bluuebunny/crossref_metadata_2025_split huggingface dataset:
VTA Lamotrigine microinfusions accelerate the development of cocaine sensitisation
Authors: Vazquez Rafael , Santos‐Vera Bermary , Arencibia‐Albite Francisco , Vaquer‐Alicea Ana , Maria‐Rios Cristina , Montiel‐Ramos Alan , Devarie‐Hornedo Marcos , Jimenez‐Rivera Carlos 
Published: November 2023

Support or Funding Information2SC1GM084854‐05A15R25GM061838‐152G12‐RR0030518G12‐MD007600Dopaminergic projections arising from ventral tegmental area (VTA) play a key role on drug induced effects in the mesocorticolimbic system. Chronic cocaine administration produces an increased VTA dopamine (DA) cell excitability. VTA DA neurons express a large hyperpolarization activated cation current, known as Ih, that contributes to the electrophysiological properties of neurons in the CNS. We hypothesized that Ih ‐enhances VTA DA cell activity during the development of cocaine sensitization. Cocaine sensitization is the progressive escalation of psychomotor responses that results with repeated cocaine administration. We performed intra VTA microinfusions of Lamotrigine (LTG), an Ih current enhancer. Male Sprague‐Dawley rats (250–300g) were anesthetized and stereotaxically implanted with bilateral 26‐gauge cannulas in the VTA. Animals were divided as following: Vehicle/Saline, LTG/Saline, Vehicle/Cocaine, LTG/Cocaine (microinjections/i.p. injections, respectively). Daily LTG microinjections (0.1ug bilateral) were administered for 7 days. Cocaine treated rats (15 mg/kg, i.p.) were injected 10–15 minutes after the LTG microinfusion. Locomotor activity was recorded for 1 hour every day. On day 8, rats received a first cocaine challenge in the absence of LTG. After a 7 days withdrawal period, a second cocaine challenge was performed. Total ambulatory and stereotype activities were analyzed using One‐Way ANOVA followed by Newman‐Keuls Test. LTG/Cocaine rats showed a significant increase in the acute response to cocaine (p< 0.01). Moreover, these animals developed sensitization two days before the control group. Their locomotor response to cocaine during days 1–3 was significantly higher (p< 0.01) compared to Vehicle/Cocaine rats. However, during cocaine challenge, when no LTG was administered the LTG/Cocaine group's locomotor activity was not significantly different from the Vehicle/Cocaine group. We postulate that LTG in the VTA, acting through the Ih current, enhances neural excitability caused by chronic cocaine administration. Taken together, our data suggest that an enhanced Ih current activity in the VTA may contribute to a greater susceptibility to cocaine neurobiological effect.
Renal Nerve Denervation Suppresses the Progression of End Organ Damage via Modulating the GABAergic Mechanisms in the Brain in Hypertensive Mice with Chronic Kidney Disease
Authors: Nishihara Masaaki , Hirooka Yoshitaka 
Published: November 2023

