Diabetes increases susceptibility to infections, including Leishmania braziliensis (Lb). Our group previously demonstrated that diabetic patients with cutaneous leishmaniasis (CL) take longer to heal lesions compared to non-diabetics. Since macrophages play a critical role in CL pathogenesis, we investigated how high glucose levels impact their response during Lb infection. Macrophages cultured in high glucose conditions showed increased parasite load than those in normal glucose conditions. The production of inflammatory mediators was similar between glucose conditions, but basal reactive oxygen species (ROS) production was elevated under high glucose conditions and remained unchanged after Lb infection, indicating glucose-induced oxidative stress does not control the parasite. In contrast, macrophages in normal glucose conditions, exhibited increased ROS production only after infection. Additionally, high glucose reduced TLR2 and TLR4 expression, which was also observed after Lb infection. TLR2/4 inhibition increased Lb infection in normal glucose conditions, mediated by TLR-dependent ROS production. However, this mechanism was absent under high glucose conditions, where elevated basal ROS production appeared TLR-independent. Biopsies from diabetic CL patients corroborated these findings, showing decreased TLR2 and TLR4 expression compared to non-diabetics. These findings suggest that high glucose levels induce oxidative stress and reduces TLR expression, impairing macrophage functions and rendering them less effective at controlling Lb infection.

As a member of the NLRs family, NLRC3 has been determined to function in the NF-κB, MAPK, and type I IFN signaling, which are crucial for the host innate immunity and inflammatory response. In this study, an NLRC3 ortholog, named as Lc-NLRC3, was cloned and identified in large yellow croaker (Larimichthys crocea). The gene characteristics analysis revealed that Lc-NLRC3 consists of 18 exons and 17 introns, with a full-length open reading frame (ORF) of 3405 bp, encoding a protein of 1134 amino acids (aa), that containing a N-terminal CARD domain, a central NACHT domain, and a C-terminal LRRs domain. It was shown that Lc-NLRC3 is predominantly found in the cytosol, and was widely distributed across various tissues/organs, with the highest expression detected in the intestine, and could be induced by poly I:C, LPS, PGN, and Pseudomonas plecoglossicida stimulation. Importantly, Lc-NLRC3 overexpression significantly activate NF-κB, TNFα, IL-1β, IRF3, IRF7, and IFN1 promoters, whereas when co-expressed with RIP2, STING, or TBK1, it down-regulated those promoter activation compared to their individual overexpression alone, thereby suppressing downstream antiviral and inflammatory gene expression. Interestingly, Lc-NLRC3 associated with TRAF6 in IRF3/IRF7 promoter activation, and enhanced the expression of IRF7, Mx, ISG15, and TNF-α. Co-immunoprecipitation assays also confirmed interactions of Lc-NLRC3 with RIP2, STING, TBK1, and TRAF6. The above results imply that Lc-NLRC3 is an important regulator in RIP2, STING, TBK1, and TRAF6 mediated type I IFN signaling and inflammatory response.

Peptide-based vaccines, formulated with an appropriate adjuvant, offer a versatile platform for targeted cancer immunotherapy. While adjuvants are usually coadministered for nucleic acid and protein vaccines, synthetic peptide antigens afford a more effective opportunity to covalently and regioselectively graft immunostimulatory motifs directly onto the antigen scaffold to yield self-adjuvanting vaccines. Herein, we explore the synthesis of two tissue-restricted cancer-testis antigens (CTAs); New York oesophageal cell carcinoma 1 (NY-ESO-1) and B melanoma antigen 4 (BAGE4), both carrying the toll-like receptor (TLR) agonist, Pam2Cys. These constructs were evaluated in vivo along with a lipid nanoparticle (LNP) preparation of the underexplored BAGE4 melanoma antigen.

This study investigated the protective effect of arachidonic acid (ARA) against the allograft-induced stress response in Pinctada fucata martensii by characterizing pearl production traits and changes in genes and lipids during postoperative care. Survival and pearl production traits were higher in the ARA treatment group (ARAG) than in the control group (CG). There were 1536 differentially expressed genes (DEGs) in CG-1d vs ARAG-1d and 833 DEGs in CG-3d vs ARAG-3d. DEGs in CG-1d vs ARAG-1d were mainly enriched in "NOD-like receiver signaling pathway," "Glycerolipid metabolism," and "Sphingolipid metabolism." DEGs in CG-3d vs ARAG-3d were mainly enriched in "Apoptosis" and "ARA metabolism." Lipidomics analysis revealed 36 types of lipids. The PC, LPE (22:5), and LPE (18:0) content at 3 d after implantation was lower in the ARAG than in the CG. The PS (37,1) content was significantly higher at 3 d after implantation and the content of ceramides was significantly lower at 1 and 3 d after implantation in the ARAG than in the CG. The results indicated that ARA may alter the composition of lipids, modify the unsaturation of lipids, and regulate apoptosis, immunity, and lipid metabolism in pearl oysters, which enhances pearl production traits. These findings provide theoretical and practical basis for further alleviating the inflammatory response of pearl oysters after implantation.

Juvenile dermatomyositis (JDM), the most common pediatric inflammatory myopathy, is associated with significant morbidity despite therapeutic advances. Distinct clinical phenotypes have emerged, which can correlate with myositis-specific antibodies. Because translational data solidify the role of type I IFNs in JDM disease pathogenesis, integration of clinical and molecular phenotyping may impact the choice of targeted therapy. This paper reviews clinical and molecular phenotyping in JDM and translational insights into immune pathogenesis that have created emerging options for targeted therapy.

Research over the past two decades has established a remarkable ability of the gut microbiota to modulate brain activity and behaviour. Conversely, signals from the brain can influence the composition and function of the gut microbiota. This bidirectional communication across the gut microbiota-brain axis, involving multiple biochemical and cellular mediators, is recognized as a major brain-body network that integrates cues from the environment and the body's internal state. Central to this network is the gut sensory system, formed by intimate connections between chemosensory epithelial cells and sensory nerve fibres, that conveys interoceptive signals to the central nervous system. In this Review, we provide a broad overview of the pathways that connect the gut and the brain, and explore the complex dialogue between microorganisms and neurons at this emerging intestinal neuroepithelial interface. We highlight relevant microbial factors, endocrine cells and neural mechanisms that govern gut microbiota-brain interactions and their implications for gastrointestinal and neuropsychiatric health.

