bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glycemic and insulinemic response to four different sweeteners in healthy individuals: A double blind, randomized controlled trial.
Authors: Jenkins Alexandra , Shelke Kantha , Vuksan Vladimir , Wolever Thomas M , Campbell Janice , Ezatagha Adish 
Published: June 2021

BackgroundThe non‐nutritive sweetener, erythritol, does not change postprandial glucose levels, whether this holds true for forms which are modulated to be more intensely sweet is not known.ObjectivesComparison of the postprandial glucose and insulin responses of two erythritol products differing in sweetness intensity.Methods15 healthy volunteers (6 M, 9F; 38±12 yr; 26.9±4.4kg/m2) consumed 4 test meals consisting of 24g sucrose, 24g erythritol (Swerve® Granular), 2.4g erythritol (Swerve® 10x) and 3g sucralose (Splenda®) mixed with 200ml of water. All meals were matched for sweetness level. Capillary blood samples were taken fasting and at 15, 30, 45, 60, 90 and 120 min after the start of the meal.ResultsPostprandial glucose and insulin levels were significantly lower after the non‐nutritive sweeteners compared to sucrose at 15, 30 and 45 min. Glucose levels were also lower after both erythritol products compared to sucralose at 15 min. At 90 and 120min, glucose levels were significantly higher after the non‐nutritive sweeteners compared to sucrose (p<0.001). Incremental glucose and insulin areas were significantly lower after the three non‐nutritive sweeteners compared to sucrose (p<0.0001).ConclusionsThis study confirms that irrespective of sweetness level, consumption of erythritol does not raise postprandial blood glucose or insulin levels significantly.
Reduced incidence and duration of acute respiratory infections (ARI) in children fed a follow‐up formula containing docosahexaenoic acid (DHA), a prebiotic blend of polydextrose (PDX) and galacto‐oligosaccharides (GOS), and yeast beta glucan
Authors: Scalabrin Deolinda , Min Xingming , Li Fei , Zhuang Wendy , Strong Paul , Liu Bryan 
Published: June 2021

Intakes of DHA, prebiotics, yeast‐β‐glucan, and other micronutrients have been associated with reduced incidence of respiratory infections.To determine if a follow‐up formula containing a combination of DHA, a prebiotic blend of PDX and GOS, and yeast β‐glucan reduced the incidence of ARI in children.In this double‐blind, randomized, controlled trial, healthy children (3–4yrs) were fed 3 servings per day of a follow‐up formula (FF; n=156) containing DHA (25mg/serving), PDX and GOS (1.2g/serving), and yeast β‐glucan (12.8mg/serving), or a control powdered cow's milk (C; n=154) for 28 weeks. The incidence and duration of ARI were obtained from medical records. Incidence of ARI was analyzed with the CMH test. Duration of ARI was analyzed with ANOVA.The FF group had fewer episodes and shorter average duration of ARI compared to the control group (Table).When compared to cow's milk, daily intake of a follow‐up formula containing DHA, a prebiotic blend of PDX and GOS, and yeast β‐glucan over a 28 week period resulted in fewer episodes and shorter duration of acute respiratory infections.
Dietary isoflavone intake modulates evoked responses to cardiometabolic stimuli in healthy volunteers
Authors: Ferguson Jane Francisca , Tuteja‐Stevens Sony , Shah Rhia Y , Patel Parth N , Rader Daniel J , Reilly Muredach P 
Published: June 2021

