bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hormone Sensitive Lipase knockout mice have higher Post Exercise Insulin Sensitivity despite accumulation of diacylglycerol
Authors: Serup Annette Karen , Alsted Thomas , Wojtaszewski Jørgen , Kiens Bente 
Published: June 2021

AimTo evaluate an accumulation of diacylglycerol (DAG) on post exercise insulin sensitivity.MethodInsulin‐stimulated 2‐deoxyglucose uptake, using a submaximal insulin concentration, was measured in incubated mouse soleus (SOL) and extensor digitorum longus (EDL) muscle from wildtype (WT) and HSL Knock Out (KO) mice 90 min after completion of 40 min treadmill running.ResultsPost exercise insulin stimulated glucose uptake was 14% and 25% higher in SOL and EDL respectively in HSL KO compared to WT. Intramyocellular triacylglycerol was reduced to the same extent in both WT and HSL KO (p<0.01). Muscle DAG was 40% higher after exercise in HSL KO mice compared to WT (p<0.05), there were no differences in muscle DAG levels at rest. Phosphorylation of AMPK thr172 and ACC ser212 were not increased post exercise in both genotypes. Insulin induced signaling (phosphorylation of AKT ser473 and AKT thr308) was similar in both genotypes in both SOL and EDL. Total GLUT 4 protein expression was 20% and 25% higher in SOL and EDL respectively (p<0.05) in HSL KO compared to WT.ConclusionPost exercise insulin sensitivity was higher in HSL KO despite accumulation of DAG. Moreover, the data suggests that reduced fatty acid availability for mitochondrial oxidation plays a role in the observed increased post exercise insulin sensitivity.
Transgenic Mice Containing two Haplotypes of Human Angiotensin Receptor Type 1 Shows Differential Gene Expression and Regulation of Blood Pressure
Authors: Jain Sudhir , Pandey Varunkumar G. , Kumar Ashok 
Published: June 2021

Most of the physiological action of renin angiotensin system (RAS) are mediated through the angiotensin receptor type 1 (AT1R). Human AT1R gene promoter has four single nucleotide polymorphisms (SNPs). Our studies have shown that variants ‐ 777T, ‐680T, ‐214A, and ‐119A almost always occur together in Caucasian subjects, creating haplotype I (TTAA or Hap I) and II (AGCG or Hap II) respectively. Our genomic DNA analysis have shown that Hap I of the hAT1R gene is associated with hypertension in Caucasian subjects (p< 0.001). Our transient transfection studies in adrenal cortical (H295R) and vascular smooth muscle (VSMC) cells show that Hap I of hAT1R gene has increased promoter activity as compared to Hap II. In order to understand the physiological effect of these haplotypes in an in vivo situation, we have generated transgenic mice containing 160Kb long hAT1R BAC DNA and differ only in 1.2Kb promoter, containing either Hap I or Hap II. Our studies show that kidney and brain tissues of 8 weeks old transgenic mice containing Hap I have increased hAT1R mRNA levels (6.32 and 8.51 folds respectively) and hAT1R protein (2.2 and 3.2 folds respectively). We also show that transgenic mice containing Hap I of hAT1R gene have a significantly increased systolic blood pressure (10mmHg) as compared to Hap II. Our results suggest that increased expression of hAT1R gene with Hap I may be a contributing factor for hypertension in Caucasian subjects.Research Support: NIH grants HL081752 and HL66296 to AK
Acute mineralocorticoid receptor blockade leads to decreased vascular endothelial function in healthy older adults
Authors: Kim Han Kyul , Hwang Moon‐Hyon , Yoo Jeung‐Ki , Luttrell Meredith J. , Meade Thomas H. , English Mark W. , Christou Demetra D. 
Published: June 2021

