bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scanning acoustic microscopy for characterization of gastric lesions
Authors: Miura Katsutoshi , Yamamoto Seiji 
Published: June 2021

Study objectiveA scanning acoustic microscope (SAM) is a device that uses ultrasound (frequency, 120 MHz) to image an object. Because the harder the tissue, the more the speed of ultrasound, SAM can provide data on the elasticity of tissues and lesions. Can SAM discriminate normal and pathological lesions of stomach?Materials and MethodsFormalin‐fixed paraffin‐embedded sections of gastric lesions 10 um in thickness were used. We compared gastric lesions between SAM and light microscope (LM) images.ResultsSAM system discriminated gastric components and demonstrated distinct acoustic images such as adenocarcinomas, carcinoids, lymphomas leiomyomas(Figure) and GIST. Areas with thick fibrous portion and desmoplastic reactions associated with cancer invasion showed the greater speed‐of‐sound (SOS). Cell density portions also demonstrated the faster SOS than sparse area.SAM provided the following benefits over LM: (1) images were acquired in only a few minutes without special stainings, (2) analysis by SAM system could be helpful to understand ultrasonic endoscopic images, and (3) digitized SOS data could be statistically compared among different lesions of stomach.This work was supported by Japan Society for the Promotion of Science KAKENHI Grant Number 24590445.
The newer therapeutic alternatives to the acid‐oriented approach via targeting endothelial metabolism in esophagoprotection by 5‐hydroxytryptamine (5‐HP) and melatonin (MT)
Authors: Zayachkivska Oksana , Savytska Maryana , Mandrusyak Solomiya , Yaschenko Antonina 
Published: June 2021

Existing treatment of erosive and nonerosive esophagitis (NEE) which incidence has risen dramatically in recent years are mostly based on potent acid suppression. Modern data revealed that the prolonged acid suppression is associated with dismotility in foregut, extraesophageal disorders, abnormal microbiota, and induction selective apoptosis for cancer. We hypothesized that endothelial metabolism is key in multifactorial esophageal mucosa (EM) defense and studied 5‐HT/MT specific effects on EM endothelial metabolism during NEE associated to stress model (WRS) and 28 days of postprandial hyperglycemia (PPH) in rats was studied without/with 5‐HT (100 mg/kg) and MT (20 mg/kg) via VEGF, EGF, IL‐1β, TNFα synthesis by ELISA; EM injury via histological score index (HSI); functional reorganization of microangioarchitecture by mannose specific labeling.ResultsNNE constantly increased HSI in 150% in binary PPH and WRS; 5‐HT/MT decreased HIS 38% & 57%, respectively; potent MT and 5‐HT modulation vascular tone were through VEGF, TNFα synthesis better then 5‐HT. Changes in alfa‐DMan>;D‐Gal EM expression confirmed key role of endothelial metabolism in NEE and MT decreased expression of endothelial dysfunction. We concluded that MT has potent esophagoprotective effect then 5‐HT via decreasing endothelial permeability, thus may be alternative to the acid‐orientated approach.
Muscle‐specific deletion of mTORC2 (Rictor) blocks insulin stimulated Akt Ser 473 phosphorylation and impairs submaximal but not maximal insulin induced glucose uptake
Authors: Kleinert Maximilian , Sylow Lykke , Jensen Thomas Elbenhardt , Oxboll Anne‐Julie , Richter Erik 
Published: June 2021

