bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of oriental plum extract on the cognitive function and the cerebral neurodegeneration‐related protein expressions in Type 2 diabetic rats
Authors: Liao Hsiang , Lee Kao‐ting , Chien Yi‐wen , Lin Shyh‐Hsiang 
Published: June 2021

Recent studies indicate that Type 2 diabetes mellitus (T2DM) is one of the risk factors of Alzheimer's disease (AD). An impaired insulin signaling caused by insulin resistance may result in abnormal protein expressions in the brain and neuron damages. The study aimed to investigate the prevention of AD type neurodegeneration by consuming polyphenols‐rich oriental plum (Prunus salicina Lindl) extract on T2DM rats. Nicotinamide/streptozotocin‐injection was performed to induce T2DM on male Wistar rats, followed by a 2 months oriental plum extract (OP) feeding intervention. The results showed that OP intervention significantly reduced insulin resistance by improving the Homeostasis model assessment‐insulin resistance (HOMA‐IR). Morris water maze results indicated the spatial learning function was improved after the OP consumption. The intervention also reduced amyloid‐β (Aβ) and phosphorylated tau (p‐tau) protein levels in the cerebral cortex and reduced Aβ deposition in the hippocampus of the T2DM rats. In conclusion, the oriental plum extract decreased the cognitive decline and reduced the expressions of AD‐type pathological proteins Aβ and p‐tau in T2DM rats.Grant Funding Source: Taipei Medical University
Visfatin and vaspin protein concentrations in different tissues and insulin resistance
Authors: Goktas Zeynep , Wang Shu 
Published: June 2021

BackgroundIn obesity, adipose tissue secretes many adipokines that have functions in insulin sensitivity. Visfatin and vaspin are known as insulin‐mimetic proteins and they might stimulate glucose uptake. Our research focuses on tissue visfatin and vaspin concentrations and their relationships to insulin resistance.MethodsThirty eight morbid obese (BMI ≥40) subjects had the subcutaneous, omental, and mesenteric adipose tissue, liver and muscle tissue samples taken at the time of Roux‐n‐Y surgeries. Visfatin and vaspin proteins were measured using ELISA kits. Fasting blood glucose and HbA1c levels and HOMA‐IR were measured before the surgery. Results were analyzed using ANOVA and Pearson correlation.ResultsLiver had significantly higher visfatin and vaspin concentrations than other tissues. There wasn't any significant difference in visfatin and vaspin concentrations among three different adipose tissues. Omental adipose tissue visfatin concentrations were positively correlated with HOMA‐IR and blood HbA1c levels (r = 0.456 and r = 0.481, respectively). Mesenteric adipose tissue vaspin concentrations were positively correlated with HOMA‐IR, blood glucose and HbA1c levels (r = 0.578, r = 0.467, and r = 0.455, respectively).ConclusionsOur findings indicate that tissue visfatin and vaspin protein concentrations are involved in the development of insulin resistance during obesity.Grant Funding Source: TTU Research Fund
A pilot study of TLR4 polymorphism in relation to intestinal dysbiosis and risk of necrotizing enterocolitis in preterm infants
Authors: Taft Diana H , Kottyan Leah , Lagomarcino Anne J , Schibler Kurt R , Yu Zhuoteng , Gevers Dirk , Ward Doyle V , Huttenhower Curtis , Newburg David S , Morrow Ardythe L 
Published: June 2021

