bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin Activates a NMDA Pathway to the RVLM to Elevate Sympathetic Nerve Activity
Authors: Bardgett Megan , Stocker Sean D 
Published: June 2021

Hyperinsulinemia elevates lumbar sympathetic nerve activity (SNA) via activation of ionotropic glutamatergic receptors in the rostral ventrolateral medulla (RVLM). Therefore, the present study determined the contribution of NMDA vs non‐NMDA receptors. Male Sprague‐Dawley rats (250–300 g) were anesthetized with α‐chloralose and infused with insulin (3.75 mU/kg/min) and 50% dextrose (.25–.75 ml/hr) for 120 min. At 90 min, hyperinsulinemia significantly increased lumbar SNA (40±6%) with no change in arterial blood pressure (ABP, 0 min: 117±5 vs 90 min: 119±6 mmHg) or plasma glucose levels (0 min: 72±5 vs 90 min: 68±5 mg/dl). RVLM microinjection of the ionotropic glutamate receptor antagonist KYN significantly reduced lumbar SNA (−28±10%) and ABP (−8±2 mmHg, p<0.05). Similarly, RVLM microinjection of the NMDA receptor antagonist AP5 significantly attenuated lumbar SNA (−30±8%) and ABP (−5±3 mmHg, P<0.05). The decrease in lumbar SNA and ABP after injection of KYN vs AP5 was not statistically different. In contrast, microinjection of the non‐NMDA receptor antagonist NBQX into the RVLM had no significant effect on lumbar SNA (6±3%) or ABP (5±4 mmHg). In addition, direct microinjection of insulin into the RVLM did not significantly increase lumbar SNA or ABP. These findings indicate that hyperinsulinemia increases lumbar SNA through a glutamatergic NMDA projection to the RVLM.Supported by NIH HL090826, AHA 0630202N & 0815372D
Toll‐like receptor expression is increased via activation of AT1 receptor in the brain associated with sympathoexcitation in mice with heart failure
Authors: Ogawa Kiyohiro , Hirooka Yoshitaka , Kishi Takuya , Sunagawa Kenji 
Published: June 2021

BackgroundPrevious studies suggest that heart failure (HF) is associated with sympathoexcitation due to oxidative stress in the brain induced by AT1 receptor (AT1R) and NAD (P) H oxidase. They are also known as an upstream of inflammatory signaling pathway mediated by Toll‐like receptor 4 (TLR4) in the brain. The aim of the present study was to determine whether AT1R‐induced sympatho‐excitation is mediated by TLR4 in the brain of heart failure model or not.Methods and ResultsAs a HF model, ligation of the left coronary artery was performed to make large myocardial infarction (MI) and subsequent HF in ICR mice. On day 10 after left coronary artery ligation, mice received either intracerebroventricular (icv) losartan (10μg/h, CHF‐Los) or vehicle (CHF‐Veh) by osmotic minipumps for 14 days. Urinary norepinephrine excretion as a parameter of sympathetic nervous system activity was significantly higher in HF than in sham mice and was significantly lower in CHF‐Los than in CHF‐Veh(0.34±0.04 vs 0.62±0.06, n=3, P<0.05). The expression of TLR4 in the whole brain determined by Western blot analysis was significantly higher in HF than in sham mice, and was significantly lower in CHF‐Los than in CHF‐Veh.ConclusionToll‐like receptor expression is increased via activation of AT1 receptor in the brain associated with sympathoexcitation in mice with heart failure.
Structural analysis of HIV‐1 protease inhibition using physical models
Authors:   Lincoln SMART Team, Colton Shannon , Herman Tim , Giles Kurt , Koo Ben , Jeske Sabine , Ollikainen Noah , Reis Julie 
Published: June 2021

