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Published: 4 June 2021
Last updated: 20 February 2023

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1

Marsolais, David, Claude H. Côté, and Jérôme Frenette. "Pifithrin-α, an inhibitor of p53 transactivation, alters the inflammatory process and delays tendon healing following acute injury." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292, no. 1 (January 2007): R321—R327. http://dx.doi.org/10.1152/ajpregu.00411.2005.

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Transcription factor p53, which was initially associated with cancer, has now emerged as an important regulator of inflammation and extracellular matrix homeostasis, two processes highly relevant to tendon repair. The goal of this study was to evaluate the effect of a p53 transactivation inhibitor, namely, pifithrin-α, on the pathophysiological sequence following collagenase-induced tendon injury. Administration of pifithrin-α during the inflammatory phase reduced the accumulation of neutrophils and macrophages by 30 and 40%, respectively, on day 3 postinjury. Pifithrin-α failed to reduce the percentage of apoptotic cells following collagenase injection but delayed functional recovery. In uninjured Achilles tendons, pifithrin-α increased metalloprotease activity 2.4-fold. Accordingly, pifithrin-α reduced the collagen content in intact tendons as well as in injured tendons 7 days posttrauma compared with placebo. The effect of pifithrin-α on load to failure and stiffness was also evaluated. The administration of pifithrin-α during the inflammatory phase did not significantly decrease the functional deficit 3 days posttrauma. More importantly, load to failure and stiffness were significantly decreased in the pifithrin-α group from day 7 to day 28 compared with placebo. Overall, our results suggest that administration of pifithrin-α alters the inflammatory process and delays tendon healing. The present findings also support the concept that p53 can regulate extracellular matrix homeostasis in vivo.
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2

Kaiser, Martin, Andrea Kuehnl, Jutta Ortiz-Tanchez, Ouidad Benlasfer, Cornelia Schlee, Sandra Heesch, Eckhard Thiel, and Claudia Baldus. "Antileukemic Activity of the HSP70 Inhibitor Pifithrin-μ." Blood 116, no. 21 (November 19, 2010): 3306. http://dx.doi.org/10.1182/blood.v116.21.3306.3306.

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Abstract Abstract 3306 Introduction: Heat shock protein (HSP) 70 is aberrantly expressed in acute leukemias and other hematologic and solid malignancies, promoting tumor cell survival and therapy resistance. Recently, the small molecule pifithrin-μ (2-phenylethynesulfonamide) has been identified as a direct inhibitor of inducible HSP70, showing antiproliferative activity in different cell lines of solid tumors. Here, we analysed the in vitro antileukemic effect of pifithrin-μ in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. In addition, incubations of pifithrin-μ with cytarabine, the histone deacetylase inhibitor SAHA, the HSP90 inhibitor 17-AAG, and the multikinase inhibitor sorafenib were performed to evaluate the potential use of combination therapies with pifithrin-μ in acute leukemias. Methods: Leukemic cell lines KG-1a (AML), K562 (CML in blast crisis), K562r (cytarabine-resistant K562), NALM-6 (B-lineage ALL), TOM-1 (B-lineage ALL, BCR-ABL pos.), Jurkat (T-lineage ALL), BE-13 (T-lineage ALL) and 9 bone marrow cell samples from newly diagnosed or relapsed AML patients were exposed to pifithrin-μ. Cell viability of all cell lines listed above was quantified by WST-1 assay. Subsequent functional analyses were performed on KG-1a and NALM-6 cells. Apoptosis was determined by annexin-V/7-AAD staining and subsequent flow cytometric analysis. Activated caspase-3 was detected by flow cytometry. Levels of the cell signaling kinase Akt were measured by intracellular staining and FACS analysis. Coincubations of pifithrin-μ with cytarabine, SAHA, 17-AAG or sorafenib were performed in KG-1a, NALM-6 and TOM-1, using WST-1 assays to analyse cytotoxic effects of combination therapies. Results: Pifithrin-μ at low micromolar concentrantions significantly inhibited viability of all acute leukemia cell lines tested, with IC50 values ranging from 2.5 to 12.7 μM independent of the differentiation lineage. Importantly, viability of both cytarabine-sensitive and -resistant K562 cells was effectively inhibited by pifithrin-μ. The median IC50 of primary AML blasts was 8.8 μM, ranging from 5.7 to 11.8 μM with no obvious differences regarding patients' clinical or genetic characteristics. Apoptosis was induced in a time- and dose-dependent fashion with a rate of specific apoptosis of 46% at 4 μM pifithrin-μ for NALM-6 and 36% at 40 μM pifithrin-μ for KG1a. In NALM-6, treatment with 3 μM pifithrin-μ for 24 hours resulted in a significant increase in the cleaved, active form of caspase-3, whereas in KG1a no increase in active caspase-3 was detected. Intracellular concentrations of Akt were markedly reduced after 12 hours incubation of NALM-6 with pifithrin-μ. In NALM-6, KG-1a, and TOM-1 combination treatment of pifithrin-μ at concentrations below the IC50 with either SAHA, 17-AAG or sorafenib resulted in a significant decrease of cell viability compared to corresponding monotherapy. Thus in NALM-6 combination of 2 μM pifithrin-μ with 0.6 μM SAHA inhibited viability by 73%, compared to 22% and 0% inhibition for either drug alone (p<0.05). Combination of 2 μM pifithrin-μ with 2 μM 17-AAG led to 58% inhibition, in contrast the monotherapy inhibited cell viability only in 31% for either drug alone. In NALM-6 and TOM-1, the combination of pifithrin-μ with cytarabine decreased viability significantly (47% and 55%, respectively), whereas the single agents were less effective (22% for 2 μM pifithrin-μ, 24% for 9 nM cytarabine in NALM-6; 26% for 3.5 μM pifithrin-μ and 41% for 40 nM cytarabine in TOM-1). Conclusion: This is, to our knowledge, the first report of the antileukemic effects of the HSP70 inhibitor pifithrin-μ. The inhibitor is highly active against all AML and ALL cell lines tested, including cytarabine resistant cell lines as well as primary leukemic cells. Effectivity of pifithrin-μ could even be increased in combination treatment with other antileukemic agents. Targeting HSP70 might be a promising new therapeutic approach for the treatment of acute leukemias to overcome drug resistance. Thus, our data might build a framework for future clinical trials. Disclosures: No relevant conflicts of interest to declare.
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3

Dagher, Pierre C., Erik M. Mai, Takashi Hato, So-Young Lee, Melissa D. Anderson, Stephanie C. Karozos, Henry E. Mang, Nicole L. Knipe, Zoya Plotkin, and Timothy A. Sutton. "The p53 inhibitor pifithrin-α can stimulate fibrosis in a rat model of ischemic acute kidney injury." American Journal of Physiology-Renal Physiology 302, no. 2 (January 15, 2012): F284—F291. http://dx.doi.org/10.1152/ajprenal.00317.2011.

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Inhibition of the tumor suppressor p53 diminishes tubular cell apoptosis and protects renal function in animal models of acute kidney injury (AKI). Therefore, targeting p53 has become an attractive therapeutic strategy in the approach to AKI. Although the acute protective effects of p53 inhibition in AKI have been examined, there is still relatively little known regarding the impact of acute p53 inhibition on the chronic sequelae of AKI. Consequently, we utilized the p53 inhibitor pifithrin-α to examine the long-term effects of p53 inhibition in a rodent model of ischemic AKI. Male Sprague-Dawley rats were subjected to bilateral renal artery clamping for 30 min followed by reperfusion for up to 8 wk. Pifithrin-α or vehicle control was administered at the time of surgery and then daily for 2 days [brief acute administration (BA)] or 7 days [prolonged acute administration (PA)]. Despite the acute protective effect of pifithrin-α in models of ischemic AKI, we found no protection in the microvascular rarefaction at 4 wk or development fibrosis at 8 wk with pifithrin-α administered on the BA schedule compared with vehicle control-treated animals. Furthermore, pifithrin-α administered on a PA schedule actually produced worse fibrosis compared with vehicle control animals after ischemic injury [21%/area (SD4.4) vs.16%/area (SD3.6)] as well as under sham conditions [2.6%/area (SD1.8) vs. 4.7%/area (SD1.3)]. The development of fibrosis with PA administration was independent of microvascular rarefaction. We identified enhanced extracellular matrix production, epithelial-to-mesenchymal transition, and amplified inflammatory responses as potential contributors to the augmented fibrosis observed with PA administration of pifithrin-α.
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4

Kooptiwut, Suwattanee, Kanokwan Samon, Namoiy Semprasert, Kanchana Suksri, and Pa-Thai Yenchitsomanus. "Prunetin Protects Against Dexamethasone-Induced Pancreatic Β-Cell Apoptosis via Modulation of p53 Signaling Pathway." Natural Product Communications 15, no. 4 (April 2020): 1934578X2091632. http://dx.doi.org/10.1177/1934578x20916328.

