In vitro evaluation of cytotoxic potential of essential oil extracted from leaves of Croton heliotropiifolius Kunth in human tumor cells.

Croton heliotropiifolius Kunth, popularly known as "velame," is a shrub that resides in northeastern Brazil. The essential oil of C. heliotropiifolius contains high concentrations of volatile compounds in the leaves and is widely used in folk medicine for many purposes as an antiseptic, analgesic, sedative, and anti-inflammatory agent. Due to the apparent limited amount of information, the aim of this study was to determine the cytotoxic potential of essential oil extracted from leaves of C. heliotropiifolius, utilizing different human cancer cell lines (HL-60, leukemia; HCT-116, colon; MDA-MB435, melanoma; SF295, glioblastoma) and comparison to murine fibroblast L929 cell line. The chemical characterization of the essential oil revealed the presence of large amounts of monoterpenes and sesquiterpenes, the majority of which were aristolene (22.43%), germacrene D (11.38%), ɣ-terpinene (10.85%), and limonene (10.21%). The essential oil exerted significant cytotoxicity on all cancer cells, with low activity on murine L929 fibroblasts, independent of disruption of cell membranes evidenced by absence of hemolytic activity. The cytotoxicity identified was associated with oxidative stress, which culminated in mitochondrial respiration dysfunction and direct or indirect DNA damage (strand breaks and oxidative damage), triggering cell death via apoptosis. Our findings suggest that extracts of essential oil of C. Heliotropiifolius may be considered as agents to be used therapeutically in treatment of certain cancers.

TECHNIQUE OF EXPOSURE OF THE ESOPHAGOGASTRIC JUNCTION OBTAINED BY THE FLEXIBLE LIVER RETRACTOR IN BARIATRIC SURGERY: A RANDOMIZED CONTROLLED TRIAL. / TÉCNICA DE EXPOSIÇÃO DA JUNÇÃO ESOFAGOGÁSTRICA OBTIDA POR MEIO DE AFASTADOR FLEXÍVEL DE FÍGADO EM CIRURGIA BARIÁTRICA: ENSAIO CLÍNICO RANDOMIZADO.

AIM: In the Roux-en-Y gastric bypass technique, classic laparoscopic surgical retractors are usually rigid, require an additional incision for its installation, or must be handled by an assistant during the surgical procedure, involving a risk of liver injury. The aim of this study was to evaluate and validate a technique of the esophagogastric junction exposure obtained by the flexible liver retractor in bariatric surgery, comparing its efficacy with the retractor classically used for this purpose. METHODS: This study was performed as a randomized, open, prospective, controlled, and comparative design in patients with medical indications of bariatric surgery. The subjects were distributed in the classic (control) and flexible (test) retractor groups. RESULTS: A total of 100 patients (n=50 control group, n=50 test group) were included. No statistically significant difference was observed in the mean duration of surgery. Regarding visibility, 100% of the patients in the flexible retractor group demonstrated an optimal visibility level, although without statistical significance concerning the classic retractor group (94%). Invariably, carrying a trocar was necessary when using the classic retractor. CONCLUSIONS: The flexible liver retractor is safe, effective, ergonomic, and inexpensive. Furthermore, it presented a satisfactory aesthetic profile, and the use of specific instruments, new adaptation curve, and training for its handling were not required.

OBJETIVOS: Os afastadores clássicos de cirurgia laparoscópica são geralmente rígidos, necessitando de uma incisão adicional para sua instalação ou de um auxiliar para manuseio durante o ato cirúrgico e ainda, podem envolvem risco de injúria hepática. Avaliar e validar uma técnica de exposição da junção esofagogástrica obtida pelo afastador flexível de fígado em cirurgia bariátrica comparando sua eficácia com a de afastador classicamente utilizado para este fim. MÉTODOS: Tratou-se de um estudo prospectivo, aberto, controlado e comparativo em pacientes com indicação de cirurgia, distribuídos de forma randomizada em dois grupos: clássico (controle) e afastador flexível (teste). RESULTADOS: Foram incluídos 100 pacientes (n=50 grupo controle, n=50 grupo teste), sem diferença estatística na distribuição por idade e por morbidades, havendo diferença estatística somente no gênero (grupo controle obteve proporção maior de homens, p=0,020). Em relação ao tempo médio de realização das operações, não foi constatada diferença estatística. No quesito visibilidade, verificou-se que 100% dos pacientes do grupo afastador flexível obteve nível de visibilidade ótima, porém sem significância estatística com relação ao grupo clássico (94%). Invariavelmente, foi necessário um portal a mais de trocarte quando do uso do afastador clássico. CONCLUSÃO: O afastador flexível de fígado demonstrou-se seguro, eficaz, ergonômico, de baixo custo, de perfil estético satisfatório, não requerendo instrumental específico para uso ou nova curva de adaptação e aprendizado para manuseio.

