First Line Of Defense Research Articles

Optimizing skin wound healing: The crucial role of the innate immune system and inflammatory microenvironment

Skin, as a part of the innate immune system, represents the first line of defense against pathogens. Each mechanical damage to the skin surface disrupts its homeostasis, thus rapidly inducing the cascade of repair processes. Wound healing comprises 4 subsequent and overlapping steps: hemostasis, inflammation, proliferation, and remodeling. The interplay of the abovementioned phases results in successful cell restoration and tissue repair. The efficiency of wound healing depends on numerous internal and external factors. The proper recruitment of immune cells, such as neutrophils and macrophages, and their interactions with keratinocytes, fibroblasts, and extracellular matrix (ECM) accounts for one of the most significant elements affecting this process. Despite the interaction of the immune cells, the development of a highly favorable microenvironment surrounding the damaged area also constitutes a vital component of successful healing. These optimal conditions combined with the inflow of stimuli, such as cytokines and growth factors, lead to complete wound closure and skin surface restoration. Nevertheless, in order to increase the efficiency of wound healing treatment and improve existing technologies, it is essential to gain a deeper understanding of the healing steps’ complexity. In this work, we elucidated basic mechanisms regarding skin injury sealing with a focus on the creation of a highly beneficial inflammatory microenvironment. The presented paper outlines current approaches to managing the excessive inflammation of the skin wound microenvironment to improve the treatment of chronic wounds. The most important perspectives in immunology phase modulation include the use of pharmaceuticals, natural bioactive compounds, immunomodulatory scaffolds, skin substitutes, cell-based therapies, and growth factors or cytokines injections.

Phenotypic and Genotypic Characterization of Candida parapsilosis complex isolates from a Lebanese Hospital.

The opportunistic fungal pathogen Candida parapsilosis is a major causative agent of candidiasis leading to death in immunocompromised individuals. Azoles are the first line of defense in treatment by inhibiting ERG11, involved in the synthesis of ergosterol, the main sterol fungal sterol. Resistance to azoles is on the increase worldwide including in Lebanon. The purpose of this study is to characterize nine hospital isolates labeled as C. parapsilosis: four resistant and five sensitive to fluconazole. Phenotypic characterization was achieved through a battery of tests that target pathogenicity attributes such as virulence, biofilm formation, stress resistance, and ergosterol content. Genotypic analysis was done through whole genome sequencing to mutations in key virulence and resistance genes. Phylogenetic comparison was performed to determine strain relatedness and clonality. Genomic data and phylogenetic analysis revealed that three of the nine C. parapsilosis isolates were misidentified; two as C. orthopsilosis and C. metapsilosis belonging to the C. parapsilosis complex, while the third was C. albicans. Moreover, several known and novel mutations in key drug resistance and virulence genes were identified such as ERG11, ERG3, ERG6, CDR1, and FAS2. Phylogenetic analysis revealed a high degree of relatedness and clonality within our C. parapsilosis isolates. Our results showed that resistant isolates had no increased ergosterol content, no statistically significant difference in virulence, but exhibited an increase in biofilm content compared to the sensitive isolates. In conclusion, our study, the first of its kind in Lebanon, suggests several mechanisms of antifungal drug resistance in C. parapsilosis hospital isolates.

Antifungal Plant Defensins as an Alternative Tool to Combat Candidiasis.

Currently, the spread of fungal infections is becoming an urgent problem. Fungi of the Candida genus are opportunistic microorganisms that cause superficial and life-threatening systemic candidiasis in immunocompromised patients. The list of antifungal drugs for the treatment of candidiasis is very limited, while the prevalence of resistant strains is growing rapidly. Therefore, the search for new antimycotics, including those exhibiting immunomodulatory properties, is of great importance. Plenty of natural compounds with antifungal activities may be extremely useful in solving this problem. This review evaluates the features of natural antimicrobial peptides, namely plant defensins as possible prototypes of new anticandidal agents. Plant defensins are important components of the innate immune system, which provides the first line of defense against pathogens. The introduction presents a brief summary regarding pathogenic Candida species, the pathogenesis of candidiasis, and the mechanisms of antimycotic resistance. Then, the structural features of plant defensins, their anticandidal activities, their mechanisms of action on yeast-like fungi, their ability to prevent adhesion and biofilm formation, and their combined action with conventional antimycotics are described. The possible mechanisms of fungal resistance to plant defensins, their cytotoxic activity, and their effectiveness in in vivo experiments are also discussed. In addition, for the first time for plant defensins, knowledge about their immunomodulatory effects is also presented.

