bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutrophil GPCRs as novel therapeutic targets
Authors: Corriden Ross 
Published: June 2021

Each year in the United States, 2 million people are infected with antibiotic resistant pathogens, such as methicillin‐resistant Staphylococcus aureus (MRSA); 23,000 patients die as a result of such infections. With the growth of antibiotic resistance and the slowing in the development of new antibiotics, the discovery of new, effective approaches to treat infections is an important unmet medical need. G protein‐coupled receptors (GPCRs) in polymorphonuclear neutrophils (PMNs), the first‐line effectors of the innate immune response, are a novel but unexplored potential class of “immune boosting” targets. Using a combination of qPCR based arrays and RNAseq analysis, we defined and quantified GPCR expression in human PMNs and found 174 GPCRs commonly expressed among healthy donors tested. To help determine which GPCRs might be involved in response to pathogens, we assessed the GPCR profile of PMNs incubated with MRSA for 3 h. We found numerous GPCRs whose expression increased at least 2‐fold upon pathogen exposure. Analyses of PMN function (e.g., chemotaxis, extracellular trap production, bacterial killing) using selective agonists/antagonists of several such GPCRs indicated that pharmacological agents can “boost” the function of PMNs, including the killing of bacteria. The results indicate that: 1) Human PMNs express a large profile of GPCRs, expression of a number of which is altered by exposure to pathogenic bacteria. 2) Previously unrecognized PMN‐expressed GPCRs can boost PMN function, including the ability to kill bacteria. These data thus suggest a new paradigm for enhancement of innate immunity: targeting of neutrophil‐expressed GPCRs as a means to treat bacterial infections, including ones caused by antibiotic‐resistant bacteria. Furthermore, such GPCRs may also represent new therapeutic targets for the treatment of inflammatory disorders driven by aberrant neutrophil function.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
1α,25‐Dihydroxy vitamin D3, the active form of vitamin D3, protects against allergeninduced airway constriction
Authors: Maarsingh Harm , Remick Adam J , Stimson David TJ , Lopez Alejandro , Bolson Anthony , DellaVecchia Matthew 
Published: June 2021

Allergen‐induced bronchoconstriction is an important hallmark of allergic asthma and is caused by the release of mediators, such as histamine, by activated mast cells. In various disease models, the vitamin D3 pathway has been shown to reduce mast cell degranulation. Vitamin D3 is converted into 25‐hydroxy vitamin D3 and subsequently into the active form 1α,25‐dihydroxy vitamin D3 by CYP enzyme activity. Vitamin D3 deficiency contributes to the pathophysiology of allergic diseases, including asthma, whereas vitamin D3 treatment reduces allergen‐induced airway hyperresponsiveness and inflammation in experimental models of asthma.In this study, we investigated the role of the vitamin D3 pathway in regulating allergen‐induced constriction of intrapulmonary airways in an animal model of allergic asthma.To this aim, precision cut lung slices (PCLS) were obtained from guinea pigs that were IgE‐sensitized to ovalbumin (OVA) and sacrificed 4–8 weeks later. Lungs were filled with 1.5% agarose, cooled with ice, harvested and 500‐μm thin PCLS were prepared. Constrictions of the intrapulmonary airways to increasing concentrations of OVA or histamine were monitored using video‐assisted microscopy. PCLS were pre‐treated with or without vitamin D3 compounds 30 minutes prior to the addition of OVA or histamine.OVA induced a dose‐dependent and full constriction of intrapulmonary airways in guinea pig PCLS. Pretreatment with 1α,25‐dihydroxy vitamin D3 (1 μM), the active form of vitamin D3, reduced the sensitivity (pD2) of the airways to OVA by more than 300‐fold (p<0.01), without affecting the maximal constriction (Emax). By contrast, the bronchoconstriction induced by exogenous histamine was not affected by pretreatment with 1α,25‐dihydroxy vitamin D3. Taken together, these findings indicate that the bronchoprotective effect of 1α,25‐dihydroxy vitamin D3 is caused by inhibiting the allergen‐induced release of mast cell mediators rather than by reducing the responsiveness to these mediators.In conclusion, treatment with 1α,25‐dihydroxy vitamin D3 reduces the airway sensitivity towards allergens and subsequent airway constriction, presumably by reducing allergen‐induced mast cell degranulation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Anti‐allergic Effect of Dan phenolic acid A from Salvia miltiorrhiza in Ovalbumin‐induced Asthma Model
Authors: Son So‐Eun , Heo Jae‐Yeong , Im Dong‐Soon 
Published: June 2021