Hepcidin is the primary regulator of vertebrate iron homeostasis. Its production is stimulated by systemic iron levels and inflammatory signals. Although the role of hepcidin in iron homeostasis is well characterized, its response to pathogenic agents is complex and diverse. In this review, we examine studies that investigate the role of hepcidin in response to infectious agents. Interleukin-6 (IL-6) is a key factor responsible for the induction of hepcidin expression. During infection, hepcidin-mediated depletion of extracellular iron serves as a protective mechanism against a variety of pathogens. However, accumulation of iron in macrophages through hepcidin-mediated pathways may increase susceptibility to intracellular pathogens such as Mycobacterium tuberculosis. Prolonged elevation of hepcidin production can lead to anemia due to reduced iron availability for erythropoiesis, a condition referred to as anemia of inflammation. In addition, we highlight the role of hepcidin upregulation in several infectious contexts, including HIV-associated anemia, iron deficiency anemia in Helicobacter pylori infection, and post-malarial anemia in pediatric patients. In addition, we show that certain infectious agents, such as hepatitis C virus (HCV), can suppress hepcidin production during both the acute and chronic phases of infection, while hepatitis B virus (HBV) exhibits similar suppression during the chronic phase.

Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.

Colorectal cancer (CRC) continues to rank among the most prevalent cancers worldwide. A growing body of research indicates that the microbiome significantly influences the onset, development, and progression of CRC, in addition to affecting the efficacy of various systemic therapies. The composition of the microbiome, shaped by factors such as bacterial strains, geography, ethnicity, gender, and dietary habits, provides essential information for CRC screening, early diagnosis, and the prediction of treatment responses. Modulating the microbiome presents a highly promising medical strategy for improving individual health. This review aims to present a thorough overview of recent research concerning the interplay between host microbiota and CRC, along with its implications for screening and the immune response against tumors in the context of cancer treatment.

Liraglutide for Injection is a GLP-1 analog that stimulates insulin secretion from pancreatic β-cells in a Glucose dependent manner for the treatment of diabetic patients, especially adult patients with type 2 diabetes, to control blood glucose levels. A generic drug of Liraglutide for injection received tentative approval by the FDA on June 21, 2024. Generic Liraglutide (synthesis) was considered to be equivalent to the original brand-name Liraglutide (recombinant), but their manufacturing processes are different. Although synthetic Liraglutide undergo strict impurity control, even trace levels of different innate immune response modulating impurities (IIRMI) may activate innate immunity in peripheral blood mononuclear cells (PBMCs), leading to the expression of cytokines and chemokines, increased antigen uptake, promotion of antigen-presenting cell (APC) processing and presentation, and enhancement of product immunogenicity [1]. Therefore, accurately assessing the IIRMI immunogenic risk of Liraglutide is a key component of immunogenic risk assessment to ensure that its immunogenic risk is similar or lower than branded Liraglutide products. This study utilized PBMC-based assays with fresh PBMC from different volunteers treated with Liraglutide drugs with or without TLR/NOD ligands to evaluate the recent and aged Liraglutide products for their immunogenicity. A method based on PBMC was established to detect IIRMI in synthetic peptide drugs. Using this method, the results showed that despite differences in manufacturing processes between synthetic Liraglutide (generic) and recombinant Liraglutide (branded), there was no statistically significant difference in their immunogenicities. It provides a novel approach for future research on the innate immunogenicity of peptide drug formulations, enabling a broader detection of trace unknown impurities compared to cell line systems.

Glaucoma is a serious cause of permanent blindness worldwide, mainly caused by inflammation and degeneration of the optic nerve. However, current treatments using systemically administered drugs have limited effectiveness due to various biological barriers that prevent their biodistribution in the eye. To overcome these challenges, we developed a new therapy that utilizes intranasal delivery to retinal lesions. In this therapy, we used platelet extracellular vesicles (pEVs) as carriers for epigallocatechin gallate (EGCG), which is known for its neuroprotective, anti-inflammatory, and immunomodulatory properties. We hypothesized that this therapy could overcome ocular barriers, increase drug bioavailability, and mitigate glaucoma progression. We conducted extensive characterization of the biochemical and biophysical properties of the EGCG-pEVs, and the results were promising. In vivo tests using an animal model of dexamethasone-induced glaucoma showed that intranasal administration of EGCG-pEVs was safe and had superior drug delivery and therapeutic efficacy, including anti-inflammatory, immunomodulatory, and intraocular pressure-reducing effects, compared to an intraperitoneal injection or ophthalmic drug administration routes. This unique mode of drug administration shows great potential for clinical applications in ophthalmology.

The relationship between the innate immune signal and the start of the adaptive immune response is the central idea of this theory. By controlling the inflammatory and tissue-repair reactions to damage, the Toll-like receptors (TLRs), as a family of PRRs, have attracted increasing attention for its function in protecting the host against infection and preserving tissue homeostasis. Microbial infection, damage, inflammation, and tissue healing have all been linked to the development of malignancies, especially gastrointestinal (GI) cancers. Recently, increased studies on TLR recognition and binding, as well as their ligands, have significantly advanced our knowledge of the various TLR signaling pathways and offered therapy options for GI malignancies. Upon activation by pathogen-associated or damage-associated molecular patterns (DAMPs and PAMPs), TLRs trigger key pathways like NF-κB, MAPK, and IRF. NF-κB activation promotes inflammation, cell survival, and proliferation, often contributing to tumor growth, metastasis, and therapy resistance. MAPK pathways similarly drive uncontrolled cell growth and invasion, while IRF pathways modulate interferon production, yielding both anti-tumor and protumor effects. The resulting chronic inflammatory environment within tumors can foster progression, yet TLR activation can also stimulate beneficial anti-tumor immune responses. However, the functions of TLR expression in GI cancers and their diagnostic and prognostic along with therapeutic value have not yet entirely been elucidated. Understanding how TLR activation contributes to anti-cancer immunity against GI malignancies may hasten immunotherapy developments and increase patient survival.

