Publications by authors named "Amy Howell"

136 Publications

Proanthocyanidins mitigate bile acid-induced changes in GSTT2 levels in a panel of racially diverse patient-derived primary esophageal cell cultures.

Mol Carcinog 2021 Nov 10. Epub 2021 Nov 10.

Department of Surgery, Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Persistent and symptomatic reflux of gastric and duodenal contents, known as gastroesophageal reflux disease (GERD), is the strongest risk factor for esophageal adenocarcinoma (EAC). Despite similar rates of GERD and other risk factors across racial groups, EAC progression disproportionately impacts Caucasians. We recently reported that elevated tissue levels of the detoxification enzyme GSTT2 in the esophagi of Blacks compared to Caucasians may contribute protection. Herein, we extend our research to investigate whether cranberry proanthocyanidins (C-PAC) mitigate bile acid-induced damage and GSTT2 levels utilizing a racially diverse panel of patient-derived primary esophageal cultures. We have shown that C-PACs mitigate reflux-induced DNA damage through GSTT2 upregulation in a rat esophageal reflux model, but whether effects are recapitulated in humans or differentially based on race remains unknown. We isolated normal primary esophageal cells from Black and Caucasian patients and assessed GSTT2 protein levels and cellular viability following exposure to a bile acid cocktail with and without C-PAC treatment. Constitutive GSTT2 levels were significantly elevated in Black (2.9-fold) compared to Caucasian patients, as were GSTT2 levels in Black patients with GERD. C-PAC treatment induced GSTT2 levels 1.6-fold in primary normal esophageal cells. GSTT2 induction by C-PAC was greatest in cells with constitutively low GSTT2 expression. Overall, C-PAC mitigated bile-induced reductions of GSTT2 and subsequent loss of cell viability regardless of basal GSTT2 expression or race. These data support that C-PAC may be a safe efficacious agent to promote epithelial fitness through GSTT2 induction and in turn protect against bile acid-induced esophageal injury.
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http://dx.doi.org/10.1002/mc.23369DOI Listing
November 2021

Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic kidney disease.

Int J Epidemiol 2021 Oct 20. Epub 2021 Oct 20.

Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Background: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization.

Methods: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included.

Results: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2.

Conclusions: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.
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http://dx.doi.org/10.1093/ije/dyab203DOI Listing
October 2021

Chemical proteomic analysis of palmostatin beta-lactone analogs that affect N-Ras palmitoylation.

Bioorg Med Chem Lett 2021 Dec 16;53:128414. Epub 2021 Oct 16.

Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. Electronic address:

S-Palmitoylation is a reversible post-translational lipid modification that regulates protein trafficking and signaling. The enzymatic depalmitoylation of proteins is inhibited by the beta-lactones Palmostatin M and B, which have been found to target several serine hydrolases. In efforts to better understand the mechanism of action of Palmostatin M, we describe herein the synthesis, chemical proteomic analysis, and functional characterization of analogs of this compound. We identify Palmostatin M analogs that maintain inhibitory activity in N-Ras depalmitoylation assays while displaying complementary reactivity across the serine hydrolase class as measured by activity-based protein profiling. Active Palmostatin M analogs inhibit the recently characterized ABHD17 subfamily of depalmitoylating enzymes, while sparing other candidate depalmitoylases such as LYPLA1 and LYPLA2. These findings improve our understanding of the structure-activity relationship of Palmostatin M and refine the set of serine hydrolase targets relevant to the compound's effects on N-Ras palmitoylation dynamics.
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http://dx.doi.org/10.1016/j.bmcl.2021.128414DOI Listing
December 2021

Unusual Transformations of Strain-Heightened Oxetanes.

Acc Chem Res 2021 10 30;54(20):3850-3862. Epub 2021 Sep 30.

Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060, United States.

Oxetanes are important motifs for drug discovery and are valuable templates in organic synthesis. Much of their use as synthetic intermediates exploits their inherent strain, often resulting in chain extensions at the expense of the heterocycle. Modifications on the carbon alpha to the oxygen of oxetanes, such as the C═O of β-lactones, extend the modes of reactivity. Nevertheless, the outcomes are still largely predictable. On the other hand, other alpha modifications, such as a ═CH, a spiro-oxiranyl moiety, or a spiro-cyclopropyl group, increase strain and open pathways not available to simple oxetanes or β-lactones. Methods in generating 2-methyleneoxetanes, 1,5-dioxaspiro[3.2]hexanes, and 4-oxaspiro[2.3]hexanes have been developed by us and others. To date, reactions of these systems have sometimes been predictable, but often the outcomes have been unexpected. This has provided fertile ground for thinking about what controls reactivity and what other reaction pathways might be accessible to these strain-heightened oxetanes.This Account summarizes the published literature on the most straightforward approaches to 2-methyleneoxetanes, dioxaspirohexanes, and oxaspirohexanes and on their reactivity. In contrast to simple oxetanes, reactions of 2-methyleneoxetanes with nucleophiles at C4 release an enolate rather than an alkoxide. Also, 2-methyleneoxetanes can be converted to homopropargyl alcohols or undergo a silicon accelerated isomerization/electrocyclic ring opening, processes accessible only because of the exocyclic double bond. In addition, oxetane oxocarbenium ions, derived from protonation of the enol ether, can react with nucleophiles to provide 2,2-disubstituted oxetanes. Oxaspirohexanes are readily prepared by Simmons-Smith cyclopropanation of 2-methyleneoxetanes. These unusual systems undergo a variety of substituent dependent rearrangements in the presence of the Lewis acid BF·EtO. In addition, upon treatment with Zeise's dimer, oxaspirohexanes are transformed to synthetically useful 3-methylenetetrahydrofurans. Dioxaspirohexanes are easily accessed by dimethyldioxirane oxidation of 2-methyleneoxetanes. Predictably, dioxaspirohexanes react with many nucleophiles to give α-functionalized-β'-hydroxy ketones. Unexpectedly, 2,2-disubstituted oxetanes can also be selectively produced. This latter pathway has led to further unusual transformations, illuminating computational studies, and novel routes to biologically relevant molecules.
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http://dx.doi.org/10.1021/acs.accounts.1c00415DOI Listing
October 2021

