968 results on '"Vincent C"'
Search Results
2. Single and Joined Behaviour of Circulating Biomarkers and Metabolic Parameters in High-Fit and Low-Fit Healthy Females
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Joëlle J. E. Janssen, Bart Lagerwaard, Arie G. Nieuwenhuizen, Xavier Escoté, Núria Canela, Josep M. del Bas, Vincent C. J. de Boer, and Jaap Keijer
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circulating biomarkers ,health ,lifestyle ,aerobic fitness level ,exercise ,human ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Biomarkers are important in the assessment of health and disease, but are poorly studied in still healthy individuals with a (potential) different risk for metabolic disease. This study investigated, first, how single biomarkers and metabolic parameters, functional biomarker and metabolic parameter categories, and total biomarker and metabolic parameter profiles behave in young healthy female adults of different aerobic fitness and, second, how these biomarkers and metabolic parameters are affected by recent exercise in these healthy individuals. A total of 102 biomarkers and metabolic parameters were analysed in serum or plasma samples from 30 young, healthy, female adults divided into a high-fit (V̇O2peak ≥ 47 mL/kg/min, N = 15) and a low-fit (V̇O2peak ≤ 37 mL/kg/min, N = 15) group, at baseline and overnight after a single bout of exercise (60 min, 70% V̇O2peak). Our results show that total biomarker and metabolic parameter profiles were similar between high-fit and low-fit females. Recent exercise significantly affected several single biomarkers and metabolic parameters, mostly related to inflammation and lipid metabolism. Furthermore, functional biomarker and metabolic parameter categories corresponded to biomarker and metabolic parameter clusters generated via hierarchical clustering models. In conclusion, this study provides insight into the single and joined behavior of circulating biomarkers and metabolic parameters in healthy females, and identified functional biomarker and metabolic parameter categories that may be used for the characterisation of human health physiology.
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- 2023
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3. Catalytic Cascade Reactions Inspired by Polyketide Biosynthesis
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Daniel Moser, Alessandro Castrogiovanni, Dominik Lotter, Reto M. Witzig, Vincent C. Fäseke, Felix C. Raps, and Christof Sparr
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aldol condensation ,atropisomers ,biomimetic synthesis ,late-stage catalysis ,stereoselectivity ,Chemistry ,QD1-999 - Abstract
Aldol reactions belong to the most important methods for carbon–carbon bond formation and are also involved in one of the most astonishing biosynthetic processes: the biosynthesis of polyketides governed by an extraordinarily sophisticated enzymatic machinery. In contrast to the typical linear or convergent strategies followed in chemical synthesis, this late-stage catalysis concept allows Nature to assemble intermediates that are diversified into a broad range of scaffolds, which assume various crucial biological functions. To transfer this concept to small-molecule catalysis to access products beyond the natural systems, a stepwise approach to differentiate increasingly complex substrates was followed by investigating arene-forming polyketide cyclizations. An outline of our efforts to develop and apply these concepts are presented herein.
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- 2020
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4. Mucosal Immunity and the Gut-Microbiota-Brain-Axis in Neuroimmune Disease
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Kathryn G. Sterling, Griffin Kutler Dodd, Shatha Alhamdi, Peter G. Asimenios, Ruben K. Dagda, Kenny L. De Meirleir, Dorothy Hudig, and Vincent C. Lombardi
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sIgA ,Alzheimer’s disease ,autism ,microbiome ,mucosal immunity ,myalgic encephalomyelitis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Recent advances in next-generation sequencing (NGS) technologies have opened the door to a wellspring of information regarding the composition of the gut microbiota. Leveraging NGS technology, early metagenomic studies revealed that several diseases, such as Alzheimer’s disease, Parkinson’s disease, autism, and myalgic encephalomyelitis, are characterized by alterations in the diversity of gut-associated microbes. More recently, interest has shifted toward understanding how these microbes impact their host, with a special emphasis on their interactions with the brain. Such interactions typically occur either systemically, through the production of small molecules in the gut that are released into circulation, or through signaling via the vagus nerves which directly connect the enteric nervous system to the central nervous system. Collectively, this system of communication is now commonly referred to as the gut-microbiota-brain axis. While equally important, little attention has focused on the causes of the alterations in the composition of gut microbiota. Although several factors can contribute, mucosal immunity plays a significant role in shaping the microbiota in both healthy individuals and in association with several diseases. The purpose of this review is to provide a brief overview of the components of mucosal immunity that impact the gut microbiota and then discuss how altered immunological conditions may shape the gut microbiota and consequently affect neuroimmune diseases, using a select group of common neuroimmune diseases as examples.
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- 2022
- Full Text
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5. Butyrate Alters Pyruvate Flux and Induces Lipid Accumulation in Cultured Colonocytes
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Anna F. Bekebrede, Thirza van Deuren, Walter J. J. Gerrits, Jaap Keijer, and Vincent C. J. de Boer
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butyrate ,glucose oxidation ,metabolite interactions ,metabolic flux ,short-chain fatty acids ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Butyrate is considered the primary energy source of colonocytes and has received wide attention due to its unique health benefits. Insight into the mechanistic effects of butyrate on cellular and metabolic function relies mainly on research in in-vitro-cultured cells. However, cells in culture differ from those in vivo in terms of metabolic phenotype and nutrient availability. For translation, it is therefore important to understand the impact of different nutrients on the effects of butyrate. We investigated the metabolic consequences of butyrate exposure under various culturing conditions, with a focus on the interaction between butyrate and glucose. To investigate whether the effects of butyrate were different between cells with high and low mitochondrial capacity, we cultured HT29 cells under either low- (0.5 mM) or high- (25 mM) glucose conditions. Low-glucose culturing increased the mitochondrial capacity of HT29 cells compared to high-glucose (25 mM) cultured HT29 cells. Long-term exposure to butyrate did not alter mitochondrial bioenergetics, but it decreased glycolytic function, regardless of glucose availability. In addition, both high- and low-glucose-grown HT29 cells showed increased lipid droplet accumulation following long-term butyrate exposure. Acute exposure of cultured cells (HT29 and Caco-2) to butyrate increased their oxygen consumption rate (OCR). A simultaneous decrease in extracellular acidification rate (ECAR) was observed. Furthermore, in the absence of glucose, OCR did not increase in response to butyrate. These results lead us to believe that butyrate itself was not responsible for the observed increase in OCR, but, instead, butyrate stimulated pyruvate flux into mitochondria. Indeed, blocking of the mitochondrial pyruvate carrier prevented a butyrate-induced increase in oxygen consumption. Taken together, our results indicate that butyrate itself is not oxidized in cultured cells but instead alters pyruvate flux and induces lipid accumulation.
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- 2021
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6. FOLFOX Therapy Induces Feedback Upregulation of CD44v6 through YB-1 to Maintain Stemness in Colon Initiating Cells
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Shibnath Ghatak, Vincent C. Hascall, Roger R. Markwald, and Suniti Misra
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CD44v6 ,YB-1 ,MDR1 ,CIC ,stemness genes ,CD44v6 CRISPR/Cas9 knockout ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1,BCL2,FZD1,GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors “CTOS” (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs.
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- 2021
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7. Catalytic Arene-forming Aldol Condensation: Stereoselective Synthesis of Rotationally Restricted Aromatic Compounds
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Vincent C. Fäseke, Reto M. Witzig, Achim Link, Dominik Lotter, and Christof Sparr
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Aldol condensation ,Arylenes ,Atropisomers ,Axial chirality ,Stereoselective catalysis ,Chemistry ,QD1-999 - Abstract
By taking inspiration from the fascinating biosynthetic machinery that creates aromatic polyketides, our group investigates analogous reactions catalyzed by small molecules. We are particularly captivated by the prospects of intramolecular aldol condensation reactions to generate different rotationally restricted aromatic compounds. In a first project of our independent research group, a highly stereoselective amine catalyzed synthesis of axially chiral biaryls, tertiary aromatic amides and oligo-1,2-naphthylenes has been developed. In this article, we outline the twists and turns for our escape from the aromatic flatland to structurally intriguing chiral arene scaffolds relevant for various fields of application.
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- 2017
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8. Functionally-Impaired HIV-1 Nef Alleles from a Mother-Child Transmission Pair
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Vincent C. Bond, Michael Powell, Warner C. Greene, Jalal A. Zuberi, Harold G. Stringer, Romas Geleziunas, Mafhuz Khan, and William W. Roth
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HIV-1 ,Nef ,in vitro ,CD4 ,MHC ,infectivity ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Abstract: Unusual HIV-1 nef alleles were isolated from a woman and her vertically infected child. Both patients eventually progressed to develop AIDS. The child died at age 6.5 years, while the mother is currently alive, 13 years since her diagnosis with HIV-1. Predicted amino acid sequences of both mother and child Nefs diverged from the HIV-1 clade B consensus. In particular, they exhibited two separate 5-amino acid deletions bracketing a Cterminal dileucine regulatory motif and Trp-Gly mutations at the site for cleavage by the HIV-1 protease. The child’s Nef showed a modest ability to enhance HIV-1 infectivity in MAGI cells, whereas the mother’s Nef did not alter HIV-1 infectivity in the assay. Both Nefs were partially functional for CD4 down-regulation. The child’s Nef was fully functional for MHC-1 down-regulation, while the maternal Nef was non-functional. To our knowledge this study is the first to describe a functional divergence between Nef alleles in a case of mother-to-child HIV-1 transmission.
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- 2002
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9. An Integrated College Freshman Natural Science Curriculum.
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Garafalo, Alfred R. and LoPresti, Vincent C.
- Abstract
Describes an integrated freshman course sequence which combines biology and chemistry and uses the process of energy flow as a unifying concept. Provides a description of the three-quarter course sequence, along with lists of topics covered in both disciplines. Includes a rationale for developing such interdisciplinary courses. (TW)
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- 1986
10. Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction
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Derek R. Duckett, Zhen Wang, Vincent C. Luca, Haitao Ji, Sylvia M Frydman, Min Zhang, Victor Quereda, and Qianqian Ming
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Male ,Antineoplastic Agents ,Mice, SCID ,Article ,Metastasis ,Structure-Activity Relationship ,Piperidines ,BCL9 ,Cell Movement ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,medicine ,Animals ,Humans ,B-cell lymphoma ,beta Catenin ,Molecular Structure ,Chemistry ,Wnt signaling pathway ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Small molecule ,Mice, Inbred C57BL ,Drug Design ,Catenin ,Cancer cell ,Cancer research ,Molecular Medicine ,Female ,Protein Binding ,Transcription Factors - Abstract
Aberrant activation of Wnt/β-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, β-catenin, is a biologically rational approach to abolish hyperactivation of β-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, ZW4864, that binds with β-catenin and selectively disrupts the protein–protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and β-catenin while sparing the β-catenin/E-cadherin PPI. ZW4864 dose-dependently suppresses β-catenin signaling activation, downregulates oncogenic β-catenin target genes, and abrogates invasiveness of β-catenin-dependent cancer cells. More importantly, ZW4864 shows good pharmacokinetic properties and effectively suppresses β-catenin target gene expression in the patient-derived xenograft mouse model. This study offers a selective chemical probe to explore β-catenin-related biology and a drug-like small-molecule β-catenin/BCL9 disruptor for future drug development.
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- 2021
11. Pharmacokinetics of Ruxolitinib in HIV Suppressed Individuals on Antiretroviral Agent Therapy from the ACTG A5336 Study
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Amy Kantor, Charles Flexner, Christina Gavegnano, Michael M. Lederman, Selwyn J. Hurwitz, Sijia Tao, Edgar T. Overton, Vincent C. Marconi, Raymond F. Schinazi, Randall Tressler, James J. Kohler, Carlos del Rio, Carlee Moser, Athe M. N. Tsibris, Yong Jiang, and Jeffrey L. Lennox
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Adult ,Cyclopropanes ,Male ,Drug ,Ruxolitinib ,Efavirenz ,Metabolic Clearance Rate ,media_common.quotation_subject ,Population ,Integrase inhibitor ,HIV Infections ,Pharmacology ,Article ,chemistry.chemical_compound ,Pharmacokinetics ,Nitriles ,Humans ,Distribution (pharmacology) ,Medicine ,Drug Interactions ,Pharmacology (medical) ,education ,Janus Kinases ,media_common ,education.field_of_study ,business.industry ,Body Weight ,Cytochrome P-450 CYP3A Inducers ,Middle Aged ,Benzoxazines ,Regimen ,Pyrimidines ,Anti-Retroviral Agents ,chemistry ,Alkynes ,Pyrazoles ,Female ,business ,medicine.drug - Abstract
Ruxolitinib is an FDA-approved orally administered Janus kinase (JAK 1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, Phase 2, open label trial, ruxolitinib (10 mg, bid) was administered to HIV(+), virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART), for 5 weeks. Study objectives were to assess safety, tolerability, pharmacokinetics (PK), and modulation of ongoing inflammation that persists even with viral suppression. Herein, we report the population PK subsequently determined from this study. Plasma concentrations of ruxolitinib (294 samples) and antiretroviral agents were measured at week 1 (wk1, N = 39 participants) and week 4 or 5 (wk4/5, N = 37). Ruxolitinib PK was adequately described with a 2-compartment model with first-order absorption and elimination with distribution volumes normalized to mean body weight (91.5 kg) and a separate typical CL for participants administered efavirenz (a known CYP3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical CL/F versus the integrase inhibitor regimen (INSTI) group (22.5 versus 12.9 L/hr; N = 14 versus 25). Post hoc predicted CL/F were likewise, more variable and higher (p < 0.0001) in those administered efavirenz. There was ~ 25% variation in ruxolitinib plasma exposures between wk1 and wk4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, INSTI based ART regimens may be preferred over efavirenz based regimens when ruxolitinib is administered to HIV(+) individuals.
