On-site delivery of bioactive agents facilitates enhancing the effectiveness of spinal fusion. However, the FDA-approved agents currently used in clinical practice are limited by side effects and cost issues, urging exploration of new alternatives.

This study aimed to investigate the effectiveness of KMN-159, a novel selective prostaglandin EP4 receptor agonist with osteopromotive properties, in spinal posterolateral fusion (PLF) surgery.

Various doses of KMN-159 were delivered locally using a mineralized collagen matrix (MCM) scaffold, and its efficacy results were compared with FDA-approved recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat lumbar PLF model. 192 male Wistar rats, aged 10 weeks, were randomized into 8 groups: 1) SHAM, 2) MCM, 3) MCM +10 μg rhBMP-2 (per scaffold), 4-8) MCM + 0.1, 1, 10, 100 or 1000 μg KMN-159 (per scaffold). PLF surgery was performed at the L4-5 level, and animals were euthanized after 3 and 6 weeks for spinal fusion evaluation.

KMN-159 exhibited dose-dependent osteopromotive effects on osteoblasts, osteoclasts, and vascular ingrowth within MCM carriers, resulting in new bone formation in a dose-dependent manner. The mid- and high-dose KMN-159 (10, 100, and 1000 μg) groups significantly enhanced PLF with biomechanical improvement, while low-dose (0.1 and 1 μg) groups were insufficient to achieve lumbar fusion.

KMN-159 emerges as a novel osteopromotive factor, coupled with its functionalized MCM scaffold presents a potential bioactive material for enhancing PLF surgery outcomes.

Monocytes infiltrating tumors acquire various states that distinctly impact cancer treatment. Here, we show that resistance of tumors to radiotherapy (RT) is controlled by the accumulation of monocyte-derived dendritic cells (moDCs). These moDCs are characterized by the expression of CD301b and have a superior capacity to generate regulatory T cells (Tregs). Accordingly, moDC depletion limits Treg generation and improves the therapeutic outcome of RT. Mechanistically, we demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF) derived from radioresistant tumor cells following RT is necessary for the accumulation of moDCs. Our results unravel the immunosuppressive function of moDCs and identify GM-CSF as an immunotherapeutic target during RT.

Heme peroxidases (HPs), an essential class of oxidoreductases that may have an important role in molluscan immune defense, remain inadequately studied in mollusks. In this study, HPs in Anadara granosa (AgHPs) were comprehensively analyzed on a genome-wide scale and their immune responses under stress from three species of Vibrio were investigated. A total of 18 AgHPs were identified in the genome of A. granosa, unequally distributed in four subfamilies, peroxinectin (Pxt), prostaglandin G/H synthase (PGHS), dual oxidases (DuOx) and peroxidasin (Pxd). AgHPs were mainly expressed in gills and mantle, with AgHP6 being the only member expressed in hemocytes. The immune response of A. granosa to Vibrio stress demonstrated dynamic alterations in gene expression, characterized by prominent upregulation of AgHP3 and AgHP4 in both gills and mantle, alongside significant downregulation of several other genes; these expression changes likely underpin antimicrobial immunity in A. granosa and suggest distinct regulatory mechanisms and functional roles. Further analyses suggest that AgHP11 (Pxt) may enhance cell adhesion when invaded by exogenous bacteria, and AgHP3 (PGHS) and AgHP4 (PGHS) contribute to the immunity by synthesizing various prostaglandins. AgHP6 (DuOx) and AgHP7 (DuOx) may activate epithelial immunity by reducing expression levels. Additionally, during the anti-Vibrio process, hemoglobin may substitute for ROS-producing HPs to provide antimicrobial defense in A. granosa. This study represents the first genome-wide identification and immune response analysis of HPs in A. granosa, laying a foundation for future research into the immune functions of HPs in mollusks.

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to severe disability and premature death in young men. As DMD is caused by the absence of dystrophin, therapeutic development has focused on strategies to restore dystrophin expression. These include readthrough of premature stop codons, exon skipping to restore the reading frame, and gene therapy. The first two methods are mutation-specific, benefiting only subsets of patients, whereas gene therapy could treat all individuals with DMD. Immunogenicity of dystrophin may challenge these efforts. The immune system can recognize dystrophin as a neo-antigen, just as it can recognize newly arising antigens present on mutated cells. An in-depth evaluation of anti-dystrophin immune response as a factor affecting the treatment effectiveness is needed. Key questions include the underlying mechanisms of immunity induction by antigenic epitopes of the re-expressed dystrophin, the impact of such responses on the therapeutic efficacy, and the role of patient-specific risk factors, such as preimmunization due to revertant fibres, chronic muscle inflammation, pre-existing T lymphocytes reactive to dystrophin, which avoided deletion in dystrophic thymus, or antigen cross-reactivity. Patients' immune status assessment before treatment may help mitigating anti-dystrophin responses. Exploring potential therapeutic strategies to enhance treatment outcomes is also essential: Since DMD can be diagnosed at birth, early dystrophin re-expression could prevent damage and also potentially induce neonatal tolerance. In older patients, carefully managed immunosuppression and tolerogenic protocols could pave the way for more successful dystrophin replacement therapies.

Head and neck cancer is the seventh most common cancer worldwide and its development is associated with viral infection. Human papillomavirus (HPV) is the major cause of oropharyngeal cancer and encodes three known oncoproteins, E5, E6, and E7. Epstein-Barr virus (EBV), which is the causative agent of most nasopharyngeal carcinoma, also employs several immunosuppressive mechanisms that contribute to the development of the disease. In this review, we synthesize and discuss several mechanisms used by these viruses to evade and escape the host immune system. In particular, we focus on the evasive tactics of HPV E5 which, we argue, is critical to establishing persistent infection and the development and progression of carcinomas. Importantly the mechanisms by which these viruses suppress immune responses may also play a key role in resistance to checkpoint blockade immunotherapies and thus impact patient outcomes.

