obtained from the children with FS within 1 h of the time of the seizure; subsequently, the serum contents of HMGB1, NLRP3, caspase-1, interleukin (IL)-1β, interleukin (IL)-6, and tumour necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. The Mann‒Whitney U test was used to compare serum cytokine levels between FS patients and controls. Spearman’s rank correlation coefficient was calculated to detect significant correlations between cytokine levels.ResultsSerum levels of HMGB1, NLRP3, caspase-1, IL-1β, IL-6, and TNF-α were significantly higher in FS patients than in febrile controls (p < 0.05). Serum levels of HMGB1 were significantly correlated with levels of NLRP3 and caspase-1 (both, p < 0.05). Serum levels of caspase-1 were significantly correlated with levels of IL-1β (p < 0.05). Serum levels of IL-1β were significantly correlated with levels of IL-6 and TNF-α (p < 0.05).ConclusionsHMGB1 is up-regulated in the peripheral serum of FS patients, which may be responsible, at least in part, for the increased expression of NLRP3 and Caspase-1. Increased expression of caspase-1 was significantly associated with elevated serum levels of IL-1β. Given that activated Caspase-1 directly regulates the expression of mature IL-1β and positively correlates with activation of the NLRP3 inflammasome, our data suggest that increased levels of peripheral HMGB1 possibly mediate IL-1β secretion through the activation of the NLRP3 inflammasome in children with FS. Thus, both HMGB1 and NLRP3 might be potential targets for preventing or limiting FS.

Correlation between neurofilament, HMGB1, MMP9, ds DNA blood levels and cognitive impairment in patients with neuropsychiatric systemic lupus erythematosus.

Diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) is challenging due to nonspecific biomarkers. High serum levels of neurofilament protein light subunit (NFL), high mobility group box 1 (HMGB1), Matrix metalloproteinase-9 (MMP-9) and have been reported in several autoimmune diseases. The aim of this study was to examine whether their plasma levels could serve as a diagnostic or prognostic biomarker for NPSLE. There were 90 SLE patients enrolled in this cross-sectional study (87.8% women and 12.2% men with a mean age of 41.67±11.05 years). We assessed the mental status of patients, also we measured the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and Systemic Lupus International Collaborating Clinics/ACR (SLICC/ ACR) Damage Index or SDI scores. Serum levels of NFL, HMGB1, MMP9, and ds-DNA were investigated to find a role in the pathophysiology of NPSLE. Among the 90 patients with SLE, 63 (70%) met the criteria of NPSLE syndrome. Our results have shown a notable difference concerning SEDIAC-2k score, SDI score, PANS, MoCA, and Beck anxiety depression, between the two groups (p < 0.05). Although serum level of all measured serum biomarkers (NFL, MMP-9, HMGB1, dsDNA) were higher in patients with NPSLE, the difference was not statistically significant. Interestingly, our results showed that the serum level of NFL was correlated with the serum level of HMGB-1 and MMP-9. (r: 0.411, P=0.003). Serum level of NFL, HMGB-1 and MMP-9 may be used to detect abnormal mental status in patients with SLE.

Correlation of serum H-FABP, sTREM-1, and HMGB1 levels with severity and prognosis of sepsis.

To investigate the correlation between serum levels of Heart-type fatty acid binding protein (H-FABP), Soluble Triggering Receptor Expressed on Myeloid Cells 1 (sTREM-1), and High mobility group box 1 protein (HMGB1) with disease severity, and their prognostic value in sepsis. A retrospective analysis was conducted using the clinical data from 86 sepsis patients admitted to West China Hospital of Sichuan University between June 2021 and December 2023, and these cases constituted the observation group. In addition, clinical data from 80 healthy individuals who underwent medical examinations at our hospital during the same period served as the control group. Serum levels of H-FABP, sTREM-1, and HMGB1 were measured in both groups. Based on disease severity, the patients were categorized into mild (n=42), severe (n=28), and shock (n=16) groups. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score was used to assess the patients' condition. Follow-up evaluations showed that 60 patients survived and 26 died. Serum levels of H-FABP, sTREM-1, and HMGB1 were significantly higher in the observation group compared to the control group (all P<0.05). Among the sepsis patients, the severe and shock groups exhibited significantly elevated levels of H-FABP, sTREM-1, and HMGB1 compared to the mild group, with the shock group showing the highest levels (all P<0.05). The levels of H-FABP, sTREM-1, and HMGB1 were positively correlated with APACHE II scores (r=0.760, r=0.715, r=0.709, all P<0.001). Furthermore, the levels of these biomarkers were significantly higher in patients who died than in survivors (all P<0.05). The AUCs of H-FABP, sTREM-1, and HMGB1 for predicting prognosis were 0.786, 0.790, and 0.781, respectively. Their combined prediction yielded an AUC of 0.834. Log-rank test showed that the survival time of patients with different expression levels of sTREM-1 (<856.50 pg/ml, ≥856.50 pg/ml) and HMGB1 (<395.80 ng/ml, ≥395.80 ng/ml) were significantly different (P<0.05). Serum levels of H-FABP, sTREM-1, and HMGB1 are elevated in sepsis patients and closely associated with the disease severity, making them valuable biomarkers for monitoring the severity of sepsis. Combined detection of serum H-FABP, sTREM-1, and HMGB1 shows promising prognostic value in sepsis, with lower levels of sTREM-1 and HMGB1 linked to improved survival.

