Epigenetics Offer New Horizons for Colorectal Cancer Prevention

In recent years, colorectal cancer (CRC) incidence has been increasing to become a major cause of morbidity and mortality worldwide from cancers, with high rates in westernized societies and increasing rates in developing countries. Epigenetic modifications including changes in DNA methylation, histone modifications, and non-coding RNAs play a critical role in carcinogenesis. Epidemiological data suggest that, in comparison to other cancers, these alterations are particularly common within the gastrointestinal tract. To explain these observations, environmental factors and especially diet were suggested to both prevent and induce CRC. Epigenetic alterations are, in contrast to genetic modifications, potentially reversible, making the use of dietary agents a promising approach in CRC for the development of chemopreventive strategies targeting epigenetic mechanisms. This review focuses on CRC-related epigenetic alterations as a rationale for various levels of prevention strategies and their potential modulation by natural dietary compounds

Transcriptome dynamics and molecular cross-talk between bovine oocyte and its companion cumulus cells

<p>Abstract</p> <p>Background</p> <p>The bi-directional communication between the oocyte and its companion cumulus cells (CCs) is crucial for development and functions of both cell types. Transcripts that are exclusively expressed either in oocytes or CCs and molecular mechanisms affected due to removal of the communication axis between the two cell types is not investigated at a larger scale. The main objectives of this study were: 1. To identify transcripts exclusively expressed either in oocyte or CCs and 2. To identify those which are differentially expressed when the oocyte is cultured with or without its companion CCs and vice versa.</p> <p>Results</p> <p>We analyzed transcriptome profile of different oocyte and CC samples using Affymetrix GeneChip Bovine Genome array containing 23000 transcripts. Out of 13162 genes detected in germinal vesicle (GV) oocytes and their companion CCs, 1516 and 2727 are exclusively expressed in oocytes and CCs, respectively, while 8919 are expressed in both. Similarly, of 13602 genes detected in metaphase II (MII) oocytes and CCs, 1423 and 3100 are exclusively expressed in oocytes and CCs, respectively, while 9079 are expressed in both. A total of 265 transcripts are differentially expressed between oocytes cultured with (OO + CCs) and without (OO - CCs) CCs, of which 217 and 48 are over expressed in the former and the later groups, respectively. Similarly, 566 transcripts are differentially expressed when CCs mature with (CCs + OO) or without (CCs - OO) their enclosed oocytes. Of these, 320 and 246 are over expressed in CCs + OO and CCs - OO, respectively.</p> <p>While oocyte specific transcripts include those involved in transcription (<it>IRF6, POU5F1, MYF5, MED18</it>), translation (<it>EIF2AK1, EIF4ENIF1</it>) and CCs specific ones include those involved in carbohydrate metabolism (<it>HYAL1, PFKL, PYGL, MPI</it>), protein metabolic processes (<it>IHH, APOA1, PLOD1</it>), steroid biosynthetic process (<it>APOA1, CYP11A1, HSD3B1, HSD3B7</it>). Similarly, while transcripts over expressed in OO + CCs are involved in carbohydrate metabolism (<it>ACO1, 2</it>), molecular transport (<it>GAPDH, GFPT1</it>) and nucleic acid metabolism (<it>CBS, NOS2</it>), those over expressed in CCs + OO are involved in cellular growth and proliferation (<it>FOS, GADD45A</it>), cell cycle (<it>HAS2, VEGFA</it>), cellular development (<it>AMD1, AURKA, DPP4</it>) and gene expression (<it>FOSB, TGFB2</it>).</p> <p>Conclusion</p> <p>In conclusion, this study has generated large scale gene expression data from different oocyte and CCs samples that would provide insights into gene functions and interactions within and across different pathways that are involved in the maturation of bovine oocytes. Moreover, the presence or absence of oocyte and CC factors during bovine oocyte maturation can have a profound effect on transcript abundance of each cell types, thereby showing the prevailing molecular cross-talk between oocytes and their corresponding CCs.</p

Effect of varying glucose and glucosamine concentration in vitro on mouse oocyte maturation and developmental competence

Published online: 7 November 2012The effects of hyper- and hypo-glycaemic conditions during the in vitro maturation of mouse cumulus–oocyte complexes on developmental competence were examined, with an emphasis on the role of the hexosamine biosynthesis pathway. A low (1 mM) glucose concentration achieved optimal oocyte competence (3-fold higher blastocyst development rate compared with high (30 mM) glucose, P < 0.05). In addition, glucose supplementation during only the first hour after release from the follicle was necessary and sufficient to support oocyte maturation and embryo development to the blastocyst stage. Glucosamine (a known hyperglycaemic mimetic and specific activator of the hexosamine pathway) was able to substitute for glucose during this first hour, indicating that flux through the hexosamine pathway is essential for oocyte competence. In the absence of glucose throughout the maturation period, glucosamine was not able to increase developmental competence, and at higher concentrations (2.5 and 5 mM) had a detrimental effect on MII and blastocyst development rates, compared with controls (P < 0.05). These experiments underscore the importance of glucose metabolic pathways during in vitro maturation and support the concept that excess flux through the hexosamine pathway has detrimental consequences.L. A. Frank, M. L. Sutton-McDowall, D. L. Russell, X. Wang, D. K. Feil, R. B. Gilchrist, and J. G. Thompso

Long-term progression of visual field defects and related factors in medically treated normal tension glaucoma

Keiji Yoshikawa,1 Kazunori Santo,2 Hiroko Hizaki,2 Masayo Hashimoto2 1Yoshikawa Eye Clinic, Tokyo, 2Medical Affairs, Santen Pharmaceutical Co. Ltd., Osaka, Japan Purpose: To analyze factors related to long-term progression of visual field defects (VFD) in patients with normal tension glaucoma (NTG) under medical therapy. Patients and methods: Clinical data from 622 eyes of 311 primary open-angle glaucoma and NTG patients were collected from April 2006 to March 2016. Of these patients, those with normal intraocular pressure (IOP); glaucomatous VFD judged by Anderson&rsquo;s criteria; corrected visual acuity&nbsp;&ge;0.7; receiving more than 6 years medical therapy; having undergone&nbsp;&ge;10&nbsp;visual field tests performed at 6-month intervals using a Humphrey field analyzer (Swedish Interactive Threshold Algorithms standard, C 24-2 program); and having reliability coefficients of visual field testing&nbsp;&lt;33% and mean deviation (MD) more than&nbsp;-20 decibels in the initial visual field test were included in data analysis. The relationship between MD slope deterioration at final observation and consecutive decreases in MD value during the observation period, as well as clinical characteristics and IOP-related factors, were analyzed. Results: Of 134 eyes in 134 NTG patients meeting all eligibility criteria, significant MD slope deterioration was observed in 80 eyes (59.7%). MD slope deterioration was significantly associated with consecutive decreases in MD values (Cochran&ndash;Armitage trend test: P=0.0000; univariate logistic regression analysis: P&lt;0.0001). While no significant relationship was observed between central corneal thickness, refractive error, or prevalence of disc hemorrhage, consecutive decreases in MD value was significantly related to MD slope deterioration (univariate logistic regression analysis: P&lt;0.0001). A reduction of IOP during the follow-up period was significantly related to nondeterioration of the MD slope (multivariate logistic regression analysis: P=0.0020). Conclusion: In this 6-year observation of NTG patients treated with medical therapy, the occurrence of three or more consecutive decreases in MD value was significantly associated with visual field deterioration. Reduction in IOP was postulated to be contributing in the prevention of VFD progression. Keywords: long-term follow-up, MD slope deterioration, consecutive decrease in MD value, intraocular pressure reductio

Effect of quantitative intraocular pressure reduction on visual field defect progression in normal tension glaucoma under medical therapy applying Markov model