Easily accessible non-aromatic heterocycles with handles: 4-bromo-2,3-dihydrofurans from 1,2-dibromohomoallylic alcohols.

Chem Sci 2021 Aug 29;12(30):10347-10353. Epub 2021 Jun 29.

Department of Chemistry, University of Connecticut Storrs CT 06269 USA

The first general preparation of 4-bromo-2,3-dihydrofurans is reported. These non-aromatic heterocycles containing a useful coupling handle are accessed Cu-catalyzed intramolecular cyclization of 1,2-dibromohomoallylic alcohols, which are themselves available in just two steps from aromatic and aliphatic aldehydes and ketones. Molecular dynamics simulations using the simple substrates and key geometric parameters provide a rationale for the selectivities observed. The synthetic utility of the 4-bromodihydrofurans is also demonstrated.
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http://dx.doi.org/10.1039/d1sc01013aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336482PMC
August 2021

ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth.

Nat Chem Biol 2021 08 29;17(8):856-864. Epub 2021 Apr 29.

Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.

Multiple Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M (Palm M) block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared with Palm M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MAP kinase kinase (MEK) inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes as regulators of the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers.
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http://dx.doi.org/10.1038/s41589-021-00785-8DOI Listing
August 2021

Differences in Urinary Bacterial Anti-Adhesion Activity after Intake of Cranberry Dietary Supplements with Soluble versus Insoluble Proanthocyanidins.

J Diet Suppl 2021 Apr 5:1-18. Epub 2021 Apr 5.

Department of Urology, New York-Presbyterian Hospital/Weill Cornell, New York, NY, USA.

A number of clinical trials support the use of standardized cranberry supplement products for prevention of urinary tract infections; however, products that are not well-characterized for sufficient levels of bioactive components may contribute to negative clinical outcomes. Cranberry supplements for consumer use are not regulated and can be formulated different ways using cranberry juice, pomace or various combinations. This can lead to consumer confusion regarding effectiveness of individual products. The current study compared two commercial supplement products, one made from cranberry juice extract and the other from a blend of whole cranberry. The influence of formulation and proanthocyanidin (PAC) solubility on in vitro and ex vivo P-fimbriated bacterial anti-adhesion activity (AAA) was determined. Both supplement products as well as whole, frozen cranberries were chromatographically separated into crude polyphenolic, sugar and acid fractions. In vitro AAA testing of all fractions confirmed that only those containing soluble PACs elicited activity. The cranberry juice extract product had higher soluble PAC content than the whole cranberry blended product, which contained mainly insoluble PACs. The influence of soluble and insoluble PAC levels in each product on the urinary (ex vivo) AAA was determined following ingestion. The juice extract product was associated with significantly higher urinary AAA than that of the whole berry blended product when consumed once daily over the 1-week intervention period.
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http://dx.doi.org/10.1080/19390211.2021.1908480DOI Listing
April 2021

Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.

Cochrane Database Syst Rev 2021 03 12;3:CD013316. Epub 2021 Mar 12.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide.

Objectives: To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide.

Search Methods: We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014.

Selection Criteria: Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis.

Data Collection And Analysis: Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals.

Main Results: We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status.

Authors' Conclusions: PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.
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http://dx.doi.org/10.1002/14651858.CD013316.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078495PMC
March 2021

"Running myself ragged": stressors faced by peer workers in overdose response settings.

Harm Reduct J 2021 02 11;18(1):18. Epub 2021 Feb 11.

BC Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC, V5Z 4R4, Canada.

Background: Peer workers or "peers" (workers with past or present drug use experience) are at the forefront of overdose response initiatives, and their role is essential in creating safe spaces for people who use drugs (PWUD). Working in overdose response settings has benefits for peer workers but is also stressful, with lasting emotional and mental health effects. Yet, little is known about the stressors peer workers face and what interventions can be implemented to support them in their roles.

Methods: This project used a community-based sequential mixed-methods research design. Eight peer researcher-led focus groups (n = 31) were conducted between November 2018 and March 2019 to assess needs of peer workers. The transcripts were thematically coded and analysed using interpretative description. These results informed a survey, which was conducted (n = 50) in September 2019 to acquire quantitative data on peer workers' perception of health, quality of life, working conditions and stressors. Frequency distributions were used to describe characteristics of participants. X distribution values with Yates correction were conducted to check for association between variables.

Results: Five themes emerged from the focus groups that point to stressors felt by peer workers: (1) financial insecurity; (2) lack of respect and recognition at work; (3) housing challenges; (4) inability to access and/or refer individuals to resources; and (5) constant exposure to death and trauma. Consistent with this, the factors that survey participants picked as one of their "top three stressors" included financial situation, work situation, and housing challenges.

