bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polyhexamethyleneguanidine phosphate‐induced cytotoxicity is mediated by endoplasmic reticulum stress
Authors: Jung Young-Suk , Kim Sou Hyun , Lee Seunghyun , Son Seung Won 
Published: April 2020

Polyhexamethyleneguanidine phosphate (PHMG‐P) is a widely used polymeric antimicrobial agent to induce significant pulmonary toxicity. Several studies have reported that the liver also can be a target organ of PHMG toxicity, but the exact effect of this compound on liver cells is not well understood. To identify the mechanism of PHMG hepatotoxicity, HepG2 cells were exposed to PHMG‐P for 72 h. Cell viability was significantly decreased by PHMG‐P in a time‐and concentration‐dependent manner. Mitochondrial membrane potential was markedly reduced by PHMG‐P and the apoptotic signaling cascade was activated. The increases observed in CHOP, p‐IRE, and p‐JNK levels in PHMG‐P‐treated cells indicated the induction of ER stress. To verify the role of ER stress in PHMG‐P‐induced cytotoxicity, HepG2 cells were pretreated with the chemical chaperone, TUDCA and then co‐treated with TUDCA and PHMG‐P for 24 h. Interestingly, TUDCA inhibited PHMG‐P‐induced ER stress and cytotoxicity in a dose‐dependent manner. Apoptotic cell death and mitochondrial depolarization were also prevented by TUDCA. Proteins involved in the apoptotic pathway were all normalized to their control levels in TUDCA‐treated cells. In conclusion, the results suggest that PHMG‐P induced significant cytotoxicity in liver cells and ER stress‐mediated apoptosis may be an important mechanism mediating this hepatotoxicity.Support or Funding InformationThis study was funded by Nano‐Material Technology Development Program through the National Research Foundation of Korea (NRF) funded by Ministry of Science and ICT (NRF‐2018M3A7B4071233).
Vitamin D Receptor Deficiency Impairs Pial Collateral Circulation in Mice
Authors: Pal Eva , Hricisak Laszlo , Lekai Agnes , Nagy Dorina , Fulop Agnes , Benyo Zoltan 
Published: April 2020

Vitamin D deficiency is a global health problem, which can increase the risk of cerebrovascular diseases including ischaemic stroke. However, the pathophysiological mechanism underlying this association is not well understood yet. The goal of the present work was to examine the impacts of vitamin D deficiency on the mouse pial collateral circulation which might provide a compensatory pathway after unilateral common carotid artery occlusion (CAO). The morphology of the leptomeningeal collaterals and the distance of the anastomotic line (half distance between the nearest branching points of the anterior cerebral artery (ACA) and the middle cerebral artery (MCA)) from the midline were evaluated after staining of the cerebral vasculature in adult male mice carrying a functionally inactive vitamin D receptor (KO, n=6) and in their wild‐type littermates (WT, n=6). The acute cerebrocortical blood flow (CoBF) changes after CAO was measured in anesthetized WT (n=8) and KO (n=8) mice using laser speckle imaging to evaluate regional differences in the territories supplied by the ACA and MCA, i.e. the frontoparietal and temporal cortices, respectively. Vitamin D deficiency decreased the number of leptomeningeal collaterals between the ACA and MCA, whereas the tortuosity of the collaterals was enhanced. The anastomotic line measured at 4 mm caudally from the frontal pole was located cc. 400 μm closer to the midline in KO than in WT mice, therefore the territory supplied by the ACA decreased. The maximal CoBF reductions were similar between the two groups in the temporal cortex, whereas in the frontoparietal cortex more severe hypoperfusion was developed in the KO animals, as the blood flow in the ipsilateral frontoparietal region showed a decrease of 13% compared to the contralateral region, whereas this difference was only 6% in WT mice. In conclusion, vitamin D deficiency leads to impaired development of leptomeningeal collaterals, as well as enhanced CoBF reduction in the frontoparietal cortex after CAO. These morphological and functional alterations can potentially compromise the cerebral circulation, therefore it may increase the risk of cerebrovascular diseases and worsen the outcome of stroke.Support or Funding InformationEFOP‐3.6.3‐VEKOP‐16‐2017‐00009, OTKA K‐112964, OTKA K‐125174, NVKP‐16‐1‐2016‐0042
Traumatic Brain Injury Alters PAQR7‐induced Vasorelaxation in Pressurized Cerebral Arteries
Authors: Goldsmith Jacob A. , Evanson Kirk W. , Levenson Cathy W. 
Published: April 2020