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- 2021
12. Temperature, pH, and Glucose Responsive Gels via Simple Mixing of Boroxole- and Glyco-Based Polymers
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Jin-Yong Lu, Ravin Narain, Dennis G. Hall, Yohei Kotsuchibashi, and Roman Vincent C. Agustin
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chemistry.chemical_classification ,Materials science ,Polymers and Plastics ,Organic Chemistry ,Mixing (process engineering) ,Chain transfer ,Polymer ,Raft ,Glucose responsive ,Inorganic Chemistry ,chemistry ,Polymerization ,Polymer chemistry ,Self-healing hydrogels ,Materials Chemistry ,Copolymer - Abstract
Statistical copolymers of N-isopropylacrylamide (NIPAAm) and 5-methacrylamido-1,2-benzoxaborole (MAAmBo) have been synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization. The solution properties of the NIPAAm homopolymers and statistical copolymers were investigated and it was found that, besides temperature and pH, the statistical copolymers were also responsive to the presence of free glucose in solution. Furthermore, responsive hydrogels and nanogels were formed spontaneously by simply mixing the statistical copolymers of P(NIPAAm-st-MAAmBO)s and well-defined glycopolymers. These gels were found to have temperature, pH, and glucose responsive properties.
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- 2022
13. Iron-Content-Dependent, Quasi-Static Dielectric Resonances and Oxidative Transitions in Bornite and Chalcopyrite Copper Iron Sulfide Nanocrystals
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Chad E. Hoyer, Sandeep Ghosh, Hongbin Liu, Soohyung Lee, Vincent C. Holmberg, and Xiaosong Li
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Materials science ,General Chemical Engineering ,chemistry.chemical_element ,Iron sulfide ,02 engineering and technology ,Dielectric ,engineering.material ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Materials Chemistry ,Bornite ,Chalcopyrite ,General Chemistry ,021001 nanoscience & nanotechnology ,Copper ,0104 chemical sciences ,chemistry ,Chemical engineering ,Nanocrystal ,visual_art ,Iron content ,engineering ,visual_art.visual_art_medium ,0210 nano-technology ,Quasistatic process - Abstract
Manipulation of material composition can often induce unprecedented optoelectronic changes in semiconductor nanocrystals (NCs). Here, we demonstrate that bornite-phase copper iron sulfide (Cu5FeS4)...
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- 2021
14. An optimized desuccinylase activity assay reveals a difference in desuccinylation activity between proliferative and differentiated cells
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David B. Lombard, Taolin Yuan, Vincent C. J. de Boer, Jaap Keijer, and Angela H. Guo
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SIRT5 ,Cellular differentiation ,Succinic Acid ,lcsh:Medicine ,Biochemical assays ,Article ,Mice ,Succinylation ,In vivo ,3T3-L1 Cells ,Animals ,Humans ,Sirtuins ,Life Science ,lcsh:Science ,Cell Proliferation ,VLAG ,Multidisciplinary ,Chemistry ,lcsh:R ,Cell Differentiation ,Energy metabolism ,In vitro ,HEK293 Cells ,Biochemistry ,Cell culture ,Human and Animal Physiology ,Enzyme mechanisms ,WIAS ,Fysiologie van Mens en Dier ,lcsh:Q ,NAD+ kinase ,Protein Processing, Post-Translational ,Deacetylase activity - Abstract
Succinylation is a novel post-translational modification identified on many proteins and is involved in multiple biological processes. Succinylation levels are dynamically regulated, balanced by succinylation and desuccinylation processes, and are closely connected to metabolic state in vivo. Sirtuins have been shown to possess NAD+-dependent desuccinylation activity in vitro and in vivo, among which the desuccinylation activity of SIRT5 is most extensively studied. Our understanding of the response of succinylation levels to different metabolic conditions, is hampered by the lack of a fast NAD+-dependent desuccinylation assay in a physiological context. In the present study, we therefore optimized and validated a fluorescence-based assay for measuring NAD+-dependent desuccinylation activity in cell lysates. Our results demonstrated that shorter and stricter reaction time was critical to approach the initial rate of NAD+-dependent desuccinylation activity in crude cell lysate systems, as compared to the desuccinylation reaction of purified His-SIRT5. Analysis of desuccinylation activity in SIRT5 knockout HEK293T cells confirmed the relevance of SIRT5 in cellular desuccinylation activity, as well as the presence of other NAD+-dependent desuccinylase activities. In addition, we were able to analyse desuccinylation and deacetylation activity in multiple cell lines using this assay. We showed a remarkably higher desuccinylase activity, but not deacetylase activity, in proliferative cultured muscle and adipose cells in comparison with their differentiated counterparts. Our results reveal an alteration in NAD+-dependent desuccinylation activity under different metabolic states.
- Published
- 2020
15. Validating Self‐Reported Unhealthy Alcohol Use With Phosphatidylethanol (PEth) Among Patients With HIV
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Yanhong Deng, Amy C. Justice, Stephen A. Maisto, Oghenowede Eyawo, Patrick G. O'Connor, Janet P. Tate, Kendall J. Bryant, James Dziura, Vincent C. Marconi, Maria C. Rodriguez-Barradas, E. Jennifer Edelman, Kathleen A. McGinnis, Nathan B. Hansen, and David A. Fiellin
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Adult ,Male ,medicine.medical_specialty ,Alcohol Drinking ,Human immunodeficiency virus (HIV) ,030508 substance abuse ,Medicine (miscellaneous) ,HIV Infections ,Alcohol ,Glycerophospholipids ,Alcohol use disorder ,Toxicology ,medicine.disease_cause ,Logistic regression ,Sensitivity and Specificity ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Aged ,Timeline followback ,Heavy drinking ,business.industry ,Middle Aged ,medicine.disease ,Dried blood spot ,Alcoholism ,Psychiatry and Mental health ,Socioeconomic Factors ,chemistry ,Female ,Phosphatidylethanol ,Self Report ,0305 other medical science ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
BACKGROUND We sought to compare self-reported alcohol consumption using Timeline Followback (TLFB) to biomarker-based evidence of significant alcohol use (phosphatidylethanol [PEth] > 20 ng/ml). Using data from patients with HIV (PWH) entering a clinical trial, we asked whether TLFB could predict PEth > 20 ng/ml and assessed the magnitude of association between TLFB and PEth level. METHODS We defined unhealthy alcohol use as any alcohol use in the presence of liver disease, at-risk drinking, or alcohol use disorder. Self-reported alcohol use obtained from TLFB interview was assessed as mean number of drinks/day and number of heavy drinking days over the past 21 days. Dried blood spot samples for PEth were collected at the interview. We used logistic regression to predict PEth > 20 ng/ml and Spearman correlation to quantify the association with PEth, both as a function of TLFB. RESULTS Among 282 individuals (99% men) in the analytic sample, approximately two-thirds (69%) of individuals had PEth > 20 ng/ml. The proportion with PEth > 20 ng/ml increased with increasing levels of self-reported alcohol use; of the 190 patients with either at-risk drinking or alcohol use disorder based on self-report, 82% had PEth > 20 ng/ml. Discrimination was better with number of drinks per day than heavy drinking days (AUC: 0.80 [95% CI: 0.74 to 0.85] vs. 0.74 [95% CI: 0.68 to 0.80]). The number of drinks per day and PEth were significantly and positively correlated across all levels of alcohol use (Spearman's R ranged from 0.29 to 0.56, all p values
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- 2020
16. Catalytic Cascade Reactions Inspired by Polyketide Biosynthesis
- Author
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Dominik Lotter, Daniel Moser, Alessandro Castrogiovanni, Christof Sparr, Felix C. Raps, Reto M. Witzig, and Vincent C. Fäseke
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Chemistry ,atropisomers ,Secondary Metabolism ,Polyketide biosynthesis ,General Medicine ,General Chemistry ,Bond formation ,stereoselectivity ,Chemical synthesis ,Combinatorial chemistry ,Catalysis ,aldol condensation ,lcsh:Chemistry ,Polyketide ,Aldol reaction ,lcsh:QD1-999 ,Cyclization ,Cascade ,Polyketides ,biomimetic synthesis ,Stepwise approach ,late-stage catalysis - Abstract
Aldol reactions belong to the most important methods for carbon–carbon bond formation and are also involved in one of the most astonishing biosynthetic processes: the biosynthesis of polyketides governed by an extraordinarily sophisticated enzymatic machinery. In contrast to the typical linear or convergent strategies followed in chemical synthesis, this late-stage catalysis concept allows Nature to assemble intermediates that are diversified into a broad range of scaffolds, which assume various crucial biological functions. To transfer this concept to small-molecule catalysis to access products beyond the natural systems, a stepwise approach to differentiate increasingly complex substrates was followed by investigating arene-forming polyketide cyclizations. An outline of our efforts to develop and apply these concepts are presented herein.
- Published
- 2020
17. BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells
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Michael Ophir, Qianqian Ming, Gunjan Mandal, Evgenii N. Tcyganov, Carmen M. Anadon, Alfredo Perales-Puchalt, Jennifer Walrath, Michael Schmidt, Paulo C. Rodriguez, Ugur Eskiocak, Carly M. Harro, Douglas C. Marchion, Jessica A. Mine, Ricardo A. Chaurio, Juan R. Cubillos-Ruiz, Subir Biswas, Julia Tchou, Kristen E. Rigolizzo, Brooke T. Mclaughlin, Jose R. Conejo-Garcia, Jason Lajoie, Dmitry I. Gabrilovich, Andrea L. Buras, Piotr Bobrowicz, Tara Lee Costich, Vincent C. Luca, and Kyle K. Payne
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0301 basic medicine ,Multidisciplinary ,biology ,Effector ,Chemistry ,T cell ,T-Cell Receptor Activation ,Immunological synapse ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Butyrophilin ,Antigen ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,medicine ,biology.protein ,Antibody - Abstract
Gamma delta (γδ) T cells infiltrate most human tumors, but current immunotherapies fail to exploit their in situ major histocompatibility complex-independent tumoricidal potential. Activation of γδ T cells can be elicited by butyrophilin and butyrophilin-like molecules that are structurally similar to the immunosuppressive B7 family members, yet how they regulate and coordinate αβ and γδ T cell responses remains unknown. Here, we report that the butyrophilin BTN3A1 inhibits tumor-reactive αβ T cell receptor activation by preventing segregation of N-glycosylated CD45 from the immune synapse. Notably, CD277-specific antibodies elicit coordinated restoration of αβ T cell effector activity and BTN2A1-dependent γδ lymphocyte cytotoxicity against BTN3A1+ cancer cells, abrogating malignant progression. Targeting BTN3A1 therefore orchestrates cooperative killing of established tumors by αβ and γδ T cells and may present a treatment strategy for tumors resistant to existing immunotherapies.
- Published
- 2020
18. Catalyst‐Controlled Transannular Polyketide Cyclization Cascades: Selective Folding of Macrocyclic Polyketides
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Daniel Häussinger, Christof Sparr, Vincent C. Fäseke, and Felix C. Raps
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010405 organic chemistry ,Chemistry ,Stereochemistry ,Regioselectivity ,Polyketide biosynthesis ,General Chemistry ,General Medicine ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,Folding (chemistry) ,Polyketide ,Biomimetic synthesis - Abstract
The biomimetic synthesis of aromatic polyketides from macrocyclic substrates by means of catalyst-controlled transannular cyclization cascades is described. The macrocyclic substrates, which feature increased stability and fewer conformational states, were thereby transformed into several distinct polyketide scaffolds. The catalyst-controlled transannular cyclizations selectively led to aromatic polyketides with a defined folding and oxygenation pattern, thus emulating β-keto-processing steps of polyketide biosynthesis.
