Deaths from viral hepatitis continue to rise around the world due to the lack of early biomarkers. We aimed here to evaluate the chemokine CXCL14, as a novel biomarker in acute viral hepatitis. We used a mouse model of acute hepatitis induced by murine hepatitis virus (MHV), a hepatotropic and lytic coronavirus, and showed that CXCL14 is overexpressed in the liver and sera of infected mice. Using primary cultures of murine and human hepatocytes, we showed that hepatocytes are the main source of CXCL14 after lytic hepatotropic virus infection and that CXCL14 expression is also induced by the pro-inflammatory cytokines IL-6 and TNFα. CXCL14 KO mice infected with MHV were partially protected and showed an attenuated antiviral immune response compared to wild-type mice. Finally, we show that CXCL14 is overexpressed in the sera of human patients infected with hepatitis viruses A, B, and E or herpes simplex virus. A positive correlation between CXCL14 and ALT levels in the sera of patients with acute herpetic hepatitis, as well as in mice models, suggests that hepatocyte lysis is necessary for the release of CXCL14. Overall, these data highlight that CXCL14 expression is associated with the occurrence of acute viral hepatitis and could be considered an alarmin and a new indicator of inflammation. CXCL14 serum levels are also associated with the severity of viral-induced liver injury.

Dendrimers and dendrimer-based self-assembly systems have emerged as promising nanocarriers for a variety of applications, including anti-cancer therapies, modulation of the tumor microenvironment, and imaging. Here, we explored the therapeutic potential of two charged dendrimers, dendritic polyglycerol sulfate (dPGS) and dendritic polyglycerol amine (dPGA), in the context of glioblastoma multiforme (GBM). Docosahexaenoic acid (DHA) has shown potential in GBM. We therefore examined dPGS and dPGA effects alone and in combination with DHA. Using 2D cell models and 3D tumoroids, we showed that DHA with dPGA reduced tumor integrity and cell viability. dPGS reduced oxidative stress, whereas dPGA reduced lysosomal acidification, contributing to cellular dysfunction. Both dendrimers influence the interaction between high mobility group box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE). The surfaces of the HMGB1-RAGE complex provide binding sites for interactions of charged molecules like dPGS and dPGA, suggesting the contribution of these interactions to cytotoxicity. In summary, our findings show that combining DHA with charged dendrimers (dPGS and dPGA) enhances GBM cytotoxicity through several mechanisms, involving lysosomal alkalinization, lipid peroxidation and modulation of the HMGB1-RAGE complex.

Exposure to ambient Ozone (O3) air pollution directly causes by its oxidative properties, respiratory epithelial cell injury, and cell death, which promote inflammation and hyperreactivity, posing a significant public health concern. Recent clinical and experimental studies have made strides in elucidating the mechanisms underlying O3-induced epithelial cell injury, inflammation, and airway hyperreactivity, which are discussed herein. The current data suggest that O3-induced oxidative stress is a central event-inducing oxeiptotic cell death pathway. O3-induced epithelial barrier damage and cell death, triggering the release of alarmins and damage-associated molecular patterns (DAMPs), with subsequent endogenous activation of Toll-like receptors (TLRs), DNA sensing pathways, and inflammasomes, activating interleukin-1-Myd88 inflammatory pathway with the production of a range of chemokines and cytokines. This cascade orchestrates lung tissue-resident cell activation in response to O3 in leukocyte and non-leukocyte populations, driving sterile innate immune response. Chronic inflammatory response to O3, by repeated exposures, supports a mixed phenotype combining asthma and emphysema, in which their exacerbation by other particulate pollutants potentially culminates in respiratory failure. We use data from lung single-cell transcriptomics to map genes of O3-damage sensing and signaling pathways to lung cells and thereby highlight potential hotspots of O3 responses. Deeper insights into these pathological pathways might be helpful for the identification of novel therapeutic targets and strategies.

A cytokine storm is marked by excessive pro-inflammatory cytokine release, and has emerged as a key factor in severe COVID-19 cases - making it a critical therapeutic target. However, its pathophysiology was poorly understood, which hindered effective treatment. SARS-CoV-2 initially disrupts angiotensin signalling, promoting inflammation through ACE-2 downregulation. Some patients' immune systems then fail to shift from innate to adaptive immunity, suppressing interferon responses and leading to excessive pyroptosis and neutrophil activation. This amplifies tissue damage and inflammation, creating a pro-inflammatory loop. The result is the disruption of Th1/Th2 and Th17/Treg balances, lymphocyte exhaustion, and extensive blood clotting. Cytokine storm treatments include glucocorticoids to suppress the immune system, monoclonal antibodies to neutralize specific cytokines, and JAK inhibitors to block cytokine receptor signalling. However, the most effective treatment options for mitigating SARS-CoV-2 infection remain vaccines as a preventive measure and antiviral drugs for the early stages of infection. This article synthesizes insights into immune dysregulation in COVID-19, offering a framework to better understand cytokine storms and to improve monitoring, biomarker discovery, and treatment strategies for COVID-19 and other conditions involving cytokine storms.

