bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular and Autonomic Modulation by Paraventricular Nucleus of Hypothalamus During Head Down Tilt in Unanesthetized Rats
Authors: Amorim Eric , Peras Vivian , de Andrade Ozahyr , Martins‐Pinge Marli
Published: June 2021

The exposure to microgravity induces autonomic and vestibular disorders as alterations in cardiovascular function. The paraventricular nucleus of the hypothalamus (PVN) is known as an important center for integrating autonomic and cardiovascular responses as blood volume reflexes. The acute effects promoted by microgravity and the PVN involvement in cardiovascular and autonomic parameters were not evaluated yet. Male wistar rats were anesthetized to guide cannulae implantation to PVN. After 3 days of surgical recovery, femoral artery and vein catheters were implanted for direct recording of blood pressure (BP) and heart rate (HR) in conscious animals to evaluate cardiovascular and autonomic changes in an acute protocol of head down tilt (HDT) in non‐anesthetized rats.During HDT, there was an increase in mean arterial pressure (MAP) (11±1mmHg) and decrease in heart rate (HR) (‐28±5 bpm). Spectral analysis of systolic arterial pressure (SAP) showed an increase in low frequency (LF) component. In addition, HDT induced a reduction in the LF and increase in high frequency (HF) component of the pulse interval (PI). PVN inhibition with muscimol reversed bradycardia and blocked the reduction of the LF and HF increases in PI during HDT. Our results suggest that PVN participates in the cardiovascular compensation during HDT, especially modulating the cardiac responses.
Dietary Nitrate improves Cerebral Perfusion, in Young Adults during Exercise: Relationship to Cognitive Performance
Authors: Rattray Ben , Egle‐Marshall Lauren , Northey Joseph , Hone Simon , Smee Disa , Brassard Patrice
Published: June 2021

Dietary nitrate increases middle cerebral artery mean velocity (MCA Vmean) during aerobic exercise but it remains unclear if this is true with the simultaneous inclusion of a cognitively demanding task. Therefore, our aim was to investigate whether nitrate supplementation would influence exercise‐induced changes in MCA Vmean, and cognitive performance.

In a double blind randomized crossover design, 12 healthy adults consumed two 70 ml doses of either beetroot juice or placebo two hours prior to exercise. Subjects then completed four 8‐min workloads of exercise set to elicit 30%, 50%, 70%, and 85% of heart rate reserve (HRR) on a cycle ergometer. Reaction time and accuracy was assessed during a modified version of the color Stroop task, with simple and complex (incongruent) response types, in the last 3 min of each workload. MCA Vmean (Transcranial Doppler) was monitored throughout.

MCA Vmean displayed a typical relationship with exercise intensity, but was significantly elevated with beetroot, especially during the complex Stroop task, at 70% (p=0.001, d=0.47) and 85% HRR (p=0.027, d=0.74). Reaction time was not statistically different between conditions regardless of the difficulty level. However, beetroot may have contributed to increased accuracy in the complex task (p=0.059) whilst cycling.

These preliminary results suggest that dietary nitrate elevates MCA Vmean during a combined exercise and cognitive challenge, which may be related to improved accuracy during the most demanding tasks.
β‐Alanine Ingestion Improves Behavioral Responses to a Predator Scent Stress
Authors: Hoffman Jay , Cohen Hagit , Stout Jeffrey , Ostfeld Ishay
Published: June 2021

β‐alanine (BA) has been proposed to reduce depression and anxiety‐like behavior. The purpose of this study was to investigate 30‐days of BA ingestion (100g•kg‐1) on the behavioral and neuroendocrine response of post‐traumatic stress disorder (PTSD) in a murine model. Following supplementation animals were exposed to a predator‐scent stress (PSS), which has been validated in an animal model stimulating PTSD‐like behavior. Behaviors were evaluated with the elevated plus maze and acoustic startle response (ASR)7 days following exposure. Immunohistochemical technique was used to detect expression of corticosterone (CS) and brain‐derived neurotrophic factor (BDNF). Animals exposed to PSS and not provided BA spent significantly less time in the open arms and more time in the closed arms of the maze than animals exposed to PSS but provided BA, or to unexposed animals. Rodents exposed, but provided BA had comparable scores to rodents unexposed and consumed BA. Anxiety index was higher (p<0.05) in animals exposed to PSS and not provided BA compared to animals exposed and consumed BA or were unexposed. The ASR and freezing was greater (p<0.05) in animals exposed to PSS compared to animals unexposed. CS expression was higher (p<0.05) in animals exposed to PSS compared to unexposed animals. BDNF expression in the CA1 and DG subregions of the hippocampus was greater (p<0.05) in animals unexposed, or animals exposed and provided BA compared to animals exposed and were not provided with BA. Results suggest that BA provides a reduction in the symptoms of PTSD‐like behavior, which may be mediated in part by changes of BDNF expression in the brain.
ICP During Daily Life in Healthy Adults: What Does Microgravity Add to the Mix?
Authors: Lawley Justin , Williams Michael , Petersen Lonnie , Zhang Rong , Whitworth Tony , Levine Benjamin
Published: June 2021

PURPOSE

Due to visual changes seen in astronauts, the primary objective is to make the first direct, invasive measurements of intracranial pressure (ICP) during changes in hydrostatic gradients experienced during daily life and induced by simulated and real microgravity.

METHODS

Subjects are four healthy adults who previously had an Ommaya reservoir implanted, which allows continuous pressure measurements to be made. Central venous pressure (CVP) is measured by a peripherally inserted central catheter. Hemodynamics are obtained upright, supine, then after 5 min, 3 hrs and 24 hrs of 6° head‐down tilt (HDT). Measurements are repeated during real microgravity (parabolic flight).

