bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hydrogen peroxide induced homeostatic regulation in endothelial cells (667.10)
Authors: Patel Hemang , Chen Juan , Kavdia Mahendra 
Published: June 2021

Transient and consistent increase in hydrogen peroxide (H₂O₂) levels is associated with several vascular pathologies. H₂O₂ has been evaluated for cytotoxic and vasoactive response to vasculature. However, its ability to regulate endothelial cell‐homeostasis remains unclear. To understand the consistent and transient H₂O₂ effects, we investigated the effect of continuous and transient H₂O₂ treatments, respectively on endothelial cells superoxide (O₂‾) production and gene expression. Following both H₂O₂ treatments, we measured gene expression levels of key ROS neutralizing enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase 1 (GPX1) and peroxiredoxin 1 (PRDX1), and cell signaling proteins such as ASK1, ATF2 and NFE2L2. We also measured O₂‾ production using dihydroethidium (DHE). Gene expression results indicated a significant down‐regulation in ASK1, CAT, TXNRD1 under continuous H₂O₂ exposure. Transient H₂O₂ exposure followed by remodeling period showed significant up‐regulation in GPX1 and TXNRD1 whereas genes expression of ASK1, SOD1 and PRDX1 returned to homeostasis. Interplay among functional and gene expression changes during continuous and transient H₂O₂ exposure suggested alternative molecular pathway regulation leading to redox homeostasis in endothelial cells.Grant Funding Source: NIH R01 HL084337
Substrate and stretch regulate muscle‐resident mesenchymal stem cells to promote myoblast proliferation (673.1)
Authors: De Lisio Michael , Jensen Tor , Sukiennik Richard , Huntsman Heather , Boppart Marni 
Published: June 2021

Mesenchymal stem cells (MSCs) reside in a variety of tissues and provide a stromal role in regulating progenitor cell function. Current studies focus on identifying the specific factors in the niche that can alter the MSC secretome, ultimately determining effectiveness and timing of tissue repair. The purpose of the present study was to evaluate the extent to which substrate and mechanical strain regulate MSC quantity, gene expression and secretome. MSCs (Sca‐1+CD45‐) isolated from murine skeletal muscle via FACS were seeded onto laminin‐(LAM) or collagen‐1‐(COL) coated membranes and exposed to a single bout of mechanical strain (10%, 1 Hz, 20 min). MSC proliferation was not directly affected by substrate or strain; however, the genetic expression of growth and inflammatory factors and ECM proteins were down‐regulated in MSCs grown on COL in a manner independent of strain. In conditioned media (CM) experiments, the combination of strain and LAM induced secretion of factors from MSCs that increased myoblast quantity 24 hours post‐treatment (5.6 fold; p<0.05), while this response was delayed in myoblasts treated with CM from MSCs grown on COL. Here, we demonstrate that exposure to COL, the primary ECM component associated with tissue fibrosis, down‐regulates MSC gene expression, and delayed their ability to stimulate myoblast proliferation.Grant Funding Source: Supported by the Ellison Medical Foundation
Characterization of particle‐endothelium interaction using particles functionalized with dual antibodies in a complex synthetic microvascular network (674.3)
Authors: Lamberti Giuseppina , Tang Yuan , Kiani Mohammad , Wang Bin 
Published: June 2021

