Acrylamide, advanced glycation end products (AGEs), and alpha-dicarbonyls are formed during the thermal processing of foods. Their dietary intake raises potential health concerns. Using food frequency questionnaires on acrylamide-rich Slovak foods, we estimated dietary acrylamide intake in 107 students aged 19-to-30 years and correlated it with salivary, plasma, skin autofluorescence; plasma levels of soluble receptor for advanced glycated end-products, and oxidative status markers (thiobarbituric acid reacting substances, ferric-reducing ability of plasma). No significant relationship was revealed between estimated daily acrylamide intake and analyzed biomarkers. As the extent of exposure to alpha-dicarbonyls and AGEs when consuming acrylamide-rich food remains unknown, we aligned acrylamide intake with that of glyoxal, methylglyoxal, 3-deoxyglucosone, and Nε-carboxymethyllysine, Nε-carboxyethyllysine, or methylglyoxal-derived hydroimidazolone. Correlation coefficients between intakes of acrylamide and alpha-dicarbonyls or AGEs reached 0.7-to-0.8 (p < 0.001, all), but, at individual levels, high intake of acrylamide was not unequivocally associated with high intake of AGEs or alpha-dicarbonyls. Our data suggest that the restriction of dietary AGEs recommended to patients with chronic non-communicable diseases must not simultaneously mitigate acrylamide intake. Nutritional research should explore the potential cumulative or synergistic adverse health effects of concurrent dietary intakes of acrylamide, AGEs, and alpha-dicarbonyls.

Selenoproteins (Sels) are a class of essential biomolecules that play critical roles in cellular homeostasis. SelO was identified as the preferential source of selenium in the liver, implying its potential as a key regulatory factor in hepatic pathophysiology. Bioinformatics analysis of data from GEO data sets revealed marked downregulation of SelO in liver injury. However, its function and regulatory mechanisms in the liver remain unclear. To address this, we investigated the effect of SelO ablation on acute liver inflammation, focusing on its association with inflammation and neutrophil extracellular traps (NETs) formation. Wild-type (WT) and SelO-knockout mice were used to establish a lipopolysaccharide (LPS) exposure model and a coculture model (AML12 cells and neutrophils) in vitro. Our findings revealed that LPS stimulation significantly reduced SelO expression in the WT mouse liver. SelO deletion promoted the expression of Hmgb1 and marker cytokines for chemokines, NETs generation, pyroptosis and inflammation, and induced an imbalance in redox homeostasis. Immunofluorescence, SYTOX staining, and scanning electron microscopy confirmed that SelO silencing promoted reactive oxygen species (ROS)-dependent NETs formation. Moreover, the coculture model demonstrated that excessive NETs formation exacerbated SelO-ablation-induced hepatic inflammation. Importantly, we confirmed the significant involvement of the Hmgb1/ROS axis in the development of acute liver inflammation in the absence of SelO. Our results demonstrated that SelO ablation promoted neutrophil recruitment and enhanced ROS-dependent NETs formation by increasing Hmgb1 expression levels, thereby aggravating LPS-induced pyroptosis and inflammation. This study not only uncovered the crucial biological functions of SelO, but also shed light on its regulatory implications in the inflammatory process.

The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor with several structural types, performing a myriad of molecular mechanisms. The RAGE-ligand interactions play important roles in maintaining latent chronic inflammation, and oxidative damage underlying various pathological conditions like metabolic syndrome (MetS), neurodegenerative diseases, stroke, cardiovascular disorders, pulmonary disorders, cancer and infections. RAGE is thoroughly explored in knockout animals and human trials, targeted by small molecule inhibitors, peptides, diet, and natural compounds. But it is yet to be incorporated in the mainstream management of any ailment. This review performs an appraisal of the pathological mechanisms influenced by RAGE to uncover its prospects as a biomarker while also assessing its power to become a promising therapeutic target.

Diabetes treatments by the control of sodium-glucose cotransporter 2 (SGLT2) is commonly conducted while there are still uncertainties about the mechanisms for the SGLT2 overexpression in kidneys with diabetes. Previously, we have reported that glomeruli and proximal tubules with diabetic nephropathy express toll-like receptor TLR2/4, and that the TLR ligand lipopolysaccharide (LPS) of periodontal pathogens have caused nephropathy in diabetic model mice. Recently, many researchers suggested that the periodontal pathogenic bacteria Fusobacterium (F.) nucleatum has the TLR4-associated strong activator of the colorectal inflammation and cancer. The present study aimed to investigate the possibility of F. nucleatum as an exacerbation factor of diabetes through the renal SGLT2 induction.

The induction of the SGLT2 by F. nucleatum LPS (Fn-LPS) were investigated in the streptozotocin-induced diabetic mouse renal tissue and cultured renal proximal epithelial cells. The changes of blood glucose levels and survival curves in diabetic mice with Fn-LPS were analyzed. The Fn-LPS-induced SGLT2 production in the diabetic mouse renal tissue and in the cultured proximal epithelial cells was examined by ELISA, quantitative RT-PCR, and immunohistochemical analysis.

The SGLT2 expression in the cultured mouse tubular epithelial cells was significantly increased by TNF- or co-culture with Fn-LPS-supplemented J774.1 cells. The period to reach diabetic condition was significantly shorter in Fn-LPS-administered diabetic mice than in diabetic mice. All Fn-LPS-administered-diabetic mice reached humane endpoints during the healthy period of all of the mice administered Fn-LPS only. The promotion of the SGLT2 expression at the inner lumen of proximal tubules were stronger in the Fn-LPS-administered-diabetic mice than in diabetic mice. The renal tissue SGLT2 mRNA amounts and the number of renal proximal tubules with overexpressed SGLT2 in the lumen were more in the Fn-LPS-administered-diabetic mice than in diabetic mice.

This study suggests that F. nucleatum causes the promotion of diabetes through the overexpression of SGLT2 in proximal tubules under the diabetic condition. Periodontitis with F. nucleatum may be a diabetic exacerbating factor.

