bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential restoration of prothrombin time / INR in plasma from warfarin‐treated patients by various prothrombin complex concentrates (833.6)
Authors: Abro Schuharazad , Hoppensteadt Debra , Eshraghi Reza , Only Arthur , Walenga Jeanine , Fareed Jawed 
Published: June 2021

Introduction ‐ Conventional oral anticoagulant drugs produce their effects by suppressing the synthesis of functional forms of clotting factors II, VII, IX and X. Excessive inhibition of these factors results in bleeding complications. Prothrombin complex concetrates (PCCs) such as the Beriplex, Profilnine, and Feiba can be used to neutralize these effects. The purpose of this study was to compare the relative restoration of prothrombin time / INR in plasma samples collected from warfarin treated patients.Materials and Methods ‐ Various PCCs were purchased and diluted at a working concentration of 10 U/ml. The plasma samples from patients treated with warfarin (n=15, PT 15‐40 sec) were supplemented with each of the different PCCs at a final concentration of 1U/ml. Saline supplemented samples from 10 individuals served as control. Prothrombin time / INR were measured using conventional methods. All results were expressed in terms of mean + 1SD and relative neutralization ratio was calculated.Results ‐ The mean prothrombin time of the oral anticoagulated patients was 24.3 + 6.4 sec. Supplementation of Beriplex results in a total neutralization of this parameter with a mean of 11.5 + 0.7 sec. Profilnine partially neutralized with a value of 16.7 + 2.9 sec. Feiba produced a strong effect and shortened the prothrombin time to 8.9 + 0.4 sec.Discussion ‐ These results suggest that Beriplex is capable of restoring the coagulant activity of the plasma samples from orally anticoagulated patients in a more efficient manner than Profilnine. Feiba produced a stronger response due to the presence of activated clotting factors.
Facilitation of urokinase‐mediated fibrinolysis by MST‐188 (833.7)
Authors: Fareed Jawed , Syed Daneyal , Emanuele Marty , Hoppensteadt Debra , Cho Jae 
Published: June 2021

Introduction MST‐188 (Mast Therapeutics, San Diego, CA.) is a highly purified form of the , triblock copolymer poloxamer 188. It exhibits potent rheologic properties that result in improved blood flow especially under low shear conditions. Initial observations suggested that endogenous fibrinolysis is facilitated by this agent. In this study we investigate the effect of MST‐188 on urokinase induced fibrinolysis.Materials and Methods A dynamic fibrinokinetic assay was used to assess both the assembly and dissolution of fibrin clots. MST‐188 (0 ‐ 10 mg/ml) was added to citrated human plasma with and without urokinase at a concentrations between 0 ‐ 2,500 U/ml (N=10‐15 donors). Clotting was initiated with the sequential addition of and calcium chloride (0.25 uM) and then thrombin (0.5u/ml). Absorbance was monitored to detect the assembly and dissolution of fibrin.Results Control studies of MST‐188 alone had a dose dependent effect on fibrin assembly as reflected by both the rate of change and peak optical density. Urokinase alone showed no effect on clot formation but a dose dependent increase in clot lysis. Supplementation of MST‐188 to urokinase facilitated its lytic profile in a concentration dependent manner accelerating the time to onset of lysis and reducing the overall AUC for clot dissolution.Discussion These results demonstrate that MST‐ 188 increases urokinase mediated fibrinolysis. The increase in the susceptibility of the formed clot to lysis in the presence of MST‐188 may be due to structural modification of the clot. MST‐188 may bind to fibrin strands, thereby modifying their accessibility to the lytic action of generated plasmin.
Potential anti‐inflammatory effects of nebulized local anesthetics on inhaled chlorine lung injury (834.8)
Authors: Clodfelder‐Miller Buffie , Dewitte Carey , Xu Shin , Doran Steve , Matalon Sadis , Ness T 
Published: June 2021

