HMGB1 Research Articles

The role of high mobility group box-1 on the development of diabetes complications: A plausible pharmacological target.

Diabetes mellitus has emerged as a pressing global concern, with a notable increase in recent years. Despite advancements in treatment, existing medications struggle to halt the progression of diabetes and its associated complications. Increasing evidence underscores inflammation as a significant driver in the onset of diabetes mellitus. Therefore, perspectives on new therapies must consider shifting focus from metabolic stress to inflammation. High mobility group box (HMGB-1), a nuclear protein regulating gene expression, gained attention as an endogenous danger signal capable of sparking inflammatory responses upon release into the extracellular environment in the late 1990s. Given the parallels between inflammatory responses and type 2 diabetes (T2D) development, this review paper explores HMGB-1's potential involvement in onset and progression of diabetes complications. Specifically, we will review and update the understanding of HMGB-1 and its inflammatory pathways in insulin resistance, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. HMGB-1 and its receptors i.e. receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) present promising targets for antidiabetic interventions. Ongoing and future projects in this realm hold promise for innovative approaches targeting HMGB-1-mediated inflammation to ameliorate diabetes and its complications.

Brain and Lung Biomarker Responses to Hyperoxic Hypobaric Decompression.

INTRODUCTION: Biomarker responses to intensive decompression indicate systemic proinflammatory responses and possible neurological stress. To further investigate responses, 12 additional brain and lung biomarkers were assayed.METHODS: A total of 15 healthy men (20 to 50 yr) undertook consecutive same-day ascents to 25,000 ft (7620 m), following denitrogenation, breathing 100% oxygen. Venous blood was sampled at baseline (T0), after the second ascent (T8), and next morning (T24). Soluble protein markers of brain and lung insult were analyzed by enzyme-linked immunosorbent assay with plasma microparticles quantified using flow cytometry.RESULTS: Levels of monocyte chemoattractant protein-1 and high mobility group box protein 1 were elevated at T8, by 36% and 16%, respectively, before returning to baseline. Levels of soluble receptor for advanced glycation end products fell by 8%, recovering by T24. Brain-derived neurotrophic factor rose by 80% over baseline at T24. Monocyte microparticle levels rose by factors of 3.7 at T8 and 2.7 at T24 due to early and late responses in different subjects. Other biomarkers were unaffected or not detected consistently.DISCUSSION: The elevated biomarkers at T8 suggest a neuroinflammatory response, with later elevation of brain-derived neurotrophic factor at T24 indicating an ongoing neurotrophic response and incomplete recovery. A substantial increase at T8 in the ratio of high mobility group box protein 1 to soluble receptor for advanced glycation end products suggests this axis may mediate the systemic inflammatory response to decompression. The mechanism of neuroinflammation is unclear but elevation of monocyte microparticles and monocyte chemoattractant protein-1 imply a key role for activated monocytes and/or macrophages.Connolly DM, Madden LA, Edwards VC, Lee VM. Brain and lung biomarker responses to hyperoxic hypobaric decompression. Aerosp Med Hum Perform. 2024; 95(9):667-674.

Parkin activates innate immunity and promotes antitumor immune responses.

The activation of innate immunity and associated interferon (IFN) signaling have been implicated in cancer, but the regulators are elusive and links to tumor suppression remain undetermined. Here, we found that Parkin, an E3 ubiquitin ligase altered in Parkinson's Disease, was epigenetically silenced in cancer and its reexpression by clinically approved demethylating therapy stimulated transcription of a potent IFN response in tumor cells. This pathway required Parkin E3 ubiquitin ligase activity, involved the subcellular trafficking and release of the alarmin High Mobility Group Box 1 (HMGB1) and was associated with inhibition of NF-κB gene expression. In turn, Parkin-expressing cells released an IFN secretome that upregulated effector and cytotoxic CD8+ T cell markers, lowered the expression of immune inhibitory receptors TIM3 and LAG3, and stimulated high content of the self renewal/stem cell factor, TCF1. PRKN-induced CD8+ T cells selectively accumulated in the microenvironment and inhibited transgenic and syngeneic tumor growth in vivo. Therefore, Parkin is an epigenetically regulated activator of innate immunity and dual mode tumor suppressor, inhibiting intrinsic tumor traits of metabolism and cell invasion, while simultaneously reinvigorating CD8 T cell functions in the microenvironment.

