bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Anticoagulant Effects of Suledoxide and Enoxaparin in Citrated Whole Blood
Authors: Adiguzel Cafer , Iqbal Omer , Hoppensteadt Debra , Cunanan Josephine , Fareed Jawed 
Published: June 2021

Suledoxide represent a novel antithrombotic agent with multiple sides of actions on blood coagulation process. This drug has been used widely in various vascular indications. Suledoxide has been recently shown to produce therapeutic effects in diabetic nephropathy. Unlike LMWH, this agent can also be used orally. The purpose of this study was to compare the anticoagulant effects of Suledoxide with a LMWH Enoxaparin which is use mainly via subcutaneous route. Suledoxide represent of mixture of fast mobilizing heparin 80% and 20% Dermatan Sulfate. Within average molecular weight of 20.8 kDa. Suledoxide may be effective in subcutaneous indications. In order to investigate the anticoagulant effect of Suledoxide this agent was supplemented to citrated whole blood at concentration of 0–25 ug/ml such blood test ha PT, aPTT, Heptest, and Thrombin time were measured. This agent was compared Enoxaparin at equigravimetric concentrations.In comparison to Enoxaparin and Suledoxide produced a stronger anticoagulant effect in the PT assay. Similarly Suledoxide produce a much stronger anticoagulant effect in the aPTT assay. In the Heptest assay, Suledoxide produced anticoagulant effects. Thrombin Time results is also much stronger with Suledoxide in comparison to Enoxaparin.These results highly suggest that Suledoxide is a relatively stronger anticoagulant than Enoxaparin. Suledoxide may also exhibit subcutaneous bioavailability. These results warrant further investigation on Suledoxide in Pharmacologic studies.
Methods for investigating integrin‐matrix interactions as a function of matrix mechanics and composition
Authors: Sazonova Olga , Nugent Matthew A , Wong Joyce Y 
Published: June 2021

To investigate the role of mechanics in cell signaling, we have engineered polyacrylamide (PAAM) gels with precisely tunable stiffness and fibronectin (FN) content. Varying the acrylamide / bis ratio alters PAAM stiffness, as determined with tensile testing and atomic force microscopy (AFM). To promote cell attachment, FN is covalently linked throughout the gel, and can then be quantified with an ELISA. Analyzing AFM data with the Hertz and Oliver‐Pharr models, we calculated gel elastic moduli ranging from 11 – 344 kPa and 7.5 – 95 kPa. We also found that stiffer gels incorporate more FN than softer gels, and that adding FN reduces the modulus of softer gels by ~10%. Controlling for these factors allowed for precise and independent changes in gel mechanics and FN content.To study integrin‐FN interactions on PAAM gels, we adapted published methods for quantifying integrin binding. After vascular smooth muscle cells (VSMCs) were grown on gels or FN‐coated plastic, bound FN‐alpha5 integrin units were cross‐linked and assayed with an ELISA. Preliminary data suggest that integrin activity per cell is reduced with decreasing stiffness or higher cell density. Future studies using the methods presented herein will provide insight into how VSMCs recognize and respond to changes in ECM composition and stiffness, aiding the rational design of new treatment for vascular disease. Supported by NIH grants HL56200 and HL72900.
Automated quantification of fibrosis in myocardium
Authors: Mouchaers Koen Thijs Bert , Hadi Awal M. , van der Laarse Willem J. , Jaspers Richard T. , Vonk‐Noordegraaf Anton , Belien Jeroen A. M. 
Published: June 2021

