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Interleukin 1β Mediates Intestinal Inflammation in Mice and Patients With Interleukin 10 Receptor Deficiency.

Interleukin 10 receptor (IL10R)-deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1β. We demonstrated that innate immune production of IL1β mediates colitis in IL10R-deficient mice. Transfer of Il1r1-/- CD4+ T cells into Rag1-/-/Il10rb-/- mice reduced the severity of their colitis (compared to mice that received CD4+ T cells that express IL1R), accompanied by decreased pro

Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.

Tityus serrulatus sting causes thousands of deaths annually worldwide. T. serrulatus-envenomed victims exhibit local or systemic reaction that culminates in pulmonary oedema, potentially leading to death. However, the molecular mechanisms underlying T. serrulatus venom (TsV) activity remain unknown. Here we show that TsV triggers NLRP3 inflammasome activation via K(+) efflux. Mechanistically, TsV triggers lung-resident cells to release PGE2, which induces IL-1β production via E prostanoid receptor 2/4-cAMP-PKA-NFκB-dependent mechanisms. IL-1β/IL-1R actions account for oedema and neutrophil rec

Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage.

Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined. Here we have used an infection model to show that the IRE1α ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC

Inflammaging in periodontal, periapical, and malignancy-associated disease: drivers of alveolar bone loss and repair.

BACKGROUND: Aging significantly impacts bone metabolism through altered osteoblast/osteoclast dynamics, reduced stem cell regeneration, and chronic inflammaging. This narrative review explores how these age-related changes influence alveolar bone loss and regeneration in the oral cavity. METHODS: The review investigates key mechanisms-including immunosenescence and inflammasome activation-across three specific pathological contexts: (1) periodontitis, (2) periapical bone resorption, and (3) malignancy-associated osteolysis. Preclinical and clinical evidence were integrated to analyze the bone

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… Inflammasome activation The inflammasome, particularly the NLR family pyrin domain containing 3 (NLRP3) inflammasome, is a cytosolic complex in immune cells that controls the activation of caspase-1 and the maturation of IL-1β and IL-18, which are key inflammatory cytokines for bone resorption. … SASP, Senescence-Associated Secretory Phenotype; NLRP3, NLR family pyrin domain containing 3 Apparent inconsistencies in the reported effects of aging on alveolar bone loss largely reflect differences in disease stage, experimental context, outcome measures, and host characteristics. …

Lipopolysaccharide-induced DC-SIGN/TLR4 crosstalk activates NLRP3 inflammasomes via MyD88-independent signaling in gastric epithelial cells.

Abnormal pattern recognition receptor (PRR) signaling plays an important role in gastric mucosal damage caused by stomach microbiota; however, the underlying molecular mechanisms remain obscure. Here, we show that DC-SIGN, a surface phenotype marker of dendritic cells, is overexpressed in gastric epithelial cells facing LPS stimulation. NLRP3 expression in gastric epithelial cells are significantly increased and related to the degree of LPS stimulation. Furthermore, DC-SIGN could interact with TLR4, promote NLRP3 and related genes expression via MyD88-independent signaling pathway and regulate

Diagnosis and treatment of multisystem amyloidosis associated with SGPL1 mutation: A case report and review of the literature.

RATIONALE: Amyloidosis is a rare, clinically heterogeneous disease, which makes its diagnosis difficult. The relationship between amyloidosis and gene mutations is insufficiently understood. We report a case of sphingosine-1-phosphate lyase 1 (SGPL1) mutation-related amyloidosis, and review the related literature. PATIENT CONCERNS: A 53-year-old man was admitted to our hospital with a 5-month history of renal dysfunction and abdominal distension, aggravated since 2 days. Five months ago, the patient was diagnosed with nephrotic syndrome, with liver dysfunction and abdominal distension. His sy

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… The systemic multi-organ amyloidosis caused by SGPL1 gene mutation may also be associated with the activation of nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) in inflammasomes. [ 52 ] The NLRP3 inflammasome complex is a multiprotein complex composed of cytoplasmic … Abbreviations: AH immunoglobulin heavy-chain amyloidosis AL immunoglobulin light-chain amyloidosis MRI magnetic resonance imaging NLRP3 nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 S1P sphingosine-1-phosphate SGPL1 sphingosine-1-phosphate lyase 1 TTR transthyretin …

Sodium-glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascu

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… Modulation of cardiomyocyte Ca 2 + /Na + homeostasis and downregulation of inflammasome The inflammasome is a multiprotein complex that plays a role in the activation and perpetuation of the inflammatory process, with nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing … AMPK 5ʹ adenosine monophosphate-activated protein kinase, CKMB Creatine Kinase MB, FGF-21 Fibroblast growth factor-21, NLRP3 nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3, NTproBNP N-terminal pro B-type natriuretic peptide, MyD88 Myeloid differentiation primary …

Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy.

