bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abnormal Reactivity of Afferent Neuronal Pathway from the Heart to the Brain in Heart Failure Patients
Authors: Suzuki Hideaki , Hirose Masanori , Wakayama Yuji , Watanabe Satoshi , Miura Shoko , Fukudo Shin , Shimokawa Hiroaki 
Published: June 2021

BackgroundThe involvement of afferent neuronal pathway from the heart to the brain in heart failure (HF) remains unknown.Methods and ResultsWe recorded cardiac cerebral evoked potentials (CEPs) induced by ventricular (VVI) pacing in 21 patients with or without HF [64.5±2.6 yrs (SEM), 16 males and 5 females] within a week after pacemaker implantation or cardiac resynchronized therapy. Electroencephalogram (EEG) was simultaneously recorded from the vertex (Cz, international 10–20 system) during the VVI pacing of control stimulation (1.5 V) and an intense stimulation [6–8 (7.21±0.15) V] at 70–100 (80.5±1.9) bpm for 2 min. We averaged 100 EEG waves triggered by the VVI pacing to obtain CEPs. Cardiac CEPs were obtained by subtracting CEPs with control stimulation from those with intense stimulation. In Stage B/C HF patients (n=7 each), cardiac CEPs were reproducibly identified with first negative (N1) peak at 67–93 msec, first positive (P1) peak at 128–147 msec and second negative (N2) peak at 180–194 msec after the stimuli, whereas no such clear CEPs were detected in the remaining 7 patients without organic heart disease and HF.ConclusionsThese results suggest that the abnormal reactivity of cardiac afferent neurons from the heart to the brain is associated with development of HF.
Neprilysin Peptidase‐Independent Complex Formation In Pulmonary Artery Smooth Muscle Cells
Authors: Wick Marilee J. , Miller York E. , Dempsey Edward C. 
Published: June 2021

Pulmonary hypertension (PHTN) results from vasoconstriction and remodeling of pulmonary arteries (PA), including accumulation and migration of smooth muscle cells (SMCs). We found that the activity/expression of the transmembrane peptidase neprilysin (NEP) is decreased in chronic hypoxic PHTN, and that chronically hypoxic NEP null mice have increased pulmonary vascular remodeling. We hypothesize that, besides peptidase effects, the peptidase‐independent mechanisms of NEP, mediated through coupling of NEP to intracellular proteins, are important in mediating the effects of NEP in PA SMCs.Silver‐stained gels of C57BL/6 wt mouse PA SMCs, co‐immunoprecipitated with an antibody to NEP, show bands of 40, 55, 65, 75, 90 and 150 kD. Western analyses (n=2–5) show that NEP forms complexes with the MAPK ERK1/2 and the protein kinase Lyn. Human PA SMCs show similar results. Future studies will investigate the growth‐ and migratory‐inhibitory properties of these complexes, as well as characterize NEP complexes with other proteins. These findings indicate that peptidase‐independent mechanisms may contribute to the mechanisms of action of NEP and may aid in understanding NEP's involvement in preventing/reversing pulmonary vascular remodeling, and in designing treatment and prevention strategies for PHTN.Research Support: NHLBI RO1 HL‐078929‐01 and PPG HL‐014985, UCD Dept. of Medicine, and the VA.
Peripheral vs central administration of NaCl differently modulates vasopressin secretion through the regulation of PVN Gαq sub‐unit proteins
Authors: Kapusta Daniel R , Wainford Richard D 
Published: June 2021

HypothesisPVN Gαq sub‐unit protein gated pathways, which are stimulatory on AVP secretion, are endogenously down‐regulated to prevent excess AVP secretion following peripheral, but not central, administration of NaCl.MethodsSprague‐Dawley rats were maintained on 0.4% or 8% NaCl chow, or were infused intracerebroventricularly (i.c.v.) with aCSF or 0.8M NaCl aCSF for 21‐days (N=5/gp). PVN tissue was examined for Gαz & Gαq protein expression (normalized to GAPDH) via immunoblotting. Plasma AVP levels were determined via ELISA. In rats treated chronically as described above, N/OFQ (peptide inhibitor of AVP) was injected i.c.v. (5.5 nmol) and urine output was collected for 90‐min (10‐min periods). Separate rats infused with 0.8M NaCl (21‐days) were pre‐treated i.c.v. with a Gαq oligodeoxynucleotide (ODN; 25 μg) 24‐h prior to plasma AVP and PVN Gαz/q protein measurement.Results

