bluuebunny/crossref_metadata_2025 huggingface dataset:
Expert recommendations for consumption frequencies of specific foods
Authors: Chavez Johanna Yvonne Andrews , Konick Jennifer , Davis Charlotte , Marino‐Costello Elizabeth , Connell Patrick , Houser Robert F.
Published: June 2021

This pilot study was conducted to assess the opinions of a sample of members of the Academy of Nutrition and Dietetics on the ideal consumption frequencies of specific foods and on Academy's policy of promoting a total diet approach to encourage healthy eating. Since the American public lacks sophisticated nutrition knowledge, specific food‐based guidelines could make it easier for consumers to adopt healthier food choices and patterns. An online survey of Massachusetts Dietetic Association members yielded 45 respondents who completed the survey. There appears to be a great deal of support for providing the public with specific food item frequency recommendations. About 50% disagreed with Academy's policy of “no bad foods, only bad diets.” We saw that many of our respondents identified several foods that should never be consumed. These were mostly processed foods. Foods that were considered appropriate for daily consumption were mostly unprocessed fruits and vegetables. Although the total diet approach admirably encourages balance, variety, moderation, and nutrient‐dense foods in the diet, as growing research identifies specific foods as key contributors to the obesity epidemic, nutrition policy should be redirected to provide guidance about what foods should be avoided or limited in the diet. Research support: unfunded.

Grant Funding Source: Unfunded
Adaptive thermogenic response to over and underfeeding occurs acutely
Authors: O'Connor Annalouise , Luo Weijun , Galanko Joseph , Brouwer Cory , Swick Andrew G.
Published: June 2021

Adaptive thermogenesis in response to underfeeding (UF) and overfeeding (OF) may impact an individual's risk of weight gain and ability to lose weight. Studies have reported energy expenditure (EE) changes after 72hrs of UF or OF. However we hypothesize that adaptive responses occur acutely and aimed to determine whether the EE response to UF and OF is detectable within 24hrs. 7 over‐weight post‐menopausal women completed a eucaloric feeding day in the metabolic chamber at UNC NRI to ascertain baseline energy requirements. Subjects were randomized to receive 72hrs of OF (150% of requirements) or UF (50% of requirements) in a cross‐over fashion, each separated by 2 weeks. 24hr EE was measured 3 times during each 72hour period. Macronutrient composition of all test meals was 30%E fat, 55%E carbohydrate and 15%E protein. A repeated regression measures mode with change in EE as the response, and time, treatment order, and pre‐treatment weight and energy intake as predictors was conducted. EE changed significantly within 24‐hours of both OF and UF. 24hr responses did not differ significantly from those at 72hrs. Resting (RMR) and sleeping metabolic rate (SMR) and diet‐induced thermogenesis (DIT) were significantly increased with OF only. That EE response to UF and OF occurs within 24hrs suggests acute energy sensing. Ongoing ‘omics profiling aims to understand mechanisms governing acute EE adaptation.

Grant Funding Source: UNC NORC NIH grant #DK056350
Perinatal bisphenol A exposure promotes hyperactivity with corresponding hormonal responses
Authors: Anderson Olivia S , Peterson Karen E , Sanchez Brisa N , Zhang Zhenzhen , Mancuso Peter , Dolinoy Dana C
Published: June 2021

The risk of adult onset diseases is influenced by perinatal exposure to altered environmental conditions. Exposure to the endocrine active chemical, bisphenol A (BPA), has been associated with obesity and diabetes. Using an isogenic murine model, we examined perinatal exposure via maternal diet to 50 ng (n=20), 50 μg (n=21) or 50 mg (n=18) BPA/kg diet, and controls (n=20), on offspring hormones and adipokines at 9 and 10 mos of age following activity phenotyping measured at 3, 6 and 9 mos. Life‐course phenotyping revealed overall increased energy expenditure among exposed females and males (all P<0.001), and increased activity among exposed females (P=0.06). Life‐course body composition measures did not differ in females or males (all P>;0.44), but weight and fat decreased in exposed females at particular ages (all P<0.08). At 9 mos, mg exposed females had lower baseline glucose and insulin (P=0.05 and 0.10, respectively) indicated by an oral glucose tolerance test. Validation with homeostatic model assessment of insulin resistance indicated insulin sensitivity (P=0.10). At 10 mos, ng and mg exposed females had increased adiponectin (P=0.02 and 0.10, respectively). Mg exposed females had increased leptin (P=0.10). Our life‐course phenotyping illustrates BPA exposure results in hyperactivity and corresponding hormone and adipokine responses, necessitating further evaluation of BPA as a potential obesogen. Support: MNORC P30 Center DK089503; NIH ES017524; UM P30 ES017885 Center; UM Children's Environmental Health P20 ES018171/RD83480001 Center.
A Randomized Double Blind Placebo Controlled Evaluation of MSM for Exercise Induced Discomfort/Pain.
Authors: Kalman Douglas , Feldman Samantha , Samson Adam , Krieger Diane
Published: June 2021

Methylsulfonylmethane (MSM) has been reported to provide anti‐inflammatory & antioxidant effects in mammals. Resistance exercise is known to induce both inflammation & oxidative stress resulting in muscular discomfort & pain. In a pilot‐proof of concept study, we determined the effects of MSM on markers of exercise recovery & performance.

Methods

In random order 24 moderately exercise‐trained men (25.5±5.6 yrs) received MSM 3.0 gm/d or PLA, for 14 days, with a 17‐day washout between. The study included 3 tests: baseline, no product & the 2nd & 3rd following 14d supplementation with MSM & PLA. Each test consisted of 2 visits. At the 1st visit, subjects performed stressing exercise; 28 total sets of leg extensions, sets 1–25, predetermined weight, 10 reps each, sets 26–28 to muscular failure at 70% 1‐RM (performance). At the 2nd visit (48 hrs later), subjects performed 12 total sets of leg ext, sets 1–9, predetermined weight, sets 10–12 to muscular failure, 70% 1‐RM (performance). Muscle discomfort/pain (10‐point VAS scale), inflammation (hs‐CRP & IL‐6), blood antioxidant status (TEAC & SOD), & homocysteine were measured before the stressing exercise and 2 & 48 hours post exercise. Exercise performance was also measured following 14d supplementation with MSM/PLA (sets 26–28 and sets 10–12). In order to eliminate sequence effects, results are provided on the 1st product as compared to baseline (comparison of the 1st & 2nd tests).

