Pathophysiology and Management of Shock
Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George in The Scientific Basis of Urology, 2010
The first of these, IRE1 (inositol-requiring transmembrane kinase and endonuclease), migrates in the plane of the membrane to form oligomers that transactivate each other by phosphorylation. Phosphorylated IRE1 is then able to initiate two separate pathways. On the one hand, its carboxy terminus acquires endonuclease activity, which removes a 26-nucleotide intron from native XBP-1 mRNA. This generates a frameshift that translates a 371 amino acid protein from the edited mRNA instead of a 267 amino acid protein from the native mRNA. Unlike the product of the native mRNA, the translation product of the edited XBP-1 mRNA is a transcription factor of the basic leucine zipper family (bZIP) responsible for the upregulation of a number of genes that code for ER chaperones (44). On the other, the phosphorylated IRE1 forms a scaffold for the attachment of TRAF2 (TNF receptor-associated factor 2), which can then bind and activate the ASK1/JNK kinase cascade. This pathway not only cross talks with the cytosolic version of the UPR by upregulating the transcription of HSF-1 but also promotes insulin resistance and gluconeogenesis by phosphorylating IRS1 (insulin receptor substrate 1) (45) at serine 307 and activating glucose-6-phosphatase, respectively. Finally, this pathway also promotes autophagy, although intermediaries in this process remain to be identified (46).
Klebsiella: Caenorhabditis elegans as a Laboratory Model for Klebsiella pneumoniae Infection
Dongyou Liu in Laboratory Models for Foodborne Infections, 2017
The p38 MAPK is a multistep mechanism that includes immune regulators like NSY-1/SEK-1/PMK-1 MAP kinase pathway, which was identified through forward genetics using mutants that had enhanced susceptibility to infection with Gram-negative bacteria P. aeruginosa [58]. This pathway is orthologous to the ASK1 (MAP kinase kinase kinase)/MKK3/6 (MAP kinase kinase)/p38 (MAP kinase) pathway in mammals, and its identification in C. elegans provided a deeper knowledge on host perspective. The p38 MAP kinase pathway acts cell-autonomously in the intestinal epithelium [59] to coordinate immune defense against a wide variety of ingested pathogens. C. elegans having a loss-of-function mutations in pmk-1 are hypersusceptible to infection by Gram-negative pathogens such as P. aeruginosa [58,60], S. entrica [61], Y. pestis [62], and S. marcescens [63]; Gram-positive pathogens E. faecalis [63] and Staphylococcus aureus [33]; and the fungus C. albicans [64,65]. Nematodes’ global transcriptional profiling analyses revealed that PMK-1 regulates the expression putative antimicrobial effectors, including C-type lectins, Shk toxins, and CUB-like domain [58], in the absence of microbial challenge, and this is termed as “basal regulation.”
Basal Redox Status Influences the Adaptive Redox Response to Regular Exercise
James N. Cobley, Gareth W. Davison in Oxidative Eustress in Exercise Physiology, 2022
Prxs have been shown to form mixed disulfide intermediates with well-known stress response signaling cascades. One study used an eloquent series of experiments to demonstrate that Prx2 can take oxidizing equivalents from hydrogen peroxide and transfer those oxidizing equivalents to the transcription factor STAT3, causing STAT3 dimerization and tetramerization, which impairs STAT3 transcriptional activity (Sobotta et al., 2015). These data indicate that Prx2 is acting as a redox middleman by taking oxidizing equivalents from H2O2 and transferring them to other redox-sensitive proteins (Sobotta et al., 2015). Prx1 has also been shown to act as a H2O2 signaling intermediate by forming mixed disulfide links with the protein ASK1 (Jarvis et al., 2012). ASK1 is required for phosphorylation and activation of p38 MAPK. ASK1 oxidation through Prx1 mediated oxidation promoted p38 phosphorylation and activation, while knockdown of Prx1 impaired p38 phosphorylation and activation (Jarvis et al., 2012). MAPK p38 signaling is an important redox-sensitive mediator of the adaptive responses to exercise (Henriquez-Olguin et al., 2016; Parker et al., 2017). Prx-mediated oxidation of ASK1 is likely a viable redox-mediated adaptive signaling process in exercise adaptations, although this has yet to be empirically determined. In addition to these findings, previous studies have demonstrated increased levels of oxidized Prx dimers in isolated PBMCs following acute exercise and increased abundance of Prx2 following an exercise intervention (Moghaddam et al., 2011). The mechanism described by the “redox relay” alleviates the inconsistencies with the floodgate model by relying on the superior kinetic efficiency of Prxs, as well as providing a mechanism for specificity through steric hindrances in protein-protein interactions between Prxs and their target redox-sensitive proteins.