BackgroundFibrosis can affect many organs and is associated with a variety of pathologies. Current quantification methods are time consuming. We developed a new automated quantification technique for fibrosis in myocardium, and validated this in a rat model for Pulmonary Hypertension (PH).MethodsPH was induced in Wistar rats by monocrotaline (40 mg/kg). Cryosections of myocardial tissue (5 μm) of PH rats (n=8) and controls (n=5) were stained using Picrosirius red and scanned with a MIRAX slide scanner (Zeiss). From these sections 21 images were taken randomly of each heart. We developed a macro for ImageJ, to automatically determine the amount of fibrosis. As comparison, fibrosis was determined in the same areas using polarisation filters. Stereology served as golden standard to validate both methods.ResultsFibrosis significantly increased in PH hearts vs. control (0.97±0.14 vs 3.30±0.42 % of total area, p=0.0002). Polarisation quantification confirmed this increase (1.14±0.09 vs 3.06±0.16%, p<0.0001). Both automated and polarisation analysis correlated linearly with stereology (p<0.0001, r2=0.77; p<0.0001, r2=0.69, respectively). A non‐linear relation between automated analysis and polarisation was found (rs=0.76), were polarisation has less discriminative power at higher percentage fibrosis.ConclusionAutomated quantification of fibrosis is feasible, objective, and time‐efficient.
Gender and estrogen specificity of the renal vasodilatory effect of nicotine in rats
Authors: El‐Mas Mahmoud M , El‐gowilly Sahar M , Goher Eman Y , Ghazal Abdel‐Rheem M 
Published: June 2021

This study investigated whether the renal vasodilatory response to acute nicotine exposure is sexually dimorphic and the role of estrogen in modulating the nicotine effect. Nicotine vasodilation was evaluated in phenylephrine‐preconstricted perfused kidneys of male, proestrus female, ovariectomized (OVX) and estrogen‐replaced OVX (OVXE2) rats. Nicotine infusion (5×10−4 M) produced significantly greater decreases in the renal perfusion pressure (RPP) in proestrus female compared with male kidneys. Inhibition of NOS by NG‐nitro‐L‐arginine abolished nicotine vasodilation in the two genders and brought the RPP of male and female kidneys to similar levels. Surgical (OVX) or physiological (diestrus phase) estrogen depletion almost abolished nicotine vasodilation. Further, estrogen or L‐arginine supplementation of OVX rats largely restored the renal vasodilatory response to nicotine. Blockade of estrogen receptors by tamoxifen attenuated the increase in nicotine vasodilation demonstrated in OVXE2 rats. Together, these findings suggest that the renal vasodilator activity of nicotine is entirely dependent on NOS activation and is more pronounced in female than in male kidneys. Also, estrogen mediates, at least partly, the renal vasodilatory effect of nicotine probably via facilitation of NOS‐NO signaling.Supported by Faculty of Pharmacy, Univ. of Alexandria, Egypt.
Ischemia Reperfusion‐Induced microRNAs are Blunted by Ischemic Preconditioning
Authors: Tsutsumi Yasuo M , Panneerselvam Mathivadhani , Roth David M , Patel Hemal H 
Published: June 2021

Introduction: MicroRNAs (miRNAs) are endogenously expressed, noncoding, small RNA molecules that regulate protein synthesis via degradation of mRNA or inhibition of translation to modulate cellular physiology. Little is known regarding the expression of miRNAs in the heart in response to ischemia/reperfusion (I/R) injury and how this expression is impacted by an ischemic preconditioning (IPC) stimulus. We hypothesized that a distinct expression of miRNA characterizes cardiac injury in response to I/R and IPC is able to normalize this expression towards basal. Methods: miRNA was isolated from hearts of four groups of C57BL/6 mice (n=4 mice/group): control; 30 min ischemia/24 hr reperfusion; 3–5 IPC‐30minischemia/24 hr reperfusion; 3–5 IPC 24 hr reperfusion. The miRNA was hybridized to the NCode miRNA microarray (Invitrogen) and expression analysis performed. miRNA were ranked in order of most highly induced in MI relative to control. Results: Analysis of miRNA expression showed an induction (>50‐fold) of 33 distinct miRNA in hearts exposed to I/R injury relative to control hearts. An IPC stimulus prior to ischemia/reperfusion resulted in a blunted expression (>40%) of 14 of the miRNA induced by I/R alone. IPC prior to I/R resulted in the induction of 14 miRNAs, 50 % of which were not induced in the I/R injury alone group.Conclusion: The results suggest that miRNAs are involved in ischemia/reperfusion injury and IPC limits deleterious miRNA expression. Targeted suppression of miRNAs induced by ischemia/reperfusion injury may represent a novel therapeutic target to mimic IPC.
Herb‐drug interaction involving oseltamivir and Chinese medicine formula
Authors: Chow Moses Sing Sum , Chang Qi , Zuo Joan 
Published: June 2021

