bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of radial diagnostics and the endoscopic surgery of diseases of maxillary sinus
Authors: Tulebayev R. , Baimenov A , Azhenov T. , Zhusupov B , Mukhamadieva G. , Papulova N. , Mustafin A
Published: June 2021

Aim of research

to increase the effectiveness of surgical treatment and diagnostic of chronic sinusitis [CS]

Material and methods

350 patients were examined, 226 (64,5%) among them with chronic maxillary sinusitis. All patients were undergone complex of laboratorial, clinical and radiological methods of examination. Along with traditional rentgenological methods we used the digital fluorography, computer scan, videoendoscopic examination of sinuses and nasal cavity. 226 patients with nose and maxillary sinus pathology were undergone surgical treatment. Functional examination of mucocilliary transport, anterior active rhinomanometry, pH‐metry and calorifer function investigation were performed.
The high resolving ability of digital fluorography allow to diagnose up to 80% true the inflammation of sinuses and to recognize the structural changes, soft tissue mass of nose and sinuses. During diagnostic of chronic rhinosinusitis: purulent, parietal, hyperplastic forms ‐ the effectiveness of digital fluorography is 80,5%. We suggested modified maxillary sinusotomy in case of chronic purulent and parietal‐hyperplastic forms of maxillary sinusitis, effectivity of this method is 86.5%. This method allows providing sanation of sinuses, restoring ventilation, drainage of maxillary sinuses and prevents scarry stricture of osteomyetal complex. Thus, modern examination methods: endoscopy of nasal cavity, digital fluorography, CS and MRT and also functional check up of the nose in pre‐ and postoperative periods prevent complications and allow estimate the effectiveness of treatment.
The Effects of Losartan on Expressions of Klotho and Wnt in the 5/6 Nephrectomy Model of Progressive Chronic Kidney Disease
Authors: Maquigussa Edgar , Pokorny Gabriel , Perez Mariana , Paterno Josne , Oliveira‐Sales Elizabeth , Schor Nestor , Boim Mirian
Published: June 2021

Klotho is a transmembrane protein expressed in different tissues but in particularly high levels in the kidney. Soluble klotho acts an endocrine factor with diverse functions including endothelium protection and reducing inflammation and fibrosis through mechanisms involving Wnt and TGFbeta1 signaling. Renal fibrosis is the end stage of the progressive chronic kidney disease (CKD) and renal klotho is markedly decreased in CKD patients. Renin angiotensin system (RAS) blockade is a relevant therapy to reduce CKD progression since it has a pivotal role in renal fibrogenesis. We investigated the effects of losartan on Klotho/Wnt signaling in 5/6 nephrectomy model of CKD in rats. Adult male Wistar rats underwent 5/6 nephrectomy (NX) were separated into 2 groups, NX control and NX treated with losartan (LOS, 25 mg/kg) in the drinking water from day 1 after nephrectomy. Blood pressure (MAP) was measured weekly. Urine was colected to determine proteinuria. After 8 weeks, rats were sacrificed and the remmnant kidney was removed and prepared to estimate the renal expression of collagen, epithelial‐to‐mesenchymal transition (EMT) marker (FSP1) and Klotho signaling (Klotho, Wnt and GSK3β) by real time PCR. NX rats presented hypertension and proteinuria that were blunted by LOS treatment. LOS also induced a reduction in the expression of the fibrosis markers collagen and FSP1. Klotho was reduced in NX animals and LOS significantly increased the expression. The LOS treatment increased Wnt3 expression and did not change the Wnt7b and GSK3β. These data suggest that besides the reduction in the MAP, the benefical renal effect of losartan may be at least in part due to upregulation of klotho expression.
Circulating RAS in Mice with Prorenin Receptor Gene Deletion Specificly in Adipose Tissue
Authors: Shamansurova Zulaykho , Tan Paul , Ahmed Basma , Michel Catherine , Kajla Sonia , Seda Ondrej , Lavoie Julie
Published: June 2021

Introduction

Adipose tissue (AT) renin‐angiotensin system (RAS) has been involved in the pathogenesis of obesity, where the role of the prorenin/renin receptor [(P)RR], which acts in an angiotensin‐dependent and ‐independent manner is not clear yet. Our previous results suggest the (P)RR plays a role in the regulation of body weight (BW), fat mass and insulin sensitivity (IS).

Material and methods

Mice with deletion of the (P)RR gene specificly in AT (KO) created by cre‐loxp technology, were kept either on regular chow (ND) or high‐fat/high‐carbohydrate diet (HF/HC) for 10 weeks. BW measured weekly. Body composition assessed by Echo‐MRI. Glucose homeostasis evaluated by OGTT. At the end of protocol, mice euthanized, subcutaneous, visceral (VF) fat pads separated, weighed, flash frozen. Plasma renin activity (PRA), Angiotensin I (Ang‐I) concentration were measured by immunoassay (DBC, Canada).

Results

Male KO mice had a 20% lower BW compared to wild‐type mice (WT), p0.001, whereas KO female mice had a 4.3% decrease on ND, p<0.01 and 14.12%, p0.001 on HF/HC. The VF mass in KO male mice was lower by 2.4 fold, p0.001 compared to WT, in female KO mice ‐1.3 fold lower on ND, p0.01 and 2.4 folds on HF/HC, p0.001. In addition, although KO and WT mice had similar glycemia during OGTT, fasting and stimulated insulinemia were lower in KO mice which suggests an improved IS. These phenotypes were not associated with any changes in circulating Ang‐I and PRA.

