bluuebunny/crossref_metadata_2025_split huggingface dataset:
High‐throughput screening for novel allosteric modulators of the D1 dopamine receptor (662.4)
Authors: Conroy Jennie , Free R. , Doyle Trevor , Southall Noel , Hazelwood Lisa , Miller Nicole , Ferrer Marc , Sibley David 
Published: June 2021

Dopamine is a critically important neurotransmitter in the CNS and peripheral nervous system, with five receptor subtypes mediating its effects. Importantly, D1 receptor (D1R)‐selective agents may prove beneficial in the treatment of many neuropsychiatric disorders. In an effort to identify novel selective allosteric modulators of the D1R we used a high throughput screening approach. 380,000 small molecules in the NIH Molecular Libraries Screening Center Network library were screened using a cell line expressing the D1R coupled to G15 resulting in a robust Ca2+ signal upon receptor stimulation. Hit compounds were triaged through secondary functional and radioligand displacement binding assays to determine subtype selectivity and their allosteric versus orthosteric nature. We initially identified 96 putative positive allosteric modulator (PAM) hits that enhanced the EC20 activity of dopamine in the Ca2+ response ‐ 6 of these were subsequently confirmed during triage and were chosen for further characterization. In addition we found approximately 115 agonist and 125 antagonist hits that failed to completely inhibit radioligand binding and have been classified as potential allosteric agonists and antagonists or negative allosteric modulators (NAMs). These compounds are currently being characterized using additional assays to confirm their selectivity, activity, and classification.Grant Funding Source: NINDS Intramural Program
Application of Einstein matrix medical treatment for HIVv/HCV therapy (668.4)
Authors: Einstein George , Echavarria Louis , Tulp Orien 
Published: June 2021

Biophotonic Therapy [Photo‐therapy] uses ultraviolet light, is a safe, non‐intrusive, drug free, cost effective, and nonspecific treatment for a broad spectrum of bacterial and viral infections Biophotonics generates and harnesses light (photons) to image, detect and manipulate biological materials, and can also be applied as a biological probe for molecular mechanisms, function and structure. Einstein Clinical Laboratories [ECL] has perfected a proprietary therapy of purification blood called Einstein's Matrix Treatment (EMT) also referred to as the EMC‐ 2001E [named for its developer &amp; inventor, Dr. George P. Einstein]. The EMT approach is to target and destroy viruses or bacteria by the application of a specific amount of photon energy that is not harmful for healthy cells. The parameters that targeted the pathogens are specific wavelength, intensity and time of exposure to the light targets the physical &amp; chemical structure of bacteria resulting in their death via a UV‐mediated intracellular coagulative process. Bacteria are much smaller than somatic cells, their shells are thinner, and are more susceptible to UV Light. Also, the amino acids phe and tyr are present in the micro‐organisms in 5x greater amounts than in somatic cells which are largely unaffected by the UV process. In pilot studies with HIV or both HIV and HCV viruses, patients remained asymptomatic and virus free throughout a 10 year followup. UVC irradiation of blood had an inhibitory influence on mRNA expression of inflammatory cytokines, IL‐1, IL‐6 whereas it stimulated production of IL‐b. Pro‐inflammatory cytokines are engaged in migration of cells to the inflammation area, as well as in stimulation, proliferation and differentiation of cells and a decrease in inflammatory markers. In conclusion, HVB was found to be safe and beneficial for patients, while UVC lends promise to the treatment of a broad range of infectious illnesses.Grant Funding Source: Institutional Resources
The effect of cancer cells on angiogenesis: engineering the cancer niche (676.13)
Authors: Sweat Richard , Phamduy Theresa , Chrisey Douglas , Murfee Walter 
Published: June 2021