The thioredoxin (Trx) system, an integral component of cellular redox regulation, preserves protein dithiol-disulfide equilibrium through its conserved Cys-Gly-Pro-Cys active site and is involved in key cellular functions, including cell proliferation, apoptosis, and signal transduction. In cancer biology, the thioredoxin system plays dual roles: overexpression can suppress oxidative stress and promote tumor growth, whereas dysfunction can trigger programmed cell death (PCD). However, a critical area for future research is to delineate how Trx modulates the intricate networks of PCD, and to id

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… (C) Trx negatively regulates inflammasome activation through caspase inhibition, thus preventing GSDMD cleavage and pyroptotic cell lysis in response to danger signals sensed by Pyrin/NLRP1/NLRP3/NLRP4. … A key sensor in the canonical pathway is NLRP1 (NOD-like receptor family pyrin domain-containing 1), the inaugural inflammasome component to be discovered. …

Роль и функции " Ирисина " : перспективы последних изменений и неевродегенеративных заболеваний.

Irisin — пептид, полученный из фибронектина типа III, содержащего домен белка 5 (FNDC5) и производимый главным образом мышечными волокнами в соответствии с регулированием пероксисомных прорациатрированных рецепторов гамма-коативатора 1-альфа (PGC1α) во время упражнения. Ирисин стал объектом обширных исследований в силу его потенциала как метаболического регулятора и его антиоксидантных свойств. В частности, она связана с защитными действиями в мозгу. Несмотря на растущий интерес, остается много вопросов относительно молекулярных механизмов, лежащих в основе их воздействия. В настоящем обзоре р

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… This myokine also influences alternative apoptosis-related mechanisms; specifically, it can attenuate pyroptosis—a highly inflammatory form of programmed cell death mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome—by inhibiting key components of the pyroptotic cascade [ 110 , … Target of Rapamycin Kinase MT-CO2 cyclooxygenase 2 MYD88 MYD88 Innate Immune Signal Transduction Adaptor NCD non-communicable disease ncRNA Non-coding RNA NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells NGF nerve growth factor NICD Active Notch intracellular domain NLRP3 NLR Family Pyrin …

Inflammasome Activation in Ankylosing Spondylitis Is Associated With Gut Dysbiosis.

OBJECTIVE: We undertook this study to evaluate the activation and functional relevance of inflammasome pathways in ankylosing spondylitis (AS) patients and rodent models and their relationship to dysbiosis. METHODS: An inflammasome pathway was evaluated in the gut and peripheral blood from 40 AS patients using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), flow cytometry, and confocal microscopy, and was compared to that of 20 healthy controls and 10 patients with Crohn's disease. Bacteria was visualized using silver stain in human samples,

NLRP3 Inflammasome Inhibition by MCC950 Reduces Atherosclerotic Lesion Development in Apolipoprotein E-Deficient Mice-Brief Report.

OBJECTIVE: Inflammasomes are multiprotein complexes, and their activation has been associated with cardiovascular disease. Inflammasome activation leads to secretion of caspase-1 by innate immune cells, resulting in the activation of interleukin-1β. Recently, a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, was described. In this study, we investigated the effect of MCC950 on atherosclerotic lesion development in apoE-/- mice. APPROACH AND RESULTS: First, we determined the efficacy of MCC950 in vitro. Bone marrow-derived macrophages and dendritic cells were stimulated with

Arsenic trioxide and other arsenical compounds inhibit the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes.

Inflammasomes are large cytoplasmic multiprotein complexes that activate caspase-1 in response to diverse intracellular danger signals. Inflammasome components termed nucleotide-binding oligomerization domain-like receptor (NLR) proteins act as sensors for pathogen-associated molecular patterns, stress, or danger stimuli. We discovered that arsenicals, including arsenic trioxide and sodium arsenite, inhibited activation of the NLRP1, NLRP3, and NAIP5/NLRC4 inflammasomes by their respective activating signals, anthrax lethal toxin, nigericin, and flagellin. These compounds prevented the autopro

Current Therapeutic Options for the Main Monogenic Autoinflammatory Diseases and PFAPA Syndrome: Evidence-Based Approach and Proposal of a Practical Guide.

