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Inflammatory diseases compromise a clinically common and diverse group of conditions, causing detrimental effects on body functions. Gasdermins (GSDM) are pore-forming proteins, playing pivotal roles in modulating inflammation. Belonging to the GSDM family, gasdermin D (GSDMD) actively mediates the pathogenesis of inflammatory diseases by mechanistically regulating different forms of cell death, particularly pyroptosis, and cytokine release, in an inflammasome-dependent manner. Aberrant activation of GSDMD in different types of cells, such as immune cells, cardiovascular cells, pancreatic cells and hepatocytes, critically contributes to the persistent inflammation in different tissues and organs. The contributory role of GSDMD has been implicated in diabetes mellitus, liver diseases, cardiovascular diseases, neurodegenerative diseases, and inflammatory bowel disease (IBD). Clinically, alterations in GSDMD levels are potentially indicative to the occurrence and severity of diseases. GSDMD inhibition might represent an attractive therapeutic direction to counteract the progression of inflammatory diseases, whereas a number of GSDMD inhibitors have been shown to restrain GSDMD-mediated pyroptosis through different mechanisms. This review discusses the current understanding and future perspectives on the role of GSDMD in the development of inflammatory diseases, as well as the clinical insights of GSDMD alterations, and therapeutic potential of GSDMD inhibitors against inflammatory diseases. Further investigation on the comprehensive role of GSDM shall deepen our understanding towards inflammation, opening up more diagnostic and therapeutic opportunities against inflammatory diseases. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a versatile environmental sensor and transcription factor found throughout the body, responding to a wide range of small molecules originating from the environment, our diets, host microbiomes, and internal metabolic processes. Increasing evidence highlights AhR's role as a critical regulator of numerous biological functions, such as cellular differentiation, immune response, metabolism, and even tumor formation. Typically located in the cytoplasm, AhR moves to the nucleus upon activation by an agonist where it partners with either the aryl hydrocarbon receptor nuclear translocator (ARNT) or hypoxia-inducible factor 1β (HIF-1β). This complex then interacts with xenobiotic response elements (XREs) to control the expression of key genes. AhR is notably present in various crucial immune cells, and recent research underscores its significant impact on both innate and adaptive immunity. This review delves into the latest insights on AhR's structure, activating ligands, and its multifaceted roles. We explore the sophisticated molecular pathways through which AhR influences immune and lymphoid cells, emphasizing its emerging importance in managing inflammatory diseases. Furthermore, we discuss the exciting potential of developing targeted therapies that modulate AhR activity, opening new avenues for medical intervention in immune-related conditions. [ABSTRACT FROM AUTHOR]

Inflammation has been shown to trigger a wide range of chronic diseases, particularly inflammatory diseases. As a result, the focus of research has been on anti-inflammatory drugs and foods. In recent years, the field of medicinal and edible homology (MEH) has developed rapidly in both medical and food sciences, with 95% of MEH being associated with plants. Phenolic acids are a crucial group of natural bioactive substances found in medicinal and edible homologous plants (MEHPs). Their anti-inflammatory activity is significant as they play a vital role in treating several inflammatory diseases. These compounds possess enormous potential for developing anti-inflammatory drugs and functional foods. However, their development is far from satisfactory due to their diverse structure and intricate anti-inflammatory mechanisms. In this review, we summarize the various types, structures, and distribution of MEHP phenolic acids that have been identified as of 2023. We also analyze their anti-inflammatory activity and molecular mechanisms in inflammatory diseases through NF-kB, MAPK, NLRP3, Nrf2, TLRs, and IL-17 pathways. Additionally, we investigate their impact on regulating the composition of the gut microbiota and immune responses. This analysis lays the groundwork for further exploration of the anti-inflammatory structure-activity relationship of MEHP phenolic acids, aiming to inspire structural optimization and deepen our understanding of their mechanism, and provides valuable insights for future research and development in this field. [ABSTRACT FROM AUTHOR]

Background: Uncaria tomentosa (Willd. ex Schult.) DC. (Rubiaceae) is traditionally used by Amazonian indigenous groups to treat inflammatory diseases. To date, there are no systematic reviews and meta-analyses on the use of U. tomentosa for inflammation control in animals supporting the traditional knowledge about this species. This study was conducted to evaluate the effect of U. tomentosa extracts in modulating inflammatory mediators and to determine which types of inflammatory diseases can be treated by this species. Methods: We conducted a systematic review and meta-analysis of preclinical studies published before 26 July 2023, identified in PubMed, Embase, and Scopus. Four independent reviewers extracted the data and assessed the risks of bias. The effects of U. tomentosa on inflammatory diseases and the inflammatory mediators involved were extracted from the studies. Standardized mean differences (SMD) and 95% confidence intervals (95%CI) of the outcomes were estimated. The meta-analyses were conducted using RevMan 5.4 (Cochrane Collaboration). This protocol was registered in PROSPERO (CRD42023450869). Results: Twenty-four of 523 studies were included. U. tomentosa extracts decreased the cytokines interleukin (IL)-6 (SMD: -0.72, 95%CI: -1.15, -0.29, p = 0.001) and transcription factor nuclear factor kappa-B (NF-κB) (SMD: -1.19, 95%CI: -1.89, -0.48, p = 0.001). However, the extracts did not significantly alter IL-1 (SMD: -0.16, 95%CI: -0.87, +0.56, p = 0.67), IL-10 (SMD: -0.05, 95%CI:-0.35, 0.45, p = 0.80), or tumor necrosis factor-alpha (TNF-α) levels (SMD: 0.18, 95%CI: -0.25, 0.62, p = 0.41). Conclusion: Many extracts of stem bark, roots, and leaves of U. tomentosa, mostly aqueous and hydroethanolic, exhibited anti-inflammatory and/or immunomodulatory activities and low toxicity. The extracts decreased NF-κB and IL-6. These findings suggest that this species has the potential to treat inflammatory diseases in which these markers are increased, according to the ethnopharmacological use. These activities are not related to a specific class of compounds. [ABSTRACT FROM AUTHOR]