Keiji Yoshikawa,1 Kazunori Santo,2 Hiroko Hizaki,2 Masayo Hashimoto2 1Yoshikawa Eye Clinic, Machida, Tokyo, Japan; 2Japan Medical Affairs, Santen Pharmaceutical Co., Ltd, Osaka, Japan Purpose: To quantitatively evaluate the association of intraocular pressure (IOP) reduction with visual field defect (VFD) progression in normal tension glaucoma (NTG) under medical therapy. Patients and methods: Clinical data for 622 eyes of 311 primary open-angle glaucoma and NTG patients were collected from April 2006 to March 2016. Of these patients, those with normal IOP, glaucomatous VFD by Anderson&rsquo;s criteria, corrected visual acuity&nbsp;&ge;0.7, &gt;5 years of medical therapy, &ge;5 visual field tests at least five times at 12-month intervals, visual field testing reliability coefficients of&nbsp;&le;33%, and mean deviation (MD) exceeding below -20&nbsp;dB in the initial visual field test were included in this retrospective data analysis. MD and IOP data were collected at baseline and after 5 years. Following MD categorization into stages I to IV, stage transition matrices were generated using a Markov model to evaluate VFD changes. Eyes were divided based on IOP reduction (0%, 10%, 15%, 20%, 25%, 30%) from baseline. VFD aggravations were compared using the Markov model and MD slopes with IOP reduction rates as cutoff values. Results: Overall, 132 eyes of 132 NTG patients fulfilled the eligibility criteria. MD decreased significantly (P&lt;0.0001) at 5 years vs baseline. During follow-up, visual field stage using the Markov model was constant in&nbsp;~60%, with transitions in&nbsp;~40%. IOP decreased significantly (P&lt;0.001) at 5 years vs baseline. Though MD slopes did not differ significantly between each of the groups that achieved the various IOP reduction cut-off values and the corresponding group that did not achieve the cut-off values, a significant difference (P=0.0432) in VFD was found between the group that achieved the 25% cut-off value and the group that did not when evaluated using the Markov model. Conclusion: In NTG patients, VFD aggravation was significantly suppressed in groups with IOP reductions of&nbsp;&ge;25% from baseline. Keywords: normal tension glaucoma, visual field defect (VFD) progression, long-term follow-up, intraocular pressure reduction, Markov mode

The 24-hour intraocular pressure control by tafluprost/timolol fixed combination after switching from the concomitant use of tafluprost and timolol gel-forming solution, in patients with primary open-angle glaucoma

Kenji Nakamoto,1 Masahiko Takeshi,2 Toshihiko Hiraoka,2,3 Mayuko Eguchi,2,4 Yuichiro Nakano,1,2 Naomi Otsuka,5 Hiroko Hizaki,5 Hiromi Akai,5 Masayo Hashimoto5 1Department of Ophthalmology, Nippon Medical School, Tokyo, Japan; 2Shinanozaka Clinic, Tokyo, Japan; 3Hiraoka Eye Clinic, Saitama, Japan; 4Musashiurawa Eye Clinic, Saitama, Japan; 5Japan Medical Affairs, Global R&amp;D, Santen Pharmaceutical Co., Ltd., Osaka, Japan Objective: The aim of this study was to evaluate the 24-hour intraocular pressure (IOP)-control effect of the tafluprost/timolol fixed combination (TAF/TIM-FC) in patients with primary open-angle glaucoma after they switched from the concomitant use of tafluprost and timolol gel-forming solution. Patients and methods: Twenty patients with primary open-angle glaucoma (12 male and 8&nbsp;female; mean &plusmn; SD age, 57.0&plusmn;7.1 years) were included in this study. The patients were treated for 8 weeks with the concomitant administration of tafluprost and timolol gel-forming solution (evening dosing). At the end of this period, the patients underwent 24-hour IOP monitoring (measured at 21:00, 01:00, 05:00, 09:00, 13:00 and 17:00). IOP was measured with Goldmann applanation tonometer (GAT) and Icare PRO at sitting position at all timepoints and additionally, at supine position with Icare PRO tonometer at 01:00 and 05:00. The patients were then all switched to TAF/TIM-FC treatment (evening dosing). After 8 weeks, the 24-hour IOP monitoring was repeated. Results: Nineteen patients completed the study. The mean 24-hour IOPs in the concomitant and TAF/TIM-FC phases were 13.8&plusmn;2.7 vs 13.3&plusmn;2.8 mmHg (P=0.0033) with the GAT in the sitting position and 13.96&plusmn;2.56 vs 13.48&plusmn;2.56 mmHg (P=0.0120) with the Icare PRO in habitual positions. In comparison with the concomitant phase, significantly lower IOP was observed for the TAF/TIM-FC phase at 21:00 and 01:00 with the GAT and at 01:00 with the Icare PRO. In&nbsp;addition, the maximum IOP and fluctuations in IOP in habitual positions were lower for the TAF/TIM-FC phase than for the concomitant phase. Conclusion: TAF/TIM-FC showed a stable 24-hour IOP-lowering effect and was equally or more effective than the concomitant use of tafluprost and timolol gel, both when sitting and when in habitual positions. Keywords: intraocular pressure, tafluprost, circadian IOP, 24-hour IOP, timolol ge