Results

MSM intervention resulted in significantly less pain/discomfort vs. PLA from baseline to 2 hrs (1.55±0.82 vs 3.75±2.58, p=0.012). Change in IL‐6 was significant within the MSM & PLA & between MSM (0.54±0.76) vs PLA (−0.58±0.97) p = 0.006. There were no significant differences between MSM & PLA noted for the other biomarkers.

Conclusion

MSM may help alleviate the discomfort/pain that can follow a stressful exercise session.
Abnormal calcium homeostasis in the aorta of the spontaneously hypertensive rat is mediated by endoplasmic reticulum stress
Authors: Spitler Kathryn , Webb R. Clinton
Published: June 2021

During hypertension, a disruption in calcium (Ca2+) homeostasis contributes to vascular dysfunction. The endoplasmic reticulum (ER) maintains cellular Ca2+ homeostasis and is easily perturbed leading to ER stress. We hypothesized that enhanced Ca2+ signaling and contraction in the aorta of the spontaneously hypertensive rat (SHR) is mediated by ER stress. Male Wistar Kyoto and SHR were treated with ER stress inhibitors, tauroursodeoxycholic acid or 4‐phenylbutryic acid (TUDCA and PBA, respectively, 100mg/kg/day, 14 days, i.p.) or vehicle (saline) and the aorta were used for vascular function studies and Western blot analysis. Expression of Ca2+ regulatory proteins sarco/(ER) Ca2+ ATPase, calreticulin and calnexin was decreased in the aorta of the TUDCA or PBA treated‐SHR compared to vehicle‐treated SHR. Aortic rings from vehicle‐treated SHR displayed enhanced store‐operated Ca2+ entry‐induced contraction (6.1 ± 0.4 mN), which was attenuated in SHR treated with either TUDCA (2.2±0.5 mN) or PBA (3.4±0.4 mN). As a measure of ER Ca2+ storage capacity, caffeine (10 mM) depletion of intracellular Ca2+stores measured as a transient contraction was greater in aortic rings from the vehicle‐treated SHR (10.2±1.1 mN) compared to SHR treated with either TUDCA (4.2±0.9 mN ) or PBA (3.9±1.4 mN). These data suggest that ER stress may be a novel therapeutic target for the treatment of hypertension by normalizing Ca2+ homeostasis.
The 5‐HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin‐enhanced Platelet Function
Authors: Lin Olivia , Espinosa Enma Veronica Paez , Khasawneh Fadi T
Published: June 2021

In an effort to define new agents for antithrombotic purposes, there is an interest in repurposing FDA‐approved drugs as antiplatelet agents. The 5‐HT2A receptor is a G‐protein coupled receptor (GPCR) expressed on many cell types, including platelets, and a known therapeutic target for many disease states. This erotonin receptor is also known to regulate platelet function. Thus Pizotifen and Cyproheptadine, two antidepressant 5‐HT2A receptor antagonists, are selected to determine if they can be repurposed and if the 5‐HT2A receptor can be targeted for antiplatelet activity. The results revealed that Pizotifen and Cyproheptadine reversed serotonin‐enhanced ADP‐induced platelet aggregation. Our study also employed a thrombosis model of the carotid artery, to determine the potential of Pizotifen and Cyproheptadine as thromboprotective agents in vivo. The results show an increased occlusion time after blood vessel injury in mice treated with Pizotifen and Cyproheptadine compared to controls. Finally, the tail‐bleeding time was employed to investigate the effect of Pizotifen and Cyproheptadine on hemostasis. Our findings show prolonged bleeding time in both Pizotifen‐, and Cyproheptadine‐treated mice compared to controls. Collectively, the data indicate that the 5‐HT2A antagonists Pizotifen and Cyproheptadine have antithrombotic effects, but their use may interfere with normal hemostasis.
Discriminative‐stimulus effects of 3,4‐methylenedioxy‐N‐methylamphetamine (MDMA) and a novel MDMA quatenary analog
Authors: Slezak Jonathan M. , Mueller Melanie , Ricaurte George A , Cao Jianjing , Newman Amy H. , Katz Jonathan L.
Published: June 2021

MDMA (ecstasy), popularized as a “club drug,” is a psychoactive and abused substance. It is often assumed that the behavioral effects of MDMA are due to central actions, though this has not been tested. Using a quaternary analog of MDMA (qMDMA) we tested that assumption by training male Sprague‐Dawley rats (n = 6) to discriminate intraperitoneal (i.p.) injections of 1.7 mg/kg of MDMA HCl from saline in a two‐lever discrimination procedure. When MDMA was administered before daily sessions, responses on one of two keys intermittently produced food presentation; responses on the alternate key produced occasional food deliveries after saline injections. MDMA produced dose‐related increases in the percentage of responses on the drug‐appropriate key with an ED50 value of 0.56 mg/kg. In addition the serotonin releaser fenfluramine (i.p.), as well as p.o. MDMA produced dose‐dependent substitution for MDMA. Neither morphine (i.p.) nor qMDMA (i.p.) substituted for MDMA across a range of doses from those having no effect to those decreasing response rates. When MDMA and qMDMA were administered via intraventricular cannulae, full substitution was obtained at 300 μg of MDMA immediately after infusion and partial substitution (~75%) was obtained with the quaternary compound at 250 μg when subjects were tested one hr after infusion. These results validate qMDMA as a tool for investigating central vs. peripheral actions of MDMA.
Hormone‐phase dependence of muscle sympathetic nerve activity in young healthy women using hormonal contraceptives
Authors: Usselman Charlotte W. , Luchyshyn Torri A. , Gimon Tamara I. , Nielson Chantelle A. , Van Uum Stan H. M. , Shoemaker J. Kevin
Published: June 2021

