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Ana Ellen Queiroz Santiago, Plinio da Cunha Leal, Ed Carlos Rey Moura, Reinaldo Salomão, Milena Karina Coló Brunialti, Rioko Kimiko Sakata Department of Anesthesia, Universidade Federal de São Paulo, São Paulo, Brazil Background: Pregabalin is an anticonvulsant and has been used for postoperative analgesia. This study aimed to assess the effect of a single preoperative dose of pregabalin for analgesia after nephrectomy. Methods: The study was prospective, randomized, comparative, and double-blinded, conducted in 40 kidney transplant donors, between 18 and 60 years, American Society of Anesthesia physical status I or II. Epidural anesthesia was performed with 15 mL of 0.5% ropivacaine single shot and general anesthesia with 3 µg/kg of fentanyl, propofol, atracurium, and sevoflurane, and 50% of oxygen without nitrous oxide. Patients in group 1 were administered 300 mg of pregabalin and those in group 2 were administered placebo, in identical capsules, 1 hour prior to surgery. Postoperative analgesia was supplemented with tramadol. The following parameters were assessed: pain intensity after 6 and 24 hours; pain threshold, from the thenar and peri-incisional region, analgesic supplementation; ILs (IL6, IL8, and IL10) prior to surgery and after 6 and 24 hours. Results: The pain intensity was lower with pregabalin after 24 hours (G1: 2.5±2.4, G2: 3.0±2.6). There was no difference in the sensitivity of the thenar and peri-incisional region after 6 and 24 hours; in the number of patients requiring supplementation (G1=15%, G2=45%); concentrations of IL-6, IL-8, and IL-10; and side effects (nausea, vomiting, dizziness, and pruritus). Conclusion: Pregabalin in a single preoperative dose of 300 mg reduced pain intensity 24 hours after lumbotomy. Keywords: pregabalin, lumbotomy, postoperative analgesia, kidney transplant, nephrectomy

Evelyn Winter,1,2,* Gustavo Jabor Gozzi,1,3,* Louise Domeneghini Chiaradia-Delatorre,4 Nathalia Daflon-Yunes,1 Raphael Terreux,5 Charlotte Gauthier,1 Alessandra Mascarello,4 Paulo César Leal,4 Silvia M Cadena,3 Rosendo Augusto Yunes,4 Ricardo José Nunes,4 Tania Beatriz Creczynski-Pasa,2 Attilio Di Pietro1 1Equipe Labellisée Ligue 2013, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France; 2Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianopolis, Brazil; 3Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Brazil; 4Department of Chemistry, Federal University of Santa Catarina, Florianopolis, Brazil; 5Bioinformatique structures et interactions, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France *These authors contributed equally to this work Abstract: A series of chalcones substituted by a quinoxaline unit at the B-ring were synthesized and tested as inhibitors of breast cancer resistance protein-mediated mitoxantrone efflux. These compounds appeared more efficient than analogs containing other B-ring substituents such as 2-naphthyl or 3,4-methylenedioxyphenyl while an intermediate inhibitory activity was obtained with a 1-naphthyl group. In all cases, two or three methoxy groups had to be present on the phenyl A-ring to produce a maximal inhibition. Molecular modeling indicated both electrostatic and steric positive contributions. A higher potency was observed when the 2-naphthyl or 3,4-methylenedioxyphenyl group was shifted to the A-ring and methoxy substituents were shifted to the phenyl B-ring, indicating preferences among polyspecificity of inhibition. Keywords: ABC transporters, breast cancer resistance protein (BCRP)/ABCG2, quinoxaline derivatives, structure–activity relationships, drug efflux

Background and Purpose: Phosphoinositide 3-kinase-γ (PI3Kγ) is implicated in many pathophysiological conditions, and recent evidence has suggested its involvement in colitis. In the present study, we investigated the effects of AS605240, a relatively selective PI3Kγ inhibitor, in experimental colitis and its underlying mechanisms.Experimental Approach: Acute colitis was induced in mice by treatment with trinitrobenzene sulphonic acid (TNBS), and the effect of AS605240 on colonic injury was assessed. Pro-inflammatory mediators and cytokines were measured by immunohistochemistry, elisa, real time-polymerase chain reaction and flow cytometry.Key Results: Oral administration of AS605240 significantly attenuated TNBS-induced acute colitis and diminished the expression of matrix metalloproteinase-9 and vascular endothelial growth factor. The colonic levels and expression of IL-1β, CXCL-1/KC, MIP-2 and TNF-α were also reduced following therapeutic treatment with AS605240. Moreover, AS605240 reduced MIP-2 levels in a culture of neutrophils stimulated with lipopolysaccharide. The mechanisms underlying these actions of AS605240 are related to nuclear factor-κ (NF-κB) inhibition. Importantly, the PI3Kγ inhibitor also up-regulated IL-10, CD25 and FoxP3 expression. In addition, a significant increase in CD25 and FoxP3 expression was found in isolated lamina propria CD4+ T cells of AS605240-treated mice. The effect of AS605240 on Treg induction was further confirmed by showing that concomitant in vivo blockade of IL-10R significantly attenuated its therapeutic activity.Conclusions and Implications: These results suggest that AS605240 protects mice against TNBS-induced colitis by inhibiting multiple inflammatory components through the NF-κB pathway while simultaneously inducing an increase in the functional activity of CD4+CD25+ Treg. Thus, AS605240 may offer a promising new therapeutic strategy for the treatment of inflammatory bowel diseases. [ABSTRACT FROM AUTHOR]