RESULTS

ICP increased by transitioning from the sitting to supine position (4±2 vs 15±2 mmHg); ICP increased further with HDT (17±3, Δ2 mmHg), but returned towards normal values after 3 hrs (16 mmHg) and 24 hrs (14 mmHg). In comparison to the supine position, CVP tended to decrease over time during HDT (5 min, Δ1 mmHg; 3 hrs, Δ2 mmHg; 24 hrs, Δ1 mmHg). ICP increased during the 1.8g (Gx) phase of the parabola (from supine 17±2 to 25±2). However, ICP fell dramatically during 0g (to 13±4, Δ12 mmHg). The magnitude of the reduction in ICP is the combination of removing the 1.8 Gx and the subsequent fall in CVP (1g, 5±4; 1.8g, 7±5; 0g, 4±3).

image

Conclusions

Elevated ICP is unlikely to be the culprit for visual impairment in space. Alternatively, visual impairments may be simply due to consistently “elevated” ICP relative to the upright posture, due to the inability to “stand‐up” in space.
Lower Body Negative Pressure Counters Simulated Microgravity‐Induced Elevations of Intracranial Pressure
Authors: Macias Brandon , Clary Erika , Hargens Alan
Published: June 2021

Ophthalmic evaluations of 7 astronauts after 6‐month missions to International Space Station show unexpected vision impairment. Lumbar punctures in 4 astronauts showed elevations of cerebrospinal fluid pressure after flight. We hypothesized that lower body negative pressure (LBNP) would counteract head down, head‐down tilt (HDT), induced elevations in intracranial pressure (ICP). Ten healthy volunteers participated in this study (mean age: 34 years) after IRB review. Cerebral and Cochlear Fluid Pressure (CCFP, noninvasive ICP surrogate) device determined relative changes in ICP. ICP, arm blood pressure, and heart rate were measured during the last minute of each condition. Subjects were positioned supine (5 mins), sitting (5 mins), 15‐degrees HDT (5 mins) and ten minutes of HDT with LBNP (25 mmHg). RMANOVA determined statistical significance (p<0.05). ICP significantly increased from the sitting to the supine posture, p=0.028. Moreover, ICP further increased when the subjects were positioned in HDT, p=0.005. However, when LBNP was activated during HDT, ICP decreased and was not significantly different from supine levels (p=0.549). Mean blood pressure and heart rate did not change significantly across all conditions. In conclusion, short duration exposures to simulated microgravity increase ICP significantly and importantly, LBNP counteracts these elevations of ICP. Therefore, spaceflight countermeasures that shift fluid to the lower body may mitigate vision problems. This project was supported by NSBRI through NASA NCC 9‐58 (to BRM), APS Undergraduate Summer Research Fellowship (to EMC), and NASA grant NNX13AJ12G (to ARH).
Lumbar Paraspinal Muscle Atrophy during Long Duration Spaceflight
Authors: Snyder Alex , Macias Brandon , Healey Rob , Holt Jacquelyn , Chang Douglas , Lotz Jeffrey , Hargens Alan
Published: June 2021

Spaceflight results in significant lumbar pain and muscle atrophy in astronauts. The rate of disc herniation is about four times greater in US astronauts than in matched controls. Muscles are vital spine stabilizers, and trunk muscle atrophy is associated with chronic back pain. Yet, it is unclear whether current countermeasures during 6‐month International Space Station (ISS) missions prevent lumbar paraspinal muscle atrophy.

PURPOSE

To quantify paraspinal muscle functional cross sectional area (FCSA) before, immediately after, and 30‐days after 6‐month ISS missions.

METHODS

To date, complete paraspinal MRI data for three astronauts were available. FCSA was measured in four lumbar paraspinal muscles (multifidus, erector spinae, quadratus lumborum, and psoas) at lumbar vertebral level 3/4. FCSA was measured by setting a threshold to isolate lean muscle.

RESULTS

Long duration spaceflight produced a significant 15.1% decrease (p=0.023) in total lumbar paraspinal muscle FCSA, as compared to before flight (Table 1). Subsequently 63.3% of FCSA loss was recovered by 30‐days post flight and was not significantly different from before flight (p=0.152).

image

CONCLUSION

Despite low sample size, paraspinal muscle atrophy is not prevented by current countermeasures on 6‐month ISS missions. However, recovery activities resulted in a 63% recovery 30‐days post flight. This suggests spaceflight induced back pain and disc herniation risk may be partly related to reduced dynamic trunk stability linked to atrophied lumbar paraspinal muscles.

Project supported by NASA grant # NNX13AM89G (to ARH) and NSBRI through NASA NCC 9‐58 (to BRM).
Satellite Cell Content Decreases and Muscle Physiology Is Altered during 2 Weeks of Physical Inactivity in Middle‐Aged Adults
Authors: Arentson‐Lantz Emily , English Kirk , Paddon‐Jones Doug , Fry Christopher
Published: June 2021

Atrophy of skeletal muscle during bed rest, an analog of spaceflight, occurs in older adults at a greater rate than young adults. Identifying the mechanism responsible for the age‐related difference is critical to promote the muscle health of the astronaut corps where the average age is approaching 50. Therefore, we sought to characterize changes in muscle physiology of middle‐aged adults after 2 weeks of bed rest. Muscle biopsies from the vastus lateralis were obtained from five (2 male, 3 female) healthy, middle‐aged adults (51±1 years) at 3 time points: prior to bed rest (pre‐BR), after 2 weeks of bed rest (post‐BR) and after one week of rehabilitation (post‐RE). Satellite cell (SC) content was determined via immunohistochemistry using an antibody against the unique satellite cell transcription factor Pax7. Muscle fiber type, cross‐sectional area and myonuclear content were also determined via immunohistochemistry and muscle loss was measured by DEXA. Subjects lost an average of 889±212 g of lean mass from their lower limbs during bed rest. SC content decreased post‐BR (0.09 SC/fiber) compared to pre‐BR (0.13 SC/fiber; 33% decrease), and partial recovery of satellite cell content occurred post‐RE (0.11 SC/fiber; 20% increase from post‐BR). The recovery in SC content occurred largely in SC associated with type 1 fibers, while content of SC associated with type 2 fibers remained relatively unchanged post‐RE. The loss of satellite cells can impair muscle regeneration following atrophy, warranting further work to determine if modulating SC activity during or following bed rest could improve skeletal muscle mass and health. This project was supported by NSBRI‐NNJ08ZSA002N, R01NR012973, and P30 AG024832.
AT1R Blockade Attenuates Reflex Cutaneous Vasoconstriction in Aged but not Young Skin
Authors: Lang James , Kolb Kelsey
Published: June 2021