Programmed necrosis, a controlled cell death method that bypasses resistance mechanisms that render apoptosis ineffective, is a potential cancer treatment target. Due to their diverse biological activities and low side effects, natural products are being explored as modulators of programmed necrosis pathways. This review highlights the potential of natural compounds to target cancer cells while preserving healthy tissues and their interaction with essential programmed necrosis mechanisms like ferroptosis and necroptosis. Recent developments have identified various types of programmable necrosis, including necroptosis, ferroptosis, pyroptosis, proptosis, mitochondrial permeability transition-driven necrosis, and oncosis. Natural compounds are increasingly being utilized as a primary source of anti-cancer medications, providing new cancer treatments. This review demonstrates the molecular mechanisms behind lipid peroxidation, mixed lineage kinase domain-like protein, and receptor-interacting protein kinases (RIPK1 and RIPK3) inducing cell death. Recent research has identified natural compounds like polyphenols, alkaloids, and terpenoids that can modulate pathways and benefit preclinical cancer models. The review underscores the potential of natural compounds in developing innovative cancer treatments by integrating pharmacology and cellular signaling knowledge. Integrating natural compound studies and programmed necrosis research presents a promising avenue for oncologists to overcome treatment resistance. Natural compounds have shown potential in developing programmed necrosis as a novel cancer treatment approach, enhancing therapeutic effectiveness and minimizing side effects through preclinical research, pharmacology, and molecular biology.

Gene electrotransfer (GET) has recently emerged as an effective nonviral approach for plasmid DNA (pDNA) delivery in gene therapy for several pathologies, including cancer. Multiple mechanisms have been identified that influence cell biology after GET, as electroporation significantly increases pDNA uptake and immunogenicity, which may directly influence target cell death. However, the molecular effects of in vivo electroporation-mediated DNA delivery have yet to be fully elucidated. In this study, we evaluated the transcriptomes of murine colorectal tumors treated with two protocols, short- and high-voltage (SHV) electric pulses or an adapted high-voltage-low-voltage (HV-LV) pulse protocol, both of which are used for reversible electroporation. Although no significant differences in clinical outcomes were observed, variations in intratumoral macrophage infiltration were reported between the two treatment methods. Transcriptomic analysis revealed that apoptosis is a predominant mode of cell death after GET by SHV pulses, whereas GET by HV-LV pulses is associated with immunogenic necrotic pathways as well as the activation of both the innate and adaptive immune response. We demonstrated that specific pulse parameters can induce distinct immunomodulatory profiles in the tumor microenvironment; therefore, these aspects should be considered carefully when selecting the most suitable GET-based approach for antitumor immunization.

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy targeting the PD-1/PD-L1 axis has revolutionized treatment, providing durable responses in a subset of patients. However, with fewer than 50% of patients achieving significant benefits, there is a critical need to expand therapeutic strategies. This review explores emerging targets in immune checkpoint inhibition beyond PD-1/PD-L1, including CTLA-4, TIGIT, LAG-3, TIM-3, NKG2A, and CD39/CD73. We highlight the biological basis of CD8 T cell exhaustion in shaping the antitumor immune response. Novel therapeutic approaches targeting additional inhibitory receptors (IR) are discussed, with a focus on their distinct mechanisms of action and combinatory potential with existing therapies. Despite significant advancements, challenges remain in overcoming resistance mechanisms and optimizing patient selection. This review underscores the importance of dual checkpoint blockade and innovative bispecific antibody engineering to maximize therapeutic outcomes for NSCLC patients.

A couple of S100 family proteins (S100s) have been reported to exert pro-inflammatory functions in the progression of renal fibrosis. Unlike some S100s which are expressed by both epithelial and stromal inflammatory cells, S100A7 is restricted expressed in epithelium. Persistent S100A7 expression occurs in some invasive carcinomas and is associated with poor prognostic factors. Whereas, whether it is implicated in renal tubular epithelial cell injury and kidney disease remains unexplored. In this study, we demonstrate that S100A7 is highly upregulated in tubular cells of both mouse renal fibrotic lesions and kidney biopsies from patients with chronic kidney disease (CKD). The level of renal S100A7 was associated with both the decline of renal function and the progression of renal fibrosis in CKD patients. Overexpressing S100A7a impaired fatty acid oxidation (FAO) and promoted lipid peroxidation in proximal tubular cells (PTCs). Mechanistically, S100A7a interacts with β-catenin, thereby preventing its ubiquitination and degradation by the β-TrCP-SCF complex, and in turn activated β-catenin signaling, downregulated the expression of PGC-1α. Additionally, S100A7a exacerbated lipid peroxidation via RAGE-p-ERK-NOX2 pathway. Specific deletion of S100a7a in tubular cells enhanced FAO and reduced lipid peroxidation, resulting in improved renal function and alleviation of renal fibrosis induced by unilateral ureteral obstruction and unilateral ischemia-reperfusion injury. Collectively, we delineate a previously unrecognized function of S100A7a in the progression of renal fibrosis.

Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with diabetes and is characterised by contractile dysfunction and left ventricular hypertrophy. The complex pathological and physiological mechanisms underlying DCM have contributed to a limited number of available treatment options. A substantial body of evidence has established that DCM is a low-grade inflammatory cardiovascular disorder, with the interleukin-1 (IL-1) family of cytokines playing crucial roles in initiating inflammatory responses and shaping innate and adaptive immunity. In this review, we aim to provide an overview of the underlying mechanisms of the IL-1 family and their relevance in DCM of various aetiologies. Furthermore, we highlighted potential therapeutic targets within the IL-1 family for the management of DCM.