BackgroundObservational studies have shown an increased risk of ocular inflammatory diseases in patients with ankylosing spondylitis (AS), but the genetically predicted association remains unclear. The aim of this study was to systematically assess the causal relationship between AS and ocular inflammatory diseases.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between AS and several common ocular inflammatory diseases based on genome-wide association study (GWAS) data and public health data. Five methods, namely, inverse-variance weighted (IVW), MR–Egger, weighted median, weighted mode, and simple mode, were used. Sensitivity analysis was performed using MR–Egger intercept, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Cochran’s Q test, outlier methods, leave-one-out analysis, and funnel plots.ResultsThe MR analysis showed a significantly increased risk of uveitis (ORIVW = 2.825, 95%CIIVW = 1.709–4.672, and PIVW < 0.001), iridocyclitis (ORIVW = 3.806, 95%CIIVW = 2.809–5.157, and PIVW < 0.001), scleritis (ORIVW = 1.738, 95%CIIVW = 1.190–2.539, and PIVW < 0.001), and episcleritis (ORIVW = 5.113, 95%CIIVW = 2.067–12.645, and PIVW = 0.004) associated with AS. However, no correlation was found between genetically predicted AS and keratitis (ORIVW = 1.041, 95%CIIVW = 0.886–1.222, and PIVW = 0.628) and optic neuritis (ORIVW = 0.868, 95%CIIVW = 0.441–1.709, and PIVW = 0.682).ConclusionAS increases the genetically predicted risk for uveitis, iridocyclitis, scleritis, and episcleritis. No potential association of AS with keratitis and optic neuritis was found. It may provide clues for the prevention of AS complications.

Selinexor, a selective inhibitor of nuclear export (SINE), is gaining recognition beyond oncology for its potential in anti-inflammatory therapy. This review elucidates Selinexor's dual action, highlighting its anti-tumor efficacy in various cancers including hematologic malignancies and solid tumors, and its promising anti-inflammatory effects. In cancer treatment, Selinexor has demonstrated benefits as monotherapy and in combination with other therapeutics, particularly in drug-resistant cases. Its role in enhancing the effectiveness of bone marrow transplants has also been noted. Importantly, the drug's impact on key inflammatory pathways provides a new avenue for the management of conditions like sepsis, viral infections including COVID-19, and chronic inflammatory diseases such as Duchenne Muscular Dystrophy and Parkinson's Disease. The review emphasizes the criticality of managing Selinexor's side effects through diligent dose optimization and patient monitoring. Given the complexities of its broader applications, extensive research is called upon to validate Selinexor's long-term safety and effectiveness, with a keen focus on its integration into clinical practice for a diverse spectrum of disorders. [ABSTRACT FROM AUTHOR]

The notion that viruses played a crucial role in the evolution of life is not a new concept. However, more recent insights suggest that this perception might be even more expansive, highlighting the ongoing impact of viruses on host evolution. Endogenous retroviruses (ERVs) are considered genomic remnants of ancient viral infections acquired throughout vertebrate evolution. Their exogenous counterparts once infected the host's germline cells, eventually leading to the permanent endogenization of their respective proviruses. The success of ERV colonization is evident so that it constitutes 8% of the human genome. Emerging genomic studies indicate that endogenous retroviruses are not merely remnants of past infections but rather play a corollary role, despite not fully understood, in host genetic regulation. This review presents some evidence supporting the crucial role of endogenous retroviruses in regulating host genetics. We explore the involvement of human ERVs (HERVs) in key physiological processes, from their precise and orchestrated activities during cellular differentiation and pluripotency to their contributions to aging and cellular senescence. Additionally, we discuss the costs associated with hosting a substantial amount of preserved viral genetic material. [ABSTRACT FROM AUTHOR]

