keyword
https://read.qxmd.com/read/38370617/broad-de-regulated-u2af1-splicing-is-prognostic-and-augments-leukemic-transformation-via-protein-arginine-methyltransferase-activation
#1
Meenakshi Venkatasubramanian, Leya Schwartz, Nandini Ramachandra, Joshua Bennett, Krithika R Subramanian, Xiaoting Chen, Shanisha Gordon-Mitchell, Ariel Fromowitz, Kith Pradhan, David Shechter, Srabani Sahu, Diane Heiser, Peggy Scherle, Kashish Chetal, Aishwarya Kulkarni, Kasiani C Myers, Matthew T Weirauch, H Leighton Grimes, Daniel T Starczynowski, Amit Verma, Nathan Salomonis
UNLABELLED: The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations is poorly understood. To reveal complex patient subtypes and putative regulators of pathogenic splicing in Acute Myeloid Leukemia (AML), we developed a new approach called OncoSplice. Among diverse new subtypes, OncoSplice identified a biphasic poor prognosis signature that partially phenocopies U2AF1 -mutant splicing, impacting thousands of genes in over 40% of adult and pediatric AML cases...
February 8, 2024: bioRxiv
https://read.qxmd.com/read/38138875/unraveling-extremely-damaging-irak4-variants-and-their-potential-implications-for-irak4-inhibitor-efficacy
#2
JOURNAL ARTICLE
Mohammed Y Behairy, Refaat A Eid, Hassan M Otifi, Heitham M Mohammed, Mohammed A Alshehri, Ashwag Asiri, Majed Aldehri, Mohamed Samir A Zaki, Khaled M Darwish, Sameh S Elhady, Nahla H El-Shaer, Muhammad Alaa Eldeen
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...
November 26, 2023: Journal of Personalized Medicine
https://read.qxmd.com/read/38116447/novel-irak4-inhibitors-for-treating-asthma-copd-cancer-autoinflammatory-diseases-and-autoimmune-diseases
#3
EDITORIAL
Ram W Sabnis
Provided herein are novel IRAK4 inhibitors, pharmaceutical compositions, use of such compounds in treating asthma, COPD, cancer, autoinflammatory diseases, and autoimmune diseases, and processes for preparing such compounds.
December 14, 2023: ACS Medicinal Chemistry Letters
https://read.qxmd.com/read/38113335/a-noncanonical-irak4-irak1-pathway-counters-dna-damage-induced-apoptosis-independently-of-tlr-il-1r-signaling
#4
JOURNAL ARTICLE
Yuanyuan Li, Richa B Shah, Samanta Sarti, Alicia L Belcher, Brian J Lee, Andrej Gorbatenko, Francesca Nemati, Honglin Yu, Zoe Stanley, Mahbuba Rahman, Zhengping Shao, Jose M Silva, Shan Zha, Samuel Sidi
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...
December 19, 2023: Science Signaling
https://read.qxmd.com/read/37818572/investigation-of-the-molecular-mechanism-underlying-the-therapeutic-effect-of-perilla-frutescens-l-essential-oil-on-acute-lung-injury-using-gas-chromatography-mass-spectrometry-and-network-pharmacology
#5
JOURNAL ARTICLE
Hou Chen, Lu Bai, Yanqiong Shi, Xiaofei Zhang, Xuan Wang, Yujiao Wang, Jiadong Hu, Peijie Zhou
OBJECTIVE: The present study aimed to investigate the molecular mechanism through which Perilla essential oil treats acute lung injury (ALI) through network pharmacology, molecular docking, and in vitro assays. METHODS: Relevant ALI targets of the active ingredients of Perilla essential oil were predicted using the SwissTargetPrediction database and meta TarFisher database. These ALI targets were then screened using GeneCards and DisGeNET, and differentially expressed ALI target genes were identified using the Gene Expression Omnibus (GEO) database...
October 10, 2023: Combinatorial Chemistry & High Throughput Screening
https://read.qxmd.com/read/37201454/design-synthesis-and-pharmacological-evaluation-of-n-3-carbamoyl-1h-pyrazol-4-yl-1-3-oxazole-4-carboxamide-derivatives-as-interleukin-1-receptor-associated-kinase-4-inhibitors-with-reduced-potential-for-cytochrome-p450-1a2-induction
#6
JOURNAL ARTICLE
Hiroshi Inami, Tsuyoshi Mizutani, Junko Watanabe, Hisashi Hayashida, Tomonori Ito, Takeshi Terasawa, Toru Kontani, Hiroaki Yamagishi, Hiroyuki Usuda, Naohiro Aoyama, Emiko Imamura, Takeshi Ishikawa
Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical molecule in Toll-like receptor/interleukin-1 receptor signaling and an attractive therapeutic target for a wide range of inflammatory and autoimmune diseases as well as cancers. In our search for novel IRAK4 inhibitors, we conducted structural modification of a thiazolecarboxamide derivative 1, a lead compound derived from high-throughput screening hits, to elucidate structure-activity relationship and improve drug metabolism and pharmacokinetic (DMPK) properties...
