Systemic Immune Responses Research Articles

Association between sleep duration and lung function among U.S. adults

BackgroundSleep’s impact on the human immune system and inflammatory responses makes it a potential risk factor for lung function impairment. However, the relationship between sleep duration and lung function impairment in middle-aged and young adults has been rarely investigated.MethodsA total of 9,284 aged 20–64 years were categorized into four groups according to sleep duration (≤ 6 h, 7 h, 8 h, and ≥ 9 h), with 7 h as the reference, by using the U.S. NHANES data, 2007–2012. Forced expiratory volume in the 1 s (FEV1), forced vital capacity (FVC), FEV1 to FVC (FEV1/FVC) ratio, peak expiratory flow (PEF), and forced expiratory flow at 25–75% (FEF25 − 75%) were measured by spirometry. Restrictive impairment was defined as baseline FVC < 80% predicted and obstructive impairment as FEV1/FVC < 0.70. Generalized linear regression and logistic regression were performed to estimate the associations between sleep duration and lung function.ResultsCompared with 7 h of sleep duration, shorter and longer sleep duration were associated with decreases in FEV1 (≤ 6 h: β=-0.010, 95% CI=-0.014 to -0.006; 8 h: β=-0.005, 95% CI=-0.009 to -0.001), FVC (≤ 6 h: β=-0.018, 95% CI=-0.014 to -0.007; 8 h: β=-0.005, 95% CI=-0.009 to -0.002), and PEF (≤ 6 h: β=-0.006, 95% CI=-0.010 to -0.002; 8 h: β=-0.007, 95% CI=-0.011 to -0.002; ≥ 9 h: β=-0.012, 95% CI=-0.020 to -0.004). Similarly, shorter (≤ 6 h: OR = 1.346, 95% CI = 1.065 to 1.700) and longer (≥ 9 h: OR = 1.827, 95% CI = 1.236 to 2.700) sleep duration were associated with increased risks of restrictive impairment. Moreover, the aforementioned associations were more pronounced among male participants.ConclusionsCompared with 7 h of sleep duration, shorter and longer sleep duration were associated with impaired lung function among adults aged 20–64 years, and these associations were stronger among males.

Effect of immune checkpoint inhibitor time-of-day infusion on survival in advanced biliary tract cancer: a propensity score-matched analysis

BackgroundCircadian rhythms in the immune system and anti-tumor responses are underexplored in cancer immunotherapy. Despite the success of immune checkpoint inhibitors (ICIs) in treating advanced biliary tract cancers (BTCs), not all patients benefit. This study examined whether the timing of ICI administration affects outcomes in advanced BTC patients.MethodsWe included advanced BTC patients from West China Hospital of Sichuan University who received ≥2 ICI treatments from October 2019 to September 2023, with follow-up until May 2024. Primary outcome was overall survival (OS), with secondary outcomes including progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Propensity score matching (1:2 ratio, caliper width 0.1) mitigated confounding factors. Cox proportional hazards regression analyzed the impact of ICI timing (post-16:30) on OS and PFS. Chi-square test assessed ORR and AE differences.ResultsAmong 221 patients, 51 received ≥20% of ICIs after 16:30; 170 received &amp;lt;20%. Post-matching, 49 late-infusion patients had significantly shorter OS (median 10.1 vs. 14.5 months, HR=1.80, P=0.012) compared to 90 early-infusion patients. Pre-matching, late-infusion patients also had shorter OS (median 9.8 vs. 13.7 months, HR=1.68, P=0.010) and PFS (median 4.9 vs. 8.1 months, HR=1.62, P=0.006). Multivariate analysis confirmed these results. No significant differences were found in ORR (χ^2 = 1.53, P=0.215) or AEs (all P&amp;gt;0.050). Sensitivity analyses supported these findings.ConclusionTiming of ICI administration affects efficacy in advanced BTC, with pre-16:30 infusions linked to better survival. Larger, prospective studies are needed to validate these results.

