Halofuginone mediated protection against radiation-induced leg contracture

Ishii, Hisanari; Choudhuri, Rajani; Mathias, Askale; Sowers, Anastasia L.; Flanders, Kathleen C.; Cook, John A.; Mitchell, James B.

doi:10.3892/ijo_00000342

Cited by 7 publications

(2 citation statements)

References 21 publications

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“…This leads to accumulation of uncharged proline tRNAs and subsequent GCN2 activation. Halofuginone has been shown to be protective in models of etiologically-diverse diseases including ischemic disorders, cardiovascular disease, and many cancers (Ishii et al ., 2009; Juarez et al ., 2012; Pines & Spector, 2015). However, apart from ISR activation, halofuginone can also promote protection through other mechanisms including inhibition of TGF β signaling (Pines & Spector, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Tyrosine kinase inhibitors such as erlotinib and sunitinib were also shown to activate GCN2 through a mechanism potentially involving direct binding to this ISR kinase (Tang et al , 2022). Like PERK activators, these other ISR kinase activators, most notably BtdCPU and halofuginone, have been shown to be protective in cellular and in vivo models of numerous disorders, further highlighting the potential for pharmacologic ISR activation in disease (Chen et al ., 2011; Ishii et al , 2009; Juarez et al , 2012; Keller et al ., 2012; Tian et al , 2021). However, the capacity for these compounds to promote adaptive mitochondrial remodeling in wild-type cells or cells deficient in PERK activity is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

Perea

Baron

Dolina

et al. 2023

Preprint

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The integrated stress response (ISR) is a network of eIF2alpha kinases, comprising PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse insults. The PERK ISR kinase regulates mitochondria in response to endoplasmic reticulum (ER) stress. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activators of other ISR kinases to rescue ISR signaling and promote mitochondrial adaptation in cells lacking PERK. We show that the HRI activator BtdCPU and the GCN2 activator halofuginone activate ISR signaling and restore ER stress sensitivity in Perk-deficient cells. However, these compounds differentially impact mitochondria. BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and ISR activation through the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and altered mitochondrial respiration, mimicking the regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK activity and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

Perea

Baron

Dolina

et al. 2023

Preprint

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Accelerated senescence in skin in a murine model of radiation-induced multi-organ injury

McCart

Thangapazham

Lombardini

et al. 2017

Journal of Radiation Research

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Accidental high-dose radiation exposures can lead to multi-organ injuries, including radiation dermatitis. The types of cellular damage leading to radiation dermatitis are not completely understood. To identify the cellular mechanisms that underlie radiation-induced skin injury in vivo, we evaluated the time-course of cellular effects of radiation (14, 16 or 17 Gy X-rays; 0.5 Gy/min) in the skin of C57BL/6 mice. Irradiation of 14 Gy induced mild inflammation, observed histologically, but no visible hair loss or erythema. However, 16 or 17 Gy radiation induced dry desquamation, erythema and mild ulceration, detectable within 14 days post-irradiation. Histological evaluation revealed inflammation with mast cell infiltration within 14 days. Fibrosis occurred 80 days following 17 Gy irradiation, with collagen deposition, admixed with neutrophilic dermatitis, and necrotic debris. We found that in cultures of normal human keratinocytes, exposure to 17.9 Gy irradiation caused the upregulation of p21/waf1, a marker of senescence. Using western blot analysis of 17.9 Gy–irradiated mice skin samples, we also detected a marker of accelerated senescence (p21/waf1) 7 days post-irradiation, and a marker of cellular apoptosis (activated caspase-3) at 30 days, both preceding histological evidence of inflammatory infiltrates. Immunohistochemistry revealed reduced epithelial stem cells from hair follicles 14–30 days post-irradiation. Furthermore, p21/waf1 expression was increased in the region of the hair follicle stem cells at 14 days post 17 Gy irradiation. These data indicate that radiation induces accelerated cellular senescence in the region of the stem cell population of the skin.

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Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model

2017

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Hypoxia is an important physiological stress signal that drives angiogenesis, the formation of new blood vessels. Besides an increase in the production of pro-angiogenic signals such as vascular endothelial growth factor (VEGF), hypoxia also stimulates the production of anti-angiogenic signals. Thrombospondin-1 (TSP-1) is one of the anti-angiogenic factors whose synthesis is driven by hypoxia. Cellular synthesis of TSP-1 is tightly regulated by different intermediate biomolecules including proteins that interact with hypoxia-inducible factors (HIFs), transcription factors that are activated by receptor and intracellular signaling, and microRNAs which are small non-coding RNA molecules that function in post-transcriptional modification of gene expression. Here we present a computational model that describes the mechanistic interactions between intracellular biomolecules and cooperation between signaling pathways that together make up the complex network of TSP-1 regulation both at the transcriptional and post-transcriptional level. Assisted by the model, we conduct in silico experiments to compare the efficacy of different therapeutic strategies designed to modulate TSP-1 synthesis in conditions that simulate tumor and peripheral arterial disease microenvironment. We conclude that TSP-1 production in endothelial cells depends on not only the availability of certain growth factors but also the fine-tuned signaling cascades that are initiated by hypoxia.

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Halofuginone mediated protection against radiation-induced leg contracture

Cited by 7 publications

References 21 publications

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells

Accelerated senescence in skin in a murine model of radiation-induced multi-organ injury

Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model

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