Conclusion

Our results suggest that AT specific deletion of the (P)RR regulates body weight, fat mass, glucose homeostasis without changing circulating RAS.
Microarray Profiling of G Protein‐coupled Receptor Signaling Responses to Overexpression of An Intracellular Angiotensin II Fusion Protein in Mouse Proximal Tubule Cells
Authors: Li Xiao , Zhuo Jia
Published: June 2021

We have recently demonstrated that overexpression of an intracellular angiotensin II (ANG II) fusion protein, ECFP/ANG II, selectively in the proximal tubule of the kidney increases blood pressure in rats and mice, but specific signaling mechanisms involved remain unknown. The present study used the Mouse GPCR Signaling Pathway Microarray to determine GPCR signaling responses to overexpression of ECFP/ANG II in mouse proximal tubule cells (mPCT). mPCTs from wild‐type and AT1a‐KO mice were transfected with or without ECFP/ANG II for 48 h, and RNA samples were extracted for microarray analysis of GPCR signaling responses to ECFP/ANG II (n=6 per group). In wild‐type mPCT cells, overexpression of ECFP/ANG II significantly upregulated dozens of GPCR signaling proteins (p<0.05). Significantly increased GPCR expression or signaling proteins included Agtrl1, Agtr2, Agtrap, Arrb1, Arrb2, Calcr, Casr, Ccl2, Ccl4, Cmklr1, Drd1a, Drd2, Edg6, Fgf2, IL4, NOS2, Nppa, Pthr1, and Vegfa etc. By contrast, significantly decreased GPCR signaling proteins included Adcy5, Calcr1, Cdkn1a, Ctgf, Cyp19a1, Edn1, Gcgr, Il1r1, Pik3cg, and Ucp1 etc. The effects of ECFP/ANG II overexpression in wild‐type mPTCs were significantly attenuated in mPCT cells of AT1a‐KO mice, which included Agtrl1, Arrb1, Arrb2, Bcl2l1, Casr, Ccl2, Ccl4, Drd2, Nppa, Pthr1, and Vegfa. Other GPCRs or signaling proteins were not significantly altered in mPCT cells of AT1a‐KO mice. These results suggest that the GPCR Signaling Pathway Microarray may be a useful approach to identify both GPCR‐dependent and GPCR‐independent signaling mechanisms underlying intracellular ANG II‐induced responses in proximal tubule cells.
Deletion of TLR4 Attenuates Adipose Tissue Inflammation in Cancer Cachexia
Authors: Henriques Felipe , Vieira Juliana , Lopes Magno , Knobl Pamela , dos Santos Kaltinaitis , Leal Luana , Franco Felipe , Seelaender Marilia , Batista Miguel
Published: June 2021

Several studies have shown that syndrome of cachexia associated with cancer induces a drastic decrease in body weight and adipose tissue. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. Inflammatory pathways are activated in tissues of cachectic animals and play an important role in cancer‐cachexia syndrome. Loss of adipose tissue mass and inflammation occurred early considering the appearance of classical cachexia markers. In this study we evaluated cachexia development in TLR4 ‐/‐ mice. Male C57BL/6 mice, with 300µl (3,5 ×105) of LLC tumor cells or vehicle‐saline. Adipose tissue (SCAT, MEAT, RPAT) were collected on 27th day after cells injection. The SVF of AT was isolated and measured the infiltrated immune cells (macrophage and T lymphocytes) by Flow cytometry. SCAT (TWT 37,2% and TM 70,7%), MEAT (TWT 27,1% and TM 28,8%), RPAT (TWT 27,4% and TM 76,9%) showed an decrease of total mass on 27th. In flow cytometry using GR and MAC1 showed an accentuated decrease in MEAT of the TLR4 ‐/‐ mice when compared whit the Wild type mice, in both groups (CWT 77,5% and TWT 66,3%). We observed an accentuated body weight loss in both groups, WT and TLR4 ‐/‐. Therefore when we look at the MEAT, compared with the other depots of TLR4 ‐/‐ mice, presents an attenuated in tissue mass, besides occurring decreased of the most important inflammatory cells in to adipose tissue, characteristic during of the cachectic syndrome. Suggesting that deletion of TLR4 protein may play a role in adipose tissue inflammation.
Mediators of the Inhibitory Effect of Sphingosine‐1‐Phosphate on Hepatic Na+/K+ ATPase
Authors: Al‐Alam Nadine , Kreydiyyeh Sawsan
Published: June 2021

We demonstrated previously an inhibitory effect of sphingosine‐1‐phosphate (S1P) on hepatic Na+/K+ ATPase. This work is an attempt to delineate the signaling pathway involved using its agonist FTY720 phosphate (FTY720‐P). HepG2 cells were used as a model and the activity of the Na+/K+ ATPased was assayed by measuring the amount of inorganic phosphate liberated in presence and absence of ouabain, a specific inhibitor of the ATPase. FTY720‐P (7.5 nM, 15 min) inhibited significantly the Na+/K+ ATPase. This effect disappeared completely in presence of JTE‐013, a specific blocker of S1P2 receptors. This inhibition was similarly abrogated by calphostin, indomethacin, RpcAMP, PTIO, and PD98059, respective inhibitors of protein kinase C (PKC), cyclooxygenase‐2(COX‐2), protein kinase A (PKA), nitric oxide synthase (NOS), and extracellular signal regulated kinase (ERK). Treatment with PGE2 or selective activators of these enzymes mimicked the effect of FTY720‐P. PGE2 was found to act via its EP2 receptor, and its effect was still manifested in the presence of calphostin, but disappeared completely in the presence of inhibitors of PKA, NOS and ERK. Furthermore, western blot analysis showed phosphorylation of ERK by dibutyryl cAMP, a PKA activator. This phosphorylation did not appear in the presence of PTIO, indicating that PKA is upstream of NO.It was concluded that FTY720‐P activates PKC via S1P2 receptors leading to PGE2 generation. PGE2 acts through its EP2 receptors and activates PKA which in turn activates NOS resulting in NO production and ERK activation. ERK then inhibits directly or indirectly the Na+/K+ ATPase.
Macrophage‐secreted Ceramides are Necessary for Skeletal Muscle Mitochondrial Disruption with LPS Treatments
Authors: Simmons Kurtis , Hansen Melissa , Bikman Benjamin
Published: June 2021