BackgroundSympathoexcitation is strongly involved in the pathogenesis of hypertension accompanied with chronic kidney disease (CKD). The paraventricular nucleus of the hypothalamus (PVN) in the brain controls the sympathetic outflow through GABA‐ergic mechanisms in hypertension. The renal nerve denervation (RDN) exerts a certain long term antihypertensive effect; however the precise mechanism is not known. In the present study, we examined whether RDN reduces sympathetic outflow through GABA in the PVN and improves the end organ damage in mice with CKD.Methods and ResultsIn 5/6‐nephrectomized ICR‐mice (Nx) at 4‐weeks after nephrectomy, systolic BP (SBP) was significantly increased (vs. Sham, 143±2 vs. 109±2mmHg, n=12–24, p<0.01), accompanied by sympathoexcitation (urinary norepinephrine (uNE): vs. Sham, 424±26 vs. 226±17μg/24hrs, n=12–24, p<0.01). Nx‐mice developed albuminuria (vs. Sham, 510±97 vs. 102±17mg/g creatinine, n=6–16, p<0.01), and echocardiographic left‐ventricular hypertrophy (LVH) (vs. Sham, 1.18±0.01 vs. 0.98±0.03mm, n=6–24, p<0.01) compared with sham‐mice. We performed RDN or sham operation and divided into 3 groups (Sham‐sham, Nx‐sham, and Nx‐RDN, n=12 for each). At 2‐weeks after RDN, SBP was significantly decreased (123±2 vs. 136±2 mmHg, n=12 for each, p<0.01), and urinary sodium excretions were increased (0.64±0.04 vs. 0.47±0.03 mmol/24hrs, n=8 for each, p<0.01) in Nx‐RDN compared with those in Nx‐sham. The uNE levels were not different between two groups. At 6‐weeks after RDN, SBP was kept decreasing (125±1 vs. 140±3 mmHg, n=12 for each, p<0.01) and uNE levels were also decreased (386±32 vs. 541±35 μg/24hrs, n=12 for each, p<0.01) in Nx‐RDN compared with those in Nx‐sham. The urinary sodium excretions were not different between two groups. Bicuculline (GABA‐A receptor antagonist, 50pmol) microinjection into PVN increased mean arterial pressure (MAP) and lumbar sympathetic nerve activity (LSNA) in all groups. The pressor responses and the change in LSNA were significantly attenuated in Nx‐sham (vs. Sham‐sham, ΔMAP/baseline MAP [%], 33±4 vs. 66±6 %; ΔLSNA (%baseline), 57±7 vs. 112±8 %, p<0.01, n=6 for each), but were enhanced in Nx‐RDN at 6‐weeks after RDN (vs. Nx‐sham, ΔMAP/baseline MAP [%], 60±6 vs. 33±4 %; ΔLSNA (%baseline), 94±5 vs. 57±7 %, p<0.05, n=6 for each). The albuminuria was suppressed (533±121 vs. 1001±192 mg/g creatinine, n=8, p<0.01), and LVH was regressed (1.08±0.02 vs. 1.24±0.03mm, n=12, p<0.05) in Nx‐RDN compared with those in Nx‐sham at 6‐weeks after RDN. The plasma aldosterone concentration (PAC) level was significantly decreased in Nx‐RDN compared with Nx‐sham (365±38 vs. 633±42pg/ml, n=12, p<0.01).ConclusionThese data indicate that long term antihypertensive effect exerted by renal nerve denervation suppresses the end organ damage, at least in part, by reducing sympathetic outflow through GABA in the PVN in hypertensive mice with CKD.
IRF6 is critical mediator of alternative macrophage activation
Authors: Tseng Alexander Mike , Cheng Chang‐An , Wang Haiqing , Lin Yu‐Lieh , Zhou Beiyan , Brehm Tyler 
Published: November 2023

Macrophages display a spectrum of activated phenotypes in response to microenvironmental signals. Pro‐inflammatory and anti‐inflammatory macrophages have important roles in promoting or resolving disease states and also regulate homeostatic conditions of the tissues they reside in, as is the case with adipose tissue macrophages (ATMs). Indeed, under obese stress ATMs expand in number and undergo predominantly pro‐inflammatory activation which propagates dysregulated metabolic and immunologic adipose tissue homeostasis. In this study, we report a new regulator, IRF6, in controlling macrophage alternative activation (M2).IRF6 is a member of the interferon regulatory transcription factors (IRFs) which share a high degree of conservation in their DNA binding domain but less similarity within their protein interaction domain. Knowledge of IRF6 is currently limited to its role in mediating epithelial cell differentiation and the epithelial innate immune response to pathogen challenge. We observed that expression of IRF6 was dramatically suppressed in M2 macrophages. Using both gain and loss of function strategies, we further confirmed that IRF6 specific shRNA enhanced M2 activation as evidenced by elevated levels of activation‐related cell surface markers CD69 and CD86 and the expression of M2‐related genes including IRF4, PPARγ, Arginase1, and IL10. Conversely, IRF6 overexpression dramatically attenuated M2 activation. Furthermore, chromatin immunoprecipitation revealed IRF6 regulates anti‐inflammatory macrophage activation by repressing the expression of PPARy, a critical mediator of macrophage polarization, through binding two IRF recognition sites located upstream of the PPARγ coding region. Our investigation also indicated IRF6 expression is significantly increased in obese ATMS, suggesting that a dysregulated IRF6/PPARγ regulatory axis suppresses anti‐inflammatory ATM responses and ultimately contributes to dysregulated metabolic and immunologic homeostasis.Support or Funding InformationThis work was supported by the Texas A&M Graduate Merit Fellowship (to A. Tseng), American Diabetes Association (1‐13‐JF‐59 to B. Zhou) and National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK 1R01DK098662 to B. Zhou).
Litter Size Reduction Alters the Lipid Metabolism of Adult Male Rat Offspring of Dams Fed a Diet with Caloric Restriction
Authors: da Silva Sartori Denise Rangel , Morceli Lilian , Stefaniszen Amanda Garcia , Barroso Bruna Artico , de Almeida Giovanna Passaroni Marques , Maeda Isabel Cabral , Gonçalves Natalia Volpi , Sartori Maria Marcia Pereira 
Published: November 2023

