Potential Association of Poly(ADP-ribose) Polymerase-1 (PARP-1) with CD133 and G2/M as Independent Predictors in Colorectal Cancer Development.

El-Emshaty, Hoda; Abdelfatah, Amina A.; Ismail, Hisham; El‐Taweel, F. M. A.; El-Hemaly, Mohamed

doi:10.21608/blj.2019.63832

Cited by 1 publication

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“…For that purpose, we used a TNBS-induced experimental colitis model in mice, which is widely accepted for studying CD, since they share many pathological (clinical, histological, and biochemical) characteristics [ 35 ]. Furthermore, enhanced PARP-1 expression was found in the colon of rodents [ 43 , 44 ] in experimental colitis models, as well as in IBD patients [ 45 ], which makes the model more valuable for studying PARP inhibitors. In this report, we explicitly focused on the epithelial barrier function, cell survival, and bioenergetics; hence, we used a Caco-2 monolayer as an in vitro model of intestinal epithelial barrier [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, we treated Caco-2 monolayer with high concentration of H 2 O 2 (1 mM) to imitate a strong oxidative stress-injured barrier, in vitro . We demonstrated that Caco-2 monolayer cells expressed PARP-1 mRNA in a high extent similarly to colonic mucosa [ 45 ]. In addition, we detected PARP-2 and PARP-3 expressions, however, in a decreasingly lower extent.…”

Section: Discussionmentioning

confidence: 99%

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Olaparib: A Clinically Applied PARP Inhibitor Protects from Experimental Crohn’s Disease and Maintains Barrier Integrity by Improving Bioenergetics through Rescuing Glycolysis in Colonic Epithelial Cells

Kovács

Vántus

Vámos

et al. 2021

Oxidative Medicine and Cellular Longevity

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Crohn’s disease (CD) is an inflammatory disorder of the intestines characterized by epithelial barrier dysfunction and mucosal damage. The activity of poly(ADP-ribose) polymerase-1 (PARP-1) is deeply involved in the pathomechanism of inflammation since it leads to energy depletion and mitochondrial failure in cells. Focusing on the epithelial barrier integrity and bioenergetics of epithelial cells, we investigated whether the clinically applied PARP inhibitor olaparib might improve experimental CD. We used the oral PARP inhibitor olaparib in the 2,4,6-trinitrobenzene sulfonic acid- (TNBS-) induced mouse colitis model. Inflammatory scoring, cytokine levels, colon histology, hematological analysis, and intestinal permeability were studied. Caco-2 monolayer culture was utilized as an epithelial barrier model, on which we used qPCR and light microscopy imaging, and measured impedance-based barrier integrity, FITC-dextran permeability, apoptosis, mitochondrial oxygen consumption rate, and extracellular acidification rate. Olaparib reduced the inflammation score, the concentration of IL-1β and IL-6, enhanced the level of IL-10, and decreased the intestinal permeability in TNBS-colitis. Blood cell ratios, such as lymphocyte to monocyte ratio, platelet to lymphocyte ratio, and neutrophil to lymphocyte ratio were improved. In H2O2-treated Caco-2 monolayer, olaparib decreased morphological changes, barrier permeability, and preserved barrier integrity. In oxidative stress, olaparib enhanced glycolysis (extracellular acidification rate), and it improved mitochondrial function (mitochondrial coupling efficiency, maximal respiration, and spare respiratory capacity) in epithelial cells. Olaparib, a PARP inhibitor used in human cancer therapy, improved experimental CD and protected intestinal barrier integrity by preventing its energetic collapse; therefore, it could be repurposed for the therapy of Crohn’s disease.

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