Objectives: The present systematic review and network meta-analysis of randomized control trials (RCTs) aimed to establish whether there are evidence-based differences in the pharmacological agents used to manage sialorrhea in patients with Parkinson's disease (PD)., Material and Methods: The authors searched the databases: MEDLINE via PubMed, EMBASE, Scopus, Web of Science, and Cochrane Library for clinical trials. Unpublished trials were searched on clinicaltrials.gov and the Brazilian Clinical Trials Registry. Means and standard deviations of changes in the salivary flow or drooling reported by participants due to the interventions were recorded., Results: The authors analyzed 13 RCTs. Compared to the placebo, types A and B of the botulinum toxin effectively reduced the salivary flow and the severity or frequency of drooling. However, the network meta-analysis did not differentiate between the botulinum toxin types. Ipratropium bromide and glycopyrrolate did not differ from the placebo. Indirect evidence showed that ipratropium had similar results to those obtained with both types of botulinum toxin. The CINeMA approach estimated the quality of the evidence as very low for all comparisons., Conclusion: The best treatment for sialorrhea in patients with PD is not fully elucidated yet. Therefore, more well-conducted randomized clinical trials are required to increase the level of evidence., Clinical Relevance: There needs to be more evidence defining the best intervention to treat sialorrhea in patients with PD. However, botulinum toxin types A and B seem to reduce sialorrhea in patients effectively., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder with a higher susceptibility to occur in men. Studies suggest that this susceptibility is related to the hormonal differences observed between men and women, being a risk factor for PD. In addition, testosterone supplementation has shown controversial results in animal models of PD and parkinsonian patients. This study evaluated the effect of chronic administration of testosterone propionate (TP) on motor behavior and neurochemical parameters in the reserpine-induced rat model of parkinsonism. Male Wistar rats received 15 injections of reserpine (RES - 0.1 mg/kg) every other day and were concomitantly treated with different doses (0.1, 1.0, or 5.0 mg/kg) of daily TP for 30 days. The rats were euthanized 48 h after the 15th injection of RES or vehicle. Brains were removed and subjected to Tyrosine hydroxylase (TH) immunohistochemistry. TP at 1.0 mg/kg reduced the damages caused by reserpine in the vacuous chewing and tong protrusion behaviors and prevented dopaminergic damage in the SNpc, VTA, and Striatum. TP at 5.0 mg/kg reduced the damages caused by reserpine in the catalepsy and tong protrusion behaviors, prevented the weight loss, and prevented dopaminergic damage in the VTA. Our results suggest that chronic administration of TP has a protective effect in a rat model of parkinsonism, improving motor alterations and dopamine depletion induced by RES., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Fear is an emotional reaction that arises in dangerous situations, inducing the adaptation to an existing condition. This behavior was conserved in all vertebrates throughout evolution and is observed in mammals, birds, fish, amphibians, and reptiles. The neurocircuitry of fear involves areas of the limbic system, cortical regions, midbrain, and brainstem. These areas communicate with each other so that there is an expression of fear and memory formation to deal with the same situation at another time. The effect of nitric oxide (NO) on fear modulation has been explored. NO is a gaseous compound that easily diffuses through the cell membrane and is produced through the oxidation reaction of l-Arginine to l-citrulline catalyzed by nitric oxide synthase (NOS). Activating the intracellular NO receptor (soluble guanylyl cyclase enzyme - sGC) triggers an enzymatic cascade that can culminate in plastic events in the neuron. NOS inhibitors induce anxiolytic-like responses in fear modulation, whereas NO donors promote fear- and anxiety-like behaviors. This review describes the neurobiology of fear in mammals and non-mammals, how NO is produced in the central nervous system, and how NO acts in fear-like behavior., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Nociception alterations are frequent non-motor symptoms of the prodromal phase of Parkinson's disease (PD). The period for the onset of symptoms and the pathophysiological mechanisms underlying these alterations remain unclear. We investigated the course of nociception alterations in a progressive model of parkinsonism induced by reserpine (RES) in rats. Male Wistar rats (6-7 months) received 5 or 10 subcutaneous injections of RES (0.1 mg/kg) or vehicle daily for 20 days. Motor evaluation and nociceptive assessment were performed throughout the treatment. At the end of the treatment rats were euthanized, the brains removed and processed for immunohistochemical analysis (TH and c-Fos). The RES-treated rats exhibited an increased nociceptive response to mechanical and chemical stimulation in the electronic von Frey and formalin tests, respectively. Moreover, these alterations preceded the motor impairment observed in the catalepsy test. In addition, the RES treatment reduced the TH-immunoreactivity in the ventral tegmental area (VTA) and increased the c-Fos expression in the ventral-lateral periaqueductal gray (vlPAG), rostral ventral medulla (RVM) and dorsal raphe nucleus (DRN) after noxious stimuli induced by formalin. Taken together, our results reinforce that nociceptive changes are one of the early signs of PD and monoamine depletion in basal ganglia can be involved in the abnormal processing of nociceptive information in PD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Hepatic artery thrombosis is an important cause of graft loss and ischemic biliary complications. The risk factors have been related to technical aspects of arterial anastomosis and non-surgical ones., Aim: To evaluate the risk factors for the development of hepatic artery thrombosis., Methods: The sample consisted of 1050 cases of liver transplant. A retrospective and cross-sectional study was carried out, and the variables studied in both donor and recipient., Results: Univariate analysis indicated that the variables related to hepatic artery thrombosis are: MELD (p=0.04) and warm time ischemia (p=0.005). In the multivariate analysis MELD=14.5 and warm ischemia time =35 min were independent risk factors for hepatic artery thrombosis. In the prevalence ratio test for analysis of the anastomosis as a variable, it was observed that patients with continuous suture had an increase in thrombosis when compared to interrupted suture., Conclusions: Prolonged warm ischemia time, calculated MELD and recipient age were independent risk factors for hepatic artery thrombosis after liver transplantation in adults. Transplanted patients with continuous suture had an increase in thrombosis when compared to interrupted suture. Re-transplantation due to hepatic artery thrombosis was associated with higher recipient mortality.

Mitochondrial Myopathy is a rare pathology caused by a defect in the mitochondrial DNA metabolism, leading to defects in the formation of adenosine triphosphate, in the Krebs citric acid cycle, fatty acid oxidation and oxidative phosphorylation. It is manifested by exercise intolerance, muscle fatigue on small efforts, muscle weakness, tachycardia, and difficulty breathing. There are few case reports on the operative management of adult patients suffering from mitochondrial myopathy. With this report, we intend to describe the anesthetic management of a patient with mitochondrial myopathy who underwent laparoscopic gastroplasty and outline some anesthetic considerations about this pathology., (Copyright © 2020 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Environmental enrichment (EE) has been used to investigate behavioral changes and neuroplasticity in brain in normal and pathological conditions. Besides, the EE has been used to understand the neurobehavioral systems involved in learning experiences, visual inputs, defensive responses, social interactions and memory. However, the required exposure duration to remove aversive memories remains lacking. Therefore, the purpose of the present study was to investigate the time-course effect of EE exposure on the extinction of aversive memory. Young adult male Wistar rats were exposed to two different EE protocols: short-term environmental enrichment (EE2 - animal kept under enriched conditions for two weeks) and long-term environmental enrichment (EE4 - animal kept under enriched conditions for four weeks). The contextual fear conditioning test was used to assess aversive memory. The both EE protocols provide changes in Zif-268 immunoreactivity in mesocorticolimbic areas such as CA1 and central amygdala; however, only short-term EE reduces the ZIF-268 immunoreactivity in VTA. Besides, both EE protocols also provide an increase in TH immunoreactivity in VTA and nucleus accumbens, but only the short-term EE modifies the TH immunoreactivity in CA1 and infralimbic region of the prefrontal cortex. The time-course effect of EE interferes differently on the extinction of aversive memory, being two weeks of exposure with EE sufficient to cause improvement in coping during aversive situations, favoring the extinction of conditioned fear memory., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Objectives: Surgical trauma, pain and opioids can cause nausea, vomiting, ileus and increased length of hospital stay. The primary objective of the study was to evaluate the time to recovery of gastrointestinal function and the time to meet hospital discharge criteria after laparoscopic bariatric surgery with intraoperative intravenous lidocaine administration. Secondary objectives were to evaluate morphine consumption during the first 24 h and the side effects of opioids., Methods: Fifty-eight patients aged 18 to 60 years who underwent bariatric surgery were allocated into two groups. Group 1 patients received intravenous lidocaine (1.5 mg/kg) 5 min before induction of anaesthesia, followed by infusion (2 mg/kg/h) until the end of surgery. Group 2 patients were given 0.9% saline solution (placebo) and infusion of 0.9% saline solution during surgery, in same volume as group 1. Anaesthesia was performed with fentanyl (5 μg/kg), propofol (2 mg/kg), rocuronium (0.6 mg/kg) and sevoflurane. Postoperative patient-controlled analgesia was with morphine. There were two groups that were evaluated: time to recovery of gastrointestinal function and time to meet discharge criteria., Results: There was no significant difference between groups regarding the time to first flatus, time to meet discharge criteria and occurrence of side effects. Consumption of intraoperative sevoflurane and morphine over 24 h was significantly lower in the lidocaine group. Side effects observed were nausea and vomiting, with no difference between groups., Conclusions: Perioperative intravenous lidocaine is feasible and easily accessible when administered at appropriate doses. Lidocaine reduces morphine consumption.