Perioperative neurocognitive disorder (PND) is a common complication of surgical anesthesia, yet its precise etiology remains unclear. Neuroinflammation is a key feature of PND, influenced by both patient -related and surgical variables. The nuclear factor-κB (NF-κB) transcription factor family plays a critical role in regulating the body's immunological proinflammatory response, which is pivotal in the development of PND. Surgery and anesthesia trigger the activation of the NF-κB signaling pathway, leading to the initiation of inflammatory cascades, disruption of the blood-brain barrier, and neuronal injury. Immune cells and glial cells are central to these pathological processes in PND. Furthermore, this study explores the interactions between NF-κB and various signaling molecules, including Tlr4, P2X, α7-nAChR, ROS, HIF-1α, PI3K/Ak, MicroRNA, Circular RNA, and histone deacetylases, within the context of PND. Targeting NF-κB as a therapeutic approach for PND shows promise as a potential treatment strategy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes that leads to vision loss. The striking features of DR are hard exudate, cotton-wool spots, hemorrhage, and neovascularization. The dysregulated retinal cells, encompassing microvascular endothelial cells, pericytes, Müller cells, and adjacent retinal pigment epithelial cells, are involved in the pathological processes of DR. According to recent research, oxidative stress, inflammation, ferroptosis, pyroptosis, apoptosis, and angiogenesis contribute to DR. Recent advancements have highlighted that noncoding RNAs could regulate diverse targets in pathological processes that contribute to DR. Noncoding RNAs, including long noncoding RNAs, microRNAs (miRNA), and circular RNAs, are dysregulated in DR, and interact with miRNA, mRNA, or proteins to control the pathological processes of DR. Hence, modulation of noncoding RNAs may have therapeutic effects on DR. Small extracellular vesicles may be valuable tools for transferring noncoding RNAs and regulating the genes involved in progression of DR. However, the roles of noncoding RNA in developing DR are not fully understood; it is critical to summarize the mechanisms for noncoding RNA regulation of pathological processes and pathways related to DR. This review provides a fundamental understanding of the relationship between noncoding RNAs and DR, exploring the mechanism of how noncoding RNA modulates different signaling pathways, and pave the way for finding potential therapeutic strategies for DR.

As a cancer with the highest incidence in recent years, lung cancer is mainly composed of three diseases: non-small cell lung cancer, small cell lung cancer and neuroendocrine tumor. The morbidity and mortality of this malignant tumor are the highest in both male and female populations worldwide. In my country, lung cancer has become the most common cancer disease and the leading cause of cancer death, so it is extremely important to find lung cancer therapeutic targets. Based on previous studies, we speculated that the TLR4-Myd88-NFκB pathway may be involved in hmgb1-induced EMT in A549 cells, and daphnetin may also inhibit hmgb1-induced EMT through the TLR4-Myd88-NFκB pathway in A549 cells, but related studies have not linked it to hmgb1-induced EMT. Therefore, the innovation of this study is to test these two conjectures and analyze how daphnetin affects the epithelial-mesenchymal transition (EMT) mechanism induced by HMGB1 in human lung adenocarcinoma cells (A549 cell line), aiming at lung adenocarcinoma cells, foundation for clinical treatment. The proliferation rate and the migrating cell number presented an obvious decrease in the HMGB1+TLR4-shRNA group and the HMGB1+daphnetin group relative to the HMGB1 group (P < 0.0001). The intracellular expression of TLR4, Myd88, NFκB, vimentin and snail1 proteins were significantly decreased (P < 0.001), while that of E-cadherin presented a remarkable increase (P < 0.001) in the HMGB1+TLR4-shRNA and HMGB1+daphnetin group compared with the HMGB1 group. TLR4-MyD88-NFκB pathway is associated with HMGB1-induced EMT in A549 cells. Daphnetin had an inhibitory effect on HMGB1-induced EMT via the TLR4-Myd88-NF-κB pathway in A549 cells.

Pyroptosis is an inflammation-associated programmed cell death, and neuroinflammation is strongly associated with severe neurological deficits in neonatal hypoxic-ischemic encephalopathy (HIE). Ethyl pyruvate (EP), a known anti-inflammatory agent, has shown promise in the treatment of hypoxic-ischemic brain damage (HIBD) rats; nevertheless, the therapeutic mechanism of EP and its capacity to suppress neuronal pyroptosis in HIBD rats remain unclear. In both the neonatal Rice-Vannucci rat model and the OGD/R model, this study examined alterations in the NLRP3/Caspase-1/GSDMD classical pyroptosis pathway in hippocampal neurons during HIE and the potential inhibitory impact of ethyl pyruvate on this pathway. We used HE staining, immunofluorescence double staining, transmission electron microscopy, and western blot to demonstrate that EP effectively inhibited hippocampal neuronal pyroptosis and attenuated the activation of the NLRP3/Caspase-1/GSDMD signaling pathway in HIBD rats, which resulted in a reduction of neuroinflammation and facilitated neural recovery. The results suggest that EP may be a promising neuroprotective agent for treating HIE.

Receptor for advanced glycation endproducts (RAGE) and toll-like receptor 4 (TLR4) are pattern-recognition receptors that bind to molecular patterns associated with pathogens, stress, and cellular damage. Diffusion plays an important role in receptor functionality in the cell membrane. However, there has been no prior investigation of the reciprocal effect of RAGE and TLR4 diffusion properties in the presence and absence of each receptor. This study reports how RAGE and TLR4 affect the mobility of each other in the human embryonic kidney (HEK) 293 cell membrane. Diffusion properties were measured using single-particle tracking (SPT) with quantum dots (QDs) that are selectively attached to RAGE or TLR4. The Brownian diffusion coefficients of RAGE and TLR4 are affected by the presence of the other receptor, leading to similar diffusion coefficients when both receptors coexist in the cell. When TLR4 is present, the average Brownian diffusion coefficient of RAGE increases by 40%, while the presence of RAGE decreases the average Brownian diffusion coefficient of TLR4 by 32%. Diffusion in confined membrane domains is not altered by the presence of the other receptor. The mobility of the cell membrane lipid remains constant whether one or both receptors are present. Overall, this work shows that the presence of each receptor can affect a subset of diffusion properties of the other receptor without affecting the mobility of the membrane.

Cancer remains a significant global challenge, with escalating incidence rates and a substantial burden on healthcare systems worldwide. Herein, we present an in-depth exploration of the intricate interplay between cancer cell death pathways and tumor immunity within the tumor microenvironment (TME). We begin by elucidating the epidemiological landscape of cancer, highlighting its pervasive impact on premature mortality and the pronounced burden in regions such as Asia and Africa. Our analysis centers on the pivotal concept of immunogenic cell death (ICD), whereby cancer cells succumbing to specific stimuli undergo a transformation that elicits robust anti-tumor immune responses. We scrutinize the mechanisms underpinning ICD induction, emphasizing the release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) as key triggers for dendritic cell (DC) activation and subsequent T cell priming. Moreover, we explore the contributions of non-apoptotic RCD pathways, including necroptosis, ferroptosis, and pyroptosis, to tumor immunity within the TME. Emerging evidence suggests that these alternative cell death modalities possess immunogenic properties and can synergize with conventional treatments to bolster anti-tumor immune responses. Furthermore, we discuss the therapeutic implications of targeting the TME for cancer treatment, highlighting strategies to harness immunogenic cell death and manipulate non-apoptotic cell death pathways for therapeutic benefit. By elucidating the intricate crosstalk between cancer cell death and immune modulation within the TME, this review aims to pave the way for the development of novel cancer therapies that exploit the interplay between cell death mechanisms and tumor immunity and overcome Challenges in the Development and implementation of Novel Therapies.