Aim: The empiric use of certain Chinese medicine formula (CMF) in combination with oseltamivir (O) is advocated for the treatment of deadly avian influenza in Asia. This study aimed to determine the interaction potential of such combination.Method: Two groups of rats received either O alone or O+CMF (Yin Qiao San/Sang Ju Yin) at equivalent human doses for 5 days. CMF was given 2 h post O dose. Following the last dose, urine as well as plasma O and its active metabolite (M) concentrations were determined, after adding dichlorvos to prevent hydrolysis of O. All drug concentrations were determined by a validated LC/MS/MS method.Result: The Cmax and area under the concentration time curve of M were significantly reduced in the combination compared to O alone group (1.3±0.2 vs 1.8±0.3 ug/ml and 326±30 vs 452±101 ug.min/ml respectively, P <0.05). The M/ O ratios were 1.96±0.25 vs 2.92± 0.69 respectively (P<0.05). A trend of greater renal clearance of M in the combination group (7.60 vs 6.24 ml/min) was also observed.Conclusion: Our results indicate that CMF can potentially cause a significant reduction of the active M concentration, most likely due to suppression of O metabolism as well as possibly enhanced M renal clearance. Pharmacokinetic interactions from herb‐drug combinations could potentially involve multiple mechanisms and should be carefully studied before their empiric use. (Funded by Hospital Authority of Hong Kong).
Macrophage‐specific LITAF (lipopolysaccharide induced TNF‐alpha factor) knockout mice (LITAF mac −/−) have a reduced inflammatory response to colonic administration of trinitrobenzene sulfonic acid (TNBS)
Authors: Bushell Kristen Nicole , Leeman Susan E , Amar Salomon , Reed Karen L , Gower Adam C , Stucchi Arthur F , Becker James M 
Published: June 2021

Dysregulation of TNF‐α secretion by lamina propria macrophages (LPM) is a hallmark of the inflammatory bowel disease Crohn's Disease (CD). LITAF has been shown to regulate TNF expression in macrophages and macrophage‐specific LITAF mac −/− mice (KO) are resistant to LPS induced sepsis. LITAF protein is increased by 30% in LPM isolated from C57BL/6 mice (WT) after TNBS administration, a well established model of CD (p<0.05). The aim of this study was to compare the colonic inflammatory responses of WT mice to LITAF mac−/− mice after administration of TNBS.Methods: WT and KO mice were administered TNBS (3 mg in 50% EtOH) rectally. After 24 hrs, body weights (BW) were determined and levels of the inflammatory marker myeloperoxidase (MPO) and TNF‐α mRNA were measured in colon tissue.Results: TNBS administration reduces BW in all animals compared to untreated controls (p<0.05); however, KO mice lost 50% less BW than the WT mice (p<0.05). MPO activity is five fold lower in KO mice compared to WT (p<0.05). Tissue levels of TNF‐α mRNA is also reduced in the KO compared to WT animals (376 ± 156 vs. 843± 253 copies) after TNBS administration.Conclusions:LITAF mac −/− have an attenuated inflammatory response to colonic TNBS administration. These results highlight a potential value of anti‐LITAF strategies for therapeutic management of CD. Research Support: BMC departments of Surgery and Pharmacology and NIDCR R01 DE014079.
AMPK ‐ the fuel gauge of the eukaryotic cell
Authors: Hardie David Grahame 
Published: June 2021