Lipopolysaccharide (LPS) is an ubiquitous endotoxin, readily consumed and absorbed from the gut into general circulation. Mounting evidence suggests LPS may exacerbate both weight gain and related metabolic disruption, including healthy skeletal muscle mitochondrial physiology. We sought to determine whether LPS disrupts skeletal muscle mitochondrial respiration. Given our previous findings of both LPS‐induced ceramide accrual and ceramide‐mediated mitochondrial fission and diminished mitochondrial respiration, we questioned whether ceramide is necessary for LPS‐induced mitochondrial disruption. We found that red gastrocnemius (RG) tissue from mice receiving I.P. LPS injections for four wk failed to respire in response to various substrates as robustly as mice receiving PBS injections. However, RG respiration from mice receiving both LPS and myriocin injections was similar to PBS‐injected animals. To determine the direct effect of LPS on myotubes, we treated murine C2C12 myotubes with similar conditions as animal injections. In contrast to the permeabilized RG fiber response to LPS, respiration from myotubes was increased with LPS alone, and even higher with both myriocin alone and myriocin with LPS. This prompted us to utilize a two‐culture system, wherein macrophages receive the treatments, followed by transfer of conditioned medium to myotubes. Myotubes incubated with medium from LPS‐treated macrophages experienced a reduction in respiration, but not when macrophages received myriocin co‐treatment. Altogether, these data suggest that the heterogeneity of skeletal muscle tissue, particularly the presence of macrophages, is necessary for the deleterious effects of LPS on skeletal muscle mitochondrial function.
NADPH Oxidases Mediate Zinc Deficiency‐Induced Oxidative Stress in Mouse Kidneys
Authors: Li Mirandy , Gooch Jennifer , Hoover Robert , Williams Clintoria
Published: June 2021

Zn2+ deficiency (ZnD) is common in diabetes. Experimental studies show that ZnD worsens diabetic complications, including diabetic kidney disease. Oxidative stress caused by increased reactive oxygen species (ROS) plays a role in the harmful effects of ZnD. However, the sources of oxidative stress continue to be identified. In diabetes, NADPH oxidases (Nox) are enzymes that promote oxidative stress in the kidneys. This study seeks to determine the role of Nox enzymes in ZnD‐induced oxidative stress in mouse kidneys. WT mice were pair‐fed a ZnD or control diet for 6 weeks. After collecting kidneys and urine, kidney damage (BCA Protein Assay), ROS levels (Amplex Red) and Nox enzymes expression (qRT‐PCR and Western blot) were examined. To further investigate the effect of Zn2+ bioavailability on Nox enzymes, mouse distal convoluted tubule (mDCT) cells were exposed to a Zn2+ chelator (TPEN) or vehicle (DMSO) for 48 hours with or without Zn2+ supplementation for the last 24 hours. Findings show that a Zn2+ restricted diet induces urinary protein that is accompanied by elevated Nox2 expression and ROS levels in mice kidneys. In mDCT cells, inhibition of Nox enzymes with DPI blocks Zn2+ depletion‐induced ROS levels. Zn2+ depletion increases ROS levels and Nox2 and Nox4 expression. Furthermore, Zn2+ supplementation reduces Zn2+ depletion‐induced Nox2 increases. These findings suggest that Nox enzymes mediate ZnD‐induced oxidative stress and kidney damage. Understanding how ZnD causes kidney injury can have an important impact on the treatment of diabetic kidney disease.

R25DK101390 (MSL), VA‐MERIT (JLG), R01DK085097 (RSH), T32‐DK00756 (CRW)
Functional Characterization of Nucleus Tractus Solitarius (NTS) Barosensitive Neurons in F344 Rats
Authors: Li Liang , Kolpakova Jenya , Gu He , Wang Wei‐Zhong , Zhang Xueguo , Cheng Zixi
Published: June 2021

Nucleus of tractus solitarius (NTS) is a complex integrating center in the brainstem that regulates baroreceptor functions. In this study, we characterized activities of NTS barosensitive neurons and examined the relationship between arterial pressure changes and NTS neuronal activity in F344 rats (3‐4 mo). We used single‐unit extracellular recording techniques to record NTS barosensitive neuron activity in response to arterial pressure changes induced by descending aorta occlusion in pentobarbital anesthetized rats (n=20). Baseline mean arterial pressure (MAP) was 102.1±2.5 mmHg and heart rate (HR) was 385.8±7.1 bpm. Aortic occlusion‐induced ΔMAP was 38.2±1.1 mmHg at a rate of 8.2±0.4 mmHg/s. The majority of NTS neurons increased firing rate in response to MAP increase,while some other neurons decreased firing upon MAP increase. We further analyzed the majority of these neurons (n=39): they had the baseline firing rate of 6.2±0.7 spikes/s and increased firing to 276.1±28.1% relative to baseline in response to ΔMAP. The average time between NTS response threshold (30% increase relative to baseline) and 5% MAP increase was 3.1±0.3 s. Data from the neurons that had short response time (蠄3 s) were used to construct logistic sigmoidal curves [y = y0+a/(1+exp(‐b(x‐x0)))] to characterize neuronal response (n = 17). Based on maximum gain, we found two populations of neurons [grp 1: 8.9±1.1 %/mmHg (Gmax), 196.2±27.9% (range of NTS response), 28.3±4.9 mmHg (MAP50); grp 2: 31.9±2.6 %/mmHg (Gmax), 555.6±63.9% (range of NTS response), 28.5±3.4 mmHg (MAP50)]. Our work will provide a method to compare functional changes of different populations of NTS neurons in disease models such as chronic intermittent hypoxia, diabetes, and aging.
Traumatic Stress Promotes Hyperalgesia via Corticotropin‐Releasing Factor Signaling in Central Amygdala
Authors: Gilpin Nicholas , Roltsch Emily , Lu Yi‐Ling , Whitaker Annie , Baynes Brittni , Baiamonte Brandon , Richardson Heather
Published: June 2021

