bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic variation in the vitamin D receptor (VDR) and the plasma proteome
Authors: Bailo Bibiana Garcia , Badawi Alaa , El-Sohemy Ahmed 
Published: June 2021

Vitamin D deficiency has been linked to numerous diseases. 1,25(OH)2D, the active vitamin D form, binds to the nuclear vitamin D receptor (VDR) and affects target gene expression in multiple pathways. However, it is not known if genetic variants in VDR affect plasma protein levels. The objective was to explore associations between VDR variants and 54 plasma proteins belonging to disease‐associated pathways in healthy young adults (n=488). 16 genetic variants across VDR were extracted from genome‐wide data available for the study cohort. Protein concentrations were measured by a multiple reaction monitoring HPLC‐MS/MS assay. Associations between proteins and variants were explored by linear regression with an additive inheritance mode. We found 32 significant associations. The strongest association (p=5.06×10−5) was observed between rs2283342 and inter‐α‐trypsin inhibitor HC (IT) (r2=0.03, β= −0.03±0.01), a serine protease inhibitor involved in inflammation. We then examined whether serum 25(OH)D, a marker of vitamin D status, affected any associations. 25(OH)D modified the association between rs2283342 and IT, as well as associations between rs2228570 (Fok1) and several apolipoproteins. These results suggest a role for vitamin D in disease associated pathways such as inflammation and lipid metabolism. Research support from the Advanced Foods and Materials Network.Grant Funding Source: Advanced Foods and Materials Network
Vitamin D‐Casein fortification of cheese and its bioavailability
Authors: Al-khalidi Banaz , Vieth Reinhold , Rousseau Derick , Chiu Winnie , Cockburn Moira , Bromberg Irvin 
Published: June 2021

Widespread vitamin D insufficiency worldwide and increased vitamin D intake recommendations from the Institute of medicine (IOM) emphasize a need to expand vitamin D fortification practices. IOM's 2011 report almost tripled the dietary guidelines for vitamin D: from 200 IU up to 600 IU daily. Vitamin D fortification practices vary and are largely voluntary in Canada and the US. Vitamin D‐fortified cheddar cheese using emulsified vitamin D3 was found to have comparable bioavailability of vitamin D with liquid supplement. Our objectives are to establish a new protocol for vitamin D fortification via incorporation of vitamin D in casein; and to evaluate the effect of baking on bioavailability. Vitamin D3 retention in lab‐scale mozzarella cheese was 54% and the loss of vitamin D3 into the whey was 1.6%. The remaining vitamin D3 was lost during mozzarella cheese processing. Large‐scale mozzarella cheese fortified with vitamin D3 will be used to cook pizza that will be consumed by study participants. Approximately 120 subjects will be randomized to weekly servings of pizza baked with fortified mozzarella cheese either at 200 IU/serving or 28,000 IU/serving. Vitamin D levels will be compared between groups. Vitamin D fortification of cheese is a good strategy to increase intakes and may benefit public health as well as dairy industry practices.Grant Funding Source: Dairy Farmers of Canada
Effect of infection and selenium status on the selenotranscriptome
Authors: Neidich Scott Daniel , Golly Elizabeth Maria , Beck Melinda A 
Published: June 2021

Previous work in our laboratory has shown that mice deficient in selenium develop heart pathology when infected with a normally benign coxsackievirus (CVB3/0). Many of the 24 selenoproteins present in mice are involved in protection from oxidative stress, which may be involved in limiting pathology post infection. In order to determine the effect of Se status and infection on the selenotranscriptome, we fed mice either a Se‐adequate or Se‐deficient diet for 4 weeks, followed by infection with CVB3/0. Uninfected mice in each diet group served as controls. We measured mRNA levels for 15 selenoproteins in the liver and heart daily for 10 days post infection. Selenoprotein mRNA expression was lower in Se‐deficient mice for GPx1, Sel M, Sel R, and Sel H independent of infection. During infection, mRNA levels for GPx1, GPx4, TR1, Sel K, and Sel N all exhibited increased expression, whereas GPx3, TR2, Sel M, and Sel W exhibited decreased expression, regardless of selenium status. These findings suggest that mRNA levels for a number of selenoproteins are influenced by infection and thus may play a role in protection and/or recovery from infectious disease.Grant Funding Source : NIH
Assessment of iron status and biomarkers of inflammation in schoolchildren with and without infection
Authors: Grijalva Maria Isabel , Garcia Karla Fabiola , Artalejo Elizabeth , Caire Graciela 
Published: June 2021

