bluuebunny/crossref_metadata_2025_split huggingface dataset:
The inhibition of AGTR1 and Aromatase as a new potential therapeutic strategy for Glioblastoma treatment.
Authors: Panza Salvatore , Gelsomino Luca , Russo Umberto , De Amicis Francesca , Barone Ines , Giordano Cinzia , Malivindi Rocco , Catalano Stefania , Andò Sebastiano 
Published: April 2020

IntroductionGlioblastoma multiforme (GBM) is the most malignant form of glioma causing 3–4% of all cancer‐related deaths. Specific cancer treatment for GBM includes surgery, radiotherapy and chemotherapy with temozolomide. Despite the continuous development of new clinical therapies, the prognosis and survival of GBM patients remain dismal. Thus, the deregulated growth, the migratory and invasive capabilities of glioma cells remain the most important obstacles to the development of effective GBM treatments. Angiotensin II (Ang II)/Ang II receptor 1 (AGTR1) axis is expressed in normal and tumoral tissues, including human GBM. It has been reported in different experimental models that Ang II is able to stimulate aromatase expression through the AGTR1 activation. Different studies have demonstrated that aromatase enzyme is expressed in GBM cells and local estrogen production may act as an autocrine or paracrine factor in enhancing glioblastoma growth and progression. In the present study, we investigated if Ang II/AGTR1 signalling may modulate aromatase expression and consequently local estrogen production, thus influencing glioblastoma survival and growth.MethodsThe Aromatase expression role under treatment with Ang II has been assessed by RT‐PCR, Western blotting, Aromatase activity assay, Transient transfection assays, ELISA assay, cell proliferation assay (Thymidine incorporation), Boyden chamber migration and invasion assays, in the GBM cell line U‐87 MG.ResultsWe identified in U‐87 MG cells that the Ang II up‐regulates the aromatase expression in terms of mRNA, protein levels, and its enzymatic activity. In order to evaluate if Ang II may activate aromatase at transcriptional level we transiently transfected U‐87 MG cells with a vector containing human aromatase promoter I.4, broadly distributed around the brain and widely expressed in glioblastoma cells. Ang II treatment induces an increased aromatase promoter transcriptional activity. Mutagenesis studies and chromatin immunoprecipitation analysis reveal that the integrity of specificity protein 1 (SP1) and interferon‐gamma activation site (GAS) binding sites, within the aromatase promoter is required for Ang II modulation of human aromatase I.4 promoter activity in U87‐MG cells. The enhanced aromatase activity was paralleled by an higher estradiol production concomitant with an increase in cell proliferation, migration and invasion in U‐87 MG cells. These effects are reversed by treatment with an AGTR1 antagonist and/or an aromatase inhibitor, such as Losartan and Anastrozole respectively.ConclusionsAng II/AGTR1 signalling through Aromatase enhances local estrogen production which in turn promotes tumor growth and invasiveness. Therefore, their combined inhibitory targeting may prospectively provide a novel therapeutic strategy for Glioblastoma treatment.
Heterogeneous distribution of ion transporters in enteroids enriched in different intestinal epithelial cell types
Authors: Pearce Sarah C. , Kishida Kunihiro , Al-Jawadi Arwa , Shiarella Reilly J. , Auvinen Madelyn J. , Flores Juan A. , Yu Shiyan , Gao Nan A. , Ferraris Ronaldo P. 
Published: April 2020