The effects of hormonal contraceptives on control of muscle sympathetic nerve activity (MSNA) are unclear. We tested the hypothesis that high‐ (HH) versus low‐hormone (LH) phases of contraceptive use would not affect MSNA. Integrated MSNA recordings were obtained at rest, during −60 to−80 mmHg lower body negative pressure (LBNP) (n=4), and during combined hypercapnia‐hypoxia stress (HC‐HX) (n=7) during LH and HH. Mean arterial pressure (MAP), heart rate (HR), and cardiac output (Q) were similar between LH and HH across all conditions. Baseline MSNA burst frequency (BF; 16±8 vs 11±6 bursts/min, P=0.04) and burst incidence (BI; 23±9 vs 16±8 bursts/100hb, P=0.056) were greater during HH than LH, respectively. During LBNP, BF was greater during HH than LH (51±10 vs 43±9 at −60, P<0.001; 59±16 vs 44±11 bursts/min at −80, P=0.03), but relative increases in BF or BI were not different. The HC‐HX protocol elicited greater BI during HH than LH (29±10 vs 23±9 bursts/100hb, P=0.047), but similar BF. A subsequent HC‐HX apnea resulted in similarly high absolute BF and BI in LH and HH. Accordingly, HH tended to produce smaller relative changes in BF (+31±11 vs +39±8 bursts/min, P=0.059) and BI (+44±18 vs +54±13 bursts/100hb, P=0.053) than LH. These data indicate that hormone phase, associated with contraceptive use, influences baseline MSNA but not responses to severe reflex stimulation. Supported by NSERC and CIHR.
The Cysteine dioxygenase knockout mouse: altered cysteine metabolism leading to excess hydrogen sulfide production
Authors: Stipanuk Martha H , Roman Heather B. , Hirschberger Lawrence L
Published: June 2021

Cysteine dioxygenase (CDO) catalyzes the first step in the oxidative metabolism of cysteine and is strongly regulated in response to dietary sulfur amino acid intake. To define the consequences of loss of CDO on cysteine metabolism at the tissue level, we determined levels of relevant metabolites and enzymes and evidence of H2S toxicity in liver, pancreas, kidney and lung of CDO−/− mice fed either a taurine‐free or taurine‐supplemented diet. CDO−/− mice had low tissue and serum taurine and hypotaurine levels and high tissue levels of cysteine, consistent with loss of CDO. CDO−/− mice had elevated urinary excretion of thiosulfate, high tissue and serum cystathionine and lanthionine levels, and evidence of inhibition and destabilization of cytochrome c oxidase, consistent with excess production of H2S. The CDO−/− mouse clearly demonstrates that H2S production in tissues can exceed the capacity of the animal to oxidize sulfide to sulfate and demonstrates that pancreas and lung are more susceptible to toxicity from endogenous H2S production than are liver and kidney. Supported by NIH Grant DK‐056649.
Five days of reduced physical activity selectively impairs endothelial function of the inactive limbs
Authors: Boyle Leryn , Credeur Daniel , Jenkins Nathan , Padilla Jaume , Thyfault John , Fadel Paul
Published: June 2021

Chronic physical inactivity promotes the development of cardiovascular diseases. However, few data exist on the effects of short‐term reductions in daily ambulatory activity on vascular function, particularly at the cellular level. Thus, we studied popliteal and brachial artery flow mediated dilation (FMD) and measured plasma levels of endothelial microparticles (EMPs) shed from apoptotic and activated endothelial cells (CD31+/CD42b− and CD62E+ EMPs, respectively) at baseline and following 5 days of reduced daily steps (<5,000 steps/day) in 6 healthy, recreationally active men (26±3 yrs). We hypothesized that popliteal FMD would be reduced and concentrations of EMPs would be increased with inactivity. Following inactivity, popliteal FMD decreased (baseline: 5.4±1.2 vs. inactivity: 1.9±1.0%, p=0.05), while brachial artery FMD was unchanged (baseline: 4.2±0.7 vs. inactivity: 5.6±1.0%, p=0.12). CD31+/CD42b− (1.3 ± 0.4 vs. 4.8 ± 2.7 per μL plasma) and CD62E+ (69.2 ± 52.0 vs. 14.7 ± 7.9 per μL plasma) EMPs were not significantly altered following inactivity. These preliminary findings suggest that the vascular consequences of reduced daily steps are primarily localized to the lower (inactive) limbs, although changes in systemic EMPs reflective of endothelial apoptosis (CD31+/CD42b− ) and activation (CD62E+) were not observed.

Grants: AHA 12PRE12080242, NIH R01‐HL093167, T32‐AR048523
Poly ADP‐Ribose polymerase (PARP‐1) and DNA damage in pulmonary arterial hypertension
Authors: Meloche Jolyane , Courboulin Audrey , Krietsch Jana , Margaillan Guillaume , Courchesne Antony , Coulombe Yan , Provencher Steeve , Poirier Guy , Masson Jean‐Yves , Bonnet Sebastien
Published: June 2021

Pulmonary arterial (PA) hypertension (PAH) is characterized by PA obstruction, associated with oxidative stress and inflammation sustained by NFAT (Nuclear factor of activated T‐cells) and HIF‐1 (Hypoxia inducible factor 1) activation. Despite these DNA damaging conditions, PAH‐PA smooth muscle cells (PASMC) are proliferative and apoptosis‐resistant, suggesting DNA repair machinery activation. PARP‐1 is a crucial enzyme implicated single strand DNA breaks (SSB) repair and regulates cell survival and expression of many genes such as NFAT and HIF‐1. We hypothesized that PARP‐1 is activated in PAH‐PASMC, inducing proliferation and survival and thus PA remodeling. Using human lung tissues and PASMC, we demonstrated that increased oxidative stress promotes SSB in PAH‐PASMC. Increased SSB triggers PARP‐1 activation, which promotes NFAT/HIF activation, increasing PAH‐PASMC proliferation and resistance to apoptosis. Finally, we showed that clinically available PARP inhibitor ABT‐888 reverses all these abnormalities both in vitro and in vivo in rats with monocrotaline and Sugen‐induced PAH. In conclusion, we demonstrated the implication of DNA repair machinery PARPs in PAH etiology and that clinically available PARP‐1 inhibitors represent new therapeutic agents for PAH treatment.