Ferroptosis represents an emerging, iron-dependent form of cell death driven by lipid peroxidation. In recent years, it has garnered significant attention in the realm of cancer immunotherapy, particularly in studies involving immune checkpoint inhibitors. This form of cell death not only enhances our comprehension of the tumor microenvironment but is also considered a promising therapeutic strategy to address tumor resistance, investigate immune activation mechanisms, and facilitate the development of cancer vaccines. The combination of immunotherapy with ferroptosis provides innovative targets and fresh perspectives for advancing cancer treatment. Nevertheless, tumor cells appear to possess a wider array of ferroptosis evasion strategies compared to CD8+T cells, which have been conclusively shown to be more vulnerable to ferroptosis. Furthermore, ferroptosis in the TME can create a favorable environment for tumor survival and invasion. Under this premise, both inducing tumor cell ferroptosis and inhibiting T cell ferroptosis will impact antitumor immunity to some extent, and even make the final result run counter to our therapeutic purpose. This paper systematically elucidates the dual-edged sword role of ferroptosis in the antitumor process of T cells, briefly outlining the complexity of ferroptosis within the TME. It explores potential side effects associated with ferroptosis-inducing therapies and critically considers the combined application of ferroptosis-based therapies with ICIs. Furthermore, it highlights the current challenges faced by this combined therapeutic approach and points out future directions for development.

The abscopal effect in radiotherapy (RT) refers to the phenomenon where localized radiation treatment causes regression of distant, nonirradiated tumors. Although rare, recent research shows that combining radiation with immunotherapies, such as immune checkpoint inhibitors, can enhance this effect. The interaction between radiation-induced cell death, immune responses, and the tumor microenvironment manifests in competing biologic mechanisms resulting in complex immunologic outcomes. In order to maximize the therapeutic advantages of the immunogenic effect of RT in the future, further studies are needed to fully understand its biologic underpinnings.

Loss of anticancer natural killer (NK) cell function in patients with acute myeloid leukemia (AML) is associated with fatal disease progression and remains poorly understood. Here, we demonstrate that AML blasts isolated from patients rapidly inhibit NK cell function and escape NK cell-mediated killing. Transcriptome analysis of NK cells exposed to AML blasts revealed increased CREM expression and transcriptional activity, indicating enhanced cyclic adenosine monophosphate (cAMP) signaling, confirmed by uniform production of the cAMP-inducing prostanoid prostaglandin E2 (PGE2) by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE2 induced a blockade of lymphocyte-specific protein tyrosine kinase (LCK)-extracellular signal-regulated kinase signaling that is crucial for NK cell activation, indicating a 2-layered escape of AML blasts with low expression of NK cell-activating ligands and inhibition of NK cell signaling. To evaluate the therapeutic potential to target PGE2 inhibition, we combined Fcγ-receptor-mediated activation with the prevention of inhibitory PGE2 signaling. This rescued NK cell function and restored the killing of AML blasts. Thus, we identify the PGE2-LCK signaling axis as the key barrier for NK cell activation in 2-layered immune escape of AML blasts that can be targeted for immune therapy to reconstitute anticancer NK cell immunity in patients with AML.

Lung cancer is characterized by a poor prognosis and is a significant comorbidity of chronic obstructive pulmonary disease (COPD). Therefore, effective chemopreventive agents are warranted. We evaluated the effects of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on the prevention of lung-carcinoma development using an intermittent smoking-induced lung-carcinoma mouse model. Additionally, we explored COX-2's role in lipid metabolism.

Male A/J mice were exposed to sham air or mainstream cigarette smoke for 20 weeks. Vehicle or celecoxib was administered via intragastric feeding once daily. Lung tissues were analyzed for tumor nodules and emphysema; the bronchoalveolar lavage fluid was collected for cell counting. COX-2 expression was measured using real-time polymerase chain reaction and western blotting; lipidomic analysis was conducted using liquid chromatography-tandem mass spectrometry. Cell proliferation and colony-forming assays were performed on LA-4 cells to assess the effects of prostaglandins and COX-2 inhibitors.

Intermittent smoking exposure increased lung adenomas, adenocarcinomas, and COX-2 expression. Lung adenomas were characterized by abundant COX-2-positive cells. Celecoxib reduced intermittent smoking-induced inflammation, emphysema, and cell counts in the bronchoalveolar lavage fluid and decreased the incidence of lung adenocarcinomas, whereas the total number of observed lung tumors was unchanged. Celecoxib markedly suppressed single-smoke-induced prostaglandin E2 (PGE2) production in the airway. PGE2 increased LA-4 cell viability via the EP4 receptor and promoted colony formation.

Celecoxib effectively inhibited lung-carcinoma development, inflammation, and emphysema, demonstrating the potential for chemoprevention in smokers and patients with COPD. Further studies on EP4 inhibitors for the prevention of emphysema and lung cancer are warranted.

Plasma lipids are essential components of biological systems, transported through interactions with proteins to maintain cellular functions. These lipids exist in various forms, such as fatty acids, glycerolipids, glycerophospholipids, sphingolipids, sterols, and prenol lipids, derived from dietary intake, adipose tissue, and biosynthesis. While the association between certain fatty acids and cardiovascular diseases has been widely recognized, polyunsaturated fatty acids (PUFAs) exhibit cardioprotective effects, reducing risks of arrhythmias and heart-related mortality. This is due to their role in the production of eicosanoids, which modulate inflammation. Chronic inflammation, particularly in obesity, is significantly influenced by fatty acids, with saturated fatty acids promoting inflammation and PUFAs mitigating it. Oxylipins, bioactive molecules derived from the oxidation of PUFAs, play crucial roles in immune regulation across various organisms, including plants, fungi, and bacteria. These molecules, such as prostaglandins, leukotrienes, and resolvins, regulate immune responses during infection and inflammation. The production of oxylipins extends beyond mammals, with fungi and bacteria synthesizing these molecules to modulate immune responses, promoting both defense and pathogenesis. This review delves into the multifaceted effects of oxylipins, exploring their impact on host and microbial interactions, with a focus on their potential for therapeutic applications in modulating infection and immune response.