HIV‐1 protease (HIV PR) is an essential enzyme for HIV replication. HIV PR cleaves immature HIV polypeptides resulting in the active protein components required for an infectious virus. Numerous HIV PR inhibitors have been developed in order to prevent and treat HIV infection, however, the rapid evolution of HIV PR has allowed HIV to become drug resistant and remain infectious. Here we examine the inhibition of HIV PR from a structural perspective by building physical 3D models of HIV PR variants in complex with different inhibitors. These models allow us to analyze the key interactions that enable the inhibition of HIV PR and provide us with visual tools for studying the structural basis of drug resistance mutations.The SMART (Students Modeling A Research Topic) program was established by the Center of BioMolecular Modeling at the Milwaukee School of Engineering and involves partnerships between university researchers and local high schools. This work is funded by NIH‐NCRR‐SEPA and HHMI.
Evolution of new exons and alternative splicing in primates
Authors: Lin Lan , Shen Shihao , Jiang Peng , Sato Seiko , Davidson Beverly L , Xing Yi 
Published: June 2021

New exons are frequently created within existing genes during the evolution of eukaryotic genomes. Based on mRNA and EST data, the vast majority of newly created exons are spliced only at very low levels. Thus, new exons have been generally considered as evolutionary intermediates that lack established functions. In this study, using a large‐scale genomic and molecular analysis of new exons derived from retrotransposons, we provided genomic evidence for the evolutionary significance of widespread exon creation during primate and human evolution. Contrary to the common belief that strong splicing activities of new exons result exclusively from disease mutations, we identified newly born exons constitutively spliced in a broad range of human tissues, as well as exons with tissue‐specific splicing. In a related study, we found hundreds of genes with human‐specific splicing events in the brain transcriptome. Some of these events modulate protein domains critical for protein‐protein interactions; others affect transcripts previously implicated in brain diseases. Together, our studies reveal substantial changes in exon usage and splicing patterns during human evolution, suggesting that alternative splicing played a central role in the acquisition of human‐specific traits.Supported by the NIH (YX), Edward Mallinckrodt Jr. Foundation (YX), Roy J. Carver Trust (BLD).
Camel's Milk alleviates Oxidative Stress and Lipid Peroxidation Induced by chronic Aluminum Chloride Exposure in Rat's Testes
Authors: Al‐Hashem Fahaid Hassan 
Published: June 2021

ObjectiveThe present study was carried out to examine the effectiveness of camel's milk in alleviating aluminum chloride (AlCl3)‐induced oxidative stress and lipid peroxidation in rat testes.ApproachWhite albino male rats (230–250 g) were divided into three groups of 10 rats: A control group, treated with normal saline and two experimental groups, the AlCl3 treated group and the camel's milk‐AlCl3 treated group. The first experimental group, the AlCl3 treated group, received 0.5 mg kg−1 of AlCl3 orally. The second experimental group was fed 1 mL of fresh camel's milk 10 min prior to the administration of oral AlCl3. All rats were treated every day for 30 days. Lipid peroxidation, as determined by plasma concentration of Thiobarbituric Acid Reactive Substances (TBARS) and Hydroperoxide (HP) levels and the oxidative stress status, as measured by glutathione (GSH) levels, Superoxide Dismutase (SOD) and Catalase (CAT) activity, were evaluated in the rat testes.ResultsOral administration of AlCl3 induced lipid peroxidation and oxidative stress in rat testes, which was indicated by a significant increase in lipid peroxidation biomarkers (TBARS and HP) and a significant decrease in the GSH content and SOD and CAT activities. When rats received camel's milk before being given AlCl3, lipid peroxidation and oxidative stress parameters were restored to normal levels. In the testes from rats fed camel's milk TBARS and HP levels were significantly reduced and, conversely, GSH content, SOD and CAT activities were significantly increased compared to rats that received only AlCl3.ConclusionTreatment with camel's milk prior to AlCl3 alleviates AlCl3‐associated hazards and protects testicular tissue from AlCl3 toxicity.Grant Funding Source: King Khalid uNIVERSITY
Improved obesity‐induced insulin resistance in mice lacking Tumor Progression Locus 2 (TPL2)
Authors: Lee Yunkyoung , Perfield James W , Chang Eugene , Hussain Sajid , Xie Chen , Tsichlis Phillip N , Obin Martin S , Greenberg Andrew S 
Published: June 2021