The interaction between leukocytes and receptors on the endothelium play a key role in the early response to tissue injury. Research has shown that drug carrier particle rolling velocity increases dramatically with the increase of carrier size which affects their final attachment efficiency. The objective of this study is to characterize the rolling and adhesion profile of different size functionalized particles in a synthetic microvascular network (SMN).Functionalized particles were prepared by coating their surfaces with different ratios of antibodies against adhesion molecules ICAM‐1 and E‐selectin. Our modified Geographic Information System (GIS) approach was used to digitize the microvascular networks and generate the SMN on PDMS. The rolling velocity and adhesion profile of functionalized 2 &amp; 10 µm particles was quantified in the SMN pre‐coated with TNF‐α activated human umbilical vein endothelial cells under shear conditions from 0 ‐ 280 sec‐1.Single antibody coated 10 µm particles roll at a higher speed than its 2 µm counterparts. Particle adhesion increased significantly with decreasing shear in SMNs. Increasing particle size from 2 µm to 10 µm did not change its binding efficiency significantly in SMNs, which is different from what have been reported in the traditional parallel plate flow channel.Particles functionalized with both a rolling molecule and an adhesion particle can more realistically mimic the leukocyte‐endothelium interaction in a SMN. These findings have important implications for better understanding the mechanisms behind inflammatory pathologies and for optimizing the design of carriers for targeted drug delivery.Grant Funding Source: Supported by Susan G. Komen for the Cure foundation
Systems biology framework for studying hyperglycemia‐induced endothelial dysfunction (676.19)
Authors: Patel Hemang , Chen Juan , Kavdia Mahendra 
Published: June 2021

Current understandings of endothelial dysfunction mechanism have failed to provide guidelines for a system wide treatment of endothelial dysfunction. In this study, we investigated and compared the effects of high glucose on HUVEC and HMVEC using a systems biology approach. Following high glucose exposure, gene expression levels of several redox enzymes, ROS neutralizing enzymes, and oxidative stress activated transcription factor were compared in both endothelial cell types. The functional changes of superoxide (O₂‾), hydrogen peroxide (H₂O₂), and mitochondrial membrane polarization (MMP) were measured in endothelial cell. Results illustrated a consistent increase of O₂‾ levels, in both endothelial cells. However, there was a variable change in underlying gene expression profile and H₂O₂ and MMP levels, during high glucose exposure in these two endothelial cells. The results showed that a hallmark increase of O₂‾ in endothelial cells across human vasculature could be a result of variable involvement of gene expression and functional changes. Our findings highlighted a unique framework for hyperglycemia‐induced endothelial dysfunction. Identifying genomic phenotype and corresponding functional changes in hyperglycemic endothelial dysfunction will provide a suitable systems biology approach for understanding underlying mechanisms and possible effective therapeutic intervention.Grant Funding Source: NIH R01 HL084337
Protection against depressive symptom‐induced impairments to cerebral vascular reactivity in female versus male rats (676.8)
Authors: Stanley Shyla , Brooks Steven , Chantler Paul , Butcher Joshua , D'Audiffret Alexandre , Frisbee Jefferson 
Published: June 2021

Chronic stress/depression alters vascular reactivity and can impact perfusion within target organs. In addition, they also can alter cerebral structure and mass ‐ leading to the question of associations between cerebrovascular reactivity and outcomes. To address this, we imposed 8 weeks of unpredictable chronic mild stress (UCMS) on rats of both genders at 9 weeks of age. In both genders, UCMS caused profound depressive symptoms, including reductions in chronic and stimulus‐induced grooming, learned helplessness and anhedonia, with elevated plasma cortisol. However, these behaviors were more severe in females. Endothelial‐dependent dilation (acetylcholine) was impaired in middle cerebral arteries (MCA) in both genders owing to a reduced NO bioavailability and increased production of ROS and TxA2. There was also a mild increase in serotonin‐induced and myogenic constriction of MCA from males. In females, alterations to constrictor and dilator reactivity were blunted, as were elevated ROS and constrictor prostanoids. These results suggest that female rats may have a protection against depression‐induced alterations to cerebrovascular reactivity.Grant Funding Source: Supported by National Institutes of Health and American Heart Association
Modeling electrical signal propagation in microvascular networks (678.12)
Authors: Lee Pilhwa , Pradhan Ranjan , Carlson Brian , Beard Daniel 
Published: June 2021