Advanced glycation end products (AGEs) are a heterogeneous group of potentially harmful molecules that can form as a result of a non-enzymatic reaction between reducing sugars and proteins, lipids, or nucleic acids. The total body pool of AGEs reflects endogenously produced AGEs as well as exogeneous AGEs that come from sources such as diet and the environment. Engagement of AGEs with their cellular receptor, the receptor for advanced glycation end products (RAGE), which is expressed on the surface of various cell types, converts a brief pulse of cellular activation to sustained cellular dysfunction and tissue destruction. The AGEs/RAGE interaction triggers a cascade of intracellular signaling pathways such as mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinases, transforming growth factor beta, c-Jun N-terminal kinases (JNK), and nuclear factor kappa B, which leads to the production of pro-inflammatory cytokines, chemokines, adhesion molecules, and oxidative stress. All these events contribute to the progression of several chronic diseases. This chapter will provide a comprehensive understanding of the dynamic roles of AGEs in health and disease which is crucial to develop interventions that prevent and mitigate the deleterious effects of AGEs accumulation.

Tissue ablation techniques have long been used in clinical settings to treat various oncologic diseases. However, many of these techniques are invasive and can cause substantial adverse effects. Histotripsy is a noninvasive, nonionizing, nonthermal tissue ablation technique that has the potential to replace surgical interventions in various clinical settings. Histotripsy works by delivering high-intensity focused ultrasound waves to target tissue. These waves create cavitation bubbles within tissues that rapidly expand and collapse, thereby mechanically fractionating the tissue into acellular debris that is subsequently absorbed by the body's immune system. Preclinical and clinical studies have demonstrated the efficacy of histotripsy in treating a range of diseases, including liver, pancreatic, renal, and prostate tumors. Safety outcomes of histotripsy have been generally favorable, with minimal adverse effects reported. However, further studies are needed to optimize the technique and understand its long-term effects. This review aims to discuss the importance of histotripsy as a noninvasive tissue ablation technique, the preclinical and clinical literature on histotripsy and its safety, and the potential applications of histotripsy in clinical practice. Keywords: Tumor Microenvironment, Ultrasound-High-Intensity Focused (HIFU), Ablation Techniques, Abdomen/GI, Genital/Reproductive, Nonthermal Tissue Ablation, Histotripsy, Clinical Trials, Preclinical Applications, Focused Ultrasound © RSNA, 2024.

The present study explores the complex roles of High Mobility Group Box 1 (HMGB1) in the context of cancer development, emphasizing glioblastoma (GBM) and other central nervous system (CNS) cancers. HMGB1, primarily known for its involvement in inflammation and angiogenesis, emerges as a multifaceted player in the tumorigenesis of GBM. The overexpression of HMGB1 correlates with glioma malignancy, influencing key pathways like RAGE/MEK/ERK and RAGE/Rac1. Additionally, HMGB1 secretion is linked to the maintenance of glioma stem cells (GSCs) and contributes to the tumor microenvironment's (TME) vascular leakiness. Henceforth, our review discusses the bidirectional impact of HMGB1, acting as both a promoter of tumor progression and a mediator of anti-tumor immune responses. Notably, HMGB1 exhibits tumor-suppressive roles by inducing apoptosis, limiting cellular proliferation, and enhancing the sensitivity of GBM to therapeutic interventions. This dualistic nature of HMGB1 calls for a nuanced understanding of its implications in GBM pathogenesis, offering potential avenues for more effective and personalized treatment strategies. The findings underscore the need to explore HMGB1 as a prognostic marker, therapeutic target, and a promising tool for stimulating anti-tumor immunity in GBM.

High mobility group box 1 (HMGB1) is a nuclear DNA-binding protein with a dual role in cancer, acting as an oncogene and a tumor suppressor. This protein regulates nucleosomal structure, DNA damage repair, and genomic stability within the cell, while also playing a role in immune cell functions. This review comprehensively evaluates the biological and clinical significance of HMGB1 in cancer, including its involvement in cell death and survival, its potential as a therapeutic target and cancer biomarker, and as a prosurvival signal for the remaining cells after exposure to cytotoxic anticancer treatments. We highlight the need for a better understanding of the cellular markers and mechanisms involved in the involvement of HMGB1in cancer, and aim to provide a deeper understanding of its role in cancer progression.

Epidemiological studies demonstrate that particulate matter 2.5 (PM2.5) exposure closely related to chronic respiratory diseases. Cellular senescence plays an important role in many diseases. However, it is not fully clear whether PM2.5 exposure could induce cellular senescence in the human lung. In this study, we generated a three-dimensional (3D) spheroid model using isolated primary human lung fibroblasts (HLFs) to investigate the effects of PM2.5 on cellular senescence at the 3D level.

3D spheroids were exposed to 25-100 μg/ml of PM2.5 in order to evaluate the impact on cellular senescence. SA-β-galactosidase activity, cell proliferation, and the expression of key genes and proteins were detected.

Exposure of the HLF spheroids to PM2.5 yielded a more sensitive cytotoxicity than 2D HLF cell culture. Importantly, PM2.5 exposure induced the rapid progression of cellular senescence in 3D HLF spheroids, with a dramatically increased SA-β-Gal activity. In exploiting the mechanism underlying the effect of PM2.5 on senescence, we found a significant increase of DNA damage, upregulation of p21 protein levels, and suppression of cell proliferation in PM2.5-treated HLF spheroids. Moreover, PM2.5 exposure created a significant inflammatory response, which may be at least partially associated with the activation of TGF-β1/Smad3 axis and HMGB1 pathway.

Our results indicate that PM2.5 could induce DNA damage, inflammation, and cellular senescence in 3D HLF spheroids, which may provide a new evidence for PM2.5 toxicity based on a 3D model which has been shown to be more in vivo-like in their phenotype and physiology than 2D cultures.

Histotripsy, a non-thermal ultrasound technique, holds significant promise in various applications within the realm of brain interventions. While its use for treating brain tumors is somewhat limited, focused ultrasound technology has been extensively investigated for a wide range of purposes within the brain, including disrupting the blood-brain barrier, supporting immunotherapy, addressing conditions like essential tremor, Parkinson's disease, Alzheimer's disease, epilepsy, and neuropathic pain. Research findings indicate that histotripsy can reduce tumor cells with fewer pulses, minimizing the risk of bleeding and cellular injury. The use of MRI sequences such as T2 and T2* enhances the evaluation of the effects of histotripsy treatment, facilitating non-invasive assessment of treated areas. Furthermore, histotripsy displays promise in creating precise brain lesions with minimal edema and inflammation, particularly in porcine models, suggesting considerable progress in the treatment of brain lesions. Moreover, studies confirm its feasibility, safety, and effectiveness in treating intracerebral hemorrhage by safely liquefying clots without causing significant harm to surrounding brain tissue., opening exciting possibilities for clinical applications. The development of transcranial MR-guided focused ultrasound systems based on histotripsy represents a significant breakthrough in overcoming the limitations associated with thermal ablation techniques. Histotripsy's ability to efficiently liquefy clots, minimize skull heating, and target shallow lesions near the skull establishes it as a promising alternative for various brain treatments. In conclusion, histotripsy offers diverse potential in the field of brain interventions, encompassing applications ranging from tumor treatment to the management of intracerebral hemorrhage. While challenges such as accurate monitoring and differentiation of treatment effects persist, ongoing research efforts and technological advancements continue to expand the role of histotripsy in both neurology and neurosurgery.

