bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gravin mutant mice show resistance to the development and progression of cardiac hypertrophy (837.12)
Authors: Singh Sonal , Diaz Diaz Andrea , Wijaya Cori , Suryavanshi Santosh , Fan Qiying , McConnell Bradley 
Published: June 2021

Gravin, an A kinase anchoring protein is involved in the desensitization cycle of the β2‐adrenergic receptors (β2‐ARs) upon agonist stimulation via localized scaffolding of important β2‐AR pathway signaling components. Gravin scaffolds key proteins including protein kinase A (PKA), protein kinase C and other signaling molecules to the β2‐AR. The goal of this study was to evaluate whether disruption of PKA/gravin interaction restricts cardiac hypertrophy induced by chronic β‐AR stimulation with isoproterenol (ISO) (60mg/kg/day for 14 days) in gravin knockout (t/t) mice. Ascorbic acid (AA) was used as control. The heart to body weight (HW/BW) ratio, an indicator of hypertrophy, showed that WT‐ISO had a significantly higher ratio compared to WT‐AA whereas there was no significant difference between t/t‐ISO and t/t‐AA groups. Left ventricular contractility was significantly lower in the WT‐ISO compared to the WT‐AA as indicated by the decreased dp/dtmax values in the WT‐ISO group with no significant difference between the t/t‐ISO and t/t‐AA groups. Also no significant difference was found in the basal PKA activity between the WT‐AA and t/t‐AA groups. However there was a significant reduction in the PKA activity in the ISO treated groups compared to their respective controls. Thus, disruption of gravin signaling renders the t/t animals resistant to the development of cardiac hypertrophy.Grant Funding Source: Source of research support was RO1HL085487
The interplay between heme oxygenase and nitric oxide synthase and downstream PI3K/sGC/ERK signaling ameliorates the estrogen‐dependent depressant effect of chronic nicotine on reflex bradycardia (837.2)
Authors: El‐Mas Mahmoud , El‐Gowelli Hanan , Fouda Mohamed , El‐Gowilly Sahar 
Published: June 2021

Chronic nicotine impairs reflex bradycardia in estrogen (E2)‐replaced, but not depleted, female rats. We tested the hypothesis that nitric oxide synthase (NOS) and/or heme oxygenase (HO) and their downstream mitogen‐activated protein kinases mediate the nicotine‐baroreflex interaction. The depressant effect of nicotine (2 mg/kg/day i.p., 2 weeks) on reflex bradycardic responsiveness to phenylephrine in E2‐replaced ovariectomized (OVXE2) rats was abolished after treatment with hemin (HO inducer) or L‐arginine (NOS substrate), denoting the importance of reduced availability of their respective gaseous products, CO and NO, in the nicotine effect. The roles of CO and NO appear to be mutually facilitated because the hemin and L‐arginine effect was abolished after NOS (L‐NAME) and HO inhibition (ZnPP), respectively. Estrogen receptor blockade (ICI 182,780) reduced baroreflexes in OVXE2 rats but failed to abolish the improved baroreflex gain caused by hemin or L‐arginine in OVXE2/nicotine rats. Baroreflex facilitation by hemin was eliminated after inhibition of PI3K (wortmannin), sGC (ODQ) or ERK (PD98059) in central neurons, in contrast to no effect for the inhibition of p38 (SB203580) or JNK (SP600125). Together, the upregulation of NOS/HO‐coupled PI3K/sGC/ERK signaling downstream of E2 receptors rectifies the E2‐dependent, nicotine‐evoked impairment of reflex bradycardia in female rats.Grant Funding Source: Supported by Grant STDF ID 502, Egypt
Resveratrol partly protect aged heart from reperfusion injury in rat (837.4)
Authors: Li Jing , Zhang Jincai , Tian Wencong , Yang Lei , Yang Liang , Qi Zhi , Tang Xiangdong 
Published: June 2021