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Long-term administration of dexamethasone results in insulin resistance and pancreatic β-cell apoptosis. Prunetin (an O-methylated isoflavone, a type of flavonoid) is demonstrated to protect diabetes, but the molecular mechanism of this protection is still unclear. This study thus aims to investigate how prunetin protects against dexamethasone-induced pancreatic β-cell apoptosis. Rat insulinoma (INS-1) cells were cultured in medium with or without dexamethasone in the presence or absence of prunetin or pifithrin-α, a p53 inhibitor. Cell apoptosis was measured by Annexin V/propidium iodide staining. Dexamethasone significantly induced INS-1 apoptosis but dexamethasone plus prunetin significantly reduced INS-1 apoptosis. Dexamethasone-treated INS-1 upregulated p53 protein expression; the induction of p53 was also reduced in the presence of RU486, a glucocorticoid receptor (GR) inhibitor. This suggested that dexamethasone induced P53 via GR. Dexamethasone-treated INS-1 significantly increased p53, Bax, and Rb protein expressions, whereas treatments of dexamethasone plus prunetin or pifithrin-α significantly decreased these protein expressions. In addition, dexamethasone significantly decreased B-cell lymphoma 2 (Bcl2), while dexamethasone plus prunetin or pifithrin-α significantly increased Bcl2. Dexamethasone significantly increased caspase-3 activity while co-treatment of dexamethasone plus prunetin or pifithrin-α significantly decreased caspase-3 activity to the control level. Taken together, our results revealed that prunetin protected against dexamethasone-induced pancreatic β-cells apoptosis via modulation of the p53 signaling pathway.
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5

Chen, Yi-Xuan, Rong Zhu, Zheng-liang Xu, Qin-Fei Ke, Chang-Qing Zhang, and Ya-Ping Guo. "Self-assembly of pifithrin-α-loaded layered double hydroxide/chitosan nanohybrid composites as a drug delivery system for bone repair materials." Journal of Materials Chemistry B 5, no. 12 (2017): 2245–53. http://dx.doi.org/10.1039/c6tb02730j.

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The self-assembly of pifithrin-α-loaded layered double hydroxide/chitosan nanohybrid composites as a drug delivery system was demonstrated for the first time to improve the cytocompatibility and enhance the osteoinductivity for the treatment of bone defects.
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6

Beauchamp, Marie-Claude, Alexia Boucher, Yanchen Dong, Rachel Aber, and Loydie A. Jerome-Majewska. "Craniofacial Defects in Embryos with Homozygous Deletion of Eftud2 in Their Neural Crest Cells Are Not Rescued by Trp53 Deletion." International Journal of Molecular Sciences 23, no. 16 (August 12, 2022): 9033. http://dx.doi.org/10.3390/ijms23169033.

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Embryos with homozygous mutation of Eftud2 in their neural crest cells (Eftud2ncc−/−) have brain and craniofacial malformations, hyperactivation of the P53-pathway and die before birth. Treatment of Eftud2ncc−/− embryos with pifithrin-α, a P53-inhibitor, partly improved brain and craniofacial development. To uncover if craniofacial malformations and death were indeed due to P53 hyperactivation we generated embryos with homozygous loss of function mutations in both Eftud2 and Trp53 in the neural crest cells. We evaluated the molecular mechanism underlying craniofacial development in pifithrin-α-treated embryos and in Eftud2; Trp53 double homozygous (Eftud2ncc−/−; Trp53ncc−/−) mutant embryos. Eftud2ncc−/− embryos that were treated with pifithrin-α or homozygous mutant for Trp53 in their neural crest cells showed reduced apoptosis in their neural tube and reduced P53-target activity. Furthermore, although the number of SOX10 positive cranial neural crest cells was increased in embryonic day (E) 9.0 Eftud2ncc−/−; Trp53ncc−/− embryos compared to Eftud2ncc−/− mutants, brain and craniofacial development, and survival were not improved in double mutant embryos. Furthermore, mis-splicing of both P53-regulated transcripts, Mdm2 and Foxm1, and a P53-independent transcript, Synj2bp, was increased in the head of Eftud2ncc−/−; Trp53ncc−/− embryos. While levels of Zmat3, a P53- regulated splicing factor, was similar to those of wild-type. Altogether, our data indicate that both P53-regulated and P53-independent pathways contribute to craniofacial malformations and death of Eftud2ncc−/− embryos.
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7

Jiang, Man, Xiaolan Yi, Stephen Hsu, Cong-Yi Wang, and Zheng Dong. "Role of p53 in cisplatin-induced tubular cell apoptosis: dependence on p53 transcriptional activity." American Journal of Physiology-Renal Physiology 287, no. 6 (December 2004): F1140—F1147. http://dx.doi.org/10.1152/ajprenal.00262.2004.

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Tubular damage by cisplatin leads to acute renal failure, which limits its use in cancer therapy. In tubular cells, a primary target for cisplatin is presumably the genomic DNA. However, the pathway relaying the signals of DNA damage to tubular cell death is unclear. In response to DNA damage, the tumor suppressor gene p53 is induced and is implicated in subsequent DNA repair and cell death by apoptosis. The current study was designed to examine the role of p53 in cisplatin-induced apoptosis in cultured rat kidney proximal tubular cells. Cisplatin at 20 μM induced apoptosis in ∼70% of cells, which was partially suppressed by carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone (VAD), a general caspase inhibitor. Of interest, cisplatin-induced apoptosis was also suppressed by pifithrin-α, a pharmacological inhibitor of p53. Cisplatin-induced caspase activation was completely inhibited by VAD, but only partially by pifithrin-α. Early during cisplatin treatment, p53 was phosphorylated and upregulated. The p53 activation was blocked by pifithrin-α, but not by VAD. Bcl-2 expression abolished cisplatin-induced apoptosis without blocking p53 phosphorylation or induction. The results suggest that p53 activation might be an early signal for apoptosis during cisplatin treatment. To further determine the role of p53, tubular cells were stably transfected with a dominant-negative mutant of p53 with diminished transcriptional activity. Expression of the mutant attenuated cisplatin-induced apoptosis and caspase activation. In conclusion, the results support an important role for p53 in cisplatin-induced apoptosis in renal tubular cells. p53 May regulate apoptosis through the transcription of apoptotic genes.
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8

Krukowski, K., X. J. Huo, M. Ozcan, C. H. Nijboer, C. J. Heijnen, and A. Kavelaars. "109. Pifithrin-μ prevents paclitaxel-induced peripheral neuropathy in a mouse model." Brain, Behavior, and Immunity 40 (September 2014): e32. http://dx.doi.org/10.1016/j.bbi.2014.06.129.

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9

Sutton, Timothy A., Jared Wilkinson, Henry E. Mang, Nicole L. Knipe, Zoya Plotkin, Maya Hosein, Katelyn Zak, Jeremy Wittenborn, and Pierre C. Dagher. "p53 regulates renal expression of HIF-1α and pVHL under physiological conditions and after ischemia-reperfusion injury." American Journal of Physiology-Renal Physiology 295, no. 6 (December 2008): F1666—F1677. http://dx.doi.org/10.1152/ajprenal.90304.2008.

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Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) and is characterized by widespread tubular and microvascular damage. The tumor suppressor p53 is upregulated after IRI and contributes to renal injury in part by promoting apoptosis. Acute, short-term inhibition of p53 with pifithrin-α conveys significant protection after IRI. The hypoxia-inducible factor-1 (HIF-1) pathway is also activated after IRI and has opposing effects to those promoted by p53. The balance between the HIF-1 and p53 responses can determine the outcome of IRI. In this manuscript, we investigate whether p53 regulates the HIF-1 pathway in a rodent model of IRI. HIF-1α is principally expressed in the collecting tubules (CT) and thick ascending limbs (TAL) under physiological conditions. However, inhibition of p53 with pifithrin-α increases the faint expression of HIF-1α in proximal tubules (PT) under physiological conditions. Twenty-four hours after IRI, HIF-1α expression is decreased in both CT and TAL. HIF-1α expression in the PT is not significantly altered after IRI. Acute inhibition of p53 significantly increases HIF-1α expression in the PT after IRI. Additionally, pifithrin-α prevents the IRI-induced decrease in HIF-1α in the CT and TAL. Parallel changes are observed in the HIF-1α transcriptive target, carbonic anhydrase-9. Finally, inhibition of p53 prevents the dramatic changes in Von Hippel-Lindau protein morphology and expression after IRI. We conclude that activation of p53 after IRI mitigates the concomitant activation of the protective HIF-1 pathway. Modulating the interactions between the p53 and HIF-1 pathway can provide novel options in the treatment of AKI.
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10

Steele, Andrew J., Archibald G. Prentice, A. Victor Hoffbrand, Birunthini C. Yogashangary, Stephen M. Hart, Elisabeth P. Nacheva, Julie D. Howard-Reeves, et al. "p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism." Blood 112, no. 9 (November 1, 2008): 3827–34. http://dx.doi.org/10.1182/blood-2008-05-156380.

