bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Therapeutic Effect of Vitamin D3 in Conjunction with Cathelicidin for Gastric Cancer
Authors: Li Mingxing , Wu William , Zhang Lin , Shen Jing , Chan Ruby , Chan Franky , Cho Chi Hin 
Published: June 2021

ObjectiveOur research aims to investigate the therapeutic effects of vitamin D3 in gastric cancer and its relationship with cathelicidin (LL37), a host defense and antimicrobial peptide, in mediating the anticancer action of vitamin D3 both in vitro and in vivo.MethodsTo assess the inhibitory action of vitamin D3 on gastric cancer cells (TMK1), MTT assay was used to measure the cell viability and flow cytometry was employed to detect the cell cycle distribution. The expressions of p21, vitamin D receptor (VDR), LL37 and LC3BII were determined by Western‐blot. An model of orthotopic gastric cancer was also established in nude mice to evaluate the anticancer action of vitamin D3 in vivo.Results1α,25(OH)2 vitamin D3 (1,25D3), the active form of vitamin D3, could significantly inhibit the proliferation and induce cell cycle arrest through stimulating the expression of p21 in TMK1 but not in the normal gastric epithelial cells (HFE145). This vitamin analogue also successfully induced the expression of LL37 and provoked autophagy in TMK1. Knockdown of LL37 by siRNA abolished the anti‐proliferative effect of 1,25D3 in gastric cancer cells. We further found that daily oral administration with vitamin D3 significantly inhibited tumor growth in the orthotopic gastric cancer model.ConclusionOur results suggest that vitamin D3 inhibits gastric cancer in a cathelicidin‐dependent manner and it could also function as a novel therapeutic agent for gastric cancer in the future.Acknowledgements: This study is supported in part by the General Research Fund from the Hong Kong Research Grant Council and the Health and Medical Research Fund from the Food and Health Bureau in Hong Kong.
miR‐126 at the dawn of angiogenic defect seen in PAH right ventricular failure.
Authors: Potus Francois , Graydon Colin , Ryan Wong , Michelakis Evangelos , Provencher Steeve , Bonnet Sébastien 
Published: June 2021

INTRODUCTIONRight ventricular (RV) failure is the most important predictor of both morbidity and mortality in pulmonary arterial hypertension (PAH). In PAH patients, hypertrophied RV is relatively ischemic, potentially because of suppressed angiogenesis. MicroRNAs (miRNAs) are important regulator of angiogenesis, especially miR‐126, which by inhibiting SPRED‐1, triggers the VEGF pathway and thus promoting angiogenesis. We hypothesized that specific miR‐126 downregulation in the RV promotes ischemia and triggers the transition from a compensated (CRV) to a decompensated (DRV) RV.ResultsWe studied RV free wall tissues from humans with normal RV (NRV) functions, CRV and PAH (DRV), and rats with NRV and DRV. In both humans and rats, PAH DRV had decreased miR‐126 and microvessels density compared to NRV. Under the same conditions, miR‐126 were unchanged in the LV. In endothelial cells (EC) isolated from human RV, miR‐126 up‐regulation increased angiogenesis in a PAH DRV (matrigel assay), while downregulation of miR‐126 in EC from controls or CRV mimicked the PAH phenotype by decreasing angiogenesis. Artificial miR‐126 up‐regulation in PAH rat model improved RV functions, increased capillarity and decreased fibrosis specifically in RV, with no effect on PAP or lung vascular remodeling. Increasing miR‐126 levels in human PAH DRV endothelial cells also increased angiogenesis (matrigel assay).CONCLUSIONWe demonstrated that 1) exclusive RV downregulation of miR‐126 contributes to the ischemic status of the DRV; 2) in vivo up‐regulation of miR‐126 specifically improves RV functions. Thus, targeting miR‐126 represents a specific new avenue of investigation in preventing and reversing the failing RV in PAH.
Considerations for Pulse Wave Analysis: Side Selection and Peripheral Arterial Blood Pressure Calibration
Authors: Martin Jeffrey , Borges Alexandra , Christy John , Beck Darren 
Published: June 2021