Spinal cord injury (SCI) is a complex central nervous system disorder characterized by multifaceted pathological processes, including inflammation, oxidative stress, programmed cell death, autophagy, and mitochondrial dysfunction. Sirtuin 1 (Sirt1), a critical NAD+-dependent deacetylase, has emerged as a promising therapeutic target for SCI repair due to its potential to protect neurons, regulate glial and vascular cells, and optimize the injury microenvironment. However, the regulatory roles of Sirt1 in SCI are complex and challenging, as its effects vary depending on activation timing, expression levels, and cell types.

A systematic literature review was conducted using PubMed, Scopus, and Web of Science to identify studies investigating Sirt1 in SCI. Relevant publications were analyzed to synthesize current evidence on Sirt1's mechanisms, therapeutic effects, and challenges in SCI repair.

Sirt1 exerts broad regulatory effects across diverse pathological processes and cell types post-SCI. It promotes neuronal survival and axonal regeneration, modulates astrocytes and microglia to resolve inflammation, supports oligodendrocyte-mediated myelination, and enhances vascular endothelial function. Proper Sirt1 activation may mitigate secondary injury, whereas excessive or prolonged activation could impair inflammatory resolution or disrupt cellular homeostasis. This review highlights Sirt1 activation as potential therapies, but challenges include optimizing spatiotemporal activation and addressing dual roles in different cell types.

Targeting Sirt1 represents a viable strategy for SCI repair, given its multifaceted regulation of neuroprotection, immunomodulation, and tissue remodeling. However, translating these findings into therapies requires resolving critical issues such as cell type-specific delivery, precise activation timing, and dosage control. This review provides a theoretical foundation and practical insights for advancing Sirt1-based treatments for SCI.

Although food is essential for the survival of organisms, it can also trigger a variety of adverse reactions, ranging from nutrient intolerances to celiac disease and food allergies. Food not only contains essential nutrients but also includes numerous substances that may have positive or negative effects on the consuming organism. To protect against potentially harmful components, all animals have evolved defense mechanisms, which are similar to antimicrobial defenses but often come at the cost of the organism's health. When these defensive responses are exaggerated or misdirected, they can lead to adverse food reactions, where the costs outweigh the benefits. Furthermore, due to the persistent toxicity of harmful food components, the failure of defense mechanisms can also result in pathological effects triggered by food. This article review presents a food quality control framework that aims to clarify how these reactions relate to normal physiological processes. Organisms utilize several systems to coexist with symbiotic microbes, regulate them, and concurrently avoid, expel, or neutralize harmful pathogens. Similarly, food quality control systems allow organisms to absorb necessary nutrients while defending against low-quality or harmful components in food. Although many microbes are lethal in the absence of antimicrobial defenses, diseases related to microbiome dysregulation, such as inflammatory bowel disease, have significantly increased. Antitoxin defenses also come with costs and may fail due to insufficiencies, exaggerations, or misdirected actions, ultimately leading to adverse food reactions. With the changes in human diet and lifestyle, the failure of defense mechanisms has contributed to the rising incidence of food intolerances. This review explores the mechanisms of antitoxin defenses and analyzes how their failure can lead to adverse food reactions, emphasizing the importance of a comprehensive understanding of food quality control mechanisms for developing more effective treatments for food-triggered diseases.

Pathogenic microorganisms can infect a variety of niches in the human body. During infection, these microbes can only persist if they adapt adequately to the dynamic host environment and the stresses imposed by the immune system. While viruses entirely rely on host cells to replicate, bacteria and fungi use their pathogenicity mechanisms for the acquisition of essential nutrients that lie under host restriction. An inappropriate deployment of pathogenicity mechanisms will alert host defence mechanisms that aim to eradicate the pathogen. Thus, these adaptations require tight regulation to guarantee nutritional access without eliciting strong immune activation. To work efficiently, the immune system relies on a complex signalling network, involving a myriad of immune mediators, some of which are quite directly associated with imminent danger for the pathogen. To manipulate the host immune system, viruses have evolved cytokine receptors and viral cytokines. However, among bacteria and fungi, selected pathogens have evolved the capacity to use these inflammatory response-specific signals to regulate their pathogenicity. In this review, we explore how bacterial and fungal pathogens can sense the immune system and use adaptive pathogenicity strategies to evade and escape host defence to ensure their persistence in the host.

Gastric precancerous lesions (GPL) typically originates from chronic gastritis (CG), and the changes in glycolysis mediated by the HIF-1α pathway during the progression from CG to GPL are unclear. Modified Zuojin pill (SQQT) is a traditional Chinese herbal formula used for treating GPL. However, the underlying mechanism has not been fully elucidated.

To investigate the changes in glycolysis mediated by the HIF-1α pathway during the progression from CG to GPL and whether SQQT can alleviate GPL by attenuating glycolysis through the HIF-1α pathway.

A rat model of GPL was established, and the changes of glycolysis mediated by the HIF-1α pathway during the progression from CG to GPL were detected in 12th, 18th, 24th, and 30th weeks. The therapeutic efficacy of SQQT was evaluated through pathological changes. In vitro, the GPL cell model (MC cell) originated from GES-1 cells intervened by MNNG. The effects of SQQT on glycolysis and the HIF-1α pathway were detected in vivo and in vitro. In vitro, HIF-1α overexpression was used to confirmed that SQQT attenuated glycolysis by targeting the HIF-1α pathway.