Recent studies have showed that nutritional changes during critical periods of development can lead to permanent alterations in the metabolism of the offspring which can become more susceptible to chronic diseases in adult age. The aim of this study was to evaluate the effect of litter size on the body weight and the lipid metabolism of adult male offspring rats born to caloric restricted dams. Dams were fed with either ad libitum standard diet (C) or a 30% caloric restricted diet (R) throughout gestation. After birth, litters were reduced to eight pups or four pups in both C and R dams. All dams were fed ad libitum during lactation. After weaning (3 wk), the male rat offspring born to control dams (C8 and C4) and male rat offspring born to restricted dams (R8 and R4) were maintained in individual cages until they were 20 weeks old. An interaction between the diet of control or restricted dams and the litter size was observed for the hepatic lipid % (P=0.015). Reduction of litter size decreased the hepatic lipid % in control rats but increased it in rats to restricted dams. The caloric restriction in the dams decreased the hepatic lipids only in the large litter offspring, but no effect on the small litter was observed. There was no interaction between litter size reduction and the diet of the dams (P=0.689). The reduction of litter size induced an increase (P=0.035) of carcass weight, regardless the diet of the dams. No effects of caloric restriction during gestation and of the litter size on body weight (P=0.187) and on blood cholesterol (P=0.171) were found in C or R adult male rat offspring. It is concluded that the effect of reduction of litter size on hepatic lipid metabolism depends on the diet of the dams during gestation. The increase of carcass weight resulting from litter size reduction is not affected by the diet of the dams.Support or Funding InformationResearch supported by Institute of Biosciences
Diminazene Aceturate Decreases Fat Mass with No Effect on Food Intake in Young Diet‐Induced Obese Rats
Authors: Bruce Erin , Sakarya Yasemin , Kirichenko Nataliya , Toklu Hale , Morgan Drake , Tumer Nihal , Carter Christy S. , Scarpace Philip J. 
Published: November 2023

Obesity is characterized as having an excessive amount of adipose tissue. Current evidence suggests that Angiotensin‐(1–7) activation of the Mas receptor may decrease body weight. We hypothesize that activation of ACE2, via Diminazene Aceturate (DIZE), will significantly reduce body weight of young obese rats.Male Fisher 344 x Brown Norway rats, age 3 months were fed either Standard Chow or 60% high fat (HF) diet for six weeks, whereupon, animals were further divided, and given either 7.5mg/kg/day DIZE s.c. (Chow+DIZE, n=8; HF+DIZE, n=8) or vehicle (Chow Control, n=8; HF Control, n=8) for another six weeks. Body weight and food intake were measured throughout the experiment. Time Domain‐Nuclear Magnetic Resonance (TD‐NMR) was used to assess body composition at weeks 0, 3, 6, 9, and 12. Retroperitoneal, perirenal, and epididymal white adipose tissue (WAT) depots, as well as the interscapular brown adipose tissue (BAT) depot, and the tibialis anterior (TA) muscle, were excised at sacrifice and weighed.After six weeks, animals fed 60% HF diet had a significant increase in bodyweight compared to Chow controls. During the six week treatment period, DIZE prevented further weight gain in both the Chow and HF fed groups. However, TD‐NMR analyses revealed a differential effect of DIZE on body composition in Chow and HF groups. There was a significant difference in absolute fat mass between HF control and HF+DIZE treated animals, but no significant difference between the Chow control and Chow+DIZE groups. Furthermore, there was no change in lean mass in either group. Tissue weights at the time of sacrifice confirm that all DIZE treated animals had significantly lower weights of WAT and BAT, with no significant difference in TA muscle weights. DIZE treatment had a greater effect on lowering perirenal fat mass and BAT mass specifically in HF fed animals. Our results indicate that DIZE may be a potential anti‐obesity agent, specifically targeting the accumulation of adipose tissue with no effect on food intake or lean mass.Support or Funding InformationR01 DK091710‐01A1, P30 AG028740, T32 HL083810‐01 Postdoctoral Fellow
Analysis of Iron Dysregulation in High‐Fat and Iron‐Deficient Rat Models
Authors: Klabacka Randy , Crandall Amy , Anderson Jacob , Wright David , Hancock Chad 
Published: November 2023