Inducing the degradation of pathological soluble antigens could be the key to greatly enhancing the efficacy of therapeutic monoclonal antibodies (mAbs), extensively used in the treatment of autoimmune and inflammatory disorders or cancer. Lysosomal targeting has gained increasing interest in recent years due to its pharmaceutical applications far beyond the treatment of lysosomal diseases, as a way to address proteins to the lysosome for eventual degradation. Mannose 6-phosphonate derivatives (M6Pn), called AMFA, are unique glycovectors that can significantly enhance the cellular internalization of the proteins conjugated to AMFA via the cation-independent mannose 6-phosphate receptor (M6PR) pathway. AMFA engineering of mAbs results in the generation of a bifunctional antibody that is designed to bind both the antigen and the M6PR. The improvement of the therapeutic potential by AMFA engineering was investigated using two antibodies directed against soluble antigens: infliximab (IFX), directed against tumor necrosis factor α (TNF-α), and bevacizumab (BVZ), directed against the vascular endothelial growth factor (VEGF). AMFA conjugations to the antibodies were performed either on the oligosaccharidic chains of the antibodies or on the lysine residues. Both conjugations were controlled and reproducible and provided a novel affinity for the M6PR without altering the affinity for the antigen. The grafting of AMFA to mAb increased their cellular uptake through an M6PR-dependent mechanism. The antigens were also 2.6 to 5.7 times more internalized by mAb-AMFA and rapidly degraded in the cells. Additional cell culture studies also proved the significantly higher efficacy of IFX-AMFA and BVZ-AMFA compared to their unconjugated counterparts in inhibiting TNF-α and VEGF activities. Finally, studies in a zebrafish embryo model of angiogenesis and in xenografted chick embryos showed that BVZ-AMFA was more effective than BVZ in reducing angiogenesis. These results demonstrate that AMFA grafting induces the degradation of soluble antigens and a significant increase in the therapeutic efficacy. Engineering with mannose 6-phosphate analogues has the potential to develop a new class of antibodies for autoimmune and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Ubiquitin-specific proteases (USPs), as one of the deubiquitinating enzymes (DUBs) families, regulate the fate of proteins and signaling pathway transduction by removing ubiquitin chains from the target proteins. USPs are essential for the modulation of a variety of physiological processes, such as DNA repair, cell metabolism and differentiation, epigenetic modulations as well as protein stability. Recently, extensive research has demonstrated that USPs exert a significant impact on innate and adaptive immune reactions, metabolic syndromes, inflammatory disorders, and infection via post-translational modification processes. This review summarizes the important roles of the USPs in the onset and progression of inflammatory diseases, including periodontitis, pneumonia, atherosclerosis, inflammatory bowel disease, sepsis, hepatitis, diabetes, and obesity. Moreover, we highlight a comprehensive overview of the pathogenesis of USPs in these inflammatory diseases as well as post-translational modifications in the inflammatory responses and pave the way for future prospect of targeted therapies in these inflammatory diseases. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AhR) is a versatile environmental sensor and transcription factor found throughout the body, responding to a wide range of small molecules originating from the environment, our diets, host microbiomes, and internal metabolic processes. Increasing evidence highlights AhR’s role as a critical regulator of numerous biological functions, such as cellular differentiation, immune response, metabolism, and even tumor formation. Typically located in the cytoplasm, AhR moves to the nucleus upon activation by an agonist where it partners with either the aryl hydrocarbon receptor nuclear translocator (ARNT) or hypoxia-inducible factor 1β (HIF-1β). This complex then interacts with xenobiotic response elements (XREs) to control the expression of key genes. AhR is notably present in various crucial immune cells, and recent research underscores its significant impact on both innate and adaptive immunity. This review delves into the latest insights on AhR’s structure, activating ligands, and its multifaceted roles. We explore the sophisticated molecular pathways through which AhR influences immune and lymphoid cells, emphasizing its emerging importance in managing inflammatory diseases. Furthermore, we discuss the exciting potential of developing targeted therapies that modulate AhR activity, opening new avenues for medical intervention in immune-related conditions.

Macrophages polarized into distinct phenotypes play vital roles in inflammatory diseases by clearing pathogens, promoting tissue repair, and maintaining homeostasis. Metabolism serves as a fundamental driver in regulating macrophage polarization, and understanding the interplay between macrophage metabolism and polarization is crucial for unraveling the mechanisms underlying inflammatory diseases. The intricate network of cellular signaling pathway plays a pivotal role in modulating macrophage metabolism, and growing evidence indicates that the Hippo pathway emerges as a central player in network of cellular metabolism signaling. This review aims to explore the impact of macrophage metabolism on polarization and summarize the cell signaling pathways that regulate macrophage metabolism in diseases. Specifically, we highlight the pivotal role of the Hippo pathway as a key regulator of cellular metabolism and reveal its potential relationship with metabolism in macrophage polarization. [ABSTRACT FROM AUTHOR]

BackgroundUncaria tomentosa (Willd. ex Schult.) DC. (Rubiaceae) is traditionally used by Amazonian indigenous groups to treat inflammatory diseases. To date, there are no systematic reviews and meta-analyses on the use of U. tomentosa for inflammation control in animals supporting the traditional knowledge about this species. This study was conducted to evaluate the effect of U. tomentosa extracts in modulating inflammatory mediators and to determine which types of inflammatory diseases can be treated by this species.MethodsWe conducted a systematic review and meta-analysis of preclinical studies published before 26 July 2023, identified in PubMed, Embase, and Scopus. Four independent reviewers extracted the data and assessed the risks of bias. The effects of U. tomentosa on inflammatory diseases and the inflammatory mediators involved were extracted from the studies. Standardized mean differences (SMD) and 95% confidence intervals (95%CI) of the outcomes were estimated. The meta-analyses were conducted using RevMan 5.4 (Cochrane Collaboration). This protocol was registered in PROSPERO (CRD42023450869).ResultsTwenty-four of 523 studies were included. U. tomentosa extracts decreased the cytokines interleukin (IL)-6 (SMD: −0.72, 95%CI: −1.15, −0.29, p = 0.001) and transcription factor nuclear factor kappa-B (NF-κB) (SMD: −1.19, 95%CI: −1.89, −0.48, p = 0.001). However, the extracts did not significantly alter IL-1 (SMD: −0.16, 95%CI: −0.87, +0.56, p = 0.67), IL-10 (SMD: −0.05, 95%CI:–0.35, 0.45, p = 0.80), or tumor necrosis factor-alpha (TNF-α) levels (SMD: 0.18, 95%CI: −0.25, 0.62, p = 0.41).ConclusionMany extracts of stem bark, roots, and leaves of U. tomentosa, mostly aqueous and hydroethanolic, exhibited anti-inflammatory and/or immunomodulatory activities and low toxicity. The extracts decreased NF-κB and IL-6. These findings suggest that this species has the potential to treat inflammatory diseases in which these markers are increased, according to the ethnopharmacological use. These activities are not related to a specific class of compounds.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=450869, Identifier CRD42023450869.