Tumor growth requires uncontrolled angiogenesis, defined as the growth of new capillaries from existing blood vessels. Developing anti‐tumor therapies necessitates understanding how cancer cells and their microenvironment synergistically influence capillary sprouting from existing vascular networks. Recently, we demonstrated the use of the rat mesentery culture model for investigating angiogenesis in an intact microvascular network scenario. The objective of this study was to demonstrate the use of this model to determine the effects of cancer cells on angiogenesis. Mesenteric tissue windows were harvested from adult male Wistar rats and cultured for 5 days according to the following experimental groups: 1) Control (MEM + 10% DMEM + 1% FBS; n = 7 tissues) and 2) Cancer Cell (MEM + 10% DMEM + 1% FBS + cells; n = 6 tissues). For the cancer cell group, 2x10^5 RFP‐transfected metastatic MDA‐MB‐231 breast cancer cells were seeded onto tissues on day 0. On day 5, cancer cells remained viable, as confirmed by live/dead assay. More importantly, cells were observed to be in the same focal plane and region as vessels along intact microvascular networks. The presence of cancer cells decreased vascular length density and the number of capillary sprouts per vascular area compared to the Control (no cell) group. Our results suggest that cancer cells alone are not sufficient to induce angiogenesis. Application of the rat mesentery culture model as a multicellular breadboard system to engineer the cancer cell/vascular niche will offer a new tool for tumor angiogenesis research.Grant Funding Source: Supported by Tulane Center for Aging and NIH 5‐P20GM103629‐02
Dichotomous estradiol and genistein effects on cutaneous endothelium‐dependent vasodilation in women with and without insulin resistance (678.6)
Authors: Wenner Megan , Taylor Hugh , Stachenfeld Nina 
Published: June 2021

17β‐estradiol (E2) cardioprotection in women includes endothelial dependent dilation (EDD), but this E2 effect is not consistent in insulin resistant women (IR). Genistein (GEN, a phytoestrogen structurally similar to E2) effects on EDD are unclear. We hypothesized E2 and GEN improve cutaneous EDD in healthy women [C, n=8, 23 (6) yr, BMI 25.0 (8.0), AUC insulin 6111 (1368) µUI/ml] but not IR [n=6, 20 (2) yr, BMI 27.3 (8.4), AUC insulin 140006 (4020) µUI/ml]. We measured cutaneous vascular conductance (CVC) with laser Doppler flowmetry during local 42°C heating with E2 or GEN skin microdialysis infusions, each with and without the eNOS inhibitor L‐NMMA; nitroprusside was then infused with 44°C heating to induce CVCmax. In C, E2 enhanced EDD [93.4 (5.8) %max, 85.0 (12.2) %max for E2, saline P<0.05], with no GEN effect [84.5 (22.2) %max], and L‐NMMA reduced EDD [81.9 (21.6) %max, GEN 73.2 % (29.1) %max P<0.05). In IR, E2 and GEN did not affect EDD [93.5 (5.5), 93.6 (5.2), 97.4 (13.0), saline, E2, GEN]; L‐NMMA reduced EDD with GEN [67.1 (18.7) %max P<0.05] but not E2 [90.5 (5.5)]. E2 and GEN did not enhance EDD in women with IR in contrast to healthy women. However, NO contributes to EDD in both groups.Grant Funding Source: Supported by National Institutes of Health HL109882
Selective activation of agouti‐related protein neurons rapidly decreases arterial pressure and sympathetic nerve activity in mice (682.4)
Authors: Shi Zhigang , Brooks Virginia 
Published: June 2021