A Canadian Thoracic Society scholarship to JM and Canadian Institutes of Health Research grants to SB supported this work.
Morphological changes of the intrinsic cardiac nervous system in experimental models of right ventricular hypertrophy.
Authors: de Jesus Gómez Villalobos Ma , Giles Ruth , Flores Gonzalo
Published: June 2021

It was characterized the morphological changes of the intrinsic cardiac nervous system (ICNS) in two experimental models of right ventricular hypertrophy (RVH) in rats through Golgi‐Cox and Glyoxylic acid methods. Male Sprague dawley rats were used. RVH was induced with monocrotaline, and carbon tetrachloride (CCl4). After 3 and 8 weeks respectively, systolic right ventricular pressure (SRVP) was recorded and after hearts were extracted, washed, and incubated for 30 days in Golgi Cox solution, sectioned by vibrotome, processed and analyzed by the Sholl method under light microscopy adapted to a camera lucida. Diameters of ganglion and nerve fiber from right ventricle were recorded in microns. Histofluorescence for catecholamine was made and analyzed qualitatively. In both experimental groups increases in SRVP and RVH were confirmed, however mortality was higher in monocrotaline group. In heart from CCl4 rat, we found clearly increased in number and size of ganglion and nerve fibers in the right ventricle, however in hearts from monocrotaline rats a decrease in number and size of ganglion were found. The results were confirmed with the histofluorescence for catecholamine. Ours results show that there is a different impact in the ICNS, related to pathologic mechanism involved in RVH, suggesting that the repercussion on the ICNS could determine the development of heart failure and mortality
Quantitative Analysis of Tetrahydrobiopterin Synthesis and Oxidation in eNOS Uncoupling
Authors: Kar Saptarshi , Kavdia Mahendra
Published: June 2021

The uncoupling of eNOS shifts the production from nitric oxide (NO) to (O2•−). The lack of availability of eNOS co‐factor tetrahydrobiopterin (BH4), which oxidizes to dihydrobiopterin (BH2) is the primary cause of eNOS uncoupling. In an earlier study, we showed that biopterin ratio (BH4:total biopterin) is an important determinant of the extent of eNOS uncoupling. However, it is not clear whether the synthesis of BH4 can lead to a significant change in the biopterin ratio. In this study, we developed a computational model based on the eNOS biochemical pathways for NO and O2•− production with provisions for changing concentration of different forms of biopterin and BH4 synthesis. The key results from the study include (i) The biopterin ratio remains unchanged under normal conditions and reduces under oxidative stress conditions, (ii) Under normal conditions eNOS uncoupling can still be restored by BH4 synthesis and (iii) Increased oxidative stress conditions significantly reduces eNOS based NO production and increases eNOS based O2•− production. The results thus show that oxidative stress and BH4 synthesis can play a regulatory role in eNOS catalysis. Supported by NIH R01 HL084337.
Chronic α 1AAR stimulation may increase adult neurogenesis and parvalbumin interneurons
Authors: Nielsen Amber , Collette Katie , Perez Dianne , Doze Van
Published: June 2021

Adult neurogenesis occurs in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus. It seems to play a role in mood, cognition, epilepsy, and schizophrenia with increases having a positive effect. Chronic stimulation of α1A‐adrenergic receptors (α1AARs) has been shown to increase adult neurogenesis in the SVZ; however, its effects have not yet been thoroughly explored in the SGZ. Persons suffering from schizophrenia have decreased numbers of parvalbumin‐positive (PV+) interneurons. Preliminary work in our lab has shown an increase in PV+ interneurons after chronic activation of the α1AAR. The present study investigated the impact of chronic α1AAR stimulation on neurogenesis and on PV+interneuron numbers in the adult SGZ. Constitutively active mutant (CAM) α1AAR mice, which have chronically activated α1AARs, were used and compared with control animals. The results indicate a possible increase in BrdU+cells and PV+ interneurons. Treatments to increase adult neurogenesis may be used to treat depression and anxiety in the future. Similarly, treatments to increase adult neurogenesis and PV+interneurons may improve symptoms of schizophrenia. Supported by North Dakota EPSCoR IIP Seed Award Grant EPS‐081442, National Center for Research Resources Grant P20RR016741 and National Institute of General Medical Sciences Grant P20GM103442 from the NIH, NHLBI Grant RO1HL61438, American Physiological Society Undergraduate Summer Research Fellowship, NSF Graduate Research Fellowship Program, and NSF MRI Grant 0619688.
Investigating jumping of various Caelifera grasshopper species over an altitudinal gradient in New York
Authors: Stamatis Ashley Rose , Townsend Olivia C. , Kirkton Scott D.
Published: June 2021

In many animals, aerobic activity declines with increasing altitude. We examined whether repeated jumping in grasshoppers showed similar trends. Grasshoppers were collected from six locations in New York state that were classified as high‐elevation (1450 m, N= 9), middle‐elevation (960–1000 m, N=16) and low‐elevation (90–150 m, N=18) Grasshoppers were forced to jump repeatedly for ten minutes in a 30 °C temperature room. After jumping, muscle mass, body mass and femur length were measured. Across all elevations, there were no significant differences in jump frequency or jump distance. However, we noted a similar herbaceous habitat at each location suggesting the similar habitats may result in similar jump performances. Although we were not able to collect the same species at every altitude, certain interesting life‐history trends were apparent. The smallest grasshoppers (Chorthippus curtipennis) had the greatest ratio of jumping muscle mass to body mass, produced the longest jumps per body size, but also fatigued fastest. Smaller grasshoppers have higher predation rates; therefore, C. curtipennis’ higher proportional muscle mass may allow it to produce farther escape jumps at the cost of higher fatigue rates. These findings suggest that across our altitudinal gradient, life‐history differences between species rather than altitude may be more important in explaining jump performance differences. Funding was provided through Union College Summer Research Grants.
Pharmacogenetic approaches in altering heart rate in Drosophila larvae
Authors: Cooper Robin L , Majeed Zana R , Titlow Josh , Stacy Audra , King Kayla , Rufer Jenna M , Nichols Charles D
Published: June 2021

