bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between ferritin, transferrin receptor and retinol biomarkers obtained from dried blood spots and anthropometric measures in Kenyan children
Authors: Haddad Ella H. , Ndiku Mueni , Haddad Victoria H. , Bahjri Khaled , Sabaté Joan 
Published: June 2021

Micronutrient deficiencies continue to be a problem in Africa and dried blood spot (DBS) specimens provide a practical means to explore their causes. This study examined the association of DBS biomarker data with age and anthropometric measurements. DBS specimens were collected from 369 children aged 0–59 months residing in four randomly selected locations in the Ukambani region of Kenya. A 0.635 cm disk was punched from the DBS on the collection card and extracted with buffer. Ferritin and transferrin receptor were assayed by ELISA and retinol by HPLC. Anthropometric measures obtained on site were used to compute malnutrition indices (z‐scores) using EPI INFO 2000. With increasing age, DBS concentration of ferritin decreased (P=0.02), transferrin receptor increased (P<0.001) and retinol showed no change. There were significant positive correlations between ferritin and weight‐for‐height, weight‐for‐age and height‐for‐age z scores, whereas transferrin receptor was negatively correlated to weight‐for‐height and height‐for‐age z scores (P<0.05). In conclusion, values for ferritin and transferrin receptor varied with age and were correlated to anthropometric measures whereas those of retinol did not show similar outcomes.Funded by the Federico Foundation, Switzerland.
In Vivo 129 Murine Model of Salmonella Infection is a Powerful Tool to Examine Human Clinical Isolates
Authors: Harrington Jane , Eckmann Lars , Guiney Donald 
Published: June 2021

Non‐typhoidal Salmonella are the leading causative agents of bacterial gastroenteritis in immuno‐competent hosts; however, Salmonella are also associated with typhoid‐like systemic infection in immuno‐compromised patients. Identification of Salmonella from stool samples of HIV+ patient suggests that bacterial genomic variations might contribute to the course of disease, in addition to immune status of the patient.We have developed a novel mouse model to examine essential factors required for systemic infection with Salmonella clinical isolates. The “highly virulent” strain, UC17, was isolated from an HIV+ patient with bacteremia. The “low virulent” strain, UC9, was cultured from a stool sample of an HIV+ patient presenting acute gastroenteritis. In vitro analysis of SpvB expression (a known virulence factor) showed that UC17 expresses abundant SpvB levels and UC9 expresses low levels of SpvB. We have observed greater infection rates in liver and spleen by UC17, as compared to UC9, with the 129 mouse model(NRAMP+). We have generated SpvR knockouts (positive regulator of spvB) in the UC9 and UC17 parental backgrounds and co‐infected 129 mice with WT/spvR knockout sets to verify that SpvB is a required virulence factor for in vivo murine infection. This model has the potential to serve as an effective experimental approach to examine the key determinants for Salmonella infection in humans.
Allosteric Modulation of Cannabinoid CB1 Receptor
Authors: Ross Ruth A. , Baillie Gemma L. , Pertwee Roger G. 
Published: June 2021

ORG27569, an allosteric modulator of the cannabinoid CB1 receptor increases the binding affinity of CB1 receptor agonists but reduces the agonist signalling efficacy. Allosteric modulators can have differential effects on various signalling pathways. The aim of the present study was to investigate the effect of ORG27569 on various agonist‐induced CB1 receptor signalling pathways.ORG27569 (100 nM) markedly reduced the efficacy of CP55940 in the [35S]GTPγS binding assay, β arrestin assay and cyclic AMP assay. In contrast, 1μM ORG2759 had no significant effect on the efficacy of CP55940 in pERK assay. These data provide evidence that cannabinoid CB1 receptor allosteric modulators can preferentially impact various signalling pathways.
Peripheral Sensory Function Enhanced Using Stochastic Noise Stimulation
Authors: Serrador Jorge , O'Laighin Gearóid , McIntosh Caroline , O'Tuathail Claire , Quinlan Leo R , Dinneen Sean F , Breen Paul 
Published: June 2021