Our study revealed that glycolysis mediated by the HIF-1α pathway exhibited dynamic changes in the progression from CG to GPL, characterized by sequential activation, deactivation, and reactivation. SQQT ameliorated gastric mucosal pathology and inflammation in GPL rats. Mechanistic studies revealed that SQQT alleviated glycolysis by targeting the HIF-1α pathway, and improved abnormal cellular proliferation and apoptosis. Importantly, HIF-1α overexpression blocked the effect of SQQT on glycolysis.

In the progression from CG to GPL, the HIF-1α pathway-mediated glycolysis was characterized by sequential activation, deactivation, and reactivation. SQQT attenuated glycolysis by targeting the HIF-1α pathway and improved abnormal cellular proliferation and apoptosis in the gastric mucosa, thereby exerting therapeutic effects on GPL.

Urticaria is a debilitating skin condition affecting up to 20% of the global population, characterized by erythematous, maculopapular lesions and significant quality of life impairment. This study focused on the role of interleukin 33 (IL-33) and its polymorphisms, particularly SNP rs1929992, in chronic spontaneous urticaria (CSU). Using demographic, clinical, and laboratory data from CSU patients and controls, we estimated allele and genotype frequencies, Hardy-Weinberg equilibrium condition, and serum IL-33 levels, using unconditional binomial logistic regression for association analysis. Results revealed that CSU patients had significantly higher frequencies of the minor allele of IL-33 rs1929992 compared to controls (31.25% vs. 17.35%, p = 0.024), and carriers of the GA genotype exhibited increased odds of CSU (adjusted OR = 2.208, p ≤ 0.001). Additionally, serum IL-33 levels were markedly elevated in CSU patients, particularly those with the GA genotype. The findings suggest that the IL-33 SNP is associated with an increased susceptibility to CSU, emphasizing its potential as a diagnostic and therapeutic biomarker. This study underscores the genetic and immunological underpinnings of CSU, paving the way for personalized treatment approaches.

Since its discovery in 1992, the receptor for advanced glycation end products (RAGE) has emerged as a key receptor in many pathological conditions, especially in inflammatory conditions. RAGE is expressed by most, if not all, immune cells and can be activated by many ligands. One characteristic of RAGE is that its ligands are structurally very diverse and belong to different classes of molecules, making RAGE a promiscuous receptor. Many of RAGE ligands are damaged associated molecular patterns (DAMPs) that are released by cells under inflammatory conditions. Although RAGE has been at the center of a lot of research in the past three decades, a clear understanding of the mechanisms of RAGE activation by its ligands is still missing. In this review, we summarize the current knowledge of the role of RAGE and its ligands in inflammation.

Interleukin (IL)-1 family cytokines are essential for host defense at epithelial barriers. The IL-1 family member IL-33 was recently linked to stress granules (SGs). Formation of SGs and other biomolecular condensates is promoted by proteins containing low-complexity regions (LCRs). Computational analysis predicts LCRs in six of the 11 IL-1 family members. Among these, IL-38 contains a long LCR including two amyloid cores. IL-38 localizes to intracellular granules in keratinocytes under oxidative stress (OS) and forms OS-induced amyloid aggregates in cells and in vitro. Interestingly, soluble and aggregated IL-38 are released from keratinocytes in an exosome-enriched extracellular vesicle fraction. Disulfide-bond mapping, in silico modeling, and mutational analysis suggest that oxidation-sensitive cysteines act as redox switches to alter IL-38 conformation and promote its aggregation. Finally, the presence of IL-38 granules in human epidermis facing environmental OS suggests that oxidation-induced amyloidogenesis, as an intrinsic property of IL-38, supports barrier function.

High Mobility Group Box Protein-1 (HMGB1), which has proinflammatory properties, is known to be involved in psychiatric disorders as far as we know, there are only one clinical studies investigating the role of HMGB1 in major depressive disorder (MDD). In this study, we aimed to investigate the role of HMGB1 in the etiopathogenesis of MDD and whether HMGB1 can be used as a biomarker in MDD by measuring the serum HMGB1 levels of depressed patients in the episode and remission periods. This study included 30 patients diagnosed with MDD in episode, 30 patients in remission and 30 healthy controls. Each group comprised 20 female and 10 male participants. In this study, serum HMGB1 levels were found to be lower in the patient group in the episode compared to the patient group in the remission period and the healthy control group. There was no significant difference between the patient group in remission and the healthy control group in terms of serum HMGB1 levels. The fact that serum HMGB1 levels were lower in the patient group in the episode compared to the patient group in the remission period and the control group may be related to the neuroprotective effects of HMGB1. HMGB1 may be used as a biomarker for MDD.