Stimulation of the angiotensin II type I receptor (AT1R) elicits vasoconstriction (VC) that may be occurring through the activation of a pathogenic vascular pathway such as Rho kinase (ROCK). We hypothesize that the reflex cutaneous VC response to whole‐body cooling (Tsk = 30.5 oC) in older humans relies in part on AT1R activation, which may explain greater ROCK activity attendant with aging. Two microdialysis (MD) fibers were placed in the forearm skin of 10 young (Y) (24 ± 1 years) and 10 older (O) (70 ± 2 years) individuals for infusion of 1) lactated Ringer's solution (control) and 2) AT1R blockade with 2 μg/L losartan. Laser Doppler flux (LDF) was measured over each MD site and cutaneous vascular conductance (CVC) was calculated as CVC = LDF/mean arterial pressure and expressed as a percent change from baseline (%ΔCVC). In older individuals the VC response to whole‐body cooling was blunted (Y = ‐34 ± 2, O = ‐17 ± 3 %ΔCVC) and this was further attenuated at the losartan site (Y = ‐34 ± 3, O = ‐9 ± 3 %ΔCVC; P < 0.05). The VC response to an exogenous 10 μM dose of angiotensin II (Y = ‐27 ± 3, O = ‐42 ± 5 %ΔCVC) was completely blocked in sites pretreated with losartan or with fasudil, a ROCK antagonist. These data suggest that AT1R activation contributes to the reflex VC response in aged but not young skin. Furthermore, the angiotensin II component of the VC response appears to occur primarily through a ROCK‐mediated mechanism.

**Funded by Iowa Osteopathic & Education Research Grant (IOER #05‐13‐05)
Spontaneously Hypertensive Rats Display Exaggerated Increase in Brain Temperature During Acute Physical Exercise in Temperate and Warm Environments
Authors: Drummond Lucas , Wanner Samuel , Kunstetter Ana , Vaz Filipe , Campos Helton , Coimbra Cândido , Natali Antônio , Prímola‐Gomes Thales
Published: June 2021

This study aimed at investigating the changes in brain temperature (Tb) in SHR subjected to acute physical exercise in temperate and warm environments. Adult male Wistar and SHR rats were subjected to implantation of an abdominal temperature (Ta) sensor and a guide cannula in the right frontal cortex, that allowed us to insert a themorresistor and measure Tb. After recovery, the animals were familiarized to run on a treadmill, and then, in alternate days, they were subjected to two constant‐speed protocols until fatigue (temperate and warm environments). The tail skin temperature (Ts), Ta and Tb were recorded. In the temperate environment, the SHR group ​​showed greater increase in Tb compared with Control group from the 13th min until the 35th min, greater increase in Ta from the 19th min until the 52th min, and lower tail skin temperature from the 13th until the 21th min of exercise. In the warm environment, the SHR group ​​showed greater increase in Tb from the 11th until the 24th min, and greater increase in Ta from the 9th min until the 36th min. The SHR group exhibited lower physical performance compared with the Control group in temperate and warm environments. We conclude that during acute exercise in temperate and warm environments, hypertensive rats present greater increases in Tb and Ta. Fapemig, Capes, and Cnpq.
Effects of Face Immersion in Cold Water on Blood Pressure and Cerebral Conductance
Authors: White Matthew , Henderson Kate , Walsh Michael
Published: June 2021

Cold‐water face immersion without breath holding gives a gasp response followed by a dive response (DR). The DR after cold‐water face immersion elicits an increase in mean arterial blood pressure (MAP) but it is not evident if cerebral perfusion is maintained during this face immersion. Cerebral auto‐regulation suggests that cerebral perfusion is maintained during substantial variations in MAP. It was hypothesized that cold water face immersion would give changes in MAP that are inversely proportional to face temperatures and this would be coupled with maintenance of the index of cerebral conductance (CVCI, cm/s/mm Hg) in the middle cerebral (MCA) and vertebral arteries (VA). Five college‐age males of normal height and weight volunteered for the study. Physiological responses were assessed with B X B metabolic cart for pulmonary ventilation (VE), thermocouples for skin temperatures (TSK), a pulse oximeter for heart rate (HR), a transcranial‐Doppler monitor for cerebral blood velocity (CBV) and a Finometer for blood pressure. Five min face immersions were in water at 5, 15, and 33°C. Outcome variables were analyzed with a 1‐factor ANOVA with levels at each water temperature; 2‐tailed, paired t‐tests were employed for post‐hoc analyses with p=0.05. The results demonstrated elevations (p<0.05) in MAP from ~ 76 mm Hg at rest to the range of ~ 90 to 82 mm Hg in 5°C to 33°C water. Relative to rest the CVCI MCA (p<0.05) decreased by ~23% in the 5°C, by ~19% in the 15°C, and by ~12% in the 33°C immersions. In conclusion, these results support during cold‐water immersion without breath holding that face skin temperature responses were inversely proportional to blood pressure responses and proportional cerebral conductance responses.
Deprivation of plasma estradiol level affects circadian rhythms of body core and tail skin temperature in female rats
Authors: Marui Shuri , Nagashima Kei
Published: June 2021

Purpose

We aimed to assess the effect of estradiol on daily changes of thermoregulatory responses of the tail vasculature in ovariectomized rats.