Aim: This study assessed the changes in color and translucency of dentin and enamel after staining and bleaching procedures as well as the contribution of the tissues to color change (CTCC)., Materials and Methods: Fifty enamel-dentin specimens were obtained from bovine incisors and grouped into 10 blocks based on the similarity of the baseline color. One specimen in each block was used as the control, and the others were intrinsically (blood) or extrinsically (coffee) stained. One stained specimen for each pigment was bleached with 35% hydrogen peroxide. The enamel was separated from the dentin, and the tooth color and translucency parameter (TP) were measured individually and after recombining these substrates. Changes in color (ΔE00), whitening index (WI), and TP caused by the staining and bleaching procedures were estimated through assessing the color differences compared with the controls. CTCC was also calculated by recombining the enamel and dentin tissues from different treatments. The data were analyzed using the paired t test or the two-way repeated measures ANOVA (α = 0.05)., Results: Extrinsic staining procedures produced higher color changes than intrinsic ones, except in dentin. The highest bleaching effect was observed in the dentin of specimens that were extrinsically stained. Similar CTCC values were observed for the dentin and enamel for both the staining and bleaching procedures. Except for the specimens that were treated with intrinsic staining and became more translucent after the bleaching procedure, the other treatments resulted in non-significant TP changes., Conclusions: Staining the specimens extrinsically resulted in higher color change than staining them intrinsically, and these specimens were more affected by the bleaching procedure. Enamel and dentin demonstrated similar CTCC values.

Background: In-office dental bleaching results in a high risk of tooth sensitivity caused by the inflammatory process of the pulpal tissue. In this systematic review, the authors aimed to evaluate the effect of administering anti-inflammatory and analgesic drugs for the prevention of tooth sensitivity associated with in-office dental bleaching., Types of Studies Reviewed: The authors searched the databases MEDLINE via PubMed, Scopus, Web of Science, and Cochrane Library for clinical trials. They searched in ClinicalTrials.gov for unpublished trials. The authors included only randomized clinical trials comparing anti-inflammatory and analgesic drugs with a placebo and evaluating tooth sensitivity after in-office bleaching. They imposed no restrictions regarding publication dates or languages., Results: The authors identified 5,050 studies after the removal of duplicates. They qualitatively and quantitatively analyzed the 11 studies remaining after the title and abstract screening. Nine studies showed a low risk of bias. The authors found no effect of the drugs on the risk (9 studies evaluated this outcome). Using a visual analog scale, the authors identified a similar level of sensitivity evaluated up to 1 hour (10 studies evaluated this outcome) and 24 hours (8 studies evaluated this outcome). They observed similar results using the numeric rate scale (8 and 6 studies used this tool, up to 1 hour and 24 hours respectively). The Grading of Recommendations Assessment, Development, and Evaluation approach showed a high level of evidence for all outcomes., Conclusions and Practical Implications: The high level of evidence available does not support the administration of anti-inflammatory and analgesic drugs to prevent tooth sensitivity caused by in-office dental bleaching., (Copyright © 2019 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Histoplasmosis is a systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum, with disseminated histoplasmosis (HD) being one of its clinical forms. As a consequence of the HIV-AIDS pandemic, HD has become prevalent not only in regions that are recognized as endemic but also in areas not considered endemic, such as Europe and Asia. Its clinical manifestations are varied and mimic several infectious diseases, mainly tuberculosis. In endemic areas, it is the first manifestation of AIDS in 50 to 70% of patients. The diagnosis of histoplasmosis is difficult and HD can lead to death if not diagnosed early and if proper treatment is not instituted. The present report presents a patient with a recent diagnosis of HIV-AIDS, in treatment for miliary tuberculosis, who was diagnosed with disseminated histoplasmosis because of his dermatological manifestations.