Assessment of Cerebral Hypoxemia and Its Impact on Cognitive and Psychological Functions in Patients With Obstructive Sleep Apnea Syndrome

Background and Objective The precise pathophysiology of cognitive impedance and mental illness in obstructive sleep apnea (OSA) patients remains elusive. Therefore, there is a need for studies on novel diagnoses and therapeutic strategies for cognitive impairment in OSA patients. This work aimed to evaluate cerebral hypoxemia, its consequences on brain metabolism, and local and systemic inflammation, and their subsequent impact on cognitive and psychological functioning.Methods This cross-sectional case-control study was conducted on 30 eligible OSA patients and 20 age/sex-matched healthy controls. All the participants underwent one-night polysomnography, and cognitive evaluation was done using the Mini-Mental State Examination, Montreal Cognitive Assessment, Brief Kingston Standardized Cognitive Assessment, D2 Test of Consideration (to evaluate attention problems), and Wisconsin card sorting test. The psychiatric assessment included the Arabic form of the Hamilton Depression Rating Scale and Beck Depression Inventory-II. A radiology assessment was done using proton magnetic resonance spectroscopy. Neurophysiological assessment was done using the potential cortical (N20) latency and amplitude of somatosensory evoked potential. Laboratory examinations included serum levels of NF-κB, HMGB1, and HIF-1α.Results Polysomnography demonstrated noteworthy increase in the apnea-hypopnea index, respiratory disturbance index, arousal index, snoring index, and wake after sleep onset. It also showed diminished sleep efficiency, total sleep time, and SaO2 nadir in the OSA group. Neuropsychological scales demonstrated poor performance in global cognitive tests, particular cognitive domains impedance, and depression in the OSA group, with noteworthy differences within the group. Magnetic resonance spectroscopy highlighted that OSA patients had a noteworthy bilateral decrement in N-acetylaspartate (NAA) peak, creatine peak, and NAA/choline proportion and an increment in choline peak, lipid peak, lactate peak, choline/creatine proportion, and NAA/creatine proportion in the frontal white matter, hippocampus, and parieto-occipital cortex. Moreover. OSA patients had either missing or decreased amplitude and delayed latency of N20. There was a noteworthy rise of serum inflammatory marker NF-κB, HMGB1, and oxidative stress marker HIF-1α in OSA patients.Conclusions Chronic intermittent hypoxia with resulting amplified inflammatory and oxidative stress in OSA patients may affect brain metabolism; consequently, leading to cognitive and psychological dysfunctions.

Could serum HMGB1 levels be a predictor associated with psoriatic arthritis?

Background/aim: Psoriasis is a chronic autoimmune disease that predominantly affects the skin and musculoskeletal system. We hypothesized that HMGB1, an inflammatory nuclear protein, may play a role in the musculoskeletal involvement of psoriasis. Methods: Forty patients with psoriasis and 45 with psoriatic arthritis were involved in the study; the results were compared with 22 healthy controls. Serum HMGB1 levels were evaluated from peripheral blood samples. Results: Serum HMGB1 levels were found to be significantly higher in patients with psoriasis regardless of joint involvement (p<0.001). Also, HMGB1 levels were correlated with the extent of psoriasis. Conclusion: Serum HMGB1 levels may contribute to the progression of psoriasis to psoriatic arthritis and correlate with the severity of skin involvement.

