bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of Doxorubicin and Doxorubicinol concentrations in rat heart and liver tissue following anthracycline administration
Authors: Chenard Pamela , Fabris Sergio , Anderson Lindsay , MacLean David 
Published: June 2021

Doxorubicin (DOX) is an anti‐cancer chemotherapeutic and although it is widely used, its accumulation over time in different tissues has not been thoroughly investigated. The purpose of this study was to examine the concentration of both DOX and its metabolite (Doxorubicinol, DOXol) in the heart and liver of male Sprague‐Dawley rats. Two doses (1.5 mg/kg and 4.5 mg/kg) were injected intraperitoneally and tissues were collected at 24, 48, 72 and 96 hrs post‐injection. In the heart, at all time points, DOX concentrations were higher (p<0.05) following the 4.5 vs 1.5 mg/kg injection (0.78±0.07 vs 1.81±0.26 nmol/g at 24 hrs, 0.37±0.06 nmol/g vs 0.96±0.06 nmol/g at 96 hrs). It was observed that DOX heart concentrations steadily decreased (p<0.05) over time for the 4.5 mg/kg dose, whereas for the 1.5 mg/kg dose, concentrations remained constant for the first 72 hrs and then decreased (p<0.05) at 96 hrs. In the liver, at all time points and for both doses, DOX concentrations were higher (p<0.05) as compared to the heart (3.85±1.1 and 5.29±0.87 nmol/g in the liver vs 0.78±0.07 and 1.81±0.26 nmol/g in the heart, at 24 hrs). While DOXol was detected in small concentrations in both heart and liver tissue, no accumulation was observed over the 96 hrs. These data suggest that in both heart and liver that DOX accumulates in a dose dependent fashion. In contrast, DOXol does not accumulate to any degree in either tissue, suggesting that it is rapidly degraded or eliminated from the tissues.Supported by NSERC.
Endothelin‐1 Expression In Vascular Adventitia
Authors: Di Wang Hui , Rätsep Matthew , Nguyen Huy , Adams Michael 
Published: June 2021

Background and hypothesisEmerging evidence indicates that the vascular adventitia is a dynamic tissue and may play a critical role in the development and progression of vascular disorders. Endothelin‐1 (ET‐1) is a potent vasoactive peptide, mediating both vascular contractile and growth responses. Endothelial cells are a major source of ET‐1, but the possibility that vascular adventitial fibroblasts generate ET‐1 has not been explored. We hypothesized that aortic adventitial fibroblasts have the ability to produce ET‐1.MethodsFor studies in cultured cells, vascular adventitial fibroblasts were isolated from the mouse (15 weeks of age) thoracic aorta and incubated with various concentrations of angiotensin II (Ang II). mRNA levels of preproET‐1 were detected by RT‐PCR. ET‐1 levels in the culture medium were measured by ELISA. In another set of study, after being anesthetized and euthanized by exsanguinations, the aortas were isolated, formalin fixed, embedded in paraffin, and then serially sectioned. The expressions of ET‐1 were determined by immunofluorescence staining.Results and ConclusionAng II induced an increase in preproET‐1 mRNA levels and the immunoreactive peptide ET‐1 levels. The increases in preproET‐1 mRNA expression and ET‐1 release were blocked by Losartan, an AT1‐receptor antagonist but not PD123319, an AT2‐receptor antagonist. In the aorta sections, although staining of ET‐1 was present throughout the vascular wall, the majority of its expression was observed in both the adventitial and endothelial layers. In conclusion, these findings demonstrate that the adventitia contributes to ET‐1 production which suggests the possibility for the adventitia to contribute to regulate vascular functions.We would like to acknowledge our granting agency the Heart and Stroke Foundation of Canada.
Modulation of Purinoceptor mediated Ca2+ signals by β‐adrenergic receptor activation in Salivary Glands
Authors: Bhattacharya Sumit , Ampem Prince , Dartt Darlene , Giovannucci David 
Published: June 2021