Association Between Visceral Fat and Lung Function Impairment in Overweight and Grade I Obese Women: A Cross-Sectional Study

Beyond the common comorbidities related to obesity, such as type 2 diabetes and cardiovascular diseases, impaired lung function is already known, but whether the fat distribution (sub-cutaneous, visceral) affects the lung function and pulmonary immune response are poorly known. Few evidence has shown that visceral fat is associated with insulin resistance, low-grade inflammation, and reduced lung function. In the present study, the body composition and fat distribution were evaluated by multi-frequency octopolar bioimpedance. This study demonstrated a possible association of increased visceral fat with impaired lung function in obesity grade I (n = 28; 45.46 ± 10.38 years old) women that was not observed in normal weight (n = 20; 43.20 ± 10.78 years old) and in overweight women (n = 30; 47.27 ± 10.25 years old). We also identified a negative correlation in FVC% (R2 = 0.9129; p &lt; 0.0236), FEV1% (R2 = 0.1079; p &lt; 0.0134), PEF% (R2 = 0.1673; p &lt; 0.0018), and VC IN% (R2 = 0.1330; p &lt; 0.0057) in the obesity grade I group, clearly demonstrating that higher levels of visceral fat correlate with reduced lung function, but not with sub-cutaneous fat. In addition, for the first time, a negative correlation among anti-fibrotic protein klotho (R2 = 0.09298; p &lt; 0.0897) and anti-inflammatory IL-10 (R2 = 0.1653; p &lt; 0.0487) in plasma was observed, in contrast to increased visceral fat. On the contrary, in breath condensate, a positive correlation for adiponectin (R2 = 0.5665; p &lt; 0.0120), IL1-Ra (R2 = 0.2121; p &lt; 0.0544), and IL1-Beta (R2 = 0.3270; p &lt; 0.0084) was found. Thus, increased visceral fat directly influences the impairment of lung function and the systemic and pulmonary immune response of women with obesity grade I.

Increased Herpes simplex virus 1, Toxoplasma gondii and Cytomegalovirus antibody concentrations in severe mental illness

Infections with Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV1) and Toxoplasma gondii (TG) have been implicated in severe mental illness. All three pathogens have high seroprevalence in the human population, are neurotropic and establish a persistent infection. We hypothesized that exposed (seropositive) patients with severe mental illness would show higher immunoglobulin G (IgG) concentrations than exposed healthy controls (HC). We included 765 patients with severe mental illness (schizophrenia n = 515, bipolar disorder n = 250) and 541 HC. CMV, HSV1 and TG IgG seropositivity and concentrations were measured with immunoassays (seropositivity: CMV, n = 447 patients vs. 296 HC; HSV1, n = 355 vs. 238; and TG, n = 159 vs. 126). Among seropositive participants, patients had higher HSV1 (p < 0.001) and TG (p = 0.003) IgG concentrations than HC. Stratifying by diagnosis, both schizophrenia (p = 0.001) and bipolar disorder (p = 0.001) had higher HSV1 IgG concentrations, while schizophrenia only had higher TG (p = 0.009) and CMV (p = 0.045) IgG concentrations than HC. In SZ, higher HSV1 IgG concentrations were associated with higher psychotic (p = 0.030) and manic (p = 0.008) symptom scores, but only among CMV- or TG-infected patients which suggests synergistic effects. Among all participants, HSV1 IgG concentrations were inversely associated with interleukin-18 (p < 0.001) and positively associated with high-sensitivity C-reactive protein (p = 0.002) and B cell-activating factor (p = 0.004), possibly indicating T cell exhaustion, enhanced inflammation, and increased B-cell response, respectively. Patients with severe mental illness exhibit a heightened immune system response to HSV1, TG, and CMV infections suggesting immune system dysfunction and/or a more severe infection. For HSV1, higher IgG concentrations were linked to a greater clinical burden.