Selinexor, a selective inhibitor of nuclear export (SINE), is gaining recognition beyond oncology for its potential in anti-inflammatory therapy. This review elucidates Selinexor’s dual action, highlighting its anti-tumor efficacy in various cancers including hematologic malignancies and solid tumors, and its promising anti-inflammatory effects. In cancer treatment, Selinexor has demonstrated benefits as monotherapy and in combination with other therapeutics, particularly in drug-resistant cases. Its role in enhancing the effectiveness of bone marrow transplants has also been noted. Importantly, the drug’s impact on key inflammatory pathways provides a new avenue for the management of conditions like sepsis, viral infections including COVID-19, and chronic inflammatory diseases such as Duchenne Muscular Dystrophy and Parkinson’s Disease. The review emphasizes the criticality of managing Selinexor’s side effects through diligent dose optimization and patient monitoring. Given the complexities of its broader applications, extensive research is called upon to validate Selinexor’s long-term safety and effectiveness, with a keen focus on its integration into clinical practice for a diverse spectrum of disorders.

The notion that viruses played a crucial role in the evolution of life is not a new concept. However, more recent insights suggest that this perception might be even more expansive, highlighting the ongoing impact of viruses on host evolution. Endogenous retroviruses (ERVs) are considered genomic remnants of ancient viral infections acquired throughout vertebrate evolution. Their exogenous counterparts once infected the host’s germline cells, eventually leading to the permanent endogenization of their respective proviruses. The success of ERV colonization is evident so that it constitutes 8% of the human genome. Emerging genomic studies indicate that endogenous retroviruses are not merely remnants of past infections but rather play a corollary role, despite not fully understood, in host genetic regulation. This review presents some evidence supporting the crucial role of endogenous retroviruses in regulating host genetics. We explore the involvement of human ERVs (HERVs) in key physiological processes, from their precise and orchestrated activities during cellular differentiation and pluripotency to their contributions to aging and cellular senescence. Additionally, we discuss the costs associated with hosting a substantial amount of preserved viral genetic material.

GPR35 is a G protein-coupled receptor with notable involvement in modulating inflammatory responses. Although the precise role of GPR35 in inflammation is not yet fully understood, studies have suggested that it may have both pro- and anti-inflammatory effects depending on the specific cellular environment. Some studies have shown that GPR35 activation can stimulate the production of proinflammatory cytokines and facilitate the movement of immune cells towards inflammatory tissues or infected areas. Conversely, other investigations have suggested that GPR35 may possess anti-inflammatory properties in the gastrointestinal tract, liver and certain other tissues by curbing the generation of inflammatory mediators and endorsing the differentiation of regulatory T cells. The intricate role of GPR35 in inflammation underscores the requirement for more in-depth research to thoroughly comprehend its functional mechanisms and its potential significance as a therapeutic target for inflammatory diseases. The purpose of this review is to concurrently investigate the pro-inflammatory and anti-inflammatory roles of GPR35, thus illuminating both facets of this complex issue. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Treg) are known to be critical for the maintenance of immune homeostasis by suppressing the activation of auto-or allo-reactive effector T cells through a diverse repertoire of molecular mechanisms. Accordingly, therapeutic strategies aimed at enhancing Treg numbers or potency in the setting of autoimmunity and allogeneic transplants have been energetically pursued and are beginning to yield some encouraging outcomes in early phase clinical trials. Less well recognized from a translational perspective, however, has been the mounting body of evidence that Treg directly modulate most aspects of innate immune response under a range of different acute and chronic disease conditions. Recognizing this aspect of Treg immune modulatory function provides a bridge for the application of Treg-based therapies to common medical conditions in which organ and tissue damage is mediated primarily by inflammation involving myeloid cells (mononuclear phagocytes, granulocytes) and innate lymphocytes (NK cells, NKT cells, gd T cells and ILCs). In this review, we comprehensively summarize pre-clinical and human research that has revealed diverse modulatory effects of Treg and specific Treg subpopulations on the range of innate immune cell types. In each case, we emphasize the key mechanistic insights and the evidence that Treg interactions with innate immune effectors can have significant impacts on disease severity or treatment. Finally, we discuss the opportunities and challenges that exist for the application of Treg-based therapeutic interventions to three globally impactful, inflammatory conditions: type 2 diabetes and its end-organ complications, ischemia reperfusion injury and atherosclerosis. [ABSTRACT FROM AUTHOR]

The microbiota gut brain (MGB) axis has been shown to play a significant role in the regulation of inflammatory and infective diseases. Exploring the structure and communication mode of MGB axis is crucial for understanding its role in diseases, and studying the signaling pathways and regulatory methods of MGB axis regulation in diseases is also of profound significance for future clinical research. This article reviews the composition, communication mechanism of MGB axis and its role in inflammatory and infective diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), autism spectrum disorder (ASD), depression, psoriasis, irritable bowel syndrome (IBS), and inflammatory bowel diseases (IBD). In addition, our investigation delved into the regulatory functions of the inflammasome, IFN-I, NF-κB, and PARK7/DJ-1 innate immune signaling pathway in the context of inflammatory and infective diseases. Ultimately, we discussed the efficacy of various interventions, including fecal microbiota transplantation (FMT), antibiotics, probiotics, prebiotics, synbiotics, and postbiotics, in the management of inflammatory and infective diseases. Understanding the role and mechanism of the MGB axis might make positive effects in the treatment of inflammatory and infective diseases. [ABSTRACT FROM AUTHOR]