- Published
- 2020
19. Photocytotoxicity of Oligothienyl‐Functionalized Chelates That Sensitize LnIIILuminescence and Generate1O2
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Ana de Bettencourt-Dias, Vincent C. Lombardi, and Katherine R Johnson
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chemistry.chemical_classification ,Tris ,Lanthanide ,Ethanol ,010405 organic chemistry ,Chemistry ,Singlet oxygen ,Organic Chemistry ,Iodide ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Chelation ,Triplet state ,Luminescence ,Nuclear chemistry - Abstract
Three new compounds containing a heptadentate lanthanide (LnIII ) ion chelator functionalized with oligothiophenes, nThept(COOH)4 (n=1, 2, or 3), were isolated. Their LnIII complexes not only display the characteristic metal-centered emission in the visible or near-infrared (NIR) but also generate singlet oxygen (1 O2 ). Luminescence efficiencies (ϕLn ) for [Eu1Thept(COO)4 ]- and [Eu2Thept(COO)4 ]- are ϕEu =3 % and 0.5 % in TRIS buffer and 33 % and 3 % in 95 % ethanol, respectively. 3Thept(COO)4 4- does not sensitize EuIII emission due to its low-lying triplet state. Near infra-red (NIR) luminescence is observed for all NIR-emitting LnIII and ligands with efficiencies of ϕYb =0.002 %, 0.005 % and 0.04 % for [YbnThept(COO)4 ]- (n=1, 2, or 3), and ϕNd =0.0007 %, 0.002 % and 0.02 % for [NdnThept(COO)4 ]- (n=1, 2, or 3) in TRIS buffer. In 95 % ethanol, quantum yields of NIR luminescence increase and are ϕYb =0.5 %, 0.31 % and 0.05 % for [YbnThept(COO)4 ]- (n=1, 2, or 3), and ϕNd =0.40 %, 0.45 % and 0.12 % for [NdnThept(COO)4 ]- (n=1, 2, or 3). All complexes are capable of generating 1 O2 in 95 % ethanol with ϕ1Ο2 efficiencies which range from 2 % to 29 %. These complexes are toxic to HeLa cells when irradiated with UV light (λexc =365 nm) for two minutes. IC50 values for the LnIII complexes are in the range 15.2-16.2 μm; the most potent compound is [Nd2Thept(COO)4 ]- . The cell death mechanisms are further explored using an Annexin V-propidium iodide assay which suggests that cell death occurs through both apoptosis and necrosis.
- Published
- 2020
20. Structural basis of GPBAR activation and bile acid recognition
- Author
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Ruirui Lu, Jiuyao Zhou, Vincent C. Luca, Qianqian Ming, Qingya Shen, Kai Zhang, Linqi Zhang, Yan Zhang, Fan Yi, Shimeng Guo, Chunyou Mao, Fajun Nan, Chenlu Zhang, Fan Yang, Peng Xiao, Yuemao Shen, Shen-Ming Huang, Xin Xie, Xiaoying Liang, Changtao Jiang, Dan-Dan Shen, Jing-Yu Lin, Lulu Guo, Xiang Wu, Jin-Peng Sun, Xiao Yu, Yuqi Ping, and Cheng Ma
- Subjects
0301 basic medicine ,Multidisciplinary ,Bile acid ,Chemistry ,G protein ,medicine.drug_class ,GTP-Binding Protein alpha Subunits ,Allosteric regulation ,Plasma protein binding ,digestive system ,G protein-coupled bile acid receptor ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Biochemistry ,Amphiphile ,medicine ,Receptor ,030217 neurology & neurosurgery - Abstract
The G-protein-coupled bile acid receptor (GPBAR) conveys the cross-membrane signalling of a vast variety of bile acids and is a signalling hub in the liver–bile acid–microbiota–metabolism axis1–3. Here we report the cryo-electron microscopy structures of GPBAR–Gs complexes stabilized by either the high-affinity P3954 or the semisynthesized bile acid derivative INT-7771,3 at 3 A resolution. These structures revealed a large oval pocket that contains several polar groups positioned to accommodate the amphipathic cholic core of bile acids, a fingerprint of key residues to recognize diverse bile acids in the orthosteric site, a putative second bile acid-binding site with allosteric properties and structural features that contribute to bias properties. Moreover, GPBAR undertakes an atypical mode of activation and G protein coupling that features a different set of key residues connecting the ligand-binding pocket to the Gs-coupling site, and a specific interaction motif that is localized in intracellular loop 3. Overall, our study not only reveals unique structural features of GPBAR that are involved in bile acid recognition and allosteric effects, but also suggests the presence of distinct connecting mechanisms between the ligand-binding pocket and the G-protein-binding site in the G-protein-coupled receptor superfamily. Using cryo-electron microscopy, the authors report the structures of G-protein-coupled bile acid receptor–Gs complexes and reveal the structural basis of bile acid recognition.
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- 2020
21. Integrated stepped alcohol treatment for patients with HIV and at-risk alcohol use: a randomized trial
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Janet P. Tate, Yanhong Deng, David A. Fiellin, Christopher J. Cutter, Vincent C. Marconi, Michael S. Simberkoff, Cynthia L. Gibert, Lynn E. Fiellin, James Dziura, Roger Bedimo, Patrick G. O'Connor, Stephen A. Maisto, E. Jennifer Edelman, Amy C. Justice, Maria C. Rodriguez-Barradas, David Rimland, Nathan B. Hansen, and Kendall J. Bryant
- Subjects
Male ,medicine.medical_specialty ,lcsh:Social pathology. Social and public welfare. Criminology ,media_common.quotation_subject ,Population ,030508 substance abuse ,HIV Infections ,Alcohol ,Motivational Interviewing ,law.invention ,lcsh:HV1-9960 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,law ,Integrated ,Humans ,Medicine ,Delivery of health care ,030212 general & internal medicine ,education ,Aged ,media_common ,education.field_of_study ,lcsh:R5-920 ,Intention-to-treat analysis ,Primary Health Care ,Alcohol-related disorders ,Delivery of Health Care, Integrated ,business.industry ,Research ,Public health ,Addiction ,HIV ,General Medicine ,Middle Aged ,Motivational enhancement therapy ,Telephone ,Health psychology ,Treatment Outcome ,chemistry ,Physical therapy ,Female ,0305 other medical science ,business ,lcsh:Medicine (General) - Abstract
Background At-risk levels of alcohol use threaten the health of patients with HIV (PWH), yet evidence-based strategies to decrease alcohol use and improve HIV-related outcomes in this population are lacking. We examined the effectiveness of integrated stepped alcohol treatment (ISAT) on alcohol use and HIV outcomes among PWH and at-risk alcohol use. Methods In this multi-site, randomized trial conducted between January 28, 2013 through July 14, 2017, we enrolled PWH and at-risk alcohol use [defined as alcohol consumption of ≥ 14 drinks per week or ≥ 4 drinks per occasion in men ≤ 65 years old or ≥ 7 drinks per week or ≥ 3 drinks per occasion in women or men > 65 years old]. ISAT (n = 46) involved: Step 1- Brief Negotiated Interview with telephone booster, Step 2- Motivational Enhancement Therapy, and Step 3- Addiction Physician Management. Treatment as usual (TAU) (n = 47) involved receipt of a health handout plus routine care. Analyses were conducted based on intention to treat principles. Results Despite a multi-pronged approach, we only recruited 37% of the target population (n = 93/254). Among ISAT participants, 50% advanced to Step 2, among whom 57% advanced to Step 3. Participants randomized to ISAT and TAU had no observed difference in drinks per week over the past 30 days at week 24 (primary outcome) [least square means (Ls mean) (95% CI) = 8.8 vs. 10.6; adjusted mean difference (AMD) (95% CI) = − 0.4 (− 3.9, 3.0)]. Conclusion An insufficient number of patients were interested in participating in the trial. Efforts to enhance motivation of PWH with at-risk alcohol use to engage in alcohol-related research and build upon ISAT are needed. Trial registration Clinicaltrials.gov: NCT01410123, First posted August 4, 2011
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- 2020
22. Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb
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Dong Liu, Ky Huynh, Miracle Thomas, Vincent C. Bond, Takerra K. Johnson, Qinglin Yang, Y. Eugene Chen, Yang Wang, and Dihan Zhu
- Subjects
Angiogenesis ,Macrophage ,Macrophage polarization ,Medicine (miscellaneous) ,Stem cells ,Exosomes ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Exosome ,Proinflammatory cytokine ,Colony stimulating factor 1 receptor ,lcsh:Biochemistry ,Mice ,Ischemia ,Animals ,lcsh:QD415-436 ,Tube formation ,lcsh:R5-920 ,microRNA ,Chemistry ,Research ,Macrophages ,Cell Biology ,Microvesicles ,Cell biology ,Hindlimb ,Endothelial stem cell ,MicroRNAs ,Molecular Medicine ,lcsh:Medicine (General) - Abstract
BackgroundM2 macrophages and exosomes from adipose-derived stem cells (ASCs) are both reported to promote angiogenesis. However, the possible synergistic effects between exogenous exosomes and endogenous M2 macrophages are poorly understood.MethodsExosomes were isolated from conditioned medium of normoxic and hypoxic ASCs using the combined techniques of ultrafiltration and size-exclusion chromatography and were identified with nanoparticle tracking analysis and immunoblotting for exosomal markers. Macrophages were collected from the mouse peritoneal cavity. M1 and M2 macrophages were detected by immunoblotting for the intracellular markers inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) and by flow cytometry for the surface markers F4/80, CD86, and CD206. Murine models of Matrigel plug and hindlimb ischemia were employed as in vivo angiogenic assays.ResultsWhen M1 macrophages were treated with exosomes from normoxic ASCs (Nor/Exo), and particularly from hypoxic ASCs (Hyp/Exo), the expression of the M1 marker iNOS decreased, and the M2 marker Arg-1 increased in a time- and dose-dependent manner. Additionally, a decrease in the M1 surface marker CD86 and an increase in the M2 surface marker CD206 were observed, which suggested that M1 macrophages were polarized to an M2-like phenotype. Conditioned medium from these M2-like macrophages presented lower levels of proinflammatory cytokines and higher levels of proangiogenic factors and promoted endothelial cell proliferation, migration, and tube formation. Furthermore, M2 polarization and angiogenesis were induced upon the administration of exosomes in mouse Matrigel plug and hindlimb ischemia (HLI) models. Interestingly, these exosomal effects were attenuated by using a colony stimulating factor 1 receptor (CSF-1R) inhibitor, BLZ945, in vitro and in vivo. Downregulation of microRNA-21 (miR-21) in hypoxic ASCs reduced the exosomal effects on M2 polarization, Akt phosphorylation, and CSF-1 secretion. A similar reduction in exosomal activity was also observed when exosomes were administered along with BLZ945.ConclusionOur findings provide evidence that exosomes from ASCs polarize macrophages toward an M2-like phenotype, which further enhances the exosomal proangiogenic effects. Exosomal delivery of miR-21 and positive feedback of secreted CSF-1 may be involved in macrophage polarization.
