bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ontogenic expression of key ADME genes and their roles in imatinib‐induced toxicity in juvenile rats
Authors: Wang Yedong 
Published: November 2023

Imatinib is an oral tyrosine kinase inhibitor that is approved for the treatment of pediatric chronic myeloid leukemia. Prepubertal growth impairment has been reported to be a major neurologic adverse effect of long‐term imatinib treatment in children. Numerous studies have demonstrated that cytochrome P450 3A4 and ABCB1 are major ADME genes that play critical roles in biotransformation and brain disposition of imatnib. In the present study, we first evaluated the relationships between ontogentic expression of ADME genes and exposure of imatinib in a neonatal rat model. The expression of Cyp3a1 and Abcb1 of rats from different postpartum days (PPD) were determined at mRNA and protein levels, and results revealed that their expression increased with age. Pharmacokinetic studies after single oral dose of imatinib (30 mg/kg) given to 7‐, 14‐, 21‐, 28‐ or 35‐day‐old rats demonstrated that brain distribution of imatinib decreased with age, with > 20 fold decrease in PPD35 rats compared with PPD7 rats, consistent with mRNA and protein expression levels of key ADME genes. Juvenile rat toxicity studies with oral imatinib were conducted to examine the relationship between Cyp3a1 and Abcb1 gene expression and growth (in particular bone formation) retardation. Preliminary data suggest a distinctive inhibitory effect of imatinib on bone growth in neonatal rats. Mechanistic investigations using osteoblasts and in vivo neonatal rat model are on‐going to delineate regulatory network between imatinib disposition and bone formation.Support or Funding InformationThe current work was supported in part by a grant from Soochow University, Suzhou, China [Grant No. Q413200711], and a grant from the National Science Foundation of China [Grant No. 81473278].
Leading the charge in sprouting angiogenesis: The roles of PKA and PDE4D in regulating tip cell invasion
Authors: MacKeil Jodi 
Published: November 2023

During angiogenic sprouting, vascular endothelial cells (VECs) either act as “tip cells” that guide blood vessel formation, or as the follower “stalk cells”, which proliferate to lengthen the newly developing vessel. While cAMP‐signaling regulates numerous VEC functions required for angiogenic sprouting, few studies have attempted to deconstruct the influences of this ubiquitous second messenger on individual functions of tip and/or stalk cells. Thus, this study was undertaken to address whether cAMP‐signaling selectively acted on VEC expressing tip or stalk phenotypes, and to begin to explore how individual components of the cAMP‐signaling system coordinated these events. Specifically, a spheroid model of angiogenic sprouting was used to assess whether knocking down the cAMP effectors expressed in human arterial VECs (HAVECs) (i.e. PKA, Epac1), or the dominant cAMP PDEs expressed by these cells (i.e. PDE4D, PDE3B), impacted tip cell matrix invasion. Using this approach, we show that while knocking down PKA‐Cα expression in HAVECs markedly enhanced tip cell invasion, knocking down EPAC1 had no effect. With respect to the dominance of individual PDE‐family variants in these processes, knocking down PDE4D expression promoted angiogenic sprouting as measured by tip cell invasion, while knocking down PDE3B markedly inhibited these processes. Indeed, tip cell matrix invasion was nearly abolished in PDE3B knockdown spheroids. Our data are consistent with the notion that individual PDE isoenzymes are involved in distinct regulatory pathways, and suggest that PDE3B and PDE4D differentially regulate angiogenic sprouting in response to pro‐angiogenic stimuli, potentially through PKA.Support or Funding InformationCanadian Institutes of Health Research (CIHR)
Memantine, the dual α7‐nAChR/NMDAR antagonist displays potent anti‐angiogenic activity in lung cancer
Authors: Robateau Zachary R , Brown Kathleen C , Chen Yi C , Egleton Richard D , Dasgupta Piyali 
Published: November 2023

