bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bypass of 8‐oxo‐G by DNA polymerase lambda
Authors: Hambardjieva Elena , Derkunt Burak , Yakubovskaya Elena , Mejia Edison , Diaz Miguel Garcia 
Published: June 2021

7,8‐dihydro‐8‐oxoguanine (8‐oxo‐G) is a common oxidative DNA lesion. Synthesis across 8‐oxo‐G leads to frequent (10–75%) misincorporation of dA. The OGG1 DNA glycosylase can remove the oxidized base and initiate base excision repair (BER). However, after an 8‐oxo‐G:dA mispair has been formed, OGG1‐initiated BER would consolidate a transversion mutation. The MUTYH glycosylase can eliminate the misincorporated dA instead, allowing a second round of synthesis opposite 8‐oxo‐G. DNA polymerase lambda (polλ) has been implicated in MUTYH‐initiated repair of 8‐oxo‐G:dA mispairs. Pol λ is unique in its preference for the correct incorporation of dC opposite this lesion. Moreover, the polymerase often polymerizes past the first incorporation, initiating long‐patch BER.We have solved crystal structures of polλ in complex with DNA containing site‐specific 8‐oxo‐G residues in order to investigate the mechanisms by which the polymerase preferentially incorporates dC opposite 8‐oxo‐G and discriminates against 8‐oxodG:dA pairs. Our data suggest a possible explanation for the discrimination against 8‐oxo‐G:dA pairs. The Glu529 residue of the thumb subdomain is shifted away from its normal conformation in structures containing 8‐oxo‐G:dA mispairs. This suggests an unfavorable interaction of Glu529 with the C8 of 8‐oxoG when the base adopts a syn conformation.This work was supported by NIH R00 ES015421.
Role of cyclooxygenase (COX)‐1 and COX‐2 in a rabbit model of lipopolysaccharide (LPS)‐induced ocular inflammation
Authors: Waterbury L. David 
Published: June 2021

ObjectiveTo evaluate relative contribution of COX‐1 and COX‐2 to the LPS‐induced ocular inflammation in rabbits.MethodsAt hour 0, 27 rabbits received either artificial tears (Refresh Tears®; Allergan, Inc.; Irvine, CA) (3 drops 20 min apart), COX‐1 inhibitors trans‐resveratrol 0.1% (TR) (3 drops 20 min apart) or FR122047 0.1% (FR) (1 drop), COX‐2 inhibitor nimesulide 0.1% (1 drop), or COX‐1 and COX‐2 inhibitor ketorolac 0.45% (Acuvail®; Allergan, Inc.; Irvine, CA) (3 drops 20 min apart). At hour 1, rabbits received intravenous injections of LPS and fluorescein isothiocyanate (FITC)‐dextran. At hour 2, aqueous samples were collected for analysis. Six additional rabbits received only FITC‐dextran 2 hours before sample collection.ResultsLPS increased aqueous prostaglandin E2 (PGE2) and FITC‐dextran levels by 4.2‐ and 137.8‐fold, respectively. Ketorolac 0.45% and COX‐1 inhibitors (TR and FR) significantly reduced PGE2 elevation (P < .01) while COX‐2 inhibitor (nimesulide) was ineffective. Of all inhibitors, only ketorolac 0.45% significantly inhibited FITC‐dextran elevation (P < .01). Inefficacy of TR and FR in reducing FITC‐dextran leakage may be due to their poor penetration into iris–ciliary body.ConclusionCOX‐1 was the primary isoenzyme responsible for early inflammatory response to LPS. Ketorolac 0.45% suppressed ocular inflammation by inhibiting PGE2 elevation and FITC‐dextran leakage.
Morphometric evaluation of masticator muscles after experimental hyperthyroidism
Authors: Rebelo Diana , Farinha Rodrigo , Loureiro Marco , Cabrita António Silvério 
Published: June 2021

