bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of platelet‐derived growth factor alpha in chronic liver injury (144.4)
Authors: Kikuchi Alexander , Monga Satdarshan 
Published: June 2021

Platelet‐derived growth factor α (PDGFRα) is a tyrosine kinase receptor that plays a role in liver development and regeneration and is upregulated in livers of patients with primary biliary cirrhosis as well as a majority of hepatocellular carcinomas (HCC). Whether PDGFRα upregulation in these settings plays a compensatory or a pathological role is unknown. This question has led us to investigate the role of PDGFRα in chronic liver injury and hepatic fibrosis ‐ a pathogenic process that is a precursor to the development of cirrhosis and HCC. In this study we show that PDGFRα is upregulated in murine liver following bile duct ligation, a model of cholestatic liver injury. In addition we show that PDGFRα and one of its ligands, PDGF‐CC, is localized to hepatocytes as well as bile duct epithelial cells. In vivo blockade of PDGFRα in mice using a previously described monoclonal antibody revealed significant attenuation of hepatocellular injury assessed through liver function analysis of animal serum. In contrast, analysis of in situ hepatic collagen deposition in these animals reveals increased fibrosis in animals treated with PDGFRα inhibitor, suggesting that fibrosis and myofibroblast activation occurs independently of hepatocellular injury in this model. These findings point towards a dichotomous contribution of PDGFRα signaling in cholestatic liver injury with opposing effects in parenchymal and non‐parenchymal cell compartments.Grant Funding Source: T32: HL094295 ANGIOPATHY TRAINING GRANT; R01: DK095498 ROLE OF PDGFRALPHA IN LIVER PATHO‐BIOLOGY
Aortopathy: a developmental defect with adult pathology? (15.5)
Authors: Riley Ashlie , Krishnamurthy Varun , Maddy Kelsey , Junor Lorain , Biechler Stefanie , Hinton Robert , Goodwin Richard 
Published: June 2021

Aortopathy is a subclinical disease characterized by aortic dilation, which can result in aortic dissection and/or aortic aneurysm. Hallmarks of aortopathy include vascular smooth muscle cell (VSMC) and elastin fiber misregulation. Elastin hemizygous (Eln+/‐) mice have a thickened and altered arterial wall structure, specifically, aortic root distension and an increase in VSMC layers along the ascending aorta. We hypothesize that aortopathy has a congenital basis with the associated defects originating in the cardiac neural crest (CNC) aorta. Aortic tissues from adult and aged wild type (WT) and Eln+/‐ mice were examined to detect anatomic and/or developmental variation. Sonic Hedgehog (a marker of CNC derived cells), SM22 (a marker of VSMCs), aggrecan and biglycan (proteoglycan markers) were utilized in a novel 3D reconstructive manner to discern spatial and temporal localization. Quantification of these findings revealed that cardiac neural crest‐derived aorta tissue is spatiotemporally associated with VSMC abnormalities, maladaptive matrix remodeling with differential proteoglycan misexpression, and biomechanical dysfunction suggesting a primary role in the development of aortopathy.Grant Funding Source: This study was supported by the AHA 11PRE7210044 (VKK), and the National Institutes of Health HL0851
l‐Citrulline protects from kidney damage in STZ‐diabetic rodents (151.10)
Authors: Romero‐Lucas Maritza , Yao Lin , Lucas Rudolf , Caldwell Robert , Bagi Zsolt 
Published: June 2021

