bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizations of the Right Ventricle in Ovalbumin/Sugen Model of Pulmonary Arterial Hypertension
Authors: Shults Nataliia V. , Wang Xinhong , Suzuki Yuichiro 
Published: November 2023

Right heart failure is the major cause of death among patients with pulmonary arterial hypertension (PAH). Thus, understanding the biology of the right ventricle (RV) should help developing new therapeutic strategies. Rats subjected to the injection of Sugen5416 (an inhibitors of vascular endothelial growth factor receptor) plus the ovalbumin immunization had increased pulmonary arterial pressure and severe pulmonary vascular remodeling. In this model, RVs of these PAH rats were hypertrophied and had severe cardiac fibrosis. No cardiac apoptosis was, however, detected. Metabolomics analysis revealed that oxidized glutathione, xanthine and uric acid had increased in PAH RVs, suggesting the production of reactive oxygen species by xanthine oxidase. PAH RVs were also found to have a 30‐fold lower level of a‐tocopherol nicotinate, consistent with oxidative stress decreasing antioxidants and also demonstrating for the first time that the nicotinate ester of vitamin E is endogenously expressed in the heart. Oxidative/nitrosative protein modifications including S‐glutathionylation, S‐nitrosylation and the nitrotyrosine formation, but not protein carbonylation, were found to be increased in RVs of rats with PAH. Mass spectrometry identified that S‐nitrosylated proteins include heat shock protein 90 and sarcoplasmic reticulum Ca2+‐ATPase. These results from the Ovalbumin/Sugen model of PAH revealed specific oxidative/nitrosative changes that are associated with RV failure.Support or Funding InformationNational Institutes of Health and National Natural Science Foundation of China
Apoptosis Signal‐regulating Kinase 1 is associated with NADPH oxidase 1‐dependent signaling
Authors: Choi Hyehun , Lamb Fred S 
Published: November 2023

Tumor necrosis factor‐α (TNFα) is pro‐inflammatory cytokine, linked to cardiovascular risk, including inflammatory vascular lesions. NADPH oxidase 1 (Nox1) is the primary source of superoxide activated by TNFα in vascular smooth muscle cells (VSMC). Apoptosis signal‐regulating kinase 1 (ASK1) is a MAPKKK that is activated by oxidation of associated thioredoxin. ASK1 in turn activtes JNK and p38 MAPKs and plays a role in vascular intimal hyperplasia. The relationship between ASK1 and Nox1‐mediated signaling in response to TNFα is poorly defined. We hypothesized that TNFα‐induced ASK1activation requires Nox1‐derived superoxide. We measured TNFα‐induced; endosomal superoxide (OxyBurst green), TNFα receptor (TNFR) endocytosis (TNFα‐biotin and FITC‐avidin), NF‐κB activation (luciferase reporter), and cell survival in VSMC. siRNA targeting ASK1 reduced TNFR endocytosis by 33%, TNFα‐mediated NF‐κB activation by 66 ± 0.7%, endosomal superoxide production by 80 ± 0.1%, and cell survival by 8.6 ± 2%. Immunoprecipitation‐western blot analysis was performed with ASK1 and the p22phox subunit of Nox1. ASK1 co‐immunoprecipitated with both Nox1 and its p22phox subunit. In Nox1 null cells, ASK1 protein expression was significantly higher than in wild type cells. Thus, ASK1 affects Nox1‐mediated inflammatory signaling in response to TNFα. These data provide a novel mechanism for Nox1‐dependent inflammatory effects in VSMC.Support or Funding InformationAmerican Heart Association (16SDG30610002)
The Effect of Hyperglycemia on the Expression of Stress Proteins of Endoplasmic Reticulum and Vascular Smooth Muscle Cell (VSMC) Migration from Normal Rats
Authors: Mejía‐Elizondo Rebeca , Hernández‐Méndez Aurelio , Chi‐Ahumada Erika , Espinosa‐Tanguma Ricardo 
Published: November 2023