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- 2020
23. Sirtuin 1 reduces hyaluronan synthase 2 expression by inhibiting nuclear translocation of NF-κB and expression of the long-noncoding RNA HAS2–AS1
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Davide Vigetti, Daiana Lujan Vitale, Giancarlo De Luca, Paola Moretto, Laura Alaniz, Elena Caravà, Vincent C. Hascall, Manuela Viola, Evgenia Karousou, Arianna Parnigoni, Alberto Passi, Barbara Bartolini, and Ilaria Caon
- Subjects
0301 basic medicine ,long noncoding RNA (long ncRNA ,Cell ,Glycobiology and Extracellular Matrices ,Biochemistry ,purl.org/becyt/ford/1 [https] ,Extracellular matrix ,SRT1720 ,Sirtuin 1 ,Hyaluronic Acid ,Aorta ,Cells, Cultured ,biology ,Chemistry ,SMC ,NF-kappa B ,Cell biology ,Hyaluronan synthase ,sirtuin ,Protein Transport ,medicine.anatomical_structure ,Sirtuin ,RNA, Long Noncoding ,lncRNA) ,HAS2–AS1 ,HAS2-AS1 ,HAS2 ,epigenetics ,extracellular matrix ,glycosaminoglycan ,hyaluronan ,inflammation ,long noncoding RNA (long ncRNA, lncRNA) ,metabolic regulation ,sirtuin 1 (SIRT1) ,Myocytes, Smooth Muscle ,Hyaluronan Synthase 2 ,Heterocyclic Compounds, 4 or More Rings ,Models, Biological ,long-noncoding RNA (long ncRNA, lncRNA) ,03 medical and health sciences ,medicine ,Humans ,purl.org/becyt/ford/1.6 [https] ,Molecular Biology ,Cell Nucleus ,Inflammation ,030102 biochemistry & molecular biology ,Tumor Necrosis Factor-alpha ,Cell Biology ,030104 developmental biology ,Gene Expression Regulation ,Cytoprotection ,Resveratrol ,biology.protein ,NAD+ kinase ,Hyaluronan Synthases - Abstract
Hyaluronan (HA) is one of the most prevalent glycosaminoglycans of the vascular extracellular matrix (ECM). Abnormal HA accumulation within blood vessel walls is associated with tissue inflammation and is prominent in most vascular pathological conditions such as atherosclerosis and restenosis. Hyaluronan synthase 2 (HAS2) is the main hyaluronan synthase enzyme involved in HA synthesis and uses cytosolic UDP-glucuronic acid and UDP-GlcNAc as substrates. The synthesis of UDP-glucuronic acid can alter the NAD+/NADH ratio via the enzyme UDP-glucose dehydrogenase, which oxidizes the alcohol group at C6 to the COO- group. Here, we show that HAS2 expression can be modulated by sirtuin 1 (SIRT1), the master metabolic sensor of the cell, belonging to the class of NAD+-dependent deacetylases. Our results revealed the following. 1) Treatments of human aortic smooth muscle cells (AoSMCs) with SIRT1 activators (SRT1720 and resveratrol) inhibit both HAS2 expression and accumulation of pericellular HA coats. 2) Tumor necrosis factor α (TNFα) induced HA-mediated monocyte adhesion and AoSMC migration, whereas SIRT1 activation prevented immune cell recruitment and cell motility by reducing the expression levels of the receptor for HA-mediated motility, RHAMM, and the HA-binding protein TNF-stimulated gene 6 protein (TSG6). 3) SIRT1 activation prevented nuclear translocation of NF-κB (p65), which, in turn, reduced the levels of HAS2–AS1, a long-noncoding RNA that epigenetically controls HAS2 mRNA expression. In conclusion, we demonstrate that both HAS2 expression and HA accumulation by AoSMCs are down-regulated by the metabolic sensor SIRT1. Fil: Caon, Ilaria. Universitá Degli Studi Dell´insubria; Italia Fil: Bartolini, Barbara. Universitá Degli Studi Dell´insubria; Italia Fil: Moretto, Paola. Universitá Degli Studi Dell´insubria; Italia Fil: Parnigoni, Arianna. Universitá Degli Studi Dell´insubria; Italia Fil: Caravà, Elena. Universitá Degli Studi Dell´insubria; Italia Fil: Vitale, Daiana Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; Argentina Fil: Viola, Manuela. Universitá Degli Studi Dell´insubria; Italia Fil: Karousou, Evgenia. Universitá Degli Studi Dell´insubria; Italia Fil: de Luca, Giancarlo. Universitá Degli Studi Dell´insubria; Italia Fil: Hascall, Vincent C.. Lerner Research Institute; Estados Unidos Fil: Passi, Alberto. Universitá Degli Studi Dell´insubria; Italia Fil: Vigetti, Davide. Universitá Degli Studi Dell´insubria; Italia
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- 2020
24. Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension
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Kevin Ni, Hanan Elajaili, Ronald J. Midura, Valbona Cali, C. Michael Hart, Vincent C. Hascall, Victor Tseng, Ayed Allawzi, Irina Petrache, Barbara Triggs-Raine, Laura Hernandez-Lagunas, Eva Nozik-Grayck, and Clare Prohaska
- Subjects
Male ,0301 basic medicine ,Glycobiology ,lcsh:Medicine ,Glycosaminoglycan ,Extracellular matrix ,Mice ,0302 clinical medicine ,Hyaluronic Acid ,Hypoxia ,lcsh:Science ,Lung ,Vascular diseases ,Mice, Knockout ,Multidisciplinary ,Chemistry ,Cell Hypoxia ,Up-Regulation ,3. Good health ,Cell biology ,Mechanisms of disease ,Cardiovascular diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,medicine.drug ,SOD3 ,Hypertension, Pulmonary ,Myocytes, Smooth Muscle ,Hyaluronoglucosaminidase ,Pulmonary Artery ,Article ,03 medical and health sciences ,Hyaluronidase ,medicine ,Animals ,Humans ,Cell Proliferation ,Superoxide Dismutase ,lcsh:R ,Hypoxia (medical) ,medicine.disease ,Pulmonary hypertension ,Cardiovascular biology ,Mice, Inbred C57BL ,030104 developmental biology ,lcsh:Q ,Homeostasis - Abstract
Chronic hypoxia leads to pathologic remodeling of the pulmonary vasculature and pulmonary hypertension (PH). The antioxidant enzyme extracellular superoxide dismutase (SOD3) protects against hypoxia-induced PH. Hyaluronan (HA), a ubiquitous glycosaminoglycan of the lung extracellular matrix, is rapidly recycled at sites of vessel injury and repair. We investigated the hypothesis that SOD3 preserves HA homeostasis by inhibiting oxidative and enzymatic hyaluronidase-mediated HA breakdown. In SOD3-deficient mice, hypoxia increased lung hyaluronidase expression and activity, hyaluronan fragmentation, and effacement of HA from the vessel wall of small pulmonary arteries. Hyaluronan fragmentation corresponded to hypoxic induction of the cell surface hyaluronidase-2 (Hyal2), which was localized in the vascular media. Human pulmonary artery smooth muscle cells (HPASMCs) demonstrated hypoxic induction of Hyal2 and SOD-suppressible hyaluronidase activity, congruent to our observations in vivo. Fragmentation of homeostatic high molecular weight HA promoted HPASMC proliferation in vitro, whereas pharmacologic inhibition of hyaluronidase activity prevented hypoxia- and oxidant-induced proliferation. Hypoxia initiates SOD3-dependent alterations in the structure and regulation of hyaluronan in the pulmonary vascular extracellular matrix. These changes occurred soon after hypoxia exposure, prior to appearance of PH, and may contribute to the early pathogenesis of this disease.
- Published
- 2020
25. ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR
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Rajarshi Ghosh, B. Gayani K. Perera, Feroz R. Papa, Venkata Narayana Vidadala, Vincent C. Auyeung, Zachary E. Potter, Alina Olivier, Julie Zikherman, Jae-Hong Kim, Dustin J. Maly, James L. Mueller, Bradley J. Backes, and Hannah C. Feldman
- Subjects
Models, Molecular ,Biochemistry & Molecular Biology ,XBP1 ,RNase P ,Endoribonuclease ,Protein Serine-Threonine Kinases ,Medicinal and Biomolecular Chemistry ,Adenosine Triphosphate ,Models ,Endoribonucleases ,Genetics ,Humans ,Molecular Biology ,Protein Kinase Inhibitors ,Protein Unfolding ,Messenger RNA ,Molecular Structure ,Chemistry ,Kinase ,Endoplasmic reticulum ,Molecular ,Cell Biology ,Cell biology ,RNA splicing ,Unfolded protein response ,Generic health relevance ,Biochemistry and Cell Biology - Abstract
The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that the RNase of IRE1α can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1α RNase (PAIRs), that partially antagonize the IRE1α RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix αC in the IRE1α kinase domain. In insulin-producing β-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory ‘sweet spot’, achieved by PAIR-bound IRE1α, captures a desirable conformation for drugging this master UPR sensor/effector. Partial antagonists of the ER transmembrane kinase/endoribonuclease IRE1ɑ were identified that preserve splicing of downstream RNA substrates such as XBP1, enabling cellular survival.
- Published
- 2021
26. Resistance Testing for Management of HIV Virologic Failure in Sub-Saharan Africa: An Unblinded Randomized Controlled Trial
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Isaac Aturinda, Henry Sunpath, Rajesh T. Gandhi, Brent A. Johnson, Nicholas Musinguzi, Vincent C. Marconi, Jaysingh Brijkumar, Suzanne M. McCluskey, Melendhran Pillay, Mark J. Siedner, Mwebesa Bwana, Tamlyn Rautenberg, Selvan Pillay, Kevin L. Ard, Mahomed-Yunus S. Moosa, Godfrey Masette, Gavin George, Winnie Muyindike, Pravikrishnen Moodley, and Rebecca F Gilbert
- Subjects
Adult ,Cyclopropanes ,Male ,medicine.medical_specialty ,Efavirenz ,HIV Infections ,Emtricitabine ,Article ,law.invention ,South Africa ,chemistry.chemical_compound ,Randomized controlled trial ,Acquired immunodeficiency syndrome (AIDS) ,law ,Antiretroviral Therapy, Highly Active ,Internal medicine ,Drug Resistance, Viral ,Internal Medicine ,Medicine ,Humans ,Uganda ,Treatment Failure ,Tenofovir ,Reverse-transcriptase inhibitor ,business.industry ,General Medicine ,Odds ratio ,Middle Aged ,Viral Load ,medicine.disease ,Benzoxazines ,Regimen ,chemistry ,Alkynes ,Female ,business ,Viral load ,medicine.drug - Abstract
Background Virologic failure in HIV predicts the development of drug resistance and mortality. Genotypic resistance testing (GRT), which is the standard of care after virologic failure in high-income settings, is rarely implemented in sub-Saharan Africa. Objective To estimate the effectiveness of GRT for improving virologic suppression rates among people with HIV in sub-Saharan Africa for whom first-line therapy fails. Design Pragmatic, unblinded, randomized controlled trial. (ClinicalTrials.gov: NCT02787499). Setting Ambulatory HIV clinics in the public sector in Uganda and South Africa. Patients Adults receiving first-line antiretroviral therapy with a recent HIV RNA viral load of 1000 copies/mL or higher. Intervention Participants were randomly assigned to receive standard of care (SOC), including adherence counseling sessions and repeated viral load testing, or immediate GRT. Measurements The primary outcome of interest was achievement of an HIV RNA viral load below 200 copies/mL 9 months after enrollment. Results The trial enrolled 840 persons, divided equally between countries. Approximately half (51%) were women. Most (72%) were receiving a regimen of tenofovir, emtricitabine, and efavirenz at enrollment. The rate of virologic suppression did not differ 9 months after enrollment between the GRT group (63% [263 of 417]) and SOC group (61% [256 of 423]; odds ratio [OR], 1.11 [95% CI, 0.83 to 1.49]; P = 0.46). Among participants with persistent failure (HIV RNA viral load ≥1000 copies/mL) at 9 months, the prevalence of drug resistance was higher in the SOC group (76% [78 of 103] vs. 59% [48 of 82]; OR, 2.30 [CI, 1.22 to 4.35]; P = 0.014). Other secondary outcomes, including 9-month survival and retention in care, were similar between groups. Limitation Participants were receiving nonnucleoside reverse transcriptase inhibitor-based therapy at enrollment, limiting the generalizability of the findings. Conclusion The addition of GRT to routine care after first-line virologic failure in Uganda and South Africa did not improve rates of resuppression. Primary funding source The President's Emergency Plan for AIDS Relief and the National Institute of Allergy and Infectious Diseases.
- Published
- 2021
27. IRE1α drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis
- Author
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Alexis Brumwell, Harold A. Chapman, Vincent C. Auyeung, Feroz R. Papa, Maike Thamsen, Michael S. Downey, Dean Sheppard, Bradley J. Backes, Jaymin J. Kathiriya, and Talia A. Wenger
- Subjects
education.field_of_study ,Lung ,Population ,Biology ,medicine.disease ,Bleomycin ,Idiopathic pulmonary fibrosis ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Fibrosis ,Pulmonary fibrosis ,medicine ,Unfolded protein response ,Cancer research ,Progenitor cell ,education - Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease of progressive interstitial fibrosis, which leads to severe debilitation, respiratory failure, and death. In IPF, environmental exposures interact with genetic risk factors to engender critical patho-etiological events in lung epithelial cells, including endoplasmic reticulum (ER) stress and TGFβ signaling, but the interactions between these disparate pathways are not well understood. We previously showed that kinase inhibitors of the IRE1α bifunctional kinase/RNase—a central mediator of the unfolded protein response (UPR) to ER stress—protected mice from bleomycin-induced pulmonary fibrosis. Here we show that a nanomolar-potent, mono-selective kinase inhibitor of IRE1α (KIRA8) decreases ER-stress induced TGFβ signaling and the senescence-associated secretory phenotype (SASP) in the lung epithelium after bleomycin exposure. A recently-described subset of “damage-associated transient progenitors” (DATPs) display IRE1α-regulated pathological gene signatures that are quelled by KIRA8, in vivo. After injury, these cells uniquely express integrin αvβ6, a key activator of TGFβ in pulmonary fibrosis. KIRA8 inhibition of IRE1α decreases both DATP number and Itgb6 expression in remaining cells, with a decrease in local collagen accumulation. Single-cell RNA sequencing from IPF lungs revealed an analogous Itgb6+ cell population that may also be regulated by IRE1α. These findings suggest that lung epithelial progenitor cells sit at the center of the fibrotic niche, and IRE1α signaling locks them into a dysfunctional state that establishes and perpetuates pathological fibrosis.