AN AYURVEDIC MANAGEMENT OF KITIBHA KUSHTHA (PSORIASIS): A CASE STUDY

Background Skin is the first line of defence for our body against harmful physical, chemical, and pathological agents. Healthy skin also contributes to a person's aesthetics. Thus, apart from daily routines, skin disorders also affect the self-confidence of the patient. Skin disorders constitute one of the largest groups of health problems in gen-eral clinical practice. Kushtha is a broad term which covers almost all the skin diseases in Ayurveda. In general, Twak vikara are mainly caused due to altered lifestyle, lack of physical exercise, poor hygiene, mental stress and improper diet. Kushtha is further divided into Maha and Kshudra Kushtha. Kitibha Kushtha is one of the Kshu-dra Kushtha. Need and scope of the study. With the rise in psoriasis and psoriatic medications for longer duration (more than a year), patients also face nu-merous side effects related to other systems. Many patients could be observed applying combination creams (steroids with psoriasis), changing the whole and sole picture of the earlier lesions. Hence, to avoid and make treatment aspect easier to prevent the recurrence. In the present case study, a 58-year-old male patient in the Kayachikitsa OPD of R.A. Podar Medical College (Ayu.), Mumbai had symptoms of hyperpigmentation with dry, scaly lesions all over body and itching all over the body, which increased during the night and was treated with Rukshan-virechan karma and Raktamokshan respectively. The symptoms were prevailing for three months. In this case, Rukshan Chikitsa helped cure Ambu dushti, whereas Virechan karma helped cure Samprapti-bhanga. Raktamokshan helped to avoid the recurrence of the medical condition. Generally, Twak Vikar is mainly caused by Tridosha, Rasa, Mansa, and Kleda dushti. Thus, treatment with Rukshan-Virechan & Raktamokshan Chikitsa provided successful relief, which was observed in the patient.

Mucin-Inspired Polymeric Fibers for Herpes Simplex Virus Type 1 Inhibition.

Mucus lines the epithelial cells at the biological interface and is the first line of defense against multiple viral infections. Mucins, the gel-forming components of mucus, are high molecular weight glycoproteins and crucial for preventing infections by binding pathogens. Consequently, mimicking mucins is a promising strategy for new synthetic virus inhibitors. In this work, synthetic mucin-inspired polymers (MIPs) as potential inhibitors of herpes simplex virus 1 (HSV-1) are investigated. By using a telechelic reversible addition-fragmentation chain-transfer (RAFT) polymerization technique, a new dendronized polysulfatep(G1AAm-OSO3)PDSwith an amide-backbone similar to the native mucin glycoproteins is synthesized.p(G1AAm-OSO3)PDSshows mucin-like elongated fiber structure, as revealed in cryo-electron microscopy (cryo-EM) imaging, and its HSV-1 inhibition activity together with its previously reported methacrylate analoguep(G1MA-OSO3)PDS is tested. Both of the sulfated MIPs show strong HSV-1 inhibition in plaque reduction assays with IC50 values in lower nanomolar range (<3× 10-9 m) and demonstrate a high cell compatibility (CC50>1.0mgmL-1) with lower anticoagulant activity than heparin. In addition, the prophylactic and therapeutic activity of both MIPs is assessed in pre- and post-infection inhibition assays and clearly visualize their high potential for application using fluorescent microscopy imaging of infected cells.

