bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal Association between Weight Gain and Hypertension: China Health and Nutrition Survey, 1991—2006
Authors: Du Shufa , Wang Huijun , Wang Xiaoshan , Popkin Barry M 
Published: June 2021

While studies showed that weight gain may increase the risk of hypertension, there are ethnic differences in associations and few studies among the Chinese population. Using longitudinal data on 46,601 subjects aged 18—69 y followed over six waves of the China Health and Nutrition Survey, we studied the effect of weight gain on blood pressure and hypertension. Trained nutritionists obtained weighed dietary data over 3 days combined with individual 24‐h records. Trained physicians collected 3 measures of blood pressure with a 30‐secondinterval between cuff inflations, weight and height data with standardized methods. Pattern mixture generalized linear mixed model was used to estimate the association. The average follow‐up was 7.5 years (2–15). Prevalence of hypertension increased rapidly from 15% in 1991 to 27.8% in 2006. The cumulative incident hypertension was 23.9%. The odds ratio (OR) of weight gain (1 kg/year) was 1.14 (95%CI: 1.10—1.20, p<0.01), controlled for age and weight at baseline, gender, education, overweight status and interaction between weight gain and overweight and other dummies. Sodium intake did not modify this relationship. Weight gain significantly increased the risk of hypertension in Chinese, particularly in the overweight and obese population.This research was supported by NIH R01‐HD30880.
Electrical vagal afferent stimulation inhibits sympathetic nervous activity irrespective of baroreflex activation without lowering blood pressure
Authors: Hosokawa Kazuya , Kawada Toru , Ando Makoto , Tanaka Atsushi , Sakamoto Takafumi , Onitsuka Ken , Murayama Yoshinori , Ide Tomomi , Sunagawa Kenji 
Published: June 2021

BackgroundThe blunted arterial baroreflex control and the imbalance of autonomic nervous system are a salient feature of heart failure. Although electrical vagal stimulation has been shown to improve survival, its effect on arterial baroreflex function remains unknown.Methods and ResultsWe vascularily isolated the bilateral carotid sinus baroreceptor regions in rats after myocardial infract (MI, n = 5) and in rats without MI (Control, n = 6). We ligated the vagal nerves and attached a pair of electrode to the central end for afferent stimulation (aVNS). We recorded sympathetic nerve activity (SNA) at the celiac region. We changed baroreceptor pressure (CSP) stepwise with and without aVNS (1 Hz, 3.0‐5.0 V). Increases in CSP sigmoidally suppressed SNA, and baroreflex induced suppression in SNA quasilinearily decreased arterial pressure (AP). aVNS induced a parallel downward shift of sigmoidal CSP‐SNA relation both in Control (−16 ± 17%, p < 0.05) and in MI (−17 ± 18%, p < 0.05), whereas it upward shifted the quasilinear SNA–AP relation both in Control (+16.2 ± 12.0 mmHg, p < 0.05) and MI (+27.2 ± 10.6 mmHg, p < 0.05). As a result of these opposite modulations, aVNS did not significantly impact the CSP‐AP relation.ConclusionaVNS inhibits SNA irrespective of baroreflex activation and thereby might have beneficial effects in heart failure. This study was supported in part by research grants from the Ministries of Japan.
Spinal cord stimulation (SCS) modifies cardiac‐related dorsal root ganglia (DRG) afferent neurons in response to myocardial ischemia
Authors: Gibbons David D , Southerland E. Marie , Armour J. Andrew , Ardell Jeffrey L. 
Published: June 2021

