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Title:
LPS protects macrophages from AIF-independent parthanatos by downregulation of PARP1 expression, induction of SOD2 expression, and a metabolic shift to aerobic glycolysis
Authors:
Regdon, Zsolt; Robaszkiewicz, Agnieszka; Kovács, Katalin; Rygielska, Żaneta; Hegedűs, Csaba; Bodoor, Khaldon; Szabó, Éva; Virág, László
Abstract:
In inflamed tissues or during ischemia-reperfusion episodes, activated macrophages produce large amounts of reactive species and are, thus, exposed to the damaging effects of reactive species. Here, our goal was to investigate the mechanism whereby activated macrophages protect themselves from oxidant stress-induced cell death. Hydrogen peroxide-treated mouse bone marrow-derived macrophages (BMDM) and THP-1 human monocyte-derived cells were chosen as models. We found a gradual development of resistance: first in monocyte-to-macrophage differentiation, and subsequently after lipopolysaccharide (LPS) exposure. Investigating the mechanism of the latter, we found that exposure to intense hydrogen peroxide stress causes poly(ADP-ribose) polymerase-1 (PARP-1) dependent programmed necrotic cell death, also known as parthanatos, as indicated by the protected status of PARP-1 knockout BMDMs and the protective effect of the PARP inhibitor PJ-34. In hydrogen peroxide-treated macrophages, however, apoptosis inducing factor (AIF) proved dispensable for parthanatos; nuclear translocation of AIF was not observed. A key event in LPS-mediated protection against the hydrogen peroxide-induced AIF independent parthanatos was downregulation of PARP1 mRNA and protein. The importance of this event was confirmed by overexpression of PARP1 in THP1 cells using a viral promoter, which lead to stable PARP1 levels even after LPS treatment and unresponsiveness to LPS-induced cytoprotection. In BMDMs, LPS-induced PARP1 suppression lead to prevention of NAD+ depletion. Moreover, LPS also induced expression of antioxidant proteins (superoxide dismutase-2, thioredoxin reductase 1 and peroxiredoxin) and triggered a metabolic shift to aerobic glycolysis, also known as the Warburg effect. In summary, we provide evidence that in macrophages intense hydrogen peroxide stress causes AIF-independent parthanatos from which LPS provides protection. The mechanism of LPS-mediated cytoprotection involves downregulation of PARP1, spared NAD+ and ATP pools, upregulation of antioxidant proteins, and a metabolic shift from mitochondrial respiration to aerobic glycolysis.
Published:
February 1, 2019
Title:
Methylglyoxal, a potent inducer of AGEs, connects between diabetes and cancer
Authors:
Bellier, Justine; Nokin, Marie-Julie; Lardé, Eva; Karoyan, Philippe; Peulen, Olivier; Castronovo, Vincent; Bellahcène, Akeila
Abstract:
Diabetes is one of the most frequent diseases throughout the world and its incidence is predicted to exponentially progress in the future. This metabolic disorder is associated with major complications such as neuropathy, retinopathy, atherosclerosis, and diabetic nephropathy, the severity of which correlates with hyperglycemia, suggesting that they are triggered by high glucose condition. Reducing sugars and reactive carbonyl species such as methylglyoxal (MGO) lead to glycation of proteins, lipids and DNA and the gradual accumulation of advanced glycation end products (AGEs) in cells and tissues. While AGEs are clearly implicated in the pathogenesis of diabetes complications, their potential involvement during malignant tumor development, progression and resistance to therapy is an emerging concept. Meta-analysis studies established that patients with diabetes are at higher risk of developing cancer and show a higher mortality rate than cancer patients free of diabetes. In this review, we highlight the potential connection between hyperglycemia-associated AGEs formation on the one hand and the recent evidence of pro-tumoral effects of MGO stress on the other hand. We also discuss the marked interest in anti-glycation compounds in view of their strategic use to treat diabetic complications but also to protect against augmented cancer risk in patients with diabetes.
Published:
February 1, 2019
Title:
Natural Disease Course of Ulcerative Colitis During the First Five Years of Follow-up in a European Population-based Inception Cohort-An Epi-IBD Study
Authors:
Burisch, Johan; Katsanos, Konstantinos H.; Christodoulou, Dimitrios K.; Barros, Luisa; Magro, Fernando; Pedersen, Natalia; Kjeldsen, Jens; Vegh, Zsuzsanna; Lakatos, Peter L.; Eriksson, Carl; Halfvarson, Jonas; Fumery, Mathurin; Gower-Rousseau, Corinne; Brinar, Marko; Cukovic-Cavka, Silvija; Nikulina, Inna; Belousova, Elena; Myers, Sally; Sebastian, Shaji; Kiudelis, Gediminas; Kupcinskas, Limas; Schwartz, Doron; Odes, Selwyn; Kaimakliotis, Ioannis P.; Valpiani, Daniela; D'Incà, Renata; Salupere, Riina; Chetcuti Zammit, Stefania; Ellul, Pierre; Duricova, Dana; Bortlik, Martin; Goldis, Adrian; Kievit, Hendrika Adriana Linda; Toca, Alina; Turcan, Svetlana; Midjord, Jóngerð; Nielsen, Kári Rubek; Andersen, Karina Winther; Andersen, Vibeke; Misra, Ravi; Arebi, Naila; Oksanen, Pia; Collin, Pekka; de Castro, Luisa; Hernandez, Vicent; Langholz, Ebbe; Munkholm, Pia; Epi-IBD Group
Abstract:
Background and Aims: Few population-based cohort studies have assessed the disease course of ulcerative colitis [UC] in the era of biological therapy and widespread use of immunomodulators. The aim of this study was to assess the 5-year outcome and disease course of patients with UC in the Epi-IBD cohort. Methods: In a prospective, population-based inception cohort of unselected patients with UC, patients were followed up from the time of their diagnosis, which included the collection of their clinical data, demographics, disease activity, medical therapy, and rates of surgery, cancers, and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis. Results: A total of 717 patients were included in the study. During follow-up, 43 [6%] patients underwent a colectomy and 163 [23%] patients were hospitalised. Of patients with limited colitis [distal to the left flexure], 90 [21%] progressed to extensive colitis. In addition, 92 [27%] patients with extensive colitis experienced a regression in disease extent, which was associated with a reduced risk of hospitalisation (hazard ratio [HR]: 0.5 95% CI: 0.3-0.8]. Overall, patients were treated similarly in both geographical regions; 80 [11%] patients needed biological therapy and 210 [29%] patients received immunomodulators. Treatment with immunomodulators was found to reduce the risk of hospitalisation [HR: 0.5 95% CI: 0.3-0.8]. Conclusions: Although patients in this population-based cohort were treated more aggressively with immunomodulators and biological therapy than in cohorts from the previous two decades, their disease outcomes, including colectomy rates, were no different. However, treatment with immunomodulators was found to reduce the risk of hospitalisation.
Published:
February 1, 2019
Title:
The Metabolic Landscape of Prostate Cancer
Authors:
Giunchi, Francesca; Fiorentino, Michelangelo; Loda, Massimo
Abstract:
Context Neoplastic cells are characterized by metabolic alterations that sustain tumor growth. Interventions aimed at modifying metabolic rewiring of cancer cells are currently being investigated in several tumor types, including prostate cancer (PC). Objective To review relevant metabolic alterations reported for PC and potential diagnostic and therapeutic opportunities that could be exploited on the basis of these discoveries. Evidence acquisition We performed a review of PubMed/Medline in March 2018 for PC in association with each of the following search terms: metabolomics; lipid, cholesterol, one-carbon, amino acid, and glucose metabolism. Fifty publications were selected for inclusion in this analysis. Evidence synthesis The reports included were grouped according to fatty acid and cholesterol metabolism (28 studies); one-carbon metabolism (9 studies); amino acid metabolism (6 studies); and glucose metabolism (7 studies). We report on multiple metabolic pathways that are dysregulated in prostate cancer. Metabolic alterations can result in at least one of the following changes: protein lipidation, oncogene activation, DNA methylation, cellular signaling, and protein-protein interactions. Conclusions Metabolic alterations play a crucial role in PC development, progression, and resistance to therapy. Increasing knowledge of metabolic rewiring is revealing novel metabolic signatures in PC. These signatures could be utilized for PC diagnosis, as well as for the discovery of novel therapeutic interventions to overcome castration resistance. Patient summary Metabolic alterations play a crucial role in the development and progression of prostate cancer and its resistance to therapy. Our knowledge of metabolic rewiring is increasing and revealing novel metabolic signatures in prostate cancer. These signatures could be used for diagnosis and for the discovery of novel therapeutic interventions aimed at overcoming castration resistance.
Published:
February 1, 2019
Title:
Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia
Authors:
Brady, Roscoe O.; Gonsalvez, Irene; Lee, Ivy; Öngür, Dost; Seidman, Larry J.; Schmahmann, Jeremy D.; Eack, Shaun M.; Keshavan, Matcheri S.; Pascual-Leone, Alvaro; Halko, Mark A.