Methods

Female Wistar rats (n=10, age of 8‐12 wk) were bilaterally ovariectomized, and placed a telemetry device for the measurements of body core temperature (Tcore) and spontaneous activity (ACT) in the abdominal cavity. Temperature of the tail surface (Ttail) was estimated by thermography. Two silicon tubes containing 17β‐estradiol (E2, 50mg) were subcutaneously placed in one group (n=5, E2 (+)), and empty tubes were placed in the other group (n=5, E2 (‐)). The tubes were removed 10 days after the surgery. Tcore, ACT, and Ttail were measured a day before and 14 days after the removal of the tubes (PRE and Day 14, respectively). Regression analysis was conducted for the relationship between the daily values of Tcore and Ttail.

Results

On the PRE, Tcore was higher (P<0.05) in the E2 (‐) group than in the E2 (+) group at 12:30‐17:00 (37.2±0.2°C and 36.5±0.2°C, respectively). Ttail was higher (P<0.05) in the E2 (‐) group than the E2 (+) group at 20:00‐0:30 (33.4±0.3°C and 31.2±0.6°C, respectively). The regression slope for Ttail and Tcore was greater (P<0.05) in the E2 (‐) group than in the E2 (+) group on the PRE (1.41±0.34 and 0.60±0.16, respectively). On Day 14, in the E2 (‐) group, circadian rhythms of Tcore and Ttail remained unchanged from those on the PRE. Tcore and Ttail were higher than those on PRE at 14:30‐18:30 and 19:00‐18:30, respectively. The regression slope was greater (P<0.05) than that of the PRE.

Conclusion

A reduction of estradiol affects circadian rhythms of Tcore and Ttail. Moreover, a lack of estradiol may decrease the ability in thermoregulatory response of the tail vasculature.
Lisinopril Improves Cutaneous Microvascular Function in Hypertensive Men and Women
Authors: Craighead Daniel , Kenney W Larry , Alexander Lacy
Published: June 2021

Hypertension is a chronic disease that induces microvascular dysfunction through upregulation of arginase and inducible nitric oxide synthase (iNOS) resulting in a loss of endothelial (e)NOS‐dependent vasodilation. Angiotensin converting enzyme inhibitors may have off‐target beneficial vascular effects on endothelial signaling and microvessel structure. We hypothesized that treatment with Lisinopril (>3 month) would improve cutaneous microvascular function in hypertensive adults. Four intradermal microdialysis fibers were placed in the forearm skin of 6 controlled hypertensive subjects (Lisinopril (LIS): MAP 94 mmHg), 9 hypertensive (HTN: MAP 111 mmHg) and 10 age matched normotensive (NTN: MAP 86 mmHg) subjects. Ringer's solution (control), 20mM L‐NAME (NOS inhibited), 0.1mM 1400w (iNOS inhibited), and 5mM BEC (arginase inhibited) were perfused through the fibers. Red cell flux was measured by laser‐Doppler flowmetry (LDF) during an acetylcholine (ACh) dose‐response (0.01mM‐100mM ACh). Cutaneous vascular conductance (CVC=LDF/MAP) was calculated and normalized to a percent of maximum (%CVCmax: 28mM SNP). SNP‐induced maximum vasodilation (CVCmax) was also assessed. There were no differences in ACh‐induced vasodilation between the LIS and NTN groups. LIS treatment improved %CVCmax responses to ACh compared to unmedicated HTN (all ACh doses 蠅 1mM p<0.05). Neither iNOS nor arginase inhibition altered the %CVCmax response to ACh in the LIS group (vs. control site). CVCmax was attenuated in HTN (1.57 ± 0.6 vs NTN 1.75 ± 0.6, p<0.05) and not improved in LIS (1.64 ± 0.5, p=0.33). These data suggest that pharmacotherapy for essential hypertension with Lisinopril improves eNOS‐dependent but not SNP‐induced maximal vasodilation in hypertensive adults.

NIH R01 HL089302
O2 Dependent Contributions of Prostaglandins (PGI2 PGE2) to Exercise Hyperaemia in Young (Y) and Older (O) Men
Authors: Junejo Rehan , Ray Clare , Marshall Janice
Published: June 2021

We have shown that breathing 40% O2 and cyclooxygenase (COX) inhibition attenuate exercise hyperaemia to similar extents in Y and O men. PGI2 synthesis is generally attributed to endothelium and PGE2, to skeletal muscle fibres. Thus, in recreationally active Y (18‐25 yrs; n=12) and O (60‐76 yrs; n=12) males, we assayed venous efflux of PGs by ELISA following rhythmic and static handgrip contractions (60% MVC for 3 min, or exhaustion), during air breathing, 40%O2, and after COX blockade with aspirin (A) in a cross over design. In Y males, forearm vascular conductance (FVC) increased from 0.06±0.01 to 0.56±0.06 conductance units (CU) after rhythmic contractions in P/air, but to only 0.44±0.04*, 0.44±0.04* and 0.45±0.03* CU in P/O2, A/air and A/O2 (*P < 0.05 vs P/air). Meanwhile, PGI2 increased from 18.0±6.1 to 349.8±61.7 pg/dl/min in P/air, but to 94.3±26.5*, 44.7±18.4* and 50.8±11.2* pg/dl/min in P/O2, A/air and A/O2, while PGE increased from 20.5±6.6 to 559.5±133.4 pg/dl/min in P/air, but to 189.8±33.8*, 165.4±52.9* and 170.3±43.0* pg/dl/min in P/O2, A/air and A/O2. Similarly in O males, FVC increased from 0.08±0.02 to 0.64±0.06 CU in P/air after rhythmic contraction, but to 0.44±0.06*, 0.46±0.05* and 0.52±0.06* CU in P/O2, A/air and A/O2. Meanwhile, PGI2 increased from 14.4±6.8 to 284.4±43.4 in P/air but to 84.6±25.9*, 52.8±20.3* and 74.6±38.1* pg/dl/min in P/O2, A/air and A/O2, while PGE increased from 16.6±6.6 to 781.6±192.5 in P/air, but to 368.8±188.8*, 357.9±106.4* and 382.3±131.0* pg/dl/min in P/O2, A/air and A/O2. Static contractions yielded similar data. Thus, we propose that PGI2 and PGE2 are released in O2‐dependent ways from endothelium and muscle fibres respectively and contribute to exercise hyperaemia in both Y and O men.
Exercise‐Induced Heat Stress Disrupts the Shear‐Dilatory Relationship in the Brachial Artery
Authors: Ives Stephen , Lefferts Wesley , Wharton Margret , Fehling Patricia , Smith Denise
Published: June 2021

Heat stress increases cardiovascular strain and is of particular concern in occupations, such as military personnel and firefighters, where individuals are required to perform strenuous work while wearing personal protective equipment (PPE). Sudden cardiac events are the leading cause of duty‐related death among firefighters, accounting for ~50% of fatalities each year. Increased cardiovascular strain may initiate an ischemic condition and heat stress may exacerbate this condition. Understanding the acute effects of exercise‐induced heat stress (EIHS) on vascular reactivity may provide insight into mechanisms precipitating acute coronary events in firefighters.