BackgroundIn Oriental countries, the root of Salvia miltiorrhiza is used to treat cardiovascular diseases, asthma, and other conditions. Dan phenolic acid B from S. miltiorrhiza extracts has been shown to improve airway hyperresponsiveness. We aimed to investigate the effects of Dan phenolic acid A and Dan Shen ketone from S. miltiorrhiza in allergic asthma using female Balb/c mice and rat RBL‐2H3 mast cells.METHODSTo elucidate whether Dan phenolic acid A, a constuent of Salvia miltiorrhiza extract has beneficial effects on allergic asthma, anti‐asthma effects were studied using female Balb/c mice and rat RBL‐2H3 mast cells. Antigen‐induced degranulation was assessed by measuring b‐hexosaminidase activity in vitro. In addition, a murine ovalbumin‐induced allergic asthma model was used to test the in vivo efficacy of Dan phenolic acid A and Dan Shen ketone.RESULTSAntigen‐induced degranulation was inhibited by Dan phenolic acid A and Dan Shen ketone. Sensitization and challenge of ovalbumin induced allergic asthma responses. Administration of Dan phenolic acid A and Dan Shen ketone decreased numbers of inflammatory cells, especially eosinophils, and reduced the expression and secretion of Th2 cytokines, including IL‐4 and IL‐13, in lung tissues and bronchoalveolar lavage fluid. Histologic studies showed administration of Dan phenolic acid A and Dan Shen ketone reduced inflammatory signs and mucin production in lungs.CONCLUSIONThese findings provide evidence that Dan phenolic acid A and Dan Shen ketone have a potential use as anti‐allergic therapeutics.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exercise Training‐MicroRNA‐126 Upregulation is Associated with Prevention of Dexamethasone‐Mediated Microvascular Rarefaction
Authors: Herrera Naiara Araújo , de Souza Francine Duchatsch Ribeiro , Tardelli Lidieli Pazin , Dionisio Thiago José , dos Santos Carlos Ferreira , Vasquez‐Vivar Jeannette , do Amaral Sandra Lia 
Published: June 2021

Dexamethasone (DEX) treatment often increases blood pressure. Exercise training is an efficient non‐pharmacological intervention to treat hypertension, which is thought to be explained by improved microvascular function. Microcirculation related‐microRNAs (miRNAs) play a role in maintaining micro vessel skeletal density. The aim of this study was to investigate if training‐induced miRNAs are associated with exercise training‐dependent prevention of DEX‐induced rarefaction. Wistar rats were trained (treadmill) for 8 weeks or not (sedentary) and then treated with DEX (50 μg/kg per day, s.c.) or saline for 14 days. Carotid artery catheterization for arterial pressure measurements was performed on last day of treatment and tibialis anterior (TA) muscle was collected for morphometric, protein and microRNAs analyses. In sedentary rats, DEX treatment induced hypertension (+27%) concomitantly with capillary density loss (CD, −20.8%) and decreased VEGF (−43.0%), p‐AKT/AKT (−39.6%) and Bcl‐2 (−23.0%) protein levels and increased caspase‐3‐cleaved protein (+34.0%) in TA muscle. In the trained group, however, microRNA‐126 expression was increased (+13.1%), which was followed by enhanced p‐AKT/AKT (+37.7%) and Bcl‐2 (+7.7%), as well as a diminished caspase‐3‐cleaved (−23.1%) protein level. The changes in miRNA‐126 expression were positively correlated with p‐AKT/AKT (r=0.7246) and VEGF (r=0.5224) protein levels. Neither DEX nor training significantly changed miRNA‐16, 21, 221, 222, 155. We concluded that miRNA‐126 upregulation, induced by training, plays an important role in controlling skeletal muscle vessel density. MiRNA126 could be a novel therapeutic agent against DEX‐induced rarefaction.Support or Funding InformationFinancial support: FAPESP (2018/06998‐7)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
ADAM17 impairs F11R/JAM‐A‐mediated wall shear stress mechanosensing and induces aging‐related inward artery remodeling
Authors: Tian Yanna , Czikora Istvan , Bagi Zsolt 
Published: June 2021

