bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for the slow reaction of hypoxia‐inducible factor prolyl hydroxylase 2 with oxygen
Authors: Flashman Emily , Hoffart Lee M. , Hamed Refaat B. , Bollinger Jr J. Martin , Krebs Carsten , Schofield Christopher J. 
Published: August 2010

The response of animals to hypoxia is mediated by the hypoxia‐inducible transcription factor. Human hypoxia‐inducible factor is regulated by four Fe(II)‐ and 2‐oxoglutarate‐dependent oxygenases: prolyl hydroxylase domain enzymes 1–3 catalyse hydroxylation of two prolyl‐residues in hypoxia‐inducible factor, triggering its degradation by the proteasome. Factor inhibiting hypoxia‐inducible factor catalyses the hydroxylation of an asparagine‐residue in hypoxia‐inducible factor, inhibiting its transcriptional activity. Collectively, the hypoxia‐inducible factor hydroxylases negatively regulate hypoxia‐inducible factor in response to increasing oxygen concentration. Prolyl hydroxylase domain 2 is the most important oxygen sensor in human cells; however, the underlying kinetic basis of the oxygen‐sensing function of prolyl hydroxylase domain 2 is unclear. We report analyses of the reaction of prolyl hydroxylase domain 2 with oxygen. Chemical quench/MS experiments demonstrate that reaction of a complex of prolyl hydroxylase domain 2, Fe(II), 2‐oxoglutarate and the C‐terminal oxygen‐dependent degradation domain of hypoxia‐inducible factor‐α with oxygen to form hydroxylated C‐terminal oxygen‐dependent degradation domain and succinate is much slower (approximately 100‐fold) than for other similarly studied 2‐oxoglutarate oxygenases. Stopped flow/UV‐visible spectroscopy experiments demonstrate that the reaction produces a relatively stable species absorbing at 320 nm; Mössbauer spectroscopic experiments indicate that this species is likely not a Fe(IV)=O intermediate, as observed for other 2‐oxoglutarate oxygenases. Overall, the results obtained suggest that, at least compared to other studied 2‐oxoglutarate oxygenases, prolyl hydroxylase domain 2 reacts relatively slowly with oxygen, a property that may be associated with its function as an oxygen sensor.Structured digital abstract
MINT‐7987711: PHD2 (uniprotkb:Q9GZT9) enzymaticly reacts (MI:0414) CODD (uniprotkb:Q16665) by enzymatic study (MI:0415)
Poly(ADP-Ribose) Polymerase Inhibition Improves Erectile Function in Diabetic Rats
Authors: Wan Zhihua H. , Li Wenzhou Z. , Li Yunzhu Z. , Chen Lin , Li Guohao H. , Hu Weifeng F. , Peng Song , Yu Jiajun J. , Guo Feng 
Published: August 2010

ABSTRACT

Introduction
Erectile dysfunction (ED) is a common and hard-to-treat complication of diabetes mellitus (DM). Multiple lines of evidence have shown that poly(ADP-ribose) polymerase (PARP) activation plays an important role in neurovascular dysfunction in diabetes, which is the crucial mechanism for diabetic ED.

Aim
To investigate the preventive benefit of a PARP inhibitor in a rat model of ED induced by diabetes.

Methods
Established streptozotocin-diabetic male Sprague-Dawley rats were given PJ-34, a selective PARP inhibitor, by oral gavage at a dose of 10 mg/kg twice daily for 8 weeks. Erectile responses under electrical stimulation of the cavernous nerve, PARP activity and reactive oxygen species (ROS) production were measured. Nitric oxide synthase (NOS) isoforms were evaluated by Western blot and real-time quantitative PCR. Nuclear factor-kappa B activition and apoptosis in corpus cavernosa (CC) were also investigated.

Main Outcome Measures
The effects of PARP inhibition on the development of diabetic ED were determined.

Results
Diabetes markedly attenuated the erectile responses (intracavernosal pressure/mean systemic arterial blood pressure) and these were partially prevented by PJ-34 treatment. Promoted oxidative stress associated PARP activation was found in CC from vehicle-treated diabetic rats. PJ-34 blocked PARP activity and the diabetes-associated ROS generation. Decreased expression and activity of constitutive NOS (cNOS), including endothelial NOS (eNOS) and neuronal NOS (nNOS), associated with enhanced inducible NOS (iNOS) expression and activity were observed in vehicle-treated diabetic rats. Although PJ-34 had no effect on eNOS expression, it significantly prevented the decrease in nNOS expression and cNOS activity, and inhibited iNOS expression and activity in diabetic rats. PARP blockade by PJ-34 to some extent prevented diabetes-associated apoptosis and NF-κB activation.