METHODS

Using a balanced crossover design, 12 young healthy males performed 100 minutes of moderate‐intensity, intermittent exercise with and without EIHS (PPE or cooling vest, respectively). Measurements of FMD and reactive hyperemia (RH) were performed pre‐ and post‐exercise. RESULTS: During EIHS core temperature was significantly greater (38±0.1 vs. 37±0.1°C). Post‐exercise FMD tended to be suppressed in both conditions, but there were no statistical differences. RH was reduced following control but was increased following EIHS. Thus, normalizing FMD to the shear stimulus (FMD/SSAUC) revealed a significant reduction in FMD following EIHS only (Pre: 0.22±0.1 and 0.13 ±0.0 vs. post: 0.26±0.1 and 0.05±0.0 %FMD/SSAUC, control vs. EIHS, respectively).

CONCLUSION

Acute intermittent moderate‐intensity exercise tends to reduce large artery endothelial function, which was aggravated by heat stress, and this may contribute to increased risk of acute coronary events. Support: DHS# EMW‐2010‐FP‐01992.
Effect of Beetroot Juice Supplementation on Conduit Artery and Microvascular Hemodynamics During Small Muscle Mass Handgrip Exercise
Authors: Craig Jesse , Broxterman Ryan , Barstow Thomas
Published: June 2021

Beetroot juice (BR) supplementation has been shown to have positive ergogenic effects on blood flow (Q) as well as mitochondrial and muscle efficiency during large muscle mass aerobic exercise in animals and man.

Purpose

To determine if the previously demonstrated effects of BR translate to small muscle mass exercise.

Methods

Subjects completed constant power two‐handed handgrip tests at 40% peak power for 10 min under both BR and placebo (PLA) conditions. Mean arterial pressure (MAP) was measured using an automated cuff, Q was measured in the brachial artery via Doppler ultrasound, and muscle oxygenation characteristics were measured in the flexor digitorum superficialis (FDS) using near infrared spectroscopy.

Results

BR decreased resting MAP (76.3 ± 3.4 vs 84.1 ± 5.7 mmHg, p=0.014) but did not significantly lower exercising values. There were no significant differences in Q or vascular conductance between conditions. There were no significant differences between FDS deoxy‐[Hb+Mb] at rest or during the first minute of exercise, but after an initial overshoot PLA deoxy‐[Hb+Mb] decreased to a lower steady‐state value, while BR remained significantly elevated (49.3 ± 0.96 vs 43.8 ± 0.31 μM, p<0.013) until min 8. BR deoxy‐[Hb+Mb] decreased to values similar to PLA for min 8 through 10. FDS total‐[Hb+Mb] was not significantly different at rest or during exercise.

Conclusion

These preliminary findings suggest that BR may have no effect on Q during moderate intensity small muscle mass exercise. Contrary to contemporary findings in large muscle mass exercise, BR may lead to an increased deoxy‐[Hb+Mb] in small muscle mass exercise.
Effects of a High Fat Diet and Voluntary Wheel Running on Cidea and Cidec mRNA in Liver, Adipose Tissue, and Skeletal Muscle of Mice
Authors: Donohue Jacob , Couldwell Sandrine , Sosinsky Alexandra , Frulla Ashton , Robinson Allegra , Puri Vishwajeet , Reynolds Thomas
Published: June 2021

Cidea and Cidec play an important role in regulating triglyceride storage in liver and adipose tissue. It is not known if the Cidea and Cidec genes respond to a high fat diet (HFD) or exercise training, two interventions that alter lipid storage. The purpose of the present study was to determine the effect of a HFD and voluntary wheel running (WR) on Cidea and Cidec mRNA expression in liver, adipose tissue, and skeletal muscle of mice. A HFD promoted a significant increase in Cidea mRNA in adipose tissue and liver, but not in skeletal muscle. The increase in Cidea mRNA in adipose tissue and liver was prevented by WR. Unlike adipose tissue and liver, WR resulted in a significant increase in Cidea mRNA in skeletal muscle of mice fed a HFD. Cidec mRNA increased in response to a HFD in all tissues, a process that was prevented by WR. Epididymal white adipose tissue (EWAT) mass was significantly related (P<0.05) to Cide proteins expression in liver (Cidea, R=.536; Cidec, R=.590), adipose tissue (Cidea, R=.618), and skeletal muscle (Cidea, R=.699; Cidec, R=.546). Area under the insulin assisted glucose tolerance curve (IAGT‐AUC), an indicator of insulin resistance, was also significantly related (P<0.05) to Cide expression in liver (Cidea, R=.810; Cidec, R=.763), adipose tissue (Cidea, R=.495; Cidec, R=.535), and skeletal muscle (Cidec, R=.827). Our findings indicate that changes in Cide expression are associated with diet‐induced obesity and insulin resistance and that exercise training may ameliorate diet‐induced obesity and preserve insulin action, in part, by preventing an increase Cide expression
Repeated Binge‐Like Alcohol Intoxication Increases Mesenteric Lymphatic Permeability Disrupting Lymphatic‐Perilymphatic Adipose Tissue Crosstalk
Authors: Souza‐Smith Flavia , Molina Patricia
Published: June 2021