Traumatic brain injury (TBI) induces acute changes in cerebrovascular function, including alterations to cerebral artery contractility, which ultimately increase the incidence of both ischemic and hemorrhagic events. Cerebrovascular tone is controlled by hormonal, neurogenic, endothelial, and myogenic responses. Progesterone, a steroid hormone, has been evaluated as a potential treatment to improve TBI outcome; however, progesterone has failed to translate to patient benefits in clinical trials, potentially due to its pleiotropic effects on multiple receptors. Progestin & adipoQ receptor 7 (PAQR7) is a plasma membrane progesterone receptor involved in the vasorelaxation of human blood vessels. However, little is known about the smooth muscle‐specific role of PAQR7 in resistance size cerebral arteries following TBI. Here, we examined PAQR7 function in pressurized endothelium‐denuded cerebral resistance size arteries 24 hours following moderately severe TBI (controlled cortical impact). Baseline myogenic tone of middle cerebral arteries (MCA) was attenuated following TBI. PAQR7‐induced vasorelaxation in pressurized MCA from TBI rats was attenuated in a concentration‐dependent manner as compared to sham controls (10−9M‐10−7M). Moreover, pre‐incubation with inhibitors of adenylyl cyclase (AC), PKA, or PKG attenuated PAQR7‐induced vasorelaxation in both groups. In conclusion, smooth muscle‐specific PAQR7 vasodilation involves an AC‐PKA/PKG pathway in cerebral resistance size arteries, and moderately severe TBI attenuates cerebral artery myogenic tone, which reduces overall arterial vasodilatory capacity.Support or Funding InformationSupported by The Florida State University Graduate School Dissertation Award Grant.
Resistance Training with or without Blood Flow Restriction Improves Short‐Term Memory in Rats
Authors: Rebelo Macario Arosti , Garcia Nádia Fagundes , Puggina Enrico Fuini , de Moraes Camila 
Published: April 2020

Low load resistance training with blood flow restriction is usually used for improvements in muscle strength in special care conditions. However, there is limited information regarding the effects of this exercise approach on memory function. The aim of this study was to investigate the effect of resistance training with or without blood flow restriction, carried out three times a week, on short‐term memory. Male Wistar Hannover rats (70 days old) were divided into four groups: Sedentary Sham (S/S, n=10), Trained Sham (T/S, n=10), Sedentary with blood flow restriction (S/BFR, n=11), Trained with blood flow restriction (T/BFR, n=9). Animals from the S/BFR and T/BFR had their right femoral artery flow restricted (blood arrival and venous return) about 36–38% and animals from sham groups were submitted to the same surgical procedures except blood restriction. Experimental protocol was approved by local ethic committee (protocol: 2016.5.80.90.4). Exercise training began two weeks after surgery procedures. The exercise sessions were carried out three times a week and consisted of climb a vertical ladder (110 cm high, 18 cm wide, 2 cm grid, 80° inclination), carrying a load (50% of 1 Maximum Repetition) for 6 sets of 10 repetitions with 1‐minute rest between sets. After four weeks of exercise training, memory performance was assessed using the Object Recognition Test and the discrimination index (dI) was calculated (dI= [(time spent exploring the novel object minus time spent exploring the familiar object)/ total exploration time]). The interval between testing sessions 1 and 2 was 30 minutes. Femoral blood flow restriction did not cause impairment on memory performance (S/SdI=0.33±0.08 vs S/BFRdI=0.37±0.03). On the other hand, exercise training improved memory performance in both groups (T/SdI=0.76±0.07 vs T/BFRdI=0.59±0.04). The resistance training, carried out 3 times a week, was effective to improve short‐term memory either with or without peripheral blood flow restriction.Support or Funding InformationSupported by FAPESP Grant # 2017/13348‐6; Grant # 2018/16712‐3
Muscle Activation Response Using a Constant Resistance Sled Trainer Within Different Tasks
Authors: Mathis Monica , Timon Stepanie , Taylor Heather , Rosario Martin G. 
Published: April 2020