Rationale. Diabetic nephropathy (DN) is a major cause of end‐stage renal disease. Hypercatabolic states are a common feature of chronic diseases such as diabetes mellitus (DM), and are accompanied by an increase of circulating inflammatory cytokines. Therefore, amino acid supplementation may be effective in counteracting the metabolic consequences of DM, including DN.Aims. To investigate whether L‐citrulline (L‐cit) supplementation represents a safe intervention in DN, and to assess the effects of L‐cit on the inflammatory profile observed in DM.Methods. STZ‐C57BL6 mice and rats received L‐cit or vehicle supplemented in the drinking water (50 mg/kg/day). Human glomerular endothelial cells (HGEC) were exposed to high glucose (HG, 25 mM)‐supplemented medium.Results. L‐cit supplementation markedly reduced urinary albumin excretion (µg/day, C=141.4 ± 23.8; STZ= 807.2 ± 205.1 p<0.001 vs C; L‐cit‐STZ= 193.4 ± 109.8 p<0.05 vs STZ), tubulo‐interstitial collagen deposition, and kidney hypertrophy observed in untreated STZ‐mice and rats. These effects were accompanied by enhanced plasma levels of the anti‐inflammatory cytokine IL‐10, and an increased expression of a marker of an anti‐inflammatory phenotype arginase II in proximal tubules. L‐cit also restored NO/ROS balance and barrier function in HG‐treated HGEC.Conclusions. L‐cit supplementation is beneficial in preserving the nephron function in STZ‐rodent models. This effect may be due to L‐citrulline’s abilities to establish an anti‐inflammatory response in the proximal tubules and in the circulation. L‐cit also protects the glomerular barrier function from hyperpermeability and NO/ROS imbalance.Grant Funding Source: Supported by NIH HL104126
Entamoeba histolytica evades innate immunity by triggering the degradation of macrophage cytoskeletal‐associated proteins (152.4)
Authors: St‐Pierre Joelle , Moreau France , Chadee Kris 
Published: June 2021

Entamoeba histolytica (Eh) is the causative agent of amebiasis, a disease responsible for ~100 000 deaths/year. In most cases, Eh colonizes the mucus layer of the colon without causing symptoms, however in some individuals Eh invades the colonic mucosa causing amebic colitis. The first response of the host at sites of Eh invasion is a robust acute inflammatory response mediated by macrophages. Eh‐macrophage interaction is thus a critical first step in determining how the innate immune response will be shaped, yet the mechanisms that regulate this interaction remain largely unknown. In this study, we investigated the early cellular events triggered in macrophages in response to Eh and the putative virulent factors involved. Through biochemical and microscopy techniques, we have unravelled that only live Eh in direct contact with human naïve macrophages triggered an instantaneous degradation of the cytoskeletal‐associated proteins Pyk2 and paxillin. This event was critically dependent on the major surface virulent factor, cysteine proteinase 5 (EhCP5) as revealed using EhCP5‐deficient Eh and protease inhibitors. As macrophage cytosketal proteins are critically involved in cell adhesion, migration and inflammation, we surmise that Eh has evolved mechanisms to “stun” macrophages during infection to dampen the innate immune response. Taken together, our findings advance a unique mechanism by which Eh modulates immune cells by interfering with the cell cytoskeleton, which may favour parasite colonization and/or altering pro‐inflammatory responses in Eh pathogenesis.Grant Funding Source: Supported by the Natural Sciences and Engineering Research Council of Canada (NSERC)
The differential spread of prion strains into the brain (153.1)
Authors: Sigurdson Christina , Bett Cyrus , Kurt Tim , Kong Qingzhong , Nilsson K. Peter , Masliah Eliezer , Oldstone Michael 
Published: June 2021

Prions are the only protein aggregates that naturally transmit as infectious agents, and recently human to human transmission has occurred through transfusion of prion‐contaminated blood. Most cases of natural transmission start with a peripheral exposure followed by prion spread to the CNS. Yet certain prions do not invade the CNS, despite prion accumulation in non‐neural organs, such as spleen or heart. Intriguingly, all of these poorly neuroinvasive prions form fibrils, which are uncommon structures in prion disease. We are investigating the molecular basis for the remarkable differences between the spread of nonfibrillar and fibrillar prions to the brain using in vivo models. We have found that the fibrillar prions were more resistant to enzyme digestion and were extraordinarily stable when exposed to protein denaturing conditions, in mice and in humans. Taken together, these results provide evidence for a striking separation in the biochemical of fibrillar and nonfibrillar prions that underlie their differences in neuroinvasion.Grant Funding Source: NIH NS069566 and NS076896
Curcumin antagonizes the effects of EPA and DHA supplementation on oxidative stress in dogs (246.7)
Authors: Martineau Anne‐Sophie , Breniaux Marion , Leray Véronique , Nguyen Patrick 
Published: June 2021