Repeated binge‐like alcohol intoxication (RBAI) episodes induce whole‐body insulin resistance, possibly increasing the risk for metabolic syndrome and type 2 diabetes. Our previous studies showed that acute alcohol intoxication increases mesenteric lymphatic permeability and circulating adiponectin levels. We hypothesize that lymphatic hyperpermeability resulting from RBAI promotes perilymphatic adipose tissue (PLAT) inflammation and dysregulates insulin signaling. Chronically instrumented (intragastric catheter) male Sprague‐Dawley rats received an intragastric bolus of 2.5 g/kg/day of alcohol (12.5% alcohol w/v) or isocaloric dextrose in Vanilla Ensure (116 kcal/kg/day) for 3 days. Mesenteric lymphatic permeability, PLAT inflammatory milieu, and insulin (0.25 U/kg)‐stimulated AKT phosphorylation were determined following alcohol/dextrose administration. RBAI resulted in greater leak of Evans Blue into PLAT, higher tissue expression of inflammatory cytokines (IL1α, IL1β, IL6, and GM‐CSF), and attenuation of insulin‐stimulated AKT phosphorylation (Ser473) compared to dextrose‐treated control animals. These results suggest that RBAI‐induced mesenteric lymphatic hyperpermeability promotes PLAT inflammatory milieu, and impairs insulin signaling in PLAT. We speculate that increased gut‐derived toxins directly mediate these early alterations, reflecting lymphatic/PLAT crosstalk, which we predict disrupts metabolic regulation and contributes to increased risk for systemic alcohol‐induced insulin resistance. Supported by NIH F32AA021049 and LSUHSC Department of Physiology.
Adipose tissue p50α/p55α abundance may drive acute high fat diet induced insulin resistance
Authors: Clayton Zachary , Hetrick Byron , McCurdy Carrie
Published: June 2021

Insulin resistance (IR), a metabolic feature of obesity, drives a number of diseases. Recently, the focus of obesity research has been adipocyte‐immune cell crosstalk and its influence on systemic insulin sensitivity (IS). Currently, obesity induced IR is thought to arise secondary to inflammation due to infiltration of adipose tissue (AT) with pro‐inflammatory immune cells. Obesity is a progressive disease, and metabolic alterations in AT following acute nutrient excess, prior to development of obesity, are not well understood. Phosphotidylinositol 3‐kinase (PI3K) has been proposed as the integration point between immune cell infiltration and adipocyte insulin action. Global knockdown of pik3r1 (gene encoding regulatory subunits (p85α/p55α/p50α) of PI3K) resulted in enhanced adipocyte and systemic IS, with parallel decrease in AT macrophage infiltration despite marked obesity. Here we demonstrate that acute (3d) high fat diet (HFD) significantly increases bodyweight due to a significant increase in food intake in wild type mice. Body composition analysis by NMR indicates a significant increase in percent body fat with a concomitant decrease in lean mass. Energy expenditure measured by indirect calorimetry was also significantly decreased after 3d HFD. Importantly, both systemic IS measured by oral glucose challenge and insulin‐stimulated adipocyte 2‐deoxyglucose uptake was significantly reduced. No difference was found in adipocyte chemokine or cytokine secretion. We propose that reduction in adipocyte IS and subsequent systemic IS, is due to an increase in AT p50α/p55α abundance and occurs prior to initiation of a pro‐inflammatory response. Identifying primary steps in development of IR may guide treatments for obesity related metabolic diseases.

NIH DK095926 (CEM)
Proteomic Analysis of the Late Effects of Intrauterine Undernutrition on Adipose Tissue of Rats
Authors: Souza Adriana , Pedroso Amanda , Tashima Alexandre , Ribeiro Eliane
Published: June 2021

Poor nutrition during early development may program adulthood diseases such as obesity. This study performed proteomic analysis of the retroperitoneal adipose tissue of adult male and female rats born from dams either fed ad libitum or restricted to 50% of ad lib intake during pregnancy. Tissue proteins were analyzed by 2‐D gel electrophoresis and Maldi‐Tof/Tof – MS. Mascot server was used to search Swiss‐Prot.

Results: The restricted female progeny developed obesity and had 18 down‐regulated and 4 up‐regulated proteins. The restricted males did not develop obesity but still had 12 down‐regulated and 17 up‐regulated proteins. Although the majority of the differentially expressed proteins are related to metabolic processes and have catalytic activity , gender differences were evident. For example, cytoplasmic malate dehydrogenase was up‐regulated only in males while glyceraldehyde‐3‐phosphate dehydrogenase was up‐regulated only in females.

Conclusion

Female but not male rats develop into obese adults when undernourished intrauterus. Important metabolic processes in adipose tissue are programmed by intrauterine undernutrition with different phenotypes between male and female adult rats. These may help explain the gender dimorphism in the obesogenic response.

Funding: FAPESP, CNPq, Capes: Brazil
GLP1R Regualtion of Gap Junction Coupling in the Islet of Langerhans
Authors: Walter Rachelle , Farnsworth Nikki , Benninger Richard
Published: June 2021

Pancreatic islets regulate glucose homeostasis through insulin secretion. β‐cells are connected by gap junctions, which regulate depolarization, calcium signaling and insulin secretion. In diabetes, pro‐inflammatory cytokines contribute to β‐cell mass depletion and dysfunction. Low levels decrease Gap Junction Coupling (GJC) in the islet, disrupting calcium signaling and insulin secretion dynamics. Cyclic adenosine monophosphate (cAMP), elevated by a Type 2 Diabetes treatment called Exendin‐4, has been shown to increase GJC. Increased cAMP acts via protein kinase A (PKA) and exchange protein activated by cAMP 2 (Epac2) to regulate GJC in other systems; however, this has not been shown in pancreatic islets. We hypothesized Exendin‐4 can overcome cytokine induced decreases in GJC through PKA and Epac2 dependent mechanisms.