ObjectiveTo determine if SCS modulates the capacity of cardiac sympathetic afferent neurons to transduce regional myocardial ischemia.MethodsUsing extracellular recording techniques in anesthetized canines, cardiac‐related DRG neurons (T1‐T3 spinal levels) were identified by multimodal stimulation of the left anterior descending (LAD) region. Then neuronal responses to transient (1 min) LAD coronary artery occlusion (CAO) were evaluated prior to and following SCS (T1‐T3 spinal level; 50Hz, 90% motor threshold; 20 min).ResultsLAD CAO caused a ~4 fold increase in cardiac afferent neuronal activity that persisted for at least 30 minutes following reperfusion. SCS doubled basal cardiac afferent neuronal activity, doing so in a stochastic manner. Following SCS, LAD CAO evoked no further increase in such activity.ConclusionTransient myocardial ischemia activates primary afferent inputs to the spinal cord well beyond stressor application. Pre‐emptive SCS obtunds sensory transduction of the ischemic myocardium to spinal cord neurons. (Supported by HL71830.)
The evolution of diabetes in non human primates: comparative physiology implications for human type 2 diabetes mellitus (T2DM)
Authors: Hansen Barbara Caleen 
Published: June 2021

T2DM develops naturally and spontaneously in humans and non human primates. We have studied prospectively a colony of >220 adult rhesus monkeys that were continuously maintained with ad libitum feeding of a high fiber low fat “healthy” diet throughout life. 87 individuals were identified that developed frank T2DM. Longitudinal analysis of the emerging dysglycemia and dyslipidemia has allowed the determination of the glycemic threshold for diagnosis (dx) of prediabetes: 80 mg/dl (4.4 mmol/L) for monkeys, shown by modeling to be comparable to 100 mg/dl (5.5 mmol/L) in humans; and overt DM dx occurs at 100 mg/kg (5.5 mmol/L) in monkeys compared to the current ≥126 mg/dl (6.9 mmol/L) defined for humans. All monkeys reaching the prediabetes diagnosis, if not intervened on to prevent progression, did in fact proceed to overt diabetes (2/3 in < 3 yrs; ~<10 yrs in humans). Sequence analysis to model the diabetes trajectory showed that acute beta cell response to glucose peaked 2 to 6 years prior to DM dx; fasting plasma insulin 1 to 4 yrs pre DM dx; and nearly all were hypertriglyceridemic 5 to 12 yrs pre DM dx. These carefully controlled studies show that in humans fasting insulin, β cell functional responses and dyslipidemia should be used to identify those progressing toward diabetes in order to implement true preventive strategies prior to β cell failure.Supported by: supported by NIA N01AG31012 and NIA HHSN2532008002C.
Effect of YWK‐II/APLP2 on neuron survival
Authors: Sun Tingting , Chan Hsiao Chang 
Published: June 2021

YWK‐II protein, the target antigen to a monoclonal antibody raised against human sperm proteins, has been recently implicated in sperm survival and anti‐apoptotic activity acting as a novel receptor for Mullerian inhibiting substance (MIS). Sequence of YWK‐II protein is highly homologous to amyloid‐precursor‐like protein 2 (APLP2) that belongs to a conserved transmembrane family including amyloid precursor protein (APP). In the present study, we investigated the potential role of YWK‐II protein in neuron survival. RT‐PCR and Western blot showed that YWK‐II is expressed in primary cultured hippocampal neuron and PC12 cells both at mRNA and protein levels, while both cells lack MIS expression. In serum withdrawal medium, viable hippocampal neuron and PC12 cells were significantly decreased as assessed by MTS assay, indicating possible cell death. Recombinant MIS (rMIS) could protect hippocampal neuron from serum‐withdrawal induced death, but it did not affect PC12. Addition of YWK‐II antibody could block the protective effect of rMIS. Moreover, the presence of YWK‐II antibody alone could reduce viable cells in both cells. The results of our study indicate the possible involvement of YWK‐II protein in neuron survival, which may be partially mediated via MIS in vivo.The present study is funded by National 973 Program (2006CB504002).
Midkine and Hypoxia Potentiate Epithelial‐to‐Mesenchymal Transition in Human Lung Cancer Cells
Authors: Zhang Hanying , Zawada Michael , Das Mita 
Published: June 2021