The AMP‐activated protein kinase (AMPK) is expressed in essentially all eukaryotic cells and acts as a sensor of cellular energy status. It is a heterotrimer comprised of catalytic alpha subunits and regulatory beta and gamma subunits, and is only active after phosphorylation at Thr‐172 within the kinase domain by upstream kinases. AMPK is activated whenever a metabolic stress causes a decrease in the cellular ATP:ADP ratio: because of the adenylate kinase reaction, this is always accompanied by a much larger increase in the AMP:ATP ratio. Binding of AMP to the gamma subunit of AMPK causes two effects that are antagonized by ATP: (i) it inhibits dephosphorylation of Thr‐172, causing a sensitive switch to the active, phosphorylated form; (ii) it allosterically activates the phosphorylated kinase. The major upstream kinase in most cells is the tumor suppressor LKB1. Since AMPK can cause an arrest of cell growth and the cell cycle, activation of AMPK may explain why LKB1 is a tumor suppressor, although LKB1 also acts upstream of a family of twelve AMPK‐related kinases. In some cell types (e.g. neurones, endothelial cells and T cells), AMPK is also activated by increases in cell calcium, which trigger phosphorylation of Thr‐172 by CaMKK‐beta.The beta subunit of AMPK in all eukaryotes contains a carbohydrate‐binding module (CBM) that in mammalian cells causes AMPK to associate with glycogen. Recent work from our laboratory suggests that the CBM is a regulatory domain that inhibits AMPK when the reserves of energy in the form of glycogen are high.
RhoA mediates cardiomyocyte survival through FAK‐dependent Akt activation
Authors: Re Dominic Del , Brown Joan Heller 
Published: June 2021

The small G‐protein RhoA is a transducer of signals from both GPCRs and the extracellular matrix, influencing cell morphology as well as gene expression. A role for RhoA in cultured cardiomyocyte hypertrophy has been established, however the possibility that RhoA can influence myocyte survival has not been examined. We find that adenoviral expression of activated RhoA protects neonatal rat cardiomyocytes from apoptotic insults induced by peroxide or glucose deprivation. Interestingly, expression of RhoA induces PI3K‐dependent activation of the cardioprotective kinase Akt. It has been reported that RhoA mediates FAK activation and that FAK can directly interact with the p85 regulatory subunit of PI3K. Accordingly, we examined the possible role of FAK in RhoA signaling to Akt. RhoA expression increased FAK phosphorylation and focal adhesion formation in cardiomyocytes in a Rho kinase‐dependent manner. Further, RhoA‐induced Akt activation is prevented by co‐expression of FRNK, a negative regulator of FAK, suggesting that FAK is not only activated but mediates this response. Expression of FRNK also blocked the protective effect afforded by RhoA further implicating FAK in this signaling pathway. The finding that RhoA activation protects cardiomyocytes through FAK‐dependent Akt activation suggests that activation of similar pathways by mechanical stretch could regulate cardiomyocyte survival.NHLBI R01 HL‐28143
Wave intensity analysis of coronary pressure and velocity for studying coronary‐ventricular interactions
Authors: Siebes Maria , Kolyva Christina , Verhoeff Bart‐Jan , van den Wijngaard Jeroen P.H.M. , Piek Jan J. , Spaan Jos A.E. 
Published: June 2021