In obese dogs, some beneficial effects of PUFAs have been reported. They affect oxidative status as they stimulate endogenous antioxidant system, and are prone to be oxidized. The addition of a polyphenol antioxidant to an EPA+DHA supplement could be useful to better understand their mechanism of action.Our aim was to check the effects of EPA and DHA w/wo curcumin on hepatic gene expression in obese dogs.Animals were given a hyperenergetic diet with EPA+DHA (970 mg EPA/d and 780 mg DHA/d) for 6 wks, then EPA+DHA+curcumin for 6 wks. Liver biopsies were taken before (T0) and at the end of each period. The mRNA levels of antioxidant enzymes (SOD1, PON1, GPx, catalase, NQO1), of nuclear factor Nrf2 and hypoxia marker HIF1 α were assayed by RT‐PCR.At the end of the EPA+DHA supplementation, the mRNA levels of SOD1, Nrf2, PON1, GPx, catalase, NQO1 and Nrf2 were higher than at T0, whereas at the end of the EPA+DHA+curcumin supplementation, the expression was not modified. The expression of HIF1 α was lower at the end of the EPA+DHA supplementation, and unchanged at the end of the EPA+DHA+curcumin supplementation.Our results suggest that the PUFAs effects could be inhibited when curcumin was added. Nevertheless, these results do not permit to conclude if the higher expression of genes involved in antioxidant system reflects a defense against oxidized products, which generation could be avoided by the antioxidant curcumin.
Do aggressive feeding guidelines eliminate first week nutrition deficits in very low birth weight infants fed exclusively mother’s own milk? (247.2)
Authors: Ng Dawn , Brennan‐Donnan Joan , Unger Sharon , Bando Nicole , Gibbins Sharyn , Nash Andrea , O'Connor Deborah 
Published: June 2021

Background: Hospitalized VLBW infants fed human milk are reported to have lower growth rates compared to those fed nutrient‐enriched formulas. Aggressive parenteral nutrition guidelines for VLBW infants have been adopted in many neonatal intensive care units (NICUs) in response to data confirming short‐term safety of this approach and potential long‐term neurocognitive benefits. However, actual intakes during the first week of life have not been extensively evaluated since adoption of these guidelines.Objective: To describe the parenteral and enteral energy and macronutrient intakes in human milk‐fed VLBW infants from NICUs with aggressive nutrition guidelines.Design: Daily parenteral and enteral intakes were prospectively collected for 96 VLBW infants fed only MOM enterally during the first week. Feeding goals included provision of protein (>2.0) and lipids (1.0 g/kg/day) on the day of birth, advancing to 3.5 (protein) and 3.0 (lipid) g/kg/day within the first few days.Results: We found that 34% and 70% of infants did not meet protein and energy goals (of 3.5 g/kg/day and 90‐100 kcal/kg/day), respectively, at the end of the first week.Conclusions: Despite the adoption of more aggressive nutrition guidelines, most MOM‐fed VLBW infants remain undernourished at the end of the first week of life. Strategies to address these deficits may significantly impact the health outcomes of this vulnerable population.Grant Funding Source: Supported by CIHR (MOP#210093).
Watermelon supplementation reduces aortic hemodynamic responses to cold exposure in obese hypertensive adults (249.4)
Authors: Figueroa Arturo , Wong Alexei , Hooshmand Shirin , Kalfon Roy 
Published: June 2021

