bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Placental Ischemia‐Induced Hypertension on Circulating Copeptin Levels of Pregnant Rats
Authors: Palei Ana Carolina , Warrington Junie P. , Granger Joey P. 
Published: November 2023

Although the etiology of preeclampsia (PE) remains unclear, evidence indicates that impaired trophoblast invasion followed by placental ischemia/hypoxia promotes the release of placental anti‐angiogenic and inflammatory factors into the maternal circulation that cause endothelial dysfunction and ultimately hypertension. Interestingly, recent reports have shown that circulating copeptin (a surrogate measurement for arginine vasopressin (AVP) synthesis and release) levels are increased in PE patients and in pregnant women who subsequently developed PE, suggesting first AVP as a potential pathogenic factor in PE and second copeptin as a predictive biomarker for PE. However, the role of AVP/copeptin in the pathophysiology of PE is unclear. The aim of this study was to evaluate the effect of placental ischemia‐induced hypertension on circulating copeptin levels. Age‐matched, timed pregnant Sprague Dawley rats were randomly assigned to the normal pregnant (NP; n=7) group or to the group that underwent reduction of uterine‐placental perfusion pressure (RUPP; n=7). On gestational day (GD) 14, RUPP rats had a silver clip (0.203 mm) placed on the abdominal aorta above the iliac bifurcation and two silver clips (0.100 mm) placed on the right and left ovarian arteries. On GD 19, mean arterial pressure (MAP) was measured consciously via carotid catheters, rats were sacrificed, individual fetuses and placentas were weighted, and blood was collected. After centrifugation of blood, serum was obtained in order to determine circulating copeptin concentration by ELISA. MAP was elevated in RUPP rats compared with NP controls (124.3±4.4 vs. 105.4±1.4 mmHg; P<0.05). In addition to reduced number of viable fetuses per rat (4.7±1.5 vs. 14.7±0.5; P<0.05), fetuses and placentas of the RUPP group were lighter than those of the NP group (1.95±0.07 vs. 2.29±0.04 g and 0.44±0.02 vs. 0.55±0.01 g, respectively; both P<0.05). However, although there was a trend for serum copeptin levels to be decreased in RUPP rats compared with NP rats, this comparison did not reach statistical significance (128.6±15.2 vs. 78.8±18.4 ng/mL; P=0.0584). We have repeated the measurement of circulating copeptin levels in another cohort of NP and RUPP rats and similar results were observed (162.4±10.9 vs. 137.5±29.2 ng/mL, respectively; P>0.05). In conclusion, our findings suggest that increased AVP/copeptin in the circulation of PE patients does not result from placental ischemia. However, our findings do not rule out the possibility that AVP may contribute to the mechanisms leading to placental ischemia in PE.Support or Funding InformationAHA 14POST18970005, NIH HL051971, and NIH HL108618.
Alterations in Cytochrome P450 Expression and Circulating 20‐HETE Levels Contribute to Maternal Hypertension and Decreased Trophoblast Migration
Authors: Murphy Sydney , Lee Nicole , Spencer Shauna‐Kay , Wallace Kedra , LaMarca Babbette 
Published: November 2023

Preeclampsia (PreE) results from an impaired vascular remodeling of the placental spiral arteries. Recent data suggests cytochromeP450 (CYP450) vasoactive eicosanoids in the etiology of the disease. Therefore, we investigated whether CYP450 expression and 20‐HETE production are elevated in preeclamptic populations and if 20‐HETE plays a role in hypertension and trophoblast migration. CYP450 enzymatic activity and circulating eicosanoids were measured in normal pregnant (NP) and PreE patients by LC/MS. In addition, the proliferative actions of 20‐HETE, a major CYP450 metabolite were investigated in an in vivo model of trophoblast syncytialisation. PreE women displayed a significant increase in CYP450 enzyme expression and 20‐HETE production relative to NP women (0.192±0.04 vs 0.119±0.06 pg/min/mg, p<0.05). Circulating 20‐HETE:EETs were statistically increased in women with PreE (1.4±0.5 vs 0.1± 0.04 mg/ml, p<0.05). BeWo cell cultures displayed an increase (45%, p<0.05) in proliferation in response to exogenous 20‐HETE (1μM), while inhibition of endogenous 20‐HETE with 17‐ODYA (10uM) and HET0016 (1nM) displayed a 10% (ns) and 75% (p<0.05) inhibition. Moreover, trophoblast migration and invasion were decreased in the presence of exogenous 20‐HETE (1μM, p<0.05). Therefore, alterations in CYP450 enzyme activity and 20‐HETE may contribute to the altered vascular remodeling seen in women PreE.Support or Funding InformationAmerican Heart Association 14SDG20160020
Organ and Tissue Perfusion Subsequent to Short‐Term Intermittent PTH 1–34 Administration in Mature and Middle‐Aged Mice
Authors: Lee Seungyong , Guderian Sophie , Prisby Rhonda 
Published: November 2023

IntroductionIntermittent parathyroid hormone (PTH) administration is used to treat osteoporosis; however, the secondary benefits of PTH treatment are under explored. PTH elicits vasodilation in the systemic vasculature, implying improved delivery of blood flow to various tissues. Intermittent administration of PTH 1–84 and PTH 1–34 for 15 days augmented and tended to augment vasodilation of the femoral principal nutrient artery in young (p<0.05; Prisby et al., 2013) and old (p=0.07; Lee et al., ASBMR 2014) rats, respectively. Further, intermittent PTH 1–84 administration enhanced skeletal tibial perfusion in mice (Roche et al., 2014). Given the influence of PTH on the vascular system, we sought to determine if short‐term intermittent PTH administration alters organ and tissue perfusion.MethodsMature (6–8mon) and middle‐aged (10–12mon) male and female C57BL/6 mice were equally divided into three groups (i.e., CON, 5dPTH and 10dPTH). Mice were given either PTH 1–34 (43 μg/kg/d) or PBS (50 μl) for 5 and 10 consecutive days. Under anesthesia, fluorescent microspheres were injected into the left ventricle. At sacrifice, the myocardium, left and right gastrocnemii, solei, and kidneys were dissected. Tissue fluorescent density (TFD, AU/g) was determined as tissue fluorescence ÷ tissue mass. Data were excluded if organs and tissues contained <200 fluorescent beads (Prinzen et al., 2000, Cardinal et al., 2007).ResultsBody and tissue masses were similar among groups. There were age‐related declines (p<0.05) in perfusion measured by TFD to the right gastrocnemius (6–8mon: 20273 ± 473 AU/g vs. 10–12mon: 17181 ± 520 AU/g), and left gastrocnemius (6–8mon: 18993 ± 473 AU/g vs. 10–12mon: 16699 ± 676 AU/g). There was a tendency (p<0.10) for lower perfusion to the right kidney (6–8mon: 19409 ± 276 AU/g vs. 10–12mon: 18498 ± 385 AU/g) and left kidney (6–8mon: 19073 ± 567 AU/g vs. 10–12mon: 17503 ± 480 AU/g) in middle‐aged mice. TFD in the myocardium and right and left solei were not altered (p>0.05) by age. In contrast, TFD in other organs and soft tissues was not altered (p>0.05) by either 5 or 10 days of PTH.ConclusionOrgan and tissue perfusion is reduced in middle‐aged vs. mature mice. However, organ and muscle perfusion did not change following short‐term intermittent PTH 1–34 administration. Additional studies are required to determine the influence of intermittent PTH administration on organ and tissue perfusion or blood flow in conscious animals.Support or Funding InformationSupported by the University of Delaware Research Foundation Strategic Initiative Grant and NIH NIAMS (7R15AR062882‐02).
Genotoxic Effect of Long‐term Cigarette and Water‐pipes Smoking on DNA Damage/Repair and Oxidative Stress Genes in Healthy Subjects
Authors: Belali Osamah M , Attafi Ibraheem M. , Korashy Hesham M. 
Published: November 2023

The present study was designed to evaluate the influence of long‐term cigarette and water‐pipe (shisha) smoke on the expression of detoxifying and DNA repair genes in human subjects. The study groups consisted of 45 subjects who were divided into three groups; healthy non‐smoker group (Control), cigarette‐smoker group (Cigarette), and Shisha‐smoker group (Shisha). A questionnaire and consent form was created according to the International Union of Pure and Applied Chemistry commission (IUPAC) and distributed to all groups. The study was approved by the College of Pharmacy Research Center Ethics Committee. Fresh blood samples were collected, and the total RNA was extracted from blood using the PAXgene Blood RNA Kit for isolation and purification (PreAnalytiX, Qiagen) and mRNA expression levels of target genes were quantified by RT‐PCR. The levels of several trace elements were measured using ICP‐MS method. The demographic data showed that among the cigarette‐smoker group, 80% smoke 20–39 cigarettes/day, whereas 12% smoke more than 40 cigarette/day. With regard to water pipe smoke, the majority (46%) smoke more than 5 times/week. Blood analysis showed that a significant increase (50%) in the plasma levels of 8‐hydroxy‐2‐deoxyguanosine, a DNA damage marker, was observed in cigarette‐smoker group whereas no significant changes were demonstrated in shisha–smokers. In addition, the mRNA expression levels of DNA repair genes (OGG1 and XRCC1) were significantly inhibited in cigarette and shisha‐smoker by approximately 30% and 60%, respectively. This was associated with a marked decrease (50%) in the expression of detoxifying genes such as GST. In addition, both cigarette‐ and shisha‐smoker volunteers exhibited significant increase in the plasma concentrations of several toxic heavy metals such as Cd (130%), Pb (47%), and Ni (30%). In conclusion: these findings clearly explore the genotoxic effect of cigarette and shisha smoking on human DNA.Support or Funding InformationNational Plan for Science, Technology and Innovation. Award Number: 12‐MED3131‐02 to HMK
Ursolic acid from shea butter tree (Vitellaria paradoxa) leaf extract synergizes with β‐lactams against methicillin‐resistant Staphylococcus aureus
Authors: Catteau Lucy , Olson Joshua , Van Bambeke Françoise , Leclercq Joelle , Nizet Victor 
Published: November 2023

Given the increasing emergence of antibiotic resistance, the discovery of novel therapeutic options for the treatment of infections is urgently needed. One strategy for overcoming bacterial resistance mechanisms is the use of drugs in combination, such as β‐lactams together with β‐lactamase inhibitors. Here, via a screen of direct and indirect antimicrobial activities of plants used in traditional medicine, we show that a dichloromethane extract of leaves from the shea butter tree (Vitellaria paradoxa) exhibited potent antimicrobial activity against methicillin‐resistant Staphylococcus aureus (MRSA), both alone and in synergistic combination with β‐lactams. Using dichloromethane extraction and an HPLC‐MS method, we detected ursolic (UA) and oleanolic acids (OA) in leaves and twigs of this species and further quantified the abundance of the two triterpenic acids by HPLC‐UV. We then compared the antimicrobial activity of crude V. paradoxa extracts against different clinical and reference strains of MRSA to that of purified UA and OA. Direct antimicrobial activity was determined as minimal inhibitory concentrations (MICs), and potential synergy with β‐lactams was assessed using checkerboard titration and calculation of fractional inhibitory concentration index (FICI), with FICI values ≤ 0.5 indicative of synergy and ≤ 1 defined as additivity. High UA (21%) and OA (6%) content correlated with the antimicrobial activity of the plant extract. UA was more active than OA, with anti‐staphylococcal MICs ranging from 8 – 32 compared to 64 – 256 μg/mL, respectively. Both triterpenic acids synergized with all three β‐lactams tested (ampicillin, oxacillin and nafcillin), indicating an activity targeting PBP2a +/− β‐lactamases. Analysis of the effects of UA and OA on host cells revealed that they inhibited reactive oxygen species production and chemotaxis of human neutrophils, with the plant extract only mimicking the inhibition of chemotaxis. UA, OA and the leaf extract also exhibited a protective effect against red blood cells hemolysis caused by MRSA and purified alpha‐toxin. Finally, we showed that local administration of UA provided a synergistic benefit to nafcillin in reducing lesion size and inflammatory cytokine (IL‐1β) production in a murine model of subcutaneous MRSA infection. Together, our findings reveal both antimicrobial and immune regulatory activities of shea butter tree leaf extract indicating its potential as a therapeutic agent for the treatment of antibiotic resistant infections and source of original lead compounds.Support or Funding InformationThe authors gratefully thank the Belgian Fonds de la Recherche Scientifique, the Faculty of Pharmacy and Biomedical Sciences of UCL and the Nizet lab of UCSD for financial support. Lucy Catteau has been a visiting graduate student at UCSD from June to November 2016 thanks to a Fulbright fellowship.
Development of In Vitro Screening Assay to Detect Inhibition of Mitochondrial RNA Polymerase by Anti‐viral Drugs
Authors: Sharapova Tatiana , Liguori Michael , Lai‐Zhang Jie 
Published: November 2023

Many antiviral agents have been shown to have an off‐target inhibitory effect on mitochondrial DNA (mtDNA) and RNA (mtRNA) polymerases. Quantification of mitochondrial DNA relative to nuclear DNA content by qPCR has been proven as a reliable and fast approach to screen for mitochondrial DNA toxicity. Methods used to assess the function of mitochondrial RNA polymerase (POLRMT) include biochemical and cell‐based assays, and are not optimal for routine screening. Here we studied the utility of RT‐qPCR for the analysis of mitochondrial gene expression as a function of POLRMT in a standard cell culture model. HepG2 cells were treated with 5 and 10mM 2′C‐methyladenosine and 10 and 50uM balapiravir (RG1626, prodrug of 4‐azidocytosine) every 48 hours for 7 and 14 days. Both test compounds have previously been shown to be chain terminators upon mtRNA transcription. 2′ 3′‐dideoxycytidine (ddC) and fialuridine were used as positive controls and 2‐epi‐fialuridine was used as negative control for the study. Upon harvest cells were counted and extracted RNA and DNA were used for gene expression and mtDNA copy number analysis. RT‐qPCR was performed for five mitochondrially encoded (MT‐ND1, MT‐ND4L, MT‐ND5, MT‐CYB, MT‐RNR2) and two nuclear (GAPDH, ACTB) genes. Gene expression analysis in cells treated with the test compounds revealed a dose dependent decrease in the expression of mitochondrial genes when compared to untreated controls, while mtDNA copy number remained unchanged. The degree of expression of each gene had a reverse correlation with the distance between the gene positon in the mitochondrial genome and the initiation transcription site ITH2. The mRNA levels of the housekeeping genes, GAPDH and ACTB, transcribed by RNA Pol II remained unchanged across all samples and could be used for data normalization. As a conclusion, analysis of mitochondrial gene expression using RT‐qPCR can be utilized as a simple and sensitive first pass method to screen for POLRMT inhibition in vitro and would aid in identification of mitochondrial toxicity of anti‐viral compounds prior to in vivo testing.Support or Funding InformationTS, JLZ, and ML are employees of Abbvie.The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication
ANTIMICROBIAL ACTIVITY OF CARESOO® ELECTROLYZED WATER AGAINST BURN ASSOCIATED INFECTION
Authors: Atanacio Ronald Comedia , Mondoy Melisa , Bigol Ursela , Atanacio Jayson Reiner , Malbas Fedelino , Galit Salvacion Rosario , Dancel Manuel 
Published: November 2023