Oncostatin M(OSM) is a pleiotropic cytokine involved in a variety of inflammatory responses such as wound healing, liver regeneration, and bone remodeling. As a member of the interleukin-6 (IL-6) family of cytokines, OSM binds the shared receptor gp130, recruits either OSMRb or LIFRb, and activates a variety of signaling pathways including the JAK/STAT, MAPK, JNK, and PI3K/AKT pathways. Since its discovery in 1986, OSM has been identified as a significant contributor to a multitude of inflammatory diseases, including arthritis, inflammatory bowel disease, lung and skin disease, cardiovascular disease, and most recently, COVID-19. Additionally, OSM has also been extensively studied in the context of several cancer types including breast, cervical, ovarian, testicular, colon and gastrointestinal, brain, lung, skin, as well as other cancers. While OSM has been recognized as a significant contributor for each of these diseases, and studies have shown OSM inhibition is effective at treating or reducing symptoms, very few therapeutics have succeeded into clinical trials, and none have yet been approved by the FDA for treatment. In this review, we outline the role OSM plays in a variety of inflammatory diseases, including cancer, and outline the previous and current strategies for developing an inhibitor for OSM signaling. [ABSTRACT FROM AUTHOR]

Nuclear receptors are ligand-regulated transcription factors that regulate vast cellular activities and serve as an important class of drug targets. Among them, peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family and have been extensively studied for their roles in metabolism, differentiation, development, and cancer, among others. Recently, there has been considerable interest in understanding and defining the function of PPARs and their agonists in regulating innate and adaptive immune responses and their pharmacological potential in combating chronic inflammatory diseases. In this review, we focus on emerging evidence for the potential role of PPARγ in macrophage biology, which is the prior innate immune executive in metabolic and tissue homeostasis. We also discuss the role of PPARγ as a regulator of macrophage function in inflammatory diseases. Lastly, we discuss the possible application of PPARγ antagonists in metabolic pathologies. [ABSTRACT FROM AUTHOR]

Despite improvements in modern medical therapies, inflammatory diseases, such as atherosclerosis, diabetes, non-alcoholic fatty liver, chronic kidney diseases, and autoimmune diseases have high incidence rates, still threaten human health, and represent a huge financial burden. N6-methyladenosine (m6A) modification of RNA contributes to the pathogenesis of various diseases. As the most widely discussed m6A methyltransferase, the pathogenic role of METTL3 in inflammatory diseases has become a research hotspot, but there has been no comprehensive review of the topic. Here, we summarize the expression changes, modified target genes, and pathogenesis related to METTL3 in cardiovascular, metabolic, degenerative, immune, and infectious diseases, as well as tumors. In addition to epithelial cells, endothelial cells, and fibroblasts, METTL3 also regulates the function of inflammation-related immune cells, including macrophages, neutrophils, dendritic cells, Th17 cells, and NK cells. Regarding therapeutic applications, METTL3 serves as a target for the treatment of inflammatory diseases with natural plant drug components, such as emodin, cinnamaldehyde, total flavonoids of Abelmoschus manihot, and resveratrol. This review focuses on recent advances in the initiation, development, and therapeutic application of METTL3 in inflammatory diseases. Knowledge of the specific regulatory mechanisms involving METTL3 can help to deepen understanding of inflammatory diseases and lay the foundation for the development of precisely targeted drugs to address inflammatory processes. [ABSTRACT FROM AUTHOR]

Oncostatin M (OSM) is a pleiotropic cytokine involved in a variety of inflammatory responses such as wound healing, liver regeneration, and bone remodeling. As a member of the interleukin-6 (IL-6) family of cytokines, OSM binds the shared receptor gp130, recruits either OSMRβ or LIFRβ, and activates a variety of signaling pathways including the JAK/STAT, MAPK, JNK, and PI3K/AKT pathways. Since its discovery in 1986, OSM has been identified as a significant contributor to a multitude of inflammatory diseases, including arthritis, inflammatory bowel disease, lung and skin disease, cardiovascular disease, and most recently, COVID-19. Additionally, OSM has also been extensively studied in the context of several cancer types including breast, cervical, ovarian, testicular, colon and gastrointestinal, brain,lung, skin, as well as other cancers. While OSM has been recognized as a significant contributor for each of these diseases, and studies have shown OSM inhibition is effective at treating or reducing symptoms, very few therapeutics have succeeded into clinical trials, and none have yet been approved by the FDA for treatment. In this review, we outline the role OSM plays in a variety of inflammatory diseases, including cancer, and outline the previous and current strategies for developing an inhibitor for OSM signaling.

Inflammation is an immune response that the host organism eliminates threats from foreign objects or endogenous signals. It plays a key role in the progression, prognosis as well as therapy of diseases. Chronic inflammatory diseases have been regarded as the main cause of death worldwide at present, which greatly affect a vast number of individuals, producing economic and social burdens. Thus, developing drugs targeting inflammation has become necessary and attractive in the world. Currently, accumulating evidence suggests that small leucine-rich proteoglycans (SLRPs) exhibit essential roles in various inflammatory responses by acting as an anti-inflammatory or pro-inflammatory role in different scenarios of diseases. Of particular interest was a well-studied member, termed fibromodulin (FMOD), which has been largely explored in the role of inflammatory responses in inflammatory-related diseases. In this review, particular focus is given to the role of FMOD in inflammatory response including the relationship of FMOD with the complement system and immune cells, as well as the role of FMOD in the diseases associated with inflammation, such as skin wounding healing, osteoarthritis (OA), tendinopathy, atherosclerosis, and heart failure (HF). By conducting this review, we intend to gain insight into the role of FMOD in inflammation, which may open the way for the development of new anti-inflammation drugs in the scenarios of different inflammatoryrelated diseases. [ABSTRACT FROM AUTHOR]

