Search Results (520)

Background/Objectives: Orthopaedic trauma management in polytrauma patients presents challenges, particularly in selecting between damage control orthopaedics (DCO) and early appropriate care (EAC). This systematic review evaluates these approaches and explores the role of biomarkers in optimising surgical timing. The primary objective of this review was to evaluate the potential clinical utility of biomarkers in guiding surgical timing and predicting perioperative complications. The secondary objective was to compare the effectiveness of DCO and EAC approaches, focusing on their impact on patient outcomes when controlled for Injury Severity Scores (ISSs). Methods: A systematic search of PubMed, MEDLINE, and Google Scholar identified studies focusing on fracture management (DCO versus EAC), timing protocols, and biomarkers in polytrauma patients. Twenty-seven studies met inclusion criteria. Results: Among the 27 studies, 12 evaluated biomarkers and 15 compared DCO and EAC. Point-of-care (POC) biomarkers, including lactate (p < 0.001; OR 1.305), monocyte L-selectin (p = 0.001; OR 1.5), and neutrophil L-selectin (p = 0.005; OR 1.56), demonstrated predictive value for sepsis, infection, and morbidity. CD16bright/CD62Ldim neutrophils were significant predictors of infection (p = 0.002). Advanced biomarkers, such as IL-6, IL-10, RNA IL-7R, HMGB1, and leptin offered prognostic insights but required longer processing times. No clear superiority was identified between DCO and EAC, with comparable outcomes when injury severity scores (ISS) were controlled. Conclusions: This systematic review highlights the challenge of translating biomarker research into clinical practice, identifying several point-of-care and advanced laboratory biomarkers with significant potential to predict complications like sepsis, infection, and MODS. Future efforts should focus on refining biomarker thresholds, advancing point-of-care technologies, and validating their role in improving surgical timing and trauma care outcomes. Full article

(1) Liver injury caused by an overdose of acetaminophen (APAP) represents a major public health concern. Paeoniflorin (PF) has been reported to have anti-inflammatory and liver-protective effects, but the underlying mechanisms remain unclear. This study aimed to investigate the effect of PF on the crosstalk between pyroptosis and NETs in AILI. (2) APAP-treated C57BL/6J mice were used to demonstrate the protective effect of PF on liver injury. HepG2 and dHL-60 cells were cultured to study the effects of PF on hepatocyte pyroptosis and neutrophil extracellular traps (NETs) in vitro. Moreover, cell co-culture experiments were performed, and mice were treated with a NETs-depleting agent and hepatocyte pyroptosis inhibitor to investigate the improvement of AILI induced by PF through regulating the crosstalk between hepatocyte pyroptosis and NETs. (3) PF significantly alleviated AILI. Additionally, PF inhibited the expression of pyroptosis-related proteins, high-mobility group box 1 (HMGB1), and NETs-associated proteins in vitro and in vivo. The co-culture experiments demonstrated that PF not only inhibited the NETs triggered by hepatocyte pyroptosis, but also suppressed the hepatocyte pyroptosis induced by NETs. In mice with depleted neutrophils, the level of hepatocyte pyroptosis notably decreased, indicating a diminished impact of PF. Similarly, NETs formation was reduced in mice receiving a pyroptosis inhibitor compared to the APAP group. Compared with DNase I alone, the reduction effect of PF combined with DNase I on serum ALT and AST levels decreased from 46.857% and 39.927% to 44.347% and 33.419%, respectively. Compared with DSF alone, PF combined with DSF reduced the ALT and AST levels from 46.857% and 39.927% to 45.347% and 36.419%, respectively. (4) PF demonstrated therapeutic effects on AILI. Its mechanism involves the regulation of the crosstalk between hepatocyte pyroptosis and NETs. This research substantiates the pharmacological promise of PF as a therapeutic intervention for acute AILI. Full article

Mitochondria are important organelles for cell metabolism and tissue survival. Their cell-to-cell transfer is important for the fate of recipient cells. Recently, bone marrow mesenchymal stem cells (BM-MSCs) have been reported to provide mitochondria to cancer cells and rescue mitochondrial dysfunction in cancer cells. However, the details of the mechanism have not yet been fully elucidated. In this study, we investigated the humoral factors inducing mitochondrial transfer (MT) and the mechanisms. BM-MSCs produced MT in colorectal cancer (CRC) cells damaged by 5-fluorouracil (5-FU), but were suppressed by the anti-high mobility group box-1 (HMGB1) antibody. BM-MSCs treated with oxidized HMGB1 had increased expression of MT-associated genes, whereas reduced HMGB1 did not. Inhibition of nuclear factor–κB, a downstream factor of HMGB1 signaling, significantly decreased MT-associated gene expression. CRC cells showed increased stemness and decreased 5-FU sensitivity in correlation with MT levels. In a mouse subcutaneous tumor model of CRC, 5-FU sensitivity decreased and stemness increased by the MT from host mouse BM-MSCs. These results suggest that oxidized HMGB1 induces MTs from MSCs to CRC cells and promotes cancer cell stemness. Targeting of oxidized HMGB1 may attenuate stemness of CRCs. Full article