Cold‐induced increase in aortic blood pressure (BP) may cause cardiac complications in adults with hypertension by increasing wave reflection and left ventricular afterload (augmentation pressure [AP] and index [AIx]). The purpose of the study was to examine the effects of L‐citrulline‐rich watermelon supplementation on aortic hemodynamic responses to cold pressor test (CPT) in hypertensive adults. Brachial (bSBP) and aortic systolic BP (aSBP), AP, AIx, AIx adjusted to 75 beats/min (AIx@75), and systolic tension time index (STI, myocardial oxygen demand) at baseline, during CPT, and magnitude of the response from baseline‐to‐CPT were evaluated in 13 adults with hypertension (10 women; age 57 ± 1 yr, bSBP 151 ± 5 mmHg). Participants were randomized to a 6‐week placebo or watermelon supplementation in a crossover design. Watermelon reduced (P< 0.05) bSBP and aSBP at baseline and during CPT, but did not affect the increases from baseline‐to‐CPT. Watermelon did not affect AP, AIx, AIx@75, and STI at baseline, but decreased (P< 0.05) AP and STI during CPT and the increases in AP (~5 mmHg) and AIx@75 (~7.3%) from baseline‐to‐CPT. Our findings indicate that watermelon supplementation reduces aortic SBP, pressure wave reflection, and myocardial oxygen demand during CPT in obese hypertensive adults. Watermelon supplementation may provide cardioprotection by attenuating cold‐induced aortic hemodynamic responses.Grant Funding Source: National Watermelon Promotional Board
Location influences snacking patterns of U.S. toddler and preschoolers: results from the Feeding Infants and Toddlers Study, 2008 (252.4)
Authors: Deming Denise , Reidy Kathleen 
Published: June 2021

Snacking patterns according to location were assessed among children from FITS, 2008. Dietary intake interviews (24‐hr recalls) were conducted by telephone with parents or primary caregivers of toddlers 12‐23 months (n=925), and preschoolers 24‐47 months (n=1,461). Parents or caregivers self‐defined snacks and location of snacking occasions. More children consumed snacks at home (AtH) than away from home (AwH) (toddlers, 73% vs 27%; preschoolers, 67% vs 33%). Mean intake of calories from snacks consumed AwH was higher than that consumed AtH differing by ~50 calories between the two locations for toddlers (346 vs 298 kcal/d, p<0.05) and for preschoolers (371 vs 326 kcal/d, p<0.05). While the contribution of snacks to TEI was not different between the two locations among toddlers (26.6% vs 27.6%), snacks consumed AwH contributed more to TEI (28.2%) than those consumed AtH (25.0%) among preschoolers (p<0.05). Snack choices were similar for toddlers and preschoolers (milk and milk products, fruit/juice, grains and sweets), but differed in frequency of consumption by location. Among toddlers, milk and milk products were the most frequently consumed snacks AtH (66%), while sweets were the top snacks consumed AwH (69%). Among preschoolers, sweets were the top snacks consumed both AtH (60%) and AwH (83%). FITS data show that location is an important factor influencing snacking patterns of young children.Grant Funding Source: Funded by Nestle
Preference and acceptability of alternative delivery vehicles for prenatal calcium supplementation among pregnant women in urban Bangladesh (256.2)
Authors: Baxter Jo‐Anna , Roth Daniel , Mahmud Abdullah , Islam Munirul , Ahmed Tahmeed , Zlotkin Stanley 
Published: June 2021