Necrotizing enterocolitis (NEC) is a devastating disease of prematurity, hypothesized to be due in part to excessive inflammatory signaling of toll‐like receptor 4 (TLR4) in response to the lipopolysaccharide (LPS) of Gram‐negative organisms. In this pilot study, we tested the hypothesis that polymorphisms in TLR4 modify the risk of developing NEC associated with intestinal dominance by Gram‐negative organisms (Proteobacteria). Using the Illumina ImmunoChip we analyzed TLR4 polymorphisms of 24 infants <29 wks gestational age enrolled in a study of the intestinal microbiome. Six infants who developed NEC after Proteobacteria dysbiosis (>;90% of the intestinal microbiome comprised of Proteobacteria) were compared to 18 control infants with varied microbial communities. One TLR4 polymorphism, rs10759932, occurred significantly more often in NEC cases (4 GA, 2 AA) compared to all controls (2 GA, 16 AA; Fisher's exact test, p=0.018) or compared only to the 7 controls identified with a Proteobacteria dysbiosis (7 AA, p=0.021). These findings support the hypothesis that NEC may occur as the result of host immune response to the microbiome. A larger study of microbial colonization and host genetics is ongoing.Project funded by NIH HD 05491, NIH T32 ES 010957–12, NIAID NIH HHS Contract No. HHSN272200900018CGrant Funding Source: NIH HD 05491, NIH T32 ES 010957–12, and NIAID NIH HHS Contract No. HHSN272200900018C
High renal calcium (Ca) excretion does not reduce femur bone density in mice fed adequate or low dietary Ca
Authors: Fernandez Perla Citlali Reyes , Fleet James C 
Published: June 2021

Active vitamin D, 1,25(OH)2D3 (1,25D) regulates intestinal Ca absorption (Ca Abs) under low dietary Ca intake by inducing gene expression through the vitamin D receptor (VDR). Vitamin D‐regulated Ca Abs is greatest in the proximal small intestine but VDR is highest in the large intestine. We generated transgenic (TG) mice using a CDX2P9.5 promoter‐Cre transgene to drive deletion of floxed VDR alleles from the lower bowel to test whether this disrupts whole body Ca metabolism. Weanling, male TG and control mice were fed diets with low (0.25%) or normal (0.5%) Ca levels until 10 wks of age. Transgene expression was seen in the distal ileum, cecum, and colon as well as the kidney, a 1,25D target tissue. Serum 1,25D was not different between genotypes and serum Ca was normal in all groups. TG mice had low serum PTH (p<0.001) which explains the 10‐fold higher urinary Ca/creatinine ratio (p<0.001) we observed. However, no genotype effects were found in femur cancellous or cortical bone density. These data show that while Ca metabolism is disturbed in TG mice, high renal Ca excretion does not negatively affect bone density or adaption to restricted Ca intake.Grant Funding Source: NIH award DK54111 (JCF)
Serum amyloid A and Toll‐like receptor 2 activation promote de‐differentiation of vascular smooth muscle cells
Authors: Pessolano Lawrence G , Seidl Stephanie E , Rich Celeste B , Schreiber Barbara M 
Published: June 2021

Smooth muscle cells (SMCs) regulate vascular tone, and during chronic inflammation associated with atherosclerosis, SMCs contribute to the disease process via de‐differentiation from a contractile state. We study the impact of acute phase serum amyloid A (SAA), a cardiovascular risk marker that localizes to atherosclerotic plaques, on SMC function. The goal of this study was to define a role for SAA in SMC phenotypic expression. SMC marker expression was down‐regulated by SAA, consistent with de‐differentiation. Myocardin, a transcriptional co‐activator of SMC marker gene expression, was down‐regulated by SAA, and its overexpression rescued the SAA‐mediated repression of the smooth muscle α‐actin and smooth muscle 22 α (SM22) promoters. SAA‐mediated down‐regulation of SM22 promoter activity was also rescued by expression of the myocardin family members, myocardin related transcription factor (MRTF)‐A and MRTF‐B. It was reported that SAA is a ligand for the Toll‐like receptor (TLR)2, which has been implicated in atherosclerosis. Interestingly, FSL‐1 and Pam3CSK4, known TLR2 ligands, down‐regulated SM22 promoter activity, and the effects were rescued with myocardin overexpression. Moreover, knockdown of TLR2 using siRNA rescued the de‐differentiated phenotype induced by SAA. These data suggest that SAA and TLR2 activation promote SMC de‐differentiation characteristic of atherosclerosis.This work was supported by NIH grant HL079201.
Cerebrovascular Endothelial Cell Activation in Paediatric Diabetic Ketoacidosis
Authors: Omatsu Tatsushi , Cepinskas Gediminas , Fraser Douglas D 
Published: June 2021

