bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peak Caspase‐1 p20 Levels During Acute Myocardial Infarction Correlate with Pre‐Existing Hypertension, Age and Post‐Infarction Cardiac Dysfunction
Authors: Greenwood Matthew , Morgan Andrew , Na Sam , Gold Courtney , Liang Brannen , Shapior Linda , Liang Bruce 
Published: November 2023

BackgroundIncreased inflammation contributes to the development of myocardial infarction (MI) and adversely impacts infarct healing. Caspase‐1 is an end effector of inflammasome activation and is an important mediator of systemic inflammation. Caspase‐1 is cleaved to produce a 20 kDa (p20) peptide upon activation. Activated Caspase‐1 activates downstream cytokines IL‐1β and IL‐18. Previous work demonstrated that the p20 is elevated in patient serum during and after acute MI.ObjectiveThe aim of this study was to further elucidate the relationship of Caspase‐1 p20 and risk factors for MI. Between 12/10/2007 and 3/28/2016, 170 eligible patients with acute MI were enrolled that had complete information on p20 levels.MethodUsing a solid phase enzyme‐linked immunosorbent assay, the 20 kDa peptide was detected in serum during ST elevation (STEMI) and non‐ST elevation (NSTEMI) MI as well as after MI. Cardiac function post‐MI was evaluated via standard‐of‐care echocardiography.ResultsThere is a positive correlation between age and peak p20 level during acute MI (P=0.01, linear regression, n=170). In STEMI but not in NSTEMI subjects, pre‐existing hypertension (HTN) was associated with a 50.3% higher average circulating peak p20 level during acute MI than those without HTN (P=0.0056, Wilcoxon, n=31 for both groups‐those with HTN and without HTN), suggesting a greater degree of inflammasome activation in HTN patients during STEMI. In these STEMI subjects, the existence of diabetes mellitus or smoking was not associated with a higher peak p20 level during acute MI. There is a trend for all acute MI patients to have a reduced post‐MI cardiac function as quantified by LV fractional shortening in echocardiography (P=0.05, Spearman correlation, r=−0.35, n=31).ConclusionOlder subjects had more elevated peak p20 levels during acute MI, consistent with the concept of a larger inflammasome response to MI as age increases. Inflammasome activation is more pronounced in HTN patients during STEMI, implying a greater degree of inflammatory response in the presence of HTN. A greater extent of inflammasome activation during STEMI may be associated with a worse LV function subsequently.Support or Funding InformationThe study is supported by the Pat and Jim Calhoun Cardiology Endowment Fund.
Long‐term effects of atenolol use on glycemia
Authors: Camacho‐Narro Carolina , Camacho‐Saavedra Luis Arturo , Bardales‐Zuta Victor Hugo , Fernández‐Rodríguez Lissett Jeanette 
Published: November 2023

There is good evidence that the antihypertensive drug atenolol can alter glycemic metabolism in patients. Although these reports offer insight into this undesirable side effect, there currently lacks sufficient information on glycemia over long‐term use of this beta‐blocker. For this reason, we designed a retrospective cohort study in which we measure glycemia in non‐obese patients before and after 6 months of treatment with atenolol (n=36) or a non‐diuretic antihypertensive drug (n=72). We observe that the incidence of hyperglycemia was 47,2% in the atenolol group and 15,3% in the control group after 6 months, which generated RR = 3,091, 95% CI [1,623 to 5,878], p <0,05. Although this increase is significant in the atenolol group, no case achieved glycemia levels that defined diabetes mellitus. However, we recommend that glycemia be measured, and if necessary, controlled during treatment with atenolol to avoid long‐term metabolic complications.Support or Funding InformationAntenor Orrego Private University
Antidiabetogenic Effects of the Seed Extracts of Picralima nitida
Authors: Ojuola Oluwatosin Moradeke , Abatan Matthew Oluwole 
Published: November 2023