While stroke represents one of the main causes of death worldwide, available effective drug treatment options remain limited to classic thrombolysis with recombinant tissue plasminogen activator (rtPA) for arterial-clot occlusion. Following stroke, multiple pathways become engaged in producing a vicious proinflammatory cycle through the release of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) and heat shock protein 70 kDa (HSP72). HMGB1, in particular, can activate proinflammatory cytokine production when acetylated (AcHMGB1), a form that prefers cytosolic localization and extracellular release. This study aimed at determining how HMGB1 and HSP72 are modulated and affected following treatment with the anti-inflammatory compound resveratrol and novel platelet membrane-derived nanocarriers loaded with rtPA (CSM@rtPA) recently developed by our group for ischemic artery recanalization. Under ischemic conditions of oxygen-glucose deprivation (OGD), nuclear abundance of HMGB1 and AcHMGB1 in microglia and macrophages decreased, whereas treatment with CSM@rtPA did not alter nuclear or cytosolic abundance. Resveratrol treatment markedly increased the cytosolic abundance of HSP72 in microglia. Using proximity ligation assays, we determined that HSP72 interacted with HMGB1 and with acetylated HMGB1. The interaction was differentially affected under the OGD conditions. Resveratrol treatment under the OGD further decreased HSP72-HMGB1 interactions, whereas, in contrast, treatment increased HSP72-AcHMGB1 interactions in microglia. This study points out a salient molecular interaction suited for a two-pronged nanotherapeutic intervention in stroke: enhancement of rtPA's thrombolytic activity and modulation of cytosolic interactions between HMGB1 and HSP72 by resveratrol.

High mobility group protein 1 (HMGB1) plays a complex role in tumor biology. When released into the extracellular space, it binds to the receptor for advanced glycation end products (RAGE) located on the cell membrane, playing an important role in tumor development by regulating a number of biological processes and signal pathways. In this review, we outline the multifaceted functions of the HMGB1/RAGE axis, which encompasses tumor cell proliferation, apoptosis, autophagy, metastasis, and angiogenesis. This axis is instrumental in tumor progression, promoting tumor cell proliferation, autophagy, metastasis, and angiogenesis while inhibiting apoptosis, through pivotal signaling pathways, including MAPK, NF-κB, PI3K/AKT, ERK, and STAT3. Notably, small molecules, such as miRNA-218, ethyl pyruvate (EP), and glycyrrhizin exhibit the ability to inhibit the HMGB1/RAGE axis, restraining tumor development. Therefore, a deeper understanding of the mechanisms of the HMGB1/RAGE axis in tumors is of great importance, and the development of inhibitors targeting this axis warrants further exploration.

Qi deficiency and blood stasis are identified to be pathological factors of pulmonary fibrosis (PF) in traditional Chinese medicine (TCM) theory. Buyang Huanwu Decoction (BYHWD) is a traditional Chinese prescription ameliorating Qi deficiency and blood stasis.

The objective of this study was to investigate the anti-fibrosis effect of BYHWD and the potential molecular mechanism in rats.

Bleomycin was used to construct PF rat models. 27 PF rats were randomly divided into three groups based on treatments: model group (saline solution, n = 9), low-dose BYHWD group (3.5 g/kg, n = 9), and high-dose BYHWD group (14.0 g/kg, n = 9). Moreover, 9 normal rats were used as the blank group. The blood viscosity, coagulation indexes (APTT, TT, PT, and FIB), platelet-related parameters (PLT, PDW, MPV, PCT, and PLCR), platelet microparticles (PMPs), and inflammatory factors (IL-2, IL-10, IL-1β, IL-6, IL-8, IL-17, IFN-γ, TNF-α, PAC-1, HMGB1, NF-κB, and TF) were determined. The lung tissue samples of rats were observed after hematoxylin-eosin (HE) staining. The full component analysis of the BYHWD extract was performed using the ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. The signaling pathway included into the study was selected on the basis of bioinformatics analysis and the results of the phytochemical analysis. The expression levels of genes and proteins involved in the selected signaling pathway were detected.

Compared to the blank group, the whole blood viscosity, PLR, PDW, MPV, PCT, PLCR, PMPs, and the levels of IL-1β, IL-6, IL-8, IL-17, TNF-α, PAC-1, HMGB1, NF-κB, and TF were increased, while the levels of IL-2 and IL-10 were decreased in the model group. Both low-dose BYHWD and high-dose BYHWD reversed these PF-induced effects in spite of the fact that low-dose BYHWD had no significant effect on the level of NF-κB. In addition, BYHWD ameliorated PF-induced inflammation in the rat lung tissue. The phytochemical analysis of the BYHWD extract combined with the bioinformatics analysis suggested that the therapeutical effect of BYHWD on PF was related to the HMGB1/NF-κB pathway, which consisted of NF-κB, IKBKB, ICAM1, VCAM1, HMGB1, and TLR4. Both RT-qPCR and western blot analyses showed that PF induced increases in the expression levels of NF-κB, ICAM1, VCAM1, HMGB1, and TLR4, but a decrease in the expression level of IKBKB. Moreover, both low-dose BYHWD and high-dose BYHWD exerted the opposite effects, and recovered the expression levels of NF-κB, ICAM1, VCAM1, HMGB1, TLR4, and IKBKB, despite the fact that low-dose BYHWD had no effects on the mRNA expression levels of NF-κB or TLR4.

In summary, BYHWD alleviated PF-induced blood stasis, platelet activation, and inflammation in the rats. Our study suggested BYHWD had a therapeutic effect on PF and was a good alternative for the complementary therapy of PF, and the potential molecular mechanism was modulation of HMGB1/NF-κB signaling pathway, and it needs further study.

Rheumatoid arthritis (RA) is characterized by synovial edema, inflammation, bone and cartilage loss, and joint degradation. Patients experience swelling, stiffness, pain, limited joint movement, and decreased mobility as the condition worsens. RA treatment regimens often come with various side effects, including an increased risk of developing cancer and organ failure, potentially leading to mortality. However, researchers have proposed mechanistic hypotheses to explain the underlying causes of synovitis and joint damage in RA patients. This review article focuses on the role of synoviocytes and synoviocytes resembling fibroblasts in the RA synovium. Additionally, it explores the involvement of epigenetic regulatory systems, such as microRNA pathways, silent information regulator 1 (SIRT1), Peroxisome proliferatoractivated receptor-gamma coactivator (PGC1-α), and protein phosphatase 1A (PPM1A)/high mobility group box 1 (HMGB1) regulators. These mechanisms are believed to modulate the function of receptors, cytokines, and growth factors associated with RA. The review article includes data from preclinical and clinical trials that provide insights into potential treatment options for RA.