This study aimed to compare the release of inflammatory mediators and post-operative pain after conservative and conventional root canal preparations of mandibular molars with asymptomatic irreversible pulpitis.

Forty-five healthy patients diagnosed with asymptomatic irreversible pulpitis were randomly assigned to three groups based on the system used for root canal preparation (n = 15): ProTaper Gold, OneShape and TruNatomy. Gingival crevicular fluid samples were collected for baseline measurements, 24 and 72 h after root canal treatment. Inflammatory mediators (Substance P, IL-6, IL-10 and PGE-2) were quantified using enzyme-linked immunosorbent assays, and post-operative pain was assessed using the visual analogue scale (VAS) and compared among groups with linear regression analysis.

All mediators exhibited an increase at 24 h and a decrease at 72 h. The release of Substance P in the OneShape group was significantly higher than in the TruNatomy and ProTaper Gold groups (Odds Ratio (OR) = 17.4 and 21.7, respectively, at 24 h and 21.5 and 15.6 at 72 h; p < .05). IL-6 and IL-10 were significantly higher in the OneShape and ProTaper Gold groups compared to TruNatomy at 24 h (p < .05). PGE2 levels were not affected by the type of instruments (p > .05). VAS scores were significantly higher at 24 h compared to baseline, with root canal preparation using OneShape significantly associated with higher post-operative pain than preparation with ProTaper Gold (p < .05). Analgesic intake was not related to the instrumentation group or any other patient- or tooth-related factors.

Conservative root canal preparation of mandibular molars with asymptomatic irreversible pulpitis decreased the release of inflammatory mediators but did not influence post-operative pain.

Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.

Liver regeneration is a complex process crucial for recovery after partial hepatectomy (PH) or ex-vivo liver resection and autotransplantation (ELRA). This study aimed to explore the molecular mechanisms involved in liver regeneration by analyzing peripheral blood samples from three patients with alveolar echinococcosis undergoing PH and ELRA. Peripheral blood samples were collected from three patients undergoing PH and three patients undergoing ELRA at three time points: pre-operation, postoperative day 1, and postoperative day 5, as well as three healthy controls. Transcriptomic analysis was performed to identify differentially expressed genes (DEGs) using RNA sequencing, while metabolomic analysis was conducted using untargeted liquid chromatography-mass spectrometry (LC-MS). Key findings were validated through real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Transcriptomic analysis revealed 3574 DEGs on post-operative day 1 compared to pre-operation in the ELRA group, and 3269 DEGs on post-operative day 5 compared to day 1. In the PH group, 1619 DEGs were identified on post-operative day 1 compared to pre-operation, and 896 DEGs were found on post-operative day 5 compared to day 1. Among these, 36 common genes were shared between both groups, primarily enriched in metabolic pathways. Integration of common genes, co-expression network analysis and Mfuzz clustering identified KLF14 as a gene correlated with liver regeneration processes, with its association with the PI3K-AKT pathway. Metabolomic analysis highlighted differentially expressed metabolites associated with lipid, amino acid, and energy metabolism. This study provides new insights into the molecular regulation of liver regeneration, identifying KLF14 and associated metabolic processes. These findings offer potential therapeutic targets for enhancing liver repair.

Osteoarthritis (OA) is the most common form of degenerative joint disease that commonly affects the knees, hips and hands. OA is a mechano-inflammatory disease characterized by low-grade inflammation, which results in breakdown of the cartilage extracellular matrix within joints, leading to pain, stiffness and inflammation. TissueGene-C (TG-C) is a cell and gene therapy investigational drug for treating knee OA that comprises human allogeneic chondrocytes and an irradiated modified cell line stably expressing transforming growth factor beta 1 (TGF-β1). Previous pre-clinical animal studies have shown that TG-C provides pain relief via its anti-inflammatory effects and cartilage structural improvement in a rat OA model. The goal of this study was to investigate the mechanism of action of TG-C, explore its anti-inflammatory activity and identify the TG-C-derived active factor(s) responsible for its efficacy.

In this study, we utilized THP-1 cell line to develop an macrophage polarization model to test the anti-inflammatory activity of TG-C.

Our data showed that TG-C induces the polarization of M2 macrophages and the upregulation of interleukin 10 (IL-10) and interleukin 1 receptor antagonist (IL-1ra) while inhibiting tumor necrosis factor alpha (TNF-α) expression. Additionally, this study identified prostaglandin E2 (PGE2) as the main bioactive factor responsible for the anti-inflammatory activity of TG-C.

Our results demonstrated that PGE2 is expressed by the TG-C chondrocyte component and modulated by TGF-β1 derived from the second component of TG-C. Finally, the present study provides insight into the mechanism of action of TG-C in the treatment of OA.

Lipids are small molecule immunomodulators that play critical roles in maintaining cellular health and function. Microglia, the resident immune cells of the central nervous system, regulate lipid metabolism both in the extracellular environment and within intracellular compartments through various mechanisms. For instance, glycerophospholipids and fatty acids interact with protein receptors on the microglial surface, such as the Triggering Receptor Expressed on Myeloid Cells 2, influencing cellular functions like phagocytosis and migration. Moreover, cholesterol is essential not only for microglial survival but, along with other lipids such as fatty acids, is crucial for the formation, function, and accumulation of lipid droplets, which modulate microglial activity in inflammatory diseases. Other lipids, including acylcarnitines and ceramides, participate in various signaling pathways within microglia. Despite the complexity of the microglial lipidome, only a few studies have investigated the effects of specific lipid classes on microglial biology. In this review, we focus on major lipid classes and their roles in modulating microglial function. We also discuss novel analytical techniques for characterizing the microglial lipidome and highlight gaps in current knowledge, suggesting new directions for future research on microglial lipid biology.

