bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypothermia/Rewarming Disrupts Excitation‐Contraction Coupling in Cardiomyocytes
Authors: Schaible Niccole , Han Young Soo , Hoang Thuy , Arteaga Grace , Tvieta Torkjel , Gary Sieck 
Published: November 2023

Hypothermia/Rewarming (H/R) is poorly tolerated by the myocardium; however, the underlying intracellular basis of H/R‐induced cardiac injury remains elusive. We hypothesized that in cardiomyocytes, H/R leads to contractile dysfunction primarily through reduced Ca2+ sensitivity of the myofilaments. To test this hypothesis, isolated rat cardiomyocytes (13–15 cells from 6 rats per group) were electrically stimulated to evoke both cytosolic Ca2+ ([Ca2+]cyto) and contractile (sarcomere shortening) responses that were simultaneously measured using an IonOptix system. These measurements were subjected to the following temperature protocols: 1) hypothermia (15°C) followed by rewarming (35°C) or 2) time‐matched control (35°C). Contractile dysfunction after H/R was indicated by reduced shortening velocity and reduced extent of shortening of sarcomere length (SL) compared to time‐matched controls. Throughout hypothermia, basal [Ca2+]cyto increased and the duration of the evoked [Ca2+]cyto transients was prolonged. Phase‐loop plots of [Ca2+]cyto versus contraction in cells exposed to H/R indicate that Ca2+ sensitivity of contraction is reduced. Consistent with decreased Ca2+ sensitivity, we found that cardiac troponin I (cTnI) phosphorylation (measured by Western blot) increased after H/R. Our results support our overall hypothesis and suggest that reduced Ca2+ sensitivity and increased cTnI phosphorylation contributes to the altered excitation‐contraction coupling of cardiomyocytes following H/R. The clinical importance of our results brings focus to Ca2+ sensitivity as a plausible therapeutic target in treating patients exposed to accidental hypothermia.Support or Funding InformationNIH Grant 5T32HL10535 (NSS)
Organ‐Specific Dietary Fatty Acid Uptake in Cold‐Acclimated Humans
Authors: Blondin Denis P. , Noll Christophe , Tingelstad Hans C. , Labbé Sébastien M. , Phoenix Serge , Guérin Brigitte , Turcotte Eric E , Richard Denis , Haman François , Carpentier André C 
Published: November 2023

In rodents, brown adipose tissue (BAT) plays an important role in producing heat to defend against the cold and in taking up and dissipating energy from dietary fat (Bartelt et al. Nat Med, 2011). Recent investigations have shown that BAT in humans can also contribute to cold‐induced thermogenesis, but its role in dietary fat metabolism remains unclear. Dietary fat may be responsible for the postprandial accretion of triglycerides in lean tissues in individuals with pre‐diabetes (Labbé SM et al. Diabetes, 2012; Kunach M et al. Diabetes 2015), which impairs insulin sensitivity. Thus, the contribution of BAT to postprandial thermogenesis and dietary fat metabolism warrants further clarification. We used our well‐established positron emission tomography (PET) method with oral administration of 18F‐fluoro‐thiaheptadecanoic acid (18FTHA) and i.v. 11C‐acetate to determine the effect of BAT metabolic activation on organ‐specific dietary fatty acid uptake and partitioning in humans. Non‐cold acclimated healthy men took part in 2 metabolic studies before and after a 4‐week cold acclimation, previously shown to increase BAT oxidative capacity (Blondin et al. JCEM, 2014). A standard liquid meal containing the fatty acid PET tracer 18FTHA was given at the beginning, while 11C‐acetate was given at time 60 min during a 4‐h acute cold exposure. Preliminary results show that fractional dietary fatty acid uptake was greater in BAT, compared to muscle or subcutaneous white adipose tissue (0.31±0.009 min−1 vs. 0.009±0.003 min−1 and 0.018±0.008 min−1, respectively). However, increasing BAT oxidative capacity 2.9‐fold, through daily cold exposure over 4 weeks, did not increase BAT uptake of dietary fatty acids any further (0.31±0.009 min−1 vs. 0.021±0.006 min−1). Dietary fatty acid partitioning was significantly lower in BAT than in the liver and heart (0.37±0.12 SUVmean vs. 2.18±0.53 SUVmean and 1.01±0.30 SUVmean, respectively), but comparable to the levels seen in abdominal subcutaneous white adipose tissues (0.17.±0.05 SUVmean) and skeletal muscles (0.17.±0.04 SUVmean). These findings show that although cold‐stimulated BAT can contribute minimally to the clearance of dietary fatty acids in humans, dietary fatty acids are not the primary source of energy for the chronic cold acclimation‐induced increase in BAT oxidative metabolism.Support or Funding InformationThis research was supported by the Canadian Institutes of Health Research (OG‐3‐10‐2970‐AC) and the Natural Sciences and Engineering Research Council of Canada (RGPIN/326967‐2011).
Effect of Combination Ice and Compression Socks on Resting Calf Blood Flow in Trained Male Athletes
Authors: Hudock Michael J , Keller Joshua L , Crecelius Anne R 
Published: November 2023