Prenatal calcium supplementation is recommended by the WHO to decrease the risk of preeclampsia when dietary calcium intake is low; yet, this recommendation has not been successfully implemented to date. We aimed to evaluate preference and acceptability of alternate delivery vehicles for prenatal calcium supplementation (conventional tablets, chewable tablets, unflavored powder, and flavored powder) among pregnant women in urban Bangladesh. In a modified discrete‐choice experiment, pregnant women (n = 132) completed a 4‐day ‘run‐in period’ in which each option was sampled once, followed by a 21‐day ‘selection period’ during which participants freely selected a single option per day. Preference was objectively based on the probability of selection of each option; acceptability was assessed using questionnaires. Conventional tablets demonstrated the highest probability of selection (62%); the probability of selection of chewable tablets (19%), flavored powder (12%), and unflavored powder (5%) were all significantly lower than for conventional tablets (P < 0.001). Conventional tablets were also more acceptable based on subjective reports. Observation of actual use and expressed perceptions showed that a conventional tablet is likely to be the most successful prenatal calcium supplement for scale‐up of the WHO recommendation in Bangladesh.Grant Funding Source: Supported by the Hospital for Sick Children and Sprinkles Global Health Initiative
Evidence for a functional intestinal‐renal axis for arginine synthesis in the neonatal pig (258.2)
Authors: Marini Juan , Premkumar Murali , Didelija Inka , Stoll Barbara , Burrin Doug 
Published: June 2021

Endogenous arginine (Arg) synthesis is a complex multiorgan process, in which citrulline (Cit) made in the gut is converted into Arg in the kidney, by what is known as the intestinal‐renal axis. In neonates, since the enzymes required to convert Cit into Arg are present in the gut, the prevailing dogma is that this axis is not functional and that Arg, but not Cit, is exported by the gut. Paradoxically, plasma Cit is also used as a marker for gut health and development in the neonate. We have determined Cit and Arg interorgan transactions (µmol•kg‐1•h‐1) in multi‐catheterized, anesthetized neonatal pigs (6‐10 d) using tracers and enzyme localization by immunohistochemistry. The gut released Cit (48±12) and Arg (41±12). Only a small fraction (4±1) of Arg was synthesized from circulating Cit. Because there was no direct utilization of ornithine for Arg synthesis, it is likely that the rest was from proteolysis. Due to enteral Arg uptake (27 ±12) the net Arg balance across the gut was not different from zero. The kidney took up Cit (37±4) and released Arg (28±3). Approximately 50% of the Arg released by the kidney originated from circulating Cit (13±3). The uptake of Arg by kidney (19±7) reduced the net output of renal Arg. Our results in neonatal pigs demonstrate a substantial Cit flux that can be explained by the lack of co‐localization of the enzymes for Cit and Arg synthesis in the gut, and the conversion of plasma Cit into Arg by the kidney.Grant Funding Source: Supported by USDA/ARS Cooperative Agreement No 58‐6250‐6‐001
L‐[2,3,3,4,5,5,5,6,6,6‐2H10]leucine improves accuracy of muscle protein synthesis determinations when using blood amino acid enrichment as the precursor pool (258.8)
Authors: Tran Lee , Masters Haley , Katsanos Christos 
Published: June 2021

The amino acid enrichment in blood (Eb) is often used in clinically relevant stable isotope studies to calculate muscle protein fractional synthesis rates (FSR), but it underestimates the FSR compared to methods using intracellular enrichment in muscle (Ei). We compared the FSR calculated with intravenous infusion of the novel tracer L‐[2,3,3,4,5,5,5,6,6,6‐2H10]leucine ([2H10]leu) to infusion of the traditional tracer L‐[13C6]phenylalanine ([13C6]phe) using Eb and Ei. Because [2H10]leu is intracellularly metabolized to [2H9]leu prior to reentry into the blood, we hypothesize that using [2H10]leu will minimize the discrepancy between FSR values calculated using Eb or Ei compared to [13C6]phe‐calculated FSR values using the corresponding Eb or Ei. To test our hypothesis, six healthy subjects received simultaneous infusions of the two stable‐isotope tracers following standard protocols. The [2H9]leu‐calculated FSR (%h‐1) was 0.08±0.01 based on Eb and 0.18±0.01 based on Ei. The corresponding [13C6]phe‐calculated FSR values were 0.06±0.01 and 0.25±0.02, respectively. Moreover, the difference in the [2H9]leu‐calculated FSR values using Ei vs Eb was significantly less (P<0.01; 0.10±0.01) compared to the difference in the corresponding [13C6]phe‐calculated FSR values (0.19±0.02). We conclude that, compared to [13C6]phe, the [2H10]leu tracer offers a more accurate approach to calculating FSR when Eb is sought as an alternative to the Ei.Grant Funding Source: Supported by NIH/NIDDK Grant# R01 DK094062; NCATS Grant# UL1 TR000135
Manuka honey with cycloPower™ ő a novel bioactive complex of manuka honey and α‐cyclodextrin (259.4)
Authors: Chepulis Lynne , Harre Vikke , Truter Elsie , Suddes Mandy , Hockey Hans 
Published: June 2021