The immune system employs innate and adaptive immunity to combat pathogens and stress stimuli. Innate immunity rapidly detects pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) via pattern recognition receptors (PRRs), whereas adaptive immunity mediates antigen-specific T/B cell responses. The NLRP3 inflammasome, a key cytoplasmic PRR, consists of leucine-rich repeat, nucleotide-binding, and pyrin domains. Its activation requires priming (signal 1: Toll-like receptors/NOD-like receptors/cytokine receptors) and activation (signal 2: PAMPs/DAMPs/particulates). NLRP3 triggers cytokine storms and neuroinflammation, contributing to inflammatory diseases. Emerging therapies target NLRP3 via nuclear receptors (transcriptional regulation), adeno-associated virus (AAV) vectors (gene delivery), and microRNAs (post-transcriptional modulation). This review highlights NLRP3's signaling cascade, pathological roles, and combinatorial treatments leveraging nuclear receptors, AAVs, and microRNAs for immunomodulation.

Inflammation is a critical part of innate immune response that is essential for exclusion of harmful stimuli and restoration of tissue homeostasis. Nonetheless, failure to resolve inflammation results in chronic inflammatory conditions, including autoimmune diseases. Conventionally, resolution of inflammation was deemed a passive process; however, evidence indicates that it entails active, highly regulated molecular and cellular events involving efferocytosis-driven macrophage reprogramming, post-transcriptional regulatory mechanisms and the production of specialized pro-resolving mediators (SPMs). These processes collectively restore tissue homeostasis and prevent chronic inflammation. Emerging therapeutic approaches targeting these pathways demonstrate promising results in preclinical studies and clinical trials, enhancing resolution and improving overall disease outcome. This resulted in a paradigm shift from conventional anti-inflammatory strategies to resolution-focused treatment. Yet, challenges remain due to the complexity of resolution mechanisms and tissue-specific differences. This review summarizes current advances in inflammation resolution, emphasizing emerging concepts of resolution pharmacology. By employing endogenous mechanisms facilitating resolution, novel therapeutic applications can effectively manage several chronic inflammatory disorders.

Increasing health consciousness among consumers has significantly driven the demand for functional foods; however, market acceptance largely hinges on flavor profiles. Functional flavor agents, which simultaneously enhance taste and provide health benefits, meet the dual consumer demand for flavor and nutrition. This review classifies functional flavor agents into five categories based on their sensory characteristics. Their health benefits are explored with a focus on their potential roles in disease prevention and treatment, including improved energy metabolism, cardiovascular support, anti-tumor effects, modulation of gut microbiota, and enhancement of immune function. Emerging trends in the food industry are highlighted, underscoring the significant influence of these agents on product innovation. However, the integration of functional flavor agents into food products presents challenges, particularly in optimizing interactions to maximize both sensory appeal and health benefits. Innovative approaches are required to navigate the complex interplay between flavor agents and food components, enhancing flavor stability and sensory quality. Ultimately, the strategic application of functional flavor agents in food production holds promise for fostering a health-oriented market that aligns with consumer expectations for taste and nutrition.

Systemic autoinflammatory diseases are rare conditions resulting from dysregulation of the innate immune system, culminating in repetitive bouts of systemic inflammation without the presence of external or self-antigens. Most systemic autoinflammatory diseases are associated with mutations in genes affecting the innate immune response. Tumor necrosis factor is a central player in the pathogenesis of numerous chronic inflammatory disorders, and anti-tumor necrosis factor therapy is widely used in the clinical management of systemic autoinflammatory diseases. Tumor necrosis factor inhibitors block the interaction of tumor necrosis factor with its 2 receptors, tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2. These inhibitors primarily target soluble tumor necrosis factor, which mainly binds to tumor necrosis factor receptor 1, exerting anti-inflammatory effects. Interestingly, tumor necrosis factor inhibitors also affect transmembrane tumor necrosis factor, which engages tumor necrosis factor receptor 2 to initiate reverse signaling. This reverse signaling can activate innate immune cells, prevent apoptosis, or paradoxically inhibit the production of pro-inflammatory cytokines. Tumor necrosis factor inhibitors also promote the release of soluble tumor necrosis factor receptor 2, which neutralizes circulating tumor necrosis factor. Some agents targeting tumor necrosis factor receptor 2 can even act as agonists, triggering reverse signaling by binding to transmembrane tumor necrosis factor. While effective, prolonged use of tumor necrosis factor inhibitors may cause significant side effects due to the widespread expression and pleiotropic functions of tumor necrosis factor receptors. A more thorough understanding of the mechanisms underlying the action of tumor necrosis factor inhibitors is required to develop a more effective and safer treatment for systemic autoinflammatory diseases. This article reviews current studies on the role of the innate immune system in systemic autoinflammatory disease pathogenesis, the impact of anti-tumor necrosis factor therapy on innate immune cells, and perspectives on developing improved agents targeting tumor necrosis factor or its receptors.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric impairments caused by Huntingtin (HTT) gene mutations, resulting in the mutant huntingtin (mHTT) protein. Both innate and adaptive immunities play crucial roles in the pathogenesis of HD. In this chapter, we explore the vital role of the gut microbiota in HD, emphasizing its impact on the immune response and brain health via the gut-brain axis. Dysbiosis influences immune responses and HD pathogenesis through microbial metabolites such as short-chain fatty acids (SCFAs) and pathogen-associated molecular patterns (PAMPs). We discuss advanced mathematical models, telemedicine, and biosensors for tracking HD progression and detecting gut dysbiosis. Nutritional interventions to restore microbiota balance and using artificial intelligence and machine learning to predict disease prognosis and personalized treatments have been highlighted. Based on their unique immune profiles and gut microbiota, personalized medicine has been proposed as a promising strategy for effective HD treatment.