Chronic diseases such as diabetes and cancer are the leading causes of mortality worldwide. Receptors for Advanced Glycation End products (RAGEs) are ubiquitous factors that catalyse Advanced Glycation End products (AGEs), proteins, and lipids that become glycated from sugar ingestion. RAGEs are cell surface receptor proteins and play a broad role in mediating the effects of AGEs on cells, contributing to modifying biological macromolecules like proteins and lipids, which can cause Reactive Oxygen Species (ROS) generation, inflammation, and cancer. We targeted RAGE inhibition analysis and screening of United States Food and Drug Administration (FDA) libraries through molecular docking studies that identified the four most suitable FDA compounds: Zytiga, Paliperidone, Targretin, and Irinotecan. We compared them with the control substrate, Carboxymethyllysine, which showed good binding interaction through hydrogen bonding, hydrophobic interactions, and π-stacking at active site residues of the target protein. Following a 100 ns simulation run, the docked complex revealed that the Root Mean Square Deviation (RMSD) values of two drugs, Irinotecan (1.3 ± 0.2 nm) and Paliperidone (1.2 ± 0.3 nm), were relatively stable. Subsequently, the Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) determined that the Paliperidone molecule had a high negative energy of −13.49 kcal/mol, and the Absorption, Distribution, Metabolism, and Excretion (ADME) properties were in control for use in the mentioned cases. We extended this with many in vitro studies, including an immunoblotting assay, which revealed that RAGEs with High Mobility Group Box 1 (HMGB1) showed higher expression, while RAGEs with Paliperidone showed lower expressions. Furthermore, cell proliferation assay and Apoptosis assay (Annexin-V/PI staining) results revealed that Paliperidone was an effective anti-glycation and anti-apoptotic drug—however, more extensive in vivo studies are needed before its use. Full article

The protease, a disintegrin and metalloproteinase with thrombospondin type 1 motif member 13 (ADAMTS13), known to cleave only the von Willebrand factor (VWF), has powerful regulatory effects on microvascular platelet adhesion, thrombosis, inflammation, and endothelial dysfunction. We study the protection against diabetes-induced retinal injury in experimental rats by supplementation with recombinant ADAMTS13. We compare human epiretinal membranes and vitreous samples from nondiabetic subjects and patients with proliferative diabetic retinopathy (PDR) and extend in vitro analyses with the use of various immunodetection and spectrofluorimetric methods on rat retina and human retinal glial and endothelial cell cultures. Functional studies include the assessment of the blood–retinal barrier (BRB), cell adhesion, and in vitro angiogenesis. In epiretinal membranes, endothelial cells and monocytes/macrophages express ADAMTS13. The levels of VWF, the platelet marker CD41, ADAMTS13, and the biomarkers of endothelial cell injury soluble VE-cadherin and soluble syndecan-1 are increased in PDR vitreous. ADAMTS13 is downregulated in diabetic rat retinas. The intravitreal administration of ADAMTS13 attenuates diabetes-induced BRB breakdown, the downregulation of VE-cadherin and β-catenin, and the upregulation of VWF, CD41, phospho-ERK1/2, HMGB1, VCAM-1, and ICAM-1. In Müller cells, ADAMTS13 attenuates MCP-1, MMP-9, and ROS upregulation induced by diabetic mimetic conditions. In HRMECs, ADAMTS13 attenuates the shedding of the soluble VE-cadherin and soluble syndecan-1 and the levels of phospho-ERK1/2, MCP-1, fractalkine, and ROS induced by diabetic mimetic conditions, the upregulation of ICAM-1 and VCAM-1 elicited by TNF-α, the adherence of monocytes induced by TNF-α, and VEGF-induced migration of human retinal microvascular endothelial cells. Our findings suggest that enhancing ADAMTS13 levels in situ ameliorates diabetes-induced retinal inflammation and vascular dysfunction. Full article