Lymphatic filariasis (LF), or elephantiasis, is a neglected tropical disease caused by filarial worms, primarily Wuchereria bancrofti, transmitted through mosquito bites. It often begins in childhood but may not show symptoms until later, leaving many individuals asymptomatic for long periods. LF disrupts the lymphatic system, causing severe swelling in the limbs and genitals, leading to deformities and disabilities. The World Health Organization estimates that around 51 million people are affected globally, with 36 million suffering from chronic conditions like lymphedema and hydrocele. In 2021, approximately 882.5 million people in 44 countries required preventive chemotherapy, making LF the second leading parasitic cause of disability, significantly impacting socioeconomic status. The immune response to filarial parasites is complex, involving both innate and adaptive immune cells. A key feature of LF immunology is the antigen-specific Th2 response, expansion of IL-10-producing CD4+ T cells, and a muted Th1 response. This T cell hypo-responsiveness is crucial for sustaining long-term infections with high parasite densities. While the correlates of protective immunity are not fully understood-due in part to a lack of suitable animal models-T cells, particularly CD4+ Th2 cells, and B cells, play essential roles in immune protection. Moreover, host immune responses contribute to the disease's pathological manifestations. A failure to induce T cell hypo-responsiveness can lead to exaggerated inflammatory conditions such as lymphedema, hydrocele, and elephantiasis. Filarial infections also induce bystander effects on various immune responses, impacting responses to other infectious agents. This intricate immune interplay offers valuable insights into the regulation of immune responses to chronic infections. This review explores recent immunological research on lymphatic filarial worms, highlighting their effects on both innate and adaptive immune responses in humans and the mechanisms underlying this neglected tropical disease.

Marine phytoplankton is an emerging source of immunomodulatory bioactive lipids (BLs). Under physiological growth conditions and upon stress challenges, several eukaryotic microalgal species accumulate lipid metabolites that resemble the precursors of animal mediators of inflammation: eicosanoids and prostaglandins. Therefore, marine phytoplankton could serve as a biotechnological platform to produce functional BLs with therapeutic applications in the management of chronic inflammatory diseases and other clinical conditions. However, to be commercially competitive, the lipidic precursor yields should be enhanced. Beside tailoring the cultivation of native producers, genetic engineering is a feasible strategy to accrue the production of lipid metabolites and to introduce heterologous biosynthetic pathways in microalgal hosts. Here, we present the state-of-the-art clinical research on immunomodulatory lipids from eukaryotic marine phytoplankton and discuss synthetic biology approaches to boost their light-driven biosynthesis.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis and facilitating tissue regeneration by fostering an environment conducive to tissue repair. However, in damaged tissues, excessive inflammatory responses can overwhelm the immunomodulatory capacity of Tregs, compromising their functionality and potentially hindering effective regeneration. Mesenchymal stem cells (MSCs) play a key role in enhancing Treg function. MSCs enhance Treg activity through indirect interactions, such as cytokine secretion, and direct interactions via membrane proteins.

This review examines the regenerative functions of Tregs across various tissues, including bone, cartilage, muscle, and skin, and explores strategies to enhance Treg functionality using MSCs. Advanced techniques, such as the overexpression of relevant genes in MSCs, are highlighted for their potential to further enhance Treg function. Additionally, emerging technologies utilizing extracellular vesicles (EVs) and cell membrane-derived vesicles derived from MSCs offer promising alternatives to circumvent the potential side effects associated with live cell therapies. This review proposes approaches to enhance Treg function and promote tissue regeneration and also outlines future research directions.

This review elucidates recent technological advancements aimed at enhancing Treg function using MSCs and examines their potential to improve tissue regeneration efficiency.

Prostaglandin E2 imparts diverse physiological effects on multiple cells through its actions on four distinct E-type prostanoid (EP) receptor subtypes (EP1-EP4), among which the EP4 is one of subtypes known to mediate the immune response in mammalian monocytes and macrophages. However, the precise characteristics and functions of EP4 in mollusks remain unclear. In the present study, an EP4 homologue (designated as CgEP4) was identified from oyster Crassostrea gigas. CgEP4 contained a seven-helix transmembrane domain, shared significant homology with its vertebrate homologs, and clustered with EP4s from other Mollusca by phylogenetic analysis. When CgEP4 was transfected and expressed in HEK293 cell line, the concentration of intracellular Ca2+ was significantly increased after treatment with its agonist PGE2, while that of cAMP was not obviously changed. The mRNA transcripts of CgEP4 were dominantly expressed in haemocytes, which was 28.37-fold (p < 0.05) higher than that in hepatopancreas. By immunofluorescence analysis, CgEP4 was found to be mainly expressed in the agranulocyte subpopulation, and CgEP4+ agranulocyte accounted for 18 % of total haemocytes. After Vibrio splendidus stimulation, the mRNA expression of CgEP4 in haemocytes was not obviously changed at the first 12 h, then significantly up-regulated at 24 h, which was 2.7-fold (p < 0.01) of that in control group. After PGE2 treatment in vivo, the phosphorylation of JNK (p-JNK) in haemocytes, but not the phosphorylated ERK (p-ERK), was significantly decreased, which was 0.64-fold (p < 0.05) of that in control group. Simultaneously, the mRNA expression levels of CgTNF-1 and CgTNF-2 in haemocytes dramatically down-regulated, which were 0.06-fold (p < 0.05) and 0.73-fold (p < 0.05) of that in control group at 24 h. When the EP4 antagonist Grapiprant was added with PGE2 treatment in vivo, the p-JNK in haemocytes significantly increased, concomitant with the up-regulation of expressions of CgTNF-1 and CgTNF-2, which were 2.86-fold (p < 0.05) and 1.31-fold (p < 0.05) of that in control group at 24 h. Collectively, these results provides the experimental evidence of a haemocyte highly-expressed EP4 receptor CgEP4 regulating TNFs' expression through MAPK pathway in the innate immune response in C. gigas, and it could be used as a surface marker to type and sort a subset of agranulocyte subpopulation among haemocytes.

