bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pterostilbene, a natural analogue of resveratrol, decreases hepatic lipid deposition by increasing triacylglycerol hydrolases activity (1116.6)
Authors: Moreira Carolina , Rodrigues Angélica , Cordeiro Letícia , Mario Érica , Rosa Damiana , Botion Leida 
Published: June 2021

In the present work the role of pterostilbene on lipid metabolism was evaluated in a rodent obesity model induced by monosodium glutamate (MSG) during the first ten days of life. At 70 days of age, control (C) and MSG (M) animals were divided into groups that received by gavage pterostilbene (P) (40 mg.kg‐1.day‐1) or vehicle (V) during 20 days. After removal of liver and adipose tissue, triacylglycerol (TAG) hydrolases activity was evaluated and SIRT‐1 (sirtuin‐1) expression was determined by real time PCR. The results obtained in fed rats showed increase in Lee index and visceral adiposity in MSG group (MV) in relation to control (CV). Treatment of obese rats with pterostilbene (MP) decreased Lee index with no change in adiposity as compared to MV. Serum TAG levels were increased in MV group (222±19 mg/dL) compared to CV (145±21 mg/dL) and MP group (212±19 mg/dL) did not show significant difference compared to MV. Fat liver deposition markedly increased in MV group when compared to CV, and decreased in MP group in relation to MV. Treatment with pterostilbene increased TAG‐hydrolytic activity in the liver of control and obese groups. In addition, SIRT‐1 mRNA expression increased in MP when compared to MV. Our data clearly established that the treatment of obese rats with pterostilbene has beneficial effects in the reduction of liver fat deposition by increasing TAG‐hydrolytic activity, probably by SIRT‐1 pathway.Grant Funding Source: Supported by CNPq, CAPES, FAPEMIG
Drug‐induced constipation alters gut microbiota stability leading to physiological changes in the host (1118.2)
Authors: Touw Ketrija , Wang Yunwei , Leone Vanessa , Nadimpalli Anuradha , Nathaniel Hubert , Gianrico Farrugia , Kashyap Purna , Chang Eugene 
Published: June 2021

Gut microbes play a significant role in development and maintenance of intestinal functions, but can contribute to pathogenesis of gastrointestinal (GI) disorders when host‐microbiome relationship is perturbed. In this study we sought to examine how constipation affects microbiome, and how these alterations in turn affect the host. Adult C57Bl/6 mice were treated with 0.1% Loperamide in drinking water for 7 days to induce constipation. Loperamide‐treated mice had increased GI transit time, indicating constipation. Bacterial DNA analysis by HiSeq sequencing showed decreased Firmicutes and increased Bacteroidetes in constipated mice. Microbiome metabolic potential was measured with tetrazolium dye assay and showed shift toward increased sugar metabolism in Loperamide‐treated mice. Microbial metabolites were measured by GC‐MS, and showed lower butyrate concentration in constipated mice. To determine constipation effects on the host, we introduced microbiota from constipated donors to germ‐free recipients. These mice had delayed GI transit time. To determine mechanism for delayed GI transit we analyzed colon tissues by qRT‐PCR and western blotting analysis, and determined lower expression of nNos mRNA and protein levels in these mice. Overall, these results suggest that delayed GI transit shifts microbiome taxonomic and metabolic profile, and these changes further contribute to development of constipation.Grant Funding Source: NIH NIDDK T32 DK07074
Chronic ethanol intake leads to differential effects on the multivalent epigenetic state in liver (1120.1)
Authors: Patra Biswanath , Kuttippurathu Lakshmi , Hoek Jan , Vadigepalli Rajanikanth 
Published: June 2021