Atherosclerosis is characterized by chronic inflammation of the arterial wall. However, the exact mechanism underlying atherosclerosis-related inflammation has not been fully elucidated. To gain insight into the mechanisms underlying the inflammatory process that leads to atherosclerosis, there is need to identify novel molecular markers. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-protein-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have gained prominence in recent years. LncRNAs/circRNAs act as competing endogenous RNAs (ceRNAs) that bind to miRNAs via microRNA response elements (MREs), thereby inhibiting the silencing of miRNA target mRNAs. Inflammatory mediators and inflammatory signaling pathways are closely regulated by ceRNA regulatory networks in atherosclerosis. In this review, we discuss the role of LncRNA/CircRNA-miRNA-mRNA axis in atherosclerotic inflammation and how it can be targeted for early clinical detection and treatment.

RAGE is a multiligand receptor for the immunoglobulin superfamily of cell surface molecules and is expressed in Müller cells, vascular endothelial cells, nerve cells and RPE cells of the retina. Diabetic retinopathy (DR) is a multifactorial disease associated with retinal inflammation and vascular abnormalities and is the leading cause of vision loss or impairment in older or working-age adults worldwide. Therapies aimed at reducing the inflammatory response and unnecessary angiogenesis can help slow the progression of DR, which in turn can save patients' vision. To maximize the efficacy and minimize the side effects, treatments that target key players in the pathophysiological process of DR need to be developed. The interaction between RAGE and its ligands is involved in a variety of cytopathological alterations in the retina, including secretion of inflammatory factors, regulation of angiogenesis, oxidative stress, structural and functional changes, and neurodegeneration. In this review, we will summarize the pathologic pathways mediated by RAGE and its ligand interactions and discuss its role in the progression of diabetic retinopathy to explore potential therapeutic targets that are effective and safe for DR.

High-mobility group box 1 (HMGB1) is a highly conserved nonhistone nuclear protein found in the calf thymus and participates in a variety of intracellular processes such as DNA transcription, replication and repair. In the cytoplasm, HMGB1 promotes mitochondrial autophagy and is involved in in cellular stress response. Once released into the extracellular, HMGB1 becomes an inflammatory factor that triggers inflammatory responses and a variety of immune responses. In addition, HMGB1 binding with the corresponding receptor can activate the downstream substrate to carry out several biological effects. Meanwhile, HMGB1 is involved in various signaling pathways, such as the HMGB1/RAGE pathway, HMGB1/NF-κB pathway, and HMGB1/JAK/STAT pathway, which ultimately promote inflammation. Moreover, HMGB1 may be involved in the pathogenesis of asthma by regulating downstream signaling pathways through corresponding receptors and mediates a number of signaling pathways in asthma, such as HMGB1/TLR4/NF-κB, HMGB1/RAGE, HMGB1/TGF-β, and so forth. Accordingly, HMGB1 emerges as a therapeutic target for asthma.

UV-induced corneal damage is a common ocular surface injury that usually leads to corneal lesions causing persistent inflammation. High mobility group box 1 (HMGB1) is identified as an inflammatory alarm in various tissue injuries. Here, this study first evaluates the repair effect of the HMGB1-selective inhibitor GLY in UV-induced corneal damage; Secondly, the inhibitory effect of GLY on UV-induced corneal damage induced inflammation and the potential therapeutic mechanism of GLY were studied. GLY effectively attenuates the expression of UV-induced inflammatory factors and HMGB1, TLR/MyD88, NF-κB signaling pathway genes at the mRNA and protein levels. In addition, RT-PCR and Western Blot experiments after knocking down HMGB1 and TLR2/9 genes showed that GLY alleviated corneal inflammation by inhibiting the HMGB1-TLR/MyD88 signaling pathway. The results of this study show that targeting HMGB1-NF-κB by GLY can alleviate the inflammatory response induced by UV induction.

Etomidate is an anesthetic agent used in hemodynamically unstable patients, but its use has been controversial in septic patients. The response of high-mobility group box 1 (HMGB1), a late-phase lethal cytokine in sepsis, to etomidate has not been reported. This study investigated the effects of etomidate on the expression and release of HMGB1 and the underlying mechanism using a cecal ligation and puncture (CLP) model. Thirty-six male Sprague-Dawley rats were divided into sham, CLP, and Etomi groups. Sepsis was induced in the CLP and Etomi groups, and intravenous etomidate (4 mg/kg) was infused for 40 min immediately after operation in the Etomi group. Serum creatinine, alanine aminotransferase (ALT), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and HMGB1 levels were measured 6 and 24 hours after surgery. Activation of nuclear factor (NF)-ĸB and HMGB1 mRNA expression in the liver, lung, kidney, and ileum tissues were measured, and immunohistochemical staining of HMGB1 was implemented. Increases of the TNF-α level 6 h after CLP and ALT and IL-6 levels 24 h after CLP were significantly inhibited by etomidate treatment. Etomidate treatment also significantly attenuated the increase in serum HMGB1 level at 6 and 24 h after CLP and suppressed the NF-ĸB and HMGB1 mRNA in multiple organs 24 h after CLP. Immunohistochemical staining also revealed that etomidate treatment inhibited HMGB1 expression. Etomidate inhibited the systemic release of HMGB1 and its expression in various organs. The mechanism may be associated with the inhibitory effects of etomidate on pro-inflammatory cytokine release and NF-ĸB activity.

High mobility group box protein B1 (HMGB1) belongs to the HMG family, is widely expressed in the nucleus of digestive mucosal epithelial cells, mesenchymal cells and immune cells, and binds to DNA to participate in genomic structural stability, mismatch repair and transcriptional regulation to maintain normal cellular activities. In the context of digestive inflammation and tumors, HMGB1 readily migrates into the extracellular matrix and binds to immune cell receptors to affect their function and differentiation, further promoting digestive tract tissue injury and tumor development. Notably, HMGB1 can also promote the antitumor immune response. Therefore, these seemingly opposing effects in tumors make targeted HMGB1 therapies important in digestive cancer. This review focuses on the role of HMGB1 in tumors and its effects on key pathways of digestive cancer and aims to provide new possibilities for targeted tumor therapy.