Chronic inflammation due to adiposity is closely related to various metabolic complications including insulin resistance and type II diabetes. TPL2 is a serine/threonine kinase that is located downstream of IKKβ and involved in the regulation of MAPKs and inflammatory cytokines such as TNFα. In this study, we utilized the TPL2 knockout (KO) mouse to test our hypothesis that TPL2 ablation would improve obesity‐induced inflammation and insulin resistance. Wild‐type (WT) and TPL2 KO mice were fed either a normal chow diet or a high fat diet (HFD) for 16 weeks. TPL2 ablation did not alter HFD‐induced adiposity; however ITTs and hyperinsulinemic euglycemic clamp studies demonstrated improved insulin sensitivity in obese TPL2 KO mice. Insulin signaling studies revealed increased Akt activation in the muscle and adipose tissue of obese TPL2KO mice. Consistent with the improved insulin sensitivity, adipose tissue of obese TPL2 KO mice had a reduced presence of crown‐like structures. Despite WT levels of obesity, gene expression of macrophage markers (F4/80, CD11c), chemokines (MCP‐1) and pro‐inflammatory cytokines (IL‐1β, TNFα) was reduced in the adipose tissue of obese TPL2 KO mice. Obesity‐induced activation of ERK and JNK was also attenuated in obese TPL2 KO mice. Furthermore, inflammatory gene expression and lipid accumulation were reduced in the livers of obese TPL2 KO mice. Overall, our results are the first to demonstrate in vivo a role for TPL2 in obesity‐associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity. Supported by ADA and NIHGrant Funding Source: NIH and ADA
Blood Pressure is Associated with BMI and Predicts Plasma Glucose Control and Triglycerides among Obese Latinos with Type 2 Diabetes
Authors: Chhabra Jyoti , Vega‐López Sonia , D'Agostino Darrin , Fernandes Maria Luz , Segura‐Pérez Sofia , Damio Grace , Pérez‐Escamilla Rafael 
Published: June 2021

The objective of this study was to examine the relationship of BMI, diastolic and systolic blood pressure (DBP, SBP), Triglycerides (TG), HDL‐Cholesterol (C), LDL‐C, Fasting Plasma Glucose (FPG), and Glycosylated Hemoglobin (HbA1c) in Latino patients with type 2 diabetes (T2D). Demographic information was gathered. Weight and height were measured. Blood sample was obtained from 211 patients ≥21 yrs, HbA1c ≥7, residing in Hartford county (M=26.5%; F=73.5%). Means: age=56.4±11.8 yrs, BMI=33.7±7.8 kg/m2, SBP=120±15.8 mm Hg, DBP=68.4±9.6 mm Hg, TG=153±95 mg/dL, HDL‐C=51±14 mg/dL, LDL‐C=98±39 mg/dL, FPG=10.4±4.5 mmol/dl (187.2±81 mg/dl), HbA1c=9.6±1.8%. 120 patients had a diagnosis of hypertension. Linear regression results revealed that BMI was related only to diastolic BP (adj. R2=0.02, Std. β=0.14, p≤0.04). DBP predicted FPG (adj. R2=0.03, Std. β=0.19, p≤0.01). On regressing both DBP and TG predicting FPG, only TG was significant (adj. R2=0.13, Std. βDBP=0.10 (p=0.15), Std. βTG=0.35(p≤0.00)). FPG was related with HbA1c (adj. R2=0.24, Std. β=0.5, p≤0.00). In an overweight/obese population, the relationship between BMI and plasma glucose among individuals with T2D may be mediated by other metabolic syndrome indicators, such as diastolic BP and TG.Funding: Connecticut NIH Export Center of Excellence for Eliminating Health Disparities among Latinos (NIH‐NCMHD grant # P20MD001765).
Adipocity‐related chemokines as early biomarkers of metabolic syndrome in Korean adults
Authors: Bae Yun‐Jung , Kim Se‐Hong , Chung Ju‐Hye , Kim Kyung‐Soo , Kwon O‐Ran , Kim Mi‐Kyung , Sung Mi‐Kyung 
Published: June 2021