Iron deficiency is the most prevalent nutritional disorder in the world and the leading cause of anemia in children; it often occurs in populations with a high prevalence of chronic and/or repeated acute infections associated with chronic inflammation.ObjetiveTo evaluate the iron deficiency in schoolchildren by serum ferritin (SF), protoporphyrin and serum transferrin receptor (sTfR) in the presence or absence of infection.Subjects and MethodsA crossectional study was performed in 195 children of 5 to 11 years old. Hemoglobin (Hb), SF, protoporphyrin and sTfR were measured, as well as the inflammation biomarkers á1‐acid glycoprotein (AGP) and C‐reactive protein (PCR), to associate iron‐status indicators with the inflammatory process.ResultsThe prevalence of anemia (Hb <11.5 g/dL) was 5%. However, a 77% of iron deficiency was detected through serum ferritin. The values of RsTf and protoporphyrin were normal, indicating that the children were in the stage I of iron status. Despite this, SF correlated positively with PCR (r=0.178, p<0.05) but not with AGP (r=0.054, p=0.449). Correlations between RsTf and the markers of inflammation, AGP and PCR, were not statistically significant (P<0.05).ConclusionThe markers of inflammation did not influence the analysis of ferritin for the detection of iron deficiency.
Spermatogonium compartment in experimental administration of semicarbazide
Authors: Costa Eduardo Leitão , Marques Pedro , Marques Rodrigo Farinha , Cabrita Silvério 
Published: June 2021

Lathyrism is a pathologic condition with deficient collagen synthesis, which can be induced in the lab animal by the administration of semicarbazide.The aim of this study is to evaluate the seminiferous tubules morphologic changes, measuring the area occupied by the spermatogonia, in the experimental administration of semicarbazide.Thirty Wistar male rats, 8 weeks‐old were randomly distributed on two groups: the control group was kept without manipulation; the animals of test group were submitted to the administration of semicarbazide incorporated in the diet in the dose of 6g/kg, during 4 weeks. All the animals were sacrificed on the 30th day, by an overdose of anaesthetics and the complete necropsy was performed.The fragments collected in the necropsy were studied under light microscopy, stained by Haematoxylin & Eosin. The testicle's slides were submitted to morphometric analysis to evaluate the area occupied by spermatogonium compartment.The statistical analysis by frequencies distribution allows observing different distributions of the different cases. Comparing both groups, we observe more cases with medium area than on the test group. The graphic of the test group presents a peak of cases with greater areas than the control ones.These results allow us to conclude that the spermatogenesis is changed on the administration of semicarbazide.
Influence Of Chronic Nicotine On Acetylcholine‐Evoked Renal Vasodilations In Female Rats: Dose Dependency And Ovarian Hormonal Modulation
Authors: El-Mas Mahmoud M , El-gowilly Sahar M , Gohar Eman Y , El-Gowelli Hanan M 
Published: June 2021