Abstract:
Published:
January 30, 2019
Title:
Musculoskeletal study of cebocephalic and cyclopic lamb heads illuminates links between normal and abnormal development, evolution and human pathologies
Authors:
Diogo, Rui; Razmadze, Daria; Siomava, Natalia; Douglas, Nora; Fuentes, Jose; Duerinckx, Andre
Abstract:
This paper is part of the emerging field of Evolutionary Developmental Pathology, dedicated to study the links between normal and abnormal development, evolution and human pathologies. We analyzed the head musculoskeletal system of several ‘natural mutant’ newborn lambs displaying various degrees of abnormality, from mild defects to cebocephaly and to cyclopia, and compared them with humans. Interestingly, muscle defects are less marked than osteological ones, and contrarily to the latter they tend to display left-right assymetries. In individuals with cebocephalic and even cyclopic skulls almost all head muscles are normal. The very few exceptions are some extraocular muscles and facial muscles that normally attach to osteological structures that are missing in the abnormal heads: such muscles are instead attached to the ‘nearest topological neighbor’ of the missing osteological structure, a pattern also found in cyclopic humans. These observations support Alberch’s ill-named “logic of monsters” - as a byproduct of strong developmental/topological constraints anatomical patterns tend to repeat themselves, even severe malformations displayed by distantly related taxa. They also support the idea that mammalian facial muscles reverted to an ancestral ‘nearest-neighbor’ muscle-bone type of attachment seen in non-vertebrate animals and in vertebrate limbs, but not in other vertebrate head muscles.
Published:
January 30, 2019
Title:
Structure-activity relationship of procyanidins on advanced glycation end products formation and corresponding mechanisms
Authors:
Chen, Yuanyuan; Tang, Shimiao; Chen, Yashu; Zhang, Roujie; Zhou, Mengzhou; Wang, Chao; Feng, Nianjie; Wu, Qian
Abstract:
Nonenzymatic glycosylation (NEG) can generate advanced glycation end products (AGEs) and its intermediates α-dicarbonyl compounds, which contribute to the risk of diabetes. This study investigated the anti-glycation mechanisms and structure–activity relationship of (+)-catechin (CC) and (−)-epicatechin (EC). The results showed that the effect of CC on inhibiting AGEs was significantly better than that of EC (p
Published:
January 30, 2019
Title:
Supplementary Material
Authors:
Diogo, Rui; Razmadze, Daria; Siomava, Natalia; Douglas, Nora; Fuentes, Jose; Duerinckx, Andre
Abstract:
Published:
January 30, 2019
Title:
The adaptor protein melanophilin regulates dynamic myosin-Va:cargo interaction and dendrite development in melanocytes
Authors:
Robinson, Christopher L.; Evans, Richard D.; Sivarasa, Kajana; Ramalho, Jose S.; Briggs, Deborah A.; Hume, Alistair N.
Abstract:
The regulation of organelle transport by the cytoskeleton is fundamental for eukaryotic survival. Cytoskeleton motors are typically modular proteins with conserved motor and diverse cargo-binding domains. Motor:cargo interactions are often indirect and mediated by adaptor proteins, for example, Rab GTPases. Rab27a, via effector melanophilin (Mlph), recruits myosin-Va (MyoVa) to melanosomes and thereby disperses them into melanocyte dendrites. To better understand how adaptors regulate motor:cargo interaction, we used single melanosome fluorescence recovery after photobleaching (smFRAP) to characterize the association kinetics among MyoVa, its adaptors, and melanosomes. We found that MyoVa and Mlph rapidly recovered after smFRAP, whereas Rab27a did not, indicating that MyoVa and Mlph dynamically associate with melanosomes and Rab27a does not. This suggests that dynamic Rab27a:effector interaction rather than Rab27a melanosome:cytosol cycling regulates MyoVa:melanosome association. Accordingly, a Mlph-Rab27a fusion protein reduced MyoVa smFRAP, indicating that it stabilized melanosomal MyoVa. Finally, we tested the functional importance of dynamic MyoVa:melanosome interaction. We found that whereas a MyoVa-Rab27a fusion protein dispersed melanosomes in MyoVa-deficient cells, dendrites were significantly less elongated than in wild-type cells. Given that dendrites are the prime sites of melanosome transfer from melanocytes to keratinocytes, we suggest that dynamic MyoVa:melanosome interaction is important for pigmentation in vivo.
Published:
January 30, 2019
Title:
Ketogenic Diet and Epilepsy: What We Know So Far
Authors:
D’Andrea Meira, Isabella; Romão, Tayla Taynan; Pires do Prado, Henrique Jannuzzelli; Krüger, Lia Theophilo; Pires, Maria Elisa Paiva; da Conceição, Priscila Oliveira
Abstract:
The Ketogenic Diet (KD) is a modality of treatment used since the 1920s as a treatment for intractable epilepsy. It has been proposed as a dietary treatment that would produce similar benefits to fasting, which is already recorded in the Hippocratic collection. The KD has a high fat content (90%) and low protein and carbohydrate. Evidence shows that KD and its variants are a good alternative for non-surgical pharmacoresistant patients with epilepsy of any age, taking into account that the type of diet should be designed individually and that less-restrictive and more-palatable diets are usually better options for adults and adolescents. This review discusses the KD, including the possible mechanisms of action, applicability, side effects, and evidence for its efficacy, and for the more-palatable diets such as the Modified Atkins Diet (MAD) and the Low Glycemic Index Diet (LGID) in children and adults.
Published:
January 29, 2019
Title:
Comparing patterns of volatile organic compounds exhaled in breath after consumption of two infant formulae with a different lipid structure: a randomized trial
Authors:
Smolinska, A.; Baranska, A.; Dallinga, J. W.; Mensink, R. P.; Baumgartner, S.; van de Heijning, B. J. M.; van Schooten, F. J.
Abstract:
Infant formulae have been used since decades as an alternative to or a complement to human milk. Human milk, the "gold standard" of infant nutrition, has been studied for its properties in order to create infant formulae that bring similar benefits to the infant. One of the characteristics of milk is the size of the lipid droplets which is known to affect the digestion, gastric emptying and triglyceride metabolism. In the current study a concept infant milk formula with large, phospholipid coating of lipid droplets (mode diameter 3-5 μm; NUTURIS, further described as "active"), was compared to a commercially available formula milk characterised by smaller lipid droplets, further described as "control" (both products derived from Nutricia). We investigated whether we could find an effect of lipid droplet size on volatile compounds in exhaled air upon ingestion of either product. For that purpose, exhaled breath was collected from a group of 29 healthy, non-smoking adult males before ingestion of a study product (baseline measurements, T0) and at the following time points after the test meal: 30, 60, 120, 180 and 240 min. Volatile organic compounds (VOCs) in breath were detected by gas chromatography-time-of-flight-mass spectrometry. Any differences in the time course of VOCs patterns upon intake of active and control products were investigated by regularised multivariate analysis of variance (rMANOVA). The rMANOVA analysis revealed statistically significant differences in the exhaled breath composition 240 min after ingestion of the active formula compared to control product (p-value < 0.0001), but did not show significant changes between active and control product at any earlier time points. A set of eight VOCs in exhaled breath had the highest contribution to the difference found at 240 minutes between the two formulas. A set of ten VOCs was different between baseline and the two formulae at T240 with p-value
Published:
January 24, 2019
Title:
Evolution of Chordate Cardiopharyngeal Muscles and the Origin of Vertebrate Head Muscles
Authors:
Ziermann, Janine; Diogo, Rui
Abstract:
Recent findings that urochordates are the closest sister-group of vertebrates have dramatically changed our understanding of chordate evolution and of the origin of the vertebrate head and its muscles. To better understand the evolution and diversity of chordates, in particular the morphological and taxonomical diversity of the vertebrates, it is crucial to investigate the origin, development and comparative anatomy of not only hard tissues, but also of soft tissues such as muscles. Building on the recent discovery of the cardiopharyngeal field in urochordates and on the comparative anatomy of chordate and vertebrate muscles, in this chapter we focus on the broader comparative and developmental anatomy of chordate muscles and the origin of vertebrate cephalic muscles.
Published:
January 24, 2019
Title:
Heads, Jaws, and Muscles - Anatomical, Functional, and Developmental Diversity in Chordate Evolution
Authors:
Ziermann, Janine; Diaz, Raul; Diogo, Rui
Abstract:
The vertebrate head is the most complex part of the animal body and its diversity in nature reflects a variety of life styles, feeding modes, and ecological adaptations. This book will take you on a journey to discover the origin and diversification of the head, which evolved from a seemingly headless chordate ancestor. Despite their structural diversity, heads develop in a highly conserved fashion in embryos. Major sensory organs like the eyes, ears, nose, and brain develop in close association with surrounding tissues such as bones, cartilages, muscles, nerves, and blood vessels. Ultimately, this integrated unit of tissues gives rise to the complex functionality of the musculoskeletal system as a result of sensory and neural feedback, most notably in the use of the vertebrate jaws, a major vertebrate innovation only lacking in hagfishes and lampreys. The cranium subsequently further diversified during the major transition from fishes living in an aquatic environment to tetrapods living mostly on land. In this book, experts will join forces to integrate, for the first time, state-of-the-art knowledge on the anatomy, development, function, diversity, and evolution of the head and jaws and their muscles within all major groups of extant vertebrates. Considerations about and comparisons with fossil taxa, including emblematic groups such as the dinosaurs, are also provided in this landmark book, which will be a leading reference for many years to come.