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The p53 protein plays a key role in securing the apoptotic response of chronic lymphocytic leukemia (CLL) cells to genotoxic agents. Transcriptional induction of proapoptotic proteins including Puma are thought to mediate p53-dependent apoptosis. In contrast, recent studies have identified a novel nontranscriptional mechanism, involving direct binding of p53 to antiapoptotic proteins including Bcl-2 at the mitochondrial surface. Here we show that the major fraction of p53 induced in CLL cells by chlorambucil, fludarabine, or nutlin 3a was stably associated with mitochondria, where it binds to Bcl-2. The Puma protein, which was constitutively expressed in a p53-independent manner, was modestly up-regulated following p53 induction. Pifithrin α, an inhibitor of p53-mediated transcription, blocked the up-regulation of Puma and also of p21CIP1. Surprisingly, pifithrin α dramatically augmented apoptosis induction by p53-elevating agents and also accelerated the proapoptotic conformation change of the Bax protein. These data suggest that direct interaction of p53 with mitochondrial antiapoptotic proteins including Bcl-2 is the major route for apoptosis induction in CLL cells and that p53's transcriptional targets include proteins that impede this nontranscriptional pathway. Therefore, strategies that block up-regulation of p53-mediated transcription may be of value in enhancing apoptosis induction of CLL cells by p53-elevating drugs.
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11

Glas, Michael, Tamara Frick, Dirk Springe, Alessandro Putzu, Patrick Zuercher, Denis Grandgirard, Stephen L. Leib, Stephan M. Jakob, Jukka Takala, and Matthias Haenggi. "Neuroprotection with the P53-Inhibitor Pifithrin-μ after Cardiac Arrest in a Rodent Model." SHOCK 49, no. 2 (February 2018): 229–34. http://dx.doi.org/10.1097/shk.0000000000000917.

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12

Hoagland, Martin S., Erica M. Hoagland, and Hollie I. Swanson. "The p53 Inhibitor Pifithrin-α Is a Potent Agonist of the Aryl Hydrocarbon Receptor." Journal of Pharmacology and Experimental Therapeutics 314, no. 2 (April 20, 2005): 603–10. http://dx.doi.org/10.1124/jpet.105.084186.

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13

Lamoth, Frédéric, Praveen R. Juvvadi, Erik J. Soderblom, M. Arthur Moseley, and William J. Steinbach. "Hsp70 and the Cochaperone StiA (Hop) Orchestrate Hsp90-Mediated Caspofungin Tolerance in Aspergillus fumigatus." Antimicrobial Agents and Chemotherapy 59, no. 8 (May 26, 2015): 4727–33. http://dx.doi.org/10.1128/aac.00946-15.

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ABSTRACTAspergillus fumigatusis the primary etiologic agent of invasive aspergillosis (IA), a major cause of death among immunosuppressed patients. Echinocandins (e.g., caspofungin) are increasingly used as second-line therapy for IA, but their activity is only fungistatic. Heat shock protein 90 (Hsp90) was previously shown to trigger tolerance to caspofungin and the paradoxical effect (i.e., decreased efficacy of caspofungin at higher concentrations). Here, we demonstrate the key role of another molecular chaperone, Hsp70, in governing the stress response to caspofungin via Hsp90 and their cochaperone Hop/Sti1 (StiA inA. fumigatus). Mutation of the StiA-interacting domain of Hsp70 (C-terminal EELD motif) impaired thermal adaptation and caspofungin tolerance with loss of the caspofungin paradoxical effect. Impaired Hsp90 function and increased susceptibility to caspofungin were also observed following pharmacologic inhibition of the C-terminal domain of Hsp70 by pifithrin-μ or afterstiAdeletion, further supporting the links among Hsp70, StiA, and Hsp90 in governing caspofungin tolerance. StiA was not required for the physical interaction between Hsp70 and Hsp90 but had distinct roles in the regulation of their function in caspofungin and heat stress responses. In conclusion, this study deciphering the physical and functional interactions of the Hsp70-StiA-Hsp90 complex provided new insights into the mechanisms of tolerance to caspofungin inA. fumigatusand revealed a key C-terminal motif of Hsp70, which can be targeted by specific inhibitors, such as pifithrin-μ, to enhance the antifungal activity of caspofungin againstA. fumigatus.
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14

Murru, Siva, C. B. Singh, Veerababurao Kavala, and Bhisma K. Patel. "A convenient one-pot synthesis of thiazol-2-imines: application in the construction of pifithrin analogues." Tetrahedron 64, no. 8 (February 2008): 1931–42. http://dx.doi.org/10.1016/j.tet.2007.11.076.

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15

Sekihara, K., N. Harashima, N. Uchida, and M. Harada. "EP-1591 COMBINED EFFECT OF HYPERTHERMIA AND A NEW HSP70 INHIBITOR, PIFITHRIN-µ, ON PROSTATE CANCER." Radiotherapy and Oncology 103 (May 2012): S610. http://dx.doi.org/10.1016/s0167-8140(12)71924-2.

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16

Shao, Chunlin, Jianghong Zhang, and Kevin M. Prise. "Differential modulation of a radiation-induced bystander effect in glioblastoma cells by pifithrin-α and wortmannin." Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms 268, no. 6 (March 2010): 627–31. http://dx.doi.org/10.1016/j.nimb.2009.12.024.

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17

Gary, Ronald K., and Derek A. Jensen. "The p53 Inhibitor Pifithrin-α Forms a Sparingly Soluble Derivative via Intramolecular Cyclization under Physiological Conditions." Molecular Pharmaceutics 2, no. 6 (October 2005): 462–74. http://dx.doi.org/10.1021/mp050055d.

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18

Yano, Toshiyuki, Koki Abe, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Tetsuji Miura, and Charles Steenbergen. "Does p53 Inhibition Suppress Myocardial Ischemia–Reperfusion Injury?" Journal of Cardiovascular Pharmacology and Therapeutics 23, no. 4 (March 19, 2018): 350–57. http://dx.doi.org/10.1177/1074248418763612.

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p53 is well known as a regulator of apoptosis and autophagy. In addition, a recent study showed that p53 is a modulator of the opening of the mitochondrial permeability transition pore (mPTP), a trigger event of necrosis, but the role of p53 in necrosis induced by myocardial ischemia–reperfusion (I/R) remains unclear. The aim of this study was to determine the role of p53 in acute myocardial I/R injury in perfused mouse hearts. In male C57BL6 mice between 12 and 15 weeks of age, 2 types of p53 inhibitors were used to suppress p53 function during I/R: pifithrin-α, an inhibitor of transcriptional functions of p53, and pifithrin-μ, an inhibitor of p53 translocation from the cytosol to mitochondria. Neither infusion of these inhibitors before ischemia nor infusion for the first 30-minute period of reperfusion reduced infarct size after 20-minute ischemia/120-minute reperfusion. Infarct sizes were similar in p53 heterozygous knockout mice (p53+/−) and wild-type mice (WT), but recovery of rate pressure product (RRP) 120 minutes after reperfusion was higher in p53+/− than in WT. The protein expression of p53 in WT was negligible under baseline conditions, during ischemia, and at 10 minutes after the start of reperfusion, but it became detectable at 120 minutes after reperfusion. In conclusion, upregulation of p53 during the late phase of reperfusion plays a significant role in contractile dysfunction after reperfusion, although p53 is not involved in cardiomyocyte necrosis during ischemia or in the early phase of reperfusion.
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19

Krukowski, K., C. H. Nijboer, X. Huo, M. Maj, A. Kavelaars, and C. J. Heijnen. "Prevention of chemotherapy-induced peripheral neuropathy by the small-molecule inhibitor Pifithrin-mu in a mouse model." Brain, Behavior, and Immunity 49 (October 2015): e25-e26. http://dx.doi.org/10.1016/j.bbi.2015.06.105.

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20

Feldherr, Carl M., Debra Akin, and Robert J. Cohen. "Regulation of functional nuclear pore size in fibroblasts." Journal of Cell Science 114, no. 24 (December 15, 2001): 4621–27. http://dx.doi.org/10.1242/jcs.114.24.4621.