Assessment of the Serum High-Mobility Group Box 1 Level in Vitiligo Patients in Comparison to Healthy Subjects and Its Relation to Total Oxidant Status and Disease Activity

Abstract Background Vitiligo is an acquired pigmentary disorder of unknown etiology, affecting approximately 1% of the world population, without predilection for race or sex. It is characterized by white macules and patches, whose size increases over time, due to the loss of melanocytes. Aim of Work The aim of work was to evaluate the serum level of high-mobility group box 1 in vitiligo patients and its relation to total oxidant status levels and disease activity. Subjects and methods This is a cross-sectional study which was carried out on 48 patients diagnosed as having vitiligo (24 active patients and 24 and non active) and 48 health controls for 6 months duration. All patients were selected from the dermatology outpatient clinic of vitiligo, Ain-Shams University Hospitals. Results The serum levels of HMGB1 among patients and controls revealed that patients had a statistically high significant levels of HMGB1 (p value 0.001), HMGB1 serum levels in vitiligo patients were significantly positively correlated to TOS serum levels and VIDA score (p value 0.001), between active and non-active group, there was a highly statistical significant difference between the two groups regarding serum level of HMGB1, as the serum HMGB1 levels were much higher in active compared to non-active patients (p value 0.001). Conclusion HMGB1 is a crucial damage associated molecular pattern molecule that links oxidative stresses to the formation of autoimmunity in the pathogenesis of vitiligo. HMGB1 is a crucial inflammatory factor involved in the progression of vitiligo. Serum HMGB1 level is a promising biomarker for monitoring disease activity in patients with vitiligo. HMGB1 may be a promising therapeutic target for the treatment of vitiligo.

Urinary and serum levels of high mobility group box 1

BackgroundHigh mobility group box 1 (HMGB-1) has been extensively studied in adults and to a certain extent in neonates as well. Clinical examination of neonates, especially unwell neonates soon after birth, should be minimally invasive. ObjectiveThis study aimed to investigate whether the urinary HMGB-1 level is comparable to the serum HMGB-1 level in neonates. MethodsIn all, 87 neonates (37.5 ± 2.9 weeks of gestation and a mean birth weight of 2588 ± 649 g) were enrolled. Of these, 53 were males and 34 were females. The umbilical cord blood and the first or second spontaneous voiding urine samples were stored, and the HMGB-1 level in the samples was measured. ResultsHMGB-1 was detected in all urinary samples. In these samples, we found acetylated HMGB-1 and may be devoid of nine residues at the N-terminal amino acid sequence. There was a significant correlation between the serum HMGB-1 level and urinary HMGB-1 level (r = 0.73, p < 0.001). Urinary HMGB1 levels in fetal neonatal asphyxia were significantly higher than those in healthy controls (p = 0.09). ConclusionUrinary excretion may be one of the metabolic pathways of HMGB-1. The urinary HMGB-1 level may be comparable to the serum HMGB-1 level in the early neonatal period.

Vitamin D supplementation reduced blood inflammatory cytokines expression and improved graft function in kidney transplant recipients.

Chronic allograft dysfunction(CAD) is the leading cause of graft loss in kidney transplant recipients (KTRs). Inflammatory process is believed to be one of the major contributors to CAD. The aim of this study is to explore the anti-inflammatory effect of vitamin D (VD) supplementation in KTRs and its role in the graft function improvement(protection). A retrospective cohort of 39 KTRs with chronic antibody mediated rejection(CAMR)or stable renal function and a prospective cohort of 42 KTRs treated or untreated with VD were enrolled. Serum levels of vitamin D metabolism and serum inflammatory cytokines, renal graft function, and routine blood biomarkers were tested and dynamically tracked within 12 months post-transplant. Compared with the stable group, the CAMR group exhibited significantly elevated serum levels of inflammatory cytokines IL-1β, IFN-γ, IL-2, IL-10, IP-10, and HMGB1 (P <0.05). The supplementation of vitamin D effectively increased the serum concentration of vitamin D in kidney transplant recipients (KTRs) in the treated group. During the course of treatment, the treated group exhibited a gradual increase in eGFR levels, which were significantly higher than those observed in the untreated group at 12 months post-transplant (p<0.05). Notably, as eGFR improved, there was a significant decrease in levels of IL-1β, IFN-γ, IL-2, IL-10, IP-10 and HMGB1 in the treated group compared to the untreated group (P<0.05). This study confirmed that immune-inflammation is a crucial factor in the development of CAD in KTRs.VD deficiency impairs its anti-inflammatory activity. By assisting in the regulation of excessive immune inflammation and restoration of immune homeostasis, effective VD supplementation contributes to protection and maintenance of graft function in KTRs.