Compression socks are common tools that are utilized in the realm of athletics. The purpose of the compression is to increase blood flow to the lower extremities, thereby increasing oxygen and energy sources needed for increased skeletal muscle function and/or recovery. Recently, a product has been marketed that combines the compression element and with cryotherapy, the goal being increased blood flow to the lower extremities while reducing inflammation post‐workout to quicken recovery. However, to our knowledge, direct measures of blood flow using this type of product have not been performed. Thus, this study looks at the effects of compression with and without cryotherapy on the blood flow of trained male athletes. The hypothesis was that compression would increase blood flow, ice would reduce it, and a combination of both would produce an intermediate result. Participants (n=5) were trained, having a body fat percentage that was not consider overweight and a minimum VO2max of 50 mL/kg/min. Those who met the criteria partook in four randomized trials during a single visit: control, compression, ice, and compression with ice. Calf blood flow (CBF; venous occlusion plethysmograph), skin temperature (temperature probe), heart rate (ECG), and blood pressure (sphygmomanometry) were monitored throughout each trial. As compared to control, compression alone decreased CBF (0.83±0.31 vs 1.66±0.33 ml/dl/min). Combined compression and ice resulted in similar CBF values (0.92±0.49 ml/dl/min) as the compression condition whereas the ice condition had minimal effect on CBF (1.39±0.48 ml/dl/min). Systemically, as per design, heart rate and blood pressure were relatively stable across all four trials. The present results indicate that compression, alone or in combination with ice do not increase CBF as measured by venous occlusion plethysmograph, at rest in trained males. Further, CBF was not attenuated during the ice alone condition. Taken together, the marketed effects of this product are questioned in the present experimental setup.Support or Funding InformationUniversity of Dayton Honors Program
Repeated Binge‐Like Alcohol Intoxication Dysregulates Mesenteric Perilymphatic Adipose Tissue Lipogenic Gene Expression
Authors: Souza‐Smith Flavia M. , Song Kejing , Molina Patricia E 
Published: November 2023

Visceral adipose tissue (VAT) inflammation is an important mediator of local insulin resistance (IR) and the consequent secretion of cytokines and adipokines may contribute to systemic IR. Repeated binge‐like alcohol intoxication (RBAI) episodes induce whole‐body IR and may potentially increase the risk for metabolic syndrome and type 2 diabetes. Previously we showed that RBAI promotes lymphatic vessels hyperpermeability leading to perilymphatic adipose tissue (PLAT – VAT isolated from blood vessels and lymphatic vessels) inflammatory milieu, impairs PLAT insulin signaling, and decreases circulating adiponectin levels. Based on a recognized shift from the traditional ‘glucocentric’ view of IR to a ‘lipocentric’ viewpoint we hypothesized that RBAI promotes impairment of PLAT lipid metabolism. Male Sprague‐Dawley rats received an intragastric bolus (intragastric catheter) 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. PLAT was isolated 30 min or 24 h after the last alcohol or dextrose administration. PLAT gene expression of markers for peroxisome proliferator–activated receptor (PPAR‐γ), Diacylglycerol O‐AcylTransferase 1 (DGAT1), Fatty Acid Synthase (FAS), and Hormone‐Sensitive Lipase (HSL) was determined by Real Time PCR. PLAT isolated from RBAI rats at 24 h had decreased PPAR‐γ, DGAT1, and FAS but no significant alteration in HSL expression compared to dextrose‐treated time‐matched control animals. These results may suggest that RBAI impairs critical steps involved in PLAT lipid synthesis, which may in turn contribute to suppressed circulating adiponectin levels previously observed. We speculate that gut‐derived toxins leaking from lymphatic vessels into PLAT directly mediate these early alterations, reflecting lymphatic/PLAT crosstalk contributing to alcohol‐induced metabolic dysregulation.Support or Funding InformationSupported by LSUHSC Department of Physiology.
Metformin Decreases Caveolin‐1 Expression in Differentiated Human Preadipocytes
Authors: Pfeifer Michaela A , Zhang Yuebo , Singh Prachi 
Published: November 2023

