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1

Ruiz, Asier, Jone Zuazo, Carolina Ortiz-Sanz, Celia Luchena, Carlos Matute, and Elena Alberdi. "Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response." International Journal of Molecular Sciences 21, no. 17 (August 24, 2020): 6088. http://dx.doi.org/10.3390/ijms21176088.

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Анотація:
Sephin1 is a derivative of guanabenz that inhibits the dephosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α) and therefore may enhance the integrated stress response (ISR), an adaptive mechanism against different cellular stresses, such as accumulation of misfolded proteins. Unlike guanabenz, Sephin1 provides neuroprotection without adverse effects on the α2-adrenergic system and therefore it is considered a promising pharmacological therapeutic tool. Here, we have studied the effects of Sephin1 on N-methyl-D-aspartic acid (NMDA) receptor signaling which may modulate the ISR and contribute to excitotoxic neuronal loss in several neurodegenerative conditions. Time-course analysis of peIF2α levels after NMDA receptor overactivation showed a delayed dephosphorylation that occurred in the absence of activating transcription factor 4 (ATF4) and therefore independently of the ISR, in contrast to that observed during endoplasmic reticulum (ER) stress induced by tunicamycin and thapsigargin. Similar to guanabenz, Sephin1 completely blocked NMDA-induced neuronal death and was ineffective against AMPA-induced excitotoxicity, whereas it did not protect from experimental ER stress. Interestingly, both guanabenz and Sephin1 partially but significantly reduced NMDA-induced cytosolic Ca2+ increase, leading to a complete inhibition of subsequent calpain activation. We conclude that Sephin1 and guanabenz share common strong anti-excitotoxic properties with therapeutic potential unrelated to the ISR.
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2

Kroemer, Guido, Guillermo Mariño, and Beth Levine. "Autophagy and the Integrated Stress Response." Molecular Cell 40, no. 2 (October 2010): 280–93. http://dx.doi.org/10.1016/j.molcel.2010.09.023.

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3

Chen, Yanan, Joseph R. Podojil, Rejani B. Kunjamma, Joshua Jones, Molly Weiner, Wensheng Lin, Stephen D. Miller, and Brian Popko. "Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis." Brain 142, no. 2 (January 17, 2019): 344–61. http://dx.doi.org/10.1093/brain/awy322.

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4

Pecoraro, Annalisa, Martina Pagano, Giulia Russo, and Annapina Russo. "Role of Autophagy in Cancer Cell Response to Nucleolar and Endoplasmic Reticulum Stress." International Journal of Molecular Sciences 21, no. 19 (October 4, 2020): 7334. http://dx.doi.org/10.3390/ijms21197334.

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Анотація:
Eukaryotic cells are exposed to many internal and external stimuli that affect their fate. In particular, the exposure to some of these stimuli induces stress triggering a variety of stress responses aimed to re-establish cellular homeostasis. It is now established that the deregulation of stress response pathways plays a central role in cancer initiation and progression, allowing the adaptation of cells to an altered state in the new environment. Autophagy is a tightly regulated pathway which exerts “housekeeping” role in physiological processes. Recently, a growing amount of evidence highlighted the crucial role of autophagy in the regulation of integrated stress responses, including nucleolar and endoplasmic reticulum. In this review, we attempt to afford an overview of the complex role of nucleolar and endoplasmic reticulum stress-response mechanisms in the regulation of autophagy in cancer and cancer treatment.
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5

Sønstevold, Tonje, Nikolai Engedal, Ýrr Mørch, Tore Geir Iversen, Tore Skotland, Kirsten Sandvig, and Maria L. Torgersen. "Structural Variants of poly(alkylcyanoacrylate) Nanoparticles Differentially Affect LC3 and Autophagic Cargo Degradation." Journal of Biomedical Nanotechnology 16, no. 4 (April 1, 2020): 432–45. http://dx.doi.org/10.1166/jbn.2020.2906.

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Nanoparticle drug carriers trigger a variety of cellular stress responses, including ER stress and antioxidant responses, but may also affect the intracellular degradative pathway autophagy. This can impose profound effects on drug delivery, cellular treatment responses, and nanoparticle cytotoxicity. We recently demonstrated that even small variations in the alkyl side chains of poly(alkylcyanoacrylate) (PACA) drug carrier nanoparticles, namely butyl (PBCA), ethylbutyl (PEBCA), or octyl (POCA), differentially induce ER stress and redox imbalance in human cell lines. Here, we systematically investigate how these PACA variants affect autophagy. Interestingly, treatment with PEBCA or POCA particles led to intracellular accumulation of the autophagosome marker LC3-II, but via different mechanisms. PEBCA induced an integrated stress response-and ATF4-mediated increase in LC3B mRNA, whereas POCA blocked autophagic degradation of LC3-II and long-lived proteins in bulk. PBCA also increased LC3B mRNA via the integrated stress response and ATF4, but unlike PEBCA, it inhibited LC3 lipidation and autophagic cargo degradation. Our data demonstrate that even subtle variations in NP structure can have profoundly different impacts on autophagy, and that careful monitoring of autophagic flux and cargo degradation is critical for drawing accurate conclusions. Our findings have important implications for the choice of PACA monomer in different therapeutic settings.
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6

Gambardella, Gennaro, Leopoldo Staiano, Maria Nicoletta Moretti, Rossella De Cegli, Luca Fagnocchi, Giuseppe Di Tullio, Sara Polletti, et al. "GADD34 is a modulator of autophagy during starvation." Science Advances 6, no. 39 (September 2020): eabb0205. http://dx.doi.org/10.1126/sciadv.abb0205.

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Cells respond to starvation by shutting down protein synthesis and by activating catabolic processes, including autophagy, to recycle nutrients. This two-pronged response is mediated by the integrated stress response (ISR) through phosphorylation of eIF2α, which represses protein translation, and by inhibition of mTORC1 signaling, which promotes autophagy also through a stress-responsive transcriptional program. Implementation of such a program, however, requires protein synthesis, thus conflicting with general repression of translation. How is this mismatch resolved? We found that the main regulator of the starvation-induced transcriptional program, TFEB, counteracts protein synthesis inhibition by directly activating expression of GADD34, a component of the protein phosphatase 1 complex that dephosphorylates eIF2α. We discovered that GADD34 plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux. Hence, the TFEB-GADD34 axis integrates the mTORC1 and ISR pathways in response to starvation.
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7

Khandros, Eugene, Christopher S. Thom, Janine D'Souza та Mitchell J. Weiss. "Integrated protein quality-control pathways regulate free α-globin in murine β-thalassemia". Blood 119, № 22 (31 травня 2012): 5265–75. http://dx.doi.org/10.1182/blood-2011-12-397729.

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Cells remove unstable polypeptides through protein quality-control (PQC) pathways such as ubiquitin-mediated proteolysis and autophagy. In the present study, we investigated how these pathways are used in β-thalassemia, a common hemoglobinopathy in which β-globin gene mutations cause the accumulation and precipitation of cytotoxic α-globin subunits. In β-thalassemic erythrocyte precursors, free α-globin was polyubiquitinated and degraded by the proteasome. These cells exhibited enhanced proteasome activity, and transcriptional profiling revealed coordinated induction of most proteasome subunits that was mediated by the stress-response transcription factor Nrf1. In isolated thalassemic cells, short-term proteasome inhibition blocked the degradation of free α-globin. In contrast, prolonged in vivo treatment of β-thalassemic mice with the proteasome inhibitor bortezomib did not enhance the accumulation of free α-globin. Rather, systemic proteasome inhibition activated compensatory proteotoxic stress-response mechanisms, including autophagy, which cooperated with ubiquitin-mediated proteolysis to degrade free α-globin in erythroid cells. Our findings show that multiple interregulated PQC responses degrade excess α-globin. Therefore, β-thalassemia fits into the broader framework of protein-aggregation disorders that use PQC pathways as cell-protective mechanisms.
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8

Pike, Luke R. G., Dean C. Singleton, Francesca Buffa, Olga Abramczyk, Kanchan Phadwal, Ji-Liang Li, Anna Katharina Simon, James T. Murray, and Adrian L. Harris. "Transcriptional up-regulation of ULK1 by ATF4 contributes to cancer cell survival." Biochemical Journal 449, no. 2 (December 14, 2012): 389–400. http://dx.doi.org/10.1042/bj20120972.

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Hypoxia in the microenvironment of many solid tumours is an important determinant of malignant progression. The ISR (integrated stress response) protects cells from the ER (endoplasmic reticulum) stress caused by severe hypoxia. Likewise, autophagy is a mechanism by which cancer cells can evade hypoxic cell death. In the present paper we report that the autophagy-initiating kinase ULK1 (UNC51-like kinase 1) is a direct transcriptional target of ATF4 (activating transcription factor 4), which drives the expression of ULK1 mRNA and protein in severe hypoxia and ER stress. We demonstrate that ULK1 is required for autophagy in severe hypoxia and that ablation of ULK1 causes caspase-3/7-independent cell death. Furthermore, we report that ULK1 expression is associated with a poor prognosis in breast cancer. Collectively, the findings of the present study identify transcriptional up-regulation of ULK1 as a novel arm of the ISR, and suggest ULK1 as a potentially effective target for cancer therapy.
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9

Clarke, Robert, Katherine L. Cook, Rong Hu, Caroline O. B. Facey, Iman Tavassoly, Jessica L. Schwartz, William T. Baumann, et al. "Endoplasmic Reticulum Stress, the Unfolded Protein Response, Autophagy, and the Integrated Regulation of Breast Cancer Cell Fate." Cancer Research 72, no. 6 (March 14, 2012): 1321–31. http://dx.doi.org/10.1158/0008-5472.can-11-3213.

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10

Muftuoglu, Muharrem, Po Yee Mak, Vivian Ruvolo, Yuki Nishida, Peter P. Ruvolo, Bing Z. Carter, and Michael Andreeff. "High Dimensional Interrogation of Stress Response Patterns and Cell Death Modes in AML." Blood 136, Supplement 1 (November 5, 2020): 15. http://dx.doi.org/10.1182/blood-2020-143371.