In this study we report on the interaction of chronic nicotine with cholinergically‐mediated renal vasodilations in female rats and its modulation by ovarian hormones. Dose‐vasodilatory response curves to cumulative bolus doses of acetylcholine (ACh, 0.01–2.43 nmol) were established in phenylephrine‐preconstricted isolated perfused kidneys obtained from sham‐operated (SO) rats treated with or without nicotine (0.5–4.0 mg/kg/day for 2 weeks). The interaction was also evaluated in OVX rats in the absence or presence of progesterone (P), estrogen (E2), or their combination. The vasodilatory effects of ACh were potentiated in a dose‐dependent fashion by the low‐dose range of nicotine (0.5 and 1 mg/kg/day). By contrast, higher nicotine doses (2 and 4 mg/kg/day) failed to alter Ach responses. The co‐existence of both gonadal hormones, P and E2, seems imperative for the display of the potentiating effect of nicotine on ACh vasodilations because: (i) the increase in ACh responses by nicotine was lost in OVX kidneys, and (ii) combined supplementation with P and E2, but not individual treatments, restored the nicotine‐evoked potentiation of ACh vasodilation. Together, the data suggests that nicotine elicits dose‐ and gonadal hormonal‐dependent facilitation of ACh renal vasodilations in female rats.This project was supported financially by the Science and Technology Development Fund (STDF), Egypt, Grant No. 502.
Left ventricular longitudinal strain and strain rate are preload dependent
Authors: Gao Zhaohui , Drew Rachel C. , Momen Afsana , Ndukwu Ifesinachi , Muller Matthew D. , Mast Jessica , Blaha Cheryl , Leuenberger Urs A. , Sinoway Lawrence I. 
Published: June 2021

2D‐speckle tracking echocardiography (STE) derived strain and strain rate measurements have been proposed as potential non‐invasive measures of myocardial deformation and function. However, the effects of left ventricular (LV) loading conditions on 2D‐STE derived LV longitudinal strain and strain rate have not been elucidated. The aim of this study was to determine whether acute preload reduction by Lower Body Negative Pressure (LBNP) would alter 2D‐STE derived LV longitudinal strain and strain rate. LBNP varied between 0, −10, −20, −30, −40 and −50 mmHg (3 min/level) as strain and strain rate were assessed in 12 healthy individuals (26±1 yrs, 6 females and 6 males). Systolic peak strain (%), systolic (S‐Sr), early and late diastolic strain rate (E‐Sr and A‐Sr) were measured from standard LV apical views at each LBNP level. Compared to baseline, LBNP caused significant decreases in LV end‐diastolic volume (P<0.05) and stroke volume (P<0.01) while heart rate increased (P<0.01). LV longitudinal strain and strain rate decreased at LBNP ≥ −40 mmHg. Our results indicate that 2D STE‐derived longitudinal strain and strain rate are sensitive to acute preload changes. Thus, the effects of preload should be considered when strain and strain rate are used as indices of systolic and diastolic function.Supported by P01 HL096570 (LIS); UL1 RR033184 (LIS).
Small left heart syndrome and post‐coronary artery ligation outcomes in mice
Authors: Haskell Sarah , Peotta Veronica , Hermann Gregory , Reinking Benjamin , Roghair Robert 
Published: June 2021

OBJECTIVETest the hypothesis that neonatal SSRI exposed mice will have worsened cardiac function and mortality following myocardial infarctions.METHODSC57BL/6 pups received saline (10 ml/kg IP) or sertraline (5 mg/kg IP) on postnatal days 1–14. At 5 months, pups were implanted with telemeters. Mice then underwent left coronary artery ligation and were monitored by telemetry until death or 4 weeks post‐ligation. Echocardiograms were obtained at baseline and weekly following infarctions. Infarct area was measured on immersion‐fixed left ventricular sections.RESULTSAt baseline, sertraline exposed mice had increased heart rates, decreased left ventricular volumes, and decreased stroke volumes. Following coronary artery ligation, sertraline exposed mice had increased heart rates compared to control mice (control 470 ± 15 bpm, sertraline 516 ± 13 bpm, p<0.05). Post‐MI echocardiography showed decreased ejection fraction in control mice (baseline 60 ± 4%, post‐MI 41 ± 2%, p <0.01) but not SSRI exposed mice. There were no differences in mortality or infarct size between the groups.CONCLUSIONSWe speculate SSRI‐induced cardiac growth restriction may provide partial protection from post‐MI dilated cardiomyopathy. With 10% of pregnancies affected by maternal depression, it is crucial to determine the long term adverse effects from early SSRI exposure.
High fructose intake induces cardiac diastolic dysfunction in rats
Authors: Araujo Iara Cristina , Mostarda Cristiano , de Souza Lima Polyana , Yamane Larissa Naomi , de Souza Marina Soares , Fonteles Manasses , Fiorino Patricia , Farah Vera 
Published: June 2021