- Published
- 2021
28. Change in Alcohol Use Based on Self-Report and a Quantitative Biomarker, Phosphatidylethanol, in People With HIV
- Author
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Kathleen A. McGinnis, Nathan B. Hansen, Christopher J. Cutter, Emily C. Williams, David A. Fiellin, E. Jennifer Edelman, Patrick G. O'Connor, Kirsha S. Gordon, Janet P. Tate, Oghenowede Eyawo, Stephen Crystal, Stephen A. Maisto, Amy C. Justice, Robert L. Cook, Maria C. Rodriguez-Barradas, Adam J. Gordon, Vincent C. Marconi, and Kendall J. Bryant
- Subjects
Male ,medicine.medical_specialty ,Social Psychology ,Alcohol Drinking ,Human immunodeficiency virus (HIV) ,Alcohol ,HIV Infections ,Glycerophospholipids ,medicine.disease_cause ,chemistry.chemical_compound ,Internal medicine ,Medicine ,Humans ,Self report ,Timeline followback ,Alcohol Use Disorders Identification Test ,business.industry ,Public Health, Environmental and Occupational Health ,Middle Aged ,Infectious Diseases ,chemistry ,Biomarker (medicine) ,Phosphatidylethanol ,Self Report ,business ,Alcohol consumption ,Biomarkers - Abstract
The timeline followback (TLFB) takes more resources to collect than the Alcohol Use Disorder Identification Test (AUDIT-C). We assessed agreement of TLFB and AUDIT-C with the biomarker phosphatidylethanol (PEth) and compared changes in TLFB and PEth among persons with HIV (PWH) using secondary data from randomized trials. We calculated operating characteristics and agreement between TLFB (> 1 and > 2 average drinks/day), AUDIT-C ≥ 4 and PEth ≥ 20 among 275 men with HIV. Median age was 57 years, 80% were African-American; and 17% white. Sixty-eight percent had PEth ≥ 20, 46% reported > 2 average drinks/day on TLFB, 61% reported > 1 average drinks/day on TLFB, and 72% had an AUDIT-C ≥ 4. Relative to PEth, sensitivity for AUDIT-C ≥ 4 was 84% (kappa = 0.36), and for TLFB > 1 average drink/day was 76% (kappa = 0.44). Change in alcohol use appeared greater using TLFB measures than PEth. Strategies to robustly assess alcohol use in PWH may require both self-report and biomarkers.
- Published
- 2021
29. Decreasing the Likelihood of Multiple Organ Dysfunction Syndrome in Burn Injury with Early Antioxidant Treatment
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Jackson P. Sterling and Vincent C. Lombardi
- Subjects
0301 basic medicine ,Burn injury ,Antioxidant ,Physiology ,medicine.medical_treatment ,Clinical Biochemistry ,vitamin C ,Review ,vitamin E ,RM1-950 ,Bioinformatics ,medicine.disease_cause ,MODS ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,medicine ,NADPH ,Molecular Biology ,chemistry.chemical_classification ,free radical ,Reactive oxygen species ,business.industry ,oxidase ,030208 emergency & critical care medicine ,Burn treatment ,Major burn ,ROS ,Cell Biology ,medicine.disease ,histamine ,030104 developmental biology ,Blood pressure ,chemistry ,Therapeutics. Pharmacology ,business ,Multiple organ dysfunction syndrome ,Oxidative stress ,xanthine oxidase - Abstract
Major burn trauma initiates a cascade of physiological events that cause profound stress on the body, resulting in significant complications which often lead to death. An understanding of these events may afford earlier and more precise interventions which, in turn, may reduce these complications, thus, improving patient outcomes. Burn trauma is associated with numerous inflammatory events that result in the release of free radicals, which promote oxidative stress and subsequent tissue damage. These mass-inflammatory events affect the body systemically, leading to several detrimental responses including complement activation, excessive histamine release, decrease in blood pressure, release of reactive oxygen species, and ultimately multiple organ dysfunction syndrome (MODS). However, recent studies conducted on the use of antioxidants as a part of a burn treatment protocol have shown promising results. In this review, we will discuss the current research and advancements in the treatment of burn trauma with the use of antioxidants, and how the early administration of antioxidant can possibly reduce the risk of developing MODS.
- Published
- 2021
30. Muscle mitochondrial capacity in high‐ and low‐fitness females using near‐infrared spectroscopy
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Jaap Keijer, Vincent C. J. de Boer, Iris Cuijpers, Joëlle J. E. Janssen, Arie G. Nieuwenhuizen, and Bart Lagerwaard
- Subjects
Adult ,medicine.medical_specialty ,Adolescent ,Physiology ,030204 cardiovascular system & hematology ,Mitochondrion ,03 medical and health sciences ,Gastrocnemius muscle ,chemistry.chemical_compound ,Oxygen Consumption ,0302 clinical medicine ,oxidative metabolism ,Physiology (medical) ,Internal medicine ,V˙Opeak ,V˙O2peak ,medicine ,QP1-981 ,Humans ,Aerobic exercise ,Muscle, Skeletal ,Young female ,Exercise ,VLAG ,Female population ,Spectroscopy, Near-Infrared ,Chemistry ,Skeletal muscle ,Original Articles ,Mitochondria, Muscle ,fitness ,mitochondria ,Endocrinology ,medicine.anatomical_structure ,NIRS ,Myoglobin ,Physical Fitness ,Human and Animal Physiology ,WIAS ,Fysiologie van Mens en Dier ,Female ,Original Article ,Hemoglobin ,030217 neurology & neurosurgery - Abstract
The recovery of muscle oxygen consumption (m (Formula presented.) O2) after exercise measured using near-infrared spectroscopy (NIRS) provides a measure of skeletal muscle mitochondrial capacity. Nevertheless, due to sex differences in factors that can influence scattering and thus penetration depth of the NIRS signal in the tissue, e.g., subcutaneous adipose tissue thickness and intramuscular myoglobin and hemoglobin, it is unknown whether results in males can be extrapolated to a female population. Therefore, the aim of this study was to measure skeletal muscle mitochondrial capacity in females at different levels of aerobic fitness to test whether NIRS can measure relevant differences in mitochondrial capacity. Mitochondrial capacity was analyzed in the gastrocnemius muscle and the wrist flexors of 32 young female adults, equally divided in relatively high ((Formula presented.) O2peak ≥ 47 ml/kg/min) and relatively low aerobic fitness group ((Formula presented.) O2peak ≤ 37 ml/kg/min). m (Formula presented.) O2 recovery was significantly faster in the high- compared to the low-fitness group in the gastrocnemius, but not in the wrist flexors (p = 0.009 and p = 0.0528, respectively). Furthermore, (Formula presented.) O2peak was significantly correlated to m (Formula presented.) O2 recovery in both gastrocnemius (R2 = 0.27, p = 0.0051) and wrist flexors (R2 = 0.13, p = 0.0393). In conclusion, NIRS measurements can be used to assess differences in mitochondrial capacity within a female population and is correlated to (Formula presented.) O2peak. This further supports NIRS assessment of muscle mitochondrial capacity providing additional evidence for NIRS as a promising approach to monitor mitochondrial capacity, also in an exclusively female population.
- Published
- 2021
31. Optically oriented attachment of nanoscale metal-semiconductor heterostructures in organic solvents via photonic nanosoldering
- Author
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E. James Davis, Elena P. Pandres, Matthew J. Crane, Vincent C. Holmberg, and Peter J. Pauzauskie
- Subjects
Materials science ,Nanostructure ,Science ,Nanowire ,Physics::Optics ,General Physics and Astronomy ,chemistry.chemical_element ,Germanium ,Nanotechnology ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Article ,General Biochemistry, Genetics and Molecular Biology ,Techniques and instrumentation ,Nanomaterials ,Bismuth ,Condensed Matter::Materials Science ,lcsh:Science ,Nanoscale materials ,Multidisciplinary ,Nanowires ,business.industry ,Heterojunction ,General Chemistry ,Condensed Matter::Mesoscopic Systems and Quantum Hall Effect ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Optical manipulation and tweezers ,chemistry ,Nanocrystal ,lcsh:Q ,Photonics ,0210 nano-technology ,business - Abstract
As devices approach the single-nanoparticle scale, the rational assembly of nanomaterial heterojunctions remains a persistent challenge. While optical traps can manipulate objects in three dimensions, to date, nanoscale materials have been trapped primarily in aqueous solvents or vacuum. Here, we demonstrate the use of optical traps to manipulate, align, and assemble metal-seeded nanowire building blocks in a range of organic solvents. Anisotropic radiation pressure generates an optical torque that orients each nanowire, and subsequent trapping of aligned nanowires enables deterministic fabrication of arbitrarily long heterostructures of periodically repeating bismuth-nanocrystal/germanium-nanowire junctions. Heat transport calculations, back-focal-plane interferometry, and optical images reveal that the bismuth nanocrystal melts during trapping, facilitating tip-to-tail “nanosoldering” of the germanium nanowires. These bismuth-semiconductor interfaces may be useful for quantum computing or thermoelectric applications. In addition, the ability to trap nanostructures in oxygen- and water-free organic media broadly expands the library of materials available for optical manipulation and single-particle spectroscopy., The use of optical traps has been limited to materials dispersed in aqueous media, which restricts the materials and range of experiments. Here, the authors demonstrate the alignment and assembly of composite structures made of a bismuth nanocrystal and a germanium nanowire in organic solvents.
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- 2019
32. SMR peptide antagonizes mortalin promoted release of extracellular vesicles and affects mortalin protection from complement-dependent cytotoxicity in breast cancer cells and leukemia cells
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James W. Lillard, Vincent C. Bond, Ming-Bo Huang, and Jennifer Y. Wu
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mortalin ,0301 basic medicine ,medicine.medical_treatment ,medicine.disease_cause ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Cancer immunotherapy ,medicine ,Extracellular ,complement ,Secretion ,Chemistry ,Cell growth ,SMR peptides ,Extracellular vesicle ,3. Good health ,Cell biology ,030104 developmental biology ,Secretory protein ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,extracellular vesicles ,Carcinogenesis ,Research Paper - Abstract
// Ming-Bo Huang 1 , * , Jennifer Y. Wu 2 , * , James Lillard 1 and Vincent C. Bond 1 1 Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA 2 Columbia College, Columbia University, New York, NY 10027, USA * These authors contributed equally to this work Correspondence to: Ming-Bo Huang, email: mhuang@msm.edu Keywords: extracellular vesicles; mortalin; complement; SMR peptides; breast cancer Received: May 14, 2019 Accepted: July 24, 2019 Published: September 10, 2019 ABSTRACT Background: Mortalin/GRP-75/mt-hsp70 is a mitochondrial chaperone protein, found in the cytoplasm, endoplasmic reticulum and cytoplasmic vesicles. It functions in many cellular processes such as mitochondrial biogenesis, intracellular trafficking, cell proliferation, signaling, immortalization and tumorigenesis. Thus, inhibition of mortalin is a promising avenue for cancer therapy. Previous studies in our lab have suggested that mortalin contributes to breast cancer development and progression. We showed that tumor extracellular vesicle secretion was decreased by knockdown of mortalin expression using HIV-1 Nef SMR peptides. Specifically, these peptides can block extracellular vesicle secretion and mediate cell cycle arrest in MDA-MB-231 and MCF-7 breast cancer cells. Aims: This study aims to investigate further the function and mechanism of interaction of PEG-SMR-CLU and SMR-CPP peptides with the chaperone protein mortalin and to explore the effect of SMR-derived peptides and mortalin expression on extracellular vesicle release and complement dependent cell toxicity in human breast cancer and leukemia cell lines. Results: Our results demonstrated additional effects reversing the tumorigenicity of these cells. First, the modified SMRwt peptides reduced the expression of the mesenchymal marker vimentin (VIM). Second, exposure to the SMRwt peptide inhibited mortalin and complement C9 expression in MDA-MB-231, MCF-7 breast cancer cells and K562 leukemia cells as measured by the Western blot analysis. Third, the SMRwt peptides blocked the cancer cells’ ability to release extracellular vesicles, which we observed blocked extracellular vesicle-mediated release of complement, re-establishing complements mediated cell death in those peptide-treated cells. Methods: We developed a series of peptides derived from the Secretion Modification Region (SMR) of HIV-1 Nef protein, modified by the addition of either a cell-penetrating peptide (CPP), a positively charged arginine-rich peptide derived from HIV-1 regulatory protein Tat, or a Clusterin-binding peptide (CLU), a molecular chaperone involved in protein secretion. Both CPP and CLU peptide sequences were added at the C-terminus of the Nef SMR peptide. The CLU-containing peptides were also modified with polyethylene glycol (PEG) to enhance solubility. After treatment of cells with the peptides, we used the MTT cell viability and complement-mediated cytotoxicity assays to confirm the inhibitory role of modified SMRwt peptides on the proliferation of MDA-MB-231 and MCF-7 breast cancer cells and K562 leukemia cells. Flow cytometry was used to determine complement mediated cell apoptosis and death. Western blot analysis was used to track SMR peptides impact on expression of mortalin, vimentin and complement C9 and to measure the expression of extracellular vesicle proteins. NanoSight analysis and acetylcholinesterase (AChE) assay were used for measuring extracellular vesicles particle size and concentration and acetylcholinesterase. Conclusions: Mortalin promotes cell proliferation, metastasis, angiogenesis, downregulate apoptotic signaling. Thus, mortalin is a potential therapeutic target for cancer immunotherapy. The novel SMRwt peptides antagonize the functions of mortalin, blocking tumor extracellular vesicle release and extracellular vesicle-mediated release of complement. This leads to decreases in breast cancer cell metastasis and allows standard treatment of these late stage tumor cells, thus having important clinical implications for late stage breast cancer chemotherapy. These findings support further investigation into the therapeutic value of the SMR peptide in cancer metastasis.