As a novel form of cell death, ferroptosis is mainly regulated by the accumulation of soluble iron ions in the cytoplasm and the production of lipid peroxides and is closely associated with several diseases, including acute kidney injury, ischemic reperfusion injury, neurodegenerative diseases, and cancer. The term "immunosuppression" refers to various factors that can directly harm immune cells' structure and function and affect the synthesis, release, and biological activity of immune molecules, leading to the insufficient response of the immune system to antigen production, failure to successfully resist the invasion of foreign pathogens, and even organ damage and metabolic disorders. An immunosuppressive phase commonly occurs in the progression of many ferroptosis-related diseases, and ferroptosis can directly inhibit immune cell function. However, the relationship between ferroptosis and immunosuppression has not yet been published due to their complicated interactions in various diseases. Therefore, this review deeply discusses the contribution of ferroptosis to immunosuppression in specific cases. In addition to offering new therapeutic targets for ferroptosis-related diseases, the findings will help clarify the issues on how ferroptosis contributes to immunosuppression.

Neuropathic pain (NP) is a chronic disease state centred on neuroinflammation with a high prevalence and limited effective treatment options. Peroxisome proliferator-activated receptor α (PPARα) has emerged as a promising target for NP management due to its anti-inflammatory properties. Recent evidence highlights the critical role of the gut microbiome and its metabolites in NP pathogenesis. This study aimed to investigate whether PPARα modulates the development and alleviation of NP by influencing gut microbial communities and serum metabolites. 16S rDNA sequencing and liquid chromatography-mass spectrometry (LC-MS/MS) untargeted metabolomics analyses performed 14 days after the establishment of a chronic constriction injury (CCI) pain model in C57BL/6 J mice showed significant changes in gut microbial and metabolite levels in CCI mice. Intraperitoneal injection of the PPARα agonist GW7647 (5 mg/kg) significantly attenuated mechanical allodynia and thermal hyperalgesia in CCI mice, whereas injection of the PPARα antagonist GW6471 (20 mg/kg) produced the opposite effect. Immunofluorescence analysis revealed that GW7647 effectively suppressed microglial activation. Additionally, PPARα agonist and antagonist treatments markedly altered the composition and abundance of intestinal microbial communities in CCI mice. Further serum LC-MS/MS analysis identified 258 potential serum metabolic biomarkers, many of which correlated with changes in gut microbial composition. These findings demonstrate that PPARα influences serum metabolite profiles by modulating gut microbiota composition, which subsequently affects NP progression. This study provides novel insights into the mechanisms underlying NP and suggests potential therapeutic avenues targeting PPARα and gut microbiota.

Cancer is a complex and heterogeneous disease characterised by uncontrolled cell growth and proliferation. One hallmark of cancer cells is their ability to undergo metabolic reprogramming, which allows them to sustain their rapid growth and survival. This metabolic reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression and evasion of the immune system. In this article, we review the mechanisms underlying metabolic reprogramming in cancer cells and discuss how these metabolic alterations contribute to the establishment of an immunosuppressive microenvironment. We also explore potential therapeutic strategies targeting metabolic vulnerabilities in cancer cells to enhance immune-mediated anti-tumour responses. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02044861, NCT03163667, NCT04265534, NCT02071927, NCT02903914, NCT03314935, NCT03361228, NCT03048500, NCT03311308, NCT03800602, NCT04414540, NCT02771626, NCT03994744, NCT03229278, NCT04899921.

Retinal diseases are characterized by progressive damage to retinal cells, leading to irreversible vision loss. Among these, glaucoma stands out as a multifactorial neurodegenerative disease involving elevated intraocular pressure, retinal ganglion cell apoptosis, and optic nerve damage, ultimately resulting in blindness in both humans and dogs. Stem cell-based therapies have emerged as a promising therapeutic option for such conditions due to their regenerative and neuroprotective potential. These therapies, particularly those based on mesenchymal stem cells, offer the potential to repair and protect retinal tissues through the bioactive molecules (growth factors, cytokines, chemokines) secreted, their secretome. However, research in this field, especially on the use of umbilical cord mesenchymal stem cells' secretome, remains sparse. Most clinical trials focus on human glaucomatous patients, leaving a significant gap in veterinary patients' application, especially in dogs, with additional research being needed to determine its usefulness in canine glaucoma treatment. Future studies should aim to evaluate these therapies across both human and veterinary contexts, broadening treatment possibilities for glaucoma.

T cells occupy a pivotal position in the immune response against cancer by recognizing and eliminating cancer cells. However, the tumor microenvironment often suppresses the function of T cells, leading to immune evasion and cancer progression. Recent research has unveiled novel connections among T cells, ferroptosis, and cancer. Ferroptosis is a type of regulated cell death that relies iron and reactive oxygen species and is distinguished by the proliferation of lipid peroxides. Emerging scientific findings underscore the potential of ferroptosis to modulate the function and survival of T cells in the tumor microenvironment. Moreover, T cells or immunotherapy can also affect cancer by modulating ferroptosis in cancer cells. This review delved into the intricate crosstalk between T cells and ferroptosis in the context of cancer, highlighting the molecular mechanisms involved. We also explored the therapeutic potential of targeting ferroptosis to enhance the anticancer immune response mediated by T cells. Understanding the interplay among T cells, ferroptosis, and cancer may provide new insights into developing innovative cancer immunotherapies.

As identified in 1936 by Hans Selye, stress is shaping diseases through the induction of inflammation. But inflammation display some yin yang properties. On one hand inflammation is merging with the innate immune response aimed to fight infectious or sterile insults, on the other hand inflammation favors chronic physical or psychological disorders. Nature has equipped the cells, the organs, and the individuals with mediators and mechanisms that allow them to deal with stress, and even a good stress (eustress) has been associated with homeostasis. Likewise, societies and the planet are exposed to stressful settings, but wars and global warming suggest that the regulatory mechanisms are poorly efficient. In this review we list some inducers of the physiological stress, psychologic stress, societal stress, and planetary stress, and mention some of the great number of parameters which affect and modulate the response to stress and render it different from an individual to another, from the cellular level to the societal one. The cell, the organ, the individual, the society, and the planet share many stressors of which the consequences are extremely interconnected ending in the domino effect and the butterfly effect.