Isoflavones, found in high concentrations in soy‐derived foods, function as phytoestrogens, have antioxidant and anti‐inflammatory activity, inhibit protein‐tyrosine kinase activity, and are thought to be atheroprotective. We hypothesized that habitual isoflavone intake modulates response to evoked endotoxemia and oral fat load.In the Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) Study, we administered low dose endotoxin (LPS 1 ng/kg) to induce inflammation in young, healthy volunteers (N=215, 50% female) and administered a separate oral fat tolerance test (OFTT). Data were analyzed using linear regression models adjusted for race, gender, age and BMI.Dietary isoflavone intake was a significant predictor of plasma tumor necrosis factor alpha (TNFα) and interleukin 6 (IL‐6) post LPS. High (>;1.5mg/day, N=64) vs low (<1.5mg/day, N=151) isoflavone consumers had higher peak TNFα (64 vs 45 pg/ml, P=0.015) and peak IL‐6 (210 vs 160 pg/ml, P=0.06). Further, the high isoflavone group had significantly higher β‐hydroxybutyrate levels post‐OFTT (442 vs 332 μmol/L, 2 hours post fat load, P=0.02).Habitual isoflavone consumption may modulate disease development through effects on inflammatory and metabolic responses in humans. For investigating nutritional effects on disease development, measuring evoked phenotypes may be more informative than describing resting characteristics.The GENE Study was supported by NIH Grant UL1TR000003 as well as a NIH‐NHLBI SCCOR Project grant (P50‐HL‐083799) to MPR. JFF is supported by an AHA postdoctoral fellowship grant (12POST11840017).
Epoxomicin Treatment before Ischemia Confers Cardioprotection through Up‐regulated Hsp22 Expression
Authors: Li Dan , Yoon Seong , Park Misun , Rashed Eman , Dai Huacheng , Park Jiyeon , Sui Xiangzhen , Vatner Dorothy , Babu Gopal 
Published: June 2021

BackgroundCell death is the cause of infarct formation in ischemic myocardium. In this study, we demonstrate that Epoxomicin (Epox), a proteosome inhibitor formerly used as an anti‐cancer drug, confers effective cardioprotection.Methods and resultsThe C57 mice (3.5 months, n=7) were injected i.p. with Epox (0.5 mg/kg/day) or vehicle for 2 weeks, and then subjected to 30 min ischemia followed by 24h reperfusion. Epox reduced the infarct size by 50% (p<0.05), despite of similar area‐at‐risk. To investigate the mechanism involved, in vitro study was performed on neonatal rat cardiac myocytes (NRCM). NRCM were treated with Epox (0.01μM) or veh for 24 hours, and then subjected to 36h hypoxia. Epox decreased hypoxia‐induced apoptosis by 50% (n=6; p<0.01). The protection was associated with up‐regulated expression of Hsp22 and its downstream effector iNOS. Deletion of Hsp22 in vitro and in vivo both abolished the iNOS expression and cardioprotection. Transcription activation analysis showed that HSF1 was highly activated in Epox treated NRCM. The Upregulation of Hsp22 expression was abolished upon the addition of KRIBB11, a specific inhibitor to HSF1.ConclusionEpox upregulates Hsp22 expression through HSF1 thereby provides cardioprotection, in vivo equivalent to preconditioning, against ischemia/reperfusion injury. Our data point to Epox as a promising therapeutic agent against ischemic heart disease.
Predicting plasma profiles following oral dosing for drug liver transporter substrates using physiologically based pharmacokinetic modeling
Authors: Gosset James Richard , Jones Hannah M , Lai Yurong , Barton Hugh A 
Published: June 2021

The aim of this work was to assess the prediction of oral plasma profiles utilizing a previously developed physiologically based pharmacokinetic (PBPK) approach using in vitro sandwich cultured hepatocytes (SCHH) to predict intravenous plasma profiles for seven liver transporter substrates (Jones et al., 2012).Utilizing physicochemical, in vitro passive permeability and solubility inputs, descriptors of oral absorption were predicted using a physiologically based gastrointestinal tract model. These inputs were then incorporated into the published transporter PBPK model with a single compartment for oral absorption.The validity of these absorption predictions were shown to be satisfactory when assessed by combining them with the transporter parameters obtained from fitting the intravenous plasma data. Prospective predictions based on SCHH utilizing scaling factors developed in the literature and predicted oral absorption parameters were performed as a test of both aspects in predicting oral plasma time course. The average fold errors for the seven compounds increased somewhat to 2.5, 3.3, and 2.4, respectively.An early prediction method has been developed using physicochemical and in vitro inputs to estimate plasma profiles and pharmacokinetic parameters for intravenous and oral dosing drugs that are substrates for liver transporters.
Improving mucosal function mitigates radiation‐induced gastrointestinal toxicity
Authors: Yin Liangjie , Vijaygopal Pooja , Menon Rajeesh , Zhang Amy , Zhang Mei , Huang Luqiang , Chen Chun , Zhang Lurong , Okunieff Paul , Vidyasagar Sadasivan 
Published: June 2021

