bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subfornical Organ Neurons Integrate Cholecystokinin and Angiotensin II Signals
Authors: Cancelliere Nicole Mariantonia , Ferguson Alastair V 
Published: November 2023

The subfornical organ (SFO) is a sensory circumventricular organ implicated in the regulation of energy and fluid balance. SFO neurons have been shown to express receptors for and respond to both cholecystokinin (CCK) and angiotensin II (ANG)‐hormones traditionally classified as energy and fluid balance signals, respectively. The purpose of this study was to investigate whether neurons that respond to CCK could also respond to ANG. SFO neurons were micro‐dissected from Sprague‐Dawley rats (21–28 day), dissociated into individual neurons, and incubated at 5mM glucose. Using the perforated patch clamp electrophysiology technique, effects on membrane potential were assessed after isolated SFO neurons were bath applied with CCK‐8S [10nM] followed by ANG II [10nM], allowing for successful washout of the hormone and recovery of the neuron (if responsive) between applications. Our results show that 25% of SFO neurons tested respond to both CCK and ANG directly, causing a depolarization of the membrane potential in response to bath application of both peptides (CCK= + 6.5 mV ± 1.7 mV; ANG= + 7.0 mV ± 1.7 mV; n=2/8), and 38% of neurons tested did not respond to either CCK or ANG (CCK= + 0.2 mV ± 1.4 mV; ANG= + 0.04 mV ± 0.03 mV; n=3/8). A separate population of neurons (38%) did not respond to CCK, and depolarized after ANG application (CCK= − 0.4 mV ± 0.5 mV; ANG= + 9.2 mV ± 4.5 mV; n=3/8). These preliminary data demonstrate that there is a subpopulation of SFO neurons which respond to both CCK and ANG, suggesting that single SFO neurons are able to integrate both of these traditionally classified energy and fluid balance signals.Support or Funding InformationThis work was supported by the Canadian Institutes of Health Research (CIHR)
Cholinergic Stimulation of Immune Cells with Nicotine Induces Renal Inflammation and Pre‐mature Development of Hypertension in Young SHR
Authors: Harwani Sailesh , Chapleau Mark , Abboud Francois 
Published: November 2023

We have shown that nicotinic cholinergic stimulation of immune cells in vitro and in vivo exaggerates pro‐inflammatory innate immune responses and increases proliferation of a CD161a+/CD68+ macrophage population in isolated bone marrow cells and splenocytes in young pre‐hypertensive Spontaneously Hypertensive Rat (SHR). In vivo administration of nicotine also led to renal infiltration of macrophages within 24 hours, without any increase in arterial pressure and independent of renal sympathetic innervation. We also found that 2 week subcutaneous infusion of nicotine not only leads to continued CD161a+/CD68+ macrophage infiltration, but also the development of premature hypertension in young SHR. We hypothesized 1) that the nicotine induced CD161a+/CD68+ macrophage infiltration is caused by increased renal expression of Vascular Cell Adhesion Molecule‐1 (VCAM‐1) and 2) this renal macrophage infiltration results in renal damage/toxicity. Nicotine (15mg/kg/day) was infused subcutaneously for 2 weeks. Systolic blood pressures (SBP) were measured twice weekly by tail cuff and urine, serum, and kidney tissue were collected at the end of nicotine infusion. Tissues and fluid were analyzed by luminex assay. Renal lysates were also analyzed by Western blot for the presence of VCAM‐1. Nicotine infusion led to the pre‐mature development of hypertension in SHR (153.2 ± 3 mmHg vs 138.6 ± 3 mmHg in saline infused SHR, respectively, n=10, p <0.001). There was no significant increase in SBP in control Wistar Kyoto (WKY) rats infused with nicotine, compared to saline. There was a greater infiltration of the kidney with CD161a+/CD68+ macrophages with nicotine infusion (16±2 cells per 400× field), compared to saline infusion (9±1 cells per 400× field) (n=6, p<0.001). In contrast, there was no significant renal macrophage infiltration in nicotine infused WKY, compared to saline (1±1 cells vs 1±1 cells per 400× field) (n=6, p>0.05). CD161a+/CD68+ renal macrophage infiltration in the young SHR was not associated with an increase in VCAM‐1 expression. However, nicotine induced renal CD161a+/CD68+ macrophage infiltration was associated with renal damage/toxicity, as measured by an increase in urinary Interleukin −18 (IL‐18) (283±42 pg/mL vs 101±10 pg/mL, n=4, p<0.001) and Monocyte Chemoattracatant Protein‐1 (MCP‐1) (241±22 pg/mL vs 145±23 pg/mL, n=4, p<0.05). We conclude that cholinergic stimulation with nicotine leads to renal infiltration with a CD161a+/CD68+ macrophage population that is not explained by renal expression of VCAM‐1, but is associated with renal damage, as well as the pre‐mature development of hypertension. Thus, renal damage from infiltration of this CD161a+/CD68+ macrophage population is one of the mechanisms involved in nicotine induced hypertension in the young pre‐hypertensive SHR.Support or Funding InformationNIH K08 HL11958NIH PPG HL014388
FEMALE RATS SHOW POST‐TRAUMATIC STRESS‐LIKE BEHAVIOR AND TNFα‐POSITIVE CARDIAC MAST CELL DEGRANULATION UPON EXPOSURE TO FEARED CUES 8 WEEKS AFTER CORONARY ISCHEMIA/REPERFUSION
Authors: Scrogin Karie , Binda Nkongho , Robbins Elizabeth , Lee Sharmaine , Vantrease Jaime , Samarel Allen 
Published: November 2023