The advent of nanotechnology has steered into a new era of medical advancements, with metal nanoparticles (MNPs) emerging as potent agents for precise regulation of the immune system. This review provides a comprehensive overview of the immunomodulatory roles of MNPs, including gold, silver, and metal oxide nanoparticles, in regulating innate and adaptive immunity. Additionally, we discuss the immunological effects of metal ions and metal complexes, offering a comparative analysis with nanoparticulate systems. We analyse cutting-edge strategies utilising MNPs to optimise vaccine efficacy, achieve targeted delivery to immune cells, and orchestrate inflammatory responses. Additionally, we discuss the therapeutic potential of MNPs in combating autoimmune diseases, cancers, and infectious agents, which is evaluated within the framework of precision medicine. Furthermore, we critically assess challenges such as biocompatibility, potential toxicity, and regulatory hurdles. Finally, we propose future directions for integrating MNPs with advanced delivery systems and other nanomaterials to propel the frontiers of immunotherapy. This review aims to provide a foundational understanding of MNP-mediated immunomodulation, inspiring further research and development in this burgeoning field.

Benzo[a]pyrene (BaP) is a representative polycyclic aromatic hydrocarbon (PAH) known for its significant toxicity and environmental persistence, capable of causing mutations, deformities, and cancer in aquatic organisms. However, systematic studies on the effects of BaP exposure on histological damage, cell apoptosis, enzyme activity changes, and gene expression in Mytilus coruscus (M. coruscus), an important ecological indicator species, remain scarce. In this study, the biological effects of BaP on M. coruscus and the immunotoxic mechanisms following BaP exposure were evaluated using histological analysis, TUNEL assay, enzyme activity assays, and transcriptome sequencing. Our findings revealed notable histopathological changes due to BaP exposure, including hemocyte infiltration, atrophy, and deformation of digestive tubules in the digestive glands, as well as epithelial cell detachment and deformation in gills. Antioxidant enzyme activities (CAT, GSH-Px, SOD, T-AOC) varied significantly across tissues under BaP stress. Additionally, significant DNA fragmentation and increased apoptosis were observed in BaP-exposed groups compared to controls. Transcriptome analysis showed that after BaP exposure, nucleotide excision repair and innate immune response pathways were suppressed, while the metabolism of xenobiotics by cytochrome P450, glutathione biosynthesis, and apoptosis pathways were upregulated. These results elucidate the toxic mechanisms of BaP on M. coruscus and the immunotoxic responses of the mussels. This study enhances our understanding of how BaP and similar pollutants affect marine bivalves, providing valuable insights for environmental monitoring and pollutant management strategies.

The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) through pattern recognition receptors (PRRs). Inflammasomes, cytoplasmic protein complexes, are activated in response to PAMPs and DAMPs, leading to the release of inflammatory cytokines such as IL-1β and IL-18. NLRP3 inflammasome is one of the best characterized inflammasomes and recently its activation has been associated with granuloma formation, structures that aggregate immune cells in response to infections, such as those caused by bacteria, fungi and parasites, and autoinflammatory diseases, such as sarcoidosis. Activation of NLRP3 inflammasomes in macrophages induces the release of cytokines that recruit immune cells, such as monocytes and lymphocytes, to the site of infection. Neutrophils, monocytes, T and B lymphocytes are important in the formation and maintenance of granulomas. Although NLRP3 plays a key role in the immune response, cell recruitment and granuloma formation, many aspects of its function in different cell types remain to be elucidated. In this review, we aim to outline the NLRP3 inflammasome not only as a protein complex that aids innate immune cells in combating intracellular pathogens but also as a platform with broader implications in orchestrating immune responses. This underexplored aspect of the NLRP3 inflammasome presents a novel perspective on its involvement in immunity. Thus, we review the current understanding of the role of the NLRP3 inflammasome in immune cell infiltration and its significance in the organization and formation of granulomas in inflammatory diseases.

Despite the global impact caused by the most recent SARS-CoV-2 pandemic, our knowledge of the molecular underpinnings of its highly infectious nature remains incomplete. We report here that SARS-CoV-2 exploits cellular CTP synthetase 1 (CTPS1) to promote CTP synthesis and suppress interferon (IFN) induction. In addition to catalyzing CTP synthesis, CTPS1 also deamidates interferon regulatory factor 3 (IRF3) to dampen interferon induction. Screening a SARS-CoV-2 expression library, we identified several viral proteins that interact with CTPS1. Functional analyses demonstrate that ORF8 and Nsp8 activate CTPS1 to deamidate IRF3 and negate IFN induction, whereas ORF7b and ORF8 activate CTPS1 to promote CTP synthesis. These results highlight CTPS1 as a signaling node that integrates cellular metabolism and innate immune response. Indeed, small-molecule inhibitors of CTPS1 deplete CTP and boost IFN induction in SARS-CoV-2-infected cells, thus effectively impeding SARS-CoV-2 replication and pathogenesis in mouse models. Our work uncovers an intricate mechanism by which a viral pathogen couples immune evasion to metabolic activation to fuel viral replication. Inhibition of the cellular CTPS1 offers an attractive means to develop antiviral therapy against highly mutagenic viruses.IMPORTANCEOur understanding of the underpinnings of highly infectious SARS-CoV-2 is rudimentary at best. We report here that SARS-CoV-2 activates CTPS1 to promote CTP synthesis and suppress IFN induction, thus coupling immune evasion to activated nucleotide synthesis. Inhibition of the key metabolic enzyme not only depletes the nucleotide pool but also boosts host antiviral defense, thereby impeding SARS-CoV-2 replication. Targeting cellular enzymes presents a strategy to counter the rapidly evolving SARS-CoV-2 variants.

Sepsis is a life-threatening condition that occurs when the body is unable to effectively combat infection, leading to systemic inflammation and multi-organ failure. Interestingly, females exhibit lower sepsis incidence and improved clinical outcomes compared to males. However, the mechanisms underlying these sex-specific differences remain poorly understood. While sex hormones have been a primary focus, emerging evidence suggests that non-hormonal factors also play contributory roles. Despite sex differences in sepsis, clinical management is the same for both males and females, with treatment focused on combating infection using antibiotics and hemodynamic support through fluid therapy. However, even with these interventions, mortality remains high, highlighting the need for more effective and targeted therapeutic strategies. Sepsis-induced cardiomyopathy (SIC) is a key contributor to multi-organ failure and is characterized by left ventricular dilation and impaired cardiac contractility. In this review, we explore sex-specific differences in sepsis and SIC, with a particular focus on mitochondrial metabolism. Mitochondria generate the ATP required for cardiac function through fatty acid and glucose oxidation, and recent studies have revealed distinct metabolic profiles between males and females, which can further differ in the context of sepsis and SIC. Targeting these metabolic pathways could provide new avenues for sepsis treatment.