Involvement of anti-inflammatory, antioxidant, and BDNF up-regulating properties in the antipsychotic-like effect of the essential oil of Alpinia zerumbet in mice: a comparative study with olanzapine.

The current drug therapy for schizophrenia effectively treats acute psychosis and its recurrence; however, this mental disorder's cognitive and negative symptoms are still poorly controlled. Antipsychotics present important side effects, such as weight gain and extrapyramidal effects. The essential oil of Alpinia zerumbet (EOAZ) leaves presents potential antipsychotic properties that need further preclinical investigation. Here, we determined EAOZ effects in preventing and reversing schizophrenia-like symptoms (positive, negative, and cognitive) induced by ketamine (KET) repeated administration in mice and putative neurobiological mechanisms related to this effect. We conducted the behavioral evaluations of prepulse inhibition of the startle reflex (PPI), social interaction, and working memory (Y-maze task), and verified antioxidant (GSH, nitrite levels), anti-inflammatory [interleukin (IL)-6], and neurotrophic [brain-derived neurotrophic factor (BDNF)] effects of this oil in hippocampal tissue. The atypical antipsychotic olanzapine (OLZ) was used as standard drug therapy. EOAZ, similarly to OLZ, prevented and reversed most KET-induced schizophrenia-like behavioral alterations, i.e., sensorimotor gating deficits and social impairment. EOAZ had a modest effect on the prevention of KET-associated working memory deficit. Compared to OLZ, EOAZ showed a more favorable side effects profile, inducing less cataleptic and weight gain changes. EOAZ efficiently protected the hippocampus against KET-induced oxidative imbalance, IL-6 increments, and BDNF impairment. In conclusion, our data add more mechanistic evidence for the anti-schizophrenia effects of EOAZ, based on its antioxidant, anti-inflammatory, and BDNF up-regulating actions. The absence of significant side effects observed in current antipsychotic drug therapy seems to be an essential benefit of the oil.

Effect of Topical Instillation of Pegaptanib Sodium Upon Inflammatory Corneal Neovascularization in Rabbits.

Purpose: To evaluate the effect of topical instillation of pegaptanib sodium upon inflammatory angiogenesis induced in the rabbit cornea by alkaline cauterization. Methods: Inflammatory angiogenesis was induced by alkaline (sodium hydroxide) cauterization in the corneas of 29 male New Zealand rabbits. The animals were divided into 4 groups: a control group treated with 0.5% carboxymethylcellulose sodium eye drops, a group treated with 1.0% prednisolone acetate eye drops, a group treated with 0.5% pegaptanib sodium diluted in 15 mL 0.5% carboxymethylcellulose sodium, and a group treated with 1.0% pegaptanib sodium diluted in 15 mL 0.5% carboxymethylcellulose sodium. After cauterization, eye drops were administered every 12 hours for 21 days. The animals were evaluated every 3 days after cauterization, and the newly formed vessels were quantified from photographs. The treatment effectiveness was analyzed with 3 parameters of antiangiogenic response: neovascularization area (NA), total vascular length (TVL), and number of blood vessels (BVN). Results: Average NA, TVL, and BVN values were significantly higher in both pegaptanib groups than in the prednisolone group. A nonstatistically significant reduction in parameters on days 18 and 21 was the minimum achieved in both pegaptanib groups. The efficacy of the treatments in relation to the control was significantly greater in the prednisolone group than in the 0.5% pegaptanib group or the 1.0% pegaptanib group (P < 0.001). Conclusion: Topical instillation of 0.5% and 1.0% pegaptanib sodium diluted in 15 mL 0.5% carboxymethylcellulose sodium had no inhibitory effect on corneal neovascularization in this rabbit model.