Epithelial‐to‐mesenchymal transition (EMT) plays an important role during progression of lung cancer. Recently, hypoxia and midkine (MK) have been shown to be key regulators of EMT in various types of cancer cells. Signal transducer and activator of transcription 3 (STAT3) also plays a critical role in this process. Therefore, we hypothesize that MK will enhance EMT in lung cancer cells grown in a hypoxic microenvironment through STAT3 activation. Human lung cancer cells (A549) were exposed to 1% oxygen in the presence of MK to test our hypothesis. EMT was evaluated by assessment of cell morphology as well as expression of marker proteins. Cell morphology was altered from cuboidal to elongated shape after 48 hours of treatments. Levels of E‐cadherin, marker of epithelial cells, were decreased. However, expression of alpha smooth muscle actin (αSMA) and vimentin, markers of mesenchymal cells, were augmented. Hypoxia/MK treatment stimulated STAT3 phosphorylation at Ser727 as well as Tyr705 residues. Interestingly, the two phosphospecies had unique subcellular localization patterns. PhophoSTAT3(Tyr705) was restricted to focal points within the cytoplasm, whereas Ser727 phosphoSTAT3 was present predominantly in the nuclear compartment. Therefore, our data strongly suggest that hypoxia/MK potentiates EMT process and this process might be mediated through STAT3 activation in human lung cancer cells.Funded by HL64917 (MD); P20RR016474 (NCRR & Wyoming INBRE)
The Role of Lung Mesenchymal Stem Cells in the Progression of Pulmonary Fibrosis
Authors: Majka Susan M , Jun Du 
Published: June 2021

IntroductionPulmonary fibrosis (PF) is often complicated by pulmonary arterial hypertension (PAH) in adults. We hypothesize that during PF and PAH the mesenchymal stem cell (MSC) differentiation program that normally generates reparative cells is altered, leading to the generation of proliferative myofibroblasts, that contribute to vascular wall thickening.MethodsTo identify putative lung MSC, we performed flow cytometry on single cell lung suspensions to isolate Hoechstlow/CD45neg cells. We then characterized the MSC phenotypic and functional characteristics of this population. Next, we tested whether lung MSC could affect the pathophysiology of PF/PAH.ResultsHoechstlow/CD45neg lung cells demonstrated multi‐lineage differentiation. We found that these cells, as mixed or clonal populations, have the capacity to differentiate into several mesenchymal cell lineages, EC and myofibroblasts. In addition, similar to bone marrow‐MSC, bleomycin induced PF and PAH was significantly attenuated in animals injected with lung MSC in the absence of detectable engraftment on day 14. However, lineage analyses using the novel SP marking system demonstrated the incorporation of endogenous MSC to fibrotic regions as well as vasculature on day 14 following bleomycin exposure.ConclusionsOur results illustrate the presence of a lung MSC population and the importance of studying stem cells in the context of their niche to understand their true role in the progression of disease processes.
High salt intake exacerbates renal tissue oxidative stress and urinary angiotensinogen excretion during AngII‐dependent hypertension.
Authors: da Silva Lara Lucienne , McCormack Michael , Kobori Hiroyuki , Shenouda Sylvia , Majid Dewan SA , Navar Luis Gabriel , Prieto Minolfa Carrasquero 
Published: June 2021

High salt (HS) intake inhibits systemic and intrarenal RAS; however, when AngII is not suppressed HS exacerbates hypertension and renal injury. We investigated the effects of HS on the magnitude of intrarenal oxidative stress associated with angiotensinogen urinary excretion (uAGT) in chronic AngII‐infused rats. In Sprague‐Dawley rats: 1) Control, normal salt diet [NS, n=5]; 2) HS diet [8% NaCl, 12 d, n=5]; 3) AngII‐infused in NS rats [AngII, 80 ng/min, 14 d, n=5] and 4) AngII‐infused in HS rats [AngII+HS, n=5] we measured systolic blood pressure (SBP), proteinuria, NADPH oxidase activity, n‐Tyr residues and uAGT. HS alone did not change SBP, but led to hypertension when combined with AngII. In contrast, HS alone led to proteinuria that was further increased in HS+AngII rats. The uAGT excretion rates increased in AngII+HS rats compared to AngII rats (AngII=107±18 vs AngII+HS=4363±1296 ng/day). Renal tissue oxidative stress measured by n‐Tyr Western blot increased in both HS and AngII+HS rats; however the NADPH oxidase activity increased only in HS+AngII rats (HS=10,674±2819; AngII+HS=18,663±1328 RLU/mg protein). HS exacerbates renal tissue oxidative stress during AngII‐dependent hypertension which might be associated with increased uAGT, proteinuria, and blood pressure in AngII‐infused rats.NIH [IdeA Program (P20RR01765906); Tulane‐BIRCWH Program (K12HGO4351)] and AHA (09PRE2209079; 09BGIA2280440)
Glucagon‐Like Peptide (GLP1) Agonist Increases GFR and Suppresses Proximal Reabsorption
Authors: Thomson Scott Culver , Kashkouli Ali , Singh Prabhleen 
Published: June 2021