The objective of this study was to characterize the effects of chronic alcohol consumption on the epigenetic state of key regulators of liver function, repair and regeneration. Rats were fed a liquid diet following established Lieber‐DeCarli protocol, with the treatment group of animals receiving 36% of total calories derived from ethanol, and pair‐fed control animals receiving an iso‐caloric liquid diet, for 5 weeks or 7 months.Chromatin immunoprecipitation (ChIP) and high‐throughput RT‐PCR assays were performed to test the level of H3K27me3, H3K9me2, H3K9ac, H3K18ac at a selected target promoters, using Diagenode autoChIP protocols. Expression of H3 methyl and acetyl protein was tested by Western blotting. Overall histone acetylation and methylation levels were found to be decreased at both 5 week and 7 month time points as revealed by Western blot assays. However, nearly all of the histone markers tested showed differential methylation and acetylation, with significant increase at several key target promoters, at either 5 week or 7 month time frame of chronic ethanol intake. Our results reveal a combinatorial epigenetic state in which multiple histone modification markers were enriched at several target promoters, and the patterns of these multivalent states were altered in a complex manner during adaptation to chronic ethanol intake. Research Support: NIH R01 AA018873, K05 AA017261, and T32 AA007463.
Chronic intermittent hypoxia is associated with elevated pro‐opiomelanocortin mRNA and reduced microRNA‐375 levels in arcuate nucleus of hypothalamus (1126.5)
Authors: Nedungadi T. Prashant , Cunningham J. Thomas 
Published: June 2021

Sleep apnea is a major risk to public health due to its close association with metabolic diseases. Exposure of rats to our 7 days of CIH protocol during their nocturnal period mimics repetitive bouts of arterial hypoxemia and elicits metabolic dysfunction characterized by reduced food intake (p<0.05, n=11), reduced body weight gain (p<0.005, n= 18), hyperinsulinemia (p<0.05, n=7) and glucose intolerance (p<0.05, n=8). However, CIH‐associated metabolic defects are not well understood because its onset is generally unknown. The arcuate nucleus of the hypothalamus (ARH) is a key hypothalamic site which integrates various metabolic cues to control energy homeostasis including anorexigenic POMC signalling. We have observed that the transcription factor FosB/ΔFosB, a well‐known marker of chronic neural transcriptional activation, is increased in ARH after CIH (p<0.05, n=6). POMC gene expression was significantly higher following CIH (P<0.05, n=4). Using miRNA PCR array (miScript‐ Qiagen), we screened for 84 miRNAs expressed in ARH punches that might be involved in energy regulation. In ARH, 29 of the 84 miRNAs tested were present in high abundance including miRNA 375, which has been previously linked as an important regulator of energy homeostasis and shown to have a negative regulatory relationship with POMC in the pituitary. Following CIH, miR‐375 was downregulated in ARH compared to normoxic controls (P<0.05, n=4). A possible association of miRNA‐375 with POMC may provide new insights concerning the regulation of POMC ARH neurons in CIH associated metabolic dysfunction.Grant Funding Source: P01 HL88052
Effect of combined V1a/V1b vasopressin receptor blockade within the paraventricular nucleus on neurocardiovascular responses (1130.2)
Authors: Rossi Noreen , Li Cailian , Chen Haiping , Maliszewska‐Scislo Maria 
Published: June 2021

The paraventricular nucleus (PVN) plays a critical role vasopressin (AVP) secretion by the neurohypophysis. AVP released from dendrites of magnocellular neurons within PVN influences systemic hemodynamics and renal sympathetic nerve activity (RSNA). Both V1a and V1b receptors exist on PVN neurons. We have shown that inhibition of either of these receptors alone blocks the rise in MAP and RSNA in response to AVP. We tested the hypothesis that combined subthreshold doses of V1a and V1b blockers within the PVN will inhibit AVP‐induced increases in MAP and RSNA. Studies were performed in awake, unrestrained,chronically instrmented male Sprague Dawley rats. Microinjection of 100 ng AVP into the PVN increased MAP 18.2±3.1 mmHg (P<0.001) while heart rate and RSNA decreased 52±21 bpm and 26.8±10.6%baseline, respectively (P<0.05). The response to combined subthreshold inhibitory doses of Manning compound (V1a, 20 ng) and nelivaptan (V1b, 0.5 ng) resulted in a significant attenuation of the rise in MAP, 13.3±3.2 mmHg, and attenuation of the reflex decrease in heart rate, 12±8 bpm, and RSNA, 7.2±4.6%baseline. Vehicle did not block any of the responses. These findings suggest that V1a and V1b activated pathways both participate and may interact to induce the pressor and sympathoexcitatory response to AVP within the PVN.Grant Funding Source: VA Merit Award
Selective expression of an angiotensin‐(1‐7)‐producing fusion protein in the brain decreases blood pressure (1130.22)
Authors: Alves Daniele , Guimaraes Priscila , Todiras Mihail , Bader Michael , Santos Robson , Campagnole‐Santos Maria 
Published: June 2021