The NOD-like receptor family, particularly the protein 3 that contains the pyrin domain (NLRP3), is an intracellular sensing protein complex responsible for detecting patterns associated with pathogens and injuries. NLRP3 plays a crucial role in the innate immune response. Currently, a wide range of research has indicated the crucial importance of NLRP3 in various inflammatory conditions. Similarly, the NLRP3 inflammasome plays a significant role in preserving intestinal balance and impacting the advancement of diseases. In addition, several randomized trials have demonstrated the safety and efficacy of targeting NLRP3 in the treatment of colitis, colorectal cancer, and related diseases. This review explores the mechanisms of NLRP3 assembly and activation in the gut. We describe its pathological significance in intestinal diseases. Finally, we summarize current and future therapeutic approaches targeting NLRP3 for intestinal diseases.

This study investigates the phytoconstituents of the less explored leaf of Piper nigrum, a common ethnomedicinal plant as an alternate source for multiple bioactivities.

Hydro-ethanolic (1:4) extract of Piper nigrum leaves (PNLE) prepared and profiled using liquid chromatography and mass spectrometry for identification of phytomolecules. Anti-oxidant activity, intracellular reactive oxygen species (ROS) expression, phagocytosis activity, and cytokine expression were estimated using cell-free and cell-based assays. Anti-cancer activity was determined with cancer cell viability, migration inhibition and colony-formation assay. Apoptosis and membrane depolarization assay were done using fluorescent microscopic staining methods while network pharmacology, and molecular docking analysis were done using open source and online tools.

Major phytomolecules identified in PNLE were pentanamide N,N-didecyl, piperettine, curcumin, myristicin, pipernonaline, sesamin, and lupenone. PNLE exhibited anti-bacterial activity with higher activity against Gram-positive bacteria, Staphylococcus aureus. PNLE also showed anti-oxidant and anti-inflammatory activity through neutralization of free radicals; inhibition of intracellular ROS generation; inhibition of phagocytosis and reduction of cytokine (IL-6 and TNF-α) levels. PNLE showed anti-proliferative activity against human breast cancer cells (MDA-MB-231), rat mammary tumor cells (LA7), and mouse melanoma cells (B16-F10) with highest activity against MDA-MB-231 cells. The extract did not inhibit human kidney cells (HEK-293). Further, PNLE treatment significantly inhibited cell migration and colony formation of MDA-MB-231 cells. Fluorescent staining techniques confirmed induction of apoptosis in cancer cells by PNLE. Further, network pharmacology and molecular docking studies revealed that the identified PNLE phytomolecules share 97 targets of out of potential breast cancer and inflammation-related target genes with four best common target proteins among the top hub genes and sesamin showed the highest binding affinity with these important cellular targets.

Overall, the phytochemical profile of PNLE showed clear presence of important phytomolecules and their association with critical human cellular mechanistic pathways responsible for exhibited bioactivities. This study further establishes the leaf of P. nigrum as an additional anatomical plant part with potent medicinal properties and  as a potential renewable source for bioactive phyomolecules.

Traumatic brain injury (TBI) remains a major cause of mortality and long-term disability worldwide, with ferroptosis and necroptosis emerging as key drivers of secondary neuronal damage. Ferroptosis, characterized by iron-dependent lipid peroxidation and mitochondrial dysfunction, exacerbates oxidative stress and neuronal cell death. In parallel, necroptosis, mediated by receptor-interacting protein kinases (RIPK1 and RIPK3), amplifies inflammation through membrane rupture and the release of cellular components. Mitochondrial dynamics, involving fission and fusion processes, play a dual role in regulating these pathways. While mitochondrial fusion preserves cellular integrity and reduces oxidative stress, excessive mitochondrial fission driven by dynamin-related protein 1 (DRP1) accelerates necroptotic signaling and neuronal injury. This intricate interplay between ferroptosis, necroptosis, and mitochondrial dynamics highlights potential therapeutic targets. Modulating these pathways through tailored interventions could reduce neuronal damage, mitigate neuroinflammation, and improve functional outcomes in TBI patients. Advancing our understanding of these mechanisms is essential for developing precision therapies that address the complex pathology of traumatic brain injury.

The posttranslational modification (PTM) of innate immune sensor proteins by ubiquitin or ubiquitin-like proteins is crucial for regulating antiviral host responses. The cytoplasmic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5) undergoes several PTMs including ISGylation within its first caspase activation and recruitment domain (CARD), which promotes MDA5 signaling. However, the relevance of MDA5 ISGylation for antiviral immunity in an infected organism has been elusive. Here, we generated knock-in mice (MDA5K23R/K43R) in which the two major ISGylation sites, K23 and K43, in MDA5, were mutated. Primary cells derived from MDA5K23R/K43R mice exhibited abrogated endogenous MDA5 ISGylation and an impaired ability of MDA5 to form oligomeric assemblies, leading to blunted cytokine responses to MDA5 RNA-agonist stimulation or infection with encephalomyocarditis virus (EMCV) or West Nile virus. Phenocopying MDA5-/- mice, the MDA5K23R/K43R mice infected with EMCV displayed increased myocardial injury and mortality, elevated viral titers, and an ablated induction of cytokines and chemokines compared to WT mice. Molecular studies identified human HERC5 (and its functional murine homolog HERC6) as the primary E3 ligases responsible for MDA5 ISGylation and activation. Taken together, these findings establish the importance of CARD ISGylation for MDA5-mediated RNA virus restriction, promoting potential avenues for immunomodulatory drug design for antiviral or anti-inflammatory applications.