Objective: We aimed to compare the anti‐aging effects of 2‐deoxy‐D‐glucose (2‐DG) and resveratrol (RSV) using conventional dietary restriction (DR) as control.Methods: Forty‐eight male SD rats were divided into 6 groups control group (Ctrl), 2‐DG group, RSV group, DR group, 2‐DG + DR group, and RSV + DR group. Parameters such as body weight (BW), left ventricular development of pressure (LVDP), and selected genes were determined and compared among different groups.Results: Compared to the Ctrl animals, all DR groups experienced a sustained weight loss paralleled by a decrease in wet weight of liver, kidneys, and epididymal fat. By comparison, animals that fed on 2‐DG or RSV alone only dropped their body weight very briefly. DR, 2‐DG, and RSV all increased mRNA expression of MnSOD and catalase, accompanied by an increase in mRNA of FOXO1, Sirt2, and Sirt1. DR or RSV protected aged animals from reperfusion injury while 2‐DG worsened them as demonstrated by Langendorff measurements and cardiac histology. At cellular level, both 2‐DG and RSV increased mRNA expression of MnSOD and catalase and protected H9c2 cells from ischemia‐reperfusion injury.Conclusions: DR and RSV could protect aged hearts from reperfusion injury, which is associated with mRNA up‐regulation of MnSOD and catalase accompanied by increased FOXO1, Sirt2 and Sirt1. 2‐DG does not seem to have any beneficial role in aged rats.Grant Funding Source: supported by NSFC 81072629; Tianjin NSF 10JCYBJC14800; Project “973” grant 2010CB945001
Inhibition of endocannabinoid‐inactivating enzymes and cannabinoid (CB1) discrimination (838.1)
Authors: Bergman Jack , Kangas Brian , Leonard Michael , Nikas Spyros , Shukla Vidya , Alapafuja Shakiru , Makriyannis Alexandros 
Published: June 2021

The discriminative‐stimulus (Sd) and other behavioral effects of CB1 ligands can be reproduced in mice by combined inhibition of the anandamide‐ (AEA‐) and 2‐arachidinoyl glycerol‐ (2‐AG‐) inactivating enzymes fatty‐acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL; Long et al. 2009). The present studies using selective and non‐selective ligands [FAAH (URB 597;AM 2018), MGL (AM 2036); mixed (AM 2129), and FAAH /CB1 (AM 3506) were conducted to further explore effects of mixed FAAH and MGL inhibition in squirrel monkeys that discriminate CB1 agonists (AM 4054;THC) from vehicle (n=4). Results indicate that: 1) mixed (but not FAAH‐ or MGL‐selective) inhibition or the combination of FAAH inhibition with some CB1 activity reproduced CB1‐related Sd effects, and 2) anandamide produced these effects after treatment with relatively low doses of non‐selective and FAAH‐selective enzyme inhibitors. Schild analysis of data from antagonism studies suggest some differences in the interaction of the several types of agonist effect with the CB1 receptor. The present data strengthen the idea that complementary, but not individual, actions of the endocannabinoids AEA and 2‐AG produce CB1‐related Sd, and perhaps subjective, effects in primate species. Grant Funding Source: Supported by NIH/NIDA RO1‐31020
Blockade of serotonin uptake by decynium‐22 enhances sociability (839.3)
Authors: Smolik Corey , Zhang Wynne , Vitella Melissa , Sanchez Jesus , Javors Martin , Koek Wouter , Daws Lynette , Gould Georgianna 
Published: June 2021