Angiotensin‐(1‐7) [(Ang‐(1‐7)] attenuates arterial hypertension and improves baroreflex control upon chronic infusion in the central nervous system. In the present study we evaluated the baseline levels, variability and circadian pattern of blood pressure (BP) and heart rate (HR), as well as, the sensitivity of baroreflex control of heart rate and level of cardiac autonomic tone in transgenic rats that exhibit increased expression of Ang‐(1‐7) (TG) in the brain. Sprague‐Dawley (control group ‐ CTL) and TG rats were instrumented with telemetry probe to measure BP (DataScience). In other animals, baroreflex bradycardia (through injection of phenylephrine) and cardiac autonomic tone (by sequential and alternating blockade of β‐adrenergic and muscarinic receptors) were assessed using direct BP recordings (Biopac System). TG rats showed a lower basal mean BP (97 ± 2 mmHg vs 103 ± 2 mmHg in CTL, during the day and 101 ± 2 mmHg vs 106 ± 2 mmHg in CTL, during the night, n=13‐15), without a significant alteration in baseline HR. However, TG rats presented an increased cardiac sympathetic tone (156 ± 6 beats/ min vs 94 ± 10 beats/ min, in CTL, n=6) without change the intrinsic HR. There was a trend to a decrease in vagal tonus of TG rats (31 ± 7 beats/ min vs 53 ± 11 beats/ min in CTL; p<0.15, n=6). In addition, no significant changes in the baroreflex bradycardia was observed. These data suggest that TG rats with a life time increase in Ang‐(1‐7) in the brain present an important change in BP and a direct or compensatory change in autonomic activity.Grant Funding Source: Support by PRONEX and INCT‐Nanobiofar Grants (CNPq and FAPEMIG) and CAPES
Differential blood pressure response in normotensive rats and rats with angiotensin II‐dependent hypertension following systemic cannabinoid CB1 receptor blockade (1140.11)
Authors: Schaich Chris , Howlett Allyn , Brosnihan K. , Diz Debra 
Published: June 2021

Evidence for interactions between the endocannabinoid (ECS) and the renin‐angiotensin (RAS) systems in brain and vasculature is emerging. In transgenic (mRen2)27 rats, an angiotensin (Ang) II‐dependent model of hypertension involving excess sympathetic nervous system activity (SNS), acute systemic blockade of CB1 cannabinoid receptors by the CB1‐selective antagonist SR141716A (SR; 10 mg/kg orally; n = 5) significantly reduced systolic blood pressure (SBP) from 176 ± 3 mmHg baseline to 134 ± 3 mmHg after 90 min (P < 0.001). SBP showed evidence of recovery after 24 h but remained significantly reduced at 146 ± 5 mmHg (P < 0.01) compared to baseline. Plasma collected at 24 h showed no differences in levels of Ang II and Ang‐(1‐7) in the SR‐treated group compared to the vehicle (0.1% Tween‐80 in dH2O) group. Interestingly, oral SR treatment in normotensive Sprague‐Dawley control rats (n = 2) modestly increased SBP from a baseline of 120 ± 3 mmHg to 135 ± 2 mmHg after 90 min, suggesting blockade of the known vasodilator actions of the CB1 receptor. After 24 h, SBP recovered to 126 ± 4 mmHg. There was no effect of vehicle on SBP in either strain. These results indicate that CB1 receptor blockade in (mRen2)27 rats may disrupt the hypertension by interfering with the upregulated RAS‐dependent excess SNS activity in these animals, overcoming the blockade of the beneficial ECS effects in the vasculature.Grant Funding Source: Supported by NIH: P01‐HL051952 and R01‐DA03690
Alterations in brain‐derived neurotrophic factor following withdrawal from a chronic, escalating dose regimen of d‐amphetamine (1145.2)
Authors: Fuller Jasmine , Murray Ryan , Horner Kristen 
Published: June 2021

