bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel treatment for X‐linked nephrogenic diabetes insipidus: the secret in secretin?
Authors: Procino Giuseppe , Milano Serena , Carmosino Monica , Nicoletti Maria Celeste , Wess Jürgen , Svelto Maria 
Published: June 2021

X‐linked nephrogenic diabetes insipidus (NDI) is a disease caused by inactivating mutations of the vasopressin (AVP) type 2 receptor (V2R) gene. V2R inactivation prevents plasma membrane expression of the water channel AQP2 in the kidney collecting duct (CD) cells and impairs the kidney concentration ability.Here we show that secretin receptor (SCTR) is functionally expressed at the basolateral membrane of the kidney collecting duct cells. Based on this observation, we infused the mouse model of X‐NDI with SCT via osmotic pumps for 14 days at a dose of 2.5 mmol/Kg/day. Interestingly, although the urinary parameters were not altered in SCT‐infused animals, SCT significantly upregulated AQP2 in the intracellular stores of CD principal cells.As we previously reported that fluvastatin (Flu) treatment increases AQP2 plasma membrane expression in the CD cells of wt mice, SCT‐infused X‐NDI mice received a single injection of Flu (50 mg/Kg). Interestingly, during the following 6 hours of observation, the diuresis of mice treated with SCT+Flu was reduced by nearly 90% and urine osmolality almost doubled. The immunolocalization analysis confirmed that SCT increased AQP2 intracellular stores and Flu injection promoted AQP2 accumulation at the plasma membrane.Taken together these evidences indicate that the combination of SCT and Flu might represent a novel and effective pharmacological treatment for X‐NDI.
Measurement of heart function for myocardial infarction model of rat by micro‐CT
Authors: Matsushita Satoshi , Naito Mayuko , Amano Atsushi 
Published: June 2021

Materials and MethodsWe demonstrated functional measurement with no (normal) and mild or severe myocardial infarction of the rat heart using micro‐computed tomography (μCT) with administration of contrast agent. The hearts were sectioned to assess pathological evaluation of the heart following with CT acquiring.ResultsThe plot curve represented by each disk volume in normal heart revealed that contraction force was peaked at middle of the heart. In the mild infarcted heart, the volume plotting curve clearly demonstrated that infarcted area was limited at the apex of the heart, whereas that in severe infarction was in larger area. The left ventricular ejection fraction in normal, mild and severe was 68.6%, 40.0% and 16.4%, respectively. In addition, the volume analysis in severe infarction at seven days after injury demonstrated ventricular dilatation, which is consisted with histological evaluation.ConclusionsFunctional analysis of rat heart by μCT was accurate. This method is useful especially in small animal with heterogeneous dysfunction of the heart, since it can be analyzed with whole heart data.
β‐arrestin‐mediated signal transduction participates in laminar shear stress‐induced production of nitric oxide in endothelial cells
Authors: dos Santos Ana Paula Carneiro , Barauna Valério Garrone , Alaniz Miriam Helena Fonseca , Girardi Adriana Castello Costa , Krieger José Eduardo 
Published: June 2021

Endothelial cells are capable of converting mechanical stimuli into intracellular signals generating vasoactive factors such as nitric oxide (NO). A great body of evidence suggests that β‐arrestins play a role not only on GPCR desensibilization but also in mechanotransduction. The aim of this study was to test the hypothesis that laminar shear stress (SS)‐induced NO production by endothelial cells requires the activation of the β‐arrestin signaling pathway. Towards this end, human saphenous vein endothelial cells (SVEC) were transfected with siRNA against the isoforms 1 and 2 of β‐arrestins and subsequently subjected to SS (15 dynes/cm2) for 10 minutes. We found that the SS‐induced production of nitrite in the cell culture medium was significantly decreased in SVEC silenced for β‐arrestin 1 and 2 compared to control cells (326±44 vs. 166±17%; P < 0.001, n=5). Furthermore, silencing of β‐arrestin 1 and 2 significantly attenuated the phosphorylation levels of AKT at the serine residue 473 (99±22 vs. 293±42% in control; P <0.001, n=5) and led to a non‐significant trend towards an increase of ERK phosphorylation (157±71 vs.107±5% in control; P= 0.3670, n=5). Altogether, we provide evidence that β‐arrestins play a role on laminar SS‐induced generation of NO associated with AKT activation in endothelial cells.Supported by FAPESP, CAPES and CNPq.
Whole‐body sweat sensitivity in burn survivors following heat acclimation
Authors: Schlader Zachary J. , Lucas Rebekah A.I. , James Pearson , Ganio Matthew S. , Crandall Craig G. 
Published: June 2021