Non‐small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) bear a strong etiological association with smoking habits. Nicotine, the addictive component of cigarettes, promotes angiogenesis in lung cancer via the α7‐nicotinic acetylcholine receptor (α7‐nAChR) subunit in human lung endothelial cells. Therefore, we conjectured that α7‐nAChR‐antagonists should display potent anti‐angiogenic and antitumor activity in lung cancers. Memantine is a dual α7‐nAChR/NMDAR antagonist, which is used in the clinic for the treatment of patients suffering from mild‐to‐moderate Alzheimer's disease. Receptor binding assays have shown that the affinity of Memantine for α7‐nAChR is greater than NMDAR. Here we show that memantine attenuates nicotine‐induced angiogenesis in human microvascular endothelial cells of the lung (HMEC‐Ls). Most interestingly, the levels of α7‐nAChR in tumor‐associated endothelial cells was greater than normal lung endothelial cells. The anti‐angiogenetic activity of memantine was mediated by the α7‐nAChR (and not by NMDARs) on lung endothelial cells. Furthermore, the α7‐nAChR antagonist memantine displayed potent anti‐angiogenic activity in the chicken chorioallantoic membrane (CAM) model. Our studies show that α7‐nAChR antagonists may be useful anti‐tumor agents relevant for the treatment of human lung cancer.Support or Funding InformationFunding for our study was supported by the an NIH R15‐AREA Grant (2R15CA161491‐02), WVU‐MU Health Partnership Grant and by ACTSI Grant from Marshall University
RNA Receptor RIG‐I Stimulation Impairs Endothelial Barrier Function through Inflammasome Activation Independent of NLRP3
Authors: Pitzer Ashley L , Zhang Yang , Bhat Owais , Li Pin‐Lan 
Published: November 2023

Retinoic acid‐inducible gene‐I (RIG‐I) as a putative cytosolic RNA sensor plays a critical role in mediating innate immune and inflammatory responses. The role of RIG‐I in vascular regulation under physiological and pathological conditions remains poorly understood. The present study tested a hypothesis that cellular RIG‐I activity regulates vascular endothelial barrier dysfunction by activation of an NLRP3‐indepdendent inflammasome. Using confocal microscopy, stimulation of RIG‐I in mouse endothelial cells (ECs) with specific agonist, 5′‐triphosphate double‐stranded RNA (3pRNA, 0.5 mg/L) was found to induce co‐localization of RIG‐I, but not NLRP3, with inflammasome components ASC (apoptosis speck‐like protein) and pro‐caspase‐1. Inflammasome activation detected via ELISA analyses showed that 3pRNA significantly increased IL‐1β production by 10 folds. Interestingly, this activation of RIG‐I inflammasome decreased expression of tight junction proteins ZO1 and ZO2 as well as adheren protein VE‐cadherin, as shown by immunofluorescence detection and Western blot analysis. To test functional changes, a permeability assay imploring an FITC conjugated dextran showed significantly increased leakage of dextran across of the EC layer during 3pRNA treatment, which was abolished by inhibition of caspase‐1 and HMGB‐1 and by ASC gene silencing. Together, these data implicate involvement of RIG‐I inflammasome activation in the disruption of vascular endothelial barrier function that triggers an early molecular event leading to vascular dysfunction.Support or Funding InformationSupported by NIH grants HL057244, HL075316 and HL122937
Evidence that NaHS inhibits the tachycardic responses induced by stimulation of the preganglionic sympathetic outflow in pithed rats
Authors: Centurion David , Castillo‐Santiago Shirley V , Becerril‐Chacón Maria E , Torres‐Perez Jose A , de la Cruz Saul Huerta , Sanchez‐Lopez Araceli 
Published: November 2023

In anesthetized rats, i.v. administration of NaHS, a donor of H2S, elicited dose‐dependent bradycardia, although the mechanisms are unknown. In this regard, we hypothesized that the inhibition of the cardioaccelerator sympathetic outflow may be partially involved. Thus, this study was designed to determine the potential capability of NaHS to mediate inhibition of the tachycardic responses induced by preganglionic sympathetic stimulation (C7‐T1). For this purpose, Wistar rats were anesthetized, pithed and cannulated for drug administration. In animals pre‐treated with gallamine, the effect of i.v. infusion of NaHS (310 and 560 μg/kg min) or its vehicle (phosphate buffer saline; 0.02 ml/min) was determined on the tachycardic responses induced by: (1) sympathetic stimulation (0.1–3.2 Hz); or (2) i.v. bolus injections of exogenous noradrenaline (0.03–3 μg/kg). The tachycardic responses induced by preganglionic sympathetic stimulation were dose‐dependently inhibited by i.v. infusion of NaHS (310 and 560 μg/kg min), but not by vehicle, particularly at high frequencies. In marked contrast, the tachycardic responses to exogenous noradrenaline were not inhibited by the above doses of NaHS or its vehicle. These results, taken together, demonstrate that NaHS inhibited the tachycardic responses induced by preganglionic sympathetic outflow by a prejunctional mechanism. This is the first evidence demonstrating this effect by NaHS that may contribute, at least in part, to the bradycardia induced by NaHS.Support or Funding InformationThe authors acknowledge to Conacyt (Grant No. 252702) for their financial support.
Amelioration by GABAB receptors of the cyclosporine‐evoked counteraction of endotoxic cardiovascular manifestations in conscious rats
Authors: Sallam Marwa Y , El‐Gowilly Sahar M , Abdel‐Galil Abdel‐Galil A , El‐Mas Mahmoud M 
Published: November 2023