Crosstalk between Ca2+ signaling pathways has been demonstrated to facilitate secretory activity. However it is not known whether such a crosstalk exists between adrenergic receptor signaling pathway and a non‐cholinergic non‐adrenergic (NANC) pathway (purinergic pathway). In this study we use enzymatically isolated mouse parotid acini along with live cell Ca2+ imaging and pharmacological manipulations to assess crosstalk between these two pathways.We showed that [Ca2+]i rises induced by selective activation of P2X4R and P2X7R were potentiated three to eightfold following treatment with the cAMP elevating compounds forskolin, 8‐cpt‐cAMP or 3‐isobutyl‐1‐methylxanthine. Importantly, rises in cAMP levels evoked by β‐adrenergic receptor activation using isoprenalin also resulted in a marked enhancement of P2X‐mediated [Ca2+]i signals.Potentiation of P2X4R‐mediated [Ca2+]i signals following β‐adrenergic receptor activation was likely mediated by PKA because protein kinase inhibitor application in the presence of forskolin or isoprenalin abolished the enhancement of evoked [Ca2+]i signals. Interestingly, application of 2‐Aminoethoxydiphenyl borate during P2X7R stimulation also abolished the enhancement of [Ca2+]i rises following isoprenalin treatment.The results from this study reveal a crosstalk between purinergic and β‐adrenergic signaling pathways and may provide novel targets for construction of therapies for salivary hypofunction patients.
The Effect of TYPE 1 DIABETES ON REPRODUCTIVE HORMONES (FOLLICLE STIMULATING, LUTEINIZING AND TESTOSTERONE HORMONES) IN HUMAN MALE SUBJECTS
Authors: Adegbesan Bukunola Oluyemisi , Ogunlabi Olugbenga O 
Published: June 2021

Diabetes mellitus is a syndrome characterized by chronic hyperglycemia (high blood sugar) either because the body does not produce enough insulin (Type 1 or Insulin Dependent Diabetes Mellitus‐IDDM), or because body cells do not properly respond to insulin that is produced (Type 2 or Non Insulin Dependent Diabetes Mellitus‐NIDDM).Diabetes Mellitus has been recognized as a clinical syndrome since ancient times and remain a crippling global health problem till today (Wild et al.,2004).This study was designed to determine the effect of Type 1 diabetes on reproductive hormones (Luteinizing hormone (LH), Follicle Stimulating Hormone (FSH) and Testosterone Hormone (TH) in human male subjects. Forty (40) human male subjects were used for the purpose of this experiment and were grouped into two ;Control group consisting of twenty (20) healthy subjects (confirmed non‐diabetic with fasting blood glucose level of < 110mg\dl) and the Experimental group consisting of 20 Type 1 diabetic patients. Blood samples were collected and immunoassay analyses were carried out to determine the levels of plasma FSH, LH and TH.The results from this study showed significant reductions ( p<0.05) in the levels of FSH, LH and TH in the diabetic group when compared with the control or non‐diabetic group confirming that diabetic condition affects reproductive activities negatively.
The direct effect of incretin hormones on glucose metabolism
Authors: Karstoft Kristian , Mortensen Stefan Peter , Knudsen Sine Haugaard , Solomon Thomas Phillip James 
Published: June 2021

ObjectiveTo assess if glucagon‐like peptide (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) have a direct effect on glucose metabolism independent of their effect on the endocrine pancreas.MethodsFive healthy males (22+/−1 years, BMI 21+/−1) with normal glucose metabolism (fasting glucose = 5.0+/−0.1 mM, HbA1c = 5.2+/−0.1%) were studied using the pancreatic clamp technique (100 ng/kg/min somatostatin infusion with basal replacement of insulin, glucagon and growth hormone) in 3 different trials (GLP‐1 [0.5 pmol/kg/min], GIP [1.5 pmol/kg/min] or saline infusion). A 2‐step clamp was performed at euglycemic (90 min) and hyperglycemic (90 min; euglycemic + 5.4 mM) levels. Peripheral blood flow and vascular function (forearm flow‐mediated dilation; FMD) were determined by ultrasound Doppler.ResultsInsulin was maintained at basal levels during euglycemia in all 3 trials, with equal decreases in C‐peptide levels. During hyperglycemia, insulin and C‐peptide levels increased in all trials (P<0.05). Glucose infusion rates were higher during euglycemia in the GLP‐1 trial as compared to the saline trial (P<0.05), also when adjusted for insulin values (P=0.10). Peripheral blood flow and vascular function did not differ between trials.ConclusionThese data suggest a direct insulin/glucagon‐independent effect of GLP‐1 on glucose metabolism during euglycemia.
Conditional deletion of biliverdin reductase in macrophages determines the sensitivity to acetaminophen injury.
Authors: Wegiel Barbara , Gallo David , Csizmadia Eva , Nemeth Zsuzsanna , Kelly Vincent , Mantle Tim , Alam Jawed 
Published: June 2021