Traumatic stress disorders are defined by persistent avoidance of trauma‐related stimuli, hyperarousal, and negative affect. Our lab uses a stress model in which rats are indexed for avoidance of a predator odor‐paired context, and divided into “Avoiders” (i.e., high stress reactivity) and “Non‐Avoiders” (i.e., low stress reactivity). Using this model, our lab showed that Avoiders exhibit altered prefrontal cortex‐amygdala neuronal activation profiles when exposed to stress‐paired stimuli, and that stress‐induced increases in thermal nociception are mediated by corticotropin‐releasing factor (CRF)‐1 receptors (CRF1Rs). Therefore, we hypothesized that CRF1R antagonist effects are mediated within the central amygdala (CeA). Here, we measured predator odor stress effects on CRF peptide content, transcript, and cell counts in CeA, and we also tested the role of CeA CRF1Rs in mediating stress‐induced thermal hyperalgesia. We observed higher CRF peptide content in CeA of Avoiders relative to Non‐Avoiders and Controls. Avoiders exhibited thermal hyperalgesia that was reversed by systemic antagonism of CRF1Rs; intra‐CeA tetrodotoxin abolished the CRF1R antagonist effect in Avoiders and produced hyperalgesia in Non‐Avoiders and Controls. Finally, intra‐CeA CRF produced thermal hyperalgesia, and this effect was blocked by antagonism of CRF1Rs or GABA‐A receptors in CeA. These results suggest that CRF1Rs are a promising therapeutic target for treatment of traumatic stress disorders. This work was supported by NIH grants AA018400, AA023305, and AA021013.
Increased ADAM17 Expression in ACE2 Knockout Mice is Associated with Increased Excitability of Paraventricular Nucleus Pre‐sympathetic Neurons
Authors: Mukerjee Snigdha , Sriramula Srinivas , Zsombok Andrea , Lazartigues Eric
Published: June 2021

We previously reported that ACE2 knockout (KO) mice, like humans, develop age‐dependent hypertension. In addition, a disintegrin and metalloprotease 17 (ADAM17) was recently shown to contribute to neurogenic hypertension. Accordingly, we hypothesized that ADAM17 in the paraventricular nucleus (PVN) of hypothalamus contributes to enhanced sympathetic tone in mice lacking ACE2. Adult 10‐12 week‐old wildtype (WT) and ACE2 KO male mice (n=2‐4/group) were injected in the kidney with a pseudorabies virus encoding a green fluorescent protein, for retrograde labeling of sympathetic neurons. After 4 days, whole‐cell patch‐clamp recordings were conducted from labeled pre‐sympathetic PVN neurons. The resting membrane potential of these PVN neurons in WT mice was ‐59.7 ±1.06 mV, while ‐52.7 ±1.6 mV in ACE2 KO mice, which may suggest an increase threshold for excitability in pre‐sympathetic PVN neurons. In another set of mice, the hypothalamus was dissected from WT and KO animals (n=4/group) for western blot analysis. ADAM17 expression showed a 2‐fold increase in KO compared to WT (P<0.05). Finally, using immunohistochemistry, ADAM17 expression was confirmed in parvocellular neurons. Taken together, our data suggest that enhanced expression of ADAM17 in the parvocellular PVN could be associated with increased excitability of pre‐sympathetic neurons in ACE2 KO mice. This dysregulation in neuronal activity might alter the intricate pressor homeostasis leading to increased blood pressure. These results suggest that ADAM17 could be a potential new target for the reduction of enhanced sympathetic activity in neurogenic hypertension.

Support: NIH HL093178
ESTROGEN RESPONSIVE NEURONS IN THE MEDIAL AMYGDALA PREVENT STRESS‐INDUCED HYPERTENSION
Authors: Hinton Antentor Othrell , Yan Xia , Henderson Alex , Reynolds Corey , Xu Yong
Published: June 2021

Psychological stress contributes to the development of hypertension in humans and this effect is partially mediated through the medial amygdala (MeA). Estrogens attenuate stress‐induced neural activity in the MeA. Estrogen receptor‐α (ERα) is highly expressed in the MeA. Thus, we hypothesize that estrogens prevent stress‐induced hypertension partly through actions on ERα expressed by MeA neurons. We used DREADD technology to selectively activate SIM1 neurons in the MeA in conscious mice and tested effects of MeA SIM1 neural activity on blood pressure (BP). In addition, Cre‐LoxP system was used to remove ERα from SIM1 neurons in female mice; in parallel, we stereotaxically injected AAV‐Cre into the MeA of ERαlox/lox female mice to delete ERα from all MeA neurons. We tested effects of estrogen replacement (vs. estrogen depletion) on stress‐induced hypertension in these mutant mice. Finally, we examined expression of glutamate receptors in amygdala in C57Bl/6 female mice with estrogen depletion or supplement, at no stress and stress conditions. We showed that selective activation of SIM1 neurons in the MeA increased basal BP and potentiated hypertensive responses provoked by psychological stress (restraint) in conscious mice. While estrogen replacement prevented stress‐induced hypertension in wild type female mice, deletion of ERα from SIM1 neurons, or deletion of ERα from the MeA attenuated these anti‐hypertensive effects of estrogens during stress. We revealed that estrogens increased glutamatergic membrane receptors under basal and stress restrain. To close, the antihypertensive effects of estrogens are partly mediated through ERα in the MeA neurons.
Activation of Brainstem Neurons in Voluntarily Diving Rats after Bilateral Sectioning of the Anterior Ethmoidal Nerve
Authors: McCulloch Paul , Warren Erik
Published: June 2021

This project was designed to investigate the functional role of the anterior ethmoidal nerve (AEN) during underwater diving in rats. The AEN innervates the nasal passages and is thought to be an important component of the afferent pathway that initiates the mammalian diving response. However recent evidence suggests that other nerves that innervate the nasal passages are also able to provide an afferent signal sufficient to initiate the autonomic responses to diving. To study this and the role of the AEN, 24 male Sprague‐Dawley rats were trained to swim and dive through a 5m underwater maze. Rats were subjected to either bilateral sectioning of the AENs (N=12) or a sham surgery (N=12). Twelve rats (6 surgical and 6 sham) had 24 post‐surgical dive trials over 2 hours to activate brainstem neurons to produce Fos, a neuronal activation marker. Twelve rats (6 surgical and 6 sham) were non‐diving controls. Brainstem tissues from all animals were immunohistochemically processed and analyzed for Fos and compared between the 4 groups. Brain regions inspected included the medullary dorsal horn, nucleus tractus solitarius, ventrolateral medulla, A5, and parabrachial region. This study further elucidates the afferent pathway(s) of the diving response and helps clarify the central integrative pathways involved in the mammalian diving response.
Central Gαi2 proteins facilitate PVN parvocellular neuronal activation during chronic elevated sodium intake to maintain sodium homeostasis
Authors: Carmichael Casey , Carmichael Alana , Vartanyan Philip , Wainford Richard
Published: June 2021

Aim

Brain Gαi2 protein‐mediated signal transduction acts as a mechanism to potentiate central sympathoinhibition to maintain fluid and electrolyte homeostasis in settings of chronic high dietary sodium intake. The current study determined if brain Gαi2 proteins impact the pattern of neuronal activation evoked during high‐salt intake to maintain sodium homeostasis.