We have previously shown that cyclosporine (CSA) counteracts the GABA receptor‐sensitive endotoxic cardiovascular manifestations such as hypotension and cardiac autonomic dysfunction. In this study we investigated whether the facilitation of central GABAergic neurotransmission blunts these favorable influences of CSA. The effects of CSA on LPS hemodynamics were determined in the absence and presence of pharmacologic maneuvers that activate GABA receptors or elevate synaptic GABA levels in conscious rats. Intravenous administration of lipopolysaccharide (LPS, 10 mg/kg) decreased blood pressure (BP), increased heart rate, and impaired cardiac autonomic activity as suggested by the reductions in time‐ and frequency domain indices of HRV (measures of cardiac autonomic control). The consequent i.v. administration of CSA (10 mg/kg) blunted the LPS‐evoked hypotension and tachycardia and associated reductions in HRV indices. The ability of CSA to reverse the LPS effects disappeared in rats treated intracisternally (i.c.) with baclofen (selective GABAB agonist, 2 mg/rat) but not muscimol (selective GABAA agonist, 1 mg/rat), indicating a preferential compromising action for central GABAB receptors on the CSA/LPS interaction. Moreover, the improvement by CSA of LPS‐evoked cardiovascular derangements was eliminated after concurrent i.c. administration of vigabatrin (GABA transaminase inhibitor, 200 mg/rat) or tiagabine (GABA reuptake inhibitor, 100 mg/rat). Overall, these results demonstrate that the activation of central GABAB receptors either directly via baclofen or indirectly following interventions that boost GABA concentrations in central synapses counterbalances the advantageous effects of CSA on endotoxemia.Support or Funding InformationSupported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895).
Peak Total‐[Hemoglobin + Myoglobin] During Incremental Dynamic Handgrip Exercise and Post Occlusive Hyperemia
Authors: Didier Kaylin D , Ade Carl J , Hammer Shane M , Barstow Thomas J 
Published: November 2023

IntroductionNear infrared spectroscopy (NIRS) has been used previously to measure changes in the total hemoglobin + myoglobin (Total‐[Hb+Mb]) signal, thought to reflect changes in microvascular hematocrit (HCT). During rest the hematocrit of the microvasculature is lower compared to the systemic hematocrit. However, during exercise microvascular hematocrit increases towards that seen in the systemic circulation. This increase in hematocrit provides an increase in the surface area available for O2 exchange. Post‐occlusive reactive hyperemia (PORH) tests have also utilized changes in NIRS signals, including Total‐[Hb+Mb], to evaluate function/dysfunction of the circulatory system. However, it is currently unclear how the peak Total‐[Hb+Mb] observed transiently following cuff release during PORH might relate to the peak Total‐[Hb+Mb] seen at task failure during incremental exercise (active hyperemia). These results could provide insight into the underlying mechanisms which control microvascular HCT.PurposeThe purpose of this investigation was to determine how the peak Total‐[Hb+Mb] achieved during incremental dynamic handgrip exercise compared to that seen during PORH.MethodsEleven men completed two testing protocols; 1) Incremental dynamic handgrip exercise to failure and 2) PORH. Exercise and PORH were performed in a supine position, with the right arm abducted to ~80° at heart level. During incremental exercise the work rate progressively increased 0.5 Watts every 30 sec until the subject could not maintain the correct contraction rate for at least 3 consecutive contractions despite verbal encouragement. The PORH test included: 1 min of baseline, 5 min occlusion of the brachial artery, and 3 min recovery after cuff release. Near‐infrared spectroscopy (NIRS) measurements were made continuously during both tests, from which the Total‐[Hb+Mb] signal was derived.ResultsThere was no difference in the mean values for peak Total‐[Hb+Mb] during the incremental test (93.0 ± 20.3 μM) and that observed during the PORH test (93.1 ± 17.7 μM) (p = 0.992). Further, peak Total‐[Hb+Mb] during PORH was significantly correlated to peak Total‐[Hb+Mb] during incremental handgrip exercise (R2 = 0.657, p = 0.002). The slope of the regression line for Peak PORH vs. Incremental was 0.930.ConclusionThese data suggest that in a given subject, similar peak values of microvascular Total‐[Hb+Mb], and thus microvascular HCT, are achieved during active and reactive hyperemia.
Microvascular Perfusion Heterogeneity Impairs Oxygenation and Contributes to Peripheral Vascular Disease in Metabolic Syndrome
Authors: McClatchey P. Mason , Woo Fan , Olfert I. Mark , Eliis Christopher , Goldman Daniel , Reusch Jane , Frisbee Jefferson 
Published: November 2023