Tumor-infiltrating lymphocytes vary in different canine soft tissue sarcoma histological types.

Soft tissue sarcomas (STSs) are conventionally viewed as poorly immunogenic tumors; however, some human STSs have recently been reported to elicit an immune response, thus representing potential candidates for immunotherapy. Data regarding immune cell infiltrates in canine STSs are limited and reported without tumor-type stratification. The aim of this study was to retrospectively assess tumor-infiltrating lymphocytes (TILs) in canine STSs of 5 different histotypes. Eighty-seven canine STSs were collected: 22 perivascular wall tumors (PWTs), 19 liposarcomas, 17 fibrosarcomas, 16 myxosarcomas, and 13 leiomyosarcomas. The tumors were graded and immunolabeled for CD3, CD20, and FoxP3, and slides were scanned. T-cell, B-cell, Treg, and total TIL densities were quantified with QuPath software and expressed as cells/mm2. The B/T-cells ratio and Treg/T-cell proportions were calculated. Total TIL densities were higher in PWTs and myxosarcomas (median = 225 and 303, respectively). PWTs had higher T-cell density but lower Treg proportion (median = 152 and 7.6% respectively). Myxosarcomas had higher Treg densities and B/T-cell ratios (median = 24.4 and 1.57, respectively). No association with grade was found among STSs as a group. In myxosarcomas, higher grade was significantly associated with higher total TILs, and CD20+ and FoxP3+ cell densities (p < .05). The results suggest that PWTs and myxosarcomas may represent the most immunogenic STS types. Myxosarcomas elicit a B-cell and Treg-rich immune response; PWTs stimulate a T-cell-rich and Treg-poor reaction. The immune system response may contribute to the more aggressive behavior of myxosarcomas and the more indolent course of PWTs.

Skin as outermost immune organ of vertebrates that elicits robust early immune responses after immunization with glycoprotein of spring viraemia of carp virus.

As the outermost immune organ in vertebrates, the skin serves as the primary interface with the external environment and plays a crucial role in initiating the early immune response. The skin contains a variety of immune cells that induce mucosal and systemic immune responses, rendering it a prime target for vaccination strategies. Insight into the mechanisms through which vaccination triggers early immune responses is paramount for advancing animal and human health, yet our current understanding remains limited. Given its significance in vertebrate evolution, teleost fish emerges as an excellent model for investigating the early immune response of skin. In this study, we demonstrate that significant quantities of vaccine can be absorbed by the skin and transported to the body through dermis and muscle metabolism by immerses immune zebrafish with glycoprotein of spring viraemia of carp virus. Immersion immunization can elicit robust and enduring immune protection, with the skin triggering a potent immune response early in the immunization process. Analysis of the skin transcriptome revealed the involvement of numerous immune-related genes in the immersion immune response, with indications that HSP70 and MAPK signals might play pivotal roles in the immune process induced by glycoprotein. Co-immunoprecipitation and cell co-localization studies confirmed the interaction between glycoprotein and HSP70. Subsequent research demonstrated that overexpression or inhibition of HSP70 could respectively enhance or impede the expression of JNK and related proteins. However, the survival rate and immune response of HSP70 inhibited zebrafish with glycoprotein treatment were significantly reduced. These findings propose that the interaction between glycoprotein and HSP70 may activate JNK, thereby modulating mucosal and systemic immune responses induced by glycoprotein. This investigation offers novel insights and a foundational understanding of early skin immune reactions.

