bluuebunny/crossref_metadata_2025_split huggingface dataset:
Common Laboratory Chow Diets Differentially Affect Energy Homeostasis and Modify Metabolic and Electrolyte Balance Effects of DOCA‐salt in Wildtype Mice
Authors: Patil Chetan N. , Oliveira Vanessa , Balapattabi Kirthikaa , Hei Megan Vande , Saravia Fatima , Wackman Kelsey , Reho John J. , Kirby John R. , Sigmund Curt D. , Grobe Justin L. 
Published: April 2020

Roughly 27% of humans with essential hypertension (HTN) exhibit low circulating renin, and this condition is experimentally modeled by subcutaneous administration of deoxycorticosterone acetate (DOCA) and high dietary sodium (the DOCA‐salt model). The quantitative effects of DOCA‐salt upon blood pressure, renal function, and energy homeostasis differ in literature reports, due to methodological differences including varied use of uninephrectomy or limiting animals to only saline drinks, with or without potassium supplementation. Here, we examined the hypothesis that the effects of DOCA‐salt on metabolic and electrolyte endpoints would be modified by diet. Male C57BL/6J mice (Jackson Labs; weaned onto LabDiet 5K52) arrived at 6 weeks of age and were immediately randomly placed onto either LabDiet 5L0D (24.1% protein, 5.2% fiber, 0.17 mEq Na/g, 2.89 kcal/g), Teklad 2920 (19.1% protein, 2.7% fiber, 0.043 mEq Na/g, 3.10 kcal/g), or Teklad 7913 (18.0% protein, 4.0% fiber, 0.130 mEq Na/g, 3.10 kcal/g), and offered autoclaved, deionized water to drink in single‐housing conditions (n=16 each). After 3 weeks, body mass differed by diet (5L0D: 3.13±0.31, 2920: 3.61±0.28, 7913: 2.48±0.16 g (mean±sem); p<0.05 by ANOVA) despite the observation that total daily caloric absorption rates (by bomb calorimetry) were similar across groups (14.6±0.3, 14.9±0.6, 14.7±0.2 kcal/d). Mice then underwent sham surgery and were maintained on assigned chow and water (n=8/diet), or were implanted with a subcutaneous 50 mg pellet of DOCA (Sigma) and offered 0.15 M NaCl drink in addition to assigned chow and water (n=8/diet). Expected major effects of DOCA‐salt (eg – to increase Na & fluid intake, urine volume, plasma Na & BUN, and renal mass while decreasing plasma K & Cl, all p<0.05) were observed in all diet groups. As hypothesized, diet significantly modified many effects of 3 weeks of DOCA‐salt (2‐way ANOVA, followed by Sidak multiple‐comparisons procedure), including: body mass (decreased (p<0.05) with DOCA‐salt on 5L0D, vs no change on 2920 or 7913), adipose masses (eg; interscapular “brown” fat mass increased (p<0.05) with DOCA‐salt on 7913, vs no change on 5L0D or 2920), total daily Na intake and urine volume (larger increases with DOCA‐salt on 5L0D vs 5L0D or 2920). We conclude that various common laboratory chow diets have significantly different effects upon aspects of energy balance and electrolyte homeostasis, and that maintenance on these different diets can quantitatively modify the effects of DOCA‐salt in mice.Support or Funding InformationHL134850, HL084207
Exercise training prevents obesity/diabetes‐induced activation of inflammatory signaling in rat brown adipose tissue
Authors: Tsuzuki Takamasa , Yoshihara Toshinori , Iwawaki Mayu , Murai Katsuyuki , Tamashiro Asuka , Nakai Natsumi , Negishi Takayuki , Yukawa Kazunori , Naito Hisashi 
Published: April 2020

Brown adipose tissue (BAT) plays a crucial role in energy expenditure and is recognized as a therapeutic target in metabolic diseases. Chronic inflammation is a common etiology of obesity and type 2 diabetes. A previous study reported increased inflammation in BAT from obese animals. Regular exercise is an effective tool for improving obesity; however, it remains unclear whether exercise training affects the inflammation in BAT from obese animals.PurposeTo examine the effects of exercise training on the activation of inflammation‐related signaling in BAT from obese/diabetic rats.MethodsMale Otsuka Long‐Evans Tokushima Fatty (OLETF) rats, a rodent model for obesity/diabetes, were randomly assigned to either sedentary (n = 11) or exercise training (n = 8) groups. Long‐Evans Tokushima Otsuka (LETO; n = 9) rats were used as the non‐diabetic sedentary control. Exercise training on the treadmill was conducted 4 days/week for 20 weeks from 5 weeks of age. An intraperitoneal glucose tolerance test was performed and interscapular BAT was dissected, and phosphorylation levels of inflammatory‐related proteins, as well as the expression levels of mitochondrial proteins, were determined by western blot analysis.ResultsThe phosphorylation levels of p65 (a subunit of NF‐κB) and mitogen‐activated protein kinases (MAPK; p38, ERK1/2, and SAPK/JNK) in the BAT were significantly higher in the sedentary OLETF rats when compared to those in the LETO rats. Exercise training attenuated the increase in the phosphorylation levels of NF‐κB and MAPKs in the BAT from the OLETF rats. Moreover, the expression levels of UCP‐1 and ‐3 and oxidative phosphorylation‐related proteins (NDUFB8, SDHB, UQCRC2, MTCO1 and ATP5A) in the BAT were significantly lower in the sedentary OLETF rats than the LETO rats, but exercise training did not alter this.ConclusionExercise training prevents obesity‐induced activation of NF‐κB and MAPK signaling in BAT from obese/diabetic rats.Support or Funding InformationThis work was supported by grants from the MEXT‐Supported Program for the Strategic Research Foundation at Private Universities (S1101008) and a Grant‐in‐Aid for JSPS Fellows (13J10819).