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Анотація:
Cellular response to stress is diverse, ranging from adaptation through activation of survival pathways to induction of cell death. We designed a multicolor flow cytometry panel to gain insight into multifaceted stress response and to assess multiple cell death modes at the single cell level. The panel included antibodies against RIP3, active caspase 3, cleaved PARP, ATF4, H2AX, p21, Ki-67 and a dead cell discriminating dye. This enabled simultaneous interrogation of a multitude of cell death modes including necrosis, necroptosis, apoptosis and parthanatos as well as proliferation, autophagy and endoplasmic reticulum (ER) stress. Notably, we utilized high dimensional analytic approaches to better elucidate stress response and cell death modes. We leveraged t-SNE for dimension reduction, PhenoGraph to identify distinct phenotypes and diffusion map to map cell trajectories. First, we aimed at delineating response patterns and cell death modes associated with targeted therapies currently being investigated for the treatment of acute myeloid leukemias (AML), including inhibitors targeting anti-apoptotic molecules (Bcl-2i and Mcl-1i), propagating p53-mediated apoptosis (MDM-2i and exportin 1i [XPO1i]), abrogating adaptive circuits through blocking autophagic degradation (SBI-0206965) and depleting anti-oxidant pool (Buthionine sulfoximine [BSO]), and mitochondrial proteasome ClpP activator (ClpPa) (ONC201). Initially, we generated two-dimensional t-SNE plots to interrogate agent-specific response landscapes. Unsupervised high-dimensional mapping demonstrated that Bcl-2 or Mcl-1 inhibition alone did not alter cellular landscape. However, treatment with MDM2i or XPO1i and ClpPa elicited divergent stress responses and cell death modes. Two-dimensional plots showed differential induction of autophagy and ER stress following treatment with MDM2i, XPO1i or ClpPa. Remarkably, we observed that MDM2i and XPO1i were associated with emergence of quiescent cells, based on high expression of p21, and higher levels of ER stress and autophagy while ClpPa induced DNA damage, and was associated with persistent Ki-67 expression and lower levels of p21. This approach enabled us to dissect single agent specific stress signatures. Next, we assessed the response landscapes of prior knowledge-based, data-driven synergistic dual drug combinations. Mapping of response landscapes of multiple dual drug combinations at single-cell resolution revealed distinct associations among integrated stress responses, divergent cellular progression trajectories and previously unidentified response patterns. We observed that autophagic cells were associated with high levels of ER stress and cell kinetic quiescence, suggesting that perturbation-specific stress responses are integrated at the cellular level and are triggered concomitantly. Unsupervised clustering and partitioning of response landscapes to identify major phenotypes revealed two distinct autophagic cell phenotypes: 1) Quiescent autophagic cells without DNA damage and 2) proliferating autophagic cells with DNA damage. Strikingly, combinatorial use of MDM2i and XPO1i almost completely eliminated all AML cells. The surviving cells were quiescent, had high levels of autophagy and ER stress, and were spared of DNA damage. On the other hand, addition of either Bcl-2i or Mcl-1i to MDM2i markedly reduced p21, ER stress and autophagy, indicating that these anti-apoptotic molecules may play a role in cellular adaptation. Addition of Bcl-2i or Mcl-1i inhibitors may specifically deplete autophagic cells with high p21 and ER stress (as we have reported, Pan et al. Cancer Cell 2017). To map cellular trajectories and identify the sequence of events we leveraged diffusion map algorithm and aligned the clusters along pseudo-time. This approach enabled us to identify the earliest stage of cell death, characterized by expression of LC3B, H2AX and cleaved PARP while dead cell dyes marked the latest stage. These findings provide proof of concept for the utility of single cell mapping of cellular stress in delineating stressor-specific response patterns and identifying potential resistance mechanisms. Single cell mapping of cell stress and cell death can inform the development of more effective combinatorial drug regimens. Disclosures Carter: Syndax: Research Funding; Ascentage: Research Funding; Amgen: Research Funding; AstraZeneca: Research Funding. Andreeff:Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy.
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11

Yu, Xinlei, and Yun Chau Long. "Autophagy modulates amino acid signaling network in myotubes: differential effects on mTORC1 pathway and the integrated stress response." FASEB Journal 29, no. 2 (November 5, 2014): 394–407. http://dx.doi.org/10.1096/fj.14-252841.

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12

Sannino, Sara, and Jeffrey L. Brodsky. "Abstract 5684: Protein homeostasis modulation is critical for cancer cell survival upon chaperone mediated proteotoxic stress." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5684. http://dx.doi.org/10.1158/1538-7445.am2022-5684.

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Abstract Cancer cells survive under extreme environments that alter protein homeostasis, thereby provoking cellular stress responses, such as the unfolded protein response (UPR) and the integrated stress response (ISR). These pathways increase the expression of molecular chaperones to prevent the accumulation of toxic proteins in the cell. One molecular chaperone in particular, Hsp70, plays a central role in both cellular protection and the response to proteotoxic insults. This is perhaps most evident in cancer cells, some of which overexpress Hsp70 and thrive even when harboring high levels of misfolded, aggregated, and/or unassembled protein complexes. In an effort to define how cells compensate for compromised proteostasis, we examined the adaptive response in breast cancer cells after challenge with a specific Hsp70 inhibitor. We first showed that established breast cancer cell lines bin into classes based on their sensitivity to the drug. We next discovered that resistant cells have higher autophagy levels compared to the more sensitive lines. Moreover, gene and protein expression studies and imaging methods showed that autophagy was further induced by Hsp70 inhibition in resistant breast cancer cells. Consistent with the fact that Hsp70 normally targets aberrant proteins for degradation, our data indicated that resistance to compromised Hsp70 activity arose from elevated levels of autophagy. We next showed that Hsp70 inhibition specifically triggers the ISR pathway. Unexpectedly, protection against the Hsp70 inhibitor was dependent on the ISR sensor, GCN2, which is most commonly associated with the amino acid starvation response. In contrast, sensitive cells succumbed to Hsp70 inhibition by activating the PERK pathway. These data reveal an unexpected route through which cancer cells can adapt to chaperone targeted-proteotoxicity and position GCN2 and autophagy as critical compensatory mechanisms for cancer cells when proteostasis is compromised. Citation Format: Sara Sannino, Jeffrey L. Brodsky. Protein homeostasis modulation is critical for cancer cell survival upon chaperone mediated proteotoxic stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5684.
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13

Bourouti, Konstantina-Eleni, Christos Konstantaros, Catherine Gaitanaki, and Ioanna-Katerina Aggeli. "Severe Hyperosmotic Stress Issues an ER Stress-Mediated “Death Sentence” in H9c2 Cells, with p38-MAPK and Autophagy “Coming to the Rescue”." Biomedicines 10, no. 6 (June 15, 2022): 1421. http://dx.doi.org/10.3390/biomedicines10061421.

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With several cardiovascular pathologies associated with osmotic perturbations, researchers are in pursuit of identifying the signaling sensors, mediators and effectors involved, aiming at formulating novel diagnostic and therapeutic strategies. In the present study, H9c2 cells were treated with 0.5 M sorbitol to elicit hyperosmotic stress. Immunoblotting as well as cell viability analyses revealed the simultaneous but independent triggering of multiple signaling pathways. In particular, our findings demonstrated the phosphorylation of eukaryotic translation initiation factor 2 (eIF2α) and upregulation of the immunoglobulin heavy-chain-binding protein (BiP) expression, indicating the onset of the Integrated Stress Response (IRS) and endoplasmic reticulum stress (ERS), respectively. In addition, autophagy was also induced, evidenced by the enhancement of Beclin-1 protein expression and of AMP-dependent kinase (AMPK) and Raptor phosphorylation levels. The involvement of a Na+/H+ exchanger-1 (NHE-1) as well as NADPH oxidase (Nox) in 0.5 M sorbitol-induced eIF2α phosphorylation was also indicated. Of note, while inhibition of ERS partially alleviated the detrimental effect of 0.5 M sorbitol on H9c2 cellular viability, attenuation of p38-MAPK activity and late phase autophagy further mitigated it. Deciphering the mode of these pathways’ potential interactions and of their complications may contribute to the quest for effective clinical interventions against associated cardiovascular diseases.
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14

Shiau, Jun-Ping, Ya-Ting Chuang, Jen-Yang Tang, Kun-Han Yang, Fang-Rong Chang, Ming-Feng Hou, Ching-Yu Yen, and Hsueh-Wei Chang. "The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products." Antioxidants 11, no. 9 (September 19, 2022): 1845. http://dx.doi.org/10.3390/antiox11091845.

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Oxidative stress and AKT serine-threonine kinase (AKT) are responsible for regulating several cell functions of cancer cells. Several natural products modulate both oxidative stress and AKT for anticancer effects. However, the impact of natural product-modulating oxidative stress and AKT on cell functions lacks systemic understanding. Notably, the contribution of regulating cell functions by AKT downstream effectors is not yet well integrated. This review explores the role of oxidative stress and AKT pathway (AKT/AKT effectors) on ten cell functions, including apoptosis, autophagy, endoplasmic reticulum stress, mitochondrial morphogenesis, ferroptosis, necroptosis, DNA damage response, senescence, migration, and cell-cycle progression. The impact of oxidative stress and AKT are connected to these cell functions through cell function mediators. Moreover, the AKT effectors related to cell functions are integrated. Based on this rationale, natural products with the modulating abilities for oxidative stress and AKT pathway exhibit the potential to regulate these cell functions, but some were rarely reported, particularly for AKT effectors. This review sheds light on understanding the roles of oxidative stress and AKT pathway in regulating cell functions, providing future directions for natural products in cancer treatment.
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15

G. Hawley, Robert, Yuzhong Chen, Irene Riz, and Chen Zeng. "An Integrated Bioinformatics and Computational Biology Approach Identifies New BH3-Only Protein Candidates." Open Biology Journal 5, no. 1 (May 4, 2012): 6–16. http://dx.doi.org/10.2174/1874196701205010006.

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In this study, we utilized an integrated bioinformatics and computational biology approach in search of new BH3-only proteins belonging to the BCL2 family of apoptotic regulators. The BH3 (BCL2 homology 3) domain mediates specific binding interactions among various BCL2 family members. It is composed of an amphipathic α-helical region of approximately 13 residues that has only a few amino acids that are highly conserved across all members. Using a generalized motif, we performed a genome-wide search for novel BH3-containing proteins in the NCBI Consensus Coding Sequence (CCDS) database. In addition to known pro-apoptotic BH3-only proteins, 197 proteins were recovered that satisfied the search criteria. These were categorized according to α-helical content and predictive binding to BCL-xL (encoded by BCL2L1) and MCL-1, two representative anti-apoptotic BCL2 family members, using position-specific scoring matrix models. Notably, the list is enriched for proteins associated with autophagy as well as a broad spectrum of cellular stress responses such as endoplasmic reticulum stress, oxidative stress, antiviral defense, and the DNA damage response. Several potential novel BH3-containing proteins are highlighted. In particular, the analysis strongly suggests that the apoptosis inhibitor and DNA damage response regulator, AVEN, which was originally isolated as a BCL-xLinteracting protein, is a functional BH3-only protein representing a distinct subclass of BCL2 family members.
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16

M, Cirone. "Could UPR Manipulation Help to Tune the Inflammatory Response in the Course of COVID-19?" Virology & Immunology Journal 4, no. 2 (July 2, 2020): 1–5. http://dx.doi.org/10.23880/vij-16000244.

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Анотація:
Highly pathogenic coronavirus SARS-CoV2, belonging to coronaviridae family, preferentially infects alveolar epithelial cells and immune cells resident or recruited in the lung, causing the disease known as COVID-19. As for other viruses, SARS-CoV2 is sensed by several PRRs, particularly TLR3 that triggers an intracellular signaling culminating in activation of transcription factors that promote the release of inflammatory and anti-viral cytokines, deeply shaping immune response. In a subgroup of patents, a massive release of inflammatory cytokines may also occur, strongly contributing to destroy alveolar cells, fibrosis and endothelial injury, thus favoring the activation of coagulation cascade. Viral infection also triggers UPR, an integrated response to stress, by activating the antiviral kinase PKR and by perturbing ER homeostasis. ER stress/UPR strongly contributes to the regulation of cytokine release also because its signaling intersects with PRR signaling at multiple levels. In this perspective we will discuss the possibility to tune the inflammatory/immune response to SARS-CoV2 infection by reducing ER stress, manipulating the different arms of UPR or inducing autophagy.
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17

McFadden, Karyn, Amy Y. Hafez, Rigel Kishton, Joshua E. Messinger, Pavel A. Nikitin, Jeffrey C. Rathmell, and Micah A. Luftig. "Metabolic stress is a barrier to Epstein–Barr virus-mediated B-cell immortalization." Proceedings of the National Academy of Sciences 113, no. 6 (January 22, 2016): E782—E790. http://dx.doi.org/10.1073/pnas.1517141113.