Bioactive lipids have a multifaceted role in health and disease and are recognized to play an important part in gut immunity and disease conditions such as inflammatory bowel disease and colon cancer. Advancements in lipidomics, enabled by mass spectrometry and chromatographic techniques, have enhanced our understanding of lipid diversity and functionality. Bioactive lipids, including short-chain fatty acids, saturated fatty acids, omega-3 fatty acids, and sphingolipids, exhibit diverse effects on inflammation and immune regulation. Short-chain fatty acids like butyrate demonstrate anti-inflammatory properties, enhancing regulatory T cell function, gut barrier integrity, and epigenetic regulation, making them promising therapeutic targets for inflammatory bowel disease and colon cancer. Conversely, saturated fatty acids promote inflammation by disrupting gut homeostasis, triggering oxidative stress, and impairing immune regulation. Omega-3 lipids counteract these effects, reducing inflammation and supporting immune balance. Sphingolipids exhibit complex roles, modulating immune cell trafficking and inflammation. They can exert protective effects or exacerbate colitis depending on their source and context. Additionally, eicosanoids can also prevent pathology through prostaglandin defense against damage to epithelial barriers. This review underscores the importance of dietary lipids in shaping gut health and immunity and also highlights the potential use of lipids as therapeutic strategies for managing inflammatory conditions and cancer.

Despite recent advancements in the diagnosis and treatment options for cancer, it remains one of the most serious threats to health. Hyperthermia (HT) has emerged as a highly promising area of research due to its safety and cost-effectiveness. Currently, based on temperature, HT can be categorized into thermal ablation and mild hyperthermia. Thermal ablation involves raising the temperature within the tumor to over 60°C, resulting in direct necrosis in the central region of the tumor. In contrast, mild hyperthermia operates at relatively lower temperatures, typically in the range of 41-45°C, to induce damage to tumor cells. Furthermore, HT also serves as an immune adjuvant strategy in radiotherapy, chemotherapy, and immunotherapy, enhancing the effectiveness of radiotherapy, increasing the uptake of chemotherapy drugs, and reprogramming the tumor microenvironment through the induction of immunogenic cell death, thereby promoting the recruitment of endogenous immune cells. This article reviews the current status and development of hyperthermia, outlines potential mechanisms by which hyperthermia inhibits tumors, describes clinical trial attempts combining hyperthermia with radiotherapy, chemotherapy, and immunotherapy, and discusses the relationship between nanoparticles and hyperthermia.

Tumor-derived prostaglandin E2 (PGE2) impairs antitumor immunity by priming suppressive functions on various immune cell types, including dendritic cells (DCs). In this way, tumors mediate DC dysfunction and hamper their antitumoral activity. PGE2 is known to modulate DC function via signaling through the E-type prostanoid receptor 2 (EP2) and EP4. Preclinical studies have demonstrated the therapeutic value of targeting EP2/4 receptor signaling in DCs. Ongoing phase 1 clinical trials with EP antagonists have shown immunomodulation in cancer patients. However, the systemic drug administration leads to off-target events and subsequent side effects. To limit the off-target effects of EP targeting, EP2 and EP4 antagonists were encapsulated in polymeric nanoparticles (NPs). In this study, we evaluated the efficacy of EP2/4-specific antagonists encapsulated in NPs to protect conventional type 2 DCs (cDC2s) from suppressive effects of tumor-derived PGE2 in different tumor models. We show that tumor-derived PGE2 signals via EP2/4 to mediate the acquisition of a suppressive phenotype of cDC2s. EP2/4 antagonists encapsulated in NPs impaired the conversion of cDC2s toward a suppressive state and inhibited the occurrence of suppressive features such as interleukin-10 production or the ability to expand regulatory T cells. Importantly, the NPs abolished the transition toward this suppressive state in different tumor models: melanoma-conditioned media, ascites fluid derived from ovarian cancer patients (2-dimensional), and upon coculture with colorectal cancer patient-derived organoids (3-dimensional). We propose that targeting the PGE2-EP2/4 axis using NPs can achieve immunomodulation in the immune system of cancer patients, alleviate tumor-derived suppression, and thus facilitate the development of potent antitumor immunity in cancer patients.

Natural killer (NK) cells are critical for anti-metastatic immunity and can eliminate metastasizing tumor cells within circulation and sites of metastatic seeding. Here, we show that disseminated tumor cells (DTCs) colonizing the mouse lung secrete prostaglandin E2 (PGE2) to locally induce NK cell dysfunction, allowing outgrowing metastases to escape immune control and establish metastatic disease. Mechanistically, PGE2 signaling through its receptors EP2 and EP4 mediates NK cell dysfunction, which leads to reprogramming of NK cell gene expression and results in impaired production of anti-metastatic cytokines. In human cancer patients, the PGE2-EP2/EP4 axis is associated with NK cell dysfunction within distant organ metastases. Disabling EP2/EP4 signaling in NK cells prevents their dysfunction in DTC-colonized lungs and achieves effective NK cell-mediated control of metastatic disease. Our findings reveal a suppressive signaling axis exploited by metastasizing tumor cells to escape immune control in distant organs that could be targeted for metastatic cancer therapy.

High levels of the polyunsaturated fatty acid arachidonic acid (AA) within the ovarian carcinoma (OC) microenvironment correlate with reduced relapse-free survival. Furthermore, OC progression is tied to compromised immunosurveillance, partially attributed to the impairment of natural killer (NK) cells. However, potential connections between AA and NK cell dysfunction in OC have not been studied.

We employed a combination of phosphoproteomics, transcriptional profiling and biological assays to investigate AA's impact on NK cell functions.

AA (i) disrupts interleukin-2/15-mediated expression of pro-inflammatory genes by inhibiting STAT1-dependent signaling, (ii) hampers signaling by cytotoxicity receptors through disruption of their surface expression, (iii) diminishes phosphorylation of NKG2D-induced protein kinases, including ERK1/2, LYN, MSK1/2 and STAT1, and (iv) alters reactive oxygen species production by transcriptionally upregulating detoxification. These modifications lead to a cessation of NK cell proliferation and a reduction in cytotoxicity.