Published:
January 24, 2019
Title:
IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling
Authors:
Sheng, Xia; Nenseth, Hatice Zeynep; Qu, Su; Kuzu, Omer F.; Frahnow, Turid; Simon, Lukas; Greene, Stephanie; Zeng, Qingping; Fazli, Ladan; Rennie, Paul S.; Mills, Ian G.; Danielsen, Håvard; Theis, Fabian; Patterson, John B.; Jin, Yang; Saatcioglu, Fahri
Abstract:
ER stress and UPR are implicated in various cancers. Here, the authors show that one of the canonical UPR pathways, IRE1α-XBP1 regulates c-MYC signaling to promote prostate tumorigenesis, and pharmacological inhibition of IRE1α with MKC8866 inhibits prostate cancer growth and synergizes with clinically used prostate cancer drugs.
Published:
January 24, 2019
Title:
Prostate Stroma Increases the Viability and Maintains the Branching Phenotype of Human Prostate Organoids
Authors:
Richards, Zachary; McCray, Tara; Marsili, Joseph; Zenner, Morgan L.; Manlucu, Jacob T.; Garcia, Jason; Kajdacsy-Balla, Andre; Murray, Marcus; Voisine, Cindy; Murphy, Adam B.; Abdulkadir, Sarki A.; Prins, Gail S.; Nonn, Larisa
Abstract:
The fibromuscular stroma of the prostate regulates normal epithelial differentiation and contributes to carcinogenesis in vivo. We developed and characterized a human 3D prostate organoid co-culture model that incorporates prostate stroma. Primary prostate stromal cells increased organoid formation and directed organoid morphology into a branched acini structure similar to what is observed in vivo. Organoid branching occurred distal to physical contact with stromal cells, demonstrating non-random branching. Stroma-induced phenotypes were similar in all patients examined, yet they maintained inter-patient heterogeneity in the degree of response. Stromal cells expressed growth factors involved in epithelial differentiation, which was not observed in non-prostatic fibroblasts. Organoids derived from areas of prostate cancer maintained differential expression of alpha-methylacyl-CoA racemase and showed increased viability and passaging when co-cultured with stroma. The addition of stroma to epithelial cells in vitro improves the ability of organoids to recapitulate features of the tissue and enhances the viability of organoids., • Co-culture with human primary prostate stroma improves epithelial organoid viability • Stromal cell contact in co-culture directs epithelial organoid branching • Prostate stromal cells express morphogenic factors unique from non-prostate fibroblasts • Co-culture with stroma maintains AMACR and increases survival of cancer derived-organoids , Bioengineering; Biological Sciences; Cell Biology; Tissue Engineering
Published:
January 23, 2019
Title:
Dietary Advanced Glycation End Products: Digestion, Metabolism and Modulation of Gut Microbial Ecology
Authors:
Snelson, Matthew; Coughlan, Melinda T.
Abstract:
The formation of advanced glycation end products (AGEs) in foods is accelerated with heat treatment, particularly within foods that are cooked at high temperatures for long periods of time using dry heat. The modern processed diet is replete with AGEs, and excessive AGE consumption is thought to be associated with a number of negative health effects. Many dietary AGEs have high molecular weight and are not absorbed in the intestine, and instead pass through to the colon, where they are available for metabolism by the colonic bacteria. Recent studies have been conducted to explore the effects of AGEs on the composition of the gut microbiota as well as the production of beneficial microbial metabolites, in particular, short-chain fatty acids. However, there is conflicting evidence regarding the impact of dietary AGEs on gut microbiota reshaping, which may be due, in part, to the formation of alternate compounds during the thermal treatment of foods. This review summarises the current evidence regarding dietary sources of AGEs, their gastrointestinal absorption and role in gut microbiota reshaping, provides a brief overview of the health implications of dietary AGEs and highlights knowledge gaps and avenues for future study.
Published:
January 22, 2019
Title:
Effect of a Low Free Sugar Diet vs Usual Diet on Nonalcoholic Fatty Liver Disease in Adolescent Boys: A Randomized Clinical Trial
Authors:
Schwimmer, Jeffrey B.; Ugalde-Nicalo, Patricia; Welsh, Jean A.; Angeles, Jorge E.; Cordero, Maria; Harlow, Kathryn E.; Alazraki, Adina; Durelle, Janis; Knight-Scott, Jack; Newton, Kimberly P.; Cleeton, Rebecca; Knott, Cynthia; Konomi, Juna; Middleton, Michael S.; Travers, Curtis; Sirlin, Claude B.; Hernandez, Albert; Sekkarie, Ahlia; McCracken, Courtney; Vos, Miriam B.
Abstract:
Importance
Pediatric guidelines for the management of nonalcoholic fatty liver disease (NAFLD) recommend a healthy diet as treatment. Reduction of sugary foods and beverages is a plausible but unproven treatment.
Objective
To determine the effects of a diet low in free sugars (those sugars added to foods and beverages and occurring naturally in fruit juices) in adolescent boys with NAFLD.
Design, Setting, and Participants
An open-label, 8-week randomized clinical trial of adolescent boys aged 11 to 16 years with histologically diagnosed NAFLD and evidence of active disease (hepatic steatosis >10% and alanine aminotransferase level ≥45 U/L) randomized 1:1 to an intervention diet group or usual diet group at 2 US academic clinical research centers from August 2015 to July 2017; final date of follow-up was September 2017.
Interventions
The intervention diet consisted of individualized menu planning and provision of study meals for the entire household to restrict free sugar intake to less than 3% of daily calories for 8 weeks. Twice-weekly telephone calls assessed diet adherence. Usual diet participants consumed their regular diet.
Main Outcomes and Measures
The primary outcome was change in hepatic steatosis estimated by magnetic resonance imaging proton density fat fraction measurement between baseline and 8 weeks. The minimal clinically important difference was assumed to be 4%. There were 12 secondary outcomes, including change in alanine aminotransferase level and diet adherence.
Results
Forty adolescent boys were randomly assigned to either the intervention diet group or the usual diet group (20 per group; mean [SD] age, 13.0 [1.9] years; most were Hispanic [95%]) and all completed the trial. The mean decrease in hepatic steatosis from baseline to week 8 was significantly greater for the intervention diet group (25% to 17%) vs the usual diet group (21% to 20%) and the adjusted week 8 mean difference was −6.23% (95% CI, −9.45% to −3.02%;P < .001). Of the 12 prespecified secondary outcomes, 7 were null and 5 were statistically significant including alanine aminotransferase level and diet adherence. The geometric mean decrease in alanine aminotransferase level from baseline to 8 weeks was significantly greater for the intervention diet group (103 U/L to 61 U/L) vs the usual diet group (82 U/L to 75 U/L) and the adjusted ratio of the geometric means at week 8 was 0.65 U/L (95% CI, 0.53 to 0.81 U/L;P < .001). Adherence to the diet was high in the intervention diet group (18 of 20 reported intake of <3% of calories from free sugar during the intervention). There were no adverse events related to participation in the study.
Conclusions and Relevance
In this study of adolescent boys with NAFLD, 8 weeks of provision of a diet low in free sugar content compared with usual diet resulted in significant improvement in hepatic steatosis. However, these findings should be considered preliminary and further research is required to assess long-term and clinical outcomes.
Trial Registration
ClinicalTrials.gov Identifier:NCT02513121
Published:
January 22, 2019
Title:
What Is Prostate Cancer? | CDC
Authors:
Abstract:
Cancer is a disease in which cells in the body grow out of control. When cancer starts in the prostate, it is called prostate cancer.
Published:
January 22, 2019
Title:
Extracellular Vesicle-Mediated Cell⁻Cell Communication in the Nervous System: Focus on Neurological Diseases
Authors:
Caruso Bavisotto, Celeste; Scalia, Federica; Marino Gammazza, Antonella; Carlisi, Daniela; Bucchieri, Fabio; Conway de Macario, Everly; Macario, Alberto J. L.; Cappello, Francesco; Campanella, Claudia
Abstract:
Extracellular vesicles (EVs), including exosomes, are membranous particles released by cells into the extracellular space. They are involved in cell differentiation, tissue homeostasis, and organ remodelling in virtually all tissues, including the central nervous system (CNS). They are secreted by a range of cell types and via blood reaching other cells whose functioning they can modify because they transport and deliver active molecules, such as proteins of various types and functions, lipids, DNA, and miRNAs. Since they are relatively easy to isolate, exosomes can be characterized, and their composition elucidated and manipulated by bioengineering techniques. Consequently, exosomes appear as promising theranostics elements, applicable to accurately diagnosing pathological conditions, and assessing prognosis and response to treatment in a variety of disorders. Likewise, the characteristics and manageability of exosomes make them potential candidates for delivering selected molecules, e.g., therapeutic drugs, to specific target tissues. All these possible applications are pertinent to research in neurophysiology, as well as to the study of neurological disorders, including CNS tumors, and autoimmune and neurodegenerative diseases. In this brief review, we discuss what is known about the role and potential future applications of exosomes in the nervous system and its diseases, focusing on cell⁻cell communication in physiology and pathology.