The innate immune response, particularly the interferon-mediated pathway, serves as the first line of defense against viral infections. During virus infection, viral pathogen-associated molecular patterns (PAMPs) are recognized by host pattern recognition receptors (PRRs), triggering downstream signaling pathways. This leads to the activation of transcription factors like IRF3, IRF7, and NF-κB, which translocate to the nucleus and induce the production of type I interferons (IFN-α and IFN-β). Once secreted, type I interferons bind to their receptors (IFNARs) on the surfaces of infected and neighboring cells, activating the JAK-STAT pathway. This results in the formation of the ISGF3 complex (composed of STAT1, STAT2, and IRF9), which translocates to the nucleus and drives the expression of interferon-stimulated genes (ISGs). Some ISGs exert antiviral effects by directly or indirectly blocking infection and replication. Among these ISGs, ISG15 plays a crucial role in the ISGylation process, a ubiquitin-like modification that tags viral and host proteins, regulating immune responses and inhibiting viral replication. However, viruses have evolved counteractive strategies to evade ISG15-mediated immunity and ISGylation. This review first outlines the PAMP-PRR-induced pathways leading to the production of cytokines and ISGs, followed by a summary of ISGylation's role in antiviral defense and viral evasion mechanisms targeting ISG15 and ISGYlation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss, affecting millions worldwide. Emerging evidence highlights the oral microbiome-a complex ecosystem of bacteria, fungi, viruses, and protozoa as a significant factor in cognitive health. Dysbiosis of the oral microbiome contributes to systemic inflammation, disrupts the blood-brain barrier, and promotes neuroinflammation, processes increasingly implicated in the pathogenesis of AD. This review examines the mechanisms linking oral microbiome dysbiosis to cognitive decline through the oral-brain and oral-gut-brain axis. These interconnected pathways enable bidirectional communication between the oral cavity, gut, and brain via neural, immune, and endocrine signaling. Oral pathogens, such as Porphyromonas gingivalis, along with virulence factors, including lipopolysaccharides (LPS) and gingipains, contribute to neuroinflammation, while metabolic byproducts, such as short-chain fatty acids (SCFAs) and peptidoglycans, further exacerbate systemic immune activation. Additionally, this review explores the influence of external factors, including diet, pH balance, medication use, smoking, alcohol consumption, and oral hygiene, on oral microbial diversity and stability, highlighting their role in shaping cognitive outcomes. The dynamic interplay between the oral and gut microbiomes reinforces the importance of microbial homeostasis in preserving systemic and neurological health. The interventions, including probiotics, prebiotics, and dietary modifications, offer promising strategies to support cognitive function and reduce the risk of neurodegenerative diseases, such as AD, by maintaining a diverse microbiome. Future longitudinal research is needed to identify the long-term impact of oral microbiome dysbiosis on cognition.

Background: Hidradenitis suppurativa (HS) is a chronic, disabling, and disfiguring inflammatory disease with a complex, incompletely elucidated pathogenesis. The role of skin dysbiosis in the development and progression of HS has not yet been clarified. Methods: We performed an observational, prospective culture-based study that included 40 HS patients and analyzed the bacterial load and diversity in HS skin lesions, their correlation with disease severity, and several host and environmental factors. Additionally, we investigated the prevalence of antibiotic resistance and determined the resistance profile of bacterial strains isolated from chronic HS lesions. Results: An impressive number and diversity of bacterial strains were isolated from both superficial and deep HS lesions. 201 aerobic and anaerobic bacterial strains were isolated, polymicrobial growth being detected in the majority of samples. The most frequently isolated bacteria were Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus lugdunensis, Peptoniphilus spp., and Enterococcus faecalis in superficial lesions and Staphylococcus epidermidis, Staphylococcus aureus, and Corynebacterium tuberculostearicum in deep lesions. A significantly higher bacterial density and diversity was found in male patients, regardless of the affected area and in patients with severe HS. The proportion of bacterial strains resistant to antibiotics was lower in our study (8.95%) compared to the previously reported data. Conclusions: Our findings indicate dysbiosis as a key player in the initiation and maintenance of the inflammatory process in HS. Further large-scale, prospective studies are required to comprehensively characterize the microbiological landscape of HS and shed light on its contribution in the pathogenesis of the disease.

CRC (Colorectal cancer) ranks among the most prevalent tumors in humans and remains a leading cause of cancer-related mortality worldwide. Numerous studies have highlighted the connection between inflammasome over-activation and the initiation and progression of CRC. The activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome is dependent on the nuclear NF-kβ (Nuclear Factor kappa-light-chain-enhancer of activated B cells) pathway, leading to the maturation and release of inflammatory cytokines such as IL-1ß (Interleukin 1 beta) and IL-18 (Interleukin 18). While inflammation is crucial for defense mechanisms and tissue repair, excessive information can pose significant risks. Mounting evidence suggests that overactivation of the inflammasome contributes to the pathogenesis of inflammatory diseases. Consequently, there is a concerted effort to tightly regulate inflammasome activity and mitigate excessive inflammatory responses, particularly in conditions such as IBD (Inflammatory Bowel Disease), which includes Ulcerative Colitis and Crohn's Disease. The tripartite motif (TRIM) protein family, characterized by a conserved structure and rapid evolutionary diversification, includes members with critical roles in ubiquitination and other regulatory functions. Their importance in modulating inflammatory responses is widely acknowledged. This article aims to investigate the interplay between TRIM proteins and the NLRP3 Inflammasome in CRC and gut inflammation, offering insights for future research endeavors and potential therapeutic strategies.

The tumor-targeted drug delivery system (TTDNS) uses nanocarriers to transport chemotherapeutic agents to target tumor cells or tissues precisely. This innovative approach considerably increases the effective concentration of these drugs at the tumor site, thereby enhancing their therapeutic efficacy. Many chemotherapeutic agents face challenges, such as low bioavailability, high cytotoxicity, and inadequate drug resistance. To address these obstacles, TTDNS comprising natural polysaccharides have gained increasing popularity in the field of nanotechnology owing to their ability to improve safety, bioavailability, and biocompatibility while reducing toxicity. In addition, it enhances permeability and allows for controlled drug delivery and release. This review focuses on the sources of natural polysaccharides and their direct and indirect mechanisms of anti-tumor activity. We also explored the preparation of various polysaccharide-based nanocarriers, including nanoparticles, nanoemulsions, nanohydrogels, nanoliposomes, nanocapsules, nanomicelles, nanocrystals, and nanofibers. Furthermore, this review delves into the versatile applications of polysaccharide-based nanocarriers, elucidating their capabilities for in vivo targeting, controlled release, and responsiveness to endogenous and exogenous stimuli, such as pH, reactive oxygen species, glutathione, light, ultrasound, and magnetic fields. This sophisticated design substantially enhances the chemotherapeutic efficacy of the encapsulated drugs at tumor sites and provides a basis for preclinical and clinical research. However, the in vivo stability, drug loading, and permeability of these preparations into tumor tissues still need to be improved. Most of the currently developed biomarker-sensitive polysaccharide nanocarriers are still in the laboratory stage, more innovative delivery mechanisms and clinical studies are needed to develop commercial nanocarriers for medical use.