Diabetes mellitus (DM) is a chronic degenerative disease characterized by high glucose levels on blood, which is the leading cause of micro and macrovascular changes observed in this disease.At cellular level DM promotes the misfolding of proteins in the endoplasmic reticulum (ER), a condition defined as ER stress. ER stress is characterized by an increase on the expression of some proteins, unfolded protein response (UPR), that promotes the decrease of the unfolded proteins translation and the increase in the expression of folding proteins or apoptosis when the damage is too great.Since research efforts on macrovascular disease secondary to DM are focused on pathological changes on endothelial cells, we are interested in evaluating the changes that occur at the level of VSMC as it has been demonstrated that they play a fundamental role in the pathophysiological process.On this research we obtained primary smooth muscle cell cultures from the thoracic aorta of normal rats by means of explant culture technique. The cells were characterized by immunofluorescence against muscle alpha‐actin and myosin and they were used on experiments were the cells were exposed to high glucose concentrations (15 mM) where we analyzed: proteins related to endoplasmic reticulum stress, expression of Ca+2 ATPase of the ER (SERCA2), cellular migration through the method of wound healing assay and the usage of the Boyden camera. Our results show that muscle cells exposed to 15 mM of glucose for 48 hours do not exhibit any changes on cell migration or in the expression of ATF‐6 and XBP‐1 proteins (analyzed by western blot), that we used as stress markers. However cells exposed for one week to 15 mM glucose showed an increase on cell migration as well as an increase on the expression of stress markers, which leads us to believe that these cells have a phenotype that is similar to those from diabetic rats. On the other hand the expression of SERCA2, analyzed by inmunoblot, seems to increase which suggests that the cells that are exposed to hyperglycemia over express SERCA2 to compensate for the damage on the ER being that the activity of this ATPase is fundamental to maintain a proper cell function. Overall these results show that the expression of smooth muscle cells to high glucose concentrations simulates the process that takes place in cells from diabetic animals, which allows us to have a study model of diabetes without inducing animals with drugs that produce severe side effects.Support or Funding InformationSupported by Conacyt to RET: 223350
Age‐dependent Changes in Aortic Valve and Mitral Valve Function in Fibrillin‐mutant Mice
Authors: Olson Mariah F , Verzosa Grace C , Roos Carolyn M , Zhang Bin , Hagler Michael A , Thalji Nassir M , Miller Jordan D 
Published: November 2023

The structural protein, fibrillin, is important for maintaining the strength and reliability of connective tissue found in blood vessels and heart valves. Mutations in fibrillin‐1 result in Marfan syndrome and leads to left‐sided heart valve regurgitation, aortic root dilatation and aortic aneurysm. While previous studies have focused predominantly on young fibrillin‐mutant mice, hemodynamically significant disease generally does not emerge in patients with fibrillin mutations until later in life. Thus, this study aims to evaluate molecular and functional changes in heart valves from aged fibrillin mutant mice. Wild‐type (+/+) or fibrillin mutant (+/C1037G) mice were fed normal chow diet for 3 months (young) or 14 months (old). Heart valve function, aortic dimensions, and cardiac function were evaluated using high‐resolution echocardiography, and gene expression was measured using qRT‐PCR. Consistent with previous reports, we found no evidence of mitral regurgitation in young mice of either genotype. In old +/C1037G mice, however, we did find evidence of mitral regurgitation (~5%). In contrast, aortic valve regurgitation was evident in a relatively large proportion of +/C1037G mice at both ages (~20% at both time points), and was not detected in any +/+ animals. Interestingly, left ventricular dimensions were not associated with the presence of mitral regurgitation, but aortic root dilatation was present in all mice with aortic valve regurgitation. To gain insight into the molecular underpinnings of these phenotypic changes, we measured expression of IL‐10 (an anti‐inflammatory gene) and Runx2 (a pro‐proliferative gene that drives matrix remodeling), both of which are genes previously implicated in the pathogenesis of mitral and aortic valve disease. In young animals, expression of IL‐10 in mitral valves tended to be increased in +/C1037G mice compared to +/+ littermates. With aging, IL‐10 increased substantially in mitral valves from in +/+ mice, and increased further in +/C1037G littermates. Similar trends were observed in expression of Runx2 in mitral valves from both genotypes of mice. While IL‐10 followed a similar pattern in aortic valve tissue from young and old mice of both genotypes, Runx2 was not significantly increased across any of the groups. Collectively, while our data suggest that there are substantial, potentially adaptive molecular changes that occur during development of regurgitant valvular diseases, aortic dilatation may be a key early factor driving development of aortic regurgitation. Future experimental work aimed at determining the relative mechanical and molecular contributions to development of heart valve regurgitation will be critical to development of novel therapeutic strategies in patients with syndromes secondary to fibrillin mutations.Support or Funding InformationNHLBI (R01‐HL111121)
Integrity of intestinal mucosa and serum concentration of some metabolites in pigs exposed to acute and chronic heat stress
Authors: Morales Adriana , Vásquez Nydia , Gómez Tania , Ibarra Nely , Bernal Hugo , Rodríguez Luis Edgar , Cervantes Miguel 
Published: November 2023