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Epstein–Barr virus (EBV) is an oncogenic herpesvirus that has been causally linked to the development of B-cell and epithelial malignancies. Early after infection, EBV induces a transient period of hyperproliferation that is suppressed by the activation of the DNA damage response and a G1/S-phase growth arrest. This growth arrest prevents long-term outgrowth of the majority of infected cells. We developed a method to isolate and characterize infected cells that arrest after this early burst of proliferation and integrated gene expression and metabolic profiling to gain a better understanding of the pathways that attenuate immortalization. We found that the arrested cells have a reduced level of mitochondrial respiration and a decrease in the expression of genes involved in the TCA cycle and oxidative phosphorylation. Indeed, the growth arrest in early infected cells could be rescued by supplementing the TCA cycle. Arrested cells were characterized by an increase in the expression of p53 pathway gene targets, including sestrins leading to activation of AMPK, a reduction in mTOR signaling, and, consequently, elevated autophagy that was important for cell survival. Autophagy was also critical to maintain early hyperproliferation during metabolic stress. Finally, in assessing the metabolic changes from early infection to long-term outgrowth, we found concomitant increases in glucose import and surface glucose transporter 1 (GLUT1) levels, leading to elevated glycolysis, oxidative phosphorylation, and suppression of basal autophagy. Our study demonstrates that oncogene-induced senescence triggered by a combination of metabolic and genotoxic stress acts as an intrinsic barrier to EBV-mediated transformation.
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Bezu, Lucillia, Alejandra WU Chuang, Allan Sauvat, Sylvere Durand, Fanny Aprahamian, Xie Wei, Juliette Humeau, Fabrice Barlesi, Oliver Kepp, and Guido Kroemer. "Antitumor effects of local anesthetic agents in vitro and in vivo." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15091-e15091. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15091.

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e15091 Background: Local anesthetics (LA) are often used during surgery in order to control postoperative pain. Observational retrospective studies showed a significant and unexpected decrease of relapse and increased overall survival after LA injection during solid cancer removal. We hypothesized that LAs used as stand-alone treatment or combined with conventional anticancer therapy may induce cytotoxic effects on cancer cells and trigger antitumor responses against dead-cell antigens. Methods: Cell stress and cell death modalities were investigated in vitro by means of specific biosensors in human osteosarcoma (U2OS) cells after treatment with LAs such as bupivacaine, chloroprocaine, levobupivacaine, lidocaine, ropivacaine and prilocaine. Moreover tumor growth and overall survival were studied in solid tumor models (MCA 205 fibrosarcoma) established in immunocompetent C57Bl/6 mice treated under general anesthesia with LAs (lidocaine or ropivacaine) alone or combined with immune checkpoint blockade (anti-PD-1). Ethical Committee: CEEA IRCIV/IGR n°26, French Ministry of Research, Ref:16946/2018100309413893v2. Results: In vitro, the tested LAs triggered autophagy and induced all arms of the integrated stress response including the phosphorylation of eIF2alpha, the activation of ATF4, the splicing of XBP1 and the proteolytic cleavage of ATF6. Cell stress was followed by apoptotic cell death, and both were inhibited when eIF2alpha kinase 3 (EIF2AK3) was genetically removed by CRISPR/CAS9, while the removal of EIF2AK1, EIF2AK2 and EIF2AK4 had no effects on cellular demise. LAs also triggered mitochondrial dysfunction, mimicking the effect of mitochondrial uncouplers (such as rotenone and CCCP) characterized by respiratory chain and inhibition of a mitochondrial transmembrane enzyme (carnitine-acylcarnitine translocase). In vivo, LAs induced effective tumor growth reduction and improved survival of immunocompetent but not immunodeficient mice, suggesting the ignition of anticancer immune responses. These anticancer immune effects were significantly potentiated when LAs were combined with PD-1 immune checkpoint blockade. LAs and mitochondrial uncouplers failed to induce anticancer effects in MCA205 tumors that were unable to induce ER stress (due to EIF2AK3 knockout) or autophagy (due to AtG5 KO), suggesting that both premortem stress responses are indispensable for inducing anticancer immunity. Conclusions: LAs induce EIF2AK3-dependent cancer cell stress including autophagy and the integrated stress response, which is followed by mitochondrial toxicity and cell death both in vitro and in cancers established in mice. These effects trigger therapeutically relevant anticancer immune responses that can be further potentiated by means of PD-1 blockade. These preclinical observations suggest that the use of LAs during oncological surgery improves clinical outcome by inducing anticancer immunity.
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19

Burton, Thomas D., Anthony O. Fedele, Jianling Xie, Lauren Y. Sandeman, and Christopher G. Proud. "The gene for the lysosomal protein LAMP3 is a direct target of the transcription factor ATF4." Journal of Biological Chemistry 295, no. 21 (April 20, 2020): 7418–30. http://dx.doi.org/10.1074/jbc.ra119.011864.

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Анотація:
Autophagy and lysosomal activities play a key role in the cell by initiating and carrying out the degradation of misfolded proteins. Transcription factor EB (TFEB) functions as a master controller of lysosomal biogenesis and function during lysosomal stress, controlling most but, importantly, not all lysosomal genes. Here, we sought to better understand the regulation of lysosomal genes whose expression does not appear to be controlled by TFEB. Sixteen of these genes were screened for transactivation in response to diverse cellular insults. mRNA levels for lysosomal-associated membrane protein 3 (LAMP3), a gene that is highly up-regulated in many forms of cancer, including breast and cervical cancers, were significantly increased during the integrated stress response, which occurs in eukaryotic cells in response to accumulation of unfolded and misfolded proteins. Of note, results from siRNA-mediated knockdown of activating transcription factor 4 (ATF4) and overexpression of exogenous ATF4 cDNA indicated that ATF4 up-regulates LAMP3 mRNA levels. Finally, ChIP assays verified an ATF4-binding site in the LAMP3 gene promoter, and a dual-luciferase assay confirmed that this ATF4-binding site is indeed required for transcriptional up-regulation of LAMP3. These results reveal that ATF4 directly regulates LAMP3, representing the first identification of a gene for a lysosomal component whose expression is directly controlled by ATF4. This finding may provide a key link between stresses such as accumulation of unfolded proteins and modulation of autophagy, which removes them.
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20

Lanzillotta, Chiara, and Fabio Di Domenico. "Stress Responses in Down Syndrome Neurodegeneration: State of the Art and Therapeutic Molecules." Biomolecules 11, no. 2 (February 11, 2021): 266. http://dx.doi.org/10.3390/biom11020266.

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Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis. Increasing evidence has recently shown that oxidative stress (OS), associated with mitochondrial dysfunction and with the failure of antioxidant responses (e.g., SOD1 and Nrf2), is an early signature of DS, promoting protein oxidation and the formation of toxic protein aggregates. In turn, systems involved in the surveillance of protein synthesis/folding/degradation mechanisms, such as the integrated stress response (ISR), the unfolded stress response (UPR), and autophagy, are impaired in DS, thus exacerbating brain damage. A number of pre-clinical and clinical studies have been applied to the context of DS with the aim of rescuing redox balance and proteostasis by boosting the antioxidant response and/or inducing the mechanisms of protein re-folding and clearance, and at final of reducing cognitive decline. So far, such therapeutic approaches demonstrated their efficacy in reverting several aspects of DS phenotype in murine models, however, additional studies aimed to translate these approaches in clinical practice are still needed.
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21

Xu, Yang, Yang, Berezowska, Gao, Liang, Marti, et al. "Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma." Cancers 11, no. 10 (October 8, 2019): 1502. http://dx.doi.org/10.3390/cancers11101502.

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Malignant pleural mesothelioma (MPM) is a lethal cancer with limited treatment options. No targeted therapy has emerged yet. Here, we performed an integrated molecular characterization of patient tumors in the TCGA dataset, and discovered that endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR) signaling are characteristically deregulated in MPM. Consequently, pharmacological perturbation of ER stress/UPR axis by HA15, an agent that induces persistent proteotoxic stress in the ER, selectively suppresses the viability of MPM cells including those refractory to standard chemotherapy. Mechanically, HA15 augments the already high basal level of ER stress in MPM cells, embarks pro-apoptotic malfunctional UPR and autophagy, which eventually induces cell death in MPM. Importantly, HA15 exerts anti-MPM effectiveness in a mouse model of patient-derived xenografts (PDX) without eliciting overt toxicity when compared to chemotherapy. Our results revealed that programs orchestrating ER stress/UPR signaling represent therapeutic vulnerabilities in MPM and validate HA15 as a promising agent to treat patients with MPM, naïve or resistant to chemotherapy.
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22

Dash, Srikanta, Yucel Aydin, and Tong Wu. "Integrated stress response in hepatitis C promotes Nrf2-related chaperone-mediated autophagy: A novel mechanism for host-microbe survival and HCC development in liver cirrhosis." Seminars in Cell & Developmental Biology 101 (May 2020): 20–35. http://dx.doi.org/10.1016/j.semcdb.2019.07.015.

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23

Soler-Agesta, Ruth, Joaquín Marco-Brualla, Martha Minjárez-Sáenz, Christina Y. Yim, Marta Martínez-Júlvez, Matthew R. Price, Raquel Moreno-Loshuertos, Tyler D. Ames, José Jimeno, and Alberto Anel. "PT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies." Cancers 14, no. 16 (August 9, 2022): 3851. http://dx.doi.org/10.3390/cancers14163851.

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Анотація:
PT-112 is a novel pyrophosphate–platinum conjugate, with clinical activity reported in advanced pretreated solid tumors. While PT-112 has been shown to induce robust immunogenic cell death (ICD) in vivo but only minimally bind DNA, the molecular mechanism underlying PT-112 target disruption in cancer cells is still under elucidation. The murine L929 in vitro system was used to test whether differential metabolic status alters PT-112’s effects, including cell cytotoxicity. The results showed that tumor cells presenting mutations in mitochondrial DNA (mtDNA) (L929dt and L929dt cybrid cells) and reliant on glycolysis for survival were more sensitive to cell death induced by PT-112 compared to the parental and cybrid cells with an intact oxidative phosphorylation (OXPHOS) pathway (L929 and dtL929 cybrid cells). The type of cell death induced by PT-112 did not follow the classical apoptotic pathway: the general caspase inhibitor Z-VAD-fmk did not inhibit PT-112-induced cell death, alone or in combination with the necroptosis inhibitor necrostatin-1. Interestingly, PT-112 initiated autophagy in all cell lines, though this process was not complete. Autophagy is known to be associated with an integrated stress response in cancer cells and with subsequent ICD. PT-112 also induced a massive accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial polarization—only in the sensitive cells harboring mitochondrial dysfunction—along with calreticulin cell-surface exposure consistent with ICD. PT-112 substantially reduced the amount of mitochondrial CoQ10 in L929 cells, while the basal CoQ10 levels were below our detection limits in L929dt cells, suggesting a potential relationship between a low basal level of CoQ10 and PT-112 sensitivity. Finally, the expression of HIF-1α was much higher in cells sensitive to PT-112 compared to cells with an intact OXPHOS pathway, suggesting potential clinical applications.
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24

Whittemore, Scott, Sujata Saraswat Ohri, Michael Forston, George Wei, and Michal Hetman. "The Proteostasis Network: A Global Therapeutic Target for Neuroprotection after Spinal Cord Injury." Cells 11, no. 21 (October 22, 2022): 3339. http://dx.doi.org/10.3390/cells11213339.