Hyperthyroidism is a clinical condition characterized by excessive production and action of thyroid hormones with various clinical manifestations, one of which being the excessive catabolic reactions in skeletal muscles. This study evaluates the morpho‐histologic effects in masticator muscles of levothyroxine administered by gavage. Ten Wistar male rats were used, randomly distributed in two groups. The control group had no manipulation. The test group had an experimental administration of levothyroxine by gavage 3 times in a week, in a dosage of 250 mg/kg. After two weeks, the animals were sacrificed and fragments from masseter and temporal muscles were collected and analysed in a morphometric program, ImageJ®.At morphometric evaluation, the masseter muscle from the control group had an average area of muscle fibers (A) of 10704±6835 for a 95% confidence interval (CI), while the test group had an A of 13621±5014 for a CI of 95%. The temporal muscle from control group had an A of 7211±2824 for a CI of 95%, while the test group had an A of 21826±12020 for a CI of 95%.According to these results, masseter muscle fibers from test group have a slightly large area when compared to control group. The temporal muscle fibers have an enlarged size when compared to the control group, with statistical significance. It suggests both temporal and masseter muscle involvement in this experimental situation.
ACETAMINOPHEN CONSUMPTION ALTERS ACHILLES TENDON COLLAGEN CONTENT IN WISTAR RATS
Authors: Whitt Jamie A , Tedeschi Jamie , McMullan David R , Del Mundo Jonathan D , Broderick Tom L , Carroll Chad C 
Published: June 2021

The purpose of this study was to evaluate the influence of acetaminophen (APAP) on collagen content in rat Achilles tendon. Ten‐week‐old male Wistar rats were given saline (SAL, n=8) or APAP (n=10; 200 mg·kg−1) once daily via oral gavage for 8 weeks. Tendon collagen content was determined by detection of the collagen specific amino acid hydroxyproline using HPLC. Following treatment, tendons, mm. gastrocnemius and soleus, fat pad, heart, liver, and femur and tibia bones were harvested. Tendon collagen content was greater (p<0.05) in the rats given APAP (SAL: 510.5±42.3; APAP: 663.4±38.0 μg collagen·mg tendon wet weight). Fat pad weight was greater (p<0.05) in the APAP group (SAL: 11.02±1.87; APAP: 15.83±1.36 g). Both femur and tibia weight [femur: (SAL: 867±19; APAP: 936±23 mg, tibia: (SAL: 644±22, APAP: 718±16 mg)] were greater (p<0.05) in the rats consuming APAP. M. soleus (SAL: 203±11; APAP: 240±9 mg) but not m. gastrocnemius (SAL: 2.73±0.05; APAP: 2.76±0.12 g) weight was greater (p<0.05) in the rats given APAP, whereas heart and liver weight was not different between groups. APAP appears to promote collagen deposition in tendon and has growth promoting affects on bone and skeletal muscle, however, the affect on skeletal muscle appears to be specific to the type I soleus muscle. The specific mechanisms of these effects require further study.MWU College of Health Sciences and MWU Office of Research and Sponsored Programs
Acute Caloric Restriction is Cardioprotective in Adult Rats
Authors: Snorek Michal , Neckar Jan , Wilhelm Jiri , Skoumalova Alice , Hodyc Daniel , Sedivy Vojtech , Tousek Frantisek , Kolar Frantisek , Herget Jan 
Published: June 2021

Reduced coronary perfusion in acute coronary syndrome causes myocardial ischemia. Also the effect of reactive oxygen species (ROS) induced ischemia‐reperfusion injury contributes to myocardial lesion. ROS generation in hypoxia is modulated by the redox state. Fasting before exposure to ischemia should increase ketogenesis that consumes reduced coenzymes and consequently reduces free radical damage.We investigated whether the 3‐day fasting affects production of ROS, incidence of ventricular arrhythmias during ischemia/reperfusion and myocardial infarction size.We analyzed production of the lipid peroxidation end products (LFP) in the heart tissue. Open‐chest rats were subjected to 20‐min LAD coronary artery occlusion followed by reperfusion. A single‐lead ECG was recorded and arrhythmias were assessed. The infarction size in excised hearts was determined by triphenyltetrazolium chloride staining and it was normalized to area at risk (IS/AR).Three day fasting reduced LFP production in heart tissue. During early reperfusion the number of premature ventricular complexes was reduced in fasting rats compared to controls, as well as ventricular tachycardia duration. In fasting rats the IS/AR reached 48.5 ± 3.3 % while in controls it was 74.3 ± 2.2 %, p<0.005.Acute caloric restriction limits free radical damage in heart, reperfusion ventricular arrhythmias and myocardial infarction size in rats.Supported by GAUK 60009/2009 and MSMT 1M 0510.
Increased NO‐dependent dilation of rat arterioles in diet‐induced obesity
Authors: Howitt Lauren , Grayson T Hilton , Morris Margaret J , Murphy Timothy V 
Published: June 2021