Mineralocorticoid receptors (MR) modulate vascular endothelial function (VEF) in chronic heart failure and in healthy young adults, but their influence in healthy older adults is unknown. To test the hypothesis that MR modulate VEF in healthy aging, we administered acute MR blockade (MRB: 100 mg Eplerenone for 2 days) in a randomized, double‐blind, placebo‐controlled cross‐over study in 22 adults (8 men, 61±1 y; mean±SE, 53–79 y) free from clinical disease. We measured VEF (brachial flow‐mediated dilation [FMD]; ultrasonography), plasma oxidized LDL and vascular endothelial cell protein expression (VECPE) of eNOS, phosphorylated Ser1177 eNOS (PeNOS), NADPH oxidase (p47‐ phox), nitrotyrosine (NT), and TNF‐α (biopsy coupled with quantitative immunofluorescence) after MRB and placebo. In the overall group, FMD decreased (6.9±0.5 vs. 5.6±0.6%, P=0.02; Eplerenone vs. placebo) with MRB. However, MRB had no effect on oxidized LDL and VECPE of eNOS, PeNOS, p47‐phox, NT and TNF‐α (P≥0.4). Greater decreases in FMD were associated with lower baseline white blood cell and neutrophil (r=0.49, P=0.02 and r=0.57, P=0.006, respectively) and greater lymphocyte (r=−0.53, P=0.01) levels. In conclusion, MR modulate VEF in healthy older adults in an immune cell‐specific manner. MR activation appears to be physiologically important for maintaining vascular function.Supported by NIH Grant AG032067 & AHA Grant 0865117F.
The Antidiabetic Activities of the Aqueous Leaf Extract of Phyllanthus amarus In Some Laboratory Animals
Authors: Adedapo Adeolu Alex , Ofuegbe Sunday Oluwaseun 
Published: June 2021

The Antidiabetic Activities of the Aqueous Leaf Extract of Phyllanthus amarus In Some Laboratory AnimalsAimsPhyllanthus amarus has gained popularity in many continents as an herbal remedy hence its aqueous leaf extract is being assessed for its safety potential and antidiabetic properties in some laboratory animals.MethodsThe anti‐diabetic activities of the aqueous extract of the plant were assessed using some standard tests as well as histological changes in liver, kidney and pancreas. Diabetes mellitus was induced in rats using alloxan while glibenclamide at 0.2mg/kg was the reference drug used in this study. Acute toxicity was carried out to determine safe doses for this plant extract.ResultsThe extract at 200 and 400mg/kg body weight caused significant reduction of fasting blood glucose, produce significant reduction in the oral glucose tolerance test, marked effect in the hypoglycaemic activity test, and pronounced reduction on the glucose level of diabetic rats. Histopathologically, the architecture of the pancreas appeared intact in the extract‐treated group. The study also showed recovery of the damaged liver cells in the extract‐ treated group.ConclusionThe plant extract produced antidiabetic activities that are comparable to that of Glibenclamide, and may have validated the basis for the traditional use of Phyllanthus amarus as antidiabetic agent.
Stromelysin‐1(MMP3) Worsens the Neurovascular Injury in Hyperglycemic Stroke.
Authors: Hafez Sherif , Abdelsaid Mohammed , Coucha Maha , Ergul Adviye 
Published: June 2021

IntroductionAcute hyperglycemia (HG) worsens stroke outcomes and increases the risk of cerebral hemorrhage especially with the co‐administration of tissue plasminogen activator (tPA). Matrix metalloproteinase 3 (MMP3) mediates tPA‐induced hemorrhagic transformation (HT) after stroke. However, the role of MMP3 in hyperglycemic stroke is unknown. The goals of the study were to evaluate the impact of the severity of HG 1) on stroke outcomes and 2) on MMP3 activity and expression.MethodsMild and severe HG were induced by glucose injections in rats that were subjected to 90 min middle cerebral artery occlusion and 22.5 h reperfusion. Stroke outcome and cerebrovascular MMP3 activity were assessed. Brain microvascular endothelial cells (BVEC) are subjected to oxygen glucose deprivation (OGD) followed by HG and MMP3 expression was measured.ResultsSevere HG significantly increased the infarct size. Mild elevation in blood glucose has significantly increased HT and MMP3 activity in cerebral vasculature. HG increased MMP3 expression in BVEC and hypoxia potentiated this effect.ConclusionMild elevation in blood glucose worsens the vascular injury without increasing the infarct size. Up‐regulation of MMP3 in the cerebrovasculature and endothelial cells suggests that MMP3 highly contributes to the HG induced vascular injury.
The atypical antipsychotic clozapine induces 5‐HT2ARmediated signaling and behavioral events in a beta‐arrestin2‐ independent but Akt‐dependent manner
Authors: Schmid Cullen L , Streicher John M , Bohn Laura M 
Published: June 2021