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Proteostasis (protein homeostasis) is critical for cellular as well as organismal survival. It is strictly regulated by multiple conserved pathways including the ubiquitin-proteasome system, autophagy, the heat shock response, the integrated stress response, and the unfolded protein response. These overlapping proteostasis maintenance modules respond to various forms of cellular stress as well as organismal injury. While proteostasis restoration and ultimately organism survival is the main evolutionary driver of such a regulation, unresolved disruption of proteostasis may engage pro-apoptotic mediators of those pathways to eliminate defective cells. In this review, we discuss proteostasis contributions to the pathogenesis of traumatic spinal cord injury (SCI). Most published reports focused on the role of proteostasis networks in acute/sub-acute tissue damage post-SCI. Those reports reveal a complex picture with cell type- and/or proteostasis mediator-specific effects on loss of neurons and/or glia that often translate into the corresponding modulation of functional recovery. Effects of proteostasis networks on such phenomena as neuro-repair, post-injury plasticity, as well as systemic manifestations of SCI including dysregulation of the immune system, metabolism or cardiovascular function are currently understudied. However, as potential interventions that target the proteostasis networks are expected to impact many cell types across multiple organ systems that are compromised after SCI, such therapies could produce beneficial effects across the wide spectrum of highly variable human SCI.
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25

Masson, Glenn R. "Towards a model of GCN2 activation." Biochemical Society Transactions 47, no. 5 (October 11, 2019): 1481–88. http://dx.doi.org/10.1042/bst20190331.

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Abstract Cells must be able to sense and adapt to their surroundings to thrive in a dynamic environment. Key to adapting to a low nutrient environment is the Integrated Stress Response (ISR), a short-lived pathway that allows cells to either regain cellular homeostasis or facilitate apoptosis during periods of stress. Central to the ISR is the protein kinase General Control Non-depressible 2 (GCN2), which is responsible for sensing starvation. Upon amino acid deficiency, GCN2 is activated and initiates the ISR by phosphorylating the translation initiation factor eIF2α, stalling protein translation, and activating the transcription factor ATF4, which in turn up-regulates autophagy and biosynthesis pathways. A key outstanding question is how GCN2 is activated from an autoinhibited state. Until recently, a model of activation focussed on the increase of deacylated tRNA associated with amino acid starvation, with deacylated tRNA binding directly to GCN2 and releasing autoinhibition. However, in vivo experiments have pointed towards an alternative, deacylated-tRNA-independent mechanism of activation. Here, we review the various factors that may facilitate GCN2 activation, including recent research showing that the P-stalk complex, a ribosome-associated heteropentameric protein complex, is a potent activator of GCN2.
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26

Ning, Xianhui, Ye Peng, Peng Tang, Yiran Zhang, Lingling Wang, Wenwen Zhang, Kai Zhang, Jie Ji, and Shaowu Yin. "Integrated Analysis of Transcriptome and Metabolome Reveals Distinct Responses of Pelteobagrus fulvidraco against Aeromonas veronii Infection at Invaded and Recovering Stage." International Journal of Molecular Sciences 23, no. 17 (September 4, 2022): 10121. http://dx.doi.org/10.3390/ijms231710121.

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Yellow catfish (Pelteobagrus fulvidraco) is an important aquaculture fish susceptible to Aeromonas veronii infection, which causes acute death resulting in huge economic losses. Understanding the molecular processes of host immune defense is indispensable to disease control. Here, we conducted the integrated and comparative analyses of the transcriptome and metabolome of yellow catfish in response to A. veronii infection at the invaded stage and recovering stage. The crosstalk between A. veronii-induced genes and metabolites uncovered the key biomarkers and pathways that strongest contribute to different response strategies used by yellow catfish at corresponding defense stages. We found that at the A. veronii invading stage, the immune defense was strengthened by synthesizing lipids with energy consumption to repair the skin defense line and accumulate lipid droplets promoting intracellular defense line; triggering an inflammatory response by elevating cytokine IL-6, IL-10 and IL-1β following PAMP-elicited mitochondrial signaling, which was enhanced by ROS produced by impaired mitochondria; and activating apoptosis by up-regulating caspase 3, 7 and 8 and Prostaglandin F1α, meanwhile down-regulating FoxO3 and BCL6. Apoptosis was further potentiated via oxidative stress caused by mitochondrial dysfunction and exceeding inflammatory response. Additionally, cell cycle arrest was observed. At the fish recovering stage, survival strategies including sugar catabolism with D-mannose decreasing; energy generation through the TCA cycle and Oxidative phosphorylation pathways; antioxidant protection by enhancing Glutathione (oxidized), Anserine, and α-ketoglutarate; cell proliferation by inducing Cyclin G2 and CDKN1B; and autophagy initiated by FoxO3, ATG8 and ATP6V1A were highlighted. This study provides a comprehensive picture of yellow catfish coping with A. veronii infection, which adds new insights for deciphering molecular mechanisms underlying fish immunity and developing stage-specific disease control techniques in aquaculture.
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27

Park, Seo-Yeon, Eun Byun, Jeong Lee, Sungjoo Kim, and Hei Kim. "Air Pollution, Autophagy, and Skin Aging: Impact of Particulate Matter (PM10) on Human Dermal Fibroblasts." International Journal of Molecular Sciences 19, no. 9 (September 12, 2018): 2727. http://dx.doi.org/10.3390/ijms19092727.

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Анотація:
A World Health Organization (WHO) report from 2016 states that over 3 million people die annually from air pollution, which places air pollution as the world’s largest single environmental health risk factor. Particulate matter (PM) is one of the main components of air pollution, and there is increasing evidence that PM exposure exerts negative effects on the human skin. To see the impact of air pollution on skin aging, we analyzed the effect of PM exposure on human dermal fibroblasts (HDFs) with Western blot, enzyme-linked immunosorbent assay (ELISA), and gene analysis. Cultured HDFs were exposed to PM10 at a concentration of 30 µg/cm2 for 24 h, and their gene/protein expression of inflammatory cytokines, fibroblast chemical mediators, and autophagy were assessed. A total of 1977 genes were found to be differentially expressed following PM exposure. We observed a significantly increased expression of pro-inflammatory genes interleukin (IL)-1β, IL-6, IL-8 and IL-33 in dermal fibroblasts exposed to PM10. Protein expression of IL-6 and IL-8 also significantly increased, which complemented our gene analysis results. In addition, there was a significant increase in cytochrome P450 (CYP1A1, CYP1B1), matrix metalloproteinase (MMP-1, MMP-3) mRNA expression, and significant decrease in transforming growth factor (TGF)-β, collagen type I alpha chain (COL1A1, COL1A2), and elastin (ELN) mRNA expression in PM-exposed dermal fibroblasts. Protein expression of MMP-1 was significantly increased and that of TGF-β and procollagen profoundly decreased, similar to the gene analysis results. Autophagy, an integrated cellular stress response, was also increased while transmission electron microscopy (TEM) analysis provided evidence of PM internalization in the autolysosomes. Taken together, our results demonstrate that PM10 contributes to skin inflammation and skin aging via impaired collagen synthesis. Increased autophagy in our study suggests a reparative role of autophagy in HDFs stressed with PM, but its biological significance requires further research.
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28

Zhang, Qian, Xiaowei Fu, Junsong Wang, Minghua Yang, and Lingyi Kong. "Treatment Effects of Ischemic Stroke by Berberine, Baicalin, and Jasminoidin from Huang-Lian-Jie-Du-Decoction (HLJDD) Explored by an Integrated Metabolomics Approach." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–20. http://dx.doi.org/10.1155/2017/9848594.

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Berberine, baicalin, and jasminoidin were major active ingredients of Huang-Lian-Jie-Du-Decoction (HLJDD), a famous prescription of traditional Chinese medicine (TCM), which has been used for the treatment of ischemic stroke. The aim of the present study was to classify their roles in the treatment effects of ischemic stroke. A rat model of middle cerebral artery occlusion (MCAO) was constructed to mimic ischemic stroke and treatment effects of berberine, baicalin, and jasminoidin, and HLJDD was assessed by neurologic deficit scoring, infarct volume, histopathology, immunohistochemistry, biochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. In addition, the 1H NMR metabolomics approach was used to assess the metabolic profiles, which combined with correlation network analysis successfully revealed metabolic disorders in ischemic stroke concerning the treatment of the three principal compounds from HLJDD for the first time. The combined results suggested that berberine, baicalin, and jasminoidin are responsible for the effectiveness of HLJDD on the treatment of ischemic stroke by amelioration of abnormal metabolism and regulation of oxidative stress, neuron autophagy, and inflammatory response. This integrated metabolomics approach showed its potential in understanding the function of complex formulae and clarifying the role of its components in the overall treatment effects.
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29

Ochi, Akinobu, Dong Chen, Wibke Schulte, Lin Leng, Nickolas Moeckel, Marta Piecychna, Luisa Averdunk, Christian Stoppe, Richard Bucala, and Gilbert Moeckel. "MIF-2/D-DT enhances proximal tubular cell regeneration through SLPI- and ATF4-dependent mechanisms." American Journal of Physiology-Renal Physiology 313, no. 3 (September 1, 2017): F767—F780. http://dx.doi.org/10.1152/ajprenal.00683.2016.

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Macrophage migration inhibitory factor (MIF) is a cytokine with pleiotropic actions that is produced by several organs and cell types. Depending on the target cell and the inflammatory context, MIF can engage its two component receptor complex CD74 and CD44 and the chemokine receptors CXCR2/4. MIF is constitutively expressed in renal proximal tubular cells, stored in intracellular preformed pools, and released at a low rate. Recently, a second MIF-like protein (i.e., MIF-2/D-DT) has been characterized in mammals. Our study was aimed at examining the role of MIF-2/D-DT, which mediates tissue protection in the heart, in tubular cell regeneration from ischemia-reperfusion injury. We found that Mif−/−, Mif-2−/−, and Cd74−/− mice had significantly worse tubular injury compared with wild-type (WT) control mice and that treatment with MIF-2/D-DT significantly improved recovery of injured epithelial cells. RNAseq analysis of kidney tissue from the ischemia-reperfusion injury model revealed that MIF-2/D-DT treatment stimulates secretory leukocyte proteinase inhibitor (SLPI) and cyclin D1 expression. MIF-2/D-DT additionally activates of eukaryotic initiation factor (eIF) 2α and activating transcription factor (ATF) 4, two transcription factors involved in the integrated stress response (ISR), which is a cellular stress response activated by hypoxia, nutrient deprivation, and oxygen radicals. MIF-2/D-DT also inhibited apoptosis and induced autophagy in hypoxia-treated mouse proximal tubular (MPT) cells. These results indicate that MIF-2/D-DT is an important factor in tubular cell regeneration and may be of therapeutic utility as a regenerative agent in the clinical setting of ischemic acute kidney injury.
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30

Raufi, Alexander G., Arielle De La Cruz, Lindsey Carlsen, Kelsey Huntington, Lanlan Zhou, Varun Prabhu, Joshua Allen, and Wafik S. El-Deiry. "Abstract 319: Imipridone ONC212 and trametinib combination therapy demonstrates anti-neoplastic effects through immune-mediated mechanisms in pancreatic ductal adenocarcinoma cell lines." Cancer Research 82, no. 12_Supplement (June 15, 2022): 319. http://dx.doi.org/10.1158/1538-7445.am2022-319.