Conclusion: Peer workers are faced with a diversity of stressors in their lives which often reflect societal stigmatization of drug use. Recognition of these systemic stressors is critical in designing interventions to ease the emotional, physical and financial burden faced by peer workers.
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http://dx.doi.org/10.1186/s12954-020-00449-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877312PMC
February 2021

Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility.

Sci Rep 2021 01 27;11(1):2329. Epub 2021 Jan 27.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.

Genome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.
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http://dx.doi.org/10.1038/s41598-021-82169-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840943PMC
January 2021

Amide-Linked C4″-Saccharide Modification of KRN7000 Provides Potent Stimulation of Human Invariant NKT Cells and Anti-Tumor Immunity in a Humanized Mouse Model.

ACS Chem Biol 2020 12 9;15(12):3176-3186. Epub 2020 Dec 9.

Department of Chemistry, The University of Connecticut, Storrs, Connecticut 06269-3060, United States.

Activation of invariant natural killer T (iNKT) cells by α-galactosylceramides (α-GalCers) stimulates strong immune responses and potent anti-tumor immunity. Numerous modifications of the glycolipid structure have been assessed to derive activating ligands for these T cells with altered and potentially advantageous properties in the induction of immune responses. Here, we synthesized variants of the prototypical α-GalCer, KRN7000, with amide-linked phenyl alkane substitutions on the C4″-position of the galactose ring. We show that these variants have weak iNKT cell stimulating activity in mouse models but substantially greater activity for human iNKT cells. The most active of the C4″-amides in our study showed strong anti-tumor effects in a partially humanized mouse model for iNKT cell responses. analysis suggested that the tether length and degree of flexibility of the amide substituent affected the recognition by iNKT cell antigen receptors of the C4″-amide substituted glycolipids in complex with their antigen presenting molecule CD1d. Our findings establish the use of stable C4″-amide linked additions to the sugar moiety for further exploration of the immunological effects of structural modifications of iNKT cell activating glycolipids and highlight the critical need for more accurate animal models to assess these compounds for immunotherapeutic potential in humans.
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http://dx.doi.org/10.1021/acschembio.0c00707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323612PMC
December 2020

"It's an emotional roller coaster… But sometimes it's fucking awesome": Meaning and motivation of work for peers in overdose response environments in British Columbia.

Int J Drug Policy 2021 02 9;88:103015. Epub 2020 Nov 9.

BC Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC, V5Z 4R4, Canada; School of Population and Public Health, University of British Columbia, 2329 West Mall, Vancouver, BC, V6T 1Z4, Canada. Electronic address:

Background: The province of British Columbia (BC), Canada is amid dual public health emergencies in which the overdose epidemic declared in 2016 has been exacerbated by restrictions imposed by the Coronavirus Disease of 2019 (COVID-19) pandemic. Experiential workers, commonly known as 'peers' (workers with past or present drug use experience) are at the forefront of overdose response initiatives and are essential in creating safe spaces for people who use drugs (PWUD) in harm reduction. Working in overdose response environments can be stressful, with lasting emotional and mental health effects. There is limited knowledge about the personal meaning that experiential workers derive from their work, which serve as motivators for them to take on these often-stressful roles.

Methods: This project used a community-based qualitative research design. The research was based at two organizations in BC. Eight experiential worker-led focus groups were conducted (n = 31) where participants spoke about their roles, positive aspects of their jobs, challenges they face, and support needs in harm reduction work. Transcripts were coded and analyzed using interpretative description to uncover the meaning derived from experiential work.

Results: Three themes emerged from focus group data that describe the meanings which serve as motivators for experiential workers to continue working in overdose response environments: (1) A sense of purpose from helping others; (2) Being an inspiration for others, and; (3) A sense of belonging.

Conclusion: Despite the frequent hardships and loss that accompany overdose response work, experiential workers identified important aspects that give their work meaning. These aspects of their work may help to protect workers from the emotional harms associated with stressful work as well as the stigma of substance use. Recognizing the importance of experiential work and its role in the lives of PWUD can help inform and strengthen organizational supports.
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http://dx.doi.org/10.1016/j.drugpo.2020.103015DOI Listing
February 2021

Population neuroimaging: generation of a comprehensive data resource within the ALSPAC pregnancy and birth cohort.

Wellcome Open Res 2020 28;5:203. Epub 2020 Aug 28.

MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol, BS8 2BN, UK.

Neuroimaging offers a valuable insight into human brain development by allowing assessment of structure, connectivity and function. Multimodal neuroimaging data have been obtained as part of three sub-studies within the Avon Longitudinal Study of Parents and Children, a prospective multigenerational pregnancy and birth cohort based in the United Kingdom. Brain imaging data were acquired when offspring were between 18 and 24 years of age, and included acquisition of structural, functional and magnetization transfer magnetic resonance, diffusion tensor, and magnetoencephalography imaging. This resource provides a unique opportunity to combine neuroimaging data with extensive phenotypic and genotypic measures from participants, their mothers, and fathers.
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http://dx.doi.org/10.12688/wellcomeopenres.16060.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531050PMC
August 2020

Immunomodulatory sphingosine-1-phosphates as plasma biomarkers of Alzheimer's disease and vascular cognitive impairment.

Alzheimers Res Ther 2020 09 30;12(1):122. Epub 2020 Sep 30.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, 117597, Singapore.