Understanding the regulatory mechanisms of adipogenesis is essential for preventing obesity. Interleukin-33 (IL-33) has recently attracted increasing attention for its role in adipogenesis. The purpose of this study was to explore the function and regulatory mechanism of IL-33 and its receptor suppression of tumorigenicity 2 (ST2) on adipogenesis. Here, Oil Red O staining was used to detect the accumulation of intracellular lipid droplets. Molecular techniques such as qRT-PCR and Western blotting were used to detect the expression of pivotal genes and adipogenic marker genes. Gains and losses of function experiments were used to explore the potential regulatory mechanism of the IL-33/ST2 axis in adipogenesis. Functionally, IL-33 is negatively associated with adipogenesis in 3T3-L1 preadipocytes, while ST2 is positively associated with it, encompassing both the trans-membrane receptor ST2 (ST2L) and the soluble ST2 (sST2). Mechanistically, the IL-33/ST2 axis affects adipogenesis by regulating the expression of the TRAF6/RelA pathway in 3T3-L1 preadipocytes. Downregulating the expression of ST2 suppressed the activation of the IL-33/ST2 axis, which subsequently inhibits the expression of TRAF6. This further attenuates the expression of RelA, ultimately resulting in the suppression of adipogenesis in 3T3-L1 preadipocytes. This study reveals a new mechanism by which the IL-33/ST2 axis regulates the differentiation of preadipocytes and provides a new idea for improving obesity prevention.

Numerous preclinical studies have demonstrated the inhibitory function of T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) on T cells as an inhibitory receptor, leading to the clinical development of anti-Tim-3 blocking antibodies. However, recent studies have shown that Tim-3 is expressed not only on T cells but also on multiple cell types in the tumor microenvironment (TME), including dendritic cells (DCs), natural killer (NK) cells, macrophages, and tumor cells. Therefore, Tim-3 blockade in the immune microenvironment not only affect the function of T cells but also influence the functions of other cells. For example, Tim-3 blockade can enhance the ability of DCs to regulate innate and adaptive immunity. The role of Tim-3 blockade in NK cells function is controversial, as it can enhance the antitumor function of NK cells under certain conditions while having the opposite effect in other situations. Additionally, Tim-3 blockade can promote the reversal of macrophage polarization from the M2 phenotype to the M1 phenotype. Furthermore, Tim-3 blockade can inhibit tumor development by suppressing the proliferation and metastasis of tumor cells. In summary, increasing evidence has shown that Tim-3 in other cell types also plays a critical role in the efficacy of anti-Tim-3 therapy. Understanding the function of anti-Tim-3 therapy in non-T cells can help elucidate the diverse responses observed in clinical patients, leading to better development of relevant therapeutic strategies. This review aims to discuss the role of Tim-3 in the TME and emphasize the impact of Tim-3 blockade in the tumor immune microenvironment beyond T cells.

Major Depressive Disorder (MDD) is a prevalent mental health condition with a complex pathophysiology involving neuroinflammation, neurodegeneration, and disruptions in neuronal and glial cell function. Microglia, the innate immune cells of the central nervous system, release inflammatory cytokines in response to pathological changes associated with MDD. Damage-associated molecular patterns (DAMPs) act as alarms, triggering microglial activation and subsequent inflammatory cytokine release. This review examines the cellular mechanisms underlying MDD pathophysiology, focusing on the lipid-mediated modulation of neuroinflammation. We explore the intricate roles of microglia and astrocytes in propagating inflammatory cascades and discuss how these processes affect neuronal integrity at the cellular level. Central to our analysis are three key molecules: High Mobility Group Box 1 (HMGB1) and S100 Calcium Binding Protein β (S100β) as alarmins, and Neuron-Specific Enolase (NSE) as an indicator of neuronal stress. We present evidence from in vitro and ex vivo studies demonstrating how these molecules reflect and contribute to the neuroinflammatory milieu characteristic of MDD. The review then explores the potential of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) as neuroinflammation modulators, examining their effects on microglial activation, cytokine production, and neuronal resilience in cellular models of depression. We critically analyze experimental data on how ω-3 PUFA supplementation influences the expression and release of HMGB1, S100β, and NSE in neuronal and glial cultures. By integrating findings from lipidomic and cellular neurobiology, this review aims to elucidate the mechanisms by which ω-3 PUFAs may exert their antidepressant effects through modulation of neuroinflammatory markers. These insights contribute to our understanding of lipid-mediated neuroprotection in MDD and may inform the development of targeted, lipid-based therapies for both depression and neurodegenerative disorders.

Cytokines are the primary mediators of age-related disorders. The IL-17/IL-10 axis plays a crucial role in bone destruction and neuro-inflammation. Additionally, a new Th2 cytokine-IL-33-has gained attention for its potential implications in aging-associated conditions. However, the involvement of IL-33 in aging-mediated bone loss and memory impairment remains unclear and needs further investigation. This study reveals the impact of IL-33 on various aspects of the immune system, bone health, and neural functions. To induce senescence, we used d-galactose for its convenience and fewer side effects. The experimental design involved treating 20-week-old C57BL/6J mice with d-galactose subcutaneously for 10 weeks to induce aging-like effects. Thereafter, IL-33 recombinant protein was administered intraperitoneally for 15 days to evaluate its impact on various immune, skeletal, and neural parameters. The results demonstrated that d-galactose-induced aging led to bone loss and compromised osteogenic parameters, accompanied by increased oxidative stress and neurodegeneration in specific brain regions. Behavioral activities were also affected. However, supplementation with IL-33 mitigated these effects, elevating osteogenic parameters and reducing senescence markers in osteoblast cells in an aging mouse model and exerted neuroprotective potential. Notably d-galactose-induced aging was characterized by high bone turnover, reflected by altered serum levels of CTX, PTH, beta-galactosidase, and P1NP. IL-33 treatment attenuated these effects, suggesting its role in regulating bone metabolism. Furthermore, d-galactose-induced aging was associated with increased differentiation of Th17 cells and upregulation of associated markers, such as STAT-3 and ROR-γt, while downregulating Foxp3, which antagonizes Th17 cell differentiation. IL-33 treatment countered these effects by suppressing Th17 cell differentiation and promoting IL-10-producing T-regulatory cells. Overall, these findings provide insights into the potential therapeutic implications of IL-33 in addressing aging-induced bone loss and memory impairment.