Parkinson's disease (PD) exhibits sexual differences in susceptibility and pathogenesis in humans, with a high incidence in men and a high severity of motor symptoms in male rodents. Furthermore, studies showed that the administration of low dose of reserpine (RES) induces a progressive appearance of motor alterations similar with parkinsonism in male rodents. Here, we investigated sex differences in motor deficits and tyrosine hydroxylase (TH) immunoreactivity induced by a progressive model of parkinsonism. Gonadally intact male and female Wistar rats and ovariectomized female rats received 15 subcutaneous injections (s.c.) every other day of 0.1 mg/kg of RES or vehicle. The repeated administration of low doses of RES (0.1 mg/kg) produces sexually dimorphic impairments on motor performance (catalepsy and open field test). Intact and ovariectomized females were more resistant to the deleterious effect of repeated administration of reserpine in the early, but this resistance in intact female disappears over time. However, intact females showed a reduction of the TH immunoreactivity in substantia nigra pars compacta, but not in ventral tegmental area and dorsal striatum. These results suggest a possible application of this model in the study of sexual dimorphism throughout the progression of PD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is mainly characterized by a dopamine deficiency accompanied by structural and functional changes in striatal neuronal projections. However, studies have considered PD as a multi-systemic disease in which the neurodegenerative process extends beyond the dopaminergic system. Therefore, the purpose of the present study was to investigate the time-course of serotonergic neuron damage in a progressive model of parkinsonism induced by a low dose of reserpine. Thus, male Wistar rats received 4 (ST, short-treatment of reserpine) or 10 (MT, middle-term treatment of reserpine) subcutaneous injections of vehicle or reserpine (0.1 mg/kg) at a volume of 1 mL/kg body weight, on alternate days. Animals were euthanized 48 h after the last injection for immunohistochemical analysis. After ST, 5-HT immunoreactivity decreased in hippocampal subareas (CA1 and CA3) and medial prefrontal cortex (mPFC) compared to vehicle. Furthermore, animals MT-treated also showed progressive decrease of 5-HT immunoreactivity in CA1 and CA3 subareas. Conversely, a significant increase of 5-HT immunoreactivity was found in mPFC and dorsal raphe nucleus (DRN) in animals submitted to MT when compared to ST exposure. The results showed that, in the repeated low-dose reserpine rat model, variations in the immunoreactivity of 5-HT start early in the course of progressive parkinsonism., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is mostly known as a dopamine deficiency syndrome due the structural and functional changes in striatal projection neurons. However, studies have considered this pathology as a multi-systemic disease in which the neurodegenerative process extends beyond the dopaminergic system. Therefore, the purpose of the present study was to investigate the morphological and immunohistochemical changes associated with behavioral and cognitive alterations in a model of parkinsonism induced by low dose of reserpine. Animals showed anxiety-like behavior and deficits in short-term recognition memory. Besides, Tyrosine Hydroxylase (TH) immunoreactive cells decreased in reserpine (RES) group in CA1 and serotonin (5-HT) immunoreactive cells decreased in RES group in CA1, CA3 and medial prefrontal cortex (mPFC). Moreover, an increase in the area (μm2) of 5 H T labeled ultrastructure (axon terminal) was observed in RES group only in CA1 and mPFC. The evidence of alterations in 5-HT immunoreactive in the premotor phase of model of parkinsonism highlights the importance of looking beyond the nigrostriatal system to elucidate the underling mechanisms and deficits in other neurotransmitters systems. This provides vital information regarding novel interventions for the management of non-motor symptoms. Additionally, the low-dose reserpine treatment has an early effect on axonal ultrastructure. As the axonopathy in PD has been increasingly recognized, the focus on axonal neurobiology is noteworthy for both neuroprotective and restorative therapeutics, and the progressive reserpine rat model can be a useful tool in this search., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This in vitro study aimed to evaluate the effect of two alternative clinical protocols on the tooth bleaching effectiveness of 37% carbamide peroxide. Thirty enamel-dentin blocks from bovine incisors were stained with a coffee solution for 1 week. After color measurement at baseline with a portable spectrophotometer, the blocks were bleached during two 45-min applications of 37% carbamide peroxide with a 2-day interval between bleaching procedures, according to one of the following protocols: 1) Control: placement of bleaching agent over dried enamel; 2) Moist enamel: placement of bleaching agent over enamel previously humidified with a damp gauze for 1 min; 3) Moist cotton pellet: covering the bleaching agent with a moist cotton pellet during the entire bleaching procedure. The tooth color was assessed 2 days after each bleaching procedure. The data of ΔL, Δa, Δb, and ΔE were individually analyzed using ANOVA and Tukey's test (α = 0.05). In general, applying the bleaching agent to the moist enamel resulted in lower Δa and Δb values, and higher ΔL and ΔE values than the control. No difference was observed between the control and the protocol of covering the bleaching agent with a moist cotton pellet. Regardless of the protocol, the second bleaching procedure resulted in a further increase in ΔL and ΔE, and a reduction in Δa. A further decrease in Δb was observed only for the moist enamel protocol. In conclusion, humidifying the enamel with a damp gauze prior to the placement of 37% carbamide peroxide improved the effectiveness of the bleaching.

Parkinson's disease (PD) is a neurodegenerative disease related to the dopaminergic system. The etiology is not fully understood, but it is known that PD is a multifactorial disease that involves genetic and environmental factors, including pesticides. One of these, Deltamethrin (DM), has been widely used for vector control in crops, farming, veterinary medicine and domestic pest control. The purpose of the present study was to investigate the effect of DM repeated administration on motor, cognitive and emotional behavior and dopaminergic parameters. Male Wistar rats received 3 intranasal (i.n.) injections of 100 μL (50 μL/nostril) of DM 0.5 μg/μl or Vehicle (saline solution 0.9%), one injection per week. We observed that DM caused memory (novel object recognition task) and emotion (contextual conditioned fear) alterations accompanied by reduction of TH immunoreactivity in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA), and increase of TH immunoreactivity in the dorsal striatum. Motor alterations (catalepsy and open field task) were not observed throughout treatment. These findings suggest a possible early disruption of the dopaminergic pathway caused by repeated DM exposure, similar to that observed in early stages of PD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

This study evaluated the effects of tooth bleaching with high-concentration of hydrogen peroxide on alterations of translucency parameter (TP) and color of dentin and enamel. The crown of five human molars was sectioned into four slices parallel to buccal surface. The dentin of external slices containing buccal/ lingual enamel was fully removed with diamond bur; while these slices were used to assess alterations on enamel. Alterations on dentin were assessed into the center of internal slices. The color of specimens was measured over white and black backgrounds using a spectrophotometer (CieL*a*b) at baseline, allowing to calculate the TP by difference between the color measured over each background. Specimens were submitted to three 15-min applications of 35% hydrogen peroxide followed by their storage in water for one-week. Afterwards, the color measurements were repeated at both backgrounds. Color (∆L, ∆a, ∆b and ∆E) and translucency (∆TP) changes were calculated and data individually analyzed by T-test (α = 0.05). Influence of hard tissue and assessment time on each color parameter was also analyzed by 2-way repeated measure ANOVA (α = 0.05). Tooth bleaching resulted in increased lightness for the enamel, whereas no alteration on this parameter occurred for dentin. No difference between the tooth hard tissues was observed regards the other color parameters and ∆E. A slightly reduction on TP was observed only for the enamel. In conclusion, 35% hydrogen peroxide caused similar color and translucency changes on dentin and enamel.

Objective: Anxiety as a uni- or multidimensional construct has been under discussion. The unidimensional approach assumes that there is a general trait anxiety, which predisposes the individuals to increases in state anxiety in various threatening situations. In this case, there should be a correlation between state and trait anxiety in any situation of threat. Therefore, the aim of this study was to investigate the correlation between trait and state anxiety in participants exposed to two different anxiogenic situations: interpersonal threat (Video-Monitored Stroop Test - VMST) and physical threat (third molar extraction - TME)., Methods: Participants with various levels of trait anxiety (general trait: State-Trait Anxiety Inventory - STAI, Hospital Anxiety and Depression Scale; specific trait: Social Phobia Inventory, Dental Anxiety Scale) had their anxious state evaluated (STAI, self-evaluation of tension level, heart rate, electromyogram activity) before, during and after the VMST or the TME., Results: In VMST, trait anxiety correlated to state anxiety (psychological parameters) in all test phases. However, in TME, the only trait measurement that correlated to state anxiety (psychological parameters) was the Dental Anxiety Scale., Conclusion: Trait anxiety correlates positively to state anxiety in situations of interpersonal threat, but not of physical threat.