Background: There has been ongoing research impetus to uncover novel blood-based diagnostic and prognostic biomarkers for Alzheimer's disease (AD), vascular dementia (VaD), and related cerebrovascular disease (CEVD)-associated conditions within the spectrum of vascular cognitive impairment (VCI). Sphingosine-1-phosphates (S1Ps) are signaling lipids which act on the S1PR family of cognate G-protein-coupled receptors and have been shown to modulate neuroinflammation, a process known to be involved in both neurodegenerative and cerebrovascular diseases. However, the status of peripheral S1P in AD and VCI is at present unclear.

Methods: We obtained baseline bloods from individuals recruited into an ongoing longitudinal cohort study who had normal cognition (N = 80); cognitive impairment, no dementia (N = 160); AD (N = 113); or VaD (N = 31), along with neuroimaging assessments of cerebrovascular diseases. Plasma samples were processed for the measurements of major S1P species: d16:1, d17:1, d18:0, and d18:1, along with pro-inflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF). Furthermore, in vitro effects of S1Ps on cytokine expression were also studied in an astrocytoma cell line and in rodent primary astrocytes.

Results: Of the S1Ps species measured, only d16:1 S1P was significantly reduced in the plasma of VaD, but not AD, patients, while the d18:1 to d16:1 ratios were increased in all cognitive subgroups (CIND, AD, and VaD). Furthermore, d18:1 to d16:1 ratios correlated with levels of IL-6, IL-8, and TNF. In both primary astrocytes and an astroglial cell line, treatment with d16:1 or d18:1 S1P resulted in the upregulation of mRNA transcripts of pro-inflammatory cytokines, with d18:1 showing a stronger effect than d16:1. Interestingly, co-treatment assays showed that the addition of d16:1 reduced the extent of d18:1-mediated gene expression, indicating that d16:1 may function to "fine-tune" the pro-inflammatory effects of d18:1.

Conclusion: Taken together, our data suggest that plasma d16:1 S1P may be useful as a diagnostic marker for VCI, while the d18:1 to d16:1 S1P ratio is an index of dysregulated S1P-mediated immunomodulation leading to chronic inflammation-associated neurodegeneration and cerebrovascular damage.
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http://dx.doi.org/10.1186/s13195-020-00694-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528375PMC
September 2020

α-Methylene-β-Lactone Scaffold for Developing Chemical Probes at the Two Ends of the Selectivity Spectrum.

Chembiochem 2021 02 11;22(3):505-515. Epub 2020 Nov 11.

Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA.

The utilities of an α-methylene-β-lactone (MeLac) moiety as a warhead composed of multiple electrophilic sites are reported. We demonstrate that a MeLac-alkyne not only reacts with diverse proteins as a broadly reactive measurement probe, but also recruits reduced endogenous glutathione (GSH) to assemble a selective chemical probe of GSH-β-lactone (GSH-Lac)-alkyne in live cells. Tandem mass spectrometry reveals that MeLac reacts with nucleophilic cysteine, serine, lysine, threonine, and tyrosine residues, through either Michael or acyl addition. A peptide-centric proteomics platform demonstrates that the proteomic selectivity profiles of orlistat and parthenolide, which have distinct reactivities, are measurable by MeLac-alkyne as a high-coverage probe. The GSH-Lac-alkyne selectively probes the glutathione S-transferase P responsible for multidrug resistance. The assembly of the GSH-Lac probe exemplifies a modular and scalable route to develop selective probes with different recognizing moieties.
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http://dx.doi.org/10.1002/cbic.202000605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114233PMC
February 2021

Whole Blueberry and Isolated Polyphenol-Rich Fractions Modulate Specific Gut Microbes in an In Vitro Colon Model and in a Pilot Study in Human Consumers.

Nutrients 2020 Sep 12;12(9). Epub 2020 Sep 12.

School of Microbiology, University College Cork, T12 K8AF Cork, Ireland.

Blueberry (BB) consumption is linked to improved health. The bioconversion of the polyphenolic content of BB by fermentative bacteria in the large intestine may be a necessary step for the health benefits attributed to BB consumption. The identification of specific gut microbiota taxa that respond to BB consumption and that mediate the bioconversion of consumed polyphenolic compounds into bioactive forms is required to improve our understanding of how polyphenols impact human health. We tested the ability of polyphenol-rich fractions purified from whole BB-namely, anthocyanins/flavonol glycosides (ANTH/FLAV), proanthocyanidins (PACs), the sugar/acid fraction (S/A), and total polyphenols (TPP)-to modulate the fecal microbiota composition of healthy adults in an colon system. In a parallel pilot study, we tested the effect of consuming 38 g of freeze-dried BB powder per day for 6 weeks on the fecal microbiota of 17 women in two age groups (i.e., young and older). The BB ingredients had a distinct effect on the fecal microbiota composition in the artificial colon model. The ANTH/FLAV and PAC fractions were more effective in promoting microbiome alpha diversity compared to S/A and TPP, and these effects were attributed to differentially responsive taxa. Dietary enrichment with BB resulted in a moderate increase in the diversity of the microbiota of the older subjects but not in younger subjects, and certain health-relevant taxa were significantly associated with BB consumption. Alterations in the abundance of some gut bacteria correlated not only with BB consumption but also with increased antioxidant activity in blood. Collectively, these pilot data support the notion that BB consumption is associated with gut microbiota changes and health benefits.
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http://dx.doi.org/10.3390/nu12092800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551244PMC
September 2020

Highbush blueberry proanthocyanidins alleviate Porphyromonas gingivalis-induced deleterious effects on oral mucosal cells.