In addition to stimulating food intake, Neuropeptide Y (NPY) acts in the hypothalamic paraventricular nucleus (PVN) to decrease sympathetic nerve activity (SNA) and arterial pressure (AP). PVN NPY inputs arise from the brainstem and the arcuate nucleus (ArcN), with the latter population co‐expressing agouti‐related protein (AgRP). However, whether ArcN AgRP/NPY neurons are sympathoinhibitory is unknown. To test this hypothesis, we employed designer receptors exclusively activated by designer drugs (DREADD) technology to specifically activate ArcN NPY/AgRP neurons in mice. In this approach, mutated stimulatory muscarinic receptors (hM3Dq) are insensitive to endogenous ligands, but following binding of the otherwise inert ligand, Clozapine‐N‐oxide (CNO), depolarize neurons. Cre‐recombinase‐dependent adeno‐associated virus (AAV)‐hM3Dq‐mCherry was nanoinjected bilaterally into the ArcN of AgRP‐Ires‐cre mice (AgRP‐Cre mice). After ~2 weeks, to functionally confirm AgRP neuronal hM3Dq expression, AgRP‐Cre mice (n=5) received ip injections of CNO (0.3 mg/kg), to activate AgRP neurons, or on another day, ip saline. After 4 hr, compared to ip saline, ip CNO increased food intake (0.95±0.07 g, CNO; 0.59±0.07 g, saline; P<0.05) and body weight (change in body weight: 0.23±0.1 g, CNO; ‐0.38±0.07 g, saline; P<0.05). Next, in AgRP‐Cre α‐chloralose‐anesthetized mice (n=3), ip CNO rapidly decreased mean AP (MAP; ‐14.1±0.3 mmHg; P<0.05), heart rate (HR; ‐42±4 bpm; P<0.05) and splanchnic SNA (SSNA; ‐41±2% control; P<0.05), and these effects were sustained for at least 1 hr; ip saline had no effects. In WT mice, neither saline nor CNO significantly altered MAP, HR or SSNA. In conclusion, direct activation of ArcN AgRP/NPY neurons is sufficient to decrease SNA, HR and MAP.Grant Funding Source: Supported by HL088552 and AHA.
Oxytocin’s role in salt appetite revealed by PEP7 blockade of angiotensin II action (683.1)
Authors: Yosten Gina , Liu Jun , Ji Hong , Sandberg Kathryn , Samson Willis 
Published: June 2021

The paradoxical mechanism by which angiotensin II (Ang II) stimulates saline intake and simultaneously releases oxytocin (OT), which profoundly inhibits Ang II‐induced saline intake, is not known. We discovered that a 7 amino acid peptide (PEP7) encoded by a short open reading frame in the 5’ leader sequence of the angiotensin type 1a receptor (AT1aR) mRNA blocks saline, but not water, intake induced by Ang II by abrogating the non‐G protein‐coupled Erk1/2 signaling pathway. We hypothesized that blockade of the MAP‐kinase‐dependent pathway uncovers the inhibitory action of OT released in response to Ang II. Pretreatment icv with PEP7 blocks the saline intake response and this can be reversed by subsequent icv administration of the OT antagonist, OVT. Thus Ang II controls electrolyte intake via two unique pathways, one stimulatory (MAP‐kinase dependent, blockable by PEP7), and the other inhibitory (G protein‐dependent, via OT release). These results together with in vitro data demonstrating PEP7 selective inhibition of the MAP‐kinase‐dependent signaling pathway suggests that PEP7 is a novel therapeutic target for pathologies involving MAP‐kinase dependent, non‐G protein‐coupled signaling of Ang II.Grant Funding Source: NIH AG/HL 19291, HL57502, AG039779, AG16902, HL066023
Influence of TRPV1 and/or TRPV4 receptors on osmoregulatory thirst in mice (683.2)
Authors: Kinsman Brian , Cowles James , Browning Kirsteen , Stocker Sean 
Published: June 2021

Recent in vitro studies suggest that hypothalamic osmolality‐sensing is mediated by either the transient receptor potential vanilloid‐1 (TRPV1) or vanilloid‐4 (TRPV4) channel expressed by neurons in the organum vasculosum of the lamina terminalis (OVLT). This study assessed whether deletion of TRPV1 and/or TRPV4 channels altered thirst responses to hyperosmolar stimuli. Wild‐type (WT), TRPV1‐/‐, TRPV4‐/‐, and TRPV1‐/‐V4‐/‐ mice (n = 9‐12 per genotype) ingested similar volumes of water 1 hr after sc injection (0.3mL) of 0.5M NaCl (0.37±0.03, 0.39±0.04, 0.42±0.04, 0.38±0.05 mL; P > 0.4) or 1.0M NaCl (0.89±0.06, 0.95±0.04, 1.07±0.11, 1.02±0.15 mL; P > 0.4). Similar results were observed after injection of 0.7M mannitol (0.38±0.06, 0.36±0.02, 0.31±0.04, 0.33±0.05 mL; P > 0.4). In addition, sole access to 2% NaCl for 48 hrs yielded similar increases in water intake across strains (0.22±0.03, 0.31±0.07, 0.21±0.02, 0.18±0.05 mL; P > 0.4). In a final experiment, injection of 0.5M NaCl generated similar increases in the number of OVLT Fos‐positive nuclei (21±4, 23±4, 16±4, 15±2; P > 0.2) across all genotypes. This investigation suggests that TRPV1 and TRPV4 receptors are not the central osmolality‐sensors that mediate osmotically‐stimulated thirst.Grant Funding Source: NIHHL113270, AHA EIA
Psychobiological assessment in offspring of Wistar rats supplemented with sodium selenite during the period of pregnancy and lactation (684.13)
Authors: Laureano‐Melo Roberto , Imperio Guínever , Almeida Claudio , Kluck George , Seara Fernando , Reis Luis , Ortiga Tania Maria , Cortes Wellington 
Published: June 2021