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Protein-NLS-coated gold particles up to approximately 250 Å in diameter are transported through the nuclear pores in normal, proliferating BALB/c 3T3 cells. This size can increase or decrease, depending on cellular activity. It has been suggested that increases in functional pore size are related to a reduction in the amount of available p53. To further test this hypothesis, we investigated the effects of cycloheximide and pifithrin-α, which inhibits p53-dependent transcriptional activation, on nuclear transport. After 3 hours in cycloheximide, there was a significant increase in the size of the gold particles that entered the nucleoplasm. When the incubation period was extended to 6 hours or longer, transport capacity returned to the control level. By using proteasome inhibitors, it was shown that the cycloheximide-dependent increase in functional pore size was due to the inhibition of protein synthesis, consistent with the fact that p53 is a short-lived protein, and requires the activity of at least two different factors. Although cycloheximide increases the functional diameter of the channel available for signal-mediated transport by approximately 60 Å, it had no significant effect on either the import rate of small NLS-containing substrates (FITC-BSA-NLS), or passive diffusion of fluorescent-labeled proteins across the envelope. This suggests that changes in transport capacity were not caused by an increase in overall pore diameter but instead are due to a transient increase in pore size that accompanies signal-mediated transport. Pifithrin-α also caused an increase in functional pore diameter without altering the import rate of FITC-BSA-NLS, providing further support for the view that p53 can initiate changes in nuclear transport capacity.
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21

Chen, Baosheng, Mark S. Longtine, Yoel Sadovsky, and D. Michael Nelson. "Hypoxia downregulates p53 but induces apoptosis and enhances expression of BAD in cultures of human syncytiotrophoblasts." American Journal of Physiology-Cell Physiology 299, no. 5 (November 2010): C968—C976. http://dx.doi.org/10.1152/ajpcell.00154.2010.

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Hypoxia is commonly assigned a role in the placental dysfunction characteristic of preeclampsia and intrauterine growth restriction. We previously showed that hypoxia upregulates p53 and enhances apoptosis in primary cultures of human cytotrophoblasts. Here we tested the hypothesis that hypoxia also induces apoptosis in syncytiotrophoblasts by upregulation of p53. Primary cultures of human cytotrophoblasts that had differentiated into syncytiotrophoblasts by 52 h were exposed for ≤24 h to 20% or <1% oxygen in the presence or absence of staurosporine or the p53 modulators nutlin-3, pifithrin-α, and pifithrin-μ. Proteins were detected by Western blot analysis or immunofluorescence. Compared with 20% oxygen, exposure of syncytiotrophoblasts to <1% oxygen upregulated hypoxia-inducible factor (HIF)-1α and rapidly downregulated p53. Activity of p53 in hypoxic syncytiotrophoblasts was reduced by the higher expression of the negative p53 regulator MDMX and by the reduction of phosphorylation of p53 at Ser392, which reduces p53 activity. Conversely, staurosporine, a kinase inhibitor, and nutlin-3, a drug that enhances p53 expression, both raised p53 levels and increased the rate of apoptosis in syncytiotrophoblasts compared with vehicle controls. Immunofluorescence staining showed p53 immunolocalized to both cytoplasm and nuclei of nutlin-3-exposed syncytiotrophoblasts. The hypoxia-induced apoptosis in syncytiotrophoblasts correlated with enhanced expression of the proapoptotic BAD and a reduced level of antiapoptotic BAD phosphorylated on Ser112. We surmise that cell death induced by extreme hypoxia in syncytiotrophoblasts follows a non-p53-dependent pathway, unlike that of a nonhypoxic stimulus and unlike hypoxic cytotrophoblasts. We speculate that downregulation of p53 activity in response to hypoxia reduces or eliminates the apoptosis transduced by the p53 pathway in syncytiotrophoblasts, thereby limiting cell death and maintaining the integrity of this critical villous component.
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Monma, Hiroyuki, Mamoru Harada, Nanae Harashima, Eiji Hira, Yasunari Kawabata, and Yoshitsugu Tajima. "Tu1870 Pifithrin-μ, a New HSP70 and Autophagy Inhibitor, Can Enhance Antitumor Effects of TRAIL on Pancreatic Cancer." Gastroenterology 144, no. 5 (May 2013): S—868. http://dx.doi.org/10.1016/s0016-5085(13)63227-8.

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YAN, Jun-hao, Xiao-mei YANG, Chun-hua CHEN, Qin HU, Jing ZHAO, Xian-zhong SHI, Li-ju LUAN, Lei YANG, Li-hua QIN, and Chang-man ZHOU. "Pifithrin-α reduces cerebral vasospasm by attenuating apoptosis of endothelial cells in a subarachnoid haemorrhage model of rat." Chinese Medical Journal 121, no. 5 (March 2008): 414–19. http://dx.doi.org/10.1097/00029330-200803010-00009.

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24

Kanno, Syu-ichi, Kaori Kurauchi, Ayako Tomizawa, Shin Yomogida, and Masaaki Ishikawa. "Pifithrin-alpha has a p53-independent cytoprotective effect on docosahexaenoic acid-induced cytotoxicity in human hepatocellular carcinoma HepG2 cells." Toxicology Letters 232, no. 2 (January 2015): 393–402. http://dx.doi.org/10.1016/j.toxlet.2014.11.016.

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25

Lin, Yunfu, Barbara Criscuolo Waldman, and Alan S. Waldman. "Suppression of high-fidelity double-strand break repair in mammalian chromosomes by pifithrin-α, a chemical inhibitor of p53." DNA Repair 2, no. 1 (January 2003): 1–11. http://dx.doi.org/10.1016/s1568-7864(02)00183-0.

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26

Liu, Xuwan, Chu C. Chua, Jinping Gao, Zhongyi Chen, Cathy L. C. Landy, Ronald Hamdy, and Balvin H. L. Chua. "Pifithrin-α protects against doxorubicin-induced apoptosis and acute cardiotoxicity in mice." American Journal of Physiology-Heart and Circulatory Physiology 286, no. 3 (March 2004): H933—H939. http://dx.doi.org/10.1152/ajpheart.00759.2003.

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The present experiments were designed to evaluate the effects of pifithrin-α (PFT-α), which is a p53 inhibitor, on doxorubicin (DOX)-induced apoptosis and cardiac injury. Administration of DOX (22.5 mg/kg ip) in mice upregulated the mRNA levels of Bax and MDM2, whereas PFT-α attenuated those levels when administered at a total dose of 4.4 mg/kg at 30 min before and 3 h after DOX challenge. DOX treatment led to an upregulation of p53 protein levels, which was preceded by elevated levels of phosphorylated p53 at Ser15. PFT-α had no effect on the level of p53 or its phosphorylated form. The protein levels of Bax and MDM2 were elevated by DOX and attenuated by PFT-α. DOX gave rise to increased apoptosis-positive nuclei in cardiac cells, elevated serum creatine phosphokinase, ultrastructural alterations, and cardiac dysfunction. PFT-α offered protection against all of the aforementioned changes. Finally, PFT-α did not interfere with the antitumor potency of DOX. This study demonstrates that PFT-α effectively inhibits DOX-induced cardiomyocyte apoptosis, which suggests that PFT-α has the potential to protect cancer patients against DOX-induced cardiac injury.
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Fetoni, Anna R., Eric C. Bielefeld, Gaetano Paludetti, Thomas Nicotera, and Donald Henderson. "A putative role of p53 pathway against impulse noise induced damage as demonstrated by protection with pifithrin-alpha and a Src inhibitor." Neuroscience Research 81-82 (April 2014): 30–37. http://dx.doi.org/10.1016/j.neures.2014.01.006.

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28

Sinn, Brigitte, Joern Schulze, Gisela Schroeder, Robert Konschak, Dorette Freyer, Volker Budach, and Ingeborg Tinhofer. "Pifithrin-α as a Potential Cytoprotective Agent in Radiotherapy: Protection of Normal Tissue without Decreasing Therapeutic Efficacy in Glioma Cells." Radiation Research 174, no. 5 (November 2010): 601–10. http://dx.doi.org/10.1667/rr2147.1.

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29

Mendjargal, Adilsaikhan, Erdenezaya Odkhuu, Naoki Koide, Hiroshi Nagata, Tsuyoshi Kurokawa, Toshiaki Nonami, and Takashi Yokochi. "Pifithrin-α, a pharmacological inhibitor of p53, downregulates lipopolysaccharide-induced nitric oxide production via impairment of the MyD88-independent pathway." International Immunopharmacology 15, no. 4 (April 2013): 671–78. http://dx.doi.org/10.1016/j.intimp.2013.02.014.

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30

Øster, Bodil, Emil Kofod-Olsen, Bettina Bundgaard, and Per Höllsberg. "Restriction of human herpesvirus 6B replication by p53." Journal of General Virology 89, no. 5 (May 1, 2008): 1106–13. http://dx.doi.org/10.1099/vir.0.83262-0.