Anaerobe 2020 Oct 29;65:102266. Epub 2020 Aug 29.

Oral Ecology Research Group, Faculty of Dentistry, Université Laval, Quebec City, QC, Canada. Electronic address:

Strong evidence points to Porphyromonas gingivalis, a Gram-negative anaerobic bacterium, as a keystone species in the development of the chronic form of periodontitis. The aim of the present study was to investigate the ability of highbush blueberry proanthocyanidins (PACs) to alleviate the P. gingivalis-induced deleterious effects on oral mucosal cells. We first showed that highbush blueberry PACs protect the integrity of the gingival keratinocyte barrier against P. gingivalis-mediated damage, as determined by measuring the transepithelial electrical resistance and paracellular flux of FITC-conjugated dextran. Moreover, the PACs prevented the translocation of P. gingivalis across the gingival keratinocyte barrier model. The proteinase activity of P. gingivalis was inhibited by the PACs suggesting that they may exert beneficial effects by reducing proteolytic degradation of the epithelial tight junctions. Regulation of gingival fibroblast inflammatory reactions may be one of the ways to prevent and control periodontal disease progression and severity. We showed that PACs significantly reduce IL-6 and IL-8 secretion by P. gingivalis-stimulated gingival fibroblasts. The present study showed the capacity of highbush blueberry PACs to protect the integrity of an in vitro model of gingival keratinocyte barrier against P. gingivalis, and to attenuate the secretion of pro-inflammatory cytokines by gingival fibroblasts infected with P. gingivalis. These results suggest beneficial effects of blueberry PACs thus supporting the need for future clinical trials on the potential of these bioactive molecules for periodontal disease prevention and/or treatment.
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http://dx.doi.org/10.1016/j.anaerobe.2020.102266DOI Listing
October 2020

Cranberry Proanthocyanidins Neutralize the Effects of Leukotoxin.

Toxins (Basel) 2019 11 14;11(11). Epub 2019 Nov 14.

Groupe de recherche en écologie buccale, Faculté de médecine dentaire, Université Laval, Quebec, QC G1V 0A6, Canada.

is a Gram-negative bacterium that has been strongly associated with localized aggressive periodontitis. The capacity of to produce a leukotoxin (LtxA) that activates pyroptosis in macrophages and induces the release of endogenous danger signals is thought to play a key role in the disease process. The aim of the present study was to investigate the effects of cranberry proanthocyanidins (PACs) on gene expression and cytotoxic activities of LtxA. We showed that cranberry PACs dose-dependently attenuate the expression of genes making up the leukotoxin operon, including and , in the two strains of tested. Cranberry PACs (≥62.5 µg/mL) protected macrophages against the cytotoxic effect of purified LtxA. Moreover, cranberry PACs reduced caspase-1 activation in LtxA-treated macrophages and consequently decreased the release of both IL-1β and IL-18, which are known as damage-associated molecular patterns (DAMPs) and contribute to the progression of periodontitis by increasing cell migration and osteoclastogenesis. In addition, cranberry PACs reduced the expression of genes encoding the P2X7 receptor and NALP3 (NACHT, LRR and PYD domains-containing protein 3), which play key roles in pore formation and cell death. Lastly, cranberry PACs blocked the binding of LtxA to macrophages and consequently reduced the LtxA-mediated cytotoxicity. In summary, the present study showed that cranberry PACs reduced LtxA gene expression in and neutralized the cytolytic and pro-inflammatory responses of human macrophages treated with LtxA. Given these properties, cranberry PACs may represent promising molecules for prevention and treatment of the aggressive form of periodontitis caused by .
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http://dx.doi.org/10.3390/toxins11110662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891731PMC
November 2019

A randomized, double-blind, placebo-controlled pilot study to assess bacterial anti-adhesive activity in human urine following consumption of a cranberry supplement.

Food Funct 2019 Dec;10(12):7645-7652

Ocean Spray Cranberries, Inc., One Ocean Spray Drive, Lakeville-Middleboro, MA 02349, USA.

Urinary tract infections (UTIs) are one of the common bacterial infections treated with antibiotics. The North American cranberry is recommended for prophylaxis in women with recurrent UTIs as a nutritional alternative. The ability of cranberry components and their metabolites to inhibit adhesion of uropathogenic Escherichia coli (E. coli) is an important mechanism by which cranberry mitigates UTIs. The objective of this study was to evaluate urinary anti-adhesion activity against type 1 and P-type uropathogenic E. coli after consumption of cranberry +health™ cranberry supplement (cranberry chew). In this randomized, double-blind, placebo-controlled, crossover design pilot trial (n = 20), subjects consumed two cranberry or placebo chews, one in the morning and one in the evening. Clean-catch urine samples collected at the baseline and post-intervention (0-3, 3-6, 6-9, 9-12, 12-24, 24-30, 30-36 h) were tested for anti-adhesion effects with a mannose-resistant human red blood cell hemagglutination assay specific for P-type E. coli, or a T24 cell line model for type 1 E. coli. Urinary anti-adhesion activity against P-type E. coli after consumption of the cranberry chew was significantly greater (p < 0.05) than that observed with placebo chew at all time points except 24-36 h. Ex vivo anti-adhesion effects on type 1 E. coli were greater (p < 0.05) after cranberry chew consumption than placebo chew at 3-6 and 6-9 h urine collections. In conclusion, consumption of cranberry +health™ cranberry supplement exhibited greater ex vivo urinary anti-adhesion activity compared to placebo, suggesting that it may have the potential to help promote urinary tract health.
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http://dx.doi.org/10.1039/c9fo01198fDOI Listing
December 2019

Antiviral effects of blueberry proanthocyanidins against Aichi virus.