Immune-Related Gene Expression Responses to In Ovo Stimulation and LPS Challenge in Two Distinct Chicken Genotypes

Background: In ovo stimulation introduces bioactive compounds, such as prebiotics, probiotics, or synbiotics into incubating eggs to enhance gut health and immune system development in chickens. This study aimed to determine the genetic and environmental effects modulating responses to in ovo stimulation in commercial broilers and Green-legged Partridge-like (GP) native chickens. Methods: Eggs were stimulated on day 12 of incubation with prebiotics (GOS—galactooligosaccharides), probiotics (Lactococcus lactis subsp. cremoris), or synbiotics (GOS + L. lactis), with controls being mock-injected. Hatched chicks were reared in group pens and challenged with lipopolysaccharide (LPS) on day 42 post-hatching. Cecal tonsils (CT) and spleens were harvested 2 h post-challenge. RT-qPCR was used to analyze the relative gene expression of cytokine genes: IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p40, and IL-17. Results: The results show that genotype influenced the expression of all immune-related genes, with broiler chickens exhibiting stronger innate inflammatory responses than native chickens. LPS induced both mucosal (CT) and systemic (spleen) immune responses in broilers but only systemic (spleen) responses in native chickens. Conclusions: In ovo stimulation had less of an impact on cytokine gene expression than LPS challenge. Broilers expressed higher inflammatory immune responses than GP native chickens.

Radioimmunotherapy: a game-changer for advanced non-small cell lung cancer

Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related deaths, with conventional treatments offering limited effectiveness in advanced stages, due to distant metastases and treatment resistance. Recent advancements in immunotherapy, specifically immune checkpoint inhibitors (ICIs), have shown promise, but their efficacy as standalone therapies are often insufficient. This has led to increased interest in combining ICIs with radiotherapy, known as radioimmunotherapy (iRT), to enhance treatment outcomes. This review explores the mechanisms that underlie the synergy between radiotherapy and immunotherapy. Radiotherapy can induce the “abscopal effect”, eliciting systemic immune responses that reduce tumor burdens outside the treated area. It also increases the expression of major histocompatibility complex class I (MHC-I) on tumor cells, improving immune recognition. Furthermore, radiotherapy can modify the tumor microenvironment by inducing metabolic reprogramming to bolster anti-tumor immunity. We discuss strategies for optimizing iRT, including considerations of radiation doses, fractionation schedules, and treatment site selection, which significantly influence immune responses by enhancing MHC-I expression or promoting T-cell infiltration. Clinical evidence supports the efficacy of iRT in NSCLC and other cancers, though challenges in standardizing treatment protocols and managing side effects persist. Overall, radioimmunotherapy presents a promising approach to improving NSCLC treatment outcomes. Ongoing research into its mechanisms and the refinement of treatment may reshape clinical practice, offering more effective and personalized options for patients with advanced lung cancer. Further studies are essential to validate these findings and optimize therapeutic protocols.

Deficient SARS-CoV-2 hybrid immunity during inflammatory bowel disease.

Patients with Inflammatory Bowel Disease (IBD) undergoing immunosuppressive therapies face heightened susceptibility to severe COVID-19. An in-depth understanding of systemic inflammation and cellular immune responses after SARS-CoV-2 vaccination and breakthrough infections (BTI) is required for optimizing vaccine strategies in this population. While the prevalence of high serological responders post- third COVID-19 vaccine dose was lower, and the antibody waning was higher in IBD patients than in healthy donors (HD), IBD patients showed an increase in anti-RBD Wild Type IgG levels and cross-reactive Spike -specific memory B cells following BTI. However, there was no significant enhancement in cellular immune responses against anti-SARS-CoV-2 post-BTI, with responses instead characterized by activation of SARS-CoV-2 specific and also bystander CD8 T cells. These results suggest a complex interaction between chronic inflammation in IBD and the generation of new immune responses, highlighting the need for tailored vaccine regimens and anti-inflammatory therapies to boost cellular immunity against SARS-CoV-2.