Obesity is a risk factor for hypertension. The large‐conductance Ca2+‐activated potassium channel (BKCa) plays a central role in the regulation of vascular tone. The aim of this study was to examine the effect of diet‐induced obesity on endothelium‐ and BKCa‐dependent dilation of rat cremaster muscle arterioles. Male Sprague‐Dawley rats (213 ± 1g) were fed a high fat or control diet for 16 weeks. Isolated, pressurized (70 mmHg) arterioles were studied. Control rats weighed 570 ± 7 g compared with obese rats 768 ± 13 g (n = 35 – 37, P < 0.05). Obesity had no effect on acetylcholine (ACh; 0.001 – 3 μM)‐induced dilation. ACh‐induced dilation of arterioles from control rats was abolished by a combination of the SKCa, IKCa, and BKCa blockers apamin, TRAM‐34 and iberiotoxin (IBTX, 0.1 μM) respectively, with no apparent role for NO. In arterioles from obese rats however, IBTX had no effect on responses to ACh while the NO/GC inhibitors L‐NAME (100 μM)/ODQ (10 μM) partially inhibited ACh‐induced dilation. Removal of the endothelium constricted arterioles from obese, but not control rats. Expression of eNOS was not altered by obesity, but expression of high molecular‐weight complexes of caveolin‐1 and ‐2 was increased. In summary, diet‐induced obesity abolished the contribution of BKCa to ACh‐mediated endothelium‐dependent dilation of rat cremaster muscle arterioles, while inducing an NO‐component.Support: NHMRC 455243.
Impaired cardiac functional reserve in type 2 diabetic db/db mice is associated with metabolic, but not structural, remodeling
Authors: Daniels Anneleen , van Bilsen Marc , Janssen Ben , Brouns Agnieszka , Cleutjens Jack , Roemen Theo , Schaart Gert , van der Velden Jolanda , van der Vusse Ger , van Nieuwenhoven Frans 
Published: June 2021

To identify the nature of myocardial alterations associated with diabetes, cardiac function, structural remodeling, and gene expression in hearts of type 2 diabetic db/db mice were studied.Db/db mice showed typical characteristics of type 2 diabetes and preserved cardiac function up to 18 wks of age under non‐challenging conditions. However, β‐adrenergic stimulation with dobutamine revealed impaired contractile and relaxation reserve capacity. Tissue analyses showed no signs of structural remodeling. Neither β1‐adrenoceptor (β1AR) expression nor phosphorylation state of contractile protein targets of β1AR – protein kinase A (PKA) signaling were altered. In contrast, the substantially increased expression of uncoupling protein‐3 (UCP3) and angiopoietin‐like‐4 (Angptl4), along with decreased phosphorylation of AMP‐activated protein‐kinase (AMPK) in the heart of diabetic animals, are indicative of altered mitochondrial efficiency, decline in plasma triacylglycerol consumption and changes in intermediary substrate metabolism, respectively, which together may compromise ATP synthesis, required for maintenance of cardiac function at increased work load.We conclude that impaired cardiac functional reserve capacity during maximal β‐adrenergic stimulation, is an early sign of cardiac dysfunction in db/db mice which is primarily associated with unfavorable changes in cardiac metabolism.
Low dose chronically infused hemoglobin induces pulmonary hypertension or excerbates hypoxia‐induced pulmonary hypertension
Authors: Irwin David , Foreman Ben , Connor Ian , Lisk Christina , Buehler Paul 
Published: June 2021