Diabetic ketoacidosis (DKA) in children is associated with intracranial vascular complications. The mechanisms of DKA‐induced vascular dysfunction are unclear. We aimed to assess the effects/mechanisms of DKA plasma on activation of human cerebrovascular endothelial cells (hCMEC/D3; provided by Dr. P.O. Couraud, INSERM).MethodsDKA‐blood plasma was obtained from paediatric patients with either DKA or well‐controlled type‐1 diabetes (control; CON). The levels of 21 inflammation‐relevant analytes in blood were assessed. In vitro hCMEC/D3 were stimulated with 20% (v/v) CON‐ or DKA‐plasma and assessed for activation markers.ResultsDKA in children resulted in increased circulating levels of IL‐2, IL‐6, IL‐8, GRO, INFα2, and G‐CSF. Stimulation of hCMEC/D3 with DKA‐plasma induced production of ROS and increased PMN‐leukocyte adhesion to hCMEC/D3 under “flow” conditions (shear stress 0.35 dyn/cm2). PMN adhesion was replicated by stimulating hCMEC/D3 with IL‐8 and/or GROα (at the levels detected in DKA‐plasma), the phenomenon that was suppressed by neutralizing anti‐CXCR1 and/or CXCR2 antibodies.ConclusionsDKA elicits systemic inflammation associated with increased oxidative stress and up‐regulation of the pro‐adhesive phenotype in cerebrovascular endothelium, potentially contributing to DKA‐associated intracranial vascular complications.
Three Rodent Strain‐wide comparisons: Cardio‐pathological markers in a mouse model subjected to repeated social aggressor
Authors: Melige Monique Marie N 
Published: June 2021

Post‐traumatic stress disorder (PTSD), a common psychiatric disorder, is associated with the risk of cardiovascular (CV) atrophy and possible thromboembolic stroke. We examined the histology of cardiac samples from three mouse strains (C57BL/6j, BALB/cj and DBA/2j) that had been subjected to aggressor exposure (Agg‐E) for 5 or 10 d. Agg‐E mice were socially stressed; housed with aggressor mice (Agg) for 6 h/d without access to food/liquid and subjected to direct exposures with Agg at 3x/d at random times. Control mice (C) were put in the same environment without Agg. Cardiac tissues were harvested 1 d or 4 wks after 10‐day Agg‐E, and 1 d or 1.5 wks after 5‐day Agg‐E schedule, and were stained and examined using bright field microscopy. Cardiac tissues from C were harvested at the same time points.Agg‐E induced cardiomyopathy, specifically degeneration and inflammation, was mostly evident 1 d after 10‐day and 5‐day schedule among the Agg‐E mice of C57BL/6j. BALB/cj displayed a modest effect of stress; whereas DBA/2j displayed no sign of ailment.Mice of all three strains showed almost no trace of CV atrophy 4wks after 10‐day Agg‐E schedule; although after 1.5 wks post 5‐day schedules, traces of CV atrophy persisted only in C57BL/6j.In conclusion, C57BL/6j showed most effect of acute stress recovered with rest period. BALB/cj displayed a modest effect of stress and DBA/2j emerged as the most resilient strain.
A novel ruthenium nitrosyl complex ameliorates L‐NAMEinduced bladder dysfunction
Authors: Santos Claudia F , Campos Rafael M , Nascimento Nilberto RF , Fonteles Manasses C 
Published: June 2021