Picralima nitida is a plant with medicinal importance including its use for lowering blood sugar levels. The extracts of the seed have been evaluated for possible blood sugar lowering properties using alloxan‐induced diabetes mellitus model in rats. The seed material of P. nitida was extracted using gradient solvent extraction with chloroform, diethyl ether, ethyl acetate and methanol. Pilot toxicity studies using a crude extract indicated that the plant was safe when administered orally at 3000mg/kg. The different solvent extracts were administered at a dose of 750mg/kg, to alloxan induced diabetic rats and their blood sugar levels monitored hourly for four hours post administration. Glibenclamide served as the standard antidiabetic drug. Results show that the different solvent extracts had significant blood lowering effects (P<0.5) compared to the untreated diabetic rats. The extracts also produced decrease in the triglyceride, total cholesterol, low density lipoprotein values and an increase in high density lipoprotein levels.The chloroform solvent extract produced the highest bioactivity and was therefore subjected to further tests. The extract was subjected to vacuum liquid chromatography (VLC) and the biograded fractions evaluated for their blood sugar lowering effects. The results showed that fraction 5 (30% ethyl acetate and 70% ethanol) produced the highest blood sugar lowering effects. Standard procedures were used to carry out phytochemical analysis which showed that the plant has alkaloids, flavonoids, saponin, tannins and cardiac glycosides. The evaluation substantiates the medicinal use of P. nitida for lowering blood sugar in diabetic patientsSupport or Funding InformationPan African University
Effects of hydroxytyrosol on cardiovascular and neuroprotective biomarkers in experimental diabetes mellitus
Authors: Gonzalez‐Correa Jose A , Rodriguez‐Perez M Dolores , Lopez‐Villodres Juan A , Medina‐Moreno Ursula , de la Vega Jose J Reyes , de la Cruz Jose P 
Published: November 2023

The aim of this study was to assess the influence of hydroxytyrosol (HT) on cardiovascular inflammation and neuroprotective effect in streptozotocin‐diabetic rats. Four groups of rats (N=10 per group) were studied for 2 months: nondiabetic rats (NDR), diabetic rats treated with saline (DR) and DR treated with HT (1, and 5 mg/kg/day p.o.). At the end of follow‐up an experimental model of hypoxia‐reoxygenation in brain slices was tested. Vascular variables: DR had higher platelet aggregation values, higher thromboxane B2, plasma lipid peroxidation, 3‐nitrotyrosine, oxidized LDL (oxLDL), myeloperoxidase, vascular cell adhesion molecule 1 (VCAM‐1) and interleukin‐1β (IL‐1β) concentrations, and lower aortic 6‐keto‐prostaglandin F1α and nitric oxide production than NDR. Aortic wall area and smooth muscle cell count were also higher in DR than in NDR. Brain variables: the DR group showed increased cell death, oxidative and nitrosative stress and an increase in brain inflammatory mediators. HT significantly reduced both oxidative and nitrosative stress, oxLDL concentration (35% and 40% of reduction respect untreated animals for 1 or 5 mg/kg/day respectively), VCAM‐1 (63% and 50%), platelet aggregation (22% and 40%) and thromboxane B2 production (22% and 25%). Morphometric values in the aortic wall were reduced to values near those in NDR. Respect the brain variables the result obtained were the following: HT significantly reduced oxidative lipid peroxidation (38% and 52 of reduction respect untreated animals for 1 or 5 mg/kg/day respectively) and nitrosative stress (47% and 50%) and peroxynitrite concentration (43% and 60%) and brain inflammatory mediators (19–30% prostaglandin E2 and 16–50% interleukin 1β concentration). Cell death was reduced by 26% and 38% after the administration of 1 or 5 mg/kg/day.In conclusion, HT influenced the major biochemical processes leading to diabetic vasculopathy, reduced cell proliferation in the vascular wall and had a neuroprotective effect in this experimental model.
M3 Muscarinic Acetylcholine Receptors Inhibit Autophagy through Activation of mTORC1 in Human Neuroblastoma Cells.
Authors: Onali Pierluigi , Dedoni Simona , Olianas Maria C 
Published: November 2023