Withdrawal from chronic, escalating doses of D‐amphetamine (AMPH) induces a syndrome with symptoms that are similar to those seen in major depressive disorder (MDD), such as dysphoria and anhedonia. These changes in affect may underlie relapse and the maintenance of addiction. Changes in brain‐derived neurotrophic factor (BDNF) may underlie the pathophysiology of MDD, but it is unclear whether alterations in BDNF occur following withdrawal from a chronic, escalating dose regimen of AMPH. The goal of this study was to examine changes in BDNF after exposure to chronic, escalating doses of D‐AMPH, followed by 24h or 4d of withdrawal. Animals were sacrificed, the tissue processed for immunohistochemistry and changes in BDNF examined in the nucleus accumbens, amygdala, hippocampus, dorsal raphe and prefrontal cortex, which are regions that mediate emotion and are impaired following psychostimulant withdrawal. Our data show that at 24h post‐AMPH BDNF protein levels are increased in the nucleus accumbens and decreased in the hippocampus. At 4d post‐AMPH, BDNF protein levels are significantly decreased in all areas examined. Our data suggest that while some of the initial dysphoric/anhedonic effects of AMPH withdrawal, mediated by increased BDNF in the nucleus accumbens, may abate as withdrawal progresses, other impairments, mediated by widespread decreases in BDNF may persist in longer‐term withdrawal from AMPH.Grant Funding Source: Mercer Univeristy Seed Grant
In vitro pharmacology of pipradrol derivatives, 3,4‐methylenedioxypyrovalerone, and naphyrone (1145.3)
Authors: Liechti Matthias , Simmler Linda , Rickli Anna , Hoener Marius 
Published: June 2021

Objective: The aim of the study was to characterize the in vitro pharmacology of novel psychoactive substances (NPS) found in “ivory wave” including the methylphenidate‐like pipradrol derivatives desoxypipradrol (2‐diphenylmethylpiperidine, 2‐DPMP) and diphenylprolinol (diphenyl‐2‐pyrrolidinemethanol, D2PM) as well as the pyrovalerone cathinones 3,4‐methylenedioxypyrovalerone (MDPV) and naphyrone (bath salts). Methods: We assessed 3H‐monoamine uptake and reverse transport in HEK 293 cells expressing the human serotonin‐, norepinephrine‐, or dopamine reuptake transporters (SERT, NET, or DAT, respectively). Binding affinities at monoaminergic receptors were assessed using displacement of radioactive ligands. Results: D2PM and 2‐DPMP were selective catecholamine transporter inhibitors without transporter‐mediated substrate‐releasing properties similar to methylphenidate. 2‐DPMP was an equally potent DAT/NET inhibitor to methylphenidate, while D2PM was less potent. Compared with classical stimulants, 2‐DPMP was a 10‐fold more potent DAT blocker compared with cocaine. The pharmacological profile of the pipradrol‐drivatives was similar to that of the pyrovalerone cathinones MDPV and naphyrone. MDPV very potently inhibited NET and DAT but not SERT. Naphyrone was equipotent at all transporters. Both MDPV and naphyrone did not release monoamines. None of the compounds exhibited relevant affinity to monoaminergic receptors. Conclusion: Taken together the pipradrol derivatives and the pyrovalerone cathinones are potent and with the exception of naphyrone selective catecholamine uptake inhibitors in line with their potent and prolonged psychostimulant actions. The pharmacological profile is also likely associated with high abuse liability and an increased risk of psychiatric complications.Grant Funding Source: Swiss National Science Foundation
Inhibitory effects of myricitrin on oxidative stress‐induced endothelial damage and early atherosclerosis in ApoE‐/‐ mice (1146.5)
Authors: Sun Guibo , Qin Meng , Meng Xiangbao , Sun Xiaobo 
Published: June 2021