Coronary wave intensity (WI) represents the energy carried by traveling waves that are generated by cardiac contraction and relaxation.Distal coronary pressure (Pd) and Doppler velocity (v) were measured in 26 patients at rest and during adenosine‐induced hyperemia before and after revascularization by stent placement. WI was calculated as (dPd/dt) x (dv/dt) and separated into forward (FW) and backward (BW) components during the cardiac cycle.We found a consistent pattern of BW and FW compression waves during ventricular contraction followed by FW and BW expansion waves in the early ventricular relaxation phase. Individual energies of expansion and compression waves traveling in the same direction were strongly correlated (P< 0.001). The size of BW compression and expansion waves was similar, while FW compression waves were in all cases larger than FW expansion waves (P<0.01). The energy of BW waves at rest was strongly correlated with that during hyperemia (P<0.001). An increase in BW wave energy after stent placement was strongly related to an increase in coronary microvascular conductance (P<0.001).Our results are consistent with the intramyocardial pump model (BW waves), higher wall stiffness at the end of systole (difference in FW waves) and similar redistribution of vascular resistance at vasodilation (rest vs hyperemia) despite different vascular anatomy.(Support: NHF grants 2000.090 and 2006B186)
Nitric oxide‐dependent regulation of coronary vascular resistance in hypertension
Authors: Levy Andrew Shawn , Rush James W.E. 
Published: June 2021

Hypertension is associated with impaired endothelium dependent relaxations in many vascular beds. Evidence from the coronary vasculature offers conflicting results. The current investigation examined the role of NO in regulating coronary vascular resistance (CVR) in spontaneously hypertensive rats (SHR) and their normotensive counterparts (WKY). Rats were anesthetized, the hearts were removed and the aorta was cannulated to allow for retrograde coronary perfusion using a constant flow Langendorff set‐up. Flow was assigned based on heart weight which was estimated from body weight. SHR had a greater baseline CVR than the WKY (6.72±0.34 vs 4.97±0.62 mmHg/ml/min, p<0.05). Following ET‐1 administration SHR had a greater resistance (9.82±0.75 vs 6.87±0.96 mmHg/ml/min, p<0.05) although the absolute change was not different. There were no differences in maximal reduction in CVR to bradykinin (BK) or sensitivity to BK. Treatment with LNAME caused an increase in resistance in both groups although the change in resistance was not different between the SHR and WKY (3.46±0.41 vs 3.02±0.69 p>0.05). LNAME completely abolished the BK induced reduction in CVR in both the SHR and WKY; the response to sodium nitroprusside was unchanged. Thus, the response to BK is NO dependent in both SHR and WKY. The CVR is elevated in the SHR and inhibition of eNOS increases CVR to a similar extent in both strains.Funded by NSERC & HSFO
CHEMICAL MICRO‐SENSORS FOR BIOMEDICAL RESEARCH
Authors: TAHA ZIAD HUSSEIN 
Published: June 2021

The design, performance and applications of chemical micro‐sensors for biomedical research are described.Nitric oxide (NO) sensors have been built to enable the users to measure NO in a wide range of biological and non‐biological samples. The sensors incorporate the sensing elements behind a gas permeable membrane to assure the selectivity of measurements in addition to isolating these elements from any ionic changes in the sample resulting in a stable measurements. Many sensors were built to fit many applications. The sensors are capable of measuring NO at the nanomolar levels with fast response time and wide linearity. The sensors have been used to measure NO in live animals, brain slices, cell culture, tissue samples, and many others. The sensors can indirectly measure nitrite at the nano‐molar level.A hydrogen sulfide sensor was designed to selectively detect hydrogen sulfide in biological samples. Sensors with tip diamater size of 200–500 micron were prepared. Other sensors include pH, oxygen and carbon monoxide were designed.
Transcriptional Regulation of GI Smooth Muscle in Normal and Diabetic Mice
Authors: Touw Ketrija , Zhou Jiliang , Herring Paul Brian 
Published: June 2021

