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Advancements in Research on Necrotizing Enterocolitis Pathogenesis and Prevention Using PIGS
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Douglas Burrin, Juan Marini, Murali Premkumar, Barbara Stoll, Per Torp Sangild
The fetal intestine develops with very limited exposure to microbiota and is bathed in amniotic fluid that is swallowed during the late stages of gestation. The abrupt transition to the extrauterine environment after birth requires the innate immune system for protection from infection (21). The mucosal epithelium is a major element of innate immunity and a key interface between the neonatal host and environmental microbiota after birth. A major function of the mucosal epithelium is to facilitate crosstalk between the commensal microbiota and the host immune system to prevent inappropriate inflammatory responses and enable tolerance. It has now become evident that the premature exposure of the mucosal epithelium to bacteria or their products (e.g., lipopolysaccharide [LPS]) before normal-term birth induces an excessive mucosal inflammatory response (22, 23). A key molecular mechanism that mediates the premature inflammatory response to LPS involves increased expression and signaling via the toll-like receptor-4 (TLR4) pathway (24). Recent animal studies confirm this hypothesis and show that exposure of the perinatal intestine to LPS after birth induces rapid loss of LPS responsiveness and NF-kB activation in epithelial cells. This appears to be mediated by posttranscriptional down-regulation of the interleukin 1 receptor–associated kinase 1 (IRAK-1), which is essential for epithelial TLR4 signaling. This pattern of epithelial immune maturation is analogous to the well-known immunological development of the lung epithelium following experimental prenatal gram-negative bacterial LPS or chorioamnionitis, a common cause of preterm delivery (25, 26). These results suggest that perinatal development of “inflammatory tolerance” to bacterial endotoxins occurs after an initial limited pre-exposure, and there is supporting evidence for this phenomenon with other bacterial TLR ligands, including flagellin (27, 28).
Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair, Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad, Ajay Pratap Singh
Canonical pathway of NF-κB has been extensively studied in different human pathological disorders such as obesity, autoimmune diseases and cancer. Canonical pathway of NF-κB activation is quick and transient, and can be activated by diverse stimuli, such as, TNF, IL-1, toll-like receptors (TLRs), lipopolysaccharide (LPS), etc. LPS and IL-1 stimulate NF-κB activation by recruiting adaptor molecules, TNFR associated factors6 (TRAF6), myeloid differentiation primary response gene 88 (MyD88) and kinase protein, interleukin-1 receptor-associated kinase (IRAK). On the other hand, binding of TNF to tumor necrosis factor receptor (TNFR) results in the recruitment of TRAF2, TNFR1-associated death domain (TRADD), cIAP1, cIAP2, along with kinase protein, receptor interacting protein1 (RIP1), to the receptor [45]. After binding to the receptor, RIP1 undergoes polyubiquitination via non-degradative linkage at Lys63 (K63) which results in the recruitment of IKK complex to the receptor in the close proximity of transforming growth factor beta activated kinase 1 (TAK1) and mitogen activated protein kinase 3 (MEKK3) for its activation [45, 46]. IKK complex is composed of two catalytic subunits (IKK1/IKKα, IKK2/IKKβ) and one regulatory subunit (IKKγ, also known as NEMO). In unstimulated conditions, family of IκB proteins, IκBα, IκBβ, and IκBε, sequesters NF-κB proteins in the cytoplasm [47]. IκBα binds to the RHD of NF-κB complex and masks nuclear localization signal (NLS) which results in the cytoplasmic retention of NF-κB proteins [48]. Once cells receive stimuli, IKK complex phosphorylates IκBα proteins at Ser-32 and Ser-36, and phosphorylated IκBα is targeted for ubiquitination and 26S proteasome degradation, ultimately rendering NF-κB (p50-p65 complex) free, which translocates to the nucleus and binds to the promoter regions of target genes [49, 50] (Fig. 2). Canonical pathway of NF-κB is very tightly regulated and can be suppressed by deubiquitinase (DUB) enzyme, A20, which removes polyubiquitin chain from the adaptor molecules and destabilizes IKK complex. Expression of A20 is under the control of NF-κB. Thus, A20 serves as negative feedback loop for NF-κB activation [51]. It has been suggested that tumor suppressive role of A20 can be compromised due to genetic mutations or its proteolytic cleavage in B cell lymphoma [52, 53]. There are some other DUBs, such as, Cezanne and cylindromatosis (CYLD), which can also negatively regulate the activation of NF-κB activation [54, 55].