Heat stress (HS) is a condition that affects organisms when ambient temperature exceeds their thermoneutral (TN) zone. HS organisms try to increase their heat loss by reducing feed intake and changing blood irrigation to peripheral tissues instead of internal organs; other metabolic changes that can be analyzed by blood chemistry occur as well. A study was conducted during summer time in the Sonoran Desert, México, using the pig as a biological model to analyze the effect of acute and chronic HS on feed intake, blood chemistry, and intestinal epithelia integrity. Eighteen pigs (36 kg body weight) housed in individual cages inside a room with air conditioned equipment were used. Pigs were fed ad libitum a balanced diet and water was freely available all the time. Pigs were maintained under TN conditions (24 °C) during the first 10 d, at the end of which the air conditioned system was turned off, and pigs were exposed to natural diurnal fluctuations on ambient temperature, 28 °C (morning) and 38 °C (evening). Pigs were divided into three groups of six pigs each, one group was euthanized after 10 d under TN condition, the second group was euthanized on d2 of HS (acute HS, AHS), and the third group on d7 under HS (chronic, CHS). Immediately after euthanasia, the intestinal segments of duodenum, jejunum and ileum were collected. Blood samples were collected from each pig one hour before euthanasia; all pigs were fasted for 12 hours before sample collection. Feed intake in AHS and CHS pigs was reduced by about 38% (P<0.01) compared with TN. Acute HS pigs showed increased counts of lymphocytes, erythrocytes, and platelets (P<0.05). HS increased serum concentration of urea, BUN, uric acid, and triglycerides (P≤0.05); and reduced calcium concentration (P<0.05). Acute HS increased glucose, cholesterol, calcium, and phosphorous (P<0.05) compared to CHS. Histological analysis showed that duodenum villus height and crypt depth were reduced in CHS pigs (P<0.05) compared to TN conditions. The jejunal villus height and crypt depth were reduced (P<0.05) because of AHS and CHS, but the AHS damage in villus height was more severe. Also, ileal villus height and crypt depth were reduced (P<0.01) under CHS compared to TN. In general, the relation between villus height and crypt depth was lower in jejunum of AHS and higher in ileum of CHS pigs. In conclusion, these data show that HS significantly affects the intestinal epithelium and modifies the blood chemistry of pigs exposed to HS conditions.Support or Funding Information18 Convocatoria Interna, UABC.
G‐Hesperidin Supplementation Impairs the Beneficial Effects of Physical Exercise on the Body Composition, Biochemistry Profile and Oxidative Stress in Obese Rats
Authors: Priviero Fernanda B. M. , Gonçalves Tiago Tomazini , Lazaro Carolina Martins , De Mateo Fernanda Gonçalves , Campos Marcela Couto Brigagão , Claudino Mario Angelo , de Oliveira Carvalho Patrícia 
Published: November 2023