Observations from examining past medical records from patients with sickle cell anemia or thalassemia suggest these diseases may be a risk factor for the development of severe pulmonary hypertension (PH). Recently it has been proposed that the chronic exposure to cell free hemoglobin is a major contributor to the development of PH in these patients. Therefore, we hypothesized that chronic infusion (3 and 6 wk) of cell free hemoglobin in rats would either induced or exacerbate PH in rats exposed to room air or hypoxia.MethodsMale, age matched (8–10 wk) Sprague dawley rats were treated with chronically infused free hemoglobin (500 ug/hr) or left untreated and either exposed to chronic hypoxia (18,000 ft; PB ~ 379 mm Hg;) or remained in normoxic conditions (5,280 ft; PB ~ 620 mm Hg). After wards, cardiac output (CO), mean pulmonary artery (Pa) and systemic pressures (MAP) and hemotocrit (Hct) were recorded, and RV/LV+S ratio was determined and lungs were examed as indication of the severity of PH.ResultsOverall, hemoglobin (Hb) infusion increased Pa pressures and lowered Hct compared to untreated cohorts. In the normoxic Hb infused animals MAP and Pa pressures increased between 3 and 6 weeks. Compared to hypoxic control rats, Pa pressures were greater at 3 and 6 wks, whereas MAP was greater only at 3 wk in Hb infused animals.ConclusionChronic infusion of CFH can induce or exacerbate hypoxic‐induced PH. However, whether CFH exerts this effect by oxidative damage, inflammation or NO scavenging is unknown.
Configurator Based Integrated Dynamic Simulation of Reverse Cholesterol Transport (RCT)
Authors: Adhikari Sam 
Published: June 2021

Major constituents of RCT include acceptors such as high density lipo‐protien (HDL) and apoliproprotein A‐1 (ApoA‐1), and enzymes such as lechtin:cholesterol acyltransferase (LCAT), Phospholipid transfer protein (PLTP), hepatic lipase (HL), and cholesterol ester transfer protein (CETP).Realistic quantitative modeling of RCT is extremely difficult through conventional methods. It requires a software configurator aided, database driven systems biology platform.Our RCT quantitative model based dynamic, integrated simulation uses many complex models including kinetics to evaluate cholesterol efflux from the macrophages to ApoA‐1 via ABCA1 and ABCG1. The model is enhanced by the quantitative RCT effects of Caveolin, Sterol 27‐hydroxylase (CYP27A1), scavenger receptor SR‐B1 transport processes, and ABCG5/G8 hepatobiliary and intestinal sterol extraction gene.The net RCT pathway is quantified with multiple parameters that can change depending on clinical in‐vivo or in‐vitro conditions. A standard relational database model holds all the objects of the quantitative simulation model. An optimization algorithm matches the aggregate model with the clinical RCT datasets. It automatically adjusts all the parameters till it can find the best solution.
Comparison of Human Adipose Derived Stem Cells with Human Bone Marrow Stem Cells in Myocardial Regenerative Therapy
Authors: Srivastava Sapna , Duong Minh , Chiu Ray , Shum‐Tim Dominique 
Published: June 2021

BackgroundCell therapy using Human Bone Marrow Stem Cells (HBMSCs) has been shown to improve heart function after a myocardial infarction. The harvesting technique involved with bone marrow stem cells is invasive and yields a low cell number. There is now an increasing interest in Human Adipose Derived Stem Cells (HADSCs) as they are abundant and readily accessible from liposuction material. The present study was undertaken to investigate if HADSCs are superior than HBMSCs in myocardial regenerative therapy.ResultsBoth HADSCs and HBMSCs proliferated in a time dependent manner, however, the proliferative ability of HADSC was greater than the HBMSCs. In addition, both cells differentiated to the osteoblast lineage confirming their multipotency, when treated with induction medium. Furthermore, treatment of both cells with 5‐AC resulted in positive immunostaining of cardiac markers, troponinI and connexin 43, however the expression of these markers was enhanced in HADSCs. This was further confirmed by western blot analysis, however 5‐AC treatment did not exhibit cell contraction or multinucleation.ConclusionThe data suggest that HADSCs may prove to be a more ideal type of cell for regenerative therapy in the future.
Determining the dose‐dependent effects of long‐chain soluble polymers in rat spinotrapezius muscle
Authors: Connery Michael , Kameneva Marina V , Pittman Roland N 
Published: June 2021