The XPO Trainer used in this inquiry is a novel device which provides low rolling resistance at low speeds with an immediate and automatic proportional gain in resistance with increased speed. Resistance exercise (RE) has been shown to induce many positive benefits to the body and mind, including hypertrophy of muscles, increased muscle performance, cardiovascular benefits, decrease risk of mortality, and decrease the risk of functional limitations.PURPOSEExamine the impact of pushing a constant resistance on gait and neuromuscular activation at low and high speeds in young, seemingly healthy adults.METHODSThe study consisted of 21 healthy adult males and females (age: 25.07±3.46 years, weight: 148.2±25.96 lbs, height: 66.57±4.14 inches). Each participant wore surface electromyography electrodes on their dominant leg for their quadriceps (QUAD), hamstring (HAM), anterior tibialis (TA), and gastrocnemius (GA). First, the maximal voluntary isometric contractions were gathered for each muscle. Then, participants performed 3 trials of 4 conditions: walking, walking and pushing, running, and running and pushing. After the data was normalized as a percentage (0–100%) for the gait tasks and the muscle activation amplitude, a repeated measures ANOVA was performed with the SPSS 24 system.RESULTSThe QUAD muscle exhibited a significantly higher muscle activation (P≤0.05) between walk (45.39±24.43) and walk push (74.40±56.73) tasks. Additionally, there is a significantly higher muscle activation (p≤0.05) between GA (81.85±37.84) and QUAD (46.06±23.93) during the walking task. A significant difference (p≤.05) was found between GA (0.33±0.17) and HAM (0.47±0.17) muscle activation timing during walking activity. During the walking activity, maximal muscle activation occurred in the GA muscle earlier than the HAM muscle. Additionally, there was a significant difference (p≤.05) in timing of the TA (0.43±0.17) vs QUAD (0.55±0.18), as well as the GA (0.41±0.10) vs the QUAD(0.55±0.18). TA and GA activation occurred significantly earlier than the QUAD activation during the walk and push task.CONCLUSIONWith the constant resistance sled being a novel device, it is important to understand how it affects the activation and response of muscles during different activities. Based on the results, patients can benefit from utilizing the sled in combination of walking and running to either promote a higher or lower muscle activation. With patients with weak QUADs or in need of QUAD strength training, a walking task is advocated. Additionally, if the goal of the intervention is to focus on endurance of the TA and GA, two of the main muscles used in postural balance, walking with the sled is recommended. Knowing all of these effects on muscle activation utilizing a constant resistance sled trainer will allow for more effective exercise training.
Identification of a CTRP9 Fragment Capable of Enhancing Bone Marrow Mesenchymal Stem Cell Cardioprotection via Cardioreparative Exosome Production Promotion
Authors: Wang Yajing , Liu Demin , Zhu Di , Lau Wayne Bond , Lopez Bernard , Christopher Theodore , Xie Dina , Zhang Zhen , Gao Erhe , Koch Walter , Ma Xinliang 
Published: April 2020

BackgroundThe safety of bone marrow mesenchymal stem cell (BMSC) therapy in ischemic heart injury has been clinically established. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for post‐infarction cardiac repair. CTRP9 is a protective cardiokine capable of improving the local microenvironment. The current study attempted to 1) identify a small biologically active CTRP9 fragment with lower immunogenicity, and 2) test a hypothesis that said CTRP9 fragment may promote a healthy microenvironment, and improve implanted stem cell survival and resultant cardioprotection.Methods and ResultsGlobular CTRP9 (gCTRP9, the most biologically active form of CTRP9) and 2 fragments of gCTRP9 (computationally predicted) were cloned and purified. In vitro experiments demonstrated that CTRP9‐F2 possesses biological activity equal to or exceeding gCTRP9. Wild‐type C57BL/6 mice were subjected to myocardial infarction and treated with BMSCs, CTRP9‐F2, or their combination. Administration of CTRP9‐F2, but not BMSCs alone, attenuated MI/R injury. Administration of CTRP9‐F2 plus BMSCs further enhanced the cardioprotective effect of CTRP9‐F2, suggesting a synergistic effect. BMSCs retention/survival in the ischemic region was significantly improved in the CTRP9‐F2 treated group. Conversely, the engrafted BMSC population was significantly reduced in the CTRP9 knockout heart. Mechanistically, CTRP9‐F2 promoted BMSC proliferation and migration, and protected BMSCs against H2O2‐induced cellular death. Interestingly, CTRP9‐F2 significantly enhanced BMSC exosome production, upregulated the exosomal cytoprotective molecule contents, and facilitated cardiomyocyte uptake of BMSC‐derived exosomes. Blockade of ERK1/2 completely abolished the effects of CTRP9‐F2 upon BMSC biology.ConclusionWe identify, for the first time, a small CTRP9 fragment capable of promoting BMSC cardioprotection via augmented exosome‐mediated BMSC‐cardiomyocyte communication.Support or Funding InformationW.W. Smith Foundation (to YJW)
Alcohol‐induced damage and death to developing and differentiated neurons.
Authors: Carter Wayne , Wijayamunige Buddhika , Wijesekara Anusha 
Published: April 2020