Obesity is a worldwide public health problem and its treatment includes limited dietary intake of saturated fats and physical activity. Obesity may be accompanied by metabolic changes and may cause several organic dysfunctions such as vascular dysfunctions due to reduced bioavailability of vasodilatory substances such as nitric oxide (NO). There are evidences that the reduced vasodilatory substances are related to increased reactive oxygen species (ROS), which leads to an oxidative stress. Additionally, the intake of antioxidant flavonoids has been largely proposed as a therapy for metabolic and cardiovascular disorders. Therefore, the aim of this work was to evaluate the effects of G‐ hesperidin supplementation (an antioxidant flavonoid) associated (or not) with physical exercise, on the body composition, lipidic metabolism, oxidative status and vascular function of obese rats. Obesity was induced by a hyperlipidic diet plus fructose given to 4 weeks‐old male Wistar rats, lasting 12 weeks. Physical training and/or antioxidant treatment started along with the 8th week of life and lasted 8 weeks further. It was evaluated the body compositon, lipid profile, oxidative status and mesenteric artery was removed for functional evaluation. After 12 weeks of hyperlipidic diet, rats presented higher body weight gain and body fat accumulation when compared to rats fed with standard chow. Treatment with G‐hesperidin did not change body weight gain and fat depot. Only physical training was able to reduce the body weight gain and fat accumulation. Furthermore, physical training modulated the oxidative status by increasing SOD activity, total antioxidant capacity and reducing lipid peroxidation. Treatment with G‐hesperidin did not affect oxidative status and when associated to physical training, decreased changes elicited by physical training. Hyperlipidic diet caused endothelial dysfunction, since the potency of acetylcholine was reduced in all groups fed with hyperlipidic diet. Treatment with G‐hesperidin and physical exercise did not alter the potency of acetylcholine. Potency of sodium nitroprusside was not changed by hyperlipidic diet whereas it was potentiated by physical training. Our results show that, in experimental model of obesity, physical exercise is able to modify body composition and biochemical parameters and improve general oxidative status of rats fed with hyperlipidic diet. Treatment with antioxidant flavonoid G‐hesperidin inhibited the benefit promoted by physical exercise.Support or Funding InformationFAPESP ‐ Fundação de Amparo à Pesquisa do Estado de São Paulo.
Regulation of microtubule dynamics by suppression of microtubule assembly kinetics
Authors: Gardner Melissa K. 
Published: November 2023

TPX2 is a widely conserved microtubule‐associated protein that is required for mitotic spindle formation and function. In this study, we explored a potential role of TPX2 in regulating microtubule assembly kinetics, which could lead to downstream consequences for its effects on the parameters of microtubule dynamic instability. We found that TPX2 acts to suppress tubulin subunit off‐rates during microtubule assembly and disassembly. This allowed for the support of unprecedentedly slow rates of plus‐end microtubule growth, and to a dramatically reduced microtubule shortening rate. These changes in microtubule dynamics could be explained in computational simulations by a moderate increase in tubulin‐tubulin bond strength upon TPX2 association with the microtubule lattice, which in turn acts to reduce the departure rate of tubulin subunits from the microtubule ends. Further, our simulations naturally reproduced the suppression of catastrophe events in TPX2 as a direct result of the suppressed tubulin subunit off‐rates, likely due to increased retention of GTP‐tubulin subunits at the microtubule tip, which would lead to a larger GTP‐cap size. Thus, the direct suppression of tubulin subunit off‐rates by TPX2 during microtubule growth and shortening could provide a molecular mechanism to explain downstream changes in the parameters of microtubule dynamic instability in the presence of TPX2.Support or Funding InformationNIGMS, National Institutes of Health
Moderate Exerciwse Buffers Against Endocrine and Behavioral Consequences of Social and Environmental Stress
Authors: Watanasriyakul Withayapon , Cox Miranda , Woodbury Matthew , Colburn William , Wardwell Joshua , McNeal Neal , Grippo Angela J. 
Published: November 2023

