bluuebunny/crossref_metadata_2025_split huggingface dataset:
Omega‐3 fatty acids are potential chemo‐sensitizing agents for the treatment of B‐cell Chronic Lymphocytic Leukemia
Authors: Fahrmann Johannes Francois , Hardman Elaine 
Published: June 2021

B‐Cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. Clinical treatment of CLL is limited due to drug resistance and therapy‐induced toxicities. We hypothesized that omega 3 fatty acids (n‐3), eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), would increase the sensitivity of B‐leukemic cell lines EHEB, JVM‐2 and MEC‐2 to doxorubicin, vincristine and/or fludarabine in vitro and that enhanced sensitivity is due, in part, to the formation of lipid peroxides and generation of reactive oxygen species (ROS).Results indicated that 1) EPA and DHA differentially sensitized EHEB, JVM‐2 and MEC‐2 to doxorubicin, vincristine and fludarabine in vitro, 2) lipid peroxidation increased in the presence of n‐3, 3) MEC‐2 illustrated increased lipid peroxidation in presence of DHA and doxorubicin versus either alone, 4) n‐3 increased generation of ROS in MEC‐2, 5) the addition of á‐tocopherol abrogated the increase in chemo‐sensitivity of MEC‐2 to doxorubicin by DHA.Omega 3 fatty acids present a promising non‐toxic approach to sensitize malignant cells to anti‐cancer drugs.Grant Funding Source: NASA WVSGC Fellowship Grant
Effects of Mung‐Bean and Black‐Bean ethanol extracts on inflammation related to obesity in the high fat induced obesity model
Authors: Lee Myoungsook , Kim Minjin , Kim Soyoung , Wi Haeri , Park Hyejin , Choi Wonhyung 
Published: June 2021

Obesity is known to induce an inflammation status that is implicated in clinical complications such as insulin resistance, diabetes and atherosclerosis. The leguminous plants are known as diet food because mung bean(MB) has lower glycemic Index and anthocyanins of the black bean(BB) has physiological effects on antioxidant, anticancer and anti‐inflammatory activity. Our purpose of this study was to determine the effects of MB and BB on inhibition of inflammation‐related to adipogenesis. C57BL/6 male mice(4wk) were fed with 45% high fat diet for 10 weeks to induce obesity and the control(CON), 45% high fat diets(HF), HF with Orlistat 0.03%(O), HF with MB ethanol extracts(1g/kg), HF with BB ethanol extract(1g/kg) were orally administrated for 12weeks. The weight of epididymal fat was significantly low in MB group. PPARγ, C/EBP and ACC expression, related to lipid synthesis, on MB and BB were lower than other groups in liver. IL‐10, inhibitor of inflammation related to adipocyte differentiation, significantly increased in BB group. HSL and AMPK genes, fat degradation enzyme, were significantly increased in BB group. ACC gene, key enzyme of fat synthesis, was significantly decreased in BB group. In conclusion, MB and BB may develop an anti‐obesity food because they have effects on inhibition of inflammation related to fat synthesis and activation of lipolysis.Grant Funding Source: Agriculture Science&Technology Development(PJ907089), Technology Commercialization Support Program, Ministry for Food, Agriculture, Forestry and Fisheries(811003031SU000), Republic of Korea.
Sex‐Dependent Depot Differences in MMPs and Inflammation of Adipose Tissue Remodeling in Mice
Authors: Wu Yuanyuan , Lee MiJeong , Fried Susan K. 
Published: June 2021