Studying the impact of probiotic agents on the pathogenetic and clinical features of generalized periodontitis

Generalized periodontitis remains one of the most prevalent dental diseases, complications of which significantly deteriorate patients’ quality of life. Currently, the use of probiotic agents is considered a promising direction to enhance the effectiveness of non-surgical treatment of this pathology. Studying the impact of different probiotics on the pathogenetic and clinical features of generalized periodontitis will allow proposing optimized protocols for comprehensive treatment, reducing patient rehabilitation periods and improving the overall dental health of the population. The aim of this study is to examine the influence of various probiotic agents on the pathogenetic and clinical characteristics, treatment effectiveness of generalized periodontitis in adult patients by analyzing professional scientific literature. The literature review provides a brief overview of various probiotic groups and discusses pathogenetic mechanisms of their interaction with the microbiota of oral biofilms. The immunomodulatory mechanisms of probiotics on local and systemic immune responses in patients with generalized periodontitis, inhibition of enzymes responsible for bone tissue resorption, are presented. The analysis results of scientific sources regarding the dynamics of changes in clinical symptoms, microbiological, immunological, and biochemical parameters of saliva and blood serum in individuals with generalized periodontitis receiving comprehensive rehabilitation using probiotic agents compared to patients treated with traditional protocols are provided. The study highlights statistical differences in clinical and laboratory indicators of periodontitis progression at different treatment intervals. Conclusions. The use of probiotic agents for treating patients with generalized periodontitis significantly influences the clinical course of the disease by altering the species composition of dental biofilms and modulating local immune and inflammatory reactions. However, the known results of experimental and clinical studies often have conflicting findings regarding the efficacy of specific probiotic strains and the duration of inflammatory process stabilization over extended periods after treatment, which means a further study is required.

The impact of gut microbiota in full-term pregnant women on immune regulation during pregnancy: A prospective, exploratory study.

This study aims to investigate the correlation between gut microbiota and both placental local immune function and the maternal systemic immune system in pregnant women. Twenty-six pregnant women were included in this study, utilizing high-throughput sequencing for gut microbiota analysis. Immune cells and cytokine levels were measured in placental tissue and peripheral venous blood. Integration of gut microbiota data with immune parameters was performed using R, and network correlation analysis was conducted with Cytoscape software. In placental tissues, gut microbiota predominantly influences B lymphocytes (CD3-CD19+/CD3-), indicating a potential bidirectional regulatory role. The impact on CD56+CD16+/CD56+CD16- and CD4+/CD8+ ratios appear minor. Notably, a significant positive correlation was observed between gut microbiota and the placental cytokine interleukin (IL)-5. In peripheral blood, gut microbiota was primarily associated with negative regulation of peripheral B lymphocytes and positive regulation of peripheral Treg cells. Minimal effects are observed on peripheral macrophages and NK cell subtypes. The most substantial impact on peripheral immune balance was reflected in the CD4+/CD8+ ratio, showing a predominant negative correlation, while the influence on the CD56+CD16+/CD56+CD16- ratio is minimal. A significant negative correlation was found between gut microbiota and peripheral cytokines IL-1 and IL-18, while the interaction with the peripheral interferon-γ/IL-4 ratio appears relatively less pronounced. The close correlation between gut microbiota and placental local immune function, as well as maternal systemic immune responses, is evident. This study contributes to a preliminary understanding of the immunomodulatory relationship of gut microbiota during pregnancy.

Modulation of the central nervous system immune response and neuroinflammation via Wnt signaling in health and neurodegenerative diseases

AbstractThe immune response in the central nervous system (CNS) is a highly specialized and tightly regulated process essential for maintaining neural health and protecting against pathogens and injuries. The primary immune cells within the CNS include microglia, astrocytes, T cells, and B cells. They work together, continuously monitor the CNS environment for signs of infection, injury, or disease, and respond by phagocytosing debris, releasing cytokines, and recruiting other immune cells. In addition to providing neuroprotection, these immune responses must be carefully balanced to prevent excessive inflammation that can lead to neuronal damage and contribute to neurodegenerative diseases. Dysregulated immune responses in the CNS are implicated in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Wnt signaling is a crucial pathway in the CNS that regulates various cellular processes critical for brain development, function, and maintenance. Despite enhancing immune responses in the health CNS, dysregulated Wnt signaling exacerbates neuroinflammation in the neurodegenerative brains. This review summarized the role of Wnt signaling in regulating immune response under different conditions. We then examined the role of immune response in healthy brains and during the development of neurodegenerative diseases. We also discussed therapeutic intervention in various neurodegenerative diseases through the modulation of the Wnt signaling pathway and neuroinflammation and highlighted challenges and limitations in current clinical trials.