ObjectiveTo test whether Rictor and Akt Ser437 phosphorylation is necessary for insulin‐stimulated glucose uptake in skeletal muscle.MethodsEDL muscle from muscle‐specific Rictor knock‐out mice (mKO) were incubated ex vivo with or without submaximal (100μU/ml) or maximal (100mU/ml) insulin concentrations. Akt Ser473 phosphorylation served as mTORC2 activity readout and muscle glucose uptake was measured with tritium‐labeled 2‐deoxyglucose.ResultsSubmaximal and maximal insulin stimulation increased Akt Ser437 phosphorylation 4‐fold and 21‐fold, respectively in EDL from WT mice (p < 0.01), but was blocked completely in mKO Rictor EDL. Akt1 and Akt2 expression in mKO Rictor muscle were reduced by 40% and 60%, respectively (p < 0.001). Conversely, expression of TRB3, a negative regulator of Akt activity, was increased 1.6‐fold (p < 0.05) in mKO Rictor muscle. Glucose uptake increased 2‐fold in WT mice with both submaximal and maximal insulin concentrations (p < 0.05). In mKO muscle submaximal insulin‐induced glucose uptake was completely blocked but was normal during maximal insulin stimulation.ConclusionDeletion of Rictor in muscle impairs Akt expression and blocks Akt Ser437 phosphorylation during insulin stimulation. Rictor and Akt Ser 473 phosphorylation are necessary for increasing muscle glucose uptake at submaximal but not maximal insulin concentrations.
Macula densa nitric oxide contributes to anomalous tubuloglomerular feedback in subtotal nephrectomy rats on high salt diet
Authors: Singh Prabhleen , Pham Hai , Khang Ser , Thomson Scott 
Published: June 2021

It is more work for the kidney to conserve NaCl than to excrete it. Tubuloglomerular feedback (TGF) normally contributes to NaCl conservation by preventing the distal NaCl delivery from increasing. The only known exception to this is the rat fed high NaCl diet (HS)) after subtotal nephrectomy (STN) in which case TGF exerts a positive feedback effect, which amplifies, rather than attenuates, the impact of SNGFR on distal delivery. NaCl‐dependent nitric oxide (NO) from the macula densa is known to blunt normal TGF‐mediated vasoconstriction. Present experiments were conducted to test hypothesis that the anomalous TGF response of STN to HS is mediated by excess NO from the macula densa. Male Wistar rats were fed HS from the time of STN or sham surgery. TGF responses were measured by micropuncture 8 days later, perfusing Henle's loop from late proximal tubule at 8 and 50–60 nl/min with artificial tubular fluid (ATF) ± NOS blocker (LNMMA 10−4M) and measuring single nephron GFR (SNGFR) by 3H inulin clearance in fluid collected from late proximal tubules.

GFR (ml/min)
Urine flow (μl/min)
SNGFR (nl/min)

LOH perfusion
N/A
N/A
Low
High
ΔSNGFR†

STN+ATF (n=15)
0.6±0.1
39±4
54±4
59±4
−5±4

STN+LNMM A (n=20)
55±4
47±4
8±4

Sham+ATF (n=10)
3.2±0.7*
34±6
50±5
24±5
26±5

Sham+LNMM A (n=19)
43±4
25±4
18±4

P<0.01 vs. STN.
P<0.02 for effect of LNMMA on TGF response in STN vs. Sham.

Local NOS blockade abolishes anomalous TGF response in STN fed HS, but does not restore the TGF response to the magnitude seen in Shams fed HS. Anomalous TGF in STN fed HS contributes to a broad effort to achieve salt balance under extreme conditions. A portion of this is mediated by increased NOS activity in the juxtaglomerular apparatus.
Individual vasodilatory response heterogeneity during progressive forearm exercise: evidence for vasodilator phenotypes
Authors: Bentley Robert F , Kellawan J Mikhail , Moynes Jackie S , Poitras Veronica J , Walsh Jeremy J , Tschakovsky Michael E 
Published: June 2021

