Generation of Reactive Oxygen Species by Polyenylpyrroles Derivatives Causes DNA Damage Leading to G2/M Arrest and Apoptosis in Human Oral Squamous Cell Carcinoma Cells

10.1371/journal.pone.0067603PLoS ONE86-POLN

Establishment of a 3D In Vitro Model to Accelerate the Development of Human Therapies against Corneal Diabetes

The authors thank Dr. John M Asara, Min Yuan, and Susanne Breitkopf for their technical help with metabolomics experiments, Dr. Ben Fowler for his technical help with TEM experiments and also Tina B McKay for many thoughtful discussions and scientific insights during the study.Purpose To establish an in vitro model that would mirror the in vivo corneal stromal environment in diabetes (DM) patients. Methods Human corneal fibroblasts from Healthy (HCFs), Type 1DM (T1DM) and Type 2DM (T2DM) donors were isolated and cultured for 4 weeks with Vitamin C stimulation in order to allow for extracellular matrix (ECM) secretion and assembly. Results Our data indicated altered cellular morphology, increased cellular migration, increased ECM assembly, and severe mitochondrial damage in both T1DM and T2DMs when compared to HCFs. Furthermore, we found significant downregulation of Collagen I and Collagen V expression in both T1DM and T2DMs. Furthermore, a significant up regulation of fibrotic markers was seen, including α-smooth muscle actin in T2DM and Collagen III in both T1DM and T2DMs. Metabolic analysis suggested impaired Glycolysis and Tricarboxylic acid cycle (TCA) pathway. Conclusion DM has significant effects on physiological and clinical aspects of the human cornea. The benefits in developing and fully characterizing our 3D in vitro model are enormous and might provide clues for the development of novel therapeutics.Yeshttp://www.plosone.org/static/editorial#pee

Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies

Connected Vertex Cover in 2-Connected Planar Graph with Maximum Degree 4 is NP-complete

This paper proves that the problem of finding connected vertex cover in a 2-connected planar graph ( CVC-2) with maximum degree 4 is NP-complete. The motivation for proving this result is to give a shorter and simpler proof of NP-Completeness of TRA-MLC (the Top Right Access point Minimum-Length Corridor) problem [1], by finding the reduction from CVC-2. TRA-MLC has many applications in laying optical fibre cables for data communication and electrical wiring in floor plans.The problem of finding connected vertex cover in any planar graph ( CVC) with maximum degree 4 is NP-complete [2]. We first show that CVC-2 belongs to NP and then we find a polynomial reduction from CVC to CVC-2. Let a graph G0 and an integer K form an instance of CVC, where G0 is a planar graph and K is an upper bound on the size of the connected vertex cover in G0. We construct a 2-connected planar graph, say G, by identifying the blocks and cut vertices of G0, and then finding the planar representation of all the blocks of G0, leading to a plane graph G1. We replace the cut vertices with cycles in such a way that the resultant graph G is a 2-connected planar graph with maximum degree 4. We consider L = K − 2t +3 di where t is the number i=1 of cut vertices in G1 and di is the number of blocks for which i th cut vertex is common. We prove that G will have a connected vertex cover with size less than or equal to L if and only if G0 has a connected vertex cover of size less than or equal to K