An Integrated Approach to Develop a Potent Vaccine Candidate Construct Against Prostate Cancer by Utilizing Machine Learning and Bioinformatics.

Prostate cancer is the most common malignancy among males. Prostaglandin G/H synthase (PGHS) is an essential enzyme in the synthesis of prostaglandins, and its activation has been linked to many malignancies, including colorectal cancer. Due to the limited effectiveness and specificity of existing prostate cancer therapies, this study was designed to formulate improved treatment techniques. Several immunoinformatic, reverse vaccinology, and molecular modeling methodologies were used to discover B- and T-cell epitopes for the glioblastoma multiforme tumor PGH2_HUMAN. This research evaluated Prostaglandin G/H synthase 2 protein as a potential vaccine candidate against the malignancy. The multi-epitope vaccine architecture is engineered to activate the immune system, with each epitope docked to its respective HLAs. Further, MD simulations analysis was performed to validate the findings. A multi-epitope subunit vaccine candidate was developed by concatenating the chosen B- and T-cell epitopes. Results yield a codon adaptive index (CAI) of 0.93 and a GC content of 56.77%. Thus, it conforms to a biological requirement for effective protein expression, suggesting competent vaccine efficacy inside the Escherichia coli system. Significant interleukin and cytokine responses were seen, characterized by elevated levels of IL-2 and IFN-γ in the immune system's response to the immunization. Molecular docking demonstrated an efficient binding affinity of -278 kcal/mol, with hydrogen bonding to several residues. Furthermore, the system total root mean square deviation (RMSD) reached 3.23 Å, with a maximum of up to 5.0 Å at the 100 ns time point but remains stable till 400 ns time intervals followed by stable root mean square fluctuation (RMSF) and radius of gyration values. The hydrogen bond cloud residues are the critical sites that significantly influence the binding energies of MMPBSA and MMGBSA via substantial van der Waals interactions. It has been determined that these in silico analyses will further augment the comprehension necessary for advancing the creation of targeted therapies for chemotherapeutic cancer treatments.

The Role of Prebiotic, Probiotic, and Synbiotic in Gut Microbiota and Gut Permeability in Children Affected by Air Pollution

Background: Air pollution has been linked with gut microbiota dysbiosis. Ingested environmental pollutants may alter gut microbiota compositions by changing the environment of the gut. Gut microbiota dysbiosis has been observed in children with asthma, linking the possible role of gut microbiota with systemic immune response and asthma. Methods: This paper aims to identify current science on how prebiotics, probiotics, and synbiotics can improve gut microbiota dysbiosis. Results: We reviewed the existing literature related to the role of pre-, pro-, and synbiotics in child health, and the evidence mapping method was chosen as the rapid review to identify gaps in knowledge and future research needs. Conclusion: In conclusion, the current evidence on the role of prebiotics, probiotics, and synbiotics on child health, while limited, showed promising results on the allergy and immunology pathway, including infection prevention for the gastrointestinal and respiratory tract.

Activation of Stimulator of Interferon Genes (STING): Promising Strategy to Overcome Immune Resistance in Prostate Cancer.