Chlorine (Cl2) is a chemical used in both industry and society alike, despite it being a highly irritant and reactive gas. Acute exposure can result in symptoms of airway obstruction such as wheezing, shortness of breath, mouth/nose/chest pain, and bronchospasm. Currently, there is no known antidote for chlorine’s poisoning effects. Potential treatments include topical exposure of the airways to nebulized drugs such as local anesthetics which have been shown to improve the mobility of monitored animals after exposure to Cl2 gas. In this research project, we assess the effects of the nebulized local anesthetics lidocaine (1% and 4%), 3% 2‐Chloroprocaine following exposure to 100 or 400 ppm of chlorine gas on biochemical measurements of injury to airway. Wet‐to‐dry lung weight ratios, bronchoalveolar lavage (BAL) cell counts and total protein, and lung homogenate cytokine levels were determined 24 hours after Cl2 gas exposure and anesthetic treatment. In mice exposed to 400 ppm Cl2 gas, 1% lidocaine had the greatest decrease of wet‐to‐dry lung weight ratio in addition to lower live cell infiltration and lower protein concentrations in BAL fluids indicating a potential anti‐inflammatory affect. Cytokine levels from lung homogenates after exposure and treatments had a decreasing trend compared to untreated animals. Levels of IL‐10, IFNγ, MCP‐1 and IL‐13 were significantly lower in the 1% lidocaine animal group. Similar but not identical results were found following treatment with 100ppm Cl2. Treatment with 4% lidocaine and 3% 2‐chloroprocaine had potential toxic effects. This study indicates that nebulized 1% lidocaine is potentially a good treatment option after chlorine induced lung injury based on behavioral and biochemical data.Grant Funding Source: Supported by 1R21ES022876
Effects of CD38 gene on TLR4 and inflammatory cytokines and its mechanisms (835.10)
Authors: Li Rong , Chen Cheng , Li Ling , Li Li , Kong Yuan , Yang Xiao , Liao Jie 
Published: June 2021

Protective mechanisms of the host will be initiated by the activation of Toll‐like receptor (TLR), including the chemotaxis and activation of immune cells. TLR4 defection always accompanied with inflammation. CD38 gene is associated with myocardial infarction. However, impact of CD38 gene on TLR4 is not well defined. Objective To study the influences of CD38 gene to the distribution of TLR4 and it's effects and mechanisms on expression of TLR4 and inflamatory cytokines. Methods Distribution of TLR4 in organs (such as heart, liver spleen, lung, kidney, cerebrum, thymus and lymph node) of C57/B6 mice and CD38‐/‐ C57/B6 mice were elucidated by polymerase chain reaction (PCR), Different expression of TLR4 in spleen of C57/B6 mice and CD38‐/‐ C57/B6 mice was analyzed by realtime PCR and westernblot (WB). Expression of inflammatory cytokines such as tumor necrosis factor‐α (TNF‐α), monocyte chemotactic protein 1 (MCP‐1), Interleukin‐1 (IL‐6) and Interleukin‐1β (IL‐1β) in spleen were analyzed by realtime PCR individually. Different expression of NF‐ĸB in spleen was analyzed by WB. Results TLR4 distribute broadly in all of the above organs in both C57/B6 mice and CD38‐/‐ C57/B6 mice. But comparing to C57/B6 mice, CD38‐/‐ C57/B6 mice showed an significantly decrease in the expression of TLR4 on both mRNA and protein level in spleen. Expression of inflammatory cytokines such as TNF‐α, MCP‐1 and IL‐6 were found to be significantly decreased accompanied by significantly increased expression of IL‐1β in spleen. Meanwhile, the expression of NF‐ĸB in spleen was greatly enhanced. Conclusions Overall, these data suggest that CD38 has a profound influence on TLR4, which may contribute to the dysregulated expression of inflammatory factors under physiological and such pathological conditions as myocardial infarction through NF‐ĸB pathway.Grant Funding Source: Supported by GJJ81302600 and 30960357
Increase of splenic lymphocyte apoptosis in septic encephalopathy (835.12)
Authors: Jeremias Isabela , Victorino Vanessa , Lima Thais , Soriano Francisco 
Published: June 2021