BACKGROUNDAs independent predictors of future cardiovascular morbidity and mortality, central arterial blood pressure and wave reflection characteristics derived non‐invasively have been increasingly employed in clinical and research settings. However, methods for peripheral blood pressure (PBP) calibration and pulse wave analysis (PWA) vary. We sought to evaluate the PBP assessment timing on subsequent PWA and to determine if differences in bilateral PWA exist.METHODSBilateral PBP and PWA were assessed by oscillometric sphygmomanometry and a pencil‐type tonometer in 34 participants (aged 21.9±2.3 years). PBP was measured before and after PWA in each arm and bilateral PWA was performed simultaneously by two investigators.RESULTSNo significant effect of PBP assessment prior to PWA was observed in the left arm, whereas there were moderate differences in some PWA parameters in the right arm. Simultaneous bilateral PWA demonstrated consistent, significant underestimation of clinical variables associated with wave reflection characteristics when calibrated to either within arm or equivalent PBP.
image26% (n=9) of participants presented with clinically significant differences (>10 mmHg) in bilateral PBP and contributed to the underestimates observed in the right arm.
imageCONCLUSIONSPWA in the right radial artery results in greater variability independent of the timing of PBP measurement and calibration pressures. Moreover, bilateral PBP measurement is imperative to identify subjects in whom a significant difference in bilateral PWA may exist and/or to prevent underestimation of aortic blood pressures if clinically significant differences in PBP go undetected.
TNF‐α Inhibits Rat Mesenteric Lymphatic Pumping via Activation of the NF‐κB and Upregulation of iNOS
Authors: von der Weid Pierre‐Yves , Chen Yingxuan 
Published: June 2021

Upregulated TNF‐α production and dysfunctional lymphatic pumping are observed in inflammatory bowel disease pathogenesis. It has been previously demonstrated that TNF‐α could decrease arterial contractility via activation of the inducible nitric oxide synthase (iNOS) and that iNOS is involved in impaired mesenteric lymphatic pumping in animal model of intestinal inflammation. We investigated the effects of TNF‐α on rat mesenteric lymphatic pumping and hypothesized that the cytokine may impair lymphatic contractile function during intestinal inflammation by upregulating the synthesis of iNOS and thus the production of nitric oxide.Using pressure myography, we examined the contractile function of isolated rat mesenteric lymphatic vessels following a 24‐hr treatment with TNF‐α. We observed that contraction frequency was significantly and concentration‐dependently decreased by TNF‐α, an effect restored following administration of inhibitors of NF‐κB (PDTC), iNOS (1400W), guanylate synthase (ODQ) and ATP‐sensitive K+ channels (glibenclamide), but not the cyclooxygenase inhibitor, indomethacin. The involvements of NF‐κB and iNOS were further confirmed by western blot analysis and quantitative real‐time PCR, which revealed upregulations of phospho‐IκB and iNOS mRNA in TNF‐α‐treated vessels that were minimized in the presence of PDTC.These findings suggest that TNF‐α decreases lymphatic contractility via activation of the NF‐κB‐iNOS pathway.
Ascorbic Acid Supplementation: Influence of Delivery Method on Vitamin C Bioavailability and Capacity to Protect Against Ischemia‐Reperfusion Injury
Authors: Davis J , Paris H , Beals J , Binns S , Giordano G , Scalzo R , Schweder M , Blair E , Bell C 
Published: June 2021