0.4% NaCl diet
8% NaCl diet
aCSF i.c.v. infusion
0.8M NaCl aCSF i.c.v. infusion
0.8M NaCl aCSF i.c.v. infusion + Gαq ODN

PVN Gαq Protein levels [ODU]
0.99±0.07
0.12±0.05*
1.16±0.06
1.09±0.08
0.22±0.04#

PVN Gαz Protein levels [ODU]
2.24±0.13
2.34±0.12
2.01±0.12
2.12±0.13
2.08±0.11

AVP [pg/ml]
1.39±0.07
1.38±0.14
1.50±0.17
2.12±0.17#
0.99±0.06#

Peak Diuresis to N/OFQ [μl/min]
199±16
191±11
177±23
54±12#
T.B.D.

*, # Sig diff vs 0.4% NaCl or aCSF gp;ConclusionIn response to a peripheral salt load, which does not elevate CSF NaCl levels, the down‐regulation of PVN Gαq proteins is an endogenous counter regulatory mechanism to prevent salt‐induced increases in plasma AVP levels and water retention. When CSF NaCl is increased, this counter‐regulatory mechanism fails, leading to increased circulating AVP and an impaired diuretic ability. AHA 2250585, DK43337, HL071212, AHA 0855293E, P20 RR018766
Hypertension in response to agonistic autoantibodies to the angiotensin II type I receptor (AT1‐AA): role of reactive oxygen species (ROS)
Authors: LaMarca Babbette , Parrish Marc , Weimer Abram , Arany Marrietta , Cockrell Kathy , Dechend Ralf 
Published: June 2021

AT1‐AA and ROS are implicated in hypertension in preeclamptic women. Administration of purified rat AT1‐AA significantly increases mean arterial pressure (MAP) and placental ROS in normal pregnant rats. The objective of this study was to determine the role of ROS in mediating AT1‐AA induced hypertension during pregnancy.To achieve this goal, MAP and ROS were analyzed in AT1‐AA induced hypertensive pregnant rats in the presence and absence of a superoxide dismutase mimetic, Tempol. Rat AT1‐AA (1:50) was infused intraperitoneally via osmotic minipumps and Tempol (30mg/kg/day)was delivered in drinking water of pregnant rats beginning on day 12 of gestation. On day 19 MAP was analyzed and placentas were collected for ROS analysis via lucigenin chemiluminescence technique.MAP was 101 + 2 in NP rats and 116 + 2 mmHg AT1‐AA rats (p=0.002). Placental basal and NADPH oxidase stimulated ROS was 29 +/− 6 and 92 +/− 10 RLUs in NP rats. These levels increased to 159 +/− 29 (P<0.01) and 287 +/− 60 RLUs (P<0.001) in AT1‐AA rats. MAP in AT1‐AA + Tempol rats was 109 +/−3 vs 109+/−2 mmHg in Tempol treated controls. Administration of Tempol decreased ROS in AT1‐AA treated rats (121+/−13; 262 +/−21 RLUs) compared to Tempol treated controls (69 +/−24; 141 +/− 33 RLUs)AT1‐AA induced hypertension is associated with placental placenta oxidative stress and is attenuated with administration of an SOD mimetic
Global knockout of AMP‐activated protein kinase alpha subunits attenuates the hypoxic ventilatory response in mice
Authors: Wyatt Christopher N , Jordan Heidi L , Barr Barbara L , Viollet Benoit , Peers Chris , Hardie D. Grahame , Evans A. Mark 
Published: June 2021