The incretin, GLP1, is released by the gut in response to fat or CHO and lowers glucose by effects on the stomach and pancreas. GLP1 receptors are also in kidney. We examined the effects of a GLP1 agonist, exenatide, on glomerular and tubular function in normal and diabetic rats.GFR (inulin clearance) and urine flow rate were measured in awake rats following exenatide (1 nmol sq) or placebo (n=5 each). Micropuncture was done in normal and hyperfiltering STZ‐diabetic rats before and during exenatide (1 nmol/h iv). Single nephron (SN) GFR and proximal reabsorption (Jprox) were measured at both extremes of tubuloglomerular feedback (TGF) activation (loop of Henle perfusion). ANCOVA with SNGFR as covariate tested for primary effects on Jprox.Conscious rats on exenatide had higher GFR (4.3±0.2 vs 2.2±0.3 ml/min, p=0.001) and urine flow (34±4 vs 12±3 ul/min, p=0.002). Micropuncture results are shown in the table‐*P<0.05 for exenatide. Total 114 tubular fluid collections from 6 rats.

SNGFR no TGF (nl/min)
SNGFR max TGF
Jprox adjusted for SNGFR

Control
40±5
29±7
26±1

+ Exenatide
70±4*
50±6*
18±1*

Diabetes
52±5
33±6
26±1

+ Exenatide
65±4*
53±6*
16±1*

Exenatide increases GFR and is a potent proximal diuretic, implying effects on both glomerulus and tubule. It is a mystery why the GLP1 receptor, whose natural agonist responds to fat ingestion, should have such capacities to raise GFR and suppress proximal reabsorption.
Dopamine D2 receptor regulation of reactive oxygen species production via paraoxonase 2
Authors: Yang Yu , Zhang Yanrong , Villar Van Anthony , Pascua Annabelle , Armando Ines , Jose Pedro A. 
Published: June 2021

An intact dopaminergic system is necessary to maintain normal blood pressure. We have reported that D2 dopamine receptor (D2R) regulates renal reactive oxygen species (ROS) production and that altered D2R function results in ROS‐dependent hypertension. Paraoxonase 2 (PON2) belongs to the paraoxonase gene family that is expressed in various tissues including the kidney and protects against cellular oxidative stress.We hypothesized that PON2 may be involved in counter‐regulating excessive renal ROS production and thus may contribute to maintain normal blood pressure. Moreover, D2R may regulate ROS production in part through regulation of PON2. ROS production decreased (42%; P<0.05; n=4) in human renal proximal tubular (iNT) cells treated with the D2R agonist, quinpirole (24h, 1μM). This effect was associated with increased PON2 expression of mRNA and protein and enzymatic activity. PON‐2 silencing (siRNA, 10nM, 48h) down‐regulated PON2 expression (50%; n=3) and activity and increased ROS (34.9%, P<0.05). Furthermore, renal PON2 expression was down‐regulated in D2−/− mice (35.6%, P<0.05).These results show that PON2 expression and/or function are closely related to ROS production and suggest that the D2R is involved in its regulation. The increased oxidative stress due to D2R disruption could be related to the failure of its stimulatory effect on the expression or function of PON2 in the kidney.This work was supported in part by grants from the National Institutes of Health, HL68686, HL23081, HL074940, HL092196 and DK39308
Endothelin‐1 (ET‐1)‐induced reactive oxygen species (ROS) generation requires calcium (Ca2+) influx in pulmonary arterial smooth muscle cells (PASMCs)
Authors: Undem Clark , Luke Trevor , Sylvester J T , Shimoda Larissa A 
Published: June 2021