Peripheral neuropathy is common with both aging and disease. This sensory loss can impair the ability to feel trauma or forces during gait increasing the risk of falling, tissue damage, foot ulceration and amputation. We hypothesized that we could improve peripheral tactile sensation in the entire plantar aspect of the foot by applying subsensory electrical noise stimulation to the sensory nerve supplying this area.We applied imperceptible levels of electrical stochastic noise stimulation to a region of the tibial nerve above the ankle. Vibrotactile perception improved in both young and older individuals despite age related neuropathy in the older group. Both groups improved ~16% despite differences in baseline levels. All sites tested showed improvement, indicating that all sensory neurons on the plantar aspect of the foot and travelling down the tibial nerve were affected to a comparable degree.These are the first data to demonstrate that modulation of axon properties with applied electrical noise can improve neural transmission and perception of tactile stimuli. We suggest that the improvement in perception is due to changes in neural synchrony, a hypothesis that is supported by a developed computational model. Currently there are no treatment options for loss of sensory function and this work may have significant implications in the development of treatment models for neurodegenerative conditions.
Acute dietary salt loading impairs endothelial‐dependent dilation in normotensive‐salt resistant adults
Authors: DuPont Jennifer J , Greaney Jody L , Wenner Megan M , Lennon-Edwards Shannon L , Farquhar William B , Edwards David G 
Published: June 2021

In humans, the effects of salt consumption on endothelial function have not been separated from the effects on blood pressure (BP). We sought to determine whether acute salt loading adversely affects endothelial function in normotensive salt‐resistant individuals. We hypothesized that brachial artery flow‐mediated dilation (FMD) would be impaired during a high salt diet in the absence of a change in BP. Fourteen healthy adults with salt‐resistant BP were studied (9M,5F; age 33±2.4 years). After a control run‐in diet, subjects were randomized to a 7 day high salt (HS) (350 mmol/day) and a 7 day low salt (LS) (20 mmol/day) diet (controlled feeding study). Salt‐resistant BP was defined as a change in 24 hour mean BP of ≤ 5 mmHg from the LS to the HS diet. FMD was measured in each subject on the last day of each diet. 24 hour mean BP was unchanged between the LS and the HS diet (LS: 85±1, HS: 85±2 mmHg). Sodium excretion significantly increased during the HS diet (LS: 29±9, HS: 231±16 mmol/24hr, p < 0.05). FMD was significantly impaired on the HS diet (LS: 10.3±0.9, HS: 7.3±0.7%, p < 0.05). These data suggest that in normotensive salt‐resistant adults, a high salt diet impairs endothelial‐dependent dilation independent of changes in arterial BP.Supported by 2 P20 RR016472‐11 and HL104106.
TRPC Channels In Ca2+ Regulation And Endothelial Function During Cardioplegic Exposure
Authors: Yang Qin , Huang Jun-Hao , He Guo-Wei , Underwood Malcolm J , Yu Cheuk-Man 
Published: June 2021

Elevation of [Ca2+]i is essential to endothelial function and depolarization of endothelial membrane results in a reduction of Ca2+ influx. We studied whether canonical transient receptor potential channels (TRPC), i.e., TRPC3, is involved in [Ca2+]i dysregulation and endothelial dysfunction caused by depolarizing cardioplegia. [Ca2+]i was measured in porcine coronary endothelial cells (PCECs) and relaxation was studied in porcine small coronary arteries. Ca2+ influx and Ca2+ influx via TRPC3 were decreased in PCECs exposed to hyperkalemic solutions (10, 20 or 120 mM K+) in a concentration‐dependent manner and similar reductions occurred in cardioplegic exposure (ST, HTK or UW solution). The reduction was prevented by TRPC3/6/7 activator OAG. Hyperkalemic or cardioplegic solutions decreased EDHF‐mediated relaxation that was restored by OAG‐addition (in 20 mM K+: 52.5±4.0% vs. 67.2±4.3%; in ST: 52.2±4.8% vs. 65.0±4.8%; p<0.01). We conclude that the decrease of Ca2+ influx via TRPC3 is involved in endothelial [Ca2+]i reduction caused by depolarizing cardioplegia. TRPC activation restores Ca2+ influx and prevents EDHF impairment. This study may provide new insight for improvement of cardioplegic solutions.Supported by GRF CUHK4789/09M; CUHK2041688; China Nat'l Ministry of Sci. & Tech. 2009DFB30560 & 2010CB529502(973); Tianjin Municipal Sci. & Tech. Commission 09ZCZDSF04200 & 10JCYBJC26400.
Steviol, an aglycone of natural sweetener stevioside, slows MDCK cyst progression by reducing activity and expression of CFTR chloride channels
Authors: Yuajit Chaowalit , Muanprasat Chatchai , Chatsudthipong Varanuj 
Published: June 2021