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- 2019
33. Temperature-Dependent Electrochemical Characteristics of Antimony Nanocrystal Alloying Electrodes for Na-Ion Batteries
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Vincent C. Holmberg, Emilee K. Paradis, Martin Affandy, Thomas B. Yoo, Grant A. Williamson, Victor W. Hu, and Charles Opie
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Battery (electricity) ,Materials science ,Energy Engineering and Power Technology ,chemistry.chemical_element ,Sodium-ion battery ,Electrochemistry ,Dielectric spectroscopy ,Antimony ,chemistry ,Nanocrystal ,Chemical engineering ,Electrode ,Materials Chemistry ,Chemical Engineering (miscellaneous) ,Gravimetric analysis ,Electrical and Electronic Engineering - Abstract
Nanostructured antimony is a highly promising alloying electrode material for both Li-ion and Na-ion battery systems, possessing a large gravimetric charge storage capacity (660 mAh g–1) combined w...
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- 2019
34. Germanium Nanowire Battery Electrodes with Engineered Surface-Binder Interactions Exhibit Improved Cycle Life and High Energy Density without Fluorinated Additives
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Elena P. Pandres, Cody W. Schlenker, Vincent C. Holmberg, and Jarred Z. Olson
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Materials science ,Energy Engineering and Power Technology ,chemistry.chemical_element ,Germanium ,Nanotechnology ,Electrode interface ,Nanowire battery ,Lithium-ion battery ,law.invention ,chemistry ,law ,Composite electrode ,Electrode ,Materials Chemistry ,Electrochemistry ,Energy density ,Chemical Engineering (miscellaneous) ,Electrical and Electronic Engineering ,Electrochemical energy storage - Abstract
Nanostructured Group-IV materials hold great promise as high-capacity alloying electrodes for electrochemical energy storage. However, in order to stabilize their cycling performance, it has been n...
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- 2019
35. Not a Disease of the Past: A Case Series of Progressive Multifocal Leukoencephalopathy in the Established Antiretroviral Era
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Nathan A. Summers, Vincent C. Marconi, Colleen F. Kelley, Wendy S. Armstrong, and Minh Ly Nguyen
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Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Weakness ,Georgia ,Neurology ,Anti-HIV Agents ,viruses ,Immunology ,HIV Infections ,Pathogenesis ,Disease ,Asymptomatic ,03 medical and health sciences ,chemistry.chemical_compound ,Dysarthria ,0302 clinical medicine ,Immune reconstitution inflammatory syndrome ,Immune Reconstitution Inflammatory Syndrome ,Virology ,medicine ,Humans ,Registries ,030212 general & internal medicine ,Asymptomatic Infections ,Maraviroc ,Polyomavirus Infections ,business.industry ,Progressive multifocal leukoencephalopathy ,Leukoencephalopathy, Progressive Multifocal ,virus diseases ,Middle Aged ,medicine.disease ,JC Virus ,030104 developmental biology ,Infectious Diseases ,chemistry ,Female ,medicine.symptom ,business - Abstract
Progressive multifocal leukoencephalopathy (PML) and PML immune reconstitution inflammatory syndrome (PML-IRIS) can be devastating neurological processes associated with HIV, but limited knowledge of their characteristics in the established antiretroviral therapy (ART) era is available. We conducted a case series to evaluate the clinical course of PML and PML-IRIS at our urban safety-net hospital in Atlanta, GA. All HIV-positive individuals with a positive John Cunningham virus DNA polymerase chain reaction in the spinal fluid between May 1, 2013 to June 1, 2017 were identified from the electronic health records (EHRs) using the HIV Disease Registry. Demographics, symptom presentation, laboratory data, imaging results, treatment, and outcomes were abstracted from the EHR. PML and PML-IRIS were defined using the American Association of Neurology criteria. Of the 32 individuals identified, 6 (19%) were felt to have asymptomatic positive results. Of the remainder, 15 (58%) HIV-positive patients had PML and 11 (42%) PML-IRIS (2 with an unmasking presentation and 9 with a paradoxical presentation). The most common presenting symptoms were motor weakness (18, 69%), cognitive deficits (15, 58%), and dysarthria (11, 42%). Corticosteroids were used in 12 patients and maraviroc in 3 patients. Outcomes were dismal with 7 (47%) patients with PML and 9 (82%) with PML-IRIS dying or being referred to hospice, with median survival times of 266 days in the PML group and 109 days in the PML-IRIS group. Despite widespread access to ART, patients with PML continue to have poor outcomes, particularly among those who develop PML-IRIS. More research is needed to understand the risks for and prevention of PML-IRIS.
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- 2019
36. pH-responsive delivery of Griffithsin from electrospun fibers
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Donghan Lee, Jill M. Steinbach-Rankins, Pravallika Kollipara, Mark Vincent C. Dela Cerna, Jinghua Duan, Kenneth E. Palmer, and Kevin M. Tyo
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Herpesvirus 2, Human ,Pharmaceutical Science ,HIV Infections ,02 engineering and technology ,Pharmacology ,medicine.disease_cause ,Antiviral Agents ,030226 pharmacology & pharmacy ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Polylactic Acid-Polyglycolic Acid Copolymer ,Cell Line, Tumor ,Microbicide ,medicine ,Humans ,Glycolic acid ,Acrylic acid ,Griffithsin ,biology ,technology, industry, and agriculture ,Epithelial Cells ,General Medicine ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,In vitro ,PLGA ,HEK293 Cells ,Herpes simplex virus ,chemistry ,Vagina ,Toxicity ,HIV-1 ,biology.protein ,Female ,0210 nano-technology ,HeLa Cells ,Biotechnology - Abstract
Human immunodeficiency virus (HIV-1) affects over 36 million people globally. Current prevention strategies utilize antiretrovirals that have demonstrated protection, but result in antiviral resistance, adverse toxicity, and require frequent administration. A novel biologic, griffithsin (GRFT), has demonstrated outstanding safety and efficacy against laboratory and primary HIV isolates and against intravaginal murine herpes simplex virus 2 (HSV-2) challenge, making it a promising microbicide candidate. However, transient activity and instability remain concerns surrounding biologic delivery, particularly in the harsh environment of the female reproductive tract (FRT). Recently, electrospun fibers (EFs) have demonstrated promise for intravaginal delivery, with the potential to conserve active agent until release is needed. The goal of this study was to fabricate and characterize pH-responsive fibers comprised of poly(lactic- co -glycolic acid) (PLGA) or methoxypolyethylene glycol- b -PLGA (mPEG-PLGA) with varying ratios of poly( n -butyl acrylate- co -acrylic acid) (PBA- co -PAA), to selectively release GRFT under pH-conditions that mimic semen introduction. Fibers comprised of mPEG-PLGA:PBA- co -PAA (90:10 w/w) demonstrated high GRFT loading that was maintained within simulated vaginal fluid (SVF), and pH-dependent release upon exposure to buffered and SVF:simulated semen solutions. Moreover, GRFT fibers demonstrated potent in vitro efficacy against HIV-1 and safety in vaginal epithelial cells, suggesting their future potential for efficacious biologic delivery to the FRT.
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- 2019
37. Periostin/β1integrin interaction regulates p21-activated kinases in valvular interstitial cell survival and in actin cytoskeleton reorganization
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Gustavo Leone, Vincent C. Hascall, Ricardo A. Moreno-Rodrigue, Suniti Misra, Shibnath Ghatak, and Roger R. Markwald
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0301 basic medicine ,Cell Survival ,Biophysics ,macromolecular substances ,CDC42 ,Periostin ,Biochemistry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,PAK1 ,Animals ,Cytoskeleton ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Chemistry ,Integrin beta1 ,Actin cytoskeleton reorganization ,Matricellular protein ,Actin remodeling ,Cell biology ,Mice, Inbred C57BL ,Actin Cytoskeleton ,030104 developmental biology ,p21-Activated Kinases ,030220 oncology & carcinogenesis ,Cell Adhesion Molecules - Abstract
The matricellular protein periostin (PN) promotes postnatal valve remodeling and maturation. Incomplete remodeling of the valve can trigger degenerative processes that lead to a myxomatous phenotype that includes loss of PN. However, signaling pathways involved that link valvular-interstitial-fibroblast cells (VICs) to proliferation, migration and actin remodeling functions are unclear. The p21-activated kinases (Paks) have been shown to regulate cytoskeleton rearrangements and cell proliferation/adhesion/migration functions in a variety of cellular contexts, including normal cells and cancer cells. This study shows that Pak1, but not Pak2 and Pak4, is a critical mediator of VIC survival and actin organization, and that the molecular signaling regulating actin-remodeling is initiated upon PN/beta-integrin-induced phosphorylation of the focal-adhesion-kinase (Fak) (Y397). Molecular and pharmacological inhibition of key components of PN/Fak/Akt1 signaling abolished the PN-induced actin polymerization and the activation of mTOR, p70S6K and Pak1. Similarly, blocking mTOR inhibited p70S6K, Pak1 phosphorylation and consequently actin-polymerization. Accordingly, inhibiting p70S6K blocked Pak1 phosphorylation and actin polymerization, and subsequently inhibited adhesion and growth of VICs. Periostin-induced Akt1 activation of Pak1 is independent of Cdc42 and Rac1 GTPases, and Akt1 is both downstream and upstream of Pak1. Further, the PN-Pak1-induced Akt1 protects cells from apoptosis through suppression of transcriptional activation of Forkhead-Transcription-Factor (FKHR). In contrast, kinase deficient Pak1 increases apoptosis by increasing FKHR-mediated transcriptional activation. These studies define new functional significance of PN-Fak-Akt1-Pak1 signaling that at least partly regulates Akt1-induced actin polymerization and FKHR-mediated transcriptional activation, which may eventually regulate the mature-valve-leaflet remodeling function, and also FKHR-mediated transcriptional activation for pro-survival of VICs.
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- 2019
38. The journey of hyaluronan research in the Journal of Biological Chemistry
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Vincent C. Hascall
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0301 basic medicine ,Disaccharide ,History, 21st Century ,Biochemistry ,Glycosaminoglycan ,03 medical and health sciences ,chemistry.chemical_compound ,Extracellular ,Humans ,Hyaluronic Acid ,Molecular Biology ,Inflammation ,chemistry.chemical_classification ,Wound Healing ,030102 biochemistry & molecular biology ,Molecular mass ,Chemistry ,JBC Reviews ,Glycosidic bond ,Cell Biology ,History, 20th Century ,Extracellular Matrix ,Hyaluronan Receptors ,030104 developmental biology ,Periodicals as Topic - Abstract
Hyaluronan has a very simple structure. It is a linear glycosaminoglycan composed of disaccharide units of GlcNAc and d-glucuronic acid with alternating β-1,4 and β-1,3 glycosidic bonds that can be repeated 20,000 or more times, a molecular mass >8 million Da, and a length >20 μm. However, it has a very complex biology. It is a major, ubiquitous component of extracellular matrices involved in everything from fertilization, development, inflammations, to cancer. This JBC Review highlights some of these processes that were initiated through publications in the Journal of Biological Chemistry.
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- 2019
39. Detoxification of Aflatoxin-Contaminated Poultry Feeds by 3 Adsorbents, Bentonite, Activated Charcoal, and Fuller’s Earth
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Vincent C. Shoyinka, Obasi C. Christian, Anthony C. Mgbeahuruike, Tochukwu E. Ejioffor, Magnus Karlsson, and Erik Nordkvist
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0301 basic medicine ,Aflatoxin ,Chemistry ,0402 animal and dairy science ,food and beverages ,04 agricultural and veterinary sciences ,engineering.material ,Contamination ,040201 dairy & animal science ,Fuller's earth ,03 medical and health sciences ,030104 developmental biology ,Adsorption ,Animal science ,Activated charcoal ,Detoxification ,Bentonite ,engineering ,Animal Science and Zoology - Abstract
SUMMARY Aflatoxicosis is a major problem associated with poultry production in the tropics. We tested the ability of 3 low-cost and locally available adsorbents (activated charcoal, bentonite, and fuller’s earth) to detoxify poultry feeds contaminated with aflatoxin. Bentonite was the most effective adsorbent and lowered the total aflatoxin concentration from 120 ± 38 μg/kg to 15 ± 5.0 μg/kg. The 3 adsorbent treatments resulted in 63%–100% weight increase of the birds, compared with birds fed the untreated, aflatoxin-containing feed. The number of white blood cells in blood samples was increased by 13%–17% in birds that consumed adsorbent-treated feed, compared with the untreated, aflatoxin-contaminated feed. Hepatic lesions were also prominent in the liver of the birds fed contaminated but untreated feed but were reduced in the group that were fed the adsorbent-treated feeds, especially in the bentonite-treated feed. Conclusively, the adsorbents were able to reduce the concentration of aflatoxin in the feed and this reflected positively on the general performance of the birds.