Intravenous administration of vitamin C has been shown to decrease oxidative stress and, in some instances, improve physiological function in adult humans. Oral vitamin C administration is typically less effective, due in part to decreased vitamin C bioavailability. The purpose of this study was to determine the efficacy of oral delivery of vitamin C encapsulated in liposomes. On 4 separate occasions, occurring in random order, 11 obese adults (age: 53 ± 2 years; body mass index: 34.1 ± 1.0 kg/m2 (mean ± SE)) were administered an oral placebo, or 4 g of vitamin C via: oral, oral liposomal, or intravenous delivery. The area under the plasma vitamin C concentration curve, determined over 4 hours, was greatest (P < 0.001) following intravenous administration (57.0 ± 6.9 (mg/dL)·h). Liposomal vitamin C delivery (10.3 ± 0.9) evoked a greater (P = 0.002) area under the curve than oral (7.6 ± 0.4) that in turn was greater (P < 0.001) than placebo (3.1 ± 0.4). Forearm ischemia‐reperfusion (20 minutes of occlusion) increased circulating thiobarbituric acid reactive substances, a marker of oxidative stress, 40 minutes post‐reperfusion (P < 0.03); this increase was prevented by all of the vitamin C treatments (P > 0.05). These data suggest that oral delivery of vitamin C encapsulated in liposomes: 1) produces circulating concentrations of vitamin C that are greater than traditional oral administration; and, 2) provides protection from ischemia‐reperfusion that is similar to the protection provided by intravenous administration.Support: Empirical Labs
Assessment of Endoplasmic Reticulum Stress by Graded Sarcoplasmic Reticulum Ca2+ Store Depletion in Coronary Smooth Muscle
Authors: Dineen Stacey , Sturek Michael 
Published: June 2021

This study examined the threshold of sarcoplasmic reticulum (SR) Ca2+ store depletion necessary for induction of endoplasmic reticulum (ER) stress in coronary smooth muscle cells (CSM). Coronary arteries from Ossabaw swine with and without coronary artery disease (CAD) were sectioned into arterial rings and denuded of endothelium for assessment of ER stress. Phosphorylation of eukaryotic initiation factor 2α was examined by immunoblot as an index of ER stress and was elevated in CAD arteries, compared to healthy. CSM were enzymatically isolated and loaded with the fluorescent intracellular Ca2+ indicator, fura‐2. In arteries with overt CAD, CSM from atherosclerotic plaques were isolated separately from the medial layer. The SR Ca2+ store was released with caffeine in Ca2+‐free physiologic salt solution (0Ca‐PSS) and the resultant transient rise in cytosolic Ca2+ was examined as an index of SR Ca2+ store. The SR Ca2+ store was increased ~1.5‐fold in CSM from arteries with mild CAD compared to healthy, but was decreased in overt CAD. Sarco/endoplasmic reticulum Ca2+ ATPase activity as assessed by recovery of cytosolic Ca2+ below baseline followed the same pattern. Following release with 1, 5, or 10 mM caffeine, the SR Ca2+ store was clamped in 0Ca‐PSS for 30 minutes, after which the remainder of the SR Ca2+ was released. This SR Ca2+ store release was assessed as a percentage of maximum. The SR Ca2+ store was depleted in a dose‐dependent manner, indicating the feasibility of clamping SR Ca2+ independent of cytosolic Ca2+. Together, these results indicate that CSM display ER stress in CAD and that SR Ca2+ store is decreased in overt CAD, providing clues to the mechanisms behind CSM changes underlying CAD progression.(Support: NIH HL062552)
Resveratrol Attenuates Thromboxane‐Prostanoid Receptor‐Mediated Vasocontraction via NO‐ and Endothelium‐ Independent Mechanisms
Authors: Holder Peter , Denniss Steven , Rush James 
Published: June 2021