The small intestine which is characterized by different cell types lining specific sites along the crypt‐villus axis plays a critical role in water, electrolyte and mineral balance. Normally, net fluid absorption by the small intestine occurs mainly because ion‐dependent fluid absorption in the villus column is greater than ion‐driven fluid secretion in the crypt. To generate these site‐specific ion gradients, appropriate transporters must be strategically located in cells lining the crypt or villus regions. The multivalent ions calcium and iron also function as essential minerals, and deficiency in these minerals is highly prevalent worldwide. The crypt‐villus site of many electrolyte and mineral transporters has been localized by immunocytochemistry, but their expression in rare cell types like stem cells (ISC) is unknown. To test the hypothesis that representative ion and mineral transporters are distributed heterogeneously among the various intestinal cell types, we made enteroids enriched in ISC, enterocytes (ENT), goblet (GOB), and Paneth (PAN) cells. We then confirmed by cell‐type specific biomarkers that ISC, ENT, GOB and PAN enteroids were enriched in stem cells (~90% of all cells per organoid), enterocytes (90%), goblet (80%) and Paneth (65%) cells, respectively. ENT and GOB enteroids had the highest mRNA levels of the chloride‐anion exchanger DRA and sodium‐hydrogen exchanger NHE3, while the sodium‐bicarbonate cotransporter NBCe1 was expressed primarily in ENT enteroids. Conversely, the chloride channel CFTR and sodium‐potassium‐chloride cotransporter NKCC1 mRNA were mainly expressed in ISC and PAN enteroids. Findings confirm previous immunocytochemical localization of NBCe1 and DRA in the villus region lined by enterocytes, with CFTR and NKCC1 mainly in intestinal crypts containing Paneth and stem cells. Basolateral NKCC1 staining was observed in ISC and PAN, but not in ENT and GOB, enteroids. The membrane location and expression of NKCC1 in crypt‐dwelling cells reflect its prominent role in intestinal fluid secretion. Members of the intestinal epithelial transport system for iron (DMT1, FTL, IREG1 and HEPH) showed homogeneous distribution in all cell types. The calcium transporters TRPV6 and PMCA1 were expressed least in ENT and GOB, respectively. Our findings depict a mostly heterogeneous distribution of ion transporters in different cell types, reflecting their likely distribution along the crypt villus axis in vivo, suggesting that appropriate expression in different cell types may be essential for ion and mineral homeostasis.Support or Funding InformationSupported by NSF 1456673, 1754783 (RF) and NIH R01AT010243 (RF, NG)
Chronic Binge Alcohol and Gonadal Hormone Loss Mediate Adipose Tissue Metabolic Maladaptations
Authors: Poret Jonquil Marie , Simon Liz , Molina Patricia 
Published: April 2020

Adipose tissue maladaptation is central to metabolic alterations in HIV, unhealthy alcohol use and obesity. This involves inflammation, adipokine disruption and dysfunction of adipocytes and the adipocyte extracellular milieu. HIV and simian immunodeficiency virus (SIV) have been shown to increase adipose tissue extracellular matrix (ECM) collagen deposition and impair adipose derived stem cell (ADSC) differentiation. Several aspects of adipocyte biology are regulated by ECM structure and composition. All proteins, regulators and secreted factors contained within the ECM are collectively called the matrisome and largely determines tissue stiffness. In several organs, tissue stiffness has been shown to disrupt normal cellular function and development, but little is known about tissue stiffness in adipose tissue. Using a relevant preclinical model of HIV‐infection, the objective of our study was to investigate the differential effects of chronic binge alcohol (CBA) administration and ovarian hormone loss on alterations in omental (OmAT) and subcutaneous (SAT) adipose tissue phenotype. CBA or isovolumetric water (VEH) was administered through an intragastric catheter for 30 minutes, 5 days a week, with blood alcohol concentrations reaching 50–60 mM. Three months after initiation of CBA administration, macaques were inoculated with SIVMac251 and 2.5 months later initiated on ART. After 1 month of ART, macaques underwent sham surgery or ovariectomy. Our preliminary data indicates that CBA administration increases viral load in adipose tissue. Depot differences were also detected between SAT and OmAT. OmAT has smaller adipocytes compared to SAT with higher anti‐fibrotic gene expression. SAT has higher collagen picrosirius red staining compared to OmAT with higher hormone sensitive lipase lipolytic gene expression. Ovariectomy produced similar effects in both adipose depots by decreasing adipocyte cell size and fibrotic gene expression. Taken together, preliminary data suggest that the maladaptive changes due to alcohol and gonadal hormone loss is potentially depot specific and is mediated by changes of the extracellular matrix. The contributing role of extracellular alterations on adipocyte function and a high fat diet to exacerbate adipose tissue maladaptation are investigated to identify adipose specific mechanisms that can be targeted to improve metabolic dysregulation.Support or Funding InformationNIH/NIAAA P60 AA009803 and 5T32AA007577‐19
XLαs is a novel activator of PLCβ4
Authors: Phan Hoa T.N. , He Qing , Bastepe Murat , Smrcka Alan V. 
Published: April 2020