BackgroundWe have previously shown that increased caveolin‐1 expression impairs leptin‐dependent activation of cellular signaling pathways and may be responsible for attenuating leptin‐mediated increases in adiponectin expression in obesity. Further, insulin and leptin cellular signaling mechanisms are closely related such that molecules known to impair insulin signaling also alter leptin signaling. Conversely, known insulin‐sensitizing drugs may improve leptin‐signaling via reducing caveolin‐1 expression. We therefore tested the hypothesis that insulin‐sensitizing drugs decrease caveolin‐1 expression.MethodsWe used an in‐vitro approach to examine the effects of different insulin‐sensitizing drugs on caveolin‐1 expression. Human white preadipocytes were cultured to confluence and differentiated for 15 days. After differentiation, cells were then treated with increasing concentrations of pioglitazone (5–30 μM), troglitazone (10–30 μM), metformin (1–5 mM), or glimepiride (20–100 μM) for 24 hours. Caveolin‐1 protein expression was determined by Western blot analysis.ResultsAmong the insulin‐sensitizers used in our experiment, only treatment with increasing concentrations of metformin resulted in a dose‐dependent decease in caveolin‐1 expression (P =0.007). Treatment with increasing concentration of troglitazone upregulated caveolin‐1 expression (p=0.005), while pioglitazone (p=0.5020) and glimepiride (p=0.0965) had no effect of caveolin‐1 protein expression.ConclusionsMetformin reduces caveolin‐1 expression in differentiated human white preadipocytes. In obesity, caveolin‐1 expression is increased which may contribute to impaired leptin signaling. Therefore, metformin may be used to decrease caveolin‐1 expression and consequently improve leptin signaling and leptin‐dependent increases in adiponectin expression in obese individuals.Support or Funding InformationMichaela Pfeifer was supported by the American Physiological Society Stride Summer Undergraduate Research Fellowship NHLBI 1 R25 HL115473‐01; Prachi Singh was supported by the American Heart Association Scientist Development Grant 11SDG7260046.
TonEBP/NFAT5 inhibits adipocyte differentiation via modulation of mitotic clonal expansion during early phase of differentiation in 3T3‐L1 cells
Authors: Kim Soo Jin , Kim Taehee , Choi Han Na , Kim Hyun‐Woo , Park Jin Bong , Jeon Byeong Hwa , Lee Sang Do 
Published: November 2023

Obesity resulting from excessive accumulation of white adipose tissue is closely related to the chronic diseases such as diabetes, hyperlipidemia, and hypertension. White adipose mass is determined by the number and size of adipocytes. Preadipocyte like 3T3‐L1 cells undergo terminal differentiation manifested by formation of lipid droplets as well as adipocyte specific protein. TonEBP/NFAT5 belongs to the Rel family of transcription factors and plays important roles in the development and maintenance of kidney, immunity, arthritis, and cancer metastasis. Although the functions of TonEBP/NFAT5 during osteogenesis, chondrogenesis and myogenesis are reported recently, its role in the adipogenesis is not well known. In this study, we analyzed the role of TonEBP/NFAT5 in adipogenesis using 3T3‐L1 cells. TonEBP/NFAT5 expression was dramatically reduced during adipocyte differentiation of 3T3‐L1 cells. RNAi‐mediated knock down of TonEBP/NFAT5 facilitated adipogenesis. Whereas sustained expression of TonEBP/NFAT5 using adenovirus suppressed the formation of lipid droplet and the expression of FABP4, marker for terminally differentiated adipocytes. Also, TonEBP/NFAT5 inhibited the expression of PPARγ, master regulator of terminal adipocytes. TonEBP/NFAT5 suppressed adipogenesis in the early phase of the differentiation via modulation of Akt activity and mitotic clonal expansion. These results suggest that TonEBP/NFAT5 may be an important regulatory factor in the differentiation of adipocytes.Support or Funding InformationThis research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (NRF‐2013R1A1A2060736, NRF‐2014R1A6A1029617)
Early Improvements in Blood Lipid Profile and Vascular Alterations after Gastric Bypass Surgery Prior to Dramatic Weight Loss
Authors: Grogg Kristin , DeVallance Evan , Lemaster Kent , Hull Robert , Tabone Lawrence , Frisbee Jefferson , Chantler Paul 
Published: November 2023