Diterpenoids from Leaves of Cultivated Plectranthus ornatus.

Two new diterpenoid derivatives 7α,12ß,17-triacetoxy-6ß,19-dihydroxy-13ß,16-spirocicloabiet-8-ene-11,14-dione ( 1: ) and 6ß-acetoxy-3ß,7α,12α-trihydroxy-13ß,16-spirocicloabiet-8-ene-11,14-dione ( 2: ) along with 11 ( 3: - 13: ) miscellaneous compounds were isolated from the leaves of Plectranthus ornatus Codd. Their structures were elucidated by spectroscopic analysis and gauge independent atomic orbitals 13C NMR calculations. The isolated compounds were screened for their effects on intestinal motility using guinea-pig ileum and duodenum and by their cytotoxicity against 4 human cancer cell lines (HCT-116, SF-295, PC-3, and HL-60). Compounds 6: and 9: were moderately cytotoxic against HL-60, whereas 6: and 13: were more active on SF-295 and HCT-116.

Técnica de exposição da junção esofagogástrica obtida por meio de afastador flexível de fígado em cirurgia bariátrica: ensaio clínico randomizado / Technique of exposure of the esophagogastric junction obtained by the flexible liver retractor in bariatric surgery: a randomized controlled trial

RESUMO - RACIONAL: Os afastadores clássicos de cirurgia laparoscópica são geralmente rígidos, necessitando de uma incisão adicional para sua instalação ou de um auxiliar para manuseio durante o ato cirúrgico e ainda, podem envolvem risco de injúria hepática. OBJETIVOS: Avaliar e validar uma técnica de exposição da junção esofagogástrica obtida pelo afastador flexível de fígado em cirurgia bariátrica comparando sua eficácia com a de afastador classicamente utilizado para este fim. MÉTODOS: Tratou-se de um estudo prospectivo, aberto, controlado e comparativo em pacientes com indicação de cirurgia, distribuídos de forma randomizada em dois grupos: clássico (controle) e afastador flexível (teste). RESULTADOS: Foram incluídos 100 pacientes (n=50 grupo controle, n=50 grupo teste), sem diferença estatística na distribuição por idade e por morbidades, havendo diferença estatística somente no gênero (grupo controle obteve proporção maior de homens, p=0,020). Em relação ao tempo médio de realização das operações, não foi constatada diferença estatística. No quesito visibilidade, verificou-se que 100% dos pacientes do grupo afastador flexível obteve nível de visibilidade ótima, porém sem significância estatística com relação ao grupo clássico (94%). Invariavelmente, foi necessário um portal a mais de trocarte quando do uso do afastador clássico. CONCLUSÃO: O afastador flexível de fígado demonstrou-se seguro, eficaz, ergonômico, de baixo custo, de perfil estético satisfatório, não requerendo instrumental específico para uso ou nova curva de adaptação e aprendizado para manuseio.

ABSTRACT - BACKGROUND: In the Roux-en-Y gastric bypass technique, classic laparoscopic surgical retractors are usually rigid, require an additional incision for its installation, or must be handled by an assistant during the surgical procedure, involving a risk of liver injury. Aim: The aim of this study was to evaluate and validate a technique of the esophagogastric junction exposure obtained by the flexible liver retractor in bariatric surgery, comparing its efficacy with the retractor classically used for this purpose. Methods: This study was performed as a randomized, open, prospective, controlled, and comparative design in patients with medical indications of bariatric surgery. The subjects were distributed in the classic (control) and flexible (test) retractor groups. Results: A total of 100 patients (n=50 control group, n=50 test group) were included. No statistically significant difference was observed in the mean duration of surgery. Regarding visibility, 100% of the patients in the flexible retractor group demonstrated an optimal visibility level, although without statistical significance concerning the classic retractor group (94%). Invariably, carrying a trocar was necessary when using the classic retractor. Conclusions: The flexible liver retractor is safe, effective, ergonomic, and inexpensive. Furthermore, it presented a satisfactory aesthetic profile, and the use of specific instruments, new adaptation curve, and training for its handling were not required.

Etomidate is devoid of genotoxicty and mutagenicity in human lymphocytes and in the Salmonella typhimurium/microsomal activation test.