ET‐1 is a potent endothelium‐derived vasoconstrictor and smooth muscle cell mitogen. During hypoxia, ET‐1 is thought to play a significant role in modulation pulmonary vascular tone. Previous studies in systemic smooth muscle have shown that both an increase in intracellular Ca2+ concentration ([Ca2+]i) and the generation of ROS via nicotinamide adenine dinucleotide phosphate‐oxidase (NADPH oxidase) are major components of ET‐1 signaling. It remains unclear, however, whether ET‐1 causes ROS generation in PASMCs. In this study, we used the ROS‐sensitive dye, DCF, and the Ca2+‐sensitive dye, fura‐2, to determine 1) the effect of ET‐1 on ROS production in transiently cultured (24–48 hr) rat PASMCs and 2) whether this response is Ca2+‐dependent. Measuring both [Ca2+]i and ROS simultaneously, we found that ET‐1 significantly increased both Ca2+ influx and ROS generation, with Ca2+ influx appearing to occur first. Pre‐treating PASMCs with the antioxidant, TEMPOL, or the NADPH oxidase inhibitor, diphenyleneiodonium chloride, had no significant effect on ET‐1‐induced Ca2+ influx but prevented ROS production. In contrast, the removal of extracellular Ca2+ or pretreatment with the Ca2+ chelator, BAPTA‐AM, prevented both the increase in [Ca2+]i and ROS production. These results indicate that, in PASMCs, Ca2+ influx may be necessary for the ET‐1‐induced initiation of ROS production from NADPH oxidase.HL67191
Inflammation enhances Na+/Ca2+ exchange in human airway smooth muscle
Authors: Sathish Venkatachalem , Thompson Michael A , Pabelick Christina M , Prakash Y S , Sieck Gary C 
Published: June 2021

Enhanced airway contractility by inflammatory cytokines involves increased intracellular Ca2+ levels in airway smooth muscle (ASM). In this study, we examined the role of the bidirectional plasma membrane Na+/Ca2+ exchanger (NCX) in human ASM Ca2+ regulation following exposure to the pro‐inflammatory cytokines tumor necrosis factor alpha (TNFα) or interleukin‐13 (IL‐13). Both cytokines significantly increased NCX1 expression, with these effects inhibited by dexamethasone (NFκB inhibitor) or PD98059 (MAPK inhibitor). In human ASM cells loaded with the Ca2+ indicator fura‐2, or the intracellular Na+ indicator SBFI, NCX‐mediated Ca2+ influx (with simultaneous Na+ efflux) was enhanced by both cytokines. NCX‐mediated Ca2+ efflux (with simultaneous Na+ influx) was also enhanced, but not to the same extent. The NCX inhibitor KBR7943 as well as NCX1 siRNA inhibited cytokine enhancement of both modes NCX and of Ca2+ responses to bronchoconstrictor agonists. These data indicate that a) NCX normally operates in human ASM; b) cytokines increase NCX expression, leading to greater NCX‐mediated Ca2+ influx, thus contributing to enhanced Ca2+ in inflamed ASM.Supported by NIH grants HL74309 (GCS), HL090595‐S2 (VS) and HL090595 (CMP).
Arachidonate‐regulated channels (ARC) and intracellular Ca2+ regulation in human airway smooth muscle
Authors: Thompson Michael A , Pabelick Christina M , Prakash Y S 
Published: June 2021