High fructose intake has metabolic impacts and induces cardiovascular alterations. The aim of this study was to evaluate morphometric and cardiac function induced by fructose intake in rats during 8 weeks. Weaned male Wistar rats with 21 days old (50–60g) were divided into 2 groups: Control (CG) and Fructose (FG, 10% in drinking water). Arterial pressure (AP) and heart rate (HR) were directly recorded using a data acquisition system (Windaq, 2KHz). Morphometric and cardiac function was evaluated under anesthesia (xilazin, 12mg/Kg and ketamin,80mg/Kg) by transthoracic echocardiography (Sequoia 512 machine, Acuson, Mountain View, CA). AP showed an increase of 17% in FG when compared to CG with no change in HR. There were no differences in systolic function and myocardial performance index between groups. However, a reduced normalized isovolumetric relaxation time and an increased E/A ratio were found in FG suggesting diastolic impairment of left ventricle. Taken together, these data suggest that high fructose intake found in western diet, increases blood pressure and determined left ventricular hypertrophy and diastolic dysfunction. These results provide support for the relationship between high fructose intake and the increased incidence of cardiovascular diseases observed in industrialized countries.Supported by: FAPESP(2009/52556‐7) and PIBIC/Mackpesquisa
PAR‐1 induced AMPK‐p38 MAPK signaling axis mediates STIM1 phosphorylation to prevent calcium entry through TRPC channels in endothelial cells
Authors: Sundivakkam Premanand , Natarajan Viswanathan , Malik Asrar B , Tiruppathi Chinnaswamy 
Published: June 2021

ObjectiveTo investigate the possible role of Ca2+ entry through TRPC channels in the signaling mechanism of STIM1 phosphorylation and thereby preventing Ca2+ entry through TRPC channels.ResultsHere we show that knockdown of TRPC1 in human endothelial cells (hECs) or deletion of TRPC4 in mouse endothelial cells (mECs), abolished thrombin‐induced Ca2+ entry, AMP‐activated protein kinase (AMPK) activation, p38 mitogen‐activated protein kinase (p38 MAPK) activation, and STIM1 phosphorylation in ECs. Pharmacological inhibition of either AMPK or its downstream target p38 MAPK, prevented PAR‐1‐ mediated STIM1 phosphorylation at Serine residues in ECs. Pretreatment of ECs with AMPK activator AICAR, enhanced basal STIM1 phosphorylation and markedly reduced PAR‐1‐induced Ca2+ entry in ECs. Interestingly, infecting ECs with adenovirus encoding wild type‐p38 MAPK increased basal STIM1 phosphorylation and blocked PAR‐1‐induced Ca2+ entry and permeability response. In contrast, expression of dominant negative‐p38 MAPK in ECs augmented PAR‐1‐mediated Ca2+ entry and permeability response.ConclusionOur findings demonstrate that PAR‐1‐induced Ca2+ entry through TRPC channels activates AMPK and p38 MAPK signaling pathway to reverse the Ca2+ entry and permeability response in ECs.
Disruption of endothelial cell/pericyte adhesion by PAI‐1 in ischemic limb of diabetic mouse
Authors: Wu Jianbo , Strawn Tammy L , William Fay P 
Published: June 2021