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

Background: Targeted therapies (e.g., ibrutinib) have markedly improved chronic lymphocytic leukemia (CLL) management; however, ~20% of patients experience disease relapse, suggesting the inadequate depth and durability of these front-line strategies. Moreover, immunotherapeutic success in CLL has been stifled by its pro-tumor microenvironment milieu and low mutational burden, cultivating poor antigenicity and limited ability to generate anti-tumor immunity through adaptive immune cell engagement. Previously, we have demonstrated how a three-carbon-linker spirocyclic dimer (SpiD3) promotes futile activation of the unfolded protein response (UPR) in CLL cells through immense misfolded-protein mimicry, culminating in insurmountable ER stress and programmed CLL cell death. Method: Herein, we used flow cytometry and cell-based assays to capture the kinetics and magnitude of SpiD3-induced damage-associated molecular patterns (DAMPs) in CLL cell lines and primary samples. Result: SpiD3 treatment, in vitro and in vivo, demonstrated the capacity to propagate immunogenic cell death through emissions of classically immunogenic DAMPs (CALR, ATP, HMGB1) and establish a chemotactic gradient for bone marrow-derived dendritic cells. Conclusions: Thus, this study supports future investigation into the relationship between novel therapeutics, manners of cancer cell death, and their contributions to adaptive immune cell engagement as a means for improving anti-cancer therapy in CLL. Full article

Wuchereria bancrofti is a parasite transmitted by mosquitoes and can cause a neglected tropical disease called Lymphatic filariasis. However, the genome of W. bancrofti was not well studied, making novel drug development difficult. This study aims to identify microRNA, annotate protein function, and explore the pathogenic mechanism of W. bancrofti by genome-wide analysis. Novel miRNAs were identified by analysis of expressed sequence tags (ESTs) from this parasite. Protein homology was obtained by a bidirectional best-hit strategy using BLAST. By an EST-based method, we identified 20 novel miRNAs in the genome. The AU content of these miRNAs ranged from 39.7% to 80.0%, with a mean of 52.9%. Among them, 14 miRNA homologs were present in mammal genomes, while six miRNA homologs were present in non-mammal genomes. By conducting a detailed sequence alignment using BLAST, we have successfully annotated the functions of 75 previously unannotated proteins, enhancing our understanding of the proteome and potentially revealing new targets for therapy. Homology distribution analysis indicated that a set of critical proteins were present in parasites and mosquitoes, but not present in mammals. By searching the literature, ten proteins were found to be involved in the pathogenic infection process of W. bancrofti. In addition, the miRNA–gene network analysis indicated that two pathogenic genes (CALR and HMGB2) are regulated by newly identified miRNAs. These genes were supposed to play key roles in the infection mechanism of W. bancrofti. In conclusion, our genome-wide analysis provided new clues for the prevention and treatment of W. bancrofti infection. Full article

Metastatic cancer is still one of the leading causes of death worldwide despite significant advancements in diagnosis and treatment. Biomarkers are one of the most promising diagnostic tools that are used alongside traditional diagnostic tools in cancer patients. DAMPs are intracellular molecules released in response to cellular stress, tissue injury, and cell death. There have been shown to be associated with worsening prognosis among such patients, and some DAMPs could potentially be used as predictive biomarkers of metastatic status. The goal of this study is to investigate DAMP expression and the probability that certain DAMPs could be predictive biomarkers of the metastatic stage in various cancer types. Forty cancer patients at Naresuan University Hospital, Thailand, were enrolled. Then, an investigation of HSP90, HMGB1, S100A9, and ATP expression and cytokine/chemokine profiling in serum was performed using an immunological-based assay. We assessed the predictive biomarker candidates and the association between DAMP expression and cytokines/chemokines using an ROC curve analysis and a correlation regression analysis. The results showed that HSP90 has strong potential as a metastatic predictive biomarker, with a cutoff value of 25.46 ng/mL (AUC 0.8207, sensitivity 82.61%, specificity 75.00%, 95% CI 0.6860–0.9553). This was followed by HMGB1 and S100A9, which exhibited sensitivity of 82.61 and 65.22%, and specificity of 68.75 and 56.25%, respectively. Interestingly, the candidate DAMPs negatively correlate with various serum cytokines, for example, HMGB1 vs. IL-15 (slope 88.05, R 0.3297, p-value 0.005), HMGB1 vs. IFN-γ (slope 2.235, R 0.3052, p-value 0.0013) and HSP90 vs. IFN-γ (slope 0.0614, R 0.2187, p-value 0.008), suggesting that they are highly elevated in advanced metastatic tumors, which is possibly associated with the immunomodulation effect. We postulated that HSP90, HMGB1, and S100A9 have the potential to be predictive biomarkers for supporting tumor metastasis categorization using histopathology. Full article