The G protein‐coupled serotonin 2A receptor (5‐HT2AR) is a prominent target for atypical antipsychotic drugs, such as clozapine. Although clozapine is known to inhibit 5‐HT2AR mediated G protein coupling, it differs from classic GPCR antagonists in that it also induces 5‐HT2AR internalization and activates Akt signaling via a 5‐HT2AR‐mediated event. The cognate neurotransmitter at the 5‐HT2AR, serotonin, also induces 5‐HT2AR internalization and Akt phosphorylation, events which require the interaction between the receptor and the intracellular scaffolding and regulatory protein, beta‐arrestin2 (βarr2). Moreover, the 5‐HT2AR/βarr2/Akt interaction is critical for serotonin‐induced, 5‐HT2AR‐mediated behavioral responses in mice. Therefore, we hypothesized that clozapine also utilizes a βarr2‐mediated mechanism to induce 5‐HT2AR signaling and regulatory events, as well as its behavioral effects in mice. Here, we demonstrate that, unlike serotonin, clozapine‐mediates 5‐ HT2AR internalization and Akt phosphorylation independent of receptor interactions with βarr2. Moreover, clozapine‐mediated suppression of MK‐801 and PCP‐induced hyperlocomotion is βarr2 independent, although it is dependent upon Akt. These results demonstrate that serotonin and clozapine utilize differential mechanisms to in the induction of similar events downstream of the 5‐HT2AR. The further elucidation of these mechanisms in vivo may allow for the development of more effective atypical antipsychotic drugs.Funding from NIDA: DA025158
Visualizing trafficking of the adenosine‐A3 receptor using a fluorescent agonist: a tool for delineating intracellular signalling
Authors: Briddon Steve , Stoddart Leigh , Vernall Andrea , Kellam Barrie , Hill Steve 
Published: June 2021

Activation of many G protein‐coupled receptors (GPCRs) leads to β‐arrestin binding and sequestration of the receptor from the cell surface. Whilst internalisation of a GPCR leads to termination of some aspects of receptor‐mediated signalling, recent reports have shown that some GPCRs continue to signal even after internalisation. Here, we show using a mutated version of the adenosine A3 receptor (W243F‐A3AR), that persistent signalling to the cAMP pathway requires receptor internalisation. To investigate this further we developed a fluorescent A3AR agonist, consisting of the agonist NECA conjugated to BODIPY‐630/650‐X via a dipeptide linker. This fluorescent agonist was highly potent at the A3AR ( pEC50 = 9.06 ± 0.17, n=4) and acted as a full agonist in Chinese Hamster Ovary cells expressing this receptor. Confocal microscopy showed a high degree of co‐localisation of the fluorescent agonist with a YFP‐tagged A3AR on the cell surface after a short incubation period (5 min). After longer incubation (30 min), A3AR‐YFP was sequestered from the cell surface to intracellular granules where co‐localisation with the fluorescent agonist was still observed. This fluorescent probe thus allows us to visualise A3AR trafficking and investigate how the receptor continues to signal to second messenger pathways upon internalisation.We thank the Medical Research Council for financial support.
Regulation of Potassium‐induced [3H]D‐Aspartate Release from Isolated Bovine Retina by 5‐epi‐5‐F3t‐Isoprostane: Role of Prostanoid Receptors
Authors: Opere Catherine A , Jamil Jamal , Salvi Ankita , Bankhele Pratik , Flowers Arnecia , Floyd Namonique , Durand Thierry , Galano Jean‐Marie , Guy Alexandre , Oger Camille , Njie‐Mbye Ya Fatou , Kulkarni Madhura , Ohia Sunny E 
Published: June 2021