Impaired social behavior occurs in several psychiatric disorders including autism, schizophrenia and depression. This symptom has proven difficult to treat with available pharmaceuticals. Based on clinical findings and experiments in rodents, serotonin (5‐HT) transmission is often disrupted in the socially‐impaired brain, and limbic regions and frontal cortex appear to be involved. Two drugs are commonly used to treat autism; risperidone curbs aggression but blunts social interaction, and fluoxetine improves social behavior somewhat, but its efficacy is diminished with reduced 5‐HT transporter (SERT) function. Our goal was to characterize the effects of blocking ancillary transporters of 5‐HT, with lower affinity but greater capacity than SERT to remove 5‐HT from extracellular fluid. These auxillary transporters, known as 'uptake 2' include organic cation and plasma membrane monoamine transporters. We utilized two models of impaired social behavior, inbred BTBR T+tf/J and SERT knock‐out (‐/‐) mice, to examine uptake 2 blockade effects on 5‐HT uptake and social behavior. The pseudoisocyanine decinium‐22 (D‐22) blocked 5‐HT uptake (Km = 92 +/‐ 12 nM) but had negligible affinity for SERT (Ki > 3000 nM) in hippocampal synaptosomes. In SERT ‐/‐ and BTBR mice, social behavior improved with acute D‐22 treatment at doses of 0.01 ‐ 0.1 mg/kg. This strategy may be an effective treatment for inpaired social behavior, and warrants further study.Grant Funding Source: Supported by CDMRP Autism Idea Award AR110109, NIH MH086708 and NIH GM097632.
Cortricotropin‐releasing factor (CRF) injected into the brain or the periphery induces protection against indomethacin‐caused gastric injury through glucocorticoids and the CRF receptors types 1 and 2 (840.10)
Authors: Filaretova Ludmila , Mayzina Marina , Bagaeva Taniana , Morozova Olga 
Published: June 2021

In the present study we investigated whether CRF injected into the brain or the periphery induces protection against indomethacin‐caused gastric injury and the role of glucocorticoids, the CRF receptor types 1 and 2 (CRF1 and CRF2 receptors) in the protection. Gastric injury was caused by indomethacin (35 mg/kg, subcutaneously) in preliminary fasted rats and CRF was injected 30 min before indomethacin administration. The participation of glucocorticoids was studied by inhibitor of glucocorticoids’ synthesis metyrapone, and glucocorticoid receptor antagonist RU‐38486. The role of the CRF1 and CRF2 receptors was investigated by the nonselective CRF1/CRF2 receptor antagonist astressin, the selective CRF1 receptor antagonist NBI 27914, and the selective CRF2 receptor antagonist astressin2‐B. Intracerebroventricular or intraperitoneal injection of CRF at the doses, which markedly increased plasma corticosterone levels, significantly suppressed the occurrence of gastric erosion induced by indomethacin. The protective effect of CRF on the gastric mucosa against indomethacin‐produced injury was significatly attenuated by metyrapone and RU‐38486 as well as by astressin, NBI 27914 and also astressin2‐B. The results suggest that CRF injected into the brain or the periphery may induce protection against indomethacin‐caused gastric injury through glucocorticoids, CRF1 and CRF2 receptors.Grant Funding Source: Supported by grants from RFBR N13‐04‐01680‐a and Programs of Presidium RAS 7P
Anti‐infammatory effect of Cucurbita maxima sweet seed extract on foregut induced injury: role of oxidative stress (840.2)
Authors: Pshyk‐Titko Irena , Zayachkivska Oksana 
Published: June 2021

The established therapy of foregut disorders has resulted in incomplete efficacy, in long term use it is risky by unexpected effects, as altered microbial profile which elicits inflammation, increased oesophageal sphincters, hypokinetic gastric dysfunctions, inhibition of activity of dimethylarginine dimethylaminohydrolase (DDAH), which increase the risk of vascular inflammation (Ghebremariam YT, 2013) etc. In this study, to investigate effect of Cucurbita Maxima sweet seed extract (CMSE) on foregut mucosal integrity during blocking gastric acid by histamine H‐2‐receptor antagonist ranitidine (R), antagonist of the muscarinic acetylcholine receptors, atropine (A) given separately or in combination with the non‐selective blocker NOS L‐NAME.Rats were used with without/with CMSE treatment (200 mg/kg) during 1 to 3 days A (3 mg/kg), R (100 mg/kg), L‐NAME (10 mg/kg) and their combination applying; oral, esophageal, gastric lesions by histology score index (HIS); NO by biochemical study, IL‐1ß, GRO/CINC‐1 via ELISA.In rats R, A and L‐NAME pre‐treatment a significant accelerated production of IL‐1ß (14,3%) GRO/CINC‐1 ‐ 191,4%, rise of HIS vs control. NO content showed increasing tendency with maximum rise after 3 days during combination of triple blocking cholinergic, histaminergic and NOS via L‐NAME administration. CMSE decrease foregut lesions and signs of inflammation and IL‐1ß and GRO/CINC‐1 secretion.Histamine and NO synthesis exert biphasic biological effect in foregut when in physiological dose are essential for natural functioning but in the high or low application seems to be a reason of cell and tissue damage. CMSE has ability to maintain foregut mucosal integrity normalizing redox system activity and inflammatory mediators.Grant Funding Source: supported by prof. S. Szabo
Palmitoylethanolamide ameliorates development of colitis caused by injection of dinitrobenzene sulfonic acid in mice (840.3)
Authors: Cuzzocrea Salvatore , Campolo Michela , Impellizzeri Daniela , Paterniti Irene , Bruschetta Giuseppe , Cordaro Marika , Esposito Emanuela 
Published: June 2021