Phospholipase C (PLC) enzymes are essential for normal cellular function. Upon stimulation by GPCRs or RTKs, PLCs hydrolyze phosphatidylinositol 4,5‐bisphosphate (PIP2) at cell membranes to generate diacylglycerol (DAG) and inositol 1,4,5‐trisphosphate (IP3). DAG and IP3 are important second messengers in signal transduction. DAG regulates activity of protein kinase C and IP3 mobilizes intracellular Ca2+, which initiate multiple signaling cascades and cellular processes. Dysregulation of PLC function gives rise to pathological processes. Among six mammalian PLC subfamilies, PLCb isozymes are activated by Gaq, Gbg, small G proteins and thus, play significant roles in various cellular activities.Extra‐large stimulatory Gα (XLαs) is a large variant of Gαs. Biochemically, XLαs activation by GPCR mediates cAMP‐ generation similarly to Gαs, however, Gαs and XLαs ‐‐‐have distinct cellular and physiological functions. He et al. suggests that XLαs is able to stimulate IP3 signaling in vivo. In this study, we aim to identify the PLC isozyme that mediates this phenomenon. By co‐expressing XLαs with different PLC constructs in cells and measuring total IP production, we identify that XLαs stimulates PLCβ4 to generate IP3. This activity is specific to XLαs because wild‐type and constitutively active Gαs do not activate PLCβ4. The G‐protein domain and membrane anchor of XLαs are required for its ability to stimulate PLCβ4. Our data also show that XLαs‐mediated PLCβ4 activation is PKA‐ and EPAC‐independent. Further studies are underway to determine whether this is a direct binding and activation event, and the role of XLαs stimulation of PLCb4 in physiological systems.Overall, we show that XLαs can stimulate PLCβ4 in cell and this novel signaling axis potentially play important roles physiologically.Support or Funding InformationThis work is funded by the NIH 5R35GM127303 (to AVS) and the Upjohn postdoctoral fellowship (to HTNP).
Cognitive function and regional body water analysis across the lifespan
Authors: Lee Jinhyun , Dudley-Javoroski Shauna A. , Dubey Olga , McCue Patrick M. , Johnson Kristin A. , Petrie Michael Arlyn , Shields Richard K. 
Published: April 2020

ObjectiveCognition decline occurs with age and adversely influences quality of life. Recent work suggests that systemic inflammation increases with age and may be associated with homeostasis of body water compartment levels. The extent to which fluid cognition is influenced by age and body water compartment distribution has not been carefully explored. Bioimpedance algorithms now enable us to analyze regional anatomical body water and determine estimates of the intra‐cellular and extra‐cellular water content levels. The ratio of the extra‐cellular water (ECW) relative to the intra‐cellular water (ICW) may provide a non‐invasive method to estimate systemic inflammation and predict cognitive function. In this study, we aspired to understand how age and water content predict fluid cognitive function in humans.PurposeWe determined the correlation between anatomical regions of the body for water content (ECW/ICW) and cognitive function as a function of age.MethodsThere were 101 participants (Male: 50, age<40: 62, age>40: 39, age mean:39.9±18.7). We used a bioimpedance analysis device (InBody S10), which can estimate six regional extracellular water (ECW) and intracellular water (ICW) readings. We calculate the ratio of ECW to ICW (ECW/ICW) for each of the six regions: left leg, left arm, right leg, right arm, trunk, and total. The NIH cognition toolbox Pattern Comparison Processing Speed (PCPS), Picture Sequence Memory (PSM), Dimensional Change Card Sort (DCCS), FLANKER inhibitory control and attention (FLANKER) and List Sorting Working memory (LSW) were used to test cognitive function. The composite score was calculated from these five tests.ResultsThe ECW/ICW of the left leg was significantly associated with all cognitive test results in the cohort with R‐squared values of 0.3, 0.46, 0.06, 0.12, 0.39, and 0.4 for FLANKER, LSW, PSM, PCPS, and the composite score, respectively. Age was highly correlated with cognitive test results in the cohort with R‐squared values of 0.32, 0.45, 0.07, 0.27, 0.5, 0.53, for the FLANKER, LSW, PSM, PCPS, and composite, respectively. FLANKER was highly correlated with bioimpedance indices in the older people with R‐squared values of 0.24, 0.22, 0.24, and 0.25 for the ECW/ICW total, ECW/ICW trunk, ECW/ICW right leg, and ECW/ICW left leg, respectively. FLANKER was not correlated with age in the older people with R‐squared value of 0.05.ConclusionsThe associations between cognitive function and bioimpedance indices were similar or higher than the associations between cognitive function and age. Future studies are needed to verify that ECW/ICW is associated with systemic inflammation and is a rigorous predictor of cognitive change, at any age.Support or Funding InformationResearch SupportThis study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development: R01HD084645, R01HD082109
Effects of acute smoking on heart rate variability in students
Authors: VOLKOVA IRINA , DIMITRIEV DMITRY , SAPEROVA ELENA , FILIPPOVA IRINA 
Published: April 2020