Outer membrane vesicles (OMVs) are spherical, bilayered, and nanosized membrane vesicles that are secreted from gram-negative bacteria. OMVs play a pivotal role in delivering lipopolysaccharide, proteins and other virulence factors to target cells. Multiple studies have found that OMVs participate in various inflammatory diseases, including periodontal disease, gastrointestinal inflammation, pulmonary inflammation and sepsis, by triggering pattern recognition receptors, activating inflammasomes and inducing mitochondrial dysfunction. OMVs also affect inflammation in distant organs or tissues via long-distance cargo transport in various diseases, including atherosclerosis and Alzheimer's disease. In this review, we primarily summarize the role of OMVs in inflammatory diseases, describe the mechanism through which OMVs participate in inflammatory signal cascades, and discuss the effects of OMVs on pathogenic processes in distant organs or tissues with the aim of providing novel insights into the role and mechanism of OMVs in inflammatory diseases and the prevention and treatment of OMV-mediated inflammatory diseases. [ABSTRACT FROM AUTHOR]

C1q is a crucial component of the complement system, which is activated through the classical pathway to perform non-specific immune functions, serving as the first line of defense against pathogens. C1q can also bind to specific receptors to carry out immune and other functions, playing a vital role in maintaining immune homeostasis and normal physiological functions. In the developing central nervous system (CNS), C1q functions in synapse formation and pruning, serving as a key player in the development and homeostasis of neuronal networks in the CNS. C1q has a close relationship with microglia and astrocytes, and under their influence, C1q may contribute to the development of CNS disorders. Furthermore, C1q can also have independent effects on neurological disorders, producing either beneficial or detrimental outcomes. Most of the evidence for these functions comes from animal models, with some also from human specimen studies. C1q is now emerging as a promising target for the treatment of a variety of diseases, and clinical trials are already underway for CNS disorders. This article highlights the role of C1q in CNS diseases, offering new directions for the diagnosis and treatment of these conditions. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are pluripotent stem cells of mesodermal origin with the ability of self-renewal and multidirectional differentiation, which have all the common characteristics of stem cells and the ability to differentiate into adipocytes, osteoblasts, neuron-like cells and other cells. Stem cell derivatives are extracellular vesicles(EVs) released from mesenchymal stem cells that are involved in the process of body's immune response, antigen presentation, cell differentiation, and anti-inflammatory. EVs are further divided into ectosomes and exosomes are widely used in degenerative diseases, cancer, and inflammatory diseases due to their parental cell characteristics. However, most diseases are closely related to inflammation, and exosomes can mitigate the damage caused by inflammation in terms of suppressing the inflammatory response, anti-apoptosis and promoting tissue repair. Stem cell-derived exosomes have become an emerging modality for cell-free therapy because of their high safety and ease of preservation and transportation through intercellular communication. In this review, we highlight the characteristics and functions of MSCs-derived exosomes and discuss the regulatory mechanisms of MSCs-derived exosomes in inflammatory diseases and their potential applications in clinical diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Receptor-interacting serine/threonine kinase 2 (RIPK2) is a vital immunomodulator that plays critical roles in nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs) signaling. Stimulated NOD1 and NOD2 interact with RIPK2 and lead to the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK), followed by the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12/23. Defects in NOD/RIPK2 signaling are associated with numerous inflammatory diseases, including asthma, sarcoidosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), multiple sclerosis, and Blau syndrome. As RIPK2 is a crucial element of innate immunity, small molecules regulating RIPK2 functions are attractive to establish novel immunotherapies. The increased interest in developing RIPK2 inhibitors has led to the clinical investigations of novel drug candidates. In this review, we attempt to summarize recent advances in the development of RIPK2 inhibitors and degraders. [ABSTRACT FROM AUTHOR]

Macrophages are the most important innate immune cells in humans. They are almost ubiquitous in peripheral tissues with a large variety of different mechanical milieus. Therefore, it is not inconceivable that mechanical stimuli have effects on macrophages. Emerging as key molecular detectors of mechanical stress, the function of Piezo channels in macrophages is becoming attractive. In this review, we addressed the architecture, activation mechanisms, biological functions, and pharmacological regulation of the Piezo1 channel and review the research advancements in functions of Piezo1 channels in macrophages and macrophage-mediated inflammatory diseases as well as the potential mechanisms involved.

Platelets, key facilitators of primary hemostasis and thrombosis, have emerged as crucial cellular mediators of innate immunity and inflammation. Exemplified by their ability to alter the phenotype and function of monocytes, activated platelets bind to circulating monocytes to form monocyte-platelet aggregates (MPA). The platelet-monocyte axis has emerged as a key mechanism connecting thrombosis and inflammation. MPA are elevated across the spectrum of inflammatory and autoimmune disorders, including cardiovascular disease, systemic lupus erythematosus (SLE), and COVID-19, and are positively associated with disease severity. These clinical disorders are all characterized by an increased risk of thromboembolic complications. Intriguingly, monocytes in contact with platelets become proinflammatory and procoagulant, highlighting that this interaction is a central element of thromboinflammation.

Receptor-interacting serine/threonine kinase 2 (RIPK2) is a vital immunomodulator that plays critical roles in nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs) signaling. Stimulated NOD1 and NOD2 interact with RIPK2 and lead to the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK), followed by the production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12/23. Defects in NOD/RIPK2 signaling are associated with numerous inflammatory diseases, including asthma, sarcoidosis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis), multiple sclerosis, and Blau syndrome. As RIPK2 is a crucial element of innate immunity, small molecules regulating RIPK2 functions are attractive to establish novel immunotherapies. The increased interest in developing RIPK2 inhibitors has led to the clinical investigations of novel drug candidates. In this review, we attempt to summarize recent advances in the development of RIPK2 inhibitors and degraders.