We reported (Grove et al, IJO, 2010) gonadal (GON) and inguinal (ING) sc adipose tissues of high fat (HF) fed obese female compared to male mice (C57/BL6) are less inflamed. Microarray and RT‐qPCR studies revealed significant sex and depot differences in the expression of metalloproteinases (MMPs), enzymes that remodel adipose tissue in obesity. We followed up by comparing the mRNA expression of MMPs, 3 and 12, and their inhibitors (TIMPs) in age‐matched mice fed low compared high fat (45% calories) diets for 14 weeks, and extended studies to the mesenteric, a visceral depot and dorsal Sc (DSC), which in contrast to the ING, does not include mammary gland. As expected, HF diets induce a robust inflammatory response that includes increases in MMP12 in males, but not females and the response was greater in the visceral than sc depots. In females, in contrast, MMP3 mRNA was higher in sc than visceral (both ING and DSC) with low fat (LF) feeding and was not affected by the HF diet. However, HF diet increased MMP3 in all depots in males. MMP3 and MMP12 were mainly expressed in the stromal cell fraction. Flow cytometry and qRT‐PCR analysis suggested MMP3 transcripts were made from Lin− CD29+Sca1+CD34+/− population enriched for preadipocyte markers, while MMP12 was expressed in macrophages. We conclude that there are major sex dependent depot differences in gene expression of MMPs and TIMPs and those differences may contribute to sex‐ and depot‐differences in adipocyte size and adipose tissue expansion.Funding sources: Evans Center for Interdisciplinary Biomedical Research and NIH(R24DK087669).
Scientific Jobs – an industrial perspective
Authors: Concha Nestor Omar 
Published: June 2021

We all have been trained in the methods and tools of scientific research in academic laboratories because, truthfully, there is no better place, but it does not follow that academic research institutions are the only places where intellectually challenging science is being done and that only academic labs have the interesting problems to be tackled. In the broadest sense, the employment market is a collection of diverse opportunities, but there is no such thing as research in academia and research in industry. Quite a bit of introspection is called for to determine one's personal long term goals, free from considerations such as “I'm selling out”, or industry is the “evil empire”. Instead, be aware that you are also interviewing your prospective boss, the company, the work they do, and the way they work. Ultimately, an outstanding team of colleagues and a clear sense of the purpose of your endeavors are the key components of a rewarding and successful career.Science in the pharmaceutical industry and biotechs is mission driven: the unmet medical needs of the patients, in delivering what is of benefit to society. Under these parameters, performance and deliverables are measure against goals and milestones. The opportunity to publish important scientific contributions is encouraged.In general, industry jobs have a favorable work‐life balance. Internships, co‐op and summer studentships provide terrific opportunities offered by many organizations to allow both students and prospective employers to know each other, to understand the sense of fitting into the larger whole, and being valued for that.
Proteinase‐activated receptors, PAR1 & PAR2, regulate porcine coronary contractility via tyrosine kinase‐MAPKinase signaling involving a cyclooxygenase (COX)‐1 product
Authors: El‐Daly Mahmoud , Saifeddine Mahmoud , Triggle Christopher R. , Hollenberg Morley D. 
Published: June 2021

ObjectivePARs 1 and 2 regulate vascular tension and also trigger both tyrosine kinase (PYK) and MAPKinase signals, in part via EGF receptor (EGFR) transactivation. We hypothesized that PAR‐triggered MAPK and PYK activities regulate porcine coronary artery (PCA) tension via EGFR activation.MethodsContractions of L‐NAME‐treated PCA rings ± functional endothelium stimulated by PAR1/2‐selective activating peptides (PAR‐APs), EGF, angiotensin‐II (AngII) and PGF2α were monitored in the absence and presence of the signal pathway inhibitors: PP1 (Src kinase), AG1478 (EGFR kinase), U0126 (MAPK), PD98059 (MAPK), and the COX inhibitors, indomethacin (INDO, COX1,2), SC560 (COX1), & NS398 (COX2).ResultsEndothelium‐independent contractions by PAR1/2‐APs, Ang‐II, and EGF (but not by PGF2α) were inhibited by PP1, U0126, & PD98059. AG1478 blocked mainly PAR2‐AP and EGF contractions, Further, PAR‐AP & Ang‐II contractions, blocked by INDO & SC560, were mimicked by arachidonate. In contrast, PGF2α‐induced contraction was not affected by any inhibitor used.ConclusionsPARs 1 & 2, like AngII, regulate coronary tension via a PYK‐MAPK pathway involving a COX1 metabolite, but by distinct GPCR mechanisms that differentially transactivate the EGFR. Support: CIHR‐Canada, Qatar Foundation NPPR and the Heart & Stroke Foundation of Canada.
The mechanism of the marine β‐carboline thromboxane B2 inhibitor Manzamine A: role of p90 ribosomal S6 kinase 1
Authors: Chandrasena Kevin , Hall Mary L , Mayer Alejandro M 
Published: June 2021