Postoperative ileus (POI) is an iatrogenic disorder marked by temporary impaired gastrointestinal (GI) motility post-abdominal surgery. Surgical handling of the intestine activates resident macrophages (Mfs), leading to inflammatory cytokine release and leukocyte recruitment into the muscularis, which compromises intestinal contractility. The mechanisms behind this activation are unclear. Recent studies suggest peritoneal Mfs, particularly large peritoneal macrophages (LPMs), might play a role in sterile intestinal inflammation by rapidly recruiting to the serosal layer of the gut and aiding in tissue damage resolution.

To identify immune cells involved in the early phase of POI, single-cell RNA sequencing (scRNA-seq) was conducted. The migration of LPMs post-surgery was studied using adoptive transfer techniques. LPMs were depleted via intraperitoneal injection of clodronate liposomes. Subsequently, flow cytometry, quantitative PCR (qPCR), and immunofluorescence were performed to assess the impact of LPM depletion and analyze cell populations and inflammatory effects.

(1) Intestinal manipulation (IM) leads to the accumulation of monocytes, neutrophils, mature Mfs, CD8+ T cells, and LPMs within 2 h post-surgery. (2) Heparin treatment does not affect gut transit or reduce IL-6, IL-1a, and IL-1b expression in the early phase of POI. (3) Depletion of LPMs via clodronate liposome does not prevent monocyte, neutrophil, and Mfs infiltration in the muscularis externa, nor does it improve gut transit or reduce cytokine expression. (4) LPMs migrate to the serosa after IM but do not enter the muscularis externa.

LPMs adhere to the intestinal serosa following intestinal manipulation but do not migrate into the intestinal muscularis or participate in the inflammatory response and delayed transit. Consequently, LPMs are not involved in the pathogenesis of POI.

Vibrio cholerae cytolysin (VCC) is a potent exotoxin secreted by Vibrio cholerae, the etiological agent of the severe diarrheal disease cholera. VCC is a membrane-damaging pore-forming toxin by nature, and is well known for its ability to cause host cell death. Using wild type V. cholerae and VCC-deleted mutant variant of the bacteria, we show that VCC plays an important role in the inflammatory responses during infection in mice. This observation supports that VCC can function as a pathogen-associated molecular pattern (PAMP). Toll-like receptors (TLRs) are the key initiators of inflammation. Upon ligand recognition, TLR1 and TLR6 generally form heterodimers with TLR2 for triggering pro-inflammatory signals. In the present study, we show that VCC engages novel TLR1/4 heterodimer assembly, and elicits pro-inflammatory responses in both dendritic cells (DCs) and macrophages. Along with TLR1/4, VCC-induced pro-inflammatory response in macrophages also involves TLR2. It has been shown earlier that VCC is implicated in the V. cholerae-mediated killing of the immune cells following biofilm formation. Here we show that TLRs play an important role in VCC-mediated killing of DCs and macrophages following V. cholerae infection. Interestingly, we find that TLR1/4 signalling is specifically crucial for the VCC-induced inflammatory and death responses in DCs, as well as in mice. Additionally, we observe that similar to DCs and macrophages, TLR1/4-MyD88 play an important role in VCC-mediated inflammatory responses in another crucial immune cell type, neutrophils. Taken together, our study shows novel TLR heterodimer formation, differential recognition of the same ligand by different TLR combination in cell type-dependent manner, and their implications in the context of V. cholerae and VCC-induced immune cell death and mortality.

Diabetes mellitus, a global health challenge, influences millions worldwide by leading to severe complications and premature death. A key factor in its pathogenesis is immune cell dysfunction, which aggravates both type 1 and type 2 diabetes. The important role that immune cell dysregulation plays in the emergence of diabetes complications is investigated in this research. It highlights the manner in which diabetes compromises the immune system's adaptive as well as innate responses. Key defects in innate immunity include impaired pathogen recognition, and dysfunctional behavior of macrophages, neutrophils, and natural killer (NK) cells. Additionally, the complement system is dysregulated, and cytokine production is altered, affecting overall immune signaling. The study investigates the dysfunction of several T and B cell subsets, such as CD4+ T cells, CD8+ T cells, regulatory T cells, and B cells, in relation to adaptive immunity. These dysfunctions collectively contribute to chronic inflammation, reduced pathogen clearance, and increased susceptibility to infections, ultimately exacerbating diabetes complications. Developing targeted therapies to reduce diabetes complications and enhance patient outcomes requires an understanding of these mechanisms.

The present investigation has been attempted for scientifically validating the traditional uses of Piper mullesua against inflammatory pathophysiology using both in vivo (albino rats) and in vitro (macrophage cells, RAW 264.7) models of inflammation caused by an endotoxin (lipopolysaccharide, LPS). Oral gavaging with PMHAE, hydroalcoholic extract of Piper mullesua leaves, dose-responsively (50, 100, or 200 mg/kg BW, 14 days) restored any alteration in the concentration of serum inflammatory cytokines, IL-6, TNF-α, IL-4, and IL-10 and decreased prostaglandin (PGE2) and nitrite count in rats injected (i.p.) with LPS (10 mg/kg BW). PMHAE supplementation (5, 10, or 20 µg/mL) further attenuated MCP-1, IL-6, and TNF-α, and increased IL-10 and IL-4 secretion and mRNA expression in LPS-treated (50 ng/mL) macrophages. PMHAE also enhanced phagocytic potential while attenuated ROS counts in LPS-treated cells. Additionally, PMHAE supplementation increased SOCS1 protein expression and decreased NF-κB phosphorylation (Serine 536), along with the expression of JAK1/STAT1 proteins in LPS-treated cells. Treatment with PMHAE did not cause any toxicity to animals and cultured cells. Phytochemical analysis (LC-MS/GC-MS) revealed various compounds, including piperine, piperlongumine, pipernonaline, phytol, methyl eugenol, and pinene, contributing to anti-inflammatory potential of PMHAE. These findings suggested Piper mullesua as a safe, effective, and potential anti-inflammatory avenue for therapeutic exploration in inflammatory pathophysiology.