This study tested the hypotheses that heat acclimation (HA) improves whole‐body sweat sensitivity in burn survivors and this improvement is related to the percent of body surface area of grafted skin (%BSA). 28 burn survivors were stratified into highly grafted (>;40 %BSA; N=10) and moderately grafted (17–40% BSA; N=18) groups. Seven uninjured subjects served as controls. Each underwent a 7 day HA regimen consisting of 90 min of daily exercise in 40°C, 30% RH. Sweat rate (SR; pre‐to‐post nude weight), change in core (intestinal) temperature (ΔTC) and sweat sensitivity (SR/ΔTC) to identical exercise bouts were measured on the first and last day of HA. HA attenuated ΔTC in all groups (P<0.01), with a greater attenuation occurring in the grafted groups (~0.4°C) compared to control (~0.1°). In all groups, SR was unaffected by HA. Between the first and last day of HA, sweat sensitivity was not different in the high (from 6.0 ± 2.6 to 9.4 ± 3.3 ml/min/°C; P=0.22) or moderate (from 12.3 ± 7.5 to 16.0 ± 7.5 ml/min/°C; P=0.07) grafted groups, or in the controls (from 17.8 ± 6.2 to 18.9 ± 4.5 ml/min/°C; P=0.75). Changes in sweat sensitivity to HA were unrelated to %BSA (r = 0.05, P=0.80), but sweat sensitivity pre‐HA was related with %BSA (r = −0.46, P<0.01) and this relationship was maintained post‐HA. These data indicate that sweat sensitivity in burn survivors is related to %BSA, but is minimally affected by HA.Supported by NIH Grant GM068865
Polyphenols prevent obesity‐induced aortic vascular stiffness in C57BL/6 mice
Authors: Weisbrod Robert Mark , Fry Jessica , Chauhan Pratibha , Cohen Richard A , Seta Francesca 
Published: June 2021

Vascular stiffness and hypertension (HTN) increase in humans with aging, diabetes, and obesity. Our lab has shown that vascular stiffness precedes by 4–5 months the development of HTN in a model of high fat high sucrose (HFHS) diet‐induced obesity by measuring aortic pulse wave velocity (PWV) and blood pressure. Polyphenols may improve blood vessel function by reducing oxidants, inflammation, and vasodilation.PurposeTo determine if polyphenols can prevent HFHS diet‐induced vascular stiffness in a mouse model.MethodsMale C57BL/6 mice were fed HFHS diet for 8 months with a synthetic polyphenol, S17834, or resveratrol (130 mg/kg/day). PWV was calculated from the difference in pulse wave transit times between two sites along the aorta using ultrasound.Results and conclusionAfter 4 months HFHS diet significantly increased BW by 33% and PWV by >;2‐fold (2.1±0.1 vs 4.8±0.7 m/s, n=6). Both polyphenols prevented the increase in PWV, but only one, S17834, slowed the increase in body weight. Similar results were found over 8 months. These results demonstrate that HFHS diet causes a significant increase aortic stiffness associated with obesity. Both S17834 and resveratrol inhibited the development of aortic stiffness caused by HFHS diet suggesting polyphenols may have therapeutic value in reducing vascular stiffness and subsequent HTN.Source:NIH RO1 HL105287, Servier.
Vascular Aging: Association between Endothelial Function and Arterial Stiffness
Authors: Heldens Manon , Tarumi Takashi , Ayaz Muhammad , Parker Rosemary , Tinajero Cynthia , Hill Candace , Tseng Benjamin Y , Liu Jie , Zhang Rong 
Published: June 2021