Background: Clinicians often use calcium hydroxide liners during stepwise treatment of advanced caries. In this randomized clinical trial, the authors compared the short-term outcome of stepwise caries removal with and without use of a calcium hydroxide liner in conjunction with provisional resin-modified glass ionomer (RMGI) restorations., Methods: The authors included in the trial 98 patients aged 15 to 30 years who had a deep carious lesion in a posterior tooth. The authors measured the dentin thickness radiographically and recorded its color, consistency, and moisture, as well as the bacterial count of the lesions. After partial caries removal, the authors assigned patients randomly to have their caries provisionally restored using RMGI with (control group) or without (test group) a calcium hydroxide liner. The primary outcome measure was tooth vitality after 90 days. Secondary outcomes included changes in dentinal, radiographic, and microbiological characteristics of the lesions., Results: The authors found no statistically significant difference between the test and control groups in tooth vitality after 90 days. Irrespective of calcium hydroxide liner use, the authors observed darker, harder, drier, and less contaminated dentin after the provisional restorations, but dentin thickness remained unchanged., Conclusions: On the basis of this 3-month clinical trial's results, the use of a calcium hydroxide liner during stepwise caries excavation and provisional restoration did not provide any additional benefit., Practical Implications: After 3 months, using a calcium hydroxide liner does not appear to offer any additional benefit when clinicians use RMGI provisional restorations during stepwise caries removal. Longer studies are needed to confirm these results., (Copyright © 2017 American Dental Association. Published by Elsevier Inc. All rights reserved.)

This article reports the use of elastic suture as an adjuvant in surgical wound closure caused by decompressive fasciotomy after compartment syndrome associated with a compound fracture of the tibia. Widely used in other medico-surgical specialties, this technique is unusual in orthopedics surgery, but the simplicity of the procedure and the successful outcome observed in this case allows for its consideration as indicated for situations similar to that presented in this study.

To characterize the role and the mechanism of action of (2E)-N'-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide (BZD) on incretin secretion, glucose uptake in skeletal muscle and α-glucosidase activity on intestine, targets for glucose homeostasis. It was assayed on glucose tolerance test (GTT) to analyze GLP-1 secretion and the activity of DPP-4 enzyme in vitro. In skeletal muscle, mechanism of action on glucose uptake was carried out by in vitro experiments. The activity of intestinal disaccharidases was performed after in vivo and in vitro experiments. The compound improved the glucose tolerance around 30%, 25%, and 20% at 15, 30, and 60 min, respectively and potentiated the sitagliptin effect, an inhibitor of the enzyme that removes GLP-1, about 50, 45, and 54% at 15, 30, and 60 min, respectively. Additionally, BZD did not modify the activity of DPP-4 enzyme. The acute effect of BZD on glucose uptake is mediated by increasing GLUT4 expression (around 140%) and its translocation to the plasma membrane in soleus muscle. The genomic effect as well as GLUT4 translocation involve the activation of PI-3K and MAPK pathways and require the microtubules integrity to the complete stimulatory effect of this compound on glucose uptake. Beyond, BZD acts in an alternative target to ameliorate glycaemia, intestinal disaccharidases. In a whole, these data point an incretino- and insulinomimetic effect of the compound for glycemic control., (© 2015 Wiley Periodicals, Inc.)

Acute Lymphoblastic Leukemia (ALL) is the most frequent childhood malignancy. In the effort to find new anti-leukemic agents, we evaluated the small drug SB225002 (N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea). Although initially described as a selective antagonist of CXCR2, later studies have identified other cellular targets for SB225002, with potential medicinal use in cancer. We found that SB225002 has a significant pro-apoptotic effect against both B- and T-ALL cell lines. Cell cycle analysis demonstrated that treatment with SB225002 induces G2-M cell cycle arrest. Transcriptional profiling revealed that SB225002-mediated apoptosis triggered a transcriptional program typical of tubulin binding agents. Network analysis revealed the activation of genes linked to the JUN and p53 pathways and inhibition of genes linked to the TNF pathway. Early cellular effects activated by SB225002 included the up-regulation of GLIPR1, a p53-target gene shown to have pro-apoptotic activities in prostate and bladder cancer. Silencing of GLIPR1 in B- and T-ALL cell lines resulted in increased resistance to SB225002. Although SB225002 promoted ROS increase in ALL cells, antioxidant N-Acetyl Cysteine pre-treatment only modestly attenuated cell death, implying that the pro-apoptotic effects of SB225002 are not exclusively mediated by ROS. Moreover, GLIPR1 silencing resulted in increased ROS levels both in untreated and SB225002-treated cells. In conclusion, SB225002 induces cell cycle arrest and apoptosis in different B- and T-ALL cell lines. Inhibition of tubulin function with concurrent activation of the p53 pathway, in particular, its downstream target GLIPR1, seems to underlie the anti-leukemic effect of SB225002.

Study Objective: Opioids are associated with hyperalgesia that can reduce their analgesic effect. The aim of this study was to determine whether the addition of ketamine reduces remifentanil-induced hyperalgesia; improves its analgesic effect; and alters interleukin 6 (IL-6), IL-8, and IL-10 levels., Design: This is a prospective, randomized, double-blind study., Setting: The setting is in a operating room and ward in a university hospital., Patients: There are 56 patients, aged ≥18 years, American Society of Anesthesiologists I or II, who underwent laparoscopic cholecystectomy., Interventions: Anesthesia was induced with remifentanil, 50% oxygen, and isoflurane. Patients randomized to group 1 received remifentanil (0.4 μg/kg per minute) and ketamine (5 μg/kg per minute), and patients randomized to group 2 received remifentanil (0.4 μg/kg per minute) and saline solution. Postoperative analgesia was achieved using morphine via patient-controlled analgesia., Measurements: The measurements were postoperative pain intensity during 24 hours; morphine consumption; time to first morphine supplementation; hyperalgesia (using monofilaments and an algometer) and allodynia (using a soft brush) in the thenar eminence of the nondominant hand and in the periumbilical region 24 hours after surgery; extent of hyperalgesia using a 300-g monofilament near the periumbilical region 24 hours after surgery; and serum levels of IL-6, IL-8, and IL-10., Main Results: Groups were similar for baseline characteristics. There were no differences in pain intensity, time to first request of morphine, and total 24 hours dose of morphine between groups. There was a difference in hyperalgesia using monofilaments 24 hours after the surgery in the thenar eminence of the nondominant hand, with a better profile for the experimental group. However, there were no differences in hyperalgesia using an algometer, in allodynia using a soft brush; in extent of hyperalgesia; or in levels of IL-6, IL-8, and IL-10., Conclusions: It was not possible to demonstrate that the addition of ketamine (5 μg/kg per minute) is effective in preventing or reducing remifentanil-induced postoperative hyperalgesia in laparoscopic cholecystectomy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy.

