Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects.

Cytokine Storm is a complex and heterogeneous state of life-threatening systemic inflammation and immunopathology. Autoinflammation is a mechanistic category of immune dysregulation wherein immunopathology originates due to poor regulation of innate immunity. The growing family of monogenic Systemic Autoinflammatory Diseases (SAIDs) has been a wellspring for pathogenic insights and proof-of-principle targeted therapeutic interventions. There is surprisingly little overlap between SAID and Cytokine Storm Syndromes, and there is a great deal to be inferred from those SAID that do, and do not, consistently lead to Cytokine Storm. This chapter will summarize how illustrations of the autoinflammatory paradigm have advanced the understanding of human inflammation, including the role of autoinflammation in familial HLH. Next, it will draw from monogenic SAID, both those with strong associations with cytokine storm and those without, to illustrate how the cytokine IL-18 links innate immune dysregulation and cytokine storm.

UNASSIGNED: Osteoarthritis (OA) is a chronic, degenerative, and debilitating disease associated with significant long-term morbidity and disability. The pathogenesis of OA is not completely understood but involves an interplay between environmental risk factors, joint mechanics, abnormal pain pathways and upregulation of inflammatory signaling pathways. Current therapeutic options for patients are limited to conservative management, minimal pharmacological options or surgical management, with significant caveats to all approaches.
UNASSIGNED: In this review, we have set out to investigate current phase II/III clinical trials by undertaking a PubMed search. Examined clinical trials have explored a myriad of potential therapeutics from conventional disease-modifying anti-rheumatic drugs and biologics usually used in the treatment of inflammatory arthritides, to more novel approaches targeting inflammatory pathways implicated in OA, cartilage degeneration or pain pathways.
UNASSIGNED: Unfortunately, most completed phase II/III clinical trials have shown little impact on patient pain scores, with the exception of the traditional DMARD methotrexate and Sprifermin. Methotrexate has been shown to be beneficial when used in the correct patient cohort (MRI proven synovitis). Sprifermin has the longest follow-up data of 5 years and has been shown to reduce loss of MRI-measured cartilage thickness and pain scores.

Autoimmunity refers to an organism\'s immune response against its own healthy cells, tissues, or components, potentially leading to irreversible damage to vital organs. Central and peripheral tolerance mechanisms play crucial roles in preventing autoimmunity by eliminating self-reactive T and B cells. The disruption of immunological tolerance, characterized by the failure of these mechanisms, results in the aberrant activation of autoreactive lymphocytes that target self-tissues, culminating in the pathogenesis of autoimmune disorders. Genetic predispositions, environmental exposures, and immunoregulatory disturbances synergistically contribute to the susceptibility and initiation of autoimmune pathologies. Within the realm of immune therapies for autoimmune diseases, cytokine therapies have emerged as a specialized strategy, targeting cytokine-mediated regulatory pathways to rectify immunological imbalances. Proinflammatory cytokines are key players in inducing and propagating autoimmune inflammation, highlighting the potential of cytokine therapies in managing autoimmune conditions. This review discusses the etiology of autoimmune diseases, current therapeutic approaches, and prospects for future drug design.