The objective of this study was to evaluate the possible occurrence of behavioral changes in offspring of female rats supplemented during pregnancy and lactation with sodium selenite. Two groups were treated during pregnancy and lactation with: saline or sodium selenite at a dose of 1 mg/kg through oral route. Thyroid status was determined by serum analysis of thyroid hormones and for gene expression analyzes, we used RT‐qPCR. At 60 days‐old, the offspring underwent a behavioral assessment in an open field test, elevated plus maze test, object recognition task and swimming forced test for five minutes. Statistical analysis was performed by t student test, considering the significant differences between means at p <0.05. According to the results, it was demonstrated that supplementation with Se causes increased levels of triiodothyronine (25%, p = 0.0001) and the expression of type 2 deiodinase in brown adipose tissue (351%, p = 0.002). Moreover, Se treatment promotes reduction of TPH2 expression (12%, p = 0.007), but increases the levels of mRNA for TH (200%, p = 0.002) in the hippocampus. It was also found that the offspring of females supplemented with Se have higher locomotor activity (50%, p = 0.004) and more rearing (77%, p <0.0001) in the open field test. In the elevated plus maze, the treated group had higher time spent in the open arms (143%, p = 0.005). Finally, through the object recognition task, the programmed offspring had a higher absolute index of discrimination (230%, p = 0.02). The results demonstrate that maternal supplementation with sodium selenite affects the physiological systems involved with learning and expression of affective behavior in adulthood. Therefore, we believe that the behavioral profile observed can be related to neurochemical changes during the critical period of the central nervous system ontogeny.Grant Funding Source: FAPERJ/CNPq
Maternal omega‐3 fatty acid consumption decreases offspring reactivity to the stress of a novel environment (684.3)
Authors: Jackson Corey , Barrett Douglas , Shumake Jason , Gonzalez‐Lima Francisco , Lane Michelle 
Published: June 2021

Prenatal supplementation with omega‐3 fatty acids (O3FAs) is common because O3FAs are integral to fetal brain development. Our objective was to assess effects of prenatal O3FA consumption on offspring behavior using a rat model. Pups were obtained from the second litter of mothers that consumed diets with or without O3FAs for two cycles of gestation and lactation. The without‐O3FA diet contained 7% sunflower oil, which depletes maternal brain O3FA levels. The with‐O3FA diet contained 7% menhaden oil (26% O3FAs). Pups were weaned at age 21 days to the facility chow diet, which contained 0.2 g O3FA/100 g. Behavioral testing began at 8 weeks of age. The offspring were tested in the open field (OF) to examine locomotor reactivity to the stress of being placed in a novel environment, the holeboard task (HBT) to assess memory, and the forced swim test (FST) to assess depression‐related behavior. Offspring from O3FA‐consuming mothers were less reactive to novel OF stress than pups from O3FA‐deficient mothers, F(1,16) = 9.613, p = 0.007. In the HBT, offspring whose mothers ate O3FAs tended to have improved working memory, F(1,15) = 3.03, p = 0.10, but more subjects are needed for statistical power. Maternal O3FA intake did not influence offspring immobility in the FST. Taken together, these data indicate that maternal consumption of O3FAs during gestation and lactation may dampen stress reactivity and improve the memory of offspring.Grant Funding Source: Research Enhancement Program of Texas State University
Stimulation of endoplasmic reticulum stress and inflammation by neuronal (pro)renin receptor is mediated by Toll‐like receptor 4 activation (686.32)
Authors: Shan Zhiying , Yuan Wei , Qi Xaioli , Chen Qinghui 
Published: June 2021