The purpose of this study was to investigate the effect of resveratrol (RSV) on thromboxane‐prostanoid receptor (TPr)‐mediated vasocontraction. Dose‐response to the TPr agonist U46619 (‐9.0 ‐ ‐6.0 LogM) was examined in vitro in tissue baths using isometrically mounted common carotid arterial rings isolated from 20‐30 week old Wistar Kyoto rats (WKY; n=8) and Spontaneously Hypertensive rats (SHR; n=8). Endothelium‐intact (E+) rings were pre‐incubated (for 30 minutes) with either no drug (ND); the nitric oxide synthase inhibitor L‐NAME (LN; 100 µM); RSV at either 20, 50, or 100 µM; or, LN+RSV‐20µM. Endothelium‐denuded (E‐) rings were pre‐incubated with either ND or RSV‐20µM. The EC50 for U46619 in E+ was decreased in LN vs. ND WKY (LN: ‐8.12±0.05 Log M vs ND: ‐7.72±0.06, p<0.05), but not SHR. The combination effect of E+ LN+RSV‐20 µM significantly decreased the maximum amplitude in WKY but not SHR. Increasing doses of RSV at 50 µM and 100 µM resulted in further increases in EC50 for both WKY (‐7.16±0.04 and ‐6.83±0.08, respectively) and SHR (‐7.17±0.06 and ‐6.80±0.04,respectively), while only WKY exhibited a significant (p<0.05) decrease in the maximum amplitude. In E‐, WKY (RSV‐20µM: ‐7.46±0.08 LogM vs. ND) and SHR (RSV‐20µM: ‐7.63±0.06 LogM vs. ND) had significantly increased EC50 with RSV‐20 µM incubation (p<0.05), while the maximum amplitude remained unaffected. These results suggest that acute pre‐incubation with RSV dose‐dependently attenuates TPr‐stimulated vasocontractile activity by a cell‐signalling mechanism that does not appear to require nitric oxide synthase or the endothelium.Funded by NSERC Canada
Myocardial Calcium Handling is Up‐Regulated During the Spontaneous Resolution of Endotoxemic Cardiomyopathy in Mice
Authors: Hobai Ion , Morse Justin , Siwik Deborah , Colucci Wilson 
Published: June 2021

Sepsis and systemic inflammation induce a specific cardiomyopathy that resolves spontaneously in surviving patients, through mechanisms that are currently unknown. Here we studied cardiomyocyte calcium (Ca2+) handling during endotoxemic cardiomyopathy (EC) resolution in mice.Male C57Bl6 mice were administered lipopolysaccharide (LPS, 7 μg/g, ip). LPS induced an inflammatory shock syndrome, cardiomyopathy and 59% mortality. We measured sarcomere shortening (SS) and Ca2+ transients (ΔCai) in externally paced cardiomyocytes, at 37o C.12h after LPS administration, SS and ΔCai were decreased to 53 ± 10% and 78 ± 5% of baseline, respectively (n >30 cells from 3 mice, 30/3, for each group; p<0.05 for this and the following) in association with a decrease in sarcoplasmic reticulum Ca2+ pump (SERCA) reuptake (to 88 ± 5% of control, n > 19/3). In surviving mice, ΔCai was fully recovered 3 days after LPS administration (Day 3, D3) and reached levels exceeding normal at D6 (124 ± 7 % of baseline, n > 18/3). ΔCai recovery was associated with SERCA supra‐normal activation (138 ± 4% of control, n > 28/3) at D3, due to phospholamban (PLB) down‐regulation (to 35 ± 9% of control, n = 6 hearts each group). At D6, membrane Na+/Ca2+ exchange (NCX) function was 51 ± 4 % of baseline (n > 12/3), contributing to the supra‐normal ΔCai levels.In conclusion, myocardial recovery during the spontaneous resolution of EC is the result of active cellular mechanisms that include down‐regulation of PLB and NCX and lead to supra‐normal ΔCai.
C‐Type Natriuretic Peptide as Mediator of an Endothelial Cell to Mast Cell Communication
Authors: Kuhn Michaela , Gassner Birgit , Rabenhorst Anja , Hartmann Karin , Chen Wen 
Published: June 2021