Activation of Gq/11‐coupled muscarinic acetylcholine receptors (mAChRs) has been shown to promote the growth and survival of different types of cancers derived from epithelial and endothelial cells [1]. Previous studies in human neuroblastoma cells have reported that M3 mAChRs prevent apoptotic cell death induced by a number of cytotoxic agents [2,3]. However, there is little information on the effect of mAChRs on autophagy, an evolutionary conserved self‐degradation process that may act as a tumor‐suppressor pathway. In the present study we show that in human SH‐SY5Y neuroblastoma cells activation of M3 mAChRs inhibits autophagy triggered by serum and L‐glutamine removal from the growth medium. Cell exposure to either the cholinergic agonist carbachol (CCh) (30 μM) or the mAChR agonist oxotremorine‐M (100 μM) inhibited the formation of the autophagosome marker LC3‐II and increased the accumulation of the autophagy substrate p62. These effects were blocked by either atropine or the M3 mAChR‐preferring antagonist darifenacin, but not MT7, a selective M1 mAChR antagonist. The inhibitory effect of CCh on autophagy was prevented by blockade of Gq/11 with YM254890 and by inhibition of protein kinase C (PKC), and was mimicked by the PKC activator phorbol 12‐myristate 13‐acetate (PMA). Both CCh and PMA induced mTORC1 activation and enhanced the phosphorylation/inactivation of ULK1, a mTORC1 substrate and a key initiator of autophagy. Inhibition of mTORC1 by rapamycin prevented CCh‐induced ULK1 phosphorylation and autophagy inhibition. The data indicate that in SH‐SY5Y cells Gq/11‐coupled M3 mAChRs inhibit autophagy by stimulating the PKC‐mTORC1 signaling pathway. The attenuation of the self‐degradation process induced by autophagy may contribute to the growth promoting effects of M3 mAChRs in human neuroblastoma cells.Support or Funding InformationSupported by Regione Autonoma della Sardegna, L.R.7,‐2012‐CRP‐60567
Time‐locked mesolimbic dopamine signals in response to pain onset and to pain offset
Authors: Isakov Bojan , Atcherley Christopher , Gee Taylor , Navratilova Edita , Heien Michael , Porreca Frank 
Published: November 2023

Relief of aversive states, including pain, is rewarding and associated with an increase in dopamine (DA) release in the mesolimbic reward circuit. Measurement of DA in the nucleus accumbens (NAc) is usually accomplished with microdialysis but this method does not allow determination of the temporal relationship to pain, and to its relief. In this study, we used isoflurane anesthetized rats to measure NAc DA release on a millisecond to second timescale using fast scan cyclic voltammetry (FSCV). Our approach was to standardize the depth of anesthesia by a reflexive pain response to noxious heat, the tail‐flick test. The depth of anesthesia was standardized to this biological response of approximately 5.0 sec latency. FSCV involves the application of a specific triangular waveform at a high scan rate, allowing for oxidation and reduction of dopamine detected by a specialized electrode previously implanted in the NAc shell. Application of noxious heat to the tail was accompanied by a decrease in the DA signal that peaked at the time of the tail‐flick. Following the tail‐flick, there was a rebound increase in DA signal that peaked after 2.9 s. The data show a time‐locked DA response to pain onset, and to pain offset, likely related to the negative and positive components of pain and its relief.Support or Funding InformationSupported by DA034975 from the NIH
Effect of Fatty Acid Amide Hydrolase (FAAH) Inhibitors Isolated from Nutmeg on Anxiety
Authors: El‐Alfy Abir T. , Jeon Andrew , An Hea Re , Kendrek Jennifer , Abourashed Ehab 
Published: November 2023

The endocannabinoid system (ECS) is a complex neuromodulatory network involved in the regulation of numerous physiological functions. These effects have been substantiated by the use of known exogenous cannabinoid, Δ9‐THC, the active component of marijuana. Thus, the ECS has emerged as an appealing pharmacologic target in drug discovery. Anecdotal reports of Myristica fragrans, commonly known as nutmeg, being used as a substitute for marijuana, suggest that one or more of its components may interact with the ECS. Previous studies in our laboratory demonstrated that administration of nutmeg extracts produced behavioral tetrad effects similar to Δ9‐THC. However, the mechanism of such action requires further exploration. Receptor binding assays revealed that nutmeg extracts did not have direct CB1 or CB2 receptor binding activity. Additional mechanistic studies showed that indirect interaction through the inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), key endocannabinoid degradation enzymes, was observed. The objective of the current study was to isolate the active components of nutmeg extract responsible for the FAAH inhibition activity and to evaluate them in an animal model of anxiety. Using bioassay guided fractionation and various chromatographic techniques, three compounds were isolated, spectroscopically characterized, and identified (MF 109‐5, MF30‐7, and MF117‐3). Concentration and time inhibition studies were conducted. The IC50 values calculated for the three compounds were 4.57 ± 0.66, 7.50 ± 2.02, and 38.29 ± 6.18 mM, respectively. The compounds were further evaluated in the elevated plus maze animal model of anxiety in comparison to diazepam as the positive control. The three nutmeg compounds were tested at doses ranging from 5 to 120 mg/kg, i.p. injection. While diazepam demonstrated a significant dose‐response increase in open arm entry and permanence time, indicative of anxiolytic action, none of the isolated compounds had a significant effect. In conclusion, the study resulted in the identification of three nutmeg compounds that significantly inhibit FAAH enzyme and hence shed light on potential mechanism of cannabis‐like action of nutmeg. While none of the compounds showed anxiolytic activity in the elevated plus maze model, additional pharmacokinetic studies are needed to optimize the dosing regimen required for significant increase in endocannabinoids that might be needed for elaboration of the anxiolytic effect.Support or Funding InformationResearch reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Number R24DA036410. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Norclozapine Reduces Beta Amyloid1‐42 Levels and Increases ChAT Levels in 3xTg‐AD Female Mice.
Authors: Burkart Ashley , Potter Pamela E , Jones Douglas C 
Published: November 2023