Biliverdin reductase (BVR) is a multifunctional enzyme, kinase, receptor as well as exhibiting transcription factor activity. We have recently elucidated mechanisms by which BV and BVR regulate the innate inflammatory response in vitro and in vivo. In this study we aimed to elucidate the role of BVR in vivo in response acetaminophen‐mediated liver injury using newly generated BVR conditional knockout mice.We confirmed lack of BVR in the Cre‐Lyz‐BVR‐fl/fl macrophages in vivo as well as in bone‐marrow derived macrophgaes. We validated decreased bilirubin levels in BVR deficient mice. Importantly after challenge with LPS+D‐Gal Cre‐Lyz‐BVR‐fl/fl mice show greater injury as compare to BVR‐fl/fl control mice. However, Cre‐Lyz‐BVR‐fl/fl mice were resistant to acetaminophen induced liver injury. Lack of BVR in macrophages led to low inflammatory responses to TLR9 ligands (CpG rich region) in vitro and in vivo. We showed that BVR binds specific DNA sequences in the membrane and may be a novel mediator of TLR9 signaling.In summary, BVR in macrophages is critical for acetaminophen mediated liver injury due to its interaction with DNA released from necrotic cells and amplification of inflammation.
Down‐regulation of TLR‐4 in Hypoxic Myoblast Cells
Authors: Thompson Jennifer Anne , Webb R. Clinton 
Published: June 2021

Intrauterine hypoxia is a common complication of human pregnancy. Intima hyperplasia and increased expression of inflammatory markers in aortae of chronically hypoxic fetuses were demonstrated previously.ObjectiveTo determine the effect of hypoxia on inflammatory markers and Toll‐like receptor (TLR‐4) expression in myoblast cells.MethodsMyoblast cells derived from embryo rat aorta (A10, ATCC) were placed in an anaerobic incubator set to provide hypoxic atmospheres of 1% O2 (5% CO2, balance N2) for 2 days. Control cells remained in 21% O2. Additional cells were treated with lipopolysaccharide (LPS, 100 ng/ml) or vehicle control. mRNA levels were measured using Real‐time PCR and expressed relative to control (S15 and ubiquitin C). Protein expression was measured by Western blot and expressed relative to β‐actin.ResultsTGFβ1 mRNA levels were increased 5.2 fold and 1.9 fold on day 1 and 2 of hypoxia, respectively. There were no changes in interleukin‐6 (IL‐6) mRNA levels in response to hypoxia. mRNA levels of IL‐6 were increased 2.4 fold on day 1 and 15.3 fold on day 2 of LPS treatment. TLR‐4 expression was reduced by 33%, MyD88, a downstream adaptor protein of TLR‐4, was decreased by 27% and P‐ERK was decreased by 23%, on day 2 of hypoxia. Stimulation of TLR‐4 by LPS also decreased expression of TLR‐4 and MyD88 by 18% and 31%, respectively.ConclusionsHypoxia increases TGFβ1 mRNA expression but not IL‐6 and reduces expression of TLR‐4 and its signaling components.
Azumolene administration during prolonged mechanical ventilation does not prevent mitochondrial reactive oxygen species emission or diaphragm atrophy
Authors: Talbert Erin E , Smuder Ashley J , Kwon Oh Sung , Sollanek Kurt J , Wiggs Michael P , Powers Scott K 
Published: June 2021

Although mechanical ventilation (MV) is a life‐saving measure in patients suffering from respiratory failure, prolonged MV causes the rapid development of diaphragm atrophy. MV‐induced diaphragm atrophy is due, in part, to increased production of reactive oxygen species (ROS) in diaphragm mitochondria. Moreover, increased cytosolic calcium in diaphragm fibers, perhaps from leakage of the ryanodine receptor (RyR), may be responsible for this increase in mitochondrial ROS production during MV and the subsequent activation of calpain and caspase‐3. Therefore, we hypothesized that blocking the RyR in diaphragm fibers with azumolene (Az) would prevent MV‐induced increases in mitochondrial ROS production, protease activation, and diaphragm atrophy. However, our results reveal that Az treatment did not attenuate the MV‐induced increase in mitochondrial ROS emission or prevent the MV‐induced activation of calpain and caspase‐3 in the diaphragm. Further, Az treatment did not prevent MV‐induced diaphragmatic fiber atrophy. We conclude that inhibition of the RyR in diaphragm muscle fibers is not sufficient to prevent MV‐induced diaphragm atrophy.Supported by NIH R01 HL087839 (SKP) and AHA 11PRE6520001 (EET).
The Two‐pore channel 2 (TPC2) mediates autophagy in skeletal muscles
Authors: Lin pei‐hui , Komazaki Shinji , Zhu hua , Park ki ho , Pan zui , Duann pu , Ma jianjie 
Published: June 2021