Maternal Glyphosate Exposure Causes Autism‐like Behaviors in Offspring through Increased Expression of Soluble Epoxide Hydrolase
Authors: Pu Yaoyu , Yang Jun , Chang Lijia , Qu Youge , Wang Siming , Zhang Kai , Xiong Zhongwei , Zhang Jiancheng , Tan Yunfei , Wang Xingming , Fujita Yuko , Ishima Tamaki , Hwang Sung Hee , Hammock Bruce D. , Hashimoto Kenji 
Published: April 2020

The number of children with autism spectrum disorder (ASD) has increased dramatically since the 1980s. Epidemiological studies suggest that exposure to pesticides (i.e., glyphosate) during pregnancy might increase the risk for ASD in offspring. Recently, we demonstrated that soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids plays a key role in the development of ASD in offspring after maternal immune activation. In the present study, we found ASD‐like behavioral abnormalities in juvenile offspring after maternal glyphosate exposure. Furthermore, we found higher levels of sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure. Oxylipin analysis showed decreased levels of epoxy‐fatty acids
(i.e., 8(9)‐EpETrE [8,9‐epoxy‐5Z,11Z,14Z‐eicosatrienoic acid] in the blood, PFC, hippocampus, and striatum of juvenile offspring after maternal glyphosate exposure, supporting increased activity of sEH in juvenile offspring. The 16S rRNA analysis demonstrated abnormal composition of gut microbiota in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU to pregnant mothers from E5 to P21 could prevent social interaction deficits, increased grooming time in the juvenile offspring after maternal glyphosate exposure. These findings suggest that maternal glyphosate exposure causes ASD‐like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH plays a key role in ASD‐like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH would represent a promising prophylactic target for ASD in offspring after maternal glyphosate exposure.Support or Funding InformationThis study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (to K.H., 17H04243), AMED (to K.H., JP19dm0107119), the National Institute of Environmental Health Sciences (NIEHS) R01 ES002710 (to B.D.H.), NIEHS Superfund Program P42 ES004699 (to B.D.H.).
Chronic Nicotine Inhalation Promotes Differential Remodeling of the Right and Left Ventricles in Mice
Authors: Fried Nicholas D. , Morris Tamara M. , Woods David C. , Oakes Joshua M. , Xu Jiaxi , Ninh Van K. , Lazartigues Eric , Yue Xinping , Gardner Jason D. 