We sought to determine if lumen narrowing inward arterial remodeling is mediated by impaired endothelial mechanosensing of wall shear stress (WSS) in aging. Previously we have shown that aging upregulates A disintegrin and metalloproteinase ADAM17 in the vascular endothelium. ADAM17 sheds F11R/JAM‐A, an important tight junction‐located endothelial cell (EC) adhesion molecule. Here we tested if ADAM17 activation promotes aging‐related inward artery remodeling by shedding F11R/JAM‐A. Human arteries were obtained from fat biopsies in 40 consecutive patients. We found that vascular ADAM17 enzyme activity increases significantly with age, whereas F11R/JAM‐A expression was reduced in older (>64 yo) subjects, which was associated with reduced luminal diameter and increased wall thickness. Cultured human ECs exposed to increasing levels of flow (0 to 8 dyne/cm2) progressively changed their orientation to the direction of flow. In the presence of recombinant ADAM17 or after siRNA‐mediated silencing of F11R/JAM‐A, ECs failed to efficiently orient with the direction of flow. Gene transfer of ADAM17 cleavage resistant, mutated JAM‐A(V227Y) resulted in a normal EC orientation to flow. Collectively, our results uncover a novel regulatory role for vascular ADAM17 in reducing F11R/JAM‐A‐dependent WSS mechanosensing, which can lead to lumen narrowing inward arterial remodeling in aging.Support or Funding InformationNIH R01AG054651This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Novel Insight Into the Determinants of Skeletal Muscle Oxygen Consumption by Dual‐Wavelength Diffuse Correlation Spectroscopy
Authors: Rosenberry Ryan , Tucker Wesley J. , Trojacek Darian , Chamseddine Houda , Arena‐Marshall Carrie , Tian Fenghua , Haykowsky Mark J. , Nelson Michael D. 
Published: June 2021

Near‐infrared diffuse correlation spectroscopy (DCS) is a promising new optical imaging technique to noninvasively quantify microvascular perfusion. Combining DCS with conventional near‐infrared spectroscopy (NIRS) provides novel insight into the determinants of skeletal muscle oxygen consumption, by measuring microvascular oxygen delivery (by DCS) and oxygen utilization (by NIRS, i.e. tissue saturation). To test this hypothesis, we compared DCS‐derived measures of skeletal muscle oxygen delivery and utilization against Doppler ultrasound and direct measures of oxygen saturation from the venous effluent of the exercising muscle. Eight healthy male subjects (age 27.2 ± 4.2; BMI 26.9 ± 4.3) performed a graded handgrip exercise test. Subjects were instructed to perform rhythmic hand grip exercise on a two‐second duty cycle, at 10, 13, 16, and 19 kg. All subjects were instrumented with the DCS probe placed over the belly of the flexor digitorum profundus, a retrograde venous catheter (deep vein) inserted into the antecubital vein, and Doppler ultrasound over the brachial artery. Heart rate was monitored by ECG and blood pressure by continuous finger‐pressure of the non‐gripping hand. The major findings were two‐fold: First, we observed a strong intra‐individual relationship between DCS‐derived muscle perfusion and Doppler‐derived brachial artery blood flow (r2 = 0.95). Second, we observed an unexpected dissociation between skeletal muscle saturation, as measured by DCS, which declined progressively with each incremental workload (BL 71.9 ± 0.29%, 10kg 68.4 ± 0.91%, 13 kg 64.2 ± 1.04%, 16kg 61.8 ± 0.54%, 19kg 59.4 ± 1.26%), while directly measured venous oxygen saturation declined with the onset of exercise but remained unchanged thereafter (BL, 65.3 ± 7.20%; 10kg, 39.8 ± 8.42%; 13 kg, 39.5 ± 7.83%, 16kg, 42 ± 4.14%, 19kg, 41 ± 3.38%). Taken together, these results support DCS as a valuable tool, capable of providing novel insight into the determinants of skeletal muscle oxygen consumption at the microvascular level. The fact that tissue saturation was dissociated from venous saturation suggests that DCS may provide insight beyond conventional measurements.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Arteriolar Vasomotion on Network Flow
Authors: Jacobsen Jens Brings 
Published: June 2021