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Human herpesvirus 6B (HHV-6B) induces significant accumulation of p53 in both the nucleus and cytoplasm during infection. Activation of p53 by DNA damage is known to induce either growth arrest or apoptosis; nevertheless, HHV-6B-infected cells are arrested in their cell cycle independently of p53, and only a minor fraction of the infected cells undergoes apoptosis. Using pifithrin-α, a p53 inhibitor, and p53-null cells, this study showed that infected epithelial cells accumulated viral transcripts and proteins to a significantly higher degree in the absence of active p53. Moreover, HHV-6B-induced cytopathic effects were greatly enhanced in the absence of p53. This suggests that, in epithelial cells, some of the functions of p53 leading to cell-cycle arrest and apoptosis are restrained by HHV-6B infection, whereas other cellular defences, causing inhibition of virus transcription, are partially retained.
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31

Xu, Haiming, Silvia Menendez, Brigitte Schlegelberger, Narae Bae, Peter D. Aplan, Gudrun Göhring, Tony R. Deblasio, and Stephen D. Nimer. "Loss of p53 accelerates the complications of myelodysplastic syndrome in a NUP98-HOXD13–driven mouse model." Blood 120, no. 15 (October 11, 2012): 3089–97. http://dx.doi.org/10.1182/blood-2012-01-405332.

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Abstract The nucleoporin gene NUP98 is fused to several genes including HOXD13 in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia, and chronic myeloid leukemia, blast crisis. Genetically engineered mice that express a NUP98-HOXD13 (NHD13) transgene (Tg) display the phenotypic features of MDS, including cytopenias, bone marrow dysplasia, and transformation to acute leukemia. Here we show that short-term treatment with the p53 inhibitor Pifithrin-α partially and transiently rescued the myeloid and lymphoid abnormalities found in NHD13+ Tg mice, with no improvement in the anemia, while the genetic deletion of 2 alleles of p53 rescued both the myeloid progenitor cell and long-term hematopoietic stem cell compartments. Nonetheless, loss of one or both alleles of p53 did not rescue the MDS phenotype, but instead exacerbated the MDS phenotype and accelerated the development of acute myeloid leukemia. Our studies suggest that while targeting p53 may transiently improve hematopoiesis in MDS, over the long-term, it has detrimental effects, raising caution about abrogating its function to treat the cytopenias that accompany this disease.
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Malacrida, Alessio, Guido Cavaletti, and Mariarosaria Miloso. "Rigosertib and Cholangiocarcinoma: A Cell Cycle Affair." International Journal of Molecular Sciences 23, no. 1 (December 25, 2021): 213. http://dx.doi.org/10.3390/ijms23010213.

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Rigosertib is multi-kinase inhibitor that could represent an interesting therapeutic option for non-resectable patients with cholangiocarcinoma, a very aggressive hepatic cancer with limited effective treatments. The Western blotting technique was used to evaluate alterations in the expression of proteins involved in the regulation of the cell cycle of cholangiocarcinoma EGI-1 cells. Our results show an increase in EMI1 and Cyclin B protein levels after Rigosertib treatment. Moreover, the phosphorylation of CDK1 is significantly reduced by Rigosertib, while PLK1 expression increased after 24 h of treatment and decreased after 48 h. Finally, we evaluated the role of p53. Its levels increase after Rig treatment, and, as shown in the cell viability experiment with the p53 inhibitor Pifithrin, its activity is necessary for the effects of Rigosertib against the cell viability of EGI-1 cells. In conclusion, we hypothesized the mechanism of the action of Rigosertib against cholangiocarcinoma EGI-1 cells, highlighting the importance of proteins involved in the regulation of cell cycles. The CDK1-Cyclin B complex and p53 play an important role, explaining the Block in the G2/M phase of the cell cycle and the effect on cell viability
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33

Endo, H., A. Saito, and P. H. Chan. "Mitochondrial translocation of p53 underlies the selective death of hippocampal CA1 neurons after global cerebral ischaemia." Biochemical Society Transactions 34, no. 6 (October 25, 2006): 1283–86. http://dx.doi.org/10.1042/bst0341283.

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p53, a tumour suppressor, is involved in DNA repair and cell death processes and mediates apoptosis in response to death stimuli by transcriptional activation of pro-apoptotic genes and by transcription-independent mechanisms. In the latter process, p53 induces permeabilization of the outer mitochondrial membrane by forming an inhibitory complex with a protective Bcl-2 family protein, resulting in cytochrome c release in several cell line systems. However, it is unclear how the mitochondrial p53 pathway mediates neuronal apoptosis after cerebral ischaemia. We examined interaction between the mitochondrial p53 pathway and vulnerable hippocampal CA1 neurons using a tGCI (transient global cerebral ischaemia) rat model. We showed mitochondrial translocation of p53 and its binding to Bcl-XL. Mitochondrial p53 translocation, interaction between p53 and Bcl-XL, and cytochrome c release from mitochondria and subsequent CA1 neuronal death were prevented by pifithrin-α, a p53-specific inhibitor. These results suggest that the mitochondrial p53 pathway plays a role in delayed CA1 neuronal death after tGCI.
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Gross, Christina. "Epilepsy Research Now in 3D: Harnessing the Power of Brain Organoids in Epilepsy." Epilepsy Currents 22, no. 2 (January 6, 2022): 135–36. http://dx.doi.org/10.1177/15357597211070391.

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Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.
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35

Wehbe, Hania, Roger Henson, Molly Lang, Fanyin Meng, and Tushar Patel. "Pifithrin-α Enhances Chemosensitivity by a p38 Mitogen-Activated Protein Kinase-Dependent Modulation of the Eukaryotic Initiation Factor 4E in Malignant Cholangiocytes." Journal of Pharmacology and Experimental Therapeutics 319, no. 3 (September 18, 2006): 1153–61. http://dx.doi.org/10.1124/jpet.106.109835.

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36

Lund, Troy C., Michelle L. Carter, Ashley C. Kramer, Nardina Nash, and Bruce R. Blazar. "The Oxidative Stress Response In Erythroid Precursors Is Mediated By tp53." Blood 122, no. 21 (November 15, 2013): 7. http://dx.doi.org/10.1182/blood.v122.21.7.7.

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Abstract Oxidative stress plays a key role in acute and especially chronic anemia as well red blood cell storage. Recent findings suggest that both erythroid precursors as well as mature red cells have increased sensitively to oxidative stress. Modeling oxidative stress in animals has been a challenge as many of the central genes in the oxidative stress response pathway are necessary for life and knockout animals die of overwhelming oxidative stress early in life. The zebrafish model allows pro-oxidant exposure early in hematopoietic development, and gata1DsRed1 transgenic animals allow clear identification of erythroid precursors. We capitalized on these advantages of the zebrafish to interrogate the effects of oxidative stress on erythroid precursors. After 72 hours of exposure to the strong pro-oxidant naphthol at 10 – 30 µg, embryonic zebrafish up-regulated several anti-oxidant genes including: hypoxia-inducible factor (hif1a), nuclear factor (erythroid derived)-like 2 (nrf2), ferritin heavy chain (fth1a), thioredoxin (txn), and heme oxygenase 1 (hmox1); 1.5, 2.3, 2.5, and 3.0-fold respectively (p < 0.05) as shown by qRT-PCR. To understand if a common pathway was driving anti-oxidant gene expression, we performed an in silico promoter analysis of these genes and discovered several tp53 binding sites within 4 kb upstream of the first exon in each gene. We showed naphthol was able to induce tp53 expression 3-fold over baseline by qRT-PCR. We next took advantage of the tp53 mutant line tp53M214K which has a mutation in the DNA binding region of tp53 rendering it non-functional similar to a complete knockout. We found that tp53M214K fish were highly sensitive to pro-oxidant exposure with 80% of embryos showing severe to moderate anemia and cardiac edema after 72 hours of exposure to naphthol (versus 25% in wild-type control animals, n = 100/group; p < 0.001). There was also a 3-fold decrease in the number of hemoglobin staining cells in naphthol treated tp53M214K animals as shown by o-dianisidine staining (versus control animals, n = 10/group; p < 0.01). A dose-response between the amount of pro-oxidant exposure and severity of anemia/edema also existed as determined by correlation of pro-oxidant concentration to an edema severity scale. We next measured the amount of reactive oxygen species (ROS) generated after naphthol exposure using CellROX detection assays and found that tp53M214K animals showed a doubling in ROS generated compared to wild-type (n = 30/group, p < 0.01) in whole animals. To disable tp53 by an alternative manner, we employed a known tp53 inhibitor, pifithrin, to inactivate tp53. Exposure of animals to pifithrin simultaneous with naphthol recapitulated the finding that inhibition of tp53 increased sensitivity to ROS as 90% of exposed embryos displayed moderate to severe anemia induced cardiac edema (versus 30% in controls, n = 100/group; p < 0.01). Although pifithrin combined with naphthol exposure caused no increase in ROS above that seen with naphthol alone. Our hypothesis is that the anemic phenotype is largely caused by hemolysis in erythroid precursors. The gata1DsRed1 zebrafish has labeled erythroid precursors, and using our experimental system we were able to specifically measure a dose responsive induction of ROS in erythroid precursors after naphthol exposure. Furthermore, gata1DsRed1 animals harboring tp53M214K showed a 20-fold increase in ROS after naphthol exposure (versus tp53+/+ animals, n = 10/group; p < 0.01). Accompanying the increase ROS is apoptosis of erythroid precursors as shown by flow cytometry for gata1DsRed1 cells. In conclusion, we show that amongst the many functions of tp53, providing an anti-oxidant response is also a mechanism though which erythroid precursors metabolize ROS after exposure to pro-oxidants. Understanding the mechanisms by which the anti-oxidant response is regulated will allow us to potentially find more effective drug-able targets to treat the oxidative stress that accompanies acute and chronic anemia’s. Disclosures: No relevant conflicts of interest to declare.
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Chua, Chu Chang, Xuwan Liu, Jinping Gao, Ronald C. Hamdy, and Balvin H. L. Chua. "Multiple actions of pifithrin-α on doxorubicin-induced apoptosis in rat myoblastic H9c2 cells." American Journal of Physiology-Heart and Circulatory Physiology 290, no. 6 (June 2006): H2606—H2613. http://dx.doi.org/10.1152/ajpheart.01138.2005.