Conclusions
Our results indicate that PARP activation plays an important role in the pathogenesis of diabetic ED and PARP inhibition may be a promising strategy to prevent development of diabetic ED.
p38 Mitogen-Activated Protein Kinase (MAPK) Increases Arginase Activity and Contributes to Endothelial Dysfunction in Corpora Cavernosa from Angiotensin-II-Treated Mice
Authors: Toque Haroldo A. , Romero Maritza J. , Tostes Rita C. , Shatanawi Alia , Chandra Surabhi , Carneiro Zidonia N. , Inscho Edward W. , Webb Robert Clinton , Caldwell Ruth B. , Caldwell Robert William 
Published: August 2010

ABSTRACTIntroductionAngiotensin II (AngII) activates p38 mitogen-activated protein kinase (MAPK) and elevates arginase activity in endothelial cells. Upregulation of arginase activity has been implicated in endothelial dysfunction by reducing nitric oxide (NO) bioavailability. However, signaling pathways activated by AngII in the penis are largely unknown.AimWe hypothesized that activation of p38 MAPK increases arginase activity and thus impairs penile vascular function in AngII-treated mice.MethodsMale C57BL/6 mice were implanted with osmotic minipumps containing saline or AngII (42 µg/kg/h) for 14 days and cotreated with p38 MAPK inhibitor, SB 203580 (5 µg/kg/day), beginning 2 days before minipump implantation. Systolic blood pressure (SBP) was measured. Corpus cavernosum (CC) tissue was used for vascular functional studies and protein expression levels of p38 MAPK, arginase and constitutive NO synthase (NOS), and arginase activity.Main Outcome MeasuresArginase expression and activity; expression of phospho-p38 MAPK, endothelial NOS (eNOS) and neuronal NOS proteins; endothelium-dependent and nitrergic nerve-mediated relaxations were determined in CC from control and AngII-infused mice.ResultsAngII increased SBP (22%) and increased CC arginase activity and expression (∼twofold), and phosphorylated P38 MAPK levels (30%) over control. Treatment with SB 203580 prevented these effects. Endothelium-dependent NO-mediated relaxation to acetylcholine was significantly reduced by AngII and this effect was prevented by SB 203580 (P &lt;0.01). AngII (2 weeks) did not alter nitrergic function. However, SB 203580 significantly increased nitrergic relaxation in both control and AngII tissue at lower frequencies. Maximum contractile responses for phenylephrine and electrical field stimulation were increased by AngII (56% and 171%, respectively) and attenuated by SB 203580 treatment. AngII treatment also decreased eNOS phosphorylation at Ser-1177 compared to control. Treatment with SB 203580 prevented all these changes.Conclusionp38 MAPK inhibition corrects penile arginase activity and protects against erectile dysfunction caused by AngII.
The Development of a Sensory Substitution System for the Sexual Rehabilitation of Men with Chronic Spinal Cord Injury
Authors: Borisoff Jaimie F. , Elliott Stacy L. , Hocaloski Shea , Birch Gary E. 
Published: August 2010

ABSTRACT

Introduction
Sexual health is often severely impacted after spinal cord injury (SCI). Current research has primarily addressed male erection and fertility, when in fact pleasure and orgasm are top priorities for functional recovery. Sensory substitution technology operates by communicating input from a lost sensory pathway to another intact sensory modality. It was hypothesized that through training and neuroplasticity, mapped tongue sensations would be interpreted as sensory perceptions arising from insensate genitalia, and improve the sexual experience.

Aim
To report the development of a sensory substitution system for the sexual rehabilitation of men with chronic SCI.

Methods
Subjects performed sexual self-stimulation while using a novel sensory substitution device that mapped the stroking motion of the hand to a congruous flow of electrocutaneous sensations on the tongue.

Main Outcome Measures
Three questionnaires, along with structured interviews, were used to rate the perceived sexual sensations following each training session.

Results
Subjects completed 20 sessions over approximately 8 weeks of training. Each subject reported an increased level of sexual pleasure soon after training with the device. Each subject also reported specific perceptions of cutaneous-like sensations below their lesion that matched their hand motion. Later sessions, while remaining pleasurable and interesting, were inconsistent, and no subject reported an orgasmic feeling during a session. The subjects were all interested in continuing training with the device at home, if possible, in the future.