Published:
January 20, 2019
Title:
Efficacy and safety of exogenous ketone bodies for preventive treatment of migraine: A study protocol for a single-centred, randomised, placebo-controlled, double-blind crossover trial
Authors:
Gross, Elena; Putananickal, Niveditha; Orsini, Anna-Lena; Schmidt, Simone; Vogt, Deborah R.; Cichon, Sven; Sandor, Peter; Fischer, Dirk
Abstract:
BACKGROUND: Currently available prophylactic migraine treatment options are limited and are associated with many, often intolerable, side-effects. Various lines of research suggest that abnormalities in energy metabolism are likely to be part of migraine pathophysiology. Previously, a ketogenic diet (KD) has been reported to lead to a drastic reduction in migraine frequency. An alternative method to a strict KD is inducing a mild nutritional ketosis (0.4-2 mmol/l) with exogenous ketogenic substances. The aim of this randomised, placebo-controlled, double-blind, crossover, single-centre trial is to demonstrate safety and superiority of beta-hydroxybutyrate (βHB) in mineral salt form over placebo in migraine prevention. METHODS/DESIGN: Forty-five episodic migraineurs (5-14 migraine days/months), with or without aura, aged between 18 and 65 years, will be recruited at headache clinics in Switzerland, Germany and Austria and via Internet announcements. After a 4-week baseline period, patients will be randomly allocated to one of the two trial arms and receive either the βHB mineral salt or placebo for 12 weeks. This will be followed by a 4-week wash-out period, a subsequent second baseline period and, finally, another 12-week intervention with the alternative treatment. Co-medication with triptans (10 days per months) or analgesics (14 days per months) is permitted. The primary outcome is the mean change from baseline in the number of migraine days (meeting International Classification of Headache Disorders version 3 criteria) during the last 4 weeks of intervention compared to placebo. Secondary endpoints include mean changes in headache days of any severity, acute migraine medication use, migraine intensity and migraine and headache-related disability. Exploratory outcomes are (in addition to routine laboratory analysis) genetic profiling and expression analysis, oxidative and nitrosative stress, as well as serum cytokine analysis, and blood βHB and glucose analysis (pharmacokinetics). DISCUSSION: A crossover design was chosen as it greatly improves statistical power and participation rates, without increasing costs. To our knowledge this is the first RCT using βHB salts worldwide. If proven effective and safe, βHB might not only offer a new prophylactic treatment option for migraine patients, but might additionally pave the way for clinical trials assessing its use in related diseases. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03132233 . Registered on 27 April 2017.
Published:
January 17, 2019
Title:
Handling and Assessment of Human Primary Prostate Organoid Culture
Authors:
McCray, Tara; Richards, Zachary; Marsili, Joseph; Prins, Gail S.; Nonn, Larisa
Abstract:
This paper describes a detailed protocol for three-dimensional (3D) culturing, handling, and evaluation of human primary prostate organoids. The process involves seeding of epithelial cells sparsely in a 3D matrix gel on a 96-well microplate with media changes to cultivate expansion into organoids. Morphology is then assessed by whole-well capturing of z-stack images. Compression of z-stacks creates a single in-focus image from which organoids are measured to quantify a variety of outputs, including circularity, roundness, and area.DNA, RNA, and protein can be collected from organoids recovered from the matrix gel. Cell populations of interest can be assessed by organoid dissociation and flow cytometry. Formalin-fixation-paraffin-embedding (FFPE) followed by sectioning is used for the histological assessment and antibody staining. Whole-mount immunofluorescent staining preserves organoid morphology and facilitates observation of protein localization in organoids in situ. Commercial assays that are traditionally used for 2D monolayer cells can be modified for 3D organoids. Used together, the techniques in this protocol provide a robust toolbox to quantify prostate organoid growth, morphologic characteristics, and expression of differentiation markers.
Published:
January 17, 2019
Title:
Novel strategies for clinical investigation and biomarker discovery: a guide to applied metabolomics
Authors:
Carneiro, Gabriel; Radcenco, Andres Lopez; Evaristo, Joseph; Monnerat, Gustavo
Abstract:
Metabolomics is an emerging technology that is increasing both in basic science and in human applications, providing a physiological snapshot. It has been highlighted as one of the most wide ranging and reliable tools for the investigation of physiological status, the discovery of new biomarkers and the analysis of metabolic pathways. Metabolomics uses innovative mass spectrometry (MS) allied to chromatography or nuclear magnetic resonance (NMR). The recent advances in bioinformatics, databases and statistics, have provided a unique perception of metabolites interaction and the dynamics of metabolic pathways at a system level. In this context, several studies have applied metabolomics in physiology- and disease-related works. The application of metabolomics includes, physiological and metabolic evaluation/monitoring, individual response to different exercise, nutritional interventions, pathological processes, responses to pharmacological interventions, biomarker discovery and monitoring for distinct aspects, such as: physiological capacity, fatigue/recovery and aging among other applications. For metabolomic analyses, despite huge improvements in the field, several complex methodological steps must be taken into consideration. In this regard, the present article aims to summarize the novel aspects of metabolomics and provide a guide for metabolomics for professionals related to physiologist and medical applications.
Published:
January 17, 2019
Title:
MicroRNAs and other non-coding RNAs in adipose tissue and obesity: emerging roles as biomarkers and therapeutic targets
Authors:
Lorente-Cebrián, Silvia; González-Muniesa, Pedro; Milagro, Fermín I.; Martínez, J. Alfredo
Abstract:
Obesity is a metabolic condition usually accompanied by insulin resistance (IR), type 2 diabetes (T2D), and dyslipidaemia, which is characterised by excessive fat accumulation and related to white adipose tissue (WAT) dysfunction. Enlargement of WAT is associated with a transcriptional alteration of coding and non-coding RNAs (ncRNAs). For many years, big efforts have focused on understanding protein-coding RNAs and their involvement in the regulation of adipocyte physiology and subsequent role in obesity. However, diverse findings have suggested that a dysfunctional adipocyte phenotype in obesity might be also dependent on specific alterations in the expression pattern of ncRNAs, such as miRNAs. The aim of this review is to update current knowledge on the physiological roles of miRNAs and other ncRNAs in adipose tissue function and their potential impact on obesity. Therefore, we examined their regulatory role on specific WAT features: adipogenesis, adipokine secretion, inflammation, glucose metabolism, lipolysis, lipogenesis, hypoxia and WAT browning. MiRNAs can be released to body fluids and can be transported (free or inside microvesicles) to other organs, where they might trigger metabolic effects in distant tissues, thus opening new possibilities to a potential use of miRNAs as biomarkers for diagnosis, prognosis, and personalisation of obesity treatment. Understanding the role of miRNAs also opens the possibility of using these molecules on individualised dietary strategies for precision weight management. MiRNAs should be envisaged as a future therapeutic approach given that miRNA levels could be modulated by synthetic molecules (f.i. miRNA mimics and inhibitors) and/or specific nutrients or bioactive compounds.
Published:
January 15, 2019
Title:
Nutrition, the visceral immune system, and the evolutionary origins of pathogenic obesity
Authors:
West-Eberhard, Mary Jane
Abstract:
The global obesity epidemic is the subject of an immense, diversely specialized research effort. An evolutionary analysis reveals connections among disparate findings, starting with two well-documented facts: Obesity-associated illnesses (e.g., type-2 diabetes and cardiovascular disease), are especially common in: ( i ) adults with abdominal obesity, especially enlargement of visceral adipose tissue (VAT), a tissue with important immune functions; and ( ii ) individuals with poor fetal nutrition whose nutritional input increases later in life. I hypothesize that selection favored the evolution of increased lifelong investment in VAT in individuals likely to suffer lifelong malnutrition because of its importance in fighting intraabdominal infections. Then, when increased nutrition violates the adaptive fetal prediction of lifelong nutritional deficit, preferential VAT investment could contribute to abdominal obesity and chronic inflammatory disease. VAT prioritization may help explain several patterns of nutrition-related disease: the paradoxical increase of chronic disease with increased food availability in recently urbanized and migrant populations; correlations between poor fetal nutrition, improved childhood (catch-up) growth, and adult metabolic syndrome; and survival differences between children with marasmus and kwashiorkor malnutrition. Fats and sugars can aggravate chronic inflammation via effects on intestinal bacteria regulating gut permeability to visceral pathogens. The extremes in a nutrition-sensitive trade-off between visceral (immune-function) vs. subcutaneous (body shape) adiposity may have been favored by selection in highly stratified premedicine societies. Altered adipose allocation in populations with long histories of social stratification and malnutrition may be the result of genetic accommodation of developmental responses to poor maternal/fetal conditions, increasing their vulnerability to inflammatory disease.