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Doxorubicin (Dox) is a chemotherapeutic agent that causes significant cardiotoxicity. We showed previously that Dox activates p53 and induces apoptosis in mouse hearts. This study was designed to elucidate the molecular events that lead to p53 stabilization, to examine the pathways involved in Dox-induced apoptosis, and to evaluate the effectiveness of pifithrin-α (PFT-α), a p53 inhibitor, in blocking apoptosis of rat H9c2 myoblasts. H9c2 cells that were exposed to 5 μM Dox had elevated levels of p53 and phosphorylated p53 at Ser15. Dox also triggered a transient activation of p38, p42/p44ERK, and p46/p54JNK MAP kinases. Caspase activity assays and Western blot analysis showed that H9c2 cells treated with Dox for 16 h had marked increase in the levels of caspases-2, -3, -8, -9, -12, Fas, and cleaved poly(ADP ribose) polymerase (PARP). There was a concomitant increase in p53 binding activity, cytochrome c release, and apoptosis. These results suggest that Dox can trigger intrinsic, extrinsic, and endoplasmic reticulum-associated apoptotic pathways. Pretreatment of cells with PFT-α followed by Dox administration attenuated Dox-induced increases in p53 levels and p53 binding activity and partially blocked the activation of p46/p54JNK and p42/p44ERK. PFT-α also led to decreased levels of caspases-2, -3, -8, -9, -12, Fas, PARP, cytochrome c release, and apoptosis. Our results suggest that p53 stabilization is a focal point of Dox-induced apoptosis and that PFT-α interferes with multiple steps of Dox-induced apoptosis.
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Fleiss, Bobbi, Vibol Chhor, Nazurah Rajudin, Sophie Lebon, Henrik Hagberg, Pierre Gressens, and Claire Thornton. "The Anti-Inflammatory Effects of the Small Molecule Pifithrin-µ on BV2 Microglia." Developmental Neuroscience 37, no. 4-5 (2015): 363–75. http://dx.doi.org/10.1159/000370031.

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Neonatal encephalopathy (NE) is a leading cause of childhood death and disability in term infants. Treatment options for perinatal brain injury are limited and developing therapies that target multiple pathways within the pathophysiology of NE are of great interest. Pifithrin-µ (PFT-µ) is a drug with striking neuroprotective abilities in a preclinical model of hypoxia-ischemia (HI)-induced NE wherein cell death is a substantial cause of injury. Work from neurons and tumor cells reports that PFT-µ is able to inhibit p53 binding to the mitochondria, heat shock protein (HSP)-70 substrate binding and activation of the NF-kB pathway. The purpose of this study is to understand whether the neuroprotective effects of PFT-µ also include direct effects on microglia. We utilized the microglial cell line, BV2, and we studied the dose-dependent effect of PFT-µ on M1-like and M2-like phenotype using qRT-PCR and Western blotting, including the requirement for the presence of p53 or HSP-70 in these effects. We also assessed phagocytosis and the effects of PFT-µ on genes within metabolic pathways related to phenotype. We noted that PFT-µ robustly reduced the M1-like (lipopolysaccharide, LPS-induced) BV2 response, spared the LPS-induced phagocytic ability of BV2 and had no effect on the genes related to metabolism and that effects on phenotype were partially dependent on the presence of HSP-70 but not p53. This study demonstrates that the neuroprotective effects of PFT-µ in HI-induced NE may include an anti-inflammatory effect on microglia and adds to the evidence that this drug might be of clinical interest for the treatment of NE.
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Steele, Andrew J., Archie Prentice, Kate Cwynarski, A. Victor Hoffbrand, and R. Gitendra Wickremasinghe. "Pifithrin α, a Selective Inhibitor of p53-Mediated Transcription, Augments Apoptotic Killing of Chronic Lymphocytic Leukemia Cells by Nutlin 3a and Cytotoxic Drugs." Blood 110, no. 11 (November 16, 2007): 1590. http://dx.doi.org/10.1182/blood.v110.11.1590.1590.

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Abstract The p53 protein plays a key role in triggering DNA damage-induced apoptosis. The classical pathway of p53-mediated apoptosis involves transcriptional upregulation of pro-apoptotic proteins Puma and Noxa. However, recent studies identified a non-transcriptional mechanism, involving direct association of p53 with mitochondrial anti-apoptotic proteins Bcl-2 or Bcl-XL. We studied the relative contributions of transcription-dependent and -independent mechanisms of p53-mediated apoptosis in CLL cells in vitro. The cytotoxic drugs chlorambucil (chl) and fludarabine (flu) were used to induce p53, as was nutlin 3a, which augments p53 levels by inhibiting interaction with its negative regulator MDM2. Using differential detergent fractionation to isolate cytosolic (cyt), mitochondrial (mt) and nuclear (nuc) fractions, we found that a significant proportion (&gt;50%) of the induced p53 was stably associated with mitochondria in cells treated with nutlin 3a (Fig 1), chl or flu. Co-immunoprecipitation studies established that p53 bound to Bcl-2. PFTα, an inhibitor of p53-mediated transcription, blocked upregulation of the known p53 targets p21CIP1, MDM2 and Puma. Surprisingly, apoptosis induction by nutlin 3a (Figure 2), chl or flu, quantified by western blot analysis of cleavage of poly(ADP ribose) polymerase (PARP), was augmented by PFTα. This observation was confirmed by morphological analysis of apoptosis. Cytochrome c release from mitochondria following p53 induction was also enhanced by PFTα. PFTα did not augment nutlin-, chl- or flu-induced killing of CLL cells lacking functional p53. Furthermore, PFTα did not augment killing by the p53-independent drug parthenolide and failed to increase apoptosis of normal T lymphocytes treated with chl or nutlin 3a. Our observations suggest that p53 induces apoptosis of CLL cells principally via its transcription-independent function, involving direct association with mitochondrial Bcl-2. p53’s transcriptional function apparently blocks apoptosis at a point between p53 association with Bcl-2 and subsequent release of cytochrome c. Therefore, therapeutic strategies aimed at blocking p53-mediated transcription may be of value in enhancing the action of agents which induce apoptosis of CLL cells via p53 upregulation. Figure 1 Figure 1. Figure 2 Figure 2.
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40

Wei, Qingqing, Guie Dong, Tianxin Yang, Judit Megyesi, Peter M. Price, and Zheng Dong. "Activation and involvement of p53 in cisplatin-induced nephrotoxicity." American Journal of Physiology-Renal Physiology 293, no. 4 (October 2007): F1282—F1291. http://dx.doi.org/10.1152/ajprenal.00230.2007.

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Cisplatin, a widely used chemotherapy drug, induces acute kidney injury, which limits its use and efficacy in cancer treatment. However, the molecular mechanism of cisplatin-induced nephrotoxicity is currently unclear. Using pharmacological and gene knockout models, we now demonstrate a pathological role for p53 in cisplatin nephrotoxicity. In C57BL/6 mice, cisplatin treatment induced p53 phosphorylation and protein accumulation, which was accompanied by the development of acute kidney injury. p53 was induced in both proximal and distal tubular cells and partially colocalized with apoptosis. Pifithrin-α, a pharmacological inhibitor of p53, suppressed p53 activation and ameliorated kidney injury during cisplatin treatment. Moreover, cisplatin-induced nephrotoxicity was abrogated in p53-deficient mice. Compared with wild-type animals, p53-deficient mice showed a better renal function, less tissue damage, and fewer apoptotic cells. In addition, cisplatin induced less apoptosis in proximal tubular cells isolated from p53-deficient mice than the cells from wild-type animals. Together these results suggest the involvement of p53 in cisplatin-induced renal cell apoptosis and nephrotoxicity.
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Beauchamp, Marie-Claude, Anissa Djedid, Eric Bareke, Fjodor Merkuri, Rachel Aber, Annie S. Tam, Matthew A. Lines, et al. "Mutation in Eftud2 causes craniofacial defects in mice via mis-splicing of Mdm2 and increased P53." Human Molecular Genetics 30, no. 9 (February 18, 2021): 739–57. http://dx.doi.org/10.1093/hmg/ddab051.