Our objective was to determine the optimal amino acid (aa) formula to mitigate the effect of radiation on the electrolyte and nutrient absorption and mucosal barrier functions of the gastrointestinal (GI) tract.Studies were conducted on small intestinal mucosa of irradiated NIH Swiss mice (0, 1, 3, 5 or 7 Gy). The mucosal barrier mechanism was studied for dilution potential, conductance, and plasma endotoxin and IL‐1β; electrolyte, glucose, and aa absorption were studied with Ussing chamber flux studies and transepithelial electrical measurements. Amino acids that improved GI functions were used to formulate a drink that was tested in survival studies.Radiation (0 vs 7 Gy) decreased anion selectivity (0.48±0.05 vs 0.91±0.07) and increased paracellular conductance (30.5±4.1 vs 54.0±10.1). Plasma endotoxin levels were elevated at 7 Gy (20 vs 120). Radiation (0 vs 7 Gy) decreased Na absorption (9.8±0.8 vs − 0.6±0.3) and increased electrogenic Cl secretion (10.1±1.5 vs 0.1±0.01). Glucose absorption exhibited a dose‐dependent decrease and was abolished in 7‐Gy mice (140.7±32.2 vs 3.2±0.8). Lysine, aspartic acid, glycine, isoleucine, threonine, tyrosine, valine, serine, and tryptophan improved GI functions. Survival studies using the aa mixture showed increased survival for lethally irradiated mice.The aa mixture improved GI mucosal function and mitigated radiotoxicity.Support provided by Enterade, LLC.
The Effect of Caffeine on Protein Synthesis Rates in Rat Gastrocnemius Muscle Tissue
Authors: Bui Steve , Shimkus Kevin L , Lee Chang Woock , Lee Teak V , Chen Vincent CW , Fluckey James D , Riechman Steve E 
Published: June 2021

BackgroundFew studies have observed caffeine's effects on resistance exercise (RE). Some studies have shown caffeine may affect several key protein synthesis pathways. Since RE is commonly performed to increase muscle protein synthesis, it would be important to determine how caffeine affects protein fractional synthesis rates (FSR).MethodsThirty‐six male Sprague‐Dawley rats were assigned into six groups: no exercise no caffeine (NENC), no exercise low caffeine (NELC), no exercise high caffeine (NEHC), exercise no caffeine (ENC), exercise low caffeine (ELC), and exercise high caffeine (EHC). Animals in the exercise groups performed four sessions of jump squats with weighted vests. On each exercise day, caffeine groups were given three caffeine injections (LC: 2mg/kg; HC: 6mg/kg). All animals were given deuterium oxide as a protein tracer on the last RE session, and the gastrocnemius muscle was collected 24 hours later and FSR was analyzed.ResultsFSR was significantly different between exercise and no exercise groups (E: 10.33±0.49; NE: 8.54±0.33, p<0.05); however, there was no effect of caffeine intake on FSR (NENC: 8.36±0.82, NELC: 8.65±0.75; NEHC: 8.56±0.82/ ENC: 10.75±0.75; ELC: 9.99±0.75; EHC: 10.25±0.75, p>;0.05).ConclusionOur data suggests that habitual caffeine intake plays little to no role in post‐RE protein FSR. This observation could be due to an increased tolerance level for caffeine.
Interactions of mechanically induced coughing and sneezing
Authors: Simera Michal , Poliacek Ivan , Dobrolubov Boris , Veternik Marcel , Jakus Jan 
Published: June 2021