Manzamine A (MZA) inhibited LPS‐treated rat microglia (BMΦ) TXB2 (IC50<0.016 μM) and O2− (IC50=0.1 μM) generation, (BMC Pharmacology 5(1) 6, 2005), LPS‐treated human BMΦ TXB2 (apparent IC50<0.7 μM) (Inflam Res. 53(S3): S217, 2004) and rat p90 ribosomal S6 kinase 1 (RSK1) (IC50 =15.01 μM) (Program 545.5, Society of Neuroscience, 2009). RSK1 is expressed in LPS‐treated rat microglia (BMΦ) (Faseb Journal 26: 1124.1, 2012). We hypothesized that in BMΦ MZA might inhibit RSK1 phosphorylation induced at residues S380 and T573 by kinases activated by PMA, a PKC activator. In order to test our hypothesis, we determined the presence of constitutive and phosphorylated RSK1 proteins in murine BV‐2 BMΦ cell line. Briefly, we prepared protein extracts from untreated, LPS (100 ng/mL)‐treated, LPS + PMA (1μM)‐treated BV‐2 BMΦ in the presence or absence of DMSO and MZA (3, 10 and 30 μM), and probed by western blot analysis using constitutive RSK1 (Cell Signaling) and phosphorylated RSK1 (pRSK1) antibodies against S380 (Epitomics) and T573 (Cell Signaling).Results1) Constitutive RSK1 and pRSK1 proteins were present in all BV‐2 BMΦ extracts tested; 2) PMA enhanced pRSK1 protein in LPS‐treated BV‐2 BMΦ; 3) MZA did not inhibit pRSK1 protein on either S380 and T573 in LPS + PMA‐treated BV‐2 BMΦ. Future studies will determine 1) whether RSK1 in primary rat microglia show a similar response to MZA, and 2) evaluate the effect of MZA on phosphorylation of RSK1 at residues S221, S154, T359, S363, S732. Support to KC by the Office of Research, Midwestern University is gratefully acknowledged.
SPAK‐independent activation of NCC in salt‐sensitive hypertension
Authors: Terker Andrew Scott , Yang Chao‐Ling , McCormick James A. , Rogers Shaunessy , Ellison David Hoadley 
Published: June 2021

BackgroundRecently, it was reported that adrenergic stimulation activates the thiazide sensitive Na‐Cl cotransporter (NCC) and causes salt‐sensitive hypertension. Here, we tested whether NCC activation is required.ResultsNorepinephrine (NE) infusion increased blood pressure (BP) after one week, an effect enhanced by salt loading. Total and phosphorylated NCC (pNCC, a marker of activation) were increased after three weeks. The salt‐dependent BP rise was greatly attenuated in NCC knockout (KO) mice. Kidneys from mice acutely treated with NE showed increased pNCC (2.83 fold increase, P<0.01) within 30 minutes, while total NCC remained unchanged. This effect was not abrogated in AT1aR KO mice. To determine the adrenergic receptor subtype involved, phenylephrine, isoproterenol, or both were administered. The combination increased pNCC more than either alone. NE stimulation did not change SPAK abundance in the DCT, so we speculated that OSR1 might be involved. NE increased pNCC abundance even in SPAK KO mice. Further, acute NE increased the apical OSR1 in the DCT of wild‐type and SPAK KO mice.ConclusionNE activates NCC acutely to cause salt‐sensitive hypertension. NCC can be activated independent of SPAK, likely by OSR1. These results identify a novel role for OSR1 and NCC in salt‐sensitive hypertension. Supported by 1RO1DK095841, RO1DK51496, and by a VA Merit Review.
The lectin‐like domain of TNF directly increases ENaC activity
Authors: Czikora Istvan , Alli Abdel A , Bao Hui‐Fang , White Richard , Shabbir Waheed , Lemmens‐Gruber Rosa , Tzotzos Susan , Fischer Bernhard , Matthay Michael A , Eaton Douglas C , Lucas Rudolf 
Published: June 2021