A bidomain formulation was developed to simulate propagation of electrical signals in endothelial cells of microvascular networks. The method is used to stimulate spatiotemporal signal propagation and attenuation in arterioles and capillaries, and analyze data from experiments on isolated vessels. A single‐vessel (capillary) segment model is parameterized based on conducted response data of isolated endothelial cells tube from mouse skeletal muscle feed arteries on changes in endothelial cell membrane voltages in response graded electrical stimulation. Simulation of the resulting model facilitates determination of appropriate boundary conditions to apply along the length in simulating signal propagation in whole capillary network. The model fits well to the observed spatial attenuation of the depolarization of endothelial cells, with activated/inactivated calcium‐activated potassium channels of the membrane, and predicts the electrical length constant dependency on acetylcholine. Simulations of realistic network topologies are then conducted to determine the effective time and space scales for metabolic signaling in the microvascular networks, especially with the vasodilator acetylcholine. This framework is a foundation for further study of spatiotemporal aspects of the electrical conduction in various microvascular networks.Grant Funding Source: U01 HL118738‐01A1
The role of brain angiotensin converting enzyme on the nocturnal thirst and sodium appetite in ovariectomized rats (683.6)
Authors: Reis Luis , Lepletier Ailin , Mecawi Andre , Fonseca Fabricia , Araujo Iracema , Almeida‐Pereira Gislaine , Antunes‐Rodrigues Jose 
Published: June 2021

We investigated the role of brain angiotensin converting enzyme (ACE) on nocturnal fluid intake (water and 0.3 M NaCl solution) in ovariectomized (OVX) and estradiol benzoate‐treated (EB‐OVX) rats placed in metabolic cages. We performed peripheral (100 mg/Kg) and central (50 ng/animal) captopril (CAP) administration with or without angiotensin I (ANG I; 100 ng/animal) microinjection. Both CAP administration routes reduced basal water and salt intake in OVX and EB‐OVX groups. Peripheral CAP administration inhibited fluids intake in both groups submitted to sodium depletion (sc furosemide 20 mg/Kg followed by 24 h low sodium diet) while icv CAP decreased fluids ingestion only in the EB‐OVX group. Following furocap protocol (sc furosemide 10 mg/Kg plus sc CAP 5 mg/Kg), icv CAP decreased fluids intake in both groups. Hypothalamic ACE‐1 mRNA expression was unaltered in both protocols comparing OVX vs EB‐OVX. EB replacement increased hypothalamic ACE‐2 mRNA expression in furosemide protocol, despite it has been lower in furocap than in furosemide protocol. Our results suggest that EB replacement attenuates sodium appetite in OVX rats due to the modulation of the brain ANG II activity. The increased ACE‐2 expression induced by EB replacement could be a plausible explanation taking into account other angiotensins produced in the brain may exert a counteracting ANG II signalling.Grant Funding Source: Supported by FAPERJ & CNPq
Idiopathic benign paroxysmal positional vertigo (ip‐bppv)of the true principal pathology and medical treatments (684.2)
Authors: Tanioka Hisaya , Kaga Kimitaka 
Published: June 2021

PURPOSE: 1) What is the true principal pathology of IP‐BPPV? 2) Where is in the free otoconia in the membranous labyrinth? 3) How is the morphological change of the vestibular end‐organs in the affected region? 4) What kind of conditions about the cerebral vasculature in BPPV? 5) How to treat BPPV? SUBJECTS and METHOD: Six unilateral affected patients were entered into this study, and follow‐up CT studies in the recovery period were performed. The axial CT data was applied to create 3D images on the work station for post processing.RESULT: 1) The utericular macula increased volume rather than both the non‐affected side and recovery period. 2) The affected ampulla and cupula showed enlargement and thickening rather than recovery period. 3) The free otoconia was identified at the affected semicircular duct by 3D virtual histology, on recovery, the free otoconia disappeared. 4) The affected semicircular duct was relatively wide diameter rather than that of normal one. 5) The cerebral vasculature showed hyperdense on CT such as hyperdense basilar sign.TREATMENT: About two days bed rest and medications cured patients of BPPV.The medications were drugs for increased blood flow and a sedative.CONCLUSIONS: IP‐BPPV was caused by poor cerebral blood circulation such as infarction. The volume of otoconia increased in affected inner ears. This cause may be secondary to poor turn over or over product.
Single unit recordings from putative presympathetic neurons in the rostral ventrolateral medulla of sedentary and physically active rats (686.35)
Authors: Huereca Daniel , Mueller Patrick 
Published: June 2021