Dinitrobenzene sulfonic acid (DNBS) induced colitis has proven to be a useful experimental model of intestinal bowel disease (IBD). N‐palmitoylethanolamide (PEA) is an endogenous fatty acid amide with important analgesic, anti‐inflammatory and neuroprotective effects.The aim of the study was to examine the effects of a new formulation of PEA (PEA ultramicronized) in mice subjected to experimental colitis. PEA was administered daily i.p, (10 mg/kg, 10% ethanol). Four days after DNBS, colon nuclear factor NF‐ kB was increased as well as TNF‐a and IL‐1b production, neutrophil infiltration and adhesion molecules expression. Immunohistochemistry for inducible nitric oxide synthase (iNOS), nitrotyrosine and poly (ADP‐ribose) polymerase (PARP) showed an intense staining in the inflamed colon. PEA significantly reduced the appearance of diarrhea and body weight loss. This was associated with a significant reduction of MPO activity, NF‐kB, pro‐inflammatory cytokines release, iNOS, nitrotyrosine and PARP and reduced up‐regulation of ICAM‐1, P‐selectin and metalloproteinases. Thus, the results of this study suggested that administration of PEA may be beneficial for treatment of intestinal inflammatory diseases.
Involvement of reactive nitrogen species production in diazoxide‐induced preconditioning in cultured cortical neurons of rats (841.1)
Authors: Dutta Somhrita , Rutkai Ibolya , Katakam Prasad , Busija David 
Published: June 2021

Diazoxide (DZ), a mitochondrial ATP‐sensitive potassium (mito K‐ATP) channel opener, has been shown to be protective in models of brain ischemia. We have previously shown that reactive oxygen species production and mitochondrial depolarization are major initiating steps in DZ preconditioning, but the signaling pathway is incomplete. We hypothesized that other signaling pathways, like those involved in RNS production, may participate in the protective effects of DZ. Confluent rat primary neuronal cultures were pre‐treated with DZ (500µM) alone or co‐treated with DZ+ Nω‐Nitro‐L‐arginine methyl ester hydrochloride (L‐NAME, 100µM or 150µM) for 3 days to block nitric oxide (NO) synthase. Additionally, NO was exogenously supplied by co‐applying SNP (5µM) with DZ and L‐NAME to potentially rescue protection by DZ. After the 3 day treatment period, neurons were subjected to 3 h oxygen glucose deprivation (OGD) followed by re‐oxygenation, an in vitro model of stroke. Neuronal viability was assessed using the MTS colorimetric assay 24 h after OGD. OGD reduced neuronal viability 24 h from 100% (time control) to 54.1±1.4% (P<0.05; n=32 wells). DZ protected cells and increased viability after OGD (67±2.4%, P<0.05; n=32 wells). Blocking RNS using L‐NAME 100µM and 150µM decreased viability to the untreated control level (53.2±3.9% and 50.6±3.9% respectively, NS compared to time control; n=32 wells). Replacing NO using SNP rescued the effect of L‐NAME treatment at both doses (63.5±6.3% and 60.8±6.5%, respectively) (NS compared to time control; n=32 wells). This study shows for the first time that RNS production is a crucial step to preconditioning using DZ in neurons.Grant Funding Source: HL‐077731, HL‐030260, HL‐065380, and HL‐093554
A calcium‐independent PKC isoform mediates cerebral vasoconstriction through actin cytoskeleton reorganization (841.2)
Authors: El‐Yazbi Ahmed 
Published: June 2021