A multifunctional nanoplatform with dual-targeted antibacterial and cascaded immunomodulatory strategy for the treatment of bacterial keratitis

Bacterial keratitis (BK) is a serious ocular infection and frequently cause irreversible damage to the corneal tissue and even blindness. Current clinical treatments using antibiotics achieve unsatisfactory outcomes due to the lower bioavailability, high risks of drug resistance and limited therapeutic functions. To address these challenges, we proposed a dual-targeted antibacterial and cascaded immunomodulatory therapy strategy, constructing a multifunctional nanoplatform (HPBH@GLA/AMP) using the 3-aminophenylboric acid (NBA) and hyaluronic acid (HA) co-modified hollow polydopamine (HPDA) to serve as a functional nanocarrier (HPBH) for loading antimicrobial peptide (AMP) and glycyrrhizic acid (GLA). The HPBH@GLA/AMP presented excellent targeting and bactericidal performance to Pseudomonas aeruginosa (P. aeruginosa), coupled with its capacity to alleviate the bacteria-triggered excessive immune response via an ingenious cascaded immunoregulatory process. Notably, the study of underlying anti-inflammatory mechanism revealed that the functional nanocarrier of HPDA could effectively scavenge the reactive oxygen species (ROS) for controlling early inflammatory responses, while inhibit the expression of late mediator high mobility group box 1 (HMGB1) chemokine through released GLA. Specially, the duel-targeted characteristic enabled this nanoplatform to recognize both the bacteria and inflammatory cells precisely and aggregate the location where bacteria and/or inflammatory cells exist persistently, effectively increased the therapeutic concentration of drugs. Featuring the antibacterial synergistic yet sequential regulation for the inflammatory response, the HPBH@GLA/AMP achieved satisfactory therapeutic effects in a BK mouse model in vivo. This study provides a bright prospect for clinical treatment of refractory bacterial keratitis (BK) and even extended to other immunotherapy in infectious disease.

Serum HMGB1 as a predictor for postoperative delirium in elderly patients undergoing total hip arthroplasty surgery.

Postoperative delirium (POD) is an acute mental disorder that occurs after surgery requiring general anesthesia. In animal studies, high-mobility group box 1 (HMGB1) plays a key role in mediating postoperative neuroinflammation and may have a direct impact on POD. The objective of this prospective observational study was to investigate the serum levels of HMGB1 in elderly POD patients undergoing total hip arthroplasty. This prospective observational study included 287 elderly patients who underwent total hip arthroplasty in our hospital from October 2019 to September 2022. Patients were assessed for the presence of POD using the Confusion Assessment Method (CAM) within 72 h of surgery. Serum HMGB1, interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) levels were measured using enzyme-linked immunosorbent assay (ELISA) before surgery, as well as at 24 h, 48 h and 72 h after surgery. Demographic and clinical data of all elderly patients were collected. The anesthesia time and surgical time in the POD group were significantly higher than those in the non-POD group. The serum levels of HMGB1, IL-6 and IL-1β in the POD group were significantly elevated compared to those in the non-POD group at all time points after surgery (p < 0.05). In addition, the serum levels of HMGB1 were positively correlated with TNF-α, IL-6 and IL-1β levels. HMGB1, IL-6 and IL-1β could be potential predictive biomarkers for the occurrence of POD in elderly patients undergoing total hip arthroplasty. Finally, we found that anesthesia time, surgical time, HMGB1, TNF-α, IL-6, and IL-1β were risk factors for POD in elderly patients undergoing total hip arthroplasty. Serum HMGB1 levels were markedly elevated in elderly POD patients undergoing total hip arthroplasty. In addition, HMGB1 could serve as a potential predictive biomarker for POD in elderly patients undergoing total hip arthroplasty.