Iron (Fe) dysregulation has been identified as a contributor to insulin resistance (IR). Fe chelators and phlebotomy have been shown to improve insulin sensitivity. Due to the central role of the liver in Fe regulation, the objective of our study was to examine hepatic total Fe and critical Fe regulatory proteins in both high‐fat (HF) fed model of IR as well as a model of Fe deficiency (FeDEF).METHODSRats in the HF group were fed a diet with 50% of calories from fat (lard and corn oil) or standard chow for a four‐week period. For the FeDEF model, rats were either fed an FeDEF diet (2–6 mg/kg Fe) or a control diet (50–58 mg/kg Fe). Western blots quantified levels for ferroportin (FPN), ferritin heavy chain (FHC), and ferritin light chain (FLC). Colorimetric analysis was used to quantify total hepatic Fe.RESULTSFPN and ferritin levels were reduced in the FeDEF group (FPN: −49%, p<0.01; ferritin: −44.7%, p < 0.01). While FHC did not show a significant difference in the HF group, FLC levels were elevated (42.1%, p<0.05) and FPN levels were reduced (−56.2%, p<0.05). Total hepatic Fe was found to be elevated in the HF group compared to control (64.1%, p < 0.05).CONCLUSIONSAs expected, in the FeDEF group we observed reductions in both Fe storage proteins (ferritin) and the Fe export protein (FPN) compared to control. Interestingly, with the HF group we observed an increase in both Fe storage proteins and total hepatic Fe while the Fe exporting protein FPN was reduced. Our findings suggest the development of IR due to HF feeding is associated with the dysregulation of hepatic Fe.Support or Funding InformationFunding was provided by Brigham Young University
Detecting Metabolism of Gluconeogenic Precursors Lactate and Pyruvate in Kidney & Liver with Hyperpolarized 13C MRI
Authors: von Morze Cornelius , Chang Gene‐Yuan , Larson Peder E , Shang Hong , Allu Prasanna KR , Bok Robert A , Crane Jason C , Olson Marram P , Tan Chou T , Marco‐Rius Irene , Nelson Sarah J , Kurhanewicz John , Pearce David , Vigneron Daniel B 
Published: November 2023

ObjectiveThe objective of this study was to apply new methods in hyperpolarized (HP) 13C magnetic resonance imaging (MRI) to characterize tissue‐specific alterations in the metabolism of hyperpolarized HP gluconeogenic precursors 13C‐lactate and 13C‐pyruvate by rat liver and kidneys in vivo in both fasting and insulin deprivation in diabetes.MethodsSolutions of 13C‐lactate and 13C‐pyruvate were magnetically hyperpolarized using the method of dissolution dynamic nuclear polarization (DNP), for use in spectroscopic MRI imaging of anesthetized rats. Seven normal rats were scanned by HP 13C MRI of both 13C‐lactate and 13C‐pyruvate in both normal fed and 24h fasting states, and seven additional rats were scanned after induction of diabetes by streptozotocin (STZ) with subsequent withdrawal of insulin (24–36h). Separate images of the injected substrates and their individual metabolic products (lactate, pyruvate, alanine, and bicarbonate) were acquired. Following the imaging experiments, phosphoenolpyruvate carboxykinase (PEPCK) expression levels were also measured in liver and kidney tissues of the STZ‐treated rats, and compared with seven vehicle‐treated controls.ResultsMultiple sets of significant metabolic modulations were detected, with graded intensity in general from fasting to diabetes (Figure 1). An approximate two‐fold reduction in the ratio of 13C‐bicarbonate to total 13C signal was observed in both organs in fasting. The ratio of HP lactate‐to‐alanine was markedly altered, ranging from a liver‐specific 54% increase in fasting, to increases of 69% and 92% in liver and kidney, respectively, in diabetes. Diabetes resulted in a 40% increase in renal lactate signal. STZ resulted in 5.86‐fold and 2.73‐fold increases in PEPCK expression in liver and kidney, respectively.ConclusionThe intermediary metabolism of gluconeogenic precursors 13C‐lactate and 13C‐pyruvate can be monitored non‐invasively in vivo using HP 13C MRI. Localized changes in the HP metabolic spectra of these probes in the liver and kidneys were detected in states of increasing gluconeogenic activity, with generally graded intensity of response from fasting to diabetes. These HP 13C methods could be extremely useful for non‐invasive monitoring of hepatic and renal components of gluconeogenesis in future preclinical and ultimately clinical studies.Support or Funding InformationWe gratefully acknowledge grant support from NIH K01DK099451, P41EB013598, and R01DK56695. We also acknowledge support from the Manning Foundation, a Ben J. LippsResearch Fellowship Award from the American Society of Nephrology, as well as T32DK007219.
Janus‐faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains
Authors: Ro Seung‐Hyun , Kim Hanseong , An Sojin , Cho Uhn‐Soo , Lee Jun Hee 
Published: November 2023