BackgroundRhythmic, spontaneous change in microvascular diameter, vasomotion, is observed across numerous species and vascular beds. So far, a plausible physiological role for vasomotion remains to be established. It appears that vasomotion is more prevalent under conditions of insufficient perfusion, suggesting a protective role in hypoxia. Alternating reduction in diameter in some vessels could potentially cause increased perfusion in neighboring branches and ensure flushing of otherwise under‐perfused regions on a regular basis.MethodsFlow simulations were performed in virtual vascular networks. First, each vessel adapted structurally to local pressure and flow, as well as to the local capillary perfusion requirement. Subsequently, the mature network was exposed to low perfusion pressure, with or without the presence of vasomotion in selected branches.ResultsIn vasodilated networks forced diameter oscillations in one branch of a stem caused a 15% flow increase in the other branch from the same stem, independent of network perfusion pressure level. Allowing the network to develop a myogenic tone that matches the local network pressure, reduces the effect of forced diameter oscillation on flow in neighboring vessels; the higher the network perfusion pressure, the smaller is the effect of vasomotion. This is due to myogenic compensation in the non‐oscillating vessel. In all cases, however, total network flow was reduced by the presence of vasomotion.ConclusionVasomotion can increase flow locally in neighboring network regions. This effect is strongest under the low tone conditions likely to be present during tissue hypoxia. On a whole‐network level, however, the presence of vasomotion reduces, rather than increases, the flow.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
ADAM17 Cleaves the Insulin Receptor α‐Subunit on Endothelial Cells and Induces Vascular Insulin Resistance in Type 2 Diabetes
Authors: de Araujo Silva Thaysa Ghiarone , Castorena‐Gonzalez Jorge , Restaino Robert M. , Foote Christopher A. , Morales‐Quinones Mariana , Wheeler Andrew A. , Rawlings Arthur L. , Staveley‐O'Carrol Kevin F. , Padilla Jaume , Martinez‐Lemus Luis A. 
Published: June 2021

Microvascular insulin resistance is a hallmark of type 2 diabetes (T2D) and an underlying event in the pathophysiology of endothelial dysfunction and cardiovascular disease. However, the molecular mechanisms by which T2D causes vascular insulin resistance remain largely unknown. Hyperglycemia and the proinflammatory state associated with T2D are characterized, in part, by an increased activity of ADAM17, an enzyme that cleaves the ectodomain of various transmembrane proteins. Here, we hypothesized that increased expression and activation of ADAM17 sheds the insulin receptor α‐subunit (IRα) from endothelial cells causing vascular insulin resistance in T2D. We tested this hypothesis in isolated resistance arteries from T2D and non‐T2D subjects undergoing bariatric surgery and in cultured human umbilical vein endothelial cells (HUVECs). Resistance arteries from T2D subjects exhibited increased ADAM17 expression, reduced presence of endothelial IRα as well as the endogenous ADAM17 inhibitor, TIMP3, and impaired insulin‐induced vasodilation, relative to arteries from non‐T2D subjects (P<0.05). Exposure of HUVECs to high glucose (30mM, 24h) increased the expression and activity of ADAM17 (P<0.05), led to increased shedding of IRα detected in the cell culture media supernatant (P<0.05) and decreased IRα on cell surfaces as observed using super‐resolution microscopy. Moreover, pharmacological inhibition of ADAM17 led to reduced shedding of IRα and improved insulin signaling in cells exposed to high glucose or the ADAM17 activator, PMA (P<0.05). Collectively, these findings suggest that T2D, and in particular hyperglycemia, leads to ADAM17 shedding of IRα from the endothelial surface and reduced insulin‐dependent vasodilation, all of which supports ADAM17 activity as a new therapeutic target to ameliorate vascular insulin resistance in T2D.Support or Funding InformationResearch support: National Institutes of Health grants: R01 HL137769 (JP), R01 HL088105 (LM‐L).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The adenosine kinase inhibitor ABT‐702 improves coronary vasodilator and left ventricle diastolic dysfunction in obese ZSF1 rats
Authors: Davila Alec , Tian Yanna , Czikora Istvan , Bagi Zsolt 
Published: June 2021