RationaleAims of this study were to investigate whether the TIP peptide, mimicking the alveolar liquid clearance (ALC)‐promoting lectin‐like domain of TNF, is able to activate amiloride‐sensitive Na+ transport in H441 cells and to directly interact with specific ENaC domains.MethodsPeptide effects on Na+‐uptake in cells pretreated or not with N‐glycosidase F, were assessed using perforated patch or single channel measurements. Peptide‐ENaC interactions were assessed upon incubating either a) biotinylated TIP or mutant TIP peptide‐coupled or b) GST‐ENaC‐α domain‐coupled beads with lysates from ENaC‐α overexpressing H441 cells or peptides, respectively.ResultsTIP, but not mutant TIP peptide activates amiloride‐sensitive Na+ currents and single ENaC channels in glycosylated, but not de‐glycosyated H441 cells. Binding to human ENaC‐α subunit occurs within the regulatory carboxy‐terminal, but not the extracellular loop or N‐terminal domains of the recombinant protein.ConclusionsThese data suggest for the first time that the lectin‐like domain of TNF, upon internalization, directly activates ENaC, by binding to the carboxy‐terminal domain of the channel's α‐subunit. This provides a rationale for the observed therapeutically promising ALC‐promoting activities of the peptide in vivo.
NF‐kB–dependent IL‐6 expression, induced by electrical stimulation, is reduced in dystrophic mdx skeletal muscle cells.
Authors: Jaimovich Enrique , Henríquez Carlos , Altamirano Francisco 
Published: June 2021

In skeletal muscle cells, membrane depolarization increases reactive oxygen species (ROS) due to NOX2 activation; this is related with changes in gene expression. Our aim was to study IL‐6 gene in wt and mdx muscle cells, and its relationship with NOX2 and NF‐kB activity. Differentiated wt and mdx myotubes were stimulated with 250p, 0.5 ms at 20 Hz. ROS production was assessed with CM‐DCFA. NOX2 was assessed using apocynin and DPI. NF‐kB transcriptional activity was studied with a luciferase reporter, p65 phosphorylation by western blot and gene expression by real time PCR.NOX2 subunits (gp91 and p47) were upregulated in mdx myotubes. After stimulation, ROS production was higher in mdx compared to wt. NF‐kB activity after both electrical and ROS stimulation increased in wt myotubes, but not in mdx. NOX2 inhibition reduced NF‐kB activation. IL‐6 gene expression induced by both electrical and ROS stimulation was higher in wt compared to mdx muscle cells.ROS production and NF‐kB activity are linked in normal cells. Altered NF‐kB, excess ROS production and differential gene expression could explain oxidative stress and progressive damage reported in DMD.Fondecyt 1110467 (EJ), AT‐24100066 (FA).
A role for Gαi2 proteins in the acute neural control of blood pressure.
Authors: Carmichael Casey Yumi , Wainford Richard D 
Published: June 2021

AimWe have demonstrated hypertension mediated by failure to upregulate hypothalamic paraventricular nucleus Gαi2 proteins in rats fed a high salt diet, but the role of this mechanism is unknown in acute settings. We examined the effect of central Gαi2 proteins in the neural control of blood pressure in response to an acute pharmacological and physiological challenge.MethodsNaïve and 24hr ICV Gαi2 oligodeoxynucleotide (ODN; 25μg/5μl)‐pretreated conscious Sprague‐Dawley rats were continuously monitored for changes in HR and MAP in response to intravenous (IV) infusion of phenylephrine and sodium nitroprusside or 3M NaCl IV bolus (0.14 ml/100g). To determine cardiac baroreflex relationships, MAP was slowly raised to ~175 mmHg using phenylephrine and lowered to ~50 mmHg using sodium nitroprusside (N=8/gp).Results24h Gαi2 ODN pretreatment did not affect the cardiac baroreflex response. In response to IV sodium, peak changes in HR were significantly greater in naïve animals vs. Gαi2 treated animals (Naïve + 3M NaCl ΔHR=−79±15 bpm vs. Gαi2 + 3M NaCl ΔHR=−59±12 bpm; P<0.05). We observed no difference in peak MAP post‐IV NaCl between groups (Naïve + 3M NaCl MAP 147±4 mmHg vs. Gαi2 + 3M NaCl MAP 149±3 mmHg). In naïve rats, MAP returned to baseline by 100 min whereas Gαi2 animals remained significantly elevated for 120 min (P<0.05).ConclusionEndogenous Gαi2 proteins are involved in neural control of HR and MAP during an acute sodium challenge. These data suggest brain Gαi2 signal transduction is required to mediate sodium‐sensitive neural responses to maintain physiologically appropriate blood pressure regulation.
The Antifibrillatory Effects of Vagus Nerve Stimulation in the Rabbit Ventricle involves cGMP‐Dependent Mechanisms
Authors: Brack Kieran , Winter James , Ng G. Andre 
Published: June 2021