Background: Triple-negative breast cancers (TNBCs) typically have a greater immune cell infiltrate and are more likely to respond to immune checkpoint inhibition (ICI) than ER+ or HER2+ breast cancers. However, there is a crucial need to optimize combining chemotherapy strategies with ICI to enhance overall survival in TNBC. Methods: Therefore, we developed a high-throughput co-culture screening assay to identify compounds that enhance CD8+ T-cell-mediated tumor cell cytotoxicity. Over 400 FDA-approved compounds or agents under investigation for oncology indications were included in the screening library. Results: Four chemotherapy agents were chosen as priority hits for mechanistic follow-up due to their ability to enhance T-cell-mediated cytotoxicity at multiple doses and multiple time points: paclitaxel, bleomycin sulfate, ispinesib, and etoposide. Lead compounds affected the expression of MHCI, MHCII, and PD-L1 and induced markers of immunogenic cell death (extracellular ATP or HMGB1). Conclusions: Based on the ability to increase tumor cell susceptibility to T-cell-mediated cytotoxicity while minimizing T-cell toxicity, bleomycin was identified as the most promising lead candidate. Overall, the results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients. Full article

The class B scavenger receptor CD36 is known to bind and mediate the transport of lipid-related ligands and it functions as a pattern recognition receptor (PRR) for a variety of pathogens, including bacteria and viruses. In this study, we assessed CD36’s role as a PRR mediating pro-inflammatory effects of several known Danger-Associated Molecular Patterns (DAMPs) used either as a single preparation or as a combination of DAMPs in the form of total cell/skeletal muscle tissue lysates. Our data demonstrated that multiple DAMPs, including HMGB1, HSPs, histone H3, SAA, and oxPAPC, as well as cell/tissue lysate preparations, induced substantially higher (~7–10-fold) IL-8 cytokine responses in HEK293 cells overexpressing CD36 compared to control WT cells. At the same time, DAMP-induced secretion of IL-6 in bone marrow-derived macrophages (BMDM) from CD36−/− mice was markedly (~2–3 times) reduced, as compared to macrophages from normal mice. Synthetic amphipathic helical peptides (SAHPs), known CD36 ligands, efficiently blocked CD36-dependent inflammatory responses induced by both cell and tissue lysates, HMGB1 and histone H3 in CD36+ cells. IP injection of total cellular lysate preparation induced inflammatory responses that were assessed by the expression of liver and lung pro-inflammatory markers, including IL-6, TNF-α, CD68, and CXCL1, and was reduced by ~50% in CD36-deficient mice compared to normal mice. Our findings demonstrate that CD36 is a PRR contributing to the innate immune response via mediating DAMP-induced inflammatory signaling and highlight the importance of this receptor as a potential therapeutic target in DAMP-associated inflammatory conditions. Full article

Recent studies have shown that long noncoding RNAs (lncRNAs) play pivotal roles in the development and progression of cancer. In the present study, we aimed to identify lncRNAs associated with lymph node metastasis in pancreatic ductal adenocarcinoma (PDAC). We analyzed data from The Cancer Genome Atlas (TCGA) database to screen for genes overexpressed in primary PDAC tumors with lymph node metastasis. Our screen revealed 740 genes potentially associated with lymph node metastasis, among which were multiple lncRNA genes located in the HOXA locus, including HOXA11-AS. Elevated expression of HOXA11-AS was associated with more advanced tumor stages and shorter overall survival in PDAC patients. HOXA11-AS knockdown suppressed proliferation and migration of PDAC cells. RNA-sequencing analysis revealed that HOXA11-AS knockdown upregulated interferon lambda (IFNL) family genes and downregulated high-mobility group box (HMGB) family genes in PDAC cells. Moreover, HMGB3 knockdown suppressed proliferation and migration by PDAC cells. These results suggest that HOXA11-AS contributes to PDAC progression, at least in part, through regulation of IFNL and HMGB family genes and that HOXA11 AS is a potential therapeutic target in PDAC. Full article

