Subcellular Energetics and Metabolism: A Cross-Species Framework

Thiele, Robert H.

doi:10.1213/ane.0000000000001773

Cited by 12 publications

(11 citation statements)

References 214 publications

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“…The UPR pathway consists of distinct signaling axes that are mediated by three endoplasmic reticulum (ER) transmembrane stress sensors: activating transcription factor 6 (ATF6), protein kinase RNA-like endoplasmic reticulum kinase (PERK) and Inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) [ 1 , 2 , 3 ]. The activation of this pathway protects the cell against protein misfolding during hypoxia [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Despite the importance of both HIFs and the UPR pathway for the cancer microenvironment and cardiovascular disorders, the relationship between the HIFs and the UPR is poorly understood, especially in the normal human endothelium [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

2020

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While the role of hypoxia and the induction of the hypoxia inducible factors (HIFs) and the unfolded protein response (UPR) pathways in the cancer microenvironment are well characterized, their roles and relationship in normal human endothelium are less clear. Here, we examined the effects of IRE1 on HIF-1α protein levels during hypoxia in primary human umbilical vein endothelial cells (HUVECs). The results demonstrated that HIF-1α levels peaked at 6 h of hypoxia along with two of their target genes, GLUT1 and VEGFA, whereas at up to 12 h of hypoxia the mRNA levels of markers of the UPR, IRE1, XBP1s, BiP, and CHOP, did not increase, suggesting that the UPR was not activated. Interestingly, the siRNA knockdown of IRE1 or inhibition of IRE1 endonuclease activity with 4µ8C during hypoxia significantly reduced HIF-1α protein without affecting HIF1A mRNA expression. The inhibition of the endonuclease activity with 4µ8C in two other primary endothelial cells during hypoxia, human cardiac microvascular endothelial cells and human aortic endothelial cells showed the same reduction in the HIF-1α protein. Surprisingly, the siRNA knockdown of XBP1s during hypoxia did not decrease the HIF1α protein levels, indicating that the IRE1-mediated effect on stabilizing the HIF1α protein levels was XBP1s-independent. The studies presented here, therefore, provide evidence that IRE1 activity during hypoxia increases the protein levels of HIF1α in an XBP1s-independent manner.

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Section: Introductionmentioning

confidence: 99%

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

2020

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“…This is consistent with other published work. Synthesis of data from multiple animal models of varying severity and time points suggests that mitochondrial dysfunction causing energy failure requires approximately 24 h of inflammation and sepsis exposure [8] and similar results have been demonstrated in septic human surgical patients [28–31].…”

Section: Discussionmentioning

confidence: 90%

“…Mitochondria play a central role in the metabolic activity of both healthy and diseased eukaryotic organisms, including during sepsis, primarily through their central role in oxidative phosphorylation. This efficient process produces ATP as electrons pass down the electron transport chain (ETC), generating a proton gradient which drives ATP synthase [8]. Oxidative phosphorylation can be altered by changes in mitochondrial oxygen supply, the availability of electron donors from the tricyclic acid (TCA) cycle, or direct inhibition of the cytochromes [8].…”

Section: Introductionmentioning

confidence: 99%

“…This efficient process produces ATP as electrons pass down the electron transport chain (ETC), generating a proton gradient which drives ATP synthase [8]. Oxidative phosphorylation can be altered by changes in mitochondrial oxygen supply, the availability of electron donors from the tricyclic acid (TCA) cycle, or direct inhibition of the cytochromes [8]. The impact of sepsis on subcellular energetics and metabolism is still not clear [8].…”

Section: Introductionmentioning

confidence: 99%

“…Oxidative phosphorylation can be altered by changes in mitochondrial oxygen supply, the availability of electron donors from the tricyclic acid (TCA) cycle, or direct inhibition of the cytochromes [8]. The impact of sepsis on subcellular energetics and metabolism is still not clear [8].…”