Coronary microvascular dysfunction contributes to the development of heart failure with preserved ejection fraction (HFpEF) for which no effective therapies are currently available. We tested the hypothesis that pharmacological inhibition of adenosine kinase (ADK), the major adenosine metabolizing enzyme, augments coronary artery vasodilation and improves left ventricle (LV) diastolic function in HFpEF. We employed the obese ZSF1 rat model of HFpEF. We assessed agonist‐induced coronary artery dilation and performed echocardiographic assessment of LV diastolic function before and after treatment with selective ADK inhibitor, ABT‐702 (1.5 mg/kg, i.p. for 8‐week). We found that obese ZSF1 rats exhibited impaired acetylcholine (ACh)‐induced coronary artery dilation and LV diastolic dysfunction, as indicated by reduced E/A ratio and increased deceleration time of mitral flow velocity. Treatment with ABT‐702 augmented ACh‐induced coronary vasodilation in obese ZSF1 rats, which was not affected by inhibition of NO synthase, with N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME). ABT‐702 treatment also improved LV diastolic function in obese ZSF‐1 rats, but had no effect on lean controls. Collectively, these data suggest that a pharmacological inhibition of ADK provides beneficial effects on both coronary vasodilator and LV diastolic function in HFpEF.Support or Funding InformationAmerican Heart Association 17GRNT33680171, NIH F31 HL142183‐01 and NIH R01AG054651This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of cigarette smoking on hypercapnia induced shear‐mediated dilation in the internal carotid artery
Authors: Suzuki Kazuya , Washio Takuro , Tsukamoto Shingo , Kato Kazunori , Iwamoto Erika , Ogoh Shigehiko 
Published: June 2021

It has been well established that chronic cigarette smoking causes peripheral endothelial dysfunction which is strongly associated with coronary and peripheral vascular diseases. Thus, smoking is a risk factor for these diseases. On the other hand, some previous studies suggest that smoking is also a risk factor for cerebral vascular disease. However, its physiological mechanism remains unknown. Under these backgrounds, we hypothesized that smoking also attenuated cerebral endothelial function. To test this hypothesis, we measured shear‐mediated dilation in the internal carotid artery (ICA) as an index of cerebral endothelial function in smokers and non‐smokers. The subject were young, healthy, male non‐smokers (n=6, age 21.2±0.8 years, BMI 21.3±4.1) and smokers (n=5, 21.8±1.6 years, BMI 19.5±1.8). Each smoker consumed an average of 9 cigarettes per day (range 6–10). Shear‐mediated dilation in the ICA was measured by using Doppler ultrasound. Shear‐mediated dilation in the ICA was induced for 3 min during inspiration of high carbon dioxide concentration gas (target end‐tidal carbon dioxide; +10mmHg from individual baseline value) and it was calculated as the percent rise in peak diameter during hypercapnia stimulation from baseline value. As a result, there was no difference in both baseline diameter and blood velocity of the ICA between smokers and non‐smokers (diameter, 4.39 ± 0.54 mm vs 4.87 ± 0.65 mm, P = 0.22; blood velocity, 35.2 ± 8.1 cm/s vs 32.7 ± 6.3 cm/s, P = 0.57). Similarly, shear‐mediated dilation in the ICA was not affected by habitual smoking (smokers vs. non‐smokers; 4.53 ± 2.34 % vs 2.23 ± 3.36 %, P = 0.23), indicating that the effect of chronic smoking on cerebrovascular endothelial function may be minimal in this age group. The findings of the present study suggest that the influence of chronic smoking on endothelial function in the brain is different from that of the peripheral vasculature.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.