PURPOSETo determine whether vasodilator and/or pressor response phenotypes are present during a perfusion pressure induced perturbation to exercising muscle oxygen delivery (O2D).METHODS10 healthy male subjects (19.5±0.4 yrs) completed two trials of progressive handgrip exercise to exhaustion (2.5kg increments every 3.5 mins) in each forearm above and below heart level (forearm arterial perfusion pressure (FAPP) Δ 29.5±0.97mmHg). Forearm blood flow ((FBF (ml/min); brachial artery Doppler and echo ultrasound), mean arterial blood pressure (MAP (mmHg); finger photoplethysmography) and O2D (ml/O2/min; venous effluents) were measured at the end of each work rate (WR).RESULTSGroup level, Δ FBF was compromised beyond the 5kg WR in above vs. below. There was no vasodilatory (P=0.21) or exercise pressor (P=0.63) response, and submax O2D, submax and peak VO2 and peak WR were compromised by reduced FAPP (all P<0.05). In contrast, individual responses revealed compensatory vasodilators (n=6) and those who did not (n=4). Vasodilators blunted the FAPP‐evoked reduction in submax O2D and VO2 compared to non‐vasodilators (P<0.05), and experienced less of a compromise to peak WR (P<0.05).CONCLUSIONSIn the current model, vasodilatory response phenotypes exist, which determine hypoperfusion susceptibility and the degree to which aerobic metabolism and exercise performance are compromised. NSERC.
The Increase of Mitochondrial DNA Copy Number Attenuates Eccentric Cardiac Remodeling In Volume Overload Model
Authors: Ikeda Masataka , Ide Tomomi , Fujino Takeo , Hata Yuko , Takehara Takako , Onitsuka Ken , Tobushi Tomoyuki , Sakamoto Kazuo , Saku Keita , Kakino Takamori , Tyynismaa Henna , Suomalainen Anu , Sunagawa Kenji 
Published: June 2021

BackgroundMitochondrial transcription factor A (TFAM) is essential for the maintenance of mitochondrial DNA (mtDNA). TFAM overexpression increases mtDNA copy number, prevents cardiac remodeling and improves survival after myocardial infarction. However, the role of the increased mtDNA copy number in volume overload (VO) remains unknown.Methods and ResultsWe used TFAM and Twinkle (TW) transgenic (TG) mice, both of which nearly doubled the mtDNA copy number in heart. One day after creating the aortocaval shunt to induce VO, left ventricular (LV) end diastolic pressures equally increased in all groups, and TFAM and TW significantly suppressed increased mRNAs of matrix metalloprotease (MMP) ‐9 and connective tissue growth factor. In 8 weeks after operation, both TFAM and TW prevented LV dysfunction (LV ejection fraction: TFAM 53.6±2.5, TW 54.0±1.0, WT 37.1±1.9, 39.1±3.0, p<0.01), dilatation (LV diastolic dimension: TFAM 4.6±0.1, TW 4.3±0.1, WT 5.0±0.1, 4.9±0.1, p<0.01) and perivascular fibrosis. They also suppressed superoxide (TFAM −21%, TW −31% vs. each wild type VO group, p<0.05) and MMP activity (TFAM −31%, TW −23% vs. each wild type VO group, p<0.05).ConclusionOverexpressed TFAM or TW equally ameliorated VO‐induced eccentric cardiac remodeling, which suggests that increased mtDNA copy number plays a key role in anti‐remodeling effects of TFAM and TW via suppression of MMP activity and fibrosis.
Selective up‐regulation of genes for MMP3 and MT‐1 MMP by substance P in cardiac fibroblasts
Authors: Dehlin Heather Marie , Monroe Andrew , Reimer Michael , Manteufel Edward , Levick Scott 
Published: June 2021

Cardiac scarring or fibrosis results from excessive generation of extra cellular matrix (ECM) by cardiac fibroblasts. Fibrosis increases the stiffness of the heart leading to impaired cellular signaling, cardiac function, and ultimately heart failure. Of particular interest is how the neuropeptide, substance P, contributes to the development of cardiac fibrosis. Substance P is a key neuropeptide in sensory nerves and is localized near the coronary vasculature and in a select population of coronary endothelial cells. This is an ideal location for substance P to be secreted in response to changes in coronary pressure or flow as in a hypertensive condition. Using the spontaneously hypertensive rat model of hypertension, we observed a continual increase in substance P gene expression, Tac1, in the left ventricle corresponding with increasing blood pressure. Substance P up‐regulates the ECM genes, MMP3 and membrane type 1 MMP (MT‐1 MMP) in a concentration dependent manner. Although cardiac fibroblasts express NFKB, this pathway does not appear to be involved. Substance P induces expression of specific, yet necessary, ECMrelated genes in cardiac fibroblasts providing causal evidence that substance P regulates factors relating to the development of fibrosis.This work is supported by project number T32 HL007792.
Doxycycline Attenuates Cardiac Injury and Improves Cardiac Function with Inhibition of Myocardial Matrix Metalloproteinase (MMP)‐2 in a Swine Model of Hypoxia‐ Reoxygenation (H‐R)
Authors: LaBossiere Joseph R. , Pelletier Jean‐Sebastien , Ali Mohammad , Bigam David , Schulz Richard , Cheung Po‐Yin 
Published: June 2021