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Abstract EFTUD2 is mutated in patients with mandibulofacial dysostosis with microcephaly (MFDM). We generated a mutant mouse line with conditional mutation in Eftud2 and used Wnt1-Cre2 to delete it in neural crest cells. Homozygous deletion of Eftud2 causes brain and craniofacial malformations, affecting the same precursors as in MFDM patients. RNAseq analysis of embryonic heads revealed a significant increase in exon skipping and increased levels of an alternatively spliced Mdm2 transcript lacking exon 3. Exon skipping in Mdm2 was also increased in O9-1 mouse neural crest cells after siRNA knock-down of Eftud2 and in MFDM patient cells. Moreover, we found increased nuclear P53, higher expression of P53-target genes and increased cell death. Finally, overactivation of the P53 pathway in Eftud2 knockdown cells was attenuated by overexpression of non-spliced Mdm2, and craniofacial development was improved when Eftud2-mutant embryos were treated with Pifithrin-α, an inhibitor of P53. Thus, our work indicates that the P53-pathway can be targeted to prevent craniofacial abnormalities and shows a previously unknown role for alternative splicing of Mdm2 in the etiology of MFDM.
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42

Fu, Shuangshuang, Xiaoru Hu, Zhengwei Ma, Qingqing Wei, Xiaohong Xiang, Siyao Li, Lu Wen, Yumei Liang, and Zheng Dong. "p53 in Proximal Tubules Mediates Chronic Kidney Problems after Cisplatin Treatment." Cells 11, no. 4 (February 17, 2022): 712. http://dx.doi.org/10.3390/cells11040712.

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Nephrotoxicity is a major side-effect of cisplatin in chemotherapy, which can occur acutely or progress into chronic kidney disease (CKD). The protein p53 plays an important role in acute kidney injury induced by cisplatin, but its involvement in CKD following cisplatin exposure is unclear. Here, we address this question by using experimental models of repeated low-dose cisplatin (RLDC) treatment. In mouse proximal tubular BUMPT cells, RLDC treatment induced p53 activation, apoptosis, and fibrotic changes, which were suppressed by pifithrin-α, a pharmacologic inhibitor of p53. In vivo, chronic kidney problems following RLDC treatment were ameliorated in proximal tubule-specific p53-knockout mice (PT-p53-KO mice). Compared with wild-type littermates, PT-p53-KO mice showed less renal damage (KIM-1 positive area: 0.97% vs. 2.5%), less tubular degeneration (LTL positive area: 15.97% vs. 10.54%), and increased proliferation (Ki67 positive area: 2.42% vs. 0.45%), resulting in better renal function after RLDC treatment. Together, these results indicate that p53 in proximal tubular cells contributes significantly to the development of chronic kidney problems following cisplatin chemotherapy.
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43

Solanki, Ashish K., Pankaj Srivastava, Bushra Rahman, Joshua H. Lipschutz, Deepak Nihalani, and Ehtesham Arif. "The Use of High-Throughput Transcriptomics to Identify Pathways with Therapeutic Significance in Podocytes." International Journal of Molecular Sciences 21, no. 1 (December 31, 2019): 274. http://dx.doi.org/10.3390/ijms21010274.

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Podocytes have a unique structure that supports glomerular filtration function, and many glomerular diseases result in loss of this structure, leading to podocyte dysfunction and ESRD (end stage renal disease). These structural and functional changes involve a complex set of molecular and cellular mechanisms that remain poorly understood. To understand the molecular signature of podocyte injury, we performed transcriptome analysis of cultured human podocytes injured either with PAN (puromycin aminonucleoside) or doxorubicin/adriamycin (ADR). The pathway analysis through DE (differential expression) and gene-enrichment analysis of the injured podocytes showed Tumor protein p53 (P53) as one of the major signaling pathways that was significantly upregulated upon podocyte injury. Accordingly, P53 expression was also up-regulated in the glomeruli of nephrotoxic serum (NTS) and ADR-injured mice. To further confirm these observations, cultured podocytes were treated with the P53 inhibitor pifithrin-α, which showed significant protection from ADR-induced actin cytoskeleton damage. In conclusion, signaling pathways that are involved in podocyte pathogenesis and can be therapeutically targeted were identified by high-throughput transcriptomic analysis of injured podocytes.
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Chang, Hsin-Han, Yi-Hsuan Lin, Tzu-Min Chen, Yu-Ling Tsai, Chien-Rui Lai, Wen-Chiuan Tsai, Yu-Chen Cheng, and Ying Chen. "ONX-0914 Induces Apoptosis and Autophagy with p53 Regulation in Human Glioblastoma Cells." Cancers 14, no. 22 (November 21, 2022): 5712. http://dx.doi.org/10.3390/cancers14225712.

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Glioblastoma is believed to be one of the most aggressive brain tumors in the world. ONX-0914 (PR957) is a selective inhibitor of proteasome subunit beta type-8 (PSMB8). Previous studies have shown that inhibiting PSMB8 expression in glioblastoma reduces tumor progression. Therefore, this study aimed to determine whether ONX-0914 has antitumor effects on human glioblastoma. The results indicated that ONX-0914 treatment inhibited survival in LN229, GBM8401, and U87MG glioblastoma cells. Cell cycle analysis showed that ONX-0914 treatment caused cell cycle arrest at the G1 phase and apoptosis in glioblastoma cells. The protein expression of BCL-2 was reduced and PARP was cleaved after ONX-0914 treatment. Furthermore, the levels of p53 and phosphorylated p53 were increased by ONX-0914 treatment in glioblastoma cells. ONX-0914 also induced autophagy in glioblastoma cells. Furthermore, the p53 inhibitor pifithrin attenuated apoptosis but enhanced autophagy caused by ONX-0914. In an orthotopic mouse model, TMZ plus ONX-0914 reduced tumor progression better than the control or TMZ alone. These data suggest that ONX-0914 is a novel therapeutic drug for glioblastoma.
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45

He, Jia, Chongde Long, Zixin Huang, Xin Zhou, Xielan Kuang, Lanying Liu, Huijun Liu, et al. "PTEN Reduced UVB-Mediated Apoptosis in Retinal Pigment Epithelium Cells." BioMed Research International 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/3681707.

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Age-related macular degeneration (AMD) is a leading cause of blindness and progressive loss of central vision in the elderly population. The important factor of AMD pathogenesis is the degeneration of retinal pigment epithelial (RPE) cells by oxidative stress. Inactivation of PTEN can disrupt intercellular adhesion in the RPE cells, but the mechanism of oxidative stress is less known. Here we presented evidence that UVB-mediated oxidative stress induced apoptosis in ARPE-19 cells. Downregulation of the expression of PTEN in UVB-irradiative RPE cells triggered DNA damage and increased the level of UVB-induced apoptosis by activating p53-dependent pathway. However, overexpression of PTEN increased cell survival by suppressing p-H2A in response to DNA damage and apoptosis. When using Pifithrin-α(one of p53 inhibitors), the level of p53-dependent apoptosis was significantly lower than untreated, which suggested that p53 was possibly involved in PTEN-dependent apoptosis. Thus, it elucidated the molecular mechanisms of UVB-induced damage in RPE cells and may offer an alternative therapeutic target in dry AMD.
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46

Danilova, Nadia, Kathleen Sakamoto, and Shuo Lin. "Imbalance of p53 Family Members as a New Target of Therapeutics for Treatment of Diamond Blackfan Anemia." Blood 110, no. 11 (November 16, 2007): 423. http://dx.doi.org/10.1182/blood.v110.11.423.423.