Secondary effects of diabetes can lead to gastroparesis and GI motility dysfunction. Recent studies suggest altered smooth muscle (SM) as well neuronal regulation in these diseases. Consistent with these studies, we found altered expression of smooth muscle contractile proteins in the gut of ob/ob diabetic mice. Utilizing the telokin promoter as a model system, we are elucidating the mechanisms regulating expression of contractile proteins in the gut under normal or diabetic conditions. Telokin is a smooth muscle‐specific protein that is highly expressed in GI SM. Analysis of hprt‐targeted telokin promoter ?‐galactosidase transgenes in vivo, identified a 370bp promoter that is able to mimic expression of endogenous telokin. Within this promoter, a 100bp region is specifically required for telokin expression in GI SM. Analysis of this region revealed evolutionarily conserved binding sites of Sox and SMAD transcription factors. qRT‐PCR analysis demonstrated that Sox4, 5, 6, 7, 12 and 13 are the most abundant Sox proteins in GI SM. Knockdown of Sox7 by siRNA, in GI SM cells, attenuated telokin expression, while knockdown of Sox4, 6 or 12 had no effect. Transduction of GI SMC with dominant negative SMAD4 also attenuated telokin expression. Together these data suggest Sox7 and SMAD proteins are important for regulating expression of contractile proteins in GI SM.Supported by NIH DK 061130, NIH DK 064466‐05
Growth Hormone supplementation up‐regulates collagen expression in human muscle and tendon
Authors: Doessing Simon , Heinemeier Katja , Holm Lars , Reitelseder Soeren , Koskinen Satu , Schjerling Peter , Kjaer Michael 
Published: June 2021

Growth Hormone (GH) potentially influences connective tissue in muscle and tendon.We studied the effect of 14 days of recombinant human GH (rhGH) supplementation and exercise, on the expression of mRNA for Insulin‐Like Growth Factor‐I (IGF‐I), collagen I and collagen III in human skeletal muscle and tendon, in a double blind, randomized, placebo‐controlled crossover design. 10 male subjects received rhGH (0.33–0,50 mg/kg/day) or placebo separated by 4 months. One‐legged exercise (10 × 10 reps at 70% of 1 RM) was performed on the last day of the supplementation period, and 24 hours later tissue was sampled bilaterally from the vastus lateralis muscle and the patella tendon. mRNA expression was measured using real‐time RT‐PCR.rhGH administration resulted in a 8‐fold rise in circulating GH and a 3‐fold increase in circulating IGF‐I. In addition tendon and muscle connective tissue mRNA expression for IGF‐I increased significantly with GH (p<0.05). Furthermore, muscle and tendon collagen I and III increased significantly in response to rhGH supplementation (p<0.05).The results indicate a role for rhGH via IGF‐I in increasing collagen content in connective tissue of both tendon and skeletal muscle.
The pathophysiology of intestinal endometriosis is exacerbated by uncontrollable stress
Authors: Cuevas Marielly , Santiago Olga I , Thompson Kenira J , Flores Idhaliz , Appleyard Caroline B 
Published: June 2021

It is not known whether stress affects the severity of endometriosis in women.Aim:Assess the effects of chronic stress in an established animal model of intestinal endometriosis.Methods:Endometriosis was surgically induced in female rats. One group of rats (endo‐stress) was subjected to uncontrollable swim stress for 10 consecutive days. Endo‐controls had endometriosis with no stress. Sham‐stress had sutures only then swim stress. On day 60 all rats were sacrificed and examined for the presence of endometriotic vesicles. The colons were removed and assessed for macroscopic damage, myeloperoxidase (MPO) activity and histology.Results:None of the sham‐stress animals developed vesicles. The endo‐control rats developed vesicles with an average total vesicle length of 6.57 ± 0.96mm per animal. This was increased to 11.26 ± 5.27mm in the endo‐stress group (n=3‐4 ± sem). The endo‐control rats had higher macroscopic and histological colonic damage scores than the sham‐stress animals, which was increased further by stress. The endo‐stress also had the shortest colon length, increased numbers of colonic mast cells, higher MPO levels, and an increase in peritoneal fluid cell infiltration.Conclusions:This study presents evidence for the first time of the negative consequences of stress in the progression of endometriosis, most likely through an effect on the immune system. 2G12RR03050, SO6GM00823 & R01HD050559