Minimal hepatic encephalopathy (MHE) is strongly associated with neuroinflammation. Nevertheless, the underlying mechanism of the induction of inflammatory response in MHE astrocytes remains not fully understood. In the present study, we investigated the effect and mechanism of S100B, a predominant isoform expressed and released from mature astrocytes, on MHE-like neuropathology in the MHE rat model. We discovered that S100B expressions and autocrine were significantly increased in MHE rat brains and MHE rat brain-derived astrocytes. Furthermore, S100B stimulates VEGF expression via the interaction between TLR2 and RAGE in an autocrine manner. S100B-facilitated VEGF autocrine expression further led to a VEGFR2 and COX-2 interaction, which in turn induced the activation of NFƙB, eventually resulting in inflammation and oxidative stress in MHE astrocytes. MHE astrocytes supported impairment of neuronal survival and growth in a co-culture system. To sum up, a comprehensive understanding of the role of S100B-overexpressed MHE astrocyte in MHE pathogenesis may provide insights into the etiology of MHE.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are major causes of blindness globally. The primary treatment option for DME and neovascular AMD (nAMD) is anti-vascular endothelial growth factor (VEGF) compounds, but this treatment modality often yields insufficient results, and monthly injections can place a burden on the health system and patients. Although various inflammatory pathways and mediators have been recognized as key players in the development of DR and AMD, there are limited treatment options targeting these pathways. Molecular pathways that are interlinked, or triggers of multiple inflammatory pathways, could be promising targets for drug development. This review focuses on the role of inflammation in the pathogenesis of DME and AMD and presents current anti-inflammatory compounds, as well as a potential multitarget anti-inflammatory compound (dazdotuftide) that could be a candidate treatment option for the management of DME and AMD.

Sepsis is a syndrome of physiological, pathological and biochemical abnormalities caused by infection. Although the mortality rate is lower than before, many survivors have persistent infection, which means sepsis calls for new treatment. After infection, inflammatory mediators were largely released into the blood, leading to multiple organ dysfunction. Therefore, anti-infection and anti-inflammation are critical issues in sepsis management.

Here, we successfully constructed a novel nanometer drug loading system for sepsis management, FZ/MER-AgMOF@Bm. The nanoparticles were modified with LPS-treated bone marrow mesenchymal stem cell (BMSC) membrane, and silver metal organic framework (AgMOF) was used as the nanocore for loading FPS-ZM1 and meropenem which was delivery to the infectious microenvironments (IMEs) to exert dual anti-inflammatory and antibacterial effects. FZ/MER-AgMOF@Bm effectively alleviated excessive inflammatory response and eliminated bacteria. FZ/MER-AgMOF@Bm also played an anti-inflammatory role by promoting the polarization of macrophages to M2. When sepsis induced by cecal ligation and puncture (CLP) challenged mice was treated, FZ/MER-AgMOF@Bm could not only reduce the levels of pro-inflammatory factors and lung injury, but also help to improve hypothermia caused by septic shock and prolong survival time.

Together, the nanoparticles played a role in combined anti-inflammatory and antimicrobial properties, alleviating cytokine storm and protecting vital organ functions, could be a potential new strategy for sepsis management.

The clinical use of cyclosporin A (CsA) has led to significant advances and achievements in the field of transplantation and immune diseases. However, the nephrotoxicity of CsA is a major concern in current immunosuppression regimens. CsA causes abnormal kidney function while treating kidney disease, causing problems for clinicians and patients. Evidence of CsA nephrotoxicity is almost always present in transplant recipients after long-term CsA administration (up to 10 years), and similar phenomena occur with other calcineurin inhibitors. In this review, we summarize the mechanisms and influencing factors of CsA for the treatment of primary nephrotic syndrome. The mechanisms of CsA nephrotoxicity, clinical-pathological features, diagnosis, prevention strategies, and risk factors are summarized. We discuss the correlates and mechanisms of the switch between kidney disease prevention and nephrotoxicity of CsA to better understand the function of CsA in the kidney and to provide a basis for the prevention and treatment of CsA nephrotoxicity.

Acute respiratory distress syndrome is an acute respiratory failure caused by cytokine storms; highly pathogenic influenza A virus infection can induce cytokine storms. The innate immune response is vital in this cytokine storm, acting by activating the transcription factor NF-κB. Tissue injury releases a danger-associated molecular pattern that provides positive feedback for NF-κB activation. Exogenous mesenchymal stem cells can also modulate immune responses by producing potent immunosuppressive substances, such as prostaglandin E2. Prostaglandin E2 is a critical mediator that regulates various physiological and pathological processes through autocrine or paracrine mechanisms. Activation of prostaglandin E2 results in the accumulation of unphosphorylated β-catenin in the cytoplasm, which subsequently reaches the nucleus to inhibit the transcription factor NF-κB. The inhibition of NF-κB by β-catenin is a mechanism that reduces inflammation.

Thioacetamide (TAA), a classic liver toxic compound, is used to establish experimental models of liver injury via induction of inflammation and oxidative stress. The current study was employed to explore the effects of canagliflozin (CANA), a sodium glucose cotransporter 2 (SGLT-2) inhibitor and antidiabetic agent, on TAA-induced acute liver injury.

A rat model of acute hepatic injury was established using single intraperitoneal injection of TAA (500 mg/kg) and rats received CANA (10 and 30 mg/kg, orally) once daily for 10 days prior to TAA challenge. Liver function, oxidative stress, and inflammatory parameters were measured in serum and hepatic tissues of rats.

Elevated levels of liver enzymes, hepatic malondialdehyde (MDA), and serum lactate dehydrogenase (LDH) were significantly attenuated by CANA. CANA also increased hepatic superoxide dismutase (SOD) and glutathione (GSH). Hepatic levels of high-mobility group box 1 (HMGB1), toll like receptor4 (TLR4), receptor for advanced glycation end products (RAGE), and pro-inflammatory cytokines (IL-6, and IL-1β) were normalized with CANA. Additionally, Hepatic expression of p-JNK/p-p38 MAPK was significantly attenuated by CANA compared to TAA-treated rats. CANA also decreased hepatic immunoexpression of NF-κB and TNF-α and attenuated hepatic histopathological alterations via reduction of inflammation and necrosis scores and collagen deposition. Moreover, mRNA expression levels of TNF-α and IL-6 were reduced upon CANA treatment.

CANA attenuates TAA-prompted acute liver damage, via suppressing HMGB1/RAGE/TLR4 signaling, regulation of oxidative stress and inflammation pathways.

Background Cardiac failure is the primary cause of death in most patients with pulmonary arterial hypertension (PH). As pleiotropic cytokines, human resistin (Hresistin) and its rodent homolog, resistin-like molecule α, are mechanistically critical to pulmonary vascular remodeling in PH. However, it is still unclear whether activation of these resistin-like molecules can directly cause PH-associated cardiac dysfunction and remodeling. Methods and Results In this study, we detected Hresistin protein in right ventricular (RV) tissue of patients with PH and elevated resistin-like molecule expression in RV tissues of rodents with RV hypertrophy and failure. In a humanized mouse model, cardiac-specific Hresistin overexpression was sufficient to cause cardiac dysfunction and remodeling. Dilated hearts exhibited reduced force development and decreased intracellular Ca2+ transients. In the RV tissues overexpressing Hresistin, the impaired contractility was associated with the suppression of protein kinase A and AMP-activated protein kinase. Mechanistically, Hresistin activation triggered the inflammation mediated by signaling of the key damage-associated molecular pattern molecule high-mobility group box 1, and subsequently induced pro-proliferative Ki67 in RV tissues of the transgenic mice. Intriguingly, an anti-Hresistin human antibody that we generated protected the myocardium from hypertrophy and failure in the rodent PH models. Conclusions Our data indicate that Hresistin is expressed in heart tissues and plays a role in the development of RV dysfunction and maladaptive remodeling through its immunoregulatory activities. Targeting this signaling to modulate cardiac inflammation may offer a promising strategy to treat PH-associated RV hypertrophy and failure in humans.