The inflammatory foreign body response (FBR) is the main driver of biomaterial implant failure. Current strategies to mitigate the onset of a FBR include modification of the implant surface, release of anti-inflammatory drugs, and cell-scale implant porosity. The microporous annealed particle (MAP) scaffold platform is an injectable, porous biomaterial composed of individual microgels, which are annealed in situ to provide a structurally stable scaffold with cell-scale microporosity. MAP scaffold does not induce a discernible foreign body response in vivo and, therefore, can be used a "blank canvas" for biomaterial-mediated immunomodulation. Damage associated molecular patterns (DAMPs), such as IL-33, are potent regulators of type 2 immunity that play an important role in tissue repair. In this manuscript, IL-33 is conjugated to the microgel building-blocks of MAP scaffold to generate a bioactive material (IL33-MAP) capable of stimulating macrophages in vitro via a ST-2 receptor dependent pathway and modulating immune cell recruitment to the implant site in vivo, which indicates an upregulation of a type 2-like immune response and downregulation of a type 1-like immune response.

It is nowadays well accepted that chronic inflammation plays a pivotal role in tumor initiation and progression. Under this aspect, the oral cavity is predestined to examine this connection because periodontitis is a highly prevalent chronic inflammatory disease and oral squamous cell carcinomas are the most common oral malignant lesions. In this review, we describe how particular molecules of the human innate host defense system may participate as molecular links between these two important chronic noncommunicable diseases (NCDs). Specific focus is directed toward antimicrobial polypeptides, such as the cathelicidin LL-37 and human defensins, as well as S100 proteins and alarmins. We report in which way these peptides and proteins are able to initiate and support oral tumorigenesis, showing direct mechanisms by binding to growth-stimulating cell surface receptors and/or indirect effects, for example, inducing tumor-promoting genes. Finally, bacterial challenges with impact on oral cancerogenesis are briefly addressed.

Localized scleroderma (LS) is an autoimmune disease characterized by inflammation and fibrosis, leading to severe cutaneous manifestations such as skin hardening, tightness, discoloration, and other textural changes that may result in disability. While LS shares similar histopathologic features and immune-fibroblast interactions with systemic sclerosis (SSc), its molecular mechanisms remain understudied. Endothelial cells (EC) are known to play a crucial role in SSc but have not been investigated in LS. Single-cell RNA sequencing (scRNA-seq) now allows for detailed examination of this cell type in the primary organ of interest for scleroderma, the skin. In this study, we analyzed skin-isolated cells from 27 LS patients (pediatric and adult) and 17 healthy controls using scRNA-seq. Given the known role of EC damage as an initial event in SSc and the histologic and clinical skin similarities to LS, we focused primarily on endothelial cells. Our analysis identified eight endothelial subclusters within the dataset, encompassing both disease and healthy samples. Interaction analysis revealed that signaling from diseased endothelial cells was predicted to promote fibrosis through SELE interaction with FGFBP1 and other target genes. We also observed high levels of JAG in arterial endothelial cells and NOTCH in capillary endothelial cells, indicating the activation of a signaling pathway potentially responsible for epidermal abnormalities and contributing to LS pathogenesis. In summary, our scRNA-seq analysis identified potential disease-propagating endothelial cell clusters with upregulated pathways in LS skin, highlighting their importance in disease progression.

Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players in MF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serum LDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1β and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1β and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets.

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 box 1 (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.

Protective immunity to opportunistic fungal infections consists of tightly regulated innate and adaptive immune responses that clear the infection. Immune responses to infections of the vaginal mucosa by Candida species are, however, an exception. In the case of vulvovaginal candidiasis (VVC), the inflammatory response is associated with symptomatic disease, rather than that it results in pathogen clearance. As such VVC can be considered an inflammatory disease, which is a significant public health problem due to its predominance as a female-specific fungal infection. Particularly, women with recurrent VVC (RVVC) suffer from a significant negative impact on their quality of life and mental health. Knowledge of the inflammatory pathogenesis of (R)VVC may guide more effective diagnostic and therapeutic options to improve the quality of life of women with (R)VVC. Here, we review the immunopathogenesis of (R)VVC describing several elements that induce an inflammatory arson, starting with the activation threshold established by vaginal epithelial cells that prevent unnecessary ignition of inflammatory responses, epithelial and inflammasome-dependent immune responses. These inflammatory responses will drive neutrophil recruitment and dysfunctional neutrophil-mediated inflammation. We also review the, sometimes controversial, findings on the involvement of adaptive and systemic responses. Finally, we provide future perspectives on the potential of some unexplored cytokine axes and discuss whether VVC needs to be subdivided into subgroups to improve diagnosis and treatment.