Our findings highlight significant AA-induced alterations in the signaling network that regulates NK cell activity. As low expression of several NK cell receptors correlates with shorter OC patient survival, these findings suggest a functional linkage between AA, NK cell dysfunction and OC progression.

Periodontal ligament is the soft connective tissue joining the roots of teeth with alveolar bone. The periodontal ligament presents significant cellular heterogeneity, including fibroblasts, endothelial cells, cementoblasts, osteoblasts, osteoclasts, and immune cells such as macrophages and neutrophils. These cells have crucial roles for periodontium homeostasis and function. However, certain cell types, such as neutrophils, remain poorly characterized in this tissue, despite their natural abundance and relevance in processes and diseases affecting the periodontal ligament.

In order to characterize neutrophils present in periodontal ligament, and get some insight into their functions, single-cell RNA sequencing data from published reports was analyzed to integrate and create a comprehensive map of neutrophil heterogeneity within the murine periodontal ligament under steady-state conditions.

Four distinct neutrophil populations were identified based on their unique transcriptional signatures. Comparison and trajectory analysis revealed that these populations represent discrete stages of neutrophils undergoing maturation. These neutrophil populations were also classified, based on their granule content-associated signatures, as azurophil, specific, a transitional stage between specific and gelatinase (specific/gelatinase), and gelatinase. This reflects the sequential order of granule formation during neutrophil development (granulopoiesis) in the bone marrow.

Together, our findings indicate that the periodontal ligament may serve as a microenvironment where the ordered and sequential maturation of neutrophils takes place. This suggests that similarly to other niches, the murine periodontal ligament can support, to some extent, hematopoietic processes such as granulopoiesis.

Tumor cell-derived prostaglandin E2 (PGE2) is a tumor cell-intrinsic factor that supports immunosuppression in the tumor microenvironment (TME) by acting on the immune cells, but the impact of PGE2 signaling in tumor cells on the immunosuppressive TME is unclear. We demonstrate that deleting the PGE2 synthesis enzyme or disrupting autocrine PGE2 signaling through EP4 receptors on tumor cells reverses the T cell-low, myeloid cell-rich TME, activates T cells, and suppresses tumor growth. Knockout (KO) of Ptges (the gene encoding the PGE2 synthesis enzyme mPGES-1) or the EP4 receptor gene (Ptger4) in KPCY (KrasG12D P53R172H Yfp CrePdx) pancreatic tumor cells abolished growth of implanted tumors in a T cell-dependent manner. Blockade of the EP4 receptor in combination with immunotherapy, but not immunotherapy alone, induced complete tumor regressions and immunological memory. Mechanistically, Ptges- and Ptger4-KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-α-induced killing, and exhibited reduced adenosine synthesis. In hosts treated with an adenosine deaminase inhibitor, Ptger4-KO tumor cells accumulated adenosine and gave rise to tumors. These studies reveal an unexpected finding - a nonredundant role for the autocrine mPGES-1/PGE2/EP4 signaling axis in pancreatic cancer cells, further nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing therapy in cancer.

Postoperative pain management is challenging. We used mice with a transverse laparotomy to study tactile allodynia measured by the von Frey test, pain at rest measured by facial pain expressions detected by an artificial intelligence algorithm, and movement-induced pain measured by reductions in exploratory activity. The standard analgesics morphine and ibuprofen induced distinct patterns of outcome-dependent effects. Whereas morphine was more effective in reversing pain at rest compared to tactile allodynia, it was unable to alter movement-induced pain. Ibuprofen showed comparable effects across the three outcomes. Administered together, the compounds induced synergistic effects in the three aspects of postoperative pain, mirroring the known advantages of multimodal analgesia used in clinical practice. We explored the impact of neuroimmune interactions using a neutrophil depletion strategy. This reversed pain at rest and movement-induced pain, but did not alter cutaneous sensitivity. Non-peptidergic (IB4+) and peptidergic (CGRP+) nociceptors are segregated neuronal populations in the mouse. We tested the effects of gefapixant, an antitussive drug targeting non-peptidergic nociceptors through P2X3 antagonism, and olcegepant, an antimigraine drug acting as a CGRP antagonist. Both compounds reversed tactile allodynia, while only gefapixant reversed pain at rest, and none of them reversed movement-induced pain. In conclusion, tactile allodynia, pain at rest, and movement-induced pain after surgery have different pharmacological profiles, and none of the three aspects of postoperative pain can predict the effects of a given intervention on the other two. Combining these measures provides a more realistic view of postoperative pain and has the potential to benefit analgesic development.

Acute respiratory infections (ARIs) affect the respiratory tract, are often caused by viruses such as respiratory syncytial virus and rhinovirus, and present symptoms such as coughing, fever, respiratory distress, and breathing difficulty. The global adherence to exclusive breastfeeding (BF) for the first 6 months of life has reached 44%, supported by the World Health Organization and United Nations International Children's Emergency Fund efforts. BF provides vital nutrients and contributes to infant immune system development, protecting against infections. The role of BF in preventing and reducing complications of ARIs in infants is gaining attention, prompting a review of current data and future research needs. This review aims to summarize the evidence on the role of BF in reducing the risk and severity of ARIs in infants, elucidate the adaptations in breast milk composition during infections, and identify relevant research needs.

Human milk (HM) is rich in immunoglobulins, antimicrobial peptides, and immunomodulatory factors that protect against various pathogens, including respiratory viruses. Several studies have demonstrated that BF is associated with a significant reduction in hospitalization, oxygen requirements, and mortality in infants with ARIs. The effectiveness of BF varies according to the specific respiratory virus, and a longer duration of exclusive BF appears to enhance its protective effect. It is documented that the composition of HM adjusts dynamically in response to infections, fortifying the infant's immune defenses. Specific immunological components of HM, including leukocytes and immunoglobulins, increase in response to infection in the infant, contributing to the enhancement of the immune defense in infants. Immune-boosting microRNAs enhance immune transfer to the infants and promote early gut maturation, and the HM microbiome along with other factors modifies the infant's gut microbiome and immune system.