Pathogenesis of polycystic kidney disease (PKD) involved cAMP‐stimulated chloride secretion into cyst lumen. The present study was aimed to investigate an inhibitory effect and detailed mechanisms of steviol and its derivatives on cyst growth and cyst formation using Madin Darby canine kidney (MDCK) cyst models. Among 4 steviol‐related compounds, steviol was found to be the most potent compound that inhibited both MDCK cyst growth and formation. Steviol at 100 μM reversibly inhibited cyst growth and cyst formation by 38.3% and 72.4 %, respectively. Steviol at doses up to 200 μM had no cytotoxic effect on MDCK cells. Determined by Ussing chamber experiments, steviol acutely inhibited forskolin‐stimulated apical chloride current in MDCK monolayers by ~40%. Interestingly, prolonged treatment (2–24 hours) with steviol produced 50–80% inhibition of forskolin‐stimulated apical chloride current across MDCK monolayers in dose and time‐dependent manners. In addition, treatment with steviol significantly reduced cystic fibrosis transmembrane conductance regulator (CFTR) expression in MDCK cells. These findings suggest that steviol retarded MDCK cyst progression, in part, by reducing both CFTR activity and expression. Steviol and related compounds represent promising natural plant‐based drug candidates for polycystic kidney disease.This work was supported by the Thailand Research Fund and the Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative.
Fasting hyperglycemia blunts the regression of impaired glucose tolerance in older adults after lifestyle modification
Authors: Malin Steven K. , Kirwan John P. 
Published: June 2021

Lifestyle modification (LM) delays the progression from prediabetes to type 2 diabetes (T2D), but no study has determined the efficacy of LM on glucose metabolism in different prediabetes subtypes.MethodsOlder (65.1 ± 0.6yr) obese adults with impaired fasting glucose (IFG; n=12), impaired glucose tolerance (IGT; n=9), and combined glucose intolerance (IFG+IGT = CGI; n=22) were compared to normal glucose tolerant (NGT; n=15) and T2D (n=18) groups after 12 weeks of LM (60 min/d for 5d/wk at ~85% HRmax). An oral glucose tolerance test was used to assess glucose levels. Insulin sensitivity (euglycemic hyperinsulinemic: 40 mU/m2·min−1) and β‐cell function (glucose induced insulin secretion corrected for insulin sensitivity) were also assessed.ResultsLM reduced weight and improved aerobic fitness and β‐cell function similarly across groups (p < 0.05). LM lowered fasting glucose levels in IFG, CGI and T2D (p < 0.05) and 2‐hour glucose levels in IGT, CGI and T2D (p < 0.05). However, 2‐hour glucose levels were not normalized in adults with CGI compared to IGT (p < 0.05). Insulin sensitivity was improved approximately 40% in IFG and IGT, but only 17% in CGI.ConclusionAfter 12‐ weeks, lifestyle modification may not be sufficient to normalize 2‐ hour glucose levels in adults with CGI. Given the high risk of progressing to T2D, adults with CGI may require more aggressive therapies to prevent diabetes. Support: RO1 AG12834 (J.P.K).
Differential effects of a High‐Fructose diet or a High‐Fat/High‐Sucrose diet on the mitochondrial ROS production and respiration in rat liver and skeletal muscle
Authors: Couturier Karine , Le Guen Marie , Coudray Charles , Feillet-Coudray Christine , Wrutniak-Cabello Chantal , Cabello Gérard , Dubouchaud Hervé 
Published: June 2021