Protein Function As Cell Surface And Nuclear Receptor In Human Diseases
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Urmila Jarouliya, Raj K. Keservani
It is well-known that innate immunity is very essential to human survival. Researches from decade in animal models have discovered the powerful toll-like receptors (TLRs) that play a central role in the immune defense system. The first mammalian homolog of Toll was identified in 1997 and after that 10 different members of TLR was identified and they are responsible for recognizing molecular patterns associated with pathogens (PAMP, pathogen-associated molecular patterns), and expressed by a broad spectrum of infectious agents. During any infection The primary response to pathogens in the innate immunity system is mediated by pattern recognition receptors (PRR) which recognize pathogen-associated molecular patterns (PAMP) present in a wide array of microorganisms [89] The most important PRR (pattern recognition receptor) are Toll-like receptors (TLR) which selectively recognize a large number of varied and complex PAMP, characteristic molecules of microorganisms such as lipopolysaccharides, flagellin, mannose, or nucleic acids from virus and bacteria. Once the PRR, and in particular the TLR, recognize these microorganism-specific molecules, an innate immune response is triggered which activates the production of inflammatory mediators such as a large number of interleukins (IL), interferons (IFN) and tumor necrosis factor alpha (TNF-α) [90]. Within the group of TLRs, two types have been identified: surface-expressed TLRs, which are predominantly active against bacterial cell wall compounds; and intracellular receptors, which preferentially recognize virus-associated pattern molecules. In addition, surface-expressed receptors trigger phagocytotic and maturation signals, while the intracellular TLRs lead to the induction of antiviral genes [91]. TLRs are type I transmembrane proteins that consist of a cytoplasmic Toll/IL-1 (TIR) domain and an extracellular domain having leucine-rich repeats (LRR). This TIR domain has the ability to bind and activate distinct molecules, among them MyD88 (myeloid differentiation factor 88), the Toll/IL1-R domain-containing adaptor protein (TIRAP), Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF), the TRIF-related adaptor molecule (TRAM), Interleukin-1 receptor-associated kinase (IRAK), tumor necrosis factor (TNF), and TNF receptor-associated factor 6 (TRAF6); all necessary to activate different pathways such as mitogen-activated protein kinases (MAPK), signal transducers and activators of transcription (STAT) and the nuclear factor-kappa B (NF-κB) pathway and interferon regulatory factor 3 (IRF3), which, in turn, induce various immune and inflammatory genes [92, 93]. A greater understanding of the TLRs and their roles in immunity holds potential for the development of therapeutics for bacterial and viral infections, allergies and cancer, and also to limit the damage caused by autoimmune disorders. Moreover, the role of TLRs in tissue repair and regeneration provides a further avenue for drug targeting [94]. It is recognized that TLRs bind to specific ligands, distribute on different cell types, and play key roles in the pathophysiology of various disorders involving both the innate and adaptive immunity [95] (Table 1.1).
Intraocular Inflammation Associated with IRAK4 Deficiency
Published in Ocular Immunology and Inflammation, 2023
John A. Gonzales, Jeremy Nortey, Amit Reddy, Thuy Doan, Nisha R. Acharya
Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase involved in the signaling pathway stimulated by Toll-like receptors (TLRs) and Interleukin-1 (IL-1). Its function is crucial to the body’s innate immunity where its recruitment by adaptor proteins, such as MYD88, leads to the release of pro-inflammatory cytokines involved in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) pathway.1 Appreciation for the role of IRAK4 in the body’s natural defense has grown over the years, and work has progressed to explore the kinase’s role in treating autoimmune diseases.2,3 In contrast, deficient IRAK4 activation can lead to serious systemic sequelae such as bacterial infections and bacteremia. Less is known about ocular manifestations in the setting of IRAK4 deficiency. While endogenous endophthalmitis has been described, non-infectious inflammation (uveitis) is rarely reported.4
Experimental drugs in clinical trials for acute myeloid leukemia: innovations, trends, and opportunities
Published in Expert Opinion on Investigational Drugs, 2023
Aleksandra Gołos, Joanna Góra-Tybor, Tadeusz Robak
Interleukin-1 receptor-associated kinase 4 (IRAK4) is engaged in toll-like receptor (TLR) and interleukin-1 receptor (IL-1 R) signaling pathways that are detected in about 50% of AML/MDS cases [79]. The oncogenic potential of IRAK4-L is due to spliceosome mutation (including SF3B1 and U2AF1) and increases nuclear factor-κB (NF-κB) activity [79]. CA-4948 (also known as emavusertib) is an oral inhibitor IRAK4 investigated in a phase 1 dose-escalation study in patients with relapsed or refractory settings in NHL (NCT03328078), AML, or high-risk MDS (NCT04278768). CA-4948 demonstrates a manageable safety profile and clinical activity in NHL patients [80]. However, the myeloid subgroup results are not yet reported. To date, several early-phase trials have emerged investigating emavusertib. A phase 1/2a dose escalation and expansion study have been ongoing to evaluate CA-4948 in monotherapy and combination with azacitidine or venetoclax in RR AML or high-risk MDS, irrespectively of spliceosome mutations status (NCT04278768). Interestingly, CA-4948 has also been evaluated in a phase II trial concerning treating anemia in low-risk MDS (NCT05178342).
Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Chao Wang, Yujing Zhang, Lingyu Shi, Shanbo Yang, Jing Chang, Yingjie Zhong, Qian Li, Dongming Xing
Interleukin-1 receptor-associated kinase 4 (IRAK4) belongs to a family of four kinases (IRAK4, IRAK1, nterleukin-1 receptor-associated kinase 4 (IRAK4) IRAK2, and IRAK-M). IRAK4 is a serine/threonine kinase that is involved in transduction pathways stimulated by the Tolllike receptors (TLRs) and the interleukin-1 (IL-1) family of receptors. Recognition of foreign pathogens and inflammatory signals by these receptors promotes IRAK4 binding to the adapter protein myeloid differentiation primary response gene (88) (MyD88) resulting in IRAK4 activation that in turn leads to the production of pro-inflammatory cytokines via the NFκβ pathway. IRAK4 deficiency or loss of function has been reported to increase susceptibility to several pathogens, while kinase activation has been linked with various autoimmune diseases such as systemic lupus erythematosus, psoriasis, rheumatoid arthritis, and cancer96,97.