Pre‐ and perimenopausal women have a higher mortality risk following myocardial infarction (MI) than men of the same age. Risk factors such as obesity, diabetes, smoking, and characteristics or treatment of MI do not fully account for this increased risk. However, MI can induce post‐traumatic stress disorder (PTSD), and post‐MI PTSD increases cardiovascular morbidity. Younger age is a risk factor for MI‐induced PTSD, and women who develop PTSD after MI have more severe symptoms. It is not clear how MI‐induced PTSD contributes to increased morbidity. However, stress is known to activate cardiac mast cells which can degranulated and release pro‐inflammatory cytokines. Here, we investigated effects of MI, sex and conditioned fear on cardiac mast cell degranulation in a rat model of coronary ischemia/reperfusion (I/R). Male and cycling female rats (in pro‐estrus) were exposed to delay fear conditioning (FC): 6 trials of tones (20 sec., 5 kHz, 90 dbl) terminated with footshock (0.5 sec, 0.3 mA), or pseudo conditioning (PC): 6 unpaired tones and footshocks. One week later, rats were randomized to coronary ischemia (45 min) and reperfusion, or sham surgery. Eight weeks later, pro‐estrus female and male FC, but not PC rats, showed initial freezing responses to presentations of the tone alone. Freezing was extinguished after 4 tone‐alone trials in all FC groups except female I/R rats which showed increased freezing in later tone‐alone trials (P<0.01). Female I/R rats subjected to FC also showed increased tone‐induced locomotion (reminiscent of escape seeking behavior) in early tone‐alone trials that was not displayed by any other group (P<0.05). Sixty minutes after the fourth tone‐alone trial, rats were euthanized and cardiac mast cell density and degranulation were determined through the dorsal base of the heart surrounding the pulmonary veins and intracardiac ganglia. Density of inflammatory cardiac mast cells did not differ between groups. However, female FC I/R rats showed more mast cell degranulation than their PC I/R control group (27.2±3.2 vs. 20.2±2.1%, P<0.05). Cardiac mast cell degranulation did not differ between any other FC group and their respective PC controls. Similar numbers of mast cells from female and male FC rats exposed to I/R showed TNF‐α expression (221.6 ± 11.3 vs 211.4 ± 12.5). Thus, I/R induces greater emotional reactivity in cycling female rats, which in turn stimulates more degranulation of mast cells containing pro‐inflammatory cytokines. These results suggest a possible link between PTSD and the increased mortality reported in pre‐ and perimenopausal women after MI.Support or Funding InformationSupported by American Heart Association Mid‐West Affiliate Grant‐in‐aid 14GRNT20380765
Impaired Autonomic Regulation in Posttraumatic Stress Disorder
Authors: Swiercz Adam P , Park Jeanie , Hopkins Lauren , Moshfegh Cassandra , Wiaderkiewicz Jan , Young Colin N , Marvar Paul J 
Published: November 2023