We studied the alterations of the mitochondrial function in response to various hypercaloric diets, and their relation with the occurrence of obesity and/or metabolic syndrome. Male Wistar rats were fed with either standard diet (Control), High‐Fructose (HF) or High‐Fat/High Sucrose (HF/HS) for 6 weeks. Rats under HF/HS displayed increase in body weight, insulin resistance, liver steatosis, and in visceral adiposity when compared to control. In HF/HS, TBARs, AOPP, and antioxidative enzymes were higher in plasma and muscle when compared to control. HF diet but not HF/HS diet was associated to a lower oxygen consumption by liver isolated mitochondria under non phosphorylating conditions whatever the substrate used excepting palmitoyl‐carnitine, compared to control (−30 to −60%). We also report a higher citrate synthase activity in liver tissue in the same condition (+53%) compared to control diet. Activities of complexes II and III are lower in HF and in HF/HS compared to control. H2O2 release by liver isolated mitochondria was higher in HF with succinate as a substrate, compared to the control suggesting alterations of both complex I and III. These results suggest that the type of diet has different effects on mitochondrial function that could related to the obesity and insulin resistance states.This work was supported by the French Agence Nationale pour la Recherche (ANR : project MitHyCal).
Decreased protein expression and activity of transglutaminases 1 and 2 in arteries from DOCA‐salt rats
Authors: Petersen-Jones Humphrey , Johnson Kyle B. , Thompson Janice M. , Watts Staphanie W. 
Published: June 2021

Transglutaminases (TGs) catalyze a variety of protein modification reactions in the vasculature, and TG‐mediated protein remodeling has been implicated in hypertension. We hypothesized that there would be a higher expression of TGs in hypertensive vs normotensive vasculature due to protein cross‐linking catalyzed by the TGs. We used aorta (RA) from deoxycorticosterone acetate (DOCA)‐salt (hypertensive) and sham (normotensive) control rats. Methods included immunohistochemistry (IHC), Western blot analysis, and in situ fluorescent detection of active TGs using the K5 (TG1) and T26 (TG2) peptides. IHC showed a decreased expression of TG1 and TG2 in DOCA‐salt rat aorta (TG1: DOCA 1.22, sham 1.44; TG2: DOCA 0.61, sham 1.61 arbitrary rank units) and in situ detection showed decreased activity of TG1 and TG2 in DOCA‐salt rat aorta (TG1: DOCA 2.0, sham 2.72; TG2: DOCA 1.79, sham 2.56 arbitrary rank units). Similarly, protein expressions of TG1 and TG2 in DOCA‐salt rat aorta were diminished compared to the control (TG1: DOCA 27.8 ± 2.52, sham 51.9 ± 13.0; TG2: DOCA 83.2 ± 3.85, sham 108 ± 5.83 arbitrary densitometry units/alpha actin; p<0.05). We conclude that there is less activity and decreased levels of TG1 and TG2 in hypertensive rat aorta compared to sham. This contradicts our hypothesis and supports the idea that lack of compensatory TGs may a role in the pathology of hypertension.POIHC70687
Physical association of Angiotensin‐II type 1 Receptor (AT1R) and NOX‐1 mediates NF‐κB and AP‐1‐dependent Interleukin‐ 18 induction and Aortic SMC Migration and Proliferation
Authors: Valente Anthony J , Yoshida Tadashi , Wekerle Ryan , Katsuyama Masato , Chandrasekar Bysani 
Published: June 2021