Prostate cancer (PCa) is the most frequent and second-lethal cancer among men. Despite considerable efforts to explore treatments like autologous cellular immunotherapy and immune checkpoint inhibitors, their success remains limited. The intricate tumor microenvironment (TME) and its interaction with the immune system pose significant challenges in PCa treatment. Consequently, researchers have directed their focus on augmenting the immune system's anti-tumor response by targeting the STimulator of the Interferon Genes (STING) pathway. The STING pathway is activated when foreign DNA is detected in the cytoplasm of innate immune cells, resulting in the activation of endoplasmic reticulum (ER) STING. This, in turn, triggers an augmentation of signaling, leading to the production of type I interferon (IFN) and other pro-inflammatory cytokines. Numerous studies have demonstrated that activation of the STING pathway induces immune system rejection and targeted elimination of PCa cells. Researchers have been exploring various methods to activate the STING pathway, including the use of bacterial vectors to deliver STING agonists and the combination of radiation therapy with STING agonists. Achieving effective radiation therapy with minimal side effects and optimal anti-tumor immune responses necessitates precise adjustments to radiation dosing and fractionation schedules. This comprehensive review discusses promising findings from studies focusing on activating the STING pathway to combat PCa. The STING pathway exhibits the potential to serve as an effective treatment modality for PCa, offering new hope for improving the lives of those affected by this devastating disease.

Periodontitis Continuum: Antecedents, Triggers, Mediators, and Treatment Strategies.

Periodontitis (PD) is a chronic inflammatory disease of the periodontium characterized by the formation of gingival pockets and gingival recession. The local inflammatory environment can lead to the destruction of the extracellular matrix and subsequent bone loss. The pathophysiology of PD involves interactions between genetic predisposition, lifestyle, environmental factors, the oral microbiota condition, systemic health disorders, innate and adaptive immune responses, and various host defenses. The review highlighted the importance of the oral cavity condition in systemic health. Thus, a correlation between harmful oral microbiota and cardiovascular disease (CVD)/diabetes/ arthritis, etc, progressions through inflammation and bacterial translocation was highlighted. Antecedents increase an individual's risk of developing PD, trigger initiate microbe-host immunologic responses, and mediators sustain inflammatory interactions. Generally, this review explores the antecedents, triggers, and mediators along the pathophysiological continuum of PD. An analysis of modern approaches to treating periodontitis, including antibiotics for systemic and local use, was carried out. The potential role of natural ingredients such as herbal extracts, phytoconstituents, propolis, and probiotics in preventing and treating PD was highlighted.

MULTIMODAL NUCLEAR FACTOR-ERYTHROID-2-RELATED FACTOR (NRF2) THERAPY IN THE CONTEXT OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) INHIBITION REPROGRAMS THE ACUTE SYSTEMIC AND PULMONARY IMMUNE RESPONSE AFTER COMBINED BURN AND INHALATION INJURY.

Severe burn injuries induce acute and chronic susceptibility to infections, which is largely attributed to a hyper-proinflammatory response followed by a chronic anti-inflammatory response. Concurrent inhalation injury (B + I) causes airway inflammation. Pulmonary macrophages and neutrophils are "hyperactive" with increased reactive oxygen (ROS) and nitrogen species (RONS) activity, but are unable to clear infection, causing airway damage upon activation. Nuclear factor-erythroid-2-related factor (NRF2) is a critical immunomodulatory component that induces compensatory anti-inflammatory pathways when activated. On the other hand, inhibition of mammalian target of rapamycin (mTOR) reduces proinflammatory responses. The therapeutic use of these targets is limited, as known modulators of these pathways are insoluble in saline and require long-term administration. A biocompatible NRF2 agonist (CDDO) and rapamycin (RAPA) poly(lactic-co-glycolic acid) (PLGA) microparticles (MP) were created, which we hypothesized would reduce the acute hyper-inflammatory response in our murine model of B + I injury. BI-injured mice that received CDDO-MP or both CDDO-MP and RAPA-MP (Combo-MP) an hour after injury displayed significant changes in the activation patterns of pulmonary and systemic immune genes and their associated immune pathways 48 h after injury. For example, mice treated with Combo-MP showed a significant reduction in inflammatory gene expression compared to untreated or CDDO-MP-treated mice. We also hypothesized that Combo-MP therapy would acutely decrease bacterial susceptibility after injury. BI-injured mice that received Combo-MP an hour after injury, inoculated 48 h later with Pseudomonas aeruginosa (PAO1), and sacrificed 48 h after infection displayed significantly decreased bacterial counts in the lungs and liver versus untreated B + I mice. This reduction in infection was accompanied by significantly altered lung and plasma cytokine profiles and immune reprogramming of pulmonary and splenic cells. Our findings strongly suggest that multimodal MP-based therapy holds considerable promise for reprogramming the immune response after burn injuries, particularly by mitigating the hyper-inflammatory phase and preventing subsequent susceptibility to infection.

