bluuebunny/crossref_metadata_2025_split huggingface dataset:
Farnesoid X receptor activation inhibits colonic epithelial CFTR expression ‐ a new target for antidiarrheal therapy?
Authors: Mroz Magdalena Slawa , Keating Niamh , Ward Jospeh BJ , Amu Sylvie , Sarker Rafiquel , Fallon Padraic Gerard , Donowitz Mark , Keely Stephen J 
Published: June 2021

Cl− secretion, a main driving force for intestinal fluid secretion, can become dysregulated in conditions of disease, leading to diarrhea. While diarrheal diseases constitute a huge global health and economic burden, available medications are unsatisfactory. We previously showed that, at physiological concentrations, deoxycholic acid (DCA), inhibits intestinal secretory function. Here, we investigated the nuclear bile acid receptor, farnesoid X receptor (FXR), as a potential target for development of antidiarrheal drugs.GW4064 was used as a specific FXR agonist. Cl− secretion was measured in Ussing chambers as increase in short‐circuit current and protein expression was determined by western blotting and qPCR.Treatment of T84 colonic epithelial cells with either GW4064 (5μM) or DCA (50μM) for 6–24 hrs induced nuclear translocation of FXR and inhibited agonist‐induced Cl− secretory responses. Furthermore, in vivo administration of GW4064 (50mg/kg) also attenuated colonic secretion and reduced stool water in a mouse model of diarrheal disease. At the molecular level, GW4064 inhibited CFTR Cl− channel currents and reduced mRNA, protein, and membrane expression of CFTR. In contrast, GW4064 did not alter the activity of ENaC or NHE3.These data reveal a new role for FXR in regulating epithelial CFTR expression and secretory function and suggest that FXR agonists may be useful in treating diarrheal diseases.
Dexamethasone Differentially Modulates the Human Angiotensinogen Gene (hAGT) Expression and Blood Pressure in Transgenic Mice Containing ‐6A and ‐6G Haplotype of the hAGT Gene
Authors: Pandey Varunkumar G. , Jain Sudhir , Kumar Ashok 
Published: June 2021

Human angiotensinogen gene (hAGT) has ‐6A/G polymorphism and ‐6A allele is associated with increased blood pressure. We have found that hAGT gene has three additional SNPs. Variants ‐ 1670A, ‐1562C, and ‐1561T almost always occur with ‐6A haplotype (Hap‐6A); and variants ‐1670G, ‐1562G, and ‐1561G almost always occur with ‐6G haplotype (Hap‐6G). We have shown that these polymorphisms affect the binding of glucocorticoid receptor to the promoter. Reporter construct containing 1.8Kb of the hAGT gene promoter with Hap‐6A has 4 fold increased glucocorticoid induced promoter activity as compared to Hap‐6G. Therefore, we have generated transgenic (TG) mice containing either Hap‐6A or Hap‐6G of the hAGT gene. These TG mice were treated with dexamethasone (DEX) (2.5μg/mL in drinking water) for 1 week. Our Q‐RTPCR results show that mice with Hap‐6A has 2 and 2.06 fold DEX induced mRNA expression of hAGT in liver and kidney respectively whereas no significant changes were observed in Hap‐6G. Q‐RTPCR results were confirmed by western blots showing 1.80, 1.94 and 1.40 fold induction of hAGT protein in liver, kidney and plasma respectively in TG mice with Hap‐6A. DEX treatment also increased the SBP of TG mice containing Hap‐6A by 12 mmHg as compared to 5 mmHg in the mice with Hap‐6G. We subjected these TG mice to variable doses of DEX and observed a dose dependent modulation of SBP. DEX dependent increase in the SBP was obliterated by losartan.Research Support: NIH grants HL081752 and HL66296 to AK
ACE2 activation ameliorates endothelial function in the right ventricles of pulmonary hypertensive rats
Authors: Sapp Glenn Herod , Abbatematteo Joseph , Cole Colleen , Shenoy Vinayak , Katovich Michael , Raizada Mohan , Muller‐Delp Judy 
Published: June 2021

Discovery of angiotensin‐converting enzyme 2 (ACE2), which converts angiotensin II to angiotensin‐(1–7) has led to investigation of ACE2 activators as therapeutic agents for improved lung and heart function in pulmonary hypertension (PH). The purpose of this study was to investigate the effects of experimental PH on endothelium‐dependent vasodilation of right ventricular resistance arteries (RVRA) and the possibility that the ACE2 activator, diminazene aceturate (DIZE), ameliorates endothelial function of RVRA of rats with experimental PH. Rats were divided into four groups: control (no treatment), monocrotaline‐treated (MCT) to induce PH, MCT and DIZE, and DIZE alone. After 4 weeks of daily treatments, relative pulmonary pressure was assessed. Endothelium‐dependent and ‐independent vasodilation were also assessed with acetylcholine and the nitric oxide donor, Dea‐NONO‐ate, respectively. We observed that endothelium‐dependent vasodilation was impaired in RVRA while responses to Dea‐NONO‐ate were not altered in RVRA from MCT‐treated rats. DIZE treatment showed a restored responsiveness to acetylcholine in RVRA from MCT‐treated rats. This suggests that the impairment of the endothelial function in resistance vasculature due to PH may be restored by activation of endogenous ACE2.NIH grants‐ HL 56921 and HL 102033
Complementary roles of KCa3.1 channels and β1‐integrin in the regulation of alveolar epithelial repair
Authors: GIRAULT alban , BASTIEN Rachel , TRINH Nguyen Thu Ngan , PRIVE Anik , MAILLE Emillie , BROCHIERO Emmanuelle 
Published: June 2021

A common feature of acute lung injury is extensive damage and remodeling of alveolar epithelium. It has been shown that epithelial regeneration and secondary lung edema resorption are crucial to patient recovery. We previously reported that KvLQT1 and KATP K+ channels regulated alveolar epithelial repair processes, but the role of another candidate, the KCa3.1, has never been evaluated.We first demonstrated that the wound‐healing rates were higher in primary rat alveolar cell monolayers cultured on a fibronectin‐collagen (FC) matrix, than on non‐coated supports. KCa3.1 inhibition, with TRAM‐34, or activation, with 1‐EBIO, respectively down‐ and up‐regulated the alveolar wound‐healing rates on FC matrix, but were without effect in absence of FC coating. Accordingly, single cell migration rates were also dependent, at least in part, of FC matrix coating and KCa3.1 activity. A possible relationship between KCa3.1 and migratory cell proteins such as the integrin, activated by fibronectin, was then assessed. Co‐immunoprecipitation experiments thus revealed a physical interaction between KCa3.1 and the β‐1 integrin subunit. Altogether, our data showed for the first time a complementary role of KCa3.1 channels, extracellular matrix and β‐1 integrin, in the regulation of alveolar repair after injury.Project funded by CIHR, RHN of FRQS, and FESP of Université de Montréal.
Impact of P.aeruginosa bacterial filtrate on CFTR channels and bronchial epithelial repair.
Authors: Trinh Nguyen Thu Ngan , Bilodeau Claudia , Maillé Émilie , Brochiero Emmanuelle 
Published: June 2021

Cystic fibrosis (CF) pathology, due to mutations in the CFTR, is characterized by bacterial colonisation and chronic inflammatory response leading to a progressive damage of the airways. It then becomes crucial to better understand the impact of these deleterious phenomena on the repair processes in attempt to restore the CF airways integrity.First, we confirmed, as in our previous studies, that the repair rates of airway epithelial CFBE‐ΔF508 (CF) monolayers were slower than that of CFBE‐wt (non‐CF) monolayers, which was, at least in part, dependent on CFTR function. We now observed that P. aeruginosa bacterial filtrate (PAF) inhibited wound closure of both non‐CF and CF CFBE monolayers. We also observed that wt‐ and ΔF508‐CFTR protein expressions, as well as Cl− currents through CFTR channels in CFBE‐wt monolayers were decreased after PAF exposure. Finally, CFTR corrector VRT‐325, initially developed to promote CFTR folding and function, was shown to be able to also improve the repair capacity of CF cell monolayers. However, its beneficial effect was abolished in the presence of PAF.This study showed that exoproducts from P. aeruginosa alter CFTR expression/function and also exhibit a deleterious effect on airway repair capacity, in basal condition or after CFTR correction. Project supported by Cystic Fibrosis Canada, the Canadian Lung Association, the CORAMH and Fondation Go.
ANTIHYPERALGESIC EFFECT OF LATEX PROTEINS FROM CALOTROPIS PROCERA: INVOLVEMENT OF INFLAMMATORY MEDIATORS
Authors: Luz Patricia Bastos , Pineiro Rachel Sindeaux Paiva , Freitas Lyara Barbosa Nogueira , Bitencourt Flavio Silveira , Aragão Karoline Saboia , Carmo Luana Davi , Couto Tatiana Souza , Ramos Marcio Viana , de Alencar Nylane Maria Nunes 
Published: June 2021

Background and aimsCalotropis procera is a tropical plant found worldwide and has been used in the traditional medicinal for the treatment of various diseases. This study aimed to evaluate the effects of protein fraction from Calotropis procera latex (LP) in the mechanical hypernociception (increase in the sensitivity of nociception).MethodsSwiss male mice were used. b) Mechanical hypernociception (MH) was evaluated using the electronic version of the Von Frey before and after the injection of carrageenan (300 μg/paw‐Cg) or LP (0.5, 5 and 50 mg/kg, iv, 30 min before Cg application) into the mice paw (1, 3 and 5 hours after Cg). c) After 3 h of Cg injection, subplantar tissue was collected for measurement of: myeloperoxidase activity (MPO); cytokines (TNF‐α and IL‐1β) and chemokine (KC) production; prostaglandin E2 (PGE2) production. d) ANOVA/Bonferroni was used as statistical tests. P<0.05 was accepted. e) Ethics Committee 61/11.ResultsLP 5 mg/kg reduced MH in 25%, 55% and 46% and LP 50 mg/kg in 39%, 64% and 60% in the 1st, 3rd and 5th hours. LP at 5 and 50 mg/kg decreased MPO concentration in 80% and 94% respectively. LP at 5mg/kg reduced the concentration of TNF‐ α, IL‐1β, KC and PGE2 at 71%, 81%, 72% and 72% respectively.ConclusionLP has antinociceptive properties in animal model of acute pain and this may be associated with the inhibition of neutrophil migration, cytokine and chemokine production. CAPES and CNPq.
Cerebro‐Vasculoprotective Effects of Azilsartan Medoxomil in Diabetes
Authors: Abdelsaid Mohammed A , Coucha Maha M , Ergul Adviye 
Published: June 2021

We have shown that glycemic control prevents diabetes‐mediated remodeling of the cerebrovasculature. However, whether the remodeling can be reversed is unknown. Given that angiotensin II Type 1 receptor blockers (ARBs) reverse pathological vascular remodeling and function independent of changes in blood pressure in other vascular beds, we hypothesized that azilsartan medoxomil, a new ARB, reverses cerebrovascular remodeling in diabetes independent of blood pressure.MethodsControl Wistar and diabetic Goto‐Kakizaki rats (n=20/group), were treated with vehicle (water) or Azilsartan medoxomil (3 mg/kg/day) from 18 to 22 weeks of age. Blood glucose and blood pressure was monitored and middle cerebral artery structure and function was evaluated using pressurized arteriography.ResultsBlood glucose was higher in the GK compared to Wistar rats. Azilsartan treatment lowered blood glucose. There was no difference in blood pressure among the groups. Diabetic animals exhibited lower myogenic tone, increased wall thickness, and cross sectional area compared to controls which were corrected by azilsartan treatment.ConclusionAzilsartan medoxomil restores diabetes‐induced cerebrovascular remodeling independent of blood pressure. This effect may be partially mediated by improvement of blood glucose. Disclosure The project is supported by Takeda Pharmaceuticals North America Inc.
The effect of a DPP4 inhibitor on morphometry of pancreatic beta cells after lactation on female wistar rats.
Authors: Suen Vivian , Ribas‐Filho Durval , Cersosimo Eugenio , Martins Alex , Marchini Julio Sergio , Azoubel Reinaldo 
Published: June 2021

