bluuebunny/crossref_metadata_2025_split huggingface dataset:
Daily Mg Supplements Above RDA Reduce High Blood Pressure in Hypertensive Human Subjects Not Taking Anti‐hypertensive Medications
Authors: Rosanoff A. 
Published: June 2021

BACKGROUND: Studies of magnesium (Mg) therapy for hypertension have led to conflicting results; this study was an attempt to lend clarity to this seeming conflict.METHODS: Forty‐one human studies testing nutritional Mg supplements with “change in blood pressure” as a measured outcome were collected, sorted as to anti‐hypertensive medication status of subjects, and listed in order of ascending Mg dose.RESULTS: Daily Mg supplements of 20 mmol or 486 mg/day were necessary to significantly lower high blood pressure in subjects treatment‐naïve or taking anti‐hypertensive medications <6 months. This level is higher than the current adult RDAs for nutritional Mg (320 mg/day for women; 420 mg/day for men). Mg supplements as low as 10 mmol (230 mg) per day significantly lowered blood pressure of hypertensive subjects treated ≥6 months with anti‐hypertensive medications (diuretics, Ca channel blockers, ACE inhibitors, beta‐blockers). Magnesium supplements as high as 25 mmol/day (607 mg) did not significantly lower blood pressure in studies where ≥40% subjects were normotensive at baseline ‐‐ treated or untreated. Mg supplements as high as 40 mmol (972 mg)/day did not lower the blood pressure of subjects speculated to be Mg‐replete by their study's authors, showing the importance of a standard, clinical test for Mg status assessment for full knowledge to come from future studies of nutritional Mg.CONCLUSIONS: Mg daily dose of 20 mmol (1.1 – 1.5 times higher than RDAs) is necessary to significantly lower high blood pressure in human subjects either treatment‐naïve or on anti‐hypertensive medication <6 months. Subjects’ anti‐hypertensive medication usage ≥6 months (diuretics, beta‐blocker, Ca channel blocker, or ACE inhibitor) reduces by half the daily Mg dose necessary to lower blood pressure in Stage 1, uncomplicated hypertension.
Pathway Analysis of Global Gene Expression Changes in rat liver following silencing of c‐met by RNA Interference.
Authors: Paranjpe Shirish , Tseng George , Chattopadhyay Ansuman , Luo Jianhua , Michalopoulos George K 
Published: June 2021

We have reported Cell cycle effects resulting from shRNA mediated inhibition of hepatocyte growth factor and its receptor c‐Met in regenerating rat livers following a partial hepatectomy (Hepatology, 45: 1471–1477). Microarray analysis of shMet and scrambled treated rat livers using Affymetrix U230.2 A chip containing 10,000 expressed sequences indicated abnormal expression of genes associated with cell cycle and apoptosis. Cluster analysis of microarray data was then carried out. Normalization and preprocessing of data from 8 chips was by dChip software. Expression intensities were log transformed and genes with expression level less than 7 or SD smaller than 0.5 were filtered out. Hierarchical clustering of the remaining 4747 genes according to similarity in pattern of gene expression produced 8 clusters. Of the 4747 genes, 805 genes whose expression value was >2 or <–2 compared to the corresponding control group were then analyzed using Ingenuity software. Networks were generated for each time point post PHx for shMet treatment and control group.It was observed that the genes associated with DNA repair, fatty acid metabolism, p38 MAPK pathway, and bile acid biosynthetic pathway were differentially regulated in shMet silenced rats when compared to scrambled treated controls.Suppression of c‐met thus caused profound alterations in multiple signalling pathways.
Realization and validation of cellular sensors to detect acetylcholine in vivo
Authors: Nguyen Quoc‐Thang , Schroeder Lee Frederick , Taylor Palmer W , Mank Marco , Griesbeck Oliver , Kleinfeld David 
Published: June 2021

In vivo detection of neurotransmitters with high temporal and spatial resolution is critical for understanding brain physiology. We adapted the use of the fluorescent cell‐based assay to create implantable Sentinel Cells to detect acetylcholine (ACh). Functional signals from these cells were imaged in vivo with two‐photon laser scanning microscopy (TPLSM).Sentinel cells were created by stably expressing the IP3/Ca2+‐coupled M1 muscarinic receptor and the genetically encoded FRET‐based Ca2+ sensor TN‐XXL into HEK293 cells. In vitro, bath application of ACh elicited a FRET signal in Sentinel Cells which increased monotonically from a treshold of ~ 30 nM (~ 30 % change in 7 s) to saturation at ~ 1 μM ACh (> 90 % change in 5 s).Sentinel cells were implanted in rat neocortex down to 200 μm from the surface and imaged by TPLSM. Acutely implanted cells had normal morphology and responded for at least 6 hours after implantation. Endogenous release of ACh was generated by electrical stimulation of the nucleus basalis magnocellularis which triggered signal changes (≥ 50%) in Sentinel cells. These responses were enhanced with the systemic injection of either tacrine or physostigmine. Following chronic intracerebral implantation, imaging of Sentinel cells could take place for up to 5 days.Our technique could potentially detect neurochemicals other than ACh by using different receptors or reporters.
Nitric oxide modulation of central imidazoline I1 receptors accounts for the hypertensive effect of cyclosporine in rats
Authors: El‐Mas Mahmoud M , Omar Amal G , Helmy Mai M , El‐Din Mahmoud M Mohy 
Published: June 2021

This study tested the hypothesis that the hypertensive action of cyclosporine (CSA) involves interaction with central α2‐receptors and/or I1‐imidazoline receptors and investigated the role of nitric oxide in the interaction. The effect of clonidine (mixed α2/I1‐receptor agonist), moxonidine (I1‐receptor agonist), or guanabenz (α2‐receptor agonist) on CSA hypertension was assessed in conscious rats. CSA (20 mg/kg i.v.) increased BP that continued for at least 45 min. CSA hypertension was inhibited by ganglionic (hexamethonium) or α1‐receptor (prazosin) blockade. Pressor responses to phenylephrine were not affected by CSA, thereby eliminating a possible role for α1‐receptors in CSA hypertension. Intravenous guanabenz (30 μg/kg), clonidine (30 μg/kg), or moxonidine (100 μg/kg) produced similar decreases in BP. Pretreatment with clonidine or moxonidine attenuated CSA hypertension whereas guanabenz had a minimal effect, suggesting a predominant role for I1‐receptor neuronal pathways in the BP effect of CSA. Central administration of moxonidine (80 nmol) into cisterna magna also attenuated CSA hypertension. NOS inhibition by NG‐nitro‐L‐arginine methyl ester abolished BP responses to moxonidine and CSA.Conclusion: facilitation of central I1‐receptor‐NO signaling accounts, at least partly, for CSA hypertension.Supported by Faculty of Pharmacy, Univ. of Alexandria, Egypt.
Statin‐induced Myotoxicity: Update on Case Characteristics and Recruitment Efficiency in a Clinical Practice‐based Setting
Authors: Mareedu Ravi K , Modhia Falgun M , Krauss Ronald M , McCarty Catherine A , Wilke Russell A 
Published: June 2021

Objectives: To characterize the clinical characteristics of the 181 research subjects participating in a retrospective case‐control study of the genetic factors underlying statin‐induced myotoxicity.Methods: Medical records of approximately 2,000,000 unique patients in a multi‐specialty group practice were interrogated electronically to identify individuals who had a serum creatinine kinase (CK) level drawn and at least one clinical note with text mentioning either atorvastatin, or, simvastatin, or, pravastatin, This yielded approximately 27,450 unique subject records. Inclusion of the upper 10th percentile for CK level (>370 IU/dL) resulted in 2745 patients. Eligibility was determined by prior physician notes reflecting an increased index of suspicion for drug intolerance.Results: Of 248 patients who met inclusion criteria, 181 subjects have chosen to enroll in the study. During physician review of these 181 cases (80 atorvastatin, 42 pravastatin, and 59 simvastatin), the clinical pain syndrome was graded using binary variables: 85/181 had diffuse pain, 52/181 had proximal pain and 36/181 had severe pain. 29/181 claimed recent vigorous physical exertion, and 20/181 reported the concomitant gemfibrozil use.Conclusions: A large subset of the validated cases had either proximal pain, diffuse pain, or severe pain. (Funding U01HL069757‐06)
Efficacious treatment of alcoholic steatosis by a pharmaceutical composition comprising metadoxine and garlic oil
Authors: Kim Sang Geon , Ki Sung Hwan 
Published: June 2021

Alcoholic steatosis is the earliest and common response to heavy alcohol intake, and may precede severe forms of liver injury. As an effort to develop an efficacious pharmaceutical composition, this study evaluated the effects of metadoxine, garlic oil or their combination on alcoholic steatosis. Feeding rats an alcohol‐containing diet for 4 weeks increased hepatic triglyceride content with CYP2E1 induction. Concurrent administration of metadoxine and garlic oil (MG, 1:1 w/w ratio) to rats synergistically abrogated both fat accumulation and CYP2E1 induction compared to the individual treatment. Histopathology confirmed the ability of MG combination to inhibit lipid accumulation. Blood biochemistry verified improvement of liver function in MG‐treated rats. Alcohol administration resulted in decreases in the AMPKα and ΑCC phosphorylations, which was restored by MG treatments. Hepatic fatty acid synthase (FAS) expression was decreased after alcohol consumption, which correlated with a decrease in AMPK activity and a commensurate increase in lipid content. Combined MG treatments allowed FAS expression restored. These results demonstrate that a pharmaceutical composition comprising MG effectively treats alcoholic steatosis, which may be associated with CYP2E1 repression and recovery of AMPK activity, promising pharmaceutical therapy for alcoholic steatosis.Supported by a contract fund from the Seoul R&BD Program (2005–2010).
Role of adenosine A2a receptor in regulation of cerebral blood flow (CBF) during induced hypotension
Authors: Kusano Yoshikazu , Miekisiak Grzegorz , Kulik Tobias , Sandler Adam , Winn Richard H. 
Published: June 2021

Introduction:The aim of this study is to evaluate the role for adenosine A2a receptor during induced hypotension in mice.Methods:Anesthetized and ventilated wild type (WT) and adenosine A2a receptor knockout (KO) mice (C57Bl/6) were used. Catheters were placed in femoral arteries for measurement of mean arterial pressure (MABP) and withdraw the arterial blood. MABP was lowered to 35 mmHg by continuously withdrawing arterial blood at a rate of 25 μl/min. CBF was measured using the laser‐Doppler flowmetery through the intact calvarium. We also studied the effects of specific A2a receptor antagonist, ZM‐241385 (1 mg/Kg and 5 mg/Kg, ip).Results:During hypotension CBF was attenuated by 38.9% in WT (n=5) and 51.1% in KO mice (n=7) (P<0.05). The low dose of ZM‐241385 (1 mg/Kg) (n=6) had no effect on reduction of CBF. However with a higher dose (5 mg/Kg) (n=6), the CBF significantly reduced by 51.3% (P<0.05).Conclusions:These results suggest that A2a receptor is involved in the attenuation of CBF during induced hypotension.Supported by NIH‐NS 21076 (HRW)
Role of Bilirubin Oxidation Products in delayed Cerebral Vasospasm after Subarachnoid Hemorrhage‐ an in vitro study
Authors: Nair Sunil G , Clark Joseph F , Wurster William L , Pyne‐Geithman Gail J 
Published: June 2021

Delayed Cerebral Vasospasm (CV) is a crucial and often fatal complication of Subarachnoid hemorrhage (SAH). The etiology and molecular mechanism of CV is still a mystery. Recent reports have shown that Bilirubin Oxidation Products (BOXes) are present in significantly greater concentrations in the cerebrospinal fluid of patients with SAH who suffer from vasospasm (CSFV) than in those who do not (CSFC). Previous studies have shown that BOXes are vasoactive in vivo and potentiate smooth muscle contraction similar to PKC activators and phosphatase inhibitors in vitro.Using tissue bath apparatus, we examined the potentiation of phenylephrine (PE)‐induced force‐generation by various concentrations of BOXes in porcine carotid artery tissue rings. 1.5 – 7 μmol/L BOXes showed significantly increased potentiation of PE‐induced contraction when compared to vehicle. This was also observed with CSFV. We also studied the cytoplasm‐to‐membrane translocation of PKC's α and δ, and Rho in the presence of three different patho‐physiologically relevant concentrations of BOXes (0.2, 2 & 20μmol/L) at two‐points (20 minutes and 3 hours). Translocation of these proteins indicates their activation. Both PKC's and Rho were translocated in a time‐ and dose‐dependent manner by BOXes.Therefore, we postulate that BOXes may be one of the major molecules responsible for the etiology of CV after SAH.
Hyperlipidemia Enhances Leukocyte Rolling in vivo by Involving Myd88‐Dependent Innate Immune Pathways
Authors: Pistea Adrian , Olofsson Katarina , Lindholm Marie , Zetterqvist Anna V , Öhman Jenny Nilsson , Gomez Maria F , Nilsson Jan , Thorlacius Henrik , Björkbacka Harry 
Published: June 2021

Background and aims:Absence of MyD88, a central signaling protein in innate immune defense, protects Apoe−/−mice from atherosclerosis (Björkbacka, Nat Med 2004). We aimed to investigate the involvement of MyD88 in the regulation of leukocyte‐endothelium interactions – a critical step in the formation of atherosclerotic lesions.Methods:Apoe−/−Myd88+/+ and Apoe−/−Myd88−/− mice were fed ad libitum chow or a high fat diet (HFD) for 4 weeks. Leukocyte rolling and adhesion were assessed in vivo in the femoral artery and vein by means of intravital microscopy; adhesion molecule expression was assessed by flow cytometry on leukocytes and by confocal microscopy in cerebral arteries.Results:Caloric intake was not affected by diet and no significant weight gain was noticed. HFD induced a significant increase in the number of circulating neutrophils in the Apoe−/−Myd88+/+ mice. HFD also increased the number of activated leukocytes, as indicated by increased CD11b surface expression. Leukocyte rolling was significantly increased by HFD in femoral veins of Apoe−/−Myd88+/+ mice, as compared to chow fed littermates or Apoe−/−Myd88−/− mice receiving HFD (p<0.01).Conclusions:High fat diet‐induced leukocyte rolling is MyD88‐dependent and may contribute to the leukocyte accumulation in the vascular wall observed in atherosclerosis.
uPA Contributes To Impairment Of SNP and PGE2 Cerebrovasodilation After Brain Injury Through Activation of LRP and ERK MAPK
Authors: Armstead William M , Christine Amy J , Higazi Abd Al‐Roof , Bdeir Khalil , Cines Douglas B 
Published: June 2021

Introduction: Pial artery dilation to prostaglandin (PG)E2 and the nitric oxide (NO) releaser sodium nitroprusside (SNP) are blunted but responses to papaverine unchanged after fluid percussion brain injury (FPI). Urokinase plasminogen activator (uPA) and ERK mitogen activated protein kinase (MAPK) are upregulated and contribute to impaired cerebrohemodynamics after FPI in the piglet. PA vascular activity is mediated by the low density lipoprotein receptor (LRP). This study investigated the role of uPA, LRP, and ERK MAPK in impaired cerebrovasodilation to PGE2 and SNP after FPI.Methods: Lateral FPI (2 atm) was induced in anesthetized 1‐5 day old piglets equipped with a closed cranial window. CSF ERK MAPK was quantified by ELISA.Results: Pretreatment with the antagonist of the vascular action of uPA, suPAR, blunted impairment of SNP and PGE2 dilation after FPI while responses to papaverine were unchanged. Similarly, pretreatment with the LRP antagonist RAP, the monoclonal antibody against LRP (Mab ag LRP) and the ERK MAPK antagonist, U 0126, all blunted impairment of SNP and PGE2 dilation post insult. In contrast, control IgG had no effect on FPI induced impairment of SNP and PGE2. Phosphorylation of CSF ERK MAPK was upregulated after FPI but such upregulation was blunted in animals pretreated with suPAR, RAP, and MAb ag LRP. Control IgG had no effect on FPI induced ERK MAPK upregulation. The ERK MAPK antagonist U 0126 blocked the upregulation of CSF ERK MAPK after FPI.Discussion: These data indicate that uPA contributes to impairment of SNP and PGE2 cerebrovasodilation after brain injury through activation of LRP and ERK MAPK.
Right ventricular wall microvascular response to increased pulmonary artery pressure with particular reference to age of onset
Authors: Beighley Patricia E. , Dong Yue , Ouchi Hideo , Zamir Mair , Ritman Erik L. 
Published: June 2021

Patients with congenital heart disease who have a morphological right ventricle (RV) serving as a systemic ventricle have an increased incidence of RV dysfunction. A different structural response of micro‐vessels to increased stress in the RV wall is a possible mechanism for this dysfunction. We examined this possibility by measuring the volume of myocardium perfused by arteries less than 200μm in lumen diameter (V) 7 weeks after a 5mg/kg IV injection of monocrotaline in three 2‐week old and three 18‐week old pigs. This information was obtained by use of 3D micro‐CT of transmural segments (~ 2cm3) of the RV wall. The table provides the average values of V (mm3/mm2 ± SD). Pulmonary artery pressures in the mature, treated pigs were 35±6 mmHg and in the juvenile were 25±2 mmHg. V did not differ from control in the treated 2.5‐month old pigs but trended down in the 6‐month old pigs.We conclude that the volume of myocardium perfused by an arteriole in the RV wall may be an indicator of the perfusion reserve available to the microcirculation in response to increased wall stress. A more definitive answer would require delayed study of the early onset treatment group at the age of 6 months.(Supported in part by NIH grant EB000305)
Endogenous hydrogen peroxide is vasoactive in mesenteric arteries of spontaneously hypertensive rat
Authors: Kroetsch Jeffrey Thomas , Rush James W.E. 
Published: June 2021

Hydrogen peroxide (H2O2) is an endogenous endothelium‐dependent dilator in resistance vessels; however, a role for H2O2 in the mesenteric vessels of the spontaneously hypertensive rat (SHR) has not been established. Mesenteric arteries were excised from SHR and normotensive (WKY) rats and myography was performed. Vessels were incubated with 3μM of the β‐blocker propranolol, pre‐contracted with norepinephrine, and cumulative dose‐response curves for acetylcholine (Ach) were conducted. Maximal dilation to Ach was impaired in SHR compared to WKY (76±4% vs 97±1%, p<0.05). Co‐incubation with the nitric oxide synthase inhibitor Nω‐nitro‐L‐arginine (L‐NAME, 0.3mM) and the cyclooxygenase inhibitor indomethacin (INDO, 5μM) reduced dilation in SHR (52±6%, p<0.05). Co‐incubation with L‐NAME, INDO, and the H2O2 scavenger catalase (CAT, 860U/mL) caused a further reduction in SHR dilation (32±3%, p<0.05). Incubation with CAT alone caused improved dilation (92±12%, p<0.05) while incubation with the superoxide dismutase mimetic 4‐hydroxy‐TEMPO (1mM) reduced dilation (59±7%, p=0.05) in SHR. WKY dilation was not altered by any treatment. Thus, in the presence of nitric oxide and prostaglandins, H2O2 acts as a constrictor; however, in the absence of nitric oxide and prostaglandins, H2O2 acts as a dilator in SHR mesenteric arteries.Funding: NSERC/Heart and Stroke Foundation of Ontario
Regulation of VEGF mRNA expression in hypoxic pulmonary artery endothelial cells (PAECs) by histone deacetylases (HDACs)
Authors: Middleton Natavia S. , Ruchko Mykhaylo , Gorodnya Olena , Gillespie Mark N. 
Published: June 2021