Published: April 2020

IntroductionCigarette smoking continues to decline in the United States, but a rise in e‐cigarette use poses a threat to human health. E‐cigarettes, oft marketed as a healthier alternative to traditional forms of tobacco consumption, still contain nicotine. Cigarette smoking is a major risk factor in a vast array of pathological conditions including cancer and cardiovascular disease. Despite knowledge regarding the risks of cigarettes, the effects of inhaled nicotine have been poorly characterized. In this study, we sought to investigate the effects of inhaled nicotine on cardiac function and remodeling.MethodsMale C57BL6/J mice were exposed to air (control) or nicotine vapor (daily, 12 hours on/12 hours off) for 8 weeks. Nicotine exposure was assessed by weekly measurement of serum cotinine levels, which showed an average of 599±54 ng/ml in nicotine‐exposed mice. A subset of mice were implanted with an Angiotensin‐II (AngII) osmotic minipump (450 ng/kg/min) for 4 weeks. Cardiac structure and function were assessed using echocardiography and cardiac catheterization, followed by tissue collection for analysis.ResultsNicotine exposure produced a significant increase in right ventricular systolic pressure (RVSP; 39.6±4.2 mmHg, n=7) compared to air‐exposed controls (22.3±1.7 mmHg, n=8, p<0.01). Nicotine‐associated RVSP elevation was similar to AngII infusion (38.0±2.0 mmHg, n=7). RVSP changes were associated with RV hypertrophy (free wall thickness of 0.50±0.02 mm in nicotine exposure versus 0.42±0.03 mm in air‐exposed control, n=8–9, p<0.05) and increased angiotensin converting enzyme expression (3.87‐fold increase in nicotine exposure versus air‐exposed control, n=5, p<0.05).Nicotine exposure alone produced no significant changes in left ventricular (LV) structure or angiotensin converting enzyme expression. Interestingly, co‐administeration of nicotine and AngII resulted in blunting of AngII‐mediated LV hypertrophy (posterior wall thickness; 0.83±0.03 mm versus 0.93±0.02 mm for AngII alone, n=19–23, p<0.01). Furthermore, we have found preliminary evidence of blunted LV hypertrophic signaling in nicotine‐exposed, AngII‐infused mice which exhibited reduced phosphorylated mTOR/mTOR compared to AngII alone (n=5, p=0.076).DiscussionTaken together, these findings led us to conclude that chronic nicotine inhalation promotes differential remodeling of the right and left heart. Nicotine inhalation alone promotes hypertrophic remodeling of the RV, but produces no significant changes in the LV. Nicotine inhalation does, however, abrogate AngII‐induced hypertrophic LV remodeling. Ongoing experiments within our laboratory are exploring the mechanisms underlying this differential remodeling and anti‐hypertrophic effect.Support or Funding InformationNational Institutes of Health R01HL135635 (JG/EL/XY).
Student Perceptions and Learning Outcomes of a Dissection Handoff Procedure in the Gross Anatomy Laboratory
Authors: Walker Paul , Kupser Elizabeth , Donohue Laura , Tran Hanna , Qadeer Afreen , Swantek Alexander , Levine Diane 
Published: April 2020

BackgroundDissection of the human body takes considerable time and effort, but also provides opportunities for the introduction of clinical skills. One skill is the safe transfer (handoff) of a patient between healthcare teams, a process dependent on the accurate exchange of information. In order to provide medical students with opportunities to practice skills in teamwork and communication while also reducing time spent in the dissection process, a handoff procedure was piloted for use in the gross anatomy laboratory. This study reports initial findings on student perceptions of time usage, wellness, teamwork & communication skills, and relevance to patient handoff, as well as impact on learning and performance through analysis of assessment data.MethodsFirst‐year medical students (n=296) at Wayne State University were briefed on how to complete handoffs and their fundamental role in care of future patients. Each anatomy group was divided into two groups, which alternated between roles as the “dissecting‐team” and “receiving‐team.” A handoff tool was developed and included written and verbal components. The written component included a standardized checklist, designed as a lab chart to ensure dissection as well as mimic a handoff document. During the verbal component, the dissecting‐team demonstrated structures to the receiving‐team and shared anticipated problems. The handoff trial took place during 10‐dissection labs covering the head and neck region. Students were asked to complete a presurvey prior to starting and a postsurvey after completing the handoff curriculum. Responses to the pre‐ and post‐ surveys were 59% and 61% of the class, respectively.ResultsOn the presurvey, 71.6% of students agreed/strongly agreed that dissection was too time consuming compared to 64.8% on the postsurvey. 82.9% agreed/strongly agreed in the postsurvey that handoffs provided students with more time to study. On the practical exam students performed better on questions covering content when they were on the dissecting‐team 69.4% correct compared to receiver‐team 65.1% (P<0.0001). 61.3% said that handoffs positively affected their overall wellness in the postsurvey (up from 51.1% in the presurvey). 42.0% felt that the handoff process facilitated development of teamwork within their group while 58.0% felt neutral (28.2%) or disagreed (29.8%). 41.4% agreed participating in the handoff process helped them develop handoff skills necessary for patient handoffs while 58.6% were neutral (29.8%) or disagreed (28.7%).ConclusionStudents scored significantly lower on exam questions regarding structures they did not dissect, but perceived they had more time to study and felt a positive effect on wellness. Improvements in the handoff procedure are needed to more directly address teamwork and communication skills pertinent to success with future patient handoffs.
Metabolic reprogramming mediates macrophage polarization following myocardial infarction
Authors: Mouton Alan J. , Flynn Elizabeth R. , Hall Michael E. , Hall John E. 