Development of the metabolic syndrome in obese Zucker rats (OZR) is associated with impaired fatigue‐resistance of in situ skeletal muscle paralleling a blunted functional hyperemia. However, recent studies suggest that reduced bulk oxygen delivery to skeletal muscle with elevated metabolic demand may not explain the compromised muscle performance. Using novel experimental data and recent insight into altered microvascular perfusion in OZR, we developed a simulation for tissue oxygenation with increasing metabolic demand in lean (LZR) and OZR skeletal muscle using physiologically‐realistic data and relationships. With elevated metabolic demand, blood flow to, and oxygen uptake by, in situ skeletal muscle increased in both strains, although the response was blunted in OZR. However, venous blood oxygen tension (PvO2) draining the muscle of OZR was elevated versus LZR across metabolic demands; a paradoxical response given assumptions of increased microvascular residency time in OZR. Using a microvascular network model of multiple Krogh cylinders supplied by a network with homogeneous flow distribution at bifurcations (γ=0.5), we were unable to simulate tissue oxygenation and PvO2 differences between LZR and OZR. However, with introduction of increasing perfusion asymmetry (γ>0.5), changes to microvascular hematocrit and increased plasma skimming throughout the network, our ability to simulate the experimental results was much improved. As a result, our data suggest that increased perfusion asymmetry (γ) within the muscle microcirculation is not only a defining characteristic of metabolic syndrome, it is required to effectively model and understand alterations in blood‐tissue oxygen exchange in this highly translationally relevant model of human disease risk.Support or Funding InformationNational Institutes of Health and American Heart Association
Beneficial Pleiotropic Anti‐Depressive Effects of Cardiovascular Disease Risk Factor Interventions in Metabolic Syndrome
Authors: Frisbee Jefferson , Stranges Saverio , Duncan Audra , Frisbee Stephanie 
Published: November 2023

While the increased prevalence and severity of clinical depression and elevated cardiovascular disease risk represent two vexing public health issues, the growing awareness of their combined presentation presents a special challenge for not only integrated health outcomes, but also for effective treatment. The obese Zucker rat (OZR), a model of the metabolic syndrome with significant elevations in CVD risk spontaneously develops significant depressive symptoms in parallel with the progression of the metabolic syndrome; thus representing a particularly compelling model for study. To begin to interrogate relationships between CVD risk factors and depressive symptom severity, we chronically treated OZR with traditional clinically relevant interventions against CVD risk to determine impacts on not only vascular function but also on behavioral outcomes and depressive symptom severity. While most of the interventions (chronic exercise, anti‐hypertensive, anti‐dyslipidemia, anti‐diabetic) were differentially effective at improving vascular function, only those interventions that also resulted in a significant improvement to oxidant stress, inflammation and arachidonic acid metabolism (PGI2 vs. TxA2) and their associated sequelae were effective at also blunting depressive symptom severity. Using multivariable analyses, discrimination between the effectiveness of treatment groups to maintain behavioral outcomes was dependent upon maintaining arachidonic acid metabolism and vascular oxidant stress together, with preventing changes in vascular stiffness, mean arterial pressure and plasma cortisol concentration (together) also being important. This initial study provides for a very compelling framework from which to further interrogate the links between CVD risk and cognitive/behavioral status, and begins to provide insight into mechanistic links and potentially effective avenues for intervention.Support or Funding InformationNational Institutes of Health, American Heart Association
Ojeoksan suppressed TNF‐α‐induced vascular inflammation in human umbilical vein endothelial cells
Authors: Han Byung Hyuk , Kim Hye Yoom , Ahn You Mee , Jin Xian Jun , Jeong Da Hye , Lee Yun Jung , Lee Ho Sub , Kang Dae Gill 
Published: November 2023