High Mobility Group Box 1 (HMGB1) is a highly conserved non-histone chromatin-associated protein across species, primarily recognized for its regulatory impact on vital cellular processes, like autophagy, cell survival, and apoptosis. HMGB1 exhibits dual functionality based on its localization: both as a non-histone protein in the nucleus and as an inducer of inflammatory cytokines upon extracellular release. Pathophysiological insights reveal that HMGB1 plays a significant role in the onset and progression of a vast array of diseases, viz., atherosclerosis, kidney damage, cancer, and neurodegeneration. However, a clear mechanistic understanding of HMGB1 release, translocation, and associated signaling cascades in mediating such physiological dysfunctions remains obscure. This review presents a detailed outline of HMGB1 structure–function relationship and its regulatory role in disease onset and progression from a signaling perspective. This review also presents an insight into the status of HMGB1 druggability, potential limitations in understanding HMGB1 pathophysiology, and future perspective of studies that can be undertaken to address the existing scientific gap. Based on existing paradigm of various studies, HMGB1 is a critical regulator of inflammatory cascades and drives the onset and progression of a broad spectrum of dysfunctions. Studies focusing on HMGB1 druggability have enabled the development of biologics with potential clinical benefits. However, deeper understanding of post-translational modifications, redox states, translocation mechanisms, and mitochondrial interactions can potentially enable the development of better courses of therapy against HMGB1-mediated physiological dysfunctions. Full article

Steroids, which are often used to treat the inflammation associated with various skin diseases, have several negative side effects. As Ecklonia cava extract has anti-inflammatory effects in various diseases, we evaluated the efficacy of Ecklonia cava-derived extracellular vesicles (EVEs) in decreasing 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation. We determined the effect of the EVEs on the TLR4/NF-κB/NLRP3 inflammasome in human keratinocytes and mouse ear skin. TPA-treated human keratinocytes showed an increased expression of TLR4 and its ligands HMGB1 and S100A8. TPA also increased the expression of (1) NF-κB; (2) the NLRP3 inflammasome components NLRP3, ASC, and caspase 1; and (3) the pyroptosis-related factors GSDMD-NT, IL-18, and IL-1β. However, the expression of these molecules decreased in the TPA-treated human keratinocytes after EVE treatment. Similar to the in vitro results, TPA increased the expression of these molecules in mouse ear skin, and EVE treatment decreased their expression. The TPA treatment of skin increased edema, redness, neutrophil infiltration, and epidermal thickness, and EVE reduced these symptoms of inflammation. In conclusion, the EVEs decreased TPA-induced skin inflammation, which was associated with a decrease in the TLR4/NF-κB/NLRP3 inflammasome. Full article

The endogenous neurosteroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) modulates inflammatory and neuroinflammatory signaling through toll-like receptors (TLRs) in human and mouse macrophages, human blood cells and alcohol-preferring (P) rat brains. Although it is recognized that 3α,5α-THP inhibits TLR4 activation by blocking interactions with MD2 and MyD88, the comprehensive molecular mechanisms remain to be elucidated. This study explores additional TLR4 activation sites, including TIRAP binding to MyD88, which is pivotal for MyD88 myddosome formation, as well as LPS interactions with the TLR4:MD2 complex. Both male and female P rats (n = 8/group) received intraperitoneal administration of 3α,5α-THP (15 mg/kg; 30 min) or a vehicle control, and their hippocampi were analyzed using immunoprecipitation and immunoblotting techniques. 3α,5α-THP significantly reduces the levels of inflammatory mediators IL-1β and HMGB1, confirming its anti-inflammatory actions. We found that MyD88 binds to TLR4, IRAK4, IRAK1, and TIRAP. Notably, 3α,5α-THP significantly reduces MyD88-TIRAP binding (Males: −31 ± 9%, t-test, p < 0.005; Females: −53 ± 15%, t-test, p < 0.005), without altering MyD88 interactions with IRAK4 or IRAK1, or the baseline expression of these proteins. Additionally, molecular docking and molecular dynamic analysis revealed 3α,5α-THP binding sites on the TLR4:MD2 complex, targeting a hydrophobic pocket of MD2 usually occupied by Lipid A of LPS. Surface plasmon resonance (SPR) assays validated that 3α,5α-THP disrupts MD2 binding of Lipid A (Kd = 4.36 ± 5.7 μM) with an inhibition constant (Ki) of 4.5 ± 1.65 nM. These findings indicate that 3α,5α-THP inhibition of inflammatory mediator production involves blocking critical protein-lipid and protein-protein interactions at key sites of TLR4 activation, shedding light on its mechanisms of action and underscoring its therapeutic potential against TLR4-driven inflammation. Full article