Published:
January 15, 2019
Title:
Colorectal Cancer and Nutrition
Authors:
Thanikachalam, Kannan; Khan, Gazala
Abstract:
Colorectal Cancer is the third most common cancer diagnosed in the US. While the incidence and the mortality rate of colorectal cancer has decreased due to effective cancer screening measures, there has been an increase in number of young patients diagnosed in colon cancer due to unclear reasons at this point of time. While environmental and genetic factors play a major role in the pathogenesis of colon cancer, extensive research has suggested that nutrition may play both a causal and protective role in the development of colon cancer. In this review article, we aim to provide a review of factors that play a major role in development of colorectal cancer.
Published:
January 14, 2019
Title:
Bacterial and viral pathogen-associated molecular patterns induce divergent early transcriptomic landscapes in a bovine macrophage cell line
Authors:
Toka, Felix N.; Dunaway, Kiera; Smaltz, Felicia; Szulc-Dąbrowska, Lidia; Drnevich, Jenny; Mielcarska, Matylda Barbara; Bossowska-Nowicka, Magdalena; Schweizer, Matthias
Abstract:
BACKGROUND: Pathogens stimulate immune functions of macrophages. Macrophages are a key sentinel cell regulating the response to pathogenic ligands and orchestrating the direction of the immune response. Our study aimed at investigating the early transcriptomic changes of bovine macrophages (Bomacs) in response to stimulation with CpG DNA or polyI:C, representing bacterial and viral ligands respectively, and performed transcriptomics by RNA sequencing (RNASeq). KEGG, GO and IPA analytical tools were used to reconstruct pathways, networks and to map out molecular and cellular functions of differentially expressed genes (DE) in stimulated cells. RESULTS: A one-way ANOVA analysis of RNASeq data revealed significant differences between the CpG DNA and polyI:C-stimulated Bomac. Of the 13,740 genes mapped to the bovine genome, 2245 had p-value ≤0.05, deemed as DE. At 6 h post stimulation of Bomac, poly(I:C) induced a very different transcriptomic profile from that induced by CpG DNA. Whereas, 347 genes were upregulated and 210 downregulated in response to CpG DNA, poly(I:C) upregulated 761 genes and downregulated 414 genes. The topmost DE genes in poly(I:C)-stimulated cells had thousand-fold changes with highly significant p-values, whereas in CpG DNA stimulated cells had 2-5-fold changes with less stringent p-values. The highest DE genes in both stimulations belonged to the TNF superfamily, TNFSF18 (CpG) and TNFSF10 (poly(I:C)) and in both cases the lowest downregulated gene was CYP1A1. CpG DNA highly induced canonical pathways that are unrelated to immune response in Bomac. CpG DNA influenced expression of genes involved in molecular and cellular functions in free radical scavenging. By contrast, poly(I:C) highly induced exclusively canonical pathways directly related to antiviral immune functions mediated by interferon signalling genes. The transcriptomic profile after poly(I:C)-stimulation was consistent with induction of TLR3 signalling. CONCLUSION: CpG DNA and poly(I:C) induce different early transcriptional landscapes in Bomac, but each is suited to a specific function of macrophages during interaction with pathogens. Poly(I:C) influenced antiviral response genes, whereas CpG DNA influenced genes important for phagocytic processes. Poly(I:C) was more potent in setting the inflammatory landscape desirable for an efficient immune response against virus infection.
Published:
January 8, 2019
Title:
Preserving Insulin Secretion in Diabetes by Inhibiting VDAC1 Overexpression and Surface Translocation in β Cells
Authors:
Zhang, Enming; Mohammed Al-Amily, Israa; Mohammed, Sarheed; Luan, Cheng; Asplund, Olof; Ahmed, Meftun; Ye, Yingying; Ben-Hail, Danya; Soni, Arvind; Vishnu, Neelanjan; Bompada, Pradeep; De Marinis, Yang; Groop, Leif; Shoshan-Barmatz, Varda; Renström, Erik; Wollheim, Claes B.; Salehi, Albert
Abstract:
Type 2 diabetes (T2D) develops after years of prediabetes during which high glucose (glucotoxicity) impairs insulin secretion. We report that the ATP-conducting mitochondrial outer membrane voltage-dependent anion channel-1 (VDAC1) is upregulated in islets from T2D and non-diabetic organ donors under glucotoxic conditions. This is caused by a glucotoxicity-induced transcriptional program, triggered during years of prediabetes with suboptimal blood glucose control. Metformin counteracts VDAC1 induction. VDAC1 overexpression causes its mistargeting to the plasma membrane of the insulin-secreting β cells with loss of the crucial metabolic coupling factor ATP. VDAC1 antibodies and inhibitors prevent ATP loss. Through direct inhibition of VDAC1 conductance, metformin, like specific VDAC1 inhibitors and antibodies, restores the impaired generation of ATP and glucose-stimulated insulin secretion in T2D islets. Treatment of db/db mice with VDAC1 inhibitor prevents hyperglycemia, and maintains normal glucose tolerance and physiological regulation of insulin secretion. Thus, β cell function is preserved by targeting the novel diabetes executer protein VDAC1.
Published:
January 8, 2019
Title:
Efficacy of inpatient psychotherapy for major depressive disorder: a meta-analysis of controlled trials
Authors:
Schefft, C.; Guhn, A.; Brakemeier, E.-L.; Sterzer, P.; Köhler, S.
Abstract:
Objective: This meta-analysis investigates the efficacy of inpatient psychotherapy in major depressive disorders compared to control conditions. Methods: In total, 14 studies were entered into the meta-analysis with a total of 1.080 patients. Primary outcome was the standardized mean differences in self-rated depression outcomes. A priori planned subgroup analyses included the influence of different control conditions: (a) no psychiatric inpatient treatment (e.g., waitlist control), (b) treatment as usual (TAU; e.g., non-manualized clinical management), (c) TAU determined by study design (manualized/’placebo’ control condition), as well as number of sessions and influence of self- vs. clinician ratings. Results: The meta-analysis of 19 available comparisons resulted in a moderate pooled effect size showing a small and statistically significant benefit of the psychotherapeutic intervention over control conditions (g = 0.24, P < 0.001, I2 = 0%). This corresponds to a number needed to treat of 7.4. The effects of the interventions were stable over 12month follow-up (g = 0.21, P
Published:
January 6, 2019
Title:
Safety, health improvement and well-being during a 4 to 21-day fasting period in an observational study including 1422 subjects
Authors:
Toledo, Françoise Wilhelmi de; Grundler, Franziska; Bergouignan, Audrey; Drinda, Stefan; Michalsen, Andreas
Abstract:
Only few studies document longer periods of fasting in large cohorts including non-obese participants. The aim of this study was to document prospectively the safety and any changes in basic health and well-being indicators during Buchinger periodic fasting within a specialised clinic. In a one-year observational study 1422 subjects participated in a fasting program consisting of fasting periods of between 4 and 21 days. Subjects were grouped in fasting period lengths of 5, 10, 15 and 20±2 days. The participants fasted according to the Buchinger guidelines with a daily caloric intake of 200–250 kcal accompanied by a moderate-intensity lifestyle program. Clinical parameters as well as adverse effects and well-being were documented daily. Blood examinations before and at the end of the fasting period complemented the pre-post analysis using mixed-effects linear models. Significant reductions in weight, abdominal circumference and blood pressure were observed in the whole group (each p<0.001). A beneficial modulating effect of fasting on blood lipids, glucoregulation and further general health-related blood parameters was shown. In all groups, fasting led to a decrease in blood glucose levels to low norm range and to an increase in ketone bodies levels (each p<0.001), documenting the metabolic switch. An increase in physical and emotional well-being (each p
Published:
January 2, 2019
Title:
l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Authors:
Koeth, Robert A.; Lam-Galvez, Betzabe Rachel; Kirsop, Jennifer; Zeneng Wang; Levison, Bruce S.; Xiaodong Gu; Copeland, Matthew F.; Bartlett, David; Cody, David B.; Dai, Hong J.; Culley, Miranda K.; Li, Xinmin S.; Xiaoming Fu; Yuping Wu; Lin Li; DiDonato, Joseph A.; Tang, W. H. Wilson; Garcia-Garcia, Jose Carlos; Hazen, Stanley L.; Wang, Zeneng
Abstract:
Background: l-Carnitine, an abundant nutrient in red meat, accelerates atherosclerosis in mice via gut microbiota-dependent formation of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) via a multistep pathway involving an atherogenic intermediate, γ-butyrobetaine (γBB). The contribution of γBB in gut microbiota-dependent l-carnitine metabolism in humans is unknown.Methods: Omnivores and vegans/vegetarians ingested deuterium-labeled l-carnitine (d3-l-carnitine) or γBB (d9-γBB), and both plasma metabolites and fecal polymicrobial transformations were examined at baseline, following oral antibiotics, or following chronic (≥2 months) l-carnitine supplementation. Human fecal commensals capable of performing each step of the l-carnitine→γBB→TMA transformation were identified.Results: Studies with oral d3-l-carnitine or d9-γBB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal l-carnitine→γBB→TMA→TMAO pathway in subjects. Moreover, a striking increase in d3-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral d3-l-carnitine ingestion, whereas fasting endogenous plasma l-carnitine and γBB levels were similar in vegans/vegetarians (n = 32) versus omnivores (n = 40). Fecal metabolic transformation studies, and oral isotope tracer studies before versus after chronic l-carnitine supplementation, revealed that omnivores and vegans/vegetarians alike rapidly converted carnitine to γBB, whereas the second gut microbial transformation, γBB→TMA, was diet inducible (l-carnitine, omnivorous). Extensive anaerobic subculturing of human feces identified no single commensal capable of l-carnitine→TMA transformation, multiple community members that converted l-carnitine to γBB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted γBB to TMA. In coculture, E. timonensis promoted the complete l-carnitine→TMA transformation.Conclusion: In humans, dietary l-carnitine is converted into the atherosclerosis- and thrombosis-promoting metabolite TMAO via 2 sequential gut microbiota-dependent transformations: (a) initial rapid generation of the atherogenic intermediate γBB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota γBB→TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic l-carnitine exposure.Trial Registration: ClinicalTrials.gov NCT01731236.Funding: NIH and Office of Dietary Supplements grants HL103866, HL126827, and DK106000, and the Leducq Foundation.