Food Microbiol 2019 Sep 6;82:202-208. Epub 2019 Feb 6.

Department of Food Science, University of Tennessee-Knoxville, Knoxville, TN, 37996, USA. Electronic address:

Blueberry polyphenols are known for their high antioxidant and antimicrobial potential. Aichi virus (AiV) is an emerging human enteric virus that causes gastroenteritis outbreaks worldwide. This study aimed to (1) determine the time- and dose-dependent effects of blueberry proanthocyanidins (B-PAC) against AiV over 24 h at 37 °C; (2) gain insights on their mode of action using pre- and post-treatment of host cells and Transmission Electron Microscopy; and (3) determine their anti-AiV effects in model foods and under simulated gastric conditions. AiV at ∼5 log PFU/ml was incubated with equal volumes of commercial blueberry juice (BJ, pH 2.8), neutralized BJ (pH 7.0), B-PAC (2, 4, and 10 mg/ml) prepared either in 10% ethanol, apple juice (AJ), 2% milk, simulated gastric fluid (SGF, pH 1.5) or simulated intestinal fluid (SIF, pH 7.5), and controls (malic acid (pH 3.0), phosphate buffered saline (pH 7.2), apple juice (pH 3.6) and 2% milk) over 24 h at 37 °C, followed by standard plaque assays. Each experiment was replicated thrice and data were statistically analyzed. Differences in AiV titers with 1 mg/ml B-PAC were 2.13 ± 0.06 log PFU/ml lower after 24 h and ≥3 log PFU/ml (undetectable levels) lower with 2 and 5 mg/ml B-PAC compared to AiV titers in PBS after 24 h and 3 h, respectively. BJ at 37 °C resulted in titer differences (lower titers compared to PBS) of 0.17 ± 0.06, 1.27 ± 0.01, and 1.73 ± 0.23 log PFU/ml after 1, 3, and 6 h and ≥3 log PFU/ml after 24 h. Pre- and post-treatment of host cells with 0.5 mg/ml B-PAC caused titer decreases of 0.62 ± 0.33 and 0.30 ± 0.06 log PFU/ml, respectively suggesting a moderate effect on viral-host cell binding. B-PAC at 2 mg/ml in AJ caused titer differences of ≥3 log PFU/ml after 0.5 h, while differences of 0.84 ± 0.03 log PFU/ml with 5 mg/ml B-PAC in milk, and ≥3 log PFU/ml with B-PAC at 5 mg/ml in SIF after 30 min were obtained. This study shows the ability of BJ and B-PAC to decrease AiV titers to potentially prevent AiV-related illness and outbreaks.
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http://dx.doi.org/10.1016/j.fm.2019.02.001DOI Listing
September 2019

Use of Mendelian andomization for dentifying isk actors for rain umors.

Front Genet 2018 12;9:525. Epub 2018 Nov 12.

Brain Tumour Research Centre, Institute of Clinical Neurosciences, University of Bristol, Bristol, United Kingdom.

Gliomas are a group of primary brain tumors, the most common and aggressive subtype of which is glioblastoma. Glioblastoma has a median survival of just 15 months after diagnosis. Only previous exposure to ionizing radiation and particular inherited genetic syndromes are accepted risk factors for glioma; the vast majority of cases are thought to occur spontaneously. Previous observational studies have described associations between several risk factors and glioma, but studies are often conflicting and whether these associations reflect true casual relationships is unclear because observational studies may be susceptible to confounding, measurement error and reverse causation. Mendelian randomization (MR) is a form of instrumental variable analysis that can be used to provide supporting evidence for causal relationships between exposures (e.g., risk factors) and outcomes (e.g., disease onset). MR utilizes genetic variants, such as single nucleotide polymorphisms (SNPs), that are robustly associated with an exposure to determine whether there is a causal effect of the exposure on the outcome. MR is less susceptible to confounding, reverse causation and measurement errors as it is based on the random inheritance during conception of genetic variants that can be relatively accurately measured. In previous studies, MR has implicated a genetically predicted increase in telomere length with an increased risk of glioma, and found little evidence that obesity related factors, vitamin D or atopy are causal in glioma risk. In this review, we describe MR and its potential use to discover and validate novel risk factors, mechanistic factors, and therapeutic targets in glioma.
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http://dx.doi.org/10.3389/fgene.2018.00525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240585PMC
November 2018

Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae.

Nat Commun 2018 10 15;9(1):4279. Epub 2018 Oct 15.

Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.

Invariant natural killer T cells (iNKT cells) are activated by lipid antigens presented by CD1d, but the pathway leading to lipid antigen presentation remains incompletely characterized. Here we show a whole-genome siRNA screen to elucidate the CD1d presentation pathway. A majority of gene knockdowns that diminish antigen presentation reduced formation of glycolipid-CD1d complexes on the cell surface, including members of the HOPS and ESCRT complexes, genes affecting cytoskeletal rearrangement, and ABC family transporters. We validated the role in vivo for the multidrug resistance protein 1 (Mrp1) in CD1d antigen presentation. Mrp1 deficiency reduces surface clustering of CD1d, which decreased iNKT cell activation. Infected Mrp1 knockout mice show decreased iNKT cell responses to antigens from Streptococcus pneumoniae and were associated with increased mortality. Our results highlight the unique cellular events involved in lipid antigen presentation and show how modification of this pathway can lead to lethal infection.
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http://dx.doi.org/10.1038/s41467-018-06646-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189046PMC
October 2018

Heterogeneous Catalytic Oxidation of Amides to Imides by Manganese Oxides.

