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Immunodeficiency Diseases
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
TLRs are Pattern Recognition Receptors (PRRs) expressed on cell surfaces or an endosomal membrane of immune and non-immune cells, they recognize Pathogen Associated Molecular Patterns (PAMPs) such as lipopolysaccharides of gram-negative bacteria, glycolipids from fungi and single or double stranded RNA and DNA. TLR activation involves the adaptor protein MyD88 and intracellular kinases such as IL-1 receptor associated kinase (IRAK) 4 and IRAK-1 resulting in the generation of NFκB and production of inflammatory cytokines such as IL-1, IL-6, TNF-α and IL-12. TLR 3, TLR7, TLR8 and TLR9 recruit other adaptor proteins such as TRIF and UNC-93B leading to generation of the Type 1 interferons—IFN α/β.
Anti-Inflammatory Properties of Bioactive Compounds from Medicinal Plants
Published in Hafiz Ansar Rasul Suleria, Megh R. Goyal, Health Benefits of Secondary Phytocompounds from Plant and Marine Sources, 2021
Muhammad Imran, Abdur Rauf, Anees Ahmed Khalil, Saud Bawazeer, Seema Patel, Zafar Ali Shah
Extracts from turmeric (@ 1 or 10 µg/mL for 14 hours) reduced LPS (50 to 100 ngmL–1), stimulated IL-1β, and TNF-α formation of THP-1 cells analyzed by ELISA. LPS-stimulated IRAk1, IκBα degradation, TLR4-MyD88 interaction, TLR4 expression, and MAPK activation were noteworthy decreased by turmeric. It also attenuated the IL-1β, aortic iNOS expression, TNF-α, vascular dysfunction, and nitrite. It also induced apoptosis and increased PARP-1 and caspase-3 activation in HL-60 cells [58].
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
Waldenström’s macroglobulinemia (WM) has a key driver mutation, MYD88L265P, in >95% of the patients; other important mutations are CXCR4 (40%), ARID1A (17%) and CD79B (15%). Copy number alterations (CNAs) resulting in gene losses occur in PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MLKN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%) and FOXP1 (37%). The most common cytogenetic deletions are in chromosome 6q, which mostly overlaps with the CNAs, and comprise of losses in PLEKHG1, HIVEP2, ARID1B and BCLAF1. Mutations in MYD88, which is associated with Toll-like receptor (TLR) and interleukin-1 receptor signalling, mediating IRAK1 and IRAK4, is involved in the NFĸB signalling by direct interaction with BTK.
Pacritinib for the treatment of patients with myelofibrosis and thrombocytopenia
Published in Expert Review of Hematology, 2022
The phase 2 and 3 data for pacritinib, including significant SVR and improvement in symptom control, clearly demonstrate that pacritinib has the potential to expand the current benefits of JAK2 inhibition to a greater proportion of patients with MF – those limited by thrombocytopenia – in either the JAK2 inhibitor-naïve or -exposed setting. The pacritinib kinome profile reveals IRAK1 as a novel, relevant, and previously underappreciated target in MF [69,86]. IRAK1 inhibition likely provides two benefits: 1) reduction of NFκB signaling through upstream targets such as alarmins and IL-1, and 2) less reliance on JAK2 inhibition since the IRAK1 pathway is an independent driver of MF disease course [69]. Pacritinib ameliorates the disease via two distinct pathways and, combined with the negligible JAK1 inhibition by pacritinib, ultimately results in potent anti-inflammatory and clinical activity with lower levels of myelosuppression [28,69,77].
Sauropus brevipes ethanol extract negatively regulates inflammatory responses in vivo and in vitro by targeting Src, Syk and IRAK1
Published in Pharmaceutical Biology, 2021
Ji Hye Kim, Jae Gwang Park, Yo Han Hong, Kon Kuk Shin, Jin Kyeong Kim, Young-Dong Kim, Ki Dong Yoon, Kyung-Hee Kim, Byong Chul Yoo, Gi-Ho Sung, Jae Youl Cho
Inhibitory effect of Sb-EE on AP-1 signalling enzymes. (A–C) RAW264.7 cells were treated with LPS (1 µg/mL) for the indicated time in the presence or absence of Sb-EE (200 μg/mL). Then, an immunoblotting assay was performed with antibodies for phospho- and total-forms of target proteins. The antibodies against p-ERK, ERK, p-JNK, JNK, p-p85 and p85 antibodies were used to detect the MAPKs (A). The antibodies against p-TAK1, TAK-1, p-MEK1/2, MEK1/2, p-MKK4/7, MKK4/7, p-MKK3/6 and MKK3/6 were used to detect the upstream enzymes of MAPKs (B, left and right panel). IRAK-1 and IRAK-4 antibodies were used to detect the initially activated enzymes in the AP-1 signalling pathway (C). (D) To examine the direct effects of Sb-EE on IRAK1 activity, an in vitro kinase assay was performed with purified IRAK1. ##p < 0.01 compared to the normal group, *p < 0.05 and **p < 0.01 compared to the control group (LPS-alone group in (A), (B, left and right panel) and (C)).
miRNA- and cytokine-associated extracellular vesicles mediate squamous cell carcinomas
Published in Journal of Extracellular Vesicles, 2020
Joseph P. Flemming, Brianna L. Hill, Mohammed W. Haque, Jessica Raad, Claudine S. Bonder, Larry A. Harshyne, Ulrich Rodeck, Adam Luginbuhl, James K. Wahl, Kenneth Y. Tsai, Peter J. Wermuth, Andrew M. Overmiller, Mỹ G. Mahoney
The mechanism by which Dsg2 activates malignant transformation and oncogenesis remains to be determined. Here, RNAseq shows dramatic down-regulation of miR-146a (Figure 7(a)) which targets the interleukin-1 receptor-associated kinase 1 (IRAK1) (Figure 7(c)) [56]. IRAK1 belongs to the serine-threonine kinase family that is involved in Toll-like receptor and IL-1 signalling activation which promotes gene expression of IL-6 and IL-8. Thus, down-regulation of miR-146a as observed here in response to Dsg2, would promote IL-8 expression and release (Figure 7(b)). IL-8 is a pro-inflammatory cytokine that plays a critical role in tumour progression and metastasis and is up-regulated in many cancers including oral SCCs [44,46]. A correlation between expression of Dsg2 and IL-8 was observed in HNSCC tumours (Figure 8(a)), and in patients’ blood plasma, we detected varying levels of IL-8 (Figure 8(b)). Interestingly, patients with higher basal levels of IL-8 were less responsive to checkpoint inhibitor treatment (Nivolumab), suggesting that treatment with IL-8 or Dsg2 inhibitor to down-regulate IL-8 levels may significantly improve the response of patients to anti-PD-1 inhibitors.