One of the primary theories regarding the development of schizophrenia revolves around genetics, indicating the involvement of hereditary factors in various processes, including inflammation. Research has demonstrated that inflammatory reactions occurring in microglia can impact the progression of the disease. It has also been established that genetically determined changes in IL-1 can contribute to schizophrenia, thereby confirming the role of the IL-1 gene cluster in disease susceptibility. The aim of this study is a computer-based assessment of the structural interactions of IL-1 proteins with their receptors in schizophrenia. The study utilized the DisGeNET database, enabling the assessment of the reliability of identified IL-1 polymorphisms. Polymorphisms were also sought using NCBI PubMed. The NCBI Protein service was employed to search for and analyze the position of the identified polymorphisms on the chromosome. Structures for modeling were extracted from the Protein Data Bank database. Protein modeling was conducted using the SWISS-MODEL server, and protein interaction modeling was performed using PRISM. Notably, this study represents the first prediction of the interactions of IL-1α, IL-1β, and IL- 1RA proteins, taking into account the presence of single-nucleotide polymorphisms associated with schizophrenia in the sequence of the corresponding genes. The results indicate that the presence of SNP rs315952 in the IL-1RA protein gene, associated with schizophrenia, may lead to a weakening of the IL-1RA binding to receptors, potentially triggering the initiation of the IL-1 signaling pathway by disrupting or weakening the IL-1RA binding to receptors and facilitating the binding of IL-1 to them. Such alterations could potentially lead to a change in the immune response. The data obtained contribute theoretically to the development of ideas about the molecular mechanisms through which hereditary factors in schizophrenia influence the interactions of proteins of the IL-1 family, which play an important role in the processes of the immune system.
Одной из основных теорий развития шизофрении является генетическая, свидетельствующая о вовлечении наследственных факторов в различные процессы, в том числе воспаление. Показано, что воспалительные реакции, протекающие в микроглии, могут влиять на развитие заболевания. Также установлено, что генетически обусловленные изменения IL-1 могут способствовать шизофрении, подтверждая роль кластера генов IL-1 в восприимчивости к болезням. Целью работы была компьютерная оценка структурных взаимодействий белков IL-1 с их рецепторами при шизофрении. Использовалась база данных DisGeNET, позволяющая оценить достоверность выявленных полиморфизмов IL-1. Проведен поиск полиморфизмов с помощью NCBI PubMed. Сервис NCBI Protein использовался для поиска и анализа положения на хромосоме найденных полиморфизмов. Из базы данных Protein Data Bank были извлечены структуры для проведения моделирования. Моделирование белков выполнялось с помощью сервера SWISS-MODEL, а моделирование белковых взаимодействий – с помощью PRISM. В настоящем исследовании впервые проведено прогнозирование взаимодействий белков IL-1α, IL-1β и IL-1RA с учетом наличия в последовательности соответствующих генов однонуклеотидных полиморфизмов, ассоциированных с шизофренией. Показано, что наличие ассоциированного с шизофренией полиморфизма rs315952 гена белка IL-1RA может привести к ослаблению связи IL-1RA с рецепторами и, предположительно, к запуску сигнального пути IL-1 путем разрыва либо ослабления связи IL-1RA с рецепторами и связыванием IL-1 с ними, что, возможно, вызовет изменение иммунного ответа. Полученные данные вносят теоретический вклад в развитие представлений о молекулярных механизмах влияния наследственных факторов шизофрении на взаимодействия белков семейства IL-1, играющих важную роль в процессах иммунной системы.

Urticarial vasculitis is a rare autoimmune disorder characterized by persistent edematous papules and plaques on the skin that last longer than 24 hours, often accompanied by systemic symptoms such as joint pain and fever. Unlike common urticaria, this condition involves inflammation of small blood vessels, leading to more severe and long-lasting skin lesions with a tendency to leave a bruiselike appearance. Diagnosis is challenging and may require a skin biopsy. Associated with underlying autoimmune diseases, treatment involves managing symptoms with medications such as antihistamines and corticosteroids, addressing the immune system\'s dysfunction, and treating any concurrent autoimmune conditions.

Inflammatory chemicals are released by the immune system in response to any perceived danger, including irritants and pathogenic organisms. The caspase activation and the response of inflammation are governed by inflammasomes, which are sensors and transmitters of the innate immune system. They have always been linked to swelling and pain. Research has mainly concentrated on the NOD-like protein transmitter 3 (NLRP3) inflammasome. Interleukin (IL)-1 and IL-18 are pro-inflammatory cytokines that are activated by the NOD-like antibody protein receptor 3 (NLRP3), which controls innate immune responses. The NLRP3 inflammasome has been associated with gum disease and other autoimmune inflammatory diseases in several studies. Scientists\' discovery of IL-1\'s central role in the pathophysiology of numerous autoimmune disorders has increased public awareness of these conditions. The first disease to be connected with aberrant inflammasome activation was the autoinflammatory cryopyrin-associated periodic syndrome (CAPS). Targeted therapeutics against IL-1 have been delayed in development because their underlying reasons are poorly understood. The NLRP3 inflammasome has recently been related to higher production and activation in periodontitis. Multiple periodontal cell types are controlled by the NLRP3 inflammasome. To promote osteoclast genesis, the NLRP3 inflammasome either increases receptor-activator of nuclear factor kappa beta ligand (RANKL) synthesis or decreases osteoclast-promoting gene (OPG) levels. By boosting cytokines that promote inflammation in the periodontal ligament fibroblasts and triggering apoptosis in osteoblasts, the NLRP3 inflammasome regulates immune cell activity. These findings support further investigation into the NLRP3 inflammasome as a therapeutic target for the medical treatment of periodontitis. This article provides a short overview of the NLRP3 inflammatory proteins and discusses their role in the onset of autoinflammatory disorders (AIDs) and periodontitis.