ObjectiveTo evaluate through cariometry and estereology if vildagliptin causes morphological changes in the endocrine pancreas of Wistar rats.MethodsSixteen male rats were selected and divided into two groups, control and treated, which received respectively physiological and vildagliptin solution through nasogastric intubation for 10 days. After the sacrifice of all animals and pancreas dissection, histological slices were obtained for cariometric and stereological studies. Computarized programs were used to analyse nuclear parameters of pancreatic islet cells, where insulin is secreted: Major Diameter and Minor Diameter. Mann‐Whitney U Test was applied for statistical analysis.Results and ConclusionVildagliptina causes significant cariometric and stereological alterations in pancreatic islet cells, with nuclear hyperplasia, without hypertrophy, and an increase in metabolism, with tissue hyperplasia.
Effect of L‐tryptophan on cytoprotection against long term postprandial hyperglycemia‐induced esophageal damage in rats
Authors: Hrytsevych Nazar Romanovych , Zayachkivska Oksana , Yaschenko Antonina 
Published: June 2021

Beneficial effects of L‐tryptophan (L‐Try) have already been described by many activities in kynurenine and serotonin synthesis, redox reactions in all living cells which play key role for cancer invasion and proliferation. Recently we revealed that postprandial hyperglycemia (PPH) which characterized by hyperglycemic spikes leads to nitro‐oxidative stress and may predispose to foregut disorders. Nevertheless, the effect of L‐Try on PPH is unknown. In this study, we elaluated effect of L‐Try on NO/NOS expression in OM during PPH and abnormal PG/COX activity.Rats were used with without/with L‐Try treatment (400 mg/kg) and indomethacin (Indo, 5 mg/kg) during PPH (Kozar, 2009); oesophagus (OM) and lower oesophageal sphincter (LOS) lesions were investigated by histology score index (HIS); esophageal NO2, cNOS and iNOS via bioanalysis.PPH caused destructive lesions in the OM and LOS, accompanied by the up‐regulation of iNOS and down‐regulation of cNOS expressions, excessive NO2‐ while Indo significantly aggravated severity of these lesions; L‐Try prevented ulcerogenic response to PPH with potent up‐regulation of cNOS but did not affect synthesis NO2‐.These results suggest that L‐Try prevents L‐Try‐induced OM and LOS damage but oesophagoprotective‐promoting effect may be associated with the stimulation of endothelial metabolism, but not through an amelioration of PG/COX activity.
Angiotensin AT2R activation prevents adiposity under high‐fat diet‐condition in ovariectomized mice
Authors: Nag Sourashish , Hussain Tahir 
Published: June 2021