Our previous studies demonstrated that brain neuronal prorenin receptor (PRR) contributes to hypertension via NF‐KappB (KB)‐cytokine signaling. This finding coupled with the important role of toll like receptor 4 (TLR4) in inflammation and endoplasmic reticulum (ER) stress suggest that brain neuronal PRR activation, in part, stimulates TLR4 and subsequently induces ER stress and NF‐KB‐cytokine signaling. Therefore blocking TLR4 activation should attenuate the cytokines and ER stress response induced by PRR activation. To test this hypothesis, primary neuronal cultures from rat brain were incubated with 20 nM of renin for 6 hours. Real time PCR was performed to analyze the expression of inflammatory cytokines, NF‐KB and ER stress markers. Renin treatment resulted in significant increases in IL1β (1200‐fold), IL6 (33‐fold), TNFα (17‐fold), NF‐KB (6‐fold) and I‐kappa B kinase (IKK) (7‐fold). In addition, the mRNA levels of ER stress marker Ddit3 and Hspa3 increased by 47%and 41% in renin treated neurons. Quinazoline (10µM), a NF‐KB activation inhibitor, effectively blocked renin‐induced increases in IL1β, IL6, TNFα and NF‐KB, by more than 85%, but failed to inhibit IKK, Ddit3 and Hspa3. In contrast, renin stimulation on all these genes was almost entirely blocked (>90%) by a TLR4 inhibitor TAK‐242 (2 µM), indicating an important role of TRL4 in this newly identified PRR mediated activation of ER stress and inflammation signaling. Further study will probe whether NF‐KB‐inflammation is mediated by ER stress in the context of hypertension.Grant Funding Source: AHA 11SDG7420029
Exogenous thyroxine (T4) attenuates glucose intolerance and insulin resistance in obese Otsuka Long‐Evans Tokushima Fatty rats (688.12)
Authors: Vazquez‐Anaya Guillermo , Martinez Bridget , Nakano Daisuke , Nishiyama Akira , Ortiz Rudy 
Published: June 2021

Thyroid hormones (TH) regulate metabolism and their levels are altered with the development of metabolic syndrome (MetS), which is associated with insulin resistance (IR) and hypertension. TH analogues and derivates may be effective treatments for glucose intolerance and IR, but their effects on the hypertension associated with MetS are not well described. To assess the effects of thyroxine (T4) on glucose regulation and systolic blood pressure (SBP), an oral glucose tolerance test (oGTT) was performed and arterial pressure monitored on four groups of rats (n=7‐8): 1) lean control strain, LETO, 2) obese OLETF, 3) LETO + T4 (8.0µg/100g BW/d x 5wks), and 4) OLETF + T4. While a strain effect on SBP was detected, T4 did not alter the pressure. T4 attenuated glucose intolerance in OLETF rats by 15 %, and improved insulin clearance by 33%. IR index (IRI) decreased 34% in treated OLETF compared to untreated OLETF. TH profiles were measured to assess the status of the hypothalamus‐pituitary‐thyroid axis. Total T4 (60 ± 11 vs. 30 ± 7 nmol/L) and total triiodothryonine (T3)(1.5± 0.2 vs. 0.67 ±0.13 nmol/L) were higher in OLETF compared to LETO. The results suggest that despite a hyperthyroid state in OLETF rats, improvements in glucose intolerance and IR with exogenous T4 were not sufficient to ameliorate the hypertension associated with the development of MetS. Furthermore, the data suggest that the associated hypertension in this model is not a consequence of metabolic derangement, but likely other factors independent of glucoregulation.Grant Funding Source: National Institute of Health (NIH)
High mobility group box protein 1 as a novel vascular permeability factor derived from endothelial inflammasome activation during obesity (688.5)
Authors: Chen Yang , Pitzer Ashley , Li Xiang , Xu Ming , Zhang Yang , Li Pin‐Lan 
Published: June 2021