Alzheimer\'s disease (AD) is a neurological condition that is much more common as people get older. It may start out early or late. Increased levels of pro-inflammatory cytokines and microglial activation, both of which contribute to the central nervous system\'s inflammatory state, are characteristics of AD. As opposed to this, periodontitis is a widespread oral infection brought on by Gram-negative anaerobic bacteria. By releasing pro-inflammatory cytokines into the systemic circulation, periodontitis can be classified as a \"low-grade systemic disease.\" Periodontitis and AD are linked by inflammation, which is recognized to play a crucial part in both the disease processes. The current review sought to highlight the effects of pro-inflammatory cytokines, which are released during periodontal and Alzheimer\'s diseases in the pathophysiology of both conditions. It also addresses the puzzling relationship between AD and periodontitis, highlighting the etiology and potential ramifications.

Community-acquired pneumonia (CAP) is a common respiratory disease in children. This prospective cohort study of 110 children with CAP and 100 healthy children investigated the relationship between the levels of vitamin A, D and E and inflammatory markers, such as tumour necrosis factor (TNF-a), interleukin-1 (IL-1), interleukin-10 (IL-10), neutrophils (NE) and C-reactive protein (CRP), in CAP. The haemoglobin, leukocyte concentration, NE, monocytes and CRP concentration in the CAP group showed significant differences (P < 0.05). The levels of vitamin A, D and E in the CAP group were lower than those in the control group, while the levels of TNF-a and IL-1 were higher than in the control group; the differences were statistically significant (P < 0.05). The IL-10 levels showed no significant differences (P > 0.05). Pearson analysis revealed that the vitamin A, D and E levels were all correlated with the TNF-a, IL-10 and CRP levels (P < 0.05). The vitamin A, D and E levels of the CAP children were lower than those of the healthy children. Thus, the content of fat-soluble vitamins is correlated with the secretion of TNF-a and IL-10. The research provides a new direction for the prevention, diagnosis and treatment of CAP.

BACKGROUND: Dementia encompasses a range of neurodegenerative disorders characterized by cognitive decline and functional impairment. The identification of reliable biomarkers is essential for accurate diagnosis and gaining insights into the mechanisms underlying diseases.
OBJECTIVE: This study aimed to investigate the plasma biomarker profiles associated with Brain- Derived Neurotrophic Factor (BDNF), Oxytocin, Neuronal Pentraxin-1 (NPTX1), Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin- 1 (IL-1), and Prolactin in Alzheimer\'s disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementias (FTD), and healthy controls.
METHODS: Serum levels of the aforementioned biomarkers were analyzed in 23 AD, 28 DLB, 15 FTD patients recruited from outpatient units, and 22 healthy controls. Diagnostic evaluations followed established criteria, and standardized clinical tests were conducted. Blood samples were collected and analyzed using ELISA and electrochemiluminescence immunoassay methods.
RESULTS: Serum BDNF and oxytocin levels did not significantly differ across groups. NPTX1, TREM2, TNF-alpha, and IL-1 levels also did not show significant differences among dementia groups. However, prolactin levels exhibited distinct patterns, with lower levels in male DLB patients and higher levels in female AD patients compared to controls.
CONCLUSIONS: The study findings suggest potential shared mechanisms in dementia pathophysiology and highlight the importance of exploring neuroendocrine responses, particularly in AD and DLB. However, further research is warranted to elucidate the role of these biomarkers in dementia diagnosis and disease progression.