Published:
January 2, 2019
Title:
A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1α-SIRT3-UCP2 Axis
Authors:
Hasan-Olive, Md Mahdi; Lauritzen, Knut H.; Ali, Mohammad; Rasmussen, Lene Juel; Storm-Mathisen, Jon; Bergersen, Linda H.
Abstract:
A ketogenic diet (KD; high-fat, low-carbohydrate) can benefit refractory epilepsy, but underlying mechanisms are unknown. We used mice inducibly expressing a mutated form of the mitochondrial DNA repair enzyme UNG1 (mutUNG1) to cause progressive mitochondrial dysfunction selectively in forebrain neurons. We examined the levels of mRNAs and proteins crucial for mitochondrial biogenesis and dynamics. We show that hippocampal pyramidal neurons in mutUNG1 mice, as well as cultured rat hippocampal neurons and human fibroblasts with H2O2 induced oxidative stress, improve markers of mitochondrial biogenesis, dynamics and function when fed on a KD, and when exposed to the ketone body β-hydroxybutyrate, respectively, by upregulating PGC1α, SIRT3 and UCP2, and (in cultured cells) increasing the oxygen consumption rate (OCR) and the NAD+/NADH ratio. The mitochondrial level of UCP2 was significantly higher in the perikarya and axon terminals of hippocampus CA1 pyramidal neurons in KD treated mutUNG1 mice compared with mutUNG1 mice fed a standard diet. The β-hydroxybutyrate receptor GPR109a (HCAR2), but not the structurally closely related lactate receptor GPR81 (HCAR1), was upregulated in mutUNG1 mice on a KD, suggesting a selective influence of KD on ketone body receptor mechanisms. We conclude that progressive mitochondrial dysfunction in mutUNG1 expressing mice causes oxidative stress, and that exposure of animals to KD, or of cells to ketone body in vitro, elicits compensatory mechanisms acting to augment mitochondrial mass and bioenergetics via the PGC1α-SIRT3-UCP2 axis (The compensatory processes are overwhelmed in the mutUNG1 mice by all the newly formed mitochondria being dysfunctional).
Published:
January 1, 2019
Title:
Association of RAGE gene four single nucleotide polymorphisms with the risk, invasion, metastasis and overall survival of gastric cancer in Chinese
Authors:
Hu, Dan; Liu, Qing; Lin, Xiandong; Zhang, Hejun; Lin, Jinxiu; Zheng, Xiongwei; Peng, Feng
Abstract:
Objectives: The receptor for advanced glycation end products (RAGE) is an oncogenic trans-membranous receptor expressed in many cells. The aim of this study was to clarify the association between RAGE gene 4 single nucleotide polymorphisms (SNPs) and the risk, invasion, metastasis and overall survival of gastric cancer., Methods and Results: We performed a hospital-based case-control study involving 369 gastric cancer patients and 493 cancer free controls. Four widely-studied SNPs, rs1800625 (T-429C), rs1800624 (T-374A), rs2070600 (Gly82Ser) and rs184003 (G1704T) in RAGE gene, were genotyped by the polymerase chain reaction - ligase detection reaction method. The RAGE gene rs1800625 TT genotype and T allele were significantly associated with a reduced risk of gastric cancer (TT vs. CC: adjusted odds ratio [OR]: 0.72, 95% CI: 0.55-0.95, p=0.021; T vs. C: adjusted OR: 0.67, 95% CI: 0.46-0.97, p=0.032). No hints of significance were detected for the other three SNPs in association with gastric cancer risk. Moreover, rs1800625 and rs184003 were significantly associated with tumor clinical stage (p=0.010 and 0.032, respectively). Survival curves differed significantly between the genotypes of rs1800625., Conclusions: RAGE gene SNP rs1800625 was significantly associated with gastric cancer risk, and rs1800625 and rs184003 were related to tumor clinical stage, indicating that RAGE gene may be a gastric cancer-susceptibility gene.
Published:
January 1, 2019
Title:
Chapter 5 - Evolutionary Diet and Evolution of Man
Authors:
Juneja, Lekh R.; Wilczynska, Agnieszka; Singh, Ram B.; Takahashi, Toru; Pella, Dominik; Chibisov, Sergey; Abramova, Maria; Hristova, Krasimira; Fedacko, Jan; Pella, Daniel; Wilson, Douglas W.
Abstract:
The evolutionary dietary patterns were characterized with wild plant foods, honey, egg, fish, and meat from running animals. The dietary intakes in Paleolithic Homo erectus, hunter-gatherers compared to Western populations, show significant differences which may be because of education, knowledge, and technological developments. With an increase in wealth and affluence, there is a decrease in the intake of omega-3 fatty acids, vitamins, antioxidants, and essential and nonessential amino acids and a significant increase in the intakes of refined carbohydrates, fat (saturated, trans fat, and linoleic acid), and salt compared to the Paleolithic period. The protein or amino acid intake was 2.5-fold greater (33% vs 13%) in the Paleolithic diet of Homo erectus compared to the modern Western diet. Prior to the Agricultural Revolution, our diet was based on an enormous variety of wild plants, eggs, fish, and seeds. However, today about 17% of plant species provide 90% of the world’s food supply which is mainly contributed by fertilizer-based rapidly grown crops of grains which may result in a decrease in nutrient density and increase in energy. The majority of the grains are high in omega-6 fatty acids and carbohydrates and low in omega-3 fatty acids and antioxidants compared to leafy green vegetables. The diets of Homo sapiens and Homo erectus populations were characterized by higher intakes of functional foods, high in protective nutrients such as potassium, magnesium, calcium, flavonoids, and omega-3 fatty acids as well as essential and nonessential amino acids. The modern Western diets are characterized with high saturated fat, omega-6 fat, and trans fat, and excess of energy-rich refined carbohydrates. Increased intake of such foods in lower-middle- and high-income countries in association with physical inactivity has been associated with an epidemic of cardiometabolic diseases and increased risk of death due to noncommunicable diseases.
Published:
January 1, 2019
Title:
Effect of lithium on suicide and mortality in mood disorders: A systematic review
Authors:
Börjesson, Joakim; Gøtzsche, Peter C.
Abstract:
OBJECTIVE: To assess if lithium treatment in patients with mood disorders, for instance depression, bipolar disorders, and schizoaffective disorders, has an effect on total mortality and suicide. DESIGN: Systematic review and meta-analysis. MAIN OUTC
Published:
January 1, 2019
Title:
Evolution of Chordate Cardiopharyngeal Muscles and the Origin of Vertebrate Head Muscles: Anatomical, Functional, and Developmental Diversity in Chordate Evolution
Authors:
Ziermann, Janine; Diogo, Rui
Abstract:
Recent findings that urochordates are the closest sister group of vertebrates have dramatically changed our understanding of chordate evolution and of the origin of the vertebrate head and its muscles. To better understand the evolution and diversity of chordates, in particular the morphological and taxonomical diversity of the vertebrates, it is crucial to investigate the origin, development, and comparative anatomy of not only hard tissues but also of soft tissues such as muscles. Building on the recent discovery of the cardiopharyngeal field in urochordates and on the comparative anatomy of chordate and vertebrate muscles, in this chapter we focus on the broader comparative and developmental anatomy of chordate muscles and the origin of vertebrate cephalic muscles.