Endothelial dysfunction is regarded as an important role in vascular inflammation. Ojeoksan (OJS), originally recorded in an ancient Korean medicinal book named “Donguibogam”(), is a well‐known blended traditional herbal formula. OJS is consist of seventeen natural herbal plants. This study was carried out to investigate the effect of OJS on tumor necrosis factor‐alpha (TNF‐α)–induced vascular inflammation in human umbilical vein endothelial cells (HUVECs).Pretreatment of OJS suppressed TNF‐α‐induced expression of cell adhesion molecules, such as intracellular adhesion molecule‐1, vascular cell adhesion molecule‐1, and endothelial selectin in TNF‐α‐stimulated HUVECs. OJS also decreased the adhesion of HL‐60 cells to HUVECs. Moreover, OJS inhibited TNF‐α‐induced matrix metalloproteinase‐2/‐9 (MMP‐2/‐9) activity; significantly decreased TNF‐α‐induced production of intracellular reactive oxygen species (ROS); and inhibited the phosphorylation of IκB‐α in the cytoplasm. Pretreatment with OJS also inhibited the translocation of NF‐κB p65 to the nucleus. OJS increased the phosphorylation of endothelial nitric oxide synthase (eNOS) and Akt (protein kinase B) which are related with NO production. In addition, OJS increased the protein expression of Nrf2 and HO‐1 in TNF‐α‐stimulated HUVECs, suggesting its protective effect against vascular inflammation.In conclusion, these results of this study suggested that OJS, the traditional herbal formula, has a protective effect on vascular inflammation. Therefore, OJS might be a potential therapeutic agent for early atherosclerosis.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2008‐0062484).
Reactivity of Basilar and Circle of Willis Arteries Measured Simultaneously at 7 Tesla
Authors: Shoemaker Leena , Al‐Khazraji Baraa , Gati Joe , Tzekeres Trevor , Shoemaker Kevin 
Published: November 2023

The subcortical conduit vessels contribute significantly to the total cerebral vascular resistance making knowledge regarding their vasoreactivity to physiological stimuli a requirement when attempting to understand regional brain perfusion. Recent evidence points to significant dilatory and constrictor potential in the middle cerebral artery. However, reactivity of the remaining conduit arteries remains poorly understood due to a need for improved imaging methods that can assess these vessels simultaneously while each receives the same stimulus. In this study we characterize the basilar and all Circle of Willis conduit arteries' reactivity to changes in end‐tidal CO2 (ETCO2). All imaging was performed on a 7T Siemens MAGNETOM neuro‐optimized MRI using an 8‐channel transmit, 32‐channel receive head coil. Cross‐sectional area (%ΔCSA) measurements were evaluated from images collected using a T1‐weighted 3D SPACE pulse sequence, optimized to produce black‐blood and high signal contrast between vessel lumen and surrounding tissue. The acquisition was tuned to produce high‐resolution (0.5mm isotropic) information with no inflow signal (TE=8.2ms, TR=700ms, FOV=224mm sagittal, radial trajectory, iPat=2) and a whole‐brain acquisition time of 5.63 minutes. Collection of isotropic data allowed us to arbitrarily re‐orient the image data to evaluate the relative change in cross‐sectional area (%ΔCSA) of the subcortical conduit arteries perpendicular to the direction of flow. Change in ETCO2 (ΔETCO2, ADInstruments) and %ΔCSA data were produced from 7 healthy individuals (age range, 18–23 years). Cerebrovascular CO2 reactivity was calculated as %ΔCSA/ΔETCO2. All 9 subcortical conduit arteries (basilar, right and left internal carotid, as well as the right and left posterior, middle and anterior cerebral arteries) were evaluated during normocapnia (37±6 mm Hg), hypercapnia (51±6 mmHg achieved by breathing a gas mixture of 5% CO2, balance oxygen), and hypocapnia (27±4 mmHg achieved by hyperventilation). Cerebral artery reactivity to hypercapnia exhibited a range of dilation from 0.27%/mm Hg in the right internal carotid artery to 2.5%/mm Hg in the left anterior cerebral artery. In response to hypocapnia, cerebral artery vasoconstriction ranged from 1.1%/mm Hg in the left anterior cerebral artery to 3.2%/mm Hg in the right posterior cerebral artery. This study demonstrated the heterogeneous cerebrovascular reactivity to hypercapnia and hypocapnia across the nine subcortical conduit arteries.Support or Funding InformationCanadian Institute of Health Research (201503MOP‐342412‐MOV‐CEEA)