We evaluated the cytoprotective effect of myricitrin on Atherosclerosis (AS) by assessing oxidative stress‐induced vascular endothelial cell (VEC) injury. The in vivo study using an ApoE−/−mouse model of AS demonstrated that myricitrin treatment protects against VEC damage and inhibits early AS plaque formation. This effect is associated with the antioxidative effect of myricitrin, as observed in a hydrogen peroxide (H2O2)‐induced rat model of artery endothelial injury and primary cultured human VECs. Myricitrin treatment also prevents and attenuates H2O2‐induced endothelial injury. Further investigation of the cytoprotective effects of myricitrin demonstrated that myricitrin exerts its function by scavenging for reactive oxygen species, as well as reducing lipid peroxidation, blocking NO release, and maintaining mitochondrial transmembrane potential. Myricitrin treatment also significantly decreased H2O2‐induced apoptosis in VECs, which was associated with significant inhibition of p53 gene expression, activation of caspase‐3 and the MAPK signaling pathway, and alteration of the patterns of pro‐apoptotic and anti‐apoptotic gene expression. The resulting indicates that myricitrin may prevent the apoptosis induced by oxidative stress injury.Grant Funding Source: The present work was supported by the Key Projects of the National Science and Technology Pillar Pro
The role of microRNA‐21 in anesthetic‐mediated cardioprotection (1155.9)
Authors: Olson Jessica , Yan Yasheng , Twaroski Danielle , Canfield Scott , Kikuchi Chika , Kriegel Alison , Bai Xiaowen , Liang Mingyu , Bosnjak Z. 
Published: June 2021

In this study, we investigate the role of microRNA‐21 in anesthetic preconditioning, and its disruption in diabetic models. Anesthetic‐mediated cardioprotection has been shown to decrease myocardial infarct size after ischemia‐reperfusion injury. This response is drastically attenuated in diabetic patients. Many cell signaling pathways have been investigated in this phenomenon; however, the role of microRNA remains unknown. MicroRNAs are short, non‐coding nucleotide sequences that negatively regulate gene expression through degradation or suppression of messenger RNA.Using qRT‐PCR, our lab has shown a continuous upregulation in microRNA‐21 after isoflurane exposure that appears to play an important role in cardioprotection through its actions on programmed cell death protein 4. This powerful protective cell signaling pathway is disrupted in multiple models of diabetes, including induced pluripotent stem cell‐derived cardiomyocytes from patients with type 2 diabetes, and in patient‐derived cardiomyocytes exposed to high glucose. Our data indicate an important role of microRNA‐21 in isoflurane‐induced cardioprotection and the impairment of this pathway by diabetic conditions. Further investigation may suggest new therapeutic targets for reducing cardiovascular morbidity and mortality in high‐risk patients.Grant Funding Source: Supported by NIH Grants RO1HL034708 and P01GM06673 for Zeljko J. Bosnjak.
Mitochondrial oxidative capacity and function in human white, beige and brown adipose tissue (1160.6)
Authors: Porter Craig , Chondronikola Maria , Chao Tony , Saraf Manish , Børsheim Elisabet , Herndon David , Sidossis Labros 
Published: June 2021