The FUT2 α1,2fucosyltransferase contributes to the synthesis of fucosylated glycans used as attachment factors by several pathogens, including noroviruses and rotaviruses, that can induce life-threatening gastroenteritis in young children. FUT2 genetic polymorphisms impairing fucosylation are strongly associated with resistance to dominant strains of both noroviruses and rotaviruses. Interestingly, the wild-type allele associated with viral gastroenteritis susceptibility inversely appears to be protective against several inflammatory or autoimmune diseases for yet unclear reasons, although a FUT2 influence on microbiota composition has been observed. Here, we studied a cohort of young healthy adults and showed that the wild-type FUT2 allele was associated with the presence of anti-RVA antibodies, either neutralizing antibodies or serum IgA, confirming its association with the risk of RVA gastroenteritis. Strikingly, it was also associated with the frequency of gut microbiota-induced regulatory T cells (Tregs), so-called DP8a Tregs, albeit only in individuals who had anti-RVA neutralizing antibodies or high titers of anti-RVA IgAs. DP8α Tregs specifically recognize the human symbiont Faecalibacterium prausnitzii, which strongly supports their induction by this anti-inflammatory bacterium. The proportion of F. prausnitzii in feces was also associated with the FUT2 wild-type allele. These observations link the FUT2 genotype with the risk of RVA gastroenteritis, the microbiota and microbiotainduced DP8α Treg cells, suggesting that the anti-RVA immune response might involve an induction/expansion of these T lymphocytes later providing a balanced immunological state that confers protection against inflammatory diseases. [ABSTRACT FROM AUTHOR]

Recently, increasing numbers of studies have demonstrated that transient receptor potential ankyrin 1 (TRPA1) can be used as a potential target for the treatment of inflammatory diseases. TRPA1 is expressed in both neuronal and nonneuronal cells and is involved in diverse physiological activities, such as stabilizing of cell membrane potential, maintaining cellular humoral balance, and regulating intercellular signal transduction. TRPA1 is a multi-modal cell membrane receptor that can sense different stimuli, and generate action potential signals after activation via osmotic pressure, temperature, and inflammatory factors. In this study, we introduced the latest research progress on TRPA1 in inflammatory diseases from three different aspects. First, the inflammatory factors released after inflammation interacts with TRPA1 to promote inflammatory response; second, TRPA1 regulates the function of immune cells such as macrophages and T cells, In addition, it has anti-inflammatory and antioxidant effects in some inflammatory diseases. Third, we have summarized the application of antagonists and agonists targeting TRPA1 in the treatment of some inflammatory diseases. [ABSTRACT FROM AUTHOR]

Various intractable inflammatory diseases caused by disorders of immune systems have pressed heavily on public health. Innate and adaptive immune cells as well as secreted cytokines and chemokines are commanders to mediate our immune systems. Therefore, restoring normal immunomodulatory responses of immune cells is crucial for the treatment of inflammatory diseases. Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are nano-sized double-membraned vesicles acting as paracrine effectors of MSCs. MSC-EVs, containing a variety of therapeutic agents, have shown great potential in immune modulation. Herein, we discuss the novel regulatory functions of MSC-EVs from different sources in the activities of innate and adaptive immune cells like macrophages, granulocytes, mast cells, natural killer (NK) cells, dendritic cells (DCs) and lymphocytes. Then, we summarize the latest clinical trials of MSC-EVs in inflammatory diseases. Furthermore, we prospect the research trend of MSC-EVs in the field of immune modulation. Despite the fact that the research on the role of MSC-EVs in regulating immune cells is in infancy, this cell-free therapy based on MSC-EVs still offers a promising solution for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Inhibitory oligodeoxynucleotides (ODNs) are short single-stranded DNA, which capable of folding into complex structures, enabling them to bind to a large variety of targets. With appropriate modifications, the inhibitory oligodeoxynucleotides exhibited many features of long half-life time, simple production, low toxicity and immunogenicity. In recent years, inhibitory oligodeoxynucleotides have received considerable attention for their potential therapeutic applications in immune-mediated inflammatory diseases (IMIDs). Inhibitory oligodeoxynucleotides could be divided into three categories according to its mechanisms and targets, including antisense ODNs (AS-ODNs), DNA aptamers and immunosuppressive ODNs (iSup ODNs). As a synthetic tool with immunomodulatory activity, it can target RNAs or proteins in a specific way, resulting in the reduction, increase or recovery of protein expression, and then regulate the state of immune activation. More importantly, inhibitory oligodeoxynucleotides have been used to treat immune-mediated inflammatory diseases, including inflammatory disorders and autoimmune diseases. Several inhibitory oligodeoxynucleotide drugs have been developed and approved on the market already. These drugs vary in their chemical structures, action mechanisms and cellular targets, but all of them could be capable of inhibiting excessive inflammatory responses. This review summarized their chemical modifications, action mechanisms and applications of the three kinds of inhibitory oligodeoxynucleotidesin the precise treatment of immune-mediated inflammatory diseases. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disease caused by deposition of oxidative low-density lipoprotein (LDL) in the arterial intima which triggers the innate immune response through myeloid cells such as macrophages. Regulatory T cells (Tregs) play an important role in controlling the progression or regression of atherosclerosis by resolving macrophage-mediated inflammatory functions. Interleukin-2 (IL-2) signaling is essential for homeostasis of Tregs. Since recombinant IL-2 has an unfavorable pharmacokinetic profile limiting its therapeutic use, we constructed a fusion protein, designated HCW9302, containing two IL-2 domains linked by an extracellular tissue factor domain. We found that HCW9302 exhibited a longer serum half-life with an approximately 1000-fold higher affinity for the IL-2Rα than IL-2. HCW9302 could be administered to mice at a dosing range that expanded and activated Tregs but not CD4+ effector T cells. In an ApoE-/- mouse model, HCW9302 treatment curtailed the progression of atherosclerosis through Treg activation and expansion, M2 macrophage polarization and myeloid-derived suppressor cell induction. HCW9302 treatment also lessened inflammatory responses in the aorta. Thus, HCW9302 is a potential therapeutic agent to expand and activate Tregs for treatment of inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]

NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is a cytosolic pattern recognition receptor (PRR) that recognizes multiple pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once activated, NLRP3 initiates the inflammasome assembly together with the adaptor ASC and the effector caspase-1, leading to caspase-1 activation and subsequent cleavage of IL-1b and IL-18. Aberrant NLRP3 inflammasome activation is linked with the pathogenesis of multiple inflammatory diseases, such as cryopyrinassociated periodic syndromes, type 2 diabetes, non-alcoholic steatohepatitis, gout, and neurodegenerative diseases. Thus, NLRP3 is an important therapeutic target, and researchers are putting a lot of effort into developing its inhibitors. The review summarizes the latest advances in the mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) is a 30-amino acid hormone secreted by L cells in the distal ileum, colon, and pancreatic a cells, which participates in blood sugar regulation by promoting insulin release, reducing glucagon levels, delaying gastric emptying, increasing satiety, and reducing appetite. GLP-1 specifically binds to the glucagon-like peptide-1 receptor (GLP-1R) in the body, directly stimulating the secretion of insulin by pancreatic b-cells, promoting proliferation and differentiation, and inhibiting cell apoptosis, thereby exerting a glycemic lowering effect. The glycemic regulating effect of GLP-1 and its analogues has been well studied in human and murine models in the circumstance of many diseases. Recent studies found that GLP-1 is able to modulate innate immune response in a number of inflammatory diseases. In the present review, we summarize the research progression of GLP-1 and its analogues in immunomodulation and related signal pathways. [ABSTRACT FROM AUTHOR]

The FUT2 α1,2fucosyltransferase contributes to the synthesis of fucosylated glycans used as attachment factors by several pathogens, including noroviruses and rotaviruses, that can induce life-threatening gastroenteritis in young children. FUT2 genetic polymorphisms impairing fucosylation are strongly associated with resistance to dominant strains of both noroviruses and rotaviruses. Interestingly, the wild-type allele associated with viral gastroenteritis susceptibility inversely appears to be protective against several inflammatory or autoimmune diseases for yet unclear reasons, although a FUT2 influence on microbiota composition has been observed. Here, we studied a cohort of young healthy adults and showed that the wild-type FUT2 allele was associated with the presence of anti-RVA antibodies, either neutralizing antibodies or serum IgA, confirming its association with the risk of RVA gastroenteritis. Strikingly, it was also associated with the frequency of gut microbiota-induced regulatory T cells (Tregs), so-called DP8α Tregs, albeit only in individuals who had anti-RVA neutralizing antibodies or high titers of anti-RVA IgAs. DP8α Tregs specifically recognize the human symbiont Faecalibacterium prausnitzii, which strongly supports their induction by this anti-inflammatory bacterium. The proportion of F. prausnitzii in feces was also associated with the FUT2 wild-type allele. These observations link the FUT2 genotype with the risk of RVA gastroenteritis, the microbiota and microbiota-induced DP8α Treg cells, suggesting that the anti-RVA immune response might involve an induction/expansion of these T lymphocytes later providing a balanced immunological state that confers protection against inflammatory diseases.

Inflammatory bowel disease (IBD) is a gastrointestinal disease with an underlying contribution of genetic, microbial, environment, immunity factors. The coding region risk markers identified by IBD genome wide association studies have not been well characterized at protein phenotype level. Therefore, this study is conducted to characterize the role of NOD2 (Arg675Trp and Gly908Arg) and IL23R (Gly149Arg and Arg381Gln) missense variants on the structural and functional features of corresponding proteins. Thus, we used different variant pathogenicity assays, molecular modelling, secondary structure, stability, molecular dynamics, and molecular docking analysis methods. Our findings suggest that SIFT, Polyphen, GREP++, PhyloP, SiPhy and REVEL methods are very sensitive in determining pathogenicity of NOD2 and IL23R missense variants. We have also noticed that all the tested missense variants could potentially alter secondary (α-helices, β-strands, and coils) and tertiary (residue level deviations) structural features. Moreover, our molecular dynamics (MD) simulation findings have simulated that NOD2 (Arg675Trp and Gly908Arg) and IL23R (Gly149Arg and Arg381Gln) variants creates rigid local structures comprising the protein flexibility and conformations. These predictions are corroborated by molecular docking results, where we noticed that NOD2 and IL23R missense variants induce molecular interaction deformities with RIPK2 and JAK2 ligand molecules, respectively. These functional alterations could potentially alter the signal transduction pathway cascade involved in inflammation and autoimmunity. Drug library searches and findings from docking studies have identified the inhibitory effects of Tacrolimus and Celecoxib drugs on NOD2 and IL23R variant forms, underlining their potential to contribute to personalized medicine for IBD. The present study supports the utilization of computational methods as primary filters (pre-in vitro and in vivo) in studying the disease potential mutations in the context of genptype-protein phenotype characteristics.