ASK1 and its role in cardiovascular and other disorders: available treatments and future prospects
Published in Expert Review of Proteomics, 2019
Mohammad Hassan Baig, Abu Baker, Ghulam M Ashraf, Jae-June Dong
Along with this, the TNF receptor-associated factor (TRAF) 2 and 6 are recruited by ASK-1-CRR (central regulatory region of ASK1) to the N-terminal region of ASK1 [41,44,47]. These set of processes promote the homophilic association through the NCC and induce an open conformation of ASK1-CRR, resulting in autophosphorylation of Thr838, further activating ASK1. There are several factors regulating the expression of ASK1. Talking about the positive regulators, the members of the TRAF family are reported to be activating ASK1 by interacting with it [45]. The members of the TRAF family (mainly TRAF2, TRAF5, and TRAF6) are found to interact with ASK1 and thereby increase its kinase activity [30,48–50]. It is a well established fact that the expression of TRAF2 and TRAF6 facilitates the NCC interaction of ASK1 and in response to H2O2, these molecules play a significant role in the activation of the ASK1-JNK/p38 signaling pathways [28,44,46,48,51]. The studies on the TRAF2/6KD mouse embryonic fibroblast (MEF) show weakened activation of ASK1 under ROS [44]. This finding suggests that under oxidative stress, TRAF2/6 play a very potent role in the phosphorylation of Thr838 and is a prominent player in the activation of ASK1 [Figure 4]. These molecules function by facilitating the NCC interaction of ASK1 (homophilic interaction) leading to the activation of the signaling pathway.
Present and emerging pharmacotherapies for non-alcoholic steatohepatitis in adults
Published in Expert Opinion on Pharmacotherapy, 2019
Yuji Ogawa, Masato Yoneda, Takashi Kobayashi, Yasushi Honda, Takaomi Kessoku, Kento Imajo, Satoru Saito, Atsushi Nakajima
In a phase 2 clinical trial, 72 NASH patients (fibrosis stage 2 or 3) were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib, administered orally once daily, with or without once-weekly injections of simtuzumab 125 mg, or simtuzumab alone [61]. Simtuzumab, which is a humanized monoclonal antibody directed against lysyloxidase-like molecule 2 (LOXL2), was used as a fibrosis suppressor, and the trial was also intended to investigate the additive effect of selonsertib; as stated above, the 72 subjects of the trial were randomized to receive selonsertib 18 mg ± simtuzumab (n = 32), selonsertib 6 mg ± simtuzumab (n = 30), or simtuzumab alone (n = 10). Since simtuzumab was not histologically effective, data from the selonsertib groups (6 and 18 mg groups) with or without concurrent simtuzumab were pooled and analyzed. The results revealed that after 24-weeks administration, improvement of fibrosis by ≥1 stage was achieved in 13 of the 30 patients in the 18 mg group (43%), in 8 of the 27 patients in the 6 mg group (30%), and in 2 of the 10 patients in the simtuzumab alone group (20%). In the study, the liver stiffness was also measured by MRE, fat was quantified by MRI-PDFF, and blood biomarkers (cytokeratin-18 [CK18]) were measured. In this trial, suppression of histological fibrosis was achieved within as short a period as 24 weeks. At present, ASK1 is the fibrosis suppressor in the most advanced stages of clinical trials in the world. A global phase 3 trial of ASK1 is ongoing, and favorable results are expected.
Apoptosis signal-regulating kinase 1 (ASK1) as a therapeutic target for neurological diseases
Published in Expert Opinion on Therapeutic Targets, 2020
Satoshi Takenaka, Takao Fujisawa, Hidenori Ichijo
Optic neuritis (ON), which is an immune-mediated inflammatory demyelinating disorder of the optic nerve, is one of the initial manifestations of MS [8]. While ON causes severe symptoms related to the eyes, its molecular mechanisms are more poorly understood than those of other MS pathogeneses. Studies using the EAE model have revealed the involvement of glial cells in the pathogenesis of ON. Chemokines derived from activated glial cells, such as microglia and astrocytes, are considered hallmarks of ON. Guo et al. demonstrated that the TLR4-ASK1-p38 pathway in astrocytes plays pivotal roles in ON pathology [9]. The researchers investigated the role of ASK1 in ON using the EAE mouse model. Comparative analysis of WT and ASK1 KO mice after EAE induction demonstrated that ASK1 deficiency attenuates neuroinflammation, demyelination and glial activation in the spinal cord and optic nerves [8,9]. The researchers investigated detailed molecular mechanisms and found that the Toll-like receptor (TLR)-ASK1-p38 pathway plays an essential role in the release of crucial chemokines from glial cells during neuroinflammation. Compared to WT mice, EAE-induced ASK1 KO mice show marked reductions in chemokine levels, which might be responsible for ON. Notably, oral administration of MSC2032964A, an ASK1 inhibitor, suppresses EAE-induced neuroinflammation in both the spinal cord and optic nerve [9]. Therefore, ASK1-targeting therapies may be useful for MS treatment.
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