Response of Rhododendron simsii and Rhododendron delavayi Superoxide Dismutase Family Genes to High-Temperature Stress

Superoxide dismutases (SODs) are the first line of defense in the antioxidant defense system, and they play an essential role in various adversity stress adaptations in Rhododendron. In this study, 9 Rhododendron simsii SODs (RsSODs) and 11 Rhododendron delavayi SODs (RdSODs) genes were identified in the genomes of R. simsii and R. delavayi. Phylogenetic relationship analysis classified SOD proteins from two Rhododendron species and other related species into three subfamilies. The results of gene structure and conserved motif analysis show that SOD proteins are strongly evolutionarily conserved, and SODs of the same subfamily have similar motif distributions, positions, and lengths. Twenty-two light-responsive elements, eight phytohormone regulatory elements, five adversity stress-related elements, and three growth and development regulatory elements were detected in the RsSOD and RdSOD promoters. Quantitative real-time fluorescence polymerase chain reaction analysis showed that among the 20 candidate genes, except for RdCSD5, the other SODs were expressed in at least one of four tissues, and all of these gene family members had high expression levels in the leaves. We then investigated the response of the RsSOD and RdSOD gene families to high-temperature stress in combination with the following specific stressors: abscisic acid, ethephon, and hydrogen peroxide treatments, followed by high-temperature stress. Different degrees of upregulated expression of the detected SOD gene family members were found for exogenous reagent treatments and different times of high-temperature stress. Thus, we provide a basis for the further functional characterization of SOD genes in R. simsii and R. delavayi in the future.

Understanding Mucosal Physiology and Rationale of Formulation Design for Improved Mucosal Immunity.

The oral and nasal cavities serve as critical gateways for infectious pathogens, with microorganisms primarily gaining entry through these routes. Our first line of defense against these invaders is the mucosal membrane, a protective barrier that shields the body's internal systems from infection while also contributing to vital functions like air and nutrient intake. One of the key features of this mucosal barrier is its ability to protect the physiological system from pathogens. Additionally, mucosal tolerance plays a crucial role in maintaining homeostasis by regulating the pH and water balance within the body. Recognizing the importance of the mucosal barrier, researchers have developed various mucosal formulations to enhance the immune response. Mucosal vaccines, for example, deliver antigens directly to mucosal tissues, triggering local immune stimulation and ultimately inducing systemic immunity. Studies have shown that lipid-based formulations such as liposomes and virosomes can effectively elicit both local and systemic immune responses. Furthermore, mucoadhesive polymeric particles, with their prolonged delivery to target sites, have demonstrated an enhanced immune response. This Review delves into the critical role of material selection and delivery approaches in optimizing mucosal immunity.

Secondary Procedures on the Palate to Correct/Improve Speech: Past, Present and Future.

Speech production in general and in patients with cleft palate in particular is multifactorial. In addition to the complex velopharyngeal mechanism, all structures of the oral cavity have some contribution for correct speech production. Therefore, in addition to the velopharynx the surgeons and other cleft/craniofacial team members need to perform a thorough and complete evaluation of all structures to fully appreciate the causative factor(s) responsible for inadequate speech production after palatoplasty and to prescribe the most appropriate, personalized management plan. The purpose of this communication is to stress the importance of areas other than the velopharyngx that could have a negative impact on speech. More specifically, the issues of palatoplasty failures and palatal revisions will be presented. This is an area of significant importance and could represent the first line of defense before considering procedures altering the anatomy of the velopharynx, such as pharyngeal flaps, pharyngoplasties, and others. Issues covering the effects of skeletal and dental problems, such as malocclusion, partial or complete edentulism can also affect speech but are outside the scope of this communication.

Recent Progress in Innate Immune Responses to Enterovirus A71 and Viral Evasion Strategies.

Enterovirus A71 (EV-A71) is a major pathogen causing hand, foot, and mouth disease (HFMD) in children worldwide. It can lead to severe gastrointestinal, pulmonary, and neurological complications. The innate immune system, which rapidly detects pathogens via pathogen-associated molecular patterns or pathogen-encoded effectors, serves as the first defensive line against EV-A71 infection. Concurrently, the virus has developed various sophisticated strategies to evade host antiviral responses and establish productive infection. Thus, the virus-host interactions and conflicts, as well as the ability to govern biological events at this first line of defense, contribute significantly to the pathogenesis and outcomes of EV-A71 infection. In this review, we update recent progress on host innate immune responses to EV-A71 infection. In addition, we discuss the underlying strategies employed by EV-A71 to escape host innate immune responses. A better understanding of the interplay between EV-A71 and host innate immunity may unravel potential antiviral targets, as well as strategies that can improve patient outcomes.

The Human Paraoxonase 2: An Optimized Procedure for Refolding and Stabilization Facilitates Enzyme Analyses and a Proteomics Approach.

The human paraoxonase 2 (PON2) is the oldest member of a small family of arylesterase and lactonase enzymes, representing the first line of defense against bacterial infections and having a major role in ROS-associated diseases such as cancer, cardiovascular diseases, neurodegeneration, and diabetes. Specific Post-Translational Modifications (PTMs) clustering nearby two residues corresponding to pon2 polymorphic sites and their impact on the catalytic activity are not yet fully understood. Thus, the goal of the present study was to develop an improved PON2 purification protocol to obtain a higher amount of protein suitable for in-depth biochemical studies and biotechnological applications. To this end, we also tested several compounds to stabilize the active monomeric form of the enzyme. Storing the enzyme at 4 °C with 30 mM Threalose had the best impact on the activity, which was preserved for at least 30 days. The catalytic parameters against the substrate 3-Oxo-dodecanoyl-Homoserine Lactone (3oxoC12-HSL) and the enzyme ability to interfere with the biofilm formation of Pseudomonas aeruginosa (PAO1) were determined, showing that the obtained enzyme is well suited for downstream applications. Finally, we used the purified rPON2 to detect, by the direct molecular fishing (DMF) method, new putative PON2 interactors from soluble extracts of HeLa cells.

NRF2-mediated regulation of lipid pathways in viral infection

The first line of defense against viral infection of the host cell is the cellular lipid membrane, which is also a crucial first site of contact for viruses. Lipids may sometimes be used as viral receptors by viruses. For effective infection, viruses significantly depend on lipid rafts during the majority of the viral life cycle. It has been discovered that different viruses employ different lipid raft modification methods for attachment, internalization, membrane fusion, genome replication, assembly, and release. To preserve cellular homeostasis, cells have potent antioxidant, detoxifying, and cytoprotective capabilities. Nuclear factor erythroid 2-related factor 2 (NRF2), widely expressed in many tissues and cell types, is one crucial component controlling electrophilic and oxidative stress (OS). NRF2 has recently been given novel tasks, including controlling inflammation and antiviral interferon (IFN) responses. The activation of NRF2 has two effects: it may both promote and prevent the development of viral diseases. NRF2 may also alter the host's metabolism and innate immunity during viral infection. However, its primary function in viral infections is to regulate reactive oxygen species (ROS). In several research, the impact of NRF2 on lipid metabolism has been examined. NRF2 is also involved in the control of lipids during viral infection. We evaluated NRF2's function in controlling viral and lipid infections in this research. We also looked at how lipids function in viral infections. Finally, we investigated the role of NRF2 in lipid modulation during viral infections.

Lipase domain effector AGLIP1 in Rhizoctonia solani triggers necrotic killing in plants.

We highlight the emerging role of the R. solani novel lipase domain effector AGLIP1 in suppressing pattern-triggered immunity and inducing plant cell death. The dynamic interplay between plants and Rhizoctonia solani constitutes a multifaceted struggle for survival and dominance. Within this complex dynamic, R. solani has evolved virulence mechanisms by secreting effectors that disrupt plants' first line of defense. A newly discovered effector, AGLIP1 in R. solani, plays a pivotal role in inducing plant cell death and subverting immune responses. AGLIP1, a protein containing a signal peptide and a lipase domain, involves complex formation in the intercellular space, followed by translocation to the plant cytoplasm, where it induces cell death (CD) and suppresses defense gene regulation. This study provides valuable insights into the intricate molecular interactions between plants and necrotrophic fungi, underscoring the imperative for further exploration in this field.

Improving Cardiovascular Disease Forecasting with Machine Learning and Electronic Medical Record Data Characteristics Within a Local Healthcare Network

The PCE Risk Calculator, developed by the ACC/AHA, is frequently utilized in the United States for the purpose of averting the onset of Atherosclerotic cardiovascular disease (ASCVD) via first-line defense strategies. However, this calculator may not accurately estimate risk for certain populations, potentially leading to either under- or over-estimation of risk. We have created calculator for ASCVD risk specific to a population by leveraging advanced Machine Learning (ML) techniques and Electronic Medical Record (EMR) data. Our study involved comparing predictive accuracy of our calculator with PCE calculator. Between January 1, 2009, and April 30, 2020, data was gathered from 101,110 distinct EMRs of patients who were actively receiving treatment. Patient datasets underwent machine learning techniques containing Longitudinal (LT) and Cross-Sectional (CS) features, or solely CS features, derived from laboratory values and vital statistics. The models' effectiveness was assessed using fresh price metric (Screened Cases Percentage @Sensitivity level). In terms of prediction accuracy, every ML model that was tested performed better than the PCE risk calculator. Area Under Curve (AUC) score of 0.902 was obtained by Random Forest (RF) ML technique when CS and LT characteristics were combined (RF-LTC). Our machine learning model only needed to screen 43% of patients in order to identify 90% of positive ASCVD cases, in contrast to the PCE risk calculator, which required screening 69% of patients. Prediction models created using ML techniques reduce the amount number of tests necessary to forecast ASCVD and increase the accuracy of ASCVD prediction when compared to using PCE calculator alone. The combination of LT and CS features in these ML models leads to a significant enhancement in comparing the ASCVD prediction to utilizing CS features exclusively.

The role of circulating T cells with a tissue resident phenotype (ex-TRM) in health and disease.

Tissue-resident memory T cells (TRM) are long-lived memory lymphocytes that persist in non-lymphoid tissues and provide the first line of defence against invading pathogens. They adapt to their environment in a tissue-specific manner, exerting effective pathogen control through a diverse T cell receptor (TCR) repertoire and the expression of proinflammatory cytokines and cytolytic proteins. More recently, several studies have indicated that TRM can egress from the tissue into the blood as so-called "ex-TRM", or "circulating cells with a TRM phenotype". The numerically small ex-TRM population can re-differentiate in the circulation, giving rise to new memory and effector T cells. Following their egress, ex-TRM in the blood and secondary lymphoid organs can be identified based on their continued expression of the residency marker CD103, alongside other TRM-like features. Currently, it is unclear whether exit is a stochastic process, or is actively triggered in response to unknown factors. Also, it is not known whether a subset or all TRM are able to egress. Ex-TRM may be beneficial in health, as mobilisation of specialised TRM and their recruitment to both their site of origin as well as distant tissues results in an efficient distribution of the immune response. However, there is emerging evidence of a pathogenic role for ex-TRM, with a suggestion that they may perpetuate both local and distant tissue inflammation. Here, we review the evidence for the existence of ex-TRM and examine their potential involvement in disease pathogenesis.

Equine herpesvirus type 1 (EHV-1) replication at the upper respiratory entry site is inhibited by neutralizing EHV-1-specific IgG1 and IgG4/7 mucosal antibodies.