Alcohol intoxication can induce foetal alcohol spectrum disorder after prenatal exposures, as well as damage neurons and contribute to neurodegeneration and cognitive decline in adults. The effect of alcohol on driving altered cellular mechanisms and post‐translational modification of proteins was investigated in both undifferentiated and differentiated human neural progenitor cells and SH‐SY5Y neuronal cells to mimic alcohol exposures during neuronal development and in adults. Human neural progenitor cells were differentiated into neuronal cells upon growth factor withdrawal, while all‐trans retinoic acid and brain‐derived nutrient factor were applied to differentiate SH‐SY5Y cells prior to a challenge with 0–200 mM alcohol for 3, 6, 12, or 24 hours. Alcohol exposure induced cell cytotoxicity in a concentration and time‐dependent fashion, with cell viability assessed using MTT, ATP, and LDH assays. Reactive oxygen species (ROS) generated in response to alcohol treatment were quantified using a dichlorofluorescin diacetate assay. The accumulation and quantitation of oxidatively damaged proteins was assessed by quantitation of protein carbonyl content and specific carbonyl group immuno‐blotting. In summary, at commonly encountered alcohol exposures, alcohol triggered cellular damage and death in developing as well as differentiated neurons.Support or Funding InformationCommonwealth Scholarship Commission
Unmasking cAMP signalling in adipocytes
Authors: Salisa Laia Reverte , Pfeifer Alexander 
Published: April 2020

In recent years, the prevalence of obesity has reached pandemic proportions. In 2016, the World Health Organisation estimated that ca. 3 million people die each year due to complications from being overweight or obese. With more overweight population than ever, finding new targets to counteract obesity has become crucial. Recruitment and activation of brown adipose tissue (BAT) has been postulated as a potential target to increase thermogenic energy expenditure (EE) in order to treat or prevent obesity and its comorbidities.Cyclic adenosine monophosphate (cAMP) is a second messenger important in many biological processes. BAT thermogenesis is primarily mediated by activation of Gs‐coupled receptors such as the beta‐3 adrenergic receptor and the adenosine A2A receptor, which both increase intracellular cAMP. In mature brown adipocytes, cAMP is well known to induce lipolysis and UCP1‐mediated mitochondrial uncoupling through activation of protein kinase A (PKA). However, the precise role of cAMP signaling in adipocyte precursor cells has so far not been well studied. Furthermore, the role of other cAMP effectors (e.g. Exchange proteins activated by cAMP (EPAC)) in adipose tissue metabolism is not clear.Treatment of brown adipocyte precursor cells using analogs specific to different cAMP effectors induce distinct cellular responses. Here, we used genetic and pharmacological approaches to decipher the role of cAMP effectors, focusing on EPAC proteins, in adipocytes. We demonstrate that activation of mature adipocytes and proliferation of brown preadipocytes require the activation of distinct effectors and signaling pathways downstream of cAMP. Furthermore, browning of white adipocytes appears to follow similar patterns. Our data indicate that, depending on the effector, either PKA or EPAC, cAMP regulates browning of white adipocytes by different mechanisms. Moreover, in vivo deletion of EPAC leads to reduced oxygen consumption after high fat diet, demonstrating that the role of cAMP in adipocytes is still not fully understood. In conclusion, we show that the effects of cAMP in BAT and browning of WAT differ vastly depending on both the state of adipocyte differentiation as well as the downstream effector.Support or Funding InformationInstitute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, GermanySFB1328, Universitätsklinikum Hamburg‐Eppendorf, 20246 Hamburg, Germany
The Effect of Different Dietary Fats on the Longevity and Muscle Strength in Drosophila
Authors: Chizhikov Daniel , Lin Jason , Persinger Aaron , Puppa Melissa 
Published: April 2020