The AMP‐activated protein kinase (AMPK) is a heterotrimer composed of catalytic α and regulatory βγ subunits. AMPK monitors the AMP:ATP ratio as an index of metabolic stress and, when activated, adjusts cell metabolism to maintain ATP supply. Previously we have proposed that AMPK may also underpin hypoxia‐response coupling in the carotid bodies, which mediate the entire ventilatory response of the body to acute hypoxia. We therefore sought to determine whether or not AMPK was sufficient and necessary for this process by global knockout of the catalytic alpha subunits in mice.AMPKα1 and AMPKα2 knockout mice (European Mutant Mouse Archive) were bred onto a C57BL/6: 129/X1 background to obtain knockout (−/−) animals. Breathing during normoxia (21% O2) and the hypoxic ventilatory response to 8% O2 (3 min) were monitored using a Respiromax plethysmography system (Columbus Instruments). Minute ventilation at rest was lower in AMPKα1−/− (1.7 ± 0.1 ml/g/min) and AMPKα2−/− (1.6 ± 0.1 ml/g/min) mice when compared to controls (2.3 ± 0.1 ml/g/min, P < 0.0004). Most significantly, the increase in minute ventilation triggered by hypoxia was attenuated in AMPKα2−/− mice (3.8 ± 2.8%) when compared with controls (19.0 ± 4.1%, P < 0.005). These data provide further support for the new hypothesis that AMPK regulates oxygen and thereby energy supply at the whole body level.Funded by the American Heart Association and the Wellcome Trust
Modulation of Acute Hypoxia on Canonical Transient Receptor Potential Channel 3
Authors: Yang Qin , Huang Jun‐Hao , Yao Xiao‐Qiang , He Guo‐Wei 
Published: June 2021

Canonical transient receptor potential channel 3 (TRPC3) is involved in intracellular Ca2+ ([Ca2+]i) regulation therefore is important in cell function. Whether this channel is affected by ischemia/hypoxia has been poorly studied. We investigated the response of the TRPC3 channel to acute hypoxia. Human embryonic kidney cells (HEK293 cells) were transiently overexpressed with TRPC3 gene and exposed to either normoxia or acute hypoxia (10 min, PO2<10 mmHg). Ionic currents were measured by patch‐clamp and protein expression was determined by western blot. Application of 1‐oleyl‐2‐acetyl‐sn‐glycerol (OAG, 100 μM) evoked significant cation currents in TRPC3‐overexpressing HEK293 cells (3.1±0.4 vs. 1.9±0.3 pA/pF, p<0.01) but not in wild‐type cells (2.0±0.4 vs. 1.9±0.4 pA/pF, p>0.05). Acute exposure to hypoxia enhanced the increase of current induced by OAG (5.7±0.9 vs. 3.0±0.4 pA/pF in normoxia, p<0.05). With the presence of specific anti‐TRPC3 antibody, OAG failed to induce current change in both normoxia (1.9±0.2 vs. 2.1±0.1 pA/pF) and hypoxia‐exposed cells (2.0±0.4 vs. 2.4±0.4 pA/pF) (p>0.05). Protein expression of TRPC3 was not altered. Acute hypoxia enhances the electrophysiological activity of the TRPC3 channel. This may be a mechanism involved in [Ca2+]i dysregulation under hypoxic/ischemic conditions.Supported by Hong Kong GRF grants CUHK4651/07M & 4789/09M and CUHK direct grant 2041457.
Maternal obesity affects MicroRNA expression in fetal muscle at mid‐gestation
Authors: Yan Xu , Zhu Mei J , Dey Arup , Ford Stephen P , Nathanielsz Peter W , Du Min 
Published: June 2021

INTRODUCTIONObesity is increasing at an alarming rate. Previous findings in our laboratory have shown that maternal obesity leads to increased adipogenesis in fetal muscle. Expression of adipogenic genes lead to adipogenesis. MicroRNAs play a crucial role in the regulation of gene expression. Using the pregnant sheep as a model, the objective was to assess microRNA expression in fetal muscle due to maternal obesity.METHODSNon pregnant ewes were randomly assigned to a control (Con, 100% of NRC recommendations, n = 5) or obesogenic (OB, 150% of NRC, n = 5) diet from 60 days before to 75 days after conception, when fetal longissimus dorsi (Ld) muscle was collected. MicroRNAs were extracted, purified and subjected to microRNA microarray analyses using the known microRNAs from human, rat, mouse and cattle.RESULTS67 microRNAs were identified in fetal LD muscle based on the generation of strong hybridization signals. Among those, 3 microRNAs, including hsa‐miR‐381, hsa‐let‐7g and bta‐miR‐376d, were differentially expressed between the Con and OB groups, which was confirmed by real‐time quantitative PCR. Hsa‐miR‐381 was 51.7 ± 17.3% higher (P < 0.05) in the OB fetal muscle compared to Con, while Hsa‐let‐7g (21.5 ± 4.9% (P = 0.06) and Bta‐miR‐376d (26.0 ± 8.8% (P < 0.05) were lower.CONCLUSIONMaternal obesity induced differential expression of microRNAs in fetal LD muscle. Since microRNAs regulate gene expression, changes in microRNA expression potentially play important roles in the development of fetal muscle, including adipogenesis, in the setting of maternal obesity. (Supported by NIH 1R03HD057506 and Wyoming INBRE P20RR016474)
Macrophage hemoglobin scavenger receptor CD163 is functionally linked to heme oxygenase‐1 and ferritin expression in human diabetic atherosclerotic plaques
Authors: Purushothaman Meerarani , Purushothaman K‐Raman , Levy Andrew P , Lento Patrick A , Fallon John T , Fuster Valentin , Sharma Samin K , Moreno Pedro R 
Published: June 2021

