Interleukin receptor associated kinase m

Alopecia areata (AA) is an autoimmune disease characterized by damage to hair follicles and hair loss. Cell-free DNA (cfDNA) has recently received attention as a biomarker of various disorders including inflammatory skin diseases. In this study, we aimed to investigate the clinical significance of cfDNA and the circulating DNAs of disease-associated cytokines in AA patients. Serum samples were obtained from 63 patients with AA and 32 healthy controls (HC). Using droplet digital polymerase chain reaction, circulating C-X-C motif chemokine ligand (CXCL) 9, CXCL10, CXCL11, C-X-C motif chemokine receptor 3, interferon (IFN)-γ, interleukin (IL) -7, IL-15, and Janus kinase (JAK) 2 were detectable in both HC and AA patients...

Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor...

OBJECTIVES: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a cytokine-driven inflammatory syndrome that is associated with substantial morbidity and mortality and frequently leads to ICU admission. Overall survival in adults with sHLH remains poor, especially in those requiring intensive care. Classical chemotherapeutic treatment exhibits myelosuppression and toxicity. Recently, inhibition of Janus kinase signaling by ruxolitinib has shown efficacy in pediatric HLH. We therefore aimed to determine the activity and safety of a ruxolitinib-based regimen, in critically ill adults with sHLH...

Inborn errors of immunity (IEI) can often be misdiagnosed early in life due to their heterogenous clinical presentations. Interleukin-1 receptor-associated kinase 4 (IRAK-4) deficiency is one of the rare innate immunodeficiency disorders. We present the case of a patient who presented at the age of 15 days with meningitis and septic shock that responded to antibiotics. She was admitted again at the age of 45 days with pseudomonas aeruginosa bacteremia that was associated with increased inflammatory markers...

Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of <u>d</u>amage-<u>a</u>ssociated <u>m</u>olecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation...

Excessive inflammatory response and increased oxidative stress play an essential role in the pathophysiology of ischemia/reperfusion (I/R)-induced acute kidney injury (IRI-AKI). Emerging evidence suggests that lipoxin A4 (LXA4), as an endogenous negative regulator in inflammation, can ameliorate several I/R injuries. However, the mechanisms and effects of LXA4 on IRI-AKI remain unknown. In this study, A bilateral renal I/R mouse model was used to evaluate the role of LXA4 in wild-type, IRG1 knockout, and IRAK-M knockout mice...

OBJECTIVES: Sepsis-associated cognitive dysfunction is a common complication in patients with sepsis and lack of effective treatment. Its pathological mechanisms remain unclear. Salt-induced kinase (SIK) is an important molecule in the regulation of metabolism, immunity, and inflammatory response. It is associated with the development of many neurological diseases. This study aims to investigate the expression of SIK in the hippocampus of septic mice, and to evaluate the role and mechanism of the SIK inhibitor HG-9-91-01 in sepsis-associated cognitive dysfunction...

Microglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Toll-like receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neurons in SOD1-G93A mouse model of ALS. qPCR (Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 60, 100 and 140 days of age...

Rosavin, a phenylpropanoid in Rhodiola rosea 's rhizome, and an adaptogen, is known for enhancing the body's response to environmental stress. It significantly affects cellular metabolism in health and many diseases, particularly influencing bone tissue metabolism. In vitro, rosavin inhibits osteoclastogenesis, disrupts F-actin ring formation, and reduces the expression of osteoclastogenesis-related genes such as cathepsin K, calcitonin receptor (CTR), tumor necrosis factor receptor-associated factor 6 (TRAF6), tartrate-resistant acid phosphatase (TRAP), and matrix metallopeptidase 9 (MMP-9)...

Microplastics (MPs) are a serious threat to the living environment of aquatic organisms. However, there are fewer studies on the toxicity of microplastics to freshwater organisms. This study aimed to establish a polystyrene microplastics (PS-MPs) model by feeding carp (Cyprinus carpio) PS-MP (1000 ng/L) particles 8 μm in size. HE staining revealed a mass of inflammatory cells infiltrated in the carp hepatopancreas. The activities of alkaline phosphatase (AKP), aspartate transaminase (AST), lactate dehydrogenase (LDH), and alanine transaminase (ALT) were strengthened considerably, suggesting that PS-MPs cause injury to the hepatopancreas of carp...

OBJECTIVE: To explore the mechanism of spleen tissue inflammatory response induced by altitude hypoxia in mice. METHODS: C57BL/6 mice were randomly assigned to a plain, i.e., low-altitude, normoxia group and an altitude hypoxia group, with 5 mice in each group. In the plain normoxia group, the mice were kept in a normoxic environment at the altitude of 400 m above sea level (with an oxygen concentration of 19.88%). The mice in the altitude hypoxia group were kept in an environment at the altitude of 4200 m above sea level (with an oxygen concentration of 14...