Alzheimer's disease (AD) is a neurodegenerative disease characterized by synaptic dysfunction and cholinergic cell death. Major pathological hallmarks include aggregations of beta‐amyloid (Aβ) proteins, intracellular neurofibrillary tau tangles, and a loss of cholinergic neurons that innervate the hippocampus and cortex. The accumulation of neurotoxic Aβ fragments in AD is caused by the improper processing of amyloid precursor protein (APP). Previous evidence suggests that insoluble Aβ1‐42 oligomers induce synaptic loss and decreases choline acetyltransferase (ChAT) levels in AD brains. In addition, activation of cholinergic receptors, specifically muscarinic M1 receptors, has been shown to reduce the inappropriate and neurotoxic processing of APP. The goal of the current study was to evaluate the effects of M1 stimulation on Aβ levels and cholinergic dysfunction in an animal model of AD, the 3xTg‐AD mouse. 3xTg‐AD female mice (~6 mos old) were randomly divided into 4 experimental groups and administered (i.p.) either saline (control), an M1 agonist (norclozapine) or an M1 antagonist (scopolamine or tolterodine) for 30 days. On day 31, mice were sacrificed and the brain harvested for analysis. ELISA results using whole brain homogenates indicated that norclozapine (8 mg/kg) significantly decreased Aβ protein levels whereas scopolamine (2 mg/kg) and tolterodine (2 mg/kg) had no significant effect on Aβ levels. Analysis of ChAT proteins in brain homogenates of treated 3xTg‐AD mice found that norclozapine significantly increased ChAT levels while neither of the antagonists had an effect. Finally, immunohistochemical (IHC) analysis of sectioned brain tissue using an antibody against Aβ revealed decreased Aβ immunoreactivity in the hippocampus and cortex of norclozapine treated animals. The present results have characterized the effects of M1 stimulation on amyloid levels and cholinergic function in a common animal model of AD. These findings also suggest that (1) the M1 agonistic properties of norclozapine may be effective in reducing the accumulation of Aβ associated with AD and (2) M1 receptor stimulation may be a valuable mechanism for the development of new drugs aimed to inhibit the progression of AD.Support or Funding InformationThis work was supported by Midwestern University Intramural and Biomedical Student funding.
Regulation of the Dopamine D4 Receptor by Angiotensin II in Rat Astrocytes
Authors: O'Connor Ann Tenneil , Trivedi Malav , Clark Michelle 
Published: November 2023

ObjectiveWe investigated whether Angiotensin (Ang) II regulates the Dopamine D4 receptor (D4) protein expression and whether this interaction is dysregulated in astrocytes isolated from Spontaneously hypertensive rats (SHRs).BackgroundA role for the cerebellum in attention and cognitive control has recently been reported. Dysregulation of the D4 receptor function in the cerebellum has been linked to neurodevelopmental disorders such as Attention deficit hyperactivity disorder (ADHD). The mechanisms underlying the dysfunction of the D4 receptor are unknown. We proposed that the angiotensin type 1 receptor (AT1R) cross talks with the D4 receptors, and this interaction may be dysregulated in neurodevelopmental disorders such as ADHD. We used the SHR which is a widely accepted animal model for ADHD. Astrocytes were used as a model brain system to explore the interaction between the two receptors.MethodsCerebellar astrocytes were prepared from 2–3 days old Wistar and SHR pups. Quiescent cells were treated with 100nM Ang II (the major AT1R ligand) for 1–48 hours. Expression of the D4 receptor protein levels was determined by Western blotting.ResultsThere were no significant differences in basal protein levels of the D4 receptor in cerebellar SHR samples as compared to the Wistar controls. In Wistar rats, Ang II downregulated the D4 receptor expression relative to untreated controls. In SHR, Ang II decreased D4 receptor protein expression at most time points examined. There was no significant difference in the ability of Ang II to reduce the D4 receptor protein levels in SHR cerebellar astrocytes as compared to the effect observed in Wistar cerebellum astrocytes.ConclusionThere is an interaction between the AT1R and the D4 receptor as demonstrated by the ability of Ang II to reduce the D4 receptor protein expression in both SHR and Wistar rat cerebellum samples. This Ang II‐mediated effect was similar in cerebellum astrocytes from both Wistar and SHRs suggesting that these cells were similarly responsive to the peptide. This interaction between the AT1R and the D4 receptor will be further investigated as a potential therapeutic target for pathophysiological conditions mediated by these two systems in other areas of the brain where there is a higher expression of the D4 receptor, such as the prefrontal cortex.
Impact of Delta‐9‐tetrahydrocannabinol on the Reinforcing Effects of Remifentanil in Rhesus Monkeys Responding Under a Food/Drug Choice Procedure
Authors: Maguire David R , France Charles 
Published: November 2023