Arachidonic acid‐derived F2‐isoprostanes (F2‐IsoPs) can regulate neurotransmitter release in bovine retina (Jamil J. et al, 2012). It is, however, unclear whether eicosapentanoic acid‐derived F3‐IsoPs can produce a similar effect in the retina.PurposeTo investigate the pharmacological actions of 5‐epi‐5‐F3t‐IsoP on K+‐induced [3H]D‐aspartate release from bovine retina. We also examined the role of prostanoid receptors on the F3‐IsoP‐induced response.MethodIsolated neural retina were incubated in oxygenated Krebs solution containing 200 nM of [3H]D‐aspartate and then prepared for studies of neurotransmitter release. Release of [3H]D‐aspartate was evoked by K+ (50 mM) stimuli applied at 90 mins (S1) and at 108 mins (S2) after the onset of superfusion.Results5‐epi‐5‐F3t‐IsoP (0.1 nM – 0.1 μM) elicited an inhibitory action on K+‐evoked [3H]D‐aspartate release in a concentration‐dependent manner, achieving a maximum inhibition of 46.9% at 0.1 μM (IC30 of 1 nM). The effect of 5‐epi‐5‐F3t‐IsoP (0.01 μM) was partially reversed by the prostanoid receptor antagonists, SC 19220 (1 μM; EP1), SC 51322 (10 μM; EP1) and AH 6809 (10 μM; EP1–3/DP1) while AH 23848 (1 μM; EP4/TP1) and SQ 29548 (10 μM; TP) had no effect on the IsoP.Conclusion5‐epi‐5‐F3t‐IsoP can inhibit K+‐evoked [3H]D‐aspartate release in isolated bovine retina, presumably via mechanisms that involve prostanoid receptors.
Neuroprotective effects of Fisetin and Diosmetin, alone and in combination, on lipopolysaccharide‐induced neuronal cells
Authors: Bhatt Pankti R , Benzeroual Kenza E 
Published: June 2021

Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) peptides and the presence of neurofibrillary tangles. Amyloid precursor protein (APP) processing into Aβ, is considered as a contributor to mitochondrial dysfunction and neurodegeneration in AD. This study investigated the neuroprotective effects of fisetin and Diosmetin, two flavonoids, in the lipopolysaccharide (LPS) injured PC12 cells. PC12 cells were pretreated with different doses of flavonoids for 2 hours prior to LPS stimulation for 48 hours. Results reported that LPS stimulation increases the expression of APP (A4), Cyclophilin D, reactive oxygen species (ROS), and reduces the level of interleukin 10. Fisetin and diosmetin, alone or in combination suppressed the expression of APP, cyclophilin D and ROS production, while increased the expression of interleukin 10 in a dose dependent manner, respectively. The results suggest that an increase of APP processing may trigger mitochondrial dysfunction and cell death leading to neurodegeneration as seen in the presence of LPS, and its prevention with flavonoids. The present study, reports that fisetin and diosmetin alone and in combination may offer therapeutic opportunities for neurodegenerative diseases such as AD.Source of research support: Provided by The Long Island University, Arnold & Marie Schwartz College of Pharmacy and Health Sciences
MALT Lymphoma Stem Cell and its Niche in Helicobacter heilmannii‐infected Mice Stomach
Authors: Nakamura Masahiko , Matsui Hidenori , Takahashi Tetsufumi , Tsuchimoto Kanji , Takahashi Shinichi 
Published: June 2021