A sedentary lifestyle has been linked to the development of cardiovascular disease (CVD). The RVLM is believed to contribute to CVD through direct activation of sympathetic preganglionic neurons. Our previous work showed that sedentary rats exhibit enhanced sympathoexcitation after glutamate activation of the RVLM compared to active counterparts. We have also recently shown increased dendritic arborization in spinally‐projecting C1 RVLM neurons from sedentary rats. We hypothesized that the RVLM exhibits increased excitability due to structural and functional differences in sedentary versus active rats (14 weeks wheel running). To our knowledge, we are the first group to have performed in vivo single unit recordings from putative presympathetic RVLM neurons in sedentary and active rats to examine functional differences in presympathetic RVLM neurons. Preliminary results from Inactin‐anesthetized rats indicate that individual presympathetic RVLM neurons from sedentary rats appeared to have higher resting firing rates (14.0±5.1 Hz, n=4) compared to active rats (8.7±3.0 Hz, n=4). RVLM neurons also appeared to have greater responses to acute increases in blood pressure (∆‐11.4±5.3 Hz vs. ∆‐5.6±1.4 Hz, respectively), but decreases in blood pressure did not appear to elicit different responses (∆+3.1±1.4 Hz vs. ∆+2.9±0.3 Hz). Though our current sample size does not yet permit us to draw definitive conclusions, these preliminary data support our hypothesis and suggest that a sedentary lifestyle may increase sympathetic nerve activity by causing an increase in the activity of individual presympathetic RVLM neurons.Grant Funding Source: HL096787, WSU Rumble Fellowship
Klotho suppresses epithelial‐mesenchymal transition in adriamycin nephropathy (690.8)
Authors: Takenaka Tsuneo , Inoue Tsutomu , Miyazaki Takashi , Hayashi Matsuhiko , Suzuki Hiromichi 
Published: June 2021

Klotho interacts with various proteins to alter their function. Experiments were performed to assess how klotho protects kidney from its injury. Adriamycin (5 mg/Kg) was injected into rats to induce nephropathy. Human recombinant klotho (K, 30 μg/kg/day), 4‐benzyl‐2‐methyl‐1,2,4‐thiadiazolidine‐3,5‐dione (GSK3β blocker, 0.2mg/kg/day, T) or vehicle (A) was administered. Rats untreated with adriamycin were used as the control (U). Animals were killed 8 weeks later. Renal expressions of Wnt1, GSK3β, TGFβ1, Twist and collagen I were assessed with RT‐PCR against GAPDH. Results were shown in Table. Our data indicate that WNT is involved in the pathogenesis of adriamycin nephropathy. Furthermore, the present findings provided the evidence that the inhibition of WNT contributed to glomerular protective actions of klotho. Finally, our results suggest that klotho suppresses epithelial‐mesenchymal transition by inhibiting TGFβ as well as WNT signaling.
Results