Methods

Male Sprague‐Dawley rats received an ICV miniosmotic‐pump infusion of a scrambled (SCR) or Gαi2 oligodeoxynucleotide (ODN; 25μg/day) and were maintained on a low (LS; 0.03% NaCl), normal (NS; 0.4%), or high salt (HS; 8%) diet for 7 days. 24‐hour metabolic balance measurements were recorded on day 5 and rats were sacrificed on day 7 for FosB/ΔFosB IHC to examine dietary sodium evoked neuronal activation.

Results

Following 5‐d of a HS, but not LS or NS, diet ICV Gαi2 ODN infusion reduced 24‐h total sodium excretion compared to SCR ODN‐infused rats (Na+ excretion [meEq/24‐h] SCR HS: 27.0±1.2 vs. Gαi2 HS: 19.6±3.3, P<0.05). Chronic HS, but not LS, diet evoked a significant increase in total PVN FosB in SCR infused rats that was not observed in Gαi2 infused rats (Δ from NS [FosB+ cells] SCR: 11±3 vs. Gαi2: 1±2, P<0.05). Specifically, Gαi2 infusion prevented increases in PVN dorsal, ventrolateral, and lateral parvocellular nuclei that were observed in SCR infused rats (P<0.05). Gαi2 infusion had no effect on sodium‐evoked increases in FosB in PVN magnocellular nuclei, the SON, and MnPO.

Conclusion

These data highlight Gαi2 protein signal transduction as a novel CNS mechanism acting to influence neuronal activation, likely at the level of PVN parvocellular neurons, upon chronic HS challenge in a salt‐resistant phenotype.
Actions of Angiotensin II at the OVLT and Voluntary Alcohol Ingestion
Authors: Collister John , Drebes Donna , Nahey David
Published: June 2021

Alcohol abuse leads to morbidity and mortality related to a variety of causes. While the hormone angiotensin II (AngII) is known to regulate sodium and water balance as well as blood pressure, there is convincing evidence that AngII is involved with voluntary alcohol consumption. Previous studies reported decreases in voluntary alcohol intake after AngII treatment that was blocked in rats with lesion of the subfornical organ (SFO), a circumventricular organ (CVO) outside the blood brain barrier accessible by circulating AngII. Others have reported that administration of central AngII actually increases alcohol intake. Our lab has reported that many chronic effects of AngII are mediated via the organum vasculosum of the lamina terminalis (OVLT), another CVO, in addition to the SFO. The AIM of the present study was to demonstrate effects of peripherally administered AngII at the OVLT on alcohol consumption. We tested the hypothesis that chronic AngII administration induces increased alcohol consumption via the OVLT. Rats were subjected to OVLT (n=4) or sham (n=4) lesion and implanted with IV catheters and aortic telemetric transmitters for recording of arterial pressure. A 4.0% NaCl diet, distilled water and 6.0% ethanol were provided ad libitum. After a 3 day control period of saline infusion, rats were intravenously infused with AngII (10 ng/kg/min) for ten days. Baseline ethanol intake was similar between OVLT lesioned (5.8±2.5 ml) and sham (4.8±1.6 ml) rats. By day 5 of AngII treatment, while alcohol intake had increased in both groups compared to control levels, this effect was attenuated in OVLT lesioned rats (9.3±3.7 ml/day) compared to sham operated rats (16.6±6.0 ml/day). These data support the hypothesis that the OVLT mediates ethanol consummatory effects of chronically administered AngII.
BDNF Influences the Excitability of Subfornical Organ Neurons
Authors: Black Emily , McIsaac William , Ferguson Alastair
Published: June 2021

Brain‐derived neurotrophic factor (BDNF) is a peptide known to be involved in several mammalian physiological processes. Expression of BDNF transcripts has been identified in the subfornical organ (SFO), a circumventricular organ involved in fluid balance and energy homeostasis. Microarray analysis has demonstrated that levels of transcript expression in the SFO are differentially regulated by fluid and food deprivation, with levels of BDNF expression increasing significantly in response to dehydration, and decreasing in response to starvation (Hindmarch et al 2008). The current study was therefore undertaken in order to determine the effects of BDNF on the excitability of SFO neurons. We used the whole‐cell patch clamp technique to determine the influence of BDNF on the membrane potential of dissociated SFO neurons as well as that of SFO neurons in slice preparation. We found that 86% of dissociated neurons responded when treated with BDNF (2 nM), all of which depolarized (mean 14 mV). Additionally, 75% of neurons tested in the slice preparation responded when treated with BDNF (2 nM). Of these, 67% showed a depolarization (mean 12 mV) and 33% hyperpolarized (mean ‐18 mV). This study suggests the SFO as a potential central nervous system site at which BDNF may act directly to influence homeostatic regulation.

Supported by the Canadian Institutes for Health Research
The Physiological Effect of Fasting the Month of Ramadan on Anthropometrics and Blood Variables
Authors: Alayafi Yahya , Alsulaiman Majed , Aljaloud Khalid , Jabbary Ali , Aljaloud Sulaiman , Aldayel Abdulaziz , Fry Andrew , Vardiman Phillip , Gallagher Philip
Published: June 2021

Manystudies have beenconducted onfastingduring the monthof Ramadan;however, their resultswerevastly inconsistent.Itis importanttonote thatnone of these studiescontrolledor evenmonitoredphysical activityandfoodintake.

Purpose

Thisstudy willdetermineifintermittentfastingwillaffectbody composition, blood lipid profile,glucose, blood proteins and hormones.

Methods

Eight healthyathletemales participatedinthisstudy.Weight,height andbody compositionofallsubjectswererecordedatbaselineoneday before Ramadan(D1),after ten daysof fastingRamadan(D10) andtwenty‐eightdaysof fastingRamadan (D28). All data was analyzed using 1x3 repeatedmeasuresANOVA(p<.05).