To test this, isolated mouse islets were cultured overnight with a cocktail of pro‐inflammatory cytokines, 10nM Exendin‐4 and activators and inhibitors of PKA and EPAC2. Changes in GJC were quantified with Fluorescent Recovery After Photo‐bleaching, and calcium signaling was measured with calcium imaging of Fluo‐4.

Cytokine+Exendin‐4 increased GJC compared to the cytokine treatment alone. PKA inhibitor decreased the Exendin‐4 recovery and had higher GJC than the cytokine treatment. PKA activator also recovered cytokine induced GJC decreases. Epac2 had little effect on recovery.

These results suggest that Exendin‐4 is acting through PKA to overcome cytokine induced decreases in GJC while EPAC2 has minimal effect. Future work is needed to determine how PKA increases GJC via Cx36 in this system. This work will be important for targeting decreased GJC in pre‐diabetic patients.
MiR‐150 Expression Significantly Reduced in the Gut After Alcohol and Burn Injury
Authors: Morris Niya , Li Xiaoling , Hammer Adam , Cannon Abigail , Earley Zachary , Choudhry Mashkoor
Published: June 2021

Alcohol is a major contributor of post burn pathology. Many of the adverse effects associated with alcohol and burn injury are linked to gut barrier disruption. The gut is the major reservoir of bacteria within the body; disruption of the gut barrier could result in bacterial translocation into extra‐intestinal sites. Recent studies demonstrated that alcohol and burn injury increases KC, IL‐6 and IL‐18 levels; which in turn could contribute to increased intestinal permeability. The mechanism underlying increased gut inflammation following alcohol and burn injury remains unknown. MicroRNAs (miR) are small noncoding RNAs that regulate gene expression. MiR‐150 is predicted to target IL‐18. Altered expression of miR‐150 could contribute to elevated IL‐18 and impaired gut permeability. Therefore, we examined miR‐150 and IL‐18 expression in small intestine epithelial cells (IEC) following alcohol and burn injury. Male mice (~25g) were gavaged with alcohol (~3 g/kg) or water. Four hours after the gavage, mice underwent a ~12.5% total body surface full thickness burn. One day following the injury, mice were euthanized; the small intestine was harvested and processed for IEC isolation. MiR‐150 expression was assessed by qRT‐PCR. IL‐18 levels were assessed by qRT‐PCR and ELISA. MiR‐150 expression was decreased by ~3‐fold following alcohol and burn injury. IL‐18 mRNA and protein levels were significantly increased following injury. The present study suggests that alcohol and burn injury reduces miR‐150 expression which contributes to elevated IL‐18. Studies are in progress examining if overexpression of miR‐150 reduces IL‐18 levels and improves gut barrier integrity. (R01AA015731, R01AA015731‐08S1, T32AA013527‐12)
Urinary Level of D‐2‐Hydroxyglutarate During Inflammation Predicts Severity of Colitis‐Associated Tumorigenesis in Mice
Authors: Theiss Arianne , Han Jie , Holm Janette , Wang Xuan , Forni Sabrina , Cheng Yulan , Genta Robert , Meltzer Stephen , Sweetman Lawrence
Published: June 2021

Although the association between inflammatory bowel diseases (IBD) and an increased risk of developing colorectal cancer is well‐established, the pathogenesis of colitis‐associated cancer is poorly understood. Quantitative metabolic profiling is a promising method to detect molecular pathways involved in disease progression from colitis to cancer. Wild‐type C57BL/6 male mice were i.p. injected with 7.6 mg/kg azoxymethane followed by 2 cycles of 3% dextran sodium sulfate (DSS; 1 week DSS and 3 weeks recovery). Urine was serially collected at baseline, the end of the first cycle of DSS (colitis stage), and the day before sacrifice (polyp stage). Urinary metabolites were analyzed using gas chromatography‐mass spectrometry. Excised colons were observed for polyp number and embedded for dysplasia scoring or scraped for mucosal extracts. Findings in the mouse model were corroborated using human mucosal biopsies of IBD and matched IBD‐associated cancer. Six urinary metabolites were significantly altered during colitis and returned to baseline at the polyp stage. Of these, urinary D‐2‐hydroxyglutarate (D‐2‐HG) during colitis, an emerging oncometabolite, directly correlated with polyp number and dysplasia score. Colonic expression of D‐2‐hydroxyglutatric dehydrogenase, an enzyme that eliminates D‐2‐HG, was decreased during DSS colitis and human IBD but restored at the polyp stage and in IBD cancer. These results suggest that elevated D‐2‐HG during colitis may play a role in progression to cancer.
Stromal Loss of mRNA‐Binding Protein IMP1 promotes a Pro‐Tumorigenic Colon Tumor Microenvironment in vivo
Authors: Chatterji Priya , Hamilton Kathryn , Lundsmith Emma , Andreas Sarah , Rustgi Anil
Published: June 2021

Background

Insulin‐like growth factor II mRNA‐binding protein 1 (IMP1) is an oncofetal protein that modulates mRNA stabilization, localization, and translation. Recent studies suggest that IMP1 may play a role in colonic mesenchymal stem cells during wound healing. We have demonstrated an oncogenic role for IMP1 in colorectal cancer (CRC) cells; however, it is not known how non‐epithelial IMP1 contributes to CRC in vivo.

Methods: Using the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis‐associated CRC, we evaluated tumorigenesis in mice with mesenchymal‐specific Imp1loss (Dermo1Cre;Imp1floxed mice;Imp1ΔMes). Furthermore, isolated mesenchyme from tumor‐bearing mice was evaluated for changes in growth factors and cytokines via antibody array.

Results: We demonstrate that Imp1 ΔMesmice treated with AOM/DSS exhibit a significant increase in tumor number, size, and load compared to controls. Isolated mesenchmye from AOM/DSS‐ treated Imp1 ΔMes mice show, among other things, a significant increase in hepatocyte growth factor (HGF) expression, suggesting that IMP1 loss favors a pro‐tumorigenic environment, potentially via up‐regulation of the HGF pathway.