Cigarette smoking is a major cause of preventable morbidity and mortality in the world. There is altered autonomic activity in smokers which also predisposes to cardiovascular morbidity and mortality. To monitor the autonomic activity, heart rate variability has emerged as efficient tool. This study attempted to clarify the acute effects of cigarette smoking on autonomic nervous function among smokers.Twenty one light smokers (smoking less than 10 cigarettes a day) with a mean age of 22.36±0.16 years take part in the study (52% men, 48% women). They were studied in the morning hours in a quiet room at a comfortable temperature. Time domain (SDNN, RMSSD, pNN50), frequency domain (TP, HF, VLF, LF and LF/HF ratio) and nonlinear (SD1, SD2, ApEn, SampEn, D2, DFA1, DFA2) parameters of HRV were obtained from all participants for 10 minutes before and 10 minutes after smoking a cigarette while subjects were resting in a supine position and. Statistical analysis was performed using Mann‐Whitney test.There were no significant differences in heart rate during non‐smoking and smoking period (70.75±2.30 vs 73.37±2.33 beat/min, p=0.217). Time domain parameters were found to be lower during smoking period than that during non‐smoking period (SDNN: 38.07±3.91 vs 50.53±5.64 ms, p=0.001; RMSSD: 39.39±4.87 vs 56.4±7.57 ms, p=0.001 and pNN50: 17.08±3.61 vs 28.63±4.28 %, p=0.002). Frequency domain measures were also significantly lower during smoking period than that during non‐smoking period (TP: 1578.31±387.76 vs 2975.75±788.91 ms2, p=0.001; VLF: 52.52±10.11 vs 108.96±24.56 ms2, p=0.008; LF: 719.5±130.54 vs 1210.54±262.29 ms2, p=0.013 and HF: 804.96±275.86 vs 1650.12±578.23 ms2, p=0.0009). Nonlinear measures were significantly lower during smoking period than that during non‐smoking period (SD1: 27.88±3.45 vs 39.92±5.36 ms, p=0.001; SD2: 45.79±4.45 vs 58.84±6.5 ms, p=0.003; D2: 1.83±0.36 vs 3.09±0.37, p=0.013). The other HRV parameters including LF/HF ratio, pLF, pHF, ApEn, SampEn, DFA1, DFA2 were not significantly different.These results suggest that acute smoking has been associated with increased activity of the sympathetic nervous system and decrease in vagal cardiac control.
The Utility of White‐Light 3D Scanning in the Cadaver Lab: Examples Applicable to Iliac Crest Grafting for Mandibular Reconstruction
Authors: Hobeika Natalie A. , Bolden Alexys M. , Burkett Jesse T. , Shockley J. Mason , Zdilla Matthew J. , Lambert H. Wayne 
Published: April 2020

Performing imaging studies such as CT and MRI on cadavers in a gross anatomy setting may be particularly challenging or not feasible. Therefore, other imaging modalities should be investigated. This report highlights the utility of white‐light 3D scanning in a gross anatomical setting as applied to a shape compatibility analysis among iliac crest grafts and native mandibular anatomy in seven cadavers. Upon resection of iliac crests and mandibles, white‐light 3D scanning was performed, digital meshes (e.g., .ply files) were edited, and geometric morphometric analysis was performed using varied software to determine regions of shape compatibility/incompatibility. The results of the white‐light scanning resemble the detail of 3D reconstructions from CT and MRI for surface renderings; though, white‐light scanning has limitations with regard to visualizing underlying structures. The study concludes that white‐light scanning has utility in the gross anatomy setting, particularly as it related to 3D surface analysis as demonstrated by the analysis of the iliac crest graft as it relates to the anatomy of the mandible. Also, digital models can be manipulated with software and also be printed to produce physical models. White‐light scanning is suited for the gross anatomy laboratory setting and provides highly accurate digital renderings that are applicable to research as well as basic science and clinical education.Support or Funding InformationWVU INTRO (Initiation to Research Opportunities) Summer Research program; WV Research Challenge Fund [HEPC.dsr.17.06]
Maternal and postnatal diet play important roles on cardiometabolic health of offspring
Authors: Merlin Andrea Chiñas , Gonzalez Kassandra , Lota Jake , Chicco Adam J. , Chung Eunhee 
Published: April 2020