Our understanding of mitochondrial oxidative capacity (oxphos) and function in brown adipose tissue (BAT) is derived from cell and murine models. Here, we determined mitochondrial oxphos and function in white adipose tissue from healthy individuals (WAT, n=9), beige adipose tissue from severely burned children (BeAT, n=8), and BAT from healthy individuals (n=3). Mitochondrial respiration was determined following the addition of 1) substrates; 2) ADP; 3) succinate; and 4) oligomycin. Thereafter, the ratios of coupled to leak and uncoupled to coupled respiration were calculated. Oxphos was higher in BAT (14.3±6.1 pmol/mg/sec; P<0.001) vs. both WAT (1.1±0.2 pmol/mg/sec) and BeAT (2.8±0.4 pmol/mg/sec). Oxphos was also significantly higher in BeAT vs. WAT (P<0.001). The ratio of coupled/leak respiration was lower in BAT vs. WAT and BeAT (P<0.01), whereas the ratio of uncoupled/coupled respiration was higher BAT and BeAT vs. WAT (P<0.05). BAT and BeAT are similar with regards to oligomycin sensitivity, suggesting a more thermogenic phenotype than WAT. However, as oxphos is higher and ADP sensitivity lower in BAT vs. BeAT, suggests that BAT is functionally distinct from BeAT in humans.Grant Funding Source: Supported by NIH (P50‐GM60338, RO1‐GM05668), NIDRR (H133P110012) and SHC (84090, 84080) grants
Cav1.1 controls ATP release to elicit gene expression in adult muscle fibers (1164.12)
Authors: Jorquera Gonzalo , Valladares Denisse , Piétri‐Rouxel France , Allard Bruno , Jacquemond Vincent , Jaimovich Enrique , Casas Mariana 
Published: June 2021

In adult muscle fibers, Cav1.1 acts as voltage sensor for both excitation‐contraction coupling and the activation of a signaling cascade that regulates gene expression. We have shown that ATP is released through pannexin‐1 channels after electrical stimulation at 20 Hz, having a key role in the induction of transcriptional changes related to fast‐to‐slow muscle fiber phenotype transition. Myotubes lacking the Cav1.1α1 subunit displayed almost no ATP release after electrical stimulation. ATP release and gene transcription was also altered in adult muscle fibers knock‐down for Cav1.1α1.In dystrophic fibers, there was also an increase in basal ATP release, but a default in the stimulation‐dependent increase in ATP release and transcription activation observed in control fibers. This can be interpreted as uncoupling between electrical stimulation and ATP release in dystrophic muscles.All these data suggest that Cav1.1 controls ATP release trough Pannexin‐1 channels, activating it after low stimulation frequencies and blocking ATP release during resting conditions. The loss of this control perturbs the normal transcriptional response to electrical activity of adult muscle fibers and may play a role in the etiology of muscular dystrophy.Grant Funding Source: ACT 1111, FONDECYT 1110467, UINICIA 0212M, CNRS‐CONICYT EDC24748
High salt intake and aldosterone independently augment the exercise pressor reflex in rats (1165.10)
Authors: Mizuno Masaki , Downey Ryan , Mitchell Jere , Smith Scott , Vongpatanasin Wanpen 
Published: June 2021

Evidence suggests the exercise pressor reflex (EPR) is overactive in hypertension. However, the underlying mechanisms are poorly understood. The purpose of this study was to determine whether excessive salt intake and/or chronic administration of aldosterone potentiates EPR function in rats. Changes in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) to stimulation of the EPR were assessed in vehicle and aldosterone treated (4 weeks via osmotic mini‐pump) Sprague‐Dawley rats given either water or saline (elevated salt load) to drink. Compared to vehicle/water‐treated rats, contraction induced stimulation of the EPR evoked significantly greater increases in RSNA in vehicle/saline, aldosterone/water and aldosterone/saline‐treated animals (39±11, 98±19, 110±20, and 154±29%/kg, respectively, P<0.01). A similar MAP response profile was likewise produced. The sympathetic and pressor responses to passive muscle stretch and intra‐arterial capsaicin administration were also augmented in the vehicle/saline group and aldosterone treated rats, suggesting both mechano‐ and metaboreflex sensitization. In conclusion, our data provide the first direct evidence for both high salt intake and aldosterone as major contributors to the neural mechanisms underlying the exaggerated rise in sympathetic activity and blood pressure during exercise in hypertension. Supported by NIH HL‐113738Grant Funding Source: Supported by NIH HL‐113738