Mutual interactions of cough and sneeze were studied on 11 spontaneously breathing pentobarbitone anesthetized cats (3.5±0.2 kg). Reflexes were induced mechanically in the nose and tracheobronchial airways, respectively. The amplitude of styloglossus muscle electromyogram (EMG) moving average during the expulsive phase of sneeze was about 16‐fold higher than that during cough (p<0.01; 9 cats). Higher inspiratory efforts occurred during coughing (p<0.01) vs. those in sneeze. Mechanical nasal stimulation (when no sneeze was evoked) had no significant effect on cough (7 cats). In the combined trials (both cough and sneeze were executed; 7 cats), the responses were classified as either sneeze or cough (no hybrid responses occurred) and they were potentiated comparing to control reflexes. Higher expiratory maxima (esophageal pressure and the amplitudes of abdominal muscles EMG) compared to control coughs and sneezes were found (p<0.05). In sneeze during combined trials also inspiratory efforts and the number of sneezes were increased (p<0.05). We conclude that mechanosensitive nasal afferents have limited effect on the tracheobronchial cough response. However, co‐expression of coughing and sneezing results in a variety of enhanced cough and sneeze responses supposedly representing improved airway defense.“This work was supported by the Slovak Research and Development Agency under the contract No. APVV‐0189–11“ The project is co‐financed from EU sources“ – ERDF – European Regional Developmental Fund, and by VEGA 1/0126/12
Heart Failure with Preserved Ejection Fraction Induces Molecular, Mitochondrial, Histological, and Functional Alterations in Rat Diaphragm Muscle
Authors: Bowen T Scott , Rolim Natale , Fischer Tina , Bækkerud Fredrik , Medeiros Alessandra , Werner Sarah , Bronstad Eivind , Rognmo Oivind , Mangner Norman , Linke Axel , Schuler Gerhard , Silva Gustavo , Wisloff Ulrik , Adams Volker 
Published: June 2021

Peripheral muscle dysfunction is a key mechanism contributing to exercise intolerance in heart failure patients with preserved ejection fraction (HFpEF), however the underlying mechanisms remain unknown. We used an animal model to better understand potential molecular, mitochondrial, histological, and functional alterations induced by HFpEF in the diaphragm.MethodsFemale Dahl salt‐sensitive rats were fed a low‐ or high‐salt diet of 0.3% or 8% NaCL for 28 weeks. Heart function and diaphragm alterations were subsequently assessed.ResultsCompared to low‐salt rats (CON; n=10), high‐salt rats (n=11) developed HFpEF, as demonstrated by impaired diastolic function, preserved left ventricular EF, left ventricular hypertrophy, elevated systolic blood pressure, increased pulmonary congestion, and elevated plasma natriuretic peptides (P<0.05). HFpEF rat diaphragm demonstrated (P<0.05): 1) a fiber type distribution shift from fast‐to‐slow twitch; 2) a decreased pro‐oxidative but increased anti‐oxidant capacity; 3) reduced proteasome activation; 4) impaired in situ mitochondrial respiration at complex I: 5) in vitro muscle weakness and increased fatigability in fiber bundles.ConclusionThese data suggest a skeletal muscle myopathy exists in HFpEF and identifies novel mechanisms of exercise intolerance in HFpEF.
Hyperglycaemia Elevates Epithelial Lactate Secretion and Alters pH of Airway Surface Liquid
Authors: Garnett James , Baker Emma , Baines Deborah 
Published: June 2021