BackgroundDisruption of pericytes and acellular capillariesare increased in the feet of human diabetic patients. Selectiveloss of adhesion of pericytes to endothelial cells is known toearly event in diabetic microangiopathy. In diabetes, increased levels of PAI‐1 are strongly associated with endothelial dysfunction and progression. Based on these findings, we investigated whether PAI‐1 plays a role in modulating endothelial/pericyte adhesion inischemic hindlimbs of diabetic mice.MethodsType I diabetes was induced by intraperitoneal administrationof streptozocin in both PAI‐1 deficient mice (PAI‐1−/−) and WT mice. Ligation of femoral arterywas conducted to develop hindlimb ischemia. Plasma was collected for measurement of PAI‐1 and advanced glycated end products (AGE) levels by ELISA. Ischemic gastroceminus muscles were isolated. Adhesion ofpericytes to endothelial cells was assessed by scanning confocal and electron microscopy.ResultsPlasma total and active PAI‐1 levels were significantly increased in WT mice with STZ‐induced diabetes. PAI‐1−/−‐STZ was found to suppress plasma AGE level compared to WT‐STZ mice (basal level: 4.74 ± 1.19 Vs. 4.28 ± 1.03, n=8; STZ status: 5.54 ± 0.28 Vs. 9.75 ± 1.73, n=8, p< 0.05). Attachment between endothelial cell andpericyte from schemic gastroceminus muscles in PAI‐1−/−‐STZ was markedly increased compared with that in WT‐STZ mice.ConclusionsIncreased PAI‐1 levels disrupt endothelial cell/pericyte adhesionin ischemic limb of the diabetic mouse. These results identify an important role for PAI‐1 in diabetic microangiopathy.
Communication between Cardiomyocytes and Cardiac Fibroblasts: Mechanistic Role of ROCK1 in Fibrotic Cardiac Remodeling
Authors: Yang Xiangsheng , li qi , Lin Xi , yue xiaojing , chang jiang 
Published: June 2021

Study objectiveOur previous study found that Rho associated coiled‐coil protein kinase 1 (ROCK1) was cleaved into an active isoform ROCKΔ1 in failing human hearts. The study is to investigate the pathological consequence of ROCKΔ1 accumulated in heart and the associated molecular mechanism.Methods and ResultsWe generated transgenic mice expressing ROCKΔ1 in cardiomyocytes to mimic human heart disease. Mutant mice developed fibrotic cardiomyopathy with diastolic dysfunction. Transgenic heart displayed the activation of TGFβ1 and NF‐κB signaling. Treatment with Rho kinase inhibitor attenuated the phenotype. Cardiac fibroblasts were differentiated into myofibroblasts by co‐culturing with transgenic cardiomyocytes but not with wild‐type cardiomyocytes. Inhibitors of Rho kinase, TGFβR1 and NF‐κB diminished the process. A new cis‐regulatory element of TGFβ1, the serum response factor‐dependent TGFβ1 regulation, was responsible for Rho kinase‐mediated TGFβ1 signaling activation.ConclusionsThe results demonstrate that ROCKΔ1 is a novel and potent fibrogenic factor. Activation of TGFβ1 and NF‐κB signaling along with a subset of cytokines released from cardiomyocytes induces cardiac fibroblast maturation, facilitates collagen deposition and macrophage infiltration. Both pathways synergistically contribute to Rho kinase‐mediated pathological fibrosis.Supported by NIH R01HL102314.
ERK1/2‐dependent bestrophin‐3 (Best‐3) expression prevents ER‐stress‐induced cell death of renal epithelial cells by reducing CHOP
Authors: Lee Wing-Kee , Chakraborty Prabir K , Roussa Eleni , Wolff Natascha A , Thévenod Frank 
Published: June 2021