In squamous cell carcinoma (SCC), macrophages responding to interleukin (IL)-33 create a TGF-β-rich stromal niche that maintains cancer stem cells (CSCs), which evade chemotherapy-induced apoptosis in part via activation of the NRF2 antioxidant program. Here, we examined how IL-33 derived from CSCs facilitates the development of an immunosuppressive microenvironment. CSCs with high NRF2 activity redistributed nuclear IL-33 to the cytoplasm and released IL-33 as cargo of large oncosomes (LOs). Mechanistically, NRF2 increased the expression of the lipid scramblase ATG9B, which exposed an "eat me" signal on the LO surface, leading to annexin A1 (ANXA1) loading. These LOs promoted the differentiation of AXNA1 receptor+ myeloid precursors into immunosuppressive macrophages. Blocking ATG9B's scramblase activity or depleting ANXA1 decreased niche macrophages and hindered tumor progression. Thus, IL-33 is released from live CSCs via LOs to promote the differentiation of alternatively activated macrophage, with potential relevance to other settings of inflammation and tissue repair.

Interleukin-1α is a suggested dual-function cytokine that diverged from interleukin-1β in mammals potentially by acquiring additional biological roles that relate to highly conserved regions in the pro-domain of interleukin-1α, including a nuclear localisation sequence and histone acetyltransferase-binding domains. Why evolution modified pro-interleukin-1α's subcellular location and protein interactome, and how this shaped interleukin-1α's intracellular role, is unknown. Here we show that TurboID proximity labelling with pro-interleukin-1α suggests a nuclear role for pro-interleukin-1α that involves interaction with histone acetyltransferases, including EP300. We also identify and validate inactivating mutations in the pro-interleukin-1α nuclear localisation sequence of multiple mammalian species, including toothed whales, castorimorpha and marsupials. However, histone acetyltransferase-binding domains are conserved in those species that have lost pro-interleukin-1α nuclear localisation. Together, these data suggest that histone acetyltransferase binding and nuclear localisation occurred together, and that while some species lost the nuclear localisation sequence in their pro-interleukin-1α, histone acetyltransferase binding ability was maintained. The nuclear localisation sequence was lost from several distinct species at different evolutionary times, suggesting convergent evolution, and that the loss of the nuclear localisation sequence confers some important biological outcome.

The NF-κB pathway plays a pivotal role in impeding the diabetic wound healing process, contributing to prolonged inflammation, diminished angiogenesis, and reduced proliferation. In contrast to modern synthetic therapies, naturally occurring phytoconstituents are well-studied inhibitors of the NF-κB pathway that are now attracting increased attention in the context of diabetic wound healing because of lower toxicity, better safety and efficacy, and cost-effectiveness. This study explores recent research on phytoconstituent-based therapies and delve into their action mechanisms targeting the NF-κB pathway and potential for assisting effective healing of diabetic wounds. For this purpose, we have carried out surveys of recent literature and analyzed studies from prominent databases such as Science Direct, Scopus, PubMed, Google Scholar, EMBASE, and Web of Science. The classification of phytoconstituents into various categorie such as: alkaloids, triterpenoids, phenolics, polyphenols, flavonoids, monoterpene glycosides, naphthoquinones and tocopherols. Noteworthy phytoconstituents, including Neferine, Plumbagin, Boswellic acid, Genistein, Luteolin, Kirenol, Rutin, Vicenin-2, Gamma-tocopherol, Icariin, Resveratrol, Mangiferin, Betulinic acid, Berberine, Syringic acid, Gallocatechin, Curcumin, Loureirin-A, Loureirin-B, Lupeol, Paeoniflorin, and Puerarin emerge from these studies as promising agents for diabetic wound healing through the inhibition of the NF-κB pathway. Extensive research on various phytoconstituents has revealed how they modulate signalling pathways, including NF-κB, studies that demonstrate the potential for development of therapeutic phytoconstituents to assist healing of chronic diabetic wounds.

While food is essential for survival, it can also cause a variety of harmful effects, ranging from intolerance to specific nutrients to celiac disease and food allergies. In addition to nutrients, foods contain myriads of substances that can have either beneficial or detrimental effects on the animals consuming them. Consequently, all animals evolved defense mechanisms that protect them from harmful food components. These "antitoxin" defenses have some parallels with antimicrobial defenses and operate at a cost to the animal's fitness. These costs outweigh benefits when defense responses are exaggerated or mistargeted, resulting in adverse reactions to foods. Additionally, pathological effects of foods can stem from insufficient defenses, due to unabated toxicity of harmful food components. We discuss the structure of antitoxin defenses and how their failures can lead to a variety of adverse food reactions.