Endothelial dysfunction and arterial stiffness are independent risk factors for cardiovascular disease. However, the relationship between these vascular parameters is not well understood during healthy aging. The purpose of this study was to determine: 1) age‐related differences in endothelial function and arterial stiffness and 2) the interrelationship between endothelial function and arterial stiffness across the lifespan from young to older adults.Methods48 healthy subjects aged between 22–78 years underwent the measurements of brachial artery flow mediated dilation (FMD) and central and peripheral pulse wave velocities (PWV).ResultsFMD, measured as percent change from baseline to maximal dilatation, was inversely correlated with age (r=−0.75, P<0.001). In addition, there was a positive association between age and the time to reach peak vasodilation after cuff release (r=0.39, P<0.01). Aortic PWV exhibited a positive association with age (r=0.63, P<0.001) and was correlated inversely with FMD (r=−0.40, p=0.004).ConclusionsEndothelial dysfunction and increases in central arterial stiffness are correlated with advancing age. Moreover, the observed inverse relationship between endothelial dysfunction and increases in arterial stiffness suggests the presence of common underlying mechanisms for changes in vascular function with aging.
cGMP‐dependent protein kinase I (PKGI) undergoes post‐translational modifications in the Golgi apparatus (GA)
Authors: Kato Shin , Roberts Jesse David 
Published: June 2021

PKGI mediates how nitric oxide and cGMP regulate vascular sooth muscle cell phenotype and pulmonary artery structure through incompletely understood mechanisms. Recently we determined that trans‐Golgi network (TGN)‐resident proprotein convertases, such as furin, stimulate PKGI proteolysis and regulate the nuclear localization of its kinase domain, PKGIγ. The current project tested whether PKGI undergoes proteolysis and glycosylation in the GA.Using specific antibodies and confocal microscopy, we observed that PKGI is colocalized with furin and TGN38, TGN‐resident proteins, in the peri‐nuclear compartment of BHK cells. Moreover, using this method and also immunoblotting, we noted that IP3 receptor‐associated cGMP kinase substrate (IRAG), overexpressed in RFL‐6 cells tethers PKGIβ to the endoplasmic reticulum and decreases PKGI proteolysis and PKGIγ nuclear translocation. Also, immunoblotting showed that brefeldin A and monensin, which decrease pre‐and intra‐GA protein transport respectively, inhibit PKGI proteolysis. Lastly, the resistance to endoglycosidase H and maintenance of PNGase F digestion of PKGIγ immunopurified from BHK cells indicated that PKGIγ is N‐glycosylated in the GA.These data demonstrate for the first time that the Golgi apparatus plays an important role in the regulation of PKGI post‐translational modifications.These studies were supported by NIH grant R01HL096779.
Mitochondrial catalase expression protects against hypoxia‐induced pulmonary hypertension
Authors: Adesina Sherry Eniola , Hart C. Michael , Sutliff Roy L. 
Published: June 2021

Pulmonary hypertension (PH) is characterized by increased pulmonary vascular remodeling, resistance, and pressures. Reactive oxygen species (ROS) contribute to PH‐associated vascular dysfunction. NADPH oxidases (Nox) and mitochondria are major sources of ROS in the vasculature. The crosstalk between these two ROS sources under hypoxic conditions is unknown.The antioxidant catalase attenuates H2O2. A mouse model with mitochondria‐targeted catalase expression (mCAT) was used to assess the role of mitochondrial H2O2 in hypoxia‐induced PH. We hypothesize that mCAT expression will reduce mitochondria‐derived ROS and hypoxia‐induced PH pathogenesis.Control and mCAT mice were exposed to normoxia (21% O2) or hypoxia (10% O2) for 3 weeks. PH development was assessed by measuring right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). ROS levels and Nox mRNA expression were measured by Amplex red assay and qRT‐PCR, respectively.Compared to control mice, mCAT mice developed less hypoxia‐induced increases in RVSP, Nox mRNA, and lung H2O2 release. mCAT expression did not prevent hypoxia‐induced increases in RVH. These studies suggest that attenuation of mitochondria‐derived ROS may be protective against pulmonary vascular derangements involved in PH pathogenesis.Research Service of the Atlanta VAMC and NIH grants DK074519/HL102167 (CMH and RLS).
Critical Role of Sox9 in the Differentiation of Mesenchymal Stem Cells to Endothelial Cells.
Authors: Agrawal Devendra K , Attairu Izuagie , Djossou Kokouvi P , Pankajakshan Divya 
Published: June 2021