Published:
January 1, 2019
Title:
The Origin and Evolution of Mammalian Head Muscles with Special Emphasis on the Facial Myology of Primates and Modern Humans: Anatomical, Functional, and Developmental Diversity in Chordate Evolution
Authors:
Diogo, Rui; Powell, Vance
Abstract:
In this chapter we focus mainly on from where the head and neck muscles arose and how they evolved within the three major extant mammalian clades: monotremes, marsupials, and placentals. Within placentals, we pay special attention to primates, the group that includes our species, Homo sapiens. In fact, primates are an emblematic case study to show that, within the fascinating morphological diversity of hard and soft tissues of the head, including the jaws and the muscles that move them, the most evolvable and diverse ones are a group of muscles that is characteristic of, and played a crucial evolutionary role in, the Mammalia: the muscles of facial expression. As an example of mammalian diversity and also of an issue that is fundamental for the evolution of our own species as well as to illustrate the highly complex linkage between the evolutionary history of muscles, external characters, behavior, and ecology, we briefly comment on the relationships between facial expression, color patterns, mobility, and social group size during primate and human evolution. Furthermore, we also provide comments about data that have been made available in developmental studies on the ontogeny of the mammalian head muscles as an example of how developmental and evo-devo data can be combined with comparative anatomy in order to provide a more integrative understanding of the evolutionary history of the mammalian head.
Published:
January 1, 2019
Title:
Up-Regulation of MiR-1915 Inhibits Proliferation, Invasion, and Migration of Helicobacter pylori-Infected Gastric Cancer Cells via Targeting RAGE
Authors:
Xu, Xin-cai; Zhang, Wen-bin; Li, Chun-xing; Gao, Hua; Pei, Qi; Cao, Bo-wei; He, Tie-han
Abstract:
Purpose Helicobacter pylori (HP)-infected gastric cancer (GC) is known to be a fatal malignant tumor, but the molecular mechanisms underlying its proliferation, invasion, and migration remain far from being completely understood. Our aim in this study was to explore miR-1915 expression and its molecular mechanisms in regulating proliferation, invasion, and migration of HP-infected GC cells. Materials and Methods Quantitative real-time PCR and western blot analysis were performed to determine miR-1915 and receptor for advanced glycation end product (RAGE) expression in HP-infected GC tissues and gastritis tissues, as well as human gastric mucosal cell line GES-1 and human GC cell lines SGC-7901 and MKN45. CCK8 assay and transwell assay were performed to detect the proliferation, invasion, and migration capabilities. MiR-1915 mimics and miR-1915 inhibitor were transfected into GC cells to determine the target relationship between miR-1915 and RAGE. Results MiR-1915 was under-expressed, while RAGE was over-expressed in HP-infected GC tissues and GC cells. Over-expressed miR-1915 could attenuate cellular proliferation, invasion, and migration capacities. RAGE was confirmed to be the target gene of miR-1915 by bioinformatics analysis and luciferase reporter assay. Moreover, HP-infected GC cellular proliferation, invasion, and migration were inhibited after treatment with pcDNA-RAGE. Conclusion MiR-1915 exerted tumor-suppressive effects on cellular proliferation, invasion, and migration of HP-infected GC cells via targeting RAGE, which provided an innovative target candidate for treatment of HP-infected GC.
Published:
January 1, 2019
Title:
“Neanderthals, vitamin C, and scurvy”
Authors:
Speth, John D.
Abstract:
This paper explores the role of vitamin C (ascorbic acid) in the foodways of hunter-gatherers—both ethnohistoric and Paleolithic—whose diet seasonally or over much of the year, of necessity, was comprised largely of animal foods. In order to stave off scurvy, such foragers had to obtain a minimum of about 10 mg per day of vitamin C. However, there is little to no vitamin C in muscle meat, being concentrated instead in various internal organs and brain. Even ruminant stomach contents, despite the abundance of partially digested plants, contains almost none. Moreover, many of the “meatiest” anatomical units in a carcass, such as the thigh muscles or “hams” associated with the femur, are extremely lean in most wild ungulates, making them nutritionally much less valuable to northern foragers than archaeologists commonly assume (for example, Inuit and other indigenous peoples of the arctic and subarctic commonly use the thigh meat as dog food). Vitamin C is also the most unstable vitamin, rapidly degrading or disappearing when exposed to water, air, light, heat, and pH levels above about 4.0. As a consequence, common methods of preparing meat for storage and consumption (e.g., drying, roasting, boiling) may lead to significant loss of vitamin C. There are two effective methods of minimizing such loss: (1) eating meat raw (fresh or frozen); and (2) eating the meat after it has been putrefied. Putrefaction has distinct advantages that make it a common, if not essential, way of preparing and preserving meat among northern latitude foragers and, for the same reasons, very likely also among Paleolithic foragers in the colder climes of Pleistocene Eurasia. Putrefaction “pre-digests” the meat (including the organs), making it much less costly to ingest and metabolize than raw meat; and it lowers the pH, greatly increasing the stability of vitamin C. These observations offer insights into critical nutritional constraints that likely had to be addressed by Neanderthals and later hominins in any context where their diet was heavily meat-based for a substantial part of the year.
Published:
January 1, 2019
Title:
Development of Head Muscles in Fishes and Notes on Phylogeny-Ontogeny Links: A Basis for Evo-Devo and Developmental Research on Fish Muscles
Authors:
Ziermann, Janine; Diogo, Rui
Abstract:
Evolution and Development of Fishes - edited by Zerina Johanson January 2019
Published:
December 31, 2018
Title:
Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness
Authors:
Girard, Timothy D.; Exline, Matthew C.; Carson, Shannon S.; Hough, Catherine L.; Rock, Peter; Gong, Michelle N.; Douglas, Ivor S.; Malhotra, Atul; Owens, Robert L.; Feinstein, Daniel J.; Khan, Babar; Pisani, Margaret A.; Hyzy, Robert C.; Schmidt, Gregory A.; Schweickert, William D.; Hite, R. Duncan; Bowton, David L.; Masica, Andrew L.; Thompson, Jennifer L.; Chandrasekhar, Rameela; Pun, Brenda T.; Strength, Cayce; Boehm, Leanne M.; Jackson, James C.; Pandharipande, Pratik P.; Brummel, Nathan E.; Hughes, Christopher G.; Patel, Mayur B.; Stollings, Joanna L.; Bernard, Gordon R.; Dittus, Robert S.; Ely, E. Wesley
Abstract:
BACKGROUND There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P = 0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522.)
Published:
December 27, 2018
Title:
Higher Fecal Short-Chain Fatty Acid Levels Are Associated with Gut Microbiome Dysbiosis, Obesity, Hypertension and Cardiometabolic Disease Risk Factors
Authors:
de la Cuesta-Zuluaga, Jacobo; Mueller, Noel T.; Álvarez-Quintero, Rafael; Velásquez-Mejía, Eliana P.; Sierra, Jelver A.; Corrales-Agudelo, Vanessa; Carmona, Jenny A.; Abad, José M.; Escobar, Juan S.
Abstract:
Fiber fermentation by gut microbiota yields short-chain fatty acids (SCFAs) that are either absorbed by the gut or excreted in feces. Studies are conflicting as to whether SCFAs are beneficial or detrimental to cardiometabolic health, and how gut microbiota associated with SCFAs is unclear. In this study of 441 community-dwelling adults, we examined associations of fecal SCFAs, gut microbiota diversity and composition, gut permeability, and cardiometabolic outcomes, including obesity and hypertension. We assessed fecal microbiota by 16S rRNA gene sequencing, and SCFA concentrations by gas chromatography/mass spectrometry. Fecal SCFA concentrations were inversely associated with microbiota diversity, and 70 unique microbial taxa were differentially associated with at least one SCFA (acetate, butyrate or propionate). Higher SCFA concentrations were associated with a measure of gut permeability, markers of metabolic dysregulation, obesity and hypertension. Microbial diversity showed association with these outcomes in the opposite direction. Associations were significant after adjusting for measured confounders. In conclusion, higher SCFA excretion was associated with evidence of gut dysbiosis, gut permeability, excess adiposity, and cardiometabolic risk factors. Studies assessing both fecal and circulating SCFAs are needed to test the hypothesis that the association of higher fecal SCFAs with obesity and cardiometabolic dysregulation is due to less efficient SCFA absorption.
Published:
December 27, 2018
Title:
Diet-Independent Correlations between Bacteria and Dysfunction of Gut, Adipose Tissue, and Liver: A Comprehensive Microbiota Analysis in Feces and Mucosa of the Ileum and Colon in Obese Mice with NAFLD
Authors:
Gart, Eveline; Souto Lima, Everton; Schuren, Frank; de Ruiter, Christa G. F.; Attema, Joline; Verschuren, Lars; Keijer, Jaap; Salic, Kanita; Morrison, Martine C.; Kleemann, Robert
Abstract:
Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host health. We present a first systematic analysis of microbiota changes in the ileum and colon using multiple diets and investigating both fecal and mucosal samples. Ldlr-/-.Leiden mice received one of three different energy-dense (ED)-diets (n = 15/group) for 15 weeks. All of the ED diets induced obesity and metabolic risk factors, altered short-chain fatty acids (SCFA), and increased gut permeability and NAFLD to various extents. ED diets reduced the diversity of high-abundant bacteria and increased the diversity of low-abundant bacteria in all of the gut compartments. The ED groups showed highly variable, partially overlapping microbiota compositions that differed significantly from chow. Correlation analyses demonstrated that (1) specific groups of bacteria correlate with metabolic risk factors, organ dysfunction, and NAFLD endpoints, (2) colon mucosa had greater predictive value than other compartments, (3) correlating bacteria differed per compartment, and (4) some bacteria correlated with plasma SCFA levels. In conclusion, this comprehensive microbiota analysis demonstrates correlations between the microbiota and dysfunctions of gut, adipose tissue, and liver, independent of a specific disease-inducing diet.
