The molecular mechanisms by which vascular tissues acquire their identities are largely unknown. Here, we report on the identification and characterization of VASCULATURE COMPLEXITY AND CONNECTIVITY (VCC), a member of a 15-member, plant-specific gene family in Arabidopsis (Arabidopsis thaliana) that encodes proteins of unknown function with four predicted transmembrane domains. Homozygous vcc mutants displayed cotyledon vein networks of reduced complexity and disconnected veins. Similar disconnections or gaps were observed in the provasculature of vcc embryos, indicating that defects in vein connectivity appear early in mutant embryo development. Consistently, the overexpression of VCC leads to an unusually high proportion of cotyledons with high-complexity vein networks. Neither auxin distribution nor the polar localization of the auxin efflux carrier were affected in vcc mutant embryos. Expression of VCC was detected in developing embryos and procambial, cambial, and vascular cells of cotyledons, leaves, roots, hypocotyls, and anthers. To evaluate possible genetic interactions with other genes that control vasculature patterning in embryos, we generated a double mutant for VCC and OCTOPUS (OPS). The vcc ops double mutant embryos showed a complete loss of high-complexity vascular networks in cotyledons and a drastic increase in both provascular and vascular disconnections. In addition, VCC and OPS interact physically, suggesting that VCC and OPS are part of a complex that controls cotyledon vascular complexity.
During myocardial ischemia/reperfusion (I/R), the generation of reactive oxygen species (ROS) contributes to post‐reperfusion cardiac injury and contractile dysfunction. Activation of protein kinase C epsilon (PKC ɛ) during I/R has been shown to increase ROS release, in part, by its stimulation of increased uncoupled endothelial nitric oxide synthase activity. We hypothesize that using a cell permeable PKC ɛ peptide inhibitor (PKC ɛ‐) (N‐myr‐EAVSLKPT, MW=1054 g/mol, 10μM or 20μM) will improve post‐reperfused cardiac function and attenuate infarct size compared to untreated controls in isolated perfused rat hearts subjected to I(30 min)/R(90 min). Male Sprague‐Dawley rats (275–325 g) were anesthetized with sodium pentobarbital (60 mg/kg) and anticoagulated with heparin 1000 units IP. PKC ɛ‐was dissolved in Krebs' buffer and infused during the first 10 min of reperfusion. PKC ɛ‐treated hearts exhibited significant improvement in post‐reperfused cardiac function at 90 min in the maximal rate of left ventricular developed pressure (+dP/dtmax): 56±5%; n=6 (10μM) and 46±3%; n=4 (20μM) compared to untreated controls (n=6) which only recovered to 32±5% of baseline values for +dP/dtmax respectively (p<0.05). Furthermore, PKC ɛ‐treated hearts showed significant reduction in infarct size of 27±2% (10μM) and 28 ±2% (20μM) compared to untreated control I/R hearts, 40±3% (p<0.05). The results suggest that PKC ɛ‐is effective in improving cardiac function and reducing infarct size and is a putative treatment that could aid in clinical myocardial infarction/organ transplantation patient recovery.Support or Funding InformationThis study was supported by the Center for Chronic Disorders of Aging, the Division of Research and the Department of Bio‐Medical Sciences at Philadelphia College of Osteopathic Medicine.