Sepsis is a systemic response to infection that can affect any organ system, including the central and peripheral nervous systems. Authors reported that changes in the nervous system are implicated in the induction or amplification of immune cell changes. We investigated the changes in brain function and late immune response in an animal model of sepsis by cecal ligation and puncture (CLP). Balb/c mice were divided into two groups: Sham operation or CLP. We evaluated brain changes by SHIRPA behavioral test, after 6h of CLP. 15 days after surgery, mice were sacrificed, the spleen was isolated and lymphocytic apoptosis was evaluated by flow cytometry. We observed that the neuropsychiatric state in SHIRPA test was significantly decreased in animals with CLP. Regarding apoptosis of lymphocytes, there was also a significant difference, in which the CLP apoptotic lymphocytes were greater than in the sham group. Correlating (r=‐0.96) the two factors we observed that the higher the neurological damage greater the number of apoptotic lymphocytes. Thus, we conclude from these preliminary results that neurological status observed 6 hours after CLP may determine delayed immune response impairment.Support: FAPESP 2012/07898‐0Grant Funding Source: Support by: FAPESP 2012/07898‐0
Novel role of cathepsin V in TLRs‐MyD88 mediated signaling revealed in HMGB1‐TLR4 inhibitor screening (835.9)
Authors: Xu Hongbo , Montenegro Marcelo , Pribis John , Billiar Timothy 
Published: June 2021

Toll‐like receptors (TLRs) recognize pathogen‐derived molecular patterns (PAMP) and danger‐associated molecular patterns (DAMP), and induce NF‐κB‐dependent pro‐inflammatory cytokines release such as TNF‐α and IL‐6. High Mobility Group Box 1 (HMGB1) is a prototypical DAMP that drives inflammation in many sterile and infectious diseases signaling through TLR4. A cell‐based high‐throughput screening identified a FDA‐approved HIV protease inhibitor Saquinavir (SQV) as a potent inhibitor of HMGB1‐TLR4 mediated signaling. We have previously identified human cathepsin V (CTSV) as a mammalian target of SQV and confirmed CTSV involves in HMGB1‐TLR4 signaling using genetic knockdown and pharmacological inhibition. In this study, we expanded these previous evidence for TLR4 and tested the effects of SQV and SID266 (a known CTSV inhibitor) on TNF‐α production induced by TLR 1/2, 4 and 9, using the TLR ligands Pam3CSK4, LPS and ODN2006, respectively. Similar to HMGB1, SQV and SID266 diminish TNF‐α production in a concentration‐dependent manner. SQV also acts upstream in the TLR‐NF‐κB pathway by attenuating phosphorylation of IRAK4 and IKKα/β. The activities of SQV are shared by SID266. Hinted from the mechanistic properties of SQV and SID266, we found that CTSV physically interacts with MyD88 in PMA‐differentiated THP‐1 cells stimulated with HMGB1, LPS or Pam3CSK4, which could be blocked by SQV administration. Our study uncovers a previously unknown mechanism of cathepsin V in TLRs‐MyD88 mediated signaling and suggests a potential novel therapeutic target in related inflammatory diseases, and paves the way for re‐purposing a drug already safely in humans.Grant Funding Source: Department of Surgery, University of Pittsburgh
Cleavage of DAP5 by coxsackievirus B3 protease 2A causes its nuclear translocation and inhibition of IRES‐containing gene transcription (836.5)
Authors: Hanson Paul , Qiu Ye , Ye Xin , Zhang Huifang Mary , Hemida Maged , Lim Travis , Gu Ada , Cho Brian , Kim Hyein , Yang Decheng 
Published: June 2021