Introducing Degradable Cationic Nanogels Carrying TLR9 Stimulating Oligonucleotides.

Cationic, core-crosslinked nanogel particles are prepared from synthetic biodegradable materials. These fully hydrophilic nanogels offer superior customizability compared to common lipid nanoparticles, thereby circumventing intrinsic immune stimulatory properties. Electrostatic loading allows for complexation of nucleic acids including the immune stimulatory Toll-like receptor 9 (TLR9) agonistCpG-ODN (cytidine-phosphate-guanosine oligodeoxynucleotide). Only when complexed inside nanogels, one can control CpG-ODN's biodistribution, prevent systemic toxicity, and increase bioavailability at target locations. Nanogels are prepared from cyclic aliphatic carbonate monomers with reactive pentafluorophenyl (PFP) esters. First, block copolymers are acquired via cationic ring opening polymerization (CROP) onto polyethylene glycol (PEG). Upon self-assembly in ethanol, the micelles' core is cationically core-crosslinked, and the resulting fully hydrophilic particles exhibit sizes of ≈20nm, also upon loading with CpG-ODN. In vitro, they promote intracellular delivery devoid of carrier-related toxicities, while retaining the immune stimulatory properties of the TLR agonist cargo. In vivo, the nanogels reduce systemic liver immune responses and remain near the injection site. Additionally, delivery into cDC1 (conventional dentritic cells type 1) antigen-presenting cells, which are highly relevant for antitumoral T-cell immune responses, is confirmed. Altogether, cationic, core-crosslinked polycarbonate nanogels show promise for nucleic acid delivery, showcasing controlled immunostimulatory cargo delivery and an enhanced hydrolytic biodegradability profile, highly valuable for cancer immunotherapy.

Layered Double Hydroxides for Radium-223 Targeted Alpha Therapy with Elicitation of the Immune Response.

Targeted Alpha therapy (TAT) has promising application prospects in tumor therapy. It is very appealing to design alpha-emitting radiopharmaceuticals that can modulate the immune microenvironment to overcome the limitations of immunotherapy. Herein, Mg/Al layered double hydroxide nanomaterials (LDH) are utilized to load the alpha-emitting nuclide Radium-223 (223Ra), achieving precise delivery of 223Ra to the tumor microenvironment. Dual-modal imaging is employed to dynamically monitor the in vivo distribution of 223Ra-LDH, ensuring its prolonged retention at the tumor site. In vitro experimentsshowed that ionizing radiation from alpha-emitting nuclides effectively reduced glutathione (GSH) and producedlarge amounts of reactive oxygen species (ROS), which damaged mitochondria and released free calcium (Ca2+), thereby aggravating tumor cell death. Additionally, DNA double-strand breaks induced by alpha-emitting radiation triggered the STING signaling pathway, which in turn effectively induced immunogenic cell death (ICD) and promoted immune cell maturation and activation. The synergistic effect with immunotherapy triggered a powerful systemic antitumor immune response. Overall, this study develops a novel TAT therapeutic strategy with sufficient antitumor immunity.

Efficacy of cryoablative local treatment for hormone receptor positive localized T1 invasive ductal carcinoma of the breast and its effects on systemic anti-tumoral immunologic response.

Efficacy of cryoablative local treatment for hormone receptor positive localized T1 invasive ductal carcinoma of the breast and its effects on systemic anti-tumoral immunologic response.