BackgroundThe macrophage hemoglobin scavenging receptor CD163 plays a major role in the clearance of hemoglobin (Hb) released from lysed red blood cells after intraplaque hemorrhage (IPH). We hypothesize that impairment in CD163 expression may alter HO‐1 and ferritin defense mechanism in the clearance of Hb in diabetic (DM) plaques inducing atherothrombosis.MethodsHuman DM atherosclerotic plaques (33) and no‐DM plaques (49) were characterized using H&E. The macrophage (CD68) and CD163 protein expressions were quantified by double label immunochemistry and gene expression in serial sections by real time PCR. The HO‐1 and ferritin protein expression was graded by immunohistochemistry.ResultsThe mean percentage of macrophages expressing CD163 was significantly decreased in DM plaques (DM 26.2 % ± 2 vs No‐DM 66.9 % ± 2, p=0.0001). The CD163 and HO‐1 mRNA expressions were down regulated in DM (DM 0.0689±0.017 vs No‐DM 0.3078±0.055, p=0.002, and DM 0.002±0.0006 vs No‐DM 0.0369±0.012, P=0.005) respectively. The protein expression of ferritin was also decreased in DM plaques (DM 0.7±0.1 vs no‐DM 2.6±0.2, p=0.0001).ConclusionCD163 may have a functional role in the induction of HO‐1 and ferritin expression. Thus, impairment in CD163 expression may alter HO‐1 and ferritin defense mechanism leading to atherothrombosis in DM plaques.
Transcription factor MafB is a mediator of retinoic acid‐induced monocytic cell differentiation
Authors: Zhang Yao , Chen Qiuyan , Ross A. Catharine 
Published: June 2021

All‐trans‐retinoic acid (RA), the major active metabolite of vitamin A, regulates monocytic cell cycle and differentiation. We asked whether MafB, a factor involved in development and hematopoiesis, is a mediator of RA‐induced differentiation in THP‐1 human monocytic cells. MafB mRNA and protein levels were up‐regulated by RA dose‐ and time‐dependently. RA and TNFα synergistically regulated MafB expression, mainly at the transcriptional level. MafB protein was highly phosphorylated. Blocking the ERK and p38 pathways reduced phospho‐MafB protein without changing mRNA levels. Next, MafB target genes were screened. SPOCK1, CCL2 and Blimp1 were identified as potential targets, due to the presence of Maf recognition elements in their putative promoter regions. These genes are related to cell communication and differentiation. By RT‐PCR analysis, the regulation of SPOCK1, Blimp1 and CCL2 mRNA levels were highly correlated with MafB mRNA. Decreased expression of SPOCK1, Blimp1 and CCL2 was observed when MafB phosphorylation was blocked. Chromatin immunoprecipitation assays showed increased MafB protein binding to the elements on the promoter regions of SPOCK1, Blimp1 and CCL2 in cells treated with RA and TNFα. We conclude that RA and TNFα‐induced MafB may play a role in monocytic cell differentiation through transcriptional regulation of SPOCK1, CCL2 and Blimp1. Support: NIH DK41479.Grant Funding Source: NIH DK41479
The Complement Split Products C3a and C5a are potent Activators of Mesenchymal Stem Cells
Authors: Schraufstatter Ingrid , Discipio Richard , Khaldoyanidi Sophia 
Published: June 2021