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2+‐mobilizing messenger that in many cells releases Ca2+ from the endolysosomal system. Recent studies have shown that NAADP‐induced Ca2+ mobilization is mediated by the two‐pore channels (TPCs). The objective of this study is to test whether TPC2 is involved in autophagy in skeletal muscle.MethodsWild type or TPC2 null animals were subjected to autophagy induction to compare the autophagy fluxes in the animals. In some experiments, isolated neonatal myoblasts were used. Detection methods include LC3 western blot and electron micrographs.Summary of results and conclusions: Our data provide evidence that TPC2 is involved in regulating autophagy flux in skeletal muscle. TPC2 mutant demonstrated defective autophagy to maintain tissue homeostasis.Summary of funding: There is no NIH funding to support this research project yet.
Epigenetic regulation of Cytochrome P450 (CYP1A1) by polycyclic aromatic hydrocarbons
Authors: del Rosario Olguin Sitlali , Camacho Rafael , Espinosa Jesus Javier 
Published: June 2021

Gene regulation involves transcription factors, responsive elements, enhancers, insulators, DNA methylation, histone methylation, acetylation, and deacetylation, among others. In an organism, such components might depend on external factors such as environmental pollution. CYP1A1 gene is inducible by polycyclic aromatic hydrocarbon (PAH) through the aromatic hydrocarbon receptor (AhR). However, exposure to PAHs may affect proteins involved in epigenetic regulation, as well as, CYP1A1 epigenetic regulation. In order to probe this, rat hepatocytes clone‐9 cell line (C9) was exposed to benzo[a]pyrene (BaP), benzofluorene (BF), 2’‐7’‐dimethylbenzantracene (DMBA), 3‐methylcholanthrene (3MC) and DNMTs inhibitor 5’‐Aza‐2’‐deoxycitidine (5AzadC).CYP1A1 gene expression was determined by qPCR and DNMT3a protein level by western blot, showing in both cases an increased with all treatments. However, this effect is exacerbated with a PAH‐AzadC treatment, especially with DMBA. Additionally, treatments also increase DNMT3a protein level in C9 culture. In respect to the positive modulation of CYP1A1 gene expression, we suggest that PAHs do not affect CYP1A1 gene expression only through AhR, but it is also affected by its epigenetic regulation.
Parents education and children nutritional status aged 2 to 5 in Zambia (1014.8)
Authors: Alalaq Hassan , Katuli Sozian , Beeson Lawrence , Ormsby Gail , Cordero‐MacIntyre Zaida 
Published: June 2021

B: The aim of this study is to evaluate the independent association of parental education on the nutritional status of the children using anthropometric measurements and body composition tools. M: The WHO standardized age and sex‐specific growth reference was used to calculate height for age Z‐scores (HAZ), weight for age Z‐scores (WAZ) and weight for height Z‐scores (WHZ). Percent body fat was calculated using the equation developed by Lohman for skinfold. Logistic regression was used to evaluate the relationships of parent’s education and the prevalence for stunting controlled for family size.R: 77 children were assessed (M=32, F=45) of whom 45(58.4%) were stunted expressed by HAZ <‐2 (Mean Z score ‐2.33±1.24) and 18 (23.3%) had acute malnutrition expressed by WAZ <‐2 (Mean Z score ‐1.25±1.12).About 41(55.4%) children were born by mothers who had no education and 20 (29.8%) whose fathers had no education. The logistic regression showed that parent’s education was not significantly associated with children nutritional status (p‐value 0.3037).C: Our results indicate that more than half of the children are stunted indicating chronic malnutrition. This may be a reflection of chronic food shortage or poverty which may affect food intake by the children. Parent’s education seems to be insignificant strategy to improving children’s nutrition in Zambia. Further studies are needed to assess other health problems in the area.Grant Funding Source: The Center for Health Research, Loma Linda University, and in participation with ADRA Zambia Child A
Evaluating the effectiveness of a nutrition‐sensitive agriculture intervention in Western Kenya: design of the Mama SASHA cohort study of vitamin A (1019.2)
Authors: Webb Girard Amy , Grant Frederick , Okuku Haile , Akelo Victor , Wanjala Rose , Levin Carol , Cole Donald , Low Jan 
Published: June 2021