No carcinogenesis or mutagenesis studies have been carried out with etomidate. The current study showed that etomidate has weak cytotoxic potential after 48 h exposure in human lymphocytes and has no hemolytic activity. The weak cytotoxicity seems to be related with redox imbalance of etomidate (40.9 and 81.9 µM) treated lymphocytes. At both etomidate concentrations, a slight decrease of the levels of GSH intracellular content and a significant increase in the amount of carbonylated proteins were observed after 48 h. The contribution of oxidative stress to genetic toxicity was only perceived when the enzyme Fpg was applied in the comet assay. Etomidate (40.9 and 81.9 µM) is a weak generator of oxidative DNA damage in lymphocytes. These damages to DNA probably were repaired, since no DNA strand breaks were detected in the standard alkaline comet assay (in the presence or absence of hepatic S9 microsomal fraction) without Fpg. Also, no micronucleated lymphocytes or carrying chromosomal aberrations were observed. Finally, etomidate (2046.8 and 4093.5 µM) was not mutagenic in the Salmonella/microsome mutagenicity assay, which used four Salmonella typhimurium strains (TA97a, TA98, TA100, and TA102) to detect frameshift and base-substitution mutations. In summary, etomidate is a weak oxidative DNA damaging anesthetic and is devoid of mutagenic properties in eukaryotic and prokaryotic models.

Impact of Bariatric Surgery on the Pharmacokinetics Parameters of Amoxicillin.

BACKGROUND: Bariatric surgery leads to several anatomo-physiological modifications that may affect pharmacokinetic parameters and consequently alter the therapeutic effect of drugs, such as antibiotics. The pharmacokinetics of oral amoxicillin after Roux-en-Y gastric bypass (RYGB) surgery is unknown. OBJECTIVES: The objective of this study was to evaluate the impact of bariatric surgery on the pharmacokinetics of amoxicillin. METHODS: This study was performed as a randomized, open-label, single-dose clinical trial, with two periods of treatment, in which obese subjects (n = 8) received an amoxicillin 500 mg capsule orally before and 2 months after the RYGB surgery. The amoxicillin plasma concentration was determined by liquid chromatography coupled to mass spectrometry (LC-MS/MS). RESULTS: After the surgery, the mean weight loss was 17.03 ± 5.51 kg, and mean body mass index (BMI) decreased from 46.21 ± 2.82 to 38.82 ± 3.32 kg/m2. The mean amoxicillin area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration (AUC0-tlast) increased significantly (3.5-fold); the maximum plasma concentration (Cmax) increased 2.8-fold after the bariatric surgery. No correlation was found between amoxicillin absorption, BMI, and weight loss percentage. CONCLUSION: The alterations observed in the amoxicillin pharmacokinetics suggest that obese subjects included in this trial had a substantially increase in amoxicillin systemic exposure after RYGB surgery. However, despite this increase, its exposure was lower than the values reported for non-obese volunteers. TRIAL REGISTRATION: Identifiers: NCT03588273.

Occupational and life-style factors-acquired mutagenicity in agric-workers of northeastern Brazil.

Pesticides are a complex mixture of chemicals used to protect crops from a number of pests and diseases. They have been considered as potential mutagenic agents. This study aims at evaluation of the mutagenic effect of pesticide exposure to agricultural workers through chromosomal aberrations (CA) and micronucleus (MN) assay in peripheral blood lymphocytes and oral mucosal cells, respectively. The exposed group was consisted with 97 farmers, while the control (un-exposed) group consisted of 55. The results showed a significant (p < 0.05) increase in frequency of CA and MN in the exposed group. Both CA and MN profiles were linked to a significant (p < 0.05) co-relation with the confounding factors such as smoking habits, alcohol, vegetables, tea/coffee, vitamins, and sweetener consumptions. More cytogenetic events were denoted in smoking and alcohol consumption as well as non-personal protective equipment (non-PPE) and low/no vegetables user farmers. In conclusion, a deficiency of dietary and medicaments-derived antioxidants, while consumption of alcohol and tobacco, as well as effects of radiation, heavy metal poisoning (especially from sweeteners), and non-PPE using habits, may contribute cytogenetic damage to the workers.

Behavioral effects induced by antitumor cleronade diterpenes from Casearia sylvestris and in silico interactions with neuron receptors.

ETHNOPHARMACOLOGICAL RELEVANCE: Casearia sylvestris is a medicinal plant traditionally used to treat snakebites, wounds, inflammation and gastric ulcers and scientific supports for have demonstrated its antitumor, antihyperlipidemic and antiparasitic properties. AIM OF THE STUDY: To assess the effects of a fraction with casearins (FC) on adult mice using classical experimental models of animal behavior and theoretical calculations to verify the interaction of Casearin X (Cas X) with neuron receptors. MATERIALS AND METHODS: Animals divided in 6 groups (n=9/group) were intraperitoneally treated with vehicle (DMSO 4%), FC (2.5, 5, 10 and 25mg/kg/day) and diazepam (2mg/kg) for 7 days. Thirty minutes after the last dose of treatment, acute toxicity and behavioral experiments were performed. RESULTS: The highest dose of FC (25mg/kg/day) caused diarrhea, weight loss and death of one animal. Elevated plus maze test showed that lower doses [2.5mg/kg/day (36.4±5.1s) and 5mg/kg/day (43.9±6.2s)] increased the time spent in open arms (TSOA). Open field test revealed reduction in the number of crossings (54.9%, 51.1%, 48% and 67.7% for 2.5, 5, 10 and 25mg/kg/day, respectively) in all doses of FC studied and decrease of rearings at 25mg/kg/day (p<0.05). Computational calculations showed that the inhibition constant (Ki) for the Cas X-D1 complex is up to 1000-fold more favourable than the Cas X-GABAA complex. All ∆G° values obtained for Cas X-D1 complexes were more negative than those seen with Cas X-GABAA complexes. CONCLUSIONS: Findings indicate a probable anxiolytic action of the FC since it reduces the number of crossings and rearings and prolonged the time spent in open arms, without sedative and myorelaxant effects, probably due to the interaction of Cas X with dopaminergic system.

Endophytic Actinobacteria from the Brazilian Medicinal Plant Lychnophora ericoides Mart. and the Biological Potential of Their Secondary Metabolites.

Endophytic actinobacteria from the Brazilian medicinal plant Lychnophora ericoides were isolated for the first time, and the biological potential of their secondary metabolites was evaluated. A phylogenic analysis of isolated actinobacteria was accomplished with 16S rRNA gene sequencing, and the predominance of the genus Streptomyces was observed. All strains were cultured on solid rice medium, and ethanol extracts were evaluated with antimicrobial and cytotoxic assays against cancer cell lines. As a result, 92% of the extracts showed a high or moderate activity against at least one pathogenic microbial strain or cancer cell line. Based on the biological and chemical analyses of crude extracts, three endophytic strains were selected for further investigation of their chemical profiles. Sixteen compounds were isolated, and 3-hydroxy-4-methoxybenzamide (9) and 2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone (15) are reported as natural products for the first time in this study. The biological activity of the pure compounds was also assessed. Compound 15 displayed potent cytotoxic activity against all four tested cancer cell lines. Nocardamine (2) was only moderately active against two cancer cell lines but showed strong activity against Trypanosoma cruzi. Our results show that endophytic actinobacteria from L. ericoides are a promising source of bioactive compounds.

Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives.

The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogs (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50µg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30±4.9, 64.6±1.8 and 46.5±19.5%, respectively) (p<0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels' number (12. 9±2.3 and 14.8±3.3%), neovascularization area (13.1±1.7 and 14.3±1.7%) and total length of vessels (9.2±1.5 and 9.9±1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogs 2a and 2b.

Pterocarpans induce tumor cell death through persistent mitotic arrest during prometaphase.

Pterocarpans, a family of isoflavonoids found in the diverse Fabaceae, display potent cytotoxic activity over a panel of tumor cell lines, and among those tested, 2,3,9- trimethoxypterocarpan displays the most potent activity. This study evaluates the effects of 2,3,9-trimethoxypterocarpan and its related derivatives on cell cycle progression and microtubule function in select breast cancer cell lines (MCF7, T47d and HS578T). The pterocarpans, with the exception of 3,4-dihydroxy-9-methoxipterocarpan, induced increased frequencies of mitotic cells by inducing arrest in prometaphase. While microtubule organization in interphase cells was not modified during treatment, mitotic cells exhibited high frequencies of monastral spindles surrounded by condensed chromosomes. Immunofluorescence staining with an anti-γ-tubulin antibody showed double-dot labeling in the spindle polar region, suggesting that pterocarpan treatment blocked centrosome segregation. We found that this mitotic arrest was reversible when the cells were treated for up to 24 h followed by recovery in drug-free medium, but not after 48-h treatment followed by incubation in drug-free medium. In that case, treated cells typically underwent cell multinucleation and apoptosis.

Synthetic chalcone derivatives as inhibitors of cathepsins K and B, and their cytotoxic evaluation.

A series of chalcone derivatives, 1-15, were prepared by Claisen-Schmidt condensation and evaluated for their cytotoxicities on tumor cell lines and also against proteolytic enzymes such as cathepsins B and K. Of the compounds synthesized, (E)-3-(3,4-dimethoxyphenyl)-1-phenylprop-2-en-1-one (12), (E)-3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (13), (E)-3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (14), and (E)-3-(4-nitrophenyl)-1-phenylprop-2-en-1-one (15) showed significant cytotoxicities. The most effective compound was 15, which showed high cytotoxic activity with an IC50 value lower than 1 µg/ml, and no selectivity on the tumor cells evaluated. Substituents at C(4) of ring B were found to be essential for cytotoxicity. In addition, it was also demonstrated that some of these chalcones are moderate inhibitors of cathepsin K and have no activity against cathepsin B.

A novel o-naphtoquinone inhibits N-cadherin expression and blocks melanoma cell invasion via AKT signaling.

The down-regulation or loss of epithelial markers is often accompanied by the up-regulation of mesenchymal markers. E-cadherin generally suppresses invasiveness, whereas N-cadherin promotes invasion and metastasis in vitro. The aim of this work is to investigate the role of biflorin, a naphthoquinone with proven anticancer properties, on the expression of N-cadherin and AKT proteins in MDA-MB-435 invasive melanoma cancer cells after 12h of exposure to 1, 2.5 and 5 µM biflorin. Biflorin inhibited MDA-MB-435 invasion in a dose-dependent manner (p<0.01). Likewise, biflorin down-regulated N-cadherin and AKT-1 expression in a dose-dependent manner. Biflorin did not inhibit the adhesion of MDA-MB-435 cells to any tested substrates. Additionally, biflorin blocked the invasiveness of cells by down-regulating N-cadherin, most likely via AKT-1 signaling. As such, biflorin may be a novel anticancer agent and a new prototype for drug design.

Inhibition of metastatic potential of B16-F10 melanoma cell line in vivo and in vitro by biflorin.

AIM: The aim of this study was to determine the antimetastatic potential of biflorin using in vivo and in vitro approaches. MAIN METHODS: Biflorin was isolated from Capraria biflora collected in Fortaleza, Ceará, Brazil. Adhesion, migration and invasion assays were performed to avail of the antimetastatic potential of this quinone. Experimental metastasis was performed to avail of the antimetastatic potential of bilflorin using in vivo assay. KEY FINDINGS: Treatment with biflorin (25 and 50mg/kg/day) was shown to be effective in reducing B16-F10 melanoma metastasis in C57BL/6 mice. The administration of biflorin at 25mg/kg/day intraperitoneally inhibited the formation of metastases by about 57% compared to untreated control animals. When the animals were treated with 50mg/kg/day intraperitoneally, there was a 71% decrease in the number of lung metastases. Morphological assays showed the presence of hemosiderin and erythrocytes in the lung parenchyma, indicating the occurrence of hemorrhage, probably a side effect of biflorin. Biflorin at non-toxic concentrations (0.5, 1.0 and 1.5g/mL) was tested directly on B16-F10 cells in vitro, and it inhibited cell adhesion to type I collagen and cell motility using the wound-healing assay. SIGNIFICANCE: These data suggest that biflorin has a promising antimetastatic potential, as shown by its anti-adhesion, anti-migration and anti-invasion properties against a metastatic melanoma cell line. However, further studies are essential to elucidate its mechanism of action.

Vasorelaxant and antihypertensive effects of methanolic fraction of the essential oil of Alpinia zerumbet.

Alpinia zerumbet is used in folk medicine in Brazil to treat hypertension. However, several pathways involved in the mechanism of vasorelaxation are still unclear. This study was designed to verify the antihypertensive effect of the methanolic fraction of the essential oil of A. zerumbet (MFEOAz) and to characterize its mechanism of action. The thoracic aortic rings from the Wistar rats were perfused in the organ chambers filled with Kreb's solution, where the tension of each ring was measured. The antihypertensive effect of MFEOAz was assessed in rats submitted to chronic hypertension by inhibition of nitric oxide synthesis by indirect measurement of blood pressure with indirect tail cuff method. MFEOAz relaxed phenylephrine and KCl-induced contraction of either endothelium-intact or endothelium-denuded rat aortic rings in a concentration-dependent manner. Pre-incubation with MFEOAz (100 and 300 µg/mL) in Ca(2+)-free Krebs solution attenuated phenylephrine- or caffeine-induced contraction. Pre-incubation with L-NAME, ODQ, wortmannin, atropine, indomethacin, catalase, SOD, TEA, 4-aminopyridine, glibenclamide, apamin, charybdotoxin, or iberiotoxin did not affect MFEOAz-induced relaxation. The intragastric administration of MFEOAz induced an antihypertensive effect. MFEOAz it seems inhibited the calcium influx via voltage-operated calcium channels and receptor-operated calcium channels, as well as inhibition of calcium mobilization from intracellular stores.

Urodynamic effects of the combination of tamsulosin and daily tadalafil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: a randomized, placebo-controlled clinical trial.

OBJECTIVES: To evaluate the effect of association of tamsulosin/tadalafil taken daily compared with tamsulosin/placebo in the lower urinary tract with urodynamic study (UDS). METHODS: All patients underwent baseline UDS before randomization to tamsulosin 0.4 mg/tadalafil 5 mg (Group 1; n = 20) or tamsulosin 0.4 mg/placebo (Group 2; n = 20) once daily for 30 days. End-of-study UDS were performed on completion of the treatment period. The primary end point was to demonstrate changes in urodynamic variables in the voiding phase, detrusor pressure at maximum flow (PdetQmax), and maximum flow rate (Qmax), from baseline to week four. RESULTS: The primary outcome measure of this clinical trial, PdetQmax, showed a significant reduction in tamsulosin/tadalafil group (13 ± 17.0) compared to tamsulosin/placebo (-1.2 ± 14.35) group (P = 0.03). Qmax increased in both groups, tamsulosin/tadalafil (1.0 ± 2.4) and tamsulosin/placebo (1.4 ± 2.4), but the difference was not significant between treatment groups (P = 0.65). Total IPSS, storage, and voiding sub-score improved significantly in tamsulosin/tadalafil compared with tamsulosin/placebo group. CONCLUSIONS: The association of tamsulosin/tadalafil reduces detrusor pressure at maximum flow without changing the maximum flow rate during micturition and significantly improves lower urinary tract symptoms compared with the isolated use of tamsulosin.

Structure elucidation and anticancer activity of 7-oxostaurosporine derivatives from the Brazilian endemic tunicate Eudistoma vannamei.

The present study reports the identification of two new staurosporine derivatives, 2-hydroxy-7-oxostaurosporine (1) and 3-hydroxy-7-oxostaurosporine (2), obtained from mid-polar fractions of an aqueous methanol extract of the tunicate Eudistoma vannamei, endemic to the northeast coast of Brazil. The mixture of 1 and 2 displayed IC50 values in the nM range and was up to 14 times more cytotoxic than staurosporine across a panel of tumor cell lines, as evaluated using the MTT assay.

Synthesis and cytotoxic activity of new acridine-thiazolidine derivatives.

Although their exact role in controlling tumour growth and apoptosis in humans remains undefined, acridine and thiazolidine compounds have been shown to act as tumour suppressors in most cancers. Based on this finding, a series of novel hybrid 5-acridin-9-ylmethylene-3-benzyl-thiazolidine-2,4-diones were synthesised via N-alkylation and Michael reaction. The cell viability was analysed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and DNA interaction assays were performed using electrochemical techniques.