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839 , starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity...

As a widespread environmental pollutant, microplastics pose a great threat to the tissues and organs of aquatic animals. The carp's muscles are necessary for movement and survival. However, the mechanism of injury of polyethylene microplastics (PE-MPs) to carp muscle remains unclear. Therefore, in this study, PE-MPs with the diameter of 8 μm and the concentration of 1000 ng/L were used to feed carp for 21 days, and polyethylene microplastic treatment groups was established. The results showed that PE-MPs could cause structural abnormalities and disarrangement of muscle fibers, and aggravate oxidative stress in muscles...

Porous precision-templated scaffolds ( PTS ) with uniform, interconnected, 40 µm pores have shown favorable healing outcomes and a reduced foreign body reaction ( FBR ). Macrophage receptor with collagenous structure ( MARCO ) and toll-like receptors ( TLRs ) have been identified as key surface receptors in the initial inflammatory phase of wound healing. However, the role of MARCO and TLRs in modulating monocyte and macrophage phenotypes within PTS remains uncharacterized. Here, we demonstrate a synergetic relationship between MARCO and TLR signaling in cells inhabiting PTS, where induction with TLR3 or TLR4 agonists to 40 µm scaffold-resident cells upregulates the transcription of MARCO...

The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded nuclear receptors and other transcriptional repressors by deacetylation of histone substrates. Recent studies provide evidence that NCoR/HDAC3 complexes can also exert coactivator functions in brown adipocytes by deacetylating and activating PPARγ coactivator 1α (PGC1α) and that signaling via receptor activator of nuclear factor kappa-B (RANK) promotes the formation of a stable NCoR/HDAC3/PGC1β complex that coactivates nuclear factor kappa-B (NFκB)- and activator protein 1 (AP-1)-dependent genes required for osteoclast differentiation...

Interleukin-1-receptor-associated kinase 4 (IRAK4) possesses a crucial function in the toll-like receptor (TLR) signaling pathway, and the dysfunction of this molecule could lead to various infectious and immune-related diseases in addition to cancers. IRAK4 genetic variants have been linked to various types of diseases. Therefore, we conducted a comprehensive analysis to recognize the missense variants with the most damaging impacts on IRAK4 with the employment of diverse bioinformatics tools to study single-nucleotide polymorphisms' effects on function, stability, secondary structures, and 3D structure...

Interleukin-1 receptor (IL-1R)-associated kinases (IRAKs) are core effectors of Toll-like receptors (TLRs) and IL-1R in innate immunity. Here, we found that IRAK4 and IRAK1 together inhibited DNA damage-induced cell death independently of TLR or IL-1R signaling. In human cancer cells, IRAK4 was activated downstream of ATR kinase in response to double-strand breaks (DSBs) induced by ionizing radiation (IR). Activated IRAK4 then formed a complex with and activated IRAK1. The formation of this complex required the E3 ubiquitin ligase Pellino1, acting structurally but not catalytically, and the activation of IRAK1 occurred independently of extracellular signaling, intracellular TLRs, and the TLR/IL-1R signaling adaptor MyD88...

Proinflammatory cytokine interleukin (IL)-6 was associated with disease severity in patients with COVID-19. The mechanism underlying the excessive IL-6 production by SARS-Cov-2 infection remains unclear. Respiratory viruses initially infect nasal or bronchial epithelial cells that produce various inflammatory mediators. Here, we show that pretreatment of human bronchial epithelial cells (NCl-H292) with interferon (IFN)-γ (10 ng/mL) markedly increased IL-6 production induced by the toll-like receptor (TLR) 3 agonist poly(I:C) (1 µg/mL) from 0...

This study was established to look into the toxicological consequences of chronic exposure to a fungicide (mancozeb; MAZ) on the immune-antioxidant response, gene expressions, hepato-renal functions, and histological pictures of Nile tilapia (Oreochromis niloticus). Additionally, the effectiveness of Indian frankincense resin extract (IFRE) to mitigate their toxicity was taken into account. Fish (n =240; average body weight: 22.45 ± 2.21 g) were randomized into four groups for eight weeks in six replicates (control, IFRE, MAZ, and IFRE + MAZ), where ten fish were kept per replicate...

UNLABELLED: Unchecked, chronic inflammation is a constitutive component of age-related diseases, including age-related macular degeneration (AMD). Here we identified interleukin-1 receptor-associated kinase (IRAK)-M as a key immunoregulator in retinal pigment epithelium (RPE) that declines with age. Rare genetic variants of IRAK-M increased the likelihood of AMD. IRAK-M expression in RPE declined with age or oxidative stress and was further reduced in AMD. IRAK-M-deficient mice exhibited increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors...