bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Castration on Mesenteric Arterial and Portal Venous Responses to Splanchnic Nerve Stimulation
Authors: Martin Doug Stuart , Kjellsen Barton 
Published: June 2021

Androgens exacerbate hypertension development. Our previous work suggested that androgens also amplify adrenergic constriction (Journal of Hypertension 23:2229). This study tested the hypothesis that male sex steroids modulate neural control of splanchnic resistance and capacitance function.Five week old male spontaneously hypertensive rats (SHR) underwent sham operation or castration and were studied at 12‐16 weeks of age. Mean arterial blood pressure (MAP) and heart rate (HR) were recorded in conscious rats. The rats were then anesthetized and instrumented for splanchnic nerve stimulation and mesenteric arterial and portal venous blood flow recording. Frequency response curves (1‐12 Hz) were constructed before and after inhibition of N type calcium channels with omega conotoxin.MAP was elevated in sham operated (151±6 mm Hg) compared to castrated SHR (135±3 mm Hg). Splanchnic nerve stimulation caused frequency dependent changes in mesenteric arterial and portal venous blood flow in both groups. However, the responses were greater in sham operated SHR compared castrated SHR. Treatment with omega conotoxin markedly attenuated the differences between groups.Collectively, these data show that castration modulates neurally mediated splanchnic resistance and capacitance vascular responses. This effect may be mediated in part via the N type calcium channel. Supported by NIH #63053 and AHA #0515443Z.
HPLC is more sensitive to assess urinary albumin than nephelometry in acute stroke patients
Authors: Toth Peter , Marko Lajos , Halmai Richard , Bosnyak Edit , Szapary Laszlo , Koller Akos , Komoly Samuel , Nagy Judit , Wittmann Istvan 
Published: June 2021

Microalbuminuria, the appearance of albumin in the urine, is one the first signs of a disease process in many pathological conditions. However, the definition or identification of "microalbuminuria" may depend on the sensitivity of methods used to measure urinary albumin. In the past, immuno‐nephelometry (NM) was used to routinely detect immunoreactive albumin. However, high‐performance liquid chromatography (HPLC) detects both immunoreactive and non‐immunoreactive albumins. Early recognition of microalbuminuria is important, because recent studies have shown that it is associated with elevated risk of stroke. We hypothesized, that use of HPLC will detect microalbuminuria in more patients with acute stroke than NM. Thus in ischemic stroke patients (n=100) the albumin to creatinine ratio was measured by HPLC and NM to characterize microalbuminuria. We have found that HPLC detected albumin in the urine of 81,8% of stroke patients, whereas NM detected it only in 46,5%. The concentration of urinary albumin detected by HPLC was significantly greater than by nephelometry (HPLC: 203,8±37 NM: 106±27 mg/mmol; p<0,001). In conclusion, HPLC can detect microalbuminuria in more stroke patients and perhaps earlier than NM can. Thus use of HPLC seems to be preferable for screening stroke patient for microalbuminuria.Grants: Hungarian Sci. Res. Funds/OTKA T48376, K71591, F68638; Health Sci. Council/ETT 364/2006, Hungarian Neuroimaging Foundation, AHA F. Aff. 0855910D, USA
Janus Kinase 2 and Tissue Inhibitor of Matrix Metalloproteinase‐1 Mediate the Protective Effects of Erythropoietin in In‐Vitro Model of Hypoxia Ischemia
Authors: Souvenir Rhonda , Fathali Nancy , Tong Wenni , Lekic Tim , Chee Priscilla , Zhang John 
Published: June 2021

Studies have shown that erythropoietin (EPO) therapy significantly reduced brain injury and improved neurological function in rat model of neonatal hypoxia ischemia. Studies have shown that increase matrix metalloproteinase‐9 (MMP‐9) contributes to hypoxia ischemic brain injury. This study investigated if tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1) and its upstream signaling molecule Janus kinase‐2 (JAK‐2) are involved in EPO‐induced neuroprotection in an in vitro model of hypoxia ischemia.Hypoxia ischemia was induced in neuronal growth factor differentiated PC12 cells by 2 hours of oxygen and glucose deprivation. The cells were treated immediately before and during hypoxia ischemia with either: EPO, EPO + AG490 (JAK‐2 inhibitor), AG490, EPO + TIMP‐1 antibody, or TIMP‐1 antibody. Cell death, phosphorylation of JAK‐2, signal transducers and activators of transcription protein‐3 (STAT‐3), TIMP‐1 expression, and MMP‐9 activity were measured and compared with normoxic group.Our data showed that EPO significantly increased cell survival, associated with increased TIMP‐1 expression, phosphorylation of JAK‐2, STAT‐3, and decreased MMP‐9 activity. These protective effects of EPO were significantly reduced by inhibition of JAK‐2 and TIMP‐1. Conclusion: JAK‐2 and TIMP‐1 are necessary for EPO‐induced neuroprotection hypoxia ischemia injury. Supported by NIH, grant NS052492.
Activation of GABA¬A receptor Protects Mitochondria and Reduces Cerebral ischemia.
Authors: Tyagi Neetu , Givvimani Srikanth , Kumar Munish , Kundu Soumi , Gillespie William M , Mishra Paras , Sathnur Pushpa Kumar , Lominadze David , Sen Utpal , Tyagi Suresh C 
Published: June 2021

Gamma‐aminobutyric acid is the inhibitory neurotransmitter and has been identified in mitochondria. Because the release of mitochondrial factors is known to correlate with acute neurological damage, we proposed to investigate the possible neuroprotective effects of GABA‐A receptors in cerebral ischemia. In this study transient ischemia was induced in mice by occlusion in the middle of the carotid artery (MACO). Effects of GABA‐A receptor agonist (muscimol) were first studied in oxygen/glucose deprivation‐induced death of neuronal cells. Mitochondrial membrane potential, cytochrome‐c release, caspase 3 activation, the infarct volume and neurological function were examined in the absence or presence of muscimol. Our results shows that GABA‐A receptor agonist inhibits oxygen/glucose deprivation‐induced cell death, loss of mitochondrial membrane potential, downstream release of cytochrome‐C, which activates the caspase apoptotic signaling cascade. Furthermore, it decreases infarct size and improves neurological scores after MACO in mice. This study indicated that GABA‐A receptor is neuroprotective against cerebral ischemia. It also suggested mitochondrial permeability transition might be a valuable therapeutic target for acute neurodegeneration.Supported by NIH grant # HL‐71010 & NS‐51568 to SCT.
Identification of a novel neuronophagic cell in the partially denervated rat neurohypophysis
Authors: Lo David , Watt John 
Published: June 2021

The objective of this study was to identify neuronophagic cells in the partially denervated neurohypophysis. This was accomplished by using a phagocytosis‐dependent labeling technique to visualize the incorporation of labeled axonal debris within neuronophagic cells in the neurohypophysis following unilateral transection of the hypothalamo‐neurohypophysial tract (HNT). Stereotaxic application of the biotin and rhodamine conjugated dextran amine Mini Ruby into the magnocellular neurons of the supraoptic nucleus led to conspicuous and stable labeling of the HNT. Following unilateral lesion of the HNT, we observed small rhodamine labeled granules within s100beta immunoreactive pituicytes, and also within immunophenotypically identified perivascular cells expressing the p75 low affinity neurotrophin receptor, the C3bi compliment receptor, and ciliary neurotrophic factor. At the ultrastructural level, we observed homogeneous labeling of magnocellular neurons and neurosecretory axons with Mini Ruby. In the partially denervated neurohypophysis, labeled axons were found to be enveloped by pituicyte processes as well as within the pituicyte cytoplasm. These results indicate that the anterograde degeneration induced by partial denervation of the rat neurohypophysis stimulates neuronophagia by both perivascular cells and pituicytes. This study was supported by COBRE 2P20RR017699‐06Grant Funding SourceCOBRE 2P20RR017699‐06
Mitochondrial content and function decrease in mouse diaphragm after chronic hypoxia
Authors: Gamboa Jorge Luis , Andrade Francisco H 
Published: June 2021

Loss of aerobic capacity induced by chronic hypoxia (i.e. diminished mitochondrial content) has been partially attributed to reduced physical activity. That is true for the limb muscles; however, hypoxia increases the workload on the diaphragm and other respiratory muscles. Thus, we hypothesized that mitochondrial content and function would not change in the mouse diaphragm following chronic hypoxia. Male C57BL/6J mice were kept in normoxia (FiO2=21%, control) or normobaric hypoxia (FiO2=10%, hypoxia) for 4 weeks. Then, mice were killed and the diaphragm and triceps surae were collected for analysis. In the diaphragm the content of electron transport chain (ETC) proteins was significantly reduced after 4 weeks of hypoxia (decreases of 25 to 30% compared to control). Mitochondrial volume density decreased after 4 weeks of hypoxia (control 33.6±5.5% vs. hypoxia 26.8±6.7%, p=0.013). A significant reduction of the ADP‐stimulated mitochondrial respiration (state 3) was also observed in the hypoxia group (159.0±28.8 vs. 112.2±38.9 nmolO2/min/mg protein, p=0.017). By contrast, no change was found in ETC protein content in triceps surae. However, chronic hypoxia decreased respiration states 2 (control 41.2±4.1 vs. hypoxia 33.2±6.7 nmolO2/min/mg protein, p=0.033) and 3 (control 196.6±32.6 vs. hypoxia 135±43.1 nmolO2/min/mg protein, p=0.018). These results disprove our initial hypothesis. Despite the increased work on ventilation, chronic hypoxia is more detrimental to mitochondrial content and function in the diaphragm than in limb muscles.Supported by NIH/NIGMS F31 GM084665
Nocturnal asthmatic responses in house dust mite (HDM)‐sensitive Cynomolgus macaques detected by respiratory inductance plethysmography (RIP)
Authors: Wang Xiaojia , Reece Shaun , Olmstead Stephen , Van Scott Michael R. , Wardle Robert L. 
Published: June 2021

RationaleNocturnal bronchoconstriction is a common symptom of asthma. The goal of this study was to document nocturnal bronchoconstriction in a nonhuman primate model of allergic asthma. RIP parameters were investigated as proxies for changes in dynamic compliance (Cdyn) and lung resistance (RL), and then were used to monitor nocturnal asthmatic responses.MethodsAnimals were anesthetized; instrumented for simultaneous measurements of Cdyn, RL, and RIP parameters; and challenged with aerosolized HDM allergen. Multiple linear regression was used to correlate changes in RIP parameters, Cdyn and RL following HDM challenge. RIP parameters of conscious animals were monitored remotely overnight, plotted against time, and quantified as the area under the curve (AUC).ResultsEffort Phase Relations (ePhRL and eBPRL) correlated with changes in Cdyn and RL: ePhRL = 30.2 ‐ 4.4 Cdyn + 1.7 RL (p = 0.001; p < 0.001)eBPRL = 26.8 ‐ 3.8 Cdyn + 1.7 RL (p = 0.003; p < 0.001)In 29 nocturnal trials, 19 subjects exhibited increases in ePhRL and eBPRL between midnight and 5 AM, with peak activity at 4 AM. ePhRL and eBPRL during the nocturnal responses differed from that of non‐responders (p < 0.03).ConclusionThe results indicate that allergic asthmatic macaques exhibit nocturnal bronchoconstriction. Studies are underway to directly measure RL at the peak of the nocturnal response.
Sarcoplasmic Reticulum Ca2+ Reuptake and Airway Smooth Muscle Inflammation
Authors: Venkatachalem Sathish , Thompson Michael , Bailey Jeffery , Pabelick Christina , Prakash Y S , Sieck Gary C 
Published: June 2021

Intracellular Ca2+ ([Ca2+]i) levels are increased in inflamed airway smooth muscle (ASM). Sarcoplasmic reticulum (SR) Ca2+ release and reuptake are key components of ASM [Ca2+]i regulation. Ca2+ reuptake occurs via the ATPase SERCA. We hypothesized that inflammation disrupts SERCA function, contributing to increased [Ca2+]i. We examined SERCA expression and regulation in human ASM exposed to pro‐inflammatory cytokines TNFα and IL‐13. Western blot analysis showed significantly decreased SERCA expression following overnight cytokine exposure. In other tissues, SERCA is regulated by the inhibitory protein phospholamban (PLB). We found that human ASM does not express PLB protein (although mRNA is detectable). Cytokine exposure did not induce PLB expression, raising the issue of how SERCA is regulated. We then found that direct SERCA phosphorylation (potentially via CaMKII) occurs in human ASM. In fura‐2 loaded human ASM cells, we examined [Ca2+]i responses to ACh or bradykinin (zero extracellular Ca2+) and found significant reduction in rates of fall of [Ca2+]i transients in cells exposed to TNF‐α or IL‐13. We further found that CaMKII antagonist KN‐93 significantly slowed the fall of [Ca2+]i transients in both controls and cytokine‐exposed human ASM cells. These data suggest that a) SERCA in human ASM is regulated by mechanisms such as CaMKII; and b) airway inflammation decreases SR refilling by blunting SERCA expression and function.Supported by NIH grants HL74309, the Flight Attendants Medical Research Institute (FAMRI), and the Department of Anesthesiology, Mayo Clinic.
Exercise‐induced angiogenesis: When Murine Double Minute‐2 and Vascular Endothelial Growth factor run together for more capillaries
Authors: ROUDIER Emilie , BIROT Olivier 
Published: June 2021

Running exercise has been described as a physiological stimulus for skeletal muscle angiogenesis. Recent data, mostly from tumor cells studies, have evidenced that the Murine Double Minute‐2 (Mdm2) oncoprotein, the main negative regulator of p53, exerts itself some angiogenic effects, mainly by stimulating endothelial cells migration.ObjectivesWe investigated whether exercise regulated Mdm2 and whether Mdm2 could thus represent a new actor of exercise‐induced muscle angiogenesis.MethodsWe developed an innovative model of ex vivo muscle explant culture allowing the time‐course study of muscle angiogenesis. Plantaris muscles from sedentary or active (70‐90 min exercise on a running treadmill, 12% slope, 25 m/min) Sprague‐Dawley rats were used for protein measurements and our ex vivo angiogenesis assay.ResultsWe showed that 1) Mdm2 protein was strongly activated by phosphorylation on Ser166 in response to exercise, 2) exercise stimulated endothelial cells migration in our ex vivo muscle explant model, 3) such exercise‐induced angiogenic effect is dependant on Mdm2 activation, 4) Mdm2 activation is mediated by the Vascular Endothelial Growth Factor (VEGF) ‐ Extracellular signal‐regulated kinase 1/2 (ERK1/2) pathway.ConclusionMdm2 is a new key actor of exercise‐induced angiogenesis in rat skeletal muscle. This work was supported by the Natural Sciences and Engineering Research Council of Canada.
VEGF165b inhibits choroidal neovascularization (CNV) in mouse model via intra‐vitreous and subcutaneous delivery
Authors: Hua Jing , Spee Christine , Barron Ernesto , Kase Satoru , Churchill Amanda J , Harper Steven J , Ryan Stephen J , Bates David O , Hinton David R 
Published: June 2021

MethodsFour CNV lesions were induced by diode laser in each eye of C57B/L6J mice. Different doses of recombinant VEGF165b or solvent were injected into vitreous (0.01, 0.1, 1, 10ng/eye weekly) or subcutaneously (100µg, twice a week). Two weeks later, fluorescein angiography (FA) was carried out before animals were sacrificed and eyes dissected for sclero‐choroid whole mount or embedded for cross‐sections and samples were assessed by isolectin B4 and H&E staining under confocal and light microscopy.ResultsIntra‐vitreous injection of VEGF165b significantly reduced leakage of lesions in FA (p<0.001 ANOVA, n=5), 3D volume (p<0.0001, ANOVA, n=24, control 5.7, with increasing dose: 1.5, 1.4, 1.2, and 1.5x105 µm3), 2D surface (p<0.0001 ANOVA, n=24, control 6.0, with increasing dose 1.9, 2.1, 1.8, 2.4x105 µm2) and cross‐section surface (p<0.0001 ANOVA, n=5‐10, control 2.9, with increasing dose 1.8, 1.1, 0.9, 1.0x105 µm2). Subcutaneous injection of VEGF165b significantly reduced the leakage (p=0.02 t‐test, n=20), 3D volume (p<0.0001 t‐test, n=25) and 2D surface (p=0.0027, t‐test, n=25) of the CNV lesions.ConclusionVEGF165b significantly inhibit the growth of CNV in a mouse model, by either intraocular or systemic application. Considering its reported epithelial and neuroprotective effects, VEGF165b maybe a favorable candidate for choroidal neovascular diseases.
Aging blunts NFκB activation and HSP expression in response to estrogen in isolated female rat cardiomyocytes
Authors: Stice James Patrick , Knowlton Anne A 
Published: June 2021

ObjectiveWe investigated the role of aging vs. estrogen loss on the cardioprotective heat shock protein (HSP) response in a rat model. We hypothesized that aging itself would lead to a blunted HSP response, while 17β‐estradiol (E2) replacement in aging rats would confer protection against cellular injury through restoration of the HSP response.MethodsCardiomyocytes were isolated from ovariectomized adult (5 mos.) and aged (22 mos.) rats with and without 9 weeks of E2 replacement forming four groups: adult ovx, adult op, aged ovx, and aged op. Myocytes were treated in culture with E2 (5nM and 100nM) and analyzed for NFκB activation at 15 minutes and HSP expression at 12 h. Some cells were subjected to 6 hours of hypoxic injury followed by 24 hours of reoxygenation (H/R).Results100nM E2 activated NFκB and increased HSP 72 and 90 expression in adult ovx and adult op (p<0.05), while both aged ovx and aged op show no changes in response to E2. Levels of HSP 27, heme oxygenase‐1, and estrogen receptor (ER) did not did not differ among groups or after E2 treatment. All groups had increased LDH release in response to H/R injury; however, aged ovx had higher LDH release before and after H/R compared to all other groups.ConclusionsAging leads to a loss of NFκB activation and HSP expression in response to E2 and this is not due to a change in ER expression.Supported by the American Heart Association Western States Affiliate (JPS), the NIA AG019327 (AAK), and the Department of Veterans Affairs (AAK)
Role of Ca2+/Calmodulin‐dependent Protein Kinase II (CaMKII) in Endothelial Cells
Authors: Wang Zhen , Ginnan Roman G. , Singer Harold A. 
Published: June 2021