Conclusions
This study is the first to show that sensory substitution is a possible therapeutic avenue for sexual rehabilitation in people lacking normal genital sexual sensations. However more research, for instance on frequency and duration of training, is needed in order to induce functional lasting neuroplasticity. In the near term, SCI rehabilitation should more fully address sexuality and the role of neuroplasticity for promoting the maximal potential for sexual pleasure and orgasm.
A New Female Rat Animal Model for Hypoactive Sexual Desire Disorder; Behavioral and Pharmacological Evidence
Authors: Snoeren Eelke M.S. , Chan Johnny S.W. , De Jong Trynke R. , Waldinger Marcel D. , Olivier Berend , Oosting Ronald S. 
Published: August 2010

ABSTRACTIntroductionFemale sexual dysfunction (FSD) affects 33–48% of women. Female rats with low sexual activity might model FSD.AimIn this study, we have investigated whether in a population of normal female rats, subpopulations of rats exist with different levels of sexual behavior.MethodsSexually experienced, intact, estradiol-primed female rats were placed in an empty compartment adjacent to a compartment with a male. The females were allowed, during 30 minutes, to switch between the compartments via a hole through which only the females could pass (paced mating). Next, we investigated the acute effects on female sexual behavior of apomorphine, a D1- and D2-type dopamine receptor agonist, (+/–)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (±8-OH-DPAT), a 5-HT1A receptor agonist, and paroxetine, a selective serotonin reuptake inhibitor.Main Outcome MeasuresTime spent in compartments, proceptive behaviors, contact–return latencies, and percentages of exits were quantified.ResultsBased on their behavior in the paced mating sex test, estradiol-primed, intact female rats can be divided into three groups: those that mostly avoid the male, a large middle group, and those that mostly approach the male. The avoiders also showed significantly less proceptive behavior than the male approachers. The sexual behavior of the females was relatively stable over time, suggesting the existence of different endophenotypes in female rats. Apomorphine and ±8-OH-DPAT had an inhibiting effect on sexual behavior, but only females dosed with apomorphine showed a different response in avoiders and approachers, more inhibiting effect in avoiders than approachers. Paroxetine had no effect on proceptive behavior.DiscussionThe stable, male-avoiding behavior of some females might correspond to the characteristics of women with FSD. Therefore, these avoiders are a promising new model for FSD, specifically for sexual desire and/or arousal disorders. Furthermore, the apomorphine data suggest that differences in the dopamine system may (partly) underlie the differences in sexual behaviors between avoiders and approachers.
Neuroimaging of Love: fMRI Meta-Analysis Evidence toward New Perspectives in Sexual Medicine
Authors: Ortigue Stephanie , Bianchi-Demicheli Francesco , Patel Nisa , Frum Chris , Lewis James W. 
Published: August 2010

ABSTRACTIntroductionBrain imaging is becoming a powerful tool in the study of human cerebral functions related to close personal relationships. Outside of subcortical structures traditionally thought to be involved in reward-related systems, a wide range of neuroimaging studies in relationship science indicate a prominent role for different cortical networks and cognitive factors. Thus, the field needs a better anatomical/network/whole-brain model to help translate scientific knowledge from lab bench to clinical models and ultimately to the patients suffering from disorders associated with love and couple relationships.AimThe aim of the present review is to provide a review across wide range of functional magnetic resonance imaging (fMRI) studies to critically identify the cortical networks associated with passionate love, and to compare and contrast it with other types of love (such as maternal love and unconditional love for persons with intellectual disabilities).MethodsRetrospective review of pertinent neuroimaging literature.Main Outcome MeasuresReview of published literature on fMRI studies of love illustrating brain regions associated with different forms of love.ResultsAlthough all fMRI studies of love point to the subcortical dopaminergic reward-related brain systems (involving dopamine and oxytocin receptors) for motivating individuals in pair-bonding, the present meta-analysis newly demonstrated that different types of love involve distinct cerebral networks, including those for higher cognitive functions such as social cognition and bodily self-representation.ConclusionsThese metaresults provide the first stages of a global neuroanatomical model of cortical networks involved in emotions related to different aspects of love. Developing this model in future studies should be helpful for advancing clinical approaches helpful in sexual medicine and couple therapy.
Erectile Dysfunction in Young Non-Obese Type II Diabetic Goto-Kakizaki Rats is Associated with Decreased eNOS Phosphorylation at Ser1177
Authors: Carneiro Fernando S. , Giachini Fernanda R.C. , Carneiro Zidonia N. , Lima Victor V. , Ergul Adviye , Webb R. Clinton , Tostes Rita C. 
Published: August 2010