Evaluation on the antibacterial activity of glycyrrhizin against Pseudomonas plecoglossicida in ayu fish (Plecoglossus altivelis)

Glycyrrhizin (GLR), an active constituent of the traditional Chinese medicine (TCM) liquorice (Glycyrrhiza uralensis Fisch), has important functions against bacterial invasions in mammals. However, studies on the antimicrobial properties of GLR in teleosts remain relatively scarce. Herein, we performed an in vitro screening of 30 monomeric TCM compounds and found that only GLR exhibited significant inhibitory activity against the bacterium Pseudomonas plecoglossicida and increased the survival rate of ayu fish challenged with it. Moreover, we explored the antimicrobial properties of GLR in in vitro antimicrobial experiments and found that it inhibited all 10 common aquatic pathogens, including P. plecoglossicida. Notably, spectrophotometry and fluorescence staining assays revealed that GLR exhibited bactericidal activity in vitro by inhibiting P. plecoglossicida biofilm formation and increasing its membrane permeability. Notably, we showed that GLR could reduce pro-inflammatory factor levels, reduce bacterium-triggered apoptosis of monocytes/macrophages (MO/Mф), and promote their phagocytosis and bactericidal capacity. Mechanically, a cellular thermal shift assay confirmed that GLR could bind to high mobility group box 1 (HMGB1), suggesting that GLR may regulate MO/Mф functions through HMGB1-mediated pathways. Overall, our findings confirm the direct bactericidal ability of GLR and resistance to pathogen invasion by modulating the immune activity of MO/Mф, providing an essential basis for the utilisation of TCM in aquatic animal protection.

Mitigating the Effects of 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol on Gastrointestinal Acute Radiation Syndrome after Total-Body Irradiation in Mice.

Total-body irradiation (TBI) with gamma rays can damage organisms in various unexpected ways and trigger several organ dysfunction syndromes, such as acute radiation syndrome (ARS). Hematopoietic cells and enterocytes are particularly sensitive to radiation due to their self-renewal ability and rapid division, which leads to hematopoietic ARS (H-ARS) and gastrointestinal ARS (GI-ARS). We previously showed that a lipid-based small molecule, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), improved 30-day survival and alleviated H-ARS symptoms in BALB/c mice after a lethal dose (LD70/30) of gamma-ray TBI. In this study, we investigated the mitigating effects of PLAG on radiation-induced GI damage that occurs under the same conditions as H-ARS in BALB/c mice. Our study showed that PLAG facilitated the structural restoration of intestinal tissues by increasing villus height, crypt depth, crypt number, mucin-producing goblet cells, and proliferating cell nuclear antigen (PCNA)-positive crypt cells. PLAG significantly improved intestinal absorptive capacity and reduced intestinal injury-induced bacterial translocation. In addition, PLAG effectively inhibited radiation-induced necroptosis signaling activation in the intestinal crypt cells, which was responsible for sustained tissue damage and the release of high mobility group box 1 (HMGB1), a typical damage-associated molecular pattern. Overall, our findings support the radiation-mitigating potential of PLAG against GI-ARS after accidental radiation exposure.

The Necroptosis Pathway Is Upregulated in the Cornea in Mice With Ocular Graft-Versus-Host Disease.