Endothelial cell (EC) barrier function and angiogenesis are partially dependent upon increases of intracellular free Ca2+ through G‐protein coupled receptor (GPCR) agonists such as thrombin and vascular endothelial growth factor (VEGF). The goal of these studies is to fully characterize the endogenous CaMKII isoform(s) in endothelial cells, and to test the hypothesis that the multifunctional Ca2+/calmodulin‐dependent serine/threonine protein kinase II (CaMKII), responds to thrombin‐ and VEGF‐stimulated Ca2+ signals and regulates EC barrier function and angiogenesis. For the 1st time, by RT‐PCR and western blotting, we successfully characterized the predominant CaMKII isoform expressed in cultured human umbilical vein endothelial cells (HUVEC) is the delta 6 (δ6) isoform, a novel δ‐isoform lacking the 21aa c‐terminal domain. We utilized siRNA approach to suppress CaMKIIδ6 protein expression and found it attenuated, only low dose (2.5nM) but not high dose (10nM), of thrombin‐induced increase of EC permeability. These data suggest a role of CaMKIIδ6 in mediating changes in barrier function in response to physiological relevant doses of thrombin. By using the same approach, we found that CaMKIIδ6 is pivotal in regulating VEGF induced HUVEC migration through Boyden Chamber. This work was supported by NIH grant to H.A.S (R01 HL‐049426).Grant Funding SourceNIH grant to H.A.S (R01 HL‐049426).
CaMKII mediates Ang‐II induced vascular smooth muscle cell hypertrophy by a pathway involving HDAC4/MEF2
Authors: Li Hui , Li Weiwei , Gupta Arun , Anderson Mark E. , Grumbach Isabella M 
Published: June 2021

IntroductionThe calcium/calmodulin‐dependent kinase II has been implicated in VSM growth and is activated by Ang‐II. Ang‐II activates the HDAC4/MEF2 dependent gene transcription which is important in muscle growth and hypertrophy. CaMKII specifically phosphorylates HDAC4 S467,632. We assessed the hypothesis that CaMKII mediates Ang‐II induced smooth muscle hypertrophy by a pathway involving HDAC4/MEF2.Methods and ResultsThe medial hypertrophy induced by Ang‐II over 10 days in C57Bl/6 mice was significantly reduced when the CaMKII inhibitor KN93 was given daily i.p.Infection of rat aortic smooth muscle cells with adenovirus expressing CaMKIIδ2 resulted in a 108% increase in 3H‐Leucine uptake with Ang‐II compared to 50% (p<0.05) increase in controls, whereas overexpression of the CaMKII peptide inhibitor CaMKIIN resulted in a 14 % increase.The phosphorylation of HDAC4 in response to Ang‐II was increased with the overexpression of CaMKIIδ2. CaMKII overexpression resulted in increased nuclear export of HDAC4, MEF2‐promoter activity and nucleoprotein complex formation in EMSA.HDAC4 overexpression led to decreased MEF2‐promoter activity and hypertrophy in response to Ang‐II. The dominant negative mutant HDAC4 S467,632A abrogated the activation.ConclusionCaMKII mediates Ang‐II induced VSM hypertrophy by derepressing HDAC4 and activating MEF2.Supported by: AHA, Carver Trust.
Gr.T. Popa in USA ‐ A hypothesis explaining his concept of upward blood flow through the hypothalamo‐pituitary portal system
Authors: Chirculescu Andy Remus Marius , Chirculescu Mihaela , Morris John F. 
Published: June 2021

The Romanian scientist Gr.T. Popa and Unna Fielding described the hypothalamo‐pituitary portal system, by 3D reconstruction of the vessels, in 1930. That started a debate on the direction of blood flow, which he postulated to be upward toward the hypothalamus. Why, then, did Popa propose an ascending direction of blood flow through the portal veins, although he made no dynamic study on microcirculation, but only analysed serial sections of the region? One possible explanation could be that a Rockefeller grant in Chicago, USA (1925‐26) gave him the opportunity to train and act as a demonstrator in embryology in C.R. Moore's lab. There it is quite likely that he would be impressed by the classical embryology concept, stated by Wolff, that any organ ascending or descending during ontogenesis keeps its original neurovascular supply and carries it to its final location. He would also have been aware that Rathke's pouch grows upward to meet the infundibular diverticulum. Therefore, when he came to London in 1930, he doubtless remembered this principle of development, and this led him to presume that blood continues to flow from the superior hypophyseal artery upward, from the pituitary to the hypothalamus, through the portal veins which he discovered.ARMC is a Senior visiting fellow of ASGBI in Dept. of Physiology, Anatomy & Genetics, University of Oxford, UK.