Recent studies have suggested that the increased circulating adipokines and inflammatory cytokines are possible mediators of metabolic syndrome (MetS)‐related disorders. The objective of this study was to establish the link between the MetS and blood markers of adipocity and inflammation in Korean adults. Study subjects included 86 MetS and their age‐matched controls (n=86). Study results indicated that the intercellular adhension molecules (ICAM) (p=.0001), monocyte chemoattractant protein‐1 (MCP‐1) (p=.0001), and oxidized LDL (oxLDL) (p=.0001) were significantly higher in MetS subjects compared to those of the control. MetS subjects had significantly lower serum concentrations of adiponectin (p=.0001) than the control. In a pooled analysis, the number of MetS component were significantly decreased with increasing adiponectin concentration (p=.0001), and increased with increasing ICAM (p=.0013), MCP‐1 (p=.0202), and oxLDL concentrations (p=.0001). These results suggest that adipocytokine and inflammation markers may be representative blood biomarkers of metabolic syndrome.<This work was supported by the Ministry of Knowledge Economy for the Regional Innovation System program in 2009(B0009639) and the SRC program of the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (2009‐0063409)>Grant Funding Source: Nutrition(ASN)
The type and amount of dietary fat and time of consumption alters hepatic lipogenesis and oxidation: role of PGC1β
Authors: Ordaz‐Nava Guillermo , Cruz‐Salazar Nataly , Lara‐Pompa Nara E , Tovar Armando R , Torres Nimbe 
Published: June 2021

There is a controversy in the modulation of hepatic lipid metabolism by the type of fatty acid in the diet. Thus, the purpose of the present work was to evaluate the effect of short‐ and long‐term consumption of different type and amount of dietary fat on hepatic lipogenesis and oxidation in rat. Short‐term consumption for seven days showed that fatty acid oxidation was increased by soybean oil (SO) and coconut oil (CO) by increasing CPT1 via PPARα coactivated by PGC1β, and the presence of cholesterol in the SO diet reduced fatty acid oxidation. The lipogenic activity mediated by SREBP‐1 and FAS was higher in the group fed CO + cholesterol and the increase in the amount of SO decreased lipogenic activity mediated by SREBP‐1 and FAS. Long‐term consumption showed that the higher the amount of fat in the diet the higher the inhibition in lipogenic and oxidation gene expression independently of the type of fat. SO with a ω3/ω6 ratio 8.4 produced a higher oxidation and lower lipogenesis than the groups fed butter or chia oil with ω3/ω6 ratio of 3 and 0.2 respectively. Thus fatty acid insaturation and amount of fat modulate hepatic fatty acid oxidation and lipogenesis.Supported by INCMNSZ.
Ketogenic therapy education modules for caregivers and healthcare professionals
Authors: Allen Hannah , Lee Katherine , Jones Lauren , Andrade Edgard , Carney Paul , Liu Zhao , Borum Peggy R. 
Published: June 2021

BackgroundKetogenic Therapy (KT) is a high fat, low carbohydrate, adequate protein diet used to treat epilepsy which requires strict adherence. Due to limited knowledge about KT, caregivers (CG) and healthcare professionals (HCP) require comprehensive education to successfully implement KT.ObjectiveTo create KT education modules for CG and HCP.MethodsEducation modules were developed to meet specific needs and refined in a clinical and research setting.ResultsEducation modules were created to meet the listed education needs.