The present work was undertaken in order to screen the ruthenium NO‐donor complex, Rut‐BPY, in urodynamic parameters of 28‐ day L‐NAME‐treated rats. Three groups were studied: 1) L‐NAME control‐ Male wistar rats treated with L‐NAME in the drinking water (~60mg/Kg) during 28 days; 2) Ru‐BPY treated – Rats received L‐NAME in the drinking water as the former group but in the 14th day a mini‐osmotic pump delivering Rut‐BPY (10ηM/Kg/h) was implanted in the neck and kept for the remaining 14 days; and 3) Control rats that did not receive L‐NAME and were sham operated. At the end of the treatment period, animals were anesthetized and a catheter coupled to a pressure transducer was implanted in the bladder dome. Saline was infused into the bladder at the rate of 100 μl/min and both filling and voiding phases were studied. This study was approved by the Committee for Ethics in Animal Experimentation (CEUA document n∘ 08628332–4). L‐NAME induced a 54,90% increase in the number of non‐voiding contractions and in the group treated with Rut‐ BPY these values were similar to the control. The voiding threshold pressure was increased in the Rut‐BPY‐treated group by 63 % when compared to the L‐NAME group. The voiding frequency was increased by 56% and the residual bladder volume was decreased by 52% by Ru‐BPY (p<0,05). Rut – BPY ameliorate some of the lower urinary tract symptoms of the L‐NAME vesical dysfunction model.Financial Support: CAPES, FUNCAP. CNPq.
The effect of glutamine and alanylglutamine as substrates for the isolated perfused rabbit kidney
Authors: Fonteles Manasses Claudino , Sousa‐Filho Jose Ernando , Nascimento Nilberto Robson Falcão , Araujo‐Filho Raimundo Messias 
Published: June 2021

Rabbit kidneys were perfused with a high K+ and Mg++ solution as previously described (J S R 21(3);169,1976). Briefly the animals were anesthetized with urethane and pentobarbital and the left kidney perfused at 37ºC with a previously dialyzed solution in an artificial heart‐lung machine custom fabricated. Several functional physiological parameters were evaluated such as perfusate and urine flow, GFR, %TNa, %TK, osmolar clearance, perfusion pressure and vascular resistance. The experiments lasted 2 hours. To measure kidney function creatinine was added to the perfusate and Na,K, and osmolarities were measured every ten minutes. Urinary flow increased 6.5‐fold in AG group when compared to control. Glutamine increased this parameter 16.5 times. The same trend was observed with GFR that was enhanced 5.5 times in the AG group while Glut 1 increased 10.6%. The fractional sodium reabsorption increased 8.87% with AG while Glut increased 11.26%. No changes were observed in the fractional transport of potassium. We conclude that these 2 substrates promote a great improvement in kidney functional preservation in this ex vivo model. These substrates could be important metabolic support when perfusing kidney for transplantation.Financial support: CNPq and FUNCAP Brazil
A Transgenic Cre Mouse Line for the Study of Kidney Pericytes and Perivascular Fibroblasts
Authors: Grgic Ivica , Hofmeister Andreas , Humphreys Benjamin 
Published: June 2021

Pericytes and perivascular fibroblasts are considered a main source of myofibroblast recruitment in fibrotic kidney disease and currently there is a lack of suitable Cre driver mouse lines to study this cell population in vivo.We generated a novel pericyte‐specific conditional Cre mouse by using the collagen1α1 promoter/enhancer to drive expression of a triple fusion protein consisting of GFP, Cre recombinase and the mutated estrogen receptor ERT2. For validation, we crossed this Coll1α1GCE mouse to several reporter lines and detected genetically labeled cells in the renal tubulointerstitium of tamoxifen‐treated bigenic offspring. In line with a pericyte identity, these cells stained positive for pericyte marker PDGFRβ but not for CD31, F4/80, CD3, αSMA or FSP1/S100A4 in healthy kidneys and displayed a close spatial association with endothelial cells. One submaximal dose of tamoxifen at P7 labeled ~1.5%, three consecutive pulses (P7‐P9) ~26.8% of all PDGFRβ+ pericytes/perivascular fibroblasts. Upon UUO surgery, fate labeled pericytes aquired αSMA positivity reflecting their differentiation into myofibroblasts. This transformation was accompanied by a notable increase in cell size and overall anatomical complexity.In summary, we have created a novel pericyte‐specific conditional Cre driver mouse as a new tool to study the biology of pericytes in health and disease.
Numerical study of blood flow in a microchannel bifurcation with the large deformation model
Authors: Ye Swe Soe , Ju Meongkeun , Ng Yan Cheng , Tan Kok Soon , Kim Sangho 
Published: June 2021