U
A
K
T

Alb/Cr
8±2
316±39*
152±21*#
163±19*#

CCr
1.1±0.1
0.9±0.1
1.0±0.1
1.0±0.1

Wnt1
0.2±0.1
3.6±0.3*
2.3±0.3*#
2.5±0.4*#

GSK3Î²
0.1±0.1
0.8±0.2*
0.4±0.1*#
0.4±0.1*#

TGFÎ²1
1.2±0.2*
0.2±0.1
0.7±0.1*#
0.6±0.2:#

Twist
0.1±0.1
1.3±0.2*
0.6±0.1*#
1.1±0.2*$

Collagen I
0.3±0.2
2.3±0.4*
0.7±0.2*#
1.4±0.3*#$

Alb/Cr: Albuminuria(mg)/Creatinine(g), CCr: creatinine clearance (ml/min/g.kidney.wt). *: p<0.05 vs U, #: P<0.05 vs A, $: p<0.05 vs K.Grant Funding Source: Japanese Ministry of Education and Culture (25461229)
Upregulation of cannabinoid receptor‐1 and fibrotic activation of mouse hepatic stellate cells during Schistosoma J. infection: role of NADPH oxidase (693.13)
Authors: Wang Mi , Abais Justine , Meng Nan , Zhang Yang , Ritter Joseph , Li Pin‐lan , Tang Wang‐Xian 
Published: June 2021

The endocannabinoid system (CS) has been implicated in schistosomiasis‐associated liver fibrosis (SSLF). However, the molecular mechanisms mediating the action of the CS in SSLF are largely unknown. The present study hypothesized that Schistosoma J. infection upregulates cannabinoid receptor (CB) signaling via activation of NADPH oxidase leading to a fibrotic phenotype in hepatic stellate cells (HSCs). A SSLF model was developed by infecting mice with Schistosoma J. cercariae in the skin. HSCs from uninfected (control) or Schistosoma J.‐infected (SSLF) mice were isolated, cultured and identified by analyzing HSC markers α‐SMA and desmin. In HSCs isolated from control or SSLF mice, both CB1 and CB2 receptors were detected, however, only the CB1 significantly increased in HSCs from SSLF mice compared to that control mice. Such increase of CB1 in HSCs was accompanied by enhanced expression of fibrotic markers α‐SMA, collagen I, and TIMP‐1. Similarly, CB1 upregulation and enhanced fibrotic changes were observed in HSCs isolated from control mice when these cells were treated with soluble egg antigen (SEA) from Schistosoma J. Interestingly, HSCs from SSLF mice or SEA‐treated HSCs from control mice exhibited enhanced superoxide (O2.‐) production as analyzed by electron spin resonance. Importantly, inhibition of O2.‐ production by knocking down NADPH oxidase genes (Nox1 or Nox4) prevented SEA‐induced upregulation of CB1 and fibrotic markers in HSCs. Further, CB1 gene silencing blocked SEA‐induced fibrotic changes in HSCs but had no effect on SEA‐induced O2.‐ production in these cells indicating a triggering role of O2.‐ production in CB1‐mediated fibrotic signaling. Taken together, these data suggest that the fibrotic activation of HSCs upon Schistosoma J. infection or SEA stimulation is associated with NADPH oxidase‐mediated redox regulation of CB1 expression, which may be a triggering mechanism for SSLF.Grant Funding Source: Supported by NIH grants HL057244, HL091464 and HL075316
Cardiac myocyte‐specific deletion of Heat shock protein 10 results in altered cytosolic and mitochondrial protein expression (699.6)
Authors: Suarez Jorge , Wang Hong , Ouyang Kunfu , Scott Brian 
Published: June 2021

Heat shock proteins (HSPs) are molecular chaperones that prevent protein damage and proteolysis. HSP10 forms mitochondrial (Mito) chaperoning complexes with HSP60 to maintain protein quality control. Studies in vitro suggest that HSP10 plays a role in normal Mito function; however, its physiological function in the heart in vivo remains to be determined. To investigate the function of cardiac HSP10, we generated a floxed allele of the Hspe1 gene, and found that cardiac specific, tamoxifen‐inducible deletion of HSP10 in adult mice resulted in death between 12 and 18 weeks after HSP10 deletion. Increased mortality after HSP10 deletion was associated with dramatically altered protein expression patterns. For instance, cardiac hypertrophic biomarkers atrial natriuretic factor (ANF), β‐Myosin Heavy Chain (βMHC) and skeletal muscle actin were increased in the HSP10 KO mice. In Addition, there was a dramatic reduction in levels of Mito respiratory complex subunits including CI‐NDUFA9, CII‐30, COX I, COX IV, and COX Vb. Furthermore, the apoptotic pathway is activated in HSP10 KO mice as revealed by the cleavage of Caspases 9 and 3. Our results suggest that mitochondrial protein damage may be the primary pathological cause of the death. In conclusion, HSP10 plays a critical and vital role in regulating mitochondrial protein homeostasis.Grant Funding Source: Supported by P. Robert Majumder Charitable Foundation.
Bone‐muscle crosstalk: more than mechanical (704.3)
Authors: Isaacson Janalee , Mo Chenglin , Brotto Leticia , Huang Jian , Spence Madoka , Vallejo Julian , Abreu Eduardo , Dallas Sarah , Johnson Mark , Bonewald Lynda , Brotto Marco 
Published: June 2021