Falcipain-2 (FP-2) is a key cysteine protease from the malaria parasite Plasmodium falciparum. Many previous studies have identified FP-2 inhibitors; however, none has yet met the criteria for an antimalarial drug candidate. In this work, we assayed an in-house library of non-peptidic organic compounds, including (E)-chalcones, (E)-N'-benzylidene-benzohydrazides and alkyl-esters of gallic acid, and assessed the activity toward FP-2 and their mechanisms of inhibition. The (E)-chalcones 48, 54 and 66 showed the lowest IC50 values (8.5 ± 0.8 µM, 9.5 ± 0.2 µM and 4.9 ± 1.3 µM, respectively). The best inhibitor (compound 66) demonstrated non-competitive inhibition, and using mass spectrometry and fluorescence spectroscopy assays, we suggest a potential allosteric site for the interaction of this compound, located between the catalytic site and the hemoglobin binding arm in FP-2. We combined structural biology tools and mass spectrometry to characterize the inhibition mechanisms of novel compounds targeting FP-2.

Chalcones are important compounds that exhibit multiple biological activities, including anti-inflammatory, antimitotic and antibacterial properties. In the present study, we have analyzed the potential anti-cancer activity of a chalcone named N9 (a hybrid chalcone-quinoxaline compound) using in vitro and in vivo experimental glioma models. Here, we report N9-induced inhibition of cell proliferation and also N9-induced cell death in a concentration-dependent manner in U87-MG glioma cells. These effects of N9 appear to be associated with its ability to inhibit the expression of cell cycle-associated proteins, and also the augmentation in the expression of the p21 (p21/Cip1) protein, a cyclin-dependent kinase inhibitor. Additionally, N9 also potentiates the production of the pro-apoptotic markers Bax and p53 via inhibition of MDM2. Moreover, our results show that N9 also significantly enhanced apoptosis of U87-MG cells with disruption of mitochondrial membrane potential, generation of ROS and caspase-9 activation. In vivo experiments carried out in a murine xenograft model of U87-MG revealed that N9 produced a significant reduction of tumors volume when compared to vehicle treated mice. Collectively, data demonstrate that N9 possess in vitro and in vivo anti-cancer activity, an effect that seems to involve the induction of p53 and p21 proteins, as well as, the activation of mitochondrial apoptosis pathway associated with the inhibition of protein MDM2. Overall, this study suggests N9 is affecting a variety of intracellular pathways related to tumor apoptosis. Perhaps N9 or derivate molecules could represent new potential drugs for cancer therapeutics., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

This study aimed to evaluate the effect of maintaining a bottle of adhesive without its lid on the solvent loss of the etch-and-rinse adhesive systems. Three 2-step etch-and-rinse adhesives with different solvents (acetone, ethanol or butanol) were used in this study. Drops of each adhesive were placed on an analytical balance and the adhesive mass was recorded until equilibrium was achieved (no significant mass alteration within time). The solvent content of each adhesive and evaporation rate of solvents were measured (n=3). Two bottles of each adhesive were weighted. The bottles were maintained without their lids for 8 h in a stove at 37 ºC, after which the mass loss was measured. Based on mass alteration of drops, acetone-based adhesive showed the highest solvent content (46.5%, CI 95%: 35.8-54.7) and evaporation rate (1.11 %/s, CI95%: 0.63-1.60), whereas ethanol-based adhesive had the lowest values (10.1%, CI95%: 4.3-16.0; 0.03 %/s CI95%: 0.01-0.05). However, none of the adhesives bottles exhibited significant mass loss after sitting for 8 h without their lids (% from initial content; acetone - 96.5, CI 95%: 91.8-101.5; ethanol - 99.4, CI 95%: 98.4-100.4; and butanol - 99.3, CI 95%: 98.1-100.5). In conclusion, maintaining the adhesive bottle without lid did not induce significant solvent loss, irrespective the concentration and evaporation rate of solvent.

Background: osteoarthrosis is a common cause of low back pain. The diagnosis is clinical and can be confirmed by imaging studies. Pain treatment and confirmation of diagnosis are made by intra-articular injection of corticosteroid and by local anesthetic use, due to clinical improvement. A direct monitoring of the procedure can be done under fluoroscopy, a classic technique, or else by an ultrasound-guided procedure., Case Report: female patient, 88 years old, 1.68 m and 72 kg, with facet osteoarthrosis at L2-L3, L3-L4 and L4-L5 for two years. On physical examination, she exhibited pain on lateralization and spinal extension. We opted in favor of an ultrasound-guided facet joint block. A midline spinal longitudinal scan was obtained, with identification of the desired joint space at L3-L4. A 25G needle was inserted into the skin by the echographic off-plane ultrasound technique. 1 mL of contrast was administered, with confirmation by fluoroscopy. After aspiration of the contrast, 1 mL of solution containing 0.25% bupivacaine hydrochloride and 10mg of methylprednisolone acetate was injected. Injections into L3-L4, L2-L3 and L1-L2 to the right were applied., Conclusions: the visualization of the facet joint by ultrasound involves minimal risk, besides reduction of radiation. This option is suitable for a large part of the population. However, fluoroscopy and computed tomography remain as monitoring techniques indicated for patients with specific characteristics, such as obesity, severe degenerative diseases and anatomical malformations, in which the ultrasound technique is still in need of further study., (Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Objective: To study the anti-herpes simplex virus (HSV) activity of a (1→6)-(1→3)-β-D-glucan isolated from Agaricus brasiliensis fruiting bodies (FR) as well as its chemically sulfated derivative (FR-S)., Methods: The antiherpetic activity and mechanism of action was studied by viral plaque assay applying different methodological strategies., Results: Although FR presented no in vitro antiherpetic action at 1 mg/ml, FR-S displayed promising anti-HSV-1 and anti-HSV-2 activities in both simultaneous and postinfection treatments, resulting in selectivity indices (CC₅₀/EC₅₀) higher than 393. FR-S had no virucidal effect, but significantly suppressed HSV-1 (EC₅₀ = 0.32 µg/ml) and HSV-2 (EC₅₀ = 0.10 µg/ml) adsorption. FR-S was less effective on adsorption inhibition of mutant virus strains devoid of gC (HSV-1 gC⁻39 and HSV-2 gCneg1), indicating a possible interaction with this glycoprotein. The reduction of viral adsorption upon cell pretreatment with FR-S also suggests its interaction with cellular components. FR-S inhibited HSV-1 (EC₅₀ = 8.39 µg/ml) and HSV-2 (EC₅₀ = 2.86 µg/ml) penetration more efficiently than heparin. FR-S reduced HSV-1 and HSV-2 cell-to-cell spread. A synergic effect between FR-S and acyclovir was also detected., Conclusions: FR-S displays an interesting mechanism of antiviral action and represents a promising candidate for the treatment and/or prevention of herpetic infections, to be used as a single therapeutic agent or in combination with acyclovir., (© 2014 S. Karger AG, Basel.)