The prevalence of obesity and type 2 diabetes mellitus (T2DM) among children is alarmingly increasing in the United States, and children born from obese mothers are at greater risk for diabetes and cardiovascular disease. Cardiac mitochondrial dysfunction may contribute to heart disease associated with T2DM and obesity. The purpose of this study was to test hypothesis that a maternal obesogenic diet would alter offspring cardiac mitochondrial function and systemic metabolism. Female CD‐1 mice were fed either a high‐fat, high‐sucrose diet (HFHS) or a refined low‐fat, low‐sucrose diet (LFLS) for eight weeks before initiation of pregnancy, gestation, and during lactation. At 21 days, male mice were randomly divided into 3 groups: offspring of HFHS dams weaned onto a standard chow diet (HC), HFHS diet (HH), or offspring of LFLS dams continue fed to LFLS diet (LL). Glucose and insulin tolerance tests were performed in 6 month‐old male offspring, followed by sacrifice for evaluation of cardiac mitochondrial respiratory function. HFHS diet‐induced maternal obesity impaired glucose tolerance and insulin sensitivity in HH offspring. Switching offspring to the control diet (HC) did not decrease body weight associated with maternal obesity, but significantly decreased subcutaneous fat mass compared to the HH, and preserved glucose tolerance and insulin responsiveness to near LL levels. In freshly isolated cardiac mitochondria, maximal oxidative phosphorylation (OXPHOS)‐linked respiratory capacity and coupling efficiency was significantly higher in the HC in the presence of fatty acid substrate (palmitoylcarnitine) compared to LL. In the absence of fatty acids, OXPHOS‐linked respiratory capacity and OXPHOS coupling control were not altered. These results indicate that both maternal and postnatal diet modulate offspring cardiac mitochondrial metabolism, favoring greater fatty acid oxidation in offspring fed a control diet following maternal obesity.Support or Funding InformationThis study was funded by the American Physiological Society Research Career Enhancement Award and the University of Texas at San Antonio, Office of the Vice President for Research and the College of Education and Human Developments.
Angiotensin II Type I Receptor Agonistic Autoantibody Blockade Improves Cerebral Blood Flow Autoregulation, Blood Brain Barrier Permeability, and Hypertension in the Pre‐Clinical Rat Model of Preeclampsia
Authors: Cunningham Mark W. , Duncan Jeremy W. , Azubuike Daniel , Booz George , Fisher Brandon , Williams Jan , LaMarca Babbette 
Published: April 2020

BackgroundPreeclampsia (PE) is a pregnancy disorder that is characterized by an increase in blood pressure, angiotensin II type1 receptor agonistic autoantibodies (AT1‐AA), and neurological complications. The pre‐clinical RUPP (reduced uterine perfusion pressure) rat model of PE displays many of the clinical pathologies associated with PE, such as increased blood pressure, AT1‐AAs, blood brain barrier (BBB) permeability, and impaired cerebral blood flow (CBF) autoregulation.HypothesisWe hypothesized that specific inhibition of AT1‐AA, using the epitope binding 7 amino acid peptide sequence (7AA), will improve blood pressure, BBB integrity, and CBF autoregulation in RUPP rats.MethodsSprague Dawley rats, were divided into 3 groups: normal pregnant (NP) (n=19), RUPP (n=19), and RUPP+AT1‐AA inhibition (7AA) (n=21). RUPP surgery was performed on gestational day (GD) 14 and 7AA (2μg/μl) was administered via osmotic minipumps. GD 19, mean arterial pressure (MAP) was determined and BBB permeability was assessed using the in‐vivo imaging system (IVIS). CBF was measured by laser Doppler flowmetry through a 4 mm x 4 mm cranial window under anesthesia. MAP was elevated step‐wise from 100–190 mmHg by infusion of phenylephrine to determine changes in CBF.ResultsMAP was increased in RUPP vs NP (124±3 vs 100±1 mmHg, p<0.05) and decreased in RUPP+7AA vs RUPP (105±2 vs 124±3 mmHg, p<0.05) rats. Using IVIS, Texas Red/FITC green fluorescent imaging was decreased in RUPP+7AA vs RUPP (0.2±0.001 vs 0.6±0.001, p<0.05), indicating improvement in BBB permeability with AT1‐AA inhibition. CBF autoregulation was impaired in RUPP vs NP rats at 140 mmHg (142±7 vs 119±4%, p<0.05) and 160 mmHg (157±10 vs 129±6%, p<0.05) (both pressures are within the normal CBF autoregulatory range). AT1‐AA inhibition prevented impaired CBF at 140mmHg (125±5 RUPP+7AA vs 142±7% RUPP, p<0.05) and 160 mmHg (125±9 RUPP+7AA vs 157±10% RUPP, p<0.05). Furthermore, the increases in CBF at pressures above the autoregulatory range, 180 mmHg (122±10 vs 198±17%, p<0.05) and 190 mmHg (123±11 vs 208±19%, p<0.05), was prevented in RUPP+7AA vs RUPP, respectively.ConclusionAT1‐AA inhibition improved blood pressure, BBB permeability, and CBF autoregulation in the pre‐clinical RUPP rat model of PE, indicating that AT1‐AA inhibition may be a potential therapy used to improve neurological complications during PE.Support or Funding InformationSupported: AHA18CDA34110264