Burns are a global public health problem, accounting for an estimated 265 000 deaths annually. The majority of these occur in low‐ and middle‐income countries and almost half occur in the Southeast Asia Region like the Philippines1. Infection is one of the common causes of burn death. The vulnerability to pathogens depends on different factors including the severity of burn and the mode of treatment. This study is intended to determine the in‐vitro antimicrobial activity of Caresoo®Hypochlorous Acid Water Generator (Delight Factory Korea) against pathogenic microorganisms.Electrolyzed water produced from Caresoo®Hypochlorous Acid Water Generator was subjected against gram (+)/(−) bacteria and a fungus in 3 different concentration of salt and distilled water (1:300,3: 300, 5:300), 3 different concentration of Mac Farland and electrolyzed water(1:1, 1: 3, 3:1,), and different exposure time interval (15, 30, 60, 120, 180seconds). The 3 concentration of electrolyzed water were also used in 24 hours incubation period under disc diffusion method to determine if it can hold the inhibitory zones.Electrolyzed water exhibited bioactivity against Staphylococcus aureus, Methicillin Resistant Staphylococcus aureus (MRSA), Methicillin Resistant Staphylococcus epidermidis, (MRSE) Pseudomonas aeruginosa, Streptococcus pyogenes, Proteus mirabilis and Candida albicans in all concentrations < 15 seconds. No antimicrobial activity noted in 24 hrs. incubation but secondary inhibitory zones were noted in each sample concentration.Electrolyzed water produced from Caresoo®Hypochlorous Acid Water Generator is potent on test microorganisms regardless of the concentration of salt solution, and MacFarland and electrolyzed water concentration. The bioactivity of electrolyzed water cannot sustain bacterial and fungal growth in 24 hours incubation time. This is because of its low stability; HOCl rapidly decomposes into its original state (saline solution).This study affirms the antimicrobial activity of the electrolyzed water from Caresoo®Hypochlorous Acid Water Generator. The inapplicability of this electrolyzed water for human use as recommended by the manufacturer is the definitive intention of this study. That is to make electrolyzed water suitable in wound care and infection control. It is recommended that the electrolyzed water produce by Caresoo®Hypochlorous Acid Water Generator should be used to other pathogenic test organisms. Toxicity test is also recommended to determine its medical significance to man.Support or Funding InformationThis was initiated and financed by the authors.
Antiviral Modalities of Multivalent Ag4O4 Nanoparticles for Clinical Infectious Disease Applications
Authors: Mack Leigh Jennings , Einstein George P , Tulp Orien L 
Published: November 2023

The purpose of this study was to demonstrate the modality of action, efficacy and safety of Ag4O4 nanoparticles in the application of hindering the targeting and acquisition of viruses on host cells. This study also illustrates how molecular frequency can change the dynamics of viral load and illustrate through both bench and clinical trials an empirical log reduction in viruses. In regard to medical devices, the new world of nanomedicine is just in it's infancy; over the next 10 years large jumps should occur connecting theory to actual medical devices and treatment protocols. To this end, we hope to add a small part to medicine as a whole by researching as well as developing new nanosized particle approaches and devices that can clearly make a difference in improving the effectiveness in wound healing, and in the lives of people and animals. We have already contributed in some specific areas of antibacterial applications but feel we have only begun to scratch the surface in this emerging field of medicine. The process of developing effective nanoparticles is an ever changing area of research. It is a series of thousands of small steps to reach an option for treatment. However, as technology increases at a rate that is exponential in nature, we will see faster and shorter development periods for both pharmaceuticals as well as medical devices. We will see computer processing and applications give us advantages that were never dreamed of previously. Today, we live in a world in which we can use technology productively to build faster and better new technology. In summary, this research was designed to pull together current research of the Ag4O4 nanoparticle and add another small study on how it eliminates specific viruses. Many researchers have alluded to this aspect of the particle, but none have directly addressed the modalities in which it works. To this end, we have illustrated two specific modalities of the Ag4O4 as antiviral in nature. The application of Ag4O4 nanoparticles in wound healing resulted in an apparent misleading of the targeting system on the virus and hindering glycoproteins from attaching to the host cells.Support or Funding InformationSupported by Institutional Resources of USAT and Einstein Medical Institute