Recently we demonstrated that the genetic deletion of angiotensin AT2 receptor (AT2R) increases adiposity in female mice on high‐fat diet (HFD). Further these changes were associated with decrease in the urinary 17,β‐estradiol (E2), a known regulator of adiposity. This study was designed to test whether AT2R activation prevents adiposity dependent on estrogen. Female C57BL/6 ovariectomized (Ovx) female mice (8‐weeks old) were supplemented with E2 pellets and/or pretreated with AT2R agonist C21 (0.3 mg/kg, daily i.p.) for 4 days. Thereafter the mice were placed on normal diet (ND) or HFD and the drugs treatment continued for next 10 days. Ovx mice had increased body weight (BW), gonadal adipose tissue weight (gATW), plasma free fatty acid (pFFA) compared to mice with intact ovary on ND. High‐fat diet (HFD) in Ovx mice further increased BW, gATW, pFFA. As expected, E2 supplementation prevented the above mentioned parameters under HFD in Ovx mice. Interestingly, C21 treatment alone in Ovx mice significantly prevented BW gain (19%), gATW (42%), pFFA (55%) despite similar energy intake compared to Ovx mice on HFD. We conclude that the pharmacological activation of AT2R alone prevents adiposity in ovariectomized mice indicating estrogen‐independent role of AT2R in preventing HFD‐induced adiposity in females.Grant Funding Source: NIH RO1 DK‐61578
Involvement of 5‐HT1A receptors into the dorsal hippocampus in the hypophagic effect caused by fluoxetine in rats
Authors: Scopinho América Augusto , de Aguiar Corrêa Fernando Morgan , Resstel Leonardo Barbosa Moraes 
Published: June 2021

AimsStudies showed changes in feeding behavior after lesions of the dorsal hippocampus (DH) suggesting the involvement of this area in the modulation of food intake. Serotonin has been known to play an important role in food intake regulation and the hippocampus receives serotoninergic innervation from the median raphe nucleus. So, the present study examined the effects of the serotonin reuptake inhibitor (fluoxetine) into the DH on food intake and the serotoninergic receptors mediating its effect.MethodsFed and fasted (18 h food‐deprived) male Wistar rats were used. Cannulae were implanted into the DH for injection of drugs: 1) vehicle (aCSF, n=6) or fluoxetine (0.2, 2 or 20 nmol/100 nL, n=6 for each dose); 2) 5‐HT1A receptor antagonist (WAY‐100635, 0.3 nmol/100 nL, n=5) or aCSF (n=5) and fifteen minutes later they received fluoxetine (2 nmol/100 nL) or aCSF. Fifteen minutes later they were submitted to the food intake test (1 hour).ResultsOur results showed that microinjection of fluoxetine into the DH evoked hypophagic effects in fasted rats (F3,40=78.5, P<0.0001) with a correlation between the doses and reduction in food consumption (r2=0,94, df=14). The microinjection of WAY‐100635 blocked the hypophagic effect caused by fluoxetine into the DH (F=22,5 P<0.0001).ConclusionThese results suggest that 5‐HT1A receptors in the DH modulate the hypophagic effect caused by local DH fluoxetine administration.
Role of the Krebs Cycle Metabolites in Retinal Angiogenesis
Authors: Duhamel François , Zaniolo Karine , Tahiri Houda , Chemtob Sylvain 
Published: June 2021

PurposeRetinopathy of prematurity (ROP), a major cause of blindness in developed countries, occurs in two phases : the cessation of normal eye development after birth and a subsequent abnormal and exaggerated vessel growth. Peripheral hypoxia occur after the first phase in premature eye and induce production of many growth factors implicated in this second destructive neovascularization phase. Our laboratory has previously demonstrated the role of succinate/GPR91 in the modulation of retinal vessel growth. Here, we investigated the role of α‐ketoglutarate (α‐KG) and its cognate receptor GPR99 in retinal angiogenesis.MethodsEffects of α‐KG on developmental retinal vascularization were assessed following intravitreal injection of Sprague‐Dawley rat pups in development. Moreover, the effects of a siGPR99 knockdown following intravitreal injection were investigated in the neovascular phase of ROP. Endogenous expression of retinal GPR99 was examined in Sprague‐Dawley rat retinas by immunohistochemistry. In vitro, we investigated the expression of GPR99 and pro‐angiogenic factors by Western blot and PCR analysis. The ability of α‐KG to promote vessel sprouting was determined by aortic rings cultured.Resultsα‐KG significantly enhanced developmental vascular densities at different time points. Neovascularization was blocked by a siGPR99 and allowed normal vessel growth in ROP. Moreover, GPR99 was robustly expressed in RGCs as confirmed by co‐labeling with neuron markers and, in vitro, mainly in neuronal cells. Conditioned media from α‐KG stimulated‐neurons induced aortic rings sprouting, in correlation with an up‐regulation of pro‐angiogenic factors expression.ConclusionsOur results disclose a pro‐angiogenic role for α‐KG and its receptor GPR99, providing additional supports for the involvement of metabolite signalling in ischemic conditions.
Regulation by RhoA of Rod photoreceptor axon retraction induced by retinal detachment
Authors: Wang Weiwei , Townes‐Anderson Ellen 
Published: June 2021