Published:
December 20, 2018
Title:
Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2
Authors:
Sanin, David E.; Matsushita, Mai; Klein Geltink, Ramon I.; Grzes, Katarzyna M.; van Teijlingen Bakker, Nikki; Corrado, Mauro; Kabat, Agnieszka M.; Buck, Michael D.; Qiu, Jing; Lawless, Simon J.; Cameron, Alanna M.; Villa, Matteo; Baixauli, Francesc; Patterson, Annette E.; Hässler, Fabian; Curtis, Jonathan D.; O'Neill, Christina M.; O'Sullivan, David; Wu, Duojiao; Mittler, Gerhard; Huang, Stanley Ching-Cheng; Pearce, Erika L.; Pearce, Edward J.
Abstract:
Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψm) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψm were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψm caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor and Δψm as a mediator of mitochondrial-directed nuclear gene expression.
Published:
December 18, 2018
Title:
ECT beyond unipolar major depression: systematic review and meta‐analysis of electroconvulsive therapy in bipolar depression
Authors:
Bahji, A.; Hawken, E. R.; Sepehry, A. A.; Cabrera, C. A.; Vazquez, G.
Abstract:
Objective: In this systematic review and meta-analysis, the response, remission, and speed of response in adults with major depressive disorder (MDD) and bipolar disorder in depressive episode (BDD) receiving an acute course of electroconvulsive therapy (ECT) were quantitatively analyzed. Methods: Using the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, 1660 citations were identified through five electronic databases. Nineteen articles met final inclusion criteria for meta-analysis. Results: The pooled response and remission rates with ECT in MDD were 74.2% (n = 1246/1680) and 52.3% (n = 850/1626), respectively. In BDD, they were 77.1% (n = 437/567) and 52.3% (n = 275/377), respectively. Although response rates to ECT were statistically higher in BDD (OR = 0.73, 95% CI: 0.56–0.95, P = 0.02), remission rates were similar (OR = 0.91, 95% CI: 0.65–1.26, P = 0.56). Individuals with BDD vs. MDD required fewer number of ECT sessions to achieve response (SMD = À0.23, 95% CI: À0.44 to À0.023, P = 0.03). There were no significant moderator effects identified. Conclusion: Response rates and speed of response are higher in individuals with BDD; however, remission rates are equivalent. These findings support increased utilization of ECT in individuals with treatment-refractory BDD.
Published:
December 16, 2018
Title:
Effect of graded calcium supplementation in low-nutrient density feed on tibia composition and bone turnover in meat ducks
Authors:
Zhang, Huaiyong; Zeng, Qiufeng; Bai, Shiping; Wang, Jianping; Ding, Xuemei; Xuan, Yue; Su, Zhuowei; Zhang, Keying
Abstract:
Both genetic selection and increasing nutrient density for improving growth performance had inadvertently increased leg problems of meat ducks, which adversely affects animal welfare. We hypothesised that slowing weight gain with improving tibia quality probably enhanced tibial mechanical properties and alleviated leg deformities. Therefore, the present study aimed to evaluate the effect of graded Ca supplementation in a low-nutrient density (LND) diet on tibia composition and bone turnover in meat ducks. A total of 720 15-d-old male meat ducks were randomly assigned and fed a standard nutrient density positive control (PC) diet containing 0·9 % Ca, and four LND diets with 0·5, 0·7, 0·9 and 1·1 % Ca, respectively. Ducks fed the 0·5 % Ca LND diet and the PC diet had higher incidence of tibial dyschondroplasia (TD). When compared with the 0·5 % Ca LND diet, LND diets with ≥0·7 % Ca significantly improved tibia composition, microarchitecture and mechanical properties, and consequently decreased the incidence of TD. Furthermore, LND diets with ≥0·7 % Ca increased osteocyte-specific gene mRNA expression, blocked the expression of osteoblast differentiation marker genes including osteocalcin , collagenase-1 and alkaline phosphatase (ALP), and also decreased the expression of osteoclast differentiation genes, such as vacuolar-type H+-ATPase, cathepsin K and receptor activator of NF-κB. Meanwhile bone markers such as serum ALP, osteocalcin (both osteoblast markers) and tartrate-resistant acid phosphatase (an osteoclast marker) were significantly decreased in at least 0·7 % Ca treated groups. These findings indicated that LND diets with ≥0·7 % Ca decreased bone turnover, which subsequently increased tibia quality for 35-d-old meat ducks.
Published:
December 14, 2018
Title:
Development and Validation of a Dementia Risk Prediction Model in the General Population: An Analysis of Three Longitudinal Studies
Authors:
Licher, Silvan; Leening, Maarten J.G.; Yilmaz, Pinar; Wolters, Frank J.; Heeringa, Jan; Bindels, Patrick J.E.; Alzheimer’s Disease Neuroimaging Initiative; Vernooij, Meike W.; Stephan, Blossom C.M.; Steyerberg, Ewout W.; Ikram, M. Kamran; Ikram, M. Arfan
Abstract:
Published:
December 11, 2018
Title:
Carbon footprint and nutritional quality of different human dietary choices
Authors:
González-García, Sara; Esteve-Llorens, Xavier; Moreira, Maria Teresa; Feijoo, Gumersindo
Abstract:
Apart from industrial activities, our eating habits also have a significant environmental cost associated with crop cultivation, manufacturing processes, packaging, refrigeration, transport cooking and waste management. In a context of growing social awareness of the role of different dietary choices in the environment, the review of different alternatives on the road to a healthy and sustainable diet should integrate relevant information on the nutritional quality of different eating habits. Since dietary choices have an effect on environmental sustainability and human health, a literature review on different dietary choices has been conducted to determine the differences in carbon footprint and nutritional quality identifying the main hotspots trying to give advice towards the identification of sustainable diets. After applying a set of criteria for reference selection, 21 peer-reviewed studies have been analysed in detail, allowing the comparison of 66 dietary scenarios. We identified that the so-called Mediterranean and Atlantic diets present high nutritional scores and low carbon footprints. On the contrary, the dietary choices identified in northern and Western Europe, as well as in the United States, have the highest carbon footprints, highlighting the contribution of dairy products as a basic source of high-quality nutrients and protein. Broadly speaking, dietary choices rich in vegetables (e.g., vegan, vegetarian as well as Indian and Peruvian) have a better environmental profile than those rich in meat (mainly ruminant meat). In line with these findings, the shift in meat consumption habits from beef and veal to chicken, pork and poultry, the introduction of alternative foods to animal protein (e.g. quinoa) and the consumption of olive oil as a major source of vegetable oil may be compatible with a healthier and more environmentally friendly diet. However, the complete elimination of meat and dairy products from the daily diet may not be feasible in case the supply of some micronutrients (e.g., calcium and vitamin D) is not guaranteed. Limitations were identified in the consulted studies related to the consideration of the different system boundaries, as well as underlying uncertainties related to data sources. Therefore, efforts should be made to develop consistent and agreed-upon methods for estimating both the carbon footprint and nutritional quality scores.
Published:
December 10, 2018
Title:
Structural assembly of the megadalton-sized receptor for intestinal vitamin B 12 uptake and kidney protein reabsorption
Authors:
Larsen, Casper; Etzerodt, Anders; Madsen, Mette; Skjødt, Karsten; Moestrup, Søren Kragh; Andersen, Christian Brix Folsted
Abstract:
Cubilin and the transmembrane protein amnionless (AMN) form the endocytic receptor cubam that is essential for intestinal vitamin B12 uptake. Here the authors present the 2.3 Å crystal structure of AMN in complex with the amino-terminal region of cubilin and discuss cubam architecture and disease causing mutations.
Published:
December 6, 2018
Title:
Vitamin E Metabolic Effects and Genetic Variants: A Challenge for Precision Nutrition in Obesity and Associated Disturbances
Authors:
Galmés, Sebastià; Serra, Francisca; Palou, Andreu
Abstract:
Vitamin E (VE) has a recognized leading role as a contributor to the protection of cell constituents from oxidative damage. However, evidence suggests that the health benefits of VE go far beyond that of an antioxidant acting in lipophilic environments. In humans, VE is channeled toward pathways dealing with lipoproteins and cholesterol, underlining its relevance in lipid handling and metabolism. In this context, both VE intake and status may be relevant in physiopathological conditions associated with disturbances in lipid metabolism or concomitant with oxidative stress, such as obesity. However, dietary reference values for VE in obese populations have not yet been defined, and VE supplementation trials show contradictory results. Therefore, a better understanding of the role of genetic variants in genes involved in VE metabolism may be crucial to exert dietary recommendations with a higher degree of precision. In particular, genetic variability should be taken into account in targets concerning VE bioavailability per se or concomitant with impaired lipoprotein transport. Genetic variants associated with impaired VE liver balance, and the handling/resolution of oxidative stress might also be relevant, but the core information that exists at present is insufficient to deliver precise recommendations.
Published:
December 4, 2018
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