Results

There wassignificantdecreasein bodymassandLeanbody masscomparingD28withD1andD10.Vigorousactivityand ModerateactivityweresignificantlydecreaseatD10andD28ofRamadan. Thepercentagewhichrecommendeddietary allowancesof caloriesfromproteinshowedsignificantdecreaseatD10andD28comparetoD1.Inaddition,the percentage of calories fromcarbohydrate showedsignificant increaseatD10andD28comparetoD1.FastedGlucoselevelsweresignificantly increasedat D10compareto D1. Glucagondecreasesignificantly at D10, but not at D28.Inaddition,Albumin levelsweresignificantlyloweratD10andD28compareto D1;however,all measurements were stillwithinnormal/healthrange.

Conclusion

Resultsshowthelevelofphysicalactivity andfoodintakeare majorcontributingfactorsonthereductioninbodyweight.Overall,thesefindingsindicatenohealthriskforfastingthe month of Ramadan.
Exercise‐Induced Amelioration of Diet‐Induced Obesity and Diabetes is Not Regulated by Irisin
Authors: Saleem Ayesha , Safdar Adeel , Haikalis Maria , Akhtar Mahmood , Suri Rahul , Tarnopolsky Mark
Published: June 2021

Physical inactivity is a primary modifiable risk factor for obesity and type 2 diabetes (T2D) – metabolic diseases that are rampant in pediatric and adult population. Endurance exercise has been shown to prevent and/or attenuate the onset and progression of obesity and T2D. The myokine 'irisin' (cleaved product of Fndc5 in response to endurance exercise) has been touted to play a role in this process but the data available thus far is controversial with respect to the efficacy of irisin. Thus, we sought to determine if irisin mediates the effect of exercise training on improving high fat diet‐induced obesity and diabetes. C57Bl/6 mice were fed high‐fat diet (HFD; 60% kcal from fat) for 6 months until the animals were hyperglycemic and glucose intolerant. Subsequently, the animals were divided into HFD control, endurance exercise (15 m/min X 60 mins X 5 days/week, END), or given intravenous injections of recombinant irisin (50 ng/kg/day, 3x/week, IR). Animals were treated for 8 weeks. END mice had lower body and inguinal fat weight, higher muscle mass, and improved glucose tolerance profile (P < 0.05). Treatment with IR had no effect on fasting glucose levels or bodyweight, but improved glucose tolerance (P < 0.05). IR mice also had a significant increase in brown fat mass, just like mice in the END group. There was a marked improvement Ucp1 expression, and COX activity in inguinal fat and quadriceps muscle in the END animals respectively (P < 0.05), which was absent in the IR group. Our data clearly reflect that while irisin plays a role in improving glucose tolerance, its effectiveness in rescuing symptoms of obesity and diabetes at the whole body level and browning of inguinal fat is limited. Supported by NSERC and CIHR.
Warm Water Immersion Similarly Reduces Arterial Blood Pressure in Obese Type 2 Diabetic and Healthy Individuals
Authors: Rivas Eric , Newmire Dan , Crandall Craig , Ben‐Ezra Vic
Published: June 2021

This project tested the hypothesis that an acute bout of hyperthermia will reduce arterial blood pressure during and following the exposure, but the response will be attenuated in obese type 2 diabetics. Eleven obese type 2 diabetics (T2D) (50.1 ± 12 y, 45 ± 7.1% fat mass, 7.5 ± 1.8% HbA1C) and nine similarly aged healthy controls (HC) (41.1 ± 13.7y; P=0.185, 33.4 ± 7.8% fat mass; P=0.009, 5.3 ± 0.4%, HbA1C; P=0.007) with similar resting blood pressure (T2D: 125 ± 27/ 77 ± 14, HC: 122 ± 14/ 81 ± 10, P>0.05) were assessed. Subjects underwent a whole body passive heated stress (1 hour resting in 39.4 ± 0.4°C water) followed by 1 hour post immersion recovery under normal ambient temperatures. Both groups were similarly heat stressed (ΔTre, 1.4 ± 0.4°; ΔTsk, 6.5 ± 0.8; and ΔHR from rest, 33.5 ± 8.3 bpm) at the end of warm water immersion. In comparison to pre‐immersion values, there were no interactive effect for mean arterial blood pressure (MAP, time x group; P=0.145). MAP was reduced (P<0.01) from minute 10 (ΔMAP, T2D: 10.2 ± 5.5, HC: 14.8 ± 8.4) through minute 60 of immersion (T2D: 12.8 ± 8.1, HC: 13.9 ± 11.2) and remained below pre‐immersion values (P=0.004) up to 20 minutes post immersion in both groups (T2D: 10.8 ± 9.6, HC 7.6 ± 6.8 mmHg). These data indicate that head‐out warm water immersion results in similar hypotensive responses in both groups. Thus, passive heat stress may offer a therapeutic benefit to both healthy and diabetic populations.
The influence of Metabo‐ and Baroreceptors on Postexercise Heat Loss
Authors: Paull Gabrielle , McGinn Ryan , Fujii Naoto , Dervis Sheila , Haqani Baies , Flouris Andreas , Kenny Glen
Published: June 2021

We studied the relative and separate contribution of metabo‐ and baroreflex activity to heat loss during postexercise recovery. Seven males (21 ± 2 years) performed 15 min of running (90% heart rate max) in the heat (35°C). During the 60 min postexercise period, four 1‐min bouts of isometric handgrip exercise (IHG) were followed by 2 min of forearm ischemia (toactivate metaboreceptors, OCC), each separated by 15 min. This was repeated on separate days during a normal seated recovery (CON) and during the application of lower body positive (LBPP, +40 mmHg) or negative (LBNP, ‐20 mmHg) pressure starting at 13 min of recovery. Forearm sweat rate and cutaneous vascular conductance (CVC) were measured continuously. For all conditions CVC returned to pre‐dynamic exercise resting levels at 45 min of recovery (P > 0.05) whereas sweating remained elevated for the duration of recovery (P < 0.05). Relative to pre‐IHG resting CVC was reduced during IHG at 15 min of recovery and subsequently returned to pre‐IHG levels during OCC in CON only. No effect of IHG on CVC was observed for LBPP or LBNP. However LBNP caused an OCC‐induced decrease in CVC from pre‐IHG levels at 15 min of recovery only (P < 0.05). Sweating increased during IHG and remained elevated at similar levels during OCC for all conditions in the final 30 min of recovery (P < 0.05). We show that metaboreceptors influence CVC during the early stages of recovery which is modulated to a certain extent by baroreceptor activity. In contrast, sweating is influenced by metaboreceptor activation in the mid‐to‐late stages of recovery independent of changes in baroreceptor activity. Support: Natural Sciences and Engineering Research of Canada.
Hypoxic Cerebral Vasodilation in Healthy and Metabolic Syndrome Adults: Distinct Interactions between Cyclooxygenase and Reactive Oxygen Species Signaling
Authors: Harrell John , Peltonen Garrett , LaPlante Kaylie , Ernst Brady , Schrage William
Published: June 2021