Sci Rep 2018 Sep 11;8(1):13649. Epub 2018 Sep 11.

Corporate Strategic Research, ExxonMobil Research and Engineering Company, 1545 US 22 East, Annandale, NJ, 08801, USA.

Herein, we report a one-step peroxide mediated heterogeneous catalytic oxidation of amides to imides utilizing a series of manganese oxides. Among them, Cs/MnO was found to be the most active catalyst for the selective partial oxidation of N-benzylbenzamide to diphenyl imide. We have been able to apply an optimized oxidation method to other aromatic substrates. The feasibility of using air as an oxidant, the heterogeneous nature, inexpensive catalytic materials, respectable turnover numbers, and chemoselectivity to imides make this methodology an attractive choice for functional group transformations of amides to imides.
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http://dx.doi.org/10.1038/s41598-018-31729-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134084PMC
September 2018

Cranberry-derived proanthocyanidins induce a differential transcriptomic response within Candida albicans urinary biofilms.

PLoS One 2018 8;13(8):e0201969. Epub 2018 Aug 8.

Section of Infectious Diseases, New Mexico VA Healthcare System, Albuquerque, NM, United States of America.

Candida albicans is one of the most common causes of hospital-acquired urinary tract infections (UTIs). However, azoles are poorly active against biofilms, echinocandins do not achieve clinically useful urinary concentrations, and amphotericin B exhibits severe toxicities. Thus, novel strategies are needed to prevent Candida UTIs, which are often associated with urinary catheter biofilms. We previously demonstrated that cranberry-derived proanthocyanidins (PACs) prevent C. albicans biofilm formation in an in vitro urinary model. To elucidate functional pathways unique to urinary biofilm development and PAC inhibition, we investigated the transcriptome of C. albicans in artificial urine (AU), with and without PACs. C. albicans biofilm and planktonic cells were cultivated with or without PACs. Genome-wide expression analysis was performed by RNA sequencing. Differentially expressed genes were determined using DESeq2 software; pathway analysis was performed using Cytoscape. Approximately 2,341 of 6,444 total genes were significantly expressed in biofilm relative to planktonic cells. Functional pathway analysis revealed that genes involved in filamentation, adhesion, drug response and transport were up-regulated in urinary biofilms. Genes involved in carbon and nitrogen metabolism and nutrient response were down-regulated. In PAC-treated urinary biofilms compared to untreated control biofilms, 557 of 6,444 genes had significant changes in gene expression. Genes downregulated in PAC-treated biofilms were implicated in iron starvation and adhesion pathways. Although urinary biofilms share key features with biofilms formed in other environments, many genes are uniquely expressed in urinary biofilms. Cranberry-derived PACs interfere with the expression of iron acquisition and adhesion genes within urinary biofilms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201969PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082538PMC
February 2019

Standardised high dose versus low dose cranberry Proanthocyanidin extracts for the prevention of recurrent urinary tract infection in healthy women [PACCANN]: a double blind randomised controlled trial protocol.

BMC Urol 2018 May 2;18(1):29. Epub 2018 May 2.

Department of Obstetrics and Gynaecology, Laval University, CHU de Québec - Université Laval, 2705, boulevard Laurier, Local A1385, Québec, Québec, G1V 4G2, Canada.

Background: Urinary tract infections (UTIs) are amongst the most common bacterial infections affecting women. Although antibiotics are the treatment of choice for UTI, cranberry derived products have been used for many years to prevent UTIs, with limited evidence as to their efficacy. Our objective is to assess the efficacy of a cranberry extract capsule standardized in A-type linkage proanthocyanidins (PACs) for the prevention of recurrent urinary tract infection.

Methods: We will perform a 1:1 randomized, controlled, double blind clinical trial in women aged 18 years or more who present ≥2 UTIs in 6 months or ≥ 3 UTIs in 12 months. One hundred and forty-eight women will be recruited and randomized in two groups to either receive an optimal dose of cranberry extract quantified and standardized in PACs (2 × 18.5 mg PACs per day) or a control dose (2 × 1 mg PACs per day). The primary outcome for the trial is the mean number of new symptomatic UTIs in women during a 6-month intervention period. Secondary outcomes are: (1) To evaluate the mean number of new symptomatic UTIs with pyuria as demonstrated by a positive leucocyte esterase test; (2) To detect the mean number of new symptomatic culture-confirmed UTIs; (3) To quantify urinary PACs metabolites in women who take a daily dose of 37 mg PACs per day compared to women who take a daily dose of 2 mg per day for 6 months; (4) To characterize women who present recurrent UTI based on known risk factors for recurrent UTI; (5) To describe the side effects of daily intake of cranberry extract containing 37 mg PACs compared to 2 mg PACs. This report provides comprehensive methodological data for this randomized controlled trial.

Discussion: The results of this trial will inform urologists, gynaecologists, family physicians and other healthcare professionals caring for healthy women with recurrent UTI, as to the benefits of daily use of an optimal dose of cranberry extract for the prevention of recurrent UTI.