Fruit fly, Drosophila melanogaster, is a good model organism to study the underlying ionic mechanism of heart rate (HR) regulation. It is already known that many neuromodulators (serotonin, dopamine, octopamine, acetylcholine) change the HR in larvae. We used genetic and pharmacological approaches to investigate the extent to which cAMP‐PKA signaling mediates the effects of serotonin (5‐HT) and dopamine (DA) on larval HR. One approach involved the use of transgenic flies that express designer receptors exclusively activated by designer drugs (DREADDs). These engineered G‐protein coupled receptors helped to demonstrate that the effect of 5‐HT, which increases HR, could be overridden by the action of Gái which in turn inhibits adenylyl cyclase (AC). Moreover, activation of AC by forskolin increased HR. However, application of dbcAMP (cAMP analogue, PKA activator) and SQ, 22,536 and ddadenosine (AC inhibitors) did not have a substantial effect on the HR. DA activates parallel signaling cascades in cardiac cells with the end result of increased HR. SKF38393 (a vertebrate D1 agonist) and quinpirole (a vertebrate D2 agonist) increase HR to various degrees. SCH23390 and spiperone (D1 and D2 antagonists) each inhibit the stimulatory effect of DA. And SQ22536 inhibits the effect of DA. Together these results indicate that serotonin and dopamine regulate fruit fly HR through canonical GPCR pathways.
Adiponectin Expression in Liver, Omental Fat, and Peripheral Circulation in Morbidly Obese Patients Undergoing Roux‐en‐Y Gastric Bypass
Authors: Sarkaria Paul , Alley Joshua , Andrew Brandon , Prot Jean‐Matthieu , Samy Sanjay , Fitzgerald Laura , Shuler Michael L. , PhD Magnolia Ariza‐Nieto
Published: June 2021

Adiponectin, a peptide hormone, promotes anti‐inflammatory and anti‐atherogenic pathways in the human body, and enhances insulin sensitivity. Hypoadiponectinemia is associated with obesity and other metabolic disorders. The degree of adiponectin dysregulation in patients with obesity appears to be linked to NAFLD (non‐alcoholic fatty liver disease) the hepatic manifestation of the metabolic syndrome. In NAFLD hyperinsulinemia could be a consequence of hypoadiponectinemia. Consequently, it is necessary to determine the level and source of hepatic adiponectin expression. This research is part of the IRB approved clinical trial GHS # 1207–27. Observations and analysis will be conducted on fifty morbidly obese patients that are undergoing Roux‐en‐Y gastric bypass. Immunohistochemistry using a specific anti‐adiponectin antibody shows distribution of adiponectin in liver and omental fat tissue. Adiponectin transcript abundance is assayed using qPCR following the MIQE guidelines. Additionally, circulating levels of total adiponectin are assayed at baseline and 12 weeks post‐surgery. An attempt to use the body‐on‐a‐chip (BOAC) to mimic modulations in adiponectin expression is underway. The BOAC combines computer models of the human body (physiologically based‐pharmacokinetic‐pharmacodinamic PBPK‐PD model) with microfabricated models based on the PBPK and living cells in each compartment. This research is funded by a pilot outreach grant from the Center on Microenvironment and Metastasis (CMM) at Cornell University and a physician's grant from the Guthrie Foundation Investigator‐Initiated Research Grant.
Hepatocyte nuclear factor 1α stimulates the compensatory axis of the renin‐angiotensin system in the pancreatic islet by specific induction of angiotensin‐converting enzyme 2 (ACE2)
Authors: Pedersen Kim Brint , Chhabra Kavaljit , Lazartigues Eric
Published: June 2021

Our laboratory has previously demonstrated that elevated pancreatic expression of angiotensin‐converting enzyme 2 (ACE2) protects beta‐cell function in diabetic mice. We have also shown that hepatocyte nuclear factor 1α (HNF1α) induces ACE2 expression in insulinoma cells. We hypothesized that HNF1α induces the compensatory axis (ACE2, Angiotensin‐(1–7), Mas) of the renin‐angiotensin system (RAS) that counteracts angiotensin II effects in the pancreatic islet. Primary cells from pancreatic islets isolated from wild‐type mice were infected with an adenovirus for expression of HNF1α or a control adenovirus. Components of the RAS which mediate signaling by angiotensin II (angiotensinogen, renin, prorenin receptor, angiotensin‐converting enzyme, angiotensin receptor type 1a, angiotensin receptor type 2) as well as components of the compensatory RAS axis were quantified by quantitative RT‐PCR. The only mRNA of the RAS that was substantially (4‐fold) induced in islet cells was ACE2 mRNA. While angiotensinogen and angiotensin receptor type 2 transcripts were significantly induced by HNF1α in a mouse insulinoma cell line, the induction was much smaller (4‐ and 9‐fold) than for ACE2 mRNA (>;100‐fold). We conclude that ACE2 is the most sensitive RAS target of HNF1α. Through induction of ACE2, HNF1α may thus counteract deleterious effects of angiotensin II on beta‐cell function. Support: NIH/NIDDK (DK084466).
Upregulation of p21 activates the intrinsic apoptotic pathway in pancreatic β cells
Authors: Hernandez Angelina M. , Colvin E. Scott , Fueger Patrick T.
Published: June 2021