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by limited therapeutic options and an extremely high mortality-to-incidence ratio. Chemotherapy remains the primary treatment for metastatic disease and results in only modest improvements in median overall survival, typically with significant toxicity. We previously reported a novel treatment approach with the combination of the imipridone ONC212 and the MEK inhibitor trametinib. This combination demonstrated synergy in multiple KRAS-mutated and KRAS wild-type pancreatic cancer cell lines (BxPC3, PANC1, HPAF-II, AsPC-1). Using Western Blot, we assessed markers of autophagy, including Beclin-1 and LC3B, as well as key second messenger pathway activation/suppression with p-AKT/AKT and p-ERK/ERK. The mechanism of this synergy appears to be heterogeneous, working through autophagy inhibition, MAPK/PI3K pathway perturbation, activation of the integrated stress response and increased cell surface expression of death receptor 5. Further investigation has revealed that ONC212 also appears to synergize with various autophagy inhibitors including hydroxychloroquine and chloroquine. We hypothesized that combining trametinib and ONC212 may also induce cell death in-part through immune cell-mediated mechanisms. To explore this, we performed immune cell co-culture experiments using HPAF-II PDAC cells and natural killer (NK-92) cells at a 1:1 effector-to-target cell ratio with or without ONC212, trametinib, or the combination of the two at different concentrations. We assessed the levels of NK cell mediated-tumor cell death 4, 8, and 24-hours after simultaneous treatment and initiation of co-culture using fluorescent microscopy. Compared to trametinib, ONC212 only treated co-culture showed greater NK cell-mediated tumor cell death. At 24-hours, we also observed an increase in NK cell-mediated killing of PDAC cells with dual treatment as compared to single agent alone or vehicle controls. Importantly, this combination did not appear to have any effect on NK or tumor cell viability. Thus, this combination may represent a potential therapeutic modality for PDAC and may hold promise if combined with immunotherapy. Further in vitro experiments will be conducted to evaluate the effect of ONC212, trametinib, and other autophagy inhibitors on the PDAC tumor microenvironment using a T cell co-culture system. Similarly, in vivo murine studies will also be performed to assess the translational potential of this combination. Citation Format: Alexander G. Raufi, Arielle De La Cruz, Lindsey Carlsen, Kelsey Huntington, Lanlan Zhou, Varun Prabhu, Joshua Allen, Wafik S. El-Deiry. Imipridone ONC212 and trametinib combination therapy demonstrates anti-neoplastic effects through immune-mediated mechanisms in pancreatic ductal adenocarcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 319.
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31

Keipert, Susanne, Mario Ost, Kornelia Johann, Francine Imber, Martin Jastroch, Evert M. van Schothorst, Jaap Keijer, and Susanne Klaus. "Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine." American Journal of Physiology-Endocrinology and Metabolism 306, no. 5 (March 1, 2014): E469—E482. http://dx.doi.org/10.1152/ajpendo.00330.2013.

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Анотація:
UCP1-Tg mice with ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) are a model of improved substrate metabolism and increased longevity. Analysis of myokine expression showed an induction of fibroblast growth factor 21 (FGF21) in SM, resulting in approximately fivefold elevated circulating FGF21 in UCP1-Tg mice. Despite a reduced muscle mass, UCP1-Tg mice showed no evidence for a myopathy or muscle autophagy deficiency but an activation of integrated stress response (ISR; eIF2α/ATF4) in SM. Targeting mitochondrial function in vitro by treating C2C12 myoblasts with the uncoupler FCCP resulted in a dose-dependent activation of ISR, which was associated with increased expression of FGF21, which was also observed by treatment with respiratory chain inhibitors antimycin A and myxothiazol. The cofactor required for FGF21 action, β-klotho, was expressed in white adipose tissue (WAT) of UCP1-Tg mice, which showed an increased browning of WAT similar to what occurred in altered adipocyte morphology, increased brown adipocyte markers (UCP1, CIDEA), lipolysis (HSL phosphorylation), and respiratory capacity. Importantly, treatment of primary white adipocytes with serum of transgenic mice resulted in increased UCP1 expression. Additionally, UCP1-Tg mice showed reduced body length through the suppressed IGF-I-GH axis and decreased bone mass. We conclude that the induction of FGF21 as a myokine is coupled to disturbance of mitochondrial function and ISR activation in SM. FGF21 released from SM has endocrine effects leading to increased browning of WAT and can explain the healthy metabolic phenotype of UCP1-Tg mice. These results confirm muscle as an important endocrine regulator of whole body metabolism.
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32

Poulain, Laury, Adrien Grenier, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Rudy Birsen, et al. "PKR-like Endoplasmic Reticulum Kinase Mediates Apoptosis Induced By Pharmacological AMP-Activated Protein Kinase Activation in Acute Myeloid Leukemia." Blood 134, Supplement_1 (November 13, 2019): 2552. http://dx.doi.org/10.1182/blood-2019-123364.

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Анотація:
Acute myeloid leukemia (AML) is a myeloid progenitor-derived neoplasm of poor prognosis, particularly among the elderly, in whom age and comorbidities preclude the use of intensive therapies. Novel therapeutic approaches for AML are therefore critically needed. Adenosine monophosphate (AMP) activated protein kinase (AMPK) is a pleiotropic serine/threonine kinase promoting catabolism that represses anabolism and enhances autophagy in response to stress1. AMPK heterotrimers comprise catalytic α- and regulatory β- and γ-subunits, the latter harboring binding sites for AMP. Targets of AMPK include a host of metabolic pathway enzymes mediating carbohydrate, lipid and protein synthesis and metabolism. Accumulating evidence implicates AMPK in cancer biology, primarily as a tumor suppressor, although minimal AMPK activity may also be required for cancer cell growth under stress conditions2,3. Pharmacological activation of AMPK thus represents an attractive new strategy for targeting AML. We previously used the selective small molecule AMPK activator GSK621 to show that AMPK activation induces cytotoxicity in AML but not in normal hematopoietic cells, contingent on concomitant activation of the mammalian target of rapamycin complex 1 (mTORC1)4. However, the precise mechanisms of AMPK-induced AML cytotoxicity have remained unclear. We integrated gene expression profiling and bioinformatics proteomic analysis to identify the serine/threonine kinase PERK - one of the key effectors of the endoplasmic reticulum stress response - as a potential novel target of AMPK. We showed that PERK was directly phosphorylated by AMPK on at least two conserved residues (serine 439 and threonine 680) and that AMPK activators elicited a PERK/eIF2A signaling cascade independent of the endoplasmic reticulum stress response in AML cells. CRISPR/Cas9 depletion and complementation assays illuminated a critical role for PERK in apoptotic cell death induced by pharmacological AMPK activation. Indeed, GSK621 induced mitochondrial membrane depolarization and apoptosis in AML cells, an effect that was mitigated when cells were depleted of PERK or expressed PERK with a loss of function AMPK phosphorylation site mutation. We identified the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) as a downstream target of the AMPK/PERK pathway, as its expression was enhanced in PERK knockdown AML cells. Moreover, selective pharmacologic activation of ALDH2 by the small molecule ALDA-1 recapitulated the protective effects of PERK depletion in the face of pharmacological AMPK activation. Corroborating the impact of the AMPK/PERK axis on mitochondrial apoptotic function, BH3 profiling showed marked Bcl-2 dependency in AML cells treated with GSK621. This dependency was abrogated in PERK-depleted cells, suggesting a role for PERK in mitochondrial priming to cell death. In vitro drug combination studies further demonstrated synergy between the clinical grade Bcl-2 inhibitor venetoclax (ABT-199) and each of four AMPK activators (GSK621, MK-8722, PF-06409577 and compound 991) in multiple AML cell lines. Finally, the addition of GSK621 to venetoclax enhanced anti-leukemic activity in primary AML patient samples ex vivo and in humanized mouse models in vivo. These findings together clarify the mechanisms of cytotoxicity induced by AMPK activation and suggest that combining pharmacologic AMPK activators with venetoclax may hold therapeutic promise in AML. References 1. Lin S-C, Hardie DG. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metabolism. 2018;27(2):299-313. 2. Hardie DG. Molecular Pathways: Is AMPK a Friend or a Foe in Cancer? Clinical Cancer Research. 2015;21(17):3836-3840. 3. Jeon S-M, Hay N. The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch. Pharm. Res. 2015;38(3):346-357. 4. Sujobert P, Poulain L, Paubelle E, et al. Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia. Cell Rep. 2015;11(9):1446-1457. Figure Disclosures Tamburini: Novartis pharmaceutical: Research Funding; Incyte: Research Funding.
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33

Hoff, Fieke W., Yihua Qiu, Brandon Brown, Robert B. Gerbing, Alan S. Gamis, Richard Aplenc, Edward A. Kolb, et al. "Valosin-Containing Protein (VCP/p97) Is Prognostically Unfavorable in Subtypes of Acute Leukemia, and Negatively Correlates with UPR-Proteins IRE1 and GRP78." Blood 138, Supplement 1 (November 5, 2021): 3447. http://dx.doi.org/10.1182/blood-2021-147066.