It is known that mesenchymal stem cells (MSC) are recruited to sites of tissue injury to fulfill their repair function. It is also known that there is complement activation, wherever there is tissue injury. We therefore determined the effect of the complement split products C3a and C5a on MSC. FACS analysis indicated that human bone marrow‐derived MSCs express cell‐surface C3a receptors (C3aR) and C5a receptors (C5aR). Both C3a and C5a induced chemotaxis of MSCs in a dose dependent fashion. Specific C3aR and C5aR inhibitors blocked the chemotactic response as did pertussis toxin, indicating that the response was mediated by the known anaphylatoxin receptors in a Gi activation‐dependent fashion.While C5a causes prolonged activation of many cell types, the response to C3a is generally transient and weak. However, in MSCs both C3a and C5a caused prolonged ERK1/2 and Akt phosphorylation. Phospho‐Akt and phospho‐ERK1/2 were translocated to the nucleus with both stimuli, which was associated with subsequent phosphorylation of the transcription factor Elk. More surprisingly, the C3aR itself was translocated to the nucleus in C3a‐stimulated MSCs. Since nuclear translocation of G‐protein coupled receptors has been shown to induce long‐term effects including transcriptional activation, this novel observation implies that C3a exerts far reaching consequences on MSC biology. The prolonged activation of C3aRs and to a lesser degree of C5aRs was associated with increased expression of several angiogenic factors in MSC including VEGF, bFGF and IL‐8. These results suggest that C3a and C5a present in injured tissues contribute to the recruitment of MSC and that means of activating the C3aR or C5aR on MSC could improve their ischemic repair potential, which would be more attractive for C3a, which lacks the inflammatory action of C5a.
Ethical and legal issues in BTB (Brain/tissue/Bio) Banking
Authors: Ravid Rivka 
Published: June 2021

BTB (Brain/Tissue/Bio) Banks form essential repositories for clinical and basic research; The collection, storage, distribution and use of biological materials in research raise many legal and ethical issues which are currently not well regulated on an international level due to differences and conflicting laws and policies.Brain/Tissue/Bio Banks currently aim at the following objectives:
Foster research in clinical and basic science and serve as a dynamic system with ongoing consultations on the many various daily issues of banking.
Achieve standardization between banks of commonly accepted criteria for the pathological diagnosis and compatibility of protocols (SOP's) for tissue procurement, management and preparation.
Facilitate multi‐center concordance studies and studies of risk factors in diseases which have genetic end environmental components.
Monitor safety measures and secure storage.
Abide by ethical and legal codes of conduct; the laws regulating consent and autopsy procedures and the ethical guidelines are significantly different in the various repositories.
To create and develop the adequate infrastructure for these activities, we are in the process of publishing an inventory of the medico‐legal and ethical framework conform local legislation. We have also made an inventory of the ethical aspects applied in daily practice of procurement, management, dissemination, confidentiality, “Financial gain” and genetic testing.These results of the inventarisation are now being incorporated into the 3rd edition of ISBER's “Ethical Issues of Human Subjects and Animals”.
Simvastatin ameliorates renal fibrosis via suppressing uterine sensitization‐associated gene‐1 (USAG‐1), a BMP‐7 antagonist, in mouse adenine‐induced tubulointerstitial injury model
Authors: Hamasaki Yoshifumi , Okamoto Koji , Doi Kent , Fujita Toshiro , Noiri Eisei 
Published: June 2021