May 3, 2023: Bioorganic & Medicinal Chemistry
https://read.qxmd.com/read/37172199/paralog-specific-signaling-by-irak1-4-maintains-myd88-independent-functions-in-mds-aml
#7
JOURNAL ARTICLE
Joshua Ruina Bennett, Chiharu Ishikawa, Puneet Agarwal, Jennifer Yeung, Avery Sampson, Emma Uible, Eric Vick, Lyndsey Bolanos, Kathleen M Hueneman, Mark Wunderlich, Amal Kolt, Kwangmin Choi, Andrew G Volk, Kenneth D Greis, Jan S Rosenbaum, Scott Hoyt, Craig J Thomas, Daniel T Starczynowski
Dysregulation of innate immune signaling is a hallmark of hematologic malignancies. Recent therapeutic efforts to subvert aberrant innate immune signaling in MDS and AML have focused on the kinase IRAK4. IRAK4 inhibitors have achieved promising, though moderate, responses in pre-clinical studies and in clinical trials for MDS and AML. The reasons underlying the limited responses to IRAK4 inhibitors remain unknown. Here, we reveal that inhibiting IRAK4 in leukemic cells elicits functional complementation and compensation by its paralog, IRAK1...
May 12, 2023: Blood
https://read.qxmd.com/read/37114129/paradoxical-activation-of-chronic-lymphocytic-leukemia-cells-by-ruxolitinib-in-vitro-and-in-vivo
#8
JOURNAL ARTICLE
David E Spaner, Tina YuXuan Luo, Guizhi Wang, Gideon Schreiber, Daniel Harari, Yonghong Shi
INTRODUCTION: Chronic lymphocytic leukemia (CLL) is characterized by an aberrant cytokine network that can support tumor growth by triggering janus kinase (JAK)/STAT pathways. Targeting cytokine-signaling should then be a rational therapeutic strategy but the JAK inhibitor ruxolitinib failed to control and seemingly accelerated the disease in clinical trials. METHODS: The effect of ruxolitinib on primary human CLL cells was studied in vitro and in vivo . RESULTS: Ruxolitinib increased phosphorylation of IRAK4, an important toll-like receptor (TLR)- signaling intermediate, in circulating CLL cells in vitro ...
2023: Frontiers in Oncology
https://read.qxmd.com/read/36798275/a-non-canonical-irak-signaling-pathway-triggered-by-dna-damage
#9
Yuanyuan Li, Richa B Shah, Samanta Sarti, Alicia L Belcher, Brian J Lee, Andrej Gorbatenko, Francesca Nemati, Ian Yu, Zoe Stanley, Zhengping Shao, Jose M Silva, Shan Zha, Samuel Sidi
Interleukin-1 receptor (IL-1R)-associated kinases (IRAKs) are core effectors of Toll-like receptor (TLR) and IL-1R signaling, with no reported roles outside of innate immunity. We find that vertebrate cells exposed to ionizing radiation (IR) sequentially activate IRAK4 and IRAK1 through a phosphorylation cascade mirroring that induced by TLR/IL-1R, resulting in a potent anti-apoptotic response. However, IR-induced IRAK1 activation does not require the receptors or the IRAK4/1 adaptor protein MyD88, and instead of remaining in the cytoplasm, the activated kinase is immediately transported to the nucleus via a conserved nuclear localization signal...
February 8, 2023: bioRxiv
https://read.qxmd.com/read/36614140/inhibitory-mechanism-of-il-6-production-by-orento-in-oral-squamous-cell-carcinoma-cell-line-cal27-stimulated-by-pathogen-associated-molecular-patterns-from-periodontopathogenic-porphyromonas-gingivalis
#10
JOURNAL ARTICLE
Yasuhiro Imamura, Yoshimasa Makita, Kazuya Masuno, Hourei Oh
Orento is a traditional Japanese medicinal kampo preparation that is also prescribed in oral care. In oral squamous cell carcinoma cell line CAL27, orento significantly inhibited periodontopathogenic bacterium Porphyromonas gingivalis lipopolysaccharide (LPS) and lipoproteins (PAMP)-stimulated production of interleukin (IL)-6. This suggests that orento negatively regulates PAMP-mediated toll-like receptor (TLR) signaling. Orento significantly suppressed PAMP-stimulated activation of the IL-6 promoter, indicating that orento may suppress the production of IL-6 by PAMP at the transcriptional level...