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Abstract Introduction: The endoplasmic reticulum (ER) is the major site of protein synthesis and folding in the cell. Three pathways are integrated to maintain ER homeostasis: ER-associated degradation (ERAD), unfolded protein response (UPR), and autophagy. One of the chief elements of ERAD is the highly conserved AAA-ATPase superfamily member valosin-containing protein (VCP, or p97). Various studies have reported an upregulation of VCP in cancer and an association between elevated VCP expression and unfavorable cancer outcome. A promising therapeutic approach relies on targeting the cellular stress response, and systemic functional genomic screens have identified VCP as potential target for inhibition in acute myeloid leukemia (AML). As clinical impact of VCP has not been studied, we wondered whether baseline protein expression levels were predictive of outcome in acute leukemia (AL). Methods: Reverse Phase Protein Array (RPPA) was performed with strictly validated antibodies, including antibodies against VCP, IRE1 and GRP78, to determine the protein expression levels of diagnostic leukemic cells from 500 pediatric AML, 818 adult AML, 268 pediatric T-ALL and 93 adult T-ALL patient samples. Pediatric patients participated on either the COG AAML1031 or AALL1231 clinical trial comparing standard therapy (ADE or AFBM) to standard therapy plus bortezomib (ADE+B or AFBM+B). Adults were treated under a variety of protocols. Pearson correlation analyses was used to identify significant protein-protein correlations. Estimates of survival was calculated using the Kaplan-Meier method. Results: VCP protein was expressed in both AML and T-ALL. Although VCP was slightly more highly expressed in AL vs normal CD34+ cells, the majority of patients had VCP expression within the normal range. In pediatric AML, VCP was more highly expressed in younger patients (< 2 y/o), KMT2A (formerly MLL)-rearrangement (p<0.001) and high WBC count (p=0.01) while it was lower in inv(16) (p=0.0003), t(8;21) (p=0.0016), c-Kit (exon 8, p=0.00061; exon 17, p=0.0003), and MYH11 (p=0.0013). FLT3, NPM1, CEBPA, NRAS, KRAS, PTPN11, IDH1/2, and GATA2 mutation status were not associated with VCP expression. Survival analysis identified a significant association between VCP and outcome. In pediatric AML, 5-yr overall survival (OS) was 81% in low-VCP vs 60% and 66% in middle and high-VCP (p<0.001) (Figure 1A). A similar observation was done for event-free survival (5-yr EFS, 59% vs 45-48%, p=0.004) and relapse risk (5-yr RR, 33% vs. 40-47%, p=0.019). This was independent of treatment (with or without bortezomib). High-VCP remained a significant independently unfavorable prognostic variable in multivariate analysis together with high-risk group (per AAML1031 definition) and age < 2 y/o (HR=1.45, HR= 1.75, HR=2.39, respectively). The same observation was seen in adult AML and T-ALL (Figure 1B-C); low-VCP did better than high VCP (AML: 5-yr OS, 32% vs 24%, p=0.029; T-ALL: 4-yr OS, 25% vs 50-60%). In pediatric T-ALL, no association with survival was found (4-yr OS; 89% vs 85%, p=0.45). Protein-protein correlations identified an inverse correlation with VCP and UPR proteins IRE1 and GRP78 in each subtype of AL. Other strong positive correlations were with proteins involved in histone modification, mTor and ribosomal proteins, and strong negative correlations with transcription factors, DNA repair and signal transduction pathways. Conclusion: Using a proteomics approach we identified low-VCP as favorable prognostic indicator. This prognostic association was independent of treatment with a proteasome inhibitor, suggesting that the prognostic effect was potentially separate from the proteasome, and points toward a potential for VCP drug inhibition. Negative correlation with VCP and IRE1 and GRP78 might imply that cells with higher VCP rely on proteasomal degradation, whereas those with low VCP are more dependent on other pathways for protein degradation. Also, adaptation in VCP levels may not be a prominent feature of the stress response to chemotherapy. More information is needed to understand what is driving VCP expression. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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34

Guieze, Romain, Vivian M. Liu, Daniel Rosebrock, Alexis Jourdain, María Hernández-Sánchez, Aina zurita Martinez, Sun Jing, et al. "Genetic Determinants of Venetoclax Resistance in Lymphoid Malignancies." Blood 132, Supplement 1 (November 29, 2018): 893. http://dx.doi.org/10.1182/blood-2018-99-118604.

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Abstract The FDA-approval of potent targeted therapies has led to great changes in the therapeutic landscape of chronic lymphocytic leukemia (CLL). As a key example, venetoclax, a first-in-class BCL-2 inhibitor, leads to response in about 80% of patients with relapsed/refractory (R/R) CLL. Disease progression on venetoclax, however, has been increasingly observed, and better biologic understanding of resistance mechanisms to this agent is needed. To systematically discover the potential mechanisms of resistance to venetoclax, we performed both genome-scale loss- (LOF) and gain-of-function (GOF) genetic modifier screens in the BCL-2-driven OCI-Ly1 lymphoma cell line using CRISPR-Cas9 sgRNA and ORF libraries, respectively. Significant hits from both screens included the BCL-2 family: the LOF screen with pro-apoptotic genes (PMAIP1, BAX, BAK1, BCL-2L11) and the GOF screen with anti-apoptotic genes (BCL2L1, BCL2L2, BCL2, MCL1). In addition, the LOF screen uncovered genes in pathways relevant to lymphoid biology (i.e, NFKBIA) and lymphoid transcription factors and modulators (IKZF5, ID3, EP300, NFIA). The GOF screen also uncovered components of the energy-stress sensor PKA/AMPK signaling pathways (ADIPOQ, PRKAR2B, PRKAA2) and regulators of mitochondrial metabolism. In parallel, we performed an integrated transcriptome, whole proteome and functional characterization of an OCI-Ly1 cell line rendered resistant to venetoclax (OCI-Ly1-R) from the parental cell line (OCI-Ly1-S). RNA-seq and spectrometry-based proteomics revealed coordinated dysregulation of transcripts and proteins in the resistant line originating from genes critical to cellular metabolism, cell cycle, B-cell biology and autophagy. Of the transcripts and proteins significantly associated with the resistant cell line, only MCL-1 overlapped with the gene hits from the genome-scale screens. Treatment of the OCI-Ly-R cells with the MCL-1 inhibitor S63845 synergized with venetoclax. Given the dysregulation of proteins critical to metabolism in both the GOF screen and in OCI-Ly1-R cells, we also evaluated the role of metabolic reprogramming in venetoclax resistance. We first assessed mitochondrial respiration by measuring the oxygen consumption rate. Compared to OCI-Ly-S cells, OCI-Ly1-R cells demonstrated markedly higher respiration levels, suggesting a state of higher oxidative phosphorylation (OXPHOS). More directly, we measured oxygen consumption following venetoclax exposure. Consistent with impairment of OXPHOS by venetoclax, we observed both an immediate decrease in oxygen consumption and an immediate burst of glycolysis following venetoclax in the OCI-Ly1-S cells, but not in the OCI-Ly1-R cells. In line with these findings, the AMPK inhibitor dorsomorphin and mitochondrial electron transport chain (mETC) inhibitors synergized with venetoclax in OCI-Ly1-S cells. Transcriptome related to ID3 (identified as one of the LOF screen targets) was characterized in isogenic ID3-knockout OCI-Ly1 lines. It revealed PRKAR2B overexpression as a key effect, suggesting a role for ID3, and perhaps of other lymphoid transcription factors in regulating metabolic reprogramming associated with resistance. Indeed, exposure of ID3 knockout lines to mETC inhibitors overcame resistance to venetoclax. To determine if there is a genetic basis for the drug resistance seen in OCI-Ly1-R cells, we compared whole-exome sequencing (WES) results of DNA isolated from the OCI-Ly1-R and OCI-Ly1-S cell lines. A clear region was amplified on chromosome 1q23, which includes MCL1 and PRKAB2 (the regulatory subunit of AMPK). Similarly, a WES-based analysis of paired CLL DNA samples isolated from 6 R/R CLL patients just prior to venetoclax initiation and at time of progression on venetoclax was performed. We did not identify any non-silent somatic single nucleotide in BCL2 or its family members at baseline or at progression, despite marked clonal shifts in all patients. We confirmed the presence of the amp(1q23) as acquired at relapse after venetoclax in 3 out of 6 patients. Our study reveals that venetoclax resistance implicates changes not only for outer mitochondrial membrane (MCL-1 expression) but also for inner membrane (oxydative metabolism). Such mitochondrial reprogramming represents a new vulnerability that can potentially be exploited through combinatorial therapy with metabolic modulators to overcome resistance. Disclosures Guieze: abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria. Thompson:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davids:Merck: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; MEI Pharma: Consultancy, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Brown:Sun Pharmaceutical Industries: Research Funding; Abbvie: Consultancy; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Janssen: Consultancy; Sunesis: Consultancy; Roche/Genentech: Consultancy; Verastem: Consultancy, Research Funding; Boehringer: Consultancy; Loxo: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Invectys: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy; Genentech: Consultancy. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Letai:AstraZeneca: Consultancy, Other: Lab research report; Novartis: Consultancy, Other: Lab research report; AbbVie: Consultancy, Other: Lab research report; Flash Therapeutics: Equity Ownership; Vivid Biosciences: Equity Ownership. Wu:Neon Therapeutics: Equity Ownership.
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35

Crespillo-Casado, Ana, Joseph E. Chambers, Peter M. Fischer, Stefan J. Marciniak та David Ron. "PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz". eLife 6 (27 квітня 2017). http://dx.doi.org/10.7554/elife.26109.

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Dephosphorylation of translation initiation factor 2 (eIF2α) terminates signalling in the mammalian integrated stress response (ISR) and has emerged as a promising target for modifying the course of protein misfolding diseases. The [(o-chlorobenzylidene)amino]guanidines (Guanabenz and Sephin1) have been proposed to exert protective effects against misfolding by interfering with eIF2α-P dephosphorylation through selective disruption of a PP1-PPP1R15A holophosphatase complex. Surprisingly, they proved inert in vitro affecting neither stability of the PP1-PPP1R15A complex nor substrate-specific dephosphorylation. Furthermore, eIF2α-P dephosphorylation, assessed by a kinase shut-off experiment, progressed normally in Sephin1-treated cells. Consistent with its role in defending proteostasis, Sephin1 attenuated the IRE1 branch of the endoplasmic reticulum unfolded protein response. However, repression was noted in both wildtype and Ppp1r15a deleted cells and in cells rendered ISR-deficient by CRISPR editing of the Eif2s1 locus to encode a non-phosphorylatable eIF2α (eIF2αS51A). These findings challenge the view that [(o-chlorobenzylidene)amino]guanidines restore proteostasis by interfering with eIF2α-P dephosphorylation.
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36

Chen, Yanan, Rejani B. Kunjamma, Molly Weiner, Jonah R. Chan, and Brian Popko. "Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment." eLife 10 (March 23, 2021). http://dx.doi.org/10.7554/elife.65469.

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The inflammatory environment of demyelinated lesions in multiple sclerosis (MS) patients contributes to remyelination failure. Inflammation activates a cytoprotective pathway, the integrated stress response (ISR), but it remains unclear whether enhancing the ISR can improve remyelination in an inflammatory environment. To examine this possibility, the remyelination stage of experimental autoimmune encephalomyelitis (EAE), as well as a mouse model that incorporates cuprizone-induced demyelination along with CNS delivery of the proinflammatory cytokine IFN-γ were used here. We demonstrate that either genetic or pharmacological ISR enhancement significantly increased the number of remyelinating oligodendrocytes and remyelinated axons in the inflammatory lesions. Moreover, the combined treatment of the ISR modulator Sephin1 with the oligodendrocyte differentiation enhancing reagent bazedoxifene increased myelin thickness of remyelinated axons to pre-lesion levels. Taken together, our findings indicate that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation, suggesting that ISR enhancement may provide reparative benefit to MS patients.
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37

Pernin, Florian, Julia Luo, Qiao-Ling Cui, Manon Blain, Milton G. F. Fernandes, Moein Yaqubi, Myriam Srour, et al. "Diverse injury responses of human oligodendrocyte to mediators implicated in multiple sclerosis." Brain, February 24, 2022. http://dx.doi.org/10.1093/brain/awac075.