Equine herpesvirus type 1 (EHV-1) is a contagious respiratory pathogen that infects the mucosa of the upper respiratory tract (URT). Mucosal immune responses at the URT provide the first line of defense against EHV-1 and are crucial for orchestrating immunity. To define host-pathogen interactions, we characterized B-cell responses, antibody isotype functions, and EHV-1 replication of susceptible (non-immune) and clinically protected (immune) horses after experimental EHV-1 infection. Nasal secretion and nasal wash samples were collected and used for the isolation of DNA, RNA, and mucosal antibodies. Shedding of infectious virus, EHV-1 copy numbers, viral RNA expression, and host B-cell activation in the URT were compared based on host immune status. Mucosal EHV-1-specific antibody responses were associated with EHV-1 shedding and viral RNA transcription. Finally, mucosal immunoglobulin G (IgG) and IgA isotypes were purified and tested for neutralizing capabilities. IgG1 and IgG4/7 neutralized EHV-1, while IgG3/5, IgG6, and IgA did not. Immune horses secreted high amounts of mucosal EHV-1-specific IgG4/7 antibodies and quickly upregulated B-cell pathway genes, while EHV-1 was undetected by virus isolation and PCR. RNA transcription analysis reinforced incomplete viral replication in immune horses. In contrast, complete viral replication with high viral copy numbers and shedding of infectious viruses was characteristic for non-immune horses, together with low or absent EHV-1-specific neutralizing antibodies during viral replication. These data confirm that pre-existing mucosal IgG1 and IgG4/7 and rapid B-cell activation upon EHV-1 infection are essential for virus neutralization, regulation of viral replication, and mucosal immunity against EHV-1.IMPORTANCEEquine herpesvirus type 1 (EHV-1) causes respiratory disease, abortion storms, and neurologic outbreaks known as equine herpes myeloencephalopathy (EHM). EHV-1 is transmitted with respiratory secretions by nose-to-nose contact or via fomites. The virus initially infects the epithelium of the upper respiratory tract (URT). Host-pathogen interactions and mucosal immunity at the viral entry site provide the first line of defense against the EHV-1. Robust mucosal immunity can be essential in protecting against EHV-1 and to reduce EHM outbreaks. It has previously been shown that immune horses do not establish cell-associated viremia, the prerequisite for EHM. Here, we demonstrate how mucosal antibodies can prevent the replication of EHV-1 at the epithelium of the URT and, thereby, the progression of the virus to the peripheral blood. The findings improve the mechanistic understanding of mucosal immunity against EHV-1 and can support the development of enhanced diagnostic tools, vaccines against EHM, and the management of EHV-1 outbreaks.

Membrane Permeability Dominates over Electrostatic Interactions in Dictating Drug Transport in Osmotically Shocked Escherichia coli.

To combat surging multidrug-resistant Gram-negative bacterial infections, better strategies to improve the efficacy of existing drugs are critical. Because the dual membrane cell envelope is the first line of defense for these bacteria, it is crucial to understand the permeation properties of the drugs through it. Our recent study shows that isosmotic conditions prevent drug permeation inside Gram-negative bacteria, Escherichia coli, while hypoosmotic stress enhances the process. Here, we unravel the reason behind such differential drug penetration. Specifically, we dissect the roles of electrostatic screening and low membrane permeability in the penetration failure of drugs under osmotically balanced conditions. We compare the transport of a quaternary ammonium compound malachite green in the presence of an electrolyte (NaCl) and a wide variety of commonly used organic osmolytes, e.g., sucrose, proline, glycerol, sorbitol, and urea. These osmolytes of different membrane permeability (i.e., nonpermeable sucrose and NaCl, freely permeable urea and glycerol, and partially permeable proline and sorbitol) clarify the role of osmotic stress in cell envelope permeability. The results showcase that under balanced osmotic conditions, drug molecules fail to penetrate inside E. coli cells because of low membrane permeabilities and not because of electrostatic screening imposed by the osmolytes. Contribution of the electrostatic interactions, however, cannot be completely overruled as at osmotically imbalanced conditions, drug transport across the bacterial subcellular compartments is found to be dependent on the osmolytes used.

Expression of defensin genes across house fly (Musca domestica) life history gives insight into immune system subfunctionalization.

Animals encounter diverse microbial communities throughout their lifetime, which exert varying selection pressures. Antimicrobial peptides (AMPs), which lyse or inhibit microbial growth, are a first line of defense against some of these microbes. Here we examine how developmental variation in microbial exposure has affected the evolution of expression and amino acid sequences of Defensins (an ancient class of AMPs) in the house fly (Musca domestica). The house fly is a well-suited model for this work because it trophically associates with varying microbial communities throughout its life history and its genome contains expanded families of AMPs, including Defensins. We identified two subsets of house fly Defensins: one expressed in larvae or pupae, and the other expressed in adults. The amino acid sequences of these two Defensin subsets form distinct monophyletic clades, and they are located in separate gene clusters in the genome. The adult-expressed Defensins evolve faster than larval/pupal Defensins, consistent with different selection pressures across developmental stages. Our results therefore suggest that varied microbial communities encountered across life history can shape the evolutionary trajectories of immune genes.

Inhibition of Microbicidal Activity of Canine Macrophages DH82 Cell Line by Capsular Polysaccharides from Cryptococcus neoformans.