BF defends infants from respiratory infections, and the investigation of the microRNAs in HM offers new insights into its antiviral properties. The promotion of BF, especially in vulnerable communities, is of paramount importance in alleviating the global burden of ARIs in infancy.

Ferroptosis and immune response correlation studies have not been reported in prostate cancer (PCa), and the main goal of this paper is to identify biomarkers that can be used for early diagnosis of prostate cancer. Data on PCa were retrieved from the TCGA and MSKCC2010 databases. Thereafter, the differentially expressed ferroptosis-related genes (DE-FRGs: ACSF2) and immune-related genes (DE-IRGs: ANGPT1, NPPC, and PTGDS) were identified using the "limma" package. Additionally, we used univariate and multivariate Cox regression analyses to obtain biochemical relapse (BCR)-free survival-related genes and construct a risk signature. Patients with high-risk scores were characterized by poor BCR-free survival, relatively low immune cell abundance, and comparably weak expression of immune checkpoint molecules. Moreover, gene set variation analysis (GSVA) was performed to explore the biological pathways related to the risk signature. Single sample gene set enrichment analysis (ssGESA) was applied to evaluate the status of immune cells in patients with PCa, which demonstrated that the risk score was intimately affiliated with immune response and cancer pathways. Ultimately, the connection between the risk score and response of PCa patients to immunotherapy was appraised using the TIDE algorithm. The TIDE algorithm implied that the high-risk score PCa population might benefit more from immunotherapy regimens. Finally, qRT-PCR were used to evaluate the expression of DE-FRGs and DE-IRGs in PCa cell and normal prostate epithelial cells. The result of qRT-PCR showed that the mRNA expression levels of ACSF2, ANGPT1, NPPC, and PTGDS in normal prostate epithelial cell were higher than that in PCa cells. Therefore, a risk score model was generated based on one DE-FRG and three DE-IRGs, which could predict the BCR-free survival and response of immunotherapy for patients with PCa.

The mechanisms underlying the state of systemic immune suppression that develops following major trauma are poorly understood. A post-injury increase in circulating levels of prostaglandin E2 (PGE2) has been proposed as a contributory factor, yet few studies have addressed how trauma influences PGE2 biology.

Blood samples from 95 traumatically-injured patients (injury severity score ≥8) were collected across the pre-hospital (≤2 hours), acute (4-12 hours) and subacute (48-72 hours) post-injury settings. Alongside ex vivo assessments of lipopolysaccharide (LPS)-induced cytokine production by monocytes, neutrophil reactive oxygen species production and phagocytosis, serum concentrations of PGE2 and its scavenger albumin were measured, and the expression of enzymes and receptors involved in PGE2 synthesis and signalling analysed. Leukocytes from trauma patients were treated with cyclooxygenase (COX) inhibitors (indomethacin or NS-398), or the protein kinase A inhibitor H89, to determine whether injury-induced immune suppression could be reversed by targeting the PGE2 pathway. The effect that trauma relevant concentrations of PGE2 had on the anti-microbial functions of neutrophils, monocytes and monocyte-derived macrophages (MDMs) from healthy controls (HC) was examined, as was the effect of PGE2 on efferocytosis. To identify factors that may trigger PGE2 production post-trauma, leukocytes from HC were treated with mitochondrial-derived damage associated molecular patterns (mtDAMPs) and COX-2 expression and PGE2 generation measured.

PGE2 concentrations peaked in blood samples acquired ≤2 hours post-injury and coincided with significantly reduced levels of albumin and impaired LPS-induced cytokine production by monocytes. Significantly higher COX-2 and phospholipase A2 expression was detected in neutrophils and/or peripheral blood mononuclear cells isolated from trauma patients. Treatment of patient leukocytes with indomethacin, NS-398 or H89 enhanced LPS-induced cytokine production and neutrophil extracellular trap generation. Exposure to physiological concentrations of PGE2 suppressed the anti-microbial activity of monocytes, neutrophils and MDMs of HC, but did not influence efferocytosis. In a formyl-peptide receptor-1 dependent manner, mtDAMP treatment significantly increased COX-2 protein expression in neutrophils and monocytes, which resulted in increased PGE2 production.

Physiological concentrations of PGE2 suppress the anti-microbial activities of neutrophils, monocytes and MDMs. Targeting the PGE2 pathway could be a therapeutic approach by which to enhance innate immune function post-injury.

Neoantigen vaccines represent an emerging and promising strategy in the field of tumor immunotherapy. Despite their potential, designing an effective neoantigen vaccine remains a challenge due to the current limitations in predicting CD4+ T cell epitopes with high accuracy. Here, we introduce a novel approach to neoantigen vaccine design that does not rely on computational prediction of CD4+ T cell epitopes. Utilizing nitrated helper T cell epitope containing p-nitrophenylalanine, termed "NitraTh epitope," we have successfully engineered a series of tumor neoantigen vaccines capable of eliciting robust neoantigen-specific immune responses. With the help of NitraTh epitope, even mutations with low predicted affinity for MHC class I molecules were successfully induced to elicit neoantigen-specific responses. In H22 cell allograft and patient-derived xenograft (PDX) liver cancer mouse models, the NitraTh epitope-based neoantigen vaccines significantly suppressed tumor progression. More strikingly, through single-cell sequencing we found that the NitraTh epitope-based neoantigen vaccines regulate macrophage reprogramming and modulate macrophages to decrease the levels of the immunosuppressive molecule prostaglandin E2 (PGE2), which in turn reshapes the tumor immunosuppressive microenvironment. In summary, NitraTh epitope-based neoantigen vaccines possess the dual effects of potently activating neoantigen-specific immunity and alleviating immunosuppression, potentially providing a new paradigm for the design of tumor neoantigen vaccines.