Background & AimsAlthough cancer and leukemia stem cells are indispensable in the initiation and enlargement of lesions, the gastric MALT lymphoma is thought to be polyclonal with the persistent infection of Helicobacter species and then change to monoclonal with genetic aberrations, and the participation of stem cells in the tumor formation remains to be elucidated. We performed a histochemical analysis in Helicobacter heilmannii‐induced gastric and hepatic MALT lymphoma in the infected alone and eradicated after infection groups.Materials and MethodsWe used a Helicobacter heilmannii sample isolated from the stomach of a cynomolgus monkey and maintained in C57BL/6 mouse stomachs. Mucosal homogenates were used to inoculate C57BL/6 mice, which were then examined over 24 months. Macroscopic observations were carried out, and PCR analysis of the bacteria of the Helicobacter species was performed at intervals over the observation period. Histochemical analysis was performed using the gastric and hepatic MALT lymphoma with monoclonal and polyclonal stem cell‐related antibodies against doublecortin‐like kinase (DCAMKL1), Musashi‐1, proliferating cell nuclear antigen (PCNA), CD44, CD133, as well as myofibroblast, endothelial, and pericyte markers.ResultsDCAMKL1, Musashi‐1, CD144 positivities were not recognized in the early stage of the lymphoma formation but gradually found in the lymphocytes located in the marginal zone of the MALT lymphoma both in the gastric and hepatic MALT lymphoma. The well‐developed microcirculatory network accompanied the stem cell rich area. The myofibroblasts were also distributed in these area, suggesting the formation of stem cell niche similar to that found in epithelial cells.ConclusionsMALT lymphoma stem cells were found to exist in the marginal zone of the lymphoma, constituting the niche by the myofibroblast and microcirculatory components.
Changes in the activity of the Renin Angiotensin System on resistance arteries in isolated perfused heart of hypertensive rats.
Authors: Calderon Emilio Lopez , Villavicencio Nallely Acevedo , Lara‐Padilla Eleazar , Guevara‐Balcazar Gustavo , Chong Enrique Hong , Castillo‐Hernandez Maria Carmen 
Published: June 2021

High blood pressure (HBP) is a disease with high morbidity and mortality worldwide and is considered one of the main etiological factors of multiple cardiac pathologies. One of the regulatory mechanisms of blood pressure is the Renin Angiotensin System (RAS). It is important consider adjuvant therapies to improve the outlook and quality of life of patients with HBP. One therapy that has been shown clinically to improve the condition of patients with HBP is hyperbaric oxygenation (HBO), that consists in subjecting a subject at a pressure greater than 2 atmospheres absolute with 100% oxygen. This therapy has been shown to improve vascular smooth muscle relaxation, increasing oxygenation of hypoxic tissues, decrease the degree of fibrosis, among other beneficial effects.MethodologyWe used rats Wystar of 340 ± 20 g. A corresponding groups were induced hypertension of renal origin by a surgical method (cellophane method) at the eighth day after surgery we began the therapy OHB. At the end of treatment, the rats were sacrificed getting heart, this was mounted on a system of isolated organ (Langendorff system). Curves to Angiotensin II (Ang II) were obtain in coronary resistance arteries.ResultsThe diastolic pressure measurement was obtained (150 ± 15 mmHg). The HBP group without treatment (control) showed an increase in vascular reactivity in comparison with the healthy group (control) after a dose of 1×10−7M of Ang II (p <0.001). Whereas the study group no presented changes in vascular reactivity to any dose of Ang II, compared to healthy control group (p>; 0.05).
The Difference Between Calculated Functional Ejection Fraction by Using Cardio Ankle Vascular Index Examination and Measured Ejection Fraction by Using Transthoracic Echocardiography
Authors: Obata Yurie , Shigemi Kenji 
Published: June 2021

These days some studies report that 40% to 50% of patient with heart failure have preserved ejection fraction and the pathogenesis of that may relate to the ratio of ventricular end‐systolic elastance (Ees) to effective arterial elastance (Ea). Ees/Ea is known to reflect not only ventricular mechanical performance but also energetic performance. Despite these useful features, we don't use it in clinical site because of need invasive technique to estimate it. Hayashi et al developed a framework to estimate Ees/Ea without measuring ventricular volume and pressure. We evaluated the difference between calculated functional ejection fraction (EFe =SV/(Ved‐V0), SV is stroke volume, Ved is end‐diastolic volume, V0 is left ventricle unstressed volume) using by Cardio Ankle Vascular Index (CAVI) examination and measured ejection fraction (EF) by using transthoracic echocardiography.First we confirmed that correlation between measured and calculated Ees/Ea by using Hayashi's original dog data. We used Newton's method to calculate equations. Second we applied this equation to CAVI examination data to calculate human EFe. Afterwards we made scatter diagram about calculated EFe and EF measured by echocardiography in 24 patients who examined CAVI and echocardiography within a period of July 2006 to June 2011 at the Hospital, Fukui University, Japan. The first analysis results showed a correlation coefficient of 0.78 (p < 0.0001, 95% confidence limits of 0.687 – 0.844).Then revised Ees/Ea was calculated by using an approximate equation(revised Ees/Ea=Ees/Ea×0.4301+0.2712). Final scatter diagram about human EF showed that patients have similar measured EF were not similar calculated EFe.There is possibility of calculate noninvasive human Ees/Ea, and it may correlate heart failure with preserved ejection fraction.
Cardiac alterations induced by moderate zinc deficiency during fetal life and growth
Authors: Arranz Cristina , Juriol Lorena , Veiras Luciana , Garrido Facundo Mendes , Gobetto Natalia , Corrales Andrea , Zilberman Judith , Elesgaray Rosana , Tomat Analia , Costa Angeles 
Published: June 2021