The intricacy of cell interactions with their microenvironment and their ability to communicate at the autocrine, paracrine, and endocrine levels continues to be revealed. Until recently, the musculoskeletal system was believed to be directed primarily by a relationship of proximity and function, dictated in large part by mechanical forces and the work of gravity. The purpose of this review is to provide an overview of the biomechanical theory of bone‐muscle interaction and to present the substantial evolution in our understanding of bones and muscles as secretory organs; including new evidence from our research labs in support of this biochemical crosstalk between bone and muscle cells. We propose that the mechanical and biochemical modes of interaction between bones and muscles are complementary and interwoven. In fact, we hypothesize that one tissue action might prime the other tissue function, thereby contributing for optimal functional unit. This perspective provides a fertile new venue for bone‐muscle crosstalk exploration, as well as the development of innovative therapies targeting musculoskeletal diseases, which currently afflict nearly 2 billion people worldwide.Grant Funding Source: Supported by NIH P01 AG039355‐01‐A1
TNF‐α alters the release and transfer of miRNAs from endothelial cells (711.7)
Authors: Alexy Tamas , Rooney Kimberly , Weber Martina , Searles Charles 
Published: June 2021

MicroRNAs (miRNAs) encapsulated within extracellular vesicles likely have a role in cell‐to‐cell signaling, but little is known as to the mechanisms by which different cell types release miRNAs. Here, we examined the release and transfer of miR‐126, miR‐21, and miR‐155 in microparticles (MPs) produced by human aortic endothelial cells (ECs) treated with TNF舉α. ECs were treated with TNF‐α (100 ng/ml), in the presence or absence of inhibitors targeting distinct MP production pathways. MPs isolated from media were assessed by flow cytometry (count) and qRT‐PCR (miRNA content). Calcein AM‐labeled MPs were used to assess uptake by recipient ECs. TNF舉α induced a 5‐fold increase in MP production after 12‐24 hours of treatment (n = 5, p < 0.05). These MPs were characterized by: 1) 70 ‐ 80% decrease in the miRNA/MP levels for miR‐126 and ‐21 but 20‐fold increase in pre‐miR‐155 (n = 10, p < 0.05); 2) 50% reduction in uptake by recipient cells (n = 3, p < 0.05); and 3) inability to transfer miR‐126 and ‐21. Co‐treatment of donor ECs with TNF舉α and caspase inhibitor (Q‐VD‐OPH; 10μM) completely abrogated TNF舉α‐induced increase in MP number, and produced MPs that had: 1) increased uptake by recipient cells; 2) enhanced miRNA/MP content; and 3) increased ability to transfer miRNA. Co‐treatment of ECs with TNF舉α and Rho‐associated kinase (ROCK) inhibitor (10 μM) produced MPs similar to those produced by TNF舉α treatment alone. Overall, our data suggest that TNF舉α induces EC release of distinct MP populations: ROCK‐dependent, miRNA‐rich MPs that can transfer their miRNA contents to recipient cells, and caspase‐dependent, miRNA‐poor MPs that do not readily transfer their contents. These data provide insight into the relationship between MP production and extracellular release of miRNA, as well as the potential of encapsulated miRNA for information transfer.Grant Funding Source: Supported by NHLBI R01 and VA Merit Award