Persistent elevation of angiotensin (Ang)‐II promotes atherosclerosis via oxidative stress and induction of inflammatory cytokines. Since NF‐κB and AP‐1 are important mediators in Ang‐ II signaling pathways, and since the pro‐mitogenic and pro‐migratory factor interleukin (IL)‐18 is an NF‐κB and AP‐1 responsive gene, we investigated whether Ang‐II‐mediated SMC migration and proliferation are IL‐18 dependent. Ang‐II stimulated the migration and proliferation of SMC isolated from rat thoracic aorta. Ang‐II induced O2− generation, IKKβ and JNK activation, p65 and c‐Jun phosphorylation, NF‐κB and AP‐1 activation, and IL‐18 transcription, effects that were attenuated by losartan, DPI, and NOX‐1 knockdown. Both αIL‐18 Ab and IL‐18BP attenuated Ang‐II induced SMC migration and proliferation. Importantly, AT1R binds NOX‐1 in vitro and in vivo. Ang‐II also induced Nox1 transcription via AP‐1. Ang‐II infusion (7 days) increased NOX‐1 mRNA expression, DPI‐inhibitable O2− generation, p65 and c‐Jun phosphorylation, and IL‐18 induction in endothelium‐denuded thoracic aorta in an AT1R‐dependent manner.ConclusionsAng‐II stimulates SMC migration and proliferation via AT1R/NOX‐1‐ mediated IKK/NF‐κB and JNK/AP‐1‐dependent IL‐18 induction, and this process may involve AT1R/NOX‐1 physical association. The AT1R/NOX‐1/IL‐18 pathway may be a critical mechanism in atherogenesis and restenosis.
ET‐1‐induced Superoxide‐dependent NFATc3 Activation
Authors: Diaz Juan Manuel Ramiro , Nitta Carlos H , Sherpa Mingma L , Bosc Laura V Gonzalez 
Published: June 2021

Endothelin‐1 (ET‐1)‐induced activation of Nuclear Factor of Activated T‐cells isoform c3 (NFATc3) is necessary for the progression of chronic hypoxia (CH)‐induced pulmonary hypertension. Reactive oxygen species (ROS) levels are elevated in CH. ET‐1 increases ROS in pulmonary artery smooth muscle cells (PASMC). ROS participates in NFAT activation in cancer cells. However, it is unknown whether ROS mediates ET‐1‐induced NFATc3 activation in PASMC. Using human PASMC electroporated with a NFATc3‐GFP plasmid, we tested the hypothesis that increased ROS participates in ET‐1‐induced NFATc3 activation. Cells were pretreated with vehicle, a superoxide dismutase mimetic (tempol), a superoxide dismutase inhibitor (diethyldithiocarbamate, DDC) or H2O2. Nuclear fluorescence was measured before and during ET‐1 treatment. To prevent NFATc3 nuclear export, the CRM1 exportin inhibitor leptomycin B was present in all experiments.Our results show that pretreatment with both tempol and H2O2 inhibited ET‐1‐induced NFATc3 nuclear import. On the other hand, DDC enhanced ET‐1‐induced NFATc3 nuclear import.To determine the intracellular source of ROS, cells were pretreated with a xanthine oxidase inhibitor, allopurinol (Allo), or a NADPH oxidase inhibitor, apocynin (Apo). Allo but not Apo inhibited ET‐1‐induced NFATc3 nuclear import.Our results suggest that in human PASMC, ET‐1‐induced NFATc3 nuclear import is dependent on xanthine oxidase‐derived superoxide and/or a reduction in H2O2 levels. Therefore, it is possible that elevated superoxide levels in CH contribute to NFATc3 activation.Funding source: R01 HL088151
Orthopedic trauma reduces renal hemodynamics in the STZ‐induced diabetic rat
Authors: Manigrasso Michaele Beth , Davis Deborah D , Lu Silu , Xiang Lusha , Hester Robert L 
Published: June 2021

Diabetes is an independent risk factor for the development of acute renal dysfunction following orthopedic trauma (OT). Whether OT affects renal hemodynamics has yet to be investigated. The hypothesis tested in this study was that OT reduces renal hemodynamics in type 1 diabetes.Male lean Zucker rats (12 wks) were divided into 4 treatment groups (n=4/gp): non‐diabetic without trauma (ND‐NT), non‐diabetic with trauma (ND‐T), STZ‐induced diabetic without trauma (D‐NT) and STZ‐induced diabetic with trauma (D‐T). Four wks after induction of diabetes, animals were implanted with catheters and OT was induced by soft tissue injury and local injection of bone components in both hind limbs. Animals were placed in metabolic cages for 12hrs to collect urine and urine albumin excretion (UAE) was measured by ELISA. 24 hrs post‐trauma, glomerular filtration rate (GFR) was measured in conscious rats. Our results show that diabetes after 4 wks causes a reduction in GFR compared to controls. However, OT caused a greater reduction in GFR in diabetics than controls. Our data suggest that OT compromises renal function in the setting of type 1 diabetes.