Advanced glycation end products (AGEs) are a class of compounds formed by nonenzymatic interactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs can alter the protein structure and activate one of their receptors, specifically the receptor for advanced glycation end products (RAGE). These phenomena impair the functions of cells, extracellular matrix, and tissues. RAGE is expressed by a variety of cells and has been linked to chronic inflammatory autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. The soluble (s)RAGE cleavage product is a positively charged 48-kDa cleavage product that retains the ligand binding site but loses the transmembrane and signaling domains. By acting as a decoy, this soluble receptor inhibits the pro-inflammatory processes mediated by RAGE and its ligands. In the present review, we will give an overview of the role of AGEs, sRAGE, and RAGE polymorphisms in several rheumatic diseases. AGE overproduction may play a role in the pathogenesis and is linked to accelerated atherosclerosis. Low serum sRAGE concentrations are linked to an increased cardiovascular risk profile and a poor prognosis. Some RAGE polymorphisms may be associated with increased disease susceptibility. Finally, sRAGE levels can be used to track disease progression.

This is a research aimed to study the effect of micro ribonucleic acid (miR)-34α on the retinal cell apoptosis in diabetic retinopathy (DR) rats and its key molecular mechanism.

Sprague-Dawley rats were randomly divided into healthy group (H group, N.=5), diabetes group (D group, N.=5), diabetes + negative control transfection group (N group, N.=5) and diabetes + miR-34α inhibitor transfection group (M group, N.=5). The rat model of diabetes was established via intraperitoneal injection of 2% streptozotocin solution (60 mg/kg). After 72 h, the urine glucose and blood glucose were detected, and the urine glucose above 3+ and the blood glucose concentration >16.7 mmol/L indicated the successful modeling. After the rats were normally fed for 4 months, the changes in expression of miR-34α in retinal tissues were detected via reverse transcription-polymerase chain reaction (RT-PCR), the pathological changes in retinal tissues were observed via hematoxylin-eosin (HE) staining, and the retinal cell apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the changes in the number of cells containing active caspase-3 in retinal tissues were determined through immunohistochemistry, and the changes in expressions of caspase-3, high mobility group box 1 (HMGB1) and nuclear factor-κB (NF-κB) in retinal tissues were determined through Western blotting.

Compared with those in H group, the cell density declined, and the cells were arranged disorderly with swelling in each retinal layer, the expression of miR-34α in retinal tissues was increased, the retinal cell apoptosis was enhanced, the number of cells containing active caspase-3 in retinal tissues rose, and the expressions of caspase-3, HMGB1 and NF-κB in retinal tissues were increased in D group, N group and M group (P<0.05). Compared with those in D group and N group, the cell density rose, and the cells were arranged less disorderly with milder swelling in each retinal layer, the expression of miR-34α in retinal tissues declined, the retinal cell apoptosis was weakened, the number of cells containing active caspase-3 in retinal tissues was decreased, and the expressions of caspase-3, HMGB1 and NF-κB in retinal tissues were reduced in M group (P<0.05).

Inhibiting miR-34α reduces the retinal cell apoptosis in DR rats through regulating the HMGB1 expression and downstream NF-κB pathway.

Type 1 diabetes (T1D) may affect the peripheral nervous system and alter the expression of proteins contributing to inflammation and cellular cytoskeleton dysfunction, in most cases leading to the development of diabetic length-dependent neuropathy (DLDN). In the present study, we performed immunohistochemistry (IHC) to probe the expression of the receptor for advanced glycation end products (RAGE); its key ligands, high-mobility group box 1 (HMGB1), S100 calcium-binding protein B (S100B), and carboxymethyl-lysine (CML - advanced glycation end products (AGE)); and its cytoplasmic tail-binding partner, diaphanous related formin 1 (DIAPH1) and associated molecules, beta-actin (ACTB) and profilin 1 (PFN1) proteins in sciatic nerves harvested from seven-month old FVB/OVE26 mice with genetically-mediated T1D. We found that the amount of RAGE, HMGB1, and S100B proteins was elevated in diabetic vs the non-diabetic groups, while the amount of DIAPH1, ACTB, as well as PFN1 proteins did not differ between these groups. Moreover, our data revealed linear dependence between RAGE and HMGB1 proteins. Interaction criss-cross of selected sets of proteins in the sciatic nerve revealed that there were connected in a singular network. Our results indicate that T1D may alter expression patterns of RAGE axis proteins and thus contribute to DLDN.

High mobility group box 1 (HMGB1) has dual functions as a nonhistone nucleoprotein and an extracellular inflammatory cytokine. In the resting state, HMGB1 is mainly located in the nucleus and regulates key nuclear activities. After spinal cord injury, HMGB1 is rapidly expressed by neurons, microglia and ependymal cells, and it is either actively or passively released into the extracellular matrix and blood circulation; furthermore, it also participates in the pathophysiological process of spinal cord injury. HMGB1 can regulate the activation of M1 microglia, exacerbate the inflammatory response, and regulate the expression of inflammatory factors through Rage and TLR2/4, resulting in neuronal death. However, some studies have shown that HMGB1 is beneficial for the survival, regeneration and differentiation of neurons and that it promotes the recovery of motor function. This article reviews the specific timing of secretion and translocation, the release mechanism and the role of HMGB1 in spinal cord injury. Furthermore, the role and mechanism of HMGB1 in spinal cord injury and, the challenges that still need to be addressed are identified, and this work will provide a basis for future studies.

This study explored the correlation between serum HMGB1 levels and postoperative vascular restenosis in patients with lower extremity arteriosclerosis obliterans (LEASO).

A total of 362 patients LEASO who received vascular intervention were recruited in this study. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay. Logistic regression analysis was used to identify the influencing factors associated with vascular restenosis. The R procedure was used to create nomogram model. Receiver operating characteristic (ROC) analysis was used to determine the predictive value of serum HMGB1 and nomogram model for vascular restenosis.