BackgroundCardiac dysfunction is common in asphyxiated neonates. Although small animal studies support attenuation of cardiac injury with the known MMP inhibitor doxycycline in H‐R, this effect has not been tested in a clinically relevant large animal model of H‐R. We hypothesized that doxycycline would improve the recovery of cardiac function in newborn piglets with H‐R.MethodsPiglets were instrumented for hemodynamic monitoring and subjected to 2 hr of hypoxia followed by 4 hr of normoxic reoxygenation. Piglets were blindly randomized to receive i.v. saline or doxycycline (3, 10, or 30 mg/kg) 5 min into reoxygenation (n=7/group). Sham piglets (n=5) received no H‐R. Markers of myocardial injury (serum and myocardial tissue troponin; myocardial lactate) and oxidative stress (lipid hydroperoxides) were measured by ELISA and Western blot. Myocardial MMP‐2 activity was quantified by gelatin zymography.ResultsDoxycycline dose‐dependently improved cardiac (CI) and stroke volume (SVI) index (30mg/kg: 84±3 (SEM)% and 78±5% of baseline vs. 65±3% and 50±5% in controls [p<0.05]). Markers of myocardial injury, oxidative stress and MMP‐2 activity were improved in doxycycline groups vs. control [all p<0.05]. Significant correlations were found between markers of myocardial injury and CI and SVI recovery (r =−0.5, p<0.01), with a negative correlation also observed between myocardial tissue and serum troponins (r =−0.4, p=0.02).ConclusionsDoxycycline attenuates cardiac injury and improves functional recovery in newborn pigs with H‐R.Funded by: Canadian Institutes of Health Research and the Women and Children's Health Research Institute
Endothelium‐dependent cutaneous vasodilation in young smokers: role of endothelial‐derived hyperpolarizing factors
Authors: Fujii Naoto , Brunt Vienna E , Francisco Michael A , Minson Christopher T 
Published: June 2021

In young humans, endothelium‐dependent cutaneous vasodilation (EDCV) relates to both nitric oxide (NO) and cyclooxygenase (COX) pathways. We have recently shown that endothelial‐derived hyperpolarizing factors (EDHFs) are also involved, and that young smokers have impaired EDCV due to diminished NO‐ and COX‐dependent vasodilation. In this study, we tested the hypothesis that EDHFs greatly contribute to EDCV in young smokers to compensate for the lack of NO‐ and COX‐dependent vasodilation. We evaluated the increase in cutaneous vascular conductance (CVC) from baseline to peak value (CVCΔpeak) during acetylcholine (ACh) infusions of 1, 10, and 100mM at four intradermal microdialysis sites: 1) Ringer (control), 2) tetraethylammonium (TEA, a calcium‐sensitive potassium channel blocker which prevents EDHF‐induced vasodilation), 3) Nω‐Nitro‐L‐arginine (L‐NNA, NO synthase inhibitor) + Ketorolac (Keto, COX inhibitor), and 4) combination of TEA, L‐NNA, and Keto. At 100mM of ACh, CVCΔpeak at Ringer sites (54.4±14.2%max) was higher than that at the TEA sites (37.8±17.8%max), but was similar to that at the L‐NNA + Keto sites (57.5±1.3%max). Similar results were also obtained with 1 and 10 mM ACh. These data suggest that NO and COX pathways are deficient in EDCV of young smokers, but that a significant EDHF component remains.Grant: NIH HL081671
Changes in expression and activity of MnSOD and CuZnSOD in carotid body and adrenal medullary cells of rats exposed to chronic intermittent hypoxia.
Authors: Moya Esteban , Varela Carlos R , Arias Paulina , Iturriaga Rodrigo 
Published: June 2021