Fat is an essential source of energy and is important for human growth and development. A high fat diet, however, leads to pathological obesity and associated comorbidities, such as reduced lifespan and muscle strength in both humans and model organisms. In this study we analyzed the effects of four dietary fats on lifespan and overall health using a Drosophila model system, which shares the mechanisms of energy processing, storage, and utilization with humans. One day old wild type male Drosophila were collected and placed on a control diet or high fat diets containing 5%, 10% or 15% of coconut oil (medium chain‐saturated fat), vegetable oil, olive oil, or flax seed oil (all three contain unsaturated fats). Lifespan was determined for 100 flies on each diet. Skeletal muscle performance was evaluated by climbing and flying assays. Among all the groups, flies on a control diet had the greatest survival with a median lifespan of 30.5 days, while flies on a 5% coconut oil diet had the second longest survival time, yielding a median lifespan of 13 days. For all other diets, the median lifespan was 2 days. Flies on the control diet also performed significantly better (p<0.05) in the flying and climbing assays relative to flies on high fat diets. Flies on a 5% coconut oil diet had a significantly higher (p<0.05) muscle strength based on the flying assay compared to flies maintained on 5% diets with unsaturated fats. Interestingly, intestinal permeability measured using the Smurf assay revealed no difference between flies maintained on a control diet, 5% coconut oil diet, and 5% vegetable oil diet, suggesting that the adverse health effects of a high fat diet did not result from the compromised function of the intestine. Taken together, these data indicate that plant based medium chain saturated fats preserved longevity and muscle function better than plant‐based fats containing high amounts of polyunsaturated fatty acids.Support or Funding InformationFunding Source: University of Memphis SHS Faculty Grant
Pharmacologic Modulation of Mitochondrial Pathogenic Changes in Alzheimer’s Aβ‐Challenged Neurons
Authors: Rostagno Agueda , Sotolongo Krystal , Ghiso Jorge 
Published: April 2020

Mitochondria play essential roles in maintaining the high levels of brain energy demands required to maintain physiological ion gradients across membranes critical for the generation of action potentials and to sustain transport systems at endothelial barriers. About 90% of the energy requirement is produced through glucose oxidation, a tightly controlled mitochondrial process leading to ATP production. As the major consumers of oxygen, mitochondria are also the most important generators of reactive oxygen species (ROS) as by‐products of the electron transport chain. Thus, it is not surprising that mitochondrial dysfunction is emerging as a major contributor to the pathobiology of age‐associated neurodegenerative disorders and is being considered a crucial player in the pathophysiology of Alzheimer’s disease (AD). In spite of numerous studies, the mechanistic links among ROS homeostasis, cellular metabolic alterations, and changes in cell bioenergetics, particularly at the level of synapsis and in relation to oligomeric forms of amyloid‐β (oligAβ), still remain elusive. Through a combination of classical biochemical and immunocytochemical approaches together with the real‐time assessment of global energy metabolism our studies provide insights into the detrimental role of oligAβ in neuronal cell lines and murine primary cortical neurons. Our findings demonstrate that oligAβ induces detrimental changes in mitochondrial function with loss of mitochondrial membrane potential, release of cytochrome C, and enhanced ROS generation. Assessment of global energy metabolism in the Seahorse metabolic analyzer after sequential addition of different modulators of the mitochondrial metabolic pathways, demonstrated an oligAβ‐mediated reduction in oxygen consumption affecting basal and maximal respiration capacity and causing decreased ATP production. Pharmacologic targeting of Aβ‐challenged neurons with compounds of known antioxidant activity restored mitochondrial integrity/function, rescuing metabolic and bioenergetic changes induced by oligAβ. Overall, our studies provide insights into the complex molecular mechanisms triggered by oligAβ which profoundly affect mitochondrial performance and highlight the potential of antioxidant pharmacologic targeting to ameliorate the metabolic/bioenergetics alterations encompassing the complex and multifactorial pathways affected in AD.Support or Funding InformationNIH grants AG059595 and AG051266, the BrightFocus Foundation grant A2015275S, and the Alzheimer’s Association ZEN‐14‐283969