Diabetes results from a loss of functional β cell mass due to decreased β cell function, survival, or proliferation. The cyclin‐dependent kinase inhibitors (CDKI) negatively regulate proliferation; however, their involvement during β cell stress is unclear. Interestingly, p21 (or cdkn1a) was the only CDKI dramatically induced in INS‐1‐derived 832/13 cells and rodent islets by two pharmacologic inducers of β cell stress and death, dexamethasone and thapsigargin. We hypothesized that p21 induction during β cell stress activates the apoptotic pathway. Thus, we adenovirally overexpressed p21 in isolated islets and 832/13 cells. p21 overexpression decreased cell proliferation measured by [3H]‐thymidine incorporation. Flow cytometry analysis revealed that p21 overexpression blocked the G1/S and G2/M transitions and increased the number of annexin‐positive stained apoptotic cells. Further, p21 overexpression increased caspase 3 cleavage. Importantly, p21‐mediated caspase 3 activation was inhibited by either overexpression of the anti‐apoptotic protein Bcl‐2 or siRNA‐mediated suppression of the pro‐apoptotic proteins Bax and Bak. Therefore, our findings indicate that p21 induction during β cell stress triggers the intrinsic apoptotic pathway, thus making p21 a potential target to inhibit for protection of β cell mass.

Supported by an APS William Porter Pre‐doctoral Fellowship and NIH grant DK078732.
Evidence for swallowing reflexes evoked by acid and mechanical stimulation of the vagal afferent nerves innervating the larynx in anesthetized guinea pigs
Authors: Tsujimura Takanori , Canning Brendan J
Published: June 2021

Purpose

Swallowing protects the lungs from aspiration and is evoked from the upper airways (UA) by activation of pharyngeal afferent nerves. We have tested the hypothesis that laryngeal (LX) afferent nerve activation may also evoke swallowing.

Methods

Sternohyoid muscle EMGs and UA airflow were used to detect swallows in anesthetized guinea pigs (GPs). Citric acid (CA; 0.01M, 50μL), applied topically to the LX mucosa, and UA pressure distensions, both applied 5× repetitively in 5 min intervals and delivered rostrally via the trachea, were used to evoke swallows.

Results

Repetitive LX CA challenge evoked swallowing (13±5 swallows; n=7). Severing both the recurrent (RLN) and superior (SLN) laryngeal nerves nearly abolished LX CA evoked swallows (0.3±0.3; n=4). Severing just the RLNs also nearly abolished the LX acid‐evoked swallows (1.3±0.9; n=4). By contrast, swallows evoked by 30sec pressure distensions of the UA were not prevented by RLN transection, with all intact (50±5; n=4) and RLN transected (26±3; n=4) GPs swallowing in response to each of 5 distensions. RLN transection did, however, delay the onset of UA distension evoked swallows (4.0±1.3s and 13.6±1.4s in intact and RLN transected GPs; n=4 each). A single, subsequent LX CA challenge evoked swallows in all 4 of these control GPs (4±1) but in none of the GPs with RLNs cut (0±0).

Conclusions

Laryngeal vagal afferent nerve activation initiates swallowing.
Hepatic Steatosis and Severe Coagulopathy Precede Premature Death in GCN2 Null Mice Treated with Asparaginase
Authors: Wilson Gabriel Josiah , She Pengxiang , Mirek Emily T , Wek Ronald C , Anthony Tracy G
Published: June 2021

The anti‐leukemic agent Asparaginase (ASNase) triggers the amino acid stress response (AAR) in liver by activating the eukaryotic initiation factor 2 (eIF2) kinase GCN2. We hypothesize that liver dysfunction and metabolic complications associated with ASNase are related to deficiencies in the GCN2‐directed AAR. To address this hypothesis, wildtype (WT) and GCN2 null mice were injected once‐daily for 14 d with 0 or 3 IU/g BW of E. Coli ASNase. WT mice administered ASNase for 14 d demonstrated no change in BW or liver size and appeared healthy. In contrast, GCN2 nulls suffered ~20% decreased bodyweight, hepatic steatosis, internal bleeding, and 100% mortality by d 12. Phosphorylation of eIF2 and expression of AAR targets ATF4, ATF5, 4E‐BP1 and CHOP were increased in the liver of WT but not GCN2 null mice treated with ASNase. Furthermore, WT mice treated with ASNase demonstrated a 17‐fold increase in FGF‐21 in liver as compared to WT mice treated with excipient; in contrast, GCN2 nulls treated with ASNase showed a 80% reduction in FGF‐21 as compared to excipient‐treated controls. FGF‐21 is critically important for inducing hepatic fat oxidation, ketogenesis and gluconeogenesis. Thus, the ability of liver metabolism to adapt to ASNase depends in part on the ability of the GCN2‐directed AAR pathway to activate FGF‐21.
Increased ACE Expression and iNOS Protein Levels in the Aorta of 2‐month‐old Syrian Cardiomyopathic Hamsters
Authors: Cruz Nildris , Quidgley Jose , El Musa Laurianne , Garcia Juan , Torres Giselle , Miranda Jorge , Crespo Maria J
Published: June 2021

Endothelial dysfunction, increased ACE activity, and oxidative stress are present in 2‐month‐old Syrian cardiomyopathic hamsters (SCH) before the clinical manifestations of heart failure. To evaluate the mechanisms underlying vascular alterations at this early stage, we assessed RNA expression and protein levels of ACE, eNOS and iNOS in aortic tissue of SCH and age matched controls (CT). RNA expression was quantified with Real‐Time RT‐PCR and protein levels with Western blot. ACE RNA expression and protein levels were higher in SCH than in CT (141 % and 1.54 AU vs. 100% and 0.030 AU respectively, P<0.05). eNOS RNA was four‐fold higher in SCH than in CT (P<0.05), although no changes in protein levels were found. In contrast, iNOS RNA expression was significantly lower in SCH (38%) than in CT (100%), whereas protein levels were higher in SCH (0.416 AU) than in CT (0.155 AU)(N=6, P<0.05). Our results suggest that overactivation of vascular ACE combined with increased iNOS protein content are crucial in the etiology of the vascular abnormalities that precede cardiac dysfunction in young SCH. Supported by MBRS‐RISE R25‐GM061838.
Asbestos increases mitochondrial Ca2+ and H2O2 generation in THP1 cells
Authors: Ryan Alan James , Carter Brent A
Published: June 2021