AimTo evaluate the cardiac function, morphology and nitric oxide synthase (NOS) activity at 81 days of life in response to fetal and postnatal growth moderate zinc deficiency. Female Wistar rats received from the beginning of pregnancy up to weaning low (L:8 ppm) or control (C:30 ppm) zinc diet. After weaning, male offspring of each group of mothers fed low (l) or control (c) zinc diet during 60 days (Cc, Ll, Lc). We determined systolic blood pressure (SBP) by indirect tail‐cuff technique, cardiac NOS activity (pmol 14C L‐citrulline/g.tissue. min), myocytes diameter (MD, μm) and TGF‐β (% total area) by immunohistochemistry in heart. Left ventricular (LV) function was assessed by echocardiography, studying diastolic (d) and systolic (s) LV wall (LVW, mm), septum (LVS, mm) and ejection fraction (EF %).Statisticst‐test.

Cc
Ll

SBP (mmHg)
122±2
141±5*

dLVS
2.3±0.1
1.8±0.1*

sLVS
3.3±0.1
2.7±0.03*

dLVW
2.7±0.2
2.1±0.1*

sLVW
3.5±0.3
2.6±0.1*

EF%
79±7
66±4*

NOS
204±6
164±10*

TGF‐β
40.2±1.5
49.9±1.5*

Major MD
31.8±0.6
26.5±0.8*

Minor MD
18.2±0.3
14.1±0.5*

Values are means±SEM; p<0.05 vs Cc; n=8 rats/group.

Adequate zinc diet in low offpring after weaning (Lc) was unable to avoid alterations induced during fetal life. Zinc restriction during fetal life and growth may program heart diseases in adult life. Supported by: UBA‐Conicet.
Cardiac stroke volume predicts progressive central hypovolemia by three different non‐invasive methods
Authors: Holme Nathalie Linn Anikken , Rein Erling Bekkestad , Walløe Lars , Thoresen Marianne , Elstad Maja 
Published: June 2021

BackgroundCardiac stroke volume (SV) has been proposed as a clinical tool to predict the magnitude of acute hemorrhage. Multiple non‐invasive measurement methods of SV exist, without a standard method. We aimed to investigate the development of SV during simulated hemorrhage, and examine differences between three non‐invasive methods of SV measurements.Methods10 healthy subjects underwent experimental central hypovolemia through lower body negative pressure (LBNP) until −60 mmHg or onset of presyncope (7/10 subjects). SV beat‐to‐beat was calculated by Ultrasound Doppler (SV_usd, SD 100), finger arterial blood pressure curve (SV_bpc, Finometer) and cardiothoracic impedance (SV_imp, Task Force). The non‐parametric median and 95% confidence intervals (CI) were calculated from epochs of 60 or 120 seconds for SV in 5 different LBNP levels.ResultsBaseline absolute values for the three methods were different: SV_usd 78 ml (95% CI: 68,93), SV_bpc 88 ml (77,99), SV_imp 103 ml (89,151). SV_usd decreased with 45% (52%, 37%), SV_bpc decreased with 39% (45%, 27%), while SV_imp decreased with 33% (48%, 21%). Differences between methods were not significant.ConclusionSV clearly reflects the development of a simulated hemorrhage. The three methods for non‐invasive SV measurements provide different absolute values of SV during LBNP, but they decrease in a comparable way. Financial support: University of Oslo.