Glucose in airway surface liquid (ASL) is normally ~0.4 mM, but rises (up to 4mM) when blood glucose is elevated (hyperglycaemia) and in respiratory disease, making the lung more susceptible to respiratory infection. We investigated whether hyperglycaemia also modified ASL lactate concentrations and the pH, of bronchoalveolar lavage (BAL) from wild type (WT) and glucokinase deficient GK+/‐ mice, and the ASL of primary human bronchial epithelial cells (HBE) and cell lines H441 & Calu3, cultured at air‐liquid‐interface.Blood glucose was elevated in GK+/‐ compared to WT mice (WT= 9.4±0.2 mM, GK+/‐= 15.1±0.6 mM; p<0.001, n=12). BAL (but not blood) lactate was elevated in GK+/‐ mice (0.052±0.002 to 0.09±0.008 mM; p<0.05, n=6) and there was a correlation between blood glucose and BAL lactate. There was no difference in BAL inflammatory cell counts between GK+/‐ and WT mice (n=6), indicating another source of lactate in GK+/‐ lung.In vitro, elevation of basolateral glucose from 5 to 15 mM increased ASL lactate concentrations (Calu‐3= 2.2±0.7 to 7.1±1.2 mM; H441= 3.7±0.3 to 8.3±1.0 mM; HBE= 0.51±0.11 to 2.2±0.12 mM; P<0.05, n=7‐13) after 6 hours, and also produced an alkalinisation of Calu‐3 and HBE monolayer ASL, but acidified Cystic Fibrosis (CF) HBE ASL. This acidification could be mimicked in normal HBE monolayers by removing HCO3‐ from the bathing solution. Inhibition of MCT1/2 with AR‐C155858 (100 nM) partially overcame the effects of hyperglycaemia on ASL lactate and pH.These data indicate that hyperglycaemia increases lactate in ASL via secretion through epithelial MCT1/2 transporters. Also, the airway epithelium compensates for MCT driven H+ secretion by secreting HCO3‐, which is defective in CF epithelia.Funded by MRC‐MICA MR/K012770/1.
The Lung Macroautophagy Substrate Proteome: A SYSTEMS BIOLOGY Analysis
Authors: Haspel Jeffrey , Chettimada Sukrutha , Lane Bill , Choi Augustine 
Published: June 2021

RationaleMacroautophagy is a lysosome‐based catabolic process that is implicated in the pathogenesis of multiple diseases. Although macroautophagy is ubiquitous, its physiologic role may be specialized in various tissue types and we know little of how this process contributes specifically to homeostasis in the lung. Since standard markers of macroautophagy cannot convey information about tissue‐specific patterns of catabolism we used a proteomic approach to compare autophagosome substrate turnover in mouse lung to that of mouse liver.Methods:We measured macroautophagic activity in the lungs and liver of GFP‐LC3 expressing transgenic mice using a leupeptin based protocol we developed previously. GFP‐LC3+ vesicles were were analyzed via 1D‐SDS PAGE followed by label‐free LC‐MS‐MS.Results:The macroautophagy substrate proteome of the lung was highly divergent than that of livers. Specific to lung macroautophagy, tight junction components were part of the substrate proteome in this organ. Lung macroautophagy had a higher predilection than liver for secreted proteins, possibly reflecting increased input from retrograde endocytic traffic to amphisomes. There was also a greater contingent of leukocyte‐associated proteins among lung macroautophagy substrates.ConclusionsA proteomics‐based approach successfully identified organ specific variations in macroautophagy. We believe this approach will prove useful for understanding how disease states reprogram macroautophagy, and conversely how macroautophagy regulation brought about by interventions are likely to affect cellular physiology in different cell types.
Neuronal Na+ Channels as a Novel Cardiac Antiarrhythmic Target
Authors: Radwanski Przemyslaw , Brunello Lucia , Knollmann Björn , Gyorke Sandor 
Published: June 2021