Coxsackievirus B3 (CVB3) is a primary causative agent of viral myocarditis which may progress to dilated cardiomyopathy (DCM), a leading cause of unexpected death in children and young adults. Upon infection, CVB3 hijacks host cellular translation machinery, generating an environment that favors viral replication. Death associated protein 5 (DAP5) is an internal ribosomal entry site (IRES) specific translation initiation factor, utilized by the cell in conditions of stress, differentiation, cell‐cycle and apoptosis. We previously showed that DAP5 is cleaved during CVB3 infection. In this study we aimed to identify the responsible protease and site of cleavage, as well as the functional impact. Our results found that DAP5 was cleaved by viral protease 2A but not by cellular proteases. We further identified the cleavage site at amino acid G434. Upon cleavage, the N‐terminal product could translocate to the nucleus and inhibited transcription of IRES‐containing pro‐survival genes such as Bcl‐2, GRP‐78 and VEGF. This is the first report to reveal the function and mechanism of DAP5 cleavage in regulating viral and host gene expression during CVB3 infection. Moreover, this study may identify key components necessary for facilitating viral pathogenesis and thus provide novel pharmaceutical targets for viral myocarditis.Grant Funding Source: Canadian Institutes of Health Research
Serum‐derived bovine immunoglobulin/protein isolate binds to pathogen‐associated molecular patterns (836.6)
Authors: Horgan Alan , Maas Kenneth , Henderson Abigail , Detzel Christopher , Weaver Eric 
Published: June 2021

A key feature of the innate immune system is the panoply of pattern recognition receptors which bind a wide array of highly conserved pathogen‐associated molecular patterns (PAMPs). Under normal conditions, PAMP binding initiates downstream signaling cascades culminating in pro‐inflammatory cytokine production, inflammation, and subsequent antigen elimination. Continual PAMP binding leads to a persistent state of inflammation associated with numerous chronic inflammatory disorders such as IBS, IBD, and HIV enteropathy. We hypothesize that immune exclusion of PAMPs through antigen/antibody interactions can reduce inflammatory signaling and lessen the gastrointestinal manifestations of these disorders.Serum‐derived bovine immunoglobulin/protein isolate (SBI) is comprised primarily of immunoglobulins (Ig) and is indicated for the clinical dietary management of gastrointestinal enteropathy under physician supervision. We investigated the binding of SBI’s Ig components (IgG, IgA, and IgM) to PAMPs associated with intestinal inflammatory disorders. Using a modified ELISA technique we have shown that IgG, IgA, and IgM contained in SBI bind to a wide array of bacterial, viral, and fungal PAMPs.Oral administration of SBI has been shown clinically to manage GI symptoms in patients with IBS‐D and HIV enteropathy; however, the mechanism of action is poorly understood. Here we show that SBI binds a wide variety of PAMPs. We propose that Ig‐PAMP binding may inhibit immune recognition and the chronic inflammation associated with persistent immune activation.
Improved diastolic function in rats with volume overload heart failure may be due to phosphodiesterase (PDE) 3 inhibition (837.1)
Authors: Lewis Kristin , Zhang Xiaojin , Lucchesi Pamela 
Published: June 2021

This study investigated whether drugs with (milrinone (Mil), levosimendan (Levo)) and without (omecamtiv mecarbil (OM)) demonstrated phosphodiesterase (PDE) 3 inhibitory activity improve diastolic function in rats with aortocaval fistula (ACF)‐induced volume overload (VO). ACF or sham surgery was performed in male Sprague‐Dawley rats (200‐240g) 8 weeks prior to acute IV infusion with either Levo (2.8 µg/kg/min), Mil (9.9 µg/kg/min), OM (11.7 µg/kg/min) or vehicle (Veh; 0.4% DMSO) for 30 min. Levo and Mil improved diastolic function compared with Veh (tau; 9.0 and 9.8, respectively vs. 10.7 msec, p<0.05), while OM worsened diastolic function compared with Veh, Levo, and Mil (tau and dP/dtmin; 12.4 msec (p<0.05 vs. ACF‐Veh and p<0.001 vs. ACF‐Levo and ACF‐Mil) and ‐5967 mmHg/sec (p<0.05 vs. ACF‐Veh and p<0.01 vs. ACF‐Levo and ACF‐Mil)). Following infusion, %FS improved in ACF‐Levo, ACF‐Mil and ACF‐OM (39.8, 37.9 and 36.8%, respectively) compared with ACF‐Veh (32.1%; p<0.01), and there was no significant decrease in mean arterial pressure and no increase in arrhythmias. These results suggest that PDE3 inhibition improves diastolic function and that Levo’s improved diastolic function may be due to PDE3 inhibition independent of changes in blood pressure.Grant Funding Source: Supported by: R01 HL‐056046 (to PAL), ACVP/STP Coalition (to KL)
Characterization of erectile dysfunction and overactive bladder in heart failure rats: model of volume overload (837.6)
Authors: Claudino Mário , Silva Fabio , Ramos‐Filho Celso , Rojas‐Moscovo Julio , Priviero Fernanda , Nucci Gilberto , Antunes Edson 
Published: June 2021

