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Novel Inhibitory Actions of Neuroactive Steroid [3α,5α]-3-Hydroxypregnan-20-One on Toll-like Receptor 4-Dependent Neuroimmune Signaling.
Biomolecules
November 2024
Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, 3027 Thurston Bowles Bldg., CB 7178, Chapel Hill, NC 27599, USA.
The endogenous neurosteroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) modulates inflammatory and neuroinflammatory signaling through toll-like receptors (TLRs) in human and mouse macrophages, human blood cells and alcohol-preferring (P) rat brains. Although it is recognized that 3α,5α-THP inhibits TLR4 activation by blocking interactions with MD2 and MyD88, the comprehensive molecular mechanisms remain to be elucidated. This study explores additional TLR4 activation sites, including TIRAP binding to MyD88, which is pivotal for MyD88 myddosome formation, as well as LPS interactions with the TLR4:MD2 complex.
View Article and Find Full Text PDFDiscovery of IRAK1/4/pan-FLT3 Kinase Inhibitors as Treatments for Acute Myeloid Leukemia.
ACS Med Chem Lett
November 2024
National Center for Advancing Translational Sciences, Rockville, Maryland 20850, United States.
We report the discovery of an imidazopyridine series of IRAK1/4/pan-FLT3 kinase inhibitors. Optimization of this series has produced compound which displays potent and selective inhibition of IRAK1, IRAK4, FLT3, and all mutant forms of FLT3, as well as good in vitro ADME and pharmacokinetic properties. In a mouse xenograft model of AML, produces survival prolongation equal to that of Gilteritinib, the leading marketed FLT3 inhibitor currently used to treat AML.
View Article and Find Full Text PDFFortunellin attenuates sepsis-induced acute kidney injury by inhibiting inflammation and ferroptosis via the TLR4/NF-κB pathway.
Histol Histopathol
October 2024
Intensive Care Unit (1), First Hospital of Qinhuangdao, Qinhuangdao, PR China.
Article Synopsis
- The study aimed to explore the protective effects of fortunellin against sepsis-induced acute kidney injury (AKI) and the mechanisms involved.
- Experiments utilized human kidney cells and a mouse model to assess fortunellin's ability to enhance cell survival, reduce inflammation, and counteract oxidative damage.
- Results indicated that fortunellin significantly mitigated inflammation and oxidative stress, likely by inhibiting the TLR4/NF-κB signaling pathway, highlighting its potential as a therapeutic agent for sepsis-induced AKI.
Small molecule inhibitors of IL-1R1/IL-1β interaction identified via transfer machine learning QSAR modelling.
Int J Biol Macromol
December 2024
Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; S&K Therapeutics, Ajou University Campus Plaza 418, 199 Worldcup-ro, Yeongtong-gu, Suwon 16502, Republic of Korea. Electronic address:
The human interleukin-1 receptor I (IL-1R1) is a cytokine receptor recognized by interleukin 1β (IL-1β), among other cytokines. Over activation of IL-1R1 has been implicated in various inflammatory conditions. This research aims to identify small-molecule inhibitors targeting the hIL1R1/IL1β interaction, employing a multi-task transfer learning approach for quantitative structure-activity relationship (QSAR) modelling.
View Article and Find Full Text PDFInterleukin-1 Receptor-Associated Kinase 1 in Cancer Metastasis and Therapeutic Resistance: Mechanistic Insights and Translational Advances.
Cells
October 2024
Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Interleukin-1 Receptor Associated Kinase 1 (IRAK1) is a serine/threonine kinase that plays a critical role as a signaling transducer of the activated Toll-like receptor (TLR)/Interleukin-1 receptor (IL-1R) signaling pathway in both immune cells and cancer cells. Upon hyperphosphorylation by IRAK4, IRAK1 forms a complex with TRAF6, which results in the eventual activation of the NF-κB and MAPK pathways. IRAK1 can translocate to the nucleus where it phosphorylates STAT3 transcription factor, leading to enhanced IL-10 gene expression.
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