Monogenic autoinflammatory diseases are rare conditions caused by genetic abnormalities affecting the innate immunity. Previous therapeutic … iated periodic fever syndrome, hyperimmunoglobulin D syndrome/mevalonate kinase deficiency, and cryopyrin-associated periodic syndromes, together with periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome, which is the most common polygenic autoinflammatory disease in children, also occurring in adult patients. Finally, ba …

Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway.

The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage u

Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study.

Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used

Никотинамид Аденин динуклеотид дополняет Cuprizone испытуемые многочисленные поведенческие изменения в C57BL/6J Mice.

ЦЕЛЬ: Изучение вопроса о том, может ли добавка никотинамида аденина динуклеотида (NAD+) улучшить поведенческие изменения в модели мыши, опьяненной мышью. МЕТОДЫ: Six- Неделю назад мыши C57BL/6J были разделены на three группы: two еда 0.2% cuprizone chow (cuprizone и cuprizone + NAD+ группы), а другая группа получила нормальную грызуновую (контрольную группу) 4 недель. Мыши в чашезоне + NAD+ группа получили 250 мг/кг/сут NAD+ interperitononyly один раз в день, в то время как другие мыши получали засос одновременно. Были проведены поведенческие тесты на пространственное воспоминание (Моррисский

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… model can be partly attributed to the activation of autophagy, the activation of the adenosine monophosphate‐activated protein kinase/sirtuin 1 pathway, the suppression of the nuclear factor kappa B signaling pathway, and the suppression of nucleotide‐binding oligomerization domain‐like receptor family pyrin …

Chronic recurrent wheals - If not chronic spontaneous urticaria, what else?

Chronic urticarial rash, mostly due to chronic spontaneous urticaria (CSU), is seen in up to 1 - 4% of the general population. Urticarial vasculitis (UV) and autoinflammatory syndromes, i.e., cryopyrin-associated periodic syndromes (CAPS) and Schnitzler syndrome (SchS), can mimic CSU-like rash but represent rare disorders with systemic symptoms including fever, headache, conjunctivitis, and arthralgia. Clinical and laboratory features can point to the presence of any of these diseases in patients initially presenting with chronic urticarial rash. These include long-lasting wheals (> 24 hours),…

Метформин репурируется в неврологических расстройствах: клинический экспериментальный ландшафт.

КОЛИЧЕСТВО: Неврологические расстройства, такие, как болезнь Альцгеймера (AD) и множественный склероз (MS), предполагают постепенную потерю нервных клеток, а текущее лечение в основном обеспечивает симптоматическое облегчение без остановки развития болезни. Для устранения этого пробела перспективным подходом является перерасчет лекарств. Метформин, широко используемый пероральный антидиабетический препарат, изучается в случае расстройств центральной нервной системы (СНС) в силу его множественных последствий, включая активацию аденосинового монофосфата, активирующего белковую киназу (АМПК), под

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… Metformin is expected to reduce inflammatory markers such as the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and nociceptive cytokines (interleukin 1β and interleukin 18) in peripheral immune cells, according to the fibromyalgia study. …

Fosfomycin Protects Mice From Staphylococcus aureus Pneumonia Caused by α-Hemolysin in Extracellular Vesicles by Inhibiting MAPK-Regulated NLRP3 Inflammasomes.

α-Hemolysin (Hla) is a significant virulence factor in Staphylococcus aureus (S. aureus)-caused infectious diseases such as pneumonia. Thus, to prevent the production of Hla when treating S. aureus infection, it is necessary to choose an antibiotic with good antibacterial activity and effect. In our study, we observed that Fosfomycin (FOM) at a sub-inhibitory concentration inhibited expression of Hla. Molecular dynamics demonstrated that FOM bound to the binding sites LYS 154 and ASP 108 of Hla, potentially inhibiting Hla. Furthermore, we verified that staphylococcal membrane-derived vesicles

SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor.

PURPOSE: We assessed whether (1) dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function Nlrp3 and inflammasome activation in diabetic mice. (2) The effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. (3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in vitro. METHODS: Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS. RESULTS: Left v