Rod photoreceptors, in response to injury, display synaptic plasticity. We are interested in rod axon retraction, which occurs after retinal detachment and results in disconnection of the synapse between photoreceptors and secondary neurons of the visual system.Our previous studies demonstrated that inhibition of RhoA and its downstream effecter Rho kinase (ROCK) blocks rod axon retraction. Here, we used time‐lapse microscopy to measure axon retraction of isolated salamander rod cells with and without inhibition of another effecter of ROCK, LIM kinase. A LIMK inhibitor (LIMKi) also blocks retraction: 35% decrease of initial rod axon length in controls after 7 hours, compared with only a 15% decrease using 10uM LIMKi.Since LIMK regulates actin filament turnover through cofilin, we examined cofilin activity in pig retina with western blots. After retinal detachment, phosphorylated cofilin increased over 24 hours; treatment with LIMKi prevented the increases.Nicardipine (Nc), a Ca channel blocker, also blocked retraction in our previous work, possibly by reducing myosin light chain (MLC) activity. Experiments with isolated rod cells showed that over 3 days LIMKi was no longer effective; however, with Nc, retraction continued to be inhibited.Thus we suggest that rod axon retraction is a result of both Ca‐MLC regulated actomyosin contraction and ROCK‐LIMK‐cofilin regulated actin filament depolymerization.
Prostacyclin Release from Stem Cell Derived Endothelial Cells
Authors: Reed Daniel Mark , Foldes Gabor , Kirkby Nicholas S , Gashaw Hime H , Starke Richard D , Paschalaki Koralia E , Randi Anna M , Harding Sian E , Mitchell Jane A 
Published: June 2021

Stem cell‐derived endothelial cells are being investigated as potential therapies. Endothelial cells for therapy can be isolated from human embryo (hESC‐EC), circulating progenitors (EPC) or induced pluripotent stem cells (iPS‐EC). Endothelial cells in vessels release the cardioprotective hormone prostacyclin, which is essential for organ homeostasis and a function to be preserved in organ regeneration programs. Prostacyclin is formed from arachidonic acid by the concerted actions of cyclooxygenase (COX) and prostacyclin synthase. Here we have compared the ability of endothelial cells derived from key stem cell phenotypes to release prostacyclin with adult endothelial cells from the lung (HMVEC). hESC‐EC, EPC (late outgrowth), iPS‐EC and HMVEC were treated for 24h +/− LPS (1μg/ml) or IL‐1β (1ng/ml) to activate prostacyclin release. Prostacyclin was measured as its breakdown product 6‐ketoPGF1α by ELISA. Endothelial cells from different phenotypes of stem cells are capable of releasing prostacyclin. The relative efficacy for prostacyclin release was EPC>;HMVEC>;iPS‐EC>;hESC‐EC (Figure 1). These observations show that, of the stem cell progenitors available, EPC‐derived endothelial cells have the greatest propensity to release prostacyclin. These observations may have important relevance in the use of engineered endothelial cells.This work was funded by the Welcome Trust, BHF and an MRC studentship awarded to DMR.