ObjectiveMesenchymal stem cells (MSCs) have been shown to replenish and repair endothelial cells (ECs) of the cardiovascular system. However, mechanisms underlying differentiation is still unclear. Exposure of MSCs to vascular endothelial growth factor (VEGF) enhances in‐vitro differentiation of MSCs to ECs. In this study, we investigated a potential role of Sex‐determining region Y related protein (Sox9) signaling in the differentiation of MSC to EC in response to VEGF.Method and ResultsPorcine bone marrow MSCs, were differentiated in media containing 50 ng/mL VEGF that induced significant increase in EC markers, PECAM, VE cadherin and vWF in 10 days. Western blot analysis revealed a 3‐fold increase in Sox9 expression in VEGF‐treated differentiating MSCs compared to control MSCs. Flow cytometry results revealed that the transfection of MSCs with siRNA‐Sox9 decreased the expression of EC markers in VEGF‐treated MSCs. Overexpression of MSCs by transfecting Sox9 cDNA, followed by culture in MSC growth media, significantly increased the expression of EC markers in differentiated MSCs. Pre‐treatment of MSCs with PD173074, a VEGFR‐2 blocker, followed by culturing in the differentiating media decreased EC marker expression with no significant change in Sox9.ConclusionSox9 plays a critical role in the differentiation of MSCs to ECs via cellular communication between phosphorylated VEGFR‐2 and Sox9.Supported by NIH R01HL090580 and R01HL104516.
Role of Na‐K‐2Cl symporter in GABA‐evoked excitation in rat enteric neurons
Authors: Liu Sumei , Ji Tuo , Ren Wei , Qu Mei‐Hua , Zhu Jin‐Xia , Wood Jackie D 
Published: June 2021

Background and AimsGamma‐aminobutyric acid (GABA) inhibits neurons in the brain and spinal cord. GABA does the opposite in neurons of the enteric nervous system (ENS) where its mechanism of excitation is unclear. We aimed to test a hypothesis that the Na+‐K+‐2Cl− symporter (NKCC) maintains high intracellular Cl− and contributes to GABA excitation in ENS neurons.MethodsIntracellular electrophysiological recording was used to record GABA‐evoked responses in the myenteric plexus of the rat colon. Immunofluorescence and Western blot analysis were used to study the expression of NKCC.ResultsBoth NKCC1 and NKCC2 proteins were expressed in ENS neurons in postnatal and adult rats. NKCC1 and NKCC2 were coexpressed with the GABAA receptor. The K+‐Cl− cotransporter 2 (KCC2), a Cl− extruder, was not expressed. GABA depolarized the membrane potential in ENS neurons with a reversed potential of −20 mV, which is near the Cl− equilibrium potential. Blockade of NKCC by bumetanide or furosemide suppressed GABA‐evoked depolarization and shifted the reversal potential in the hyperpolarizing direction. Neither the KCC blocker nor the Cl−/HCO3− exchange inhibitor suppressed GABA‐evoked depolarization.ConclusionsNKCCs contribute to the elevation of intracellular Cl− and resulting excitatory actions of GABA in ENS neurons.
Cystathione‐γ‐lyase deficiency protects mice from galactosamine/LPS‐induced acute liver failure
Authors: Shirozu Kazuhiro , Tokuda Kentaro , Marutani Eizo , Lefer David , Wang Rui , Ichinose Fumito 
Published: June 2021