Cannabinoid receptor agonists such as delta‐9‐tetrahydrocannabinol (THC) enhance some (e.g., antinociceptive) but not other effects of mu opioid receptor agonists such as morphine, indicating that opioid/cannabinoid mixtures might be a safe and effective treatment for pain. In rhesus monkeys, cannabinoids fail to enhance and often decrease self‐administration of the mu opioid receptor agonist heroin, suggesting that opioid/cannabinoid mixtures do not have greater reinforcing effects (abuse potential) as compared to opioids alone. Previous studies on the self‐administration of opioid/cannabinoid mixtures in monkeys used single‐response procedures which do not easily differentiate changes in reinforcing effects from other (e.g., generalized rate decreasing) effects, so the interaction between opioids and cannabinoids with regard to reinforcing effects remains unclear. This study used a choice procedure to examine the reinforcing effects of opioid/cannabinoid mixtures relative to food. Rhesus monkeys (n=3) responded under a concurrent schedule wherein responding on one lever delivered 3 sucrose pellets and responding on the other lever delivered i.v. infusions of the mu opioid receptor agonist remifentanil (0.032–1.0 μg/kg/infusion) alone or in combination with THC (32 or 100 μg/kg/infusion). Each session comprised 4 sample trials (2 per reinforcer) followed by 20 choice trials; trials were separated by 10 min. When saline or small doses of remifentanil alone were available, monkeys responded predominantly for food. Responding for drug infusions increased, and responding for food decreased, as the dose of remifentanil increased. For two monkeys, THC did not appear to impact the relative reinforcing effects of remifentanil as the dose‐effect curves for the remifentanil/THC mixtures did not differ from the curves for remifentanil alone. However, for a third monkey, the dose‐effect curve for the remifentanil/THC mixture was shifted leftward compared with the curve for remifentanil alone, suggesting that THC increased the reinforcing potency of remifentanil. In all monkeys, THC (particularly the larger dose of 100 μg/kg/infusion) initially decreased the number of trials completed but that effect dissipated across sessions, suggesting that tolerance developed to rate‐decreasing effects of THC. Overall, these results extend previous studies and show that cannabinoids do not substantially enhance the reinforcing effects of mu opioid receptor agonists and demonstrate the utility of choice procedures for studying the reinforcing effects of drug mixtures.Support or Funding InformationSupported by the US National Institutes of Health (R01DA005018) and the Welch Foundation (AQ‐0039).
Synthesis and Biological Evaluation of a Novel Series of G Protein‐Coupled Estrogen Receptor Antagonists for The Treatment of Gallstone Disease
Authors: DeLeon Chlelsea , Wilhelm McKenna , Sweeney Patrick , Arnatt Christopher 
Published: November 2023

The prevalence of gallstone disease is a major public health issue globally. While laparoscopic cholecystectomy is the current standard of treatment, new research suggests that medicinal therapy may offer a non‐surgical option for patients with a functioning gallbladder. The G protein‐coupled estrogen receptor (GPER) is known to induce gallstone formation in response to 17b‐Estradiol (E2) treatment. Therefore, the design of GPER antagonist may significantly reduce gallstone formation and enable non‐surgical management of gallstone disease. Using a computational homology model of GPER, a novel series of antagonists were designed and synthesized. An original high‐throughput screening (HTS) biochemical assay was designed to analyze GPER activity. Preliminary results show no agonism of intended GPER antagonists.Support or Funding InformationSaint Louis University