With 6.6% of adults in the U.S. classified as morbidly obese, excess bodyweight is now the sixth most significant risk factor contributing to the overall burden of disease, emerging as one of the most serious public health concerns in the 21st century. Bariatric surgery has been shown to eliminate comorbid conditions associated with obesity. The aim of this study is to evaluate the effect of weight reduction following laparoscopic Roux‐en Y gastric bypass (RYGB) on remodeling and improvements in arterial function, in addition to immediate reversal of metabolic deviations as weight is lost.Patients that meet protocol inclusion criteria are invited to join the study during their 1 week pre‐operative clinical appointment. At this time patients are consented and instructed to lie supine for 10 minutes of quite relaxation. Patients then begin a sequence of non‐invasive examinations starting with a 12‐lead electrocardiogram, followed by an echocardiogram, carotid artery ultrasound, radial applanation tonometry, and endothelial function analysis using EndoPAT technology. Upon completion of the non‐invasive procedures a fasting blood sample is taken for analysis.Preliminary findings show that RYGB results in significant body weight reduction (pre: 131.8 ±5.6 to post: 125 ±5.2 kg) in morbidly obese subjects, along with reductions in BMI (pre: 45.2 ±2.3 to post: 42.9 ± 2.2) and waist circumference (pre: 122.1 ±5.0 to post: 111.9 ± 3.2 cm) at the 1‐week time point. Decrease in body size and weight was aided by a reduction in low‐density lipoprotein (pre: 127 ±6.2 to post: 113 ±4.5 mg/dL), as well as suggested decreases in glucose levels. Such changes can be associated with an improvement of the lipid and glucose metabolism. However, these results appear before subjects have lost a substantial amount of weight (one week post‐operative), suggesting that noteworthy cardiovascular improvements post‐RYGB are achieved prior to the hypothesized weight‐related change. In addition, a number of improvements to the cardiovascular system were also marked at the 1‐week time point. Estimated left ventricular end systolic pressure and direct measure of left ventricular end systolic volume (pre: 66 ±4 to post: 55 ±3 mmHg) declined post‐GBS with an array of additional markers supporting alterations in central systolic blood pressure and myocardial oxygen demand. The data suggests that vascular changes are happening in the early stages of recovery, prior to dramatic weight loss, thus suggesting vascular modifications are a result of an alternate surgical benefit.
Substance P (SubP) is Sufficient to Induce Frequency Plasticity in Neonatal Rat Isolated Brainstem‐spinal cord Preparations in the Absence of Hypoxia
Authors: Johnson Stephen Mark , Watters Jyoti J , Kunz Morgan K , Gardner Alyssa N 
Published: November 2023

The capacity for expressing respiratory neuroplasticity in neonates is poorly understood. One example is frequency plasticity, which is a persistent increase in breath frequency following a perturbation. Intermittent hypoxic exposures induce frequency plasticity in P14–P15 intact rats and in rhythmic medullary slices from neonatal P0–P7 mice. However, mutant mice lacking neurokinin‐1 receptors for which SubP is the endogenous ligand, do not express frequency plasticity following intermittent hypoxia, suggesting that SubP may be necessary for intermittent hypoxia‐induced frequency plasticity. Thus, we hypothesized that intermittent bath‐application of SubP is sufficient to induce frequency plasticity in isolated neonatal rat (P0–P3) brainstem‐spinal cord preparations. Intermittent SubP application (100 nM; 3 min on/7 min off; ×3 applications; n=13) to the entire brainstem‐spinal cord preparation increased burst frequency from 11.6 bursts/min (baseline) to 14.3 bursts/min (peak response). Burst frequency was still elevated to 12.7 and 12.1 bursts/min at 30 and 60 min following intermittent SubP exposure, indicating that acute SubP application induces a persistent effect. Respiratory burst frequency in time control experiments (n=13) was 11.5 bursts/min (baseline) and decreased by 25% over an equivalent time period. One bout of sustained SubP application (100 nM; 9 min; n=6) did not induce a persistent increase in respiratory burst frequency, suggesting a pattern sensitivity to this form of frequency plasticity. Likewise, intermittent SubP application at 10 (n=11) or 1.0 nM (n=7) did not induce frequency plasticity. Thus, intermittent SubP application is sufficient to induce frequency plasticity in a dose‐ and pattern‐dependent manner in the absence of hypoxia. Current studies are aimed at identifying if sexual dimorphisms exist, and understanding the role of inflammation in abrogating this form of frequency plasticity.Support or Funding InformationSupported by R01 HL111598, the Vilas Family Foundation and a private donation.
Cervical Spinal Stimulation and Respiratory Recovery after Upper Cervical Spinal Cord Injury
Authors: Dale Erica Arden , Zhong Hui , Edgerton V Reggie 
Published: November 2023