IntroductionAcute liver failure is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective effects in variety of organs. Here, we examined the role of cystathione‐γ‐lyase (CSE, an enzyme produces H2S) in the acute liver failure induced by galactosamine (Gal) and lipopolysaccharide (LPS).MethodsWild‐type (WT) and CSE‐deficient (CSEKO) mice were challenged with Gal/LPS.ResultsCSEKO exhibited better survival rate and lower plasma alanine aminotransferase (ALT) levels compared with WT after Gal/LPS challenge. Administration of DL‐propargylglycine (PAG, a CSE inhibitor) also prevented Gal/LPS‐induced increase of plasma ALT in WT. CSE deficiency markedly attenuated Gal/LPS‐induced upregulation of inflammatory cytokines and activation of caspase 3 and PARP in liver tissue. On the other hand, CSE deficiency increased nuclear translocation of Nrf2 and upregulated gene expression of anti‐oxidant proteins in the liver. Liver levels of thiosulfate was markedly increased in CSEKO compared to WT. Finally, administration of sodium thiosulfate attenuated the Gal/LPS‐induced increase of plasma ALT in WT.ConclusionsThese results suggest that CSE deficiency increases liver levels of thiosulfate and protects mice from acute liver failure at least in part by inhibition of caspase 3 activation and by augmentation of Nrf2 signaling pathway.
Cockroach Allergen Proteinases Regulate Proteinase‐Activated Receptor‐1 (PAR1) Signalling
Authors: Polley Danny , Mihara Koichiro , Ramachandran Rithwik , Vliagoftis Harissios , Boitano Scott , Hollenberg Morley D. , Daines Michael 
Published: June 2021

ObjectiveTo assess potential pro‐fibrotic PAR1 MAPKinase signaling by cockroach allergen‐derived trypsin‐like proteinases.MethodsCockroach allergen‐derived trypsin‐like enzymes, known to cause lung inflammation, were identified with serine proteinase activity‐based probes (ABP). Enzymes were purified (ion‐exchange chromatography) and analyzed for their ABP reactivity & substrate‐inhibitor kinetic profiles. Each enzyme was evaluated for causing calcium (Fluo‐4) and MAPKinase signaling (western blot) in PAR1‐expressing KNRK cells. Additionally, the cleavage‐internalization of fluorescently‐tagged PAR1 constructs was monitored as an index of receptor activation.ResultsCockroach allergen contained three ABP‐labeled 20–26 kDa MW proteinases with distinct enzyme kinetics. The allergen‐derived enzymes activated PAR1 MAPK and calcium signaling, but with distinct concentration‐effect kinetics. PAR1 cleavageinternalization caused by the allergen proteinases was similar to that caused by trypsin, but NOT thrombin.ConclusionsCockroach allergen contains three different trypsin‐like proteinases that can activate “biased” PAR1 pro‐fibrogenic MAPKinase (but not Ca++) signaling pathways. We suggest that the allergen proteinases can act as pro‐fibrotic factors in the setting of airway allergic inflammation and asthma. Support: CIHR, NIH USA and Lung Assn. of AB & NWT
Hydrogen Sulfide Increases Aqueous Humor Outflow in Porcine Trabecular Meshwork
Authors: Robinson Jenaye Danielle , Njie‐Mbye Ya Fatou , Okpobiri Anita , Chitnis Madhura , Opere Catherine A , Ohia Sunny E 
Published: June 2021