Of the 362 LEASO patients included, 103 (28.45%) developed restenosis within 6 months of postoperative follow-up. Postoperative HMGB1 levels were significantly higher in patients with restenosis compared to those with non-restenosis. Postoperative HMGB1 levels were significantly and positively correlated with the severity of postoperative restenosis (r = 0.819). The AUC of postoperative HMGB1 for the diagnosis of postoperative restenosis was 0.758 (95% CI: 0.703-0.812), with a sensitivity and specificity of 56.31% and 82.24%, respectively. Multivariate logistic regression analysis showed that diabetes, smoking, regular postoperative medication, increased fibrinogen, decreased red blood cells, increased hs-CRP, and increased postoperative HMGB1 were independently associated with postoperative restenosis in patients with LEASO. The C-index of the nomogram prediction model constructed based on the seven influencing factors mentioned above was 0.918. The nomogram model was significantly more predictive of postoperative restenosis in LEASO patients compared with a single postoperative HMGB1 (AUC: 0.918, 95% CI: 0.757-0.934).

Postoperative serum HMGB1 is an independent risk factor associated with postoperative vascular restenosis in patients with LEASO, and a novel nomogram model based on postoperative serum HMGB1 combined with clinical characteristics may help to accurately predict the risk of postoperative restenosis in patients with LEASO.

Avian pathogenic E. coli (APEC) is typically the cause of avian colibacillosis, which can result in oxidative stress, inflammation, and intestinal damage (APEC). Luteolin, in the form of glycosylation flavone, has potent anti-inflammatory and anti-oxidative properties. However, its effects on APEC-induced intestinal oxidative stress and NF-κB-mediated inflammation in chicks remains poorly understood. After hatching, one-day-old chicks were stochastically assigned to four groups: a control group (basic diet), an E. coli group (basic diet) and L10 and L20 groups (with a dry matter of luteolin diet 10 mg/kg and 20 mg/kg, respectively), with fifteen chicks in each group and one repeat per group. They were pretreated for thirteen days. The body weight, mortality, histopathological changes in the ileum, antioxidant status, and the mRNA and protein-expression levels of factors associated with the HMGB1/TLR4/NF-κB signal axis of the chicks were measured. The results showed that luteolin treatment decreased the mRNA and protein-expression level of the related factors of HMGB1/TLR4/NF-κB signal axis in the ileum, reduced inflammation, increased antioxidant enzyme activity, and reduced intestinal injury. Collectively, luteolin alleviated APEC-induced intestinal damage by means of hindering the HMGB1/TLR4/NF-κB signal axis, which suggests that luteolin could be a good method for the prevention and treatment of avian colibacillosis.

Mesenchymal stem cell-derived conditioned medium (MSC-CM) improves cardiac function after myocardial infarction; however, this cardioprotective effect is moderate and transient. Lipopolysaccharide (LPS) pretreatment partially improves MSC-CM-mediated cardioprotective effects owing to the presence of paracrine factors. However, the mechanism underlying these improved effects remains unknown. To study the effect of LPS-pretreated MSC-CM on hypoxia/reoxygenation (H/R)-induced injury, MSCs were treated with or without LPS (400 ng/mL) for 48 h, and the supernatant was collected (MSC-CM). Subsequently, H9c2 cells were co-cultured with Nor-CM (CM derived from LPS-untreated MSCs) and LPS-CM (CM derived from LPS-pretreated MSCs) for 24 h and subjected to H/R. MSC-CM inhibited the progression of H/R-induced injury in H9c2 cells, and this protective effect was enhanced via LPS pretreatment as evidenced by the improved apoptosis assessment index (i.e. caspase-3 and B-cell lymphoma-2 [Bcl-2] expression) and decreased levels of lactic dehydrogenase (LDH) and cardiac troponin (cTn). In addition, the results of haematoxylin-eosin staining (H&E), transmission electron microscopy (TEM) and TdT-mediated dUTP nick-end labelling (TUNEL) validated that MSC-CM inhibited H/R-induced injury in H9c2 cardiomyocytes. LPS pretreatment downregulated the expression of high mobility group box-1 (HMGB1) and BTB and CNC homology-1 (Bach1) proteins in MSCs but upregulated the expression of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and insulin-like growth factor (IGF). HMGB1 knockdown (MSC/siHMGB1-CM) significantly decreased the expression of Bach1 and increased the expression of VEGF, HGF and IGF. Bach1 knockdown (MSC/siBach1-CM) did not alter the production of HMGB1 but increased the expression of VEGF and IGF. LPS pretreatment did not alter the expression of the paracrine factors VEGF and HGF in the MSC/siHMGB1 group but increased their expression in the MSC/siBach1 group. The myocyte anti-apoptotic effects of MSCs/siBach1-CM were similar to those of untreated MSCs, which were not enhanced by LPS. LPS-pretreated MSC-CM protects H9c2 cells against H/R-induced injury partly through the HMGB1/Bach1 signalling pathway.

Subarachnoid hemorrhage (SAH) is one of the common clinical neurological emergencies. Its incidence accounts for about 5-9% of cerebral stroke patients. Even surviving patients often suffer from severe adverse prognoses such as hemiplegia, aphasia, cognitive dysfunction and even death. Inflammatory response plays an important role during early nerve injury in SAH. Toll-like receptors (TLRs), pattern recognition receptors, are important components of the body's innate immune system, and they are usually activated by damage-associated molecular pattern molecules. Studies have shown that with TLR 4 as an essential member of the TLRs family, the inflammatory transduction pathway mediated by it plays a vital role in brain injury after SAH. After SAH occurrence, large amounts of blood enter the subarachnoid space. This can produce massive damage-associated molecular pattern molecules that bind to TLR4, which activates inflammatory response and causes early brain injury, thus resulting in serious adverse prognoses. In this paper, the process in research on TLR4-mediated inflammatory response mechanism in brain injury after SAH was reviewed to provide a new thought for clinical treatment.

Immunogenic cell death (ICD) is a regulated cell death (RCD) pathway. In response to physical and chemical signals, tumor cells activate specific signaling pathways that stimulate stress responses in the endoplasmic reticulum (ER) and expose damage-associated molecular patterns (DAMPs), which promote antitumor immune responses. As a result, the tumor microenvironment is altered, and many tumor cells are killed. The ICD response in tumor cells requires inducers. These inducers can be from different sources and contribute to the development of the ICD either indirectly or directly. The combination of ICD inducers with other tumor treatments further enhances the immune response in tumor cells, and more tumor cells are killed; however, it also produces side effects of varying severity. New induction methods based on nanotechnology improve the antitumor ability and significantly reduces side effects because they can target tumor cells precisely. In this review, we introduce the characteristics and mechanisms of ICD responses in tumor cells and the DAMPs associated with ICD responses, summarize the current methods of inducing ICD response in tumor cells in five distinct categories: chemical sources, physical sources, pathogenic sources, combination therapies, and innovative therapies. At the same time, we introduce the limitations of current ICD inducers and make a summary of the use of ICD responses in clinical trials. Finally, we provide an outlook on the future of ICD inducer development and provide some constructive suggestions.