Post‐traumatic stress disorder (PTSD) is associated with a significantly increased risk of cardiovascular disease (CVD) and accumulating clinical evidence suggests that autonomic dysregulation due to sympathetic overactivity and/or parasympathetic insufficiency may contribute to progression of CVD in PTSD. Therefore, utilizing a translational approach, we sought to examine autonomic function in both a clinical PTSD population as well as in an animal model of PTSD. In experimental studies, mice were instrumented with radiotelemetry probes to evaluate autonomic indices following Pavlovian fear conditioning. Fear conditioning involves the pairing of a conditioned stimulus (e.g. tone) paired with an aversive uconditioned stimulus (e.g. foot shock) that evokes a conditioned response (e.g. freezing). Twenty‐four hours following fear conditioning, spectral analysis of heart rate was performed and the low‐to high‐frequency ratio (LF:HF) was used as an index of sympathovagal balance. Fear conditioned animals displayed a significant increase in the LF:HF ratio relative to baseline (1.21 ± 0.46; p<0.05) indicating a shift in sympathovagal balance. Two weeks following fear conditioning, we assessed the contribution of sympathetic activity to the maintenance of blood pressure using the ganglionic blocker chlorisondamine (12ug/g i.p.). In response to sympathetic nervous system blockade, fear conditioned animals had a greater fall in blood pressure compared to control (Δ Systolic −71.7± 1.9 vs −39.8 ± 5.8 mmHg; p<0.05). Collectively, these results suggest impairments in autonomic control in an animal model of PTSD prior to the onset of CVD. Finally, these findings will be compared to an ongoing clinical study using a population of combat‐related PTSD (n=13) versus age‐matched controls without PTSD (n=9). Continuous elecrocardiography, beat‐to‐beat arterial blood pressure (BP) measurements, and 24‐hour ambulatory BP measurements have been collected at rest, during, and following mental stress. In an effort to translate our pre‐clinical results, these data will be analyzed for spectral analysis of heart rate variability, BP variability, and 24‐hour ambulatory BP patterns.Support or Funding InformationNIH R00 HL107675‐03 American Heart Association ‐ 15CSA24340001
Pigs Fed a Western Diet Develop Elevated Fasting Glucose and a Microbiome Analogous to Human Obesity
Authors: Hintze Korry , Cox Lindsay , Lefevre Michael , Isom S. Clay 
Published: November 2023

Previously we developed the Total Western Diet (TWD) for mice, a basal diet that emulates average American intakes for both macro and micronutrients. To extend the model, the TWD for pigs was formulated using the principle of nutrient density (mass of nutrient/kcal/day). As a model for a typical Western Diet, we selected the 50th percentile daily intake levels for macro and micronutrients from the National Health and Nutrition Examination Survey (NHANES). The relative contribution of total carbohydrates, fats, protein and micronutrients to total calories consumed at the NHANES 50th percentile was determined; these ratios were then used to formulate the pig TWD. The carbohydrate content of the TWD was further portioned into either simple or complex carbohydrates to match NHANES data. The fat portion of the TWD contains a diverse set of fat sources in order to match the dietary fatty acid profile reported in NHANES. To determine effects of the TWD on metabolism and the microbiome, ten female, mature pigs were assigned to either the TWD (n=5) or a control (CON), low‐fat commercial sow diet (n=5). Pigs were fed for 12 weeks and allowed ad lib access to diets. Blood and fecal samples were collected at baseline, 6 weeks and 12 weeks to determine effects of treatment on fasted glucose and taxonomy of the microbiome. Pigs fed the TWD gained significantly more weight, 92.8 ± 9.5 vs. 54.2 ± 11.2 kg (p < 0.001) and had an increased fasted blood glucose, 123.2 ± 13.7 vs 91.4 ± 7.9 mg/dl (p < 0.01) compared to control pigs. Principal coordinates analysis using unweighted Unifrac distance revealed that dietary treatment caused distinct microbiomes after 6 weeks of feeding. Moreover, pigs fed the TWD shifted from a Bacteroidetes to Firmicute dominated microbiome after 12 weeks on treatment (p < 0.01). The microbiome of pigs fed the CON diet remained Bacteroidetes dominant. These data suggest that the American diet pattern when fed to pigs is obesegenic, diabetogenic and causes shifts in the microbiome associated with obesity in humans.Support or Funding InformationUtah Sate University SPARC Grant Program
Soluble and Insoluble Fiber Differentially Impact Canine Fecal Microbiome and Circulating Metabolome
Authors: Jackson Matthew Irick , Jewell Dennis Edward 
Published: November 2023