In chronic heart failure (CHF) 85% of patients have been reported some episode of erectile dysfunction and 34% reported overactive bladder. We evaluate the muscle reactivity of isolated corpus cavernosum (CC) and detrusor muscle (DM) of CHF rats (CHFR). Concentration responses curves to phenilephrine (PE) in CC (4wks); and carbachol (CCh), KCl in DSM were obtained from CHFR (4‐12wks). Nitrergic and neurogenic responses induced by electrical field stimulation were obtained in CC and DM (respect). Intracavernosal pressure (ICP) and cystometry (in vivo, respect.) also were evaluated. PE contracted CC with a potency (pEC50) of 5.44 ± 0.04. The pEC50 of PE did not change in CHFR (5.36 ± 0.06), but, the maximal response (Emax) was increased (2.5 ± 0.1mN/mg; P<0.05) compared with sham rats (SR; 1.9 ± 0.1 mN/mg). Nitrergic relaxation in CC was significantly decreased at higher frequencies in CHFR. ICP was reduced in CHFR vs SR (P<0.05). CCh and KCl contracted DM with a pEC50 of 5.42 ± 0.07 and 0.90 ± 0.12, respectively. The pEC50 of CCh and KCl did not change in CHFR (5.68 ± 0.07; 1.34 ± 0.11, respect.), but, the Emax were increased (1.09 ± 0.07; 0.88 ± 0.05mN/mg, respect; P<0.05) vs SR (1.45 ± 0.10; 1.29 ± 0.11 mN/mg, respect.). In CHFR neurogenic contractions in DM were significantly increased in all frequencies vs SR. Cystometry were increase in CHFR vs SR (P<0.05). In conclusion, CHFR exhibit an impaired nitrergic response (CC) and erectile function, and an increase of contractile‐mechanism in DSM and cystometry featuring the genitourinary dysfunctions in CHFR.Grant Funding Source: FAPESP/CNPq
Functional consequences of synthetic cannabinoid metabolites and CYP2C9 polymorphisms (838.4)
Authors: Allen Catherine , Patton Amy , Seely Kathryn , Fantegrossi William , Radominska‐Pandya Anna , Prather Paul , Ford Benjamin , James Laura , Moran Jeffery 
Published: June 2021

Synthetic cannabinoid (SC) abuse is a growing problem. Previous studies using recombinant cytochrome P450 (CYP) enzymes identified CYP2C9 as an isozyme responsible for SC oxidation, but the role of genetic variability in SC metabolism has not been studied. To examine the relationship of CYP2C9 polymorphisms and SC effects, mice were treated with JWH‐018 or the chiral (ω‐1)‐hydroxyl metabolite ((ω‐1)‐OH) that is formed via CYP2C9 action. Administration of JWH‐018 (i.p. 3 mg/kg) produced Δ9‐THC‐like effects on core temperature and locomotor activity in mice that corresponded to brain concentrations of 10 ng/g for JWH‐018 and 2 ng/g for (R/S)‐(ω‐1)‐OH. Administration of purified (R)‐ or (S)‐(ω‐1)‐OH enantiomers (i.p. 3 mg/kg) equally reduced locomotor activity and core temperature in the mice. Pre‐treatment with the cannabinoid receptor‐1 antagonist rimonabant attenuated the physiologic effects associated with administration of the chiral (ω‐1)‐OH metabolites. Both enantiomers also retained nanomolar affinity and intrinsic activity at cannabinoid receptors. In vitro enzyme kinetic assays performed using human recombinant CYP2C9 variants (*1, *2, and *3) showed reduced metabolite formation with the CYP2C9*3 variant. Thus, data demonstrate comparable biologic activity for the chiral (ω‐1)‐OH metabolites of CYP2C9 and suggest a potential role for CYP2C9 polymorphisms as a modulator of drug toxicity.Grant Funding Source: Supported by NIH grants RR020146 and RR029884 and an institutional ASPET SURF award.
Differential contributions of the two cell surface G‐protein coupled neurotensin (NT) receptors (NTr1 and NTr2) in open field accommodation (839.7)
Authors: Smith Misty , Nielsen Shannon , Wada Etsuko , Wada K , Fleckenstein Annette , Hanson Glen 
Published: June 2021