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- 2018
40. Impact of pre-existing drug resistance on risk of virological failure in South Africa
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Selvan Pillay, Daniel R. Kuritzkes, Brent A. Johnson, Mahomed-Yunus S. Moosa, Marc Noguera-Julian, Roger Paredes, Natalia Stella, Henry Sunpath, Manish Chandra Choudhary, Jay Brijkumar, Vincent C. Marconi, Alex Edwards, Jonathan Z. Li, Aneela Javed, Katherine Rodriguez, and Heather J. Ribaudo
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Microbiology (medical) ,medicine.medical_specialty ,Efavirenz ,Anti-HIV Agents ,Population ,HIV Infections ,Drug resistance ,Emtricitabine ,chemistry.chemical_compound ,South Africa ,Acquired immunodeficiency syndrome (AIDS) ,Internal medicine ,Drug Resistance, Viral ,medicine ,Humans ,Pharmacology (medical) ,Treatment Failure ,education ,Original Research ,Pharmacology ,education.field_of_study ,business.industry ,Proportional hazards model ,Viral Load ,medicine.disease ,Infectious Diseases ,chemistry ,Cohort ,Mutation ,HIV-1 ,business ,HIV drug resistance ,medicine.drug - Abstract
Objectives There is conflicting evidence on the impact of pre-existing HIV drug resistance mutations (DRMs) in patients infected with non-B subtype virus. Methods We performed a case–cohort substudy of the AIDS Drug Resistance Surveillance Study, which enrolled South African patients initiating first-line efavirenz/emtricitabine/tenofovir. Pre-ART DRMs were detected by Illumina sequencing of HIV pol and DRMs present at Results The evaluable population included 178 participants from a randomly selected subcohort (16 with VF, 162 without VF) and 83 additional participants with VF. In the subcohort, 16% of participants harboured ≥1 majority DRM. The presence of any majority DRM was associated with a 3-fold greater risk of VF (P = 0.002), which increased to 9.2-fold (P Conclusions In a South African cohort, the presence of majority DRMs increased the risk of VF, especially for participants receiving
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- 2021
41. Genome-Wide Identification of Rare and Common Variants Driving Triglyceride Levels in a Nevada Population
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Robert W Read, Elizabeth T. Cirulli, James T. Lu, Joseph J. Grzymski, Karen Schlauch, Vincent C. Lombardi, and Nicole L. Washington
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0301 basic medicine ,lcsh:QH426-470 ,Population ,Genome-wide association study ,030204 cardiovascular system & hematology ,Biology ,Phenome ,Genome ,whole exome sequencing ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,rare variant analysis ,Genetics ,GWAS ,education ,Gene ,Exome ,triglycerides ,Genetics (clinical) ,Exome sequencing ,Original Research ,education.field_of_study ,Triglyceride ,PheWAS ,lcsh:Genetics ,030104 developmental biology ,chemistry ,Molecular Medicine - Abstract
Clinical conditions correlated with elevated triglyceride levels are well-known: coronary heart disease, hypertension, and diabetes. Underlying genetic and phenotypic mechanisms are not fully understood, partially due to lack of coordinated genotypic-phenotypic data. Here we use a subset of the Healthy Nevada Project, a population of 9,183 sequenced participants with longitudinal electronic health records to examine consequences of altered triglyceride levels. Specifically, Healthy Nevada Project participants sequenced by the Helix Exome+ platform were cross-referenced to their electronic medical records to identify: (1) rare and common single-variant genome-wide associations; (2) gene-based associations using a Sequence Kernel Association Test; (3) phenome-wide associations with triglyceride levels; and (4) pleiotropic variants linked to triglyceride levels. The study identified 549 significant single-variant associations (p < 8.75 × 10–9), many in chromosome 11’s triglyceride hotspot: ZPR1, BUD13, APOC3, APOA5. A well-known protective loss-of-function variant in APOC3 (R19X) was associated with a 51% decrease in triglyceride levels in the cohort. Sixteen gene-based triglyceride associations were identified; six of these genes surprisingly did not include a single variant with significant associations. Results at the variant and gene level were validated with the UK Biobank. The combination of a single-variant genome-wide association, a gene-based association method, and phenome wide-association studies identified rare and common variants, genes, and phenotypes associated with elevated triglyceride levels, some of which may have been overlooked with standard approaches.
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- 2021
42. Free fatty acid receptor 4 inhibitory signaling in delta cells regulates islet hormone secretion in mice
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Marcus F. Flisher, Glyn M. Noguchi, Sabrina Granziera, Julien Ghislain, Caroline Tremblay, Kevin Vivot, Arthur Guillaume, Marine L. Croze, Vincent Poitout, Mark O. Huising, Scott A. Campbell, and Vincent C. Castillo
- Subjects
0301 basic medicine ,Male ,GPR120 ,Physiology ,Fatty Acids, Nonesterified ,Inbred C57BL ,Receptors, G-Protein-Coupled ,Mice ,0302 clinical medicine ,Insulin-Secreting Cells ,Receptors ,Insulin Secretion ,Glucose homeostasis ,Insulin ,Homeostasis ,2.1 Biological and endogenous factors ,Aetiology ,Mice, Knockout ,Somatostatin receptor ,Chemistry ,Fatty Acids ,Diabetes ,Glucagon secretion ,3. Good health ,Somatostatin ,5.1 Pharmaceuticals ,Original Article ,Female ,Development of treatments and therapeutic interventions ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,medicine.medical_specialty ,endocrine system ,lcsh:Internal medicine ,Somatostatin-Secreting Cells ,Somatostatin secretion ,Knockout ,1.1 Normal biological development and functioning ,030209 endocrinology & metabolism ,Glucagon ,03 medical and health sciences ,Islets of Langerhans ,G-Protein-Coupled ,FFAR4 ,Underpinning research ,Internal medicine ,medicine ,Animals ,Secretion ,lcsh:RC31-1245 ,Molecular Biology ,Metabolic and endocrine ,Delta cell ,Cell Biology ,Glucose Tolerance Test ,Islet of langerhans ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Glucose ,Glucagon-Secreting Cells ,Nonesterified ,Biochemistry and Cell Biology ,Digestive Diseases - Abstract
Objective Maintenance of glucose homeostasis requires the precise regulation of hormone secretion from the endocrine pancreas. Free fatty acid receptor 4 (FFAR4/GPR120) is a G protein-coupled receptor whose activation in islets of Langerhans promotes insulin and glucagon secretion and inhibits somatostatin secretion. However, the contribution of individual islet cell types (α, β, and δ cells) to the insulinotropic and glucagonotropic effects of GPR120 remains unclear. As gpr120 mRNA is enriched in somatostatin-secreting δ cells, we hypothesized that GPR120 activation stimulates insulin and glucagon secretion via inhibition of somatostatin release. Methods Glucose tolerance tests were performed in mice after administration of selective GPR120 agonist Compound A. Insulin, glucagon, and somatostatin secretion were measured in static incubations of isolated mouse islets in response to endogenous (ω-3 polyunsaturated fatty acids) and/or pharmacological (Compound A and AZ-13581837) GPR120 agonists. The effect of Compound A on hormone secretion was tested further in islets isolated from mice with global or somatostatin cell-specific knock-out of gpr120. Gpr120 expression was assessed in pancreatic sections by RNA in situ hybridization. Cyclic AMP (cAMP) and calcium dynamics in response to pharmacological GPR120 agonists were measured specifically in α, β, and δ cells in intact islets using cAMPER and GCaMP6 reporter mice, respectively. Results Acute exposure to Compound A increased glucose tolerance, circulating insulin, and glucagon levels in vivo. Endogenous and/or pharmacological GPR120 agonists reduced somatostatin secretion in isolated islets and concomitantly demonstrated dose-dependent potentiation of glucose-stimulated insulin secretion and arginine-stimulated glucagon secretion. Gpr120 was enriched in δ cells. Pharmacological GPR120 agonists reduced cAMP and calcium levels in δ cells but increased these signals in α and β cells. Compound A-mediated inhibition of somatostatin secretion was insensitive to pertussis toxin. The effect of Compound A on hormone secretion was completely absent in islets from mice with either global or somatostatin cell-specific deletion of gpr120 and partially reduced upon blockade of somatostatin receptor signaling by cyclosomatostatin. Conclusions Inhibitory GPR120 signaling in δ cells contributes to both insulin and glucagon secretion in part by mitigating somatostatin release., Graphical abstract Image 1, Highlights • Gpr120 was enriched in mouse somatostatin-secreting δ cells. • GPR120 activation in mouse δ cells inhibited cAMP generation and somatostatin release. • GPR120 activation in mouse δ cells potentiated insulin and glucagon secretion.
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- 2021
43. Significance of the Different Exposed Surfaces of ZnO Single Crystals and Nanowires on the Photocatalytic Activity and Processes
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Adrien Baillard, Estelle Appert, Laetitia Rapenne, Véronique Jacob, Alexandre Dieulesaint, Jean‐Michel Chauveau, and Vincent Consonni
- Subjects
chemical bath deposition ,photocatalysis ,planes ,single crystals ,ZnO nanowires ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
The heterogeneous photocatalysis of organic dyes using ZnO nanowires (NWs) is of high interest to face the challenge of eco‐efficient water remediation. However, the effects of the wurtzite structure of ZnO and hence of the shape of nanostructures on the photocatalytic processes are still under debate. Herein, it is shown that the photocatalytic activity of ZnO single crystals with five different orientations follows a pseudo‐first‐order kinetics as: (0001¯)
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- 2024
- Full Text
- View/download PDF
44. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis
- Author
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Nevens, F, Andreone, P, Mazzella, G, Strasser, S, Bowlus, C, Drenth, J, Pockros, P, Regula, J, Beuers, U, Trauner, M, Jones, D, Floreani, A, Hohenester, S, Luketic, V, Shiffman, M, van Erpecum, K, Vargas, V, Vincent, C, Hirschfield, G, Shah, H, Hansen, B, Lindor, K, Marschall, H, Kowdley, K, Hooshmand Rad, R, Marmon, T, Sheeron, S, Pencek, R, Macconell, L, Pruzanski, M, Shapiro, D. Collaborator: Carbone, INVERNIZZI, PIETRO, DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE, Facolta' di MEDICINA e CHIRURGIA, AREA MIN. 06 - Scienze mediche, Gastroenterology & Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, Graduate School, Other departments, Nevens, F., Andreone, P., Mazzella, G., Strasser, S.I., Bowlus, C., Invernizzi, P., Drenth, J.P.H., Pockros, P.J., Regula, J., Beuers, U., Trauner, M., Jones, D.E., Floreani, A., Hohenester, S., Luketic, V., Shiffman, M., Van Erpecum, K.J., Vargas, V., Vincent, C., Hirschfield, G.M., Shah, H., Hansen, B., Lindor, K.D., Marschall, H.-U., Kowdley, K.V., Hooshmand-Rad, R., Marmon, T., Sheeron, S., Pencek, R., Macconell, L., Pruzanski, M., Shapiro, D., Nevens, F, Andreone, P, Mazzella, G, Strasser, S, Bowlus, C, Invernizzi, P, Drenth, J, Pockros, P, Regula, J, Beuers, U, Trauner, M, Jones, D, Floreani, A, Hohenester, S, Luketic, V, Shiffman, M, van Erpecum, K, Vargas, V, Vincent, C, Hirschfield, G, Shah, H, Hansen, B, Lindor, K, Marschall, H, Kowdley, K, Hooshmand Rad, R, Marmon, T, Sheeron, S, Pencek, R, Macconell, L, Pruzanski, M, Shapiro, and D., C
- Subjects
Liver Cirrhosis ,Male ,0301 basic medicine ,Cirrhosis ,Fibroblast Growth Factor ,medicine.medical_treatment ,Clinical Trial, Phase III ,Placebo-controlled study ,Liver transplantation ,Gastroenterology ,Pruritu ,chemistry.chemical_compound ,0302 clinical medicine ,Primary biliary cirrhosis ,Bone Density ,Chenodeoxycholic acid ,Adult ,Aged ,Alkaline Phosphatase ,Bile Acids and Salts ,Chenodeoxycholic Acid ,Double-Blind Method ,Female ,Fibroblast Growth Factors ,Humans ,Liver Cirrhosis, Biliary ,Middle Aged ,Pruritus ,Non-U.S. Gov't ,Medicine (all) ,Research Support, Non-U.S. Gov't ,Biliary ,Obeticholic acid ,General Medicine ,Clinical Trial ,Bile Acids and Salt ,Multicenter Study ,Randomized Controlled Trial ,030211 gastroenterology & hepatology ,Human ,medicine.medical_specialty ,Randomization ,Liver Cirrhosi ,Research Support ,Placebo ,03 medical and health sciences ,Phase III ,Internal medicine ,Journal Article ,medicine ,business.industry ,medicine.disease ,Surgery ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,030104 developmental biology ,chemistry ,business - Abstract
none 32 BACKGROUND Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. METHODS In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. RESULTS Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P
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- 2016
45. Novel standardized method for extracellular flux analysis of oxidative and glycolytic metabolism in peripheral blood mononuclear cells
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Vincent C. J. de Boer, R. J. Joost van Neerven, Joëlle J. E. Janssen, Huub F. J. Savelkoul, Jaap Keijer, Bart Lagerwaard, and Annelies Bunschoten
- Subjects
Adult ,0301 basic medicine ,Cell biology ,Adolescent ,Molecular biology ,Physiology ,Coefficient of variation ,Science ,Immunology ,Celbiologie en Immunologie ,Buffy coat ,Peripheral blood mononuclear cell ,Article ,Oxidative Phosphorylation ,Young Adult ,03 medical and health sciences ,Oxygen Consumption ,0302 clinical medicine ,Metabolic flux analysis ,Extracellular ,Animals ,Humans ,Life Science ,VLAG ,Multidisciplinary ,Chemistry ,Oxidative Stress ,030104 developmental biology ,Cell Biology and Immunology ,Human and Animal Physiology ,Leukocytes, Mononuclear ,WIAS ,Fysiologie van Mens en Dier ,Medicine ,Female ,Glycolysis ,Immortalised cell line ,Flux (metabolism) ,Biomarkers ,Blood Chemical Analysis ,030217 neurology & neurosurgery ,Ex vivo - Abstract
Analyzing metabolism of peripheral blood mononuclear cells (PBMCs) provides key opportunities to study the pathophysiology of several diseases, such as type 2 diabetes, obesity and cancer. Extracellular flux (XF) assays provide dynamic metabolic analysis of living cells that can capture ex vivo cellular metabolic responses to biological stressors. To obtain reliable data from PBMCs from individuals, novel methods are needed that allow for standardization and take into account the non-adherent and highly dynamic nature of PBMCs. We developed a novel method for extracellular flux analysis of PBMCs, where we combined brightfield imaging with metabolic flux analysis and data integration in R. Multiple buffy coat donors were used to demonstrate assay linearity with low levels of variation. Our method allowed for accurate and precise estimation of XF assay parameters by reducing the standard score and standard score interquartile range of PBMC basal oxygen consumption rate and glycolytic rate. We applied our method to freshly isolated PBMCs from sixteen healthy subjects and demonstrated that our method reduced the coefficient of variation in group mean basal oxygen consumption rate and basal glycolytic rate, thereby decreasing the variation between PBMC donors. Our novel brightfield image procedure is a robust, sensitive and practical normalization method to reliably measure, compare and extrapolate XF assay data using PBMCs, thereby increasing the relevance for PBMCs as marker tissue in future clinical and biological studies, and enabling the use of primary blood cells instead of immortalized cell lines for immunometabolic experiments.