Section: Introductionmentioning

confidence: 99%

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Impact of inflammation on brain subcellular energetics in anesthetized rats

et al. 2019

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Background Emerging data suggests that volatile anesthetic agents may have organ protection properties in the setting of critical illness. The purpose of this study was to better understand the effect of inflammation on cerebral subcellular energetics in animals exposed to two different anesthetic agents—a GABA agonist (propofol) and a volatile agent (isoflurane). Results Forty-eight Sprague–Dawley rats were anesthetized with isoflurane or propofol. In each group, rats were randomized to celiotomy and closure (sham) or cecal ligation and puncture (inflammation [sepsis model]) for 8 h. Brain tissue oxygen saturation and the oxidation state of cytochrome aa 3 were measured. Brain tissue was extracted using the freeze-blow technique. All rats experienced progressive increases in tissue oxygenation and cytochrome aa 3 reduction over time. Inflammation had no impact on cytochrome aa 3 , but isoflurane caused significant cytochrome aa 3 reduction. During isoflurane (not propofol) anesthesia, inflammation led to an increase in lactate (+ 0.64 vs. − 0.80 mEq/L, p = 0.0061). There were no differences in ADP:ATP ratios between groups. In the isoflurane (not propofol) group, inflammation increased the expression of hypoxia-inducible factor-1α (62%, p = 0.0012), heme oxygenase-1 (67%, p = 0.0011), and inducible nitric oxide synthase (31%, p = 0.023) in the brain. Animals exposed to inflammation and isoflurane (but not propofol) exhibited increased expression of protein carbonyls (9.2 vs. 7.0 nM/mg protein, p = 0.0050) and S -nitrosylation (49%, p = 0.045) in the brain. RNA sequencing identified an increase in heat shock protein 90 and NF-κβ inhibitor mRNA in the inflammation/isoflurane group. Conclusions In the setting of inflammation, rats exposed to isoflurane show increased hypoxia-inducible factor-1α expression despite a lack of hypoxia, increased oxidative stress in the brain, and increased serum lactate, all of which suggest a relative increase in anaerobic metabolism compared to propofol. Differences in oxidative stress as well as heat shock protein 90 and NF-κβ inhibitor may account for the differential expression of cerebral hypoxia-inducible factor-1α during inflammation. Electronic supplementary material The online version of this article (10.1186/s12868-019-0514-8) contains supplementary material, which is available to authorized users.

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Smart Hydrogels for Tissue Regeneration

Xie,

Xu,

Wang

et al. 2023

Macromolecular Bioscience

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The rapid growth in the portion of the aging population has led to a consequent increase in demand for biomedical hydrogels, together with an assortment of challenges that need to be overcome in this field. Smart hydrogels can autonomously sense and respond to the physiological/pathological changes of the tissue microenvironment and continuously adapt the response according to the dynamic spatiotemporal shifts in conditions. This along with other favorable properties, make smart hydrogels excellent materials for employing toward improving the precision of treatment for age‐related diseases. The key factor during the design of smart hydrogels is on accurately identifying the characteristics of natural tissues and faithfully replicating the composition, structure, and biological functions of these tissues at the molecular level. Such hydrogels can accurately sense distinct physiological and external factors such as temperature and pH, biologically active molecules, mechanical signals, and other stimuli, so they may in turn actively and promptly adjust their response, by regulating their own biological effects, thereby promoting damaged tissue repair. This review summarizes the design strategies employed in the creation of smart hydrogels, their response mechanisms, as well as their applications in field of tissue engineering; and concludes by briefly discussing the relevant challenges and future prospects.This article is protected by copyright. All rights reserved

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Subcellular Energetics and Metabolism: A Cross-Species Framework

Cited by 12 publications

References 214 publications

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

IRE1 Endoribonuclease Activity Modulates Hypoxic HIF-1α Signaling in Human Endothelial Cells

Impact of inflammation on brain subcellular energetics in anesthetized rats

Smart Hydrogels for Tissue Regeneration

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