Long‐chain soluble polymers (LSPs) have been shown to have profound hemodynamic effects at very low concentrations. At only 5 ppm in blood, LSPs increase blood flow and reduce vascular resistance. Despite studies showing therapeutic value in cases of hemorrhage, myocardial infarction, and atherosclerosis, the mechanism of action is unknown. The purpose of this study was to determine the dose‐dependency of LSPs on systemic and microcirculatory variables. Sprague‐Dawley rats were anesthetized and their spinotrapezius muscles isolated for transillumination. The experimental group (n=2) was given serial injections of the LSP polyethylene oxide (mol wt 4500 kDa) dissolved in saline to reach blood concentrations of 0.12, 0.4, 1.2 and 4 ppm. The control group (n=8) was given serial injections of the same volumes of saline. At 4 ppm, mean arterial pressure was lower in the LSP group (90 ± 2 mmHg vs 108 ± 17 mmHg). Interstitial PO2, as measured by phosphorescence quenching, was higher in the LSP group at 0.12 ppm (67 ± 3 mmHg vs 60 ± 4 mmHg) and 0.4 ppm (66 ± 2 mmHg vs 60 ± 4 mmHg). These findings are consistent with previous reports of this polymer.Support: NHLBI HL18292 and HL079087
Role of caveolin‐1 in angiotensin II‐induced hypertrophy and remodeling of cerebral arterioles
Authors: Houwen Frederick Keith , Chan Siu Lung , Baumbach Gary L 
Published: June 2021

We examined effects of caveolin‐1 deficiency on structural alternations induced in cerebral arterioles by angiotensin II (Ang II). Caveolin‐1 deficient (Cav1−/−) and wild‐type (WT) mice were infused with either Ang II (1000 ng/kg/day) or saline via osmotic minipumps. After 4‐weeks of infusion, pressure and diameter were measured in cerebral arterioles before and during maximal dilatation (EDTA) through an open cranial window under anesthetized conditions. Cross‐sectional area of the vessel wall was measured histologically. Chronic infusion of Ang II increased cerebral arteriolar mean pressure in both WT (50±1 vs 39±1 mmHg in saline infused, P<0.05) and Cav1−/− mice (52±2 vs 34±1 mmHg, P<0.05). Ang II reduced external diameter (ED) and increased cross‐sectional area of the vessel wall (CSA) in WT mice (ED = 57±2 vs 63±2 μm; CSA = 411±38 vs 300±20 μm2; P<0.05), but not in Cav1−/− mice (ED = 64±2 vs 64±2 μm; CSA = 331±24 vs 305±16 μm2). These findings suggest that caveolin‐1 may play an important role in Ang II‐induced inward remodeling and hypertrophy of cerebral arterioles.This work was supported by an award from the American Heart Association.
Mitochondrial subpopulation‐specific proteomic alterations in the type 2 diabetic heart
Authors: Croston Tara Lyne , Dabkowski Erinne R , Williamson Courtney L , Baseler Walter A , Hollander John M 
Published: June 2021