The role of PKC in force production and vasoconstriction in resistance arterioles is hypothesized to be through several mechanisms including: increased calcium influx, calcium sensitization, and thin filament regulation. PKC involvement in these pathways was proposed based on pharmacological experiments without direct biochemical measurement of the phosphoproteins. We studied the effect of phorbol dibutyrate (PDBu, 1 microM) on rat middle cerebral artery in a pressure myography setup. A slow profound constriction was obtained as a result of PDBu treatment. The constriction was associated with increased myosin light chain (LC20) phosphorylation that was similar to that evoked by a maximal dose of 5‐HT producing a smaller constriction. PDBu constrictions were abolished by GF109302X, but neither with a calcium‐dependent PKC inhibitor, nor with calcium‐free Krebs’, though the latter reduced LC20 phosphorylation. There was no evidence of increased phosphorylation of caldesmon and calponin, ruling out a role for thin filament regulation. G‐actin content was greatly reduced in both regular and calcium‐free Krebs’ solution together with an increase in paxillin phosphorylation in both conditions implicating actin cytoskeleton reorganization as a potential mechanism contributing to force generation independent of LC20 phosphorylation following PKC activation.Grant Funding Source: Supported by CIHR MOP‐97988
Preserved mitochondrial function in cerebral arteries following ischemia‐reperfusion in the rat: the role of endothelium (841.7)
Authors: Rutkai Ibolya , Dutta Somhrita , Walter Korey , Katakam Prasad , Busija David 
Published: June 2021

Mitochondrial function following IR in the cerebral circulation has not been examined. We examined the effects of IR on the mitochondrial‐endothelial axis in middle cerebral arteries (MCAs) exposed to 10‐100 μM of diazoxide (DZ), a mitoKATP opener, and 10 μM of bradykinin (BK) from Sprague‐Dawley rats exposed to 90 min of ischemia by the occlusion of the MCA followed by 4 and 48 h of reperfusion. At both 4 and 48 h, responses to BK were reduced on the ischemic (IPSI) compared with the non‐ischemic (CONTRA) sides whereas DZ responses at 4 h were normal on both sides compared with Control. At 48 h, DZ responses were substantially reduced on the CONTRA compared with IPSI (5.4±2 μm vs 22.6±3 μm at 50 μM; n= 22) and Control (21.1±2 μm). At 48 h, eNOS phosphorylation and mitochondrial mass, determined by western blot for voltage dependent anion channel, Complex V, and mitoDNA were greater on the IPSI compared with CONTRA. Endothelium denudation completely eliminated the response to DZ in IPSI but not in Control, indicating that endothelial mechanisms predominate in previously ischemic arteries. Our findings suggest that targeting the mitochondria in endothelium in cerebral arteries may be a new therapeutic target in stroke treatment for improving blood flow. Our data also revealed for the first time that non‐ischemic cerebral arteries are compromised by IR occurring at a distant site in the brain.Grant Funding Source: NIH grants HL‐077731, HL‐030260, HL‐065380, and HL‐093554.
Enhanced in vitro cancer cell cytotoxicity of dual ligand‐targeted liposomes (842.10)
Authors: Sriraman Shravan Kumar , Torchilin Vladimir 
Published: June 2021