In the intricate realm of interactions between hosts and pathogens, Toll-like receptors (TLRs), which play a crucial role in the innate immune response, possess the ability to identify specific molecular signatures. This includes components originating from pathogens such as SARS-CoV-2, as well as the resulting damage-associated molecular patterns (DAMPs), the endogenous molecules released after cellular damage. A developing perspective suggests that TLRs play a central role in neuroinflammation, a fundamental factor in neurodegenerative conditions like Alzheimer's and Parkinson's disease (PD). This comprehensive review consolidates current research investigating the potential interplay between TLRs, their signaling mechanisms, and the processes of neurodegeneration following SARS-CoV-2 infection with an aim to elucidate the involvement of TLRs in the long-term neurological complications of COVID-19 and explore the potential of targeting TLRs as a means of implementing intervention strategies for the prevention or treatment of COVID-19-associated long-term brain outcomes.

Developing drugs for the treatment of Metabolic Associated Steatohepatitis (MASH) has always been a significant challenge. Researchers have been dedicated to exploring drugs and therapeutic strategies to alleviate disease progression, but treatments remain limited. This is partly due to the complexity of the pathophysiological processes, and inadequate knowledge of the cellular and molecular mechanisms in MASH. Especially, the liver non-parenchymal cells (NPCs) like Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells which play critical roles in live function, immune responses, fibrosis and disease progression. Deciphering how these cells function in MASH, would help understand the pathophysiological processes and find potential drug targets. In recent years, new technologies have been developed for single-cell transcriptomic sequencing, making cell-specific transcriptome profiling a reality in healthy and diseased livers. In this review, we discussed how the use of single-cell transcriptomic sequencing provided us with an in-depth understanding of the heterogeneous, cellular interactions among non-parenchymal cells and tried to highlight recent discoveries in MASH by this technology. It is hoped that the summarized features and markers of various subclusters in this review could provide a technical reference for further experiments and a theoretical basis for clinical applications.

Barrier organs rely on a limited set of pattern recognition receptors (PRRs) to detect diverse immunogenic challenges. How organs assess threats and adjust immune responses to balance host protection with collateral tissue damage remains unclear. Here, by analyzing influenza infection in the lung using single-molecule imaging and spatial transcriptomics, we discovered a tiered threat-sensing strategy at the tissue scale, where the probability of detecting and responding to infection is lowest in the outermost epithelia and highest in the inner stroma. This strategy emerges from spatially graded PRR expression that results in cell-type-specific probabilities of threat-sensing across the tissue, a design broadly adopted by barrier organs. Selectively increasing PRR expression in lung epithelia in vivo exacerbated tissue damage upon inflammatory challenge. These results reveal a spatially tiered strategy to tolerate threats restricted within the epithelia, and yet enable progressively potent immune responses as threats invade deeper into the tissue.

Recent emergence of zoonotic monkeypox virus (Mpox) in human has triggered the virologists to develop plausible preventive measures. Hitherto, our understanding on the mechanism of immunopathogenesis of Mpox infection is elusive. However, available experimental evidences suggest induction of inflammation as the main cause of pathogenesis. Toll-like receptors (TLRs) are critical in initiating and modulating the host immune response to pathogens. Inflammatory responses observed in various poxvirus infections have, in fact, been shown to be mediated through TLR activation. Therefore, by in silico approaches, this study seeks to identify the Mpox antigen(s) (MAg) that are most likely to interact with human cell-surface TLRs. The Mpox proteomics data available in UniProt database contain 174 protein sequences, among which 105 immunoreactive proteins were modeled for 3D structure and examined for comparative protein-protein interactions with the TLRs through molecular docking and molecular dynamics simulation. F14, an 8.28 kDa infective protein of Mpox, was found to exhibit strong binding affinity (ΔG=-12.5 Kcal mol-1) to TLR1/2 dimer to form a compact thermodynamically stable protein complex. Interestingly, a significant level of conformational change was also observed in both F14 and TLR6 while forming F14-TLR1/2 complex. Based on these data we propose F14 as a putative ligand of human TLR1/2 to initiate proinflammatory signaling in the Mpox-infected host.

Infection with the Zika virus (ZIKV) poses a threat to human health. An improved understanding of the host Toll-like receptor response, disease onset, and viral clearance in vivo and in vitro may lead to the development of therapeutic or prophylactic interventions against viral infections. Currently, no clinically approved ZIKV vaccine is available, highlighting the need for its development. In this study, we discuss the progress in the Zika vaccine, including advances in the use of Toll-like receptor agonists as vaccine adjuvants to enhance vaccine efficacy.

P2 × 7R is crucial in the pathogenesis of chronic inflammatory diseases, and its activation leads to the release of pro-inflammatory cytokines, exacerbating the inflammatory response. Two new series of scarce cyclic N, O-acetals (ATF 61-74) and corresponding opened N, N-aminals (CS 1-14) have been designed as novel potential P2RX7 antagonists, then synthesized and evaluated for their anti-inflammatory properties through investigating the pro-inflammatory markers and also for their antifungal activity against Candida albicans. Three compounds (ATF 64, CS 8, and CS 9) exhibited dual antifungal and anti-inflammatory properties. ATF 64, CS 8, and CS 9 reduced ROS production and IL-1β expression in macrophages and intestinal cells in a manner correlated with NF-KB expression. These compounds showed excellent antifungal activity against clinical isolates of C. albicans resistant to fluconazole and caspofungin, and reduced C. albicans biofilm formation. Treatment with CS 8 or CS 9 protected the nematode Caenorhabditis elegans against infection with C. albicans and enhanced antimicrobial gene expression. This duality of action offers a promising new pharmacological strategy to counteract inflammatory diseases and propels N, N-aminals as promising candidates for future optimization and investigation.