Education Needs

Appropriate expectations for KT and skills needed for administration

Support through continual contact, education, and data collection

Current information about KT provided on a quarterly basis

A collection of peer reviewed literature to increase KT awareness and to be used for evidence based patient care

Documentation of patient's progress on KT with emphasis on progress since last KT clinic visit

Documentation of macronutrient content of all ingested substances

A spreadsheet calculator with instructions on how to prepare meals and administer the KT diet prescription

ConclusionEducation modules are available on the internet for continual use and to aid in long term compliance. These modules for CG and HCP can be used in a typical clinical setting and at other KT centers.
Metabolism of prostaglandin glyceryl esters (PG‐Gs) by human carboxylesterases, CES1 and CES2, and its inhibition by bioactive metabolites of organophosphate (OP) insecticides
Authors: Ross Matt K. , Borazjani Abdolsamad , Potter Philip M , Xie Shuqi 
Published: June 2021

PG‐Gs are derived from the oxidation of 2‐arachidonoylglycerol by COX‐2 and have roles in inflammation and pain. Currently, the enzyme(s) responsible for degrading PG‐Gs are not well defined. Carboxylesterases (CES) are nonspecific hydrolases and candidate enzymes. Two CES isoforms are found in human tissues, CES1 and CES2. Here, we determined if PG‐Gs are hydrolyzed by human CES and then investigated the hydrolytic metabolism of these compounds in human THP1 monocytes/macrophages. Further, we determined if metabolites of OP insecticides could inhibit PG‐G metabolism in these cells. We show that recombinant human CES1 and CES2 effectively hydrolyze PGF2α‐G and PGE2‐G [CES1: (kcat/Km)PGF2α‐G = 0.60 min−1 μM−1and (kcat/Km)PGE2‐G = 0.37 min−1μM−1; CES2: (kcat/Km)PGF2α‐G = 1.7 min−1μM−1and (kcat/Km)PGE2‐G = 0.23 min−1μM−1]. In THP1 monocytes/macrophages, we demonstrated using selective CES1 inhibitors, immunoprecipitation, and immunoblotting that CES1 is likely the main enzyme responsible for hydrolyzing PGE2‐Gs, and that MAGL and FAAH do not have significant roles. In addition, pre‐treatment of intact cells with OP metabolite (0.1–10 μM paraoxon) significantly reduced the hydrolysis rate of exogenously added PGE2‐G (~20–70%, p<0.05). These findings suggest that exposure of CES1‐ and/or CES2‐expressing cells to bioactive OP metabolites may perturb the PG‐G tone in tissues composed of these cells, thus potentially inducing a pro‐inflammatory state.Supported by NIH R15 ES015348.
Diabetic pregnancy impairs EDHF‐dependent uteroplacental vasodilation mediated by intermediate‐conductance Ca2+‐activated K+ channels
Authors: Gokina Natalia I , Kuzina Olga Y , Vance Amanda M , Phillips Julie K 
Published: June 2021

Diabetes in pregnancy is associated with such adverse outcomes as hypertension, preeclampsia and stillbirth. Increased uteroplacental vascular resistance due to endothelial dysfunction may be an underlying mechanism. This study aimed to (1) Characterize the effect of diabetes on EDHF‐mediated uteroplacental vasodilation; (2) Explore the role of endothelial intermediate‐conductance (IKCa) K+ channels in impaired of EDHF responses. Diabetes was induced by injection of streptozotocin (STZ) on day 2 pregnant rats. Uteroplacental arteries from day 20 of pregnancy were cannulated, pressurized and loaded with fura 2. The vasodilator and smooth muscle cell (SMC) [Ca2+]i responses to ACh, EBIO or NS309 were studied in pre‐constricted arteries in the presence of L‐NNA and indomethacin. STZ injection produced sustained hyperglycemia in treated rats. ACh‐induced vasodilation and reduction in SMC [Ca2+]i were attenuated by diabetes. EDHF responses were not affected by iberiotoxin or apamin but abolished by charybdotoxin or TRAM‐34. EBIO‐ or NS309‐induced vasodilation was abolished by TRAM‐34 and was significantly impaired in hyperglycemic rats. Diabetes in pregnancy results in a marked impairment of EDHF‐mediated vasodilation most likely due to dysfunction of endothelial IKCa channels, which may serve as a target of future pharmacotherapy to improve uteroplacental blood flow.Supported by NIH HL088245
Inflammatory Markers in Isolated Endothelial Cells of the Spontaneously Hypertensive Rat
Authors: Xiu Ruijuan , DeLano Frank A , Hongwei Li , Ailine Li , Schmid‐Schönbein Geert W 
Published: June 2021