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Abstract Early multiple sclerosis lesions feature relative preservation of oligodendrocyte cell bodies with dying back retraction of their myelinating processes. Cell loss occurs with disease progression. Putative injury mediators include metabolic stress (low glucose/nutrient), pro-inflammatory mediators (interferon γ and tumor necrosis factor α), and excitotoxins (glutamate). Our objective was to compare the impact of these disease relevant mediators on the injury responses of human mature oligodendrocytes. In the current study, we determined the effects of these mediators on process extension and survival of human brain derived mature oligodendrocytes in vitro and used bulk RNA sequencing to identify distinct effector mechanisms that underlie the responses. All mediators induced significant process retraction of the oligodendrocytes in dissociated cell culture. Only metabolic stress (low glucose/nutrient) conditions resulted in delayed (4-6 days) non-apoptotic cell death. Metabolic effects were associated with induction of the integrated stress response, which can be protective or contribute to cell injury dependent on its level and duration of activation. Addition of Sephin1, an agonist of the integrated stress response induced process retraction under control conditions and further enhanced retraction under metabolic stress conditions. The antagonist ISRIB restored process outgrowth under stress conditions, and if added to already stressed cells, reduced delayed cell death and prolonged the period in which recovery could occur. Inflammatory cytokine functional effects were associated with activation of multiple signaling pathways (including Jak/Stat-1) that regulate process outgrowth, without integrated stress response induction. Glutamate application produced limited transcriptional changes suggesting a contribution of effects directly on cell processes. Our comparative studies indicate the need to consider both the specific injury mediators and the distinct cellular mechanisms of responses to them by human oligodendrocytes to identify effective neuroprotective therapies for multiple sclerosis.
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38

Sannino, Sara, Megan E. Yates, Mark E. Schurdak, Steffi Oesterreich, Adrian V. Lee, Peter Wipf, and Jeffrey L. Brodsky. "Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised." eLife 10 (June 28, 2021). http://dx.doi.org/10.7554/elife.64977.

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Molecular chaperones, such as Hsp70, prevent proteotoxicity and maintain homeostasis. This is perhaps most evident in cancer cells, which overexpress Hsp70 and thrive even when harboring high levels of misfolded proteins. To define the response to proteotoxic challenges, we examined adaptive responses in breast cancer cells in the presence of an Hsp70 inhibitor. We discovered that the cells bin into distinct classes based on inhibitor sensitivity. Strikingly, the most resistant cells have higher autophagy levels, and autophagy was maximally activated only in resistant cells upon Hsp70 inhibition. In turn, resistance to compromised Hsp70 function required the integrated stress response transducer, GCN2, which is commonly associated with amino acid starvation. In contrast, sensitive cells succumbed to Hsp70 inhibition by activating PERK. These data reveal an unexpected route through which breast cancer cells adapt to proteotoxic insults and position GCN2 and autophagy as complementary mechanisms to ensure survival when proteostasis is compromised.
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39

Tian, Ai-Ling, Qi Wu, Peng Liu, Liwei Zhao, Isabelle Martins, Oliver Kepp, Marion Leduc, and Guido Kroemer. "Lysosomotropic agents including azithromycin, chloroquine and hydroxychloroquine activate the integrated stress response." Cell Death & Disease 12, no. 1 (January 2021). http://dx.doi.org/10.1038/s41419-020-03324-w.

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AbstractThe integrated stress response manifests with the phosphorylation of eukaryotic initiation factor 2α (eIF2α) on serine residue 51 and plays a major role in the adaptation of cells to endoplasmic reticulum stress in the initiation of autophagy and in the ignition of immune responses. Here, we report that lysosomotropic agents, including azithromycin, chloroquine, and hydroxychloroquine, can trigger eIF2α phosphorylation in vitro (in cultured human cells) and, as validated for hydroxychloroquine, in vivo (in mice). Cells bearing a non-phosphorylatable eIF2α mutant (S51A) failed to accumulate autophagic puncta in response to azithromycin, chloroquine, and hydroxychloroquine. Conversely, two inhibitors of eIF2α dephosphorylation, nelfinavir and salubrinal, enhanced the induction of such autophagic puncta. Altogether, these results point to the unexpected capacity of azithromycin, chloroquine, and hydroxychloroquine to elicit the integrated stress response.
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40

Wu, Yongshu, Zhidong Zhang, Yanmin Li, and Yijing Li. "The Regulation of Integrated Stress Response Signaling Pathway on Viral Infection and Viral Antagonism." Frontiers in Microbiology 12 (February 11, 2022). http://dx.doi.org/10.3389/fmicb.2021.814635.

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The integrated stress response (ISR) is an adaptational signaling pathway induced in response to different stimuli, such as accumulation of unfolded and misfolded proteins, hypoxia, amino acid deprivation, viral infection, and ultraviolet light. It has been known that viral infection can activate the ISR, but the role of the ISR during viral infection is still unclear. In some cases, the ISR is a protective mechanism of host cells against viral infection, while viruses may hijack the ISR for facilitating their replication. This review highlighted recent advances on the induction of the ISR upon viral infection and the downstream responses, such as autophagy, apoptosis, formation of stress granules, and innate immunity response. We then discussed the molecular mechanism of the ISR regulating viral replication and how viruses antagonize this cellular stress response resulting from the ISR.
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41

Jenkins, Edmund Charles, Mrittika Chattopadhyay, and Doris Germain. "Folding Mitochondrial-Mediated Cytosolic Proteostasis Into the Mitochondrial Unfolded Protein Response." Frontiers in Cell and Developmental Biology 9 (September 23, 2021). http://dx.doi.org/10.3389/fcell.2021.715923.

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Several studies reported that mitochondrial stress induces cytosolic proteostasis. How mitochondrial stress activates proteostasis in the cytosol remains unclear. However, the cross-talk between the mitochondria and cytosolic proteostasis has far reaching implications for treatment of proteopathies including neurodegenerative diseases. This possibility appears within reach since selected drugs have begun to emerge as being able to stimulate mitochondrial-mediated cytosolic proteostasis. In this review, we focus on studies describing how mitochondrial stress activates proteostasis in the cytosol across multiple model organisms. A model is proposed linking mitochondrial-mediated regulation of cytosolic translation, folding capacity, ubiquitination, and proteasome degradation and autophagy as a multi layered control of cytosolic proteostasis that overlaps with the integrated stress response (ISR) and the mitochondrial unfolded protein response (UPRmt). By analogy to the conductor in an orchestra managing multiple instrumental sections into a dynamically integrated musical piece, the cross-talk between these signaling cascades places the mitochondria as a major conductor of cellular integrity.
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42

de la Cruz-Ojeda, Patricia, Rocío Flores-Campos, Elena Navarro-Villarán, and Jordi Muntané. "The Role of Non-Coding RNAs in Autophagy During Carcinogenesis." Frontiers in Cell and Developmental Biology 10 (March 2, 2022). http://dx.doi.org/10.3389/fcell.2022.799392.

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Macroautophagy (autophagy herein) is a cellular stress response and a survival pathway involved in self-renewal and quality control processes to maintain cellular homeostasis. The alteration of autophagy has been implicated in numerous diseases such as cancer where it plays a dual role. Autophagy serves as a tumor suppressor in the early phases of cancer formation with the restoration of homeostasis and eliminating cellular altered constituents, yet in later phases, autophagy may support and/or facilitate tumor growth, metastasis and may contribute to treatment resistance. Key components of autophagy interact with either pro- and anti-apoptotic factors regulating the proximity of tumor cells to apoptotic cliff promoting cell survival. Autophagy is regulated by key cell signaling pathways such as Akt (protein kinase B, PKB), mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) involved in cell survival and metabolism. The expression of critical members of upstream cell signaling, as well as those directly involved in the autophagic and apoptotic machineries are regulated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Consequently, non-coding RNAs play a relevant role in carcinogenesis and treatment response in cancer. The review is an update of the current knowledge in the regulation by miRNA and lncRNA of the autophagic components and their functional impact to provide an integrated and comprehensive regulatory network of autophagy in cancer.
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43

Kulkarni, Abhishek, Charanya Muralidharan, Sarah C. May, Sarah A. Tersey та Raghavendra G. Mirmira. "Inside the β cell: Molecular Stress Response Pathways in Diabetes Pathogenesis". Endocrinology, 1 листопада 2022. http://dx.doi.org/10.1210/endocr/bqac184.

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Abstract The pathogeneses of the two major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing β-cells is common to virtually all forms of diabetes. Although the mechanisms underlying β-cell dysfunction remain incompletely characterized, recent years have been witness to major advances in our understanding of the molecular pathways that contribute to the demise of the β-cell. Cellular and environmental factors contribute to β-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and β-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the identification of genes and proteins specifically involved in β-cell dysfunction during diabetes pathogenesis. Here, we review the critical stress response pathways that are activated in β-cells in the context of the animal models.
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44

Clarke, Robert, Ayesha N. Shajahan, Yue Wang, John J. Tyson, Rebecca B. Riggins, Louis M. Weiner, William T. Bauman, et al. "Endoplasmic reticulum stress, the unfolded protein response, and gene network modeling in antiestrogen resistant breast cancer." Hormone Molecular Biology and Clinical Investigation 5, no. 1 (January 1, 2011). http://dx.doi.org/10.1515/hmbci.2010.073.

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AbstractLack of understanding of endocrine resistance remains one of the major challenges for breast cancer researchers, clinicians, and patients. Current reductionist approaches to understanding the molecular signaling driving resistance have offered mostly incremental progress over the past 10 years. As the field of systems biology has begun to mature, the approaches and network modeling tools being developed and applied therein offer a different way to think about how molecular signaling and the regulation of crucial cellular functions are integrated. To gain novel insights, we first describe some of the key challenges facing network modeling of endocrine resistance, many of which arise from the properties of the data spaces being studied. We then use activation of the unfolded protein response (UPR) following induction of endoplasmic reticulum stress in breast cancer cells by antiestrogens, to illustrate our approaches to computational modeling. Activation of UPR is a key determinant of cell fate decision-making and regulation of autophagy and apoptosis. These initial studies provide insight into a small subnetwork topology obtained using differential dependency network analysis and focused on the UPR gene XBP1. The XBP1 subnetwork topology incorporates BCAR3, BCL2, BIK, NF-κB, and other genes as nodes; the connecting edges represent the dependency structures among these nodes. As data from ongoing cellular and molecular studies become available, we will build detailed mathematical models of this XBP1-UPR network.
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45

Lu, Lixin, Lihua Ren, Lisheng Jiang, Xiaohui Xu, Weijun Wang, Yanwei Feng, Zan Li, Jianmin Yang, and Guohua Sun. "Integrative proteomics and metabolomics reveal the stress response of semicarbazide in the sea cucumber Apostichopus japonicus." Frontiers in Marine Science 9 (December 2, 2022). http://dx.doi.org/10.3389/fmars.2022.992753.