Published: April 2020

Macrophages play critical roles in mediating inflammation and cardiac remodeling after myocardial infarction (MI). Metabolic transitioning between glycolysis and oxidative phosphorylation (OXPHOS) is associated with macrophage polarization to pro‐inflammatory (M1) and anti‐inflammatory (M2) phenotypes. M1 macrophages rely on glycolysis and M2 macrophages rely on OXPHOS. However, the role of metabolism in macrophage polarization after MI is unknown. Thus, we hypothesized that inhibiting glycolysis after MI would promote macrophage polarization to an anti‐inflammatory M2 phenotype and improve post‐MI outcomes. MI was induced in adult male C57BL/6J mice by permanent left anterior coronary artery ligation for 1, 3, and 7 days. To directly assess macrophage glycolysis and OXPHOS after MI, macrophages (CD11b+Ly6−) were isolated from the infarct region (n=3 for D1 and D3) or healthy control hearts (day 0 or D0; n=3) by immunomagnetic separation or flushed from the peritoneal cavity and subjected to Seahorse analysis to determine the extracellular acidification rate (ECAR) and the oxygen consumption rate (OCR). To assess the role of macrophage metabolism, a separate group of mice was administered dimethyl fumarate (DMF, 15mg/kg I.P.) or vehicle solution as a control, for the first 3 days after MI to inhibit macrophage glycolysis during the acute inflammatory response, and studied at day 7. DMF is a clinically approved anti‐inflammatory drug with immunometabolic properties. Left ventricular (LV) function was assessed by echocardiography. Infarct macrophage phenotypes were determined by flow cytometry. By Seahorse analysis, DMF inhibited glycolysis in vitro in peritoneal macrophages. The basal glycolytic ECAR was increased in macrophages at D1 (0.3±0.1 mPh/min D0 versus 4.2±1.0 mPh/min D1) and further increased at D3 (8.9±1.2 mPh/min D3). Maximal glycolytic capacity was similarly increased in D1 and D3 versus D0 (6.0±1.3 mPh/min D1 and 10.8±1.7 mPh/min D3 versus 0.4±0.5 mPh/min D0). No differences were observed in basal, maximal or spare capacity OCR, indicating that increased glycolysis alone mediates macrophage polarization after MI. Treatment with DMF improved the post‐MI survival rate after 7 days by 11%. Of the surviving mice (n=3 each group), no differences in the LV, RV, lung, or spleen mass were observed. By echocardiography, DMF did not affect LV diastolic or systolic volumes, ejection fraction, or anterior wall thinning, but prevented MI‐induced LV posterior wall thinning (0.73±0.14 mm DMF versus 0.42±0.09 mm vehicle). By flow cytometry, DMF increased the number of M2 macrophages (CD45+CD11b+Ly6G−CD206high) in the infarcted region (62±13% DMF versus 40±2% vehicle). In conclusion, macrophage metabolic reprogramming underlies polarization after MI, and targeting macrophage metabolism may improve post‐MI LV remodeling and survival.Support or Funding InformationNHLBI‐PO1HL51971, NIGMS P20GM104357 and U54GM115428; AHA 18POST34000039.
Y‐Chromosome Gene, Uty, Protects Against Pulmonary Hypertension by Reducing Lung Pro‐Inflammatory Cytokines
Authors: Cunningham Christine Marie , Umar Soban , Doshi Mitali , Li Min , Ruffenach Gregoire , Hrncir Haley , Arnold Arthur P. , Eghbali Mansoureh 
Published: April 2020

RATIONALEIdiopathic pulmonary arterial hypertension (PAH) is a terminal vascular lung disease up to 4x more common in females. We published that the Y‐Chromosome (Chrm) is protective against hypoxia (Hx)‐induced pulmonary hypertension (PH) in mice and identified four Y‐Chrm genes expressed in the lung. Here, we identify Uty as the protective Y‐Chrm gene and investigate its mechanism of protection against PH to illuminate novel therapeutic targets.METHODS AND RESULTSTo test the effect of Y‐Chrm candidate genes on PH development, each of the four candidate YChrm genes were independently knocked‐down in the lungs of male mice exposed to Hxinduced PH via sequential intratracheal instillation of siRNA. Knockdown of Y‐Chrm gene Uty, but none of the other genes, resulted in more severe PH measured by increased right ventricular systolic pressure (RVSP) and decreased pulmonary arterial acceleration time (PAAT) when compared to experimental controls (n=4/group; RVSP: Uty‐KD= 48.93 mmHg, Control= 37.33 mmHg, p=0.04; PAAT: Uty‐KD= 11.88 ms, Control= 14.43 ms, p= 0.01). Pathway enrichment analysis of RNAseq data (Uty‐Knockdown vs