New unconventional approaches to the development of antimicrobial drugs must target inhibition of infection stages leading to host colonisation or virulence itself, rather than bacterial viability. Amongst the most promising unconventional targets for the development of new antimicrobial drugs is bacterial adherence and biofilm formation as well as their control system, the quorum-sensing (QS) system, a mechanism of communication used to co-ordinate bacterial activities. Here we describe the evaluation of synthetic organic compounds as bacterial biofilm inhibitors against a panel of clinically relevant Gram-positive and Gram-negative bacterial strains. This approach has successfully allowed the identification of five compounds (GEt, GHex, GOctad, G19 and C33) active not only against bacterial biofilms but also displaying potential to be used as antagonists and/or inhibitors of bacterial QS., (Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.)

Background and Objectives: The combination of ketamine and remifentanil seems to be associated with better analgesia and duration. The aim of this study was to evaluate whether a ketamine- remifentanil combination promotes improved postoperative analgesia., Methods: Prospective, randomized, double blind study of 40 patients undergoing video laparoscopic cholecystectomy. Anesthesia was performed with remifentanil, propofol, atracurium, and 50% oxygen. Group 1 (GI) patients received remifentanil (0.4 mcg.kg(-1).min(-1)) and ketamine (5 mcg.kg(-1).min(-1)) and Group 2 (G2) received remifentanil (0.4 mcg.kg(-1).min(-1)) and saline solution. Morphine 0.1 mg.kg(-1) was administered at the end of the procedure, and postoperative pain was treated with morphine via PCA. We evaluated the severity of postoperative pain by a numerical scale from zero to 10 during 24 hours. We registered the time to the first analgesic supplementation, amount of morphine used in the first 24 hours, and adverse effects., Results: There was a decrease in pain severity between extubation and other times evaluated in G1 and G2. There was no significant difference in pain intensity between the groups. There was no difference between G1 (22 ± 24.9 min) and G2 (21.5 ± 28.1 min) regarding time to first dose of morphine and dose supplement of morphine consumed in G1 (29 ± 18.4 mg) and G2 (25.1 ± 13.3 mg)., Conclusion: The combination of ketamine (5 mcg.kg(-1).min(-1)) and remifentanil (0.4 mcg.kg(-1).min(-1)) for cholecystectomy did not alter the severity of postoperative pain, time to first analgesic supplementation or dose of morphine in 24 hours., (Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Background and Objectives: Despite advances, inappropriate analgesic treatment for burn patients is still seen. The objective of this review was to collect data on pain management in burn patients., Content: We reviewed the mechanisms of pain, burn patient assessment, as well as pharmacological and non-pharmacological treatment., Conclusion: Pain management in burn patients is still a challenge for the multidisciplinary team. Frequent and continuous evaluation of the patient's response is very important due to the various stages that the hospitalized burn patient goes through, as well as a combination therapy with analgesic and non-pharmacological measures. Understanding the complexity of the pathophysiological, psychological, and biochemical changes a burn patient presents is the first step to achieve success in analgesic management., (Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Background and Objectives: Despite advances, inappropriate analgesic treatment for burn patients is still seen. The objective of this review was to collect data on pain management in burn patients., Content: We reviewed the mechanisms of pain, burn patient assessment, as well as pharmacological and non-pharmacological treatment., Conclusion: Pain management in burn patients is still a challenge for the multidisciplinary team. Frequent and continuous evaluation of the patient's response is very important due to the various stages that the hospitalized burn patient goes through, as well as a combination therapy with analgesic and non-pharmacological measures. Understanding the complexity of the pathophysiological, psychological, and biochemical changes a burn patient presents is the first step to achieve success in analgesic management., (Copyright © 2013 Elsevier Editora Ltda. All rights reserved.)

This study evaluated the relevance of CXCR2 chemokine receptors in oral squamous cell carcinoma, by means of in vitro and in vivo approaches. The in vitro incubation of the selective and non-peptide CXCR2 receptor antagonist N-(2-hydroxy-4-nitrophenyl)-N9-(2-bromophenyl) Urea (SB225002; 25 to 800 nM) produced a time- and concentration-dependent inhibition of SCC158 (rat) and HN30 (human) cell lines viability. Conversely, this antagonist did not significantly affect the viability of the immortalized keratinocyte lineage, HaCaT. Additionally, the incubation of human IL-8 and rat CINC-1 CXCR2 agonists produced a concentration-related increase on HN30 and SCC158 proliferation. The submucosal injection of SCC158 cells (5 × 10(6) cells) into the tongue of Fischer 344 rats induced tumor development, which displayed typical clinical features. Immunohistochemical analysis of rat tongue biopsies revealed a marked increase of CXCR2 receptor immunoreactivity, which was accompanied by augumented expression of VEGF and caspase-3. Our data suggests an important role for CXCR2 receptors in oral squamous cell carcinoma.

Gliomas are the most common and devastating tumors of the central nervous system (CNS). Many pieces of evidence point out the relevance of natural compounds for cancer therapy and prevention, including chalcones. In the present study, eight synthetic quinoxaline-derived chalcones, structurally based on the selective PI3Kγ inhibitor AS605240, were evaluated for anti-proliferative activity and viability inhibition using glioma cell lines from human and rat origin (U-138 MG and C6, respectively), at different time-periods of incubation and concentrations. The results revealed that four chalcones (compounds 1, 6, 7 and 8), which present methoxy groups at A-ring, displayed higher efficacies and potencies, being able to inhibit either cell proliferation or viability, in a time- and concentration-dependent manner, with an efficacy that was greater than that seen for the positive control compound AS605240. Flow cytometry analysis demonstrated that incubation of C6 cells with compound 6 led to G1 phase arrest, likely indicating an interference with apoptosis. Furthermore, compound 6 was able to visibly inhibit AKT activation, allied to the stimulation of ERK MAP-kinase. The chalcones tested herein, especially those displaying a methoxy substituent, might well represent promising molecules for the adjuvant treatment of glioma progression., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