To identify molecular signatures specific for ocular graft-versus-host disease (GVHD) by proteomic analysis of corneas from mice with GVHD. We identified differentially expressed proteins (DEPs) in corneal samples from GVHD model mice and syngeneic control mice 4 weeks after bone marrow transplantation. Data-independent acquisition analysis was performed on individual samples, and the roles of DEPs in biological pathways related to GVHD were evaluated via bioinformatics and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Three important signaling pathways were upregulated in the cornea in mice with GVHD: (1) the necroptosis pathway, (2) the mitogen-activated protein kinase (MAPK) pathway, and (3) as previously reported, the neutrophil extracellular trap (NET) pathway. In those signaling pathways, we identified new upregulated molecules, including (1) receptor-interacting protein kinase 1 (RIPK1), RIPK3, interferon regulatory factor 9, the interferon-induced double-stranded RNA-activated protein kinase lipoxygenase, and high mobility group box1 (HMGB1) which are damage-associated molecular patterns (DAMPs) in the necroptosis pathway; (2) the sequentially upregulated interleukin 1 (IL-1) receptor-associated kinase (IRAK), an evolutionarily conserved signaling intermediate in the Toll pathway (ECSIT), and p38, which is downstream of the IL-1 receptor and increased CDC42/Rac (Rac2), a Rho family GTPase in the MAPK pathway; and (3) the integrin components CR3 and macrophage-1 antigen (MAC-1), which are DAMPs, and the pyroptosis-related protein gasdermin D (GSDMD) in the NET pathway. These novel molecules may help researchers elucidate the pathogenesis of GVHD and identify new therapeutic targets for corneal changes in patients with ocular GVHD.

Circ-0044539 promotes lymph node metastasis of hepatocellular carcinoma through exosomal-miR-29a-3p

Lymph node metastasis (LNM) is a common invasive feature of hepatocellular carcinoma (HCC) associated with poor clinical outcomes. Through microarray profiling and bioinformatic analyses, we identified the circ-0044539-miR-29a-3p-VEGFA axis as a potential key factor in the progression of HCC LNM. In HCC cells and nude mice, circ-0044539 downregulation or miR-29a-3p upregulation was associated with small tumor size, PI3K-AKT-mTOR pathway inactivation, and downregulation of the key LNM factors (HIF-1α and CXCR4). Furthermore, circ-0044539 was also responsible for exosomal miR-29a-3p secretion. Exosomal miR-29a-3p was then observed to migrate to the LNs and downregulate High-mobility group box transcription factor 1 (Hbp1) in Polymorphonuclear Myeloid-derived suppressor cells (PMN-MDSCs), inducing the formation of a microenvironment suitable for tumor colonization. Overall, circ-0044539 promotes HCC cell LNM abilities and induces an immune-suppressive environment in LNs through exosomes, highlighting its potential as a target for HCC LNM and HCC immunotherapy.

Serum Level of High-mobility Group Box Protein-1 in Children with Sepsis, Severe Sepsis and Septic Shock

Serum Level of High-mobility Group Box Protein-1 in Children with Sepsis, Severe Sepsis and Septic Shock

Noninflammatory 97-amino acid High Mobility Group Box 1 derived polypeptide disrupts and prevents diverse biofilms

Bacterial biofilm communities are embedded in a protective extracellular matrix comprised of various components, with its' integrity largely owed to a 3-dimensional lattice of extracellular DNA (eDNA) interconnected by Holliday Junction (HJ)-like structures and stabilised by the ubiquitous eubacterial DNABII family of DNA-binding architectural proteins. We recently showed that the host innate immune effector High Mobility Group Box 1 (HMGB1) protein possesses extracellular anti-biofilm activity by destabilising these HJ-like structures, resulting in release of biofilm-resident bacteria into a vulnerable state. Herein, we showed that HMGB1's anti-biofilm activity was completely contained within a contiguous 97 amino acid region that retained DNA-binding activity, called 'mB Box-97'. We engineered a synthetic version of this 97-mer and introduced a single amino acid change which lacked any post-translational modifications, and tested its activity independently and in combination with a humanised monoclonal antibody that disrupts biofilms by the distinct mechanism of DNABII protein sequestration. mB Box-97 disrupted and prevented biofilms, including those formed by the ESKAPEE pathogens, and importantly reduced measurable proinflammatory activity normally associated with HMGB1 in a murine lung infection model. Herein, we discuss the value of targeting the ubiquitous eDNA-dependent matrix of biofilms via mB Box-97 used singly or in a dual host-augmenting/pathogen-targeted cocktail to resolve bacterial biofilm infections. This work was supported by NIH/NIDCD R01DC011818 to L.O.B. and S.D.G. and NIH/NIAID R01AI155501 to S.D.G.

