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Radiation Causes Tissue Damage By Dysregulating Inflammasome-Gasdermin D Signaling In Both Host And Transplanted Cells, Jianqiu Xiao, Chun Wang, Juo-Chin Yao, Yael Alippe, Tong Yang, Dustin Kress, Kai Sun, Kourtney L. Kostecki, Joseph B. Monahan, Deborah J. Veis, Yousef Abu-Amer, Daniel C. Link, Gabriel Mbalaviele
Radiation Causes Tissue Damage By Dysregulating Inflammasome-Gasdermin D Signaling In Both Host And Transplanted Cells, Jianqiu Xiao, Chun Wang, Juo-Chin Yao, Yael Alippe, Tong Yang, Dustin Kress, Kai Sun, Kourtney L. Kostecki, Joseph B. Monahan, Deborah J. Veis, Yousef Abu-Amer, Daniel C. Link, Gabriel Mbalaviele
Open Access Publications
Radiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages tissues, thereby unleashing signals that indiscriminately activate the inflammasome pathways in host and transplanted cells. We find that a clinically relevant high dose of radiation causes severe damage to bones and the spleen through mechanisms involving the NLRP3 and AIM2 inflammasomes but not the NLRC4 inflammasome. Downstream, we demonstrate that gasdermin D (GSDMD), the common effector of …
Selective Inhibition Of The P38Α Mapk-Mk2 Axis Inhibits Inflammatory Cues Including Inflammasome Priming Signals, Chun Wang, Yael Alippe, Yousef Abu-Amer, Gabriel Mbalaviele, Et Al
Selective Inhibition Of The P38Α Mapk-Mk2 Axis Inhibits Inflammatory Cues Including Inflammasome Priming Signals, Chun Wang, Yael Alippe, Yousef Abu-Amer, Gabriel Mbalaviele, Et Al
Open Access Publications
p38α activation of multiple effectors may underlie the failure of global p38α inhibitors in clinical trials. A unique inhibitor (CDD-450) was developed that selectively blocked p38α activation of the proinflammatory kinase MK2 while sparing p38α activation of PRAK and ATF2. Next, the hypothesis that the p38α-MK2 complex mediates inflammasome priming cues was tested. CDD-450 had no effect on NLRP3 expression, but it decreased IL-1β expression by promoting IL-1β mRNA degradation. Thus, IL-1β is regulated not only transcriptionally by NF-κB and posttranslationally by the inflammasomes but also posttranscriptionally by p38α-MK2. CDD-450 also accelerated TNF-α and IL-6 mRNA decay, inhibited inflammation in …
Potential Role Of Orexin And Sleep Modulation In The Pathogenesis Of Alzheimer's Disease, Jee Hoon Roh, Hong Jiang, Mary Beth Finn, Floy R. Stewart, Thomas E. Mahan, John R. Cirrito, Ashish Heda, B. Joy Snider, Mingjie Li, Masashi Yanagisawa, Luis De Lecea, David M. Holtzman
Potential Role Of Orexin And Sleep Modulation In The Pathogenesis Of Alzheimer's Disease, Jee Hoon Roh, Hong Jiang, Mary Beth Finn, Floy R. Stewart, Thomas E. Mahan, John R. Cirrito, Ashish Heda, B. Joy Snider, Mingjie Li, Masashi Yanagisawa, Luis De Lecea, David M. Holtzman
Open Access Publications
Age-related aggregation of amyloid-β (Aβ) is an upstream pathological event in Alzheimer's disease (AD) pathogenesis, and it disrupts the sleep-wake cycle. The amount of sleep declines with aging and to a greater extent in AD. Poor sleep quality and insufficient amounts of sleep have been noted in humans with preclinical evidence of AD. However, how the amount and quality of sleep affects Aβ aggregation is not yet well understood. Orexins (hypocretins) initiate and maintain wakefulness, and loss of orexin-producing neurons causes narcolepsy. We tried to determine whether orexin release or secondary changes in sleep via orexin modulation affect Aβ pathology. …