In this study the in vivo and in vitro antidiabetic effects of four acylhydrazone derivatives were investigated in rats. The secretagogue action, oral glucose tolerance, insulinogenic index and mechanism of action of these acylhydrazones in relation to calcium uptake in pancreatic islets were studied. Also, the insulinomimetic effect on glycemia in diabetic rats was verified. Of the acylhydrazones studied, 1 and 4 were able to increase glucose tolerance in an acute time-course. A powerful secretagogue effect was exhibited by 1 and glibenclamide with an insulinogenic index around 3.9 and 1.3-fold higher than that of the hyperglycemic group, respectively. Moreover, an acute and dose-dependent effect of glibenclamide and 1 on calcium uptake in pancreatic islets was observed. The rapid stimulatory effect of 1 on calcium uptake seems to be mediated, at least in part, by ATP-dependent K+ channels (K+-ATP) since the stimulatory effect of 1 was similar to that observed for glibenclamide but was not potentiated by sulphonylurea. Furthermore, both extracellular and calcium from stocks mediate the signal transduction of stimulatory effect of 1 on calcium uptake which may contribute to insulin secretion. In addition, the insulinomimetic effect of 1 was evidenced through the level of serum glucose lowering in alloxan-induced diabetic rats. Also, 1 induced a significant increase in glycogen content in vivo and glucose uptake in soleus muscle in vitro. The results of this study indicate dual physiological targets for the acylhydrazone 1, i.e., pancreatic islets and skeletal muscle, as a result of insulin secretagogue and insulinomimetic action.

The ankyrin-repeat transient receptor potential 1 (TRPA1) has been implicated in pathological conditions of the bladder, but its role in overactive bladder (OAB) following spinal cord injury (SCI) remains unknown. In this study, using a rat SCI model, we assessed the relevance of TRPA1 in OAB induced by SCI. SCI resulted in tissue damage, inflammation, and changes in bladder contractility and in voiding behavior. Moreover, SCI caused upregulation of TRPA1 protein and mRNA levels, in bladder and in dorsal root ganglion (DRG; L6-S1), but not in corresponding segment of spinal cord. Alteration in bladder contractility following SCI was evidenced by enhancement in cinnamaldehyde-, capsaicin-, or carbachol-induced bladder contraction as well as in its spontaneous phasic activity. Of relevance to voiding behavior, SCI induced increase in the number of nonvoiding contractions (NVCs), an important parameter associated with the OAB etiology, besides alterations in other urodynamic parameters. HC-030031 (TRPA1 antagonist) treatment decreased the number and the amplitude of NVCs while the TRPA1 antisense oligodeoxynucleotide (AS-ODN) treatment normalized the spontaneous phasic activity, decreased the cinnamaldehyde-induced bladder contraction and the number of NVCs in SCI rats. In addition, the cinnamaldehyde-induced bladder contraction was reduced by exposure of the bladder preparations to HC-030031. The efficacy of TRPA1 AS-ODN treatment was confirmed by means of the reduction of TRPA1 expression in the DRG, in the corresponding segment of the spinal cord and in the bladder, specifically in detrusor muscle. The present data show that the TRPA1 activation and upregulation seem to exert an important role in OAB following SCI.

Trichilia catigua is a native plant of Brazil; its barks are used by some local pharmaceutical companies to prepare tonic drinks, such as Catuama. The present study was addressed to evaluate the effects of T. catigua hydroalcoholic extract in mouse nociception behavioral models, and to evaluate the possible mechanisms involved in its actions. Male Swiss mice were submitted to hot-plate, writhing and von Frey tests, after oral treatment with T. catigua extract (200 mg kg(-1), p.o.). The extract displayed antinociceptive effect in all three models. For characterization of the mechanisms involved in the antinociceptive action of the extract, the following pharmacological treatments were done: naloxone (2.5 mg kg(-1), s.c.), SR141716A (10 mg kg(-1), i.p.), SCH23390 (15 μg kg(-1), i.p.), sulpiride (50 mg kg(-1), i.p.), prazosin (1 mg kg(-1), i.p.), bicuculline (1 mg kg(-1), i.p.) or dl-p-chlorophenylalanine methyl ester (PCPA, 100 mg kg(-1), i.p.). In these experiments, the action of T. catigua extract was evaluated in the hot-plate test. The treatment with SCH23390 completely prevented the antinociceptive effect, while naloxone partially prevented it. The possible involvement of the dopaminergic system in the actions of T. catigua extract was substantiated by data showing the potentiation of apomorphine-induced hypothermia and by the prevention of haloperidol-induced catalepsy. In conclusion, the antinociceptive effects of T. catigua extract seem to be mainly associated with the activation of dopaminergic system and, to a lesser extent, through interaction with opioid pathway.

Hemorrhagic cystitis (HC) is a common side effect observed in patients under chemotherapy with cyclophosphamide (CYP). The urotoxic side effects of CYP are attributed to the metabolic compound acrolein, and can be partially prevented by the uroprotector agent 2-mercaptoethene sulfate (Mesna). The present study analyzed the anti-inflammatory and the antinociceptive effects of compounds MV8608 and MV8612 obtained from Mandevilla velutina in the rat model of CYP-induced HC. Male Wistar rats were used (six to eight per group, 220-250 g). HC was induced by a single administration of CYP (100 mg/kg, ip). Three behavioral parameters--breathing rate, closing of the eyes, and specific posture--were used as nociception indexes, and scored at different time intervals (15-180 min) after cystitis induction. As inflammatory parameters, hemorrhage presence, edema formation, and bladder weight were determined at 24 h after CYP administration. The neutrophil migration was assessed by means of myeloperoxidase (MPO activity), 4 h after cystitis induction. As expected, Mesna treatment was able to reduce in a significant manner all the inflammatory and the nociceptive parameters induced by CYP. Of note, the administration of MV8608 significantly inhibited the hemorrhage formation and the neutrophil recruitment, while the MV8612 treatment markedly reduced the bladder weight, without interfering with neutrophil influx. Interestingly, the treatment with either MV8608 or MV8612 markedly reduced the nociceptive responses. The present results clearly indicate that MV8608 and MV8612 might represent important alternatives to prevent side effects, especially the nociception, following chemotherapy with CYP.

Overexpression of the Saccharomyces cerevisiae ABC transporter Pdr5p confers resistance to a range of structurally unrelated xenobiotics. This property allows Pdr5p to be used as a target for novel multidrug resistance reversal reagents or chemosensitizers. Herein, we report the effects of gallic acid derivatives with substitutions either on the ester moiety or in the benzene ring on the activity of Pdr5p. Compounds with a longer side chain (8-16 carbons) resulted in greater inhibition of Pdr5p ATPase. Derivatives with side chains of 8-12 carbons that retained hydroxyl groups on the benzene ring extensively inhibited Pdr5p ATPase activity. These compounds almost completely inhibited the efflux of the Pdr5p fluorescent substrate Rhodamine 6G and at 25 muM chemosensitized the Pdr5p-overexpressing strain AD124567 to fluconazole (0.4 mg mL(-1)). Gallic acid derivatives may be a new class of Pdr5p inhibitors.