Diabetic cardiomyopathy is the leading cause of mortality in patients who suffer from diabetes mellitus (DM). Mitochondria dysfunction contributes to the cardiac complications associated with type 2 DM. Cardiomyocytes contain two spatially distinct mitochondrial subpopulations, interfibrillar mitochondria (IFM) and subsarcolemmal mitochondria (SSM). The goal of this study was to determine whether the proteomic profiles of the two cardiac mitochondrial subpopulations were influenced differently by type 2 diabetic insult. Db/db mice and WT controls were sacrificed at 18 weeks of age and cardiac mitochondrial subpopulations were isolated. Proteomic analysis revealed a decrease in proteins involved in the electron transport chain (ETC) complexes in the SSM. Specifically, ubiquinol cytochrome c reductase core protein 2 (complex III) and cytochrome c oxidase subunit VIIa1 (complex IV) were downregulated in db/db SSM. Further, peroxiredoxin V (PRDX5), an antioxidant, and adenine nucleotide transporter 1 (ANT1), an inner mitochondrial membrane transport protein, were also significantly decreased only in db/db SSM. These results suggest that the SSM are at greater risk for protein loss as a result of type 2 DM, which may contribute to the pathogenesis of diabetic cardiomyopathy.(Supported by NIH DP2 DK083095, AHA0815406D, AHA0855484D)
Increased contractile responses in corpora cavernosa of heart failure rats
Authors: Carneiro Fernando S , Biancardi Vinicia C , Carneiro Zidonia N , Stern Javier E , Webb R Clinton , Tostes Rita C 
Published: June 2021

IntroductionHeart failure (HF) is a risk factor for erectile dysfunction (ED). HF patients experience a decreased libido, frequency of coitus and sexual performance. The mechanisms underlying the association of HF and ED are unknown. We hypothesize that HF increases cavernosal reactivity.Methods and ResultsHF was induced, in Wistar male rats (8 week‐old), by left coronary artery ligation for 6 weeks. Ejection fraction (Sham: 85.5±3.3 vs HF: 33.9±3.0, %) and fractional shortening (Sham: 63.9±3.8 vs HF: 17.3±1.7, %) were measured to confirm the presence of HF. HF rats displayed increased cavernosal contractile responses to KCl (Sham: 0.55±0.07 vs HF: 0.82±0.06, mN/mg) and phenylephrine in the absence (Sham: 0.71±0.05 vs HF: 0.97±0.05, mN/mg) or in the presence of L‐NAME (Sham: 0.70±0.05 vs HF: 1.14±0.06, mN/mg). Sympathetic‐mediated contractile responses were increased in cavernosal strips of HF rats in the absence (Sham: 0.55±0.09 vs HF: 1.03±0.08, mN/mg) and in the presence of L‐NAME (Sham: 0.67±0.1 vs HF: 1.33±0.1, mN/mg). HF rats displayed increased cavernosal relaxation to sodium nitroprusside (Sham: 57.8±3.4 vs HF: 76.5±5.7, % of relaxation), but no changes were observed in nonadrenergic‐noncholinergic‐ (NANC)‐induced relaxation.ConclusionOur results suggest that increased contractility of the cavernosal tissue in HF rats may represent the mechanism of ED associated with HF.
Effect Of PPADS On Mesenteric Arterial And Portal Venous Flow Responses To Splanchnic Nerve Stimulation
Authors: Martin Doug , Kjellsen Barton 
Published: June 2021

Our previous work suggested that splanchnic nerve stimulation may exert differential effects on mesenteric arterial and portal venous hemodynamics. This study tested the hypothesis that ATP contributes to the differences in mesenteric arterial and portal venous responses to splanchnic nerve stimulation.Spontaneously hypertensive rats (SHR) were anesthetized with urethane/chloralose and fitted with catheters to record arterial pressure. The rats were also instrumented for splanchnic nerve stimulation and for mesenteric arterial and portal venous blood flow recording. Frequency response curves (1–15 Hz) were constructed before and after treatment with pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate (PPADS; 20 mg/kg), an ATP P2X receptor antagonist.Splanchnic nerve stimulation caused frequency dependent decreases in mesenteric arterial and portal venous blood flow. Treatment with PPADS caused a rightward displacement of the frequency response curves for both mesenteric arterial flow and portal venous flow. The magnitude of this displacement was less than that observed following omega conotoxin treatment.Collectively, these data suggest that ATP contributes to both mesenteric arterial and portal venous responses to splanchnic nerve stimulation. Supported by NIH #2RO1HL63053‐ARRA (DM) and USD SSOM bridge funds.