Nitro‐oxidative stress is associated with hypertension and enhanced carotid body (CB) chemosensory responses induced by chronic intermittent hypoxia (CIH). Since, ROS levels are regulated by cytoplasmic (CuZnSOD) and mitochondrial (MnSOD) superoxide dismutases; it is plausible that changes in their expression or enzymatic activity due to tyrosine nitration may contribute to the chemosensory potentiation. We studied effects of CIH on 3‐nitrotyrosine (3‐NT), SODs levels and activities, and MnSOD nitration in CB and adrenal medullary cells from Sprague‐Dawley male rats exposed to CIH (5% O2, 12 times/h for 8 h/day) for 7 days. To determine the contribution of mitochondrial ROS to the chemosensory potentiation, we studied the effects of the mitochondrial targeted antioxidant MitoTEMPO on the CIH‐induced CB chemosensory potentiation. CIH increased the 3‐NT levels in the CB and adrenal cells, the MnSOD level and activity in the CB, but not in adrenal medullary cells. CuZnSOD levels did not increase in any tissue. MitoTEMPO treatment prevented the CIH‐induced CB chemosensory potentiation. These results indicate that mithochondrial ROS are crucial for the chemosensory potentiation, while the increased CB MnSOD level and activity may be the result of a compensatory mechanism to the increased oxidative stress.Supported by FONDECYT 1100405 & AT 24110172
N‐acetylcysteine administration modulates NADPH oxidase in skeletal muscle of rats with heart failure
Authors: Martinez Paula F , Fernandes D C , Bonomo C , Cezar M D M , Oliveira S A , Zornoff L A M , Okoshi K , Laurindo F R , Okoshi M P 
Published: June 2021

This study aimed to evaluate the influence of antioxidant N‐acetylcysteine on NADPH oxidase (NOX) activity and gene expression in soleus muscle of rats with myocardial infarctioninduced heart failure.MethodsMyocardial infarction (MI) was induced by left coronary occlusion. Four months later, rats were assigned to three groups: Sham (n=8), MI‐C (MI without treatment, n=8), and MI‐NAC (MI treated with N‐acetylcysteine, 120 mg/kg/day, n=8). Rats with small MI were excluded. Six months after surgery, NOX activity was assessed by HPLC analysis of dihydroethidium oxidation fluorescent products in soleus muscle. Gene expression of NOX complex subunits was evaluated by RT‐PCR.ResultsMI size did not differ between MI‐C and MI‐NAC groups (p>;0.05, Student's t test). NADPH oxidase activity was not different between MI‐C and Sham, but it was reduced in MI‐NAC compared to MI‐C group. Table shows the RT‐PCR results (ANOVA and Bonferroni; *p<0.05 vs. Sham, #p<0.05 vs. MI‐C):ConclusionN‐acetylcysteine administration reduces NADPH oxidase activity and gene expression in soleus muscle during heart failure. Support: FAPESP and CNPq.
ERM proteins colocalize with the Na+/H+ exchanger NHE1 in MCF‐7 breast cancer cell invadopodia and affect invadopodia number
Authors: Roest Gemma Anna Brigitta , Pedersen Stine Falsig 
Published: June 2021