Lung cancer has the highest United States and worldwide rate of cancer mortality, exceeding the mortality rates of colorectal, breast and prostate cancers combined. Tobacco smoking is well established as the major etiological risk factor for lung cancer, contributing to an increased risk in long-term smokers compared with non-smokers. The risk of the development of lung cancer in lifelong smokers is 20-40 times higher than that in non-smokers. Moreover, tobacco use accounts for 30% of overall lung cancer mortality. Given the large population at increased risk of developing lung cancer, the development of approaches to prevent smoking related lung cancer would have great clinical benefit. Pomegranate (Punica granatum, Punicaceae), is an edible fruit cultivated in Mediterranean countries, Afghanistan, India, China, Japan, Russia and the United States. Based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis, pomegranate fruit extract (PFE) was found to contain anthocyanins (such as delphinidin, cyanidin and pelargonidin) and several hydrolyzable tannins (such as punicalin, pedunculagin, punicalagin, gallagic and ellagic acid esters of glucose) which account for 92% of the antioxidant activity of the whole fruit. We have earlier reported that PFE inhibits prosurvival signaling pathways in human lung carcinoma A549 cells and tumor growth in athymic nude mice (Carcinogenesis 2007; 28:163-73) and A/J mice (Cancer Res 2007; 67:3475-82). In this study, the effect of PFE consumption during progression of lung adenomas to adenocarcinomas was investigated in two mouse tumor protocols. NNK, a tobacco-specific N-nitrosamine, is believed to be one of the most promising candidates of lung carcinogen in humans. B(a)P is one of the most ubiquitous environmental polycyclic aromatic hydrocarbons present in automobile exhaust and cigarette smoke and it induces lung tumors in mice. Since majority of current and ex-smokers have small nodules, it is highly desirable to prevent additional growth of lung cancer after the appearance of nodules. To mimic this situation, PFE (0.2% PFE, w/v) was given to A/J mice in drinking water after the establishment of lung adenomas induced by NNK and B(a)P. Treatment with PFE significantly reduced the lung tumor multiplicity by 33% in mice treated with NNK and 29% in B(a)P-treated mice. PFE also caused significant reduction in the expression of COX-2, RAR-β, VEGF, CD-31 and angiopoietin-2 in lungs of mice treated with NNK and B(a)P. On administration of PFE, there was decrease in the multiplicity and incidence of lung adenomas and adenocarcinomas in mice treated with NNK and B(a)P. Thus, our results indicate that PFE has the potential to be developed as an agent against tobacco smoke-induced lung cancer and for improving the quality of life of early stage lung cancer patients and ex-smokers. Citation Format: Naghma Khan, Ruth Sullivan, Tien Hoang, Tejaswi Dittakavi, Hasan Mukhtar. Delay in the progression of lung adenoma to adenocarcinoma in mice by oral consumption of pomegranate fruit extract. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 194. doi:10.1158/1538-7445.AM2013-194
Preliminary studies in mice have shown that a novel tri‐peptide (Phe‐D‐Arg‐Phe‐Amide, MW=468 g/mol) attenuates ventilation induced diaphragm dysfunction when given as a pretreatment. Tri‐peptide is structurally similar to the SS‐20 peptide (Phe‐D‐Arg‐Phe‐Lys‐Amide), which has been shown to be cardioprotective when given before ischemia, but thought not to have opioid properties (Cho et al., 2007). Our study aims to determine whether pre‐ or posttreatment with tri‐peptide is more efficacious in attenuating the deleterious effects of myocardial ischemia/reperfusion (I/R) injury and whether this cardioprotection is mediated by opioid receptor activation. This was tested by observing whether tri‐peptide‐induced cardioprotection was abolished when administered in conjunction with naloxone, a nonselective opioid receptor antagonist. Tri‐peptide (50μM) was administered prior to I (pretreatment, n=8) or during R (posttreatment, n=8) in isolated perfused rat hearts subjected to I(30 min)/R(45 min) and compared to untreated control hearts (n=7) and hearts pre‐treated with tri‐peptide (50 μM) + naloxone (Nlx, 10μM, n=8). Tri‐peptide pretreatment hearts significantly recovered post‐reperfused left ventricular developed pressure (LVDP) to 59±6% of initial baseline values compared to untreated control, posttreatment tri‐peptide, and pretreatment tri‐peptide + Nlx hearts in which LVDP recovered to only 33±7%, 34±8%, and 26±4% of initial baseline values respectively (p<0.01). Furthermore, tri‐peptide pretreatment hearts exhibited significantly reduced infarct sizes of 26±1% compared to untreated control and posttreatment tri‐peptide hearts, in which infarct sizes were 38±4% and 37±2% respectively (p<0.05) assessed using 1% triphenyltetrazolium chloride staining. Pretreated tripeptide + Nlx hearts showed infarct sizes of 32±3% which was not significantly different from untreated controls. These data suggest that pretreatment and not posttreatment with this novel tri‐peptide was cardioprotective and that this protection was mediated via opioid receptor activation. Future studies will attempt to determine the specific opioid receptor subtype involved in tri‐peptide cardioprotection by testing whether delta or kappa opioid receptor antagonists block the cardioprotective effects of tri‐peptide pretreatment.Support or Funding InformationThis study was supported by the Center for Chronic Disorders of Aging, the Division of Research and the Department of Bio‐Medical Sciences at Philadelphia College of Osteopathic Medicine.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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