Dietary fiber comprises polysaccharides having heterogeneous properties; a practical distinction in fiber types is soluble versus insoluble. All fiber types bypass digestion and absorption in the upper gastrointestinal tract to become available for metabolism by colon‐resident gut microbiota. We sought to gain insight into the impact of dietary fiber type on the gut microbiome and circulating metabolome in healthy canines. Two diets were formulated to contain approximately equal macronutrient makeup and total dietary fiber, but to differ in soluble fiber percentage (high soluble fiber = 3.9%; low soluble fiber = 0.8%) with balance provided by insoluble fiber. We compared the time resolved changes in fecal microbiome (weekly) and serum metabolome (monthly) dogs consuming these two levels of soluble fiber (n =15) for 13 weeks. Dogs were housed in pairs, provided daily group exercise in outdoor grassy runs and had access to natural light that varied with season. Health was monitored via clinical and physical indices. Blood and fecal collections were carried out under IACUC approved protocols. Endpoints included serum metabolome and fecal microbiome; multiple coinertial analysis was used to indicate the relative capacity of these ‘Omes to explain sample variation. Typical patterns of microbiome response encountered were: 1) Taxa changes similar in direction and magnitude for both Diets (increased Bifidobacterium, Blautia, Ruminococcus); 2) Taxa changes similar in direction but not magnitude (increased Bacteroides, Prevotella‐less so with high soluble fiber); 3) Taxa changes in opposite direction for each Diet (Lactobacillus). A machine learning genetic algorithm provided microbial taxa best defining diet group identity. Microbial‐derived metabolites were also altered in serum according to diet consumed. Circulating tryptophan metabolites (e.g. indolelactate, indoleacetate, indoleacrylate) were decreased by low soluble fiber but increased by high soluble fiber. Somewhat similarly, circulating p‐cresol sulfate, O‐methylcatechol sulfate and catechol sulfate were decreased by low, but not high soluble fiber consumption. In contrast, 4‐ethylphenylsulfate and its unsaturated congener 4‐vinylphenylsulfate were decreased by both diets. Serum metabolite changes were associated with gut microbial function via ecological RLQ‐4th Corner analysis on PICRUSt imputed metabolic potential. In summary, differential dietary soluble fiber levels produced changes in canine fecal microbiome and serum metabolome, and these changes are in part correlated through imputed microbial gene functional capacity.Support or Funding InformationBoth authors employed by, and study funded by, Hill's Pet Nutrition, Inc. Science and Technology Center, Topeka, KS 66601
Responses of Inflammatory Cytokines Following Moderate Intensity Walking Exercise in Overweight or Obese Individuals
Authors: Garza Gustavo Axel , Solis Leslie , Park Kyung‐Shin , Koh Yunsuk 
Published: November 2023

Chronic low‐grade inflammation is associated with physical inactivity as well as overweight and obesity. Levels of pro‐/anti‐inflammatory cytokines are affected as body fat changes. However, the response of these cytokines to short term moderate intensity exercise training is not yet known.PURPOSEThe current study investigated the effects of a 4‐week moderate intensity walking exercise on levels of C‐reactive protein (CRP), TNF‐alpha and adiponectin in overweight or obese individuals.METHODSTwenty seven (13 males and 14 females) physically inactive, overweight or obese (BMI > 25.0 kg/m2) individuals participated in the study. Each participant was randomly assigned to either exercise (EX, N=15) or control (CON, N=12) group. The exercise group performed moderate intensity walking exercise on a treadmill for 60 minutes at 70% of HRmax for 4 weeks (3 days/week), while the control group did not perform any physical activity. Overnight fasting blood samples were collected before and after the study period (PRE and Post) to analyze levels of pro‐/anti‐inflammatory cytokines such as C‐reactive protein (CRP), TNF‐α, and adiponectin. Two‐way repeated measures ANOVA and Tukey post hoc tests were used for data analysis.RESULTSCRP and adiponectin as well as body weight and body composition were not significantly altered following the 4‐week exercise intervention. However, there was a significant group*time interactions for TNF‐α. The follow‐up simple effects tests revealed that only the exercise group significantly lowered level of TNF‐α (EX : 55.18±2.57pg/mL, Mean±SE, ← 50.31±2.22 P=.0084 vs. CON : 55.50±2.88 ← 58.19±2.48, P=.25). EX Post is also significantly lower as compared to CON Post (P=.032). Values for CRP and Adiponectin were as follows; CRP (EX : 637.8±113.3ng/mL, ← 510.5±114.2 P=.060 vs. CON : 644.2±126.7 ← 654.1±127.7, P=.76) and Adiponectin (EX : 7.1±1.3 ug/mL, ← 7.2±1.3 P=.87 vs. CON : 9.8±1.5 ← 9.9±1.5, P=.83).CONCLUSIONAlthough there was no change in fat mass, 4 weeks of aerobic exercise was long enough to decrease levels of TNF‐α indicating physical activity independent from change in fat mass may affect level of inflammation . Results confirmed previous research that longer period of training accompanied with weight loss is required to induce changes in CRP and adiponectin.
Exercise‐induced protection against ventilator‐induced diaphragm atrophy is dependent upon increased diaphragmatic levels of manganese superoxide dismutase
Authors: Morton Aaron B , Smuder Ashley J , Wiggs Michael p , Hall Stephanie E , Wawrzyniak Nicholas R , Powers Scott K 
Published: November 2023