Manuka honey is recognised for its health‐promoting properties and its use in medicine is well documented. However, the actions of Manuka honey are limited by rapid digestion and the inactivation of bioactive components such as methylglyoxal (MG). Cyclodextrins are naturally‐occurring glucose rings that improve stability and bioactivity of products. This study investigates the tolerability and bioactivity of α‐cyclodextrin‐complexed Manuka honey called Manuka Honey with CycloPower™ (MH‐CP).Product tolerability was evaluated in a randomized, double‐blind, ascending dose study. Healthy participants (n=64) consumed 400‐4800mg or placebo for two weeks. MH‐CP was well tolerated. The most common events were headache and temporary mild/ moderate gastrointestinal disturbances (diarrhea, nausea). The rate of adverse events (AEs) was not dose‐related and most AEs resolved within 48 hours. A further study assessed the glycemic index (GI) of MH‐CP and revealed that the GI was significantly reduced (GI=18 vs 55) compared with uncomplexed Manuka honey. In addition, a suite of in vitro analyses indicated that MH‐CP has enhanced antimicrobial efficacy against a range of common gut organisms compared with Manuka honey. This demonstrates that Manuka honey with CycloPower™ is a well‐tolerated product with enhanced bioactive properties.
γ‐Tocopherol supplementation attenuates arterial dysfunction in db/db mice (260.8)
Authors: Li Youyou , Quan Ying , Panneerseelan Leena , Mah Eunice , Guo Yi , Hawkins Makenzie , Jalili Thunder , Bruno Richard , Symons J David 
Published: June 2021

γ‐Tocopherol (γ‐T) prevents endothelial dysfunction evoked by acute hyperglycemia. We hypothesized that γ‐T supplementation would attenuate arterial dysfunction induced by chronic hyperglycemia. Wild‐type (WT) mice were fed a diet with no γ‐T and db/db mice were fed 0 or 500 mg/kg γ‐T for 8 wk. Db/db mice had higher (p<0.05) plasma glucose and liver malondialdehyde (MDA) vs. WT animals. Compared to db/db controls, db/db mice fed γ‐T had higher (p<0.05) plasma γ‐T and hepatic levels of its metabolite γ‐carboxyethyl‐hydroxychroman (γ‐CEHC), and reduced (p<0.05) hepatic MDA, while plasma glucose was similar between groups. Relaxation to acetylcholine in precontracted femoral arteries was impaired in db/db controls vs. WT animals, and γ‐T reduced the severity of impairment in db/db mice. Arterial responses to sodium nitroprusside were similar among groups. p‐eNOSS1177 / total eNOS was lower (p<0.05) in arteries from db/db controls vs. WT and db/db mice fed γ‐T. In human aortic endothelial cells exposed (24 h) to 25 mM glucose, 3 µM γ‐CEHC prevented (p<0.05) glucose‐induced increases in reactive oxygen species, and decreases in p‐eNOSS1177 / total eNOS and nitrates + nitrites. These data suggest that γ‐T, either directly and/or indirectly through γ‐CEHC, protects against arterial dysfunction evoked by chronic hyperglycemia, potentially by lowering oxidative stress and improving NO bioavailability.Grant Funding Source: UU‐VPR‐0981