TARGETED TEMPERATURE MANAGEMENT AT 36°C IMPROVES SURVIVAL AND PROTECTS TISSUES BY MITIGATING THE DELETERIOUS INFLAMMATORY RESPONSE FOLLOWING HEMORRHAGIC SHOCK.

Hemorrhagic shock (HS) is a life-threatening condition with high mortality rates despite current treatments. This study investigated whether targeted temperature management (TTM) could improve outcomes by modulating inflammation and protecting organs following HS. Using a rat model of HS, TTM was applied at 33°C and 36°C after fluid resuscitation. Surprisingly, TTM at 33°C increased mortality, while TTM at 36°C significantly improved survival rates. It also reduced histological damage in lung and kidney tissues, lowered serum lactate levels, and protected against apoptosis and excessive reactive oxygen species production. TTM at 36°C inhibited the release of high mobility group box 1 protein (HMGB1), a key mediator of inflammation, and decreased proinflammatory cytokine levels in the kidneys and lungs. Moreover, it influenced macrophage behavior, suppressing the harmful M1 phenotype while promoting the beneficial M2 polarization. Cytokine array analysis confirmed reduced levels of proinflammatory cytokines with TTM at 36°C. These results collectively highlight the potential of TTM at 36°C as a therapeutic approach to improve outcomes in HS. By addressing multiple aspects of injury and inflammation, including modulation of macrophage responses and cytokine profiles, TTM at 36°C offers promising implications for critical care management after HS, potentially reducing mortality and improving patient recovery.

Exercise Preconditioning of the Donor Liver Decreases Cold Ischemia/Reperfusion Injury in a Mouse Model.

Liver transplantation stands as the primary treatment for end-stage liver disease, with demand surging in recent decades because of expanded indications. However, hepatic ischemia/reperfusion injury can lead to liver transplant failure in both deceased donor and living donor transplantation. This study explored whether preconditioning donor livers through exercise training (ExT) could mitigate cold ischemic injury posttransplantation. Donor C57BL/6 mice underwent ExT via treadmill running or remained sedentary. After 4 wk, the donor liver underwent cold storage and subsequent orthotopic liver transplantation or ex vivo warm reperfusion. Donor liver from mice subjected to ExT showed significantly decreased hepatic injury on reperfusion. Tissue histology revealed decreased sinusoidal congestion, vacuolization, and hepatocellular necrosis in livers from ExT mice, and immunofluorescence staining further revealed a decreased number of apoptotic cells in ExT grafts. Livers from ExT donors expressed decreased intragraft inflammatory cytokines cascade, decreased neutrophil infiltration and neutrophil extracellular traps, and increased M2 phenotype of recipient macrophages compared with grafts from sedentary mice. After cold storage, liver grafts from ExT donors showed decreased accumulation of reactive oxygen species and decreased levels of cytochrome c and high mobility group box 1 released in the liver effluent. In addition, ExT grafts showed upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and higher levels of mitochondrial content. Similar effects of decreased hepatic injury were observed in wild-type mice when pretreated with a PGC-1α stimulator ZLN005 instead of ExT. These findings suggest that augmenting hepatocytic mitochondrial content through donor exercise or PGC-1α stimulation may offer therapeutic avenues to mitigate postreperfusion inflammation and improve transplant outcomes.

High-Intensity Interval Training Decreases Circulating HMGB1 in Individuals with Insulin Resistance; Plasma Lipidomics Identifies Associated Cardiometabolic Benefits.