We have evidence that the colorless gas, hydrogen sulfide (H2S), can produce pharmacological actions in the eye. In the present study, we tested the hypothesis that the intraocular pressure lowering effect of H2S (using H2S‐releasing compounds as donors) is mediated by an increase in aqueous humor (AH) outflow in porcine trabecular meshwork (TM) tissues.MethodsPorcine ocular anterior segments explants were perfused with Dulbecco's Modified Eagle's Medium maintained at 37ºC, 5% CO2 and constant pressure of 7.35 mmHg. Once outflow was stable, explants were administered with H2S‐releasing compounds; sodium hydrosulfide (NaHS, 1 nM, 100 nM), L‐cysteine (100 nM), and outflow was monitored for 4 hours. Vehicle (0.1% saline) was run in parallel.ResultsNaHS (1 nM), a fast‐releasing H2S compound significantly increased AH outflow by 38% for only 1 hour when compared to vehicle. Furthermore, there was a concentration‐dependent increase in AH outflow with administration of 1 nM and 100 nM of NaHS. L‐cysteine (100 nM), a slow‐releasing H2S compound caused a significant (p<0.01) increase in outflow facility. Interestingly, the duration of the effects of L‐cysteine on AH outflow lasted longer than that of NaHS.ConclusionH2S‐releasing compounds can increase AH outflow in porcine TM indicating a pharmacological role for H2S in the regulation of IOP.
Coronary artery reactivity is increased in the aged SHR, a model of postmenopausal vascular physiology.
Authors: McCarthy Joseph , Gerevics Rebecca , Ramirez Rolando J.J. , Novak Jacqueline 
Published: June 2021

Women have a decreased risk of cardiovascular disease compared to men until after menopause when the risk is similar between men and women. The mechanism for cardioprotective effect is unclear. In order to study the physiological changes which occur in the cardiovascular system of women after menopause it is necessary to identify animal models. One model of post‐menopausal physiology is the aged spontaneously hypertensive female rats (SHR). The endocrine and blood pressure changes have been previously reported by Reckelhoff and colleagues. However, the vascular changes have not been characterized. The purpose of this study was to characterize the vascular behavior of coronary arteries in the aged female SHR. Septal coronary arteries were isolated from old and young SHR and studied in a pressure arteriograph. Active and passive diameters were measured over a range of pressures ranging from 10 to 100mmHg. Percent tone was calculated (1‐(Dactive‐Dpassive)*100%) at each pressure step. At each pressure step from 20–100 mmHg the percent tone was greater in the old SHR (19.8 + 1.5%) compared to young female SHR (7.7+ 0.2%). These results indicate that the aged SHR can be used as a model to study post‐menopausal increases in the coronary vascular reactivity.Funded by NIH R15HL097343
Leptin induces adiponectin expression: Implications in obesity
Authors: Singh Prachi , Sahakyan Karine R , Sert‐Kuniyoshi Fatima H , Romero‐Corral Abel , Delacroix Sinny , Davison Diane E , Jensen Michael D , Somers Virend K 
Published: June 2021

BackgroundExpression of adiponectin, an anti‐atherogenic and insulin‐sensitizing adipokine, is decreased in obesity. Mechanisms underlying this reduction are not well understood. Increased adiponectin in obesity may protect against development of cardiac and metabolic disorders.ObjectiveTo investigate the role of leptin in regulating adiponectin expression in humans.Design1) determining the relationship between leptin and adiponectin in healthy humans during modest weight gain; 2) in‐vitro validation of the role of leptin in adiponectin expression.ResultsModest weight gain of 3.8 ± 1.2 kg over 8 weeks of overfeeding in normal weight healthy subjects (n=33, 22 men, 30±7 years) increased both leptin and adiponectin. Changes in leptin during weight gain correlated with changes in adiponectin (rho=0.35, p=0.045), suggesting that leptin may regulate adiponectin expression. In cultured differentiated human white preadipocytes, leptin increased adiponectin mRNA and protein expression.ConclusionsLeptin induces adiponectin expression. In obesity, adipose tissue may be resistant to leptin signaling thus preventing increases in adiponectin. Therefore, impaired leptin signaling may contribute to low adiponectin in obesity. Targeting leptin resistance may be beneficial in preventing obesity‐associated cardiac and metabolic disorders.Support: AHA 11SDG7260046, R21 DK81014