Excess reactive oxygen species (ROS) limit hypoxia‐mediated cerebral vasodilation in animal models of metabolic syndrome (MetSyn). Cyclooxygenase (COX) may be a source of ROS, but data are lacking in humans. We hypothesized ROS limit hypoxic cerebral vasodilation in human MetSyn, but COX is not the source. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound in 12 MetSyn adults (34±2 yr) and 12 healthy adults (28±1 yr) during baseline and steady‐state hypoxia (SPo2=80%). Intravenous ascorbic acid suppressed ROS during the first steady‐state hypoxia. Oral indomethacin was administered to inhibit COX prior to a second hypoxia trial to investigate the combined roles of ROS and COX during hypoxia. MCAv was normalized for MABP as cerebrovascular conductance index [CVCi = (MCAv ÷ MABP) * 100], and a change in CVCi from baseline (ΔCVCi) indicated hypoxic dilation. ΔCVCi was ~50% lower in adults with MetSyn during control hypoxia (p<0.05). Ascorbic acid infusion increased ΔCVCi in MetSyn adults (p<0.05), but not healthy adults. Combined ascorbic acid and indomethacin increased ΔCVCi in MetSyn adults (p<0.05) similar to ascorbic acid alone. Surprisingly in healthy adults, combined ascorbic acid and indomethacin reduced ΔCVCi by ~75% (p<0.05). This contrasts previous data in healthy adults that indicated no effect of indomethacin alone. In summary, healthy adults express a ROS‐COX redundancy, whereby ROS suppression increased reliance on COX products to achieve hypoxic cerebral vasodilation. MetSyn disrupts this complementary role of ROS, such that COX‐derived ROS restrain hypoxic cerebral vasodilation.
Does Adenosine make an O2 Dependent Contribution to Exercise Hyperaemia?
Authors: Ray Clare , Junejo Rehan , Marshall Janice
Published: June 2021

Our previous studies showed that breathing 40% O2 attenuated hyperaemia evoked in human forearm by static or rhythmic contractions and that cyclooxygenase (COX) blockade alone, or together with 40% O2 produced similar attenuation. This suggested the contribution of prostaglandins (PGs) to exercise hyperaemia is O2 dependent. Adenosine is also implicated in exercise hyperaemia; in the rat, its contribution is ~20% and is mediated by A2A receptors. We have now performed similar experiments to test its O2 dependency in male Wistar rats anesthetised with Alfaxan (20‐23 mg/kg/hr i.v.). 5 periods of rhythmic contraction were evoked by stimulating a sciatic nerve for 5 min each at 4 Hz (S1‐5) whilst recording arterial blood pressure (ABP) and femoral blood flow (FBF). In a Time control group (n‐7), responses evoked by S2‐5 were fully comparable. In the Experimental group (n‐8), integrated femoral vascular conductance (FVC; FBF/ABP) increased from 0.016±0.002 to 0.037±0.003 ml/min/mmHg in response to S2 when breathing air, but to only 0.029±0.002* (*P < 0.01 vs. S2; 2‐way repeated measures ANOVA) during S3 when breathing 40% O2. After A2A receptor blockade with ZM241385 (0.05 mg/kg i.v.) when breathing 40% O2, S4 similarly increased FVC to only 0.03±0.004* ml/min/mmHg. Further, after subsequent blockade of COX with diclofenac (1 mg/kg i.v.), S5 again increased FVC to 0.03±0.003* ml/min/mmHg during 40% O2. Baseline FVC and the evoked muscle tension were unchanged. Thus, the increase in FVC was attenuated ~20% by breathing 40% O2 and in contrast to known effects during air breathing, A2A receptor blockade and COX blockade caused no further reductions during 40% O2. These results indicate that the contribution of adenosine to exercise hyperaemia, like that of PGs, is O2 dependent.
Attenuated Cerebral Vasodilatory Capacity in Response to Hypercapnia in Young Obese Individuals
Authors: Terwoord Janée , Hurr Chansol , Brothers R Matthew
Published: June 2021

Obese individuals are at a greater risk for the development of a variety of cardio and cerebral vascular diseases including hypertension, atherosclerosis, coronary artery disease and stroke. Furthermore, obesity is also associated with cognitive impairment and is a risk factor for dementia and Alzheimer's disease. The exact mechanisms of this elevated risk are not fully characterized; however, impaired microvascular function is believed to be a contributor. This study tested the hypothesis that the cerebral vasodilatory capacity in response to hypercapnia is reduced in obese individuals relative to age and sex matched lean counterparts. Cerebral blood velocity (CBFV) was measured using transcranial Doppler before and during rebreathing‐induced hypercapnia in obese (Obese, n=14) and lean (Lean, n=14) subjects. Cerebral vascular conductance (CVCI) was calculated as CBFV / mean arterial pressure (MAP), and a four parameter logistic regression was applied for sigmoidal curve fitting of the relationship between % change in CVCI and end‐tidal CO2 tension (PETCO2). The magnitude of hypercapnia (Δ PETCO2) during rebreathing was similar between groups (Obese 14 ± 3 mmHg vs. Lean: 15 ± 2 mmHg; P = 0.13). The maximum increase in CVCI (Obese: 155 ± 17% vs. Lean: 176 ± 23%; P < 0.05) and the total range of change in CVCI (Obese: 50 ± 15% vs. Lean: 75 ± 22%; P < 0.01) during rebreathing were reduced in the obese relative to the lean individuals. These data indicate that cerebral vasodilatory capacity in response to changes in PETCO2 during hypercapnia is attenuated in obese individuals compared with lean individuals.