A broad variety of cancer cells over‐express different types of cell surface receptors like transferrin (TfR) and folate (FR) receptors compared to normal cells. This receptor expression increases as the tumor progresses and grows aggressively. With this in mind, polyethylene glycol (PEG)‐coated long‐circulating liposomes targeted with varying densities of transferrin and folic acid were loaded with doxorubicin (Dox), a frequently used chemotherapeutic drug.Purpose: To enhance the uptake of drug‐loaded liposomes by cancer cells using the combination of these two tumor‐specific ligands resulting in increased cytotoxic effects even at low drug concentrations.Methods: Transferrin and folic acid were conjugated to the distal ends of the PEG chain and post‐inserted into liposomes made of eggphosphatidylcholine (ePC), cholesterol and dioleoylphosphatidylethanolamine (DOPE). For cell association studies, the liposomes were fluorescently labeled with rhodamine. The optimized formulations were loaded with Dox, and their in vitro cytotoxic potential was evaluated with human cervical cancer (HeLa) cells.Results: Flow cytometry demonstrated a 7‐fold increase in cell association of the dual ligand‐targeted liposomes (DL) compared to any single ligand‐targeted liposomes (SL). The association and subsequent internalization of the DL was further confirmed using the confocal microscopy. The DL also significantly increased cytotoxicity of Dox when compared to SL and non‐targeted Dox‐liposomes in vitro. The IC50 for DL was also decreased by almost 7‐fold compared to SL.Conclusions: Simultaneous targeting of TfR and FR has been shown to be an effective strategy to deliver drugs and enhance their cytotoxic effects on cancer cells in vitro. The decrease in IC50 of DL allows us to work with lower drug concentrations thereby reducing the off‐target drug toxicity.Grant Funding Source: 86R01CA128486
Stable knockdown of LDH‐A in MDA‐MB‐231 breast cancer cells does not affect cell survival or lactate production (842.14)
Authors: Mack Nzinga , Mazzio Elizabeth , Soliman Karam 
Published: June 2021

A well‐known characteristic of tumor cells involves the propensity to produce lactate under normoxia and hyperoxia, also referred to as the Warburg effect. High levels of lactate are believed to be associated with elevated expression of lactate dehydrogenase A (LDHA), also up‐regulated in diverse aggressive malignancies. In this study, ShRNAs were used to permanently silence the expression of LDHA in human breast cancer MDA‐MB 231 cells using five different strains of lentaviral vectors. Cells were cloned,selected and evaluated for LDHA gene and protein expression using diverse methodologies. The data suggest that [1] LDHA is the predominant form of LDH in the transcriptome of MDA‐MB 231 cells [2], cells can survive with stable silenced transduction and [3] silencing LDHA does not correlate to halted production of lactic acid. These findings show a lack of correlation between LDHA and lactate suggesting there is likely another dominant pathway involved with maintaining lactate production in tumor cells.Grant Funding Source: Supported by NIMHD G12 MD007582 and P20 MD006738
Effects of selective inhibitors of the isoprenoid biosynthetic pathway on androgen‐dependent and independent prostate cancer cells (842.6)
Authors: Reilly Jacqueline , Zhou Xiang , Tong Huaxiang , Wiemer David , Hohl Raymond 
Published: June 2021

The isoprenoid biosynthetic pathway (IBP) provides substrates, such as geranylgeranyl diphosphate (GGDP), which are used to post‐translationally modify proteins that are key regulators of malignant cell properties such as proliferation, migration, and invasion. Clinically relevant IBP inhibitors, including statins and nitrogenous bisphosphonates, affect these malignant cell properties. However, they broadly deplete all mevalonate derivatives, thus affecting farnesylated proteins and cholesterol. XZ‐1‐269 and XZ‐4‐37 were developed as selective inhibitors of GGDP synthase to reduce protein GGation. In the androgen‐dependent prostate cancer (PCa) cell line LNCaP and the highly metastatic androgen‐independent PCa cell line PC3, lovastatin and XZ‐1‐269 more potently reduce protein GGation and cell viability than digeranyl bisphosphonate, XZ‐4‐37, and zoledronate. In the androgen‐independent PCa cell line 22Rv1, all compounds are less potent in reducing protein GGation and cell viability than in LNCaP and PC3 cells. Our findings detail novel compounds for selectively reducing protein GGation in three prostate cancer cell lines. Further work defining the isoprenoid proteins involved in advancing PCa will identify new targets for therapeutic intervention.Grant Funding Source: Supported by NIH Pharmacological Sciences Training Grant T32 GM067795