Structural Heteropolysaccharide Binding to the Visceral Mesothelial Glycocalyx
Authors: Servais Andrew , Kienzle Arne , Valenzuela Cristian , Ysasi Alexandra , Wagner Willi , Ackermann Maximilian , Tsuda Akira , Mentzer Steven 
Published: November 2023

Bioadhesives are biopolymers with potential applications in wound healing, drug delivery and tissue engineering. Pectin, a plant‐based heteropolysaccharide, has recently demonstrated potential as a mucoadhesive in the bowel. Since mucoadhesion is a process likely involving the interpenetration of the polymer with mucin chains, we hypothesized that pectin may also be effective at targeting the glycocalyx of visceral mesothelium. To explore the potential role of pectin as a mesothelial bioadhesive, we studied the interaction of various pectin formulations with the mesothelium of lung, liver and bowel. Peel strength and tensile strength of the bioadhesive‐mesothelial interaction was measured by tensilometry. In both high and low methoxyl pectins, bioadhesion was greatest with an equal weight/% formulation with carboxymethylcellulose. Largely independent of the carboxymethylcellulose concentration, the peel strength and tensile strength of the high methoxyl pectin was nearly 3‐fold greater than comparable adhesion of low methoxyl or amidated low methoxyl pectin (p<0.05). Although tissue‐specific variations were observed in lung, liver and bowel mesothelial adhesion, high methoxyl pectin adhesion was consistently greater than low methoxyl formulations. Consistent with a mechanism of polymer‐glycocalyx interpenetration, the high methoxyl pectin adhesion to tissue mesothelium was reversed with hydration and limited by enzyme treatment (pronase). These data indicate that high methoxyl pectins, in an equal weight/% formulation with carboxymethylcellulose, are a promising mesothelial bioadhesive. Further characterization of apparent tissue differences in the mesothelial glycocalyx offers the potential for selective targeting of lung, liver and bowel mesothelium.Support or Funding InformationNIH T32 HL007734NIH R01 HL94567
Naturally Occurring Oxidant‐Mediated Protein Amino Acid Conversion
Authors: Suzuki Yuichiro J. 
Published: November 2023

Growth factors use reactive oxygen species (ROS) as second messengers. Exact mechanisms of how ROS trigger cell signaling are, however, largely unknown. My laboratory previously demonstrated that protein carbonylation is promoted by ligand/receptor‐mediated cell signaling. Further, ligand/receptor‐mediated protein carbonylation was found to be followed by the reduction of protein carbonyls in a process, which we named ‘decarbonylation’. The discovery of protein decarbonylation suggested that protein carbonylation is reversible. For example, proline residues get oxidized and become glutamyl semialdehyde with a carbonyl group. The present study provides evidence that biological systems contain a mechanism that catalyzes the reduction of glutamyl semialdehyde to proline. Further, since an oxidative product of arginine residues is also glutamyl semialdehyde, protein arginine residues could be converted to proline residues in biological systems. Mass spectrometry analyses supported this hypothesis by showing that two arginine residues (Arg106 and Arg108) of the peroxiredoxin 6‐protein molecule can become proline residues in cultured smooth muscle cells in response to platelet‐derived growth factor. These results reveal that proteins can undergo a naturally occurring oxidant‐mediated protein engineering process, which represents a novel biological mechanism.Support or Funding InformationNIH