Control) revealed an induction of proinflammatory cytokines including Cxcl9 (Log2FC: 1.3, p‐adjusted= 0.05) and Cxcl10 (Log2FC: 0.9, p‐adjusted=0.002). We found Cxcl9 and Cxcl10 were also significantly up‐regulated in human PAH lungs vs healthy (RT‐qPCR) and female PAH lungs vs male (GSE15197). Fluorescent in‐situ hybridization revealed Uty expression co‐localized with CD68+ macrophages, Cxcl9 and Cxcl10 in the lung. Upon stimulation, macrophages derived from bone marrow of male Uty‐knockout mice displayed increased expression of Cxcl9 and Cxcl10 compared to wildtype mice. Human pulmonary artery endothelial cells treated with Cxcl9 and Cxcl10 in‐vitro exhibited significantly increased cell death compared to those treated with vehicle.CONCLUSIONY‐Chrm gene, Uty, is protective against PH development and may explain Y‐Chrm protection in PH. Since Uty inhibition (both in‐vitro and in‐vivo) results in an increase in pro‐inflammatory cytokines, we hypothesize that a reduction or absence of Uty in the lungs of PAH patients or females results in an increase in lung pro‐inflammatory cytokines which contributes to vascular endothelial dysfunction and more severe PH.Support or Funding InformationAmerican Heart Association grant 17PRE33420159 (C.M.C.), Iris Cantor‐UCLA Women’s Health Center Executive Advisory Board NCATS UCLA CTSI Grant Number UL1TR001881 (C.M.C.), and NIH grants R01HL129051 (M.E.), R01HL131182 (M.E. and A.P.A.).
Noise‐induced vascular dysfunction, oxidative stress and inflammationare improved by pharmacological heme oxygenase‐1 induction
Authors: Jimenez Maria Teresa Bayo , Steven Sebastian , Kröller-Schön Swenja , Frenis Katie , Kalinovic Sanela , Stamm Paul , Oelze Matthias , Daiber Andreas , Münzel Thomas 
Published: April 2020

Endothelial dysfunction, vascular oxidative stress and inflammation are consequences of traditional cardiovascular risk factors and triggers of cardiovascular disease. However, emerging environmental stressors such as traffic noise exposure may facilitate the development of cardiovascular and metabolic diseases.C57BL/6J mice were exposed to aircraft noise (maximum sound level of 85 dB(A), average sound pressure level of 72 dB(A)) applied for 1, 2 and 4 days caused an increase in systolic blood pressure, stress hormones and induced endothelial dysfunction, oxidative stress and inflammation (Eur Heart J 2017). We also observed reduced vascular NO levels due to eNOS uncoupling and increased levels of nitrotyrosine, interleukin‐6, NADPH oxidase isoform Nox2 and endothelin‐1 in the mice exposed to aircraft noise. More recently, we have shown that aircraft noise induces also cerebral oxidative stress and a neuroinflammatory phenotype that is up‐stream of the observed adverse cardiovascular effects, all of which was normalized by genetic deletion of NADPH oxidase isoform Nox2 (Eur Heart J 2018).The role of heme oxygenase‐1 (HO‐1) as an antioxidant response is currently being investigated. C57BL/6J mice were treated with the HO‐1 activator hemin (25 mg/kg i.p.). Our preliminary data show a protective effect of hemin infusion on aircraft noise exposure (4 days) induced increase of systolic blood pressure and vascular dysfunction. There was also a trend of normalization of noise‐triggered oxidative stress ny hemin infusion. Within the ongoing studies, we will address the impact of HO‐1 induction in noise‐exposed mice on expression of genes and proteins involved in pathways of oxidative stress and systemic inflammation. In a later stage of the study, we will also test whether genetic deficiency of HO‐1 (HO‐1+/− mice) aggravates and the Nrf2 activator dimethyl fumarate (DMF) ameliorates noise‐triggered cardiovascular complications. The present study aims at identifying new targets for mitigation strategies against adverse health effects of environmental noise exposure of the general population. Since HO‐1 and Nrf2 induction can be achieved by natural dietary constituents, these pathways represent promising targets for preventive measures.Support or Funding InformationOur experimental studies on noise effects in mice were supported by vascular biology research grants from the Else‐Kröner‐Fresenius Foundation for “Noise and arterial hypertension” (2017_A106) and the Boehringer Ingelheim Foundation for the collaborative research group „Novel and neglected cardiovascular risk factors: molecular mechanisms and therapeutic implications”.