Mild chronic environmental stress has been associated with emotional disturbances and negative physiological changes, such as hypothalamic‐pituitary‐adrenal (HPA) dysfunction. This dysfunction may lead to cardiovascular diseases as well as psychological disorders such as depression. Further, social and environmental stressors may have synergistic damaging effects. Socially isolated individuals who also experience chronic stress may be more susceptible to depression and HPA axis dysregulation. However, physical activity has been shown to combat the detrimental effects of stress; as elevated mood, decreased plasma glucose, and increased metabolism are beneficial outcomes of exercise. The current study examined the potential stress buffering effects of exercise against social isolation and chronic mild stress (CMS) using a prairie vole model. Prairie voles are a socially monogamous rodent species with a similar social structure to humans, including forming social bonds and living in family groups. Adult female prairie voles were separated from a same‐sex sibling and housed individually for 4 weeks. During the final 2 weeks of the isolation period, all animals underwent a CMS paradigm involving mild unpredictable stressors. Furthermore, during this 2‐week period, half of the voles were allowed access to a running wheel (vs. sedentary control). At the end of the isolation period, all animals underwent a forced swim test (FST) and an elevated plus maze (EPM), to assess depressive‐ and anxiety‐behaviors, respectively. In addition, plasma was collected for corticosterone (CORT) assay. A high variability of activity was noted in the Exercise group; therefore, animals were split into 3 subgroups: low (< 0.01 km/day), moderate (0.01 – 3.5 km/day), and high (> 3.5 km/day). Voles in the Exercise group displayed significantly lower levels of immobility during the FST, and spent more time in the open arms of the EPM compared to animals in the Sedentary group, indicative of reduced depressive‐ and anxiety‐behaviors, respectively. Voles in the Exercise group had significantly lower plasma CORT levels compared to voles in the Sedentary group. Interestingly, animals that moderately exercised displayed less immobility during the FST and had lower CORT levels compared to animals in the low and high exercise subgroups. The current study provides evidence that physical activity can have protective effects against social isolation as well as CMS. Moreover, targeting the optimum level of activity may have additional benefits, as animals with moderate exercise levels exhibited fewer behavioral and endocrine signs of depression and anxiety. Thus, moderate exercise may lead to superior behavioral and physiological outcomes as a buffer against social and environmental stressors in humans.Support or Funding InformationHL112350
Effects of Repeated Whole Body Heating on Sleep Architecture and Chronic Lower Back Pain
Authors: Smith Caroline J. , Collier Scott R. , Clarke Megan M. , Bouldin Erin L. , Uher David T. 
Published: November 2023

Chronic lower back pain (CLBP) is recognized as a critical public health problem, yet understanding and treating chronic pain conditions remains challenging. Poor sleep quality, including frequent sleep disturbances and prolonged sleep onset latency, are some of the most commonly reported complaints in individuals suffering chronic pain conditions. Our aim was to investigate the effects of repeated systematic, whole body heating (WBH) on sleep architecture and pain symptoms in individuals experiencing CLBP. Eight CLBP sufferers (49±7 yrs; 4 male, 4 female) with no known sleep disturbances completed baseline measures (BL) of sleep architecture utilizing an ambulatory sleep monitor (Sleep profiler™) and McGill Pain Questionnaires. Seven consecutive evenings of whole body heating (WBH) to a 0.8°C core temperature (Tcore) rise were conducted using a water perfused suit (48°C water). Two subjects completed a control protocol utilizing 34°C water, in randomized order and following a 3 month washout period. McGill pain questionnaires and ambulatory sleep measures were recorded each evening throughout the protocol, and 48 hours and 2 weeks following. Sleep architecture was assessed using stages N1, N2, N3 and REM. Pain scores were significantly reduced from 22 at BL to 14 after 5 day of WBH (p<0.05), and remained significantly lower for the remainder of the heating protocol and at the 48 hour follow‐up (p<0.05). Whilst pain was reduced following heating on all days, the initial 4 days and the 2‐week follow‐up were not significantly different from baseline. Sleep architecture showed a significant increase in REM from BL to day 1 of heating (1.20±0.3 Vs. 1.77±0.97 hrs; P=0.044), with all other days approaching significance. N3 approached significance following all heating days and at the 48h follow‐up (p>0.05). Stage N1 decreased from baseline to heating day 7 (0.40±0.23 Vs. 0.30 0.25 hrs, p=0.06), which was close to significance. Taken together these preliminary data suggest the potential for WBH as a non‐pharmacological method to improve sleep architecture and reduce pain symptoms in CLBP patients.Support or Funding InformationNone.