We have previously shown that vagus nerve stimulation (VNS) increases effective refractory period (ERP) and ventricular fibrillation threshold (VFT) whilst reducing electrical restitution slope, via an acetycholine independent ‐ nitric oxide (NO) dependent mechanism. NO activates soluble guanylyl cyclase [sGC] to produce cyclic guanylyl monophosphate (cGMP) to modulate cardiac function. Our aim was to investigate if the effects of the VNS‐NO pathway on ERP, VFT and restitution slope were mediated via cGMP mechanisms. The innervated rabbit heart was used (n=5, 2.5–3kg) in constant flow Langendorff mode. Ventricular ERP was determined using a single extrastimulus protocol (300ms cycle length) and maximal restitution slope was measured. VFT was the minimum current needed to induce sustained VF with burst pacing (30×30ms). These were measured at baseline [BL] and during VNS [10Hz, 9V] in control (Ctrl) and following sGC inhibition with (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one [ODQ], 10μM). Data are mean±SEM, Student's T‐Test, P<0.05 * vs BL, ** vs Ctrl. VNS increased ERP and VFT whilst reducing restitution slope. During sGC inhibition, the vagal effect on restitution slope and VFT were reduced, whilst the effect on ERP was preserved. Cyclic GMP is involved in the protective effects of VNS‐NO pathway against VF but concurrent cGMP independent mechanisms could also be at work.
KEB is supported by a British Heart Foundation IBSR Fellowship

Table
ERP (ms)
Slope
VFT (mA)

Ctrl BL
131.0±3.3
1.48±0.2
3.6 ±0.7

Ctrl VNS
158.0±9.3*
0.99±0.21*
7.0±0.6*

Change
16.8±5.9
−0.5±0.1
3.4±0.2

ODQ BL
144.2±4.5
1.3±0.1
3.5±0.7

ODQ VNS
159.0±7.6*
1.2±0.1
5.2±0.8*

Change
12.0±3.0
−0.1±0.1**
1.7±0.1**
Phosphodiesterase 5 inhibition rescues functional sympatholysis in Duchenne Muscular Dystrophy
Authors: Nelson Michael , Martin Elizabeth A. , Tang Xiu , Johannes Jimmy , Lewis Joshua , Gurudevan Swaminatha V. , Nelson Stanley , Miceli Carrie , Victor Ronald G. 
Published: June 2021

We recently reported that functional sympatholysis (i.e., muscle contraction‐induced attenuation of reflex vasoconstriction) is impaired in Becker Muscular dystrophy and rescued by phosphodiesterase (PDE)5 inhibition with tadalafil. However, tadalafil failed to rescue sympatholysis in one BMD patient with a rapidly progressive disease resembling Duchenne Muscular Dystrophy. Thus, we tested the ability of two different phosphodiesterase inhibitors, tadalafil and sildenafil, to rescue sympatholysis in DMD. In 6 boys with DMD (ages 7–13) and 8 healthy controls, we measured reflex vasoconstriction (decreased forearm muscle oxygenation [ΔHb02, near infrared spectroscopy] evoked by lower body negative pressure) at rest and during rhythmic handgrip exercise. First, we confirm that sympatholysis is impaired in DMD, because handgrip greatly attenuated vasoconstriction in controls (ΔHb02: −22±6 vs. −9±5 %, p<.05; rest vs. HG) but caused no attenuation in DMD (−17±2 vs. −15±3%). Then, in a randomized single dose (0.5 mg/kg) cross‐over trial of tadalafil vs. sildenafil, we show that sympatholysis is rescued in DMD by either PDE5 inhibitor (tadalafil: −21±3 vs. −11±4; sildenafil, −22±4 vs. −12±3%; ΔHb02 rest vs. HG). PDE5 inhibition therefore constitutes a putative therapeutic treatment option for patients with either Becker or Duchenne Muscular Dystrophy.Support: Parent Project Muscular Dystrophy
Purinergic receptor antagonism does not attenuate the exercise pressor reflex in hypertensive adults
Authors: Greaney Jody L , Boggs Mary E , Matthews Evan L , Edwards David G , Farquhar William B 
Published: June 2021