Invadopodia are actin‐rich membrane protrusions which have been assigned essential roles in cancer cell invasiveness. Here, we investigate the roles of ezrin, radixin and moesin (ERM), three closely related F‐actin‐plasma membrane linker proteins implicated in metastasis, and their binding partner the Na+/H+ exchanger isoform 1 (NHE1), in the formation and function of invadopodial rosettes in MCF‐7 human breast cancer cells. ERM proteins colocalized strongly with NHE1 in invadopodia in MCF‐7 cells +/− constitutively active, N‐terminally truncated ErbB2 (ΔNErbB2). In contrast, the tumor suppressor Merlin which is more distantly related to the ERM proteins, did not. siRNA‐mediated knockdown of NHE1 increased the average number of invadopodia per cell in ΔNErbB2‐expressing cells but not in vector controls. Overexpression of either dominant negative (DN) or constitutively active (CA) ezrin decreased the number of invadopodia per cell, in vector control cells only. Average invadopodial rosette diameter was unaffected by knockdown of ezrin or NHE1, or by expression of DN‐ or CA‐ezrin. Thus, in MCF‐7 cells, NHE1 colocalizes strongly with ERM proteins in invadopodial rosettes and both NHE1 and ezrin appear to affect their formation. Studies are ongoing to determine the generality and roles of these interactions in cancer invasiveness.Funding: Danish Cancer Society, Danish Research Council
ENaC gating is coupled to the distance between the α‐and βENaC subunits at the base of the thumb and wrist domains
Authors: Collier Daniel M , Snyder Peter M 
Published: June 2021

The extracellular domain of ENaC functions as a sensor that modulates channel activity in response to changing extracellular conditions. However, the mechanism by which the extracellular domain influences channel gating is not known. In previous work, we determined that αK477 plays a role in ENaC pH sensing. Based on the ASIC1a crystal structure, we predict that αK477 forms an interface with βV85 and hypothesize that movement at this interface is coupled to channel gating. In the current work, we investigated potential intersubunit interactions at the single channel level. In Xenopus oocytes expressing αK477CβV85CγENaC, treatment with a long cysteine reactive cross‐linking reagent (MTS‐14‐MTS) resulted in an increase in open probability (Po) from 0.4 (± .06) to 0.6 (± .04, p = .04). Because ENaC Po varies widely, we introduced a mutation in the γENaC subunit that prevents endogenous cleavage and causes the channel to favor the closed state (Po = 0.03 ± .06). MTS‐14‐MTS increased the Po of these channels four fold to 0.12 (± .06, p = .02). To test the effect of a short cross‐linking reagent (MTS‐2‐MTS), we performed single channel studies in low extracellular Li+ conditions to cause the channel to favor the open state (Po = 0.67 ± .13). Under these conditions, treatment with MTS‐2‐MTS decreased ENaC Po to 0.2 (± .08, p = .01). The data suggest that movement at the interface between αK477 and βV85 influences channel gating, providing a potential link between extracellular pH sensing, extracellular domain conformational changes, and channel gating.DMC was supported by NIH 2T32HL007121–36 and PMS by HL072256
Specific and Progressive Diaphragmatic Myopathy During the Development of Heart Failure
Authors: Foster Andrew James , Arkell Alicia , Platt Mathew , Simpson Jeremy A. , Murrant Coral L. 
Published: June 2021

Respiratory dysfunction is a prominent feature of heart failure (HF) but remains to be fully understood. Our objective was to characterize diaphragmatic myopathy that manifests during the development of HF.MethodsHF was induced in mice by transaortic constriction (TAC). Cardiorespiratory function was measured in vivo and diaphragm strips were used for histology and in vitro contractile function in mice at 2, 4 or 18 weeks TAC or in sham mice.ResultsIn vivo respiratory frequency and pressure did not differ at any time point in anaesthetized animals suggesting absence of respiratory workload. In vitro force production was significantly elevated at 2 weeks (p<0.05) with a similar trend at 4 weeks; by 18 weeks, force production returned to sham levels. Indices of contractile performance (peak tension/time & dF/dt) at 2 and 4 weeks were significantly increased (p<0.05) and returned to sham levels by 18 weeks. Fatiguing stimulations revealed impaired relaxation at both 2 and 4 weeks TAC (p<0.05). Diaphragmatic atrophy (reduced cross sectional area) and fibrosis were evident at 4 weeks (p<0.05) and continued to develop by 18 weeks.ConclusionsDiaphragmatic myopathy develops in the absence of increased workload and is demonstrated by contractile alterations, atrophy and fibrosis.