Background & PurposeIt is known that BMP‐7 counteracts with TGF‐β, the dominant molecule promoting renal fibrosis, and that uterine sensitization‐associated gene‐1(USAG‐1), the dominant BMP‐7 antagonist expressing in distal tubular epithelial cells, promotes renal fibrosis. In this study, we investigated whether simvastatin (SIM), one of the HMG‐CoA reductase inhibitors, attenuates renal fibrosis by modulating BMP‐7 and USAG‐1 mediated pathway.Method & ResultsC57/BL6 mice fed by 0.2% adenine‐containing diet for 4 weeks showed significant increase of blood urea nitrogen (BUN) accompanied with severe tubulointerstitial fibrosis. SIM treatment for two weeks (50mg/kg/day) significantly reduced BUN compared with the control group (p<0.01). In pathological analysis, the area of fibrosis and the expression of alpha smooth muscle actin were significantly attenuated by SIM (p<0.05). In quantitative real‐time PCR, USGA‐1 expression was significantly lower in the SIM group (p<0.05). MDCK cells (distal epithelial tubular cells) incubated with TGF‐β (5ng/ml) for 72 hours showed increased expression of USAG‐1. SIM significantly reduced USAG‐1 expression (p<0.01). Several database analyses predicted the binding sites of HOXA‐13, a transcriptional factor, in the promoter region of USAG‐1 gene. The expression assay in vitro suggested that HOXA13 functions as a suppressor of the USAG‐1 gene and SIM decreased USAG‐1 expression by enhancing HOXA13.ConclusionOur data showed that SIM ameliorated renal fibrosis by suppressing USAG‐1. Decreased USAG‐1 levels may enhance the counteract effect of BMP‐7 against TGF‐β. We also demonstrated that HOXA13 plays a crucial role in the mechanism of this action by SIM.
Effect of the Valsalva maneuver on cardiac‐coronary interaction studied by coronary wave intensity in humans
Authors: Rolandi Cristina , Nolte Froukje , Remmelink Maurice , Baan Jan , Piek Jan , Spaan Jos A.E. , Siebes Maria 
Published: June 2021

Coronary wave intensity (WI) reflects the effects of cardiac contraction and relaxation on coronary blood flow dynamics. The typical coronary WI pattern shows backward and forward compression waves in early systole (BCW and FCW, resp.), followed by forward and backward expansion waves (FEW and BEW, resp.) during early relaxation. The severe cardiovascular stress imposed by a Valsalva maneuver (VM) was studied in relation to coronary WI.In 8 patients undergoing cardiac catheterization, we simultaneously recorded left ventricular (LV) and aortic pressure (Pa), and intracoronary pressure (Pd) and flow velocity (v), while the patients performed a VM. WI was computed as WI = (dPd/dt)·(dv/dt). Changes in the peaks of the dominant waves were compared to changes in pulse pressure (PPa) and LV contractility (LVdPdt).During the strain phase of the VM, forward WI was reduced by almost 80% (p < 0.015). The intensity of the BEW dropped to less than half of the BCW (p < 0.02). PPa was highly correlated to the FCW and FEW (r = 0.94, p < 0.006) and LVdPdt was the major determinant of the BEW (r = 0.97, p < 0.001).We conclude that the VM strongly attenuated cardiac‐coronary interaction. Reduced LV filling and contractility during the strain decreased the energy transmission from the heart to the coronary waves. The resulting decline in the early systolic FCW and early diastolic BEW served to impede coronary inflow.(Support: NHF grant 2006B186)
Hyperglycemia protects the heart after myocardial infarction: aspects of programmed cell survival and cell death
Authors: Malfitano Christiane , Loureiro Tatiana Carolina Alba , Rodrigues Bruno , Sirvente Raquel , Rabechi Nara B , Lacchini Silvia , Curi Rui , Irigoyen Maria Claudia C 
Published: June 2021

This study was designed to evaluate the role of diabetic hyperglycemia after myocardial infarction on cardiac function and on programmed cell survival and death in rats (Wistar) hearts divided into 4 groups: control (C), diabetic (D), myocardial infarction (MI) and diabetic myocardial infarction (DI). The size of MI, systolic and diastolic function by echocardiography, cytokines expression by ELISA (TNF‐α, IL‐1β, IL‐6 and IL‐10), gene expression by real time PCR (Bax, Fas, p53, Bcl‐2, HIF‐1a, VEGF and IL8r), caspase 3 activity by espectrofluorimetric assay, capillary density and fibrosis by histological analysis. The systolic function (ejection fraction and shortening) was improved by hyperglycemia in DI group although these changes were accompanied by maintenance of diastolic dysfunction (isovolumetric relaxation time and peak E deceleration time). Reduction of 36% in MI size, pro‐inflammatory cytokines reduction, apoptosis activation and increase in cell survival factors (HIF‐1a, VEGFa and IL8r) were observed after 15 days of myocardial infarction. Moreover the hyperglycemic status probably induced angiogenesis (increase of capillary density) before and after MI, accompanied by reduction in fibrosis. In conlusion, these results suggest greater plasticity and cellular resistance to ischemic injury induced by chronic diabetic hyperglycemia in heart rats.Financial support: CNPq and CAPES