Neurotensin (NT) is an endogenous neuropeptide with diverse central and peripheral effects. Open field accommodation is a dopamine (DA) ‐related behavioral model that appears to be sensitive to NT systems. Although NT has previously been shown to have modulatory effects on CNS DA activity and to be involved in motivation, the relative contribution of the two cell surface G‐protein coupled NT receptors (NTr1 and NTr2) to exploratory drive in a novel open field is unknown: to investigate their roles in this model, C57BL/6J mice deficient in either NTr1 (‐/‐) or NTr2 (‐/‐) were compared to wild‐type, littermate C57BL/6J (WT +/+) mice. Open field locomotor activity (40 cm L × 40 cm W × 30 cm H) was quantified using the automated Accuscan activity monitoring system (OmniTech Instruments Inc., Columbus, OH) in 10 min epochs for up to 4 hours. The total distance travelled, horizontal activity, and vertical activity were compared between groups and statistically analyzed using Two way ANOVA with repeated measures (GraphPad Prism, La Jolla, CA). Compared to WT (+/+) mice, mice deficient in the NTr1 receptor accommodated to the open field significantly less, whereas, mice deficient in the NTrs2 receptor accommodated faster, than WT (+/+) mice in all three parameters of locomotor activity quantified. These results suggest that the NTr1 subtype of the NT system facilitates, whereas NTr2 subtype inhibits, locomotor accommodation in a novel environment. The significance of these opposing effects of the NTr1 and 2 receptors will be discussed.Grant Funding Source: Supported by NIDA DA031883 (GRH), NIDA DA000378 (GRH), & NIDA DA019447 (AEF)
The impact of hydrogen sulfide in oesophagoprotection (840.15)
Authors: Hrytsevych Nazar , Zayachkivska Oksana , Yaschenko Antonina 
Published: June 2021

Various studies have shown that novel cytoprotective gasotransmitter hydrogen sulfide (H2S) has cytoprotective and preventive effects in the gastrointestinal system (Wallace J., 2010‐2012). However, the mechanism of H2S on oesophageal barrier remains unclear. Therefore, the aim of present study was to examine the protective role of endogenous H2S in oeosphageal mucosal (OM) lesions related to stress‐associated injury and postprandial hyperglycemia (PHG) which we recently recognized as a serious trigger in the oesophageal injury genesis (Hrytcevych N., 2011‐2013).Aim: To determine whether or not H2S attenuates oesophageal mucosal cytoprotection in rats with nonerosive oeosphagitis and long term PHG, and explored the underlying mechanisms may be involved.Methods: Rats without and with 3,5 h water immersion and restraint stress (WIRS) and 28 days of PHG received i.p. of vehicle, cystathionine gama‐lyase (CSE) inhibitor, DL‐propargylglycine (PAG, 25 mg/kg i.p.), CBS inhibitor, beta‐cyano‐alanine (BCA, 50 mg/kg i.p.), or H2S donor NaHS (100 mlmol/kg) prior to WIRS. Scoring lesion index (LI), vascular index (VI) by OM histomorphology, IL‐10, IL‐17 by ELISA.Results: WIRS &amp; PHG induced non‐erosive injury which characterized by rise LI and VI vs control. PAG or BCA pretreatment enhanced EM lesions escalating LI and VI in twice, drop IL‐10 and rise IL‐17. NaHS mediated decrease of OM lesions via decreased LI, VI and increase IL‐10 and decrease IL‐17 scores vs control.Conclusion: These results indicate that endogenous H2S plays oesophagoprotective role by inhibiting inflammation, oedeme and vasodilator effect, highlighting the therapeutic potential for H2S donor in postprandial hyperglycemic stress‐associated conditions.