December 31, 2022: International Journal of Molecular Sciences
https://read.qxmd.com/read/36500579/recent-update-on-the-anti-inflammatory-activities-of-propolis
#11
REVIEW
Felix Zulhendri, Ronny Lesmana, Steven Tandean, Andreas Christoper, Kavita Chandrasekaran, Ilham Irsyam, Auliya A Suwantika, Rizky Abdulah, Nasrul Wathoni
In recent years, research has demonstrated the efficacy propolis as a potential raw material for pharmaceuticals and nutraceuticals. There is limited report detailing the mechanisms of action of propolis and its bioactive compounds in relation to their anti-inflammatory properties. Thus, the aim of the present review is to examine the latest experimental evidence (2017-2022) regarding the anti-inflammatory properties of propolis. A systematic scoping review methodology was implemented. After applying the exclusion criteria, a total of 166 research publications were identified and retrieved from Scopus, Web of Science, and Pubmed...
December 2, 2022: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/36267130/novel-irak-degraders-for-treating-cancer
#12
EDITORIAL
Ram W Sabnis
Provided herein are novel compounds used as IRAK4 degraders, their pharmaceutical compositions, the use of such compounds in treating cancer, and processes for preparing such compounds.
October 13, 2022: ACS Medicinal Chemistry Letters
https://read.qxmd.com/read/36234844/design-of-novel-irak4-inhibitors-using-molecular-docking-dynamics-simulation-and-3d-qsar-studies
#13
JOURNAL ARTICLE
Swapnil P Bhujbal, Weijie He, Jung-Mi Hah
Treatment of several autoimmune diseases and types of cancer has been an intense area of research over the past two decades. Many signaling pathways that regulate innate and/or adaptive immunity, as well as those that induce overexpression or mutation of protein kinases, have been targeted for drug discovery. One of the serine/threonine kinases, Interleukin-1 Receptor Associated Kinase 4 (IRAK4) regulates signaling through various Toll-like receptors (TLRs) and interleukin-1 receptor (IL1R). It controls diverse cellular processes including inflammation, apoptosis, and cellular differentiation...
September 24, 2022: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://read.qxmd.com/read/36226067/interleukin-1-receptor-associated-kinase-1-irak1-is-epigenetically-activated-in-luminal-epithelial-cells-in-prostate-cancer
#14
JOURNAL ARTICLE
Undraga Schagdarsurengin, Vanessa Breiding, Maria Loose, Florian Wagenlehner, Temuujin Dansranjav
The use of immune adjuvants such as toll-like receptor (TLR) agonists reflects a novel strategy in prostate cancer (PCa) therapy. However, interleukin-1 receptor associated kinase 1 (IRAK1), a central effector of TLR signaling, has been shown to be responsible for resistance to radiation-induced tumor cell death. In order to better understand the function and epigenetic regulation of IRAK1 in PCa, we performed in vitro cell culture experiments together with integrative bioinformatic studies using the latest single-cell RNA-sequencing data of human PCa and normal prostate (NOR), and data from The Cancer Genome Atlas...
2022: Frontiers in Oncology
https://read.qxmd.com/read/36142231/recent-advances-in-protacs-for-drug-targeted-protein-research
#15
REVIEW
Tingting Yao, Heng Xiao, Hong Wang, Xiaowei Xu
Proteolysis-targeting chimera (PROTAC) is a heterobifunctional molecule. Typically, PROTAC consists of two terminals which are the ligand of the protein of interest (POI) and the specific ligand of E3 ubiquitin ligase, respectively, via a suitable linker. PROTAC degradation of the target protein is performed through the ubiquitin-proteasome system (UPS). The general process is that PROTAC binds to the target protein and E3 ligase to form a ternary complex and label the target protein with ubiquitination. The ubiquitinated protein is recognized and degraded by the proteasome in the cell...