HMGB1 is related to disease activity in children with celiac disease

IntroductionWe aim to evaluate of the relationship between high mobility gene box-1 (HMGB1) levels and clinical, laboratory and histopathological findings at diagnosis and in remission in children with Celiac Disease (CD). Material and MethodsThe study included 36 celiac patients at diagnosis, 36 celiac patients in remission, and 36 healthy controls. Patients with intestinal pathologies other than CD, and accompanying inflammatory and/or autoimmune diseases were excluded. Relationship between HMGB1 levels and clinical, laboratory and histopathological findings were evaluated. ResultsA total of 72 celiac patients [36 (18 girls, 18 boys, mean age 9.41±3.9 years) in group 1 and 36 (18 girls, 18 boys, mean age 9.91±3.36 years) in group 2] and 36 healthy controls in group 3 (19 girls, 17 boys, mean age 9.56±4 years) were included. The HMGB1 level was significantly higher in group 1 compared to group 2 and group 3 [36.63 (17.98–54.72) ng/ml vs 20.31 (16.89–29.79) ng/ml, p = 0.028 and 36.63 (17.98–54.72) ng/ml vs 20.38 (17.54–24.53) ng/ml p = 0.012, respectively]. A serum HMGB-1 level of 26.553 ng/ml was found to be a cut-off value for the CD with 61% sensitivity, 83% specificity, 78% positive predictive value, and 68% negative predictive value. Higher HMGB1 values were seen in patients with intestinal findings, anemia, anti-tissue transglutaminase IgA levels that were greater than 10 times upper limit of normal, and patients with a higher degree of atrophy as classified by Marsh-Oberhuber. ConclusionsIn conclusion, it was thought that HMGB-1 might be a marker that reflects the severity of atrophy at the time of diagnosis and could be used to control dietary compliance in the follow-up. However, there is need for larger population studies in order to evaluate its value as a serological marker for the diagnosis and follow-up of CD and to find a more reliable cut-off value.

HMGB1/STAT3/p65 axis drives microglial activation and autophagy exert a crucial role in chronic Stress-Induced major depressive disorder

IntroductionNeuroinflammation and autophagy are implicated in stress-related major depressive disorder (MDD), but the underlying molecular mechanisms remain largely unknown. ObjectivesHere, we identified that MDD regulated by HMGB1/STAT3/p65 axis mediated microglial activation and autophagy for the first time. Further investigations were performed to uncover the effects of this axis on MDD in vivo and in vitro. MethodsBioinformatics analyses were used to re-analysis the transcriptome data from the dorsolateral prefrontal cortex (dlPFC) of post-mortem male MDD patients. The expression level of HMGB1 and its correlation with depression symptoms were explored in MDD clinical patients and chronic social defeat stress (CSDS)-induced depression model mice. Specific adeno-associated virus and recombinant (r)HMGB1 injection into the medial PFC (mPFC) of mice, and pharmacological inhibitors with rHMGB1 in two microglial cell lines exposed to lipopolysaccharide were used to analyze the effects of HMGB1/STAT3/p65 axis on MDD. ResultsThe differential expression of genes from MDD patients implicated in microglial activation and autophagy regulated by HMGB1/STAT3/p65 axis. Serum HMGB1 level was elevated in MDD patients and positively correlated with symptom severity. CSDS not only induced depression-like states in mice, but also enhanced microglial reactivity, autophagy as well as activation of the HMGB1/STAT3/p65 axis in mPFC. The expression level of HMGB1 was mainly increased in the microglial cells of CSDS-susceptible mice, which also correlated with depressive-like behaviors. Specific HMGB1 knockdown produced a depression-resilient phenotype and suppressed the associated microglial activation and autophagy effects of CSDS-induced. The effects induced by CSDS were mimicked by exogenous administration of rHMGB1 or specific overexpression of HMGB1, while blocked by STAT3 inhibitor or p65 knockdown. In vitro, inhibition of HMGB1/STAT3/p65 axis prevented lipopolysaccharide-induced microglial activation and autophagy, while rHMGB1 reversed these changes. ConclusionOur study established the role of microglial HMGB1/STAT3/p65 axis in mPFC in mediating microglial activation and autophagy in MDD.