A previous study reported that purinergic (P2) receptor antagonism attenuated the blood pressure (BP) response to static handgrip (HG) in healthy adults. The aim of this study was to determine if pyridoxine HCl is an effective in vitro P2 receptor antagonist and if localized P2 receptor antagonism with pyridoxine in vivo blunts the exaggerated exercise pressor reflex (EPR) in older hypertensive (HTN) adults. For in vitro studies, dorsal root ganglion (DRG) cells isolated from mice were loaded with fura 2‐AM and incubated in control buffer (HBSS) or 100μM pyridoxine. Following incubation, the effect of 10μM ATP on intracellular Ca2+ was measured. The Ca2+ response was attenuated in DRG cells incubated with pyridoxine (HBSS: Δ130±10 nM v pyridoxine: Δ13±2 nM; P<0.05). For in vivo studies, 8 HTN adults (6M; 67±1 yrs; BP 141±5/81±4 mmHg) completed a control (0.9% saline; NS) and P2 receptor blockade (730mM pyridoxine) trial (randomized; 1 month apart). BP (Finometer) was measured at baseline and during static HG at 40% maximal voluntary contraction followed by post‐exercise ischemia (PEI). P2 receptor blockade did not blunt the increases in mean BP during HG (NS: Δ21±4 v P2: Δ23±5 mmHg; P>;0.05) or PEI (NS: Δ15±3 v P2: Δ17±3 mmHg; P>;0.05). These preliminary data suggest that pyridoxine is an effective in vitro P2 receptor antagonist but indicate that in vivo P2 receptor antagonism does not attenuate the EPR in older HTN adults.Supported by AHA 11PRE7580029 and ACSM Foundation.
EGF suppresses intestinal epithelial cell shedding both in vitro and in vivo via a MEK/ERK dependent pathway
Authors: Frey Mark R , Miguel Jennifer C , Lien Ching‐Ling , Watson Alastair J 
Published: June 2021

Epithelial cell shedding from the intestinal villus is a key element of normal tissue turnover. Increased cell shedding is associated with inflammatory bowel diseases. The signals regulating this process are not well understood. In this study, we asked whether shedding is controlled by epidermal growth factor (EGF) receptor, an important driver of intestinal growth and differentiation.METHODSCell extrusion events in vivo (zebrafish midgut) or in vitro (MDCK or IEC‐6 cells) were identified by rhodamine‐phalloidin labeling of condensed actin rings. In vitro, shedding rates were assessed by counting extruded cells in the culture media over time. EGF, with or without MEK inhibitor (U0126), was given by intraperitoneal injection (fish) or in culture media (cells).RESULTSEGF reduced detectable shedding events on zebrafish villi (34% decrease, p<0.05) and from MDCK (49% decrease, p<0.01) or IEC‐6 (42% decrease, p<0.01) cell monolayers. Pharmacological blockade of MEK/ERK reversed these effects both in vitro and in vivo. In contrast, inhibitors to other EGF‐stimulated pathways such as PI3K/Akt or PKC had no effect.CONCLUSIONSEGF receptor suppresses cell shedding in the intestinal epithelium through a specific MEK/ERK dependent pathway. These results may open the door to new therapeutic avenues for targeting excessive cell turnover in conditions such as inflammatory bowel diseases.