Group
Body Weight (g)
Glucose (mg/dL)
UAE (mg/day)
GFR/KW (ml/min/g)

ND‐NT
396±25
81±6
0.5±0.1
1.37±0.09

ND‐T
415±20
85±4
1.2±0.7
1.52±0.08

D‐NT
298±12*#
358±27*#
3.3±0.6*#
1.17±0.08#

D‐T
330±14*#
366±15*#
4.6±0.3*#
1.06±0.07*#

Avg±SEM;
P<0.05 vs. ND‐NT;
P<0.05 vs. ND‐T
Role of Aquaporin2 (Aqp2) in the increased urinary flow of K‐adapted mice
Authors: Contreras Jacob I. , Hatcher Lori I , Cornelius Ryan J. , Sansom Steven C. 
Published: June 2021

Mice fed a high K diet maximize K excretion partly by increasing distal flow, which activates large, Ca‐activated K channels in connecting tubules (CNT) and cortical collecting ducts (CCD). Flow is increased by medullary K recycling and inhibition of Cl absorption in the thick ascending limb; however, other events may increase flow. We hypothesized that diuresis of a high K diet is partly due to less Aqp2 in the apical membranes of CNT cells and principal cells (PC) of the CCD. We found that flow increased from 1.3 ±0.5 ml/day in mice fed a control diet (Na =0.3%, K = 0.6%) to 6.7 ±0.5 ml/day in high K fed mice (HK; Na = 0.3%, K =5%). The urine osmolality of control was 2296 ±201 mosm/L and of HK was 1487 ±46 mosm/L. HK consumed three‐fold more water; however, the hematocrits (control =41.5 ±0.3%; HK = 42.3 ±0.6%) were not different, indicating that the diuresis was not the result of a primary increase in water consumption. Estimated urea excretions for controls (1831 ±191 μmoles/day) and HK (1909 ±224 μmoles/day) were not different. Using immunohistochemical staining with anti‐Aqp2, we found that Aqp2, which was intensely stained (26.4±1.6 AU) on the apical membranes of CNT and PC of control, exhibited significantly less apical staining (20.2±1.3 AU) in HK.ConclusionThe increased flow of HK is not the result primary drinking or an osmotic urea diuresis, but may be partly the result of reduced Aqp2‐mediated water reabsorption.
Elevated oxygen utilization and superior energetic reserve in superhealer mesenchymal stem cells
Authors: Hughey Curtis C , Alfaro Maria P , Belke Darrell D , Rottman Jeffrey N , Young Pampee P , Wasserman David H , Shearer Jane 
Published: June 2021

ObjectiveIschemia‐induced death impedes the efficacy of cell‐based therapies in the treatment of a myocardial infarction. Superhealer MRL/MpJ mesenchymal stem cells (MRL‐MSCs) exhibit increased engraftment resulting in reduced infarct size and enhanced contractile function.Methods and ResultsHigh resolution respirometry was employed to evaluate differences in mitochondrial oxidative phosphorylation that explain the enhanced cellular survival and engraftment of MRL‐MSCs. Compared to wild type MSCs, MRL‐MSCs exhibited an increase in physiological respiration and maximal electron transport capacity by 2.0‐ and 3.5‐fold, respectively. When routine oxygen utilization is expressed as a portion of maximal cellular oxygen flux, the MRL‐MSCs have a greater energetic reserve. Additionally, succinate‐supported oxygen consumption is elevated 1.4‐fold in the MRL‐MSCs.ConclusionMRL‐MSCs exhibit a greater reliance on and capacity for aerobic metabolism. These characteristics may diminish cell death upon transplantation into the infarcted heart by increasing ATP synthesis per unit substrate and preventing glycolysis‐mediated acidosis. This work was supported by CIHR, AHFMR, CDA, HSF and NIH Grant [R01‐ HL088424].