Conclusions

Our results thus far indicate a novel, protective role for stromal IMP1 in colon tumorigenesis, likely via negative regulation of HGF signaling in the setting of colitis‐associated CRC. Future studies will determine the direct mechanisms for IMP1 regulation of the HGF pathway and may define a previously unknown, therapeutically tractable mechanism of stromal:epithelial crosstalk in CRC.

Funding : NIH RO1 DK056645 (AKR), NIH K01 DK100485 (KEH) HHMI Medical Fellowship (ETL), NIH UO1 DK085551 (NIDDK/NIAID Intestinal Stem Cell Consortium)
The X‐Ray Crystal Structure of a Mutant Glycerol Dehydrogenase from Bacillus coagulans with Acquired Lactate Dehydrogenase Activity
Authors: Jones Grace , Hurlbert Jason
Published: June 2021

Successful metabolic evolution of an industrial biocatalyst depends on accumulation of desired genetic changes that enhance product titer, yield and productivity. During the development of a strain of Bacillus coagulans for production of D‐lactic acid, a glycerol dehydrogenase (GDH) evolved to catalyze reduction of pyruvic acid to D‐lactic acid (D‐LDH) by acquisition of two mutations, D121N and F245S. The native GDH oxidized glycerol and a variety of diols, but displayed very low D‐LDH activity. The evolved enzyme has a 10‐fold lower level of glycerol oxidation activity and a 15‐fold higher D‐LDH activity than the wild type enzyme. In order to explain these kinetic data, we have determined the x‐ray crystallographic structure of B. coagulans GDH D121N/F245S. The protein crystallized within 48 hours in 0.2M ammonium citrate dibasic, pH 4.5 with 10% PEG3350 at room temperature. The crystals belonged to the orthorhombic space group C2221 and had unit cell parameters of 211 Å, 211 Å and 149 Å with α=β=γ=90°. Diffraction data were collected to 2.5 Å resolution on beamline 22‐ID at the Advanced Photon Source at Argonne National Laboratory, and an initial model was created using the automated molecular replacement software MrBUMP. Multiple rounds of model building and refinement were performed using Coot and Refmac, respectively. Comparison of the mutant protein to a homologous protein from Geobacillus stearothermophilus has revealed that the acquired mutations in the B. coagulans GDH D121N/F245S protein significantly alter the geometry of the active site. The active site of the double mutant enzyme is better able to bind carboxyl functionalities in substrates in addition to having a decreased affinity for the hydroxyl groups of the original substrate diols.
Identification of A Novel Inhibitor of 5‐Lipoxygenase
Authors: Subramanian Preeti , Mendez Emily , Becerra S. Patricia
Published: June 2021

Arachidonate 5‐lipoxygenase (5‐LOX) is a member of the lipoxygenase family of enzymes that plays a key role in arachidonic acid metabolism. Arachidonic acid, upon oxygenation by 5‐LOX, forms 5‐hydroperoxyeicosatetraenoic acid (5‐HPETE), which is further converted into proinflammatory leukotrienes such as LTB4 that can have detrimental biological effects. The PNPLA2 gene codes for PEDF‐R, a lipase involved in cell survival and lipid metabolism, found in the RPE and retina. We have identified human PEDF‐R peptide regions E5b (I193–L232) and P1 (T210‐L249) that efficiently protected human retinal pigment epithelial ARPE‐19 and pig primary RPE cells from oxidative stress. We investigated whether binding and inhibiting 5‐LOX by the PEDF‐R peptides are critical to protect RPE cells during oxidative stress conditions. Peptide affinity chromatography showed that human recombinant 5‐LOX binds to immobilized P1. The binding decreased with increasing NaCl concentrations, implying an ionic nature for the interaction. Moreover, full length PEDF‐R bound 5‐LOX in a dose‐response fashion. Interestingly, PNPLA2 expression decreased with increasing oxidative stress with no effect on 5‐LOX expression. Peptides E5b and P1 bound and inhibited the activity of soybean lipoxygenase‐V (LOX‐V) in vitro. The LOX‐V enzymatic inhibition was attenuated when PEDF‐R peptides were captured specifically with a P1 binding protein, fluorescein‐conjugated PEDF (Fl‐PEDF). Moreover, measurement of the 5‐LOX product LTB4 showed that P1 inhibited the formation of LTB4 in ARPE‐19 cells under oxidative stress. Our results support that PEDF‐R is a novel inhibitor of 5‐LOX and PEDF‐R derived peptides, i.e., P1, have therapeutic potential in diseases in which oxidative stress plays a role, such as age‐related macular degeneration. Supported by NIH‐IRP.
Evaluating the Efficacy of a Video Dissection Guide Tailored to the Louisiana State University Health Sciences Center Gross Anatomy Curricula
Authors: Campeau Lisa , Mussell Jason
Published: June 2021

In an effort to close the educational gap caused by low instructor to student ratios in gross anatomy labs, a new video dissector based on the required written text used at Louisiana State University (LSU), Grant's Dissector 15th edition, is being created by the gross anatomy faculty. As currently available video guides are more demonstrative and less instructional, our goal is easing the perfunctory dissection burden by describing dissection techniques and characteristic structures so critical dissection of historically difficult‐to‐identify structures can be carried out more quickly with less dissection damage. It is hypothesized that these LSU‐specific videos will be of greater aid to students in identifying structures than guides already in existence or than written text alone. To test this hypothesis, the class will be divided into 3 groups: written dissector only, traditional anatomy video specifically Acland's Video Atlas of Human Anatomy, and LSU video dissection guide. Accuracy of structure identification will be assessed by a simple questionnaire administered to all 3 groups. Either the students will identify a given structure or it will be located by the faculty if they cannot. Also, video group assignation will be compared to gross anatomy practical exam scores for each dissection block. It is hypothesized that assignment to the LSU video dissection guide will result in higher practical exam scores than either traditional anatomy video or written dissector alone.

Source of Support: Dept of Cell Biology and Anatomy, Louisiana State University Health Sciences New Orleans, LA