Cryptococcus neoformans is a lethal fungus that primarily affects the respiratory system and the central nervous system. One of the main virulence factors is the capsule, constituted by the polysaccharides glucuronoxylomannan (GXM) and glucuronoxylomanogalactan (GXMGal). Polysaccharides are immunomodulators. One of the target cell populations for modulation are macrophages, which are part of the first line of defense and important for innate and adaptive immunity. It has been reported that macrophages can be modulated to act as a "Trojan horse," taking phagocytosed yeasts to strategic sites or having their machinery activation compromised. The scarcity of information on canine cryptococcosis led us to assess whether the purified capsular polysaccharides from C. neoformans would be able to modulate the microbicidal action of macrophages. In the present study, we observed that the capsular polysaccharides, GXM, GXMGal, or capsule total did not induce apoptosis in the DH82 macrophage cell line. However, it was possible to demonstrate that the phagocytic activity was decreased after treatment with polysaccharides. In addition, recovered yeasts from macrophages treated with polysaccharides after phagocytosis could be cultured, showing that their viability was not altered. The polysaccharides led to a reduction in ROS production and the mRNA expression of IL-12 and IL-6. We observed that GXMGal inhibits MHC class II expression and GXM reduces ERK phosphorylation. In contrast, GXMGal and GXM were able to increase the PPAR-γ expression. Furthermore, our data suggest that capsular polysaccharides can reduce the microbicidal activity of canine macrophages DH82.

Esaxerenone Inhibits Interferon-γ Induced Pyroptosis of Macrophages in the Lungs of Aldosterone-treated Mice.

Lung immune cells such as lymphocytes and macrophages can induce an inflammatory response due to the activation of mineralocorticoid receptor (MR), which is manifested by the infiltration of inflammatory cells and the secretion of inflammatory cytokines and subsequent apoptosis, pyroptosis and necrosis of intrinsic lung cells and immune cells. Macrophages are immune cells that are abundant in the lung and act as the first line of defense against pathogens but are also aggravating factors of infection. The activation of the renin-angiotensin-aldosterone system (RAAS), especially aldosterone-stimulated MR activation, can induce macrophage and CD8+T cell aggregation and the secretion of cytokines such as tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ). Increased IFN-γ secretion can induce macrophage pyroptosis and the release of interleukin 1-β (IL-1β), aggravating lung injury. In this study, lung injury in C57BL/6 mice was induced by subcutaneous micro-osmotic pump infusion of aldosterone. After 12weeks of administration, the kidney, heart, blood vessels and lungs all showed obvious inflammatory injury, which manifested as rapid accumulation of macrophages. The overexpression of IFN-γ in the lungs of aldosterone-treated mice and the stimulation of MH-S and RAW264.7 alveolar macrophages (AMs) with aldosterone in vitro showed that IFN-γ induced pyroptosis of macrophages via the activation of the inflammasome, and the MR blocker esaxerenone effectively inhibited this effect and alleviated lung injury. In addition, IFN-γ secreted by CD8+T cells is associated with macrophage pyroptosis. In conclusion, the inhibition of macrophage pyroptosis can effectively alleviate lung injury.

Unraveling the Complexities of Toll-like Receptors: From Molecular Mechanisms to Clinical Applications.

Toll-like receptors (TLRs) are vital components of the innate immune system, serving as the first line of defense against pathogens by recognizing a wide array of molecular patterns. This review summarizes the critical roles of TLRs in immune surveillance and disease pathogenesis, focusing on their structure, signaling pathways, and implications in various disorders. We discuss the molecular intricacies of TLRs, including their ligand specificity, signaling cascades, and the functional consequences of their activation. The involvement of TLRs in infectious diseases, autoimmunity, chronic inflammation, and cancer is explored, highlighting their potential as therapeutic targets. We also examine recent advancements in TLR research, such as the development of specific agonists and antagonists, and their application in immunotherapy and vaccine development. Furthermore, we address the challenges and controversies surrounding TLR research and outline future directions, including the integration of computational modeling and personalized medicine approaches. In conclusion, TLRs represent a promising frontier in medical research, with the potential to significantly impact the development of novel therapeutic strategies for a wide range of diseases.