Besides an elevated blood pressure, the spontaneously hypertensive rat (SHR) has inflammation, extensive cell injury, microvascular and parenchymal cell dysfunction and vascular lesions. Current evidence in‐vivo shows that both excessive oxidative stress and proteolytic activity are involved, but their source is uncertain, We hypothesize that isolated endothelial cells of the SHR without the involvement of other sources (e.g. adrenal hormones) have elevated levels of oxygen free radical and degrading enzyme. To separate endothelial mechanisms from others, we isolated and cultured rat aortic endothelial cells (RAOEC) of adult SHR and control Wistar rats and propagated them with minimal loss of morphologic and phenotypic characteristics. The expression of oxidative enzymes (xanthine oxidase, XO; nicotinamide adenine dinucleotide phosphate, NADPH), apoptotic enzymes (BAX; BCl‐2) and matrix metalloproteinase (MMP‐9) was determined in cultured second passage RAOEC by immunoperoxidase detection of RAOEC using a standardized avidin/biotin immunolabeling technique and digitally measured by optical intensity. Compared to Wistar endothelium measurements, protein levels of XO, NADPH, MMP‐9 as well as the apoptotic marker BAX, were significantly enhanced in the SHR endothelium with attenuated BCL‐2 protein levels. These results suggest that even isolated aortic endothelium of the SHR has upregulation of proteins as seen previously in‐vivo that may promote inflammation and lesion formation and even in the absence of an elevated blood pressure.(Supported by: 1Grant of “Knowledge Innovation Project”, Academy of Science, China No. KJCX1‐SW‐07, 1Grant of IM0608, CAMS and 2NIH HL‐10081)
Effects of ganoderma lucidum spores on changes of both caspase‐8 and nestin in epilepsy rats
Authors: Wang Shu‐Qiu , Kang Yu‐Ming , Li Xiao‐Jie , Liu Lei , Liu Jun‐Xing , Zhao Xiao‐Lian , Wang Fang‐Fang , Zhao Lu 
Published: June 2021

To investigate the effects of ganoderma lucidum spores on caspase‐8 and nestin in brain tissue of rats by pentylenetetrazol (PTZ) induced epilepsy, and to further study the pathogenesis of epilepsy and the anti‐epilepsy mechanism of ganoderma lucidum spores. Thirty‐six male Sprague‐Dawley rats were divided into three groups randomly: control, PTZ epilepsy and ganoderma lucidum spores (GLS) groups. The results showed that caspase‐8‐positive cell's number in rats of PTZ model group were higher than that of normal control and GLS group, while the number of caspase‐8‐positive cells were decreased in the GLS group compared with that of the epileptic model group. The content of nestin were higher in PTZ model group than those of control group and GLS group in cortex and hippocampus, the level expression of nestin in GLS group were higher than control group.ConclusionGanoderma lucidum spores can effectively reduce the expression of apoptosis cell and inhibit the caspase‐8 activations in the epileptic rat′s brain tissue, strengthen the function of anti‐oxidize in brain tissue, and GLS can supply recovering of epilepsy nerve cell with important basis by reducing the content of nestin neural internality protect mechanism can be strengthened to reduce the damage on nerve system induced by falling sickness. Ganoderma lucidum spores is an assistant medicine to cure epilepsy, it could be very useful in clinical application.