Background: Exercise is a fundamental primary standard of care for cardiometabolic health. Body Weight (BW) High-Intensity Interval Training (HIIT) is an effective strategy for reducing cardiometabolic markers in individuals with insulin resistance and Type-2 diabetes (T2D). High-mobility group box 1 (HMGB1), a ubiquitous nuclear factor, plays an ample role beyond an alarmin in T2D development and progression. Our group has described this novel role previously, showing the beneficial effect of whole body HMGB1 silencing in decreasing hyperglycemia in diabetic mice. In the present study we tested the hypothesis that BW-HIIT as an effective exercise training modality will decrease cardiometabolic risk with a concomitant decrease in circulating HMGB1 more prominently in insulin resistant individuals compared to non-insulin resistant individuals contrasting to what we can evidence in a preclinical murine model of insulin resistance; Methods: Human and mouse pre- and post-exercise serum/plasma samples were analyzed for Lipidomics as well as Metabolic and Cytokine Multiplex assays. Standard of care, as well as cardiometabolic parameters, was also performed in human subjects; Results: insulin resistant individuals had the most positive effect, primarily with a decrease in the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). as an index of insulin resistance as well as decreased HMGB1 post-exercise. Lipidomic analysis illustrated the highly beneficial effect of exercise training using a modified HIIT program, showing an enhanced panel of circulating lipids post-exercise exclusively in insulin resistant individuals. Plasma multiplex revealed significant translational heterogeneity in our studies with distinct metabolic hormone responses to exercise conditioning with a decrease in inflammatory markers in insulin resistant individuals; Conclusions: The current study demonstrated that 6-week BW-HIIT training improves cardiometabolic, anti-inflammatory markers, metabolic hormones, and insulin sensitivity in humans, strongly associated with decreased circulating HMGB1. Overall, these experiments reinforce the potential of HMGB1 as a marker of changes in insulin resistance and the positive effect of exercise training on insulin resistance possibly preventing the development of T2D and associated complications.

A Preliminary Finding: N-butyl-phthalide Plays a Neuroprotective Role by Blocking the TLR4/HMGB1 Pathway and Improves Mild Cognitive Impairment Induced by Acute Cerebral Infarction.

Most acute cerebral infarctions (ACI) may develop vascular dementia (VD), which involves almost all types of cognitive impairment. Unfortunately, there is currently no effective treatment for VD. Most patients exhibit mild cognitive impairment (MCI) before the development of VD. N-butyl-phthalide (NBP) is used to treat ACI and improve cognitive function. The oxygen and glucose deprivation (OGD) model of neurons is an in vitro model of ischemia, hypoxia, and cognitive dysfunction. We conducted clinical studies and in vitro experiments to investigate the clinical efficacy and mechanism of action of NBP for treating ACI-induced MCI. Patients with ACI-induced MCI were randomly divided into control (Ctrl) and NBP groups. We assessed various indicators, such as clinical efficacy, montreal cognitive assessment scale (MOCA), activities of daily living (ADL), and cerebral infarct size in both groups before and after treatment. We observed the morphology of neurons and detected the survival rate, action potentials (APs), expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and the interaction between TLR4 and HMGB1. The MOCA and ADL scores increased significantly after treatment in the NBP group. A OGD model of neurons was established, and the neurons were divided into Ctrl and NBP groups. We observed that the survival rate and APs amplitude of the neurons were significantly increased in the NBP group, whereas TNF-α expression was decreased. Furthermore, the interaction between TLR4 and HMGB1 decreased in the NBP group. NBP plays a neuroprotective role by inhibiting the TLR4/HMGB1 pathway and ameliorating ACI-induced MCI.

Mar1, a high mobility group box protein, regulates n-alkane adsorption and cell morphology of the dimorphic yeast Yarrowia lipolytica.