The present study investigated the red blood cell (RBC) strain‐stiffening behaviour in a microchannel bifurcation flow. The numerical model employed the Lattice Boltzmann Method and the Immersed Boundary Method. Vitally, a large deformation model was developed for the extensional and bending behaviour of the RBC membrane at high shear condition. Two sets of simulations were conducted for a 90° bifurcation microchannel with 55% inlet hematocrit over a range of non‐dimensional shear rate G from 0.0125 to 0.4; one simulation set employed the large deformation membrane model while the other was conducted with the Neo‐Hookean membrane model. The highly elongated RBCs simulated by the Neo‐Hookean model fail to match experimental observations of RBC shapes at the corresponding shear rates whereas the simulation set conducted with the large deformation model exhibited limited RBC deformation that is in good agreement with experimental results at high shear rates. Consequently the large deformation model predicts a lower incidence of RBCs travelling into the plasma‐rich daughter channel. In conclusion, this comparative study underlines the necessity of representing finite strain behaviour of RBCs when subjected to high shear stress present at the bifurcation zone.This work was supported by NMRC/CBRG/0019/2012.
Anatomically unbiased analysis of renal BOLD magnetic resonance images reveals disruption of corticomedullary gradient during chronic angiotensin II infusion
Authors: Menzies Robert Ian , Zammit‐Mangion Andrew , Hollis Lyam M , Lennen Ross J , Jansen Maurits A , Webb David J , Mullins John J , Dear James W , Sanguinetti Guido , Bailey Matthew A 
Published: June 2021

Oxygenation defects may contribute to renal disease progression but are difficult to define in vivo without invasive methods. BOLD MRI provides a non‐invasive alternative but the signal is physiologically complex and data analysis often rely on region of interest selection, excluding biological information.We present an analysis pipeline that compartmentalizes voxels into distinct clusters. In control rats, low R2* clustering was located predominantly within the cortex and higher R2* clustering within the medulla, consistent with a cortico‐medullary oxygen gradient. An intravenous bolus of acetylcholine caused a transient reduction of the R2* signal in both clustered segments. This was nitric oxide dependent and temporally distinct from hemodynamic effects. Rats were then chronically infused with angiotensin II and rescanned three days later. Clustering demonstrated a disruption of the cortico‐medullary gradient, producing less distinctly segmented mean R2* clusters. The acetylcholine‐induced attenuation of the R2* signal was abolished by chronic angiotensin II infusion, indicative of reduced nitric oxide bioavailabilityOur more inclusive analysis pipeline may be more robust in defining deficits in renal oxygenation than the absolute magnitude of R2* in small, manually selected and averaged regions of interest.
Deletion of myostatin improves vascular function in obese mice
Authors: Qiu Shuiqing , Mintz James , Nernpermpisooth Nitirut , Salet Christina , Fulton David J , Stepp David W 
Published: June 2021

Exercise improves endothelial function in obese patients. Salutatory effects of exercise include increases in muscle size and quality, reduction in fat mass and alterations of the plasma milieu. The relationships between these changes and improvements in vascular function are poorly defined.HypothesisIncreasing muscle mass by deletion of muscle growth negative regulator myostatin, improves vascular function in mesenteric arteries from obese db/db mice. Myostatin deletion increases muscle mass in both lean (gastrocnemius 57.93%, gluteus maximus 60.95%, Triceps 57.64%) and obese mice (gastrocnemius 79.64%, gluteus maximus 112.32%, Triceps 103.61%). Myostatin deletion increases muscle fiber size in lean and obese mice (p< 0.05) but has no significant effects on adipocyte size in obese mice. Fasting glucose, HbA1c and glucose tolerance are improved in obese myostatin null mice. Obese mice demonstrate superoxide‐mediated impairment of ACh‐induced vasodilation compared to lean mice. Deletion of myostatin in obese mice improved ACh‐induced vasodilation in mesenteric arteries without effects in lean mice. This improvement was blunted by L‐NAME. PGI2 and EDHF mediated vasodilation were preserved in obese mice, and unaffected by myostatin deletion. Taken together, these data suggested that increasing muscle mass by deletion of myostatin improves NO not PGI2 or EDHF mediated vasodilation in obese mice.
Protein S‐nitrosylation regulates Ca2+ handling and myofilament Ca2+ sensitivity in beta‐adrenergic signaling
Authors: Irie Tomoya , Sips Patrick , Tokuda Kentaro , Ichinose Fumito 
Published: June 2021