Asbestosis is an important cause of pulmonary fibrosis. We have shown that hydrogen peroxide (H2O2) released from macrophages contributes to the genesis of fibrosis. Because mitochondrial calcium (Ca2+) influx can increase mitochondrial H2O2 production, we examined if Ca2+ influx and H2O2 generation could be altered in macrophages exposed to asbestos. Using THP1 cells loaded with the Ca2+‐sensitive fluorescent dye Fura‐2, we found that intracellular Ca2+ increased by ~2 fold within 4–8 min after asbestos exposure and remained elevated for 60 min. Cells loaded with MitoTracker Red plus Ca2+‐sensitive Fluo3 (or Ca2+‐indicator Rhod2) showed that mitochondrial Ca2+levels were elevated within min after asbestos exposure. Since mitochondrial Ca2+ uptake is driven by a negative mitochondrial membrane potential (ΔΨ), we evaluated ΔΨ in cells loaded with JC‐1. We found that ΔΨ was reduced by ~25–50% in cells exposed to asbestos, a finding consistent with expected net charge changes associated with mitochondrial Ca2+ entry. Finally, to evaluate the role of mitochondrial Ca2+ entry on H2O2 generation, we treated cells with Ru360, an inhibitor of mitochondrial Ca2+ uniporter (MCU), and found that Ru360 reduced H2O2 generation in cells exposed to asbestos. These findings suggest that asbestos rapidly increases mitochondrial Ca2+ via the MCU, which contributes to mitochondrial H2O2 generation in macrophages. (Supported by 2R01ES015981–06, R01ES014871, VA Merit Review 1BX001135 to A.B.C.)
Role of Hydrogen Sulfide in the Regulation of Coronary Blood Flow
Authors: Casalini Eli , Owen Meredith K , Goodwill Adam G , Moberly Steven P , Berwick Zachary C , Tune Johnathan D
Published: June 2021

This study examined mechanisms by which hydrogen sulfide (H2S) regulates coronary blood flow. Experiments were conducted in open‐chest anesthetized dogs while coronary perfusion pressure was held constant at 100 mmHg with a servo‐controlled roller pump. We found that intracoronary (ic) administration of H2S (0.1–3 mM) increased coronary flow from 0.49 ± 0.08 to 2.65 ± 0.13 ml/min/g (P < 0.001). This increase in flow was unaffected by inhibition of Kv channels with 4‐aminopyridine (0.3 mM, ic) but was significantly attenuated (57%) by the KATP channel antagonist glibenclamide (3mg/kg, iv; P < 0.001). Coronary responses to H2S were not diminished by inhibition of NO synthesis with L‐NAME (150 ug/min, ic). Immunohistochemistry revealed expression of the H2S producing enzyme cystathionine gamma‐lyase (CSE) in myocardium. Inhibition of CSE with β‐cyano‐L‐alanine (BCA) (10 μM, ic) had no effect on baseline coronary flow or flow responses to a brief coronary artery occlusion; repayment/debt ratio for control and BCA responses were 465 ± 42% vs. 453 ± 27% respectively. These findings indicate that H2S produces marked, endothelium‐independent vasodilation in the coronary circulation via activation of smooth muscle KATP channels. Despite these effects, our data suggest that endogenous production of H2S is not required for regulation of baseline coronary flow or vasodilation in response to myocardial ischemia. (Support: HL092245)
High Fat Diet During Pregnancy And Lactation Induces Hypertension In Adult Offspring Rats
Authors: dos Santos Robervan Vidal , Melo Vitor U. , Macedo Fabrício , Alves José Luiz Brito , Santos Márcio Roberto Viana , Oliveira Larissa R. , Santana Michael Nadson Santos , Matiotti Mário , Brito Luciana C. , Nascimento Elizabeth , Silva João Henrique Costa , Santana‐Filho Valter J.
Published: June 2021

An adequate nutritional support is important to ensure a normal development of the fetuses. Changes in the nutritional support during gestation may lead to transitory or permanent structural and functional changes of several organs of the offspring. We aimed to investigate the impact of a high fat diet during the gestation on cardiovascular and autonomic nervous systems (ANS) in the offspring of rats. High fat diet was given from day 1 of gestation until weaning of puppies. Sixty‐day‐old offspring from High Fat Diet dams (HFDD, n= 6) or Normal Diet dams (NDD, n= 6) had femoral arteries surgically assessed for the measurements of heart rate (HR), mean (MAP), systolic (SAP) and diastolic arterial pressure (DAP), and spontaneous baroreflex sensitivity (BRS). To investigate the balance of ANS, we established the high (HF) and low frequency (LF) bands of pulse interval (PI) and LF band of SAP spectrum. HFDD had increased MAP (135 ± 2vs 103± 1 mmHg, p<0.05), SAP (160 ± 3 vs 128 ± 4 mmHg, p<0.05), DAP (111 ± 2vs 91 ± 2 mmHg, p<0.05) and HR (417 ± 23 vs 352 ± 8 bpm, p<0.05) when compared to NDD. After spectral analysis of PI and SAP, LF band of SAP spectrum (6.19 ± 0.84 vs 2.29 ± 0.56 mmHg2, p<0.05) and LF/HF ratio of PI (0.71 ± 0.22 vs 0.14 ± 0.016 p<0.05) was higher in HFDD under spontaneous condition. These findings suggest that high fat diet during pregnancy and lactation leads to autonomic misbalance and hypertension in adult offspring rats.
Effect of chronic stress on cardiovascular function in adolescent and adult.
Authors: Duarte Josiane O. , Cruz Fabio C. , Leão Rodrigo M. , Planeta Cleopatra S. , Crestani Carlos C.
Published: June 2021