The dimorphic yeast Yarrowia lipolytica possesses an excellent ability to utilize n-alkane as a sole carbon and energy source. Although there are detailed studies on the enzymes that catalyze the reactions in the metabolic processes of n-alkane in Y. lipolytica, the molecular mechanism underlying the incorporation of n-alkane into the cells remains to be elucidated. Because Y. lipolytica adsorbs n-alkane, we postulated that Y. lipolytica incorporates n-alkane through direct interaction with it. We isolated and characterized mutants defective in adsorption to n-hexadecane. One of the mutants harbored a nonsense mutation in MAR1 (Morphology and n-alkane Adsorption Regulator 1) encoding a protein containing a high mobility group box. The deletion mutant of MAR1 exhibited defects in adsorption to n-hexadecane and filamentous growth on solid media, whereas the strain that overexpressed MAR1 exhibited hyperfilamentous growth. Fluorescence microscopic observations suggested that Mar1 localizes in the nucleus. RNA-sequencing analysis revealed the alteration of the transcript levels of several genes, including those encoding transcription factors and cell surface proteins, by the deletion of MAR1. These findings suggest that MAR1 is involved in the transcriptional regulation of the genes required for n-alkane adsorption and cell morphology transition.IMPORTANCEYarrowia lipolytica, a dimorphic yeast capable of assimilating n-alkane as a carbon and energy source, has been extensively studied as a promising host for bioconversion of n-alkane into useful chemicals and bioremediation of soil and water contaminated by petroleum. While the metabolic pathway of n-alkane in this yeast and the enzymes involved in this pathway have been well characterized, the molecular mechanism to incorporate n-alkane into the cells is yet to be fully understood. Due to the ability of Y. lipolytica to adsorb n-alkane, it has been hypothesized that Y. lipolytica incorporates n-alkane through direct interaction with it. In this study, we identified a gene, MAR1, which plays a crucial role in the transcriptional regulation of the genes necessary for the adsorption to n-alkane and the transition of the cell morphology in Y. lipolytica. Our findings provide valuable insights that could lead to advanced applications of Y. lipolytica in n-alkane bioconversion and bioremediation.

Inhibition of ALOX12-12-HETE Alleviates Lung Ischemia-Reperfusion Injury by Reducing Endothelial Ferroptosis-Mediated Neutrophil Extracellular Trap Formation.

Lung ischemia-reperfusion injury (IRI) stands as the primary culprit behind primary graft dysfunction (PGD) after lung transplantation, yet viable therapeutic options are lacking. In the present study, we used a murine hilar clamp (1 h) and reperfusion (3 h) model to study IRI. The left lung tissues were harvested for metabolomics, transcriptomics, and single-cell RNA sequencing. Metabolomics of plasma from human lung transplantation recipients was also performed. Lung histology, pulmonary function, pulmonary edema, and survival analysis were measured in mice. Integrative analysis of metabolomics and transcriptomics revealed a marked up-regulation of arachidonate 12-lipoxygenase (ALOX12) and its metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which played a pivotal role in promoting ferroptosis and neutrophil extracellular trap (NET) formation during lung IRI. Additionally, single-cell RNA sequencing revealed that ferroptosis predominantly occurred in pulmonary endothelial cells. Importantly, Alox12-knockout (KO) mice exhibited a notable decrease in ferroptosis, NET formation, and tissue injury. To investigate the interplay between endothelial ferroptosis and NET formation, a hypoxia/reoxygenation (HR) cell model using 2 human endothelial cell lines was established. By incubating conditioned medium from HR cell model with neutrophils, we found that the liberation of high mobility group box1 (HMGB1) from endothelial cells undergoing ferroptosis facilitated the formation of NETs by activating the TLR4/MYD88 pathway. Last, the administration of ML355, a targeted inhibitor of Alox12, mitigated lung IRI in both murine hilar clamp/reperfusion and rat left lung transplant models. Collectively, our study indicates ALOX12 as a promising therapeutic strategy for lung IRI.

IL-6 and HMGB1 Levels for Predicting Major Adverse Vascular Events after Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome

Objective: This study aims to investigate the value of interleukin 6 (IL-6) and high-mobility group box 1 (HMGB1) in predicting major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). Methods: Patients with ACS who were treated in our hospital from October 2022 to October 2023 were divided into MACE and no-MACE groups according to the occurrence of MACE after PCI. The baseline data and IL-6 and HMGB1 levels in the two groups were observed, and the influencing factors of MACE in patients with ACS after PCI were evaluated with a logistic regression test. The receiver operator characteristic curve (ROC) values of IL-6 and HMGB1 in the prediction of MACE after PCI in patients with ACS were calculated. Results: No significant differences in age, sex, body mass index (BMI), and other general data were found between the groups. Compared with the patients in the no-MACE group, the patients in the MACE group had a history of smoking (p = 0.011), hypertension (p &lt; 0.001), diabetes (p &lt; 0.001), more coronary lesions (p = 0.013), longer coronary lesions (p = 0.006), higher preoperative Gensini score (p &lt; 0.001), and lower left ventricular ejection fractions (LVEF) (p &lt; 0.001). The levels of IL-6 and HMGB1 in the MACE group were significantly higher than those in the no-MACE group. Coronary lesion length, Gensini score, LVEF, IL-6, and HMGB1 had good predictive value for MACE after PCI. The area under the curve (AUC) scores were 0.683, 0.941, 0.816, 0.878, and 0.737. The sensitivity was 53.13%, 81.25%, 84.37%, 78.12%, and 53.13%, and the specificity was 87.50%, 93.18%, 63.64%, 86.36%, and 86.36%, respectively. Analysis of IL-6 and HMGB1 levels showed that the AUC was 0.922, the sensitivity was 90.62%, the specificity was 82.95%, and the 95% confidence interval (CI) was (0.858–0.963; p &lt; 0.05). Conclusion: IL-6 and HMGB1 have good predictive value for MACE after PCI for patients with ACS and can be used as clinical evaluation indexes.

High mobility group box1 (HMGB1) is a potential disease biomarker in cell and mouse models of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder affecting 1:3500 male births and is associated with myofiber degeneration, regeneration, and inflammation. Glucocorticoid treatments have been the standard of care due to immunomodulatory/immunosuppressive properties but novel genetic approaches, including exon skipping and gene replacement therapy, are currently being developed. The identification of additional biomarkers to assess DMD-related inflammatory responses and the potential efficacy of these therapeutic approaches are thus of critical importance. The current study uses RNA sequencing of skeletal muscle from two mdx mouse models to identify high mobility group box1 (HMGB1) as a candidate biomarker potentially contributing to DMD-related inflammation. HMGB1 protein content was increased in a human iPSC-derived skeletal myocyte model of DMD and microdystrophin treatment decreased HMGB1 back to control levels. In vivo, HMGB1 protein levels were increased in vehicle treated B10-mdx skeletal muscle compared to B10-WT and significantly decreased in B10-mdx animals treated with adeno-associated virus (AAV)-microdystrophin. However, HMGB1 protein levels were not increased in D2-mdx skeletal muscle compared to D2-WT, demonstrating a strain-specific difference in DMD-related immunopathology.

Effects of artemisinin and cisplatin on the malignant progression of oral leukoplakia. In vitro and in vivo study

ObjectivesChemoprevention can be a treatment for potentially malignant lesions (PMLs). We aimed to evaluate whether artemisinin (ART) and cisplatin (CSP) are associated with apoptosis and immunogenic cell death (ICD) in vitro, using oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) cell lines, and whether these compounds prevent OL progression in vivo.MethodsNormal keratinocytes (HaCat), Dysplastic oral cells (DOK), and oral squamous cell carcinoma (SCC-180) cell lines were treated with ART, CSP, and ART + CSP to analyze cytotoxicity, genotoxicity, cell migration, and increased expression of proteins related to apoptosis and ICD. Additionally, 41 mice were induced with OL using 4NQO, treated with ART and CSP, and their tongues were histologically analyzed.ResultsIn vitro, CSP and CSP + ART showed dose-dependent cytotoxicity and reduced SCC-180 migration. No treatment was genotoxic, and none induced expression of proteins related to apoptosis and ICD; CSP considerably reduced High-mobility group box-1 (HMGB-1) protein expression in SCC-180. In vivo, there was a delay in OL progression with ART and CSP treatment; however, by the 16th week, only CSP prevented progression to OSCC.ConclusionExpression of proteins related to ICD and apoptosis did not increase with treatments, and CSP was shown to reduce immunogenic pathways in SCC-180, while reducing cell migration. ART did not prevent the malignant progression of OL in vivo; CSP did despite significant adverse effects.