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Semicarbazide (SMC), also known as carbamoyl hydrazide, is a key intermediate for the organic synthesis of drugs, pesticides, and a panoply of other applications. It is also regarded as a landmark metabolite of nitrofurazone, a banned veterinary drug. SMC produced in different ways will eventually enter the ocean and become an emerging marine pollutant, affecting the physiological metabolism, behavioral activities, and even survival of aquatic organisms. Sea cucumbers are sediment-feeding organisms, and their risk of exposure to pollutants has attracted increasing attention. In this study, an integrated proteomic and metabolomic approach was used to investigate the responses of Apostichopus japonicus treated with SMC (3.72 g/L) for 72 h. After SMC treatment, the proteins and metabolites of A. japonicus intestine changed significantly. The results showed that 342 differentially expressed proteins were identified, of which 174 were upregulated, 168 were downregulated, and 74 differentially expressed metabolites, of which 62 were upregulated and 12 were downregulated. These differential proteins and metabolites were primarily involved in energy metabolism, lipid metabolism, signal transduction, immune regulation, autophagy, and apoptosis. On the basis of a combination of proteomic and metabolomic data, a hypothetical network of proteins, metabolites, and pathways in sea cucumbers was also described; the resulting network indicated several significant biological activities in response to SMC. This work offers a thorough analysis of the intricate mechanisms by which sea cucumbers respond to SMC stress and indicates numerous possible indicators for further research on creatures exposed to SMC. Further, our results provide scientific guidance for pollution control of Apostichopus japonicus culture to ensure healthy breeding.
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46

Lopez-Soler, Reynold I., Azadeh Nikouee, Matthew Kim, Saman Khan, Lakshmi Sivaraman, Xiangzhong Ding, and Qun Sophia Zang. "Beclin-1 dependent autophagy improves renal outcomes following Unilateral Ureteral Obstruction (UUO) injury." Frontiers in Immunology 14 (February 16, 2023). http://dx.doi.org/10.3389/fimmu.2023.1104652.

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BackgroundInterstitial Fibrosis and Tubular Atrophy (IFTA) is the most common cause of long-term graft failure following renal transplant. One of the hallmarks of IFTA is the development of interstitial fibrosis and loss of normal renal architecture. In this study, we evaluated the role of autophagy initiation factor Beclin-1 in protecting against post-renal injury fibrosis.MethodsAdult male wild type (WT) C57BL/6 mice were subjected to Unilateral Ureteral Obstruction (UUO), and kidney tissue samples were harvested at 72-hour, 1- and 3-week post-injury. The UUO-injured and uninjured kidney samples were examined histologically for fibrosis, autophagy flux, inflammation as well activation of the Integrated Stress Response (ISR). We compared WT mice with mice carrying a forced expression of constitutively active mutant form of Beclin-1, Becn1F121A/F121A.ResultsIn all experiments, UUO injury induces a progressive development of fibrosis and inflammation. These pathological signs were diminished in Becn1F121A/F121A mice. In WT animals, UUO caused a strong blockage of autophagy flux, indicated by continuously increases in LC3II accompanied by an over 3-fold accumulation of p62 1-week post injury. However, increases in LC3II and unaffected p62 level by UUO were observed in Becn1F121A/F121A mice, suggesting an alleviation of disrupted autophagy. Beclin-1 F121A mutation causes a significant decrease in phosphorylation of inflammatory STING signal and limited production of IL6 and IFNγ, but had little effect on TNF-α, in response to UUO. Furthermore, activation of ISR signal cascade was detected in UUO-injured in kidneys, namely the phosphorylation signals of elF2S1 and PERK in addition to the stimulated expression of ISR effector ATF4. However, Becn1F121A/F121A mice did not reveal signs of elF2S1 and PERK activation under the same condition and had a dramatically reduced ATF level at 3-week post injury.ConclusionsThe results suggest that UUO causes a insufficient, maladaptive renal autophagy, which triggered downstream activation of inflammatory STING pathway, production of cytokines, and pathological activation of ISR, eventually leading to the development of fibrosis. Enhancing autophagy via Beclin-1 improved renal outcomes with diminished fibrosis, via underlying mechanisms of differential regulation of inflammatory mediators and control of maladaptive ISR.
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47

Trudu, Matteo, Laura Oliva, Ugo Orfanelli, Alessandra Romano, Francesco Di Raimondo, Francesca Sanvito, Maurilio Ponzoni, and Simone Cenci. "Preclinical evidence of a direct pro-survival role of arginine deprivation in multiple myeloma." Frontiers in Oncology 12 (September 8, 2022). http://dx.doi.org/10.3389/fonc.2022.968208.

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Анотація:
Multiple myeloma grows by establishing multiple interactions with bone marrow cells. These include expansion of myeloid-derived suppressor cells, which drive immunoevasion via mechanisms that include arginase-1-driven depletion of L-arginine, thus indirectly promoting myeloma cell survival and tumor progression. The peculiar biology of malignant plasma cells postulates that arginine depletion may benefit their fitness also directly, e.g., by engaging the integrated stress response, or by stimulating autophagy through mTORC1 inhibition. We thus investigated the direct impact of arginine deprivation on myeloma cells and challenged its pathophysiological relevance in vitro and in vivo. First, we found that partial arginine depletion spared proliferation of human multiple myeloma cells at concentrations that arrest human T cells. Next, we asked if arginine shortage activates putative adaptive pathways in myeloma cells. Low arginine failed to activate the integrated stress response, as indicated by unmodified phosphorylation of the eukaryotic initiation factor 2α, but sizably inhibited mTORC1, as revealed by reduced phosphorylation of ribosomal protein S6. Notably, depressed mTORC1 activity was not sufficient to increase autophagy, as assessed by the lysosomal digestion rate of the autophagosome-associated protein, LC3-II. Rather, it stimulated mTORC2, resulting in increased phosphatidylinositol-3 kinase-dependent AKT phosphorylation and activity, leading to heightened inhibitory phosphorylation of the pro-apoptotic BAD protein. We then tested whether arginine depletion-activated AKT may protect malignant plasma cells from cell death. Indeed, culturing myeloma cells in low arginine medium significantly reduced the apoptotic effect of the first-in-class proteasome inhibitor, bortezomib, an outcome prevented by pharmacological inhibition of AKT phosphorylation. Finally, we challenged the relevance of the identified circuit in vivo. To gauge the pathophysiologic relevance of low arginine to myeloma growth independently of immunoevasion, we xenotransplanted human myeloma cells subcutaneously into T cell-deficient Rag2–/–γc–/– recipient mice and treated palpable tumor-bearing mice with the clinical-grade arginase inhibitor CB1158. Arginase inhibition significantly raised serum arginine concentration, reduced tumor growth by caliper assessment, and decreased intra-tumor AKT phosphorylation in vivo. Altogether, our results reveal a novel direct pro-survival effect of arginine deprivation on myeloma cells, with potential therapeutic implications.
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48

Fidalgo da Silva, E., J. Fong, A. Roye-Azar, A. Nadi, C. Drouillard, A. Pillon, and L. A. Porter. "Beyond Protein Synthesis; The Multifaceted Roles of Tuberin in Cell Cycle Regulation." Frontiers in Cell and Developmental Biology 9 (January 14, 2022). http://dx.doi.org/10.3389/fcell.2021.806521.

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Анотація:
The ability of cells to sense diverse environmental signals, including nutrient availability and conditions of stress, is critical for both prokaryotes and eukaryotes to mount an appropriate physiological response. While there is a great deal known about the different biochemical pathways that can detect and relay information from the environment, how these signals are integrated to control progression through the cell cycle is still an expanding area of research. Over the past three decades the proteins Tuberin, Hamartin and TBC1D7 have emerged as a large protein complex called the Tuberous Sclerosis Complex. This complex can integrate a wide variety of environmental signals to control a host of cell biology events including protein synthesis, cell cycle, protein transport, cell adhesion, autophagy, and cell growth. Worldwide efforts have revealed many molecular pathways which alter Tuberin post-translationally to convey messages to these important pathways, with most of the focus being on the regulation over protein synthesis. Herein we review the literature supporting that the Tuberous Sclerosis Complex plays a critical role in integrating environmental signals with the core cell cycle machinery.
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49

Qin, Qiuhai, Lixiu Qin, Ruitang Xie, Shuihua Peng, Chao Guo, and Bin Yang. "Insight Into Biological Targets and Molecular Mechanisms in the Treatment of Arsenic-Related Dermatitis With Vitamin A via Integrated in silico Approach." Frontiers in Nutrition 9 (May 23, 2022). http://dx.doi.org/10.3389/fnut.2022.847320.

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Анотація:
Exposure to arsenic (As), an inorganic poison, may lead to skin lesions, including dermatitis. Vitamin A (VA), a fat-soluble vitamin essential for mucous membrane integrity, plays a key role in skin protection. Although the beneficial actions of VA are known, the anti-As-related dermatitis effects of VA action remain unclear. Hence, in this study, we aimed to interpret and identify the core target genes and therapeutic mechanisms of VA action in the treatment of As-related dermatitis through integrated in silico approaches of network pharmacology and molecular docking. We integrated the key VA-biological target-signaling pathway-As-related dermatitis networks for identifying core drug targets and interaction pathways associated with VA action. The network pharmacology data indicated that VA may possess potential activity for treating As-related dermatitis through the effective regulation of core target genes. An enrichment analysis in biological processes further revealed multiple immunoregulation-associated functions, including interferon-gamma production and negative regulation of T-cell activation and production of molecular mediator of immune response. An enrichment analysis in molecular pathways mainly uncovered multiple biological signaling, including natural killer cell mediated cytotoxicity, autophagy, apoptosis, necroptosis, platelet activation involved in cell fate, and immunity regulations. Molecular docking study was used to identify docked well core target proteins with VA, including Jun, tumor protein p53 (TP53), mitogen-activated protein kinase-3 (MAPK3), MAPK1, and MAPK14. In conclusion, the potential use of VA may suppress the inflammatory stress and enhance the immunity against As-related dermatitis. In the future, VA might be useful in the treatment of dermatitis associated with As through multi-targets and multi-pathways in clinical practice.
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50

Shrungeswara, Akhila Hosur, and Mazhuvancherry Kesavan Unnikrishnan. "Energy provisioning and inflammasome activation: The pivotal role of AMPK in sterile inflammation and associated metabolic disorders." Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry 19 (September 16, 2020). http://dx.doi.org/10.2174/1871523019666200916115034.

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Background: Body defenses and metabolic processes probably co-evolved in such a way that rapid, energyintensive acute inflammatory repair is functionally integrated with energy allocation in a starvation/ infection / injury-prone primitive environment. Disruptive metabolic surplus, aggravated by sedentary lifestyle, induces chronic under-activation of AMPK, the master regulator of intracellular energy homeostasis. Sudden increase in chronic, dysregulated ‘sterile’ inflammatory disorders probably results from a shift towards calorie rich, sanitized, cushioned, injury/ infection free environment, repositioning inflammatory repair pathways towards chronic, non-microbial, ‘sterile’, ‘low grade’, ‘parainflammation’. AMPK, (at the helm of energy provisioning) supervises the metabolic regulation of inflammasome activation, a common denominator in lifestyle disorders. Discussion: In this review we discuss various pathways linking AMPK under-activation and inflammasome activation. AMPK under-activation, the possible norm in energy-rich sedentary lifestyle, could be the central agency that stimulates inflammasome activation by multiple pathways such as: [1] decreasing autophagy, and accumulation of intracellular DAMPs, (particulate crystalline molecules, advanced glycation end-products, oxidized lipids etc.) [2] stimulating a glycolytic shift (pro-inflammatory) in metabolism, [3] promoting NF-kB activation and decreasing Nrf2 activation, [4] increasing reactive oxygen species (ROS) formation, unfolded protein response( UPR) and endoplasmic reticulum (ER) stress. Conclusion: The ‘inverse energy crisis’, associated with calorie-rich, sedentary lifestyle, advocates dietary and pharmacological interventions for treating chronic metabolic disorders by overcoming / reversing AMPK under-activation.
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