ABSTRACTIntroductionDiabetes mellitus (DM) is a risk factor for erectile dysfunction (ED). Although type 2 DM is responsible for 90–95% diabetes cases, type 1 DM experimental models are commonly used to study diabetes-associated ED.AimGoto-Kakizaki (GK) rat model is relevant to ED studies since the great majority of patients with type 2 diabetes display mild deficits in glucose-stimulated insulin secretion, insulin resistance, and hyperglycemia. We hypothesized that GK rats display ED which is associated with decreased nitric oxide (NO) bioavailability.MethodsWistar and GK rats were used at 10 and 18 weeks of age. Changes in the ratio of intracavernosal pressure/mean arterial pressure (ICP/MAP) after electrical stimulation of cavernosal nerve were determined in vivo. Cavernosal contractility was induced by electrical field stimulation (EFS) and phenylephrine (PE). In addition, nonadrenergic-noncholinergic (NANC)- and sodium nitroprusside (SNP)-induced relaxation were determined. Cavernosal neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) mRNA and protein expression were also measured.Main Outcome MeasureGK diabetic rats display ED associated with decreased cavernosal expression of eNOS protein.ResultsGK rats at 10 and 18 weeks demonstrated impaired erectile function represented by decreased ICP/MAP responses. Ten-week-old GK animals displayed increased PE responses and no changes in EFS-induced contraction. Conversely, contractile responses to EFS and PE were decreased in cavernosal tissue from GK rats at 18 weeks of age. Moreover, GK rats at 18 weeks of age displayed increased NANC-mediated relaxation, but not to SNP. In addition, ED was associated with decreased eNOS protein expression at both ages.ConclusionAlthough GK rats display ED, they exhibit changes in cavernosal reactivity that would facilitate erectile responses. These results are in contrast to those described in other experimental diabetes models. This may be due to compensatory mechanisms in cavernosal tissue to overcome restricted pre-penile arterial blood supply or impaired veno-occlusive mechanisms. Carneiro FS, Giachini FRC, Carneiro ZN, Lima VV, Ergul A, Webb RC, and Tostes RC. Erectile dysfunction in young non-obese type II diabetic Goto-Kakizaki rats is associated with decreased eNOS phosphorylation at Ser1177.
The Role of the Dopamine Transporter in Dopamine‐Induced DNA Damage
Authors: Fazeli Gholamreza , Oli Rajaraman Gnana , Schupp Nicole , Stopper Helga 
Published: August 2010

AbstractThe neurotransmitter dopamine causes DNA damage, oxidative stress and is involved in the pathology of neurological diseases. To elucidate this potential link we investigated the mechanism of dopamine‐induced DNA damage. We studied the role of the dopamine transporter (DAT) in MDCK and MDCK‐DAT cells, containing the human DAT gene. After treatment with dopamine, only MDCK‐DAT cells showed elevated chromosomal damage and dopamine uptake. Although stimulation of dopamine type 2 receptor (D2R) with quinpirole in the absence of dopamine did not induce genotoxicity in rat neuronal PC12 cells, interference with D2R signaling by inhibition of G‐proteins, phosphoinositide 3 kinase and extracellular signal‐regulated kinases reduced dopamine‐induced genotoxicity and affected the ability of DAT to take up dopamine. Furthermore, the D2R antagonist sulpiride inhibited the dopamine‐induced migration of DAT from cytosol to cell membrane. To determine whether oxidation of dopamine by monoamine oxidase (MAO) is relevant in its genotoxicity, we inhibited MAO, which reduced the formation of micronuclei and of the oxidative DNA adduct 8‐oxodG. Overall, dopamine exerted its genotoxicityin vitroupon transport into the cells and oxidation by MAO. D2R signaling was involved in the genotoxicity of dopamine by affecting activation and cell surface expression of DAT and hence modulating dopamine uptake.
Mutation Analysis of CCM1, CCM2 and CCM3 Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation
Authors: D'Angelo Rosalia , Marini Valeria , Rinaldi Carmela , Origone Paola , Dorcaratto Alessandra , Avolio Maria , Goitre Luca , Forni Marco , Capra Valeria , Alafaci Concetta , Mareni Cristina , Garrè Cecilia , Bramanti Placido , Sidoti Antonina , Retta Saverio Francesco , Amato Aldo 
Published: August 2010

AbstractCerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities. CCMs can occur as sporadic or familial autosomal dominant form. Familial cases are associated with mutations in CCM1[K‐Rev interaction trapped 1 (KRIT1)], CCM2 (MGC4607) and CCM3 (PDCD10) genes. In this study, a three‐gene mutation screening was performed by direct exon sequencing, in a cohort of 95 Italian patients either sporadic or familial, as well as on their at‐risk relatives. Sixteen mutations in 16 unrelated CCM patients were identified, nine mutations are novel: c.413T > C; c.601C > T; c.846 + 2T > G; c.1254delA; c.1255‐4delGTA; c.1681‐1682delTA in CCM1; c.48A > G; c.82‐83insAG in CCM2; and c.396G > A in CCM3 genes. The samples, negative to direct exon sequencing, were investigated by MLPA to search for intragenic deletions or duplications. One deletion in CCM1 exon 18 was detected in a sporadic patient. Among familial cases 67% had a mutation in CCM1, 5.5% in CCM2, and 5.5% in CCM3, whereas in the remaining 22% no mutations were detected, suggesting the existence of either undetectable mutations or other CCM genes. This study represents the first extensive research program for a comprehensive molecular screening of the three known genes in an Italian cohort of CCM patients and their at‐risk relatives.
Development of an ErbB‐overexpressing A‐431 Optical Reporting Tumor Xenograft Model to Assess Targeted Photodynamic Therapy Regimens
Authors: Savellano Mark D. , Owusu‐Brackett Nicci , Son Ji , Callier Thierri , Savellano Dagmar Högemann 
Published: August 2010

AbstractTo better assess the efficacy of erbB‐targeted therapies, it would help to have optical reporting human tumor xenograft models that abundantly express erbB receptors. A‐431 cells have frequently been used in erbB1‐targeting studies, but a well‐characterized optical reporting version of the cell line has not been readily available. In this study, optical reporting A‐431 clones were developed that express both a fluorescent protein reporter (green, GFP; or red, RFP) and a bioluminescent reporter, firefly luciferase. Reporter genes were transduced into cells using commercial lentiviral vectors, and clonal selection was carried out using a series of procedures. A number of clones were isolated for further characterization. A GFP/luciferase clone, A‐431/D4, and an RFP/luciferase clone, A‐431/G4, were obtained that exhibit erbB1 expression levels and tumor growth kinetics similar to the parental cells. To demonstrate the utility of the optical reporting clones, A‐431/G4 tumors were grown subcutaneously in nude mice and treated with vascular‐targeted photodynamic therapy (PDT), which targets the angiogenic consequences of erbB signaling. The A‐431/G4 tumor model permitted highly sensitive longitudinal monitoring of PDT treatment response using optical imaging. A‐431/D4 and A‐431/G4 optical reporting tumor models should also prove useful for assessing therapies that directly target the erbB1 receptor.
Inhibition of Histidine Ammonia Lyase by 8‐Methoxypsoralen and Psoralen‐oxidized Photoproducts
Authors: Reilly John T. , Troester Kyle A. , Tyner Trista T. , Vitale Dominick A. , Risher Tiffiany R. 
Published: August 2010

AbstractThe effect of 8‐methoxypsoralen‐UVA therapy on the catalysis of histidine to trans‐urocanic acid by histidine ammonia lyase (HAL, EC 4.3.1.3) was examined using an enzymatic assay from Sigma‐Aldrich where the growth of the trans‐urocanic acid peak at 277 nm was monitored. A Rayonet Photochemical Mini Reactor (Model RMR‐600) equipped with eight, 3500 Å light sources and a custom UVA filter (Model S‐BAL3 2.9 mm), from the Solar Light Company, were used to expose various reaction mixtures to broadband UVA light and UVA/UVB light. A UV‐Vis spectrophotometer (Model Shimadzu UV 2540) with a temperature‐controlled cell holder (Model TCC240) was used to monitor the growth of the trans‐urocanic peak. Results of dark‐binding experiments of 8‐methoxypsoralen in denatured ethanol indicate no inhibition of enzyme activity due to ethanol but noncompetitive inhibition due to 8‐methoxypsoralen. The effects of preirradiated 8‐methoxypsoralen, with both broadband UVA and UVA/UVB, indicate that inhibition was due to psoralen‐oxidized photoproducts. Inhibition of HAL was found when exposed to broadband UVA/UVB and to a lesser extent when exposed to broadband UVA.