- Published
- 2021
46. Propionate hampers differentiation and modifies histone propionylation and acetylation in skeletal muscle cells
- Author
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Lotte Grevendonk, Marjanne D. van der Hoek, Joris Hoeks, Vincent C. J. de Boer, Bart Lagerwaard, Jaap Keijer, Arie G. Nieuwenhuizen, Nutrition and Movement Sciences, and RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health
- Subjects
0301 basic medicine ,CHROMATIN ,Aging ,LIVER ,Acylation ,Muscle Fibers, Skeletal ,MyoD ,Histones ,ACTIVATION ,0302 clinical medicine ,COA CARBOXYLASE ,Skeletal muscle differentiation ,Histone Acetyltransferases ,biology ,Chemistry ,Muscle cell differentiation ,Cell Differentiation ,ACIDURIA ,Cell biology ,Histone acylation ,Histone ,medicine.anatomical_structure ,Human and Animal Physiology ,lipids (amino acids, peptides, and proteins) ,C2C12 ,Propionylation ,DISORDERS ,METABOLISM ,complex mixtures ,Cell Line ,03 medical and health sciences ,Protein acylation ,Acetyl Coenzyme A ,medicine ,Humans ,MyoD Protein ,VLAG ,LANDSCAPE ,Skeletal muscle ,GENE ,030104 developmental biology ,Acetylation ,biology.protein ,WIAS ,Fysiologie van Mens en Dier ,Acyl Coenzyme A ,Propionates ,MYOD ,Chromatin immunoprecipitation ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Protein acylation via metabolic acyl-CoA intermediates provides a link between cellular metabolism and protein functionality. A process in which acetyl-CoA and acetylation are fine-tuned is during myogenic differentiation. However, the roles of other protein acylations remain unknown. Protein propionylation could be functionally relevant because propionyl-CoA can be derived from the catabolism of amino acids and fatty acids and was shown to decrease during muscle differentiation. We aimed to explore the potential role of protein propionylation in muscle differentiation, by mimicking a pathophysiological situation with high extracellular propionate which increases propionyl-CoA and protein propionylation, rendering it a model to study increased protein propionylation. Exposure to extracellular propionate, but not acetate, impaired myogenic differentiation in C2C12 cells and propionate exposure impaired myogenic differentiation in primary human muscle cells. Impaired differentiation was accompanied by an increase in histone propionylation as well as histone acetylation. Furthermore, chromatin immunoprecipitation showed increased histone propionylation at specific regulatory myogenic differentiation sites of the Myod gene. Intramuscular propionylcarnitine levels are higher in old compared to young males and females, possibly indicating increased propionyl-CoA levels with age. The findings suggest a role for propionylation and propionyl-CoA in regulation of muscle cell differentiation and ageing, possibly via alterations in histone acylation.
- Published
- 2021
47. Butyrate alters pyruvate flux and induces lipid accumulation in cultured colonocytes
- Author
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Walter J. J. Gerrits, Jaap Keijer, Vincent C. J. de Boer, Thirza van Deuren, and Anna F Bekebrede
- Subjects
Bioenergetics ,Animal Nutrition ,Colon ,QH301-705.5 ,Metabolic flux ,chemistry.chemical_element ,Butyrate ,Mitochondrion ,Oxygen ,Article ,Catalysis ,Inorganic Chemistry ,HT29 Cells ,Metabolite interactions ,Short-chain fatty acids ,Oxygen Consumption ,In vivo ,Cell Line, Tumor ,Pyruvic Acid ,Humans ,Glycolysis ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,VLAG ,Chemistry ,Organic Chemistry ,Lipid Droplets ,General Medicine ,Diervoeding ,Mitochondria ,Computer Science Applications ,Cell biology ,Butyrates ,Glucose ,Human and Animal Physiology ,WIAS ,Fysiologie van Mens en Dier ,Glucose oxidation ,Flux (metabolism) - Abstract
Butyrate is considered the primary energy source of colonocytes and has received wide attention due to its unique health benefits. Insight into the mechanistic effects of butyrate on cellular and metabolic function relies mainly on research in in-vitro-cultured cells. However, cells in culture differ from those in vivo in terms of metabolic phenotype and nutrient availability. For translation, it is therefore important to understand the impact of different nutrients on the effects of butyrate. We investigated the metabolic consequences of butyrate exposure under various culturing conditions, with a focus on the interaction between butyrate and glucose. To investigate whether the effects of butyrate were different between cells with high and low mitochondrial capacity, we cultured HT29 cells under either low- (0.5 mM) or high- (25 mM) glucose conditions. Low-glucose culturing increased the mitochondrial capacity of HT29 cells compared to high-glucose (25 mM) cultured HT29 cells. Long-term exposure to butyrate did not alter mitochondrial bioenergetics, but it decreased glycolytic function, regardless of glucose availability. In addition, both high- and low-glucose-grown HT29 cells showed increased lipid droplet accumulation following long-term butyrate exposure. Acute exposure of cultured cells (HT29 and Caco-2) to butyrate increased their oxygen consumption rate (OCR). A simultaneous decrease in extracellular acidification rate (ECAR) was observed. Furthermore, in the absence of glucose, OCR did not increase in response to butyrate. These results lead us to believe that butyrate itself was not responsible for the observed increase in OCR, but, instead, butyrate stimulated pyruvate flux into mitochondria. Indeed, blocking of the mitochondrial pyruvate carrier prevented a butyrate-induced increase in oxygen consumption. Taken together, our results indicate that butyrate itself is not oxidized in cultured cells but instead alters pyruvate flux and induces lipid accumulation.
- Published
- 2021
48. The acquisition of tin in Bronze Age southwest Asia
- Author
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Vincent C. Pigott
- Subjects
Plateau ,geography.geographical_feature_category ,Civilization ,Middle East ,media_common.quotation_subject ,Central asia ,chemistry.chemical_element ,Archaeology ,Tin bronze ,Geography ,chemistry ,Bronze Age ,2nd millennium BC ,Tin ,media_common - Abstract
Fundamental to understanding the transmission of tin bronze metallurgy across Eurasia is the evidence for known tin sources that may have been available to metalworking populations in Bronze Age Southwest Asia. The Anatolian evidence from the tin-mining complex of Kestel-Goltepe and that from the Erciyes Dag stratovolcano sites is discussed first. New research on the 2nd millennium BC Old Assyrian tin trade into central Anatolia to Kultepe/Kanesh follows with an emphasis on the southern Mesopotamian end of the trade and its potential links to neighboring Elam. Next, the tin-mining complex at Deh Hosein, on the northern periphery of Elam and its potential as a tin source for many bronze-producing sites in the ancient Near East is examined. Finally, recent fieldwork in Afghanistan documenting its remarkable mineral reserves (e.g., tin, gold, lapis) in relation to its wealth of archaeological sites is reviewed. Here the Oxus Civilization/Bactria-Margiana Archaeological Complex (BMAC) enters the discussion with its proximity to major ancient tin mines as well as its potential as a source of tin bronze metallurgy for the Iranian plateau. Whether or not Afghanistan’s and neighboring Central Asia’s tin sources were supplying their mineral wealth to urban elite consumers to the West remains a question for debate. The Elamites’ potential role as tin-trading middlemen moving tin westward from nearby sources or from as far afield as Afghanistan closes the discussion.
- Published
- 2020
49. Management of hepatocellular carcinoma after progression on first-line systemic treatment: defining the optimal sequencing strategy in second line and beyond
- Author
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Carla P Amaro and Vincent C. Tam
- Subjects
Sorafenib ,Oncology ,medicine.medical_specialty ,second-line management ,Carcinoma, Hepatocellular ,Cabozantinib ,Hepatocellular carcinoma ,Review Article ,Ramucirumab ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Regorafenib ,Internal medicine ,Humans ,Medicine ,030212 general & internal medicine ,Protein Kinase Inhibitors ,neoplasms ,business.industry ,third-line management ,Mortality rate ,Liver Neoplasms ,medicine.disease ,digestive system diseases ,Clinical trial ,chemistry ,030220 oncology & carcinogenesis ,Immunotherapy ,treatment sequencing ,business ,Lenvatinib ,medicine.drug - Abstract
Hepatocellular carcinoma (hcc) is one of the most common cancers in the world. It has a high mortality rate, especially when localized treatments fail. For about a decade, the only systemic treatment shown to improve survival was sorafenib. Recently, lenvatinib was found to be noninferior to sorafenib for overall survival, and combination atezolizumab&ndash, bevacizumab improved survival compared with sorafenib. Similarly, in the post-sorafenib setting, a number of recent positive clinical trials have been reported, and they indicate that regorafenib, cabozantinib, and ramucirumab are effective and safe in the second-line setting.
- Published
- 2020
- Full Text
- View/download PDF
50. Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress
- Author
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Tsai-Hsuan Yang, Eugene Yu-Chuan Kang, Pei-Hsuan Lin, Benjamin Ben-Chi Yu, Jason Hung-Hsuan Wang, Vincent Chen, and Nan-Kai Wang
- Subjects
mitochondria ,retinal ganglion cells ,oxidative stress ,metabolism ,glaucoma ,autosomal dominant optic atrophy ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor in the pathogenesis of various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. This review highlighted the critical role of mitochondria in RGCs, which provide metabolic support, regulate cellular health, and respond to cellular stress while also producing reactive oxygen species (ROS) that can damage cellular components. Maintaining mitochondrial function is essential for meeting RGCs’ high metabolic demands and ensuring redox homeostasis, which is crucial for their proper function and visual health. Oxidative stress, exacerbated by factors like elevated intraocular pressure and environmental factors, contributes to diseases such as glaucoma and age-related vision loss by triggering cellular damage pathways. Strategies targeting mitochondrial function or bolstering antioxidant defenses include mitochondrial-based therapies, gene therapies, and mitochondrial transplantation. These advances can offer potential strategies for addressing mitochondrial dysfunction in the retina, with implications that extend beyond ocular diseases.
- Published
- 2024
- Full Text
- View/download PDF
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