Sestrins are stress‐inducible metabolic regulators with two seemingly unrelated but physiologically important functions: reduction of reactive oxygen species (ROS) and inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). How Sestrins fulfil this dual role has remained elusive so far. Here we report the crystal structure of human Sestrin2 (hSesn2), and show that hSesn2 is twofold pseudo‐symmetric with two globular subdomains, which are structurally similar but functionally distinct from each other. While the N‐terminal domain (Sesn‐A) reduces alkylhydroperoxide radicals through its helix‐turn‐helix oxidoreductase motif, the C‐terminal domain (Sesn‐C) modified this motif to accommodate physical interaction with GATOR2 and subsequent inhibition of mTORC1. These findings clarify the molecular mechanism of how Sestrins can attenuate degenerative processes such as aging and diabetes by acting as a simultaneous inhibitor of ROS accumulation and mTORC1 activation.Support or Funding InformationThis research was supported mainly by a Pilot and Feasibility Grant from the Michigan Diabetes Research and Training Center (NIH Grant 2P30‐DK020572 to U.‐S.C. and J.H.L.) and partially by grants from Ellison Medical Foundation (AG‐NS‐0932‐12 to J.H.L.) and NIH (1R21AG050903 to U.‐S.C. and J.H.L., 1R01DK102850 to J.H.L.)
Histamine receptor‐mediated sustained post‐exercise vasodilation in young trained and untrained adults
Authors: Luttrell Meredith J , Abdala Pedro M , Ely Matthew R , Sieck Dylan C , Mangum Joshua E , Halliwill John R 
Published: November 2023

Histamine‐mediated sustained post‐exercise vasodilation in response to one hour of dynamic knee extension has been established in young, recreationally active adults. Endurance training leads to an increased muscle blood flow from vascular remodeling and enhanced vasodilation during exercise in young adults. However, it is unknown whether endurance exercise training modifies histamine mediated post‐exercise arterial vasodilation in young adults. The purpose of this study was to test the hypothesis that sedentary young adults have similar histamine receptor mediated sustained post‐exercise vasodilator responses compared to endurance trained young adults. A randomized, double‐blind placebo‐controlled crossover study including 6 endurance trained (3F, 3M; ages 18–26) and 5 sedentary (3F, 2M; ages 22–29) adults was completed. Subjects orally consumed either a combined histamine H1 and H2 receptor blockade with 540 mg fexofenadine (Allegra, H1 receptor blocker) and 300mg ranitidine (Zantac, H2 receptor blocker), or placebo pills containing only the inactive ingredients of fexofenadine and ranitidine. Femoral vascular conductance was calculated by dividing femoral artery blood flow obtained using duplex Doppler ultrasound by brachial artery blood pressure measurements. Pre‐exercise measurements were made every 30 minutes for 90 minutes, while post‐exercise measurements were made every 30 minutes for 2 hours. After 90 minutes of supine rest, subjects completed 1 hour of dynamic knee extension exercise at 60% of maximal work rate. Subject demographics and baseline variables were analyzed using independent t‐tests. Post‐exercise differences between groups in the blockade and placebo conditions were analyzed using a mixed effect model ANOVA with repeated measures. All values are reported as mean ± SE. The endurance trained group had higher self‐reported weekly physical activity compared to the sedentary group (73.03 ± 10.5 vs. 27.4 ± 9.5 METhr/wk, p=0.012). Pre‐exercise mean arterial pressure was not different between the two groups in either placebo or blockade conditions (trained placebo: 83±2, trained blockade: 84±2, sedentary placebo: 84±1, sedentary blockade: 86±3 mmHg, p=0.745). Baseline femoral vascular conductance was not different between groups in either placebo or blockade condition (p=0.905). At 60 minutes post exercise, the change in femoral vascular conductance from baseline was not different between the groups for either placebo or blockade condition, although there was a trend towards drug effect of histamine receptor blockade (p=0.192). These preliminary results suggest that there is no difference in post‐exercise femoral vascular conductance between endurance trained and sedentary young adults.Support or Funding InformationSupport provided by NIH grant HL115027