The 2013 Lancet Maternal and Child Nutrition series identified evaluations of nutrition‐sensitive agricultural interventions as a research priority. The Mama SASHA study in Western Kenya links delivery of vitamin A (VA) rich orange‐flesh sweet potato (OFSP) to antenatal care to improve VA and nutritional status of pregnant and lactating women and their children. The evaluation strategy includes a nested longitudinal study following women and their infants from pregnancy to 9 months postpartum. VA status is assessed using infection‐adjusted plasma retinol binding protein and breastmilk retinol (postpartum). Maternal and child infection, iron, and anemia status, anthropometry, diet, health services uptake, and food security status are also measured. 505 eligible pregnant women, attending ANC at 4 control and 4 intervention facilities, were consented and enrolled. At enrollment women in control and intervention communities did not differ with respect to VA, iron, anemia or anthropometric status; food security or dietary diversity scores; demographic characteristics; awareness of vitamin A; or consumption of vitamin A rich foods in the past 7 days. Only 10 women consumed OFSP in the previous 7 days; all in intervention communities. The longitudinal study will contribute to rigorous evaluation of the OFSP intervention on maternal and child VA status and allow assessment of program impact pathways.Grant Funding Source: Bill and Melinda Gates Foundation
Seasonality in women’s dietary intake: preliminary results from the Life in all Seasons study (1022.5)
Authors: Jahns Lisa , Johnson LuAnn 
Published: June 2021

Objective: Seasonal variation in foods consumed may bias estimates of long‐term food and nutrient intake in observational studies. We present dietary results from the first cohort of subjects in a year‐long study of predictors of change in body composition.Methods: Longitudinal design; 27 women ages 40‐60 y completed online diet recalls approximately every 10 days (N=972) using the Automated Self‐administered 24‐hour Recall system. Reported intakes were compared to Dietary Guidelines for Americans (DGA) recommendations and seasonal differences tested by mixed model analysis of variance.Results: Mean energy intake was not significantly different from estimated requirements (P = 0.23). Compared to Dietary Reference Intakes, recommendations, intakes of fiber, vitamin E, potassium, and vitamin D were inadequate and did not differ by season. Over the year, women reported consuming 63 ± 3% of the DGA recommended number of servings for vegetables, fruits (73 ± 10%); whole grains (36 ± 4%), seafood (54 ± 9%) and dairy (63 ± 5%). Grain intake was significantly higher in the fall compared to spring and summer (P<0.05) and intake of “other” vegetables was higher in summer than winter (P<0.05).Conclusions: Nutrient intake did not vary seasonally in this sample of women. Intakes of key nutrients and nutrient‐rich food groups of public health significance were suboptimal.Grant Funding Source: Supported by USDA‐ARS 5450‐51000‐049‐00D
Gender effects of supplemental amino acids on non‐alcoholic fatty liver disease and chronic inflammation (1025.14)
Authors: Belalcazar L. Maria , Spratt Heidi , Green Melanie , Volpi Elena , Hurren Nicholas , Wolfe Robert , Børsheim Elisabet 
Published: June 2021

Background: Non‐alcoholic liver disease increases with age. There is scant information on gender differences in relation to its behavior, health consequences and treatment response.Aims: 1). To examine gender effect on changes (Δ) in liver fat, body fat, and high‐sensitivity C‐reactive protein (hs‐CRP), a marker of subclinical inflammation and increased cardiovascular risk, in response to supplemental essential amino acids (sEAA); 2) To correlate Δ in liver and body fat with hs‐CRP Δ.Methods: 12 subjects (7 women) with impaired glucose tolerance, age 67 years, ingested 22 g of sEAA daily for 8 weeks, after a placebo run‐in. Participants did not change diet or physical activity. Liver fat (nuclear magnetic spectroscopy; n=7), body fat (DEXA) and hs‐CRP levels (ELISA) were measured.Results: Liver fat (0.403 to 0.209,intrahepatic triglyceride/Intralipid standard) and hs‐CRP (2.28 to 1.55 mg/L), but not body fat, decreased at 8 weeks from baseline. Analysis of variance showed a gender effect (p=0.047) for Δ in liver fat and hs‐CRP. Liver fat Δ, but not body fat Δ, was associated with hs‐CRP Δ in women (Spearman coefficients 0.63, p=0.067 overall; 0.9, p=0.037 in women; p=0.2 in men).Conclusion: There may be significant gender differences on the effects of sEAA on hepatic steatosis and hs‐CRP levels.Grant Funding Source: AG033761 , D34HP18956, UL1TR000071‐05, AG024832