This study was supported by institutional start‐up funds awarded to R. Matthew Brothers.
Prevalence and Activation of Human Brown Adipose Tissue
Authors: Gifford Aliya , Walker Ronald , Welch E , Towse Theodore
Published: June 2021

The role of brown adipose tissue (BAT) in human lipid metabolism and whole‐body energy expenditure is not well understood. To study BAT in humans it is necessary to reliably measure the quantitative properties of BAT. The purpose of this study is to assess the volume and activity of BAT prospectively using PET in a cohort of healthy male and female adult humans.Twenty‐five subjects (10 male), aged 21 to 41 years, with a BMI of 20.15 to 31.48 kg/m2 were scanned on a GE Discovery STE PET/CT scanner using the radioactive tracer 18F‐FDG. Each subject underwent two PET‐CT scans on two separate days, once after two hours of cold exposure (16°C) and once after two hours of thermoneutral exposure (24°C). BAT activation was observed on the PET scans of 19 subjects after cold exposure. The PET scans for two representative subjects from this dataset are shown in Fig 1. The resulting PET and CT values (mean ± 95% CI) from the clavicular BAT depots for these two subjects are listed in Table 1.The results of this study show the ability to measure the presence of brown adipose tissue in healthy adults with a variety of ages and BMI levels. Although it is likely this method does not capture the entire volume of BAT or the full degree of activation for a specific subject, this method can detect activated BAT in adult humans in an automated fashion. One advantage of this research over existing studies is that the same subjects are scanned after exposure to both thermoneutral and cold conditions, which enables a comparison of the images between temperatures.

Funding

1R21DK096282 from NIDDK/NIH & UL1 TR000445 from NCATS/NIH

image

Cold Exposure BAT Values
Thermoneutral Exposure BAT Values

PET Standardized Uptake Value [SUV]
CT Hounsfield Units [HU]
PET Standardized Uptake Value [SUV]
CT Hounsfield Units [HU]
BAT Volume [cm3]

Subject 1
5.2 ± 0.1
‐49.5 ± 0.9
0.6 ± 0.0
‐71.1 ± 1.3
23.7

Subject 2
3.4 ± 0.1
‐64.1 ± 1.7
0.4 ± 0.0
‐93.2 ± 2.4
8.5
Body Mass Index, Serum Adiponectin, leptin, resistin levels, lipid profile in Local Libyan Subjects
Authors: Sheriff dhastagir , Sheriff Sultan
Published: June 2021

Aim

The preliminary study was undertaken to evaluate the serum adiponectin, leptin, resistin levels in local Libyan normal, obese and diabetic subejcts.

Materials and Methods

Among the 1500 patients visiting the Department of Medicine, Faculty of Medicine, Benghazi University hospital for medical check up, 650 subjects were taken for the study. 200 subjects taken as controls( 100 –males; 100‐ females) and 250 (100‐males; 150‐females) subjects formed the obese group and 200 formed the diabetes group(100 males and 100 females).Fasting glucose, total cholesterol (TC), HDL‐cholesterol (HDL‐C), triglyceride (TG) were measured by an enzymatic colorimetric methods.Serum adiponectin levels were measured by enzyme linked immunosorbent assay (ELISA) with a sensitivity of 3 ng/ml. Serum leptin levels were measured by an active human leptin ELISA (DSL, Diagnostic System Laboratories, USA) with a sensitivity of 0.05 ng/ml. Serum resistin levels were measured by ELISA (Linco Research, USA) with a sensitivity of 0.16 ng/ml. Fasting serum insulin levels were measured and homeostatic model assessment (HOMA index) was calculated by HOMA index calculator using fasting blood glucose level and insulin level.

Results and Discussion

In the present study BMI values for control subjects were 29.5, 34.5 for obese subjects and 36.50 for T2DM subjects. WC values for control was 104cm,114 cm for obese subjects and 120 for T2DM subjects. These values clearly indicate that majority of the population are either over‐weight or obese. Serum adiponectin level is comparatively lower in normal Libyan subjects when compared to other Arab and western population. Paradoxically the level of serum adiponectin is found to be higher in diabetic Libyan subjects.The presence of dyslipidemia and insulin resistance in obese and Libyan subjects are observed.

The serum level of adiponectin in this population may reflect the pattern of distribution of adipose tissue in local Libyan subjects.
C‐peptide Modulates VEGF Release: Implications for Diabetic Retinopathy
Authors: Yosten Gina , Kolar Grant
Published: June 2021

Diabetic retinopathy (DR) is one of the leading causes of non‐traumatic blindness in the developed world and is characterized by the neovascularization of the retina with weak blood vessels that may eventually break, potentially leading to blindness. The underlying etiology of DR is not fully understood; however, the hypersecretion of VEGF in the retina appears to play a major role. VEGF normally is released from the retinal pigment epithelium (RPE) and maintains the fenestrated choriocapillaris. However, in the setting of high glucose, the RPE secretes pathologically high levels of VEGF, which can stimulate aberrant retinal neovascularization. Current therapeutic strategies targeting VEGF hypersecretion are extremely invasive, and while effective, are not curative and at best stall the progression of DR. Alternative, non‐invasive strategies to prevent the development of DR are of high interest, such as the development of proinsulin C‐peptide‐based therapeutics, since C‐peptide has been shown to ameliorate blood flow abnormalities associated with DR in both experimental animals and in humans. We have found that GPR146, the putative receptor of C‐peptide, is expressed in the human RPE and in the human RPE cell line, ARPE‐19. Given C‐peptide's known protective actions in the eye, we hypothesized that C‐peptide would reduce VEGF release from ARPE‐19 cells. We found that C‐peptide inhibited both basal and glucose‐stimulated VEGF secretion, and furthermore, that C‐peptide partially reversed insulin‐induced VEGF release from ARPE‐19 cells. While future experiments will determine the mechanisms underlying this effect, these results suggest that C‐peptide may serve as a therapeutic target for the reduction of VEGF hypersecretion and the progression of DR.