The early onset of type II diabetes in obese individuals is characteristic of increased vascular permeability leading to diabetic vasculopathy. However, it remains unknown how obesity instigates endothelial dysfunction resulting in vascular hyperpermeability. Here, we tested a hypothesis that visfatin, an injurious adipokine activates endothelial Nlrp3 inflammsome to produce high mobility group box protein 1 (HMGB1) and that HMGB1 serves as a novel vascular permeability factor to mediate the onset of obesity‐associated vascular hyperpermeability. In coronary arteries of Nlrp3+/+ mice fed high fat diet (HFD) for 6 weeks, confocal microscopic analysis showed significantly lower expression of gap junction proteins (GJPs) including VE‐Cadherin, ZO‐2 and occludin in the coronary arterial endothelium compared to mice on normal diet (ND). In vivo assessment of vascular integrity demonstrated that more Evans blue was extravasated into the myocardium in mice on HFD compared to mice on ND. However, such HFD‐induced decrease in endothelial GJP level and increase in vascular permeability were significantly attenuated in Nlrp3‐/‐ mice. Accompanied with these vascular permeability alterations, interestingly, HMGB1 expression was elevated in coronary arterial endothelium of HFD‐treated Nlrp3+/+ mice, but not in Nlrp3‐/‐ mice. In cultured mouse microvascular endothelial cells (MVECs), visfatin markedly decreased expression of GJPs and increased endothelial permeability. These visfatin‐induced changes in GJPs and endothelial permeability were blocked when MVECs were treated with HMGB1 inhibitor glycyrrhizin, caspase‐1 inhibitor WEHD or siRNA targeting HMGB1 receptor RAGE, respectively. Together, these data suggest that during obesity Nlrp3 inflammasome is activated due to the action of increased adipokines such as visfatin, which produces HMGB1 to serve as a vacular permeability factor leading to the onset of diabetic vasculopathy and ultimately resulting in atherosclerosis.Grant Funding Source: Supported by NIH grants HL057244, HL091464 and HL075316
Effect of bee’s propolis on fasting blood sugar and its antioxidant properties in diabetic rats (693.6)
Authors: Usman Umar 
Published: June 2021

In Africa, hundreds of plants and plant products are used traditionally for the management of diabetes mellitus. This study was undertaken to evaluate the anti hyperglycemic effects and anti oxidative properties of Bee’s Propolis in diabetic Wister rats. Thirty five adult male Wister rats weighing (120‐ 180) grams of about 18 to 20 weeks of age were used. The animals were assigned into seven groups of five rats each. Group VII(untreated DM), served as the positive control group receiving 0.9% normal saline( 5mls/kg) alone via oral rout. Group 1 (normoglycemic) while groups II, III, IV, V and VI were treated with alloxan and after the induction of diabetes received orally, 250mg/kg(Metformin), 100mg/kg, 200mg/kg, 400mg/kg(Bee’s Propolis) and 100mg/kg( Vitamin C) daily for four weeks. FBS are recorded weekly and serum is taken on the last day for oxidative stress markers. The results showed 100mg/kg and 400mg/kg of Bee’s Propolis Significantly decrease fbs Levels to (4.62±0.32mmol/l) and (4.22±0.14mmol/l) compared with group II as (5.94±0.21mmol/l) and group vii (22.67±1.14mmol/l). While 200mg/kg and 400mg/kg of Bee’s Propolis significantly decreased Malandoaldehyde to (1.91±0.14nmol/ml) and (1.89±0.14nmol/ml), compared to group II and group V as (2.39 ±0.15) and (1.83±0.16). Serum activities of catalase significantly increased in group III, IV and V (57.14±2.48ug/mgprot), (55.29±4.71u/mgprot) and (58.71±2.24u/mgprot) compared with group VI and group II as (39.86±3.03u/mgprot) and (54.86±1.08u/mgprot). Serum glutathione peroxidate was significantly lower in the group II and group VI (36.86± 3.91u/mgprot) and (46.43±4.25u/mgprot) compared with the groups treated with different doses of Propolis as (44.86±1.82u/mgprot), (42.14±2.96u/mgprot) and (43.00±2.50u/mgprot). The results of the study showed that Bee’s Propolis Possesses anti‐ hyperglycemic and ant oxidative potentials which doe’s not depend on the dose administer.Grant Funding Source: USMANU DANFODIYO UNIVERSITY SOKOTO, NIGERIA