Upon ER stress induction, cells endeavor to survive by engaging the adaptive stress response, known as the unfolded protein response, or by removing aggregated proteins. Chronic ER stress leads to apoptosis through induction of pro‐apoptotic CHOP. Here, we show that Best‐3, a Ca2+‐activated Cl−channel, is upregulated by the ER stressors, thapsigargin (TG, 3 μM), tunicamycin (TUN, 6 μM) and the toxic metal Cd2+ (25 μM). In cultured rat kidney proximal tubule cells, ER stress after 6 h by Cd2+, TG and TUN was downstream of reactive oxygen species formation and attenuated by Ca2+ chelator BAPTA‐AM (10 μM) or general antioxidant α‐tocopherol (100 μM). Immunofluorescence staining localized Best‐3 to the plasma membrane, nuclei and intracellularly, though not in the ER, in cultured cells and rat kidney cortex sections. ER stress augmented Best‐3 mRNA and was decreased by α‐tocopherol, BAPTA‐AM, calmodulin kinase inhibitor calmidazolium (40 μM), ERK1/2 inhibitor U0126 (10 μM), and ERK1/2 RNAi. Knockdown of Best‐3 resulted in decreased cell number consequentially of cell death, as determined by nuclear staining and PARP‐1 cleavage. Furthermore, Best‐3 overexpression reduced cell death by Cd2+, TG and TUN, attributed to diminished CHOP. From our novel data, we conclude that ERK1/2‐dependent Best‐3 activation regulates cell fate decisions during ER stress by suppressing CHOP induction and death.Funded by DFG TH345/10‐1
Specific targeting of pancreatic β‐cells for imaging and therapy using multivalent targeting of receptor combinations
Authors: Hart Nathaniel , Vagner Josef , Chung Woo Jin , Weber Craig , Limesand Sean , de Silva Channa , Lynch Ronald 
Published: June 2021

Perturbations in pancreatic β‐cell mass (BCM) and function underlie the development of Diabetes Mellitus. Current treatments and analysis of BCM are limited by inadequate specificity of β‐cell targeting agents. We propose improved specificity of β‐cell agents can be obtained by targeting unique combinations of cell surface proteins that distinguish β‐cells from other cells within the abdomen. We synthesized a multivalent ligand composed of two different receptor binding moieties: Glucagon Like Peptide‐1 (GLP‐1) and Glibenclamide (Glb, Sulfonyurea ligand, SUR1). Both GLP1R and SUR1 are expressed in the βTC3 cell line. The bivalent ligand binds to βTC3 cells with an apparent Km of ~10nM, and binding is right‐shifted by competition with monomeric GLP‐1 or Glb, indicating higher affinity binding is due to multivalent interactions. GLP‐1 elevates cAMP while Glb increases Ca2+in β‐cells. We observe that the GLP‐1/Glb elicits a half maximal Ca 2+response at ~10nM reflecting its Km but the magnitude of the Ca 2+ response was at least 10X less than monomeric Glb. Unlike the Ca 2+response, cAMP production was depressed by only ~20% compared to monomeric GLP‐1. Although signaling is depressed, glucose activated insulin secretion is potentiated to similar levels by both monomeric GLP‐1 and GLP1/Glb. Our findings indicate that multivalent ligands may provide cell type specific agents with tunable functional behavior.Supported by Juvenile Diabetes Research Foundation.
Caveolin isoform switch in differentiating C2C12 cells is not prevented by palmitate
Authors: Pinz Ilka M. , Vittorioso Melissa , Knowles Catherine J. 
Published: June 2021

Caveolae are membrane invaginations and important for cellular signaling. In skeletal muscle the expression of caveolin‐3 (cav3) is required for normal muscle fiber orientation and function, and caveolin‐1 (cav1) is constitutively expressed. Palmitate (palm) decreases membrane localization of cav3 in cardiomyocytes. Thus, we tested the hypothesis that palm impairs myotube formation in differentiating C2C12 cells. Two time points were tested: 1) After myotube formation: C2C12 myoblasts and myotubes were treated with 0.4 mM palm for 18 hours and 2) during differentiation: C2C12s were treated at 50–60% confluency. Western blot, IP and confocal microscopy determined expression and localization of cav1 and 3. In controls an isoform switch from cav1 in myoblasts to cav3 in myotubes occurred. Palm exposure after tube formation suppressed cav3 expression in confocal images. During differentiation, C2C12s form myotubes in the presence of palm, however the morphology was changed to long and spindly compared to controls. Palm increased the number of myotubes, but considering the changed morphology this suggests inhibition of fusion to larger myotubes. These data suggest that a caveolin isoform switch occurs in the differentiation of C2C12s from cav1 to cav3, and that cav3 expression is important for the correct morphology of myotubes formed.Support by AHA SDG 0930260N to IMP