Trial Registration: Clinicaltrials.gov, identifier: NCT02572895 October 8th 2015.
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http://dx.doi.org/10.1186/s12894-018-0342-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930667PMC
May 2018

Anthelmintic efficacy of cranberry vine extracts on ovine Haemonchus contortus.

Vet Parasitol 2018 Apr 15;253:122-129. Epub 2018 Feb 15.

Department of Fisheries, Animal, and Veterinary Sciences, University of Rhode Island, 120 Flagg Road, CBLS Rm 177, Kingston, RI, 02881, United States.

The discovery that plant secondary compounds, including proanthocyanidins (PAC), suppress gastrointestinal nematode (GIN) infection has provided promise for alternative methods of GIN control in small ruminants. This investigation is the first to examine the anthelmintic potential of cranberry vine (CV) against the GIN Haemonchus contortus. The purpose of this study was to explore the anti-parasitic activity of CV in the form of a specific organic proanthocyanidin extract (CV-PAC) and an aqueous extract (CV-AqE) containing PAC and other compounds. In vitro egg hatching, first (L1) and third (L3) stage larval and adult worm motility and L3 exsheathment were evaluated after a 24-h incubation with CV products. In addition, CV treated worms were observed via scanning electron microscopy, and a preliminary investigation of the efficacy of CV powder against an experimental infection of H. contortus was conducted. The in vivo effect on an experimental infection was determined by administering 21.1 g CV powder to lambs (n = 9 per group) for three consecutive days, and collecting fecal egg count data for four weeks post-treatment. The effect of CV-PAC on egg hatching, L3 motility and exsheathment was limited. However, a substantial effect was observed on motility of post-hatch L1 (EC 0.3 mg PAC/mL) and adults (EC 0.2 mg PAC/mL). The CV-AqE showed more effect on egg hatching (EC 5.3 mg/mL containing 0.6 mg PAC/mL) as well as impacting motility of L1 (EC 1.5 mg/mL with 0.2 mg PAC/mL) and adults (EC 3.4 mg/mL with 0.4 mg PAC/mL), but like CV-PAC, did not substantially effect L3 motility or exsheathment. Scanning electron microscopy revealed an accumulation of aggregate on the cuticle around the buccal area of adult worms incubated in CV-AqE and CV-PAC. In the preliminary in vivo study, there was a significant effect of treatment over time (p = .04), although differences in individual weeks were not significant. In summary, both extracts inhibited motility of L1 and adult worms. The higher efficacy of CV-AqE than CV-PAC at levels that contained the same concentrations of PAC tested alone, suggest that other secondary compounds in the CV-AqE contributed to the observed effects on the parasites. This first study of the in vitro and in vivo effects of CV suggest that this readily available plant product may have utility in integrated control of H. contortus and support the need for additional testing to provide further information.
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http://dx.doi.org/10.1016/j.vetpar.2018.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056019PMC
April 2018

Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity.

Cell Chem Biol 2018 05 22;25(5):571-584.e8. Epub 2018 Mar 22.

Department of Chemistry, The University of Connecticut, Storrs, CT 06269-3060, USA. Electronic address:

Glycosylceramides that activate CD1d-restricted invariant natural killer T (iNKT) cells have potential therapeutic applications for augmenting immune responses against cancer and infections. Previous studies using mouse models identified sphinganine variants of α-galactosylceramide as promising iNKT cell activators that stimulate cytokine responses with a strongly proinflammatory bias. However, the activities of sphinganine variants in mice have generally not translated well to studies of human iNKT cell responses. Here, we show that strongly proinflammatory and anti-tumor iNKT cell responses were achieved in mice by a variant of α-galactosylceramide that combines a sphinganine base with a hydrocinnamoyl ester on C6″ of the sugar. Importantly, the activities observed with this variant were largely preserved for human iNKT cell responses. Structural and in silico modeling studies provided a mechanistic basis for these findings and suggested basic principles for capturing useful properties of sphinganine analogs of synthetic iNKT cell activators in the design of immunotherapeutic agents.
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http://dx.doi.org/10.1016/j.chembiol.2018.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025895PMC
May 2018

Re: Cranberry capsules to prevent nosocomial urinary tract bacteriuria after pelvic surgery: a randomised controlled trial: Cranberry for prevention of bacteriuria?

BJOG 2017 11;124(12):1907

Marucci Center for Blueberry Cranberry Research, Rutgers University, Chatsworth, NJ, UK.

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http://dx.doi.org/10.1111/1471-0528.14770DOI Listing
November 2017

Rh-Catalyzed Conjugate Addition of Aryl and Alkenyl Boronic Acids to α-Methylene-β-lactones: Stereoselective Synthesis of trans-3,4-Disubstituted β-Lactones.

Org Lett 2017 09 15;19(17):4460-4463. Epub 2017 Aug 15.

Department of Chemistry, University of Connecticut , Storrs, Connecticut 06269-3060 United States.

A one-step preparation of 3,4-disubstituted β-lactones through Rh-catalyzed conjugate addition of aryl or alkenyl boronic acids to α-methylene-β-lactones is described. The operationally simple, stereoselective transformation provides a broad range of β-lactones from individual α-methylene-β-lactone templates. This methodology allowed for a direct, final-step C-3 diversification of nocardiolactone, an antimicrobial natural product.
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http://dx.doi.org/10.1021/acs.orglett.7b01994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834916PMC
September 2017
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