The aim of this study was to compare the effects of two distinct protocols ‐ repeated restrain stress (RRS) and variable stress (VS) over the mean arterial pressure (MAP), systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and heart rate (HR) in adult and adolescent rats. Furthermore, we investigated whether the effects observed in adolescent rats could persist to adulthood. In this way, 54 male Wistar rats (21 or 60 days old) were divided into 9 groups: 3 control groups (adolescent, adult, adult stressed in adolescence), 3 VS groups ( adolescent, adult and adult stressed in adolescence) and 3 RRS groups ( adolescent, adult and adult stressed in adolescence). The animals were submitted during 10 days to stress, once a day, the RRS persisted during 60 minutes and VS consisted in different stressors conditions. The cardiovascular functions were measured at the 11° day. Our results showed that adolescent animals presented high HR values (P<0.05), when compared to the adult animals. The adolescent animals submitted to VS protocol showed increased MAP, SAP, DAP and HR (P<0.05). All the effects observed in adolescent animals were reverted at the adulthood (P>;0.05). VS and RS increased the MAP, SAP and DAP (P<0.05) in adult rats, but just the VS increased the HR (P<0.05). In this way, our results suggest that chronic variable stress protocols seems to be more dangerous to the cardiovascular function in adult and adolescent. Furthermore, was observed that stress during adolescence were reverted during the adulthood. FAPESP 2012/01888–2.
Antibiotic‐Induced Gut Microbiota Alters Period‐2 Circadian Gene Expression in Liver
Authors: Leone Vanessa A , Huang Edmond , Wang Yunwei , Devkota Suzanne , Zale Elizabeth , Dalal Sushila , Chang Eugene B
Published: June 2021

The circadian gene network in peripheral tissues has been shown to play a crucial role in driving and maintaining host metabolism. Studies suggest that gut microbiota also play a crucial role in host metabolism. A clear link between circadian gene network, host metabolism, and gut microbiota has yet to be elucidated. Our lab has shown circadian gene expression is altered in the absence of gut microbiota (germ‐free; GF). Liver samples from GF mice exhibited significant upregulation of circadian genes Cry2, Per1–3, and DBP, while Clock and Bmal‐1 expression were downregulated when compared to specific pathogen‐free mice (SPF). We then tested whether reducing gut microbes via antibiotic treatment alters circadian clock gene expression, similar to that seen in GF mice. SPF mice were exposed to antibiotic drinking water for 10 days and activity was monitored pre and post‐treatment. Mice were then harvested every 4 hours over a 24‐hour period and liver was analyzed for circadian gene expression. No differences in activity were exhibited between control and antibiotic‐treated animals. Only Per2 gene expression was significantly downregulated at t16:00 as compared to controls, resulting in a phase shift and reduced amplitude. While these results differ from those seen in GF mice, alterations in gut microbiota play a role in maintaining circadian gene expression in peripheral tissues.
Long‐lived and Obesity Resistant Mice Exhibit 24 h Locomotor Circadian Rhythms at Young and Old Age
Authors: Gutman Roee , Froy Oren
Published: June 2021

Ageing is associated with disruption of circadian homeostasis, including reduced entraiment to light‐dark cycles, reduced amplitude and desynchronization of circadian physiological rhythms, and shortening or lengthening of the endogenous circadian period length (tau). αMUPA mice carry a transgene encoding the urokinase‐type plasminogen activator, an extracellular protease implicated in fibrinolysis, tissue remodeling, and brain plasticity. Female αMUPA mice spontaneously eat ~25% less, live ~20% longer, and show high‐amplitude circadian rhythms in food intake, body temperature, and in hepatic clock gene expression levels, compared with WT mice. Herein we examined the tau of locomotor activity of mature (8‐month old) and aged (18‐month old) female αMUPA and WT mice under total darkness. We show that tau changed in WT mice from a period <24 h at 8 months to a period >;24 h at 18 months. However, tau of αMUPA mice was ~24 h at both ages. Deviation of tau from 24 h has shown to be inversely related to life span of rodents and nonhuman primates. Hence, our results suggest that the sustainable endogenous period of ~24 h in αMUPA mice may contribute to their longevity. These results support the hypothesis that although a non‐24‐h tau has an adaptive significance in allowing a better response to natural daylight changes, such a lack of resonance between tau and external period length entails a life‐shortening metabolic cost.
Adaptation to hypoxia prevents endothelial dysfunction of coronary and non‐coronary blood vessels during myocardial ischemia and reperfusion injury
Authors: Manukhina Eugenia , Terekhina Olga L , Belkina Ludmila M , Abramochkin Denis V , Downey H Fred
Published: June 2021

Prior adaptation to intermittent hypoxia (AIH) is cardioprotective during myocardial ischemia‐reperfusion injury (IR). This study investigated the possibility that AIH would lessen endothelial dysfunction (EDF) in rat hearts during IR. AIH was performed in a normobaric chamber (5–8 cycles/d for 20 d, FIO2 9.5–10% for 5–10 min/cycle, with intervening 4‐min normoxia). Endothelium‐dependent (ED) function of coronary blood vessels was evaluated by the flow response to acetylcholine (ACH) in Langendorf isolated hearts after in vitro IR. Also, ED relaxation of noradrenaline‐precontracted isolated aortic rings was evaluated by response to ACH after in situ myocardial IR. With no IR, coronary flow and response to ACH were similar in hearts of non‐AIH (n=9) and AIH (n=10) rats. IR injury decreased ED dilation of coronary arteries to 10.4±1.7% of the pre‐IR response to ACH in non‐AIH (n=10) rats and to 76±20% in AIH (n=9) rats (p<0.05). In the aorta, IR reduced ED relaxation from 45±4% (n=8) of the precontraction magnitude to 9.7±1.2% (n=10) in non‐AIH rats and to 30±3% (n=10) in AIH (p<0.05). Therefore, 1) IR heart injury induced EDF of both coronary and remote, non‐coronary blood vessels; and 2) AIH blunted EDF of both coronary and noncoronary vessels. These data suggest that adaptation to hypoxia is not only cardioprotective but also vasoprotective during myocardial IR injury. Supported by RFBR grant 10–04‐00980.