The initiation of migraine headaches and the involvement of neuroinflammatory signaling between parenchymal and meningeal cells remain unclear. Experimental evidence suggests that a cascade of inflammatory signaling originating from neurons may extend to the meninges, thereby inducing neurogenic inflammation and headache. This review explores the role of parenchymal inflammatory signaling in migraine headaches, drawing upon recent advancements. BODY: Studies in rodents have demonstrated that sterile meningeal inflammation can stimulate and sensitize meningeal nociceptors, culminating in headaches. The efficacy of relatively blood-brain barrier-impermeable anti-calcitonin gene-related peptide antibodies and triptans in treating migraine attacks, both with and without aura, supports the concept of migraine pain originating in meninges. Additionally, PET studies utilizing inflammation markers have revealed meningeal inflammatory activity in patients experiencing migraine with aura, particularly over the occipital cortex generating visual auras. The parenchymal neuroinflammatory signaling involving neurons, astrocytes, and microglia, which eventually extends to the meninges, can link non-homeostatic perturbations in the insensate brain to pain-sensitive meninges. Recent experimental research has brought deeper insight into parenchymal signaling mechanisms: Neuronal pannexin-1 channels act as stress sensors, initiating the inflammatory signaling by inflammasome formation and high-mobility group box-1 release in response to transient perturbations such as cortical spreading depolarization (CSD) or synaptic metabolic insufficiency caused by transcriptional changes induced by migraine triggers like sleep deprivation and stress. After a single CSD, astrocytes respond by upregulating the transcription of proinflammatory enzymes and mediators, while microglia are involved in restoring neuronal structural integrity; however, repeated CSDs may prompt microglia to adopt a pro-inflammatory state. Transcriptional changes from pro- to anti-inflammatory within 24 h may serve to dampen the inflammatory signaling. The extensive coverage of brain surface and perivascular areas by astrocyte endfeet suggests their role as an interface for transporting inflammatory mediators to the cerebrospinal fluid to contribute to meningeal nociception.

We propose that neuronal stress induced by CSD or synaptic activity-energy mismatch may initiate a parenchymal inflammatory signaling cascade, transmitted to the meninges, thereby triggering lasting headaches characteristic of migraine, with or without aura. This neuroinflammatory interplay between parenchymal and meningeal cells points to the potential for novel targets for migraine treatment and prophylaxis.

Alcohol ingestion is a widespread habituation that evolved along with a growing population, altering physiological conditions through immunomodulatory function. There is much research that has reported that consumption of alcohol at low and heavy levels causes different biological impacts, including cellular injury, leading to systemic dysfunction and increased inflammatory markers. In the fate of professional phagocytic cells, efferocytosis is an inevitable mechanism activated by the apoptotic cells, thus eliminating them and preventing the accumulation of cell corpses/debris in the microenvironment. Subsequently, it promotes the tissue repair mechanism and maintains cellular homeostasis. Unfortunately, defective efferocytosis is widely found in several inflammatory and age-related diseases such as atherosclerosis, autoimmune diseases, lung injury, fatty liver disease, and neurodegenerative diseases. Alcohol abuse is one of the factors that provoke an immune response that increases the rate of morbidity and mortality in parallel in systemic disease patients. Information regarding the emergence of immunomodulation during alcoholic pathogenesis and its association with efferocytosis impairment remain elusive. Hence, here in this review, we discussed the mechanism of efferocytosis, the role of defective efferocytosis in inflammatory diseases, and the role of alcohol on efferocytosis impairment.

Interleukin-33 (IL-33), secreted by astrocytes, regulates the synapse development in the spinal cord and hippocampus and suppresses autoimmune disease in the central nervous system (CNS). However, the mechanism of unconventional protein secretion of this cytokine remains unclear. In this study, we found that IFN-γ promotes the active secretion of IL-33 from astrocytes, and the active secretion of IL-33 from cytoplasm to extracellular space was dependent on interaction with transmembrane emp24 domain 10 (TMED10) via the IL-1 like cytokine domain in astrocytes. Knockout of Il-33 or its receptor St2 induced hippocampal astrocyte activation and depressive-like disorder in naive mice, as well as increased spinal cord astrocyte activation and polarization to a neurotoxic reactive subtype and aggravated passive experimental autoimmune encephalomyelitis (EAE). Our results have identified that IL-33 is actively secreted by astrocytes through the unconventional protein secretion pathway facilitated by TMED10 channels. This process helps maintain CNS homeostasis by inhibiting astrocyte activation.

Galectins are multifunctional effectors in cellular homeostasis and dysregulation. Oxidation of human galectin-1 (Gal-1) with its six sulfhydryls produces a disulfide-bridged oxidized form that lacks normal lectin activity yet gains new glycan-independent functionality. Nevertheless, the mechanistic details as to how Gal-1 oxidation occurs remain unclear. Here, we used 15N and 13C HSQC NMR spectroscopy to gain structural insight into the CuSO4-mediated path of Gal-1 oxidation and identified a minimum two-stage conversion process. During the first phase, disulfide bridges form slowly between C16-C88 and/or C42-C66 to produce a partially oxidized, conformationally flexible intermediate that retains the ability to bind lactose. Site-directed mutagenesis of C16 to S16 impedes the onset of this overall slow process. During the second phase, increased motional dynamics of the intermediate enable the relatively distant C2 and C130 residues to form the third and final disulfide bond, leading to an unfolded state and consequent dimer dissociation. This fully oxidized end state loses the ability to bind lactose, as shown by the hemagglutination assay. Consistent with this model, we observed that the Gal-1 C2S mutant maintains intermediate-state structural features with a free sulfhydryl group at C130. Incubation with dithiothreitol reduces all disulfide bonds and allows the lectin to revert to its native state. Thus, the sequential, non-random formation of three disulfide bridges in Gal-1 in an oxidative environment acts as a molecular switch for fundamental changes to its functionality. These data inspire detailed bioactivity analysis of the structurally defined oxidized intermediate in, e.g., acute and chronic inflammation.