Thromboxane A(2) and prostaglandin F-2 alpha mediate inflammatory tachycardia

authorSystemic inflammation induces various adaptive responses including tachycardia. Although inflammation-associated tachycardia has been thought to result from increased sympathetic discharge caused by inflammatory signals of the immune system^1, definitive proof has been lacking. Prostanoids-including prostaglandin (PG) D_2, PGE_2, PGF_, PGI_2, and thromboxane (TX) A_2-exert their actions through specific receptors: DP, EP (EP_1, EP_2, EP_3, EP_4), FP, IP, and TP, respectively^2. Here we have examined the roles of prostanoids in inflammatory tachycardia with the use of mice lacking each of these receptors individually. The TXA_2 analog I-BOP and PGF_ each increased the beating rate of the isolated atrium of wild-type (WT) mice in vitro through interaction with TP and FP, respectively. The cytokine-induced increase in beating rate was markedly inhibited in atria from mice lacking either TP or FP. The tachycardia induced in WT mice by injection of lipopolysaccharide (LPS) was greatly attenuated in TP-/- or FP-/- mice and was completely absent in mice lacking both TP and FP. Propranolol failed to block the LPS-induced increase in heart rate in WT animals. Our results show that inflammatory tachycardia is caused by a direct action on the heart of TXA_2 and PGF_ formed under systemic inflammatory conditions

Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation

Bone remodeling, comprising resorption of existing bone and de novo bone formation, is required for the maintenance of a constant bone mass. Prostaglandin (PG)E(2) promotes both bone resorption and bone formation. By infusing PGE(2) to mice lacking each of four PGE receptor (EP) subtypes, we have identified EP4 as the receptor that mediates bone formation in response to this agent. Consistently, bone formation was induced in wild-type mice by infusion of an EP4-selective agonist and not agonists specific for other EP subtypes. In culture of bone marrow cells from wild-type mice, PGE(2) induced expression of core-binding factor α1 (Runx2/Cbfa1) and enhanced formation of mineralized nodules, both of which were absent in the culture of cells from EP4-deficient mice. Furthermore, administration of the EP4 agonist restored bone mass and strength normally lost in rats subjected to ovariectomy or immobilization. Histomorphometric analysis revealed that the EP4 agonist induced significant increases in the volume of cancellous bone, osteoid formation, and the number of osteoblasts in the affected bone of immobilized rats, indicating that activation of EP4 induces de novo bone formation. In addition, osteoclasts were found on the increased bone surface at a density comparable to that found in the bone of control animals. These results suggest that activation of EP4 induces bone remodeling in vivo and that EP4-selective drugs may be beneficial in humans with osteoporosis