The mechanism by which HDACs regulate gene expression in hypoxia is not understood. Some evidence suggests that HDACs act directly on HIF‐1, a key transcription factor, to facilitate binding to the hypoxic response element (HRE). Other studies indicate that HDACs impact chromatin‐remodeling processes and modulate access of the HRE to transcriptional proteins. To explore these possibilities, we first used Western immunoblot and DNA affinity precipitation analyses to determine if the HDAC inhibitor, trichostatin A (TSA), altered abundances and DNA binding activities, respectively, of HIF‐1, p300, and HDAC1 in normoxic and hypoxic PAEC nuclear extracts. While HDAC inhibition caused minor changes in nuclear abundances of these transcriptional proteins, their association with a 65‐mer oligonucleotide sequence of the VEGF HRE was unaffected. Next, using chromatin immunoprecipitation assays to examine transcriptional complex formation in intact PAECs, we found that TSA suppressed HIF‐1, p300, and HDAC1 binding to the HRE of the VEGF gene. Nuclease digestion assays showed that TSA redistributed the VEGF HRE from transcriptionally active mononucleosomes to highly condensed chromatin structures. These findings suggest HDACs are recruited to the VEGF HRE in PAECs where they regulate hypoxia‐induced VEGF expression by remodeling chromatin and facilitating transcriptional complex formation.Supported by NIH and AHA
Role of ErbB tyrosine kinase receptors in aging‐related cardiac dysfunction
Authors: RAJAGOPALAN VISWANATHAN , ZUCKER IRVING H , MA YING J 
Published: June 2021

Background: Multiple factors are known to be involved in aging‐related cardiac dysfunction. We and others have showed that inhibition of cardiac ErbB tyrosine kinase receptor signaling lead to cardiac dysfunction. Also, ErbB expression is downregulated in aging‐related neural dysfunction. We hypothesized that compromised ErbB signaling is associated with aging‐related cardiac dysfunction.Methods: Young adult (4–7 mo), middle aged (9–12 mo) and aged adult (18–22 mo) mice (n=4–5/group) were studied for cardiac function parameters using high frequency echocardiography and radiotelemetry (conscious). RT‐PCR and Western Blotting were performed to study ErbB expression.Results: Compared to young adult mice, aged mice had significantly decreased ejection fraction (%; 55.3±1.5 vs. 66.6±3.1; p<0.01), fractional shortening and left ventricular (LV) dP/dtmax (mmHg/s; 3420±494.2 vs. 8423±486.2; p<0.001) but significantly increased LV systolic internal diameter (mm; 2.7±0.1 vs. 2.3±0.2; p<0.05), end‐diastolic pressure (mmHg; 22.8±0.8 vs. 6.2±0.5; p<0.001) and mass (mg/g b.w.; 4.3±0.2 vs. 3.3 ±0.2; p<0.05). Ligand‐binding ErbB‐1 and ErbB‐4 receptor expression of mRNA, protein and phosphorylated protein were significantly diminished in aged mice compared to young mice (OD; p<0.01).Conclusion: Compromised ErbB signaling may be an important factor mediating aging‐related cardiac dysfunction.