Over half of all spinal cord injuries (SCI) occur at the cervical level leading to disruption of bulbospinal pathways to respiratory motor neurons, respiratory muscle paralysis, and diminished breathing capacity. Of the 6,000 new cervical spinal injuries per year, ~20% will require mechanical ventilatory support. Even when mechanical ventilation is not necessary, breathing impairment greatly increases susceptibility to life‐threatening lung infections. In fact, the leading cause of morbidity and mortality in cervical SCI is respiratory impairment. In this study, rats were implanted with bilateral cervical (C4) stimulating electrodes and bilateral diaphragm EMG recording electrodes. Our previous data have shown that cervical spinal stimulation elicits evoked potentials and modulates diaphragm EMG (Dale et al., 2015). In this study, after obtaining baseline data, rats were given a C2 hemisection (C2HS). After recovery, rats were placed in either control (evoked potentials only; n=6) or Quipazine + stimulation (n=8) groups and were tested at 1, 2, and 4 weeks post‐C2HS. After eliciting spinal evoked potentials (SEP) of increasing intensity, rats received Quipazine (0.3mg/kg; IP), a broad‐spectrum serotonergic agonist, and diaphragm EMG was recorded for 20 min. Next, each rat received 3 bouts (interspersed with 5 min no stim) of cervical stimulation (bipolar) at increasing frequencies but at sub‐motor threshold intensity (5 min at 40Hz, 5min at 80Hz, and 5 min at 100Hz). Another set of SEPs was elicited upon stimulation completion. Our goal is to restore respiratory function in a rat model of cervical spinal injury by utilizing cervical spinal epidural electrical stimulation in combination with serotonergic agonists (e.g. quipazine). By inducing respiratory plasticity after synergistic modulation of the phrenic motor network (e.g. cervical epidural stimulation plus quipazine), we hypothesize that enhancing the contributions from spared motor neurons could be an avenue for preserving ventilatory capacity. This project may lead to novel therapies to extend and improve life for patients with cervical spinal cord injury by preserving breathing.Support or Funding InformationChristopher and Dana Reeve Foundation and NIH U01EB007615
Electrophysiological properties of abdominal muscle‐projecting expiratory motoneurons of rats
Authors: da Silva Melina P. , Moraes Davi J.A. , Bonagamba Leni G.H. , Varanda Wamberto A. , Machado Benedito H. 
Published: November 2023

Expiration is considered a passive process during resting breathing condition. There is a lack of information about the intrinsic electrophysiological properties of expiratory motoneurons and their possible changes in conditions in which the expiration becomes an active process, such as hypoxia. Considering that abdominal expiratory muscle activity depends on excitability of these motoneurons, here we aimed to characterize the electrophysiological properties of abdominal muscle‐projecting expiratory motoneurons combining retrograde tracer, immunofluorescence and whole cell patch clamp, in thoraco‐lumbar spinal cord slices from juvenile Wistar rats. Three different types of cholinergic expiratory motoneurons with similar capacitance were recorded: neurons with spontaneous action potentials whose resting potential hyperpolarizes (−65 ± 5 mV vs −69.7 ± 4 mV, n=9) and firing frequency decreases (8.5 ± 2 Hz vs 1.7 ± 1.3 Hz, n=9) after synaptic blockade. The passive properties of these motoneurons, such as input resistance and excitability, did not change after synaptic blockade (Ri = 0.16 ± 0.03 GΩ vs 0.13 ± 0.03 GΩ; Excitability = 40 ± 10 Hz vs 32 ± 11 Hz, n=9). The second group of motoneurons also exhibited spontaneous action potentials, but showed spike frequency adaptation, slowing or ceasing firing frequency during a maintained stimulus. Their membrane potential also hyperpolarized (−60 ± 1 mV vs −66 ± 1 mV, n=4) and firing frequency was abolished by synaptic blockade. On the other hand, no differences in the input resistance was observed (0.13 ± 0.01 GΩ vs 0.11 ± 0.01 GΩ, n=4). The third group did not show spontaneous action potential and synaptic blockade did not change membrane potential (−72.2 ± 2 mV vs −76 ± 3 mV, n=6) or input resistance (0.1 ± 0.04 GΩ vs 0.06 ± 0.02 GΩ, n=6). However, synaptic blockade decreased their intrinsic excitability. Overall, our data show that there are three different populations of abdominal muscle‐projecting expiratory motoneurons in rats, which may contribute to recruitment of expiratory muscles in different physiological and pathophysiological conditions.Support or Funding InformationFAPESP, CAPES, CNPQ