Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391

Exploring Public Health's roles and limitations in advancing food security in British Columbia

OBJECTIVES: This research analyzes the roles and limitations of Public Health in British Columbia in advancing food security through the integration of food security initiatives into its policies and programs. It asks the question, can Public Health advance food security? If so, how, and what are its limitations? METHODS: This policy analysis merges findings from 38 key informant interviews conducted with government and civil society stakeholders involved in the development of food security initiatives, along with an examination of relevant documents. The Population Health Template is used to delineate and analyze Public Health roles in food security. RESULTS: Public Health was able to advance food security in some ways, such as the adoption of food security as a core public health program. Public Health's leadership role in food security is constrained by a restricted mandate, limited ability to collaborate across a wide range of sectors and levels, as well as internal conflict within Public Health between Food Security and Food Protection programs. CONCLUSIONS: Public Health has a role in advancing food security, but it also faces limitations. As the limitations are primarily systemic and institutional, recommendations to overcome them are not simple but, rather, require movement toward embracing the determinants of health and regulatory pluralism. The results also suggest that the historic role of Public Health in food security remains salient today

<em>Enterococcus faecalis</em> Infection Causes Inflammation, Intracellular Oxphos-Independent ROS Production, and DNA Damage in Human Gastric Cancer Cells

Background: Achlorhydria caused by e.g. atrophic gastritis allows for bacterial overgrowth, which induces chronic inflammation and damage to the mucosal cells of infected individuals driving gastric malignancies and cancer. Enterococcus faecalis (E. faecalis) can colonize achlohydric stomachs and we therefore wanted to study the impact of E. faecalis infection on inflammatory response, reactive oxygen species (ROS) formation, mitochondrial respiration, and mitochondrial genetic stability in gastric mucosal cells. Methods: To separate the changes induced by bacteria from those of the inflammatory cells we established an in vitro E. faecalis infection model system using the gastric carcinoma cell line MKN74. Total ROS and superoxide was measured by fluorescence microscopy. Cellular oxygen consumption was characterized non-invasively using XF24 microplate based respirometry. Gene expression was examined by microarray, and response pathways were identified by Gene Set Analysis (GSA). Selected gene transcripts were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Mitochondrial mutations were determined by sequencing. Results: Infection of MKN74 cells with E. faecalis induced intracellular ROS production through a pathway independent of oxidative phosphorylation (oxphos). Furthermore, E. faecalis infection induced mitochondrial DNA instability. Following infection, genes coding for inflammatory response proteins were transcriptionally up-regulated while DNA damage repair and cell cycle control genes were down-regulated. Cell growth slowed down when infected with viable E. faecalis and responded in a dose dependent manner to E. faecalis lysate. Conclusions: Infection by E. faecalis induced an oxphos-independent intracellular ROS response and damaged the mitochondrial genome in gastric cell culture. Finally the bacteria induced an NF-kappa B inflammatory response as well as impaired DNA damage response and cell cycle control gene expression

Challenge clusters facing LCA in environmental decision-making—what we can learn from biofuels

Purpose Bioenergy is increasingly used to help meet greenhouse gas (GHG) and renewable energy targets. However, bioenergy’s sustainability has been questioned, resulting in increasing use of life cycle assessment (LCA). Bioenergy systems are global and complex, and market forces can result in significant changes, relevant to LCA and policy. The goal of this paper is to illustrate the complexities associated with LCA, with particular focus on bioenergy and associated policy development, so that its use can more effectively inform policymakers. Methods The review is based on the results from a series of workshops focused on bioenergy life cycle assessment. Expert submissions were compiled and categorized within the first two workshops. Over 100 issues emerged. Accounting for redundancies and close similarities in the list, this reduced to around 60 challenges, many of which are deeply interrelated. Some of these issues were then explored further at a policyfacing workshop in London, UK. The authors applied a rigorous approach to categorize the challenges identified to be at the intersection of biofuels/bioenergy LCA and policy. Results and discussion The credibility of LCA is core to its use in policy. Even LCAs that comply with ISO standards and policy and regulatory instruments leave a great deal of scope for interpretation and flexibility. Within the bioenergy sector, this has led to frustration and at times a lack of obvious direction. This paper identifies the main challenge clusters: overarching issues, application and practice and value and ethical judgments. Many of these are reflective of the transition from application of LCA to assess individual products or systems to the wider approach that is becoming more common. Uncertainty in impact assessment strongly influences planning and compliance due to challenges in assigning accountability, and communicating the inherent complexity and uncertainty within bioenergy is becoming of greater importance. Conclusions The emergence of LCA in bioenergy governance is particularly significant because other sectors are likely to transition to similar governance models. LCA is being stretched to accommodate complex and broad policy-relevant questions, seeking to incorporate externalities that have major implications for long-term sustainability. As policy increasingly relies on LCA, the strains placed on the methodology are becoming both clearer and impedimentary. The implications for energy policy, and in particular bioenergy, are large

Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets

Lowering the glycemic index of white bread using a white bean extract

<p>Abstract</p> <p>Background</p> <p>Phase 2^®is a dietary supplement derived from the common white kidney bean (Phaseolus vulgaris). Phase 2 has been shown to inhibit alpha-amylase, the complex carbohydrate digesting enzyme, in vitro. The inhibition of alpha-amylase may result in the lowering of the effective Glycemic Index (GI) of certain foods. The objective of this study was to determine whether the addition of Phase 2 would lower the GI of a commercially available high glycemic food (white bread).</p> <p>Methods</p> <p>An open-label 6-arm crossover study was conducted with 13 randomized subjects. Standardized GI testing was performed on white bread with and without the addition of Phase 2 in capsule and powder form, each in dosages of 1500 mg, 2000 mg, and 3000 mg. Statistical analysis was performed by one-way ANOVA of all seven treatment groups using unadjusted multiple comparisons (t tests) to the white bread control.</p> <p>Results</p> <p>For the capsule formulation, the 1500 mg dose had no effect on the GI and the 2000 mg and 3000 mg capsule doses caused insignificant reductions in GI. For the powder, the 1500 mg and 2000 mg doses caused insignificant reductions in the GI, and the 3000 mg dose had a significant effect (-20.23 or 34.11%, p = 0.023)</p> <p>Conclusion</p> <p>Phase 2 white bean extract appears to be a novel and potentially effective method for reducing the GI of existing foods without modifying their ingredient profile.</p> <p>Trial Registration</p> <p>Trial Registration: ISRCTN50347345</p

Cannabinoid Regulation of Nitric Oxide Synthase I (nNOS) in Neuronal Cells

In our previous studies, CB1 cannabinoid receptor agonists stimulated production of cyclic GMP and translocation of nitric oxide (NO)-sensitive guanylyl cyclase in neuronal cells (Jones et al., Neuropharmacology 54:23–30, 2008). The purpose of these studies was to elucidate the signal transduction of cannabinoid-mediated neuronal nitric oxide synthase (nNOS) activation in neuronal cells. Cannabinoid agonists CP55940 (2-[(1S,2R,5S)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), WIN55212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), and the metabolically stable analog of anandamide, (R)-(+)-methanandamide stimulated NO production in N18TG2 cells over a 20-min period. Rimonabant (N-(piperidin-lyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-H-pyrazole-3-carboxamide), a CB1 receptor antagonist, partially or completely curtailed cannabinoid-mediated NO production. Inhibition of NOS activity (NG-nitro-l-arginine) or signaling via Gi/o protein (pertussis toxin) significantly limited NO production by cannabinoid agonists. Ca2+ mobilization was not detected in N18TG2 cells after cannabinoid treatment using Fluo-4 AM fluorescence. Cannabinoid-mediated NO production was attributed to nNOS activation since endothelial NOS and inducible NOS protein and mRNA were not detected in N18TG2 cells. Bands of 160 and 155 kDa were detected on Western blot analysis of cytosolic and membrane fractions of N18TG2 cells, using a nNOS antibody. Chronic treatment of N18TG2 cells with cannabinoid agonists downregulated nNOS protein and mRNA as detected using Western blot analysis and real-time polymerase chain reaction, respectively. Cannabinoid agonists stimulated NO production via signaling through CB1 receptors, leading to activation of Gi/o protein and enhanced nNOS activity. The findings of these studies provide information related to cannabinoid-mediated NO signal transduction in neuronal cells, which has important implications in the ongoing elucidation of the endocannabinoid system in the nervous system

Proteome changes in platelets activated by arachidonic acid, collagen, and thrombin

<p>Abstract</p> <p>Background</p> <p>Platelets are small anucleated blood particles that play a key role in the control of bleeding. Platelets need to be activated to perform their functions and participate in hemostasis. The process of activation is accompanied by vast protein reorganization and posttranslational modifications. The goal of this study was to identify changes in proteins in platelets activated by different agonists. Platelets were activated by three different agonists - arachidonic acid, collagen, and thrombin. 2D SDS-PAGE (pI 4-7) was used to separate platelet proteins. Proteomes of activated and resting platelets were compared with each other by Progenesis SameSpots statistical software; and proteins were identified by nanoLC-MS/MS.</p> <p>Results</p> <p>190 spots were found to be significantly different. Of these, 180 spots were successfully identified and correspond to 144 different proteins. Five proteins were found that had not previously been identified in platelets: protein CDV3 homolog, protein ETHE1, protein LZIC, FGFR1 oncogene partner 2, and guanine nucleotide-binding protein subunit beta-5. Using spot expression profile analysis, we found two proteins (WD repeat-containing protein 1 and mitochondrial glycerol-3-phosphate dehydrogenase) that may be part of thrombin specific activation or signal transduction pathway(s).</p> <p>Conclusions</p> <p>Our results, characterizing the differences within proteins in both activated (by various agonists) and resting platelets, can thus contribute to the basic knowledge of platelets and to the understanding of the function and development of new antiplatelet drugs.</p

A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme

Δ9-Tetrahydrocannabinol (THC) and other cannabinoids inhibit tumour growth and angiogenesis in animal models, so their potential application as antitumoral drugs has been suggested. However, the antitumoral effect of cannabinoids has never been tested in humans. Here we report the first clinical study aimed at assessing cannabinoid antitumoral action, specifically a pilot phase I trial in which nine patients with recurrent glioblastoma multiforme were administered THC intratumoraly. The patients had previously failed standard therapy (surgery and radiotherapy) and had clear evidence of tumour progression. The primary end point of the study was to determine the safety of intracranial THC administration. We also evaluated THC action on the length of survival and various tumour-cell parameters. A dose escalation regimen for THC administration was assessed. Cannabinoid delivery was safe and could be achieved without overt psychoactive effects. Median survival of the cohort from the beginning of cannabinoid administration was 24 weeks (95% confidence interval: 15–33). Δ9-Tetrahydrocannabinol inhibited tumour-cell proliferation in vitro and decreased tumour-cell Ki67 immunostaining when administered to two patients. The fair safety profile of THC, together with its possible antiproliferative action on tumour cells reported here and in other studies, may set the basis for future trials aimed at evaluating the potential antitumoral activity of cannabinoids