ObjectiveTo assess the impact of increased rotein denitrosylation on beta‐adrenergic receptor (b‐AR)‐dependent signaling and to evaluate effects of augmented denitrosylation during nitrosative stress in cardiomyocytes.Methods and ResultsWe studied cardiomyocytes isolated from wild‐type (WT) and cardiomyocytespecific S‐nitrosoglutathione reductase (GSNOR) overexpressing transgenic (GSNOR‐CMTg) mice. Stimulation of the b‐AR with isoproterenol (ISO)increased sarcomere shortening in both genotypes, while systolic Ca2+ release and sarcoplasmic Ca2+ load only increased in WT. This effect was correlated with increased myofilament Ca2+ sensitivity in ISO‐treated GSNOR‐CMTg cells. Both genotypes showed similar increases in phosphorylation of phospholamban (PLN) and troponin I after b‐AR stimulation while S‐nitrosylation of PLN and troponin C was only increased in WT. Exposure of ISO‐stimulated WT cells to S‐nitrosocysteine severely depressed contractility and systolic Ca2+ release, associated with sarcoplasmic Ca2+ leak and increased ryanodine receptor (RyR2) S‐nitrosylation. GSNOR overexpression prevented RyR2 S‐nitrosylation and preserved contractile function during nitrosative stress.ConclusionThese results suggest that b‐AR‐induced S‐nitrosylation of excitation‐contraction coupling proteins is required for b‐AR‐induced augmentation of cardiomyocyte function.
The dual‐specificity phosphatase 8 (Dusp8) regulates cardiac hypertrophic response in vitro and in vivo
Authors: Liu Ruijie 
Published: June 2021

BackgroundPhosphorylation and dephosphorylation of mitogen‐activated protein kinases (MAPKs) play important roles in regulating cardiac hypertrophy, remodeling, and heart failure. Dual‐specificity phosphatases (Dusps) directly dephosphorylate and inactivate each of the MAPK terminal kinases (ERK, p38, JNK) within 30 to 60 minutes activation. In this study, we generated mice and mouse embryonic fibroblasts (MEFs) lacking DUSP8 gene and determined the role of Dusp8 in regulating c‐Jun N‐terminal kinases (JNK1/2) signaling in neonatal myocyte culture and mouse heart. We hypothesized that knockout of Dusp8 will lead to increased JNK phosphorylation and decreased cardiac hypertrophy.MethodsDUSP8 null mice were generated using traditional gene‐targeting approach to delete exon 5 and 6. Phenylephrine was injected at final concentration of 10 mg/kg using 2‐month‐old mice.Results: Adenovirus mediated Dusp8 overexpression in cultured cardiomyocytes resulted in decreased JNK1/2 phosphorylation but not that of p38 and ERK1/2, indicating Dusp8 is specific for JNK dephosphorylation. In contrast, injection of Dusp8 null mice with phenylephrine led to sustained JNK phosphorylation compared to that of WT mice, which was also true for the JNK signaling in Dusp8 null MEF cells. Dusp8 null mice had reduced left ventricular weight/body weight ratio at both baseline and angiotensin II/phenylephrine stimulation condition. At cellular level, we found that overexpression of Dusp8 led to increased nuclear accumulation of NFAT and expression of hypertrophy gene ANF.ConclusionsThe results of the present study indicate that knockout of Dusp8 is cardioprotective through increasing JNK phosphorylation to prevent NAFT signaling induced cardiomyopathy.