Mast cells (MC) play a critical role in leukocyte recruitment to sites of inflammation after ischemia/reperfusion (I/R). They reside in the perivascular tissue and release proteases and chemokines having detrimental effects on their immediate surroundings, such as endothelial cells. The triggers and counterregulators of MC activation are still enigmatic. We investigated whether endothelial C‐type natriuretic peptide (CNP) via its cGMP forming guanylyl cyclase B (GC‐B) receptor modulates the activity of MC and inflammation after I/R.Intravital microscopy was used to visualize the microcirculation within the cremaster muscle of anesthetized mice. Blood flow was temporally blocked for 30 min of ischemia. FITC‐Dextran was used to quantify macromolecule leakage during reperfusion. Ruthenium Red was used to stain perivascular degranulated MC. I/R provoked marked degranulation of perivascular resident MC (~7‐fold vs controls) and prominent leakage of FITC‐Dextran from postcapillary venules to the adjacent interstitial space. Local superfusion of CNP during reperfusion, significantly reduced the number of degranulated MC (to ~1.8‐fold vs controls) and concomitantly prevented vascular leakage. These effects were mimicked by the membrane‐permeable cGMP analog, 8‐bromo cGMP. In cultured murine bone marrow and human MC CNP activated GC‐B/cGMP signaling and cGMP protein kinase I‐dependent phosphorylation of the cytoskeleton‐associated vasoactive stimulated phosphoprotein (VASP) at Ser237.Our study indicates that the endothelial peptide CNP inhibits I/R‐induced degranulation of perivascular MC and thereby attenuates microvascular inflammation.Supported by SFB 688 and CHFC Würzburg
Signaling Magnitude of the G‐Protein Coupled Bradykinin Receptor Depends on Flow: Role of the Glycocalyx
Authors: Jiménez Azucena , Espinosa Ricardo , Rubio Rafael 
Published: June 2021

Flow is a stimulus whose mechanism is still under discussion and may act on the luminal endothelial glycocalyx (LEG), generating paracrine messengers targeting specific functions and metabolisms of the parenchymal cells. We have shown that LEG's lectinic transmembrane proteins such as GPCR (L) and diverse oligosaccharides (O) are required for flow detection. Since L and O have affinity toward each other, then, flow may disturb the endothelial paracrine signaling. This hypothesis could explain the molecular mechanism of action of flow and also why the flow is a multifunctional stimulus. Methods: Isolated carotid arteries from guinea pigs (500 g) were cannulated on its proximal end with a catheter, perfused with Krebs‐Henseleit solution at 11 or 16 ml/min and GPCR (L) identified and challenged by its specific agonist Bradykinin (Bk). In addition, artery distal ends were cannulated to have a resistance to flow. Perfusion pressure an indicator of smooth muscle tone was continuously recorded. At each level of flow dose‐response curves (signaling of GPCR) for Bk was determined before and after either enzymatic removal of specific O or addition of exogenous synthetic O.ResultsWe show that level of flow alters the sensitivity to the hormone (D‐R curve). In addition, the D‐R curves are altered by removal of LEG hyaluronidate, but not by heparinate or by addition of exogenous synthetic O that likely compete with the endogenous O for lectinic binding. Clearly, D‐R curve (GPCR signaling) depends 1) on the level of flow, 2) at a given flow on the O composition of LEG. Supported by Conacyt to RET (223350‐M).
Different Roles for P2Y2 and P2Y6 Receptors in Large and Smaller Coronary Arteries
Authors: Haanes Kristian , Larsen Stine , Syberg Susanne , Jorgensen Niklas , Robaye Bernard , Boeynaems Jean‐Marie , Edvinsson Lars 
Published: June 2021

A clear understanding of the physiological regulation of the coronary blood flow is important in order to recognize the changes after a pathological incident, such as a heart attack. Extracellular pyrimidines activate P2Y receptors on both smooth muscle cells and endothelial cells in the vasculature, leading to vasoconstriction and relaxation respectively. The aim of the present study was to examine the receptor profiles along the vasculature, particularly in the coronary circulation. We studied this in arteries utilizing stable pyrimidine analogues and P2Y2 and P2Y6 receptor KO mice in a myograph setup and also performed blood pressure measurements. The results show that P2Y6 mediates most of the UTP and UDP induced contraction in the larger coronary arteries (lumen diameter ~150 µm) and that P2Y2 is an endothelia dependent relaxing receptor. In the smaller coronary arteries (lumen diameter ~ 50 µm) the expression is opposite, with P2Y2 being the contractile receptor and P2Y6 the relaxant receptor, although together with P2Y2. We therefore propose that released UTP can act as a vasodilator downstream of its release, after being degraded to UDP, also without affecting the contractile pyrimidine receptors.The obtained results gives a completely new view of the purinergic regulation in the vascular bed and can be used as an explanation of the many differences in the expression of purinergic receptors both between species and in various arteries.Funding: Lundbeck foundation (R167‐2013‐15379) and Lundbeck Grant of excellence
Chronic Hypoxia Alters the Response of Fetal Ovine Middle Cerebral Arteries to Endothelin‐1 (ET‐1)
Authors: Silpanisong Jinjutha , Kim Dahlim , Williams James , Adeoye Olayemi , Thorpe Richard , Pearce William 
Published: June 2021