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Abstract Diamond-Blackfan anemia (DBA) is characterized by defective erythropoiesis, congenital anomalies and risk of malignancies. Ribosomal protein (RP) S19 is mutated in about 25% of patients and RPS24 in 2%. RPS19 deficiency impairs ribosomal biogenesis. It still remains unknown how impaired ribosome biogenesis and function lead to DBA. We found that RPS19 deficiency in zebrafish results in hematopoietic and developmental abnormalities resembling DBA. Our data suggest that the RPS19-deficient phenotype is mediated by upregulation of the p53 family genes. DeltaNp63 is BMP4 target and during gastrulation, required for specification of non-neural ectoderm. Its upregulation suppresses the development of neural structures and is likely to contribute to brain and craniofacial defects observed in RPS19 deficient zebrafish and DBA. In response to ribosomal stress from RPS19 deficiency, deltaNp63 expression is induced in erythroid progenitors suggesting a role for deltaNp63 in hematopoiesis. Similar to other vertebrates, zebrafish experience two waves of blood formation, primitive, producing mostly erythrocytes and macrophages and definitive producing all types of blood cells. Erythroid progenitors proliferate and differentiate into mature erythrocytes in the Intermediate Cell Mass (ICM), a region between the dorsal aorta and axial vein. We found that number of blood cells in the ICM was reduced in RPS19-deficient embryos and their differentiation was delayed. Morphologically, erythrocytes from morphants differed from wild-type cells. They varied in size and some cells retained a blast-like phenotype. The hemoglobin level was also decreased in morphants. The immature phenotype of RPS19-deficient erythroid cells and their inability to differentiate into mature erythrocytes may be explained by DNp63 induction. Importantly, downregulation of expression of both p53 and DNp63 can rescue the RPS19 deficient phenotype in zebrafish. Our findings suggest that suppression of p53 pathway might be beneficial for DBA patients with RPS19 mutations. Several drugs were reported to be effective in the treatment of DBA although the mechanism of their action is unknown. They include such dissimilar compounds as corticosteroids, cyclosporine A, and valproic acid. Metoxyclopramide was reported as effective by some authors but not others. We treated RPS19-deficient embryos with these drugs and found that dexamethasone, cyclosporine A, and valproic acid improve RPS19-deficient phenotype. We further found that treatment of embryos with dexamethasone and cyclosporine A influences p53 level. Metoxyclopramide was not effective in rescuing RPS19-deficient embryos and had no effect on p53 level. We next questioned if known compounds inhibiting p53 pathway can improve the phenotype and survival of RPS19-deficient zebrafish. Pifithrin m inhibits p53 binding to mitochondria by reducing its affinity to antiapoptotic proteins Bcl-xL and Bcl-2. It specifically suppresses the mitochondria branch of the p53 pathway but does not affect other p53 functions. Pifithrin has no effect of the p53 level in zebrafish embryos but was efficient in improving RPS19-deficient phenotype. These data suggest that suppression of p53 activity might be a mechanism of action of some drugs currently used for DBA treatment and open new directions for development of novel drugs.
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47

ZHANG, YINGJIE, and DA XING. "PUMA PROMOTES BAX ACTIVATION IN A FOXO3a-DEPENDENT MANNER IN STS-INDUCED APOPTOSIS." Journal of Innovative Optical Health Sciences 03, no. 01 (January 2010): 31–38. http://dx.doi.org/10.1142/s1793545810000800.

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PUMA (p53 up-regulated modulator of apoptosis, also called Bbc3) was first identified as a BH3-only Bcl-2 family protein that is transcriptionally up-regulated by p53 and activated upon p53-dependent apoptotic stimuli, such as treatment with DNA-damaging drugs or UV irradiation. Recently, studies have shown that PUMA is also up-regulated in response to certain p53-independent apoptotic stimuli, such as growth factor deprivation or treatment with glucocorticoids or STS (staurosporine). However, the molecular mechanisms of PUMA up-regulation and how PUMA functions in response to p53-independent apoptotic stimuli remain poorly understood. In this study, based on real-time single cell analysis, flow cytometry, and western blotting technique, we investigated the function of PUMA in living human lung adenocarcinoma cells (ASTC-a-1) after STS treatment. Our results show that FOXO3a was activated by STS stimulation and then translocated from cytosol to nucleus. The expression of PUMA was up-regulated via a FOXO3a-dependent manner after STS treatment, while p53 had little function in this process. Moreover, cell apoptosis and Bax activation induced by STS were not blocked by Pifithrin-α (p53 inhibitor), which indicated that p53 was not involved in this signaling pathway. Taken together, these results suggest that PUMA promoted Bax activation in a FOXO3a-dependent pathway during STS-induced apoptosis, while p53 was dispensable in this process.
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48

Roy, Julie, Pragathi Pallepati, Ahmed Bettaieb, and Diana A. Averill-Bates. "Acrolein induces apoptosis through the death receptor pathway in A549 lung cells: role of p53This review is one of a selection of papers published in a Special Issue on Oxidative Stress in Health and Disease." Canadian Journal of Physiology and Pharmacology 88, no. 3 (March 2010): 353–68. http://dx.doi.org/10.1139/y09-134.

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Acrolein, a highly reactive α,β-unsaturated aldehyde, is an omnipresent environmental pollutant. Chronic and acute human exposures occur through exogenous and endogenous sources, including food, vapors of overheated cooking oil, house and forest fires, cigarette smoke, and automobile exhaust. Acrolein is a toxic byproduct of lipid peroxidation, which has been implicated in pulmonary, cardiac, and neurodegenerative diseases. This study shows that p53 is an initiating factor in acrolein-induced death receptor activation during apoptosis in A549 human lung cells. Exposure of cells to acrolein (0–50 µmol/L) mainly caused apoptosis, which was manifested by execution phase events such as condensation of nuclear chromatin, phosphatidylserine externalization, and poly(ADP-ribose) polymerase (PARP) cleavage. Levels of necrosis (~5%) were low. Acrolein triggered the death receptor pathway of apoptosis, causing elevation of Fas ligand (FasL) and translocation of adaptor protein Fas-associated death domain to the plasma membrane. Acrolein caused activation of caspase-8, caspase-2, caspase-7, and the cross-talk pathway mediated by Bid cleavage. Activation of p53 and increased expression of p53-upregulated modulator of apoptosis (PUMA) occurred in response to acrolein. FasL upregulation and caspase-8 activation were decreased by p53 inhibitor pifithrin-α and antioxidant polyethylene glycol catalase. These findings increase our knowledge about the induction of cell death pathways by acrolein, which has important implications for human health.
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49

Pesi, Rossana, Simone Allegrini, Mercedes Garcia-Gil, Lucia Piazza, Roberta Moschini, Lars Petter Jordheim, Marcella Camici, and Maria Grazia Tozzi. "Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway." International Journal of Molecular Sciences 22, no. 13 (June 29, 2021): 7004. http://dx.doi.org/10.3390/ijms22137004.

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Cytosolic 5′-nucleotidase II (cN-II) is an allosteric catabolic enzyme that hydrolyzes IMP, GMP, and AMP. The enzyme can assume at least two different structures, being the more active conformation stabilized by ATP and the less active by inorganic phosphate. Therefore, the variation in ATP concentration can control both structure and activity of cN-II. In this paper, using a capillary electrophoresis technique, we demonstrated that a partial silencing of cN-II in a pulmonary carcinoma cell line (NCI-H292) is accompanied by a decrease in adenylate pool, without affecting the energy charge. We also found that cN-II silencing decreased proliferation and increased oxidative metabolism, as indicated by the decreased production of lactate. These effects, as demonstrated by Western blotting, appear to be mediated by both p53 and AMP-activated protein kinase, as most of them are prevented by pifithrin-α, a known p53 inhibitor. These results are in line with our previous observations of a shift towards a more oxidative and less proliferative phenotype of tumoral cells with a low expression of cN-II, thus supporting the search for specific inhibitors of this enzyme as a therapeutic tool for the treatment of tumors.
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50

Liu, Ze, Yong Li, Yongmei He, and Junjie Wang. "Numb Promotes Autophagy through p53 Pathway in Acute Kidney Injury Induced by Cisplatin." Analytical Cellular Pathology 2022 (June 27, 2022): 1–10. http://dx.doi.org/10.1155/2022/8213683.

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Acute kidney injury (AKI) is an important public health concern and characterized as tubular death involved in apoptosis and necrosis. Autophagy is rapidly induced in tubules and associates with renal tubular cells homeostasis to have a complex link with tubular death in AKI. Numb is a multifunctional protein and exerts protective role in tubular death in AKI induced by Cisplatin. However, the effect of Numb on tubular autophagy remains to be investigated. In the present study, the protein expression of LC3 and Beclin-1 related to autophagy was analyzed in Cisplatin-induced AKI mice with knocking down Numb. In model of tubular injury induced by Cisplatin in vitro, downregulation of Numb in NRK-52E cells also inhibited the activation of autophagy accompanied with the decreased protein level of p53. Overexpression of Numb in NRK-52E cells activated autophagy with increased LC3 and Beclin-1 expression accompanied with increased protein level of p53. Moreover, autophagy activation following Numb overexpression was suppressed by p53 inhibitor pifithrin-α. These data indicate that Numb promotes p53-mediated activation of tubular autophagy in AKI induced by Cisplatin and therefore may provide important targets for the treatment of AKI.
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