BackgroundCertain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum. Surprisingly, CPVT patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains elusive.MethodsConfocal microscopy and patch‐clamp recordings ofventricular myocytes isolated from CPVT mouse model with genetic ablation of cardiac calsequestrinwere used to assess Ca2+ handling and Na+ current density during various pharmacological interventions, while surface electrocardiograms were performed during catecholamine challenge.ResultsA subpopulation of Na+ channels (neuronal‐ and not cardiac‐type Na+ channels) colocalize with RyR2. Disruption of the cross‐talk between these by neuronal Na+ channel blockade abolished persistent Na+ current and reduced DCR in cells (Fig a).imageSuch reduction of DCR on cellular level translated in decreased arrhythmias in vivo (Fig b). On the other hand, augmentation of the neuronal Na+ channel activity with β‐Pompilidotoxin (β‐PMTX) increased DCR and caused frequent arrhythmias.ConclusionThese data suggest that neuronal Na+ channels can potentially serve as an antiarrhythmic target. As current antiarrhythmic drugs are all cardiac‐type Na+ channel blockers, this is a major conceptual shift in cellular arrhythmogenesis.
Clonal Growth Capacity and Phenotype of Ex Vivo Expanded Oral Mucosal Tissue
Authors: Islam Rakibul , Utheim Tor , Eidet Jon , Lippestad Marit , Messelt Edward , Griffith May , Dartt Darlene 
Published: June 2021

PurposeCultured oral mucosal epithelial cells can treat stem cell deficiency of the cornea. The present study aims to determine the best site for harvesting oral mucosal cells and the effects of four media on these cultured cells.MethodsPieces of oral epithelium were used from four locations: buccal mucosa (BM), hard palate (HP), lower lip (LL), and transition zone of the lower lip (TZ) of Sprague‐Dawley rats. Explants were grown in four different culture media for six days. The media were 1) RPMI 1640; 2) EpiLife; 3) oral keratinocyte medium (OKM); and 4) DMEM and Ham 12 (1:1 mixture). Morphology, phenotype, and colony forming efficiency were analyzed.ResultsDMEM and RPMI yielded higher explant outgrowth than OKM and EpiLife. Using DMEM and RPMI, fold growth was superior from LL biopsies (36.43 ± 7.42 and 32.34 ± 12.22, respectively) compared to biopsies from HP (7.46 ± 0.69 and 10.14 ± 1.14, respectively), BM (11.15 ± 2.94 and 22.40 ± 8.45, respectively) and TZ (19 ± 3 and 15 ± 4.02, respectively) (p<0.05; N=4‐11). The percentage of PCNA+ cells was lower near the explant than at the leading edge whereas the percentage of NGF P75+ was not significantly different in any of the locations. In DMEM, cells from TZ showed higher colony forming efficiency (0.059% ± 0.004%) than cells from BM, HP and LP (p<0.05; N=5).ConclusionsThe transition zone of the lower lip, which showed the highest colony forming ability, may be most effective in treating limbal stem cell deficiency.
B Vitamin Damage and its Repair or Pre‐Emption
Authors: Hanson Andrew 
Published: June 2021

Two increasingly recognized facts about metabolism are that (i) metabolites are damaged by spontaneous and enzymatic side‐reactions that form potentially toxic products, and (ii) cells have conserved enzymes that repair or pre‐empt such damage. B vitamins and the corresponding cofactors are highly damage‐prone, yet must be kept intact because they are essential. It is therefore no surprise that B vitamin/cofactor metabolism provides iconic examples of metabolite damage and its repair or pre‐emption, such as the following.Repair of NADH and NADPH. These cofactors undergo enzymatic and chemical reactions that produce R and S forms of NAD(P)H hydrates [NAD(P)HX], which can inhibit dehydrogenases. The hydrates are repaired by the tandem action of an ADP‐dependent dehydratase that converts (S)‐NAD(P)HX to NAD(P)H and an epimerase that interconverts the R and S forms. The dehydratase and epimerase are triple‐targeted to plastids, mitochondria, and cytosol, enabling them to reconvert NAD(P)HX to NAD(P)H throughout the plant cell.Pre‐empting damage in riboflavin biosynthesis. The first two intermediates of riboflavin biosynthesis in plants and bacteria are reactive potential damage agents, and may be over­produced because the biosynthetic enzymes lack feedback controls. Excesses of these intermediates are disposed of by COG3236, a protein that is fused to different riboflavin pathway enzymes in plants and bacteria. COG3236 cleaves the N‐glycosidic bond of riboflavin intermediates, yielding fairly harmless products and thus pre‐empting damage to the riboflavin pathway.