This study explores the hypothesis that chronic hypoxia alters the expression and intracellular coupling of endothelin receptors to induce phenotypic transformations of smooth muscle cells within the arteries of fetal cerebrovasculature. Endothelium‐denuded middle cerebral arteries (MCAs) harvested from term fetuses of pregnant adult sheep kept at sea level or 3820m for 110 days were used in contractility experiments or cultured with ET‐1 and various kinase inhibitors. Chronic hypoxia had no effect on plasma levels of ET‐1 but altered contractile responses to ET‐1 and increased ETA receptor expression in fetal MCAs. ET‐1 treatment increased arterial thicknesses in both normoxic and hypoxic arteries. Organ culture of MCAs with ET‐1 decreased colocalization of MLCK and α‐actin and this effect was attenuated by chronic hypoxia. ET‐1 also decreased MLC20 and MLCK colocalization, but this effect was similar in normoxic and hypoxic arteries. The effects of ET‐1 on colocalization were reversed by inhibitors of either PKC (7 µM chelerythrine) or p38 (10 µM SB203580) in both normoxic and hypoxic arteries. From these results we conclude that chronic hypoxia modulates phenotypic responses of fetal cerebrovascular smooth muscle to ET‐1 through elevated expression of ET‐1 receptors, which act downstream through PKC and p38 dependent pathways on contractile protein expression.This work was supported by National Institutes of Health Grants HL‐54120, HD‐31266, HL‐64867, and NS‐076945 and the Loma Linda University School of Medicine.
Endothelium‐Dependent and ‐Independent Vasodilation in Women at Risk of Hypertension
Authors: Harvey Ronee , Laughlin‐Tommaso Shannon , Stewart Elizabeth , Curry Timothy , Joyner Michael , Barnes Jill 
Published: June 2021

Women with uterine fibroids (UF), benign tumors of the myometrium, have a greater prevalence of hypertension than women without UF. The mechanism of this predisposition is unclear. Individuals with borderline hypertension have endothelial dysfunction in the form of decreased endothelium‐dependent vasodilation in response to intra‐arterial acetylcholine infusion. It is possible that women with UF also demonstrate impaired endothelium‐dependent vasodilation prior to overt clinical hypertension. We measured forearm blood flow (FBF) using venous occlusion plethysmography at baseline and during intra‐arterial acetylcholine (ACH; 1.0‐4.0 μg/100 ml tissue/min) and sodium nitroprusside (SNP; 0.25‐2.00 μg/100 ml tissue/min) infusions in 4 normotensive women with UF (41±3 y) and 4 age‐matched normotensive women without UF. These women did not differ in body mass index or mean arterial pressure (97±4 vs. 103±6 mmHg, Control vs. UF; p>0.05). Baseline FBF was not different between the two groups (1.6±0.4 vs. 3.0±1.3 ml/100 ml tissue/min; Control vs. UF; p>0.05). FBF increased significantly from baseline in both groups at the highest doses of ACH and SNP; however, the change in FBF was not significantly different between groups (ACH: Δ8.6±1.6 vs. 9.5±4.1 ml/100 ml tissue/min; SNP: Δ9.8±3.0 vs. 13.1±4.6 ml/100 ml tissue/min; Control vs. UF; p>0.05). Our preliminary results suggest that FBF responses to ACH and SNP do not differ between women with and without UF; thus, impairments in endothelium‐dependent and ‐independent vasodilation do not appear to contribute to hypertension risk in normotensive women with UF. Funded by AHA and NIH.