September 7, 2022: International Journal of Molecular Sciences
https://read.qxmd.com/read/36040792/activation-of-targetable-inflammatory-immune-signaling-is-seen-in-myelodysplastic-syndromes-with-sf3b1-mutations
#16
JOURNAL ARTICLE
Gaurav S Choudhary, Andrea Pellagatti, Bogos Agianian, Molly A Smith, Tushar D Bhagat, Shanisha Gordon-Mitchell, Srabani Sahu, Sanjay Pandey, Nishi Shah, Srinivas Aluri, Ritesh Aggarwal, Sarah Aminov, Leya Schwartz, Violetta Steeples, Robert N Booher, Murali Ramachandra, Maria Samson, Milagros Carbajal, Kith Pradhan, Teresa V Bowman, Manoj M Pillai, Britta Will, Amittha Wickrema, Aditi Shastri, Robert K Bradley, Robert E Martell, Ulrich G Steidl, Evripidis Gavathiotis, Jacqueline Boultwood, Daniel T Starczynowski, Amit Verma
Background: Mutations in the SF3B1 splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood. Methods: RNA-seq data from SF3B1 mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 ( IRAK4) isoforms were determined...
August 30, 2022: ELife
https://read.qxmd.com/read/35964872/glycoside-oleandrin-downregulates-toll-like-receptor-pathway-genes-and-associated-mirnas-in-human-melanoma-cells
#17
JOURNAL ARTICLE
Canan Eroğlu Güneş, Fatma Seçer Çelik, Mücahit Seçme, Levent Elmas, Yavuz Dodurga, Ercan Kurar
Melanoma accounts for the majority of skin cancer-related deaths. Nerium oleander is a plant known to be toxic and consumed due to the cardiac glycosides it contains. Oleandrin is a cardiac glycoside obtained from of N. oleander. Beside capable of inhibiting proliferation and metastasis of cancer cells, cardiac glycoside derivative compounds cause cardiovascular side effects. Because of cardiovascular toxicity of clinically used cardiac glycosides, it is necessary to investigate cardiac glycoside derivative compounds capable of inhibiting proliferation and metastasis of cancer cells...
August 11, 2022: Gene
https://read.qxmd.com/read/35113284/investigation-of-the-effects-of-the-toll-like-receptor-4-pathway-on-immune-checkpoint-vista-in-pancreatic-cancer
#18
JOURNAL ARTICLE
Kubra Sena Bas Topcu, Emine Nedime Korucu, Esma Menevse, Nadir Kocak, Tugce Duran
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors of the pancreas. Preclinical studies show that it evades the immune system with immune checkpoints and promotes tumor development. V-domain Ig suppressor of T cell activation (VISTA) is a new immune-check point from the B7 family and is highly expressed in cancer cells. Overexpression of toll like receptor 4 (TLR4) in pancreatic adenocarcinoma is associated with induced tumorigenesis, tumor growth, resistancy to chemotherapy...
June 2022: Investigational New Drugs
https://read.qxmd.com/read/34952143/osteosarcoma-exocytosis-of-soluble-lgals3bp-mediates-macrophages-toward-a-tumoricidal-phenotype
#19
JOURNAL ARTICLE
Jing Li, Chenguang Zhao, Yuhuan Li, Junxiang Wen, Shuang Wang, Difan Wang, Hui Dong, Dong Wang, Yonglin Zhao, Xiaohui Wang, Xijing He, Jie Qin
This study aimed to elucidate the interactions between osteosarcoma (OS) and M1 macrophages infiltrated into the tumor microenvironment and to explore the underlying mechanisms whereby M1 macrophages influence the growth of OS, so that novel treatments of OS can be developed. A transwell co-culture system, an indirect conditioned medium culture system and two orthotopic bearing OS models were established to assess for the interplay between M1 macrophages and OS. We found that the co-culture of M1 macrophages with OS cells significantly inhibited the growth of the tumor cells by inducing apoptosis...
March 1, 2022: Cancer Letters
https://read.qxmd.com/read/34786609/proteomic-analysis-of-differential-expression-of-lung-proteins-in-response-to-highly-pathogenic-avian-influenza-virus-infection-in-chickens
#20
JOURNAL ARTICLE
Periyasamy Vijayakumar, Ashwin Ashok Raut, Santhalembi Chingtham, Harshad V Murugkar, Diwakar D Kulkarni, Richa Sood, Vijendra Pal Singh, Anamika Mishra
Elucidation of the molecular pathogenesis underlying virus-host interactions is important for the development of new diagnostic and therapeutic strategies against highly pathogenic avian influenza (HPAI) virus infection in chickens. However, the pathogenesis of HPAI virus in chickens is not completely understood. To identify the intracellular signaling pathways and critical host proteins associated with influenza pathogenesis, we analyzed the lung proteome of a chicken infected with HPAI H5N1 virus (A/duck/India/02CA10/2011/Agartala)...
January 2022: Archives of Virology
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