Mechanical ventilation (MV) is a life‐saving intervention for patients unable to sustain adequate pulmonary gas exchange on their own. Unfortunately, prolonged MV results in rapid atrophy and contractile dysfunction of the diaphragm, collectively termed ventilator‐induced diaphragm dysfunction (VIDD). Although the mechanisms responsible for VIDD remain elusive, it is established that increased mitochondrial production of reactive oxygen species is required for the development of VIDD. Notably, recent evidence reveals that endurance exercise training performed prior to MV is sufficient to protect the diaphragm against VIDD. While the mechanisms responsible for exercise‐induced prevention of VIDD remain unknown, evidence suggests that endurance exercise training may reduce diaphragm oxidative damage by elevating endogenous antioxidant enzyme expression. Therefore, these experiments tested the hypothesis that endurance exercise‐induced protection against VIDD is dependent upon increased diaphragmatic levels of the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD). Cause and effect was determined by administering an antisense oligonucleotide against MnSOD to prevent the exercise‐induced increase in diaphragmatic MnSOD. Our data confirm that exercise training performed prior to prolonged MV results in protection against VIDD. Importantly, prevention of the exercise‐induced increases in diaphragmatic MnSOD resulted in a loss of exercise‐mediated protection against MV‐induced diaphragm atrophy. In contrast, prevention of exercise‐induced increases in MnSOD did not result in a loss of exercise‐induced protection against MV‐induced diaphragm contractile dysfunction. Collectively, these results reveal that while increases in diaphragmatic levels of MnSOD contribute to exercise induced protection against VIDD, increased MnSOD is not the sole mechanism responsible for exercise‐induced protection against VIDD.Support or Funding InformationSupported by NIH R01 AR064189 awarded to SKP
14 days of bed rest induces a decline in satellite cell content and robust atrophy of skeletal muscle fibers in middle‐aged adults
Authors: Arentson‐Lantz Emily J , English Kirk L , Paddon‐Jones Doug J , Fry Christopher S 
Published: November 2023

We examined the effect of 14 days of bed rest on skeletal muscle satellite cell content and fiber type atrophy and in middle‐aged adults. Bed rest, a ground‐based space flight analog, induces robust atrophy of skeletal muscle, an effect that is exacerbated with increasing age. With the average age of astronauts increasing, we wanted to determine the mechanistic changes during bed rest on an understudied age‐cohort. Muscle biopsies were obtained from the vastus lateralis of healthy middle‐aged adults (n=7 [4M;3F]; age: 51.0±0.6 y) before (Pre‐BR) and after (Post‐BR) 14 days of bed rest. Immunohistochemical analyses were used to quantify myosin heavy chain (MyHC) isoform expression, cross‐sectional area (CSA), satellite cell and myonuclear content and capillary density. Peak oxygen consumption and body composition were measured Pre‐ and Post‐BR. Post‐BR MyHC Type 2a fiber percentage was reduced and mean CSA decreased in all fiber types (25% decrease; P<0.05). Satellite cell content was also reduced Post‐BR (41% decrease; P<0.05), while Pre‐BR Type 2 satellite cell frequency was correlated with the decline in leg lean mass as measured by DXA scan. A decline in capillary density was observed Post‐BR (25% decrease; P<0.05), and Post‐BR capillary density was associated with Post‐BR peak oxygen consumption. A subtle decline in myonuclear content occurred during bed rest. The rapid maladaptation of skeletal muscle to 14 days of mechanical unloading in middle‐aged adults emphasizes the need for appropriate counter measures to preserve muscle function in astronauts.Support or Funding InformationFunded by NSBRI grant NNJ08ZSA002N, NIH R01NR012973 (Paddon‐Jones), a Texas Space Grant Consortium Fellowship (English), NIH grant T32HD007539, and in part by the UTMB Claude D. Pepper Older Americans Independence Center NIH/NIA grant #P30 AG024832 and grant 1UL1RR029876‐01 from the National Center for Research Resources. The study was conducted with the support of UTMB's Institute for Translational Sciences, supported in part by a Clinical and Translational Science Award (UL1TR000071) from the National Center for Advancing Translational Sciences (NIH).