Plasma membrane Ca2+ influx and sarcoplasmic reticulum (SR) Ca2+ release are key components of intracellular Ca2+ regulation in airway smooth muscle (ASM). We and others have previously found that ASM Ca2+ regulation involves propagating Ca2+ oscillations via these mechanisms. Ca2+ oscillations in non‐excitable cells involve influx via arachidonic acid (AA) regulated channels (ARC); however, little is known about ARC in ASM. In human ASM cells loaded with fura2 (5 μM), we found that 10 μM AA triggered Ca2+ oscillations. OAG, oleic acid and palmitic acid (10 μM) failed to elicit Ca2+ responses. Pre‐incubation with LaCl3 1 μM and 1mM; 5 min) inhibited AA‐induced oscillations. Inhibition of SR Ca2+ release (ryanodine 10 μM and IP3 channel inhibitor Xestospongin C 10 μM; 30 min), decreased Ca2+ oscillation frequency and amplitude. Inhibitors of receptor‐operated channels (SKF‐96365; 10 μM), lipoxygenase (zileuton; 10 μM), or cyclooxygenase (indomethacin; 1 μM), did not affect oscillations. Finally, siRNA for Caveolin‐1, STIM1 and Orai3 (25nM) reduced frequency and amplitude of AA‐induced oscillations. These results indicate a novel caveolar Ca2+ influx mechanism in human ASM mediated via AA that interacts with SR to produce repetitive SR Ca2+ release. Such AA‐mediated influx could potentially contribute to increased Ca2+ in ASM during inflammation.Supported by NIH grants HL090595 (CMP) and HL088029 (YSP)
Galanin (GAL)‐immunoreactive (ir) axons closely appose parvalbumin (Parv)‐immunoreactive neurons in the rat ventral respiratory column (VRC)
Authors: Llewellyn‐Smith Ida J. , Jung Kyoung L. , McCrimmon Donald R. , Alheid George F. 
Published: June 2021

The neurochemistry of VRC neurons correlates with their function. Two‐thirds of large bulbospinal VRC neurons contain Parv and ~40% of chemosensitive neurons in the retrotrapezoid nucleus (RTN) contain GAL, which affects breathing when injected into the VRC. Here, we investigated whether GAL‐ir axons innervate Parv‐ir VRC neurons using double immunoperoxidase staining. In the VRC, GAL‐ir axons (black) closely apposed large Parv‐ir cell bodies (brown). We also identified two groups of black GAL‐ir somata. A rostral group occurred medial and ventral to the caudal end of the facial nucleus and are likely RTN neurons. A caudal group lay immediately ventral and slightly lateral to the column of Parv neurons, a location suggesting that some PreBötzinger (PreBöt) neurons might also be GAL‐ir. Since many PreBöt neurons contain the neurokinin‐1 receptor (NK1R), we double stained for GAL (brown) and NK1R (black). Some of the caudal GAL‐ir neurons were also NK1‐ir. These data suggest that GAL may influence respiration via PreBöt and/or RTN neurons releasing GAL onto Parv‐ir VRC neurons, which innervate spinal motor neurons that control respiratory pump muscles.Support: NH&MRC of Australia & NIH grant HL088580.
Prediction of murine liver kinetics from plasma lipoprotein distributions
Authors: Tiemann Christian , van den Berg Sjoerd , van Klinken Jan Bert , van Dijk Ko Willems , Jeneson Jeroen , Hilbers Peter , van Riel Natal 
Published: June 2021

The role of liver in lipid metabolism has been studied extensively. However, due to the complexity of in vivo liver measurements, many experimental efforts have focused on studying liver responses by measuring plasma lipoprotein distributions. The characteristics of these distributions co‐determine several metabolic disease risks and depend on production, clearance and remodeling of lipoproteins, all regulated by the liver. A challenge remains to determine the kinetics and distribution of fluxes in the complex network of metabolic pathways in the liver that give rise to these distributions. Here, we report on a computational approach to obtain this information.A computational multi‐compartment model was constructed including reactions representing lipogenesis, cholesterol synthesis, fatty acid handling and lipoprotein metabolism in liver and lipoprotein remodeling in plasma. We consider a high‐resolution grid of different lipoprotein classes, from which lipoprotein distributions are calculated. Novel in this approach is the inclusion of lipoprotein kinetics, yielding additional information to constrain internal liver predictions and vice versa. In future, the model will be used to study the dynamic interactive behavior of plasma lipoprotein metabolism and metabolic pathways in murine liver for different physiological conditions. Funded by the Netherlands Consortium for Systems Biology.